Recommendations for treatment of childhood non-severe pneumonia

WHO recommendations for early antimicrobial treatment of childhood pneumonia have been eff ective in reducing childhood mortality, but the last major revision was over 10 years ago. The emergence of antimicrobial resistance, new pneumonia pathogens, and new drugs have prompted WHO to assemble an international panel to review the literature on childhood pneumonia and to develop evidence-based recommendations for the empirical treatment of non-severe pneumonia among children managed by fi rst-level health providers. Treatment should target the bacterial causes most likely to lead to severe disease, including Streptoccocus pneumoniae and Haemophilus infl uenzae. The best fi rst-line agent is amoxicillin, given twice daily for 3-5 days, although co-trimoxazole may be an alternative in some settings. Treatment failure should be defi ned in a child who develops signs warranting immediate referral or who does not have a decrease in respiratory rate after 48-72 h of therapy. If failure occurs, and no indication for immediate referral exists, possible explanations for failure should be systematically determined, including non-adherence to therapy and alternative diagnoses. If failure of the fi rst-line agent remains a possible explanation, suitable secondline agents include high-dose amoxicillin-clavulanic acid with or without an aff ordable macrolide for children over 3 years of age.

# Introduction
Each year, clinical pneumonia occurs in an estimated 156 million children aged under 5 years, 1 and causes approximately a fi fth of all deaths among such children, most of whom are in low-income nations. 2 To reduce the morbidity and mortality of pneumonia in children, guidelines currently known as the Integrated Management of Childhood Illness (IMCI) have been developed by WHO and partners for fi rst-level health systems. IMCI has been implemented by many organisations and reduces mortality eff ectively, 3,4 although implementation can be improved. 5,6 These guidelines include recommendations for the case management of acute respiratory illness. They indicate when referral is needed and specify appropriate antimicrobial agents when referral is not needed. WHO recommendations for the treatment of pneumonia have provided critical guidance to fi rst-level health-care workers worldwide, but the last major revision is more than 10 years old. The fi rst WHO recommendations for respiratory disease case management were published in a 1981 WHO memorandum. The memorandum was aimed at encouraging a systematic approach to the management of children with possible pneumonia in resource-poor settings, based on simple algorithms and empirical treatment. Recommended agents included drugs available at the time of publication, with both intramuscular and oral drugs listed, such as procaine penicillin, ampicillin, erythromycin, co-trimoxazole, and sulfamethoxypyridazine, and noted that there was as yet little experience with co-trimoxazole. Second-line agents for use in children still ill after 48 h included chloramphenicol or oxacillin. WHO published a revised document in 1991, after much experience had been gained with the case-management approach and empirical treatment. For treatment of non-severe pneumonia at the fi rst-level health facility, this document recommended oral co-trimoxazole as the preferred agent, with injectable procaine penicillin and oral amoxicillin as alternatives. A 2005 technical update of the WHO IMCI guidelines recommended oral amoxicillin (50 mg/kg per dose, in two divided doses) or co-trimoxazole (8 mg/kg trimethoprim per dose, in two divided doses) for the treatment of non-severe pneumonia; 9 if antimicrobial resistance to co-trimoxazole was high, oral amoxicillin was preferred.
During the past decade, various organisations have issued recommendations for paediatric pneumonia treatment. 10-14 These recommendations are primarily intended for high-income to middle-income nations. New information on antimicrobial resistance, the changing epidemiology of pneumonia, and the availability of a broader range of fi rst-line and second-line antimicrobial agents provides the impetus for updated recommendations for antimicrobial treatment of nonsevere pneumonia among children assessed by fi rst-level health providers, often with basic health training.
The WHO Department of Child and Adolescent Health and Development selected and assembled this panel to review the current literature on childhood pneumonia and to defi ne further the most appropriate antimicrobial agents for treatment of non-severe pneumonia. Specifi cally, we were asked to defi ne the appropriate fi rstline antimicrobial agent, treatment failure, when to change therapy, and appropriate second-line antimicrobial agents.

# Methods
The international panel consisted of nine clinicians and researchers with experience in defi ning and treating Review pneumonia among children in various settings. We communicated by regular conference calls and by email. After reviewing the available evidence, we discussed issues such as interpretation of aetiological study results and antimicrobial resistance data. The initial focus was to identify appropriate fi rst-line and second-line antimicrobial agents for the empirical treatment of nonsevere pneumonia in children by fi rst-level health-care workers. However, we determined that to address secondline therapy, a defi nition of treatment failure and determination of when to change therapy were required (panel).

## Search strategy
A literature search was done to generate a foundation for recommendations. The results for appropriate fi rst-line and second-line antimicrobial agents (webtable) were similar those obtained by a Cochrane review. Evidence was collected with a focus on publications from January, 1991 (the date of the last recommendations) through September, 2008, by searches of PubMed, EMBASE, and the Cochrane Central Registrar of Controlled Trials, in addition to bibliographies of relevant articles and the author's records. Search terms were "pneumonia", "child", "childhood", "pediatric", "paediatric", "antibiotic", "trial", and "cohort", and was limited to available articles in English or an English abstract that included children with pneumonia under age 5 years in the study. For the selection of antimicrobial agents, 36 articles that assessed more than one antimicrobial agent and the seven articles that assessed diff erent durations or doses of antimicrobial agents by use of a randomised controlled trial were included in the review. Articles were excluded if no treatment failure data were available as an outcome or if they exclusively enrolled children with very severe pneumonia. If an article presented results of children with a spectrum of diagnosis (eg, sinusitis, otitis media, and pneumonia) only results for children with pneumonia were included, if possible. These articles provide the basis, along with the panel's experience, for the recommendations.

## Development of recommendations
Initial recommendations were drafted and then circulated to a broader group of reviewers for comment. The broader group included experts with experience in the treatment and epidemiology of pneumonia, as well as representatives from the WHO regional offi ces. [fig_ref] Table 1: Outline of recommendations [/fig_ref] outlines the recommendations developed, with strength of each major recommendation and the quality of supporting evidence based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The GRADE quality of evidence categories include high, intermediate, low, and very low, and was determined by the panel's review of the literature. The studies available for this review, with few exceptions, were observational in nature rather than blinded randomised trials, and therefore, the GRADE quality of evidence was rarely higher than intermediate. After the review by the broader group, the strength of each recommendation was determined by the panel members.

## Recommendation 1
Amoxicillin is the preferred initial antimicrobial agent for the treatment of non-severe pneumonia. The dose of amoxicillin is 50 mg/kg per day in two divided doses for a 3-day treatment course in areas with low HIV prevalence, and 5 days in areas of high HIV prevalence. In some situations, such as where local evidence clearly indicates infrequent resistance, co-trimoxazole (8 mg/kg trimethoprim in two divided doses) may be an acceptable alternative.

## Rationale and evidence summary
Pneumonia is, strictly speaking, a pathological diagnosis, determined by clinical means. Radiological consolidation is commonly used as a surrogate, but is often not feasible at fi rst-level health facilities. Review validated to identify children with specifi c treatment needs, 7 such as those needing antimicrobial therapy or referral to higher levels of care. Non-severe pneumonia is diagnosed in a child with cough or diffi culty breathing accompanied by tachypnoea, defi ned as a respiratory rate of at least 40 breaths per min in a child aged 12-59 months, or at least 50 breaths per min in an infant aged 2-11 months. Use of these criteria identifi es 80% of children with pneumonia who need antimicrobial therapy. 7 Children aged 2-59 months require immediate referral if they have signs of severe or very severe pneumonia (lower chest indrawing or central cyanosis), stridor when calm, or IMCI-defi ned danger signs (inability to drink or breastfeed, convulsions, persistent vomiting, lethargy, or unconsciousness). Children aged less than 2 months with pneumonia have, by defi nition, severe pneumonia due to their higher risk for mortality, and thus require referral. Identifi cation or prediction of the likely organisms that cause pneumonia is the most important step in determining appropriate antimicrobial therapy. Despite the importance of understanding the aetiology of pneumonia, few recent studies have been done in resource-poor settings, [bib_ref] Antimicrobial susceptibility patterns of Haemophilus isolates from children in eleven developing nations, Weinberg [/bib_ref] [bib_ref] The epidemiology of acute respiratory tract infection in young children: comparison of..., Selwyn [/bib_ref] or in areas with high HIV prevalence. [bib_ref] A trial of a 9-valent pneumococcal conjugate vaccine in children with and..., Klugman [/bib_ref] [bib_ref] Failure of standard antimicrobial therapy in children aged 3-59 months with mild..., Jeena [/bib_ref] The most useful studies that have been done generally use one of two approaches: vaccine probe methods or comprehensive diagnostic testing protocols.
Vaccine probe studies may provide the best possible estimates of pathogen-specifi c pneumonia burden because they are not limited by insensitive diagnostic testing practices. [bib_ref] Bacterial pneumonia vaccines and childhood pneumonia: are we winning, refi ning, or..., Obaro [/bib_ref] However, these studies are extremely costly and generally estimate only the role of vaccine-type strains of the pathogen and often focus on severe or hospitalised pneumonia cases. By contrast, studies that incorporate a wide range of diagnostic tests off er the possibility of detecting many pathogens. The diagnostic tests used, however, are often insensitive and sometimes not specifi c, which limits data quality. [bib_ref] Pneumonia research to reduce childhood mortality in the developing world, Scott [/bib_ref] Directly obtaining specimens from the site of infection by lung aspiration before antimicrobial administration, potentially a gold-standard approach in children, produces positive results in 62% of appropriately selected cases, according to a review of 13 studies. [bib_ref] Etiology of severe pneumonia in children in developing countries, Shann [/bib_ref] Although this approach produces a relatively high yield, it is limited to peripheral lobar pneumonias that may selectively decrease the yield of several pathogens and therefore may not be representative of all severe pneumonia.
The results of aetiological studies require cautious interpretation because estimates of the proportion of pneumonia caused by the diff erent pathogens do vary. The sensitivity of culture-based techniques for identifying bacteria is compromised by previous antimicrobial administration, which is often not assessed. If antimicrobial exposure before culture is common, the measured results in culture-based studies may signifi cantly underestimate those organisms that are sensitive to commonly prescribed antimicrobial agents, such as Streptococcus pneumoniae and Haemophilus infl uenzae, and overestimate organisms such as Staphylococcus aureus.
Although the limitations listed above are numerous, successful treatment ultimately depends on targeting the causative agents. Therefore, despite these limitations, Estimates based on proportion of radiographically confi rmed pneumonia prevented by vaccination with 7-valent and 9-valent vaccine (vaccine probe studies), [bib_ref] A trial of a 9-valent pneumococcal conjugate vaccine in children with and..., Klugman [/bib_ref] [bib_ref] Effi cacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal..., Cutts [/bib_ref] [bib_ref] The impact of a 9-valent pneumococcal conjugate vaccine on the public health..., Madhi [/bib_ref] and supported by lung aspiration studies [bib_ref] Etiology of severe pneumonia in children in developing countries, Shann [/bib_ref] Haemophilus infl uenzae 0-31% Increasing use of highly effi cacious vaccine against disease by H infl uenzae type b may decrease its role as a pathogen Non-type b may play a greater role in non-severe pneumonia than type b [bib_ref] Haemophilus infl uenzae pneumonia: type b or non-type b?, Shann [/bib_ref] Found to be a signifi cant cause of pneumonia in all vaccine probe studies, 29-31 except one, [bib_ref] Incidences of vaccine-preventable Haemophilus infl uenzae type b pneumonia and meningitis in..., Gessner [/bib_ref] and in lung aspiration studies [bib_ref] Etiology of severe pneumonia in children in developing countries, Shann [/bib_ref] Staphylococcus aureus 1-33% Presents clinically as a severe, necrotising pneumonia with rapid progression [bib_ref] Etiology of severe pneumonia in children in developing countries, Shann [/bib_ref] Non-typhoidal salmonellae 0-28% Bacteraemia may present with features consistent with a clinical diagnosis of pneumonia [bib_ref] Use of clinical syndromes to target antibiotic prescribing in seriously ill children..., Berkley [/bib_ref] [bib_ref] Nontyphoidal Salmonella infections of children in tropical Africa, Graham [/bib_ref] [bib_ref] Importance of enteric bacteria as a cause of pneumonia, meningitis and septicemia..., O&apos;dempsey [/bib_ref] Estimates are based on studies from tropical Africa [bib_ref] Use of clinical syndromes to target antibiotic prescribing in seriously ill children..., Berkley [/bib_ref] [bib_ref] Improvements in nutritional management as a determinant of reduced mortality from community-acquired..., Bahwere [/bib_ref] Associated with non-severe pneumonia in some malaria-endemic regions of Africa 34
Mycoplasma pneumoniae 5% Limited diagnostic capacities in low-income countries [bib_ref] Etiology and treatment of community-acquired pneumonia in ambulatory children, Wubbel [/bib_ref] [bib_ref] Etiology of childhood pneumonia: serologic results of a prospective, population-based study, Heiskanen-Kosma [/bib_ref] [bib_ref] The role of Chlamydia pneumoniae in acute respiratory tract infections in young..., Weber [/bib_ref] [bib_ref] Agacfi dan A. Role of Mycoplasma pneumoniae and Chlamydia pneumoniae in children..., Somer [/bib_ref] Proportion of pneumonia associated with infection increases with age, the greatest burden is in children aged >3 years [bib_ref] Epidemiology of severe pneumonia caused by Legionella longbeachae, Mycoplasma pneumoniae, and Chlamydia..., Phares [/bib_ref] Assumption that infections do not cause signifi cant morbidity or mortality lacks evidence to be either validated or invalidated [bib_ref] Pneumonia associated with infection with pneumocystis, respiratory syncytial virus, chlamydia, mycoplasma, and..., Shann [/bib_ref] [bib_ref] Chlamydial pneumonia in children requiring hospitalization: eff ect of mixed infection on..., Tsai [/bib_ref] Chlamydophila pneumoniae 3-10% Limited diagnostic capacities in low-income countries [bib_ref] Etiology and treatment of community-acquired pneumonia in ambulatory children, Wubbel [/bib_ref] [bib_ref] Etiology of childhood pneumonia: serologic results of a prospective, population-based study, Heiskanen-Kosma [/bib_ref] [bib_ref] The role of Chlamydia pneumoniae in acute respiratory tract infections in young..., Weber [/bib_ref] Proportion of pneumonia associated with infection increases with age, the greatest burden is in children aged >3 years [bib_ref] Epidemiology of severe pneumonia caused by Legionella longbeachae, Mycoplasma pneumoniae, and Chlamydia..., Phares [/bib_ref] Poor quality serological data for very young children [bib_ref] Antibody response to Chlamydia pneumoniae infection in children with respiratory illness, Kutlin [/bib_ref] Moraxella catarrhalis 0-9% Often not the focus of pneumonia microbiological studies [bib_ref] Reappraisal of lung tap: review of an old method for better etiologic..., Vuori-Holopainen [/bib_ref] Klebsiella pneumoniae 0-4% One study noted a higher proportion of 14% in children with previous antimicrobial use [bib_ref] Reappraisal of lung tap: review of an old method for better etiologic..., Vuori-Holopainen [/bib_ref] Rare exception in malnourished children 46

## Viral (9-64%)
Respiratory syncytial virus 1-39% Particularly important in young infants [bib_ref] Respiratory syncytial virus infection in tropical and developing countries, Weber [/bib_ref] Infl uenza viruses 0-22% Important cause throughout age range [bib_ref] Respiratory syncytial virus infection in tropical and developing countries, Weber [/bib_ref] Increasingly documented in the tropics [bib_ref] Global patterns in seasonal activity of infl uenza A/H3N2, A/H1N1, and B..., Finkelman [/bib_ref] Adenoviruses 0-54% Limited diagnostic testing and use of poor or insensitive tests [bib_ref] Respiratory syncytial virus infection in tropical and developing countries, Weber [/bib_ref] Parainfl uenza viruses 0-46% Occurrence in alternating years means that single-year studies have limited value [bib_ref] Seasonal trends of human parainfl uenza viral infections: United States, Fry [/bib_ref] Human metapneumovirus 2-8% Recent but well-documented cause of pneumonia [bib_ref] Human metapneumovirus as a cause of community-acquired respiratory illness, Stockton [/bib_ref] [bib_ref] Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and..., Williams [/bib_ref] [bib_ref] Human metapneumovirus-associated lower respiratory tract infections among hospitalized human immunodefi ciency virus..., Madhi [/bib_ref] [bib_ref] Human metapneumovirus infection in the United States: clinical manifestations associated with a..., Esper [/bib_ref] Others (including bocavirus, coronaviruses, and rhinoviruses)

## 4-30%
Recent PCR-based studies more consistently identify new viruses, but their signifi cance remains to be defi ned [bib_ref] Detection and typing by molecular techniques of respiratory viruses in children hospitalized..., Pierangeli [/bib_ref] [bib_ref] Human coronavirus infections in rural Thailand: a comprehensive study using real-time reverse-transcription..., Dare [/bib_ref] [bib_ref] Human bocavirus: a novel parvovirus epidemiologically associated with pneumonia requiring hospitalization in..., Fry [/bib_ref] *These estimates of aetiological burden have wide ranges. Variation may be real, due to increased proportions of aetiologies due to high HIV prevalence, as well as seasonal (eg, infl uenza) and geographical (eg, Salmonella) variability. However, the primary source of variability may be due to measurement, either enrolment criteria (hospitalised versus outpatient enrolment), inadequate diagnostic testing of blood cultures with low yield (eg, blood culture), or misclassifi cation (eg, urine antigen testing). Previous antimicrobial administration also may result in underestimation of some agents, and poor laboratory quality can also play an important part. [bib_ref] Microbial surveillance for Streptococcus pneumoniae in rural Thailand: lessons learned, laboratory capacity,..., Fischer [/bib_ref] Zero percentages (except in the case of Klebsiella) are often due to lack of diagnostic testing and the use of poor or insensitive tests, which are the important reasons for failure to consistently identify these pathogens, although in some cases true seasonal or geographical variations may contribute. Review estimates of the common pathogens that cause pneumonia in children are required to determine appropriate empirical antimicrobial therapy. Whereas these recommendations are for non-severe pneumonia, it is important to remember that aetiological studies usually enrol hospital inpatients with severe pneumonia. The common bacterial and viral causes of pneumonia pathogens are shown in table 2. Estimates include rather broad ranges of the plausible aetiological fractions. Most studies lack comprehensive investigation of viral causes of pneumonia, but in the studies that do provide such estimates, approximately 25% (range 9-64%) of pneumonia acquired in the community has a positive viral diagnostic test. [bib_ref] Human metapneumovirus as a cause of community-acquired respiratory illness, Stockton [/bib_ref] [bib_ref] Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and..., Williams [/bib_ref] [bib_ref] Human metapneumovirus-associated lower respiratory tract infections among hospitalized human immunodefi ciency virus..., Madhi [/bib_ref] [bib_ref] Human metapneumovirus infection in the United States: clinical manifestations associated with a..., Esper [/bib_ref] Identifi cation of a virus does not necessarily imply that the pneumonia is exclusively caused by that virus, because viral and bacterial agents may coexist, making the role of each pathogen uncertain. [bib_ref] Etiology of acute lower respiratory tract infections in Gambian children: I. Acute..., Forgie [/bib_ref] [bib_ref] Diagnoses of acute lower respiratory tract infections in children in Rawalpindi and..., Ghafoor [/bib_ref] [bib_ref] Etiology of acute lower respiratory tract infection in children from Alabang, Metro..., Tupasi [/bib_ref] [bib_ref] A role for Streptococcus pneumoniae in virus-associated pneumonia, Madhi [/bib_ref] These recommendations for non-severe pneumonia are limited by the lack of data on the causes of pneumonia among children treated outside hospital, as described above. However, an important goal of treatment for non-severe pneumonia is to prevent the progression to severe pneumonia. Therefore, directing antimicrobial therapy for non-severe pneumonia towards the pathogens known to cause severe pneumonia is believed to be appropriate.
Pathogens such as S pneumoniae and H infl uenzae are prominent treatable causes of severe pneumonia, and fi rst-line antimicrobial therapy has historically been directed primarily at these pathogens. An approach that targets these two aetiological agents has been repeatedly shown to be eff ective at reducing pneumonia morbidity and overall mortality through studies and clinical experience during the past 15 years. 3 Altering empirical fi rst-line treatment to better cover atypical agents, S aureus, non-typhoidal salmonellae, or others, might be considered on theoretical grounds based on the abovereferenced studies, but such an approach lacks evidence that it would reduce morbidity or mortality.
Many studies have compared the effi cacy of diff erent antimicrobial agents for treating pneumonia in children (webtable). However, despite the large number of studies, most are limited by small sample sizes, and lack the power to conclusively show non-inferiority. These studies are also hampered by the inability to accurately and consistently defi ne treatment failure, largely due to the limited resources available in the fi eld.
Interpretation is also limited by the so-called "Pollyanna phenomenon". In settings where an antimicrobial agent is compared with a standard agent, the potentially dangerous subset of bacterial cases that are the intended target of study are diluted by the inclusion of milder, selflimited, viral disease, which results in poor antimicrobial agents seeming to be more effi cacious, and superior antimicrobial agents seeming less effi cacious against the standard agent, as noted by Marchant and colleagues 62 in the setting of otitis media.
The lack of bacterial endpoints complicate our understanding of the clinical relevance of antimicrobial resistant for the management of pneumonia in the community. Our perceptions of the clinical relevance of amoxicillin, macrolide, and co-trimoxazole resistance for oral outpatient management of pneumonia are all based on the failure of these oral agents to eradicate resistant S pneumoniae from the middle ear. [bib_ref] Measuring the comparative effi cacy of antibacterial agents for acute otitis media:..., Marchant [/bib_ref] Although Straus and colleagues [bib_ref] Antimicrobial resistance and clinical eff ectiveness of co-trimoxazole versus amoxycillin for pneumonia..., Straus [/bib_ref] suggest that co-trimoxazole has a higher failure rate in severe pneumonia treatment than amoxicillin, the role of resistance was unclear, even though resistance has been the most frequently proposed explanation. A sub-analysis did not show a signifi cant increase in failure among co-trimoxazole-resistant S pneumoniae or H infl uenzae treated with co-trimoxazole. [bib_ref] Antimicrobial resistance and clinical eff ectiveness of co-trimoxazole versus amoxycillin for pneumonia..., Straus [/bib_ref] Few pneumonia studies have described the clinical impact of co-trimoxazole resistance on the treatment of pneumonia. [bib_ref] Response to cotrimoxazole in the management of childhood pneumonia in fi rst-level..., Noorani [/bib_ref] In-vitro resistance to co-trimoxazole correlates with poor clinical outcome in the treatment of these pathogens in acute otitis media. Trials of treatment for acute otitis media have measured bacteriological failures by use of tympanocentesis, comparing middle-ear fl uid cultures before and after therapy to show bacterial eradication with treatment. In one tympanocentesis study, [bib_ref] Bacteriologic and clinical effi cacy of trimethoprim-sulfamethoxazole for treatment of acute otitis..., Leiberman [/bib_ref] co-trimoxazole resistance resulted in higher rates of bacteriological failures for H infl uenzae and S pneumoniae. A caveat is that middle-ear fl uid concentrations of many drugs are substantially lower than comparable lung concentrations, and therefore antimicrobial agents used in therapy for acute otitis media may perform more poorly against strains with decreased susceptibility than antimicrobials used in pneumonia therapy. With this caveat, the available data suggest that in vitro co-trimoxazole resistance is meaningful in some clinical circumstances. This conclusion, if relevant for pneumonia, has important implications for countries where co-trimoxazole resistance is common.
First-line antimicrobial agents should be eff ective, reliable, widely available, and aff ordable in resource-poor settings. The 2005 technical update of the WHO IMCI guide lines recommended oral amoxicillin or co-trimoxazole as fi rst-line treatment for non-severe pneumonia because of their low cost and wide spectrum of coverage. Historically, co-trimoxazole and amoxicillin have been evaluated for the treatment of non-severe pneumonia. Two studies, both done in Pakistan, have compared amoxicillin to co-trimoxazole in children aged under 5 years. [bib_ref] Antimicrobial resistance and clinical eff ectiveness of co-trimoxazole versus amoxycillin for pneumonia..., Straus [/bib_ref] [bib_ref] Clinical effi cacy of co-trimoxazole versus amoxicillin twice daily for treatment of..., Catchup Study Group [/bib_ref] The absolute diff erence in treatment failure between children with treatment failure after taking co-trimoxazole relative to amoxicillin is illustrated in fi gure 1. The study by Straus and colleagues 63 included children with both severe and non-severe pneumonia, whereas the study by the CATCHUP (Co-trimoxazole Amoxicillin Trial in CHildren Under 5 years for Pneumonia) study group [bib_ref] Clinical effi cacy of co-trimoxazole versus amoxicillin twice daily for treatment of..., Catchup Study Group [/bib_ref] included only children with non-severe pneumonia.
The duration and dosage of amoxicillin therapy has been assessed and summarised in a WHO 2003 consultative meeting report.Two clinical trials in India and Pakistan examined 3-day (short) versus 5-day (standard) amoxicillin treatment courses for pneumonia and showed equal eff ectiveness of the two durations. [bib_ref] Clinical effi cacy of 3 days versus 5 days of oral amoxicillin..., Pakistan Multicentre Amoxycillin [/bib_ref] [bib_ref] Three day versus fi ve day treatment with amoxicillin for non-severe pneumonia..., Agarwal [/bib_ref] Shortened courses have not been as well studied in areas of high HIV prevalence, where a substantially greater burden of severe bacterial pneumonia among HIVinfected persons exists. Prudence indicates that shortening treatment to a 3-day course should be studied before being implemented in such settings. Variations of amoxicillin dose have not been well studied for the treatment of childhood pneumonia. One study of 836 children compared 3 days of amoxicillin in 45 mg/kg versus 90 mg/kg doses and did not show a signifi cant diff erence in treatment failure 5 days after initiation of therapy. 70

## Recommendation 2
Treatment failure is defi ned as the development of lower chest-wall indrawing, central cyanosis, stridor while calm, or IMCI-defi ned danger signs at any time during a child's illness or a persistently raised respiratory rate at 72 h (48 h in an area of high HIV prevalence).

## Rationale and evidence summary
Treatment failure was previously vaguely defi ned as "the same" (ie, a respiratory rate persistently above the ageappropriate IMCI cut-off ) or deterioration after 2 or 3 days of therapy. 8 Deterioration is development of chest indrawing, central cyanosis, stridor when calm or IMCI-defi ned danger signs. If the child does not deteriorate, these signs and symptoms are traditionally assessed at a scheduled follow-up visit 48 h after the initiation of therapy. However, on the basis of results of a study in Pakistan, 72 h may be acceptable in countries with low HIV prevalence. [bib_ref] Can WHO therapy failure criteria for non-severe pneumonia be improved in children..., Hazir [/bib_ref] These results should be replicated in other low-income countries, particularly those with high HIV prevalence. We believe that children who have a persistently raised respiratory rate and no indication for immediate referral should undergo a brief but systematic assessment to determine whether second-line therapy would be benefi cial.

## Recommendation 3
A brief but systematic assessment should be used for children who have failed therapy for non-severe Hospital assessment *Common agents may be responsible for at least a third of outpatient pneumonia treatment failures; uncommon agents may be responsible for a minor fraction; rare agents are probably responsible for only occasional treatment failures; globally uncommon agents may be common in certain geographic areas, although they are uncommon as causes for pneumonia treatment failure globally. Based on data from Heff elfi nger et al [bib_ref] Evaluation of children with recurrent pneumonia diagnosed by World Health Organization criteria, Heff Elfi Nger [/bib_ref] and discussions of the panel based on their clinical experience. Note that referral to the next level facility instead of a hospital may occasionally be appropriate, depending on the resources at the facility and the suspected condition.

## Rationale and evidence summary
The literature does not describe when treatment failure should prompt a change of therapy. Treatment failure may occur for many reasons, only one of which is use of a drug to which the infecting agent is not susceptible. Many of these reasons are described in table 3, and most require assessment in hospital and specifi c therapies. If a child develops signs indicative of the need for immediate referral, before or after treatment is initiated, they should be referred immediately. 7,9 We believe that children who fail to improve but do not require immediate referral should be systematically assessed before changing antimicrobial agents. This assessment can begin with the fi rst-level health worker determining whether failure is due to inability or unwillingness to take the medicine appropriately. If the health worker believes that the child has taken the antimicrobial agent correctly, other conditions resulting in treatment failure should be considered. If an initial assessment by the health worker indicates that these considerations are unlikely and referral is not warranted, a second-line agent should expand coverage. This assessment by the fi rst-level health worker may be guided by an algorithm. The effi cacy of algorithms has been shown in the assessments of initial case management by acute respiratory illness guidelines. 3,4,7 However, we are not aware of any studies that show the effi cacy of an algorithm that systematically assesses a child who does not improve after therapy. [fig_ref] Figure 2: Example algorithm of how to systematically assess children aged >2 months and... [/fig_ref] shows an example of an algorithm developed by us, which aims to be simple for health workers to use accurately and consistently. It addresses the major causes of treatment failure, but is not a validated tool, and is off ered here purely as an example.

## Recommendation 4
In the setting of fi rst-level health providers, children initially treated with amoxicillin who have a persistently raised respiratory rate and no indication for referral should receive high-dose amoxicillin with clavulanic acid (80-90 mg/kg per day amoxicillin) for second-line therapy to provide coverage for the major pathogens likely to cause severe disease. A 5-day treatment course should be prescribed for the second-line antimicrobial agents. For children over 3 years of age, an aff ordable macrolide or azalide (eg, 50 mg/kg erythromycin in four divided doses for 7 days) may be added to the existing regimen for a 5-day or 7-day treatment course. For children failing fi rst-line treatment with co-trimoxazole, the recommendation is to switch to a 5-day course of amoxicillin (50 mg/kg).

## Rationale and evidence summary
We defi ne second-line antimicrobial agents as those that are used in the setting of treatment failure when no indication for immediate referral is present (ie, IMCI danger signs, lower chest indrawing, stridor, or central cyanosis) and other reasons for treatment failure have been excluded. No studies were identifi ed that assessed second-line antimicrobial agents; therefore, second-line antimicrobial agents should logically be selected to treat organisms that fail fi rst-line therapy. Whereas a substantial proportion of failures of fi rst-line agents may be due to mild and self-limited viral infections, the second-line agent should ensure coverage of resistant organisms and cover a broader range of organisms that would not be treated with typical fi rst-line agents; in some settings, coverage may be extended to include S aureus or non-typhoidal salmonellae.
A second-line antimicrobial agent should broaden or enhance coverage in the setting of treatment failure. Our recommendations on the best second-line anti microbial If Integrated Management of Childhood Illness guidelines have been followed, the child should have been assessed for malnutrition and HIV in settings with high prevalence. This fi gure is off ered only as an example of such an algorithm that can be developed. *yyy=multiple trials with strong trial evidence, yy=some trials with good evidence, y=minimal trials and evidence. Pharmacokinetic/pharmacodynamic (PK/PD) properties are used to help determine the susceptibility breakpoints of antimicrobial agents and therefore the agent's likely effi cacy. PK/PD properties for drug classes are as follows: aminopenicillins, penicillins, and cephalosporins=time above minimum inhibitory concentration (MIC) 40%; macrolides and fl uoroquinolones=area under the curve/MIC above 30. Costs for non-oral medications do not include administration, syringe, or needle costs. Treatment course was 5 days and dose was based on a 10 kg child, except intramuscular penicillin and ceftriaxone, for which cost includes only the drug cost and does not include needles and administration. Although drug cost may be a critically important consideration, it may be acceptable for a second-line antimicrobial agent to be more expensive than fi rst-line agents. Treatment course prices of US$050, $1, and $2 were used as cut-off s to assess agent's acceptability [fig_ref] Table 4: Antimicrobial agents used for treatment of community-acquired pneumonia [/fig_ref]. Appropriate second-line agents must enhance coverage not already provided by the fi rst-line agent. Parenteral antimicrobial agents are often used in hospital settings, but are rarely used in outpatient clinics in low-income countries. The perception by some patients and providers that parenteral agents are always more eff ective than oral agents can be diffi cult to correct. Therefore, introduction of a parenteral antimicrobial agent such as ceftriaxone to peripheral settings may be impractical for these and other reasons in most situations.

## Review
If a child was initially taking co-trimoxazole at the correct pneumonia treatment dose, the preferred secondline agent would be oral amoxicillin at 50 mg/kg in two divided doses for 5 days. If the fi rst-line agent was amoxicillin, the second antimicrobial agent choice should expand the spectrum or enhance coverage. Use of highdose amoxicillin-clavulanic acid (80-90 mg/kg daily of divided doses of amoxicillin with a maximum of 64 mg/kg clavulanic acid daily) is another possibility to enhance activity against beta-lactamase-producing H infl uenzae and resistant S pneumoniae, but would not cover atypical bacteria.
Most oral second-generation and third-generation cephalosporin antimicrobial agents are more expensive, but have improved coverage against beta-lactamaseproducing H infl uenzae. Cefuroxime and cefi xime are reasonably priced, although they are not as active as highdose amoxicillin-clavulanic acid against S pneumoniae. [bib_ref] Antimicrobial resistance among pediatric respiratory tract infections: clinical challenges, Jacobs [/bib_ref] In addition, these agents do not provide coverage for M pneumoniae or C pneumoniae.
Oral chloramphenicol palmitate is a less desirable second-line agent for non-severe pneumonia. This antimicrobial agent is bacteriostatic against a wide range of potential pathogens and bactericidal against most S pneumoniae and H infl uenzae, although there is some resistance to chloramphenicol. Bone-marrow toxicity includes reversible, dose-dependent suppression, as well as aplastic anaemia, the latter occurring in approximately one in 24 500 to 40 000 courses. [bib_ref] Chloramphenicol: a review of its use in clinical practice, Feder [/bib_ref] [bib_ref] Prescribing practices and attitudes toward giving children antibiotics, Paluck [/bib_ref] Although chloramphenicol is active against a wide range of causal agents and is inexpensive, the potential for bone-marrow toxicity limits its use as a fi rst-line agent and as a universal second-line agent. Some panel members expressed reservations about this agent because of safety concerns with its use as an oral agent for mild disease in the outpatient setting. Also important are concerns about driving resistance in settings where parenteral chloramphenicol may be the sole agent to treat meningococcal meningitis. Oral chloramphenicol may be useful in children if intramuscular antimicrobial agents are not available and immediate transportation to a higher level of care, such as a hospital, is not possible.
Although tetracycline is the appropriate drug for the treatment of some paediatric infections, the small risk of associated side-eff ects outweigh the potential advantages of widespread use of the drug for non-severe pneumonia treatment. Similarly, the respiratory fl uoroquinolones are not optimum second-line drugs for outpatient pneumonia because of the theoretical risk of toxic eff ects in young children, as well as the measurable risk of promoting resistance to this valuable class of antimicrobial agents.
Azithromycin, clarithromycin, and erythromycin are reasonably priced, but the role of these agents is limited to extending the antimicrobial spectrum to atypical organisms, because these agents are relatively inactive against H infl uenzae and there is increasing resistance among S pneumoniae. [bib_ref] Antimicrobial resistance among pediatric respiratory tract infections: clinical challenges, Jacobs [/bib_ref] Therefore, an aff ordable macrolide or azalide may be considered for a child who is not better but not worsening at time of re-assessment and is over 3 years of age, when these atypical infections are more likely. Erythromycin may be used in three or four divided doses for a 5-day treatment course at a daily dose of 40 mg/kg. [bib_ref] Etiology and treatment of community-acquired pneumonia in ambulatory children, Wubbel [/bib_ref] Advantages of erythromycin over azithromycin or clarithromycin include low-cost and wide availability and disadvantages include gastrointestinal disturbance and frequent dosing. Macrolides or azalides are also indicated for those who have a documented allergy to penicillin or other beta-lactam agents. Co-trimoxazole was not considered as a secondline agent because co-trimoxazole resistance in S pneumoniae often co-exists with penicillin resistance, and, if the fi rst-line agent used was amoxicillin, the addition of co-trimoxazole would probably not be of benefi t.
These general recommendations may need to be modifi ed for children living in areas where HIV or malaria are common, or if referral is not possible.

## Review
Countries introducing algorithms for empirical use by fi rst-level health workers should identify such areas and consider modifi cation of the recommendations.

## Areas with a high prevalence of hiv
Special attention is required in regions where HIV prevalence has consistently exceeded 5% in at least one defi ned subpopulation, as is the case in much of eastern, central, and southern Africa, and certain regions of Asia and Latin America. In these high prevalence areas, HIV counselling and testing is recommended for all children aged under 10 years seen in paediatric health services.The burden of HIVassociated pneumonia in such regions is substantial. One study in an area with an HIV-positive prevalence of 5% among children aged under 5 years reported that 45% of hospitalised pneumonia and 85% of pneumonia deaths occurred among HIV-positive children. [bib_ref] Increased burden of respiratory viral associated severe lower respiratory tract infections in..., Madhi [/bib_ref] Prophylactic co-trimoxazole has been shown to improve survival and to reduce pneumonia-related deaths in HIV-infected children and should therefore be administered. [bib_ref] Co-trimoxazole as prophylaxis against opportunistic infections in HIV-infected Zambian children (CHAP): a..., Chintu [/bib_ref] Children presenting with pneumonia should be assessed for symptomatic HIV infection in areas where HIV is a public-health problem and should be tested if indicated by use of methods such as that described by Horwood and colleagues. [bib_ref] Diagnosis of paediatric HIV infection in a primary health care setting with..., Horwood [/bib_ref] For children living in areas of high HIV prevalence, or who have clinical suspicion or a diagnosis of HIV infection, and who present with nonsevere pneumonia, the recommended treatment is amoxicillin, irrespective of co-trimoxazole prophylaxis status. Pneumocystis jirovecii is known to be a cause of severe, progressive pneumonia, especially among children aged 2-6 months, 84 but its role in non-severe pneumonia in HIV-infected children was not evaluated as part of this review. If such a child fails fi rst-line therapy for non-severe pneumonia, the child should be referred to hospital for management by WHO guidelines,including HIV testing and broad-spectrum parenteral antimicrobial agents. Finally, children in high prevalence areas without clinical suspicion or a diagnosis of HIV infection who fail to improve on fi rst-line therapy should be treated according to the standard recommendations outlined in this review.

## Malaria-endemic areas
The clinical overlap between malaria and pneumonia in children is well recognised. [bib_ref] Usefulness of clinical case-defi nitions in guiding therapy for African children with..., Redd [/bib_ref] Symptomatic malaria may have clinical features consistent with a diagnosis of pneumonia, whereas children with pneumonia may have co-incidental malaria parasitaemia. [bib_ref] Overlap in the clinical features of pneumonia and malaria in African children, O&apos;dempsey [/bib_ref] Co-trimoxazole therapy for non-severe pneumonia was recommended in some countries where malaria diagnosis was unavailable at fi rst-level facilities, in part because co-trimoxazole has some activity against both malaria and common bacterial causes of pneumonia in children. [bib_ref] Co-trimoxazole for childhood febrile illness in malaria-endemic regions, Bloland [/bib_ref] [bib_ref] Effi cacy of trimethoprim-sulfamethoxazole compared with sulfadoxine-pyrimethamine plus erythromycin for the treatment..., Hamel [/bib_ref] However, co-trimoxazole is not a fi rst-line anti-malaria drug, and amoxicillin, which does not have anti-malarial activity, is now preferred to co-trimoxazole as fi rst-line therapy for non-severe pneumonia. Therefore, if a child has clinical features of non-severe pneumonia but malaria cannot be excluded, the recommended fi rstline therapies for malaria and pneumonia should both be prescribed. Caution should be exercised in the use of erythromycin as a second-line agent if mefl oquine or halofantrine are prescribed for malaria, due to the increased the risk of arrhythmia.
A complication of malaria is severe anaemia that, like pneumonia, can cause rapid breathing. In malariaendemic regions, children presenting with rapid breathing should be assessed for severe anaemia. If laboratory assessment is not available, marked pallor may be assessed by examining the palms of the hands, nail beds, and conjunctivae. Any child with a clinical diagnosis of pneumonia who also has severe anaemia should be referred to hospital for assessment.

## Areas where referral is not possible
A child who fails treatment and meets criteria for referral should be transported to and assessed at a centre that can provide more intensive therapy. However, referral is impossible in some areas. In these situations, the child should receive treatment with agents that provide broader coverage and high activity against pathogens that cause severe pneumonia. These antimicrobial agents include injectable antimicrobial agents such as ceftriaxone, penicillin/gentamicin, or chloramphenicol.

# Conclusions
The WHO-recommended systematic case-management approach has greatly reduced the mortality of children with pneumonia. These updated recommendations, now identifying amoxicillin as the preferred fi rst-line agent and specifying the approach to changing to an appropriate second-line agent in the event of treatment failure (table 1), aim to improve treatment protocols for fi rstlevel health providers for children with non-severe pneumonia. These recommendations were developed by use of the available evidence for the treatment of children with pneumonia in low-income countries. The evidence basis for some of the recommendations was limited, and more research is needed in several areas. These areas include an improved understanding of the aetiology of pneumonia in children, both severe and non-severe, using optimum diagnostic testing, a better understanding of the reasons for treatment failure, and the determination of the best systematic method for the assessment of treatment failure by fi rst-level health workers. In the meantime, adaptation of these general recommendations to fi t country-specifi c treatment algorithms should help to resolve some of the uncertainty surrounding the appropriate management of young children with nonsevere pneumonia.

## Search strategy and selection criteria
These are described in detail in the Methods section.

## Review

## Confl icts of interest
We declare that we have no confl icts of interest.
[fig] Figure 1: Absolute percentage diff erence in treatment failure among children with pneumonia treated with co-trimoxazole versus amoxicillin Analysis of two studies done in Pakistan and their pooled results given with 95% CIs. Straus et al 63 showed a signifi cant diff erence in the proportion of children with severe pneumonia who were treatment failures from 33% failing co-trimoxazole to 18% failing amoxicillin. The CATCHUP group 66 showed 19% of children failing co-trimoxazole and 16% failing amoxicillin. [/fig]
[fig] Figure 2: Example algorithm of how to systematically assess children aged >2 months and <5 years, initially diagnosed and treated with non-severe pneumonia and who returned for follow-up, in low HIV prevalence settings, based on the experience and recommendations of the panel This assessment is intended to supplement and not to replace the clinical judgment of the fi rst-level health worker. [/fig]
[table] Table 1: Outline of recommendations [/table]
[table] Table 2: Common pathogens that cause pneumonia in otherwise healthy children aged 2-59 months [/table]
[table] Table 3: Potential reasons for treatment failure for WHO-defi ned pneumonia at 72 h and possible solutions [/table]
[table] Table 4: Antimicrobial agents used for treatment of community-acquired pneumonia [/table]