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223（ 9 ）A study on the management of
acute respiratory tract infection in adults
YOSHIHIRO YAMAMOTO1, MITSUHIDE OHMICHI2, AKIRA WATANABE3,
YOSHITO NIKI4, NOBUKI AOKI5, SHIN KAWAI6, KINGO CHIDA7,
KEIICHI MIKASA8, MASAFUMI SEKI9, TADASHI ISHIDA10,JUN-ICHI KADOTA11, HIROTO MATSUSE12, JIRO FUJITA13 and SHIGERU KOHNO141

Department of Clinical Infectious Diseases, Graduate School of Medicine andPharmaceutical Sciences for Research, University of Toyama
2
Ohmichi Clinic of Internal and Respiratory Medicine
3
Research Division for Development of Anti-Infective Agents, Institute ofDevelopment, Aging and Cancer, Tohoku University
4
Department of Clinical Infectious Diseases,
Showa University School of Medicine
5
Department of Internal Medicine, Shinrakuen Hospital
6
Department of Infectious Diseases, Division of Comprehensive Medical Care,
Kyorin University School of Medicine
7Internal Medicine, Hamamatsu-Toyooka Hospital
8
Center for Infectious Diseases, Nara Medical University
9
Division of Infection Control and Prevention, Osaka University Hospital
10
Department of Respiratory Medicine, Kurashiki Central Hospital
11
Department of Respiratory Medicine and Infectious Diseases,
Oita University Faculty of Medicine
12
Department of Respiratory Medicine, Toho University Ohashi Medical Center
13First Department of Internal Medicine, Faculty of Medicine,
University of the Ryukyus
14
Second Department of Internal Medicine, Nagasaki University Hospital(Received for publication May 26, 2014)

Antimicrobials are commonly used to treat acute respiratory tract infection in
DGXOWV)XUWKHUPRUHWKHLURYHUXVHKDVUDLVHGFRQFHUQ:HFRQGXFWHGD¿HOGVXUYH\
study that included 170 medical institutions from January 2008 to June 2010. The
purpose of this study was to clarify the relationship between the rate of antimicrobial
use and patient outcomes with each indication. The study included 1753 patientsdiagnosed with acute respiratory tract infection. Antimicrobials were used fortreatment of 1420 of these patients, whereas 333 cases were not treated with
antimicrobials. After 3 days of treatment, patients administered antimicrobials
experienced a higher improvement rate than those who did not receive antimicrobial224（ 10 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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treatment (92.2% vs. 83.3%, p＜0.0001). However, after 7 days of treatment, therates of improvement for patients in both groups were similar (95.0% and 93.4%,
respectively, p＝0.2391). In addition, according to the criteria for the usage ofantimicrobials described in the Japanese Respiratory Society guidelines for the
PDQDJHPHQWRIUHVSLUDWRU\WUDFWLQIHFWLRQLQDGXOWVWKHSDWLHQWVZHUHFODVVL¿HGLQWR
the 3 categories (6 indication factors for antimicrobial use): Grade 1, 侑2 factors;
Grade 2, 3–4 factors; Grade 3, 5–6 factors). The indication factors considered were
the following: 1) temperature; 2) purulent sputum or nasal discharge; 3) tonsillar
HQODUJHPHQW DQG WRQVLOOROLWKZKLWH SXVV   PLGGOH RWLWLVVLQXVLWLV   LQÀDPPDWRU\reaction; and 6) high-risk patients. The results indicate that the improvement
REVHUYHGDIWHUGD\VRIWUHDWPHQWLQ*UDGHDQG*UDGHSDWLHQWVZDVVLJQL¿FDQWO\higher with antimicrobial treatment than without antimicrobial treatment.
In conclusion, the administration of antimicrobials is not recommended in younger
patients with no underlying disease. However, the use of antimicrobials is requiredin patients with a higher relative risk that corresponds to the presence of 侒3 of the 6
indication factors for antimicrobial use.

Introduction
The Japanese Respiratory Society established the committee for the preparation of a guideline (GL) for respiratory organ infection in 1998, and published the basic policy on the treatmentof respiratory infection in the Japanese Respiratory Society guidelines for the management ofcommunity-acquired pneumonia in adults in March 20001), the Japanese Respiratory Society
guidelines for the management of hospital-acquired pneumonia in adults in March 20022), and theJapanese Respiratory Society guidelines for the management of respiratory tract infection in
adults in June 20033)7KHUHDIWHUWKHFRPPLWWHHSHUIRUPHGYDOLGDWLRQVWXGLHVRQWKH¿UVWWZR*/V
and published a revised version of the community-acquired pneumonia GL in 2005 (a pocketablecondensed version, and authenticated version in 2007)4) and hospital-acquired pneumonia GL in
20085) (a pocketable and authenticated version)—The GL for the management of respiratory tract
infection in adults—which remains the standard GL for treatment.
Antimicrobials often have little effect on the resolution of cold syndromes, since most arecaused by viruses. In addition, many studies describe the effect of facile utilization of antimicrobials in promoting the generation of resistant bacteria6,7). Patients with underlying diseases suchas malignant tumor or diabetes, in particular, are at risk of developing serious diseases if bacterial
infection is not considered. Hence, the treatment of acute respiratory tract infection by antimicrobials should not be ruled out8,9). Therefore, to identify an optimal therapeutic policy for the treatPHQWRIDFXWHUHVSLUDWRU\WUDFWLQIHFWLRQVZHSHUIRUPHGD¿HOGVXUYH\RQDQDWLRQDOSDWLHQWEDVH
and attempted to verify the GL for acute respiratory tract infection in adults.

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225（ 11 ）Patients and Methods
Subjects
Total of 170 medical institutions (Table 1) were participated from January, 2008 to June,
2010, and 2173 adult patients (aged 侒20 years) with one of following acute respiratory infections
such as 1) acute pharyngitis presenting acute sore throat, 2) acute tonsillitis presenting enlarged
tonsil and/or tonsillolith, or 3) acute bronchitis presenting prominent cough and/or sputum were
HQUROOHG7KHGLDJQRVLVZDVPDGHE\HDFKSULPDU\SK\VLFLDQEDVHGRQWKHGH¿QLWLRQGHVFULEHGLQ
the Japanese Respiratory Society guidelines for the management of respiratory tract infection in
adults in June 20033). Informed consent was acquired from all the patients prior to starting the research. After completion of therapeutic intervention, information related to the therapeutic process was collected for the survey. Items surveyed were as follows: patient background (bodyweight, height, age at start of therapy or date of birth, sex, inpatient/outpatient), disease information (underlying and complicating disease), medical agent used (therapeutic agent, prior-therapeutic agent, concomitant drugs, or concurrent medication), clinical improvement, bacteriologicaltest results, and adverse events of clinical intervention.
The patients with the following 6 indication factors for antimicrobial use were recruited: 1)
persistent high body temperature (侒3 days); 2) purulent sputum or nasal discharge; 3) tonsillar
HQODUJHPHQWDQGWRQVLOOROLWKDGKHVLRQRIZKLWHSXVV PLGGOHRWLWLVVLQXVLWLV VHYHUHLQÀDPmatory reaction (leukocytosis, C-reactive protein positive, or elevated erythrocyte sedimentationrate); 6) high-risk patients, as described in treatment policy of so called “cold syndromes” in“&KDSWHU9$FXWHXSSHUUHVSLUDWRU\LQÀDPPDWLRQ” in the Japanese Respiratory Society guidelines
for the management of respiratory tract infection in adults3). These six factors were evaluated byeach primary physician. (Grade 1, 侑2 factors; Grade 2, 3–4 factors; Grade 3, 5–6 factors) Risk
factors included the following: 1) older age (侒65 years); 2) underlying heart or respiratory disHDVHDQG GLDEHWHVUHQDOGLVHDVHRULPPXQRVXSSUHVVLRQ7KH¿QDOGHFLVLRQIRUWUHDWPHQWZLWK
antimicrobials was made by each primary physician, and the dosing period was set at 3–7 days,
depending on the patientʼs symptoms. In the statistical analysis, p values were calculated using a
FKLVTXDUHWHVWDQGWKHVLJQL¿FDQFHOHYHOZDVVHWDWS＝0.05.
Evaluation of clinical improvement
Clinical improvements were assessed on days 3 and 7 after starting therapy (hereafter, abbreYLDWHGDVGD\DQGGD\UHVSHFWLYHO\ $SULPDU\SK\VLFLDQMXGJHGLPSURYHPHQWE\FRQ¿UPLQJ
symptoms such as high temperature, sputum, nasal discharge, and tonsillar enlargement.
Exclusion criteria
The following patients were excluded from the study: patients with contraindications for an-Table 1. Participating institutions

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227（ 13 ）timicrobial use; patients with a medical or family history of allergy to any antimicrobial; patientswith poor oral intake or intake of parenteral nutrients; patients with severe renal diseases; and paWLHQWVZLWKLQÀXHQ]DRUDW\SLFDOSDWKRJHQLQIHFWLRQVMicrobiological test
Prior to starting treatment and on days 3 and 7, test specimens including sputum were collected from the patients in each medical institution and sent to a central medical institute for (DeSDUWPHQWRI/DERUDWRU\+RNXV\R&KXR+RVSLWDO VHSDUDWLRQLGHQWL¿FDWLRQRIEDFWHULDDQGGHWHUmination of colony count.

Results
Subjects
A total of 2173 patients were registered for this study. Of those patients, 420 with missing reFRUGVQRFOLQLFDOMXGJPHQWRURWKHUUHDVRQVZHUHH[FOXGHG$VDUHVXOWHI¿FDF\DQGVDIHW\RIDQtimicrobials were analyzed in 1753 patients. Table 2 shows the characteristics of the 1753 patients on intention-to-treat basis in the study. The medical institutions (170 facilities) were
FODVVL¿HGDVIROORZVFOLQLFVZLWKQRIDFLOLW\WRDGPLWSDWLHQWVRUZLWKDIDFLOLW\WRDGPLW 侑19
patients (GP), and 82 hospitals with a facility to admit 侒20 patients or (HP).
7KHSDWLHQWVZHUHFODVVL¿HGDFFRUGLQJWRWKHW\SHRIPHGLFDOLQVWLWXWLRQSDWLHQWVTable 2. Characteristics of the patients228（ 14 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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Aug. 2014(33.9%) were in HP, and 1158 (66.1%) were in GP. The primary diagnosis was acute pharyngitis
in 734 patients (41.9%), acute tonsillitis in 195 patients (11.1%), acute bronchitis in 715 (40.8%),
and others in 109 (6.2%). The number of patients treated with antimicrobials was 1420 (81.0%),
whereas 333 (19.0%) were not treated with antimicrobials. The use of antimicrobials is presented
E\PHGLFDOLQVWLWXWLRQDQGGLDJQRVLVLQ7DEOH7KHUDWHVRIWKHDQWLPLFURELDOXVHZHUHVLJQL¿cantly different between HP and GP at 73.6% and 84.8%, respectively (p＜0.0001). In particular,
WKHUDWHRIDQWLPLFURELDOXVHLQWKHWUHDWPHQWRISDWLHQWVZLWKDFXWHSKDU\QJLWLVZDVVLJQL¿FDQWO\different between HP and GP at 55.1% and 81.5%, respectively (p＜0.0001).
The number of patients with underlying disease or complicating disease was 769 (43.9%).
The comorbid diseases included respiratory diseases (31%), hypertension (18%), diabetes (6%),
dyslipidemia (5%), and others (40%). Concerning respiratory diseases, the proportion of patientswith bronchial asthma was the highest with 64%.
Table 3. Therapy contents by diagnosis※ p＜0.0001 by the chi-square test

Table 4. Clinical improvement and antimicrobials usage

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229（ 15 ）Clinical improvement and antimicrobial use
Table 4 compares the relationship between clinical improvement and the use of antimicrobials between groups. The clinical improvement rate was 92.2% on day 3 in patients treated with
antimicrobials, and 83.3% in patients not treated with antimicrobials (p＜0.0001). The clinicalimprovement rate on day 7 was similar between the groups (p＝0.2391). The major antimicrobials used were quinolones (43.4%), followed by cephems (36.8%) and macrolides (17.6%). The
improvement rate using macrolides was predicted to be slightly lower than those of other antimicrobials on day 3 (p＝0.0173) and day 7 (p＝0.0461).
Clinical improvement with each grade
7KHSDWLHQWVZHUHFODVVL¿HGLQWRWKUHHJUDGHVDFFRUGLQJWRWKHQXPEHURIIDFWRUVUHODWHGWR
diagnosis (6 indication factors for antimicrobial use). Table 5 presents the relative clinical improvement according to diagnosis grade.
Clinical improvement was noted in Grade 2 and Grade 3 patients treated with antimicrobials
on day 3 (p＜0.0001, p＝ 5HJDUGOHVVRIDQWLPLFURELDOXVHWKHUHZDVQRVLJQL¿FDQWGLIIHUence in the clinical improvement rate in Grade 1 patients on day 3 and Grade 1, 2, and 3 patientson day 7.
Bacteriological examination
Microbiological examination was performed for 92 patients, and 30 patients were comSOHWHO\H[DPLQHG8SRQ¿QDOSDWLHQWDVVHVVPHQWSDWLHQWVZHUHVXFFHVVIXOO\WUHDWHGWKUHHSDtients were not successfully treated. The isolated bacterial strains included Staphylococcus aureus, Streptococcus pneumoniae, and +DHPRSKLOXVLQÀXHQ]DH (including the BLNAR strain).

Table 5. Clinical improvement rate with each grade230（ 16 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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Adverse events
A total of 29 adverse events were reported in 24 patients (1.37%): 11 gastrointestinal sympWRPV QLQHSDWLHQWV ¿YHQHUYRXVV\VWHPHYHQWV ¿YHSDWLHQWV RQHGHUPDWRSDWK\ RQHSDWLHQW 
10 abnormal clinical laboratory test values (seven patients); and two other events (two patients).
There were no serious adverse events. Exception for 5 patients in whom antimicrobials were discontinued, no adverse events required special treatment.

Discussion
Most acute respiratory tract infections are caused by viruses; hence, antimicrobials are notused in treatment. TOMII et al. reported that the rate of antimicrobial usage was within 10% in paWLHQWVDJHG±\HDUVZLWKDFXWHXSSHUUHVSLUDWRU\LQÀDPPDWLRQDQGQRXQGHUO\LQJGLVHDVH,Q
addition, there was no difference in the satisfaction level between patients who were administeredantimicrobials and those who were not10). On the basis of the results of two clinical trials on antiLQÀXHQ]DGUXJV GRXEOHEOLQGFRPSDULVRQVWXG\ WATANABE11) suggested that approximately 10%of healthy adults and approximately 40% of high-risk patients developed secondary bacterial inIHFWLRQDWWKHWLPHRILQÀXHQ]DYLUXVLQIHFWLRQ7KHUHIRUHLQVXFKSDWLHQWVWKHDGPLQLVWUDWLRQRI
antimicrobials is required at an early stage. On the other hand, the number of patients diagnosed
in a medical institution is small when their symptoms are mild, which indicates that patients obtain medicines such as OTC from pharmacies for treatment at home, before consultation at a
medical institution12).
In the current study, we attempted to better elucidate issues surrounding the actual use of antimicrobials in adults with acute respiratory tract infection in medical institutions. Approximately
1420 patients (81% of the total patient population in this study) were administered antimicrobials,
and this number is higher than that in previous studies. The administration rates of antimicrobials
for acute tonsillitis and acute bronchitis did not differ between GP and HP. The administration
rate of antimicrobials for acute pharyngitis was higher in GP than in HP, and this is similar to thatreported in a previous study13).
6LJQL¿FDQWLPSURYHPHQWZDVREVHUYHGRQGD\LQWKHJURXSXVLQJDQWLPLFURELDOVFRPSDUHGZLWKWKDWLQWKRVHQRWWUHDWHGZLWKDQWLPLFURELDOV,QDGGLWLRQQRVLJQL¿FDQWGLIIHUHQFHREVHUYHG
LQFOLQLFDOLPSURYHPHQWZDVQRWHGRQGD\LQ*UDGHSDWLHQWV+RZHYHUVLJQL¿FDQWGLIIHUHQFHV
were observed in Grade 2 and Grade 3 patients. These results indicate the possibility of bacterial
LQIHFWLRQ +RZHYHU EHFDXVH WKHUH ZDV QR VLJQL¿FDQW GLIIHUHQFH LQ WKH FOLQLFDO LPSURYHPHQW RQ
day 7 between the groups, the bacterial infection was not very severe and patients might have recovered even if antimicrobials were not used. Other possible reasons are mild underlying diseases
and a mean age of approximately 50 years.
The indication of antimicrobials administration for acute respiratory tract infection is dis-Aug. 2014

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231（ 17 ）cussed from the both sides of cost and satisfaction of the patients. The result of this study indicates that the antimicrobials use is not essential for all Grade 2 and 3 patients. However, antimiFURELDOVDUHEHQH¿FLDODQGWKHLULQGLFDWLRQPLJKWEHFRQVLGHUHGLQHDFKFDVH,WLVGHVLUHGWKDWWKH
administration should be taken into consideration from multiple points of view and factors, which
acquired from better relationship between attending physician and patient based on good communication.
In conclusion, administration of antimicrobials is not recommended for the treatment of
acute respiratory tract infections in younger patients with no underlying disease. On the other
hand, it is needed for treatment of patients with 侒3 of the 6 indication factors for antimicrobialuse. A more detailed and proper clinical investigation using objective indices is warranted in the
future.
Acknowledgements
This clinical research investigation was a multicenter study in which the medical institutes
shown in Table 1 participated. The authors greatly thank the responsible physicians and physicians-in-chief at each medical institute for their collaboration.
7KHVWXG\ZDVIXQGHGE\WKHQRQSUR¿WRUJDQL]DWLRQ1DJDVDNL(YDOXDWLRQ2UJDQL]DWLRQIRU
Clinical Interventions (NEOCI) and Shionogi & Co., Ltd.

References
1) MATSUSHIMA, T.; S. KOHNO, A. SAITO, et al.: The Japanese Respiratory Society guidelines for the
management of community-acquired pneumonia in adults, 20002) MATSUSHIMA, T.; H. AOKI, S. KOHNO, et al.: The Japanese Respiratory Society guidelines for the
management of hospital-acquired pneumonia in adults, 2002
3) MATSUSHIMA, T.; H. AOKI, S. KOHNO, et al.: The Japanese Respiratory Society guidelines for the
management of respiratory tract infection in adults, 2003
4) KOHNO, S.; T. MATSUSHIMA, A. SAITO, et al.: The Japanese Respiratory Society guidelines for the
management of community-acquired pneumonia in adults, 2007
5) KOHNO, S.; A. WATANABE, K. MIKASA, et al.: The Japanese Respiratory Society guidelines for the
management of hospital-acquired pneumonia in adults, 2008
6) WATANABE, A.: Cold syndrome—To what extent, is antibacterial drug required? Infection Front 2:
8〜9, 2004
7) GONZALES, R.; J. G. BARTLETT, R. E. BESSER, et al.: Principles of appropriate antibiotic use for
DFXWHUHVSLUDWRU\WUDFWLQIHFWLRQVLQDGXOWVEDFNJURXQGVSHFL¿FDLPVDQGPHWKRGV$QQ,QWHUQ
Med. 134: 479〜486, 2001
8) ALAN, L. B.; A. G. MICHAEL, M. G. JACK, et al.: Practice guidelines for the diagnosis and management of group A streptococcal pharyngitis. Clin. Infect. Dis. 35: 113〜125, 2012
9) MIYAGI, S.: Special issue: Reconsidering of treatments of cold syndrome, ambulatory prescription
and guidance of self-medication. Clinics & Drug Therapy 13: 1009〜1012, 1994
10) TOMII, K.; Y. MATSUMURA, K. MAEDA, et al.: Minimal use of antibiotics for acute respiratory tract232（ 18 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

67―4

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infections: validity and patient satisfaction. Intern. Med. 46: 267〜272, 2007
11) WATANABE, A.: Application of use of antimicrobials to outpatients in the standard therapy—Coldsyndrome and bronchitis. J. Therapy 90: 2833〜2837, 200812) MIYATA, M.; Y. MURAKAMI & K. WATANABE: OTC drugs and self-medication. Kanahara & Co.,
Ltd., Tokyo: 41〜51, 201213) HIGASHI, T. & S. FUKUHARA: Antibiotic prescription for upper respiratory tract infection in Japan.
Intern. Med. 48: 1369〜1375, 2009