JAID/JSC Guidelines for the Treatment of Respiratory Infectious Diseases: The Japanese Association for Infectious Diseases/Japanese Society of Chemotherapy  The JAID/JSC Guide to Clinical Management of Infectious Disease/Guideline-preparing Committee Respiratory Infectious Disease WG



# Introduction
The Japanese Association for Infectious Diseases (JAID) and Japanese Society of Chemotherapy (JSC) announced the "Guide for the Use of Antimicrobial Drugs" in 2001 and the "Guidelines for the Use of Antimicrobial Drugs" in 2005. Subsequently, the "The JAID/ JSC guide to clinical management of infectious diseases 2011" was published. With its revision, guidelines were newly prepared.
Concerning respiratory infectious diseases, in Japan, the Japanese Respiratory Society published guidelines for the management of community-acquired pneumonia, hospital-acquired pneumonia, respiratory tract infection, and -/nursing and healthcare-associated pneumonia. Furthermore, the Japanese Society of Pediatric Pulmonology and Japanese Society for Pediatric Infectious Diseases announced the "Guidelines for the Management of Respiratory Infectious Diseases in Children in Japan". Internationally, many guidelines, including those established by the American Thoracic Society and Infectious Diseases Society of America, have been published from various countries. Thereafter, clinical research on respiratory infectious diseases has advanced, leading to the accumulation of many outcomes regarding epidemiology, clinical diagnosis, and treatment. However, the types of microorganisms that cause respiratory infectious diseases have increased with the number of resistant bacteria. In addition, conditions have also varied with causative microorganisms through the recent compromised host's severe status. The place of treatment varies: from the outpatient clinic to the ICU. Physicians responsible for treatment also vary: practitioners, hospital doctors, pulmonologists, emergency physicians, board certified member of JAID, Japanese antimicrobial chemotherapy physician. There are a large number of options of antimicrobial drugs that are available, including new drugs; therapeutic strategies are confused. On the other hand, recently, the entity of PK-PD has been commonly recognized, and the importance of scientifically using antimicrobial drugs has been emphasized. In addition, the Japanese Society of Chemotherapy established a system for antimicrobial chemotherapy-certified physicians, and promoted the widespread, adequate use of antimicrobial drugs. Based on these, the two societies prepared the JAID/JSC Guidelines for the Treatment of Respiratory Infectious Diseases. If specific treatment guidelines can be presented, this may contribute to an improvement in the treatment responses of respiratory infectious diseases, a reduction in health expenditure, and the prevention of resistant bacteria.
The guidelines were prepared based on the EBM so that they reflected the management of respiratory infectious diseases in Japan and covered all such diseases in adults and children. To prepare the guidelines, a committee was established in 2012, and a draft was published on homepage based on an approval from the boards of directors at the two societies through a review-based consensus. Opinions were collected from the two societies' members. In Japan, there have been no such guidelines covering respiratory infectious diseases. In the future, with further advances in research, the contents of the guidelines must be revised. However, we successfully provided treatment guidelines that are the most advanced at present.
The guidelines were prepared for all clinicians to understand the Treatment of Respiratory Infectious Diseases and manage them with antimicrobial drugs adequately. They do not limit treatment by individual physicians or affect their rights to select it. The guidelines may be commonly applied for respiratory infectious disease management/research/education in Japan, improving the quality of respiratory infectious disease management, preventing an increase in the number of resistant bacteria, and contributing to national health. We hope that the guidelines will be utilized by a large number of clinicians in respiratory infectious disease management. Lastly, we thank the committee members and secretariat staff for their cooperation.
1. Descriptions on the recommendation grade and evidence level 2. Definition of firstand second-choice drugs 3. Precautions -In this article, with respect to the administration method (especially doses) of antimicrobial drugs, they are recommended based on sufficient doses. Considering the products adopted at each medical institution, antibiograms, severity, underlying disease, age, and presence or absence of organ disorder, the dose should be increased or decreased if necessary.
-The spectra of third-generation cephems for intravenous injection, CTX and CTRX, are similar, but CTX, which is excreted in the kidney, should be primarily used when liver dysfunction is present, and CTRX, which is excreted in bile, should be primarily used when renal dysfunction is present. -As quinolones exhibit antitubercular actions, patients with pulmonary tuberculosis should be excluded for use. [bib_ref] Nationwide survey on the 2005 guide-lines for the management of community-acquired adult..., Watanabe [/bib_ref]. A list of antimicrobial drug abbreviations and doses for neonates are presented at the end of this volume.

## Pneumonia (adults)
2.1. Community-acquired pneumonia 2.1.1. Empiric therapy ---Executive summary---Patient with bacterial pneumonia should be treated primarily with high-dose penicillin (AII). In elderly patients and those with underlying lung diseases, the use of respiratory quinolones may be considered positively (BII).
In case of atypical pneumonia, a macrolide or tetracycline is the first choice. Respiratory quinolones should be reserved as alternative drugs (BII), but may be used depending on local circumstances about drug resistance (CIII). In case of whether pneumonia or atypical pneumonia dose not diagnose, comobination with high-dose penicillin and a macrolide or tetracycline should be attempted first (BII). Respiratory quinolones should be reserved as alternative drugs (BII).
In severer cases requiring treatment in the ICU, a macrolide or new quinolone should be used aggressively in combination with a broad spectrum b-lactam such as high-dose penicillin from the beginning of treatment (AII).
---Explanation---Community-acquired pneumonia refers to hospital-acquired pneumonia that develops 48 h or more after admission or pneumonia that develops in healthy adults on social activities other than medical practice-/nursing-associated pneumonia . As signs and symptoms, cough, sputum, thoracic pain, and dyspnea appear, and this disease acutely occurs with systemic symptoms such as fever and general malaise . However, these symptoms are not marked in some elderly patients. Furthermore, atypical pneumonia including Mycoplasma is characterized by a small amount of sputum, and can be differentiated [bib_ref] Nationwide survey on the 2005 guide-lines for the management of community-acquired adult..., Watanabe [/bib_ref] [bib_ref] Evaluation of an assessment system for the JRS 2005: a-DROP for the..., Kohno [/bib_ref].
Concerning examination, Gram staining and culture of sputum are used to identify causative microorganisms and select subsequent treatment strategies [bib_ref] Sputum gram stain assessment in community-acquired bacteremic pneumonia, Gleckman [/bib_ref] [bib_ref] Assessment of the usefulness of sputum culture for diagnosis of communityacquired pneumonia..., Garcia-V Azquez [/bib_ref] (AII). Kits for rapid diagnosis with urine or nasal swab are also used for auxiliary diagnosis [bib_ref] Detection of Legionella pneumophila antigen in urine samples by the BinaxNOW immunochromatographic..., Helbig [/bib_ref] [bib_ref] Rapid urinary antigen test for diagnosis of pneumococcal community-acquired pneumonia in adults, Marcos [/bib_ref] (AII). A blood test shows inflammatory findings such as leukocytosis and an increase in the CRP level, facilitating a certain assessment of the disease [bib_ref] Evaluation of an assessment system for the JRS 2005: a-DROP for the..., Kohno [/bib_ref] [bib_ref] Revision of the severity rating and classification of hospital-acquired pneumonia in the..., Seki [/bib_ref]. On thoracic imaging, consolidation or a ground glasslike shadow is observed [1e5] (II).
When patients are in an immunosuppressive state related to an underlying disease, a causative microorganism test should be performed, considering the possibility of opportunistic infection [1e3,(A). In elderly patients, aspiration pneumonia is frequently observed, and the management of this disorder is necessary (Refer to the section "2.4 Aspiration pneumonia" on Page. [bib_ref] Combination anti-biotic therapy with macrorides improves survival in intubated patients with community-acquired..., Martin-Loeches [/bib_ref]. In the presence of renal dysfunction, the type and dose of an antimicrobial drug must be carefully selected(AII).
Bacterial pneumonia should be differentiated from atypical pneumonia in accordance with "The JRS Guidelines for the Management of Community-acquired pneumonia in Adults in 2007" (edited by the Committee to Prepare Guidelines regarding Respiratory Infectious Diseases, Japanese Respiratory Society) (Tables 1 and 2). Although Legionella pneumonia is routinely classified as atypical pneumonia, various types of atypical pneumonia do not include Legionella pneumonia in this differentiation method. a. Bacterial pneumonia (1) Outpatient treatment Bacterial pneumonia is primarily caused by Sterptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis [1e5, [bib_ref] Nationwide surveillance of bacterial respiratory pathogens conducted by the Surveillance Committee of..., Watanabe [/bib_ref] [bib_ref] Prospective multi center study of the causative organisms of communityacquired pneumonia in..., Saito [/bib_ref] (II). Basically, these types of pneumonia should be treated by orally administering high-dose penicillin [1e4] (AII). In Japan, macrolide-resistant S. pneumoniae is detected in most cases; therefore, macrolides are not recommended as the first choice, differing form those in Europe and the United States [bib_ref] Nationwide survey on the 2005 guide-lines for the management of community-acquired adult..., Watanabe [/bib_ref] [bib_ref] Evaluation of an assessment system for the JRS 2005: a-DROP for the..., Kohno [/bib_ref] [bib_ref] Revision of the severity rating and classification of hospital-acquired pneumonia in the..., Seki [/bib_ref] [bib_ref] Nationwide surveillance of bacterial respiratory pathogens conducted by the Surveillance Committee of..., Watanabe [/bib_ref] [bib_ref] Prospective multi center study of the causative organisms of communityacquired pneumonia in..., Saito [/bib_ref] (AII).
For outpatient treatment, b-lactamase inhibitorcontaining penicillin is commonly used. Therapy with CVA/AMPC or SBTPC (2 tablets/3e4 times a day) is recommended with respect to the efficacy and suppression of resistant bacteria [bib_ref] Nationwide survey on the 2005 guide-lines for the management of community-acquired adult..., Watanabe [/bib_ref] (AII). However, such high-dose prescriptions are not always accepted by health insurance system in Japan, and the following prescriptions (examples) should also be considered.
In elderly patients or those with underlying lung diseases such as COPD/old pulmonary tuberculosis, the use of respiratory quinolones should be considered positively from the perspective of the effects on penicillin-resistant Pneumococcus and tissue transfer [bib_ref] Prospective multi center study of the causative organisms of communityacquired pneumonia in..., Saito [/bib_ref] [bib_ref] Clinical evaluation of levofloxacin versus oral b-lactams for acute exacerbation of COPD, Higashiyama [/bib_ref] (BII). However, many new quinolones also have antimicrobial activities against Mycobacterium tuberculosis; therefore, the presence or absence of active tuberculosis must be strictly checked before administration [bib_ref] Fluoroquinolone exposure prior to tuberculosis diagnosis is associated with an increased risk..., Van Der Heijden [/bib_ref] (AII).
(2) Hospital treatment For hospital treatment, injection is primarily used. However, basic concepts for drug selection are similar to those at the outpatient clinic. Considering S. pneumoniae, H. influenzae, and M. catarrhalis, high-dose penicillin or cephems, which are effective for these microorganisms, should be selected [1e4] (AII). If more potent treatment is required, respiratory quinolone injection should be used [bib_ref] Clinical evaluation of levofloxacin versus oral b-lactams for acute exacerbation of COPD, Higashiyama [/bib_ref] [bib_ref] A Worldwide perspective of atypical pathogens in community-acquired pneumonia, Arnold [/bib_ref] (BII).
---Drugs to be recommended---(1) Outpatient treatment A First choices -CVA/AMPC, oral (125/250 mg), 2 tablets/3e4 times a day -SBTPC, oral (375 mg), 2 tablets/3e4 times a day * Concerning CVA/AMPC and SBTPC, up to 1000 mg of AMPC or up to 750 mg of ABPC are approved dosage in Japan.
Combination therapy with AMPC (oral preparation) should also be considered.
[Example] CVA/AMPC, oral (125/250 mg), 1 tablet/3 times a day  AMPC, oral (250 mg), 1 tablet/3 times a day <> Second choices -LVFX, oral, 500 mg/once a day -GRNX, oral, 400 mg/once a day -STFX, oral, 100 mg/1e2 times a day -MFLX, oral, 400 mg/once a day -TFLX, oral, 300 mg/twice a day (2) Hospital treatment A First choices -SBT/ABPC, intravenous drip, 3 g/3e4 times a day -CTX, intravenous drip, 1e2 g/2e3 times a day -CTRX, intravenous drip, 2 g/once a day or 1 g/twice a day <> Second choice -LVFX, intravenous drip, 500 mg/once a day b. Atypical pneumonia (1) Outpatient treatment Atypical pneumonia is primarily caused by Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila [1e5, [bib_ref] Revision of the severity rating and classification of hospital-acquired pneumonia in the..., Seki [/bib_ref] [bib_ref] Nationwide surveillance of bacterial respiratory pathogens conducted by the Surveillance Committee of..., Watanabe [/bib_ref] [bib_ref] Prospective multi center study of the causative organisms of communityacquired pneumonia in..., Saito [/bib_ref] (II). The oral administration of a macrolide or tetracycline is the first choice [bib_ref] Nationwide survey on the 2005 guide-lines for the management of community-acquired adult..., Watanabe [/bib_ref] [bib_ref] Evaluation of an assessment system for the JRS 2005: a-DROP for the..., Kohno [/bib_ref] [bib_ref] Assessment of the usefulness of sputum culture for diagnosis of communityacquired pneumonia..., Garcia-V Azquez [/bib_ref] (AII). To suppress resistant bacteria, respiratory quinolones should be reserved as alternative drugs [bib_ref] Nationwide survey on the 2005 guide-lines for the management of community-acquired adult..., Watanabe [/bib_ref] (BII).
However, recently, the appearance of macrolideresistant M. pneumoniae in adults has raised an issue in Japan. Respiratory quinolones must be used as the first choice depending on local circumstances about drug resistance(CIII).
(2) Hospital treatment For hospital treatment, injection is primarily used. However, basic concepts for drug selection are similar to those at the outpatient clinic. If more potent treatment is required, new quinolone injection should be used (BII).
---Drugs to be recommended---(1) Outpatient treatment A First choices -AZM sustained-release preparation, oral, 2 g/single dose -CAM, oral, 200 mg/twice a day -MINO, oral, 100 mg twice a day <> Second choices -LVFX, oral, 500 mg/once a day -GRNX, oral, 400 mg/once a day -STFX, oral, 100 mg/1e2 times a day -MFLX, oral, 400 mg/once a dayItems used to differentiate between bacterial and atypical pneumonia.
1. Under 60 years of age 2. No or minor underlying diseases 3. Stubborn cough 4. Poor chest auscultatory findings 5. No sputum, or no identified aetiological agent by rapid diagnosis 6. A peripheral white blood cell count below 10,000/mL Criteria for differentiation.
In cases using the 6 items in -TFLX, oral, 300 mg/twice a day (2) Hospital treatment -AZM, intravenous drip, 500 mg/once a day -MINO, intravenous drip, 100 mg/twice a day -LVFX, intravenous drip, 500 mg/once a day -CPFX, intravenous drip, 300 mg/twice a day.
-PZFX, intravenous drip, 500 to 1000 mg/twice a day c. Cases in which whether the disease is bacterial pneumonia or atypical pneumonia is unclear (1) Outpatient treatment In this case, combination therapy with high-dose penicillin and a macrolide or tetracycline should be selected as the first choice to cover both bacterial and atypical pneumonia [1e4, [bib_ref] Nationwide surveillance of bacterial respiratory pathogens conducted by the Surveillance Committee of..., Watanabe [/bib_ref] [bib_ref] Prospective multi center study of the causative organisms of communityacquired pneumonia in..., Saito [/bib_ref] [bib_ref] A Worldwide perspective of atypical pathogens in community-acquired pneumonia, Arnold [/bib_ref] (BII).
As respiratory quinolones cover both bacterial and atypical pneumonia, they are convenient, but should be reserved as alternative drugs from the perspective of suppression of resistant bacteria [1e4, [bib_ref] Clinical evaluation of levofloxacin versus oral b-lactams for acute exacerbation of COPD, Higashiyama [/bib_ref] [bib_ref] A Worldwide perspective of atypical pathogens in community-acquired pneumonia, Arnold [/bib_ref] (BII).
However, in elderly patients or those with underlying lung diseases such as COPD/old pulmonary tuberculosis, the use of respiratory quinolones should be considered positively from the perspective of the effects on penicillin-resistant Pneumococcus and tissue transfer [bib_ref] Prospective multi center study of the causative organisms of communityacquired pneumonia in..., Saito [/bib_ref] [bib_ref] Clinical evaluation of levofloxacin versus oral b-lactams for acute exacerbation of COPD, Higashiyama [/bib_ref] (BII). Recently, the appearance of macrolideresistant M. pneumoniae in adults has raised an issue. Respiratory quinolones may be used as the first choice depending on local circumstances about drug resistance(CIII).
(2) Hospital treatment For hospital treatment, injection is primarily used. However, basic concepts for drug selection are similar to those at the outpatient clinic. If more potent treatment is required, new quinolone injection should be used [1e4, [bib_ref] Clinical evaluation of levofloxacin versus oral b-lactams for acute exacerbation of COPD, Higashiyama [/bib_ref] (BII).
(3) Severer cases requiring treatment in the ICU In severer cases requiring treatment in the ICU, S. pneumoniae should be initially considered, and a macrolide or new quinolone should be used aggressively in combination with a broad spectrum b-lactam such as high-dose penicillin from the beginning of treatment primarily to cover latent atypical bacteria (in particular, when L. pneumophila is not covered, the condition may become fatal) [1e4, [bib_ref] A Worldwide perspective of atypical pathogens in community-acquired pneumonia, Arnold [/bib_ref] (AII). In particular, combination therapy with a macrolide is recommended from immunological aspects to suppress excessive inflammation related to cytokines [bib_ref] Combination anti-biotic therapy with macrorides improves survival in intubated patients with community-acquired..., Martin-Loeches [/bib_ref] (CII).
As the possibility that causative microorganisms may be enteric bacteria including ESBL-producing bacteria cannot be ruled out, carbapenem injection should be used as a first-choice drug in patients with a background factor for which ESBL-producing bacteria are frequently detected [bib_ref] Antibiotic therapy for Klebsiella pneumoniae bacteremia: implications of production of extended-spectrum b-lactamases, Paterson [/bib_ref] (BII).
The sensitivity of a urinary antigen kit to S. pneumoniae and Legionella spp. is approximately 60%. Therefore, even when the patient is negative for these bacteria in the initial phase, the possibility of pneumonia related to these bacteria should not be ruled out [1e4, [bib_ref] Detection of Legionella pneumophila antigen in urine samples by the BinaxNOW immunochromatographic..., Helbig [/bib_ref] [bib_ref] Rapid urinary antigen test for diagnosis of pneumococcal community-acquired pneumonia in adults, Marcos [/bib_ref] (II).
---Drugs to be recommended---(1) Outpatient treatment A First choices -CVA/AMPC, oral (125/250 mg), 2 tablets/3e4 times a day -SBTPC, oral (375 mg), 2 tablets/3e4 times a day * Concerning CVA/AMPC and SBTPC, up to 1000 mg of AMPC or up to 750 mg of ABPC are approved dosage in Japan. Combination therapy with AMPC (oral preparation) should also be considered.
[Example] CVA/AMPC, oral (125/250 mg), 1 tablet/3 times a day  AMPC, oral (250 mg),1 tablet/3 times a day  one of the followings:
-AZM sustained-release preparation, oral, 2 g/single dose -CAM, oral, 200 mg/twice a day -MINO, oral, 100 mg/twice a day <> Second choices -LVFX, oral, 500 mg/once a day -GRNX, oral, 400 mg/once a day -STFX, oral, 100 mg/1e2 times a day -MFLX, oral, 400 mg/once a day -TFLX, oral, 300 mg/twice a day (2) Hospital treatment A First choices -SBT/ABPC, intravenous drip, 3 g/3e4 times a day -CTX, intravenous drip, 1e2 g/2e3 times a day -CTRX, intravenous drip, 2 g/once a day or 1 g/twice a day  one of the followings:
-AZM, intravenous drip, 500 mg/once a day -MINO, intravenous drip, 100 mg/twice a day -CAM, oral, 200 mg/twice a day <> Second choices -LVFX, intravenous drip, 500 mg/once a day -PZFX, intravenous drip, 500 to 1000 mg/twice a day (3) Severer cases requiring treatment in the ICU -TAZ/PIPC, intravenous drip, 4.5 g/3e4 times a day -IPM/CS, intravenous drip, 0.5e1 g/2e4 times a day -MEPM, intravenous drip, 1 g/2e3 times a day -BIPM, intravenous drip, 0.3e0.6 g/3e4 times a day -DRPM, intravenous drip, 0.5e1 g/3 times a day  one of the followings: -AZM, intravenous drip, 500 mg/once a day -LVFX, intravenous drip, 500 mg/once a day -CPFX, intravenous drip, 300 mg/twice a day -PZFX, intravenous drip, 500 to 1000 mg/twice a day -MINO, intravenous drip, 100 mg/twice a day

## Definitive therapy
---Executive summary----When causative microorganisms are identified based on the results of microbial examination of good-quality sputum, blood culture, and urinary antigen (S. pneumoniae, L. pneumophila) tests and drug susceptibility testing of the causative agents, definitive therapy should be performed if possible [bib_ref] Infectious diseases society of America/American thoracic society consensus guidelines on the management..., Mandell [/bib_ref] (BIII). -The place of treatment and drugs should be selected in accordance with the severity of the disease [bib_ref] Infectious diseases society of America/American thoracic society consensus guidelines on the management..., Mandell [/bib_ref] (AII). -Antimicrobial drugs should be selected in reference to the susceptibility of isolated bacteria to antimicrobial drugs or a drugsusceptibility tendency in the area [bib_ref] Infectious diseases society of America/American thoracic society consensus guidelines on the management..., Mandell [/bib_ref] [bib_ref] Nationwide surveillance of bacterial respiratory pathogens conducted by the Surveillance Committee of..., Watanabe [/bib_ref] [bib_ref] the Study group on antimicrobial susceptibility of pathogens isolated from respiratory infections...., Goto [/bib_ref] when these data are available (AII). -The administration period of an antimicrobial drug is determined in accordance with the improvement of symptoms and laboratory data, with a target of 5e7 days [bib_ref] Infectious diseases society of America/American thoracic society consensus guidelines on the management..., Mandell [/bib_ref] (BIII). -When the patient is infected with L. pneumophila or C. pneumoniae, the optimal administration period is about 14 days(BIV).
a. Streptococcus pneumoniae -The Clinical and Laboratory Standards Institute (CLSI) has established higher criteria for breakpoints for penicillin susceptibility on the administration of parenteral antimicrobial drugs for S. pneumoniae infections other than meningitis, based on the following findings: patients with severe pneumonia due to S. pneumoniae with a low PCG susceptibility (MIC: 0.12e4 mg/mL) showed no difference in responses to PCG and outcome [bib_ref] Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in, Pallares [/bib_ref] [bib_ref] Rationale for revised penicillin susceptibility breakpoints versus Streptococcus pneumoniae: coping with anti..., Weinstein [/bib_ref] (II). For the treatment of pneumococcal pneumonia, the dose of penicillin should be increased [bib_ref] BTS guidelines for the management of community acquired pneumonia in adults: 2009..., Lim [/bib_ref] (A). -In Japan, most S. pneumoniae isolates are macrolide resistant [bib_ref] Nationwide surveillance of bacterial respiratory pathogens conducted by the Surveillance Committee of..., Watanabe [/bib_ref] [bib_ref] the Study group on antimicrobial susceptibility of pathogens isolated from respiratory infections...., Goto [/bib_ref]. -Respiratory quinolones have potent anti-pneumococcal activities (III). The clinical effects of such quinolones are similar to those of high-dose AMPC [bib_ref] CAP 5 Moxifloxacin Study Group. Oral moxifloxacin vs high-dosage amoxicillin in the..., Petitpretz [/bib_ref] (II). -In Japan, quinolone-resistant S. pneumoniae is detected in 2e3% of the isolates [bib_ref] Nationwide surveillance of bacterial respiratory pathogens conducted by the Surveillance Committee of..., Watanabe [/bib_ref]. As quinolone resistance may be readily induced by point mutations of DNA gyrase or topoisomerase genes [bib_ref] Spafloxacin resistance in clinical isolates of Streptococcus pneumoniae: involvement of multiple mutations..., Taba [/bib_ref] , quinolones must be used adequately (AIII).
b. Haemophilus influenzae -The ABPC-resistant mechanism of H. influenzae involves blactamase production and/or PBP mutation. Previously, blactamase production was primarily involved, but, recently, PBP mutation-mediated b-lactamase-negative ABPC-resistant (BLNAR) strains have been increasingly detected. ABPCresistant strains with both b-lactamase production and PBP mutation are classified as b-lactamase-positive CVA/ABPCresistant (BLPACR) strains. -According to a national survey in Japan, 49 (39.8%) and 7 (5.7%) of 123 H. influenzae strains were BLNAR and b-lactamase-producing strains, respectively [bib_ref] Nationwide surveillance of bacterial respiratory pathogens conducted by the Surveillance Committee of..., Watanabe [/bib_ref].
-BLNAR strains are also resistant to firstand secondgeneration cephems. -PIPC exhibits an antimicrobial activity against BLNAR strains.
However, it is ineffective for BLPACR strains.
c. Klebsiella spp., Escherichia coli, Proteus spp.
-The proportion of extended spectrum b-lactamase (ESBL)producing bacteria has slightly increased among isolates from respiratory samples. -According to a national survey in Japan, ESBL-producing bacteria account for 1.8e3.4% of respiratory sample-derived Klebsiella spp. strains [bib_ref] Nationwide surveillance of bacterial respiratory pathogens conducted by the Surveillance Committee of..., Watanabe [/bib_ref] [bib_ref] Nationwide surveillance of bacterial respiratory pathogens condected by Japanese Society of Chemotherapy..., Niki [/bib_ref]. -Most ESBL-producing strains are simultaneously resistant to quinolones [bib_ref] Molecular characteristics of extended-spectrum b-lactamase-producing Escherichia coli in Japan: emergence of CTX-M-15-producing..., Kuroda [/bib_ref]. Antimicrobials should be selected according to the drug susceptibility of isolated bacteria. -In Japan, carbapenemase-producing strains are extremely rare.
d. Mycoplasma pneumoniae -In the field of pediatrics, the detection rate of macrolideresistant M. pneumoniae has markedly increased. In adults, that of macrolide-resistant M. pneumoniae also increase [bib_ref] Macrolide-resistant Mycoplasma pneumoniae: characteristics of isolates and clinical aspects of communityacquired pneumonia, Morozumi [/bib_ref] [bib_ref] Macrolide-resistant Mycoplasma pneumoniae in adolescents with communityacquired pneumonia, Miyashita [/bib_ref]. -Tetracyclines exhibit potent clinical effects on macrolideresistant M. pneumoniae [bib_ref] Rapid effectiveness of minocycline or doxycycline against macrolide-resistant Mycoplasma pneumoniae infection in..., Okada [/bib_ref]. -Respiratory quinolones have good activities against M. pneumoniae [bib_ref] In vitro and in vivo antibacterial activities of DC-159a, a new fluoroquinolone, Hoshino [/bib_ref] [bib_ref] In vitro activities of 11 antimicrobial agents against macrolide-resistant Mycoplasma pneumoniae isolates..., Akaike [/bib_ref].
e. Legionella spp.
-It should be noted that pneumonia related to Legionella spp. other than L. pneumophila SG1 cannot be diagnosed using Legionella urinary antigen testing.
-As neither b-lactams nor aminoglycosides have antimicrobial activities against Legionella spp., which proliferates within host cells, they are clinically ineffective. -Quinolones, macrolides, and tetracyclines have been confirmed to exhibit clinical effects on Legionella spp. Previously, EM was the first choice for this infection, but many recent studies have showed the clinical efficacies of LVFX and AZM [bib_ref] Antimicrobial chemotherapy for Legionnaires disease: levofloxacin versus macrolides, Bl Azquez Garrido [/bib_ref] [bib_ref] Macrolides versus quinolones in Legionella pneumonia: results from the community-acquired pneumonia organization..., Griffin [/bib_ref]. -RFP is effective when combined with EM. The combination of EM and RFP is useful. A study suggested the effects of combination therapy with LVFX and a macrolide [bib_ref] Community-acquired Legionella pneumonia in the intensive care unit: impact on survival of..., Rello [/bib_ref] (CIII). -Although there are no marked differences in antimicrobial drug susceptibility among Legionella spp., clinical reviews to verify this are limited [bib_ref] Infection due to Legionella species other than L. pneumophila, Muder [/bib_ref].
f. Chlamydophila pneumoniae -Only a few studies have supported the clinical effects of antimicrobial drugs against C. pneumoniae pulmonary infections. -Tetracyclines, macrolides, and quinolones may be effective.
These drugs are recommended primarily based on the results of basic studies [bib_ref] In vitro and in vivo antibacterial activities of DC-159a, a new fluoroquinolone, Hoshino [/bib_ref] [bib_ref] In vitro activities of azithromycin, clarithromycin, and other antibiotics against Chlamydia pneumoniae, Kuo [/bib_ref].
g. Staphylococcus aureus -With respect to Staphylococcus aureus in Japan, there has been an increase in the number of methicillin-resistant strains even in patients with community-acquired pneumonia. In particular, recently, municipal-onset-type MRSA (CA-MRSA) with Panton-Valentine-Leucocidine (PVL) has been detected in Japan, raising an issue [bib_ref] Dissemination of Panton-Valentine leukocidine positive metchicillinresistant Staphylococcus aureus in Okinawa, Mine [/bib_ref]. -In cases of MSSA infection (bacteremia), the clinical effects of CEZ are superior to those of VCM [bib_ref] Comparative effectiveness of nafcillin or cefazolin versus vancomycin in metchicillin susceptible Staphylococcus..., Schweizer [/bib_ref]. -As the susceptibility of MRSA to oral antimicrobial drugs differs among isolates, drugs should be selected according to its drug susceptibility Results.
h. Streptococcus spp.
-Among various types of Streptococcus, the Streptococcus anginosus group is frequently detected, and characterized by strong abscess-forming features [bib_ref] The Streptococcus milleri group as a cause of pulmonary infections, Shinzato [/bib_ref]. Streptococcus pyogenes and Streptococcus agalactiae may also cause pneumonia. The former may lead to serious pulmonary infection [bib_ref] Review of 17 cases of pneumonia caused by Streptococcus pyogenes, Barnham [/bib_ref] (V). -There is no penicillin resistance, but macrolide resistance is observed at a low frequency [bib_ref] Distribution of emm type and antibiotic susceptibility of group A streptococci causing..., Wajima [/bib_ref]. -The anti-Streptococcus activities of quinolones vary. Among quinolones, GRNX, MFLX, and STFX have relatively potent antimicrobial activities [bib_ref] Nationwide surveillance of bacterial respiratory pathogens conducted by the Surveillance Committee of..., Watanabe [/bib_ref] [bib_ref] In vitro activities of sitafloxacin compared with several fluoroquinolones against Streptococcus anginosus..., Yamamoto [/bib_ref].
i. Moraxella catarrhalis -The number of b-lactamaseproducing strains has increased since the 1990's. Currently, most strains produce b-lactamase [bib_ref] Nationwide surveillance of bacterial respiratory pathogens conducted by the Surveillance Committee of..., Watanabe [/bib_ref] [bib_ref] Moraxella catarrhalis: from emerging to established pathogen, Verduin [/bib_ref].
b-lactamase produced by M. catarrhalis decomposes penicillin.
-In Japan, macrolide-or quinolone-resistance have not been reported [bib_ref] Nationwide surveillance of bacterial respiratory pathogens conducted by the Surveillance Committee of..., Watanabe [/bib_ref].
j. Anaerobes -Most anaerobes that cause pneumonia exist in the oral cavity. Peptostreptococcus spp., Prevotella spp., and Fusobacterium spp. are involved. Mixed infection with microaerophilic Streptococci is often observed. -In many cases, infection with anaerobes may be associated with aspiration.
-Most oral anaerobes (Prevotella spp., Fusobacterium spp., and Porphyromonas spp.) are susceptible to combination drugs consisting of penicillin and a b-lactamase inhibitor, CLDM and MNZ [bib_ref] Antimicrobial susceptibility of 800 anaerobic isolates from patients with dentoalveolar infection to..., Kuriyama [/bib_ref].
k. Pseudomonas aeruginosa -In patients with chronic respiratory tract infection, Pseudomonas aeruginosa colonizes in the airway, and may cause community-acquired pneumonia [bib_ref] Community-acquired pneumonia due to gram-negative bacteria and Pseudomonas aeruginosa: incidence, risk, and..., Arancibia [/bib_ref]. -As the susceptibility of P. aeruginosa to antimicrobial drugs differs among clinical isolates, drugs should be selected according to its drug susceptibility results.
---Drugs to be recommended----The drug susceptibility of each clinical isolate should be classified in accordance with the CLSI criteria. -Establishment of prescriptions recommended in this article * Antimicrobials have been approved for specific diseases and specific causative agents by Japanese Ministry of Health and Welfare. The approvals are based on the results of clinical studies with Good Clinical Practice. As a general rule, the recommendations in this section refer to this (AII). However, recent trends in drug susceptibility are also considered. * The recent drug susceptibility results of the nationwide studies in Japan were referred [bib_ref] Nationwide surveillance of bacterial respiratory pathogens conducted by the Surveillance Committee of..., Watanabe [/bib_ref] [bib_ref] the Study group on antimicrobial susceptibility of pathogens isolated from respiratory infections...., Goto [/bib_ref]. * The recommendations without the approvals by Japanese Ministry are graded by evidence levels.
[ -When the susceptibility of identified causative microorganisms is clarified, or after the treatment responsiveness is evaluated, whether or not de-escalation is possible should be reviewed [50e53] (AII).
---Explanation---Definition: Hospital-acquired pneumonia is defined as "pneumonia that newly develops 48 h or more after admission". In many cases, treatment is difficult due to unfavorable patient conditions such as the presence of an underlying disease, immune capacity, and general condition [50e52].
Laboratory findings: Patients meeting 2 of 3 items, fever, an abnormal leukocyte count, and purulent secretes, in addition to the appearance of an abnormal shadow of the chest should be diagnosed with hospital-acquired pneumonia [50e52].
1) Ventilator-associated pneumonia (VAP): VAP refers to pneumonia that newly develops 48 h or more after endotracheal intubation/ventilator initiation. Its onset within 4e5 days after endotracheal intubation is classified as early-type, and its subsequent onset as late-type [bib_ref] International conference for the development of consensus on the diagnosis and treatment..., Rello [/bib_ref] [bib_ref] Ventilator-associated pneumonia, Chastre [/bib_ref]. 2) Hospital-acquired pneumonia other than VAP: Several types of hospital-acquired pneumonia other than VAP include (1) immunodeficiency (for example, neutropenia during anticancer therapy, cell-mediated immunodeficiency related to the administration of steroids or immunosuppressive drugs) and (2) aspiration pneumonia including latent aspiration (Refer to the section "2.4 Aspiration pneumonia" on Page 19). Appropriate management and selection of antimicrobial drugs in accordance with individual conditions are necessary.
With respect to microorganisms that are expected, refer to the section "2.2 Hospital-acquired pneumonia---2.2.2 Empiric therapy: Cases in which Gram staining is available" (p. 10).
---Drugs to be recommended--a. Cases in which there is no risk of resistant bacteria Antimicrobial drugs should be selected, targeting Streptococcus pneumoniae, H. influenzae, and Klebsiella spp. as causative microorganisms [50e52] (BIII). Although it is difficult to estimate/identify causative microorganisms using sputum samples, bacteria that are not isolated/cultured from goodquality sputum may not be causative microorganisms. If resistant bacteria such as MRSA and P. aeruginosa are not detected on sputum culture and there is no deterioration of clinical symptoms, an initial drug should be continued(BIII). In patients in whom aspiration episodes are clear, those in whom oral hygiene is not maintained, or those with consciousness disorder, drugs with anti-anaerobe activities should be selected, considering the involvement of anaerobes(BIII). If an adequate antimicrobial drug is administered, the treatment period may be 7e10 days, excluding MRSA and P. aeruginosa [bib_ref] HAP study group: multicenter survey on hospital-acquired pneumonia and the clinical efficacy..., Watanabe [/bib_ref] (BII). A First choices -SBT/ABPC, intravenous drip, 3 g/3e4 times a day -CTX, intravenous drip, 1e2 g/3 times a day -CTRX, intravenous drip, 2 g/once a day or 1 g/twice a day * If the involvement of anaerobes is suspected, SBT/ABPC should be selected. <> Second choice -LVFX, intravenous drip, 500 mg/once a day (As its antimicrobial activity against anaerobes is weak, monotherapy with this drug should be avoided in patients with aspiration pneumonia.).
b. Cases in which there is a risk of multi-drug-resistant bacteria To cover multi-drug-resistant bacteria including P. aeruginosa, broad-spectrum antimicrobial drugs with anti-P. aeruginosa activities should be selected [50e52] (AIII). Considering the frequency of ESBL in each institution, carbapenems should be considered even when enteric bacteria, including Klebsiella spp. and Escherichia coli, are suspected (BIV). If P. aeruginosa is not isolated on good-quality sputum culture, a treatment option should be de-escalated to drugs for cases in which there is no risk of resistant bacteria [50e52] (AII). If aspiration is suspected, or if the involvement of grampositive bacteria is suggested, combination therapy with CLDM must be considered (BIV). If there is a risk of MRSA carrier , combination therapy with anti-MRSA drugs should also be considered.
The mean administration period of antimicrobial drugs with respect to causative bacteria in patients with an improvement was approximately 10 days. However, that for resistant bacteria such as P. aeruginosa and MRSA was approximately 12 days [bib_ref] HAP study group: multicenter survey on hospital-acquired pneumonia and the clinical efficacy..., Watanabe [/bib_ref] (BII). If appropriate antimicrobial drugs can be administered after clarifying causative bacteria, a treatment period of approximately 10 days is recommended [bib_ref] HAP study group: multicenter survey on hospital-acquired pneumonia and the clinical efficacy..., Watanabe [/bib_ref] [bib_ref] Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive..., Singh [/bib_ref] [bib_ref] Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia..., Chastre [/bib_ref] (BII). A First choices -TAZ/PIPC, intravenous drip, 4.5 g/3e4 times a day -IPM/CS, intravenous drip, 0.5 g/4 times a day or 1 g/3 times a day -MEPM, intravenous drip, 1 g/3 times a day -DRPM, intravenous drip, 0.5e1 g/3 times a day -BIPM, intravenous drip, 0.3e0.6 g/3e4 times a day <> Second choices -CFPM, intravenous drip, 1e2 g/2e4 times a day -CPFX, intravenous drip, 300 mg/twice a day -PZFX, intravenous drip, 500 to 1000 mg/twice a day If the involvement of anaerobes is suspected, one of the following options should be combined with one of the above regimens: -CLDM, intravenous drip, 600 mg/2e4 times a day -SBT/ABPC, intravenous drip, 3 g/3e4 times a day c. Severe cases One of the following options must be combined with one of the regimens for cases in which there is a risk of multi-drugresistant bacteria. When comparing the results between patients undergoing appropriate and inappropriate treatments, the prognosis of the latter was significantly poorer [bib_ref] Nosocomial pneumonia: a multivariate analysis of risk and prognosis, Celis [/bib_ref] [bib_ref] Study Group of the Italian Society of Internal Medicine. Outcomes of patients..., Venditti [/bib_ref] (BII). However, a study reported that the prognosis in a group with compliance with recommended drug selection was significantly poorer than in a non-compliance group in patients in whom infection with drug-resistant bacteria in the ICU was suspected even among those in whom the etiology was bacteriologically investigated [bib_ref] Implementation of guidelines for management of possible multidrugresistant pneumonia in intensive care:..., Kett [/bib_ref] (BII). Therefore, it must be considered that, even when resistant bacteria are etiologically involved, the administration of an appropriate antimicrobial drug that covers them does not always improve the prognosis.
-TAZ/PIPC, intravenous drip, 4.5 g/3e4 times a day -IPM/CS, intravenous drip, 0.5 g/4 times a day or 1 g/3 times a day -MEPM, intravenous drip, 1 g/3 times a day -DRPM, intravenous drip, 0.5e1 g/3 times a day -BIPM, intravenous drip, 0.3e0.6 g/3e4 times a day One of the following options should be combined with one of the above regimens: should be estimated based on the results of the clinical microbiological culture (CMC: Gram staining and culture) of a lower airway sample immediately before the start of treatment, and not based on bacteria isolated on active surveillance culture (ASC), which was conducted as a strategy to prevent/ control infection prior to onset [bib_ref] Role of serial routine microbio-logic culture results in the initial management of..., Hayon [/bib_ref]. -Microorganisms that cause pneumonia or (colonization of) the lower airway should be estimated based on the presence or absence of neutrophils or phagocytosis (excluding those patients with neutropenia or functional impairment of neutrophil)(BII).
[formula] A [/formula]
---Explanation---[Gram staining] Diagnostic accuracy of hospital-acquired pneumonia is improved by confirming neutrophils and bacterial cells using Gram staining of airway samples. This observation has also been confirmed through an increase in the likelihood ratio of hospital-acquired pneumonia in patients with a clinical pulmonary infection score (CPIS) of 6 points or higher [bib_ref] Diagnosing pneumonia during mechanical ventilation: the clinical pulmonary infection score revisited, Fartoukh [/bib_ref]. As bacteria isolated from the lower airways of inpatients are common colonizers in many cases, Gram staining is also useful for discerning colonization from infection by evaluating the presence or absence of neutrophil and phagocytosis. Therefore, it is desirable to combine bacterial culture with Gram staining .
Antimicrobial-drug selection based on Gram staining findings leads to appropriate empiric therapy in two-thirds of patients with hospital-acquired pneumonia, and it can be continued as definitive therapy in many cases [bib_ref] Value of Gram stain examination of lower respiratory tract secretions for early..., Blot [/bib_ref].
If there are no bacterial cells on Gram staining of lower airway sample in whom an antimicrobial regimen was not changed within the past 72 h, it is unlikely that the focus of infection/inflammation is within the lungs (lower airway). In this case, the possibility of pneumonia mimic, such as pleural effusion, atelectasis, and pulmonary edema, is suggested if the lung field opacity still remains in chest X-ray. If there is no other infectious focus, the discontinuation of an antimicrobial drug may be warranted [bib_ref] Role of serial routine microbio-logic culture results in the initial management of..., Hayon [/bib_ref].
A study has reported that the culture results of ASC performed as a strategy of routine infection control measure prior to the development of nosocomial pneumonia accurately predicted the causative pathogen in only 35% of cases [bib_ref] Role of serial routine microbio-logic culture results in the initial management of..., Hayon [/bib_ref]. Therefore, it is necessary to submit airway samples for clinical microbiological culture (CMC) immediately before the start of presumptive treatment.
[Causative microorganisms and their origin]
Microorganisms that cause hospital-acquired pneumonia are derived from the oropharynx, airway (including the nasal cavity and nasal sinus), digestive tract, and environment. Gastrointestinal tract-derived causative microorganisms are enteric bacteria (primarily, Klebsiella spp., E. coli and others such as Proteus spp., Enterobacter spp., Serratia spp., Morganella spp., and Citrobacter spp.). Those derived from the upper airway include S. pneumoniae, H. influenzae, Moraxella catarrhalis, S. aureus (namely methicillin sensitive strain), and oral anaerobes. Those derived from the environment include methicillin-sensitive S. aureus, Pseudomonas spp., Acinetobacter spp., and Stenotrophomonas spp. [bib_ref] Hospital-acquired pneumonia in the 21st century: a review of existing treatment options..., Koulent [/bib_ref] [bib_ref] Clinical practice guidelines for hospital-acquired pneumonia and ventilatorassociated pneumonia in adults, Rotstein [/bib_ref].
As the above bacteria derived from the airway and gastrointestinal tract basically exert strong virulence to the airway, they can be considered a core pathogen group of hospital-acquired pneumonia. Their potential for developing airway inflammatory response is generally believed stronger than those caused by environmental pathogen [bib_ref] Clinical practice guidelines for hospital-acquired pneumonia and ventilatorassociated pneumonia in adults, Rotstein [/bib_ref]. Risk factors for multi-drug-resistant bacteria.
1. Previous use of antimicrobial drugs within 90 days 2. Interval of 5 days or more from admission 3. Admission from an area/hospital in which resistant bacteria are frequent 4. Immunosuppressive state or treatment Risk factors for carrying MRSA.
Conditions under which anti-MRSA drug therapy should be considered (including gram stain) MRSA---" (p. 13). (2) Diplococcus consisting of a pair of two cocci (GPDC: Grampositive diplococci) S. pneumoniae should initially be suspected. Enterococcus is also a GPDC in microscopic appearance, but is basically considered a non-pulmonary pathogen.
<> Cases in which there have been no previous treatment with antimicrobial drugs or risks of penicillin-resistant Pneumococcus -PCG, intravenous drip, 2,000,000 to 3,000,000 units/4e6 times a day -ABPC, intravenous drip, 2 g/4e6 times a day <> Cases in which previous treatment with antimicrobial drugs or a risk of PRSP is present -CTRX, intravenous drip, 1 g/twice a day or 2 g/once a day -CTX, intravenous drip, 1e2 g/2e3 times a day -LVFX, intravenous drip, 500 mg/once a day -VCM, intravenous drip, 1 g/twice a day (TDM should be conducted so that a trough is 15e20 mg/mL(3) Gram-positive coccus in either short or long chain (GPC in chain)
aor b-hemolytic streptococci is indicated.
-PCG, intravenous drip, 2,000,000 to 3,000,000 units/ 4e6 times a day -ABPC, intravenous drip, 2 g/4e6 times a day (4) Gram-positive bacillus with a rod-like morphology (GPR:
Gram-positive rod) Corynebacterium spp. may be indicated.
-VCM, intravenous drip, 1 g/twice a day (TDM should be conducted so that a trough is 15e20 mg/mLc. Gram-negative bacteria ---Executive summary----When gram-negative bacteria are observed, H. influenzae, M. catarrhalis, Enterobacteriaceae, P. aeruginosa, Acinetobacter spp., and Stenotrophomonas spp. may be indicated [50e52, [bib_ref] Hospital-acquired pneumonia in the 21st century: a review of existing treatment options..., Koulent [/bib_ref] [bib_ref] Clinical practice guidelines for hospital-acquired pneumonia and ventilatorassociated pneumonia in adults, Rotstein [/bib_ref] (BII).
-It is difficult to estimate the type of bacteria based on the morphology on Gram staining in comparison with grampositive bacteria. -Gram-negative bacteria frequently detected as causative microorganisms include enteric bacteria and P. aeruginosa. -It is encouraged important to recognize the basic antimicrobial drug susceptibility pattern of each type (group) of bacteria to make sure that the empiric antimicrobial therapy is appropriate .
---Drugs to be recommended---
(1) Cases of early-onset hospital-acquired pneumonia in which there have been no previous administration of antimicrobial drugs or risk of resistant bacteria Aero-respiratory pathogen, such as H. influenzae and M. catarrhalis, and enteric bacteria, such as Klebsiella spp., are indicated. -SBT/ABPC, intravenous drip, 3 g/3e4 times a day -CTRX, intravenous drip, 1 g/twice a day or 2 g/once a day -CTX, intravenous drip, 1e2 g/2e3 times a day -LVFX, intravenous drip, 500 mg/once a day (2) Cases of late-onset hospital-acquired pneumonia or ventilator-associated pneumonia in which the risk of resistant bacteria is high An antimicrobial drug with anti-pseudomonal activity that targets non-glucose-fermentative gram-negative rod should be administered [bib_ref] Clinical practice guidelines for hospital-acquired pneumonia and ventilatorassociated pneumonia in adults, Rotstein [/bib_ref] -To treat polymicrobial infection, the administration of an antimicrobial drug with an activity against obligate anaerobe is not always necessary [bib_ref] The role of an aerobes in patients with ventilatorassociated pneumonia and aspiration..., Marik [/bib_ref]. -In non-severe cases, the administration of antimicrobial agents with anti-MRSA activity may be withheld in the initial phase even when Staphylococcus-like bacterial cells are observed [bib_ref] The role of an aerobes in patients with ventilatorassociated pneumonia and aspiration..., Marik [/bib_ref].
---Explanation---When several types of bacteria differing in Gram staining and morphology are observed, the condition is commonly interpreted as aspiration pneumonia, suggesting the involvement of anaerobes. However, the number of hospital-acquired pneumonia (including VAP) caused by anaerobes have been reported relatively smaller than generally anticipated., Polymicrobial infection does not always require the prompt antimicrobial therapy that covers anaerobes. Even though when aspiration pneumonia is suspected, SBT/ABPC is frequently prescribed assuming anaerobic infection, which actually works good on many occasions, it has to be acknowledged that SBT/ABPC exert good antimicrobial activity not solely against anaerobes, but also aero-enteric pathogen of pneumonia such as Streptococcus pneumonia, oral streptococci, H. influenzae, M. catarrhalis, and Klebsiella pneumonia.
Inpatients are often exposed to gram-negative bacteria residing in the hospital environment. Furthermore, there are many opportunities to undergo antimicrobial drug therapy that affects the indigenous microflora. For such reasons, gram-negative bacillus (enteric bacteria or P. aeruginosa) frequently colonize within the oropharyngeal region of the elderly patients or long-term bedbound patients, many of whom need airway suctioning or have tracheostomy that may serve as portal of entry of environmental pathogen. Oropharyngeal microflora primarily consisting of these gram-negative bacteria can be aspirated into the airway after surgery requiring sedation or anesthesia, or during or after endoscopic examination [bib_ref] Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia..., Chastre [/bib_ref] [bib_ref] Physiologic factors contributing to a transition in oral immunity among mechanically ventilated..., O&apos;neal [/bib_ref] [bib_ref] Indigenous microflora and innate immunity of the head and neck, Hull [/bib_ref]. Briefly, anaerobes may be an occasional pathoen in polymicrobial infection as seen on Gram staining of patients with suspected aspiration pneumonia, but S. pneumoniae, H. influenzae, S. aureus, Klebsiella spp., P. aeruginosa, and Acinetobacter spp. are more commonly involved in many cases, being similar to the microorganisms that are thought to be the major pathogen of hospital-acquired pneumonia. This is in contrast with the community-onset aspiration pneumonia, represented by lung abscess, in that anaerobes are primarily involved.
Anaerobes involved in hospital-acquired pneumonia include facultative anaerobic a-hemolytic streptococci in the oral cavity and obligate anaerobes. Oral obligate anaerobes include grampositive coccus (Peptostreptococcus sp.), gram-negative coccus (Veillonella sp.), and gram-negative bacillus "oral pigmented" Bacteroides (Bacteroides melaninogenicus), Prevotella sp., Porphyromonas sp., and Fusobacterium sp.). Many of these types of bacteria are susceptible to b-lactams that do not contain a b-lactamase inhibitor, new quinolones, macrolides, and tetracyclines. Therefore, patients with hospital-acquired pneumonia may be basically treated by standard empiric therapy for hospital-acquired pneumonia even when aspiration pneumonia related to several types of bacteria is suspected.
---Drugs to be recommended---(1) Cases in which it is not necessary to consider the involvement of multi-drug-resistant bacteria, or early hospitalacquired pneumonia The involvement of oral Streptococcus, oral anaerobes, S. pneumoniae, H. influenzae, and enteric bacteria should be considered.
-SBT/ABPC, intravenous drip, 3 g/3e4 times a day -CTRX, intravenous drip, 2 g/once a day or 1 g/twice a day -CTX, intravenous drip, 1e2 g/2e3 times a day -LVFX, intravenous drip, 500 mg/once a day (2) Late-onset hospital-acquired pneumonia or cases in which there is a risk of multi-drug-resistant bacteria In addition to the above pathogens, the involvement of non-glucose-fermentative gram negative bacteria or ESBLproducing enteric bacteria must be considered. -CFPM, intravenous drip, 1e2 g/2e4 times a day -CZOP, intravenous drip, 1e2 g/2e4 times a day -TAZ/PIPC, intravenous drip, 4.5 g/3e4 times a day Basic susceptibility of various pathogen groups to antimicrobial drugs. ---Explanation---If drug susceptibility test is not conducted for some reasons after the identification of causative microorganisms, an antimicrobial drug should be selected with reference to the susceptibility pattern (local sensitivity) of the identified bacteria at each institution. If the local sensitivity is not obtained, a drug should be selected based on the basic susceptibility of various pathogens to antimicrobial drugs [bib_ref] Antimicrobial treatment of hospital-acquired pneumonia, Chastre [/bib_ref].
[formula] GNR a GNR b ESBL-GNR c P. aeruginosa Acinetobacter Gram() d ABPC  e /A /A PIPC    /A  /A SBT/ABPC   f  g  h  TAZ/PIP   f  g  /A   CTX,CTRX   i  CPZ   i   CAZ   i    CFPM   j    Carbapenem     i   Monobactam   /A  /A CPFX   i  i   k -MEPM, [/formula]
In the treatment of hospital-acquired pneumonia, the duration of antimicrobial therapy generally tends to be longer than required for the following reasons: opacity on chest X-ray often remains for reasons other than pneumonia even after the start of antimicrobial drug treatment; and there may be a large number of latent nonpneumonia (or non-infectious-disease) factors that may cause increase in body temperature or CRP level in inpatients. However, if appropriate antimicrobial drug treatment is performed, it is possible to complete treatment in 1 week [bib_ref] Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia..., Chastre [/bib_ref]. In strains such as Enterobacter spp., Serratia spp., Citrobacter spp., and Morganella spp. GNR b ), the expression of intrinsic antimicrobial-drugresistance genes encoded in chromosome genes is induced during antimicrobial drug treatment, a phenomenon which is basically rarely seen in E. coli, Klebsiella spp., H. influenzae, and M. catarrhalis GNR a ) [bib_ref] Antimicrobial treatment of hospital-acquired pneumonia, Chastre [/bib_ref] [bib_ref] b-lactam resistance in the 21st century, Jacoby [/bib_ref] [bib_ref] Updated functional classification of b-lactamases. Antimicrob, Bush [/bib_ref]. Therefore, if adequately chosen treatment parameters are improved, antimicrobial treatment could be completed with careful follow up of patients' condition. Although it is useful to recognize these pathogens, abbreviated as SPACE (Serratia, Pseudomonas, Acinetobacter, Citrobacter, and Enterobacter), as a representative microorganism group that causes hospital-acquired pneumonia, the SPACE group is essentially a common colonizer. Therefore it is important to bear in mind that antimicrobial drug is not always indicated upon the isolation of SPACE to avoid selection of antimicrobial resistant bacteria related to unnecessary or long-term antimicrobial therapy [bib_ref] Hospital-acquired pneumonia in the 21st century: a review of existing treatment options..., Koulent [/bib_ref]. LZD should be selected [bib_ref] MRSA Working Party of he British Society for Antimicrobial Chemotherapy. Guidelines (2008)..., Gould [/bib_ref] [bib_ref] Clinical practice guidelines by the Infectious Diseases Society of America for the..., Liu [/bib_ref] (AI). The therapeutic efficacy of LZD is similar to those of glycopeptides [bib_ref] Linezolid versus vancomycin for the treatment of infections caused by methicillin-resistant Staphylococcus..., Kohno [/bib_ref]. The penetration of LZD into the alveolar epitheliumlining fluid and intra-alveolar sputum is more favorable. Therefore, use of LZD should be encouraged in cases of restricted sputum expectoration, such as VAP(BII). Exclusive use of a single drug may accelerate the acquisition of resistance to the agent [81e83] (CI). As DAP is inactivated by pulmonary surfactants, its use should be avoided for MRSA pneumonia. -Glycopeptides should be selected as first-line drug for pneumonia caused by Corynebacterium sp [bib_ref] Clinical microbiology of Coryneform bacteria, Funke [/bib_ref] (AII).
---Explanation---There is no significant difference in the therapeutic efficacy for MRSA pneumonia between glycopeptides and LZD. Several studies reported that the overall clinical efficacy of LZD, including the incidence of side effects, was superior to VCM in patients with hospital-acquired pneumonia caused by MRSA [bib_ref] Linezolid vs vancomycin: analysis of two double-blind studies of patients with methicillin-resistant..., Wunderink [/bib_ref] [bib_ref] the Linezolid Nosocomial Pneumonia Study Group. Linezolid (PNU-100766) versus vancomycin in the..., Rubinstein [/bib_ref]. However, since the dosing of VCM in these studies have been considered suboptimal, further study is needed [bib_ref] Guidelines for UK practice for the diagnosis and management of methicillin-resistant Staphylococcus..., Nathwani [/bib_ref]. Some investigators have recommended that, when MRSA is susceptible to CLDM or MINO on a susceptibility test, LZD, a protein synthesis inhibitor should be administered given the possible involvement of the Panton-Valentine leukocidin [bib_ref] MRSA Working Party of he British Society for Antimicrobial Chemotherapy. Guidelines (2008)..., Gould [/bib_ref] [bib_ref] Oral antibiotic therapy of serious systemic infections, Cunha [/bib_ref]. If a prompt improvement is achieved by the intravenous drip of LZD 600 mg q12h, or if the patient's condition is not critical, switch from the intravenous administration to an oral preparation of LZD, which shows high bioavailability [bib_ref] Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus, Fowler [/bib_ref] , is encouraged. As DAP is inactivated by pulmonary surfactants, it should not be used to treat MRSA pneumonia. This may not apply to the treatment of septic pulmonary embolism [bib_ref] Treatment of severe pneumonia in hospitalized patients: results of a multicenter, randomized,..., Fink [/bib_ref].
---Drugs to be recommended---(1) MRSA A First choices -VCM, intravenous drip, 1 g/twice a day -TEIC, intravenous drip, 400 mg for the first 2 days/ twice a day for loading, 400 mg/once a day from Day 3 * TDM should be conducted so that the trough levels of VCM and TEIC range from 15 to 20 mg/mL.
-LZD, intravenous drip or oral administration, 600 mg/ twice a day <> Second choices -ABK, intravenous drip, 300 mg/once a day (A trough level was established as 2 mg/mL using TDM.)
-ST combination drug (SMX at 400 mg/TMP at 80 mg), oral administration, 2 tablets/twice a day or intravenous drip, 960 mg/twice a day -CLDM, intravenous drip, 600 mg/2e4 times a day (The results of drug susceptibility testing must be confirmed). [non-extended-spectrum b-lactamase (ESBL)-producing bacteria] (2) Hospital treatment " (p.7).
(2) E. coli, Klebsiella spp., Proteus mirabilis (ESBL-producing bacteria) Refer to the section "2.1 Community-acquired pneumonia---2.1.2 Definitive therapy--- [bib_ref] Detection of Legionella pneumophila antigen in urine samples by the BinaxNOW immunochromatographic..., Helbig [/bib_ref] Klebsiella spp.
[ESBL-producing bacteria] (2) Hospital treatment" (p. 7).
(3) Enterobacter spp., Serratia spp., Citrobacter spp., Morganella spp., Proteus vulgaris A Third-generation cephems or quinolones should be administered [bib_ref] Clinical practice guidelines for hospital-acquired pneumonia and ventilatorassociated pneumonia in adults, Rotstein [/bib_ref] (AII).
-CTRX, intravenous drip, 2 g/once a day or 1 g/twice a day -CTX, intravenous drip, 1e2 g/2e3 times a day -LVFX, intravenous drip, 500 mg/once a day -CPFX, intravenous drip, 300 mg/twice a day -PZFX, intravenous drip, 1000 mg/twice a day <> If a strain is estimated to constantly express cephalosporinase (highly resistant to b-lactamase inhibitorcontaining b-lactams, oxyimino [143rd generation] cephalosporin and cephamycin, through plasmid genes) on an antimicrobial drug susceptibility test, fourthgeneration cephems or carbapenems should be administered.
-CFPM, intravenous drip, 1e2 g/4 times a day -CZOP, intravenous drip, 1e2 g/4 times a day -MEPM, intravenous drip, 1 g/3 times a day -DRPM, intravenous drip, 0.5e1 g/3 times a day (4) P. aeruginosa
Anti-pseudomonal penicillins, third-generation or later cephems, carbapenems, or new quinolones should be administeredRefer to the section "2.1 Community-acquired pneumonia---2.1.2 Definitive therapy---H. influenza (ABPCsusceptible), [bib_ref] Nationwide survey on the 2005 guide-lines for the management of community-acquired adult..., Watanabe [/bib_ref] H. influenza (b-lactamase-producing), [bib_ref] Evaluation of an assessment system for the JRS 2005: a-DROP for the..., Kohno [/bib_ref] H. influenza (b-lactamase-negative ampicillin-resistant (BLNAR), and [bib_ref] Sputum gram stain assessment in community-acquired bacteremic pneumonia, Gleckman [/bib_ref] H. influenza (b-lactamase-positive amoxicillin clavulanate-resistant (BLPACR)" (p. 6e7).
---Explanation---According to some investigators, enteric bacteria are classified into 2 types: sensitive, Gram-negative rods, such as E. coli, Klebsiella pneumoniae, and P. mirabilis, which are susceptible to first-generation cephalosporin, and resistant, Gram-negative rods, such as Enterobacter spp., Serratia spp., and Citrobacter spp., which show an intrinsic or inducible resistance to third-generation cephalosporin through chromosomal AmpC genes [bib_ref] Antimicrobial treatment of hospital-acquired pneumonia, Chastre [/bib_ref] [bib_ref] b-lactam resistance in the 21st century, Jacoby [/bib_ref] [bib_ref] Updated functional classification of b-lactamases. Antimicrob, Bush [/bib_ref]. In addition, the number of extended spectrum of b-lactamase (ESBL)-producing strains of E. coli, Klebsiella, and Proteus sp. that are resistant to all cephalosporin has increased. Among resistant GNRs, such as Enterobacter spp., strains that constantly produce AmpCtype b-lactamase (cephalosporinase) (plasmid type) must also be considered [bib_ref] b-lactam resistance in the 21st century, Jacoby [/bib_ref] [bib_ref] Updated functional classification of b-lactamases. Antimicrob, Bush [/bib_ref].
Concerning non-fermentative bacteria, their intrinsic susceptibility to antimicrobial agents differs among P. aeruginosa, Stenotrophomonas spp., and Acinetobacter spp. A study indicated that, in patients with P. aeruginosa pneumonia, monotherapy with a new quinolone might show unfavorable bacteria-eradicating effects or lead to recrudescence [bib_ref] Treatment of severe pneumonia in hospitalized patients: results of a multicenter, randomized,..., Fink [/bib_ref]. In some patients, combination therapy with a b-lactam (PIPC, CAZ, CFPM, or carbapenems), which has an anti-pseudomonal activity, and aminoglycoside or new quinolone may be considered [bib_ref] Treatment of severe pneumonia in hospitalized patients: results of a multicenter, randomized,..., Fink [/bib_ref] [bib_ref] Alvarez-Beltr an M. Levofloxacin in the treatment of ventilator-associated pneumonia, Alvarez-Lerma [/bib_ref]. Most strains of Stenotrophomonas spp. are susceptible to MINO or an ST combination drug.
M. catarrhalis and Acinetobacter spp. are the frequent types of Gram-negative coccus detected in patients with early and late hospital-acquired pneumonia, respectively.
Many strains of the former produce b-lactamase. The latter is a GNR existing in the hospital environment, and may be resistant to many antimicrobial drugs. However, in Japan, the multi-drug resistance of this type of bacteria has not widely distributed. Carbapenems and new quinolones should be selected. However, the vast majority of Acinetobaccter strains are susceptible to SBT/ABPC. In particular, SBT has an antimicrobial activity against this type of bacteria, and their susceptibility to SBT/ABPC should routinely be confirmed. Primary test drugs for an antimicrobial susceptibility of this type of bacteria (drugs appropriate for a routine examination panel) are SBT/ABPC, CAZ, IPM/CS, MEPM, GM, TOB, LVFX, and CPFX.
Pan-sensitive strains of H. influenzae are b-lactamase (BL)-negative, ABPC-sensitive (BLNAS) strains. However, there are various resistance patterns: BL-producing, ABPCresistant (BLPAR), BL-negative, ABPC-resistant (BLNAR), and BL-producing, AMPC/CVA-resistant (BLPACR) strains. BLNAS strains can be treated with ABPC, but SBT/ABPC therapy is required to control BLPAR strains. The administration of CTRX or new quinolones is necessary for BLNAR or BLPACR.
A randomized-controlled trial with multivariate analysis has shown that factors for favorable bacteriological effects included the absence of P. aeruginosa-related pneumonia (<0.01), a higher body weight (<0.01), a low APACHE II score (severity) (0.03), and CPFX therapy (0.04) [bib_ref] Treatment of severe pneumonia in hospitalized patients: results of a multicenter, randomized,..., Fink [/bib_ref]. Conditions suggesting the use of new quinolones include allergy to b-lactams, the presence of or concern for nephropathy (an aminoglycoside cannot be combined with a b-lactam), necessity of covering obligate intracellular pathogen, or situations in which switching to an oral preparation is indicated [bib_ref] Alvarez-Beltr an M. Levofloxacin in the treatment of ventilator-associated pneumonia, Alvarez-Lerma [/bib_ref]. An in vitro study indicated that the alveolar epithelial lining fluid (ELF) concentration of LVFX reached as high as its serum concentration. Furthermore, a prospective open-label study reported that switching of intravenous drip to oral administration decreased the ELF concentration, but it was within the range at which many pathogens are deemed sensitive based on the cumulative data of minimum inhibitory concentrations for causative microorganisms [bib_ref] Alvarez-Beltr an M. Levofloxacin in the treatment of ventilator-associated pneumonia, Alvarez-Lerma [/bib_ref].

## Nursing and healthcare-associated pneumonia
---Executive summary----Nursing and healthcare-associated pneumonia (NHCAP) is a category independently defined in Japan based on medical circumstances.
-The attending physician proposes a treatment category (Groups A to D) by evaluating what treatment is necessary as the most important item based on the patient's and his/her family's will [fig_ref] 1: Community-acquired pneumonia---2 [/fig_ref].
-Risk factors for resistant bacteria are categorized into two items, and initial treatment options are recommended, assuming target causative microorganisms (CIV). -In patients in whom the general condition is unfavorable due to complications or in terminal-stage patients, initial treatment options are recommended considering side effects from the perspective of innocent properties (CIV). -In Group D, in which intensive care is required, combination therapy with broad-spectrum (involving resistant bacteria and Legionella) and potent antimicrobial drugs is recommended (BI).
---Explanation---

## [characteristics and classification of diseases]
In 2011, the Japanese Respiratory Society issued the "Guidelines for the Management of Nursing and Healthcare-associated Pneumonia (NHCAP)", considering medical circumstances in Japan with reference to the entity of healthcare-associated pneumonia (HCAP) proposed in the Untied States. The definition of NHCAP is shown in . As this committee has no objection to the entity itself, the selection of drugs will be explained based on evidence to avoid duplications with the above guidelines.
The mortality rate and frequency of resistant bacteria in patients with NHCAP are intermediate between community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP). However, NHCAP may be primarily regarded as being similar to geriatric pneumonia [bib_ref] Health-care-associated pneumonia among hospitalizes patients in a Japanese community hospital, Shindo [/bib_ref] [bib_ref] A prospective comparison of nursing homeacquired pneumonia with health care associated pneumonia..., Maruyama [/bib_ref]. There is no fact that the rate at which resistant bacteria are isolated increases with severity [bib_ref] Health-care-associated pneumonia among hospitalizes patients in a Japanese community hospital, Shindo [/bib_ref]. Even when pneumonia is not severe, the host's activities of daily living (ADL) and an underlying disease/immunodeficiency reduce the prognosis in many cases [bib_ref] A prospective comparison of nursing homeacquired pneumonia with health care associated pneumonia..., Maruyama [/bib_ref]. As this type of pneumonia develops in a variety of uneven populations, it is difficult to simply determine severity classification. Therefore, considering various conditions, the entity of "treatment category", involving the ethical aspects of geriatric care, was introduced based on evaluation by the attending physician who knows the patient well [fig_ref] 1: Community-acquired pneumonia---2 [/fig_ref]. Frequent basic conditions or concomitant diseases for NHCAP in Japan include an advanced age, central nervous diseases, aspiration, a reduction in ADL, and tubal feeding. Their factors are aspiration pneumonia itself or risk factors, and HCAP in Japan may overlap with aspiration pneumonia [bib_ref] Characteristics and disease severity of healthcare-associated pneumonia among patients in a hospital..., Seki [/bib_ref]. On the other hand, in NHCAP patients, MRSA, P. aeruginosa, and anaerobes are more frequently isolated in comparison with CAP patients. It is necessary to switch therapeutic strategies, considering these causative microorganisms. Refer to the next section "2.4 Aspiration pneumonia" (p. [bib_ref] Combination anti-biotic therapy with macrorides improves survival in intubated patients with community-acquired..., Martin-Loeches [/bib_ref].
[Type and frequency of causative microorganisms] Concerning causative microorganisms in NHCAP patients, resistant bacteria are frequently detected, differing from CAP patients. However, with respect to microorganisms that cause HCAP, the distribution and frequency of Streptococcus pneumoniae and H. influenzae, which are frequently isolated in CAP patients, as well as MRSA, P. aeruginosa, and Gram-negative bacillus, which are frequently detected in HAP patients, differ among countries, areas, and institutions due to their variety (III). Concerning causative microorganisms, a study reported that there was no marked difference between NHCAP and CAP [bib_ref] Health care-associated pneumonia requiring hospital admission: epidemiology, antibiotic therapy, and clinical outcomes, Carratal A [/bib_ref]. On the other hand, a study in the United States indicated that S. aureus was frequently detected [bib_ref] Epidemiology and outcomes of healthcare-associated pneumonia: results from a large US database..., Kollef [/bib_ref] , and another study in Italy, where the rapid aging of society is advanced, as described for Japan, reported that aspiration pneumonia, H. influenzae, S. aureus, and Gram-negative bacillus were more frequent than in patients with CAP [bib_ref] Study Group of the Italian Society of Internal Medicine. Outcomes of patients..., Venditti [/bib_ref]. As a result, the rate of resistant bacteria increased, and inappropriate antimicrobial drugs were selected in a high proportion of patients. In addition, the mortality rate was higher than in CAP patients, suggesting the association between the two factors.
Representative causative microorganisms with respect to the presence or absence of risk factors for resistant bacteria are presented in . Of these, resistant bacteria, which are not targeted in CAP patients, were isolated in approximately 20%. However, the value was lower than in HAP patients. This is a current status of Japan (III). However, we must consider that patients in whom isolated bacteria are unclear account for approximately 50%, with the involvement of aspiration as a background factor [bib_ref] Characteristics and disease severity of healthcare-associated pneumonia among patients in a hospital..., Seki [/bib_ref]. In addition to bacteria commonly isolated in CAP patients, the frequency of enteric bacteria and anaerobes has increased [bib_ref] What is health-care associated pneumonia, and how should it be treated?, Craven [/bib_ref].
[Rules of antimicrobial drug therapy]
Risk factors for resistant bacteria in NHCAP patients include "the previous use of antimicrobial drugs for 2 days or more within 90 days" and "tubal feeding". Risk factors for involvement by drug-resistant pathogens.
-If no antibiotic therapy in the preceding 90 days or current tube feeding, the patient can be assumed to have no risk of involvement by drug-resistant pathogens. -However, if past medical history indicates isolation of MRSA, the patient should be assumed to have risk of involvement by MRSA. *1) Inappropriate when aspiration pneumonia is suspected, because it has insufficient activity against anaerobic bacteria. *2) Because of insufficient activity against anaerobic bacteria, when used to treat suspected aspiration pneumonia, it should be used in combination with an antibiotic that has activity against anaerobic bacteria (e.g., MNZ, CLDM, SBT/ABPC).

## Table 6
Definition of NHCAP.
1. Pneumonia diagnosed in a resident of an extended care facility or nursing home 2. Pneumonia diagnosed in a person who has been discharged from a hospital within the preceding 90 days 3. Pneumonia diagnosed in an elderly or disable d person who is receiving nursing care 4. Pneumonia diagnosed in a person who is receiving regular endovascular treatment as an outpatient (dialysis, antibiotic therapy, chemotherapy, immunosuppressant therapy) Standards for nursing care Patients whose performance statues is PS 3 (capable of only limited self-care, confined to bed or a chair more than 50% of their waking hours) or more. Item 1 incudes patients on psychiatric wards. not isolated in those who had made favorable daily life activities without a history of antimicrobial drug therapy [bib_ref] Indicators of potentially drug-resistant bacteria in severe nursing home acquired pneumonia, El Solh [/bib_ref]. Another study indicated that tubal feeding was an independent risk factor for infection with P. aeruginosa (odds ratio: 13.9) [bib_ref] Community-acquired pneumonia through Enterobacteriaceae and Pseudomonas aeruginosa: diagnosis, incidence and predictors, Baum [/bib_ref] (II). This is the reason why Treatment Category C was established in the Guidelines. Briefly, patients who do not meet the above two items are regarded as having no risk factor for resistant bacteria, and assigned to Group B. Patients meeting 1 or 2 items or those in whom MRSA was previously isolated are assigned to Group C. Respective drugs to be recommended were separately established. Patients in whom outpatient treatment is considered to be appropriate are assigned to Group A, and those in whom the attending physician considers ventilator or ICU management necessary to Group D. Drugs to be recommended were added, and a treatment category algorithm [fig_ref] 1: Community-acquired pneumonia---2 [/fig_ref] was prepared. Concerning HCAP treatment in Europe and the United States, there is a gap between drugs used in clinical practice and those recommended in guidelines [bib_ref] The HCAP gap: differences between self-reported practice patterns and published guidelines for..., Seymann [/bib_ref] (II). Therefore, treatment category-based empiric therapy in Japan may be acceptable in clinical practice; future investigation is necessary.

## [administration period of antimicrobial drugs]
There is no evidence regarding the administration period of antimicrobial drugs. An administration period of 7e10 days, which is routinely adopted in the highest percentage of patients, is appropriate (BIV). When administering antimicrobial drugs for a longer period, equivalent-spectrum antimicrobial drugs should be selected, or de-escalation of antimicrobial drugs should be performed. In this case, fever, CRP, and leukocyte counts are often used as indices of the treatment response. In cases of aspiration pneumonia in which aspiration recurs during treatment despite the efficacy of antimicrobial drugs, it is necessary to evaluate whether the effects of antimicrobial drugs are not obtained or recurrence occurs.
---Drugs to be recommended--a. Empiric therapy [fig_ref] 1: Community-acquired pneumonia---2 [/fig_ref] (1) Cases in which there is no risk of resistant bacteria and outpatient treatment is performed (Group A) According to a study, Chlamydophila spp. and M. pneumoniae accounted for 34.7 and 9.3% of patients in whom the type of microorganisms that cause NHCAP was clarified in Japan, respectively [bib_ref] A prospective comparison of nursing homeacquired pneumonia with health care associated pneumonia..., Maruyama [/bib_ref]. The results suggested that Chlamydophila spp. is a target of treatment, as described for CAP. Therefore, in Group A, combination therapy with a b-lactam and macrolide or monotherapy with a respiratory quinolone should be performed (BII). In Group D, an anti-P. aeruginosa drug should be combined with CPFX, PZFX, or AZM for injection, considering Legionella or Chlamydophila spp. pneumonia. However, concerning combination therapy with a macrolide (CII) in patients without "severe pneumonia requiring intensive care", as described below, the evidence level is not always high from the perspectives of medical economics, side effects, and resistant bacteria [bib_ref] How good is the evidence for the recommended empirical antimicrobial treatment of..., Oosterheert [/bib_ref]. Some studies examined the mortality rate with respect to the presence or absence of treatment covering atypical pathogens, and reported that the mortality rate was significantly lower in the presence of such treatment [bib_ref] A Worldwide perspective of atypical pathogens in community-acquired pneumonia, Arnold [/bib_ref]. A recent meta-analysis also showed a difference [bib_ref] Macroride-based regimens and mortality in hospitalized patients with communityacquired pneumonia: a systematic..., Asadi [/bib_ref].
Respiratory quinolones were established as an option (BII) based on many references describing that their effects are similar to or more potent than those of combination therapy with a b-lactam and macrolide. However, this must be further examined, considering factors such as severity and the presence or absence of concomitant sepsis [bib_ref] Respiratory fluoroquinolones for the treatment of community-acquired pneumonia: a meta-analysis of randomized..., Vardakas [/bib_ref]. Furthermore, the prevalence of penicillinresistant Pneumococcus, which has been internationally emphasized as an issue, and macrolide-resistant Pneumococcus, which has been markedly observed in Japan, was also a background factor for establishing respiratory quinolones as an option [bib_ref] Combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia, Baddour [/bib_ref]. The previous use of antimicrobial drugs, which is often observed in patients with NHCAP, is considered to be a risk factor for resistant Pneumococcus [bib_ref] Risk factors and response to antibiotic therapy in adults with bacteremic pneumonia..., Pallares [/bib_ref]. A study reported that penicillin or EM resistance in HCAP patients was more advanced than in CAP patients [bib_ref] Health care-associated pneumonia requiring hospital admission: epidemiology, antibiotic therapy, and clinical outcomes, Carratal A [/bib_ref]. A study indicated that the efficacy of oral therapy with LVFX was similar to that of CTRX injection therapy in 619 patients with CAP [bib_ref] A comparative study of levofloxacin and ceftriaxone in the treatment of hospitalized..., Norrby [/bib_ref]. Another study reported that, among 680 patients with non-severe HCAP, oral LVFX was useful in those with no description of causative microorganisms [bib_ref] Effect of a clinical pathway to reduce hospitalizations in nursing home residents..., Loeb [/bib_ref]. However, when aspiration pneumonia is suspected, GRNX or MFLX should be selected, because the effects of LVFX on anaerobes are weak. Furthermore, several studies suggested the usefulness of MFLX, which is not influenced by the kidney function and does not require dose regulation, in elderly patients with NHCAP [bib_ref] Randomized controlled trial of sequential intravenous (i.v.) and oral moxifloxacin compared with..., Finch [/bib_ref] [bib_ref] Moxifloxacin monotherapy is effective in hospitalized patients with community-acquired pneumonia: the MOTIV..., Torres [/bib_ref].
As treatment is completed with a single, high dose, compliance is favorable. AZM sustained-release preparations [115e117], which simultaneously cover bacteria and atypical pathogens, and STFX, which shows a favorable MIC for anaerobes, may also be recommended [bib_ref] In vitro antibacterial activity of DX-619, a novel des-fluoro (6) quinolone, Fujisawa [/bib_ref]. A First choices -CVA/AMPC, oral (125/250 mg), 2 tablets/3e4 times a day -SBTPC, oral (375 mg), 2 tablets/3e4 times a day [fig_ref] Table 8: [96] [/fig_ref] Risk factors for involvement by drug-resistant pathogens a in NHCAP.
History of antibiotic therapy for 2 or more days in the preceding 90 days Current tube feeding
The risk of MRSA should be taken into account whenever there is past history of MRSA isolation. When attempting to predict the isolation of drug-resistant pathogens based on the presence of these risk factors, it should be borne in mind that their sensitivity and negative predictive value are high, but their specificity and positive predictive value are low. a Drug-resistant pathogens include Pseudomonas aeruginosa, MRSA, Acinetobacter, ESBL-producing enteric bacteria, and Stenotrophomonas maltophilia. Possible pathogens isolated from NHCAP patients.
When an NHCAP patient has no risk factors for involvement by drug-resistant pathogens Pneumococcus MSSA Gram-negative enteric bacteria (including Klebsiella and E. coli) Haemophilus influenzae Oral Streptococci Atypical pathogens (particularly Chlamydophila) When an NHCAP patient has a risk factor for involvement by drug-resistant pathogens (the following will be considered in addition to the above-mentioned pathogens) Pseudomonas aeruginosa MRSA Acinetobacter ESBL-producing enteric bacteria  one of the followings: -AZM sustained-release preparation, oral, 2 g/single dose -CAM, oral, 200 mg/twice a day <> Second choices -MFLX, oral, 400 mg/once a day -GRNX, oral, 400 mg/once a day -STFX, oral, 100 mg/L to 2 times a day or -CTRX *1 , intravenous drip, 2 g/once a day or 1 g/twice a day -CTX *1 , intravenous drip, 1e2 g/2e3 times a day  one of the followings:
-AZM sustained-release preparation, oral, 2 g/single dose -CAM, oral, 200 mg/twice a day *1) As the antimicrobial activity of the drug against anaerobes is insufficient, it is inappropriate under a tentative diagnosis of aspiration pneumonia.
(2) Cases in which there is no risk of resistant bacteria and hospital treatment is performed (Group B) In this category, we recommend monotherapy from the perspectives of causative microorganisms resembling those for CAP and side effect-based "innocent properties". A study reported that initial treatment with narrow-spectrum antimicrobial drugs did not always lead to a poor prognosis [bib_ref] Management of patients with community-acquired pneumonia treated in hospital in Sweden, Hedlund [/bib_ref]. In particular, according to two articles [bib_ref] A comparison of culture-positive and culture-negative health-care-associated pneumonia, Labelle [/bib_ref] [bib_ref] Effect of antibiotic guidelines on outcomes of hospitalized patients with nursing home-acquired..., El-Solh [/bib_ref] , it is not necessary to consider resistant bacteria in HCAP patients in whom causative microorganisms are unclear; treatment in accordance with CAP treatment is sufficient (BII). However, an advanced age, central nervous diseases, aspiration, and a reduction in ADL are the clinical characteristics of aspiration pneumonia. The condition of NHCAP in Japan overlaps with aspiration pneumonia [bib_ref] Health-care-associated pneumonia is primarily due to aspiration pneumonia, Teramoto [/bib_ref]. Therefore, in Group B, to which patients admitted for the first time, with no recent use of antimicrobial drugs, correspond, antimicrobial therapy with b-lactamase inhibitor-containing penicillins is appropriate, as described for CAP. However, when aspiration pneumonia is suspected, CTRX and LVFX should be avoided (BIV). For the management of enteric bacteria, candidate drugs for Group B, PAPM/BP, may be selected. Actually, it is not necessary to consider P. aeruginosa in patients with CAP or non-ICU HAP. A study indicated that ertapenem, which is not effective for P. aeruginosa, was useful [bib_ref] Ertapenem versus cefepime for initial empirical treatment of pneumonia acquired in skilled-care..., Yacovlev [/bib_ref] , as demonstrated for PAPM/BP. However, another study reported that the widespread use of ertapenem induced the cross resistance of P. aeruginosa to other carbapenems; the use of PAPM/BP alone should be avoided [bib_ref] Selectivity of ertapnem for Psudomonas aeruginosa mutants cross-resistant to other carbapenems, Livemore [/bib_ref] (BIV). In elderly persons, with a high risk of aspiration, who are repeatedly admitted and discharged, Klebsiella is often involved. TAZ/PIPC is more useful according to a study [bib_ref] Retrospective investigation of the clinical effects of tazobactam/piperacillin and sulbactam/ampicillin on aspiration..., Tsukada [/bib_ref] (BII). In patients in whom Gram-negative bacillus is detected on Gram staining of sputum or those in whom the involvement of enteric bacteria is suspected, PAPM/BP or TAZ/PIPC should be selected (BIV).
-SBT/ABPC, intravenous drip, 3 g/3e4 times a day -CTRX *1 , intravenous drip, 2 g/once a day or 1 g/twice a day -CTX *1 , intravenous drip, 1e2 g/2e3 times a day -LVFX *1 , intravenous drip, 500 mg/once a day -PAPM/BP, intravenous drip, 0.5e1 g/2e4 times a day *1) As the antimicrobial activity of the drug against anaerobes is insufficient, it is inappropriate under a tentative diagnosis of aspiration pneumonia.
(3) Cases in which there is a risk of resistant bacteria and hospital treatment is performed (Group C)
The target microorganisms include P. aeruginosa, MRSA, and Acinetobacter spp. in addition to frequent microorganisms that cause respiratory infection [bib_ref] Health-care-associated pneumonia among hospitalizes patients in a Japanese community hospital, Shindo [/bib_ref] [bib_ref] Characteristics and disease severity of healthcare-associated pneumonia among patients in a hospital..., Seki [/bib_ref] [bib_ref] Indicators of potentially drug-resistant bacteria in severe nursing home acquired pneumonia, El Solh [/bib_ref]. As antimicrobial drugs, TAZ/PIPC, with an antimicrobial activity against P. aeruginosa, fourth-generation cephems, carbapenems, and quinolones (CPFX, PZFX) are recommended. TAZ/ PIPC exhibits effects similar to those of IPM/CS and MEPM in patients with nursing and healthcare-associated pneumonia [bib_ref] Prospective randomized comparison study of piperacillin/tazobactam and meropenem for health care-associated pneumonia..., Yamamoto [/bib_ref] (BII). PZFX also has an antimicrobial activity against S. pneumoniae when used at a high dose (2 g/day). When pneumonia related to atypical pathogens such as Chlamydophila spp. is suggested, quinolones should be selected. As the antimicrobial activities of fourth-generation cephems and quinolones against anaerobes are weak, these drugs should be combined with MNZ, CLDM, or SBT/ABPC. Recently, the resistance of the Bacteroides fragilis group to CLDM has advanced [bib_ref] Clinical evaluation of bedridden patients with pneumonia receiving home health care, Fukuyama [/bib_ref]. Therefore, in Europe and the United States, MNZ is selected as a first-choice antimicrobial drug against anaerobes. However, the rate at which the B. fragilis group is involved in oral anaerobes is low, and combination therapy with CLDM may be selected [bib_ref] National survey on the susceptibility of Bacteroides fragilis group: report and analysis..., Snydman [/bib_ref] [bib_ref] Examination of anaerobes in patients with respiratory infectious diseases using the transtracheal..., Mikasa [/bib_ref]. Therefore, for combination therapy with fourth-generation cephems, we recommend the two drugs. When there is a risk of MRSA, such as previous admission, they should be combined with VCM, TEIC, or LZD. If there is no abscess formation, ABK is also effective. A First choices -TAZ/PIPC, intravenous drip, 4.5 g/3e4 times a day -IPM/CS, intravenous drip, 0.5e1 g/2e4 times a day -MEPM, intravenous drip, 1 g/2e3 times a day -DRPM, intravenous drip, 0.5e1 g/3 times a day <> Second choices -CFPM* 2 , intravenous drip, 1e2 g/2e4 times a day -CPR *2 , intravenous drip, 1e2 g/2e4 times a day  one of the followings:
-CLDM, intravenous drip, 600 mg/2e4 times a day -MNZ, intravenous drip, 500 mg/4 times a day or -CPFX *2 , intravenous drip, 300 mg/twice a day -PZFX *2 , intravenous drip, 1000 mg/twice a day  one of the followings:
-CLDM, intravenous drip, 600 mg/2e4 times a day -SBT/ABPC, intravenous drip, 3 g/3e4 times a day *In addition to the above drugs, if MRSA infection is suspected, antimicrobial drugs should be added in accordance with the section "MRSA pneumonia". *2) As the antimicrobial activity of the drug against anaerobes is insufficient, it should be combined with a drug with an antimicrobial activity against anaerobes (MNZ, CLDM, or SBT/ABPC) under a tentative diagnosis of aspiration pneumonia. (4) Severe cases requiring intensive care (Group D)
To cover L. pneumophila and atypical pathogens, which are rare as causative microorganisms but may cause severe conditions, Group-C antimicrobial drugs should be combined with CPFX, PZFX, or AZM injection (BI). Concerning the usefulness of combination therapy with a b-lactam and macrolide injection for severe pneumonia, evidence has been accumulated [bib_ref] Impact of initial antibiotic choice on clinical outcomes in community-acquired pneumonia: analysis..., Brown [/bib_ref]. A study indicated that, in severe community-acquired pneumonia patients with sepsis or requiring ICU management, combination therapy with a blactam and macrolide led to a more favorable prognosis compared to that with a quinolone (I), suggesting that antiinflammatory actions are involved in the mechanism [bib_ref] Management of community-acquired pneumonia, Waterer [/bib_ref]. In addition, another study reported that, among pneumonia patients with acute pulmonary disorder, both the ventilator withdrawal and survival rates in a macrolide-treated group were higher than in a non-macrolide-treated group [bib_ref] Combination anti-biotic therapy with macrorides improves survival in intubated patients with community-acquired..., Martin-Loeches [/bib_ref] (I).
Several meta-analyses also support them [bib_ref] Macroride-based regimens and mortality in hospitalized patients with communityacquired pneumonia: a systematic..., Asadi [/bib_ref] [bib_ref] Macrolide antibiotics and survival in patients with acute lung injury, Walkey [/bib_ref]. A First choices -TAZ/PIPC, intravenous drip, 4.5 g/3e4 times a day -IPM/CS, intravenous drip, 0.5e1 g/2e4 times a day -MEPM, intravenous drip, 1 g/2e3 times a day -DRPM, intravenous drip, 0.5e1 g/3 times a day  one of the followings:
-CPFX *2 , intravenous drip, 300 mg/twice a day -PZFX *2 , intravenous drip, 1000 mg/twice a day -AZM, intravenous drip, 500 mg/once a day <> Second choices -CFPM *2 , intravenous drip, 1e2 g/2e4 times a day -CPR *2 , intravenous drip, 1e2 g/2e4 times a day  one of the followings:
-CLDM, intravenous drip, 600 mg/2e4 times a day -MNZ, intravenous drip, 500 mg/4 times a day  one of the followings:
-CPFX *2 , intravenous drip, 300 mg/twice a day -PZFX *2 , intravenous drip, 1000 mg/twice a day -AZM, intravenous drip, 500 mg/once a day In addition to the above drugs, *If MRSA infection is suspected, antimicrobial drugs should be added in accordance with the section "MRSA pneumonia". *2) As the antimicrobial activity of the drug against anaerobes is insufficient, it should be combined with a drug with an antimicrobial activity against anaerobes (MNZ, CLDM, or SBT/ABPC) under a tentative diagnosis of aspiration pneumonia.

## B. definitive therapy
Antimicrobial drugs against identified causative microorganisms should be selected in accordance with the section "2.2 Hospital-acquired pneumonia" (p. 8).

## Aspiration pneumonia
---Executive summary----As oral indigenous bacteria, including anaerobes, cause aspiration pneumonia, b-lactamase inhibitor-containing penicillins are appropriate (BII). -In cases of nosocomial onset, it is necessary to cover Gramnegative bacillus, including P. aeruginosa. -In cases of severe ventilator-associated pneumonia (VAP), the selection of broad-spectrum antimicrobial drugs or combination therapy with them should not be hesitated (AI). -The detection rate of ESBL-producing Gram-negative bacillus has increased, and antimicrobial drugs should be carefully selected. -It is important to prevent subclinical aspiration through oral care and the prevention of gastroesophageal reflux, such as head lifting (BII). -To prevent aspiration pneumonia, it is also important to improve the nutritional status and avoid the overuse of sleeping pills/ sedatives (BII).
---Explanation---[Characteristic and classification of diseases] Aspiration pneumonia occurs with a background factor, dysphagia, which is frequently observed in the presence of a reduction in ADL or systemic functions, especially cerebrovascular disorder. Its onset is associated with dietary ingestion in elderly persons [bib_ref] Aspiration pneumonitis and aspiration pneumonia, Mrik [/bib_ref]. Currently, aspiration pneumonia is accurately defined only in the Guidelines for the Management of Hospitalacquired Pneumonia (HAP) in Adults, which were prepared by the Japanese Respiratory Society. The guidelines present conditions that may cause dysphagia, which were proposed by the Japanese Study Group on Aspiration Pulmonary Disease , modified). In our guidelines, we primarily explain antimicrobial drugs to be selected for patients with such conditions.
The above definition is also adopted in the Guidelines for the Management of Nursing and Healthcare-associated Pneumonia (NHCAP). In elderly persons admitted to long-term care beds or nursing homes, risk factors include dysphagia and tubal feeding according to international data on pneumonia that develops in nursing homes [137e139]. In Japan, frequent underlying diseases in patients with NHCAP also include central nervous diseases and dementia, which are closely associated with aspiration. The proportion of patients after percutaneous endoscopic gastrostomy (PEG) is high [bib_ref] Hospitalized nursing home-acquired pneumonia: comparison with community-acquired pneumonia in older adults, Tani [/bib_ref]. However, among various types of community-acquired pneumonia, a diagnosis of aspiration pneumonia is made based on onset factor-based classification, and is not equal to NHCAP diagnosed primarily based on the place of onset or grade of nursing. According to data in Spain, aspiration pneumonia accounts for 20.6% of patients with healthcareassociated pneumonia (HCAP) requiring admission. This percentage was markedly higher than in those with communityacquired pneumonia (CAP) requiring admission (3.6%), but corresponded to no more than 1/5 [bib_ref] Health care-associated pneumonia requiring hospital admission: epidemiology, antibiotic therapy, and clinical outcomes, Carratal A [/bib_ref]. On the other hand, a multicenter cooperative study involving inpatients with pneumonia in Japan, where the rapid aging of society is advanced, reported that 60.1% of patients who were admitted with CAP had aspiration pneumonia. Even in patients with CAP, which is not classified as NHCAP, the involvement of aspiration cannot be ignored [bib_ref] High incidence of aspiration pneumonia in community-and hospital-acquired pneumonia in hospitalized patients:..., Teramoto [/bib_ref]. Furthermore, the study indicated the involvement of aspiration in 86.7% of patients, aged over 70 years, with CAP/ HAP [bib_ref] High incidence of aspiration pneumonia in community-and hospital-acquired pneumonia in hospitalized patients:..., Teramoto [/bib_ref]. In the future, the significance of distinguishing aspiration pneumonia among patients with NHCAP or HAP and changing therapeutic strategies should be examined. However, NHCAP more markedly affects ADL compared to CAP, and the aspect of elderly pneumonia is emphasized; it may be significant to positively diagnose aspiration pneumonia and establish therapeutic strategies different from those for CAP [bib_ref] Rethinking the concepts of communityacquired and health-care-associated pneumonia, Ewig [/bib_ref].
Concerning HAP, a reduction in the immune function is a background factor. HAP has two aspects: pneumonia with a high risk of resistant bacteria and that in which central nervous diseaserelated aspiration is involved. In the Guidelines for the Management of Hospital-acquired Pneumonia in Adults, which were prepared by the Japanese Respiratory Society, Mendelson syndrome and VAP are categorized as a group, and 3 classifications, involving diffuse deglutition-related bronchiolitis, in which there are no findings of pneumonia, are proposed. In addition, a flow chart for diagnosis is presented [fig_ref] 2: MSSA Refer to the section "2 [/fig_ref]. With respect to the condition and treatment of VAP, refer to a review described by Chastre et al. [bib_ref] Ventilator-associated pneumonia, Chastre [/bib_ref] Management other than antimicrobial drug therapy should also be considered, and bundle-based prevention should be performed [bib_ref] Effectiveness of a multi dimensional approach for prevention of ventilator-associated pneumonia in..., Rosenthal [/bib_ref] (AII).
[Type and frequency of causative microorganisms]
Streptococcus pneumoniae, S. aureus, and Enterobacteriacae have been reported. A study indicated that K. pneumoniae was frequent. The involvement of oral indigenous bacteria, such as Streptococcus anginosus group. and anaerobes, has been suggested [bib_ref] Pathogenic bacteria in aspiration pneumonia, Higa [/bib_ref] [bib_ref] Microbiology of severe aspiration pneumonia in institutionalized elderly, El-Solh [/bib_ref]. In cases of nosocomial onset, Gram-negative bacillus, including P. aeruginosa, must also be considered. Concerning E. coli, Klebsiella spp., and Proteus spp., the number of ESBL-producing strains may increase in the future.
[Rules of antimicrobial drug therapy]
If appropriate antimicrobial drug therapy is not selected under a diagnosis of aspiration-related pneumonia, insufficient treatment may lead to a fatal condition, or excessive treatment may increase the number of resistant bacteria, showing negative effects. There may be differences in options for empiric therapy between patients with VAP (most patients show severe conditions) and those with diffuse deglutition-related bronchiolitis, in whom the start of treatment is not accelerated. On the other hand, approaches to prevent pneumonia after aspiration or avoid aspiration are important. Oral care, head lifting, and improvement in the nutritional status must be considered, and the overuse of sleeping pills/ sedatives should be avoided (BII).
The best option for standard-type aspiration pneumonia is an antimicrobial drug that exists an antimicrobial activity against both aerobes and anaerobes. SBT/ABPC and TAZ/PIPC are effective for anaerobes frequently isolated in the respiratory system, such as Fusobacterium spp., Prevotella spp., and Peptostreptococcus spp. [bib_ref] Ampicillin  sulbactam vs clindamysin  cephalosporin for the treatment of aspiration..., Allewelt [/bib_ref] [bib_ref] Tazobactam/piperacillin for moderate-to-severe pneumonia in patients with risk for aspiration: comparison with..., Ito [/bib_ref]. As the resistance rates of these types of bacteria to the two regimens are low, these regimens are also recommended as first choices in the guidelines established by the Japanese Association for Anaerobic Infection Research.
However, a study reported that the previous administration of antimicrobial drugs and ADL were correlated with the frequency of Enterobacteriacae-or P. aeruginosa-related pneumonia [bib_ref] Indicators of potentially drug-resistant bacteria in severe nursing home-acquired pneumonia, El-Solh [/bib_ref]. A retrospective study involving 90 patients with aspiration pneumonia showed that the frequency of K. pneumoniae-related pneumonia was 25% [bib_ref] Changing bacteriology of adult community-acquired lung abscess in Taiwan: Klebsiella pneumoniae versus..., Wang [/bib_ref]. Based on these studies, drugs to be selected should be changed in accordance with the previous administration of antimicrobial chemotherapeutic drugs in patients admitted to general or medical wards. Among patients with hospital-acquired pneumonia, broad-spectrum drugs should be selected in those with severe aspiration pneumonia or VAP (BII). When causative microorganisms are identified and an improvement in the condition is achieved, de-escalation should be performed.
---Drugs to be recommended--a. Empiric therapy  No risk of resistant bacteria Drugs with potent antimicrobial activities against oral anaerobes are presented. However, no article has provided high-level evidence regarding aspiration pneumonia. As the following drugs affect the intestinal flora, antimicrobial drugassociated diarrhea may occur. If symptom improvement is delayed, patients must be promptly admitted, and drip Conditions that may cause dysphagia.

## Table 10
Bundles for the prevention of ventilator-associated pneumonia.
(1) Upper body lifting The head should be lifted at 30e45 .
(2) Discontinuation of sedatives A sedative should be discontinued once a day to evaluate whether or not extubation is possible.
(

## 3) prevention of gastrointestinal hemorrhage (4) prevention of deep venous thrombosis (dvt)
In addition to the above items, methods to prevent aspiration pneumonia include oral care, the administration of drugs that improve the deglutition function, such as ACE inhibitors and cilostazol, improvement in the nutritional status, eating/swallowing rehabilitation, and anti-Pneumococcus vaccination.
infusion therapy should be performed (outpatient treatment should not be prolonged).
(1) Outpatient treatment A First choices -CVA/AMPC, oral (125/250 mg), 2 tablets/3e4 times a day -SBTPC, oral (375 mg), 2 tablets/3e4 times a day <> Second choices -MFLX, oral, 400 mg/once a day -STFX, oral, 100 mg/1e2 times a day -GRNX, oral, 400 mg/once a day (2) Hospital treatment When a diagnosis of aspiration pneumonia is made, SBT/ABPC is most frequently used in Japan [bib_ref] Survey regarding antimicrobial drug therapy for aspiration pneumonia, Shiraishi [/bib_ref]. reported that the sensitivity of oral anaerobes that may cause aspiration pneumonia, such as Peptostreptococcus spp., Prevotella spp., and Fusobacterium spp., to SBT/ABPC was 100%, similar to that to TAZ/PIPC [bib_ref] Treatment of aspiration pneumonia based on the antimicrobial susceptibility pattern of oral..., Kaneko [/bib_ref].
The effects of CLDM on aspiration pneumonia or a pulmonary abscess are similar to those of SBT/ABPC (BI) [bib_ref] Pathogenic bacteria in aspiration pneumonia, Higa [/bib_ref]. SBT/ABPC and CLDM showed similar effects and tolerance on aspiration pneumonia (67.5 and 63.5%, respectively) [bib_ref] Ampicillin  sulbactam vs clindamysin  cephalosporin for the treatment of aspiration..., Allewelt [/bib_ref]. Oral anaerobes, excluding Bacteroides spp., are still susceptible to CLDM. A randomized clinical trial (RCT) indicated that CLDM was more potent than cephems [bib_ref] Reappraisal of clindamycin IV monotherapy for treatment of mild-tomoderate aspiration pneumonia in..., Kadowaki [/bib_ref]. A First choice -SBT/ABPC, intravenous drip, 3 g/3e4 times a day <> Second choice -CLDM, intravenous drip, 600 mg/2e4 times a day  Cases in which there is a risk of resistant bacteria or severe cases In cases in which there is a risk of resistant bacteria or severe cases, drugs should be selected in accordance with options for Group C for NHCAP. Tubal feeding is a risk factor for aspiration, and is also a risk factor for resistant bacteria [bib_ref] Health-care-associated pneumonia among hospitalizes patients in a Japanese community hospital, Shindo [/bib_ref]. When the involvement of Enterobacteriacae, such as K. pneumoniae and E. coli, is suggested, empiric therapy should be selected in accordance with cases in which there is a risk of resistant bacteria [bib_ref] Ventilator-associated pneumonia, Chastre [/bib_ref]. In Japan, the proportion of ESBL-producing bacteria on sputum culture in patients with respiratory infectious diseases is 5% or less [bib_ref] Nationwide surveillance of bacterial respiratory pathogens conducted by the Surveillance Committee of..., Watanabe [/bib_ref] , but the number of ESBL-producing bacteria has slightly increased; this must be considered in the future [bib_ref] Regional variation in the prevalence of extended-spectrum b-lactamase-producing clinical isolates in the..., Hirakata [/bib_ref] [bib_ref] Special issue, current topics on urological infectious diseases---Refractory factors and management---, 2..., Muratani [/bib_ref]. A study reported that the clinical effects of TAZ/PIPC on non-ESBLproducing K. pneumoniae were more potent than those of SBT/ABPC; caution is needed [bib_ref] Retrospective investigation of the clinical effects of tazobactam/piperacillin and sulbactam/ampicillin on aspiration..., Tsukada [/bib_ref]. It must be considered that, in cases of aspiration pneumonia classified as HCAP, Enterobacteriacae is isolated at a frequency that cannot be ignored. Concerning aspiration pneumonia that occurs in hospitals, some reviews proposed that antimicrobial drugs should be selected, regarding the condition as hospitalacquired pneumonia; empiric therapy may be selected in accordance with the Guidelines for the Management of Hospital-acquired Pneumonia, which were published by the Japanese Respiratory Society [bib_ref] Anaerobic bacterial infection of the lung, Bartlett [/bib_ref]. According to a study, BIPM, which does not cause kidney dysfunction in elderly patients, is also effective (CIV); therefore, it is presented as an option for cases in which there is a risk of resistant bacteria [bib_ref] Evaluation of the efficacy and safety of biapenem against pneumonia in the..., Karino [/bib_ref].
The mortality rate in patients with VAP is high. If causative microorganisms cannot be initially covered, the mortality rate may increase. Therefore, drugs should be selected, regarding the condition as severe aspiration pneumonia. Three studies reported that, in a group in which TAZ/PIPC was selected as a drug to be combined with aminoglycosides for VAP treatment, the mortality rate was lower than in a group in which CAZ was selected [159e161]. In particular, when pneumonia was caused by P. aeruginosa, the clinical effects of TAZ/PIPC were more potent than those of IPM/CS (BII). For monotherapy, information on the culture of protected specimen brush (PSB) samples or broncho-alveolar lavage (BAL) fluid is strongly recommended [bib_ref] The role of an aerobes in patients with ventilatorassociated pneumonia and aspiration..., Marik [/bib_ref] [bib_ref] Preemptive antibiotic treatment based on gram staining reduced the incidence of ARDS..., Matsushima [/bib_ref]. On the other hand, an observational study indicated that threedrug therapy (two anti-P. aeruginosa drugs  an anti-MRSA drug) deteriorated the prognosis; an RCT should be conducted in the future [bib_ref] Implementation of guidelines for management of possible multidrugresistant pneumonia in intensive care:..., Kett [/bib_ref]. Therefore, if there is a risk of resistant bacteria, at least broad-spectrum antimicrobial drugs must be used for empiric therapy. However, assuming causative microorganisms with reference to Gram staining reactions, minimum necessary antimicrobial drugs should be selected based on local factors (antimicrobial drug susceptibility pattern of each type of bacteria in each hospital). Recently, the entity of ventilator-associated tracheobronchitis (VAT) was proposed, and the disadvantages of aggressive treatment have been discussed [bib_ref] Ventilator-associated tracheobronchitis: the impact of targeted antibiotic therapy on patient outcomes, Craven [/bib_ref]. In a multicenter cooperative study, patients with VAT, which occurred in the ICU, were divided into two groups with and without antimicrobial drug therapy, and the results were compared. In the former, the incidence of VAP was significantly lower, and the mechanical ventilation-free period was significantly longer. In addition, the ICU mortality rate was significantly lower. On the other hand, there was no significant difference in the appearance of resistant bacteria between the two groups [bib_ref] Antimicrobial treatment for ventilator-associated tracheobronchitis: a randomized, controlled, multicenter study, Nseir [/bib_ref]. A First choices -TAZ/PIPC, intravenous drip, 4.5 g/3e4 times a day -IPM/CS, intravenous drip, 0.5e1 g/2e4 times a day -MEPM, intravenous drip, 1 g/2e3 times a day -DRPM, intravenous drip, 0.5e1 g/3 times a day -BIPM, intravenous drip, 0.3e0.6 g/3e4 times a day <> Second choices -CFPM, intravenous drip, 1e2 g/2e4 times a day -CPR, intravenous drip, 1e2 g/2e4 times a day  one of the followings:
-CLDM, intravenous drip, 600 mg/2e4 times a day -MNZ, intravenous drip, 500 mg/4 times a day or -LVFX, intravenous drip, 500 mg/once a day -CPFX, intravenous drip, 300 mg/twice a day -PZFX, intravenous drip, 500 to 1000 mg/twice a day  one of the followings:
-CLDM, intravenous drip, 600 mg/2e4 times a day -MNZ, intravenous drip, 500 mg/4 times a day -SBT/ABPC, intravenous drip, 1.5e3 g/3e4 times a day *If MRSA infection is suspected, antimicrobial drugs should be administered in accordance with the section "MRSA pneumonia" in addition to the above drugs.
[Administration period of antimicrobial drugs] It is recommended that the treatment period of hospitalacquired pneumonia should be 7e10 days. However, the treatment period should be 14 days in patients with pneumonia related to non-glucose-fermenting bacteria such as P. aeruginosa [bib_ref] Infectious diseases society of America/American thoracic society consensus guidelines on the management..., Mandell [/bib_ref] (BII). Concerning VAP, a study reported that there was no difference in the clinical effects between 8 and 15 days [bib_ref] Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia..., Chastre [/bib_ref].

## B. definitive therapy
To control identified causative microorganisms, antimicrobial drugs should be selected in accordance with the section "Hospital-acquired pneumonia". If MRSA infection is suspected, antimicrobial drugs should be selected in accordance with the section "MRSA pneumonia". (BII). -In severe or refractory cases in which the efficacy of initial treatment is not sufficient, combination therapy with an antifungal drug should also be considered [171e173] (BII). -As the effects of combination therapy with an azole and AMPH-B preparation antagonize in some strains, a combination of these drugs should be avoided [bib_ref] Triazole-polyene antagonism in experimental invasive pulmonary aspergillosis: in vitro and in vivo..., Meletiadis [/bib_ref] (AIII). -For the target treatment of this disease, an antifungal drug of which the class is different from that of a drug used for preventive administration should be used (BIII).
---Explanation---[Characteristics of the disease] -Symptoms: This disease develops in severe immunocompromised hosts such as patients received chemotherapy for leukemia or hematopoietic stem cell/organ transplantation. Symptoms such as fever that does not respond to broadspectrum antimicrobial drugs, cough, dyspnea, sputum, and bloody sputum/hemoptysis are observed. -Laboratory findings: Chest X-ray shows an infiltrative shadow (typically, a wedge shadow involving the pleura as the base). On thoracic CT, infiltrative and nodular shadows (with a halo sign in some cases) are observed. In the recovery phase of neutrophils, an air crescent sign is noted. An increase in the inflammatory marker such as the CRP level, Aspergillus galactomannan antigen-positive reactions, and an increase in the (1 / 3)-b-D-glucan level are useful for diagnosis. However, neither the sensitivity nor specificity is sufficient. The results should be carefully evaluated. -Causative microorganisms: Aspergillus fumigatus is frequently detected, but, recently, an increase in the number of patients with non-fumigatus Aspergillus-related IPA has been indicated. -Specific condition: Lesions are sometimes formed in the nasal sinus and brain; caution is needed. -Early diagnosis: Early treatment is important for successful treatment for this disease.
---Drugs to be recommended---A study reported that, in a group in which VRCZ was used for the initial treatment of IPA, the results of treatment were more favorable than in a group in which d-AMPH was used [bib_ref] Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis, Herbrecht [/bib_ref]. Furthermore, another study indicated that therapy with L-AMB at 3 mg/kg/day was safer than that at 10 mg/kg/ day, although there was no significant difference in the clinical efficacy [bib_ref] Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized..., Cornely [/bib_ref]. CPFG, MCFG, and ITCZ also have anti-Aspergillus activities, and can be used. It is important to consider different strategies in accordance with the appearance of the host's allergy or adverse events and interactions with drugs used to treat an underlying disease. b. Chronic progressive pulmonary aspergillosis (CPPA) ---Executive summary----In Japan, various disease types such as aspergilloma with infiltration and enlargement of an existing cavity are included. CPPA includes various diseases such as chronic necrotizing pulmonary aspergillosis (CNPA), chronic cavitary pulmonary aspergillosis (CCPA), and chronic fibrosing pulmonary aspergillosis (CFPA). It refers to a series of syndrome for which the administration of antifungal drugs is essential. -Treatment should be started with injection. If symptoms and findings are stabilized, injection should be switched to oral drugs. -Initial treatment with MCFG or CPFG should be performed [bib_ref] Intravenous micafungin versus voriconazole for chronic pulmonary aspergillosis: a multicenter trial in..., Kohno [/bib_ref] [bib_ref] A doubleblind comparative study of the safety and efficacy of caspofungin versus..., Kohno [/bib_ref] (AI). -Initial treatment with ITCZ, VRCZ, or L-AMB can also be selected in accordance with the host's underlying disease or drugs used to treat the underlying disease. -For maintenance therapy, ITCZ and VRCZ oral preparations are recommended (AIII).
---Explanation---[Characteristics of the disease] -Symptoms: This disease develops in hosts with organic diseases such as a cavity or cystic disease of the lung or bronchus. Symptoms such as fever, sputum, bloody sputum/ hemoptysis, and dyspnea are observed. -Laboratory findings: Chest X-ray and CT show an infiltrative shadow, enlargement of a cavity, thickening of the cavity wall/pleura, and a niveau in the cavity. There is an increase in the CRP level in many patients. Most patients are positive for anti-Aspergillus precipitating antibody. Neither Aspergillus galactomannan antigen nor b-D-glucan is a clue to diagnosis.
-Causative microorganisms: A. fumigatus is frequently detected. Non-fumigatus Aspergillus-related CPPA is also often observed.
---Drugs to be recommended---A clinical study in Japan indicated that there was no marked difference in the efficacy of treatment between MCFG-and VRCZ-treated groups, whereas MCFG was safer [bib_ref] Intravenous micafungin versus voriconazole for chronic pulmonary aspergillosis: a multicenter trial in..., Kohno [/bib_ref]. Another study reported that there was no difference in treatment results between MCFG and CPFG [bib_ref] A doubleblind comparative study of the safety and efficacy of caspofungin versus..., Kohno [/bib_ref]. In the phase of severe symptoms such as fever and bloody sputum, treatment should be started using these injections. -Pulmonary aspergilloma is classified into two types: simple and complex aspergilloma based on the grade of difficulty in resection. The former refers to aspergilloma formation in a focus with a thin wall, such as a cyst, without accessory lesions at the periphery. The latter refers to aspergilloma formation in a cavity derived from a strongly destructed existing structure of the lung, such as old pulmonary tuberculosis and bronchiectasis, with marked destructive lesions or pleural adhesion at the periphery of the cavity.
---Drugs to be recommended---Resection should be selected as a first choice. When resection is impossible, medical treatment can be considered.
In preparation, such as L-AMB, and 5-FC should be performed for 2 weeks or more. Subsequently, treatment should be continued using FLCZ or F-FLCZ. -In Japan, Cryptococcus gattii infection has also been reported.
If possible, causative fungus must be isolated/identified.
---Explanation---[Characteristics of the disease] -Symptoms: This disease is often asymptomatic, and is detected on a health checkup in many cases. -Laboratory findings: Chest X-ray and CT show solitary or multiple nodular and infiltrative shadows.
-Some cavities are observed in a lot of cases. There is no enhancement of the inflammatory marker in many cases, but glucuronoxylomannan antigen-positive reactions are detected. -Causative microorganisms: This disease is caused by Cryptococcus neoformans. Recently, infection with C. gattii has been reported in Vancouver, Canada and the North area of the West Coast of the United States of America; caution is needed. -C. gattii is primarily distributed in the tropical and subtropical zones. Infection in humans has been considered to be rare. However, since 1999, patients infected with C. gattii have been reported in the Pacific Coast of North America. Even healthy adults are infected with C. gattii, and the mortality rate is high.
---Drugs to be recommended---Although there is no evidence regarding pulmonary cryptococcosis, FLCZ tablets, which have a potent activity against Cryptococcus, are frequently selected when the patient's condition is stable in the absence of an underlying disease. Azoles other than this drug can also be selected. [bib_ref] Primary treatment of zygomycosis with liposomal amphotericin B: analysis of 28 cases, Shoham [/bib_ref] (AII). -If the lesion is localized, resection should be considered.
-Combination therapy with an iron chelating agent and L-AMB should be avoided [bib_ref] The Deferasirox-AmBisome Therapy for Mucormycosis (DEFEAT Mucor) study: a randomized, double-blinded, placebo-controlled..., Spellberg [/bib_ref] (AI).
---Explanation--- Recently, an increase in the incidence of infection with Cunninghamella has also been indicated. -Specific condition: Nasal/brain-type, dermal, and disseminated zygomycosis is observed.
---Drugs to be recommended---Currently, only AMPH preparations may be clinically useful for treating zygomycosis among antifungal drugs that are available in clinical practice in Japan. As high-dose therapy must be started as early as possible, not d-AMPH but L-AMB should be selected.
-L-AMB, intravenous drip, 5 mg/kg/once a day Precautions for the use of antifungal drugs (Confirm the package inserts.)  VRCZ Vision disorder, liver dysfunction, and neurological/ mental adverse events may occur.
Combination therapy with RFP, RBT, efavirenz, ritonavir, carbamazepine, long-acting barbiturate, pimozide, quinidine sulfate, ergot alkaloid, or triazolam is contraindicated. This drug is also contraindicated for pregnant women. As a rule, it is contraindicated for patients with a Ccr of <30 mL/ min (injection only).
As the blood concentration of VRCZ may vary, TDM should be conducted. In patients with mild to moderate liver dysfunction, the dose should be regulated.  ITCZ Hepatopathy and congestive heart failure may occur. Combination therapy with pimozide, quinidine, bepridil, simvastatin, triazolam, azelnidipine, ergotamine, nisoldipine, dihydroergotamine, vardenafil, eplerenone, blonanserin, sildenafil, tadalafil, aliskiren, dabigatran(ITCZ oral only), rivaroxaban, ergometrine, or methylergometrine is contraindicated. This drug is contraindicated for patients with severe liver diseases, pregnant women. Patients with a Ccr of <30 mL/min are also contraindicated (injection only).  FLCZ Hepatopathy and a prolongation of QT may occur. Combination therapy with triazolam, ergotamine, dihydroergotamine, quinidine, or pimozide is contraindicated. This drug is also contraindicated for pregnant women.  F-FLCZ Combination therapy with triazolam, ergotamine, dihydroergotamine, quinidine, or pimozide is contraindicated. This drug is also contraindicated for pregnant women.  L-AMB Adverse events such as nephropathy, hypopotassiumemia, and fever may occur.
This drug is contraindicated during leukocyte transfusion.  CPFG This drug is safe, but hepatopathy may occur. Caution is needed for combination therapy with cyclosporin, tacrolimus, RFP, efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine.  MCFG This drug is safe, but hepatopathy may occur.
 5-FC Anorexia and myelopathy may occur. Combination therapy with tegafur-/gimeracil-/oteracil potassium-containing drugs is contraindicated. Even after the discontinuation of tegafur-/gimeracil-/oteracil potassium-containing drugs, combination therapy should be avoided within 7 days. This drug is also contraindicated for pregnant women. ---Drugs to be recommended---ST combination drugs are used as a gold standard of PCP treatment. However, there have been a large number of patients in whom treatment was discontinued due to their side effects. Recently, atovaquone also became available in Japan as a second-choice drug. In patients with mild PCP, atovaquone tablets were as effective as ST combination drugs. In those with moderate PCP, ST combination drugs were more effective, but there was no significant difference due to a small number of subjects. In atovaquone-treated patients, the incidence of adverse events for which administration was discontinued was lower than in ST combination drug-treated patients, suggesting that the tolerance is high [bib_ref] Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in..., Hughes [/bib_ref].

## A first choices
The administration period should be 21 days in HIVinfected patients and 14 days in non-HIV-infected patients. A target daily dose of trimethoprim should be 15e20 mg/kg. -ST combination drug, oral, 3 to 4 tablets/3 times a day -ST combination drug, intravenous drip, 240e320 mg as trimethoprim/3 times a day (infused over 1e2 h) <> Second choices -Pentamidine, intravenous drip, 4 mg/kg/once a day (infused over 1e2 h) -Atovaquone oral suspension, 5 mL (750 mg as atovaquone)/twice a day for 21 days (orally administered after meals) * Adjuvant therapy In patients with a PaO 2 of <70 mmHg or A-aDO 2 of >35 mmHg in room air, one of the above drugs should be combined with a corticosteroid from the start of treatment. However, the dose may be reduced or administration may be discontinued in the early phase in accordance with symptoms. When the respiratory state is extremely unfavorable, pulse therapy should also be considered. Prednisolone Days 1e5: Oral, 30e40 mg/twice a day Days 6e10: Oral, 15e20 mg/twice a day Days 11e21: Oral, 7.5e10 mg/twice a day ---Precautions for each drug---(Confirm the package inserts.)  ST combination drug (Baktar tablets) Fever, exanthema, digestive symptoms, hepatopathy, nephropathy, and blood disorder may occur.
This drug may interact with methotrexate, sulfadoxine, pyrimethamine, diaphenylsulfone, sulfonyl amide/sulfonylurea oral drugs for diabetes, warfarin, phenytoin, cyclosporin, zidovudine, digoxin, tricyclic antidepressants, and lamivudine.
This drug is contraindicated for neonates, low-birthweight infants, pregnant women, and patients with G-6-PD deficiency. In patients with renal dysfunction, dose reduction must be considered.

##  pentamidine
Side effects such as hypoglycemia, hypotension, nephropathy, taste disorder, numbness of the tongue/lips, ventricular arrhythmia, exanthema, and fever may occur. Combination therapy with zalcitabine, PFA, or amiodarone is contraindicated. This drug is contraindicated for patients with severe ventilatory disturbance.  Atovaquone Nausea/vomiting, exanthema, and diarrhea may occur. This drug should be carefully administered to patients with severe kidney or liver dysfunction. This drug may interact with RFP, RBT, tetracycline, metoclopramide, zidovudine, acetaminophen, benzodiazepines, aciclovir, opioid analgesic drugs, cephalosporin antibiotics, antidiarrheal drugs/laxatives, and indinavir.
h. Cytomegalovirus (CMV) pneumonia ---Executive summary----In the field of transplantation, preemptive treatment with GCV should be conducted through CMV antigenemia test monitoring. -The efficacy of preemptive treatment with vGCV or PFA is similar to that of GCV. -If a diagnosis of CMV pneumonia is made, treatment with GCV should be promptly started [bib_ref] International consensus guidelines on the management of cytomegalovirus in solid organ transplantation, Kotton [/bib_ref] (AII). -vGCV and PFA are recognized as alternative drugs for GCV [bib_ref] Oral valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus..., Asberg [/bib_ref] [bib_ref] Forscarnet vs ganciclovir for cytomegalovirus (CMV) antigenemia after allogeneic hemopoietic stem cell..., Moretti [/bib_ref] (BII). -Combination therapy with an antiviral drug and high-dose immunoglobulin should be performed [bib_ref] Treatment of interstitial pneumonitis due to cytomegalovirus with ganciclovir and intravenous immune..., Ljungman [/bib_ref] (AIII).
---Explanation--- ---Antimicrobial drugs to be recommended---A first-choice drug for CMV pneumonia treatment is GCV, which has been frequently used. PFA has been used to treat CMV infection in AIDS patients, but experience on its use is limited in patients after hematopoietic stem cell transplantation.
(1) Initial administration A First choice -GCV, intravenous drip, 5 mg/kg (over 1 h or more)/ every 12 h for 2e3 weeks  anti-CMV high-titer gamma globulin, intravenous drip, 2.5e5 g/once a day for the first 3 days <> Second choices -PFA, intravenous drip, 60 mg/kg (over 1 h or more)/3 times a day, every 8 h for 2e3 weeks or more  anti-CMV high-titer gamma globulin, intravenous drip, 2.5e5 g/once a day for the first 3 days or -PFA, intravenous drip, 90 mg/kg (over 2 h or more)/ twice a day, every 12 h for 2e3 weeks or more  anti-CMV high-titer gamma globulin, intravenous drip, 2.5e5 g/once a day for the first 3 days (2) Maintenance administration A First choices -GCV, intravenous drip, 5 mg/kg (over 1 h or more)/once a day, 7 days a week or -GCV, intravenous drip, 6 mg/kg (over 1 h or more)/once a day, 5 days a week * This regimen should be completed after confirming the disappearance of clinical symptoms and negative reactions on two consecutive CMV antigenemia tests.
<> Second choice -PFA, intravenous drip, 90e120 mg/kg (over 2 h or more)/once a day (In clinical practice in Japan, there have been few case reports on once-a-day administration at 120 mg/ kg as maintenance therapy. A dose exceeding 120 mg/ kg should be avoided. For administration at 120 mg/kg, twice-a-day administration at 60 mg/kg is commonly selected.) * This regimen should be completed after confirming the disappearance of clinical symptoms and negative reactions on two consecutive CMV antigenemia tests.
---Precautions for each drug---(Confirm the package inserts.)  GCV Severe leukopenia, neutropenia, anemia, thrombopenia, pancytopenia, aplastic anemia, and bone marrow suppression may occur. An animal experiment showed that this drug induced transient or irreversible spermatogenic dysfunction and reduced fertility. In humans, this drug may cause spermatogenic dysfunction. An animal experiment demonstrated the teratogenicity, mutagenicity, and carcinogenicity of this drug. In the presence of renal hypofunction, it is necessary to regulate the dose.
This drug is contraindicated for patients with marked bone marrow suppression (neutrophil count: <500/mm 3 or platelet count: <25,000/mm 3 ) and pregnant women.
It may interact with didanosine, zidovudine, IPM/CS, bone marrow-suppressing and kidney function-affecting drugs, zalcitabine, ST combination drugs, cyclosporin, probenecid, and mycophenolate mofetil.  VGCV This is a prodrug of GCV.  PFA Acute renal failure, shock, heart failure, thrombophlebitis, and convulsion may occur.
It is necessary to regulate the dose in accordance with the kidney function. Combination therapy with pentamidine is contraindicated. This drug is contraindicated for patients with a Ccr of <0.4 mL/min/kg.

## Pneumonia (children)

## Community-acquired pneumonia
---Executive summary---For the treatment of community-acquired pneumonia in children, antimicrobial drugs should be selected, considering age and severity.
---Explanation---

## [characteristics and classification of the disease]
Patients with acute respiratory infectious disease symptoms, such as fever, nasal discharge, pharyngeal pain, and cough, and the appearance of a new infiltrative shadow in the lung on imaging examinations such as chest X-ray and CT are regarded as having pneumonia. In patients with pneumonia, thoracic auscultation findings often include accessory murmurs and the attenuation of respiratory sounds. Most patients with respiratory infectious diseases consult hospitals with fever and cough. The lesion site of the airway is estimated based on symptoms and physical findings [fig_ref] Figure 3: Differentiation of major childhood respiratory infectious diseases[189] [/fig_ref]. In addition to thoracic findings, it is necessary to check the presence or absence of dyspnea signs, such as tachypnea, nasal alar breathing, retractive breathing, shoulder breathing, orthopnea, groaning, and cyanosis. To consider the need of antimicrobial-drug administration and options of antimicrobial drugs, pneumonia is classified into three types: bacterial, viral, and atypical pneumonia based on causative microorganisms.
[Type and frequency of causative microorganisms]
Microorganisms that cause childhood community-acquired pneumonia differ among ages. According to the data on investigation of causative microorganisms based on lavage sputum culture in Japan, bacterial and viral pneumonia is frequent in infants/children aged 1 year or younger. In those aged 2e6 years, the incidences of bacterial, viral, and atypical pneumonia are similar. In those aged over 6 years, the incidence of atypical pneumonia is the highestinsufficient. However, a review reported similar findings [bib_ref] Community-acquired pneumonia in children, Mcintosh [/bib_ref]. In children, it is not easy to investigate causative microorganisms. In institutions in which it is impossible to investigate causative microorganisms, treatment must be performed based on the statistical frequency of causative microorganisms described below. However, in those in which investigation is possible, the etiology should be investigated if possible.
[Rules of antimicrobial drug therapy]
It is important to improve the efficacy of treatment by accurately predicting causative microorganisms and selecting an appropriate antimicrobial drug and its administration method. Whether or not an antimicrobial drug should be indicated must be comprehensively evaluated by differentiating bacterial, viral, and atypical pneumonia with reference to age, severity, clinical symptoms, physical findings, laboratory data, and X-ray findings. As a rule, a single antimicrobial drug should be selected. When the type of microorganisms that caused pneumonia is identified, an antimicrobial drug should be selected through de-escalation, considering drug susceptibility and pharmacokinetics.
[Clinical symptoms, physical findings]
Wet cough and tachypnea are frequently observed in children with bacterial pneumonia. The proportion of labored breathingfree patients is high in children with Mycoplasma pneumonia [bib_ref] Community-acquired pneumonia in children, Mcintosh [/bib_ref] [bib_ref] Fifth Pediatric Respiration Seminar. Review of chest X-ray findings of pneumonia, childhood..., Kurosaki [/bib_ref]. Auscultation findings include intermittent accessory murmurs (rales) regardless of the type of pneumonia. In children with Mycoplasma pneumonia, the proportion of those in whom auscultation findings are not marked is significantly higher than in other groups. In children with Chlamydia pneumonia, fever is mild, and cough is protracted. Thus, clinical symptoms and physical findings show characteristics related to causative microorganisms, but it is difficult to identify causative microorganisms based on clinical symptoms and physical findings alone in individual patients .

## [laboratory findings]
Concerning laboratory findings on admission in children with bacterial and viral pneumonia, there are significant differences in the leukocyte count, CRP level, and erythrocyte sedimentation rate between the two groups (p < 0.01). However, measurements overlapping in about one-third of patients are presented [bib_ref] Etiology of pediatric inpatients with pneumoniaeanalysis of clinical symptoms, physical examination and..., Ishiwada [/bib_ref]. Briefly, it is impossible to accurately differentiate bacterial from viral pneumonia based on inflammatory responses reflected by the leukocyte count, CRP level, and erythrocyte sedimentation rate. Mycoplasma pneumonia is characterized by increases in the CRP level and erythrocyte sedimentation rate, but many patients show normal leukocyte counts or a slight decrease in this parameter. Furthermore, it is difficult to differentiate Mycoplasma from viral pneumonia based on laboratory data [bib_ref] Basic examination regarding "the Guidelines for the Management of Pneumonia in Children",..., Kurosaki [/bib_ref].
[Chest X-ray] Chest X-ray findings show characteristics related to causative microorganisms to some degree, but it is difficult to identify causative microorganisms in individual patients [bib_ref] Differential diagnosis of viral, mycoplasmal and bacteraemic pneumococcal pneumonias on admission to..., P [/bib_ref].

## [classification of severity]
It is important to evaluate the severity of pneumonia, for selecting outpatient or hospital treatment and reviewing the necessity of antimicrobial drugs and route of administration (oral or intravenous). The classification of severity in the Guidelines for the Management of Respiratory Infectious Diseases in Children in Japan 2011 is presented. Causative microorganisms with respect to age in children with community-acquired pneumonia [bib_ref] Limitations of the etiological diagnosis of bronchopulmonary infectious diseases---Appearance of EMB, Nakamura [/bib_ref]. the severity classification of childhood pneumonia has not been reached in Japan or internationally. This should be examined in the future.
[Standards for outpatient/hospital treatment] As a rule, outpatient treatment should be performed in mildstatus patients evaluated according to the severity classification, and hospital treatment in mild-status patients with dehydration. In addition, it is necessary to determine admission when outpatient treatment does not lead to an improvement in symptoms or considering social adaptation.
[Initial antimicrobial drug therapy]
When examining children with pneumonia, treatment must be started without any precise information about causative microorganism in many cases. Basically, empiric therapy should be performed, considering the severity of pneumonia and causative microorganisms.
-The type of causative microorganisms depends on age and severity. Therefore, the necessity of antimicrobial drugs should be examined, and selected, considering age and severity. In addition, bacterial, viral, or atypical pneumonia should be differentiated, and comprehensively evaluated in reference to clinical symptoms, physical findings, laboratory findings, and Xray findings. In particular, acute bronchitis/pneumonia related to intermediately susceptible H. influenzae (MIC: 2 mg/mL) can be managed with oral AMPC or ABPC intravenous injection therapies [bib_ref] Annual change of ampicillin susceptibility of H. influenzae and the clinical efficacy..., Kurosaki [/bib_ref]. Recently, the number of ABPC-susceptible strains has annually decreased [bib_ref] Current status of pneumonia in children, review of chest X-ray findings, Ishiwada [/bib_ref] [bib_ref] Nationwide survey of the development of drug-resistant pathogens in the pediatric field:..., Sato [/bib_ref]. The proportion of BLNAR strains (MIC: 4 mg/Age-related distribution of microorganisms that cause pneumonia in children.
Immediately after birth to [bib_ref] Antibiotic therapy for Klebsiella pneumoniae bacteremia: implications of production of extended-spectrum b-lactamases, Paterson [/bib_ref]. Inflammatory response on admission in children with pneumonia [bib_ref] Basic examination regarding "the Guidelines for the Management of Pneumonia in Children",..., Kurosaki [/bib_ref]. mL or more) has increased, raising an issue with respect to drug selection. When the involvement of BLNAR strains is suspected, high-dose AMPC or new oral cephems may be necessary at outpatient clinics [bib_ref] Increased prevalence of penicillin-resistant viridans group streptococci in Japanese children with upper..., Mogi [/bib_ref]. The efficacy of outpatient antimicrobial drugs for BLNAR strains, which will increase in the future, should be carefully monitored. Concerning hospital treatment, the clinical effects of ABPC intravenous injection for 3e4 days until the results of a susceptibility test were clarified were investigated, and approximately 80% of patients responded to this therapy. There was no exacerbation in any patient. In non-responders or patients in whom clinical effects are insufficient, it is necessary to switch the antimicrobial drug. PIPC, CTX, and CTRX have stable antimicrobial activities. When reviewing the clinical effects of PIPC on childhood bronchopulmonary infection, the response rate was 95%; the results were satisfactory [bib_ref] Clinical effects of piperacillin and tazobactam/piperacillin on Haemophilus influenzae lower respiratory tract..., Sudo [/bib_ref].
-Concerning treatment for M. catarrhalis pneumonia, M. catarrhalis produces b-lactamase. However, when examining the clinical course, AMPC is effective [bib_ref] Clinical effects of piperacillin and tazobactam/piperacillin on Haemophilus influenzae lower respiratory tract..., Sudo [/bib_ref] [bib_ref] Clinical studies on lower respiratory tract infections caused by Moraxella catarrhalis in..., Oshima [/bib_ref]. This is because the enzymatic activity of b-lactamase produced by M. catarrhalis is low [bib_ref] Clinical studies on lower respiratory tract infections caused by Moraxella catarrhalis in..., Oshima [/bib_ref]..
[Evaluation of the treatment response and administration period] The administration period of antimicrobial drugs is shown in.

## Table 12
Classification of the severity of community-acquired pneumonia in children.

## Mild
Moderate Severe . Increases in the number of resistant strains of S. pneumoniae and H. influenzae derived from respiratory infectious diseases [bib_ref] Problems associated with high prevalence of multidrug-resistant bacteria in patients with community-acquired..., Ubukata [/bib_ref].
To treat community-acquired pneumonia, antimicrobial drugs should be administered for 3e7 days. The treatment response should be evaluated after 2e3 days. In children, disease progression is often prompt, and the first evaluation should be performed after 2 days in younger and severe-status children, and not after 3 days. If an improvement in clinical symptoms or laboratory data is achieved, the same antimicrobial drug should be continued until an appropriate antimicrobial drug and drug susceptibility are clarified. With respect to the administration period of antimicrobial drugs, factors such as the type of causative microorganisms and patient background differ among individual patients; therefore, it is difficult to establish standardized criteria. As M. pneumoniae and C.
pneumoniae slowly proliferate, the treatment period is prolonged. In patients infected with general bacteria, the administration of antimicrobial drugs can be discontinued 3 days after pyretolysis. However, further antimicrobial drug therapy is necessary to treat S. aureus pneumonia.
[Management for non-responders to antimicrobial drugs] When there are no therapeutic effects of antimicrobial drugs on pneumonia, whether or not a diagnosis of pneumonia is correct should be initially investigated. The possibility of diseases other than pneumonia, with a pneumonia-like shadow, must be reviewed. If it can be ruled out, whether or not the expected type of pathogenic microorganisms is correct should be examined. If the type of causative microorganisms is the same as expected, the possibility of resistant microorganisms should be considered. New therapeutic strategies should be devised carefully and promptly. When the condition further exacerbates despite treatment switching, additional examination should be conducted..

## Table 14
Concepts regarding the diagnosis and treatment of childhood Mycoplasma pneumonia.
1. As it is often difficult to make a diagnosis of Mycoplasma pneumoniae infection based on serum antibody titer-positive findings in the acute stage alone, the Mycoplasma pneumoniae nucleic acid identification test (LAMP method) should be conducted to make a definitive diagnosis in the acute stage. 2. As first-choice drugs for Mycoplasma pneumonia, macrolides should be used.. The effects of macrolides can be evaluated based on pyretolysis within 2e3 days after administration. 4. To treat pneumonia that does not respond to macrolides, the administration of tosufloxacin or tetracyclines should be considered if necessary.
However, as a rule, tetracyclines are contraindicated for children aged 7 years or younger. 5. These antimicrobial drugs should be administered in accordance with administration periods recommended for individual drugs. 6. In patients with severe pneumonia, systemic steroid therapy must be considered. However, easy steroid administration should be avoided. However, Mycoplasma pneumoniae is not included in bacterial types for which this preparation may be indicated.
---Drugs to be recommended---

## Empiric therapy  two months after birth to 5 years (1) outpatient clinic (mild)
A First choices 1) Cases in which there is no risk of resistant bacteria -AMPC, oral, 10e15 mg/kg/3 times a day -SBTPC, oral, 10 mg/kg/3 times a day -CDTR-PI, oral, 3 mg/kg/3 times a day -CFPN-PI, oral, 3 mg/kg/3 times a day -CFTM-PI, oral, 3 mg/kg/3 times a day 2) Cases in which infection with resistant bacteria is suspected i) Two years or younger, ii) Pretreatment with an antimicrobial drug (within 2 weeks), iii) Concomitant development of otitis media, iv) History of pneumonia/repeated otitis media -AMPC, oral, 20e30 mg/kg/3 times a day -CVA/AMPC (1:14 preparation), oral, 48.2 mg/ kg/twice a day -CDTR-PI, oral, 6 mg/kg/3 times a day -CFPN-PI, oral, 6 mg/kg/3 times a day -CFTM-PI, oral, 6 mg/kg/3 times a day 3) Cases in which onset/recurrence/recrudescence is observed despite previous treatment 2) -TBPM-PI, oral, 4e6 mg/kg/twice a day -TFLX, oral, 6 mg/kg/twice a day <> Second choices -AZM, oral, 10 mg/kg/once a day for 3 days -CAM, oral, 7.5 mg/kg/twice a day (2) Admission (Moderate, general ward)
A First choices -ABPC, intravenous injection or drip, 50 mg/kg/3 times a day -PIPC, intravenous injection or drip, 50 mg/kg/3 times a day -SBT/ABPC, intravenous injection or drip, 75 mg/kg/ 3 times a day * When M. pneumoniae, Chlamydia trachomatis, or C. pneumoniae infection is strongly suspected, one of the above regimens should be combined with a macrolide [With respect to the administration method/ dose, refer to the section " Six years or older---(1) Outpatient clinic (Mild)".].
<> Second choices -CTX, intravenous injection or drip, 40 mg/kg/3 times a day -CTRX, intravenous injection or drip, 25e60 mg/kg/ once to twice a day (50e60 mg/kg/day) (3) Admission -PAPM/BP, intravenous drip, 20 mg/kg/3 times a day -MEPM, intravenous drip, 20 mg/kg/3 times a day -TAZ/PIPC, intravenous drip, 112.5 mg/kg/3 times a day * When legionellosis cannot be ruled out, one of the above regimens should be combined with a macrolide [With respect to the administration method/dose, refer to the section " Six years or older---(2) Admission (Moderate, general ward)".].  Six years or older (1) Outpatient clinic (Mild) A First choices -AZM, oral, 10 mg/kg/once a day for 3 days -CAM, oral, 7.5 mg/kg/twice a day <> Second choices -AMPC, oral, 10e15 mg/kg/3 times a day -SBTPC, oral, 10 mg/kg/3 times a day -CDTR-PI, oral, 3 mg/kg/3 times a day -CFPN-PI, oral, 3 mg/kg/3 times a day -CFTM-PI, oral, 3 mg/kg/3 times a day -MINO, oral, 1e2 mg/kg/twice a day (In children aged 7 years or younger, the use of this drug is limited to those in whom other drugs cannot be used or nonresponders to other drugs.) 

## 2) admission (moderate, general ward)
A First choices 1) Cases in which bacterial pneumonia is suspected -ABPC, intravenous injection or drip, 50 mg/kg/3 times a day -PIPC, intravenous injection or drip, 50 mg/kg/3 times a day -SBT/ABPC, intravenous injection or drip, 75 mg/ kg/3 times a day -CTX, intravenous injection or drip, 40 mg/kg/3 times a day -CTRX, intravenous injection or drip, 25e60 mg/ kg/once to twice a day (50e60 mg/kg/day) 2) Cases in which atypical pneumonia is suspected -AZM, oral, 10 mg/kg/once a day for 3 days -CAM, oral, 7.5 mg/kg/twice a day -EM, intravenous drip, 10 mg/kg/3e4 times a day -MINO, oral or intravenous drip, 1e2 mg/kg/twice a day (In children aged 7 years or younger, the use of this drug is limited to those in whom other drugs cannot be used or non-responders to other drugs.)
3) Cases in which it is impossible to differentiate bacterial from atypical pneumonia One drug each should be selected from choices 1) and 2), and combined. -EM, oral, 10e15 mg/kg/3 times a day -AZM, oral, 10 mg/kg/once a day for 3 days -CAM, oral, 7.5 mg/kg/twice a day -EM, intravenous drip, 10 mg/kg/3e4 times a day -MINO, oral or intravenous drip, 1e2 mg/kg/twice a day (In children aged 7 years or younger, the use of this drug is limited to those in whom other drugs cannot be used or non-responders to other drugs.)

## Hospital-acquired pneumonia (including ventilator-associated pneumonia: vap)
---Executive summary---For the treatment of hospital-acquired pneumonia in children, antimicrobial drugs should be selected, considering severity and the involvement of resistant bacteria. Empiric therapy should be started by combining two drugs if necessary, considering various resistant microorganisms, differing from that for communityacquired pneumonia (BIII).

## [characteristics and classification of the disease]
Hospital-acquired pneumonia is defined as pneumonia that newly develops 48 h or more after admission. Ventilator-associated pneumonia is defined as pneumonia that develops 48 h or more after endotracheal intubation. These conditions may become severe due to an underlying disease, reduced immune capacity, or the deterioration of the general condition, and are caused by drugresistant microorganisms in many cases; treatment is difficult in most cases.

## [type and frequency of causative microorganisms]
Not only microorganisms acquired in the community but also those existing in the hospital environment cause hospital-acquired pneumonia in children, as reported in the adult field. Bacteria that cause community-acquired pneumonia (S. pneumoniae, H. influenzae), enteric bacteria (E. coli, K. pneumoniae), S. aureus, non-glucose-fermenting bacteria, such as P. aeruginosa, and Acinetobacter spp., and anaerobes cause hospital-acquired pneumonia [bib_ref] Ventilator-associated pneumonia in neonatal and pediatric intensive care unit patients, Foglia [/bib_ref]. In addition, not only general bacteria but also fungus and viruses sometimes cause hospital-acquired pneumonia in patients with immunodeficiency. Among patients with nosocomial infection, causative microorganisms differ, and drug-resistant microorganisms are involved in many cases. In children, it is not easy to investigate causative microorganisms, but, if drug susceptibility is clarified, it contributes to successful treatment. Therefore, lavage or aspiration sputum culture should be conducted to investigate the etiology, if possible.
[Rules of antimicrobial drug therapy]
Basically, empiric therapy should be performed, considering the severity of pneumonia, an underlying disease, and causative microorganisms. In particular, the involvement of drug-resistant microorganisms, such as MRSA, extended-spectrum b-lactamase (ESBL)-producing bacteria, and multi-drug-resistant P. aeruginosa (MDRP), must always be considered for treatment. Empiric therapy should be started by combining two drugs if necessary, considering various resistant microorganisms, differing from that for community-acquired pneumonia. As the state of resistant bacteria differs among institutions, antimicrobial drug options should be customized based on records on antimicrobial drug susceptibility (antibiograms) at each institution.
A consensus regarding the administration period of antimicrobial drugs has not been reached. With respect to the administration period of antimicrobial drugs, factors such as the type of causative microorganisms and patient background differ among individual patients with nosocomial infection; therefore, it is difficult to establish standardized criteria. However, when complications such as severe immunodeficiency, pulmonary suppuration, lung abscess, and pleuritis are absent, antimicrobial drugs should be administered for 5 days after pyretolysis (7e10 days). Considering an underlying disease or the immune state, flexible management must be performed. In children, disease progression is often prompt, and the first evaluation should be performed after 2 days in younger and severe-status children, and not after 3 days. If an improvement in clinical symptoms or laboratory data is achieved, the same antimicrobial drug should be continued until an appropriate antimicrobial drug and drug susceptibility are clarified. When the type of microorganisms that caused pneumonia is identified, a target-focused antimicrobial drug should be selected through de-escalation, considering drug susceptibility and pharmacokinetics.
Concerning multi-drug-resistant microorganisms, it is important to promote standard preventive strategies and those to control nosocomial infection, such as the prevention of droplet/contact infection, thoroughly. Furthermore, oral care and devised postures (if there is no medical contraindication, the head should be lifted at 30e45 .) are necessary to prevent VAP.
In this article, the classification of severity, p. 30) in the Guidelines for the Management of Respiratory Infectious Diseases in Children in Japan 2011 was used(Refer to the section "3. Pneumonia (Children), 3.1 Community-acquired pneumonia".).
---Drugs to be recommended---

## Empiric therapy (1) mild (general ward)
A First choices -CAZ, intravenous injection or drip, 50 mg/kg/3 times a day -CZOP, intravenous injection or drip, 40 mg/kg/3e4 times a day -CPR, intravenous injection or drip, 40 mg/kg/3e4 times a day If necessary, one of the above regimens should be combined with one of the following drugs: 1) Cases in which anaerobe infection is suspected (such as aspiration pneumonia) -CLDM, intravenous drip, [bib_ref] Revision of the severity rating and classification of hospital-acquired pneumonia in the..., Seki [/bib_ref] 

## Pneumonia in the presence of immunodeficiency/blood diseases

## ---executive summary---
In children with immunodeficiency-/blood disease-related pneumonia, antimicrobial drugs should be selected, considering an underlying disease, the grade of immunodeficiency, and involvement of various causative microorganisms. Initial antimicrobial drug therapy should be started by combining two drugs if necessary, considering various causative microorganisms, differing from that for community-acquired pneumonia (BIII).
[Characteristics and classification of the disease]
As immunodeficiency-/blood disease-related pneumonia in children often develops in hospitals, it has the characteristics of hospital-acquired pneumonia in many cases. It may become severe due to the patient's unfavorable conditions, such as an underlying disease, reduced immune capacity, and the deterioration of the general condition. Even non-pathogenic microorganisms may cause pneumonia in many cases. Furthermore, drug-resistant microorganisms often cause pneumonia; treatment is difficult in many cases. To achieve multidisciplinary, comprehensive treatment to save children, it is necessary to cooperate with other special fields.
[Type and frequency of causative microorganisms] Not only microorganisms acquired in the community in the presence of various immunodeficiency states but also nonpathogenic microorganisms existing in the hospital environment cause immunodeficiency-/blood disease-related pneumonia in children. Bacteria that cause community-acquired pneumonia (S. pneumoniae, H. influenzae), enteric bacteria (E. coli, K. pneumoniae), S. aureus, non-glucose-fermenting bacteria, such as P. aeruginosa, and Acinetobacter spp., and anaerobes cause this type of pneumonia. In addition, not only general bacteria but also fungus and viruses often cause this type of pneumonia. Furthermore, drugresistant microorganisms are involved in many cases, as indicated for hospital-acquired pneumonia.
[Type of immunodeficiency, causative microorganisms to be monitored, and precautions for diagnosis]  Humoral immunodeficiency: As bacterial opsonization and complement activation are affected, patients with humoral immunodeficiency are prone to be infected with general bacteria. Among immunodeficiency patients with hyper-IgM-emia, Pneumocystis pneumonia should be considered in those with conditions related to CD40 ligand abnormalities.  Cellular immunodeficiency: In addition to infection with general bacteria, infection with intracellular parasitic bacteria, fungus, or Protozoa may become severe, and be protracted. As the differentiation and induction of B and killer T cells by CD4-positive lymphocytes are affected, the eradication of virus-infected cells is inhibited [bib_ref] Clinical practice guideline for the use of antimicrobial agents in neutropenic patients..., Freifeld [/bib_ref].
 Neutrophil abnormalities: Neutrophil abnormalities are classified into two types: neutropenia and neutrophil functional disorders. Patients with a peripheral blood absolute neutrophil count (ANC) of <500/mL or those in whom the ANC is estimated to reach <500/mL within 48 h are regarded as having neutropenia [bib_ref] Clinical practice guideline for the use of antimicrobial agents in neutropenic patients..., Freifeld [/bib_ref]. Of these, the risk is higher in patients with an ANC of 100/mL or less in whom the period is estimated to exceed 7 days. Many patients with neutropenia do not show purulent sputum or abnormal findings on chest X-ray even in the presence of pneumonia. Therefore, when fever persists, thoracic CT should be performed in the early stage. All microorganisms including general bacteria (gram-positive bacteria, gramnegative bacteria), fungus, and viruses may cause pneumonia. In particular, in addition to neutropenia early after homologous hematopoietic stem cell transplantation, infection-prone features associated with humoral/cellular immunodeficiency related to the administration of immunosuppressives persist over a long period. Furthermore, the concomitant development of acute/chronic graft-versus-host disease (GVHD) is a risk factor for the onset of pneumonia. In addition, non-infectious pulmonary disorder related to drugs/radiation for pretreatment may occur, and it is important to differentiate it from infectious diseases [fig_ref] Figure 9: Pulmonary complications after homologous hematopoietic stem cell transplantation[213] [/fig_ref] [bib_ref] Indicative therapy during blood disease treatment, Misawa [/bib_ref].
A representative neutrophil functional disorder, chronic granulomatosis, induces active oxygen production disorder of neutrophils, affecting bactericidal actions. Therefore, patients with this disorder are prone to be infected with non-H 2 O 2 -producing catalase-positive bacteria (S. aureus, K. pneumoniae, E. coli, Candida spp., Aspergillus spp.).  Complement deficiency: Patients with complement deficiency are prone to be infected with bacteria with capsules, such as S. pneumoniae, H. influenzae (capsule strains), and Neisseria meningitidis.
In children, it is not easy to investigate causative microorganisms, but, if drug susceptibility is clarified, it contributes to successful treatment. Therefore, various cultures should be conducted to investigate the etiology, if possible. In addition, testing of various antigens, such as urinary S. pneumoniae/Legionella antigens, b-Dglucan, Aspergillus antigen, Cryptococcus antigen, Candida antigen, and Cytomegalovirus antigen, and tests using nucleic acid amplification methods, such as the PCR method, should be utilized, if possible.
[Rules of antimicrobial drug therapy] Initial antimicrobial drug therapy should be performed, considering the severity of pneumonia and an underlying disease. For the treatment of immunodeficiency-/blood disease-related pneumonia in children, antimicrobial drug therapy should also be basically selected, considering causative microorganisms. As described for nosocomial infection, the involvement of drugresistant microorganisms, such as MRSA, extended-spectrum blactamase (ESBL)-producing bacteria, and multi-drug-resistant P. aeruginosa (MDRP), must always be considered for treatment. Initial antimicrobial drug therapy should be started by combining two drugs, if necessary, considering various resistant microorganisms, differing from that for community-acquired pneumonia. As the state of resistant bacteria differs among institutions, antimicrobial drug options should be customized based on records on antimicrobial drug susceptibility (antibiograms) at each institution.
A consensus regarding the administration period of antimicrobial drugs has not been reached. With respect to the administration period of antimicrobial drugs, factors such as the type of causative microorganisms and patient background differ among individual patients with nosocomial infection; therefore, it is difficult to establish standardized criteria. In children, disease progression is often prompt, and the first evaluation should be performed after 2 days in younger and severe-status children, and not after 3 days. If an improvement in clinical symptoms or laboratory data is achieved, the same antimicrobial drug should be continued until an appropriate antimicrobial drug and drug susceptibility are clarified. When the type of microorganisms that caused pneumonia is identified, a target-focused antimicrobial drug should be selected through de-escalation, considering drug susceptibility and pharmacokinetics.
Monitoring culture of the airway is useful for treating immunodeficiency-/blood disease-related pneumonia in children.
General preventive methods are presented in. In addition, long-term low-dose macrolide therapy or the intermittent administration of b-lactams to prevent P. aeruginosa fixation is effective in some patients with chronic bronchitis [bib_ref] Experience on long-term therapy with macrolides in the field of pediatrics, Kuroki [/bib_ref]. In those with chronic granulomatosis, the oral administration of ITCZ (4e6 mg/kg/day, maximum: 100 mg/day) or subcutaneous injection of IFN-g (250,000 domestic standard units/m 2 , 1e3 times a week) is useful for preventing infection [bib_ref] Itraconazole to prevent fungal infections in chronic granulomatous disease, Gallin [/bib_ref]. In this article, the classification of severity, p. 30) in the Guidelines for the Management of Respiratory Infectious Diseases in Children in Japan 2011 was used (Refer to the section "3. Pneumonia (Children), 3.1 Community-acquired pneumonia".).
---Drugs to be recommended---

## Empiric therapy
(1) Pneumonia related to mild immunodeficiency in the initial phase after admission -SBT/ABPC, intravenous injection or drip, 75 mg/kg/3e4 times a day -CTX, intravenous injection or drip, 40 mg/kg/3e4 times a day -CTRX, intravenous injection or drip, 50 mg/kg/twice a day (2) Pneumonia related to moderate/severe immunodeficiency -CAZ, intravenous injection or drip, 50 mg/kg/3e4 times a day -CZOP, intravenous injection or drip, 50 mg/kg/3e4 times a day -CPR, intravenous injection or drip, 50 mg/kg/3e4 times a day In severe cases, -PAPM/BP, intravenous drip, 20 mg/kg/3 times a day -MEPM, intravenous drip, 20 mg/kg/3 times a day -DRPM, intravenous drip, 20 mg/kg/3 times a day -TAZ/PIPC, intravenous drip, 112.5 mg/kg/3 times a day -VCM, intravenous drip, 15 mg/kg/3 times a day -ABK, intravenous drip, 4e6 mg/kg/once a day -TEIC, intravenous drip, 10 mg/kg/every 12 h, 3 times, subsequently: 6e10 mg/kg/once a day When there is no response, -AMK, intravenous drip, 5e7.5 mg/kg/twice a day -TOB, intravenous drip, 3.3 mg/kg/3 times a day If necessary, an antifungal drug (MCFG) and ST combination drug should be additionally administered.
When Aspergillus infection is suspected, treatment should be started with VRCZ or L-AMB instead of MCFG.
In patients with cellular immunodeficiency, one of the above drugs should be combined with MCFG and an ST combination drug in the early stage.
In those with neutrophil abnormalities, one of the above drugs should be combined with MCFG in the early stage.
When legionellosis cannot be ruled out in the severest cases, one of the above regimens should be combined with a macrolide (With respect to the administration method/dose, refer to the section "3.1 Community-acquired pneumonia--- Six years or older---(2) Admission (Moderate, general ward)" (p. 32).). In the presence of GCV resistance, the intravenous drip of PFA (foscarnet), 60 mg/kg/3 times a day should be performed.

## Definitive therapy

## Neonatal pneumonia
---Executive summary---In the treatment of neonatal pneumonia, antimicrobial drugs should be selected after differentiating congenital from acquired pneumonia.
Initial antimicrobial drug therapy should be started by combining two drugs, regarding the condition as severe systemic infection and considering various causative microorganisms. The administration method and dose should be selected based on the age (days) and birth weight (BIII).
[Characteristics and classification of the disease] The incidence of neonatal pneumonia is not high. According to Sakata, pneumonia occurred in only 40 (0.25%) of approximately 16,000 neonates who were admitted during a 10-year period [bib_ref] Special issue---Respiratory infectious disease---neonatal pneumonia, Sakata [/bib_ref]. Neonatal pneumonia is frequently observed as a portion of systemic infection represented by sepsis, and not as a single condition. It is classified into two types: congenital and acquired pneumonia.
In most cases, neonatal pneumonia does not cause any typical symptoms such as fever or cough in comparison with infantile/ childhood pneumonia. The neonatal protective capacity against infection is physiologically immature, often leading to a severe condition. In the neonatal phase, artificial respiration management is performed in many cases, and ventilator-associated pneumonia (VAP) is frequently observed [222e224]. In addition, many neonates are admitted to the neonatal intensive care unit (NICU) for a long period; therefore, the incidence of nosocomial infection is high.
[Type and frequency of causative microorganisms] Several types of congenital pneumonia include transplacental infection, intrauterine infection related to aspiration of infected amniotic fluid on premature rupture, and birth canal infection with vaginal discharge on delivery. These types of congenital pneumonia are primarily caused by various viruses (Cytomegalovirus, herpes simplex virus), bacteria (Streptococcus agalactiae (GBS), E. coli, Listeria monocytogenes), Chlamydia, and fungus.
The clinical onset of perinatal pneumonia is frequently observed immediately to 7 days after birth.
Postnatal pneumonia usually develops 2 weeks or more after birth. It is caused by viruses and bacteria. Viral infection may occur when RS virus, parainfluenza virus, or adenovirus prevails in the ward. However, it rarely leads to the onset of pneumonia. Frequent causative bacteria include S. aureus, E. coli, P. aeruginosa, Acinetobacter spp., Enterobacter spp., and Legionella spp., which exist in the environment. These often cause nosocomial infection. In premature babies, Gram staining of tracheal aspirate samples is useful for selecting antimicrobial drugs to be administered in the initial phase [bib_ref] Usefulness of Gram staining of tracheal aspirates in initial therapy for ventilatorassociated..., Katayama [/bib_ref].
In children, it is not easy to investigate causative microorganisms, but, if drug susceptibility is clarified, it contributes to successful treatment. Therefore, blood or bronchial lavage fluid culture should be conducted to investigate the etiology, if possible.
[Rules of antimicrobial drug therapy] As many neonates have systemic infection in an immunodeficiency state, the same administration method and dose as selected for the treatment of sepsis should be used. Therefore, the severity of pneumonia is not considered. When bacterial pneumonia is suspected, combination therapy with ABPC and CTX is commonly selected as initial treatment. Considering L. monocytogenes infection, combination therapy with ABPC is recommended. After causative microorganisms are identified, antimicrobial drugs should be selected with reference to their drug susceptibility. In cases of VAP, antimicrobial drug options should be customized based on records on the drug susceptibility (antibiograms) of microorganisms that cause nosocomial infection at each institution.
In neonates, there are marked age-related differences in the pharmacokinetics of antimicrobial drugs; therefore, these drugs must be carefully administered in the neonatal phase. Concretely, the same dose as established in the field of pediatrics should be used, and the administration interval should be prolonged in accordance with age. In cases of severe asphyxia or acute renal failure, the administration interval must be further prolonged. It should be shortened with an improvement in the kidney function .
A consensus regarding the administration period of antimicrobial drugs has not been reached. However, the standard administration period is 14 days. With respect to the administration method/dose, refer to the section "XI. Doses for neonates".
In neonates, disease progression is often prompt, and the treatment response should be evaluated after 2 days, and not after 3 days. If an improvement in clinical symptoms or laboratory data is achieved, the same antimicrobial drug should be continued until an appropriate antimicrobial drug and drug susceptibility are clarified. When the type of microorganisms that caused pneumonia is identified, a target-focused antimicrobial drug should be selected through de-escalation, considering drug susceptibility and pharmacokinetics.
---Drugs to be recommended---

## Adults
---Executive summary----Pyothorax refers to a condition in which pus accumulates in the thoracic cavity. Usually, pleural effusion puncture is performed, and a diagnosis of pyothorax is made based on the results of various examinations, such as (macroscopic) purulent pleural effusion, microorganisms detected on Gram staining or culture of pleural effusion, or pleural effusion pH: <7.2 (BIII). -In patients with acute pyothorax related to community-acquired pneumonia, treatment should be performed in accordance with that for community-acquired pneumonia, considering microorganisms that cause community-acquired pneumonia, such as Streptococcus pneumoniae (BIII). -In patients with slowly progressing pyothorax, mixed infection with oral aerobes/anaerobes is frequently observed. Combination therapy with PCG or ABPC and CLDM or MNZ, which show anti-anaerobe activities, or therapy with a single antimicrobial drug with an anti-anaerobe activity, such as SBT/ABPC, should be selected (BIII). -When there is a risk of multi-drug-resistant bacteria, monotherapy with a carbapenem, combination therapy with a fourthgeneration cephalosporin and CLDM or MNZ, and combination therapy with a quinolone and CLDM or MNZ should be considered, assuming ESBL-producing enteric bacteria, resistant P. aeruginosa, anaerobes, and Acinetobacter (BIII). -If the results of culture/susceptibility tests are clarified, antimicrobial drugs should be changed in accordance with them (AIII). -The penetration of aminoglycosides to the thoracic cavity is poor, and their activities reduce when the pH is low. Therefore, the use of aminoglycosides should be avoided as a rule (BIII). -If a diagnosis of pyothorax is made, the administration of an appropriate antimicrobial drug should be started, and drainage must be performed (AII). If possible, the attending physician should consult a surgeon in the early stage (AIII). -In some patients with marked pleural thickening or multilocular pleural effusion, thoracoscopic debridement is necessary (BIII). In addition, a fibrinolytic drug, such as streptokinase, is administered through a thoracic drain, or surgical interventions such as thoracotomy or decortication is performed in some cases (BIII).
---Explanation---
[Diagnosis] -Pyothorax is defined as a condition in which pus accumulates in the thoracic cavity, but this definition has no diagnostic objectivity. For this reason, usually, pleural effusion puncture is performed, and a diagnosis of pyothorax is made based on the results of various examinations, such as (macroscopic) purulent pleural effusion, microorganisms detected on Gram staining or culture of pleural effusion, or pleural effusion pH: <7.2 [bib_ref] Medical and surgical treatment of parapneumonic effusions: an evidence-based guideline, Colice [/bib_ref] [bib_ref] Parapneumonic effusions and empyema, Light [/bib_ref].
[Causative microorganisms] -Pleural effusion appears in 30e40% of patients with bacterial pneumonia, but leads to pyothorax in 0.5e2%. Other etiological factors for pyothorax include surgery, trauma, and esophageal perforation. -Microorganisms that cause pyothorax depend on its etiology and course. In the presence of bacterial pneumonia, pyothorax is caused by the same microorganisms as caused bacterial pneumonia. Furthermore, acute pyothorax is frequently caused by S. pneumoniae and S. aureus. However, in many patients with chronic pyothorax, mixed infection primarily with anaerobes is involved. Among anaerobes, Fusobacterium spp. (especially Fusobacterium nucleatum), Prevotella spp., Peptostreptococcus spp., and Bacteroides spp. are frequently detected [232e234]. According to recent studies, the detection rate of the Streptococcus anginosus group is high [bib_ref] Thoracic empyema in patients with community-acquired pneumonia, Ahmed [/bib_ref] [bib_ref] Controlled trial of intrapleural streptokinase for pleural infection, Maskell [/bib_ref]. -In many cases, pyothorax with a relatively slow course is associated with M. tuberculosis. It must be considered that pulmonary lesions do not always concurrently exist with tuberculous pleuritis.
[Treatment] -No randomized comparative study regarding antimicrobial drug treatment for pyothorax has been conducted. An antimicrobial drug with an activity against microorganisms expected or obtained on culture should be selected and administered. In acuteonset patients in whom there is no risk of resistant bacteria, for example, those with pyothorax accompanying communityacquired pneumonia, antimicrobial drugs such as PCG and ABPC should be initially selected, considering S. pneumoniae. These drugs simultaneously cover Fusobacterium, Peptostreptococcus, and the viridans Streptococcus group. However, Prevotella and Bacteroides produce b-lactamase; therefore, when the results of culture are not obtained, combination therapy with antimicrobial drugs with activities against anaerobes, such as CLDM and MNZ, or therapy with such a single drug, such as SBT/ABPC, should be selected. -When there is a risk of multi-drug-resistant bacteria, monotherapy with a carbapenem should be selected as a first choice, assuming ESBL-producing enteric bacteria, resistant P. aeruginosa, and Acinetobacter. A fourth-generation cephalosporin should be combined with CLDM, or a quinolone should be combined with CLDM or SBT/ABPC. -If the results of culture/susceptibility tests are clarified, antimicrobial drugs should be changed in accordance with them. However, the culture of anaerobes is difficult, or is not conducted in some cases. Therefore, this should be confirmed to the laboratory. When only one type of bacteria are detected on a culture test despite several types of bacteria detected on Gram staining of pleural effusion, anaerobes must also be considered. -The penetration of aminoglycosides to the thoracic cavity is poor, and their activities reduce when the pH is low. Therefore, for pyothorax treatment, the use of aminoglycosides should be generally avoided [237e240].
[Treatment period] -The pyothorax treatment period has not been established. However, when pneumonia promptly responds to treatment and thoracic drainage is successfully achieved in patients with pneumonia-related pyothorax, a treatment period of 10e14 days is required. In patients in whom drainage is unsuccessful, those with marked pleural thickening, or those with encapsulated/septum-like pyothorax, a treatment period of about 4 weeks is often required.
[Treatments other than antimicrobial drug therapy] -After a diagnosis of pyothorax is made, the administration of an appropriate antimicrobial drug should be promptly started, and drainage is necessary. When the pleural fluid is purulent and viscous in the absence of a multilocular pattern, chest-tube insertion is routinely performed. The position of insertion should be confirmed using thoracic CT within 24 h after insertion. Wozniak et al. performed multivariate analysis involving 104 patients with pyothorax and indicated that failure in the first drainage was strongly correlated with mortality, suggesting the necessity of early consultation with surgeons [bib_ref] Choice of first intervention is related to outcomes in the management of..., Wozniak [/bib_ref]. -In some patients with marked pleural thickening or multilocular pleural effusion, thoracoscopic debridement is necessary. In addition, a fibrinolytic drug, such as streptokinase, is administered through a thoracic drain, or surgerical interventions such as thoracotomy or decortication is performed in some cases [bib_ref] Management of pleural infection in adults: British thoracic society pleural disease guideline..., Davies [/bib_ref].
---Drugs to be recommended---

## Empiric therapy  cases in which there is no risk of multi-drug-resistant bacteria
A First choice -SBT/ABPC, intravenous drip, 3 g/3e4 times a day <> Second choices -PCG, intravenous drip, 2,000,000 to 3,000,000 units/4 times a day -ABPC, intravenous drip, 2 g/3e4 times a day  one of the followings: -CLDM, intravenous drip, 600 mg/2e4 times a day -MNZ, intravenous drip, 500 mg/4 times a day  Cases in which there is a risk of multi-drug-resistant bacteria A First choices -TAZ/PIPC, intravenous drip, 4.5 g/3e4 times a day -IPM/CS, intravenous drip, 0.5e1 g/2e4 times a day -MEPM, intravenous drip, 1 g/2e3 times a day -DRPM, intravenous drip, 0.5e1 g/3 times a day <> Second choices (I) -CFPM, intravenous drip, 1e2 g/2e4 times a day -CZOP, intravenous drip, 1e2 g/2e4 times a day -CPR, intravenous drip, 1e2 g/2e4 times a day  one of the followings: -CLDM, intravenous drip, 600 mg/2e4 times a day -MNZ, intravenous drip, 500 mg/4 times a day <> Second choices (II) -LVFX, intravenous drip, 500 mg/once a day -CPFX, intravenous drip, 300 mg/twice a day -PZFX, intravenous drip, 500 to 1000 mg/twice a day  one of the followings:
-CLDM, intravenous drip, 600 mg/2e4 times a day -SBT/ABPC, intravenous drip, 3 g/3e4 times a day -MNZ, intravenous drip, 500 mg/4 times a day * With respect to the risk of multi-drug-resistant bacteria, refer to the section "2.2 Hospital-acquired pneumonia" (p. 10).
* In particular, MRSA infection must be considered in patients with nosocomial onset or the previous administration of antimicrobial drugs. When Staphylococcus infection is suspected on Gram staining of pleural effusion, an anti-MRSA drug should be used as an empiric therapy. If MSSA is identified as causative bacteria, deescalation should be performed. 2. Definitive therapy -Antimicrobial drugs against causative microorganisms identified should be selected in accordance with the section "2.

## Children
---Executive summary---For the treatment of pyothorax in children, antimicrobial drugs should be administered after investigating the etiology using thoracentesis or blood culture, if possible. In addition to antimicrobial drug therapy, treatment for retention fluid (pleural effusion drainage, continuous drainage) must also be considered (BIII).
[Characteristics and classification of the disease] Pleuritis refers to inflammation of the pleura. Fluid (pleural effusion) is retained in the pleural cavity. Pleuritis is classified into 3 types: fibrinous (dry) pleuritis, exudative (wet) pleuritis, and purulent pleuritis (pyothorax) based on conditions. On auscultation, the attenuation of respiratory sounds, as well as pleural friction rubs, are heard. Percussion dullness is noted. In the chronic stage, localized pleural thickening in various shapes is observed. When pus is obtained on thoracentesis, a definitive diagnosis of pyothorax is made. When the protein level in nonpurulent pleural effusion is high, tuberculous pleuritis should be differentiated [bib_ref] Pleural tuberculosis, Chakrabarti [/bib_ref].
[Type and frequency of causative microorganisms] Previously, pyothorax was associated with S. aureus in many cases. However, recently, such cases have been rare. According to data form a national survey in the former half of the 1990's, there were only a few patients with S. pneumoniae-or anaeroberelated pyothorax. In many cases, pleuritis follows M. pneumoniae-or virus-related pneumonia. Decubitus-view imaging shows the retention of pleural effusion in approximately 20% of patients with Mycoplasma pneumonia [bib_ref] Radiological study of mycoplasma pneumonia in children, Odagiri [/bib_ref]. If the drug susceptibility of causative microorganisms is clarified, it contributes to successful treatment. Therefore, pleural effusion obtained by thoracentesis should be cultured to investigate the etiology, if possible.

## [rules of antimicrobial drug therapy]
When bacterial infection-related pyothorax is suspected, the intravenous injection or drip of SBT/ABPC, CTX, or CTRX should be selected in community-onset patients without an underlying disease. On the other hand, combination therapy with SBT/ABPC (intravenous injection or drip) and CLDM (intravenous drip) or carbapenem therapy (intravenous drip) should be started in those with an underlying disease or nosocomial onset, considering S. pneumoniae, anaerobes, H. influenzae, and S. aureus. Based on the Gram staining reactions of pleural effusion, causative microorganisms should be estimated, and antimicrobial drugs must be reviewed. If necessary, tuberculosis should also be investigated.
The administration period of antimicrobial drugs must be longer than that for pneumonia. As the type of causative microorganisms, patient background, and state of retention-fluid drainage differ among individual patients, it is difficult to establish standardized criteria. However, target administration periods for S. pyogenes (GAS)-, S. pneumoniae-, and S. aureus-related pyothorax are 10, 14, and 21 days or more, respectively.
The treatment response should be evaluated 3e4 days after the start of administration. If an improvement in clinical symptoms or laboratory data is achieved, the same antimicrobial drug should be continued until causative microorganisms and their drug susceptibility are clarified. When the type of microorganisms that caused pneumonia is identified, a targetfocused antimicrobial drug should be selected through deescalation, considering drug susceptibility and pharmacokinetics.
For the treatment of pyothorax, treatment for retention fluid (pleural effusion drainage) is also a basic procedure in addition to antimicrobial drug therapy. If necessary, continuous drainage should be performed. If pleural thickening leads to underexpanded lung, decortication should be indicated. The widespread application of thoracoscopic surgery has facilitated minimally invasive surgery.
---Drugs to be recommended---

## Empiric therapy
(1) Community onset (without an underlying disease) -SBT/ABPC, intravenous injection or drip, 75 mg/kg/3 times a day -CTX, intravenous injection or drip, 40 mg/kg/3e4 times a day -CTRX, intravenous injection or drip, 50 mg/kg/twice a day (2) Community-acquired infection (with an underlying disease), nosocomial onset -CLDM, intravenous drip, 10 mg/kg/3 times a day  -SBT/ABPC, intravenous injection or drip, 75 mg/kg/3 times a day or one of the following drugs alone should be administered: -TAZ/PIPC, intravenous drip, 112.5 mg/kg/3 times a day -PAPM/BP, intravenous drip, 20 mg/kg/3 times a day -MEPM, intravenous drip, 20 mg/kg/3 times a day -DRPM, intravenous drip, 20 mg/kg/3 times a day 2. Definitive therapy Refer to the section "3.1 Community-acquired pneumonia---3.1.2 Definitive therapy" (p. 33) or "3.2 Hospital-acquired pneumonia---3.2.2 Definitive therapy" (p. 34).Indications for continuous drainage.
 Cases in which pleural effusion obtained on thoracentesis is purulent  Cases in which clinical effects are not achieved by antimicrobial drug therapy alone (within 72 h)  Cases in which retention fluid affects the respiratory function

## Mycobacterium infection

## Adults

## Pulmonary tuberculosis
---Executive summary----As initial treatment, four drugs (INH, RFP, and PZA  EB or SM) should be administered for 2 months. Subsequently, as a rule, standard treatment (A), in which two drugs, INH and RFP, are administered for 4 months, should be performed as maintenance treatment (AI). -When PZA cannot be used for initial treatment for some reason, INH, RFP, and EB or SM, should be administered for 2 months as initial treatment. Subsequently, standard treatment (B), in which two drugs, INH and RFP, are administered for 7 months, should be performed as maintenance treatment (AII). -In patients in whom chest X-ray shows a cavity on initial consultation to during initial treatment and the septum culture is still positive at the completion of initial treatment, maintenance treatment should be prolonged over 3 months. In addition, the prolongation of maintenance treatment should also be considered in patients with severe tuberculosis, such as military tuberculosis and tuberculosis of the central nervous system, those with immune depression, and those with relapse of tuberculosis (AII). -For the treatment of latent tuberculosis infection, INH should be administered for 6 or 9 months (AI). When M. tuberculosis, as the source of infection, is resistant to INH, or when the oral administration of INH is difficult due to side effects, RFP should be used as a second-choice drug for 4 or 6 months (AI).
---Explanation--- [bib_ref] Infectious Diseases Society of America: treatment of tuberculosis, Blumberg [/bib_ref]. In particular, this method is named "standard treatment (A)" in the Guidelines for the Management of Tuberculosis in 2012 in Japan. In this article, this name is also used. -The secondary assessment of a study examining the efficacy of rifapentine and INH showed that factors for unsuccessful treatment/recurrence included a cavity on chest X-ray at the start of treatment and positive findings on culture at the completion of initial treatment for 2 months [bib_ref] Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a..., Benator [/bib_ref]. Similarly, when the treatment period was extended from 6 to 8 months in patients with silicotuberculosis, in whom the unsuccessful treatment/recurrence rates are high, the recurrence rate decreased from 22 to 7%. Therefore, various guidelines recommend that maintenance treatment should be prolonged over 3 months in patients with a cavity and those showing positive findings on septum culture at the completion of initial treatment [bib_ref] Infectious Diseases Society of America: treatment of tuberculosis, Blumberg [/bib_ref]. -In 1990, Combs et al. compared the results of treatment between a group treated with INH, RFP, and PZA for 2 months and, then, with INH and RFP for 4 months and that treated with INH and RFP for 9 months, and reported that the efficacy and incidence of side effects were similar [bib_ref] USPHS tuberculosis short-course chemotherapy trial 21:effectiveness, toxicity, and acceptability. The report of..., Combs [/bib_ref]. Based on such a study, the following regimen is recommended as standard treatment (B) in the Guidelines for the Management of Tuberculosis in 2012 in Japan: when PZA cannot be used for some reason, INH, RFP, and EB or SM, are administered for the first 2 months, and, subsequently, two drugs, INH and RFP, are administered for 7 months. -Patients who are infected with M. tuberculosis, but do not develop tuberculosis are regarded as having latent tuberculosis infection (LTBI). INH administration for LTBI decreases the incidence of tuberculosis by 25e92% [bib_ref] Controlled chemoprophylaxis trials in tuberculosis. A general review, Ferebee [/bib_ref]. Previously, this was called preventive therapy, but is currently termed LTBI treatment. The decrease in the incidence of tuberculosis is correlated with compliance with INH, and more marked preventive effects may be achieved when compliance is higher [258e260]. In a study involving INH administration to LTBI patients with an old shadow on chest X-ray, this therapy inhibited the onset of tuberculosis in 65 and 75% of patients treated for 6 and 12 months, respectively (there was no significant difference between the two groups). Based on the data, some studies recommended that the period of standard INH administration for LTBI should be 9 months [262e264]. However, a consensus regarding an effective administration period (6 or 9 months) has not been reached from various aspects including the efficacy, compliance, expenses, and incidence of side effects. Actually, the administration period should be determined based on compliance and the incidence of side effects. -In LTBI treatment, RFP should be used for 4 or 6 months as an alternative drug when the oral administration of INH is impossible for some reason. The preventive effects of RFP on the onset of tuberculosis in LTBI patients may be similar to those of INH. Furthermore, the incidence of liver dysfunction is lower than that related to INH [265e267]. However, for the use of RFP, drug interactions must be considered.
---Drugs to be recommended---A First choice -INH, oral, 5 mg/kg/once a day (maximum: 300 mg/ day)  RFP, oral, 10 mg/kg/once a day (maximum: 600 mg/ day, orally administered before meals as a rule)  PZA, oral, 25 mg/kg/once a day (maximum: 1500 mg/day)  EB, oral, 15 mg/kg/once a day (maximum: 750 mg/day) or SM, intramuscular injection, 15 mg/kg/once a day (maximum: 750 mg/day)/2e3 times a week.
* The above 4 drugs should be administered for 2 months, and, subsequently, two drugs, INH and RFP, should be administered for 4 months.
<> Second choice -INH, oral, 5 mg/kg/once a day (maximum: 300 mg/ day)  RFP, oral, 10 mg/kg/once a day (maximum: 600 mg/ day, orally administered before meals as a rule)  EB, oral, 15 mg/kg/once a day (maximum: 750 mg/day) or SM, intramuscular injection, 15 mg/kg/once a day (maximum: 750 mg/day)/2e3 times a week. * The above 3 drugs should be administered for 2 months, and, subsequently, two drugs, INH and RFP, should be administered for 7 months. [bib_ref] Clarithromycin regimens for pulmonary Mycobacterium avium complex. The first 50 patients, Jr [/bib_ref]. In Japan, Tanaka et al. conducted combination therapy with CAM (10 mg/kg) and EB/RFP/KM in 39 patients, and indicated that 89.5% of those who underwent initial treatment became negative for MAC [bib_ref] Effect of clarithromycin regimen for Mycobacterium avium complex pulmonary disease, Tanaka [/bib_ref]. Concerning CAM, many studies have reported a correlation between the in vitro drug susceptibility and treatment response [271e273]. Furthermore, a study indicated that AZM was as effective as CAM [bib_ref] Azithromycin activity against Mycobacterium avium complex lung disease in patients who were..., Griffith [/bib_ref]. -RBT, which was published in the drug price in NHI scheme in Japan in 2008, was also approved for tuberculosis and non-tuberculous Mycobacterium infection, including pulmonary MAC infection. The drug interactions of RBT are less marked than those of RFP, and RBT is used as a first-choice drug for disseminated MAC infection in HIV-infected patients [bib_ref] Two controlled trials of rifabutin prophylaxis against Mycobacterium avium complex infection in..., Nightingale [/bib_ref]. On the other hand, RBT induces side effects such as uveitis. In elderly patients, in whom pulmonary MAC infection frequently develops, various side effects, such as gastrointestinal disorder, make long-term therapy difficult [bib_ref] Infectious Disease Society of America. An official ATS/IDSA statement: diagnosis, treatment, and..., Griffith [/bib_ref]. In addition, no study has indicated that RBT is more effective than RFP for pulmonary MAC infection in non-HIV-infected patients. Therefore, RFP should be selected as a first-choice drug for pulmonary MAC infection in non-HIV-infected patients. -Kobashi et al. divided 146 patients with pulmonary MAC infection into two groups: a group treated with CAM, RFP, EB, and SM (intramuscularly injected at 15 mg/kg 3 times a week for 3 months) and a group treated with saline, and conducted a randomized, double-blind, comparative study [bib_ref] A double-blind randomized study of aminoglycoside infusion with combined therapy for pulmonary..., Kobashi [/bib_ref]. In the SM-treated group, the rate at which the culture of sputum became negative was higher than in the salinetreated group (71.2 vs. 50.7%, respectively). There has been no high-quality study demonstrating the usefulness of combination therapy with aminoglycosides other than their study. However, various guidelines recommend that combination therapy with SM, AMK, or KM should be performed for 2e3 months in the initial phase of treatment in patients with a cavity or severe nodular/bronchodilatation type infection based on experience [bib_ref] Infectious Disease Society of America. An official ATS/IDSA statement: diagnosis, treatment, and..., Griffith [/bib_ref]. Guidelines in the United States recommend SM or AMK, and comment that no study has showed which of two drugs, SM and AMK, is more effective, although SM has been more frequently used [bib_ref] Infectious Disease Society of America. An official ATS/IDSA statement: diagnosis, treatment, and..., Griffith [/bib_ref]. In Japan, SM or KM is recommended. -Based on the results of these studies, the Non-tuberculous Mycobacterium Infection Control Committee, Japanese Society for Tuberculosis recommends the following doses and administration methods for chemotherapy for pulmonary MAC infection in the "Opinions regarding Chemotherapy for Pulmonary Non-tuberculous Mycobacterium Infection---Revision in 2012": RFP: 10 mg/kg (up to 600 mg)/day, once a day, EB: 15 mg/kg (up to 750 mg)/day, once a day, CAM: 600e800 mg/day (15e20 mg/kg), once a day or two divided doses (800 mg: two divided doses), and SM or KM: 15 mg/kg or less (up to 1000 mg), intramuscularly injected 2 or 3 times a week. -A cooperative statement on non-tuberculous Mycobacterium infection by the American Thoracic Society/Infectious Diseases Society of America recommends therapy with CAM at 500 to 1000 mg/day or AZM at 250 mg/day, EB at 15 mg/kg/day, and RFP at 10 mg/kg/day (up to 600 mg) for patients with a cavity or severe nodular/bronchodilatation type infection. In addition, it is recommended that combination therapy with SM or AMK (8e10 mg/kg, 2e3 times a week, patients aged over 50 years: 500 mg or less) for 2e3 months in the initial phase should be considered [bib_ref] Infectious Disease Society of America. An official ATS/IDSA statement: diagnosis, treatment, and..., Griffith [/bib_ref]. -The treatment period is established as about 1 year after the culture becomes negative in the above guidelines, but this is not based on evidence. In the Guidelines for the Management of Non-tuberculous Mycobacterium Infection, which were published by the British Thoracic Society, the treatment period of pulmonary MAC infection is established as 2 years. In the future, an optimal treatment period should be investigated.
---Drugs to be recommended----CAM, oral, 200 mg/3 times a day or 400 mg/twice a day  RFP, oral, 10 mg/kg/once a day (maximum: 600 mg/ day, orally administered before meals as a rule)  EB, oral, 15 mg/kg/once a day (maximum: 750 mg/day) * Severe-status patients and those with cavity-type lesions In addition to the above regimen, the intramuscular injection of SM or KM should be added. abscessus is sometimes susceptible to LZD, TGC (tigecycline), and ketolides, but it is unclear whether there is a correlation between the drug susceptibility and clinical effects [bib_ref] Pulmonary disease caused by rapidly growing mycobacteria, Daley [/bib_ref] [bib_ref] Mycobacterium abscessus from respiratory isolates: activities of drug combinations, Cremades [/bib_ref]. -Combination therapy with CAM and several intravenous antimicrobial drugs (AMK, CFX, and IPM/CS) may control the symptoms and progression of pulmonary infection with M. abscessus [bib_ref] Antibiotic treatment of Mycobacterium abscessus lung disease: a retrospective analysis of 65..., Jeon [/bib_ref] [bib_ref] Clinical and microbiologic outcomes in patients receiving treatment for Mycobacterium abscessus pulmonary..., Jarand [/bib_ref]. However, actually, hospitalization is required to administer these intravenous antimicrobials, and the administration period is limited to 2e3 months. Subsequently, treatment with oral drugs is performed, but CAM is the only reliable oral drug, as described above. On the other hand, monotherapy with CAM should be avoided from the perspective of resistance induction. Although some studies reported combination therapy with LZD or quinolones, its efficacy has not been established. -Based on such a background, a combination of surgical resection of the lesion and combination chemotherapy is the only treatment that is expected to achieve the complete cure of pulmonary infection with M. abscessus in which the lesion is localized [bib_ref] Clinical features of pulmonary disease caused by rapidly growing mycobacteria. An analysis..., Griffith [/bib_ref] [bib_ref] Antibiotic treatment of Mycobacterium abscessus lung disease: a retrospective analysis of 65..., Jeon [/bib_ref] [bib_ref] Clinical and microbiologic outcomes in patients receiving treatment for Mycobacterium abscessus pulmonary..., Jarand [/bib_ref].
---Drugs to be recommended---
A First choice Based on the results of a drug susceptibility test, the following antimicrobial drugs should be combined: -CAM, oral, 200 mg/3 times a day or 400 mg/twice a day  AMK, intravenous drip, 15 mg/kg/once a day  IPM/CS, intravenous drip, 0.5 g/4 times a day or 1 g/3 times a day * Surgery must be considered. The treatment period should be at least 12 months after culture becomes negative.

## Children
---Executive summary----For the treatment of childhood tuberculosis, several drugs should be combined, and administered for a specific period (AII). -For the treatment of non-tuberculous Mycobacterium infection, several drugs should be combined, and administered for a specific period. However, Mycobacterium often resists treatment. If there is no treatment response, surgery must be considered (CIII).
---Explanation---
[Characteristics and classification of the disease] In Japan, tuberculosis is still an important infectious disease. When encountering patients with chronic infection who do not respond to general antimicrobial drugs, tuberculosis should be considered for differential diagnosis. Mycobacteria that can be cultured are classified into two types: M. tuberculosis complex and non-tuberculous Mycobacteria (NTM). M. tuberculosis is a major type of M. tuberculosis complex, and has a strong infectivity from humans to humans. Childhood tuberculosis is classified into two types based on age. Briefly, primary tuberculosis represented by hilar lymph node tuberculosis and meningitis, which develop following primary infection, is characteristic of infants and children. The interval from infection until onset is short, and the morbidity rate is high. In addition, this disease may lead to a severe condition. Pulmonary/hilar lymph node tuberculosis in infants and children is asymptomatic, or the general condition is favorable even in the presence of fever or cough in many cases. When primary tuberculosis is detected based on dyspnea or an unfavorable general condition in addition to fever or cough, many infants/children have military tuberculosis or meningitis. On the other hand, secondary tuberculosis with a cavity lesion or nodular shadow in the lung field is frequent in junior high school students or older. Symptoms such as cough, sputum, fever, and thoracic pain are often observed. In most children, the source of infection can be clarified through detailed peripheral contact screening at the time of onset. Usually, the source of infection is clarified in 2/3 to 3/4 of children. It is often their fathers/mothers or grandfathers/grandmothers [290e292].
As childhood tuberculosis does not form a cavity in the lung field, the M. tuberculosis level in the focus is lower than in adults. In many cases, it is difficult to bacteriologically or histologically make a definitive diagnosis in comparison with adult tuberculosis. Usually, it is possible to make a definitive diagnosis by comprehensively evaluating epidemiological/clinical information such as opportunities for the source of infection to contact with tuberculosis patients, tuberculin reaction-or QuantiFERON TB (QFT)-based verification of infection, imaging findings suggestive of tuberculosis, such as chest X-ray findings, verification of M. tuberculosis from sputum or gastric juice, and individuals' resistance including the grade of BCG vaccination-acquired immunity and age, as well as by considering treatment responses in some cases. QFT is a very useful testing method to quantitatively measure IFN-g and diagnose tuberculosis infection without being influenced by BCG. However, assessment in infants/children should be further examined in the future. When a definitive diagnosis of pulmonary tuberculosis cannot be made based on chest X-ray findings alone, thoracic CT, which facilitates the detailed evaluation of the presence or absence and extent of tuberculous lesions, is useful for diagnosis. Furthermore, imaging findings of tuberculosis do not change in a short period in many cases.
Non-tuberculous Mycobacterium belongs to Mycobacterium, the same category as reported for M. tuberculosis. Therefore, it is often detected as a Mycobacterium-positive smear of sputum, that is, Gaffky's positive reaction. Initially, some patients are regarded as having infectious tuberculosis, and admitted to a tuberculosis ward. Symptoms and imaging findings are also similar between nontuberculous Mycobacterium-and M. tuberculosis-infected patients. Unless detected bacteria are identified, or unless either gene is detected using the nucleic acid amplification method, it is difficult to differentiate the two types of bacteria. However, it is important to recognize that tuberculosis and non-tuberculous Mycobacterium infection are different diseases [bib_ref] Infectious Disease Society of America. An official ATS/IDSA statement: diagnosis, treatment, and..., Griffith [/bib_ref] [bib_ref] Japanese new guidelines for nontuberculous mycobacterial pulmonary disease, Kurashima [/bib_ref]. The most important point is that non-tuberculous Mycobacterium infection does not transmit from humans to humans, differing from tuberculosis, an infectious disease in humans. Therefore, it is not necessary to isolate the patient, and, as a rule, patients requiring admission should be managed in a general ward. As there are no public hygieneassociated problems, it is not necessary to submit a report to a health center.
[Type and frequency of causative microorganisms]
In Japan, the number of patients with childhood tuberculosis has markedly decreased. The number of newly registered patients with tuberculosis decreased from to in children aged 0e14 years [290e292]. However, a decrease in the incidence of smear-positive pulmonary tuberculosis, which is important as the source of infection, is not marked in great urban areas. We cannot conclude that the opportunity of infection in children is favorably decreasing; caution is needed.
The number of patients who newly develop non-tuberculous Mycobacterium infection in Japan is estimated to be approximately 8000. In the adult field, it accounts for about 1/3 of that of patients who newly develop tuberculosis. However, it is relatively low in children. Approximately 80% of patients with non-tuberculous Mycobacterium infection are infected with M. avium complex (M. avium and Mycoboterium intracellulare, pulmonary MAC infection), and approximately 15% are infected with M. cansasii.
[Rules of antimicrobial drug therapy] -The characteristics of antitubercular chemotherapy in children are that children are tolerable to a relatively high dose per body weight in comparison with adults with respect to pharmacokinetics, and that the incidence of side effects is low.
In the pediatric field, 6-month treatment with INH, RFP, and PZA for childhood pulmonary tuberculosis is internationally selected as standard chemotherapy: three drugs, INH, RFP, and PZA, are administered every day for the first 2 months, and INH and RFP every day for the subsequent 4 months. When drug resistance is suspected, these drugs should be combined with SM or EB in the initial phase until the results of a resistance test are clarified. In patients with secondary tuberculosis, 4-drug combination therapy with INH, RFP, PZA, and SM (or EB) should be initially performed. In addition, as a rule, follow-up must be continued for 2 years after the completion of treatment [290e292].
On the other hand, drug resistance, referral to another hospital, and discontinued treatment are present among patients who drop out of treatment, although the number of such patients is small. It is necessary to support the resistance and continuation of treatment. In particular, recently, the number of patients in whom it is difficult to continue treatment has increased. Potent compliance support must be considered in connection with direct observed therapy (DOT) by health centers and welfare activities. Side effects during treatment include liver dysfunction. However, if the maximum AST or ALT levels are approximately 100, administration should be carefully continued without discontinuing treatment. If these levels exceed 100, treatment should be transiently discontinued, and additional administration at a low dose should be conducted after confirming the normalization of the liver function. The dose should be gradually increased. Liver dysfunction requiring a change of treatment is not frequent. Furthermore, there is an increase in the serum uric acid level, but continuous treatment leads to normalization. There have been few patients with arthralgia.
-Prevention of tuberculosis: To prevent the onset of tuberculosis in uninfected persons, BCG vaccination should be performed. Concerning its efficacy, a consensus regarding its potent preventive effects on severe disseminated tuberculosis, such as tuberculous meningitis and military tuberculosis, has been reached. Considering the importance of tuberculous meningitis prevention, BCG vaccination in the early phase of infancy (5e8 months after birth, or earlier in accordance with the state of peripheral tuberculosis prevalence) is still necessary in Japan. -Treatment for latent tuberculosis: To prevent the onset of tuberculosis in persons with a history of tuberculosis, treatment for latent tuberculosis (conventional chemoprevention) should be conducted. A large-scale controlled study reported that INH therapy decreased the incidence of tuberculosis by approximately 50e60%. For drug administration, the risk of tuberculosis onset should be concretely and flexibly evaluated based on the tuberculin reaction, opportunity of infection, age, and state of BCG vaccination in individual patients. -Treatment for non-tuberculous Mycobacterium infection: Nontuberculous Mycobacterium infection is refractory despite combination therapy with antitubercular drugs. In particular, there is no evidence regarding treatment in children [bib_ref] Infectious Disease Society of America. An official ATS/IDSA statement: diagnosis, treatment, and..., Griffith [/bib_ref]. The effects of monotherapy are weak, and monotherapy with CAM may lead to the appearance of CAM-resistant bacteria within a few months; therefore, this therapy should be avoided. The responses of M. kansasii to antitubercular drugs are relatively favorable, and cure may be achieved. However, pulmonary MAC infection is often resistant to treatment. If there is no response, surgery must be considered. Recurrence after the completion of treatment is also often observed.
---Drugs to be recommended--- * As the administration period is longer than that for tuberculosis patients, the development of vision disorder should be considered even at these doses. * If there is no response, surgery must be considered. ---Explanation---Acute bronchitis is characterized by cough that persists for 5 days or more. In most cases, cough persists for 1e3 weeks, but spontaneously subsides [bib_ref] Clinical practice. Acute bronchitis, Wenzel [/bib_ref] [bib_ref] Uncomplicated acute bronchitis, Gonzales [/bib_ref]. Sputum is present in some cases, but is absent in others. Sputum may be purulent even when viral infection is etiologically involved. Neither chest X-ray nor CT shows the appearance of a new abnormal shadow, differing from pneumonia.
[formula]  M. tuberculosis A First choice -RFP  INH  [/formula]
Viruses . There is no evidence that infection with other bacteria directly causes acute bronchitis in adults without an underlying disease [bib_ref] Uncomplicated acute bronchitis, Gonzales [/bib_ref]. However, in a study using the transtracheal aspiration method in Japan, H. influenzae, S. pneumoniae, and M. catarrhalis were primarily isolated in patients diagnosed with bacterial acute bronchitis in the absence of a chronic lower respiratory infectious disease as an underlying disease [bib_ref] Clinical study of acute bacterial bronchitis, Konishi [/bib_ref].
In cases of pertussis, cough persists particularly over a long period, and paroxysmal coughing, inspiratory whooping, and vomiting after coughing may occur [bib_ref] Health burden of pertussis in adolescents and adults, Wards [/bib_ref]. Acute bronchitis caused by M. pneumoniae also induces severe, persistent cough. In cases of influenza, fever, headache, general malaise, and arthralgia are observed. Furthermore, acute viral bronchitis may lead to acute bacterial exacerbation in patients with chronic respiratory lesions as underlying diseases; fever and an increase in the amount of purulent sputum are observed.
As a rule, when an underlying disease or complication is absent, the routine administration of antimicrobial drugs for acute bronchitis is not recommended [bib_ref] Principles of appropriate antibiotic use for treatment of uncomplicated acute bronchitis: background, Gonzales [/bib_ref] [bib_ref] Chronic cough due to acute bronchitis: ACCP evidence-based clinical practice guidelines, Braman [/bib_ref]. To control symptoms such as cough, symptomatic therapy should be performed if necessary. On the other hand, antimicrobial drug treatment with macrolides is indicated for patients with pertussis. Treatment after the catarrhal period does not reduce the degree or duration of cough, but antimicrobial drugs are necessary to prevent infection to peripheral persons [bib_ref] Recommended antimicrobial agents for the treatment and post-exposure prophylaxis of pertussis: 2005..., Tiwari [/bib_ref]. When performing antimicrobial drug treatment for acute bronchitis caused by M. pneumoniae or C. pneumoniae, macrolides should be selected as first-choice drugs. However, an increase in macrolide-resistant M. pneumoniae must be considered [bib_ref] Increased macrolide resistance of Mycoplasma pneumoniae in pediatric patients with community-acquired pneumonia, Morozumi [/bib_ref]. In cases of influenza, anti-influenza therapy should be conducted within 48 h after onset [bib_ref] Antivirals for treatment of influenza: a systematic review and meta-analysis of observational..., Hsu [/bib_ref].
In patients with underlying diseases or elderly persons with complications, bacterial (e.g., S. pneumoniae) infection may occur following viral infection, although this is not frequent in healthy adults. When acute bronchitis related to bacterial infection, including secondary infection, is strongly suspected based on cough/sputum, fever, leukocytosis, or findings suggestive of the presence of causative microorganisms on Gram staining of sputum despite the absence of a new infiltrative shadow on chest X-ray, antimicrobial drug treatment is considered in accordance with treatment for community-acquired bacterial pneumonia [bib_ref] Antibiotic prescribing for self limiting respiratory tract infections in primary care: summary..., Tan [/bib_ref].
---Drugs to be recommended---

##  acute bronchitis caused by viruses
When there are no complications such as chronic respiratory diseases, the administration of antimicrobial drugs for acute bronchitis are not recommended as a rule (With respect to the selection of antimicrobial drugs for acute bronchitis complicated by chronic respiratory diseases with secondary bacterial infection, refer to the section "6.

## Table 21
Miller & Jones classification of purulent sputum. M1: Saliva, complete mucous sputum M2: Mucous sputum containing a small volume of purulent sputum P1: Sputum in which the purulent area comprises 1/3 or smaller P2: Sputum in which the purulent area comprises 1/3 to 2/3 P3: Sputum in which the purulent area comprises 2/3 or greater fever and shortness of breath, in addition to bacterial infection-related respiratory symptoms, such as increases in the frequency of cough, volume of purulent sputum, and degree of purulence, from the chronic, stable conditions of underlying diseases, such as COPD, bronchiectasis, and old pulmonary tuberculosis. Concerning laboratory data, inflammatory responses involving the leukocyte count and CRP level are enhanced, and PaO 2 is often reduced on blood gas analysis.
[Imaging findings]
Imaging findings are necessary to differentiate chronic respiratory disease-related airway infection from pneumonia. The absence of a shadow must be confirmed. CT should also be performed to evaluate underlying diseases such as pulmonary emphysema and bronchiectasis.
[Estimation of causative microorganisms and Gram staining]
It is possible to collect sputum in many patients. Gram staining is useful for predicting causative microorganisms or differentiating respiratory tract infection in the presence of chronic respiratory disease from persistent infection. According to a study, the tone of sputum suggests the presence of pathogenic microorganisms rather than the degree of purulence; macroscopic examination is also necessary [bib_ref] Sputum colour and bacteria in chronic bronchitis exacerbations: a pooled analysis, Miravitlles [/bib_ref]. Sputum involves much information, and is the most important sample. Samples should be collected before the administration of antimicrobial drugs. Those collected on waking-up early in the morning are ideal. To evaluate the degree of sputum purulence, the Miller & Jones classificationis used, but, if samples are evaluated as P2 or higher, causative microorganisms may be predicted using Gram staining. On Gram staining, an area where the number of inflammatory cells is large should be initially searched at a low magnification, and detailed observation should be conducted at a high magnification. Before the administration of antimicrobial drugs, sputum should always be submitted for a susceptibility test.

## [causative microorganisms]
As causative microorganisms, H. influenzae, P. aeruginosa, M. catarrhalis, and S. pneumoniae are frequently detected. Persistent infection with P. aeruginosa is often observed, but it must be differentiated from acute exacerbation based on clinical symptoms and laboratory data. In addition, S. aureus and K. pneumoniae should be considered [bib_ref] Infection in the pathogenesis and course of chronic obstructive pulmonary disease, Sethi [/bib_ref]. The involvement of atypical pathogens such as C. pneumoniae or mixed infection with viruses and bacteria must also be considered.
[Treatment]
The purpose of treatment is to reduce clinical symptoms, prevent recurrence, prolong the interval until subsequent exacerbation, and inhibit lung tissue damage. The administration of appropriate antimicrobial drugs relieves clinical symptoms, and maintains the respiratory function [bib_ref] Antibiotics are associated with lower relapse rates in outpatients with acute exacerbations..., Adams [/bib_ref]. On the other hand, inappropriate antimicrobial drugs may deteriorate the prognosis, inducing recurrence.
In Japan, the resistance of S. pneumoniae and H. influenzae to macrolides and b-lactams is advanced [bib_ref] Nationwide surveillance of bacterial respiratory pathogens conducted by the Surveillance Committee of..., Watanabe [/bib_ref] [bib_ref] Nationwide surveillance of bacterial respiratory pathogens condected by Japanese Society of Chemotherapy..., Niki [/bib_ref]. Several studies have reported that new quinolones are more useful than b-lactams . Respiratory quinolones have potent antimicrobial activities against all types of causative microorganisms, and against resistant bacteria [321e323]. Concerning the administration period, a study indicated that the efficacy of administration for 5 days was similar to that for 7 days, and that the former was safer than the latter. The administration period should be shortened [bib_ref] Randomized, double-blind study comparing 5-and 7-day regimens of oral levofloxacin in patients..., Masterton [/bib_ref].
---Drugs to be recommended--a. Empiric therapy Internationally, some studies have supported the usefulness of b-lactams [bib_ref] The efficacy of cefditoren pivoxil in the treatment of lower respiratory tract..., Granizo [/bib_ref] [bib_ref] Role of oral extended-spectrum cephems in the treatment of acute exacerbation of..., Anzueto [/bib_ref]. However, in Japan, the resistance of S. pneumoniae and H. influenzae to macrolides and b-lactams is advanced, and P. aeruginosa is also sometimes isolated. Therefore, the use of b-lactams and macrolides is limited to patients without risk factors. An international comparative study reported that the efficacy of AZM sustained-release preparations was similar to that of new quinolones [bib_ref] Efficacy and safety of 3-day azithromycin versus 5-day moxifloxacin for the treatment..., Zervos [/bib_ref]. However, in Japan, the long-term administration of macrolides is performed in many patients; therefore, circumstances differ. Beta-lactamase-producing strains are detected in approximately 10e20% of H. influenzae strains. Beta-lactamasenegative, ampicillin-resistant (BLNAR) strains account for approximately 20%. Therefore, when drug susceptibility is unclear, new quinolones should be selected as first-choice oral antimicrobial drugs. If drug susceptibility is clarified, they should be switched to effective and narrow-spectrum drugs. As injection, penicillins should be initially selected, followed by b-lactamase inhibitor-containing penicillins, carbapenems, and new quinolones.  M. catarrhalis Beta-lactamase-producing strains account for 100% of M. catarrhalis strains. As oral antimicrobial drugs, macrolides should be initially selected, followed by b-lactamase inhibitor-containing penicillins, second-/third-generation cephems, and new quinolones. As injection, b-lactamase inhibitor-containing penicillins, second-/third-generation cephems, new quinolones, or carbapenems should be selected.  P. aeruginosa
As oral drugs, new quinolones should be selected. As injection, anti-P. aeruginosa penicillins, cephems, monobactums, carbapenems, or new quinolones should be selected. As the drug susceptibility of this type of bacteria markedly differs among strains, drugs should be selected based on the results of culture tests.  S. pneumoniae
As oral drugs, penicillins should be initially selected, followed by new quinolones. In patients with a risk of resistant bacteria, respiratory quinolones such as LVFX and GRNX should be selected. As injection, penicillins or CTRX should be selected, but carbapenems must be considered in severestatus patients. ---Explanation---[Characteristics/classification of the disease] DPB is a chronic inflammatory disease of the respiratory tract, which is frequently observed in East Asians including Japanese. There is no gender difference, and this disease frequently develops in persons aged 40e50 years. It is often detected in patients with a history of chronic sinusitis or in those with the concomitant development of chronic sinusitis. This disease is classified as the category of sinobronchial syndrome.
[Symptoms]
The most typical symptoms of DPB are persistent cough and purulent sputum. Symptoms such as exertional shortness of breath and dyspnea appear in accordance with disease progression. In patients with a complication of chronic sinusitis, purulent nasal discharge and nasal obstruction are observed.

## [laboratory findings]
Chest X-ray shows pulmonary overexpansion or a diffuse scattered nodular shadow. Thoracic HRCT reveals a diffuse centrilobular nodular shadow. Furthermore, obstructive respiratory dysfunction, hypoxemia, and an increase in the cold agglutinin value (64-fold or more on the hemagglutination method) are observed.
[Type and frequency of causative microorganisms]
In patients with DPB, persistent respiratory tract infection with H. influenzae, S. pneumoniae, or M. catarrhalis is often observed. However, the incidence of persistent infection with P. aeruginosa increases with progression.
[Long-term macrolide therapy]
Previously, the prognosis of DPB was unfavorable; respiratory failure gradually progressed through repeated acute exacerbation related to respiratory tract infection, leading to a fatal outcome; however, the prognosis of DPB has been markedly improved since long-term macrolide therapy with low-dose administration of EM or other 14-membered ring macrolides was established [328e340]. Early diagnosis/treatment have facilitated the complete cure of DPB. Therefore, if once a diagnosis of DPB is made, long-term macrolide therapy should be started promptly.
---Drugs to be recommended--- Persistent infection -The oral administration of EM at 400e600 mg/day should be continued for 6 months to be evaluated its clinical effects. -In many cases, an improvement in symptoms (such as a decrease in the volume of sputum) will be achieved within 1e3 months after the start of administration. -In addition, an improvement in imaging findings or the respiratory function will be achieved after 3e6 months of treatment. Croup syndrome is characterized by acute laryngeal stenosisassociated respiratory disturbance such as barking cough, hoarseness, and inspiratory stridor. Most lesions involve not only the larynx but also the trachea/bronchus. This disease is sometimes called laryngotracheobronchitis [bib_ref] Acute inflammatory upper airway obstruction (Croup, epiglottitis, laryngitis, and bacterial tracheitis), Roosevelt [/bib_ref]. Etiological factors are classified into two types: infectious and non-infectious (allergy-/ foreign body-related) factors [bib_ref] Acute inflammatory upper airway obstruction (Croup, epiglottitis, laryngitis, and bacterial tracheitis), Roosevelt [/bib_ref]. The incidence of infectious croup syndrome is high in infants/children aged 7 monthse3 years [bib_ref] Croup: an 11-year study in a pediatric practice, Denny [/bib_ref] [bib_ref] Croup hospitalizations in Ontario: a 14-year time-series analysis, Segal [/bib_ref].
[Type and frequency of causative microorganisms]
Croup syndrome is primarily caused by viruses. Parainfluenza virus type 1 is the most common virus [bib_ref] A current perspective, Klassen [/bib_ref]. In addition, parainfluenza virus type 2/3, influenza A/B virus, RS virus, human metapneumovirus, coronavirus, adenovirus, and measles virus are relatively frequently isolated [bib_ref] Respiratory viruses in laryngeal croup of young children, Rihkanen [/bib_ref].
[Rules of antimicrobial drug therapy]
In most cases, croup syndrome is caused by viruses, and antimicrobial drugs are not necessary. Therefore, no study has evaluated the efficacy of antimicrobial drugs in patients with croup syndrome. There are no treatment guidelines regarding croup syndrome in which antimicrobial drugs are recommended [bib_ref] Croup: an overview, Zoorob [/bib_ref] [bib_ref] Croup-assessment and management, Rajapaksa [/bib_ref].

## Bronchiolitis
---Executive summary---Bronchiolitis is caused by viruses, and the administration of antimicrobial drugs is not necessary (AI).
---Explanation---

## [characteristics and classification of the disease]
Bronchiolitis is an acute, inflammatory, obstructive disease involving the bronchiole. Narrowing of the bronchiolar lumen related to mucosal epithelial injury, inflammatory-cell infiltration, interstitial edema, or an increase in mucus secretion causes air trapping in the peripheral respiratory tract, leading to obstructive respiratory disorder. This disease frequently develops in children aged 2 years or younger. However, infants aged 11 months or younger account for 80% or more [bib_ref] Wheezing, bronchiolitis, and bronchitis, Watts [/bib_ref].
[Type and frequency of causative microorganisms] Bronchiolitis is primarily caused by viruses. RS virus accounts for 60e80%. In addition, parainfluenza virus, human metapneumovirus, adenovirus, and influenza virus are relatively frequently isolated [361e363].
[Rules of antimicrobial drug therapy]
In most cases, bronchiolitis is caused by viruses, and antimicrobial drugs are not necessary. Basic treatment is symptomatic therapy. In double-blind comparative studies involving ABPC and non-treated groups [bib_ref] Antibiotic treatment of epidemic bronchiolitisea double-blind trial, Field [/bib_ref] , AZM and non-treated groups [bib_ref] Azithromycin does not improve disease course in hospitalized infants with respiratory syncytial..., Kneyber [/bib_ref] , and ABPC intravenous injection/oral EM and non-treated groups [bib_ref] Management of bronchiolitis without antibiotics: a multicentre randomized control trial in Bangladesh, Kabir [/bib_ref] , respectively, there were no significant differences in the admission period or symptom improvement. However, a small-scale doubleblind comparative study reported that the interval until recovery in the CAM-treated group was shorter than in the non-treated group [bib_ref] Clarithromycin in the treatment of RSV bronchiolitis: a double-blind, randomised, placebo-controlled trial, Tahan [/bib_ref]. According to another study, the incidence of secondary bacterial infection during the course of RS virus-related bronchiolitis was 1.2%, and there was no difference between antimicrobial drug-treated and non-treated groups [bib_ref] Risk of secondary bacterial infection in infants hospitalized with respiratory syncytial viral..., Hall [/bib_ref]. Therefore, it is not necessary to administer antimicrobial drugs to children with bronchiolitis for routine treatment or the prevention of secondary bacterial infection. However, follow-up must be carefully continued during the course of bronchiolitis. When a diagnosis of secondary bacterial infection-related pneumonia or otitis media is made, antimicrobial drug therapy should be started.

## Bacterial tracheitis
---Executive summary---Bacterial tracheitis is a bacterial disease with the rapid progression of dyspnea. If symptoms are progressive, antimicrobial drugs should be used even when a definitive diagnosis is not made (AIII).
---Explanation---

## [characteristics and classification of the disease]
Fever and croup syndrome-like cough/stridor initially appear, and respiratory disorder rapidly progresses, but there is no specific posture, salivation, or dysphagia, which are characteristic of acute epiglottitis. A definitive diagnosis can be made based on characteristic clinical features and purulent secretion in the respiratory tract. In some cases, a lateral view of the larynx on X-ray shows stenosis below the larynx [bib_ref] Acute inflammatory upper airway obstruction (Croup, epiglottitis, laryngitis, and bacterial tracheitis), Roosevelt [/bib_ref]. This disease frequently develops in children aged 3e8 years [bib_ref] Bacterial tracheitis in children: approach to diagnosis and treatment, Al-Mutair I [/bib_ref].
[Type and frequency of causative microorganisms] S. aureus-related tracheitis accounts for approximately 60%, followed by that related to M. catarrhalis, H. influenzae, Streptococcus pneumoniae, and Streptococcus pyogenes [370e373]. Mixed infection with viruses and bacteria is frequent, and parainfluenza virus type I [bib_ref] Is bacterial tracheitis changing? A 14-month experience in a pediatric intensive care..., Bernstein [/bib_ref] and influenza A virusare often detected.
[Rules of antimicrobial drug therapy] Antimicrobial drugs should be intravenously administered for the following reasons: this disease rapidly progresses, and oral administration is difficult in many cases. As empiric therapy, combination therapy with VCM, which may be effective for infection with S. aureus (including MRSA), and third-generation cephems (CTRX, CTX), which have potent antimicrobial activities against M. catarrhalis, H. influenzae, S. pneumoniae, and S. pyogenes, should be performed. The administration period is 10e14 days [bib_ref] Bacterial tracheitis in children: approach to diagnosis and treatment, Al-Mutair I [/bib_ref].
---Drugs to be recommended---Refer to the section "3. Pneumonia (Children)---Drugs to be recommended 2. Definitive therapy---" (p. 33).

## Acute bronchitis
---Executive summary---Acute bronchitis is primarily caused by viruses, and the necessity of antimicrobial drug administration is low (AI).
When acute bronchitis is caused by M. pneumoniae, C. pneumoniae, or B. pertussis, antimicrobial drugs should be administered if necessary (AIII).
Secondary infection with S. pneumoniae or H. influenzae may occur, although its incidence is unclear. Therefore, when there is no improvement, the administration of antimicrobial drugs should be considered (AIII).
---Explanation---[Characteristics and classification of the disease]
Bronchitis causes symptoms such as cough, fever, and general malaise. Various causative microorganisms induce inflammation of the epithelial tracheobronchial tissue, leading to the onset of bronchitis. Clinically, there are no special findings on auscultation, or only rough respiratory sounds (intermittent accessory murmurs) are heard. Chest X-ray does not also show any marked infiltrative shadow. Usually, patients in whom the interval after onset is less than 3 weeks are regarded as having acute bronchitis [bib_ref] Wheezing, bronchiolitis, and bronchitis, Watts [/bib_ref].
However, bronchitis diagnosed in Japan slightly differs from that in Europe and the United States. The latter primarily causes persistent cough. In Japan, patients in whom there are no findings on chest X-ray despite clinical signs of pneumonia or those in whom chest X-ray is not performed are often diagnosed with bronchitis; the disease entity must be arranged.
[Type and frequency of causative microorganisms] Viruses, such as rhinovirus, influenza virus, RS virus, adenovirus, parainfluenza virus, human metapneumovirus, and human bocavirus, account for 90% of causative microorganisms. M. pneumoniae, C. pneumoniae, and B. pertussis also cause bronchitis, although such cases are relatively rare [bib_ref] Wheezing, bronchiolitis, and bronchitis, Watts [/bib_ref].
[Rules of antimicrobial drug therapy] Acute bronchitis is primarily caused by viruses, and the administration of antimicrobial drugs is not necessary. A metaanalysis compared adults to whom antimicrobial drugs were administered for bronchitis treatment with non-treated adults, and indicated that there was no difference in the efficacy [bib_ref] Antibiotics for acute bronchitis, Smucny [/bib_ref]. Few reports on clinical studies involving children have been published, and the scale is small; objective data are insufficient, but no study has reported that antimicrobial drugs are effective [377e379]. However, if secondary bacterial infection following viral infection causes fever, purulent sputum, leukocytosis, or an increase in the CRP level, antimicrobial drugs should be administered, considering S. pneumoniae and H. influenzae.
Other indications for antimicrobial drug administration include M. pneumoniae-, C. pneumoniae-, or B. pertussis-related bronchitis with protracted cough. As M. pneumoniae-or C. pneumoniae-related bronchitis tends to show spontaneous cure, the administration of antimicrobial drugs is not always necessary, but the necessity of administration should be evaluated, considering the severity of symptoms and course (With respect to indications and administration methods, refer to the section "3. Pneumonia (Children)".). First-choice drugs for M. pneumoniae-, C. pneumoniae-, or B. pertussis-related bronchitis are macrolides. In patients with B. pertussis-related bronchitis, antimicrobial drugs relieve symptoms only during the catarrhal period, but, if B. pertussis-related bronchitis is suspected based on clinical symptoms, previous vaccination, lymphocyte-predominant leukocytosis, an anti-PT antibody titer, and LAMP findings, antimicrobial drugs should be used. However, 16-membered ring macrolides are ineffective for B. pertussis-related bronchitis.
Symptoms are similar to those of pneumonia, but, when chest X-ray does not show any abnormalities, or, when it is impossible to strictly differentiate bronchitis from pneumonia due to difficulty in chest X-ray, treatment should be performed in accordance with pneumonia.
---Drugs to be recommended---

## Empiric therapy
Secondary bacterial infection after viral infection (Cases in which fever, purulent sputum, leukocytosis, or an increase in the CRP level is observed) A First choices -AMPC, oral, 10e15 mg/kg/3 times a day -SBTPC, oral, 10 mg/kg/3 times a day -CDTR-PI, oral, 3 mg/kg/3 times a day -CFPN-PI, oral, 3 mg/kg/3 times a day -CFTM-PI, oral, 3 mg/kg/3 times a day <> Second choices -AZM, oral, 10 mg/kg/once a day, 3 days -CAM, oral, 7.5 mg/kg/twice a day 2. Definitive therapy  B. pertussis -EM, oral, 10e15 mg/kg/3 times a day -CAM, oral, 7.5 mg/kg/twice a day -AZM, oral, 10 mg/kg/once a day, 3 days  M. pneumoniae  Macrolide-sensitive strains -EM, oral, 10e15 mg/kg/3 times a day -AZM, oral, 10 mg/kg/once a day, 3 days -CAM, oral, 7.5 mg/kg/twice a day  Macrolide-resistant strains -MINO, oral or intravenous drip, 1e2 mg/kg/twice a day (In children aged 7 years or younger, the use of this drug is limited to those in whom other drugs cannot be used or non-responders.) -TFLX, oral, 6 mg/kg/twice a day (Administration is limited to children aged 7 years or younger in whom MINO cannot be used.)  Chlamydia (C. pneumoniae, C. psittaci, C. trachomatis) -EM, oral, 10e15 mg/kg/3 times a day -AZM, oral, 10 mg/kg/once a day, 3 days -CAM, oral, 7.5 mg/kg/twice a day 8. Influenza

## Adults
---Executive summary----Both M2 protein inhibitors and neuraminidase inhibitors (NAIs) are commercially available as anti-influenza drugs as of July 2013. -Influenza viruses A (H3N2) and A (H1N1) pdm09 (seasonal influenza) have been reported to be resistant to amantadine, an M2 protein inhibitor which can be used in Japan. The use of this drug as an anti-influenza drug should be avoided for a while. -During the influenza outbreak period, anti-influenza therapy should be promptly started based on a clinical diagnosis even when patients with influenza-like symptoms show negative results on a rapid diagnosis kits (because influenza cannot be completely ruled out) [bib_ref] Accuracy of rapid influenza diagnostic tests. A meta-analysis, Chartrand [/bib_ref] (AI). -NAIs significantly improve influenza survival, and NAI administration within 2 days after onset significantly reduces the rate at which the condition becomes severe [bib_ref] Critically ill patients with 2009 influenza A (H1N1) in Mexico, Dominguez-Cherit [/bib_ref] [bib_ref] Enteric absorption and pharmaco-kinetics of oseltamivir in critically ill patients with pandemic..., Ariano [/bib_ref] (AI). -Currently, the following NAIs can be selected in Japan. During the outbreak period, an appropriate drug should be selected based on the patient background and latest information on a prevalent influenza strain:
-Oseltamivir (oral), Efficacy: A (H1N1) pdm09, A (H3N2), B, Resistance: H275Y mutant -Zanamivir (inhalation), Efficacy: type A/B -Laninamivir (inhalation), Efficacy: type A/B -Peramivir (intravenous drip), Efficacy: type A/B ---Drugs to be recommended---There is no meta-analysis of anti-influenza drugs other than oseltamivir and zanamivir as of July 2013. However, it has been shown that the early introduction of anti-influenza therapy for influenza significantly inhibits not only the mortality and admission rates but also the incidences of influenza-associated pneumonia, otitis media, and ischemic heart disease in comparison with symptomatic therapy. NAIs such as laninamivir and peramivir have also been confirmed to be as effective as oseltamivir at the time of development [bib_ref] Antivials for treatment of influenza. A systemic review and meta-analysis of observation..., Hsu [/bib_ref] (AI).
<>Outpatient treatment -Oseltamivir, oral, 75 mg/twice a day, 5 days (As a rule, administration to children/adolescents aged 10e19 years should be avoided.) -Zanamivir, inhalation, 10 mg/twice a day, 5 days -Laninamivir, inhalation, 40 mg/single dose -Peramivir, intravenous drip, 300 mg/single dose <>Hospital treatment  Patients with severe, life-threatening influenza In patients with severe, life-threatening influenza requiring admission, respiratory failure or encephalopathy is present. In either case, the complication must be treated, but, as a rule, NAIs should be introduced within 48 h after the onset of influenza to obtain their effects. -Oseltamivir, oral, 75 mg/twice a day, 5 days (As a rule, administration to children/adolescents aged 10e19 years should be avoided.) -Peramivir, intravenous drip, 600 mg/single dose (This drug can be repeatedly administered every day in accordance with symptoms.)  Non-life-threatening influenza patients with pneumonia -Oseltamivir, oral, 75 mg/twice a day, 5 days (As a rule, administration to children/adolescents aged 10e19 years should be avoided.) -Peramivir, intravenous drip, 300 mg (600 mg for patients in whom the condition may become severe)/single dose (This drug can be repeatedly administered every day in accordance with symptoms.)  Non-life-threatening influenza patients without pneumonia -Oseltamivir, oral, 75 mg/twice a day, 5 days (As a rule, administration to children/adolescents aged 10e19 years should be avoided.) -Zanamivir, inhalation, 10 mg/twice a day, 5 days -Laninamivir, inhalation, 40 mg/single dose -Peramivir, intravenous drip, 300 mg/single dose (This drug can be repeatedly administered every day in accordance with symptoms.) * Patients with A (H7N9) -Basic treatment is the early administration of anti-influenza drugs. -According to an article, there were no significant differences in the viral level or mortality rate 5 days after the start of administration between double-and standard-dose oseltamivir therapies. However, treatment was not started within 48 h after onset in all patients in the article.

## Children
---Executive summary---Influenza is caused by influenza virus. Antimicrobial drugs are not necessary. It is recommended that neuraminidase inhibitors should be administered within 48 h after onset (AI).
If pneumonia or otitis media occurs through secondary bacterial infection, the administration of antimicrobial drugs must be considered (BIII).
---Explanation---[Characteristics and classification of the disease] Influenza often appears with sudden fever and shivering/ headache/general malaise/muscular pain/dry cough, followed by marked respiratory or digestive symptoms. In underlying diseasefree children, recovery is achieved after 3e7 days [bib_ref] Influenza viruses, Wright [/bib_ref]. However, during the outbreak period, even underlying disease-free children are often admitted with serious symptoms such as encephalopathy, myocarditis, and pneumonia requiring artificial respiration. Although the outbreak period is from December until March every year, outbreaks are observed in the summer in some areas [bib_ref] Influenza viruses, Wright [/bib_ref].
[Type and frequency of causative microorganisms]
Since influenza A (H1N1) pdm09 prevailed in 2009, the outbreaks of 3 types of influenza, A (H1N1) pdm09, A (H3N2), and B, have been repeated. Their incidences differ among years.
[Rules of antimicrobial drug therapy]
No antimicrobial drug is indicated for influenza. It is recommended that neuraminidase inhibitors should be administered within 48 h after onset. The doses of neuraminidase inhibitors approved in Japan are presented in . During the course of influenza, bacterial infection such as pneumonia and otitis media may occur. Previously, the incidence of secondary bacterial infection in children exceeded 10% [bib_ref] A study of illness in a group of clevel and families. XVII...., Jr [/bib_ref] , but it has been 3% or less since neuraminidase inhibitors were developed [bib_ref] Clinical characteristics of pediatric hospitalizations associated with 2009 pandemic influenza A (H1N1)..., Wieching [/bib_ref] [bib_ref] Otolaryngological complications in patients infected with the influenza A (H1N1) virus, Gutierrez [/bib_ref]. However, bacterial infection is observed in 25e33% of severe-status patients requiring intensive care [bib_ref] Severe influenza cases in paediatric intensive care units in Germany during the..., Streng [/bib_ref] [bib_ref] Critically ill children during the 2009d2010 influenza pandemic in the United States, Randolph [/bib_ref]. Streptococcus pneumoniae, S. aureus, and H. influenzae are frequently detected as causative microorganisms [bib_ref] Influenza viruses, Wright [/bib_ref] [bib_ref] Severe influenza cases in paediatric intensive care units in Germany during the..., Streng [/bib_ref] [bib_ref] Critically ill children during the 2009d2010 influenza pandemic in the United States, Randolph [/bib_ref].
No study has demonstrated that the prophylactic administration of antimicrobial drugs at the onset of influenza prevents secondary bacterial infection. Among children with influenza, antimicrobial drug therapy should be considered in those in whom signs of pneumonia or otitis media do not subside despite the administration of a neuraminidase inhibitor.
9. Parasitic diseases of the respiratory system ---Executive summary----Parasitic diseases are widely distributed throughout the world.
In addition to domestic infection, Japanese travelers may be infected in overseas endemic areas. Furthermore, parasitic diseases always considered in foreign patients from endemic areas [bib_ref] The current status of parasitic diseases in Japan, Nakamura-Uchiyama [/bib_ref] (BIV). -When peripheral blood eosinophilia is observed in addition to respiratory symptoms and abnormal findings of the chest imaging, examinations should be performed to differentiate parasitic diseases [bib_ref] The current status of parasitic diseases in Japan, Nakamura-Uchiyama [/bib_ref] (BIV). -Parasitic diseases of the respiratory system are caused by Paragonimus spp., Ascaris lumbricoides, Ancylostoma duodenale, Necator americanus, Strongyloides stercoralis, Toxocara canis, Toxocara cati, Wuchereria bancrofti, Brugia malayi, or Dirofilaria immitis. -There are two major diagnostic tests for parasitic diseases:detection of parasite eggs or larvae in sputum or stools, and (2) detection of parasite-specific antibodies using serum or pleural effusion samples (immunodiagnosis). -An anti-parasite antibody screening test against 12 species of parasite is commercially available; Paragonimus spp., Strongyloides sp., T. canis, D. immitis, Ascaris suum, Anisakis simplex, Gnathostoma spp., Fasciola hepatica, Clonorchis sinensis, Spirometra erinaceieuropaei, and Cysticercus cellulosae. -Diagnosis/treatment consultations regarding parasitic diseases by the Japanese Society of Parasitology are available (as of 2013). Refer to the homepage (http://jsp.tm.nagasaki-u.ac.jp).
---Explanation----Paragonimus spp. Several Paragonimus species are known to cause human infection. Paragonimus westermani and P. miyazakii are distributed in Japan. Infection occurs through the consumption of freshwater crabs (intermediate host: Eriocheir japonica, E. sinensis, Geothelphusa dehaani) or wild boars (paratenic host:Sus scrofa) contaminated with metacercaria (infective larvae) as a raw or insufficiently cooked food.
Typical symptoms are cough, sputum, thoracic pain, and exertional dyspnea. In patients with such symptoms, the presence of peripheral blood eosinophilia suggests this disease. In many cases, a diagnosis is made based on the peripheral blood eosinophilia, a history taking of food and Standard doses of neuraminidase inhibitors in children.

## Drug name administration method dose
Oseltamivir a Oral 2 mg/kg, twice a day, 5 days (The use of this drug should be avoided in children/adolescents aged 10e19 years.) Zanamivir b Inhalation 10 mg, twice a day, 5 days Laninamivir Inhalation 10 years or older: 40 mg 9 years or younger: 20 mg, single dose Peramivir Intravenous drip 10 mg/kg, once a day a The preventive administration of this drug at 2 mg/kg (once a day) for 10 days was approved, but is not covered by health insurance. b The preventive administration of this drug at 10 mg (once a day) for 10 days was approved, but is not covered by health insurance.
immunodiagnosis. Some of paragonimiasis patients are asymptomatic, and the presence of lung lesions is detected on a health checkup. Extrapulmonary paragonimiasis such as cutaneous and cerebral paragonimiasis are classically known form of the ectopic infection with Paragonimus spp. In cases of cutaneous paragonimiasis, a slowly moving nodular lesion in the subcutaneous tissue is a characteristic symptom. The worms may migrate through mediastinal soft tissues to the brain, causing eosinophilic meningitis or cerebral paragonimiasis in some cases. Since Paragonimus spp. is widely distributed around the world, Japanese travel to endemic area such as China, Korea, Thailand, and Philippines possible to infect with Paragonimus spp. As well as foreign patients from endemic areas, this disease always is considered when a patient has respiratory symptoms and/or lung lesions with eosinophilia [bib_ref] Paragonimiasis cases recently found among immigrants in Japan, Obara [/bib_ref]. Chest X-ray findings vary: not only pulmonary parenchymal lesions, such as nodular (cavity formation) and infiltrative shadows, but also pleural lesions, such as the retention of pleural effusion and pneumothorax, are sometimes observed [bib_ref] Clinicoradiologic features of pleuropulmonary Paragonimus westermani on Kyusyu Island, Mukae [/bib_ref]. Many patients show peripheral blood eosinophilia and/or elevated serum total IgE. Immunodiagnosis to detect parasite-specific antibody has been proven as the most useful and reliable tool. Not only patient's serum but also pleural effusion could examine by immunological test. Commercially available anti-parasite antibody screening test is including Paragomimus spp. In Japan, egg-detection rate among paragonimiasis patients nowadays is low; for example 51.2% in sputum and 53.8% in BALF [bib_ref] Role of serial routine microbio-logic culture results in the initial management of..., Hayon [/bib_ref] , 66.7% in bronchoscopic aspirate [bib_ref] Clinicoradiologic features of pleuropulmonary Paragonimus westermani on Kyusyu Island, Mukae [/bib_ref].
After a definitive diagnosis is made, oral treatment should be started. The type of treatment to be selected, outpatient or hospital treatment, depends on the patient's general condition. However, usually, outpatient treatment is possible. In patients having pleural effusion, pleural fluid must be extensively drained off before starting chemotherapy(BIII). In patients with chronically encapsulated pleural effusion, surgery is required [bib_ref] A case of chronic pleural empyema by Paragonimus westermani infection resistant to..., Tomita [/bib_ref] (CIII).
---Drugs to be recommended---A First choice (same dose for adults and children) -Praziquantel, oral, 25 mg/kg/3 times a day, 2e3 days [bib_ref] Paragonimiasis: experimental and clinical experience with praziquantel in Korea, Rim [/bib_ref] (AIII) -A. lumbricoides, A. duodenale, N. americanus
The larvae of these parasites pass through the lung in the human body, causing asthma-or pneumonia-like symptoms such as transient fever, cough, and dyspnea. On chest X-ray, transient nodular/infiltrative shadows are observed. Many patients show peripheral blood eosinophilia and/or elevated serum total IgE. Previously, the condition was called Loffler syndrome. Currently, it is classified as simple pulmonary eosinophilia in the category of PIE syndrome [bib_ref] Paragonimiasis: experimental and clinical experience with praziquantel in Korea, Rim [/bib_ref].
Symptoms appear 1e2 weeks after the oral ingestion of A. lumbricoides embryonated eggs. The latency period of percutaneous infection with N. americanus larvae or percutaneous/oral infection with A. duodenale larvae is approximately 10 days. Larvae appeared in the small intestine penetrate the intestinal wall, enter the portal vein, migrate through liver to heart/lung. Larvae penetrate the human skin transfer to the lung with blood flow. Then these larvae migrate up the bronchi and trachea, over the epiglottis, down the esophagus/stomach, and reach the small intestine. In the intestine the larvae develop into mature adults [bib_ref] Parasitic infections of the lung:a guide for the respiratory physician, Kunst [/bib_ref].
Simple pulmonary eosinophilia related to parasites spontaneously resolved in a few weeks. In many cases, a definitive diagnosis is made based on parasite eggs detected on a stool examination, although larvae are sometimes detected in sputum [bib_ref] Parasitic infections of the lung:a guide for the respiratory physician, Kunst [/bib_ref].
---Drugs to be recommended---A First choice (same dose for adults and children) -Pyrantel pamoate, oral, 10 mg/kg/single-dose administration * Dry syrup for children is available. * This drug is effective for adult worms in the intestinal tract, but not for larvae migrating in the human body. Therefore, a stool examination should be performed 2 weeks after oral administration. If parasite eggs are detected, additional administration should be conducted. <> Second choices (same dose for adults and children) -Albendazol, oral, 400 mg/single-dose administration -Mebendazole, oral, 100 mg/twice a day, 3 days, or 500 mg/single-dose administration -Ivermectin, oral, 150e200 mg/kg/single-dose administration (after fasting) -S. stercoralis
In Japan, S. stercoralis is distributed in Nansei Islands, chain of islands extending from southwestern Kyushu to northern Taiwan. There are few young persons newly infected with S. stercoralis, but the incidence of infection is high in elderly persons [bib_ref] Current status of strongyloides infection in Okinawa, Asato [/bib_ref]. Internationally, S. stercoralis is widely distributed in tropical/subtropical areas. Not only domestic infection but also Japanese travel to endemic area possible to infect with this parasite. Foreign patients from endemic areas, strongyloidiasis always considered when a patient has respiratory symptoms and/or lung lesions with eosinophilia.
S. stercoralis percutaneously infects humans. Larvae penetrate the human skin transfer to the lung with blood flow. Then these larvae migrate up the bronchi and trachea, over the epiglottis, down the esophagus/stomach, and reach the small intestine. In the intestine the larvae develop into mature adults. Parasite eggs delivered by adults are hatched while descending the intestinal tract, and larvae excreted in stools. Some larvae developed to infective form again invade/transfer through the mucosa around the anus, maintaining a life cycle in the human body. Such a mode of infection is termed autoinfection.
With the transfer of larvae to the lung, asthma-or pneumonia-like symptoms, such as transient fever, cough, and dyspnea, appear, as indicated for simple pulmonary eosinophilia related to A. lumbricoides, A. duodenale, or N. americanus. On chest X-ray, transient nodular/infiltrative shadows are observed. Many patients show peripheral blood eosinophilia and/or an increase in the total IgE level.
In immunocompromised patients, suppressing the cellmediated immunity such as ATL patients, HIV/AIDS patients, those receiving immunosuppressive drugs, the number of S. stercoralis increases through acceleration of autoinfection, and larvae are disseminated in various organs, leading to a severe condition (disseminated strongyloidiasis). In such cases, stridor, bloody sputum, tachypnea, protein-losing gastroenteritis, ileus, and mobile exanthema are observed. Furthermore, severe pneumonia related to enteric bacteria disseminated with larvae, lung abscess, or bacterial meningitis concomitantly occurs [bib_ref] Parasitic infections of the lung:a guide for the respiratory physician, Kunst [/bib_ref]. A diagnosis is made based on S. stercoralis larvae detected in stools/sputum. Immunological diagnosis is also useful [bib_ref] Parasitic infections of the lung:a guide for the respiratory physician, Kunst [/bib_ref].
---Drugs to be recommended---A First choice (same dose for adults and children) -Ivermectin, oral, 200 mg/kg/single-dose administration (after fasting), additional administration at the same dose after 2 weeks (AI) * Repeated administration must be considered in cases of disseminated strongyloidiasis [bib_ref] Pulmonary strongyloidiasis: the varied clinical presentations, Mokhlesi [/bib_ref]. * A study reported that transrectal or percutaneous administration was useful in patients in whom oral administration was difficult due to digestive symptoms [bib_ref] Non-oral treatment with ivermectin for disseminated strongyloidiasis, Fusco [/bib_ref]. <> Second choice (same dose for adults and children) -Albendazol, oral, 400 mg/twice a day, 7 days (BI) -T. canis, T. cati Infection to humans occurs through the oral ingestion of the embryonated eggs of T. canis or T. cati [bib_ref] How common is human toxocariasis? Towards standardizing our knowledge, Smith [/bib_ref]. It also occurs through the consumption of beef/chicken liver or meat contaminated with larvae as a raw or insufficiently heated food. This is considered to be a dominant route of infection in Japan [bib_ref] How common is human toxocariasis? Towards standardizing our knowledge, Smith [/bib_ref]. As humans are not definitive host for T. canis and T. cati, they do not become adults in the human body [bib_ref] Toxocariasis in Japan, Akao [/bib_ref]. Larvae invading the human body transfer to various organs with blood flow through the intestinal mucosa. Target organs are the lung, liver, eyes, and central nervous system including spinal cord. Toxocariasis is a typical larva migrans.
Lesions are often observed in the lung/liver (visceral larva migrans). There are few symptoms, or nonspecific symptoms are present. In many cases, a diagnosis is made based on peripheral blood eosinophilia and multiple nodular shadows of the lung or liver on CT. Ocular or central nervous symptoms appear in some patients. It is impossible to make a diagnosis on a stool examination due to larva migrans. Immunological diagnosis is useful. After a definitive diagnosis is made, treatment should be started. When visceral larva migrans is asymptomatic, follow-up may be continued.
---Drugs to be recommended---A First choice (same dose for adults and children) -Albendazol, oral, 5 mg/kg/2 or 3 times a day, 4e8 weeks [bib_ref] Lessons from eight cases of adult pulmonary toxocariasis :abridged republication, Yoshikawa [/bib_ref] (BIII) * This drug should be taken with meals for 28 days. A 14-day period of discontinuation should be established and then restarted drug if required. <> Second choices (same dose for adults and children) -Albendazol, oral, 400 mg/twice a day, 5 days [bib_ref] Thiabendazole vs. albendazole in treatment of toxocariasis: a clinical trial, Sturchler [/bib_ref] (BIII) -Mebendazole, oral, 100e200 mg/twice a day, 5 days [bib_ref] A case of adult hepatic toxocariasis, Hossack [/bib_ref] (CIII) -W. bancrofti, B. malayi W. bancrofti and B. malayi are called lymphatic filaria. Infection occurs when these parasites are transmitted to humans through mosquitoes. The pathogenesis of lymphatic filariasis is relate to structural and functional abnormality of lymphatic channels induced by parasitized adult worms. Infection with W. bancrofti is characterized by febrile attacks, lymphedema/elephantiasis, hydrocele, and chyluria. In patients infected with B. malayi, neither hydrocele nor chyluria is observed, and lymphedema of the lower limbs/ elephantiasis are localized in the lower thighs. Microfilaria produced by adult worms is not pathogenic, but rarely induces allergic reactions in the lung, contributing to tropical pulmonary eosinophilia (TPE) [bib_ref] Parasitic infections of the lung:a guide for the respiratory physician, Kunst [/bib_ref]. This condition shows a chronic course, differing from simple pulmonary eosinophilia. Cough, dyspnea, and stridor with exacerbation at night are observed. Fever, malaise, and weight loss are noted in some patients. On chest X-ray, bilateral reticular nodular lesions are detected. Peripheral blood eosinophilia and an increase in the anti-filaria antibody titer are observed. In case of TPE, no microfilaria is detected [bib_ref] Parasitic infections of the lung:a guide for the respiratory physician, Kunst [/bib_ref]. If treatment is not performed, the condition may gradually exacerbate. It is important to adequately make a diagnosis for the differentiation of this disease. In the world, 130,000,000 persons are infected with lymphatic filaria, but TPE occurs in less than 0.5% of these. The risk of this disease in travelers is unclear, and most patients consist of foreign persons from endemic areas [bib_ref] Tropical pulmonary eosinophilia: a case series in a setting of nonendemicity, Boggild [/bib_ref].
---Drugs to be recommended---A First choice (same dose for adults and children) -Diethylcarbamazine, 2 mg/kg/3 times a day, 12 days * In cases of malayan filariasis, marked side effects, such as digestive symptoms, fever, lymphangitis/ lymphadenitis, and orchitis/epididymitis, may appear. Therefore, a half dose (1 mg/kg) should be administered 3 times a day for 12 days. -D. immitis D. immitis parasitize in the dog right ventricle and pulmonary artery, where mature female worms produce microfilaria that circulate in peripheral blood. Infection to humans is mediated by microfilaria-ingesting mosquitoes. D. immitis larvae in human subcutaneous tissue inserted by mosquito bite, some larvae migrate to the heart and die. Dead worms produce infarcts then they lodge in pulmonary vessels. There are few symptoms [bib_ref] Paragonimiasis: experimental and clinical experience with praziquantel in Korea, Rim [/bib_ref]. In patients with symptoms, thoracic pain, cough, bloody sputum, stridor, and fever have been reported. Typical chest X-ray findings include solitary coin lesions. In many cases, an abnormal shadow of the chest X-ray is indicated on a health checkup, and D. immitis infection is pathologically diagnosed from a tissue specimen extirpated under a tentative diagnosis of lung cancer. At this point, peripheral blood eosinophilia is rarely observed [bib_ref] Parasitic infections of the lung:a guide for the respiratory physician, Kunst [/bib_ref].
---Drugs to be recommended (same dose for adults and children)----As a diagnosis is made using pathological specimens in many patients, oral treatment is not necessary. -If necessary, diethylcarbamazine at 2 mg/kg should be orally administered 3 times a day for 12 days.
---Precautions for each drug---

##  praziquantel
In the Japanese package inserts, it is described that this drug at 40 mg/kg/day should be orally administered twice a day for 2 days for the treatment of paragominiasis. However, we recommend administration at 75 mg/kg/day (3 times a day) for 2e3 days based on Reference No. 400.
The incidence of side effects is low, but fever, abdominal discomfort, nausea, diarrhea, and headache are sometimes observed.
[fig] -: Executive summaryIf several bacterial cells differing one another in Gram staining and/or morphology are observed (polymicrobial infection), anaerobes may be involved. Polymicrobial infection commonly reflects microaspiration of oropharyngeal secretions into the lower airway. [/fig]
[fig] 2: MSSA Refer to the section "2.1 Community-acquired pneumonia---2.1.2 Definitive therapy---[12] MSSA (2) Hospital treatment" (p. 8). (3) S. pneumoniae Refer to the section "2.1 Community-acquired pneumonia---2.1.2 Definitive therapy---[1] S. pneumoniae (PC-susceptible) and [2] S. pneumoniae (PC-resistant)" (p.6). (4) Corynebacterium sp.VCM and TEIC should be administered, as described for MRSA. [/fig]
[fig] Figure 3: Differentiation of major childhood respiratory infectious diseases[189]. [/fig]
[fig] Figure 4: Causative microorganisms with respect to age in children with community-acquired pneumonia [190]. [/fig]
[fig] Figure 7: Increase in the number of macrolide-resistant M. pneumoniae strains[189]. [/fig]
[fig] Figure 8: Changes in the criteria for the drug susceptibility of Pneumococcus established by the Clinical and Laboratory Standards Institute (CLSI) [/fig]
[fig] 3: Admission (Severe, ICU) A First choices -PAPM/BP, intravenous drip, 20 mg/kg/3 times a day -MEPM, intravenous drip, 20 mg/kg/3 times a day -TAZ/PIPC, intravenous drip, 112.5 mg/kg/3 times a day * When legionellosis cannot be ruled out, one of the above regimens should be combined with a macrolide [With respect to the administration method/ [/fig]
[fig] Figure 9: Pulmonary complications after homologous hematopoietic stem cell transplantation[213]. [/fig]
[fig] 1: Community-acquired pneumonia---2..2 Definitive therapy" (p. 4) or "2.2 Hospital-acquired pneumonia---2.2.3 Definitive therapy" (p. 3). -If MRSA infection is suspected, antimicrobial drugs should be selected in accordance with the section "2.2 Hospital-acquired pneumonia---2.2.3 Definitive therapy---() MRSA" (p. 3). -Tuberculous pleuritis should be treated in accordance with the treatment of pulmonary tuberculosis (p. 42). [/fig]
[table] Table 8: [96] (II). A study reported that, even among severe NHCAP patients who were managed with a ventilator or in the ICU, resistant bacteria were Presence of a Severe Condi on Requiring Intensive Care, e.g., Mechanical Ven la onFig. 1. Recommendations of initial empiric antibiotic therapy [/table]
[table] modified: Old/acute cerebrovascular disorder Degenerative nervous and neuromuscular diseases, Parkinson's disease Consciousness disorder, dementia Gastroesophageal reflux, after gastrectomy (especially total gastrectomy), achalasia, scleroderma Being bedridden Laryngeal/pharyngeal tumors Oral abnormalities (tooth occlusion disorder, inadaptation of dentures, dry mouth) Tracheotomy, nasogastric tube (tubal feeding) Drugs that induce dry mouth, such as sedatives, sleeping pills, and anticholinergic drugsFig. 2. Diagnostic flow chart for aspiration pulmonary disorders [/table]