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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Background
  5. Objective
  6. Methods
  7. Results
  8. Discussion
  9. Implications for Practice
  10. Implications for Research
  11. Acknowledgements
  12. Declarations of Interest
  13. References

Background

Globally, pneumonia is the leading cause of death among children and also results in significant morbidity. The most common treatment options include anti-pyretics and antibiotics. Other treatments include vitamins and over-the-counter cough syrup.

Objective

This overview presents a summary of the results of previous Cochrane reviews on the treatment of community acquired pneumonia (CAP) in children.

Methods

The Cochrane Database of Systematic Reviews was searched for all systematic reviews examining the treatment of pediatric pneumonia or lower respiratory tract infections. All reviews that were under the heading “pneumonia” on the Cochrane Acute Respiratory Infections (ARI) Group's Topic List and the ARI group were consulted. Data were extracted and entered into tables; data were synthesized using qualitative and quantitative methods.

Main Results

Eight reviews and one protocol were identified and data were available from seven reviews. Azithromycin and amoxicillin-clavulanate appeared to be equivalent for CAP in developed countries. In comparing beta-lactams, one small low-quality trial showed a higher cure rate with amoxicillin-clavulanate than with amoxicillin. In comparing macrolides, the efficacy of azithromycin, clarithromycin, and erythromycin appeared to be equal. Azithromycin was better tolerated than was amoxicillin-clavulanate. For CAP in developing countries, the failure rate was lower for amoxicillin than for co-trimoxazole. Initial therapy with oral or parenteral antibiotics were equivalent in children with non-severe pneumonia. A 3-day course of amoxicillin or of co-trimoxazole had an equivalent clinical cure rate, treatment failure rate and relapse rate when compared to a 5-day course. Inconsistent outcomes were shown in studies of vitamin A for therapy of non-measles pneumonia. There were insufficient children in the studies of over-the-counter medications for cough in children with pneumonia to reach meaningful conclusions.

Conclusions

Although thousands of children have been enrolled in trials of CAP treatments, limited conclusions can be reached about the ideal treatment, route and duration in developed or developing countries and for children of various ages. The primary reason for this is the multitude of interventions studied in diverse populations. Another major problem is that the diagnosis of pneumonia was often clinical rather than radiographic—often by necessity in developing countries. Even when pneumonia was diagnosed radiographically, differentiating viral from bacterial pneumonia was often not practical. Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. The Cochrane Collaboration


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Background
  5. Objective
  6. Methods
  7. Results
  8. Discussion
  9. Implications for Practice
  10. Implications for Research
  11. Acknowledgements
  12. Declarations of Interest
  13. References

Overview of reviews, compiling evidence from multiple Cochrane reviews into one accessible and usable document, will be a regular feature of this journal. Our aim for each overview is to focus on the treatment question, “which treatment should I use for this condition?”, and to highlight the Cochrane reviews and their results in doing so. It is our hope that the overviews will serve as a “friendly front end” to the Cochrane Library, allowing the reader a quick overview (and an exhaustive list) of Cochrane reviews relevant to the clinical decision at hand.

Background

  1. Top of page
  2. Abstract
  3. Introduction
  4. Background
  5. Objective
  6. Methods
  7. Results
  8. Discussion
  9. Implications for Practice
  10. Implications for Research
  11. Acknowledgements
  12. Declarations of Interest
  13. References

Community acquired pneumonia (CAP) is a common infection acquired outside of a hospital setting among previously healthy individuals1. In low income countries, the annual incidence of clinical pneumonia is estimated to be 0.29 episodes per child, or 150.7 million new cases, of which 11 to 20 million require hospitalization2. Each year, approximately 2 million children under the age of 5 years die from pneumonia in developing countries3, 4, 5, making it the leading cause of death in this age group6 and resulting in more deaths than human immunodeficiency virus (HIV), malaria and measles combined7. In this same age group, pneumonia is responsible for 19% of all deaths and 8% of disability adjusted life years worldwide8. Pediatric pneumonia also remains a serious problem in developed countries; in the United States, pneumonia results in the greatest number of infection related deaths and is the sixth most common cause of death in children9.

Description of the condition

Pneumonia is usually caused by viral or bacterial infection of the lung tissue, resulting in inflammation and exudates within the bronchial and alveolar airspaces. This infection is especially life threatening for children versus adults because their air passages are narrower and thus less able to tolerate inflammation or secretions.

In high income countries the major causes of bacterial pneumonia in children beyond the neonatal period are thought to be Streptococcus pneumoniae and Mycoplasma pneumoniae with there being less data from developing countries. It is vital to consider the possibility of tuberculosis in appropriate settings, as this disease will not respond to management aimed at other causes of pneumonia. Influenza and respiratory syncytial virus (RSV) are thought to be the most common causes of viral pneumonia10. Even in developed countries, the etiologic agent of pneumonia often remains unclear11, 12. Although molecular testing of upper respiratory tract specimens (typically a nasopharyngeal aspirate or swab) has revolutionized the diagnosis of viral pneumonia12, there are undoubtedly etiologic viruses we do not yet know to test for. Diagnosis of the etiologic agent of typical bacterial pneumonia is complicated by the fact that unless the blood culture is positive, a lower respiratory tract specimen is most accurate for testing and such specimens are obtained only in very severe cases, and even then, often after the patient has received antibiotics. The sensitivity and specificity of serology and of molecular testing of upper or lower respiratory tract specimens for the common agents of atypical bacterial pneumonia (M. pneumonia and Chlamydia pneumoniae) is not yet certain13.

Description of the interventions and rationale for their use

Hypoxic children should be admitted to hospital for oxygen treatment; a threshold of oxygen saturation of approximately 92% is commonly recommended11. Despite the recognition that a large proportion of CAP is viral, antibiotics are a common treatment choice, especially in countries where viral studies, chest radiographs and bloodwork are not readily available so a bacterial etiology must be assumed rather than proven14. The World Health Organization (WHO) recommends treating non-severe suspected pneumonia in children 2 months to 5 years of age in developing countries with co-trimoxazole for 5 days and more severe disease with oral amoxicillin or with intramuscular ampicillin or penicillin for 7 days, reserving chloramphenicol for children with “danger signs”15, 16. However, there is increasing pneumococcal resistance to these drugs worldwide17. Guidelines for antibiotics for suspected bacterial pneumonia in developed countries vary widely, but commonly recommend emphasizing pneumococcal coverage in all age groups but covering for M. pneumoniae in children over age 4 years11.

Vitamin A deficiency is a problem in developing countries; increasing vitamin intake may prevent or treat pneumonia by acting as an antioxidant or by altering immunological function2.

Other interventions are intended to relieve symptoms rather than to hasten recovery. Over the counter (OTC) cough syrups are used to suppress cough symptoms; however suppressing the cough reflex could theoretically prolong pneumonia symptoms by trapping airway debris19. Anti-pyretics are commonly used but have not specifically been studied in pediatric CAP.

Why it is important to do this review

Optimal treatment needs to be determined to reduce morbidity and mortality associated with this common respiratory disease. Determining the best treatment could reduce pneumonia-related costs and prevent drug resistance resulting from use of incorrect or unnecessary antibiotics20.

Objective

  1. Top of page
  2. Abstract
  3. Introduction
  4. Background
  5. Objective
  6. Methods
  7. Results
  8. Discussion
  9. Implications for Practice
  10. Implications for Research
  11. Acknowledgements
  12. Declarations of Interest
  13. References

This overview presents a summary of the results of previous Cochrane reviews on the treatment of community acquired pneumonia.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Background
  5. Objective
  6. Methods
  7. Results
  8. Discussion
  9. Implications for Practice
  10. Implications for Research
  11. Acknowledgements
  12. Declarations of Interest
  13. References

Search strategy

The Cochrane Database of Systematic Reviews was searched for all systematic reviews examining the treatment of pediatric pneumonia or lower respiratory tract infections with clinical or radiographic pneumonia. Two clinicians on our team examined all of the reviews that were under the heading “pneumonia” on the Cochrane Acute Respiratory Infections (ARI) Group's Topic List. We also consulted with the ARI group to ensure that no relevant reviews had been missed. By this means, we found eight reviews and one protocol examining pneumonia and/or lower respiratory tract infection treatments. Reviews that included both pediatric and adult trials were included, providing the pediatric results could be extracted. A protocol that studied the efficacy of zinc did not contain any data21 and a review of vitamin C for the treatment and prevention of pneumonia did not identify any treatment trials among children22. Therefore only seven systematic reviews were included.

Description of the Cochrane reviews identified

Criteria for including studies in the reviews

This overview includes Cochrane reviews that analyzed studies of treatments of childhood pneumonia using drugs included in the WHO Model List of Essential Medicines for Children23 and azithromycin and clarithromycin as these drugs are commonly used for CAP in developed countries. The individual reviews are described in Table 1. Four of the seven reviews included RCTs1, 14, 18, 19 while the other three reviews also included quasi-randomized trials2, 24, 25. Five reviews included only pediatric populations: two included children less than 18 years of age14, 18, one included children less than 15 years of age2, and two included children less than 5 years of age1, 24. Results for children less than 18 years of age were extracted from the other two reviews 19, 25.

Table 1. Characteristics of included reviews
TitleAuthorsDate of most substantive amendmentNumber of studiesStudy sample size rangePopulation developing vs developed countryDefinition of pneumoniaInterventionControlOutcomes
  1. LOS: length of stay; LRTI: lower respiratory tract infection.

Short-course versus long-course antibiotic therapy for non-severe community-acquired pneumonia in children aged 2 months to 59 months1Haider BA, Saeed MA, Bhutta ZASept 200731095–2188Children aged 2–59 months Developing countriesNon-severe community-acquired pneumoniaShort-course treatment of the same antibiotic for three daysLong-course treatment of the same antibiotic for five daysPrimary: Clinical cure rate (return to age-specific respiratory rate)
          Secondary: Treatment failure (indrawing, convulsions, drowsiness, inability to rink, high respiratory rate, O2SAT < 90%, loss to follow-up or withdrawal)
         Relapse rate within 7 days
         Additional interventions
         Morality at 1 month
Vitamin A for non-measles pneumonia in children2Ni J, Wei J, Wu TAug 2007639–687Children < 15 years and hospitalized Developing countriesNon-measles pneumonia (clinical case, radiological, or both)Vitamin A and standard treatmentPlacebo and standard treatmentPrimary: Mortality during hospitalization
         Secondary: Signs of pneumonia Clinical severity (O2SAT, mechanical ventilation, supplemental O2, crepitations, bronchial breathing, LOS, change in antibiotics, failure of first-line treatment)
         Adverse events
Over-the-counter (OTC) medications to reduce cough as an adjunct to antibiotics for acute pneumonia in children and adults19Chang CC, Cheng AC, Chang ABJuly 20074 (1 study examining only children)120Children and adults Developed countriesCough of < 4 weeks related to pneumoniaOTC cough medicine and antibioticsPlacebo and antibioticsPrimary: Not cured or substantially improved at follow-up
         Secondary: Not cured at follow-up Change in quantitative differences in cough (frequency, score, cough diary)
         Adverse events Complications
Antibiotics or community acquired pneumonia in children14Kabra SK, Lodha R Pandey RMMay 20062085–1702Children < 18 years treated in hospital or an ambulatory basis Countries not reportedWHO defined or radiologically confirmed CAPAntibioticAntibioticPrimary: Clinical cure (symptom and clinical recovery at the end of treatment)
         Secondary: Treatment failure rate (chest indrawing, convulsions, drowsiness, inability to drink, high respiratory rate, O2SAT, loss to follow-up or withdrawal)
         Relapse rate (pneumonia or severe disease within 14 days)
         Hospitalization rate LOS Complications (additional antibiotics, IV, mortality)
Oral antibiotics vs parenteral antibiotics for severe pneumonia in children24Rojas MX, Granados Rugeles CJune 20054 (1 study indentified by authors as ongoing and now published)131-1702Children aged 3–59 months Developing countriesSevere pneumoniaOral antibioticsParenteral antibioticsPrimary: Absence or persistence of respiratory signs consistent with pneumonia
         Time to recovery of respiratory symptoms
         Death within 14 days of randomization
         Secondary: Clinical deterioration requiring a change in treatment
         Infectious complications Ventilation Side effects LOS
Azithromycin for acute lower respiratory tract infections25Panpanich R, Lerttrakarnnon P, Laopaiboon MSept 200715 (3 in children with community acquired pneumonia88-420Children and adults Developed countriesAcute LTRI (bronchitis, pneumonia, exacerbation of chronic bronchitis) Only CAP studies were includedAzitromycinAmoxycillian/clavulanicPrimary: Clinical failure (persistence pr deterioration)
         Secondary: Serious complications
         Adverse rug events Eradication of organism
Antibiotics for community acquired lower respiratory tract infections (LRTI) secondary to Mycoplasma pneumoniae in children18Gavranich JB, Chang ABMay 20056110-456Children < 18 years Developing countriescommunity acquired LTRI secondary to Mycoplasma pneumoniaeAntimicrobialsPlacebo or other antibioticsPrimary: Failure to improve at follow-up
         Secondary: Mean difference in signs and symptoms
         Hospitalization
         Pulmonary complications
         Non-pulmonary complications
         Adverse events Complications

The seven reviews looked at varying types of pneumonia defined as non-severe CAP1, severe pneumonia as per WHO criteria based on respiratory rate, and presence of chest in-drawing in the absence of clinical indicators of very severe pneumonia24, any pneumonia as defined by the WHO criteria or radiologically confirmed pneumonia19, non-measles pneumonia of any severity2, clinical acute lower respiratory tract infections (with all 3 pediatric studies including only patients with proven or suspected CAP)25, pneumonia accompanied by cough for less than four weeks19, and lower respiratory tract infection secondary to M. pneumoniae18.

The primary outcome was clinical cure (two studies)1, 14 clinical failure (three studies with one of these studies placing emphasis on cough as the most important clinical outcome)18, 19, 25, mortality2, and multiple outcomes (presence of respiratory signs, time of recovery from symptoms, and death within 14 days of randomization into treatment group)24.

Search strategies

The search strategies used to identify the included studies were comparable. All seven reviews searched the Cochrane Controlled Trials Register, MEDLINE, and EMBASE. Three reviews also searched LILACS1, 2, 24, and Haider et al also searched the Database of Abstracts of Reviews of Effects1. Ni et al conducted the most comprehensive search of electronic databases2 as in addition to the abovementioned databases, they searched CINAHL, Biological Abstracts, Current Contents, and Chinese Biomedicine Database. Five reviews examined the reference lists of the studies being reviewed1, 2, 14, 18, 24. Relevant organizations, researchers, conference proceedings, clinical practice guidelines, and/or pharmaceutical companies were searched by three reviews1, 24, 25. Five reviews did not impose language restriction1, 2, 19, 24, 25.

Description of studies

Table 1 describes the inclusion criteria of the included reviews. The number of pediatric trials in the reviews ranged from one19 to twenty14. The sample sizes of the individual trials ranged from 88 to 2,188. Two reviews identified studies published in foreign languages2, 25. Among three reviews identified trials were conducted in developed countries1, 2, 24 and two reviews identified trials completed only in developed countries19, 25. The other two reviews identified trials from both developing and developed countries14, 18.

Methodological quality

The methods used to evaluate methodological quality varied by review. Three reviews used the Jadad Scale, a five- point scale that assesses randomization and double-blinding techniques and documentation of losses and withdrawals. The median Jadad scores were 218, 19 and 314. One study used the Guyatt criteria26 while the other three studies used less standard criteria. Adequate allocation concealment ranged from 0% (0/1)19 to 50% (3/6)2, 1/224 of the studies in the reviews.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Background
  5. Objective
  6. Methods
  7. Results
  8. Discussion
  9. Implications for Practice
  10. Implications for Research
  11. Acknowledgements
  12. Declarations of Interest
  13. References

The results are presented by the various definitions of CAP and type of treatment. Table 2 describes clinical cure and failure by type of treatment and Table 3 describe the symptoms and improvement by type of treatment.

Table 2. Clinical cure or failure
OutcomeComparisonDetailed comparisonNumber of subjects (Studies)InterventionControlEffect estimateResult (95% CI)Interpretation
Clinical cureShort vs long course of the same antibiotic3 vs 5 day amoxicillin4012 (2)1783/20131794/1999RR0.99 (0.97, 1.01)No significant difference
 Short vs long course of the same antibiotic3 vs 5 day cotrimoxazole1751 (1)799/879790/872RR1.00 (0.97, 1.03)No significant difference
 Antimicrobials vs placebo or other antibioticsAzithromycin vs amoxycillian-clavulanate611 (2)AzithromycinAmoxycillian-clavulanateStudies not pooledNA 
    Study 1: 95.1%Study 1: 90.1%   
    Study 2: 67.2%Study 2: 66.7%   
 Antibiotic vs a second antibioticCo-trimoxazole vs amoxicillin1459 (1)Co-trimoxazole:Amoxicillin:RR0.97 (0.92, 1.01)No significant difference
    595/734608/725   
 Antibiotic vs a second antibioticAmoxicillin clavulanate vsamoxicillin100 (1)Amoxicillin clavulanate:Amoxicillin:RR1.57 (1.24, 1.99)Favors amoxicillin clavulanate
    47/5030/50   
 Antibiotic vs a second antibioticBenzathin penicillin vs procaine penicillin281 (2)Benzathin penicillin:Procaine penicillin:RR0.89 (0.79, 1.00)No significant difference
    100/135111/146   
 Antibiotic vs a second antibioticCo-trimoxazole vs procaine penicillin723 (2)Co-trimoxazole:Procaine penicillin:RR0.96 (0.91, 1.02)No significant difference
    328/349319/374   
 Antibiotic vs a second antibioticCo-trimoxazole vs single dose procaine penicillin and oral ampicillin134 (1)Co-trimoxazole:Single dose procaine penicillin and oral ampicillin: 61/68RR1.01 (0.91, 1.13)No significant difference
    60/66    
 Antibiotic vs a second antibioticAmoxicillin vs procaine penicillin134 (1)Amoxicillin:Procaine penicillin:RR1.01 (0.91, 1.13)No significant difference
    60/6661/68   
 Antibiotic vs a second antibioticAzithromycin vs erythromycin362 (3)Azithromycin:Erythromycin:RR1.04 (0.92, 1.17)No significant difference
    179/230100/133   
 Antibiotic vs a second antibioticAmpicillin vs penicillin with chloramphenicol101 (1)Ampicillin:Penicillin with chloramphenicol:RR0.90 (0.76, 1.06)No significant difference
    42/5244/49   
 Antibiotic vs a second antibioticAzithromycin vs amoxicilinamoycilin47 (1)Azithromycin:Amoycilin:RRNot estimable 
    23/2324/24   
 Antibiotic vs a second antibioticCo-trimoxazole vs chloramphericol111 (1)Co-trimoxazole:Chloramphericol:RR1.02 (0.80, 1.30)No significant difference
    39/5539/56   
 Antibiotic vs a second antibioticAmoxicillinAmoxycillin vs chloramphericol796 (1)Amoxicillin:Chloramphericol:RR1.53 (1.23, 1.89)Favor chloramphenicol
    608/72539/71   
 Antibiotic vs a second antibioticAzithromycin vs Amoxicillin clavulanate188 (1)Azithromycin:Co-amoyclavulate:RR1.01 (0.81, 1.25)No significant difference
    84/12542/63   
 Antibiotic vs a second antibioticClarithromycin vs erythromycin234 (1)Clarithromycin:Erythromycin:RR1.10 (0.96, 1.25)No significant difference
    104/12484/110   
Time to recoveryOral vs parenteral antibioticsOral amoxicillin vs IV benzyl penicillin246 (1)IV: 1.3 daysOral: 1.2 daysMD0.30 (0.21, 0.40)Favors oral
    (IQR: 1.1–1.7)(IQR: 0.9–1.6)   
Time to clinical cureAntimicorbials vs placebo or other antibioticsErythromycin vs amoxicillin120 (1)Erythromycin 3.79 daysAmoxicillin 3.96 daysNot calculatedNA 
Treatment failureShort vs long course of the same antibiotic3 vs 5 day amoxicillin4012 (2)230/2013205/1999RR1.11 (0.94, 1.33)No significant difference
 Short vs long course of the same antibiotic3 vs 5 day co-timoxazole1751 (1)80/87982/872RR0.97 (0.72, 1.30)No significant difference
 OTC cough medicine and antibiotics vs placebo and antibioticsMucolytic and antibiotics vs placebo and antibiotics120 (1)15/6029/60RR0.52 (0.31, 0.86)Favors mucolytic
 Oral vs parenteral antibioticsOral amoxicillin vs injectable penicillin(1)Injection:19%Oral:18%RD0.2 (−3.0, 3.9)No significant difference
 Oral vs parenteral antibioticsOral co-trimoxazole vs injectable procain penicillin131 (1)Injection: 5/65Oral: 5/66RD− 0.1% (−9, 9)No significant difference
 Antibiotic vs a second antibioticamoxicillinAzithromycin vs amoxillin or amoxicillinamoxycillin-clavulanate384 (3)Azithromycin: 17/219Amoxillin or amoxicillinamoxicillin-clavulanate: 13/165RR0.93 (0.45, 1.94)No significant difference
 Antibiotic vs a second antibioticCo-trimoxazole vs amoxicillin2054 (2)Co-trimoxazole:Amoxicillin:RR1.26 (1.04, 1.53)Favors amoxicillin
    231/1132147/922   
 Antibiotic vs a second antibioticAmoxicillin clavulanate vs amoxicillin100 (1)Co-amoxyclavulanate:Amoxicillin:RR0.10 (0.01, 0.75)Favors amoxicillin clavulanate
    1/5010/50   
 Antibiotic vs a second antibioticBenzathin penicillin vs procaine penicillin281 (2)Benzathin penicillin:Procaine penicillin:RR2.84 (1.39 5.84)Favors procaine penicillin
    21/1359/146   
 Antibiotic vs a second antibioticAmoxicillin vs penicillin1702 (1)Amoxicillin:Penicillin:RR1.04 (0.89, 1.21)No significant difference
    231/845221/857   
 Antibiotic vs a second antibioticCo-trimoxazole vs procaine penicillin614 (1)Co-trimoxazole:Procaine penicillin:RR3.08 (0.13, 75.29)No significant difference
    1/3030/311   
 Antibiotic vs a second antibioticCo-trimoxzole vs amoxicillin1459 (1)Co-trimoxzole:Amoxicillin:RR1.17 (0.94, 1.47)No significant difference
    139/734117/725   
 Antibiotic vs a second antibioticCo-trimoxazole vs Amoxicillin clavulanate1232 (2)Co-trimoxazole:Amoxicillin clavulanate:RR10.49 (2.65, 41.50)Favors amoxicillin clavulanate
    231/11322/100   
 Antibiotic vs a second antibioticAmoxicillinAmoxicillin vs procaine penicillin154 (1)Amoxicillin:Procaine penicillin:RR0.76 (0.19, 3.06)No significant difference
    3/685/86   
 Antibiotic vs a second antibioticAzithromycin vs erythromycin392 (3)Azithromycin:Erythromycin:RR0.57 (0.16, 1.95)No significant difference
    5/2366/156   
 Antibiotic vs a second antibioticCo-trimoxazole vs chloramphericol111 (1)Co-trimoxazole:Chloramphericol:RR1.02 (0.57, 1.83)No significant difference
    16/5516/56   
 Antibiotic vs a second antibioticAmoxicillin vs chloramphericol1065 (2)Amoxicillin:Chloramphericol:RR0.70 (0.49, 0.99)Favors amoxicillin
    147/92332/142   
 Antibiotic vs a second antibioticAzithromycin vs co-amoxyclavulanate276 (2)Azithromycin:Co-amoxyclavulanate:RR1.20 (0.45, 3.21)No significant difference
    12/1646/112   
 Antibiotic vs a second antibioticClarithromycin vs erythromycin234 (1)Clarithromycin:Erythromycin:RR0.53 (0.13, 2.18)No significant difference
    3/1245/110   
Relapse rateShort vs long course of the same antibiotic3 vs 5 day amoxicillin3577 (2)44/178342/1794RR1.05 (0.69, 1.60)No significant difference
 Short vs long course of the same antibiotic3 vs 5 day co-trimoxazole1589 (1)62/79955/790RR1.11 (0.79, 1.58)No significant difference
 Antibiotic vs a second antibioticCo-trimoxazole vs chloramphericol111 (1)Co-trimoxazole:Chloramphericol:RR1.02 (0.27, 3.87)No significant difference
    4/554/56   
 Antibiotic vs a second antibioticClarithromycin vs erythromycin226 (1)Clarithromycin:Erythromycin:RR0.17 (0.02, 1.46)No significant difference
    1/1215/105   
MortalityVitamin A and standard treatment vs placebo and standard treatmentNA1446 (3)17/73013/716RR1.29 (0.63, 2.62)No significant difference
 Oral vs parenteral antibioticsOral amoxicillin vs injectable penicillinNR (1)IV: 0.2%Oral: 1.0%RD− 0.6% (−0.1, 1.3)No significant difference
 Antibiotic vs a second antibioticAmoxicillin vs penicillin1702 (1)Amoxicillin:Penicillin:RR0.07 (0.00, 1.16)No significant difference
    0/8457/857   
 Antibiotic vs a second antibioticCo-trimoxazole vs procaine penicillin614 (1)Co-trimoxazole:Procaine penicillin:RR1.71 (0.41, 7.10)No significant difference
    5/3033/311   
 Antibiotic vs a second antibioticProcaine penicillin vs ampicillin134 (1)Procaine penicillin:Ampicillin:RR0.21 (0.01, 4.21)No significant difference
    0/662/68   
 Antibiotic vs a second antibioticCo-trimoxzole vs amoxicillin2050 (2)Co-trimoxzole:Amoxicillin:RR2.10 (0.23, 19.50)No significant difference
    2/11320/918   
 Antibiotic vs a second antibioticCo-trimoxazole vs single dose procaine penicillin and oral ampicillin134 (1)Co-trimoxazole:Single dose procaine penicillin and oral ampicillin: 2/68RR0.21 (0.01, 4.21)No significant difference
    0/66    
 Antibiotic vs a second antibioticChloramphericol vs penicillin plus gentamicin1116 (1)Chloramphericol:Penicillin plus gentamicin:RR1.24 (0.77, 1.99)No significant difference
    36/55929/557   
 Antibiotic vs a second antibioticCo-trimoxazole vs chloramphericol111 (1)Co-trimoxazole:Chloramphericol:RR2.04 (0.65, 6.37)No significant difference
    8/554/56   
 Antibiotic vs a second antibioticChloramphericol vs chloramphericol plus penicillin748 (1)Chloramphericol:Chloramphericol plus penicillin:RR0.76 (0.54,1.08)No significant difference
    48/37762/371   
Table 3. Symptom recovery, improvement, absence, and persistence
OutcomeComparisonDetailed comparisonNumber of subjects (studies)InterventionControlEffect estimateResult (95% CI)Interpretation
  1. ST: Standard Treatment; SD: Standard Deviation.

Time with feverVitamin A and ST vs placebo and STNA958 (3)NANAWMD− 1.11 (−5.66, 3.44)No significant difference
Fever at 7 daysAntibiotic vs a second antibioticAzithromycin vs amoxyilin47 (1)Azithromycin: 16/23Amoxyilin: 15/24RR1.11 (0.74, 1.68)No significant difference
Time with rapid breathingVitamin A and ST vs placebo and STNA926 (2)NANAWMD0.03 (−0.32, 0.38)No significant difference
Time with hypoxiaVitamin A and ST vs placebo and STNA926 (2)NANAWMD0.07 (−0.21, 0.34)No significant difference
Time with coughVitamin A and ST vs placebo and STNA38 (1)NANAMD− 2.00 (−3.51, − 0.49)MD < 0 favors vitamin A
Cough score at day 3OTC cough medicine and antibiotics vs placebo and antibioticsMucolytic and antibiotics vs placebo and antibiotics120 (1)1.2 (SD: 0.2)1.45 (SD: 0.25)MD− 0.25 (−0.33, − 0.17)MD favors mucolytic (ambroxol)
Cough score at day 10OTC cough medicine and antibiotics vs placebo and antibioticsMucolytic and antibiotics vs placebo and antibiotics120 (1)0.1 (SD: 0.05)0.25 (SD: 0.05)MD− 0.15 (−0.17, − 0.13)MD favors mucolytic
Short-term effects: slight improvementVitamin A and ST vs placebo and STNA80 (1)2/4018/40RR0.11 (0.03, 0.45)Favors vitamin A
Long-term effects: no improvementVitamin A and ST vs placebo and STNA80 (1)3/4016/40RR0.19 (0.06, 0.59)Favors vitamin A
ImprovedAntibiotic vs a second antibioticAzithromycin vs co-amoxyclavulanate188 (1)Azithromycin: 30/125Amoxicillin clavulanate: 17/63RR0.89 (0.53, 1.48)No significant difference
Not improvedOTC cough medicine and antibiotics vs placebo and antibioticsMucolytic and antibiotics vs placebo and antibiotics120 (1)3/607/60RR0.43 (0.12, 1.58)No significant difference
Required change in antibioticsVitamin A and ST vs placebo and STNA472 (1)43/23959/233RR0.71 (0.50, 1.01)No significant difference
Clinical responseAntimicorbials vs placebo or other antibioticsAzithromycin vs amoxicillin-clavulanate335 (1)Azithromycin 99%Amoxicillin-clavulanate 98%Not calculatedNA 

Comparisons of specific antibiotics for CAP

Outpatients

In a review of three pediatric trials with a combined total of 384 children aged 6 months to 16 years with CAP, treatment failure was equivalent for therapy with azithromycin versus amoxicillin or amoxicillin clavulanate, with all three studies using amoxicillin clavulanate (RR: 0.93; 95% CI: 0.45, 1.94)25. Two of these three trials plus 18 other trials were included in a review of comparisons of antibiotics for CAP14. This review found an additional small study comparing azithromycin to amoxicillin (47 children) with all children recovering. There were no important differences in outcome in trials comparing erythromycin to azithromycin (623 children in four trials) or to clarithromycin (260 children in one trial). Comparing different beta-lactams, cure rate was higher for amoxicillin clavulanate than for amoxicillin (100 children—single trial with a low Jadad score of 2 out of 5) (RR: 1.57; 95% CI: 1.24, 1.99). Two high-quality large trials of 2054 outpatients aged 2 to 59 months of age in Pakistan (Jadad scores of 5 out of 5) in 1998 and 2002 showed higher failure rates for co-trimoxazole than for amoxicillin (RR: 1.26; 95% CI: 1.04, 1.53) but no difference in cure rates for the one trial that reported this outcome (RR: 0.97; 95% CI: 0.92, 1.01). Comparing oral to parenteral antibiotics in outpatients, two trials from 1990 and 1994 of 723 children aged 3 months to 12 years of age in Zimbabwe and Istanbul respectively showed better cure rates (OR 2.64; 95% CI:1.57, 4.45) and a trend towards lower hospitalization rates (OR 2.52; 95% CI:0.88, 7.25) with use of parenteral procaine penicillin versus co-trimoxazole but these advantages were not shown in a study of 134 children less than 5 years of age in Gambia randomized to the same regime but with only one dose of procaine penicillin followed by oral ampicillin. A trial of 170 children aged 6 months to 18 years of age showed no difference in failure rates for procaine penicillin versus amoxicillin (OR 0.75; 95% CI:0.17, 3.25).

Inpatients

Injectable penicillin had equivalent failure rates to amoxicillin in 1702 children aged 3 to 59 months Asia, Africa, and South America (RD 0.2%; 95% CI: − 3.0, 3.9%)14. Procaine and single dose benzathine penicillin were compared in 2 trials (281 children) with equivalent cure rates (RR: 0.89; 95% CI: 0.79, 1.00) but a higher failure rate in the benzathine group (RR: 2.84; 95% CI: 1.39, 5.84).

A trial with 1116 children aged 1 month to 5 years of age in Papua New Guinea in 2002 showed similar outcomes for chloramphenicol versus penicillin and gentamicin except that there was a higher readmission rate within 30 days in the former group. Smaller trials showed equivalent outcomes in both groups for chloramphenicol plus penicillin versus ampicillin (115 patients), chloramphenicol versus co-trimoxazole (111 children), and chloramphenicol plus penicillin versus ceftriaxone (97 children).

Antibiotics for CAP due to M. pneumoniae

A review included any trial that compared antibiotics that would cover Mycoplasma pneumoniae to placebo or to any other class of antibiotics and then tried to separate out children with proven M. pneumoniae infection18. There was overlap of one trial in the review of azithromycin for CAP mentioned above25. Seven eligible studies were found but assigned therapy for those with proven M. pneumonia infection was provided for a total of only 38 children from two studies. Therefore, the number of patients was too small to reach conclusions on the efficacy of any class of antibiotics18.

Oral versus parenteral antibiotics for CAP

A review of oral versus parenteral antibiotics for severe pneumonia in children aged 3 to 59 months of age found only two previously mentioned published studies with both showing equivalent results when parenteral penicillin followed by an oral penicillin was compared to oral co-trimoxazole in 134 outpatients in Gambia or to oral amoxicillin in 1702 inpatients in Asia, Africa, and South America (24). Therapies were not masked and some outcomes were not blinded in these two studies. The review mentioned another study in inpatient 6 months to 16 years of age in the UK that was pending publication comparing initial parenteral penicillin to oral amoxicillin. This trial has since been published. The time for fever to resolve and for oxygen requirement to cease for those needing oxygen was similar in the two groups (median time 1.3 days for IV and 1.2 days for oral, p = 0.03). However, the median length of hospital stay was significantly shorter in the oral group than the IV group (1.8 days versus 2.1 days, p < 0.001) (27).

Duration of antibiotics for CAP

A review of different durations of the same antibiotic in children aged 2 to 59 months of age with non-severe CAP found two studies comparing 3 to 5 days amoxicillin (4012 children) or co-trimoxazole (1751 children) with no significant differences in clinical cure, treatment failure, or relapse rate1. Both studies were conducted in Asia.

Therapeutic interventions other than antibiotics for CAP

A review found six trials of vitamin A for non-measles pneumoniae2. Trials were from Africa, South America, or China and included 1740 children treated with total doses ranging from 50,000 to 200,000 IU given over 1 to 26 days. There was significant heterogeneity in the chosen outcomes, but in general outcomes were equivalent among those treated with vitamin A and standard treatment and those receiving placebo and standard treatment. Exceptions were that one trial showed duration of cough was shortened with vitamin A (MD − 2.00; 95% CI: − 3.51, − 0.49), another showed higher rates of slight improvement (RR: 0.11; 95% CI: 0.03, 0.45) with vitamin A, another demonstrated more rapid clinical improvement in the vitamin A group only if the basal serum retinol was > 200 micrograms/L (MD: − 61.40; 95% CI: − 119.10, − 3.7), while a fourth trial showed that the vitamin A group had lower oxygen saturation and a higher respiratory and heart rate when compared over time.

A review found only two studies that looked at the effect of over-the counter medications on cough in children with pneumonia—all of whom also received antibiotics19. Pediatric data could be extracted from only one of the two trials. This trial of the mucolytic ambroxol in 120 children was of low quality (Jadad score was 2 out of 5) but demonstrated improved cough scores from Day 3 onwards (MD: − 0.25; 95% CI: − 0.33, − 0.17). There was no difference in the primary outcome of “not cured or not substantially improved at follow-up” (RR: 0.43; 95% CI: 0.12, 1.58) but more children in the control group had the secondary outcome of “not cured at follow up” (RR: 0.52: 95% CI: 0.31, 0.86). Although not reported in the Cochrane review, the authors of the trial also reported more rapid radiographic resolution of pneumonia in treated children28.

Adverse events

The risk of side effects and adverse events were similar among those treated with oral versus parenteral antibiotics24, vitamin A and standard treatment versus standard treatment and placebo2, and OTC cough medicine and antibiotics versus placebo and antibiotics19. Haider et al did not evaluate adverse events in the review of shorter durations of antibiotics1.

Specific antibiotics

There was no significant difference in adverse events for children treated with amoxicillin-clavulanate compared to amoxicillin14. Two trials compared amoxicillin-clavulanate and azithromycin and both found a higher proportion of adverse events among those treated with amoxicillin-clavulanate (17.1% and 42.3%) compared to azithromycin (11.3% and 12.1%); tests of statistical significance were not performed. Two trials compared azithromycin, amoxicillinclavulante, and erythromycin and both found a similar proportion of adverse events for azithromycin (11% and 14%) and erythromycin (25% and 27%) but the proportion differed for amoxicillin-clavulante (30% and 67%). Compared to amoxicillin-clavulanate, there were fewer adverse events among those treated with azithromycin (RR: 0.76; 95% CI: 0.57, 1.00).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Background
  5. Objective
  6. Methods
  7. Results
  8. Discussion
  9. Implications for Practice
  10. Implications for Research
  11. Acknowledgements
  12. Declarations of Interest
  13. References

Although thousands of children have been entered in trials of therapy for CAP, limited definitive conclusions can be reached about ideal choice, route and duration of antibiotics or about the efficacy of non-antibiotic therapies in developed or developing countries. The primary reason for this is the multitude of interventions studied in diverse populations. Another major problem is that the diagnosis of pneumonia was clinical rather than radiographic in many trials—often by necessity in developing countries. This will predictably result in enrollment of children who have bronchiolitis rather than pneumonia, as suggested by the high rates of wheezing described in some trials14. Although none of the reviews specifically mention exclusion of children with viral pneumonia, the only reviews where it would have been appropriate to include children with viral pneumonia were the ones studying vitamin A2 and OTC medications19. Nonetheless, children with viral rather than bacterial pneumonia would have probably been enrolled in all trials as differentiation is often not possible, diluting the efficacy of antibiotics. Some of the reviews did not specifically exclude hospital-acquired pneumonia or pneumonia in children with underlying conditions19, 24 but it is likely the majority of children in these reviews had CAP.

It is important to note that even for proven bacterial pneumonia, the etiologic agent can vary markedly by age and country so studies of specific antibiotics must be interpreted with caution. A further problem is that increasing resistance of bacteria (especially S. pneumoniae) to common antibiotics may render the results of studies done in the 1990s no longer valid. Recently, methicillin-resistant Staphylococcus aureus has emerged as an etiologic agent of CAP29. Should this agent become more common, choice of antibiotics will change again as most of the regimes studied in this overview would not cover this agent. There is some evidence from adult studies that dual antibiotics may have improved efficacy for severe CAP30. However, currently there is no Cochrane review of dual versus monotherapy. Given all these caveats, the conclusions derived from this overview that follow may all change over time.

A common dilemma for clinicians is use of a macrolide versus a beta-lactam for children with CAP. This choice should be influenced by the age of the child, the clinical picture, and the radiographic findings, with there being no evidence in the current overview to help the clinician. Azithromycin appears to be better tolerated than is amoxicillin-clavulanate. However, this must be balanced against the knowledge that azithromycin promotes bacterial resistance as it has such a long half-life31. The use of azithromycin (daily doses per 1000 inhabitants per day) is up to 40 times higher in the USA compared to some countries in Western Europe32. All macrolides have a small risk for cardiac arrhythmia and it has therefore been argued that the use of macrolides should be minimized33.

If a beta lactam is to be used, the only evidence to use in selecting one is a small low-quality trial showing a higher cure rate with amoxicillin-clavulanate than with amoxicillin14. Despite no difference in adverse events in this trial, most pediatricians believe that amoxicillin has less gastrointestinal side effects than does amoxicillin-clavulanate. If a macrolide is chosen, the efficacy and adverse events of azithromycin, clarithromycin, and erythromycin appears to be equal in the review that compared them (18). Although this review suggested the adverse events are also equivalent for these three antibiotics, many North American pediatricians would disagree; the gastrointestinal adverse events of erythromycin often interfere with administration of a full course so use is often restricted to situations where cost precludes use of the newer macrolides14. For CAP in developing countries, evidence shows amoxicillin to be a better choice than is co-trimoxazole14. The effect of increasing pneumococcal resistance to both drugs on this choice is not clear and future studies would be of benefit.

Initial therapy with oral antibiotics appears to be equivalent to parenteral antibiotics in children with non-severe pneumonia24. Unless children have other indications for hospitalization (such as severe disease or empyema), therapy at home with oral antibiotics should be the norm. This situation may change if continuing abuse of antibiotics leads to a world with widespread resistance of pneumococcus to all oral antibiotics.

The duration of therapy for CAP is usually based on local practice rather than evidence. The current overview shows that 3-day courses may be as effective as longer courses for non-severe pneumonia.

There is not enough evidence to routinely treat pneumonia with vitamin A, but further studies would appear to be warranted. There were insufficient children in the studies of over-the-counter medications for cough in children with pneumonia to reach meaningful conclusions19. Although a mucolytic appeared to possibly improve cough score, there are no high quality studies looking at the effect of such medications on more relevant outcomes in severe pneumonia. Safety concerns about use of such medications in children under 4 years of age would appear to trump any improvement in cough duration34, and further studies are required in older children before use could be recommended.

Implications for Practice

  1. Top of page
  2. Abstract
  3. Introduction
  4. Background
  5. Objective
  6. Methods
  7. Results
  8. Discussion
  9. Implications for Practice
  10. Implications for Research
  11. Acknowledgements
  12. Declarations of Interest
  13. References

A current practice guideline for treating CAP in children is needed and should be made widely available to the global health care community. Based on the existing evidence from Cochrane Reviews, the recommendations should include the following:

  • Three days of antibiotic therapy (amoxicillin or co-trimoxazole) is as effective as a longer treatment for non-severe pneumonia in children under 5 years of age1.

  • Co-amoxicillinclavulanate may be more efficacious than amoxicillin which is more efficacious than co-trimoxazole.

  • Oral antibiotics are effective and safe in hospitalized children with severe pneumonia who do not have any serious signs or symptoms14, 24.

  • Azithromycin may be superior to amoxicillin and equal to amoxicillin-clavulanate25. However, azithromycin causes much bacterial resistance31.

  • It has not been possible to show any better effect on Mycoplasma pneumoniae pneumonia by macrolide antibiotics compared to non-macrolide antibiotics but the studies are small18.

  • There were insufficient children in the studies of over-the-counter medications for cough in children with pneumonia to reach meaningful conclusions. Do not use medications containing codeine and antihistamines in young children (<4 years)19.

Implications for Research

  1. Top of page
  2. Abstract
  3. Introduction
  4. Background
  5. Objective
  6. Methods
  7. Results
  8. Discussion
  9. Implications for Practice
  10. Implications for Research
  11. Acknowledgements
  12. Declarations of Interest
  13. References

There are several areas where additional research could potentially streamline treatment of CAP. Firstly, improved diagnostics would lead to more rational use of antibiotics. Further comparisons of common antibiotic regimes should be done in different setting and age groups, followed by studies of duration of therapy. Detailed reporting of adverse events is missing in many trials. The cost of treatment options needs to be compared. Consideration of these costs is necessary to ensure that recommendations and guidelines can be afforded by the health care agencies in developing countries. In addition, the role of dietary supplements, including vitamins and minerals, in preventing and treating CAP needs to be further explored.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Background
  5. Objective
  6. Methods
  7. Results
  8. Discussion
  9. Implications for Practice
  10. Implications for Research
  11. Acknowledgements
  12. Declarations of Interest
  13. References

The authors would like to thank Lorne Becker, chair of the Cochrane Umbrella Reviews Working Group, for his guidance with this manuscript.

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  1. Top of page
  2. Abstract
  3. Introduction
  4. Background
  5. Objective
  6. Methods
  7. Results
  8. Discussion
  9. Implications for Practice
  10. Implications for Research
  11. Acknowledgements
  12. Declarations of Interest
  13. References
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