Antibiotics for community-acquired pneumonia in children

  • Conclusions changed
  • Review
  • Intervention

Authors

  • Sushil K Kabra,

    Corresponding author
    1. All India Institute of Medical Sciences, Pediatric Pulmonology Division, Department of Pediatrics, Ansari Nagar, New Delhi, India
    • Sushil K Kabra, Pediatric Pulmonology Division, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India. skkabra@rediffmail.com.

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  • Rakesh Lodha,

    1. All India Institute of Medical Sciences, Department of Pediatrics, Ansari Nagar, New Delhi, India
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  • Ravindra M Pandey

    1. All India Institute of Medical Sciences, Department of Biostatistics, Ansari Nagar, New Delhi, India
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Abstract

Background

Pneumonia caused by bacterial pathogens is the leading cause of mortality in children in low-income countries. Early administration of antibiotics improves outcomes.

Objectives

To identify effective antibiotics for community acquired pneumonia (CAP) in children by comparing various antibiotics.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, issue 2) which contains the Cochrane Acute Respiratory Infections Group's Specialised Register; MEDLINE (1966 to September 2009); and EMBASE (1990 to September 2009).

Selection criteria

Randomised controlled trials (RCTs) in children of either sex, comparing at least two antibiotics for CAP within hospital or ambulatory (outpatient) settings.

Data collection and analysis

Two review authors independently extracted data from full articles of selected studies.

Main results

There were 27 studies, which enroled 11,928 children, comparing multiple antibiotics. None compared antibiotic with placebo.

For ambulatory treatment of non-severe CAP, amoxycillin compared with co-trimoxazole had similar failure rates (OR 0.92; 95% CI 0.58 to 1.47) and cure rates (OR 1.12; 95% CI 0.61 to 2.03). (Three studies involved 3952 children).

In children hospitalised with severe CAP, oral amoxycillin compared with injectable penicillin or ampicillin had similar failure rates (OR 0.95; 95% CI 0.78 to 1.15). (Three studies involved 3942 children). Relapse rates were similar in the two groups (OR 1.28; 95% CI 0.34 to 4.82).

In very severe CAP, death rates were higher in children receiving chloramphenicol compared to those receiving penicillin/ampicillin plus gentamycin (OR 1.25; 95% CI 0.76 to 2.07). (One study involved 1116 children).

Authors' conclusions

There were many studies with different methodologies investigating multiple antibiotics. For treatment of ambulatory patients with CAP, amoxycillin is an alternative to co-trimoxazole. With limited data on other antibiotics, co-amoxyclavulanic acid and cefpodoxime may be alternative second-line drugs. For severe pneumonia without hypoxia, oral amoxycillin may be an alternative to injectable penicillin in hospitalised children; however, for ambulatory treatment of such patients with oral antibiotics, more studies in community settings are required. For children hospitalised with severe and very severe CAP, penicillin/ampicillin plus gentamycin is superior to chloramphenicol. The other alternative drugs for such patients are ceftrioxone, levofloxacin, co-amoxyclavulanic acid and cefuroxime. Until more studies are available, these can be used as a second-line therapy.

There is a need for more studies with larger patient populations and similar methodologies to compare newer antibiotics.

摘要

背景

兒童社區型肺炎的抗生素治療

肺炎是兒童的主要致死原因。在發展中國家,肺炎通常是由細菌病原引起。早期給予抗生素會改善病人的臨床癒後。目前對這主題沒有臨床試驗的系統性回顧。

目標

籍由比較不同的抗生素,以確認對兒童社區型肺炎(CAP)有效的抗生素藥物。

搜尋策略

搜尋Cochrane Central Register of Controlled Trials(CENTRAL)(The Cochrane Library,2005年第4期),MEDLINE(OVID)(1966年至2006年1月)和EMBASE(WebSPIRS)(1990年至2005年9月)。沒有語言上的限制。

選擇標準

隨機對照試驗,對象為不分性別的兒童(住院或門診的社區型肺炎病患都納入),且比較至少兩種抗生素。

資料收集與分析

兩位作者各自從收錄研究的全文文章中摘錄資料。

主要結論

研究的回顧資料建議在肺炎治療上,cotrimoxazole的效益比amoxycillin(失敗率之odds ratio(OR)值 1.33;95% CI值1.05 to 1.67)及procaine penicilline(治癒率之OR值 2.64;95% CI值 1.57 to 4.45)來的低。Penicillin合併使用gentamycin比單獨使用chloramphenicol來的好(再住院率之OR值 1.61;95% CI值 1.02 to 2.55)。Coamoxyclavulanic acid比單獨使用amoxycillin好(治癒率之OR值 10.44;95% CI值 2.85 to 38.21)。下列藥物比較沒有明顯的差異:注射型penicillin與口服amoxycillin(失敗率之OR值1.03;95% CI值 0.81 to 1.31);azithromycin與erythromycin (治癒率OR值1.17;95% CI值0.70 to 1.95);cefpodoxime與amoxycillin (治癒率OR值0.69;95% CI值0.18 to 2.60);或azithromycin與coamoxyclavulanic acid (治癒率OR值 1.02;95% CI值0.54 to 1.95,失敗率OR值 1.42;95% CI值 0.43 to 4.66)。

作者結論

有許多研究分別利用不同的方法研究多種抗生素。治療社區型肺炎的門診病人,amoxycillin比cotrimoxazole效果好;azithromycin與erythromycin,或cefpodoxime與coamoxyclavulanic acid間則無差異。對於治療住院病人,procaine penicillin優於cotrimoxazole,而penicillin合併使用gentamycin也優於單獨使用chloramphenicol。注射型penicillin與口服amoxycillin有相似的失敗率。對於其他的抗生素比較,目前只有一篇研究可供參考。為了比較更新一代的抗生素,我們需要更多使用類似研究方法的大規模試驗。

翻譯人

本摘要由慈濟醫院朱培元翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

我們比較不同抗生素對小於18歲的社區型肺炎病童,在住院及門診治療的效果。肺炎是小於5歲兒童的主要致死原因。發展中國家絕大多數的社區型肺炎是由細菌致病的。這篇系統性的回顧找到了20篇抗生素比較的隨機對照試驗,大多數抗生素都只有一篇研究。我們發現,在肺炎的門診治療,amoxycillin或 procaine penicillin比cotrimoxazole更有效。在住院兒童的肺炎治療,penicillin合併gentamycin比單獨使用 chloramphenicol有效。對於肺炎的住院治療,口服amoxycillin與注射型penicillin的結果相似。

Résumé

Antibiotiques pour la pneumonie communautaire chez l'enfant

Contexte

La pneumonie provoquée par des agents pathogènes bactériens est la première cause de mortalité chez les enfants vivant dans des pays à faible revenu. L'administration précoce d'antibiotiques améliore les résultats.

Objectifs

Identifier les antibiotiques efficaces pour le traitement de la pneumonie communautaire (PC) chez l'enfant, en comparant divers antibiotiques.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre Cochrane des essais contrôlés (CENTRAL) (Bibliothèque Cochrane 2009, numéro 2) qui contient le registre spécialisé du groupe Cochrane sur les infections respiratoires aiguës, ainsi que dans MEDLINE (1966 à septembre 2009) et EMBASE (1990 à septembre 2009).

Critères de sélection

Les essais contrôlés randomisés (ECR) impliquant des enfants des deux sexes et comparant au moins deux antibiotiques pour le traitement de la PC en milieu hospitalier ou ambulatoire (consultation externe).

Recueil et analyse des données

Deux auteurs de revue ont extrait, de manière indépendante, les données des articles complets des études sélectionnées.

Résultats Principaux

Il y avait 27 études qui comprenaient 11 928 enfants et comparaient plusieurs antibiotiques. Aucune ne comparaît un antibiotique à un placebo.

Pour le traitement ambulatoire de la PC non grave, l'amoxicilline, par rapport au cotrimoxazole, obtenait des taux d'échec (RC 0,92 ; IC à 95 % entre 0,58 et 1,47) et de guérison similaires (RC 1,12 ; IC à 95%, entre 0,61 et 2,03). (Trois études impliquaient 3952 enfants).

Chez les enfants hospitalisés souffrant d'une PC grave, l'amoxicilline par voie orale, comparée à la pénicilline ou ampicilline injectable, présentait des taux d'échec similaires (RC 0,95 ; IC à 95%, entre 0,78 et 1,15). (Trois études impliquaient 3942 enfants). Les taux de rechute étaient semblables dans les deux groupes (RC 1,28 ; IC à 95%, entre 0,34 et 4,82).

Pour la PC très grave, le taux de mortalité était plus élevé chez les enfants recevant le chloramphénicol par rapport à ceux recevant la pénicilline/ampicilline associée à la gentamicine (RC 1,25 ; IC à 95%, entre 0,76 et 2,07). (Une étude comprenait 1116 enfants).

Conclusions des auteurs

Il y avait beaucoup d'études étudiant plusieurs antibiotiques selon différentes méthodologies. Pour le traitement des malades externes souffrant d'une PC, l'amoxicilline est une alternative au cotrimoxazole. Avec le peu de données relatives aux autres antibiotiques, l'amoxicilline/acide clavulanique et la cefpodoxime peuvent être des médicaments de deuxième intention alternatifs. En ce qui concerne la pneumonie grave sans hypoxie, l'amoxicilline par voie orale peut être une alternative à la pénicilline injectable chez les enfants hospitalisés. Toutefois, pour le traitement antibiotique par voie orale de ces patients en consultation externe, davantage d'études en milieu communautaire sont nécessaires. Pour les enfants hospitalisés souffrant d'une PC grave ou très grave, la pénicilline/ampicilline associée à la gentamicine est supérieure au chloramphénicol. Les autres médicaments alternatifs, pour ce type de patients, sont la ceftriaxone, la lévofloxacine, l'amoxicilline/acide clavulanique et la céfuroxime. Jusqu'à ce que d'autres études soient disponibles, ils peuvent être utilisés en tant que traitement de seconde intention.

Il est nécessaire de réaliser plus d'études, avec des méthodologies similaires et de plus grandes populations de patients, pour comparer des antibiotiques plus récents.

Plain language summary

Different antibiotics for community-acquired pneumonia in children younger than 18 years of age in both hospital and ambulatory (outpatient) settings

Pneumonia is the leading cause of mortality in children under five years of age. Most cases of community-acquired pneumonia (CAP) in low-income countries are caused by bacteria. This systematic review identified 27 randomised controlled trials, enroling 11964 children, comparing antibiotics for treatment of CAP in children; most were single studies only. We found that for outpatient treatment of pneumonia, amoxycillin is an alternative treatment to co-trimoxazole. Oral amoxycillin in hospitalised children with severe pneumonia without hypoxia (decreased level of oxygen) may be effective. However, for outpatient treatment, more studies in community settings are required. For very severe pneumonia, a combination of penicillin or ampicillin and gentamycin is more effective than chloramphenicol alone.

Résumé simplifié

Antibiotiques pour la pneumonie communautaire chez l'enfant

Différents antibiotiques pour la pneumonie communautaire chez l'enfant de moins de 18 ans traitée en milieux hospitaliers et ambulatoires (malades en consultation externe)

La pneumonie est la première cause de mortalité chez les enfants de moins de cinq ans. Dans les pays à faible revenu, la plupart des cas de pneumonie communautaire (PC) sont d'origine bactérienne. Cette revue systématique a identifié 27 essais contrôlés randomisés portant sur 11964 enfants et comparant des antibiotiques pour le traitement de la PC chez l'enfant. La plupart étaient seulement des études indépendantes. Nous avons constaté que pour le traitement de la pneumonie chez les malades externes, l'amoxicilline est un traitement alternatif au cotrimoxazole. Chez les enfants hospitalisés souffrant d'une pneumonie grave sans hypoxie (diminution de la quantité d'oxygène dans les tissus), l'amoxicilline par voie orale peut être efficace. Pour le traitement des malades externes, néanmoins, davantage d'études en milieux communautaires sont nécessaires. Quant à la pneumonie très grave, l'association de la pénicilline ou de l'ampicilline avec la gentamicine s'avère plus efficace que le chloramphénicol seul.

Notes de traduction

Traduit par: French Cochrane Centre 1st December, 2012
Traduction financée par: Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux

Background

Pneumonia is the leading single cause of mortality in children aged less than five years, with an estimated incidence of 0.29 and 0.05 episodes per child-year in low-income and high-income countries respectively. It is estimated that a total of around 156 million new episodes occur each year and most of these occur in India (43 million), China (21 million), Pakistan (10 million) and Bangladesh, Indonesia and Nigeria (six million each) (Rudan 2008). Pneumonia is responsible for about two million deaths each year in children below five years of age and these occur mainly in the African and South-East Asian regions. Pneumonia contributes to about one-fifth (19%) of all deaths in children aged less than five years, of which more than 70% take place in sub-Saharan Africa and South-East Asia (Rudan 2008). To reduce the infant and under-five child mortality, it is important to reduce mortality due to pneumonia by appropriate intervention in the form of antibiotics. Selection of first-line antibiotics for empirical treatment of pneumonia is crucial for office practice as well as public health.

Description of the condition

Pneumonia is defined as infection of lung parenchyma (alveoli) by microbial agents. It is difficult to identify the causative organism in most cases of pneumonia. The methods used for identification of the aetiologic agents include blood culture, lung puncture, nasopharyngeal aspiration and immune assays of blood and urine tests. Lung puncture is an invasive procedure associated with significant morbidity and hence cannot be performed routinely in most cases. The yield from blood cultures is too low (5% to 15% for bacterial pathogens) to be relied upon (MacCracken 2000).There are few studies that document the aetiology of pneumonia in children below five years of age from low-income countries. Most studies carried out blood cultures for bacterial aetiology of pneumonia. Some studies carried out nasopharyngeal aspirates and identification of atypical organisms. A review of 14 studies involving 1096 lung aspirates taken from hospitalised children prior to administration of antibiotics reported bacterial pathogens in 62% of cases (Berman 1990). In 27% of patients, the common bacterial pathogens identified were Streptococcus pneumoniae (S. pneumoniae) and Haemophilus influenzae (H. influenzae) (Berman 1990). Studies using nasopharyngeal aspirates for identification of viral agents suggest that about 40% of pneumonia in children below five years of age is caused by viral agents, with the commonest viral pathogen being respiratory syncytial virus (Maitreyi 2000). In infants under three months of age, common pathogens include S. pneumoniae, H. influenzae, gram-negative bacilli and Staphylococcus (WHOYISG 1999). The causative organisms are different in high-income countries and include more viral and atypical organisms (Gendrel 1997; Ishiwada 1993; Numazaki 2004; Wubbel 1999). Therefore, treatment regimens may be different in high-income and low-income countries.

Description of the intervention

Administration of appropriate antibiotics at an early stage of pneumonia improves the outcome of the illness, particularly when the causative agent is bacterial. The World Health Organization (WHO) has provided guidelines for early diagnosis and assessment of the severity of pneumonia on the basis of clinical features (WHOYISG 1999) and suggests administration of co-trimoxazole as a first-line drug. The commonly used antibiotics for community-acquired pneumonia (CAP) include co-trimoxazole, amoxycillin, oral cephalosporins and macrolide drugs. Despite evidence of rising bacterial resistance to co-trimoxazole (IBIS 1999; Timothy 1993), studies conducted in the same time period showed good clinical efficacy of oral co-trimoxazole for non-severe pneumonia (Awasthi 2008; Rasmussen 1997; Straus 1998). However, one study reported a doubling of clinical failure rates with co-trimoxazole treatment when compared to treatment with amoxycillin in severe and radiologically confirmed pneumonia (Straus 1998). A meta-analysis of all the trials on pneumonia based on the case-management approach proposed by WHO (identification of pneumonia on clinical symptoms/signs and administration of empirical antimicrobial agents) has found reduction in mortality as well as pneumonia-related mortality (Sazawal 2003). To meet the public health goal of reducing child mortality due to pneumonia, empirical antibiotic administration is relied upon in most instances. This is necessary in view of the inability of most commonly available laboratory tests to identify causative pathogens.

Why it is important to do this review

Empirical antibiotic administration is the mainstay of treatment of pneumonia in children. Administration of the most appropriate antibiotic as first-line medicine may improve outcome of pneumonia. There are multiple antibiotics prescribed for treatment of pneumonia, therefore it is important to know which work best for pneumonia in children. The last review of all available randomised controlled trials (RCTs) on antibiotics used for pneumonia in children was published in 2006 (Kabra 2006). Since then, several new studies (Asghar 2008; Atkinson 2007; Aurangzeb 2003; Bansal 2006; Bradley 2007; Esposito 2005; Hasali 2005; Hazir 2008; Lee 2008; Lu 2006) have been published. It is therefore important to update the information by including all the new clinical trials.

Objectives

To identify effective antibiotic drug therapies for community-acquired pneumonia (CAP) in children by comparing various antibiotics.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) comparing antibiotics for community-acquired pneumonia (CAP) in children. We considered only those studies using the case definition of pneumonia (as given by the World Health Organization (WHO)) or radiologically-confirmed pneumonia in this review.

Types of participants

We included children under 18 years of age with CAP treated in a hospital or community setting. We excluded studies describing pneumonia post-hospitalisation in immunocompromised patients (for example, following surgical procedures).

Types of interventions

We compared any intervention with antibiotics (administered by intravenous route, intramuscular route, or orally) with another antibiotic for the treatment of CAP.

Types of outcome measures

Primary outcomes
  • Clinical cure. Definition of clinical cure is symptomatic and clinical recovery by the end of treatment.

  • Treatment failure rates. Definition of treatment failure is the presence of any of the following: development of chest in-drawing, convulsions, drowsiness or inability to drink at any time, respiratory rate above the age-specific cut-off point on completion of treatment, or oxygen saturation of less than 90% (measured by pulse oximetry) after completion of the treatment. Loss to follow up or withdrawal from the study at any time after recruitment was taken as failure in the analysis.

Secondary outcomes

The clinically relevant outcome measures were as follows.

  • Relapse rate: defined as children declared 'cured', but developing recurrence of disease at follow up in a defined period.

  • Hospitalisation rate (in outpatient studies only). Defined as need for hospitalisation in children who were getting treatment on an ambulatory (outpatient) basis.

  • Length of hospital stay: duration of total hospital stay (from day of admission to discharge) in days.

  • Need for change in antibiotics: children required change in antibiotics from the primary regimen.

  • Additional interventions used: any additional intervention in the form of mechanical ventilation, steroids, vaso-pressure agents, etc.

  • Mortality rate.

Search methods for identification of studies

We retrieved studies through a search strategy which included cross-referencing. We checked the cross-references of all the studies by hand.

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, issue 2), which contains the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to September 2009) and EMBASE (1990 to September 2009). There were no language or publication restrictions. We combined the MEDLINE search with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity- and precision-maximising version (2008 revision); Ovid format (Lefebvre 2008). See Appendix 1 for the EMBASE search strategy.

MEDLINE (OVID)

1 exp PNEUMONIA/
2 pneumonia
3 or/1-2
4 exp Anti-Bacterial Agents/
5 antibiotic$
6 or/4-5
7 exp CHILD/
8 exp INFANT/
9 (children or infant$ or pediatric or paediatric)
10 or/7-9
11 3 and 6 and 10

Searching other resources

We also searched bibliographies of selected articles to identify any additional trials not recovered by the electronic searches.

Data collection and analysis

Selection of studies

Two review authors (SKK, RL) independently selected potentially relevant studies based on their title and abstract. The complete texts of these studies were retrieved electronically or by contacting the trial authors. Two review authors (SKK, RL) independently reviewed the results for inclusion.

Data extraction and management

All the relevant studies were masked for authors' names and institutions, the location of the study, reference lists and any other potential identifiers. The papers were then given a serial number by a person who was not involved in the review. Two review authors (SKK, RL) independently reviewed the results for inclusion in the analysis. Differences about study quality were resolved through discussion. We recorded data on a pre-structured data extraction form. We assessed publication bias using the Cochrane Collaboration's 'Risk of bias' tool. Before combining the studies for each of the outcome variables, we carried out assessment of heterogeneity with Breslow's test of homogeneity using the Review Manager (RevMan) software (version 5.0) (RevMan 2008). We performed sensitivity analysis to check the importance of each study in order to see the effect of inclusion and exclusion criteria. We computed both the effect size and summary measures with 95% confidence intervals (CI) using RevMan software. For all the outcome variables, we used a random-effects model to combine the study results.

We collected data on the primary outcome (cure rate/failure rate) and secondary outcomes (relapse rate, rate of hospitalisation and complications, need for change in antibiotics, need for additional interventions and mortality). When available, we also recorded additional data on potential confounders such as underlying disease, prior antibiotic therapy and nutritional status.

We did multiple analyses, firstly on studies comparing the same antibiotics. We also attempted to perform indirect comparisons of various drugs when studies with direct comparisons were not available. For example, we compared antibiotics A and C when a comparison of antibiotics A and B was available and likewise a separate comparison between antibiotics B and C. We only did this type of comparison if the inclusion and exclusion criteria of these studies, the dose and duration of the common intervention (antibiotic B), baseline characteristics and the outcomes assessed were similar (Bucher 1997).

Assessment of risk of bias in included studies

We assessed risk of bias in all included studies using the Cochrane Collaboration's 'Risk of bias' tool (Higgins 2008):

1. Sequence generation: assessed as yes, no or unclear
Yes: when the study described the method used to generate the allocation sequence in sufficient detail.
No: sequence not generated.
Unclear: when it was not described or incompletely described.

2. Allocation concealment: assessed as yes, no or unclear
Yes: when the study described the method used to conceal the allocation sequence in sufficient detail.
No: described details where allocation concealment was not done.
Unclear: when it was not described or incompletely described.

3. Blinding of participants, personnel and outcome assessors: assessed as yes, no or unclear
Yes: when it was a double-blind study.
No: when it was an unblinded study.
Unclear: not clearly described.

4. Incomplete outcome data: assessed as yes, unclear
Yes: describe the completeness of outcome data for each main outcome, including attrition and exclusions from the analysis.
Unclear: either not described or incompletely described.

5. Free of selective outcome reporting: assessed as yes, no or unclear
Yes: results of study free of selective reporting. Details of all the patients enrolled in the study are included in the paper.
No: details of all the enrolled patients not given in the paper.
Unclear: details of all the enrolled patients incompletely described.

6. Other sources of bias
Among the other sources of potential bias considered was funding agencies and their role in the study. We recorded funding agencies as governmental agencies, universities and research organisations or pharmaceutical companies. We considered studies supported by pharmaceutical companies to be unclear unless the study defined the role of the pharmaceutical companies. We also considered studies not mentioning the source of funding as unclear under this heading.

Assessment of heterogeneity

For each of the outcome variables, we carried out assessment of heterogeneity with Breslow's test of homogeneity using RevMan software (as described in data extraction and analysis section).

Assessment of reporting biases

Before combining the study results we checked for publication bias by using a funnel plot. For each of the outcome variables (cure rate, failure rate, relapse rate, rate of hospitalisation, the complications needed for change in antibiotics and mortality rate) we used a two-by-two table for each study and performed Breslow's test of homogeneity to determine variation in study results.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

Results of the search

Two review authors (SKK, RL) screened the article titles. Forty-four studies were short-listed as potential randomised controlled trials to be included and we attempted to collect the full-text articles; we obtained the full text for 43. These papers were blinded by a third person who was not involved in the review. Two review authors (SKK, RL) independently extracted data by using a pre-designed data extraction form; the extracted data matched completely.

Included studies

We identified 27 studies for inclusion, with the following comparisons.

  • Azithromycin with erythromycin: four studies (Harris 1998; Kogan 2003; Roord 1996; Wubbel 1999), involving 457 children aged two months to 16 years.

  • Clarithromycin with erythromycin: one study (Block 1995), involving 357 children below 15 years of age with clinical or radiographically diagnosed pneumonia treated on an ambulatory basis.

  • Co-trimoxazole with amoxycillin: two studies (CATCHUP 2002; Straus 1998), involving 2066 children aged two months to 59 months.

  • Co-trimoxazole with procaine penicillin: two studies (Keeley 1990; Sidal 1994), involving 723 children aged three months to 12 years.

  • Chloramphenicol with penicillin and gentamycin together: one study (Duke 2002), involving 1116 children aged one month to five years.

  • Single-dose benzathine penicillin with procaine penicillin: two studies (Camargos 1997; Sidal 1994), involving 176 children between two and 12 years of age in one study (Sidal 1994) and 105 children aged between three months to 14 years in the other similar study (Camargos 1997).

  • Amoxycillin with procaine penicillin: one study (Tsarouhas 1998), involving 170 children aged six months to 18 years.

  • Ampicillin with chloramphenicol plus penicillin: one study (Deivanayagam 1996), involving 115 children aged five months to four years.

  • Co-trimoxazole with single-dose procaine penicillin followed by oral ampicillin: one study (Campbell 1988), involving 134 children aged below five years.

  • Penicillin with amoxycillin: two studies (Addo-Yobo 2004; Atkinson 2007), involving 1905 children aged three months to 59 months.

  • Co-trimoxazole with chloramphenicol: one study (Mulholland 1995), involving 111 children aged under five years.

  • Cefpodoxime with co-amoxyclavulanic acid: one study (Klein 1995), involving 348 children aged three months to 11.5 years.

  • Azithromycin with amoxycillin: one study (Kogan 2003), involving 47 children aged one month to 14 years.

  • Amoxycillin with co-amoxyclavulanic acid: one study (Jibril 1989), involving 100 children aged two months to 12 years.

  • Chloramphenicol in addition to penicillin with ceftriaxone: one study (Cetinkaya 2004), involving 97 children aged between two to 24 months admitted to hospital with severe pneumonia.

  • Levofloxacin and comparator (co-amoxyclavulanic acid or ceftriaxone): one study (Bradley 2007) involving 709 children aged 0.5 to 16 years of age with community-acquired pneumonia treated in hospital or ambulatory care.

  • Parenteral ampicillin followed by oral amoxycillin with home-based oral amoxycillin: one study (Hazir 2008) involving 2037 children between three months to 59 months of age with WHO-defined severe pneumonia.

  • Chloramphenicol with ampicillin and gentamycin: one study (Asghar 2008), involving 958 children between two to 59 months with very severe pneumonia.

  • Penicillin and gentamicin with co-amoxyclavulanic acid (Bansal 2006), involving 71 children with severe and very severe pneumonia between two months to 59 months of age.

  • Co-amoxyclavulanic acid with cefuroxime or clarithromycin: one study (Aurangzeb 2003), involving 126 children between two to 72 months of age.

Excluded studies

We excluded a total of 17 studies.

Risk of bias in included studies

Details of sequence generation were described in 16 studies (Addo-Yobo 2004; Asghar 2008; Atkinson 2007; Awasthi 2008; Bansal 2006; Camargos 1997; CATCHUP 2002; Cetinkaya 2004; Deivanayagam 1996; Duke 2002; Hazir 2008; Jibril 1989; Keeley 1990; Mulholland 1995; Roord 1996; Shann 1985), were not clear in nine studies (Aurangzeb 2003; Block 1995; Bradley 2007; Campbell 1988; Harris 1998; Klein 1995; Straus 1998; Tsarouhas 1998; Wubbel 1999) and sequence was not generated in two studies (Kogan 2003; Sidal 1994).

Allocation

Allocation concealment was adequate in 16 studies (Addo-Yobo 2004; Asghar 2008; Atkinson 2007; Awasthi 2008; Bansal 2006; Camargos 1997; CATCHUP 2002; Cetinkaya 2004; Deivanayagam 1996; Duke 2002; Harris 1998; Hazir 2008; Keeley 1990; Mulholland 1995; Shann 1985; Tsarouhas 1998), it was unclear in eight studies (Aurangzeb 2003; Block 1995; Bradley 2007; Campbell 1988; Jibril 1989; Klein 1995; Straus 1998; Wubbel 1999) and no concealment was done in three studies (Kogan 2003; Roord 1996; Sidal 1994) (see Table 1).

Table 1. Assessment of risk of bias in included studies
StudyWas the allocation sequence adequately generated?
Yes/Unclear
Was allocation adequately concealed?
Yes/No/Unclear
Was knowledge of the allocated intervention adequately prevented during the study?
Yes/No/Unclear
Were incomplete outcome data adequately addressed?
Yes/No/Unclear
Was there selective reporting of data?
Yes/No/Unclear
Any other bias?
Addo-Yobo 2004YesYesNoYesYesYes
Asghar 2008YesYesNoYesYesYes
Atkinson 2007YesYesNoYesUnclearYes
Aurangzeb 2003UnclearUnclearNoYesUnclearUnclear
Awasthi 2008YesYesNoYesYesYes
Bansal 2006YesYesNoYesYesUnclear
Block 1995UnclearUnclearNoYesYesUnclear
Bradley 2007UnclearUnclearNoUnclearUnclearUnclear
Camargos 1997YesYesNoUnclearYesUnclear
Campbell 1988UnclearUnclearNoUnclearUnclearUnclear
CATCHUP 2002YesYesYesYesYesYes
Cetinkaya 2004YesYesYesYesYesYes
Deivanayagam 1996YesYesNoUnclearUnclearUnclear
Duke 2002YesYesNoYesYesYes
Harris 1998UnclearYesYesUnclearUnclearUnclear
Hazir 2008YesYesNoYesYesYes
Jibril 1989YesYesNoUnclearUnclearUnclear
Keeley 1990YesUnclearNoUnclearUnclearYes
Klein 1995UnclearUnclearNoUnclearUnclearUnclear
Kogan 2003NoNoNoYesYesUnclear
Mulholland 1995YesYesYesYesYesYes
Roord 1996YesNoNoYesYesUnclear
Shann 1985YesYesNoUnclearUnclearUnclear
Sidal 1994NoNoNoUnclearUnclearUnclear
Straus 1998UnclearUnclearYesYesYesUnclear
Tsarouhas 1998UnclearYesNoYesYesUnclear
Wubbel 1999UnclearUnclearNoYesUnclearUnclear

Blinding

Only five studies (CATCHUP 2002; Cetinkaya 2004; Harris 1998; Mulholland 1995; Straus 1998) were double-blinded (Table 1). The rest of the studies were unblinded.

Incomplete outcome data

Data was fully detailed in 18 studies (Addo-Yobo 2004; Asghar 2008; Atkinson 2007; Aurangzeb 2003; Awasthi 2008; Bansal 2006; Block 1995; Camargos 1997; CATCHUP 2002; Cetinkaya 2004; Duke 2002; Hazir 2008; Kogan 2003 Mulholland 1995; Roord 1996; Straus 1998; Tsarouhas 1998; Wubbel 1999) and in the remaining studies details of attrition and exclusions from the analysis were unavailable.

Selective reporting

Selective reporting of data was unclear in 12 studies (Atkinson 2007; Aurangzeb 2003; Bradley 2007; Campbell 1988; Deivanayagam 1996; Harris 1998; Jibril 1989; Keeley 1990; Klein 1995; Shann 1985; Sidal 1994; Wubbel 1999). The rest of the studies scored 'yes' for being free from selective reporting.

Other potential sources of bias

The source of funding was not mentioned in eight studies (Aurangzeb 2003; Bansal 2006; Cetinkaya 2004; Deivanayagam 1996; Jibril 1989; Klein 1995; Sidal 1994; Tsarouhas 1998). Six studies were funded by pharmaceutical companies (Block 1995; Bradley 2007; Duke 2002; Harris 1998; Roord 1996; Wubbel 1999). Twelve studies were supported by the WHO, Medical Research Council or universities (Addo-Yobo 2004; Asghar 2008; Atkinson 2007; Awasthi 2008; Camargos 1997; Campbell 1988; Hazir 2008; Keeley 1990; Mulholland 1995; Shann 1985; Sidal 1994; Straus 1998). One study (CATCHUP 2002) was supported by the WHO in addition to pharmaceutical companies. Information on clearance by Ethics Committees or Institutional Review Boards was available for all except four studies (Aurangzeb 2003; Jibril 1989; Keeley 1990; Sidal 1994).

Effects of interventions

Studies comparing ambulatory treatment of non-severe pneumonia

Azithromycin versus erythromycin (Analysis 1)

Four studies (Harris 1998; Kogan 2003; Roord 1996; Wubbel 1999) compared erythromycin with azithromycin and enrolled 623 children. One study (Harris 1998) was double-blinded with adequate allocation concealment and three studies (Kogan 2003; Roord 1996; Wubbel 1999) were unblinded and did not have adequate allocation concealment. Information on the presence of wheezing was available in two studies (Harris 1998; Kogan 2003): 104 out of 318 (33%) children experienced wheezing in the azithromycin group, while 62 out of 161 (39%) in the erythromycin group experienced wheezing. The failure rates in the azithromycin and erythromycin groups were six out of 236 (2.5%) and seven out of 156 (4.4%), respectively (OR 0.57; 95% CI 0.14 to 2.33) There were no significant side effects in either group. Three studies reported data on aetiologic organisms separately for each of the two treatment groups (Harris 1998; Kogan 2003; Roord 1996); there were 234 organisms identified in the azithromycin group and 135 in the erythromycin group (Roord 1996). The distribution of different organisms was similar in the two groups. There were 24 organisms identified in the fourth study (Wubbel 1999) in 59 participants tested.

Clarithromycin versus erythromycin (Analysis 2)

One study (Block 1995) compared erythromycin and clarithromycin; 234 children below 15 years of age with clinical or radiographically diagnosed pneumonia were treated on an ambulatory basis. The trial was single-blinded and allocation concealment was unclear. The following outcomes were similar between the two groups: cure rate (OR 1.61; 95% CI 0.84 to 3.08), clinical success rate (OR 1.92; 95% CI 0.45 to 8.23), failure rate (OR 0.52; 95% CI 0.12 to 2.23), relapse rate (OR 0.17; 95% CI 0.02 to 1.45) and adverse events (OR 1.07; 95% CI 0.6 to 1.90). Resolution of pneumonia (diagnosed radiologically) was more frequent in the clarithromycin group as compared to the erythromycin group (OR 2.51; 95% CI 1.02 to 6.16). However, there were no differences in the improvement rates (OR 3.55; 95% CI 0.7 to 18.04) or decline rates (OR 0.34; 95% CI 0.06 to 1.80), both of which were established with radiological evidence.

Azithromycin versus co-amoxyclavulanic acid (Analysis 3)

Two studies (Harris 1998; Wubbel 1999) compared these two drugs in 283 children below five years of age. One study (Harris 1998) was double-blinded and allocation concealment was adequate while the other study (Wubbel 1999) was unblinded with inadequate allocation concealment. The cure rates (available for one study) (OR 1.02; 95% CI 0.54 to 1.95), failure rates (available for both studies) (OR 1.21; 95% CI 0.42 to 3.53) and improvement rates (OR 0.85; 95% CI 0.43 to 1.71) were similar in the two groups. There were fewer side effects reported in the azithromycin group (OR 0.15; 95% CI 0.04 to 0.61). The organisms isolated were S. pneumoniae in 28 children, H. influenzae in one, Mycoplasma pneumoniae (M. pneumoniae) in 36 and Chlamydia pneumoniae (C. pneumoniae) in 20. The separate data for isolation of organisms in the two groups was available in one study only (Harris 1998). The organisms isolated in this study (Harris 1998) were S. pneumoniae and H. influenzae in one patient each in the azithromycin group. Investigations for mycoplasma were positive in 21 out of the 129 children (16%) tested in the azithromycin group and 9 out of the 66 children (14%) tested in the co-amoxyclavulanic acid group. Investigations for C. pneumoniae were positive in 13 out of the 129 children (10%) tested in the azithromycin group and four out of the 66 children (6%) tested in the co-amoxyclavulanic acid group.

Azithromycin versus amoxycillin (Analysis 4)

One study involving 47 children aged between one month and 14 years with classical pneumonia compared these two drugs (Kogan 2003). Children treated with azithromycin were older than those treated with amoxycillin (OR 58.1; 95% CI 35.59, 80.61). The study was unblinded and allocation concealment was also inadequate. All children recovered at the end of treatment in both the groups. There were 19 organisms identified in the 47 children tested (10 in the azithromycin group and nine in the amoxycillin group). The identification rates were similar in the two groups. Organisms included M. pneumoniae (in five and three children for the azithromycin and amoxycillin groups, respectively), S. pneumoniae (in four and three respectively) and others (in one and three, respectively).

Amoxycillin versus procaine penicillin (Analysis 5)

One study involved 170 children aged six months to 18 years was identified (Tsarouhas 1998). The study was unblinded but allocation concealment was adequate. The age distribution in the two groups was comparable. The failure rates were similar in the two groups (OR 0.75; 95% CI 0.17 to 3.25).

Co-amoxyclavulanic acid versus amoxycillin (Analysis 6)

One study involving 100 children between two and 12 years of age. It was an open-label study on children suffering from clinically diagnosed bacterial pneumonia (Jibril 1989). The study was unblinded and allocation concealment was also inadequate. Age and sex distribution, presence of wheeze and mean weight in the two groups were comparable. Cure rate was better with co-amoxyclavulanic acid (OR 10.44; 95% CI 2.85 to 38.21).

Co-trimoxazole versus amoxycillin (Analysis 7)

Three multicentre studies (Awasthi 2008; CATCHUP 2002; Straus 1998) involving 3952 children (2067 in the co-trimoxazole group and 1885 in the amoxycillin group) between two months and 59 months of age have compared co-trimoxazole and amoxycillin. The diagnosis of pneumonia was based on clinical criteria. Two studies (CATCHUP 2002; Straus 1998) were double-blinded and allocation concealment was adequate. A third study (Awasthi 2008) was open-label and cluster-randomisation was done (the randomisation unit was Primary Health Centre) and in this study assessment of the primary outcome of treatment failure was done on day four for the amoxycillin group and day six for the co-trimoxazole group. All studies included children with non-severe pneumonia; one study (Straus 1998) also included 301 children with severe pneumonia. In pooled data the failure rate in non-severe pneumonia was similar in the two groups (OR 0.92; 95% CI 0.58 to 1.47). The cure rate could be extracted in two studies (Awasthi 2008; CATCHUP 2002) and it was not different in either treatment group (OR 1.12; 95% CI 0.61 to 2.03). Loss to follow up was comparable in the two groups (OR 0.88; 95% CI 0.67 to 1.16). There were only two deaths in both the groups. The organisms isolated from blood cultures were H. influenzae in 79 children (52 in the co-trimoxazole group and 27 in the amoxycillin group) and S. pneumoniae in 49 children (36 in the co-trimoxazole group and 13 in the amoxycillin group); the distribution was similar in the two groups. In view of the difference in the time of assessment for primary outcome in one study (Awasthi 2008) we performed analysis for failure rates in non-severe pneumonia after excluding this study. The results did not alter significantly; failure rates in the two groups were similar (OR 1.19; 95% CI 0.92 to 1.53). Failure rates in severe pneumonia available in one study was similar in the two groups (OR 1.71; 95% CI 0.94 to 3.11).

Co-trimoxazole versus procaine penicillin (Analysis 8)

Two studies (Keeley 1990; Sidal 1994) enrolled 723 children between three months and 12 years of age. Both studies were unblinded and allocation concealment was adequate in one study (Keeley 1990). The cure rate was similar in the two groups (OR 1.58; 95% CI 0.26 to 9.69). Rate of hospitalisation was available in only one study and was similar in the two groups (OR 2.52; 95% CI 0.88 to 7.25). There was only one death.

Co-trimoxazole versus single-dose procaine penicillin followed by oral ampicillin for five days (Analysis 9)

One study was included that had enrolled 134 children below five years of age with severe pneumonia as defined by WHO criteria (Campbell 1988). The study was unblinded and allocation concealment was not clearly stated. The cure rates (OR 1.15; 95% CI 0.36 to 3.61), hospitalisation rates (OR 1.57; 95% CI 0.25 to 9.72) and death rates were similar for the two groups.

Cefpodoxime versus co-amoxyclavulanic acid (Analysis 10)

One multicentre study (Klein 1995) enrolled 348 children between three months and 11.5 years of age. The study was unblinded and allocation concealment was inadequate. The age distribution in the two groups was comparable. The response rate at the end of 10 days of treatment was comparable in the two groups (OR 0.69; 95% CI 0.18 to 2.60). Organisms were isolated in 59 cases. These organisms were H. influenzae in 28 participants (47.5%), S. pneumoniae in 14 (23%), M. catarrhalis in seven (11.9%) and H. parainfluenzae in four (6.8). There was no significant difference in the bacteriologic efficacy of either group (100% versus 96.4%).

Studies comparing treatment of hospitalised children with severe/very severe pneumonia

Chloramphenicol versus penicillin plus gentamycin (Analysis 11)

One multicentre study including 1116 children aged between one month and five years compared chloramphenicol with penicillin and gentamycin. This was an open-label RCT in children with severe pneumonia that was carried out in Papua New Guinea (Duke 2002). Allocation concealment was adequate. There was no significant difference between the two groups in positive cultures, children who had received antibiotics earlier and loss to follow up. Need for change in antibiotics (OR 0.80; 95% CI 0.54 to 1.18), death rates (OR 1.25; 95% CI 0.76 to 2.07) and adverse events (OR 1.26; 95% CI 0.96 to 1.66) were similar in the two groups. However, re-admission rates before 30 days favoured the penicillin-gentamycin combination over chloramphenicol (OR 1.61; 95% CI 1.02 to 2.55). Bacterial pathogens were identified in 144 children (67 in children receiving chloramphenicol and 77 in the other group). Isolation rates or sensitivity of the organism and failure rates did not differ between the two groups.

Chloramphenicol with ampicillin and gentamycin (Analysis 12)

One multicentre study was identified; this study enrolled 958 children who were hospitalised with WHO defined very severe pneumonia (Asghar 2008). The study was unblinded and allocation concealment was adequate. Mean age, proportion of boys and number of children who had received antibiotics before enrolment were comparable in the two groups. Failure rates on day five (OR 1.51; 95% CI 1.04 to 2.19), day 10 (OR 1.46; 95% CI 1.04 to 2.06) and day 21 (OR 1.43; 95% CI 1.03 to 1.98) were significantly higher in those receiving chloramphenicol as compared to ampicillin and gentamycin. Death rates were higher in those receiving chloramphenicol (OR 1.65; 95% CI 0.99 to 2.77).

Chloramphenicol plus penicillin versus ceftriaxone (Analysis 13)

One double-blind study fulfilled the inclusion criteria; the study enrolled 97 children between 2 and 24 months of age diagnosed with severe CAP with probable bacterial aetiology (Cetinkaya 2004). Allocation concealment was adequate. Ages in the two groups were comparable (details not available). Cure rates in the two groups were similar (OR 1.36; 95% CI 0.47 to 3.93).

Chloramphenicol alone versus chloramphenicol plus penicillin (Analysis 14)

One study (Shann 1985) from Papua New Guinea involved 748 hospitalised children (age not clear) with severe pneumonia. The study was unblinded but allocation concealment was adequate. Need for change in antibiotics (OR 0.49; 95% CI 0.12 to 1.97), loss to follow up (OR 1.11; 95% CI 0.80, 1.53) and deaths rates (OR 0.73; 95% CI 0.48 to 1.09) were comparable in the two groups.

Ampicillin alone versus penicillin with chloramphenicol (Analysis 15 )

One trial involving 115 children between five months and four years of age was identified (Deivanayagam 1996). The study was unblinded and allocation concealment was adequate. Age and sex distribution and proportion of children with severe malnutrition were comparable in the two groups. The cure rates (OR 0.48; 95% CI 0.15 to 1.51) and duration of hospitalisation were similar in the two groups (weighted mean difference (WMD) 0.1; 95% CI -1.13 to 0.93).

Benzathine penicillin versus procaine penicillin (Analysis 16)

Two studies fulfilled the inclusion criteria; one which included 176 children between two and12 years of age with chest X-ray films showing lobar consolidation or infiltration (presumed streptococcal infection) (Camargos 1997) and another study of 105 children between three months and 14 years of age (Sidal 1994). Both studies were unblinded and allocation concealment was adequate in one (Camargos 1997). Cure rates were not significantly different in the two groups (OR 0.53; 95% CI 0.27 to 1.01). Failure rates were also similar between the groups (OR 3.17; 95% CI 0.9 to 11.11). Bacterial pathogens were identified in only one study. The isolation rate for S. pneumoniae was six out of 90 blood cultures performed (four patients in the benzathine group and two in the procaine penicillin group). The clinical outcome did not differ in relation to the organism identified.

Amoxycillin versus penicillin (Analysis 17)

Two multicentre non-blinded studies were identified; these enrolled 1702 children between three months and 59 months of age, suffering from severe pneumonia (diagnosed on the basis of WHO criteria) (Addo-Yobo 2004) and 203 children with radiographically confirmed pneumonia (Atkinson 2007). The studies were unblinded and allocation concealment was adequate. The second study (Atkinson 2007) measured outcome as time from randomisation until the temperature was < 38 degrees celsius for 24 hours and oxygen requirement had ceased. However, it provided data on need for change of antibiotics due to worsening of respiratory/radiological findings. For the purposes of this analysis we considered them as failure on day five. Age, sex, severe malnutrition, breast feeding and the number of children who had received antibiotics in the last week were similar in both the groups. The failure rates measured at 48 hours (OR 1.03; 95% CI 0.81 to 1.31), five days (OR 1.15; 95% CI 0.58, 2.30) and 14 days (OR 1.04; 95% CI 0.84 to 1.29) were similar in both groups. There were seven deaths in the group receiving penicillin in one study ( Addo-Yobo 2004) while no deaths were observed in the other study (Atkinson 2007).

Amoxycillin with intravenous (IV) ampicillin (Analysis 18)

One non-blinded study, involving 237 children between two and 59 months of age with severe pneumonia was identified (Hazir 2008). Allocation concealment was adequate. Number of infants in each group, sex distribution and presence of wheeze were comparable in the two groups. Failure rates (OR 0.86; 95% CI 0.63 to 1.19), relapse rates (OR 0.78; 95% CI 0.46 to 1.33) and death rates (OR 0.25; 95% CI 0.03 to 2.21) were similar in the two groups.

Amoxycillin with cefuroxime (Analysis 19)

One randomised, non-blinded controlled study was identified; this included 83 children with non-severe and severe pneumonia (Aurangzeb 2003). Allocation concealment was unclear. Baseline data in the form of mean age and proportion of boys were similar in the two groups. Cure rates (OR 2.05; 95% CI 0.18 to 23.51) and failure rates (OR 0.49; 95% CI 0.04 to 5.59) were similar in the two groups.

Amoxycillin with clarithromycin (Analysis 20)

One randomised, non-blinded controlled study compared these two drugs; 85 children with non-severe and severe pneumonia were enrolled (Aurangzeb 2003). The sequence generation and allocation concealment in the study is not clear. Baseline data in form of mean age and proportion of boys were similar in the two groups. Cure rates (OR 1.05; 95% CI 0.06 to 17.40) and failure rates (OR 0.95; 95% CI 0.06 to 15.74) were similar in the two groups.

Penicillin and gentamycin with co-amoxyclavulanic acid (Analysis 21)

One study involving 71 children between two months and 59 months of age with very severe pneumonia fulfilled the inclusion criteria (Bansal 2006). The study was non-blinded and allocation concealment was adequate. Baseline characteristics, including number of infants and sex distribution, were comparable. Failure rates in the two groups were similar (OR 0.86; 95% CI 0.05 to14.39).

Levofloxacin with comparator group (Analysis 22)

One non-blinded study, involving 709 children below 16 years of age, compared oral levofloxacin with either ceftriaxone or co-amoxyclavulanic acid (Bradley 2007). Sequence generation and allocation concealment is not clear from the study. The mean age, sex and number who received antibiotics before enrolment were comparable in the two groups. Cure rates were similar in the two groups (OR 1.05; 95% CI 0.46 to 2.42).

Cefuroxime with clarithromycin (Analysis 23)

One randomised, non-blinded, controlled study involving 85 children with non-severe and severe pneumonia was identified (Aurangzeb 2003). Allocation concealment was unclear. Baseline data in the form of mean age and proportion of boys were similar in the two groups. Cure rates (OR 0.51; 95% CI 0.04 to 5.89) and failure rates (OR 2.05; 95% CI 0.18 to 23.51) were similar in the two groups.

Co-trimoxazole versus chloramphenicol (Analysis 24)

One double-blind study involving 111 malnourished children under five years of age fulfilled the inclusion criteria for this review (Mulholland 1995). Allocation concealment was adequate. The age and sex distribution, nutritional status, children with wheezing and numbers excluded were similar in the two groups. Cure rates (OR 1.06; 95% CI 0.47 to 2.40), failure rates (OR 1.03; 95% CI 0.45 to 2.33), number of patients requiring a change in antibiotics (OR 1.42; 95% CI 0.46 to 4.40), relapse rates (OR 1.02; 95% CI 0.24 to 4.30) and death rates (OR 2.21; 95% CI 0.63 to 7.83) were similar in the two groups.

Oral treatment of severe pneumonia with parenteral treatment (Analysis 25)

There were three studies that compared oral amoxycillin with injectable penicillin in two studies (Addo-Yobo 2004; Atkinson 2007) or ampicillin in one study (Hazir 2008). A total of 3942 children were enrolled. Two studies (Addo-Yobo 2004; Hazir 2008) enrolled 3739 children below five years of age, while the third study (Atkinson 2007) enrolled a total of 203 children; of these 36 were above 60 months of age. The baseline characteristics in the form of age and sex distribution in the two groups and proportion of children who had received antibiotics before enrolment were comparable in the two groups. Failure rates were available in all three studies and were similar in the two groups (OR 0.95; 95% CI 0.78 to 1.15). Death rates were significantly more in those who received injectable treatment (OR 0.15; 95% CI 0.03 to 0.87). There were no deaths in one study (Atkinson 2007), seven deaths in another study (but all happened in those getting injectable medications (Addo-Yobo 2004)) and five deaths in the third study (one in the oral group and four in the injectable group) (Hazir 2008). Reanalysis after removing one study (Addo-Yobo 2004) with seven deaths in only one group suggests no significant difference in the two groups (OR 0.87; 95% CI 0.65 to 1.15). Relapse rates could be derived from two studies (Atkinson 2007; Hazir 2008) and were similar in the two groups (OR 1.28; 95% CI 0.34 to 4.82).

Identification of aetiological agents

Out of 27 studies reviewed, attempts were made to isolate or demonstrate the aetiological organisms in 13 studies. The methods used in these studies for identification of bacteria were a blood culture, sputum examination or urinary antigen detection. For this review, results of a throat swab for bacterial isolation were ignored. Bacterial pathogens could be identified in blood cultures or serology/sputum in 513 (10.8%) out of 4742 patients tested. Out of the bacterial pathogens identified, 212 (41%) patients had S. pneumoniae, 129 (25%) had H. influenzae, 58 (11%) had Staphylococcus aureus (S. aureus) and 114 (22%) had other pathogens including the gram negative bacilli M. catarrhalis and Staphylococcus albus (S. albus) (Table 2).

Table 2. Bacterial isolation
Study/total testedS. pneumoniaeH. influenzaeStaphylococcusOthers
Asghar et al / 9582284733
Bansal et al / 713200
Block et al / 1222200
Bradley et al / 70921703
Camargos et al / 906000
Duke et al / 11164101036
Harris et al / 3515200
Klein et al / 3481428017
Kogan et al / 477004
Mulholland et al / 11110208
Roord et al / 951119113
Straus et al / 595794900
Wubbel et al / 12935000
Total / 4742212 (4.5%)129 (2.7%)58 (1.2%)114(2.4%)
Out of total bacterial isolates212/513 (41%)129/513 (25%)58/513 (11%)114/513 (22%)

Information regarding the sensitivity pattern of bacterial isolates was available in four studies (Asghar 2008; Bansal 2006; Mulholland 1995; Roord 1996). This information was only available for the antibiotics studied and sensitivity was not tested in all the isolates. In the study by Asghar et al, out of a total of 22 S. pneumoniae isolates, 13/14 were sensitive to chloramphenicol, 12/17 to gentamycin, 15/16 to ampicillin and 12/12 to third generation cephalosporins (Asghar 2008). Out of a total of eight isolates of H. influenzae, 6/7 were sensitive to chloramphenicol, 12/17 to gentamicin, 15/16 to ampicillin and 6/6 to third generation cephalosporins. Out of a total of 47 isolates of Staphylococcus aureus 19/37 were sensitive to chloramphenicol, 29/45 to gentamycin, 15/16 to ampicillin and 6/6 to third generation cephalosporins. In the study by Bansal (Bansal 2006), all the three isolates of S. pneumoniae were sensitive to penicillin, amoxycillin, erythromycin and gentamycin. However, out of two isolates of H. influenzae, one was sensitive and the other isolate was resistant to penicillin, amoxycillin, erythromycin and gentamycin. The one that was resistant was sensitive to ciprofloxacin, cefotaxime and chloramphenicol. In the study by Mulholland (Mulholland 1995), all 10 isolates of S. pneumoniae were susceptible to co-trimoxazole and nine of these were also susceptible to chloramphenicol. All three Salmonella spp. isolates were susceptible to co-trimoxazole and chloramphenicol. A single isolate of H. influenzae was resistant to co-trimoxazole. In the study by Roord (Roord 1996), all 20 isolates were sensitive to azithromycin while three organisms were resistant to erythromycin.

Nasopharyngeal aspirates were tested for respiratory syncytial virus (RSV) in four studies (Atkinson 2007; Addo-Yobo 2004; Mulholland 1995; Wubbel 1999) involving 1916 children. RSV was identified in 403 children (21%). Identification of atypical organisms was attempted in five studies (Block 1995; Bradley 2007; Harris 1998; Kogan 2003; Wubbel 1999). Out of the 1594 patients tested for M. pneumoniae, 381 (24%) were tested positive. In patients aged under five years 141 out of 659 (21%) tested positive for mycoplasma. Tests for Chlamydia spp. were positive in 158 out of 1534 (10%) patients. In children under five years, there were positive test results for Chlamydia spp. in 45 out of 658 (7%) patients.

Indirect comparison

We attempted to compare various antibiotics (A and C) when comparisons of antibiotics A and B were available and B and C were available. We utilised this process to compare co-trimoxazole with co-amoxyclavulanic acid (Analysis 26), amoxycillin with cefpodoxime (Analysis 27) and amoxycillin with chloramphenicol (Analysis 28). Baseline data for age and sex were not comparable in the first two comparisons and therefore no valid comparison could be carried out. In the comparison of amoxycillin with chloramphenicol (CATCHUP 2002; Mulholland 1995; Straus 1998) sex distribution was not comparable although age distribution was. Cure rates were better in the amoxycillin group compared to the chloramphenicol group (OR 4.26; 95% CI 2.57 to 7.08) and failure rates were lower in the amoxycillin group (OR 0.64; 95% CI 0.41 to 1.00).

Discussion

The aim of this review was to establish the most effective antibiotics for first-line empirical treatment of community-acquired pneumonia (CAP). A limited number of randomised controlled trials (RCTs) fulfilled the inclusion criteria. Most of the antibiotic comparisons were available in single studies only.

Summary of main results

Studies comparing ambulatory treatment of pneumonia suggest that co-amoxyclavulanic acid was better than amoxycillin. Amoxycillin and co-trimoxazole were associated with similar failure rates. Resolution of radiologic pneumonia was better with clarithromycin as compared to erythromycin and side effects were fewer with azithromycin as compared to co-amoxyclavulanic acid. For children with severe pneumonia treatment with oral amoxycillin was similar to that of injectable ampicillin or penicillin. Death rates were higher in children getting chloramphenicol as compared to those getting penicillin/ampicillin plus gentamycin.

For severe/very severe pneumonia, penicillin/ampicillin plus gentamycin was associated with lower re-admission rates as compared to chloramphenicol.

For very severe pneumonia failure rates were significantly higher as compared to ampicillin and gentamycin

The rest of the comparisons for ambulatory treatment involved azithromycin with erythromycin, clarithromycin, clarithromycin with erythromycin, amoxycillin with procaine penicillin, co-trimoxazole with single dose procaine penicillin followed by oral ampicillin, and cefpodoxime with co-amoxyclavulanic acid and there were no statistically significant differences in these comparisons.

Comparison for severe and very severe pneumonia involved chloramphenicol plus ampicillin with penicillin, amoxycillin with cefuroxime, amoxycillin with clarithromycin, penicillin and gentamycin with co-amoxyclavulanic acid, levofloxacin with ceftriaxone or co-amoxyclavulanic acid, cefuroxime with clarithromycin and chloramphenicol with co-trimoxazole and were comparable.

Overall completeness and applicability of evidence

Treatment of pneumonia depends on the age of the child, the severity of illness, the likely aetiological agents and their resistance pattern. The aetiological agents vary with age and possibly geographic location. Most of the studies included in this review were from under-developed countries with age groups below five years and identification of aetiological agents was limited to a few studies. The burden of pneumonia is significant in infants from developing countries. Attempts to isolate aetiological agents may not be cost-effective and therefore empirical treatment of pneumonia is justified. The results of this review may therefore be more applicable to the management of pneumonia in developing countries. However, data comparing two different antibiotics may also be useful in guiding antibiotic therapy in industrialised countries.

The World Health Organization (WHO) recommends treatment of non-severe pneumonia with co-trimoxazole as a first-line empirical antimicrobial treatment in countries with an infant mortality higher than 40 per 1000 live births (WHO 1991). Concerns about increasing resistance of common pathogens (S. Pneumoniae and H. Influenzae) to co-trimoxazole have been raised and amoxycillin has been suggested as an alternative. This review suggests that amoxycillin and co-trimoxazole are associated with similar failure rates. It can be concluded that there are insufficient data to show superiority of amoxycillin to co-trimoxazole. It should be noted that amoxycillin is more expensive than co-trimoxazole for five days of treatment for a child weighing between 5 and 10 kg (in India US $0.6 versus $0.3). Two recent studies (Agarwal 2004; MASCOT Group 2002) reported similar cure rates with amoxycillin given for three or five days. The cost of amoxycillin would be reduced to some extent if the treatment duration of amoxycillin was lowered to three days. Most studies comparing co-trimoxazole and amoxycillin used clinical case definition of pneumonia (rapid respiration). Respiratory symptoms and rapid respiratory rates in children may be due to bacterial pneumonia, viral infection associated wheeze, asthma etc. In a study from Pakistan chest radiographs were normal in 82% of children diagnosed with non-severe pneumonia using the WHO case definition (Hazir 2006). The majority of such children, except those with bacterial pneumonia, may not require antimicrobial agents and are likely to recover over three to seven days with supportive care. Giving them co-trimoxazole or amoxycillin or any other antibiotics may not alter their outcome. Therefore, it is important to have well-designed clinical trials in children with true pneumonia (radiologically confirmed/direct or indirect evidence of bacterial pneumonia).

Alternative antibiotics for community-acquired pneumonia include macrolides, co-amoxyclavulanic acid, cefpodoxime, procaine penicillin and benzathine penicillin. Comparison of various macrolides shows similar efficacy, with the exception of more radiological clearance with clarithromycin without any clinical implications. Macrolides may acquire resistance very fast if used indiscriminately (Inoue 2006). Amoxycillin was comparable with macrolides (azithromycin and clarithromycin), procaine penicillin and cefuroxime. Amoxycillin may therefore be preferable over these drugs. Co-amoxyclavulanic acid has been shown to give better results than amoxycillin and comparable results to azithromycin and cefpodoxime. The results are based on single study for each. This drug is relatively more expensive and may be used as a second-line drug. Cefpodoxime was comparable with co-amoxyclavulanic acid in a single study and may be an alternative second-line drug where co-amoxyclavulanic acid cannot be administered. Injectable penicillins (procaine penicillin or benzathine penicillin) are of limited use in non-severe pneumonia.

The WHO recommends admission to hospital and treatment with penicillin for severe pneumonia and chloramphenicol for very severe pneumonia (WHO 1999). In this review it emerged clearly that children with severe pneumonia without hypoxia who are feeding well can be treated with oral amoxycillin in hospital. The mortality rates were higher in children receiving injectable antibiotics. Quality assessment of three trials comparing oral with injectable medications reveals adequate allocation concealment but all were unblinded. There is no explanation for the increased death rates in those who received injectable antibiotics, as they were treated with either ampicillin/penicillin or amoxycillin. After excluding one study (Addo-Yobo 2004) that reported seven deaths in children receiving injections, the difference in death rate becomes non-significant. In view of the similar antimicrobial spectrum of all these drugs (ampicillin/amoxycillin/penicillin) and the possible benefit of better bioavailability with parenteral administration of antibiotics, a better outcome could be expected with use of injectable antibiotics for the treatment of children with severe pneumonia. The studies were carried out in a controlled environment (either in hospitals or with careful follow up) and so it is desirable to wait for more studies in community settings for ambulatory treatment of severe pneumonia with oral antibiotics. In children with severe or very severe pneumonia, it was evident that chloramphenicol was inferior to the combination of penicillin/ampicillin plus gentamycin. There is therefore a need to change the WHO guidelines. Alternative antibiotics for hospitalised children with severe and very severe pneumonia include ceftrioxone, levofloxacin, co-amoxyclavulanic acid and cefuroxime. However, comparisons were based on single studies and these drugs are relatively more expensive. They could therefore be considered for second-line therapy if a patient fails to respond to penicillin/ampicillin plus gentamycin.

Cure and failure rates of CAP depend not only on the choice of antibiotics but also on the aetiology of the pneumonia, the age of the patient, the sensitivity pattern of the bacterial pathogen, the severity of disease and any antibiotic usage in the recent past. While information on resistance patterns was not included in the studies evaluated in the review, this is likely to be of major importance in the future, in terms of both clinical practice and research.

In the management of CAP, isolation of bacterial pathogens in order to make a decision about the choice of antibiotics is not feasible in most circumstances. Even if bacterial pathogens are isolated, the child will need to be treated with empirical antibiotics until the result of the culture is available. In this review identification of bacterial pathogens was attempted in 13 studies (Asghar 2008; Bansal 2006; Block 1995; Bradley 2007; Camargos 1997; Duke 2002; Harris 1998; Klein 1995; Kogan 2003; Mulholland 1995; Roord 1996; Straus 1998; Wubbel 1999). Bacterial pathogens could be isolated in only 11% of the study participants. S. pneumoniae and H. influenzae constituted 67% of all the bacterial isolates. Therefore, empirical antibiotic therapy for CAP should be effective against these two pathogens.

Respiratory syncytial virus could be isolated in 21% of patients, suggesting that a sizeable proportion of patients may have a viral aetiology of CAP. These patients may not need antibiotics. A child with viral pneumonia can be identified from rapid diagnostic tests such as nasopharyngeal aspirates (Maitreyi 2000) and can avoid administration of antibiotics. However, the possibility of mixed infection (bacterial agents with viruses) has been observed in 10% to 40% of cases (Kabra 2003). At present, it is policy to treat all children with pneumonia with antibiotics due to a lack of tests that can reliably rule out bacterial pneumonia.

The aetiology of pneumonia depends on the age of the patient. In the present review the majority of enrolled subjects were below five years of age and separate data according to age were not available for primary and secondary outcomes in the studies that also enrolled older children. Therefore recommendations based on the evidence are more applicable to children below five years of age.

Another important issue is the aetiological role of atypical organisms (Chlamydia and Mycoplasma spp.) in CAP (Chaudhary 1998; Normann 1998; Pandey 2005). Five studies included in this review identified atypical organisms (Block 1995; Bradley 2007; Harris 1998; Kogan 2003; Wubbel 1999). Out of 1594 children tested for M. pneumoniae, 381 (24%) tested positive. The positivity for Mycoplasma in children under five years age was 21% (158/1534). Tests for Chlamydia spp. were positive in 158 out of the 1534 children (10%). In children under five years of age, positive tests for Chlamydia spp. occurred in 45 out of 658 (7%). The most effective antibiotics against atypical organisms are tetracycline and macrolides. In this review, the studies that attempted to identify atypical organisms showed equal cure rates between erythromycin and azithromycin. Two studies (Harris 1998; Wubbel 1999) comparing azithromycin with co-amoxyclavulanic acid in children under five years of age also showed equal cure and failure rates. In these studies the incidence of atypical organisms in children under five years of age was 15% and 11% for Mycoplasma spp. and Chlamydia, respectively. The cure rates in children receiving co-amoxyclavulanic acid were comparable to those receiving azithromycin. From this observation it can be inferred that either the diagnostic tests used for atypical organisms in these studies may not indicate invasive infections, or that the study was not adequately powered to detect small differences.

The sensitivity of the pathogens isolated in various studies was not available in all the studies. Wherever it was available it was not uniformly tested for common antibiotics.

Exposure to antibiotics in the recent past may adversely affect the outcome of bacterial pneumonia as the chances of infection with a resistant organism increases (Chenoweth 2000). In this review, information on past antibiotic use was available in seven studies (Addo-Yobo 2004; Asghar 2008; Atkinson 2007; Bradley 2007; Duke 2002; Hazir 2008; Straus 1998). The distribution of patients who had received antibiotics in the recent past was similar in the two treatment groups in all the studies. However, subgroup analysis was not available in these studies. In one study (Hazir 2008) antibiotic use in the last week was associated with increased failure rates on univariate analysis. In a study comparing co-trimoxazole and amoxicillin the number of patients who had received antibiotics in the recent past was higher in the amoxycillin group (34% compared with 25.6% in the co-trimoxazole group) (Straus 1998). The failure rates were higher in the co-trimoxazole group (19% compared with 16% in the amoxicillin group) (OR 1.33; 95% CI 1.05 to 1.67). The cure rates were better in the amoxycillin group compared to the co-trimoxazole group (81% in the co-trimoxazole group and 84% in the amoxycillin group) (OR 0.82; 95% CI 0.63 to 1.08) even though the proportion of children who had received antibiotics in the past week was higher in the amoxycillin group. This may indirectly indicate the superior efficacy of amoxycillin over co-trimoxazole in the treatment of pneumonia; evident even in those children who had recently received antibiotics.

Malnutrition may affect the treatment outcome of pneumonia. There was only one study in malnourished children (Mulholland 1995) which compared co-trimoxazole and chloramphenicol. The study did not show any significant difference in cure rates, failure rates or need for change in antibiotics.

There are limitations in reviewing antibiotic usage in CAP. Comparisons are often performed among groups of children for whom identification of aetiological agents is lacking. This means that if the distribution of viral cases is not uniform, the conclusions regarding the efficacy of antibiotics can be debatable. Several individual factors, such as malnutrition, can deeply modify the evolution of CAP and the response to antibiotic therapy. In the present review, only one study addressed this problem; it is highly probable that this issue can influence the correct evaluation of the data. No data regarding antibiotic resistance were reported in the majority of the studies. It is well known that in some cases the level of resistance to commonly used antibiotics can have a great influence on the response to therapy. The role of atypical bacteria in the determination of CAP in children living in low-income countries is not established, probably because the methods for identifying these pathogens are too complicated or too expensive, or both. These data are needed to more accurately define the best antibiotic therapy. The results may be more applicable for developing countries as most studies were done in these countries.

Quality of the evidence

Five out of 27 studies were double-blind studies and allocation concealment was adequate. Another 11 studies were unblinded but had adequate allocation concealment, classifying them as good quality studies. There was more than one study comparing co-trimoxazole with amoxycillin, oral amoxycillin with injectable penicillin/ampicillin and chloramphenicol with ampicillin/penicillin and studies were of good quality, suggesting the evidence for these comparisons is of high quality compared to other comparisons.

Potential biases in the review process

In this review we included one study (Awasthi 2008) of which one of the authors of present review (Kabra) was a co-author.

Agreements and disagreements with other studies or reviews

The important changes in this updated review in comparison to the previous version (Kabra 2006) include the following.

  1. The efficacy of co-trimoxazole and amoxycillin for ambulatory treatment of pneumonia was similar. This followed the inclusion of a study (Awasthi 2008) that compared three days of amoxycillin with five days of co-trimoxazole for CAP. In this study children receiving amoxycillin or co-trimoxazole were evaluated on day four and day six, respectively.

  2. Treatment of severe pneumonia with oral antibiotics in a controlled setting (hospitalised children or close follow up) is feasible.

  3. In very severe pneumonia penicillin/ampicillin plus gentamycin was superior to chloramphenicol.

A review comparing oral and injectable antibiotics in pneumonia suggested no difference in cure and failure rates in children getting oral or injectable antibiotics for the treatment of pneumonia in children (Rojas-Reyes 2006). In the present review we also found that oral and injectable antibiotics (amoxycillin) versus penicillin/ampicillin and co-trimoxazole versus procaine penicillin) for pneumonia are equally effective.

Authors' conclusions

Implications for practice

For the treatment of ambulatory patients with CAP, amoxycillin is an alternative to co-trimoxazole. There are no apparent differences between azithromycin and erythromycin, azithromycin and co-amoxyclavulanic acid or cefpodoxime and co-amoxyclavulanic acid. There is limited data on other antibiotics: co-amoxyclavulanic acid and cefpodoxime may be alternative second-line drugs. Severe pneumonia without hypoxia and good oral acceptance can be managed in hospital/controlled settings with oral amoxycillin. Further community-based studies are required to determine the efficacy of oral antibiotics in the ambulatory management of severe pneumonia in the community. For children hospitalised with severe and very severe CAP, penicillin/ampicillin plus gentamycin is superior to chloramphenicol. The other alternative drugs for such patients are ceftrioxone, levofloxacin, co-amoxyclavulanic acid and cefuroxime. Until more studies are available these can be used as a second-line therapy.

More randomised controlled trials are required for a review of these antibiotics in order to make more accurate recommendations for their prescription.

Implications for research

There are many new antimicrobials available for the management of non-severe and severe CAP. There is a need for more studies, using similar methodologies and large numbers of patients, to compare amoxycillin with co-amoxyclavulanic acid, macrolides with amoxycillin and amoxycillin with oral cephalosporins. There is need for high quality trials to validate the efficacy of oral amoxycillin in the treatment of severe pneumonia in community settings.

Acknowledgements

We acknowledge all the help and infrastructure provided by the All India Institute of Medical Sciences, New Delhi, where all the authors serve as faculty. We acknowledge the help provided by Elizabeth Dooley, Managing Editor and Sarah Thorning, Trials Search Co-ordinator of the Cochrane Acute Respiratory Infections Group, for doing the EMBASE search and getting full text articles of studies. We also acknowledge the help provided by Dr Sunil Saharan in masking the study articles. We are very thankful to the referees Dr Roger Damoiseaux, Dr Yingfen Hsia, Dr Rajni Bhatia and Dr Max Bulsara for their input in improving the quality of this updated review.

Data and analyses

Download statistical data

Comparison 1. Azithromycin versus erythromycin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Mean age (months)3369Mean Difference (IV, Random, 95% CI)-4.48 [-18.54, 9.57]
2 Male sex3564Odds Ratio (M-H, Random, 95% CI)0.83 [0.58, 1.18]
3 Wheezing present2479Odds Ratio (M-H, Random, 95% CI)1.23 [0.31, 4.87]
4 Cure rate3363Odds Ratio (M-H, Random, 95% CI)1.22 [0.50, 2.94]
5 Failure rate3392Odds Ratio (M-H, Random, 95% CI)0.57 [0.14, 2.33]
6 Side effects2153Odds Ratio (M-H, Random, 95% CI)0.92 [0.18, 4.73]
7 Organisms identified by serology or nasopharyngeal cultures3368Odds Ratio (M-H, Random, 95% CI)0.75 [0.30, 1.87]
Analysis 1.1.

Comparison 1 Azithromycin versus erythromycin, Outcome 1 Mean age (months).

Analysis 1.2.

Comparison 1 Azithromycin versus erythromycin, Outcome 2 Male sex.

Analysis 1.3.

Comparison 1 Azithromycin versus erythromycin, Outcome 3 Wheezing present.

Analysis 1.4.

Comparison 1 Azithromycin versus erythromycin, Outcome 4 Cure rate.

Analysis 1.5.

Comparison 1 Azithromycin versus erythromycin, Outcome 5 Failure rate.

Analysis 1.6.

Comparison 1 Azithromycin versus erythromycin, Outcome 6 Side effects.

Analysis 1.7.

Comparison 1 Azithromycin versus erythromycin, Outcome 7 Organisms identified by serology or nasopharyngeal cultures.

Comparison 2. Clarithromycin versus erythromycin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Age below five years1260Odds Ratio (M-H, Random, 95% CI)0.93 [0.56, 1.55]
2 Cure rates1234Odds Ratio (M-H, Random, 95% CI)1.61 [0.84, 3.08]
3 Clinical success rate1234Odds Ratio (M-H, Random, 95% CI)1.92 [0.45, 8.23]
4 Failure rates1234Odds Ratio (M-H, Random, 95% CI)0.52 [0.12, 2.23]
5 Relapse rates1226Odds Ratio (M-H, Random, 95% CI)0.17 [0.02, 1.45]
6 Radiologic resolution1209Odds Ratio (M-H, Random, 95% CI)2.51 [1.02, 6.16]
7 Radiologic success1209Odds Ratio (M-H, Random, 95% CI)3.55 [0.70, 18.04]
8 Radiologic failure1209Odds Ratio (M-H, Random, 95% CI)0.34 [0.06, 1.80]
9 Adverse events1260Odds Ratio (M-H, Random, 95% CI)1.07 [0.60, 1.90]
10 Bacteriologic response145Odds Ratio (M-H, Random, 95% CI)1.0 [0.15, 6.67]
Analysis 2.1.

Comparison 2 Clarithromycin versus erythromycin, Outcome 1 Age below five years.

Analysis 2.2.

Comparison 2 Clarithromycin versus erythromycin, Outcome 2 Cure rates.

Analysis 2.3.

Comparison 2 Clarithromycin versus erythromycin, Outcome 3 Clinical success rate.

Analysis 2.4.

Comparison 2 Clarithromycin versus erythromycin, Outcome 4 Failure rates.

Analysis 2.5.

Comparison 2 Clarithromycin versus erythromycin, Outcome 5 Relapse rates.

Analysis 2.6.

Comparison 2 Clarithromycin versus erythromycin, Outcome 6 Radiologic resolution.

Analysis 2.7.

Comparison 2 Clarithromycin versus erythromycin, Outcome 7 Radiologic success.

Analysis 2.8.

Comparison 2 Clarithromycin versus erythromycin, Outcome 8 Radiologic failure.

Analysis 2.9.

Comparison 2 Clarithromycin versus erythromycin, Outcome 9 Adverse events.

Analysis 2.10.

Comparison 2 Clarithromycin versus erythromycin, Outcome 10 Bacteriologic response.

Comparison 3. Azithromycin versus co-amoxyclavulanic acid
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Cure rate1188Odds Ratio (M-H, Random, 95% CI)1.02 [0.54, 1.95]
2 Failure rate2276Odds Ratio (M-H, Random, 95% CI)1.21 [0.42, 3.53]
3 Improved1188Odds Ratio (M-H, Random, 95% CI)0.85 [0.43, 1.71]
4 Side effects2276Odds Ratio (M-H, Random, 95% CI)0.15 [0.04, 0.61]
5 Organisms isolated1188Odds Ratio (M-H, Random, 95% CI)1.27 [0.24, 6.74]
6 Mycoplasma serology positive1192Odds Ratio (M-H, Random, 95% CI)1.19 [0.64, 2.22]
Analysis 3.1.

Comparison 3 Azithromycin versus co-amoxyclavulanic acid, Outcome 1 Cure rate.

Analysis 3.2.

Comparison 3 Azithromycin versus co-amoxyclavulanic acid, Outcome 2 Failure rate.

Analysis 3.3.

Comparison 3 Azithromycin versus co-amoxyclavulanic acid, Outcome 3 Improved.

Analysis 3.4.

Comparison 3 Azithromycin versus co-amoxyclavulanic acid, Outcome 4 Side effects.

Analysis 3.5.

Comparison 3 Azithromycin versus co-amoxyclavulanic acid, Outcome 5 Organisms isolated.

Analysis 3.6.

Comparison 3 Azithromycin versus co-amoxyclavulanic acid, Outcome 6 Mycoplasma serology positive.

Comparison 4. Azithromycin versus amoxycillin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Age in months176Mean Difference (IV, Random, 95% CI)58.10 [35.59, 80.61]
2 Duration of illness147Mean Difference (IV, Random, 95% CI)-0.10 [-1.50, 1.30]
3 Wheezing present147Odds Ratio (M-H, Random, 95% CI)2.02 [0.59, 6.96]
4 Cure rate clinical147Odds Ratio (M-H, Random, 95% CI)Not estimable
5 Cure rate radiological147Odds Ratio (M-H, Random, 95% CI)Not estimable
6 Fever day seven147Odds Ratio (M-H, Random, 95% CI)1.37 [0.41, 4.61]
Analysis 4.1.

Comparison 4 Azithromycin versus amoxycillin, Outcome 1 Age in months.

Analysis 4.2.

Comparison 4 Azithromycin versus amoxycillin, Outcome 2 Duration of illness.

Analysis 4.3.

Comparison 4 Azithromycin versus amoxycillin, Outcome 3 Wheezing present.

Analysis 4.4.

Comparison 4 Azithromycin versus amoxycillin, Outcome 4 Cure rate clinical.

Analysis 4.5.

Comparison 4 Azithromycin versus amoxycillin, Outcome 5 Cure rate radiological.

Analysis 4.6.

Comparison 4 Azithromycin versus amoxycillin, Outcome 6 Fever day seven.

Comparison 5. Amoxycillin versus procaine penicillin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Median age1170Mean Difference (IV, Random, 95% CI)0.30 [-0.52, 1.12]
2 Failure rate1154Odds Ratio (M-H, Random, 95% CI)0.75 [0.17, 3.25]
Analysis 5.1.

Comparison 5 Amoxycillin versus procaine penicillin, Outcome 1 Median age.

Analysis 5.2.

Comparison 5 Amoxycillin versus procaine penicillin, Outcome 2 Failure rate.

Comparison 6. Co-amoxyclavulanic acid versus amoxycillin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Poor or no response1100Odds Ratio (M-H, Random, 95% CI)0.08 [0.01, 0.67]
2 Cure rate1100Odds Ratio (M-H, Random, 95% CI)10.44 [2.85, 38.21]
3 Complications1100Odds Ratio (M-H, Random, 95% CI)5.21 [0.24, 111.24]
4 Age (months)1100Mean Difference (IV, Random, 95% CI)4.80 [-8.09, 17.69]
5 Weight1100Mean Difference (IV, Random, 95% CI)1.10 [-1.06, 3.26]
6 Male sex1100Odds Ratio (M-H, Random, 95% CI)1.31 [0.57, 3.03]
7 Wheeze present1100Odds Ratio (M-H, Random, 95% CI)0.58 [0.18, 1.92]
8 Side effects1100Odds Ratio (M-H, Random, 95% CI)5.21 [0.24, 111.24]
Analysis 6.1.

Comparison 6 Co-amoxyclavulanic acid versus amoxycillin, Outcome 1 Poor or no response.

Analysis 6.2.

Comparison 6 Co-amoxyclavulanic acid versus amoxycillin, Outcome 2 Cure rate.

Analysis 6.3.

Comparison 6 Co-amoxyclavulanic acid versus amoxycillin, Outcome 3 Complications.

Analysis 6.4.

Comparison 6 Co-amoxyclavulanic acid versus amoxycillin, Outcome 4 Age (months).

Analysis 6.5.

Comparison 6 Co-amoxyclavulanic acid versus amoxycillin, Outcome 5 Weight.

Analysis 6.6.

Comparison 6 Co-amoxyclavulanic acid versus amoxycillin, Outcome 6 Male sex.

Analysis 6.7.

Comparison 6 Co-amoxyclavulanic acid versus amoxycillin, Outcome 7 Wheeze present.

Analysis 6.8.

Comparison 6 Co-amoxyclavulanic acid versus amoxycillin, Outcome 8 Side effects.

Comparison 7. Co-trimoxazole versus amoxycillin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Age less than one year34083Odds Ratio (M-H, Random, 95% CI)1.02 [0.82, 1.28]
2 Male sex33965Odds Ratio (M-H, Random, 95% CI)0.77 [0.60, 1.00]
3 Mean Z score for weight22066Mean Difference (IV, Random, 95% CI)-0.06 [-0.27, 0.15]
4 Received antibiotics in previous one week1595Odds Ratio (M-H, Random, 95% CI)0.67 [0.46, 0.97]
5 Non-severe pneumonia1595Odds Ratio (M-H, Random, 95% CI)0.97 [0.69, 1.37]
6 Severe pneumonia1595Odds Ratio (M-H, Random, 95% CI)1.03 [0.73, 1.45]
7 Failure rate in non-severe pneumonia33759Odds Ratio (M-H, Random, 95% CI)0.92 [0.58, 1.47]
8 Failure rate severe pneumonia clinical diagnosis1302Odds Ratio (M-H, Random, 95% CI)1.71 [0.94, 3.11]
9 Failure rate radiological positive pneumonia1153Odds Ratio (M-H, Random, 95% CI)2.14 [0.96, 4.78]
10 Failure rate radiological negative pneumonia1424Odds Ratio (M-H, Random, 95% CI)1.72 [0.96, 3.09]
11 Death rate22050Odds Ratio (M-H, Random, 95% CI)2.08 [0.22, 20.06]
12 Lost to follow up34048Odds Ratio (M-H, Random, 95% CI)0.88 [0.67, 1.16]
13 Wheeze positive11471Odds Ratio (M-H, Random, 95% CI)0.76 [0.49, 1.19]
14 Cure rate23468Odds Ratio (M-H, Random, 95% CI)1.12 [0.61, 2.03]
15 Change of antibiotics11459Odds Ratio (M-H, Random, 95% CI)1.26 [0.95, 1.69]
16 Failure rates after excluding study by Awasthi 200821750Odds Ratio (M-H, Fixed, 95% CI)1.19 [0.92, 1.53]
Analysis 7.1.

Comparison 7 Co-trimoxazole versus amoxycillin, Outcome 1 Age less than one year.

Analysis 7.2.

Comparison 7 Co-trimoxazole versus amoxycillin, Outcome 2 Male sex.

Analysis 7.3.

Comparison 7 Co-trimoxazole versus amoxycillin, Outcome 3 Mean Z score for weight.

Analysis 7.4.

Comparison 7 Co-trimoxazole versus amoxycillin, Outcome 4 Received antibiotics in previous one week.

Analysis 7.5.

Comparison 7 Co-trimoxazole versus amoxycillin, Outcome 5 Non-severe pneumonia.

Analysis 7.6.

Comparison 7 Co-trimoxazole versus amoxycillin, Outcome 6 Severe pneumonia.

Analysis 7.7.

Comparison 7 Co-trimoxazole versus amoxycillin, Outcome 7 Failure rate in non-severe pneumonia.

Analysis 7.8.

Comparison 7 Co-trimoxazole versus amoxycillin, Outcome 8 Failure rate severe pneumonia clinical diagnosis.

Analysis 7.9.

Comparison 7 Co-trimoxazole versus amoxycillin, Outcome 9 Failure rate radiological positive pneumonia.

Analysis 7.10.

Comparison 7 Co-trimoxazole versus amoxycillin, Outcome 10 Failure rate radiological negative pneumonia.

Analysis 7.11.

Comparison 7 Co-trimoxazole versus amoxycillin, Outcome 11 Death rate.

Analysis 7.12.

Comparison 7 Co-trimoxazole versus amoxycillin, Outcome 12 Lost to follow up.

Analysis 7.13.

Comparison 7 Co-trimoxazole versus amoxycillin, Outcome 13 Wheeze positive.

Analysis 7.14.

Comparison 7 Co-trimoxazole versus amoxycillin, Outcome 14 Cure rate.

Analysis 7.15.

Comparison 7 Co-trimoxazole versus amoxycillin, Outcome 15 Change of antibiotics.

Analysis 7.16.

Comparison 7 Co-trimoxazole versus amoxycillin, Outcome 16 Failure rates after excluding study by Awasthi 2008.

Comparison 8. Co-trimoxazole versus procaine penicillin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Age less than one year2723Odds Ratio (M-H, Random, 95% CI)1.30 [0.96, 1.75]
2 Age one to five years1614Odds Ratio (M-H, Random, 95% CI)0.84 [0.61, 1.16]
3 Age 5 to 12 years2723Odds Ratio (M-H, Random, 95% CI)0.79 [0.45, 1.39]
4 Duration of illness in days2723Mean Difference (IV, Fixed, 95% CI)-0.15 [-0.49, 0.20]
5 Male sex1614Odds Ratio (M-H, Random, 95% CI)0.93 [0.67, 1.27]
6 Cure rate2723Odds Ratio (M-H, Random, 95% CI)1.58 [0.26, 9.69]
7 Hospitalisation rate1614Odds Ratio (M-H, Random, 95% CI)2.52 [0.88, 7.25]
8 Well at end of follow up1614Odds Ratio (M-H, Random, 95% CI)0.90 [0.51, 1.57]
9 Death1614Odds Ratio (M-H, Random, 95% CI)3.09 [0.13, 76.13]
10 Treatment failure1614Odds Ratio (M-H, Random, 95% CI)1.72 [0.41, 7.27]
Analysis 8.1.

Comparison 8 Co-trimoxazole versus procaine penicillin, Outcome 1 Age less than one year.

Analysis 8.2.

Comparison 8 Co-trimoxazole versus procaine penicillin, Outcome 2 Age one to five years.

Analysis 8.3.

Comparison 8 Co-trimoxazole versus procaine penicillin, Outcome 3 Age 5 to 12 years.

Analysis 8.4.

Comparison 8 Co-trimoxazole versus procaine penicillin, Outcome 4 Duration of illness in days.

Analysis 8.5.

Comparison 8 Co-trimoxazole versus procaine penicillin, Outcome 5 Male sex.

Analysis 8.6.

Comparison 8 Co-trimoxazole versus procaine penicillin, Outcome 6 Cure rate.

Analysis 8.7.

Comparison 8 Co-trimoxazole versus procaine penicillin, Outcome 7 Hospitalisation rate.

Analysis 8.8.

Comparison 8 Co-trimoxazole versus procaine penicillin, Outcome 8 Well at end of follow up.

Analysis 8.9.

Comparison 8 Co-trimoxazole versus procaine penicillin, Outcome 9 Death.

Analysis 8.10.

Comparison 8 Co-trimoxazole versus procaine penicillin, Outcome 10 Treatment failure.

Comparison 9. Co-trimoxazole versus procaine penicillin and ampicillin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Mean age in months1134Mean Difference (IV, Random, 95% CI)Not estimable
2 Age less than one year1134Odds Ratio (M-H, Random, 95% CI)0.80 [0.39, 1.64]
3 Male sex1134Odds Ratio (M-H, Random, 95% CI)1.29 [0.65, 2.58]
4 Cure rate1134Odds Ratio (M-H, Random, 95% CI)1.15 [0.36, 3.61]
5 Hospitalisation rate1134Odds Ratio (M-H, Random, 95% CI)1.57 [0.25, 9.72]
6 Death rate1134Odds Ratio (M-H, Random, 95% CI)0.20 [0.01, 4.25]
Analysis 9.1.

Comparison 9 Co-trimoxazole versus procaine penicillin and ampicillin, Outcome 1 Mean age in months.

Analysis 9.2.

Comparison 9 Co-trimoxazole versus procaine penicillin and ampicillin, Outcome 2 Age less than one year.

Analysis 9.3.

Comparison 9 Co-trimoxazole versus procaine penicillin and ampicillin, Outcome 3 Male sex.

Analysis 9.4.

Comparison 9 Co-trimoxazole versus procaine penicillin and ampicillin, Outcome 4 Cure rate.

Analysis 9.5.

Comparison 9 Co-trimoxazole versus procaine penicillin and ampicillin, Outcome 5 Hospitalisation rate.

Analysis 9.6.

Comparison 9 Co-trimoxazole versus procaine penicillin and ampicillin, Outcome 6 Death rate.

Comparison 10. Cefpodoxime versus co-amoxyclavulanic acid
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Cure rate (response rate) at end of treatment1278Odds Ratio (M-H, Random, 95% CI)0.69 [0.18, 2.60]
2 Mean age (months)1348Mean Difference (IV, Random, 95% CI)Not estimable
3 Adverse effects1278Odds Ratio (M-H, Random, 95% CI)0.46 [0.16, 1.35]
4 Age in years1348Mean Difference (IV, Random, 95% CI)Not estimable
5 Follow up1278Odds Ratio (M-H, Random, 95% CI)0.37 [0.11, 1.31]
Analysis 10.1.

Comparison 10 Cefpodoxime versus co-amoxyclavulanic acid, Outcome 1 Cure rate (response rate) at end of treatment.

Analysis 10.2.

Comparison 10 Cefpodoxime versus co-amoxyclavulanic acid, Outcome 2 Mean age (months).

Analysis 10.3.

Comparison 10 Cefpodoxime versus co-amoxyclavulanic acid, Outcome 3 Adverse effects.

Analysis 10.4.

Comparison 10 Cefpodoxime versus co-amoxyclavulanic acid, Outcome 4 Age in years.

Analysis 10.5.

Comparison 10 Cefpodoxime versus co-amoxyclavulanic acid, Outcome 5 Follow up.

Comparison 11. Chloramphenicol versus penicillin plus gentamicin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Adverse events11116Odds Ratio (M-H, Random, 95% CI)1.26 [0.96, 1.66]
2 Death11116Odds Ratio (M-H, Random, 95% CI)1.25 [0.76, 2.07]
3 Change of antibiotics11116Odds Ratio (M-H, Random, 95% CI)0.80 [0.54, 1.18]
4 Readmission before 30 days11116Odds Ratio (M-H, Random, 95% CI)1.61 [1.02, 2.55]
5 Absconded11116Odds Ratio (M-H, Random, 95% CI)1.31 [0.83, 2.09]
6 Age (months)11116Mean Difference (IV, Random, 95% CI)Not estimable
7 Culture positive11116Odds Ratio (M-H, Random, 95% CI)0.85 [0.60, 1.21]
8 Male sex11116Odds Ratio (M-H, Random, 95% CI)0.88 [0.69, 1.12]
9 Received antibiotics in previous one week11116Odds Ratio (M-H, Random, 95% CI)0.96 [0.75, 1.22]
10 Lost to follow up11116Odds Ratio (M-H, Random, 95% CI)1.31 [0.83, 2.09]
Analysis 11.1.

Comparison 11 Chloramphenicol versus penicillin plus gentamicin, Outcome 1 Adverse events.

Analysis 11.2.

Comparison 11 Chloramphenicol versus penicillin plus gentamicin, Outcome 2 Death.

Analysis 11.3.

Comparison 11 Chloramphenicol versus penicillin plus gentamicin, Outcome 3 Change of antibiotics.

Analysis 11.4.

Comparison 11 Chloramphenicol versus penicillin plus gentamicin, Outcome 4 Readmission before 30 days.

Analysis 11.5.

Comparison 11 Chloramphenicol versus penicillin plus gentamicin, Outcome 5 Absconded.

Analysis 11.6.

Comparison 11 Chloramphenicol versus penicillin plus gentamicin, Outcome 6 Age (months).

Analysis 11.7.

Comparison 11 Chloramphenicol versus penicillin plus gentamicin, Outcome 7 Culture positive.

Analysis 11.8.

Comparison 11 Chloramphenicol versus penicillin plus gentamicin, Outcome 8 Male sex.

Analysis 11.9.

Comparison 11 Chloramphenicol versus penicillin plus gentamicin, Outcome 9 Received antibiotics in previous one week.

Analysis 11.10.

Comparison 11 Chloramphenicol versus penicillin plus gentamicin, Outcome 10 Lost to follow up.

Comparison 12. Chloramphenicol with ampicillin and gentamicin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Mean age1958Mean Difference (IV, Random, 95% CI)-0.10 [-1.12, 0.92]
2 Male sex1958Odds Ratio (M-H, Random, 95% CI)0.85 [0.66, 1.11]
3 Number received antibiotics in past one week1950Odds Ratio (M-H, Random, 95% CI)0.87 [0.67, 1.14]
4 Failure rates on day 51958Odds Ratio (M-H, Random, 95% CI)1.51 [1.04, 2.19]
5 Failure rates on day 101958Odds Ratio (M-H, Random, 95% CI)1.46 [1.04, 2.06]
6 Failure rates on day 211958Odds Ratio (M-H, Random, 95% CI)1.43 [1.03, 1.98]
7 Need for change in antibiotics (day 5)1958Odds Ratio (M-H, Random, 95% CI)1.81 [1.10, 2.98]
8 Need for change in antibiotics (day 10)1958Odds Ratio (M-H, Random, 95% CI)1.71 [1.10, 2.66]
9 Need for change in antibiotics (day 21)1958Odds Ratio (M-H, Random, 95% CI)1.65 [1.09, 2.49]
10 Death rates1958Odds Ratio (M-H, Random, 95% CI)1.65 [0.99, 2.77]
Analysis 12.1.

Comparison 12 Chloramphenicol with ampicillin and gentamicin, Outcome 1 Mean age.

Analysis 12.2.

Comparison 12 Chloramphenicol with ampicillin and gentamicin, Outcome 2 Male sex.

Analysis 12.3.

Comparison 12 Chloramphenicol with ampicillin and gentamicin, Outcome 3 Number received antibiotics in past one week.

Analysis 12.4.

Comparison 12 Chloramphenicol with ampicillin and gentamicin, Outcome 4 Failure rates on day 5.

Analysis 12.5.

Comparison 12 Chloramphenicol with ampicillin and gentamicin, Outcome 5 Failure rates on day 10.

Analysis 12.6.

Comparison 12 Chloramphenicol with ampicillin and gentamicin, Outcome 6 Failure rates on day 21.

Analysis 12.7.

Comparison 12 Chloramphenicol with ampicillin and gentamicin, Outcome 7 Need for change in antibiotics (day 5).

Analysis 12.8.

Comparison 12 Chloramphenicol with ampicillin and gentamicin, Outcome 8 Need for change in antibiotics (day 10).

Analysis 12.9.

Comparison 12 Chloramphenicol with ampicillin and gentamicin, Outcome 9 Need for change in antibiotics (day 21).

Analysis 12.10.

Comparison 12 Chloramphenicol with ampicillin and gentamicin, Outcome 10 Death rates.

Comparison 13. Chloramphenicol plus penicillin versus ceftrioxone
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Cure rates197Odds Ratio (M-H, Random, 95% CI)1.36 [0.47, 3.93]
Analysis 13.1.

Comparison 13 Chloramphenicol plus penicillin versus ceftrioxone, Outcome 1 Cure rates.

Comparison 14. Chloramphenicol versus chloramphenicol plus penicillin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Need for change of antibiotics1748Odds Ratio (M-H, Random, 95% CI)0.49 [0.12, 1.97]
2 Death rates1748Odds Ratio (M-H, Random, 95% CI)0.73 [0.48, 1.09]
3 Lost to follow up1748Odds Ratio (M-H, Random, 95% CI)1.11 [0.80, 1.53]
Analysis 14.1.

Comparison 14 Chloramphenicol versus chloramphenicol plus penicillin, Outcome 1 Need for change of antibiotics.

Analysis 14.2.

Comparison 14 Chloramphenicol versus chloramphenicol plus penicillin, Outcome 2 Death rates.

Analysis 14.3.

Comparison 14 Chloramphenicol versus chloramphenicol plus penicillin, Outcome 3 Lost to follow up.

Comparison 15. Ampicillin alone versus penicillin with chloramphenicol
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Cure rates1101Odds Ratio (M-H, Random, 95% CI)0.48 [0.15, 1.51]
2 Age (months)1101Mean Difference (IV, Random, 95% CI)-1.69 [-5.54, 2.16]
3 Male sex1101Odds Ratio (M-H, Random, 95% CI)0.88 [0.41, 1.93]
4 Duration of hospital stay1101Mean Difference (IV, Random, 95% CI)-0.10 [-1.13, 0.93]
5 Grade 2 to 4 malnutrition1101Odds Ratio (M-H, Random, 95% CI)0.88 [0.41, 1.93]
Analysis 15.1.

Comparison 15 Ampicillin alone versus penicillin with chloramphenicol, Outcome 1 Cure rates.

Analysis 15.2.

Comparison 15 Ampicillin alone versus penicillin with chloramphenicol, Outcome 2 Age (months).

Analysis 15.3.

Comparison 15 Ampicillin alone versus penicillin with chloramphenicol, Outcome 3 Male sex.

Analysis 15.4.

Comparison 15 Ampicillin alone versus penicillin with chloramphenicol, Outcome 4 Duration of hospital stay.

Analysis 15.5.

Comparison 15 Ampicillin alone versus penicillin with chloramphenicol, Outcome 5 Grade 2 to 4 malnutrition.

Comparison 16. Benzathine penicillin versus procaine penicillin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Cure rate2281Odds Ratio (M-H, Random, 95% CI)0.53 [0.27, 1.01]
2 Failure rate2281Odds Ratio (M-H, Random, 95% CI)3.17 [0.90, 11.11]
3 Male sex2281Odds Ratio (M-H, Random, 95% CI)1.09 [0.67, 1.76]
4 Age between two to six years2301Odds Ratio (M-H, Fixed, 95% CI)1.14 [0.72, 1.79]
5 Age between 7 to 12 years2301Odds Ratio (M-H, Random, 95% CI)0.52 [0.31, 0.88]
6 Lost to follow up1176Odds Ratio (M-H, Random, 95% CI)1.80 [0.16, 20.25]
Analysis 16.1.

Comparison 16 Benzathine penicillin versus procaine penicillin, Outcome 1 Cure rate.

Analysis 16.2.

Comparison 16 Benzathine penicillin versus procaine penicillin, Outcome 2 Failure rate.

Analysis 16.3.

Comparison 16 Benzathine penicillin versus procaine penicillin, Outcome 3 Male sex.

Analysis 16.4.

Comparison 16 Benzathine penicillin versus procaine penicillin, Outcome 4 Age between two to six years.

Analysis 16.5.

Comparison 16 Benzathine penicillin versus procaine penicillin, Outcome 5 Age between 7 to 12 years.

Analysis 16.6.

Comparison 16 Benzathine penicillin versus procaine penicillin, Outcome 6 Lost to follow up.

Comparison 17. Amoxycillin versus penicillin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Nasopharyngeal aspirates for S. pneumoniae11486Odds Ratio (M-H, Random, 95% CI)0.90 [0.72, 1.13]
2 Age less than one year11702Odds Ratio (M-H, Random, 95% CI)1.06 [0.87, 1.29]
3 Male sex21905Odds Ratio (M-H, Random, 95% CI)1.04 [0.87, 1.25]
4 Weight below 2 Z score (indicating severe malnutrition)11686Odds Ratio (M-H, Random, 95% CI)0.92 [0.70, 1.19]
5 Breast fed11702Odds Ratio (M-H, Random, 95% CI)1.12 [0.92, 1.37]
6 Received antibiotics in last one week21905Odds Ratio (M-H, Random, 95% CI)0.97 [0.69, 1.38]
7 Failure rate at 48 hours11702Odds Ratio (M-H, Random, 95% CI)1.03 [0.81, 1.31]
8 Failure rate on day five21905Odds Ratio (M-H, Random, 95% CI)1.15 [0.58, 2.30]
9 Failure rate on day 1411702Odds Ratio (M-H, Random, 95% CI)1.04 [0.84, 1.29]
10 Death rates21905Odds Ratio (M-H, Random, 95% CI)0.07 [0.00, 1.18]
11 Nasopharyngeal H. influenzae11482Odds Ratio (M-H, Fixed, 95% CI)1.00 [0.78, 1.29]
12 Respiratory syncytial virus (RSV) in nasopharyngeal swabs21731Odds Ratio (M-H, Random, 95% CI)1.04 [0.83, 1.31]
13 Mean age1203Mean Difference (IV, Random, 95% CI)Not estimable
14 Blood culture positive for S. Pneumoniae1203Odds Ratio (M-H, Random, 95% CI)0.34 [0.03, 3.29]
Analysis 17.1.

Comparison 17 Amoxycillin versus penicillin, Outcome 1 Nasopharyngeal aspirates for S. pneumoniae.

Analysis 17.2.

Comparison 17 Amoxycillin versus penicillin, Outcome 2 Age less than one year.

Analysis 17.3.

Comparison 17 Amoxycillin versus penicillin, Outcome 3 Male sex.

Analysis 17.4.

Comparison 17 Amoxycillin versus penicillin, Outcome 4 Weight below 2 Z score (indicating severe malnutrition).

Analysis 17.5.

Comparison 17 Amoxycillin versus penicillin, Outcome 5 Breast fed.

Analysis 17.6.

Comparison 17 Amoxycillin versus penicillin, Outcome 6 Received antibiotics in last one week.

Analysis 17.7.

Comparison 17 Amoxycillin versus penicillin, Outcome 7 Failure rate at 48 hours.

Analysis 17.8.

Comparison 17 Amoxycillin versus penicillin, Outcome 8 Failure rate on day five.

Analysis 17.9.

Comparison 17 Amoxycillin versus penicillin, Outcome 9 Failure rate on day 14.

Analysis 17.10.

Comparison 17 Amoxycillin versus penicillin, Outcome 10 Death rates.

Analysis 17.11.

Comparison 17 Amoxycillin versus penicillin, Outcome 11 Nasopharyngeal H. influenzae.

Analysis 17.12.

Comparison 17 Amoxycillin versus penicillin, Outcome 12 Respiratory syncytial virus (RSV) in nasopharyngeal swabs.

Analysis 17.13.

Comparison 17 Amoxycillin versus penicillin, Outcome 13 Mean age.

Analysis 17.14.

Comparison 17 Amoxycillin versus penicillin, Outcome 14 Blood culture positive for S. Pneumoniae.

Comparison 18. Amoxycillin with IV ampicillin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Age below one year12037Odds Ratio (M-H, Random, 95% CI)0.94 [0.79, 1.13]
2 Male sex12037Odds Ratio (M-H, Random, 95% CI)1.09 [0.91, 1.30]
3 Wheezing in infants11311Odds Ratio (M-H, Random, 95% CI)1.03 [0.78, 1.37]
4 Wheezing in age group one to five years1726Odds Ratio (M-H, Random, 95% CI)0.77 [0.56, 1.04]
5 Failure rates12037Odds Ratio (M-H, Random, 95% CI)0.86 [0.63, 1.19]
6 Relapse rates11873Odds Ratio (M-H, Random, 95% CI)0.78 [0.46, 1.33]
7 Death rates12037Odds Ratio (M-H, Random, 95% CI)0.25 [0.03, 2.21]
8 Lost to follow up12037Odds Ratio (M-H, Random, 95% CI)0.45 [0.17, 1.20]
9 Protocol violation12037Odds Ratio (M-H, Random, 95% CI)0.92 [0.43, 1.96]
Analysis 18.1.

Comparison 18 Amoxycillin with IV ampicillin, Outcome 1 Age below one year.

Analysis 18.2.

Comparison 18 Amoxycillin with IV ampicillin, Outcome 2 Male sex.

Analysis 18.3.

Comparison 18 Amoxycillin with IV ampicillin, Outcome 3 Wheezing in infants.

Analysis 18.4.

Comparison 18 Amoxycillin with IV ampicillin, Outcome 4 Wheezing in age group one to five years.

Analysis 18.5.

Comparison 18 Amoxycillin with IV ampicillin, Outcome 5 Failure rates.

Analysis 18.6.

Comparison 18 Amoxycillin with IV ampicillin, Outcome 6 Relapse rates.

Analysis 18.7.

Comparison 18 Amoxycillin with IV ampicillin, Outcome 7 Death rates.

Analysis 18.8.

Comparison 18 Amoxycillin with IV ampicillin, Outcome 8 Lost to follow up.

Analysis 18.9.

Comparison 18 Amoxycillin with IV ampicillin, Outcome 9 Protocol violation.

Comparison 19. Amoxycillin with cefuroxime
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Mean age in months184Mean Difference (IV, Random, 95% CI)4.47 [-1.45, 10.39]
2 Male sex185Odds Ratio (M-H, Random, 95% CI)0.11 [0.01, 0.90]
3 Cure rates184Odds Ratio (M-H, Random, 95% CI)2.05 [0.18, 23.51]
4 Failure rates184Odds Ratio (M-H, Random, 95% CI)0.49 [0.04, 5.59]
Analysis 19.1.

Comparison 19 Amoxycillin with cefuroxime, Outcome 1 Mean age in months.

Analysis 19.2.

Comparison 19 Amoxycillin with cefuroxime, Outcome 2 Male sex.

Analysis 19.3.

Comparison 19 Amoxycillin with cefuroxime, Outcome 3 Cure rates.

Analysis 19.4.

Comparison 19 Amoxycillin with cefuroxime, Outcome 4 Failure rates.

Comparison 20. Amoxycillin with clarithromycin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Mean age185Mean Difference (IV, Random, 95% CI)-3.16 [-10.30, 3.98]
2 Male sex185Odds Ratio (M-H, Random, 95% CI)1.55 [0.55, 4.35]
3 Cure rates182Odds Ratio (M-H, Random, 95% CI)1.05 [0.06, 17.40]
4 Failure rates182Odds Ratio (M-H, Random, 95% CI)0.95 [0.06, 15.74]
Analysis 20.1.

Comparison 20 Amoxycillin with clarithromycin, Outcome 1 Mean age.

Analysis 20.2.

Comparison 20 Amoxycillin with clarithromycin, Outcome 2 Male sex.

Analysis 20.3.

Comparison 20 Amoxycillin with clarithromycin, Outcome 3 Cure rates.

Analysis 20.4.

Comparison 20 Amoxycillin with clarithromycin, Outcome 4 Failure rates.

Comparison 21. Penicillin and gentamycin with co-amoxyclavulanic acid
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Number of children less than one year age171Odds Ratio (M-H, Random, 95% CI)0.54 [0.20, 1.43]
2 Male sex163Odds Ratio (M-H, Random, 95% CI)1.35 [0.42, 4.32]
3 Failure rates171Odds Ratio (M-H, Random, 95% CI)0.86 [0.05, 14.39]
Analysis 21.1.

Comparison 21 Penicillin and gentamycin with co-amoxyclavulanic acid, Outcome 1 Number of children less than one year age.

Analysis 21.2.

Comparison 21 Penicillin and gentamycin with co-amoxyclavulanic acid, Outcome 2 Male sex.

Analysis 21.3.

Comparison 21 Penicillin and gentamycin with co-amoxyclavulanic acid, Outcome 3 Failure rates.

Comparison 22. Levofloxacin with comparator (co-amoxyclavulanic acid/ceftrioxone)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Mean age1709Mean Difference (IV, Random, 95% CI)0.05 [-0.64, 0.74]
2 Male sex1709Odds Ratio (M-H, Random, 95% CI)0.97 [0.69, 1.36]
3 Numbers received antibiotics in past one week1709Odds Ratio (M-H, Random, 95% CI)0.93 [0.64, 1.35]
4 Cure rates1539Odds Ratio (M-H, Random, 95% CI)1.05 [0.46, 2.42]
Analysis 22.1.

Comparison 22 Levofloxacin with comparator (co-amoxyclavulanic acid/ceftrioxone), Outcome 1 Mean age.

Analysis 22.2.

Comparison 22 Levofloxacin with comparator (co-amoxyclavulanic acid/ceftrioxone), Outcome 2 Male sex.

Analysis 22.3.

Comparison 22 Levofloxacin with comparator (co-amoxyclavulanic acid/ceftrioxone), Outcome 3 Numbers received antibiotics in past one week.

Analysis 22.4.

Comparison 22 Levofloxacin with comparator (co-amoxyclavulanic acid/ceftrioxone), Outcome 4 Cure rates.

Comparison 23. Cefuroxime with clarithromycin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Mean age183Mean Difference (IV, Random, 95% CI)-7.03 [-13.16, -0.90]
2 Male sex184Odds Ratio (M-H, Random, 95% CI)14.55 [1.78, 118.76]
3 Cure rates182Odds Ratio (M-H, Random, 95% CI)0.51 [0.04, 5.89]
4 Failure rates184Odds Ratio (M-H, Random, 95% CI)2.05 [0.18, 23.51]
Analysis 23.1.

Comparison 23 Cefuroxime with clarithromycin, Outcome 1 Mean age.

Analysis 23.2.

Comparison 23 Cefuroxime with clarithromycin, Outcome 2 Male sex.

Analysis 23.3.

Comparison 23 Cefuroxime with clarithromycin, Outcome 3 Cure rates.

Analysis 23.4.

Comparison 23 Cefuroxime with clarithromycin, Outcome 4 Failure rates.

Comparison 24. Co-trimoxazole versus chloramphenicol
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Age in months1111Mean Difference (IV, Random, 95% CI)1.90 [-0.64, 4.44]
2 Male sex1111Odds Ratio (M-H, Random, 95% CI)0.89 [0.42, 1.89]
3 Weight for age1111Mean Difference (IV, Random, 95% CI)Not estimable
4 Wheezing positive1111Odds Ratio (M-H, Random, 95% CI)0.67 [0.11, 4.15]
5 Cure rate1111Odds Ratio (M-H, Random, 95% CI)1.06 [0.47, 2.40]
6 Failure rate1111Odds Ratio (M-H, Random, 95% CI)1.03 [0.45, 2.33]
7 Excluded1111Odds Ratio (M-H, Random, 95% CI)0.94 [0.42, 2.12]
8 Relapse rate1111Odds Ratio (M-H, Random, 95% CI)1.02 [0.24, 4.30]
9 Need for change in antibiotics1111Odds Ratio (M-H, Random, 95% CI)1.42 [0.46, 4.40]
10 Death rate1111Odds Ratio (M-H, Random, 95% CI)2.21 [0.63, 7.83]
11 Organisms isolated on blood culture or lung puncture1111Odds Ratio (M-H, Random, 95% CI)1.25 [0.47, 3.30]
Analysis 24.1.

Comparison 24 Co-trimoxazole versus chloramphenicol, Outcome 1 Age in months.

Analysis 24.2.

Comparison 24 Co-trimoxazole versus chloramphenicol, Outcome 2 Male sex.

Analysis 24.3.

Comparison 24 Co-trimoxazole versus chloramphenicol, Outcome 3 Weight for age.

Analysis 24.4.

Comparison 24 Co-trimoxazole versus chloramphenicol, Outcome 4 Wheezing positive.

Analysis 24.5.

Comparison 24 Co-trimoxazole versus chloramphenicol, Outcome 5 Cure rate.

Analysis 24.6.

Comparison 24 Co-trimoxazole versus chloramphenicol, Outcome 6 Failure rate.

Analysis 24.7.

Comparison 24 Co-trimoxazole versus chloramphenicol, Outcome 7 Excluded.

Analysis 24.8.

Comparison 24 Co-trimoxazole versus chloramphenicol, Outcome 8 Relapse rate.

Analysis 24.9.

Comparison 24 Co-trimoxazole versus chloramphenicol, Outcome 9 Need for change in antibiotics.

Analysis 24.10.

Comparison 24 Co-trimoxazole versus chloramphenicol, Outcome 10 Death rate.

Analysis 24.11.

Comparison 24 Co-trimoxazole versus chloramphenicol, Outcome 11 Organisms isolated on blood culture or lung puncture.

Comparison 25. Oral treatment of severe pneumonia with parenteral treatment
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Male sex23739Odds Ratio (M-H, Random, 95% CI)1.07 [0.94, 1.22]
2 Received antibiotics in the past week33942Odds Ratio (M-H, Random, 95% CI)1.14 [0.86, 1.52]
3 Children with wheezing12037Odds Ratio (M-H, Random, 95% CI)0.89 [0.73, 1.10]
4 Failure rates on day 333942Odds Ratio (M-H, Random, 95% CI)0.95 [0.78, 1.15]
5 Relapse rates22076Odds Ratio (M-H, Random, 95% CI)1.28 [0.34, 4.82]
6 Death rates33942Odds Ratio (M-H, Random, 95% CI)0.15 [0.03, 0.87]
7 Lost to follow up12037Odds Ratio (M-H, Random, 95% CI)0.45 [0.17, 1.20]
8 Age below 12 months23739Odds Ratio (M-H, Random, 95% CI)1.00 [0.87, 1.14]
9 Failure rates on day 633942Odds Ratio (M-H, Random, 95% CI)0.93 [0.74, 1.16]
10 Failure rate after removing one study22240Odds Ratio (M-H, Fixed, 95% CI)0.87 [0.65, 1.15]
Analysis 25.1.

Comparison 25 Oral treatment of severe pneumonia with parenteral treatment, Outcome 1 Male sex.

Analysis 25.2.

Comparison 25 Oral treatment of severe pneumonia with parenteral treatment, Outcome 2 Received antibiotics in the past week.

Analysis 25.3.

Comparison 25 Oral treatment of severe pneumonia with parenteral treatment, Outcome 3 Children with wheezing.

Analysis 25.4.

Comparison 25 Oral treatment of severe pneumonia with parenteral treatment, Outcome 4 Failure rates on day 3.

Analysis 25.5.

Comparison 25 Oral treatment of severe pneumonia with parenteral treatment, Outcome 5 Relapse rates.

Analysis 25.6.

Comparison 25 Oral treatment of severe pneumonia with parenteral treatment, Outcome 6 Death rates.

Analysis 25.7.

Comparison 25 Oral treatment of severe pneumonia with parenteral treatment, Outcome 7 Lost to follow up.

Analysis 25.8.

Comparison 25 Oral treatment of severe pneumonia with parenteral treatment, Outcome 8 Age below 12 months.

Analysis 25.9.

Comparison 25 Oral treatment of severe pneumonia with parenteral treatment, Outcome 9 Failure rates on day 6.

Analysis 25.10.

Comparison 25 Oral treatment of severe pneumonia with parenteral treatment, Outcome 10 Failure rate after removing one study.

Comparison 26. Co-trimoxazole versus co-amoxyclavulanic acid
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Children below one year of age21232Odds Ratio (M-H, Random, 95% CI)117.90 [16.39, 848.37]
2 Male sex21232Odds Ratio (M-H, Random, 95% CI)0.54 [0.33, 0.88]
3 Failure rate21232Odds Ratio (M-H, Random, 95% CI)12.98 [3.18, 53.06]
Analysis 26.1.

Comparison 26 Co-trimoxazole versus co-amoxyclavulanic acid, Outcome 1 Children below one year of age.

Analysis 26.2.

Comparison 26 Co-trimoxazole versus co-amoxyclavulanic acid, Outcome 2 Male sex.

Analysis 26.3.

Comparison 26 Co-trimoxazole versus co-amoxyclavulanic acid, Outcome 3 Failure rate.

Comparison 27. Amoxycillin versus cefpodoxime
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Age in months1284Mean Difference (IV, Random, 95% CI)Not estimable
2 Male sex151Odds Ratio (M-H, Random, 95% CI)1.71 [0.07, 44.09]
3 Response/cure rate1238Odds Ratio (M-H, Random, 95% CI)0.20 [0.08, 0.53]
Analysis 27.1.

Comparison 27 Amoxycillin versus cefpodoxime, Outcome 1 Age in months.

Analysis 27.2.

Comparison 27 Amoxycillin versus cefpodoxime, Outcome 2 Male sex.

Analysis 27.3.

Comparison 27 Amoxycillin versus cefpodoxime, Outcome 3 Response/cure rate.

Comparison 28. Amoxycillin versus chloramphenicol
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Age (mean/median)21032Mean Difference (IV, Random, 95% CI)-6.60 [-10.52, -2.68]
2 Male sex21032Odds Ratio (M-H, Random, 95% CI)2.34 [1.55, 3.53]
3 Cure rate1796Odds Ratio (M-H, Random, 95% CI)4.26 [2.57, 7.08]
4 Failure rates21065Odds Ratio (M-H, Random, 95% CI)0.64 [0.41, 1.00]
Analysis 28.1.

Comparison 28 Amoxycillin versus chloramphenicol, Outcome 1 Age (mean/median).

Analysis 28.2.

Comparison 28 Amoxycillin versus chloramphenicol, Outcome 2 Male sex.

Analysis 28.3.

Comparison 28 Amoxycillin versus chloramphenicol, Outcome 3 Cure rate.

Analysis 28.4.

Comparison 28 Amoxycillin versus chloramphenicol, Outcome 4 Failure rates.

Appendices

Appendix 1. EMBASE search strategy

EMBASE (WebSPIRS)
#1 explode 'pneumonia-' / all subheadings in DEM,DER,DRM,DRR
#2 (pneumonia in ti) or (pneumonia in ab)
#3 #1 or #2
#4 'antibiotic-agent' / all subheadings in DEM,DER,DRM,DRR
#5 (antibiotic* in ti) or (antibiotic* in ab)
#6 #4 or #5
#7 'child-' / all subheadings in DEM,DER,DRM,DRR
#8 (child in ti) or (child in ab)
#9 (children in ti) or (children in ab)
#10 'infant-' / all subheadings in DEM,DER,DRM,DRR
#11 (infant* in ti) or (infant* in ab)
#12 #7 or #8 or #9 or #10 or #11
#13 #3 and #6 and #12
#14 explode 'randomized-controlled-trial' / all subheadings
#15 explode 'controlled-study' / all subheadings
#16 explode 'single-blind-procedure' / all subheadings
#17 explode 'double-blind-procedure' / all subheadings
#18 explode 'crossover-procedure' / all subheadings
#19 explode 'phase-3-clinical-trial' / all subheadings
#20 (randomi?ed controlled trial in ti) or (randomi?ed controlled trial in ab)
#21 ((random* or placebo* or double-blind*)in ti) or ((random* or placebo* or double-blind*)in ab)
#22 (controlled clinical trial* in ti) or (controlled clinical trial* in ab)
#23 #14 or #15 or #16 or #17 or 318 or #19 or #290 or #21 or #22
#24 (nonhuman in der) not ((human in der) and (nonhuman in der))
#25 #23 not #24
#26 #13 and #25

What's new

Last assessed as up-to-date: 17 September 2009.

DateEventDescription
4 January 2010New citation required and conclusions have changedSeven new studies included and we have added new information on ambulatory treatment for severe pneumonia and the superiority of ampicillin/penicillin with gentamycin instead of chloramphenicol for the treatment of very severe pneumonia to the conclusions.
18 September 2009New search has been performedSearches conducted.

History

Protocol first published: Issue 3, 2004
Review first published: Issue 3, 2006

DateEventDescription
1 August 2009AmendedConverted to new review format.
6 January 2006New citation required and major changesSearch conducted.

Contributions of authors

Dr Sushil K Kabra (SK) and Dr Rakesh Lodha (RL) jointly prepared and edited the review.
Dr RM Pandey (RP) contributed to the sections on data extraction, data analysis, quality assessment and statistical methods; in addition to editing the review.

Declarations of interest

One of the authors (Kabra) was co-author in one study (Awasthi 2008) included in the review.

Sources of support

Internal sources

  • All India Institute of Medical Sciences, New Delhi, India.

External sources

  • No sources of support supplied

Differences between protocol and review

In protocol we decided to include studies with an outcome in form of cure rate. However, there were a few studies that did not have cure rates. We therefore decided to include studies that gave either cure rates or treatment failure rates as one of the outcomes.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Addo-Yobo 2004

MethodsRCT comparing amoxycillin and penicillin
ParticipantsChildren 3 to 59 months with severe pneumonia
InterventionsDaily IM penicillin 200,000 IU/kg or PO amoxycillin 45 mg/kg/day
OutcomesFailure rate at 48 hours, 5 days and 14 days and death rate
NotesExclusion criteria: asthma, audible wheeze, non-severe pneumonia, very severe disease, clinical HIV, persistent vomiting, penicillin allergy
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?Yes 
Allocation concealment?YesRandomisation codes were sealed in opaque envelops in accordance with allocation sequence, stratified by site and prepared in advance by the WHO
Blinding?
All outcomes
No 
Incomplete outcome data addressed?
All outcomes
Yes 
Free of selective reporting?Yes 
Free of other bias?YesFunded by World Heath Organization and Applied Research Child Health Project, Boston University

Asghar 2008

MethodsRandomised, non-blinded, multi-site efficacy study
ParticipantsChildren between 2 to 59 months of age with very severe pneumonia
InterventionsAmpicillin plus gentamicin (ampicillin 200 mg/kg/d in 4 doses every 6 hours, and gentamicin 7.5 mg/kg/d as in a single daily dose) or chloramphenicol (75 mg/kg/d given in 3 doses) every 8 hours for minimum of 5 days. After that first group received oral amoxycillin (45 mg/kg/day in 3 divided doses) and the other group received oral chloramphenicol 75 mg/kg/day to complete 10 days
Outcomes

Primary outcome

  1. Treatment failure by 5 days after admission, defined as new development or persistence of at least 2 of the following: inability to drink; tachypnoea (≥ 50 breaths/minute in children aged 2 to 11 months and ≥ 40 breaths/minute in children aged 12 to 59 months), and abnormally sleepy or difficult to wake

  2. Development or diagnosis of any of the following: bacterial meningitis, empyema, septic shock, renal failure, or newly diagnosed co-morbid conditions. Serious adverse drug reaction

  3. Modification of antibiotic treatment

  4. Voluntary withdrawal or absconding

  5. Death

Secondary outcomes
Treatment failure as defined above at 48 to 60 hours
Treatment failure as defined above plus relapse (hypoxaemic pneumonia at 10 to 12 days and 21 to 30 days, with oxygen saturations ≤ 90%, or ≤ 88% in the 2 high altitude sites in Mexico and Yemen)
Death by 30 days after enrolment
Bacterial pathogens isolated from blood or other sterile sites
Antimicrobial susceptibility of the isolated pathogens

NotesExclusion criteria: wheezing, with a history of 3 or more attacks, or known asthma, known heart disease, duration of present illness more than 10 days, history of serious adverse reaction to any of the study drugs, previous enrolment in the study
Admission to hospital for more than 24 hours within past 7 days
Documented evidence of injectable antibiotic treatment for more than 24 hours before enrolment, stridor, known renal failure or not passed urine during past 6 hours, evidence of cerebral malaria
Evidence of bacterial meningitis, clinical jaundice, residence of patient in an area where follow-up was not possible, empyema or presence of pneumatoceles on chest radiograph
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesSequence generated by World Health Organization by using variable size blocks
Allocation concealment?YesSeparate randomisation lists were prepared for each site examination, and individual patient assignments were placed in opaque sealed envelopes. Before opening each envelope the doctor in charge signed and dated the opening flap of the envelope
Blinding?
All outcomes
No 
Incomplete outcome data addressed?
All outcomes
Yes 
Free of selective reporting?Yes 
Free of other bias?YesFunded by World Health Organization and Center of International Health and Development, Boston University and Johns Hopkins Bloomberg School of Public Health, Baltimore

Atkinson 2007

MethodsMulticentre randomised controlled trial
ParticipantsChildren admitted with pneumonia in 8 hospitals. At least 3 inclusion criteria for diagnosis of pneumonia. Respiratory symptoms or signs, fever > 37.5°C, radiological diagnosis of pneumonia (defined as confluent area of consolidation agreed subsequently by 2 independent radiologists)
InterventionsOral amoxycillin (doses for 6 months to 12 years of age 8 mg/kg/dose 3 times a day above 12 years of age 500 mg 3 times a day) or IV benzyl penicillin (doses 25 mg/kg/dose 4 times a day)
Outcomes

The primary outcome measure was time from randomisation until the temperature was 38 °C for 24 continuous hours and oxygen requirement had ceased (the latter only applicable to those children who required oxygen during the admission)

Secondary outcomes included time in hospital, complications (empyema, re-admission, further courses of antibiotics), duration of oxygen requirement and time to resolution of illness

Notes

Exclusion criteria were wheeze, oxygen saturations, 85% in air, shock requiring 20 ml/kg fluid resuscitation, immunodeficiency, pleural effusion at presentation requiring drainage, chronic lung condition (excluding asthma), penicillin allergy and age 6 months

Treatment with oral antibiotics in the 5 days prior to admission, including amoxicillin, was not an exclusion criterion

Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?Yes 
Allocation concealment?YesA block randomisation sequence stratified by centre was produced using a random number generator. The sequence was accessed via the Internet, therefore allowing concealment of allocation
Blinding?
All outcomes
No 
Incomplete outcome data addressed?
All outcomes
Yes 
Free of selective reporting?UnclearWhile the authors mention the primary outcome as "the time from randomization until the temperature was less than 38 degree celsius for 24 continuous hours and oxygen requirement had ceased", they calculated the sample size based on the proportion meeting the primary outcome measure at any time. The authors have not reported on these proportions in the results
Free of other bias?YesFunded by the British Lung Foundation

Aurangzeb 2003

MethodsRandomised, non-blinded controlled clinical trial
ParticipantsChildren between 3 to 72 months of age, admitted in the hospital with community-acquired pneumonia
InterventionsThe patients were randomly allotted to 1 of the 3 groups
Group 1 was given amoxicillin 75 mg/kg/d IV in 3 divided doses, Group 2 was given cefuroxime 75 mg/kg/d IV in 3 divided doses and Group 3 was given clarithromycin 15 mg/kg/d IV divided into 2 divided doses
Outcomes

1. Improvement defined as slower respiratory rate (either back to normal for the age of the child), or more than 5 as compared to the previous day evaluation without retractions. The same defined as still breathing fast as before as or higher than that with no chest in drawing or danger signs

2. Worse was defined as development of severe pneumonia or very severe disease

3. Cure was defined as return of respiratory rate to age specific normal range

Notes
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearNot mentioned
Blinding?
All outcomes
No 
Incomplete outcome data addressed?
All outcomes
Yes 
Free of selective reporting?UnclearThere are discrepancies in the number of patients in different study arms
Free of other bias?UnclearSource of funding not mentioned

Awasthi 2008

MethodsCluster-randomised, open-label trial
ParticipantsChildren of either sex, between 2 months to 59 months with WHO defined non-severe pneumonia
InterventionsEligible children were randomised to receive oral dispersible scored amoxycillin (125 mg per tablet) given thrice a day (TDS) for 3 days or co-trimoxazole (20 mg trimethoprim per tablet) given twice a day (BD) for 5 days. Doses of amoxycillin were between 31 to 51 mg/kg/day and trimethoprim 7 to 11 mg/kg/day
Outcomes

Primary outcome measure was clinical failure defined as presence of at least one of the following: (i) development of signs of WHO defined severe pneumonia or very severe disease (ii) respiratory rate above age specific cut-off, (iii) documented axillary temperature > 38.3 °C on the day of outcome assessment, that is day 4 for amoxycillin and day 6 for co-trimoxazole arm, (iv) death within the follow-up period of 14 days, (v) lost to follow up on day 4 or day 6 in the amoxycillin and co-trimoxazole arms, respectively, or (vi) withdrawal at any time (requirement of intention-to-treat (ITT) analysis)

The secondary outcome measure was clinical relapse on day 13 to 15, defined as development of signs of WHO-defined pneumonia among the clinically cured in either arm

Notes
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?Yes 
Allocation concealment?YesThis was an open-label study and the unit of randomisation was primary health centre
Blinding?
All outcomes
No 
Incomplete outcome data addressed?
All outcomes
Yes 
Free of selective reporting?Yes 
Free of other bias?YesFunded by Indian Council of Medical Research

Bansal 2006

MethodsOpen-label randomised controlled trial
ParticipantsChildren aged 2 to 59 months with WHO-defined severe or very severe pneumonia with hypoxaemia (Sp02 < 90%) were included in the study
InterventionsPatients in Group A received crystalline penicillin (benzyl penicillin) - 50,000 IV/kg IV, q6h and gentamycin 2.5 mg/kg, IV, q8h for at least 3 days. After that, oral amoxycillin 15 mg/kg 8-hourly was substituted for crystalline penicillin. Group B patients were given amoxicillin-clavulanate 30 mg/kg IV q12h for at least 3 days and were changed to oral amoxycillin-clavulanic acid when able to feed
OutcomesTreatment failure was defined as any change, modification or discontinuation of allocated antibiotic therapy because of deterioration in patient's condition, development of serious intercurrent illness or complications such as refractory septic shock, acute renal failure, meningitis etc., persistence of danger signs such as inability to drink after 48 hours of treatment, or relapse of the hypoxaemic pneumonia during the following 2 weeks
NotesPatients with fever > 10 days, bacterial meningitis, prior antibiotic therapy > 24 hours, stridor, heart disease and allergy to any of the study drugs were excluded
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?Yes 
Allocation concealment?YesRandomisation list was prepared before starting the study and random treatment assignment was placed in serially-labelled sealed envelopes. The assignment was opened when the patient had met all the inclusion and exclusion criteria and written consent was available
Blinding?
All outcomes
No 
Incomplete outcome data addressed?
All outcomes
Yes 
Free of selective reporting?Yes 
Free of other bias?UnclearSource of funding not mentioned

Block 1995

MethodsRCT comparing clarithromycin with erythromycin in children with pneumonia
ParticipantsChildren between 3 to 16 years of age with radiographically diagnosed pneumonia
InterventionsPO clarithromycin (15 mg/kg/day) for 10 days or erythromycin 40 mg/kg/day for 10 days
OutcomesCure rates, resolution of signs and symptoms, improvement, improved but non-resolution of signs and symptoms, failure or worsening
NotesExclusion: hypersensitivity to macrolides, severe renal or hepatic diseases, active tuberculosis, severe infections requiring intravenous antibiotics
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearNot mentioned clearly. Open label study. Study drugs were dispensed and compliance was monitored by third party
Blinding?
All outcomes
No 
Incomplete outcome data addressed?
All outcomes
Yes 
Free of selective reporting?Yes 
Free of other bias?UnclearFunded by Abbott Laboratories and role of funding agency not clear

Bradley 2007

MethodsThis was a randomised (3:1, levofloxacin:comparator), open-label, active-comparator, non-inferiority, multicentre study
ParticipantsChildren between 0.5 to 16 years old with a diagnosis of community-acquired pneumonia (CAP). A diagnosis of CAP was defined as radiographic evidence of pulmonary infiltrate consistent with acute infection requiring antibiotic therapy, and the presence of 2 or more of the indications of pneumonia: fever (rectal or oral temperature 38 °C for children 2 years, or 38.3 °C for children 0.5 to 2 years), shortness of breath, cough, chest pain, abnormal white blood cell count (15,000/L or 5000/L), or physical signs of pneumonia on examination (e.g. rales on auscultation, dullness to percussion, egophony)
InterventionsLevofloxacin or a comparator antibiotic for 10 days. Levofloxacin and comparators were given either orally or by intravenous (iv) administration. The patients were randomised in a 3:1 levofloxacin:comparator ratio within 14 strata in the study (1 for the 2 age groups within each country). For Group I (6 months to 5 years), levofloxacin was administered (a) 10 mg/kg/dose as oral suspension bid (up to 500 mg/d) or (b) 10 mg/kg/dose IV q12 hours (up to 500 mg/d). The comparator administration was (a) amoxicillin and clavulanic acid (7:1) oral suspension bid, with dose determined by calculating amoxicillin 22.5 mg/kg/dose (up to 875 mg/d), or (b) ceftriaxone 25 mg/kg/dose IV q12 hours (up to 4 g/d).
For Group II (5 to 16 years), levofloxacin was administered (a) as 10 mg/kg/dose as oral suspension qd (up to 500 mg/d), (b) as one 250 mg tablet qd (for children weighing 22.5 to 27.5 kg) or 2 250 mg tablets qd (for children weighing 45.5 kg), or (c) 10 mg/kg/dose IV q24 hours (up to 500 mg/d). The comparator administration was (a) clarithromycin 7.5 mg/kg/dose as oral suspension (or as a 250 mg tablet) bid (up to 250 mg bid), clarithromycin 250 mg oral tablet bid, or (b) ceftriaxone 25 mg/kg/dose IV q12 hours (up to 4 g/d), with either erythromycin lactobionate 10 mg/kg/dose IV q6 hours (up to 4 g/24 hours) or clarithromycin 7.5 mg/kg/dose as oral suspension (or as a 250 mg tablet) bid (up to 250 mg bid)
OutcomesClinical response was categorised as cured, improved, clinical failure, relapse at test-of-cure visit (TOCV) 10 to 17 days after the last dose of study drug. (1) cured: resolution of signs and symptoms associated with active infection along with an improvement or lack of progression of abnormal findings of chest roentgenogram; (2) improved: continued incomplete resolution of signs and symptoms with no deterioration or relapse after post-therapy visit (PTV) and no requirement for additional antimicrobial therapy; (3) clinical relapse: resolution or improvement of signs and symptoms at PTV evaluation with reappearance or deterioration of signs and symptoms of infection at test of cure visit (TOCV); (4) failure: patient was considered a clinical failure at PTV, response was carried forward to TOCV; and (5) unable to evaluate: unable to determine response because patient was not evaluated after PTV
NotesExclusion criteria: received systemic antibiotics for more than 24 hours immediately before enrolment, required a systemic antibiotic other than the study drugs, or had a suspected infection with microorganisms known to be resistant to the study drugs. Other exclusion criteria included hospitalisation or residence in a long-term care facility for 14 or more days before the onset of symptoms; infection acquired in a hospital (48 hours after hospital admission and 7 days after hospital discharge); signs and symptoms of a bacterial infection of the central nervous system; history or presence of arthropathy or periarticular disease or any other musculoskeletal signs or symptoms that in the opinion of the investigator may have confounded a future safety evaluation of musculoskeletal complaints
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearNot mentioned clearly in the paper
Blinding?
All outcomes
No 
Free of other bias?UnclearFunded by Johnson & Johnson Pharmaceutical Research and Development; details of role of funding agency not mentioned

Camargos 1997

MethodsRCT comparing benzathine penicillin and procaine penicillin
ParticipantsChildren 2 years to 12 years with non-severe pneumonia
InterventionsSingle dose of benzathine penicillin (600,000 U for patients below 20 kg weight and 1,200,000 U for those above 20 kg), procaine penicillin 300,000 IU/kg/day IM for 7 days
OutcomesCure rate, failure rate, lost to follow up
NotesExclusion criteria: severe disease, atelectasis, post-measles pneumonia, sickle cell cardiomyopathy, immunodeficiency, allergic to penicillin, hospitalisation in previous 2 weeks
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?Yes 
Allocation concealment?YesRandomisation done by trained staff member blinded to control or treatment using 4 identifying letters randomly selected for benzathine (W and Z) and procaine (X Y) enclosed in sealed envelope
Blinding?
All outcomes
No 
Incomplete outcome data addressed?
All outcomes
Yes 
Free of selective reporting?Yes 
Free of other bias?UnclearSource of funding not mentioned

Campbell 1988

MethodsRCT comparing co-trimoxazole for 5 days and procaine penicillin single dose with ampicillin for 5 days
ParticipantsChildren 1 month to 4 years of age with non-severe pneumonia
InterventionsDaily co-trimoxazole PO for 5 days or single dose procaine penicillin with daily PO ampicillin
OutcomesCure rate, hospitalisation rate and death rate
NotesExclusion criteria: very severe disease, refusal of consent, unable to take tablets
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearEligible children were allocated sequentially to 2 treatment groups by study physician
Blinding?
All outcomes
No 
Free of other bias?UnclearSource of funding not mentioned

CATCHUP 2002

MethodsRCT comparing amoxycillin and co-trimoxazole in non-severe pneumonia
ParticipantsChildren 2 to 59 months with non-severe pneumonia
InterventionsPO amoxycillin 25 mg/kg/day for 5 days or co-trimoxazole 20/4 mg/kg/day for 5 days
OutcomesCure rate, failure rate, change of antibiotics
NotesBlinded, exclusion criteria: severe pneumonia, very severe disease, chronic illness, past history of 2 or more episodes of wheeze, acute bronchial asthma, antibiotics in past 48 hours
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesRandom numbers generated using a computer program
Allocation concealment?YesThe drug assignment was concealed from patients parents and study personnel
Blinding?
All outcomes
Yes 
Incomplete outcome data addressed?
All outcomes
Yes 
Free of selective reporting?Yes 
Free of other bias?YesFunded by World Health Organization

Cetinkaya 2004

MethodsRCT comparing chloramphenicol in combination with penicillin with ceftriaxone
ParticipantsChildren aged 6 months to 16 years with clinical or radiological evidence of pneumonia
InterventionsIV chloramphenicol 15 mg/kg every 6 hours plus penicillin 25,000 IU/kg every 4 hours for 10 days and ceftriaxone 50 mg/kg every 12 hours
OutcomesClinical recovery
NotesBlinded, children clinically diagnosed with bacterial pneumonia were enrolled
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?Yes 
Allocation concealment?Yes 
Blinding?
All outcomes
Yes 
Incomplete outcome data addressed?
All outcomes
Yes 
Free of selective reporting?Yes 
Free of other bias?Yes 

Deivanayagam 1996

MethodsRCT comparing ampicillin in combination with penicillin with chloramphenicol for pneumonia diagnosed by clinical/radiological evidence
ParticipantsChildren 5 months to 4 years with pneumonia admitted to hospital
InterventionsIM/IV ampicillin (100 mg/kg/day) for 48 hours than PO, IV penicillin (100000 IU/kg/day) plus chloramphenicol (100 mg/kg/day)
OutcomesCure rate, failure rate
NotesNot blinded. Exclusion criteria: acute bronchiolitis, allergy to penicillin, antibiotics in past 2 days, other drugs by treating physician receiving anti-tuberculosis drugs
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?Yes 
Allocation concealment?Yes 
Blinding?
All outcomes
NoOpen-label study
Incomplete outcome data addressed?
All outcomes
UnclearNo intention-to-treat analysis and details of excluded patients not clear
Free of other bias?UnclearSource of funding not mentioned

Duke 2002

MethodsRCT comparing chloramphenicol with combination of penicillin and gentamicin in children with severe pneumonia
ParticipantsChildren aged 1 to 59 months age, with severe pneumonia
InterventionsIM chloramphenicol (25 mg/ kg 6-hourly for at least 5 days) versus penicillin (50 mg/ kg 6 hourly ) and gentamicin (7.5 mg/kg/d single dose) for at least 5 days
OutcomesAdverse outcome (death, change in antibiotics, absconded, readmission within 30 days), rate of hospitalisation, duration of hospital stay
NotesNot blinded
Exclusion criteria: wheezing, bronchiolitis, meningitis, tuberculosis, CHD, renal failure, jaundice, received study antibiotics for more than 48 hours in last 1 week
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesComputer-generated
Allocation concealment?YesEligible children were randomly assigned to one protocol
Blinding?
All outcomes
No 
Incomplete outcome data addressed?
All outcomes
Yes 
Free of selective reporting?Yes 
Free of other bias?YesFunded by the World Health Organization and the Papua New Guinea Health Department

Harris 1998

MethodsRCT comparing azithromycin, co-amoxyclavulanic acid and erythromycin in pneumonia
ParticipantsChildren aged 6 months to 16 years with clinical or radiological evidence of pneumonia
InterventionsPO azithromycin (10 mg/kg/day 1 followed by 5 mg/kg/day for 4 days) or amoxycillin clavulanic acid (40 mg/kg/day) for 10 days or erythromycin (40 mg/kg/day) for 10 days
OutcomesCure rate (day 15 to 19), improvement rate, failure rate
NotesExclusion criteria: known hypersensitivity, intolerance to drugs, pregnancy, lactation, need for parental antibiotics, severe pneumonia, antibiotics in past 72 hours, chronic steroid therapy, on carbamazepine, ergotamine, terfenadine, loratadine
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearSequence generation not mentioned
Allocation concealment?YesDouble-blind trial
Blinding?
All outcomes
Yes 
Incomplete outcome data addressed?
All outcomes
UnclearIntention-to-treat analysis not performed and no details of excluded patients
Free of other bias?UnclearFunded by Pfizer Inc., New York

Hazir 2008

MethodsRandomised, open-label equivalency trial
ParticipantsChildren aged 3 to 59 months with WHO-defined severe pneumonia
InterventionsOral amoxicillin syrup (80 to 90 mg/kg per day in 2 doses) and were sent home (ambulatory group), or to receive intravenous ampicillin (100 mg/kg per day in 4 doses) for 48 hours as an inpatient (hospitalised group)
OutcomesPrimary outcome (treatment failure up to or on day 6). Any of the following: clinical deterioration; inability to take oral medication due to persistent vomiting; development of a comorbid condition requiring an antibiotic; persistence of fever > 38 ºC with lower chest indrawing (LCI) from day 3 to day 6; either fever or lower chest indrawing alone at day 6; hospitalisation related to pneumonia; serious adverse event; left against medical advice or lost to follow up; voluntary withdrawal of consent; death
Secondary outcome (treatment failure between day 6 and day 14; relapse). Any of the following: clinical deterioration; development of a comorbid condition requiring an antibiotic; development of lower chest indrawing or fast breathing non-responsive to 3 trials of nebulisation in children with wheeze
NotesExclusion criteria: known asthma, those with a history of 3 or more episodes of wheezing in 1 year, or those in whom lower chest indrawing resolved after 3 doses of a bronchodilator over 30 minutes were excluded. Children showing signs of WHO-defined very severe pneumonia (panel 1) were also excluded; such individuals were admitted to hospital for treatment with intravenous antibiotics. Children who were known to have anaphylactic reactions to penicillin or amoxicillin, those with persistent vomiting, those who had been hospitalised within the previous 2 weeks, and those with other infectious diseases that needed antibiotic treatment, were also excluded
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?Yes 
Allocation concealment?YesThe randomisation scheme was generated by a computer program in uneven blocks of 4, 6 and 8 by an individual not involved in study. Randomisation codes were sealed in opaque envelopes in accordance with the allocation sequence and stratified by site. After being deemed eligible for enrolment, participants were assigned the next envelope in the sequence to determine treatment assignment. The randomisation code was held at the coordinating centre and was broken at the time of data analysis
Blinding?
All outcomes
No 
Incomplete outcome data addressed?
All outcomes
Yes 
Free of selective reporting?Yes 
Free of other bias?YesFunded by the World Health Organization and Family Applied Research Project, Boston University

Jibril 1989

MethodsRCT comparing amoxycillin and co-amoxyclavulanic acid with amoxycillin alone in bacterial pneumonia (non-severe)
ParticipantsChildren aged 2 years to 12 years age, with non-severe pneumonia
InterventionsAmoxycillin and co-amoxyclavulanic acid (250 mg + 62.5 mg or 500 + 125 mg tds) with amoxicillin (250 mg or 500 mg tds) for 10 days
OutcomesPoor or no response; cure rate
NotesExclusion criteria: renal/hepatic impairment; hypersensitivity to penicillin/cephalosporin
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?Yes 
Allocation concealment?UnclearNot mentioned
Blinding?
All outcomes
No 
Free of other bias?UnclearSource of funding not mentioned

Keeley 1990

MethodsRCT comparing co-trimoxazole and procaine penicillin
ParticipantsChildren aged 3 months to 12 years with non-severe pneumonia
InterventionsCo-trimoxazole per oral for 5 days. Procaine penicillin IM daily for 5 days
OutcomesCure rate, treatment failure, hospitalisation, well at final follow up and death rate
NotesExclusion criteria: children with chest indrawing, unable to feed and requiring immediate referral
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?Yes 
Allocation concealment?YesUsed sealed envelops
Blinding?
All outcomes
No 
Free of other bias?YesFunded by University of Zimbabwe, Harare

Klein 1995

MethodsRCT comparing cefpodoxime and co-amoxyclavulanic acid in LRTI
ParticipantsChildren aged 3 months to 11.5 years
InterventionsCefpodoxime 5 to 12 mg/kg/day PO for 10 days or co-amoxyclavulanic acid 6 to 13 mg/kg/day for 10 days
OutcomesResponse rate
NotesExclusion criteria: nosocomial infection, antibiotics in past 48 hours, allergy to beta lactam antibiotics, suspected/confirmed TB, congenital anomalies
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearNo mention about details of allocation concealment
Blinding?
All outcomes
No 
Incomplete outcome data addressed?
All outcomes
UnclearNo intention-to-treat analysis. No details of children excluded from the analysis
Free of selective reporting?UnclearNo intention-to-treat analysis. No details of children excluded from the analysis
Free of other bias?UnclearSource of funding not mentioned

Kogan 2003

MethodsRCT comparing azithromycin and amoxycillin
ParticipantsChildren aged 1 month to 14 years with non-severe pneumonia
InterventionsAzithromycin (10 mg/kg/day) PO for 3 days or amoxycillin PO 75 mg/kg/day for 7 days
OutcomesClinical and radiological cure rates fever on day 3 and day 7, chest X-ray on day 14
NotesExclusion criteria: chronic pathology, preterm, received antibiotics in past 5 days
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?No 
Allocation concealment?NoNot used
Blinding?
All outcomes
No 
Incomplete outcome data addressed?
All outcomes
Yes 
Free of selective reporting?Yes 
Free of other bias?UnclearSource of funding not mentioned

Mulholland 1995

MethodsRCT comparing chloramphenicol and co-trimoxazole in malnourished children with clinical or radiological pneumonia
ParticipantsChildren below 5 years of age with malnutrition and clinical or radiological evidence of pneumonia
InterventionsCefpodoxime 5 to 12 mg/kg/day PO for 10 days or co-amoxyclavulanic acid 6 to 13 mg/kg/day for 10 days
OutcomesCure rate, relapse rate, failure rate and exclusion, death rate
NotesBlinded
Exclusion criteria: already receiving antibiotics, clinical or radiological signs of TB, severe pneumonia
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?Yes 
Allocation concealment?YesDouble-blind study. Randomisation codes were kept with senior nurse and pharmacist
Blinding?
All outcomes
Yes 
Incomplete outcome data addressed?
All outcomes
Yes 
Free of selective reporting?Yes 
Free of other bias?YesFunded by the World Health Organization

Roord 1996

MethodsRCT comparing azithromycin and erythromycin in non-severe pneumonia (acute LRTI)
ParticipantsChildren aged 2 months to 16 years with non-severe pneumonia (acute LRTI)
InterventionsAzithromycin 10 mg/kg/day for 3 days or erythromycin 40 mg/kg/day for 10 days
OutcomesCure rate, failure rate at day 10 to 14, improvement at day 10, and between days 25 to 30
NotesExclusion criteria: not able to take oral medications, known hypersensitivity to azithromycin or erythromycin, cystic fibrosis, immunodeficiency, need for oxygen, nosocomial pneumonia, leucocyte count less than 300,000 per litre, bacteraemia, receiving alternative treatment
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?Yes 
Allocation concealment?NoOpen-label randomised controlled trial. Block randomisation. No mention about allocation concealment
Blinding?
All outcomes
No 
Incomplete outcome data addressed?
All outcomes
Yes 
Free of selective reporting?Yes 
Free of other bias?UnclearFunded by Pfizer - BV

Shann 1985

MethodsRCT comparing chloramphenicol and chloramphenicol in combination with penicillin in severe pneumonia
ParticipantsChildren
InterventionsIM chloramphenicol daily until switched over to oral, or IM chloramphenicol with benzyl penicillin until switched over to oral
OutcomesDischarge from hospital and good improvement of symptoms
NotesNot blinded
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?Yes 
Allocation concealment?YesSealed numbered envelopes used
Blinding?
All outcomes
No 
Free of other bias?UnclearSource of funding not mentioned

Sidal 1994

MethodsRCT comparing co-trimoxazole and penicillin in non-severe pneumonia (including moderate pneumonia)
ParticipantsChildren aged 3 months to 14 years with non-severe pneumonia (including moderate pneumonia)
InterventionsPO co-trimoxazole (40 mg/kg/day) for 10 days or IM procaine penicillin (50,000 IU/kg/day) for 10 days
OutcomesCure rate at day 5 and day 10, evident improvement at day 5 and day 10, failure rate
NotesExclusion criteria: severe chest in-drawing, inability to eat or drink, moderate to severe malnutrition, antibiotics in last 2 weeks, wheezing
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?No 
Allocation concealment?NoNo details of randomisation or allocation concealment
Blinding?
All outcomes
No 
Free of other bias?UnclearSource of funding not mentioned

Straus 1998

MethodsRCT comparing co-trimoxazole and amoxycillin in non-severe pneumonia
ParticipantsChildren aged 2 months to 59 months with non-severe pneumonia
InterventionsPO co-trimoxazole 20 mg/kg/day for 5 days or amoxycillin 45 mg/kg/day for 5 days
OutcomesFailure rate, determined by clinical and radiological evidence
NotesBlinded. Exclusion criteria: very severe pneumonia, antibiotics in past 48 hours, hospitalisation in past 7 days, hypoxaemia
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearSequence generation not mentioned
Allocation concealment?UnclearDrug allotment was concealed from participants. Details not clear
Blinding?
All outcomes
Yes 
Incomplete outcome data addressed?
All outcomes
Yes 
Free of selective reporting?Yes 
Free of other bias?UnclearSource of funding not mentioned

Tsarouhas 1998

MethodsRCT comparing procaine penicillin and amoxycillin for radiographically diagnosed pneumonia
ParticipantsChildren aged 6 months to 18 years with pneumonia
InterventionsPO amoxycillin (50 mg/kg/day) or procaine penicillin IM (50,000 IU/ kg/day)
OutcomesHospitalisation rate, failure rate, temperature more than 38.5 °C, ill appearance, increased respiratory rate
NotesUnblinded
Exclusion criteria: chronic illness, asthma, sickle cell disease, cystic fibrosis, allergy to amoxycillin, or penicillin, antibiotics in past 1 week, wheezing, concurrent febrile illness
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearSequence generation not mentioned
Allocation concealment?YesSealed envelope opened by Emergency Department nurse
Blinding?
All outcomes
No 
Incomplete outcome data addressed?
All outcomes
Yes 
Free of selective reporting?Yes 
Free of other bias?UnclearSource of funding not mentioned

Wubbel 1999

  1. a

    bd: twice a day
    CHD: congenital heart disease
    CPZ: carbamazepine
    IM: intramuscular
    IV: intravenous
    LRTI: lower respiratory tract infection
    PO: orally
    PTV: post therapy visit
    q6h: every 6 hours
    q8h: every 8 hours
    q12h: every 12 hours
    RCT: randomised controlled trial
    Sp02: oxygen saturation
    TB: tuberculosis
    tds: three times a day
    TOCV: test of cure visit

MethodsRCT comparing azithromycin and erythromycin in children over 5 years of age with pneumonia; and comparing azithromycin with co-amoxyclavulanic acid in children under 5 years of age
ParticipantsChildren aged between 6 months a 16 years with pneumonia
InterventionsPO azithromycin (10 mg/kg on day 1 followed by 5 mg/kg/day for next 4 days) or co-amoxyclavulanic acid 40 mg/kg/day for 10 days in children under 5 years of age; and erythromycin 40 mg/kg/day for 10 days in children over 5 years
OutcomesClinically diagnosed cure rates, failure rates and improvement
NotesNon-blinded. Exclusion criteria: hypersensitivity to study drugs, nosocomial pneumonia, hospitalisation, antibiotics in last 7 days
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearAllocation concealment not clearly described
Blinding?
All outcomes
No 
Incomplete outcome data addressed?
All outcomes
Yes 
Free of other bias?UnclearFunded by Pfizer Inc.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Agostoni 1988Compares minocycline and amoxycillin in 23 children between 3 to 11.5 years with pneumonia. Not a RCT
Al-Eiden 1999Describes results of sequential antibiotic therapy (SAT) in 89 patients with severe lower respiratory tract infection. The sequential antibiotic use was the reason for exclusion
Bonvehi 2003Compared clarithromycin and co-amoxyclavulanic acid in adult patients with CAP due to penicillin-resistant and/or macrolide-resistant S. pneumoniae. The study was excluded because of its adult study population
Esposito 2005Compared azithromycin in addition to symptomatic treatment with symptomatic treatment alone in children with recurrent respiratory tract infections. The study did not compare 2 or more antibiotics for pneumonia
Fogarty 2002Compared cefditoren with co-amoxyclavulanic acid in the management of community-acquired pneumonia in adult patients. The study had an adult population
Haffejee 1984A single-blind therapeutic trial using cefotaxime or a benzyl-penicillin-gentamycin combination in 68 hospitalised paediatric patients with 72 episodes of severe infection (septicaemia, pneumonia, neonatal meningitis and others). No separate data were available for pneumonia
Hasali 2005A randomised comparative study of clarithromycin and erythromycin in the treatment of community acquired pneumonia in children. Outcome in form of cure or failure available only for children with mycoplasma or chlamydia pneumonia
Higuera 1996Compared oral cefuroxime axetil and oral co-amoxyclavulanic acid in the treatment of community-acquired pneumonia in adult patients. The study was in adult patients
Lee 2008A randomised controlled trial comparing ampicillin versus ampicillin + gentamycin in children with community-acquired pneumonia. Outcome variables were total hospital stay and time taken for improvement in clinical symptoms. No clear data on cure or failure rates
Lu 2006Full paper could not be obtained
Mouallem 1976Compared cephradine and cephalexin for the treatment of bacterial infections in 162 children between 4 months and 11 years of age. There were no separate data for pneumonia
Paupe 1992Compares cefetamet (2 doses) with cefaclor. The doses of antibiotics were inconsistent
Petola 2001Describes results of treatment with a short (4-day) duration of antibiotics
Ruhrmann 1982Randomised controlled study. Compared erythromycin with amoxycillin in the treatment of 120 children with community-acquired pneumonia. Measured outcomes were duration of clinical symptoms, aetiology of pneumonia and side effects of antibiotics. The study does not provide cure rates, failure rates, death rates or relapse rates
Sanchez 1998Randomised controlled trial involving 409 patients admitted to internal medicine department. Compared ceftriaxone, cefuroxime and amoxycillin-clavulanic acid. Study does not provide separate data for children
van Zyl 2002Randomised controlled trial compared cefditoren with cefpodoxime in community-acquired pneumonia in adult patients. The study had an adult study population
Vuori-Holopaine 2000Compares procaine penicillin and cefuroxime in children between 3 months and 15 years of age with suspected sepsis. There were no separate data for pneumonia available

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