Antibiotic therapy versus no antibiotic therapy for children aged two to 59 months with WHO-defined non-severe pneumonia and wheeze

  • Review
  • Intervention

Authors


Abstract

Background

Worldwide, pneumonia is the leading cause of death among children under five years of age and accounts for approximately two million deaths annually. The World Health Organization (WHO) has developed case management guidelines based on simple clinical signs to help clinicians decide on the appropriate pneumonia treatment. Children and infants who exhibit fast breathing (50 breaths per minute or more in infants two months to 12 months of age and 40 or more in children 12 months to five years of age) and cough are presumed to have non-severe pneumonia and the WHO recommends antibiotics. Implementation of these guidelines to identify and manage pneumonia at the community level has been shown to reduce acute respiratory infection (ARI)-related mortality by 36%, although apprehension exists regarding these results due to the questionable quality of evidence. As WHO guidelines do not make a distinction between viral and bacterial pneumonia, these children continue to receive antibiotics because of the concern that it may not be safe to do otherwise. Therefore, it is essential to explore the role of antibiotics in children with WHO-defined non-severe pneumonia and wheeze and to develop effective guidelines for initial antibiotic treatment.

Objectives

To evaluate the efficacy of antibiotic therapy versus no antibiotic therapy for children aged two to 59 months with WHO-defined non-severe pneumonia and wheeze.

Search methods

We searched CENTRAL (2014, Issue 1), MEDLINE (1946 to March week 3, 2014), EMBASE (January 2010 to March 2014), CINAHL (1981 to March 2014), LILACS (1982 to March 2014), Networked Digital Library of Theses and Dissertations (23 July 2013) and Web of Science (1985 to March 2014).

Selection criteria

Randomised controlled trials (RCTs) evaluating the efficacy of antibiotic therapy versus no antibiotic therapy for children aged two to 59 months with non-severe pneumonia and wheeze. We considered studies that defined non-severe pneumonia as cough or difficulty in breathing with a respiratory rate above the WHO-defined age-specific values (respiratory rate of 50 breaths per minute or more for children aged two to 12 months, or a respiratory rate of 40 breaths per minute or more for children aged 12 to 59 months) and wheeze for inclusion. We have excluded non-RCTs (quasi-RCTs).

Data collection and analysis

Two review authors independently assessed the search results and extracted data.

Main results

We did not identify any study that completely fulfilled our inclusion criteria.

Authors' conclusions

There is a clear need for RCTs to address this question in representative populations. We do not currently have evidence to support or challenge the continued use of antibiotics for the treatment of non-severe pneumonia, as suggested by WHO guidelines.

Résumé scientifique

Traitement antibiotique par rapport à l'absence de traitement antibiotique chez les enfants âgés de 2 à 59 mois et souffrant de pneumonie non sévère et de respiration sifflante définies par l'OMS

Contexte

Dans le monde, la pneumonie est la principale cause de décès chez les enfants de moins de cinq ans et représente environ deux millions de décès par an. L'Organisation Mondiale de la Santé (OMS) a développé des directives pour la prise en charge basées sur de simples signes cliniques pour aider les cliniciens à décider du traitement idéal pour la pneumonie. Les enfants et les nourrissons présentant une respiration rapide (de 50 respirations par minute ou plus chez les nourrissons de 2 à 12 mois d'âge et de 40 ou plus chez les enfants de 12 mois à cinq ans) et une toux sont présumés souffrir de pneumonie non sévère et l'OMS recommande les antibiotiques. La mise en Suvre de ces directives pour identifier et prendre en charge la pneumonie à l'échelle de la communauté a démontrée réduire la mortalité liée à l'infection respiratoire aiguë (IRA) de 36%, bien que la qualité discutable des preuves suscite une appréhension concernant ces résultats. Comme les directives de l'OMS ne permettent pas de faire la distinction entre la pneumonie virale et bactérienne, ces enfants continuent de recevoir des antibiotiques car un autre traitement pourrait ne pas être sûr. Par conséquent, il est essentiel d'explorer le rôle des antibiotiques chez les enfants souffrant de pneumonie non sévère et de respiration sifflante définies par l'OMS et de développer des directives efficaces pour le traitement antibiotique initial.

Objectifs

Évaluer l'efficacité du traitement antibiotique par rapport à l'absence de traitement antibiotique chez les enfants âgés de 2 à 59 mois souffrant de pneumonie non sévère et de respiration sifflante définies par l'OMS.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans CENTRAL (2014, numéro 1), MEDLINE (de 1946 à la 3ème semaine de mars 2014), EMBASE (de janvier 2010 à mars 2014), CINAHL (de 1981 à mars 2014), LILACS (de 1982 à mars 2014), la bibliothèque numérique en réseau de thèses et de mémoires (23 juillet 2013) et Web of Science (de 1985 à mars 2014).

Critères de sélection

Essais contrôlés randomisés (ECR) évaluant l'efficacité du traitement antibiotique par rapport à l'absence de traitement antibiotique chez les enfants âgés de 2 à 59 mois souffrant de pneumonie non sévère et de respiration sifflante. Pour l'inclusion, nous avons pris en compte les études ayant défini la pneumonie non sévère comme une toux ou une respiration difficile avec une fréquence respiratoire supérieure à la valeur spécifique à l'âge prédéfinie par l'OMS (fréquence respiratoire de 50 respirations par minute ou plus pour les enfants âgés de 2 à 12 mois, ou une fréquence respiratoire de 40 respirations par minute ou plus pour les enfants âgés de 12 à 59 mois) et une respiration sifflante. Nous avons exclus les études n'étant pas des ECR (quasi-ECR).

Recueil et analyse des données

Deux auteurs de la revue ont indépendamment évalué les résultats de la recherche et extrait les données.

Résultats principaux

Nous n'avons pas identifié d'étude qui répondait entièrement à nos critères d'inclusion.

Conclusions des auteurs

Il y a un besoin évident de réaliser des ECR auprès des populations représentatives afin de répondre à cette question. Nous ne disposons actuellement pas de preuves pour soutenir ou contester la poursuite de l'utilisation d'antibiotiques pour le traitement de la pneumonie non sévère, comme suggéré par les directives de l'OMS.

Plain language summary

Comparing treatment of non-severe pneumonia in children aged 2 to 59 months with and without antibiotics

Background
Pneumonia is an infection of the lungs. In children it is one of the leading causes of childhood deaths across the globe. Pneumonia can be classified based on the World Health Organization (WHO) guidelines. This classification involves assessment of certain clinical signs and symptoms and the severity of disease. The treatment is then tailored according to the classification. For non-severe pneumonia, the WHO recommends the use of oral antibiotics for treatment. However, pneumonia is caused more commonly by viruses that do not require antibiotic management but rather supportive care. On the other hand, pneumonia caused by bacteria needs management with antibiotics to avoid complications. Since there is no clear way to distinguish quickly which organism actually caused pneumonia, it is considered safe to give antibiotics. However, it may lead to the development of antibiotic resistance and thus limit their use in future infections. Thus the question arises as to whether the use of antibiotics is justified in non-severe pneumonia.

Review question
We have tried to identify evidence as to whether there is a difference in the outcomes of treatment with or without antibiotics for non-severe pneumonia in children aged 2 to 59 months.

Key results
We performed a search for clinical trials published until March 2014 that evaluated this question. We were unable to identify any studies that were conducted on our review question.

Résumé simplifié

Comparaison du traitement de la pneumonie non sévère chez les enfants âgés de 2 à 59 mois avec et sans antibiotiques

Contexte
La pneumonie est une infection des poumons. Chez les enfants, elle est l'une des principales causes de décès infantile dans le monde entier. La pneumonie peut être classée selon les directives de l'Organisation Mondiale de la Santé (OMS). Cette classification implique l'évaluation de certains signes cliniques et symptômes, ainsi que de la gravité de la maladie. Le traitement est ensuite conçu selon la classification. Pour la pneumonie non sévère, l'OMS recommande l'utilisation d'antibiotiques oraux pour le traitement. Cependant, la pneumonie est plus couramment causée par des virus qui ne nécessitent pas d'antibiotiques, mais plutôt des soins palliatifs. Par contre, la pneumonie provoquée par des bactéries nécessite une prise en charge avec des antibiotiques pour éviter les complications. Étant donné qu'il n'est pas évident de distinguer rapidement quel organisme a effectivement causé la pneumonie, il est considéré comme sûre d'administrer des antibiotiques. Cependant, cela pourrait entraîner le développement de résistance aux antibiotiques et donc limiter leur utilisation dans les futures infections. Par conséquent, la question se pose de savoir si l'utilisation d'antibiotiques est justifiée dans la pneumonie non sévère.

Question de la revue
Nous avons cherché à identifier des preuves permettant de savoir s'il existe une différence dans les résultats du traitement avec ou sans antibiotiques pour la pneumonie non sévère chez les enfants âgés de 2 à 59 mois.

Résultats principaux
Nous avons effectué une recherche dans les essais cliniques publiés jusqu'en mars 2014 ayant évalué cette question. Nous ne sommes pas parvenus à identifier d'études portant sur la question de notre revue.

Notes de traduction

Traduit par: French Cochrane Centre 6th August, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Santé du Canada, Ministère de la Santé et des Services Sociaux du Québec, Fonds de recherche du Québec-Santé et Institut National d'Excellence en Santé et en Services Sociaux; pour la France : Ministère en charge de la Santé

Background

Description of the condition

Pneumonia is an acute respiratory infection (ARI) that affects the lungs. The World Health Organization (WHO) guidelines define pneumonia as an acute disease episode with cough or difficult breathing combined with fast breathing (with age-specific cut-off values) (WHO 2010). Worldwide, pneumonia is the leading cause of mortality among children under five years of age and accounts for approximately 1.2 million deaths annually (Walker 2013). Around 120 million episodes of pneumonia in children under five years of age were estimated in 2010 alone (Walker 2013). The estimated incidence of pneumonia is 0.29 per person-year in low-income countries compared to 0.05 per person-year in high-income countries (Rudan 2008). In 2008, the estimated incidence of clinical pneumonia was highest in South-East Asia (0.36 episodes per child-year) and lowest in European countries (0.06 episodes per child-year) (Rudan 2008). The current estimates as of 2013 show that the incidence in South-East Asia has declined to 0.26 episodes per child-year, while the incidence is still high in African regions with 0.27 episodes per child-year (Walker 2013). It is estimated that Afghanistan, Angola, Burkina, Faso, China, Democratic republic of Congo, Ethiopia, Indonesia, India, Kenya, Mali, Niger, Nigeria, Pakistan, Tanzania and Uganda are the 15 countries that contribute to around 65% of the global burden of pneumonia (Walker 2013). Moreover, patients with any co-morbid condition have a higher likelihood of developing pneumonia.

The increasing focus on the reduction of child mortality arising from the Millennium Development Goal (MDG) 4 has generated renewed interest in developing more accurate assessments of the correct cause and number of deaths in children aged less than five (Rudan 2008). In recent years, data on cause-specific mortality have been available. However, data on the pathogen-specific causes of pneumonia are limited.

The most common causes of severe pneumonia among children in low-income countries are the bacterial pathogens Streptococcus pneumoniae (S. pneumoniae) and Haemophilus influenzae (H. influenzae). Viruses more commonly cause non-severe pneumonia, although to a lesser extent bacteria can also be a cause (UNICEF/WHO 2006). Some less common bacteria and fungi can also cause pneumonia in children, however their aetiologic information is unavailable (UNICEF/WHO 2006). Recent data from the global burden of disease study show that S. pneumoniae is the leading cause of deaths from lower respiratory tract infections in children aged one to five years. This is followed by H. influenzae, while mortality associated with viral infections is much less in this age group (Lozano 2012).

Description of the intervention

Chest X-rays and laboratory tests are accurate measures when confirming pneumonia, including the extent and location of the infection and its cause. However, in resource-poor settings where qualified personnel and diagnostic facilities are often unavailable, suspected cases of pneumonia are diagnosed by their clinical symptoms. The WHO has developed community-based case management guidelines that include education, awareness and prompt management of pneumonia based on identification of simple clinical signs to help clinicians decide on the appropriate pneumonia treatment (WHO 1991). Children and infants who exhibit fast breathing (50 breaths per minute or more in infants two months to 12 months of age and 40 or more in children 12 months to five years of age) and cough are presumed to have non-severe pneumonia and the WHO recommends antibiotics (UNICEF/WHO 2006). Children and infants who exhibit fast breathing (as above), with stridor and chest wall in-drawing are presumed to have severe pneumonia and WHO recommends intravenous antibiotics for treatment in an inpatient facility (UNICEF/WHO 2006).

How the intervention might work

Based on findings from a meta-analysis, implementation of these guidelines to identify and treat pneumonia at the community level has been shown to reduce ARI-related mortality by 36% (95% confidence interval 20% to 49%) (Sazawal 2003). However, the review suggests that this reduction in mortality should be viewed with caution since the included studies were neither randomised nor blinded. There was also some degree of uncertainty and misclassification in establishing the cause of death in the included studies. However, a recent review on community case management with antibiotics showed a 21% reduction in acute respiratory infection related mortality in children aged 0 to 5 years (Theodoratou 2010). According to Hazir and Mulholland, many children who are classified as having non-severe pneumonia (cough and fast breathing) were usually found not to have clinical pneumonia when assessed by physicians or by examining chest X-rays (Hazir 2006; Hazir 2011; Mulholland 1992). Therefore, prescribing antibiotics for fast breathing alone may lead to the spread of antibiotic resistance, as fast breathing may be caused by other conditions and affected by other factors, such as fever.

Another concern is the addition of wheeze into the algorithm. According to the trial by Hazir (Hazir 2004), 62% of children presenting with non-severe pneumonia and wheeze responded to bronchodilators. Among these responders, only 15% showed clinical deterioration on follow-up. A prospective observational study by Lochindarat found that 85% of children who met the WHO criteria for non-severe pneumonia and wheeze responded to bronchodilators and only 4% on day three and 3% on days five to seven deteriorated (Lochindarat 2008).

Another study from Bangladesh prescribed antibiotics (either ampicillin or erythromycin) to two-thirds of children presenting with runny nose, cough, breathing difficulties, chest in-drawing and rhonchi and a placebo to one-third of the children. There was no significant difference in clinical improvements between the groups (Kabir 2009). Previously conducted studies from all over the world have shown that wheeze is more common in viral infections, particularly respiratory syncytial virus infection (Cherian 1990; Forgie 1991; Nunez 1988; Selwyn 1990; Sobĕslavský 1997; Videla 1998; Weber 1998). Similarly, a recent Cochrane Review of infants with bronchiolitis found no difference in clinical outcomes when comparing antibiotics with a placebo (Spurling 2011).

Why it is important to do this review

A recently published Cochrane review (Haider 2008), and Cochrane protocol (Zaidi 2009) focus on short-course versus long-course antibiotic therapy of non-severe pneumonia and severe pneumonia in children. There are no reviews on whether supportive treatment without antibiotics in non-severe pneumonia may or may not be beneficial. As WHO guidelines do not make a distinction between viral and bacterial pneumonia, children diagnosed with non-severe pneumonia continue to receive antibiotics because of the concern that it may not be safe to do otherwise. Therefore, it is essential to explore the role of antibiotics in children with WHO-defined non-severe pneumonia and wheeze and to develop effective guidelines for initial antibiotic treatment.

Objectives

To evaluate the efficacy of antibiotic therapy versus no antibiotic therapy for children aged two to 59 months with WHO-defined non-severe pneumonia and wheeze.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs) evaluating the efficacy of antibiotic therapy versus no antibiotic therapy for children aged two to 59 months with non-severe pneumonia and wheeze. We considered for inclusion studies that defined non-severe pneumonia as cough or difficulty in breathing with a respiratory rate above the WHO-defined age-specific values (respiratory rate of 50 breaths per minute or more for children aged two to 12 months, or a respiratory rate of 40 breaths per minute or more for children aged 12 to 59 months) and wheeze. We excluded non-RCTs (quasi-RCTs).

Types of participants

Inclusions
  • Children aged two to 59 months with a cough or difficulty in breathing or rapid breathing (as per WHO-classified non-severe pneumonia) and wheeze*.

*Breathing with a hoarse whistling or rattling sound in the chest, as a result of obstruction in the air passages.

Exclusions
  • Children who have severe or very severe pneumonia (defined on the basis of chest in-drawing, inability to drink, convulsions and difficulty waking).

  • Any chronic illness or conditions requiring antibiotics.

  • Children who have received antibiotics in the past 48 hours.

  • Hospitalisation in the past two weeks.

  • Children who have experienced measles within the last month.

Types of interventions

Any antibiotic therapy compared with no other medical treatment or placebo.

Types of outcome measures

Primary outcomes
  1. Clinical cure: symptomatic and clinical recovery by the end of treatment (if the child has a fever, their temperature returns to normal and the respiratory rate drops to normal).

  2. Treatment failure: 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.

Secondary outcomes
  1. Relapse: defined as children declared 'cured' but who develop recurrence of disease at follow-up within a defined period.

  2. Mortality: deaths within one month.

  3. Harms of treatment: any adverse events or side effects associated with antibiotic therapy.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 1) (accessed 28 March 2014), which contains the Cochrane Acute Respiratory Infections (ARI) Group's Specialised Register, MEDLINE (1946 to March week 3, 2014), EMBASE (January 2010 to March 2014), CINAHL (1981 to March 2014), LILACS (1982 to March 2014), Networked Digital Library of Theses and Dissertations (23 July 2013) and Web of Science (1985 to March 2014).

We used the same search strategy to search CENTRAL and MEDLINE (Appendix 1). 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 2011). We adapted the search strategy to search EMBASE (Appendix 2), CINAHL (Appendix 3), LILACS (Appendix 4), Web of Science (Appendix 5) and the Networked Digital Library of Thesis and Dissertations (NDLTD) (Appendix 6). To identify child studies in each of the electronic databases, we combined the topic terms with a filter for identifying child studies based on the work of Boluyt (Boluyt 2008). We did not impose any language or publication restrictions.

Searching other resources

We searched the Database of Abstracts of Reviews of Effects (DARE) 2013, Issue 2 of 4, April, part of The Cochrane Library, www.thecochranelibrary.com (accessed 23 July 2013) in order to scan through the reference lists of relevant reviews. We searched the WHO ICTRP (http://www.who.int/ictrp/en/) and ClinicalTrials.gov (http://clinicaltrials.gov/) for completed and ongoing trials (28 March 2014). In addition we searched related conference proceedings for relevant abstracts. We also tried to contact organisations and researchers in the field and pharmaceutical companies for information on unpublished and ongoing trials. We checked the reference lists of all trials identified by the above methods.

Data collection and analysis

Selection of studies

Two review authors (ZSL, RK) independently assessed the eligibility of the trials. We selected potentially relevant studies by screening the titles and abstracts. We retrieved and reviewed the full text of the article if we were not able to ascertain the relevance of studies by screening the title and abstract. We resolved disagreements by discussion.

Data extraction and management

We retrieved full texts of all potentially relevant articles and independently assessed their eligibility by filling out eligibility forms that we designed in accordance with the specified inclusion criteria. We carried out data extraction using a data extraction form, which was designed and pilot tested by the review authors. We extracted the following information:

  1. study setting (for example, country, type of facility and type of population);

  2. description of antibiotic used (including type of drug, dose, duration and frequency);

  3. ethics approval for trial protocol and informed consent from trial participants (parents/guardian in this case);

  4. sample size;

  5. length of follow-up;

  6. randomisation procedure and blinding information;

  7. outcomes as listed above; and

  8. funding/sponsorship for the trials.

Assessment of risk of bias in included studies

We planned to assess independently the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We planned to resolve all disagreements by discussion.

1. Sequence generation (checking for possible selection bias)

We planned to describe for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups. We planned to assess the method as:

  • low risk of bias (any truly random process, e.g. random number table; computer random number generator);

  • high risk of bias (any non-random process, e.g. odd or even date of birth; hospital or clinic record number);     

  • unclear risk of bias.    

 2. Allocation concealment (checking for possible selection bias)

We planned to describe for each included study the method used to conceal allocation to interventions prior to assignment and to assess whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment. We planned to assess the methods as:        

  • low risk of bias (e.g. telephone or central randomisation; consecutively numbered, sealed, opaque envelopes);        

  • high risk of bias (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);       

  • unclear risk of bias.   

3.1. Blinding of participants and personnel (checking for possible performance bias)

We planned to describe for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We planned to assess blinding separately for different outcomes or classes of outcomes. We planned to assess the methods as:

  • low, high or unclear risk of bias for participants;      

  • low, high or unclear risk of bias for personnel.

3.2 Blinding of outcome assessment (checking for possible detection bias)

We planned to describe for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received.  We planned to assess blinding separately for different outcomes or classes of outcomes. We planned to assess methods used to blind outcome assessment as:

  • low;

  • high; or

  • unclear.

4. Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

We planned to describe for each included study and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We also planned to state whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported and whether missing data were balanced across groups or were related to outcomes. We planned to assess methods as:

  • low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups); 

  • high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; 'as treated' analysis done with substantial departure of intervention received from that assigned at randomisation);

  • unclear risk of bias. 

5. Selective reporting (checking for reporting bias)

We planned to describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found. We planned to assess the methods as:

  • low risk of bias (where it is clear that all of the study's pre-specified outcomes and all expected outcomes of interest to the review have been reported);     

  • high risk of bias (where not all the study's pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);

  • unclear risk of bias.

6. Other bias (checking for bias due to problems not covered by 1 to 5 above)

We planned to describe for each included study any important concerns we have about other possible sources of bias. We planned to assess whether each study was free of other problems that could put it at risk of bias:

  • low risk of other bias;

  • high risk of other bias;

  • unclear whether there is risk of other bias.

7. Overall risk of bias

We planned to make explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). With reference to (1) to (6) above, we planned to assess the likely magnitude and direction of the bias and whether to consider if it is likely to impact on the findings. We planned to explore the impact of the level of bias through undertaking sensitivity analyses. We also planned to note the funding agency under this point.

Measures of treatment effect

We planned to present results as summary risk ratios (RR) with 95% confidence intervals (CI) for dichotomous data. We also planned to report the absolute difference for the dichotomous outcome variables. We planned to use the mean difference (MD) if outcomes were measured in the same way between trials for continuous data and standardised mean difference (SMD) to combine trials that measured the same outcome but used different methods. We planned to express outcomes in terms of RR and 95% CIs.

Unit of analysis issues

We planned to deal with cluster-RCTs and cross-over trials as specified in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Dealing with missing data

We planned to note levels of attrition for included studies. We planned to explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis. We planned to carry out analyses, for all outcomes, as far as possible, on an intention-to-treat (ITT) basis, i.e. to attempt to include all participants randomised to each group in the analyses and all participants analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome planned in each trial was the number randomised minus any participants whose outcomes are known to be missing.

Assessment of heterogeneity

We planned to apply tests for heterogeneity between trials, if appropriate, using the I² statistic. We planned to explore high levels of heterogeneity among the trials (I² value exceeding 50% and Chi² test P value of < 0.1) by subgroup analysis, as specified below. We planned to use a random-effects model as an overall summary where appropriate.

Assessment of reporting biases

We planned to use funnel plots to assess reporting biases but we did not find any study that met our inclusion criteria.

Data synthesis

We planned to carry out statistical analysis using the Review Manager software (RevMan 2012). We planned to used Mantel–Haenszel fixed-effect meta-analysis for combining data where it was reasonable to assume that studies estimated the same underlying treatment effect: i.e. where trials were examining the same intervention and we judged the trials' populations and methods sufficiently similar. In case of clinical heterogeneity, we planned to use Mantel–Haenszel random-effects meta-analysis to produce an overall summary if we considered an average treatment effect across trials clinically meaningful.

We planned to set out the main findings of the review in 'Summary of findings' tables prepared using the GRADE approach (Guyatt 2008), using GRADE profiler software. We planned to list the outcomes for each comparison with estimates of relative effects along with the number of participants and studies contributing data for those outcomes. For each individual outcome, we planned to assess the quality of the evidence using the GRADE approach, which involves consideration of within-study risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias. We planned to rate the quality of the body of evidence for each key outcomes as 'high, 'moderate', 'low' or 'very low'.

Subgroup analysis and investigation of heterogeneity

We planned to perform a subgroup analysis on the basis of following:

  1. type of antibiotic used;

  2. dosage and frequency of antibiotics used; and

  3. industry-sponsored trials versus other types of trials.

Sensitivity analysis

We planned to carry out a sensitivity analysis to explore the effect of trial quality (assessed by concealment of allocation), by excluding studies with clearly inadequate allocation concealment.

Results

Description of studies

Results of the search

We identified a total of 2933 records using the search criteria mentioned above. After removing duplicates, we screened a total of 312 abstracts for possible inclusion and further assessed a total of eight full-text articles for eligibility. In the end we were unable to identify any study that completely fulfilled our inclusion criteria. The study by Hazir 2011 has been included in the Characteristics of studies awaiting classification table until further information is available from the authors. See Figure 1.

Figure 1.

Study flow diagram.

Included studies

We did not identify any trial that fulfilled our inclusion criteria.

Excluded studies

We excluded a total of five studies after review of full text (Agarwal 2004; Awasthi 2008; Fontoura 2010; Hazir 2007; MASCTM Pakistan 2002). We excluded four of these studies as they had neither a placebo group nor a no treatment arm and hence did not meet our inclusion criteria (Agarwal 2004; Fontoura 2010; Hazir 2007; MASCTM Pakistan 2002). However, we excluded the study by Awasthi 2008, which was conducted in India, because they only included children with WHO-defined non-severe pneumonia and those who had characteristic findings on chest X-ray. We excluded this trial because performing chest X-rays is not part of the WHO algorithm for diagnosing non-severe pneumonia.

Risk of bias in included studies

We could not carry out a 'Risk of bias' assessment as no trials were eligible for inclusion.

Effects of interventions

Primary outcomes

1. Clinical cure

We did not identify any trial that fulfilled our inclusion criteria.

2. Treatment failure

We did not identify any trial that fulfilled our inclusion criteria.

Secondary outcomes

1. Relapse

We did not identify any trial that fulfilled our inclusion criteria.

2. Mortality

We did not identify any trial that fulfilled our inclusion criteria.

3. Harms of treatment

We did not identify any trial that fulfilled our inclusion criteria.

Discussion

Summary of main results

We were unable to identify any trials that fulfilled our inclusion criteria. However, we have categorised the study by Hazir 2011 as awaiting classification.

This study was a double-blind, randomised, placebo-controlled trial carried out in four hospitals in three cities of Pakistan (Islamabad, Lahore and Rawalpindi). The study followed the World Health Organization (WHO) algorithm for diagnosing non-severe pneumonia in children. However, children with both wheeze and without wheeze were included in the trial. The study population consisted of 900 children aged between two and 59 months. Almost 50% of the study population had wheeze but separate results for these children were not given. The children were treated with a three-day course of 45 mg/kg per day amoxicillin or placebo and followed up for a total of two weeks. The primary outcome was therapy failure defined a priori at 72 hours. In per-protocol analysis at day three, 31 (7.2%) of the 431 children in the amoxicillin arm and 37 (8.3%) of the 442 in the placebo group experienced therapy failure, although this difference was not statistically significant. As separate data for children with wheeze were not available, we therefore decided not to include the study in our analysis until further data are obtained from the trial authors.

Potential biases in the review process

We were aware of the possibility of introducing bias at every stage of the reviewing process. Therefore, we tried to minimise bias in a number of ways: two review authors independently assessed eligibility for inclusion, carried out data extraction and assessed risk of bias. Nevertheless, the process of assessing risk of bias, for example, is not an exact science and includes many personal judgements. Furthermore, the process of reviewing research studies is known to be affected by prior beliefs and attitudes. It is difficult to control for this type of bias in the reviewing process.

While we attempted to be as inclusive as possible in the search strategy, the literature identified was predominantly written in English and published in North American and European journals. Although we did attempt to assess reporting bias, time constraints meant that this assessment largely relied on information available in the published trial reports and, thus, reporting bias was not usually apparent.

Agreements and disagreements with other studies or reviews

We have not come across any other meta-analysis carried out on the question addressed in this review. However, a recent review on acute respiratory infections in children questions the use of antibiotics in non-severe pneumonia with wheeze (Rizal 2010). The discussion is based on two observational studies that show low failure rates with amoxicillin and hence consider the antibiotic as an appropriate choice. However, it clearly brings up the issues of unnecessary use of antibiotics leading to antibiotic resistance in the aetiological agents responsible for lower respiratory tract infection that were previously thought to have low potential for developing resistance to treatment. The in-depth review in The Lancet on pneumonia treatment guidelines strongly recommends the use of antibiotics in non-severe pneumonia (Grant 2009). One of the rationales is that viral and bacterial infection can coexist and thus empirical treatment for the possible causative agents is necessary. However, the recommendation is based on clinical trials comparing different types or regimens of antibiotics. Studies on antibiotics versus no antibiotics (one of which was recently published) are not included in the review. Regardless, the issues highlighted by both of these reviews are ones to ponder upon. While a recent Lancet series on childhood pneumonia and diarrhoea highlights the significance of appropriate management of pneumonia with antibiotics in neonates, little emphasis is given to not using empirical antibiotics for non-severe pneumonia (Bhutta 2013). As of now, randomised controlled trials should be conducted to provide an answer to this dilemma.

Authors' conclusions

Implications for practice

Based on epidemiological data we do know that aetiological agents for pneumonia in this age group range from a number of viruses to bacterial pathogens. Although many studies do describe viruses as being more prevalent in this age group (Rudan 2008; Rudan 2013), bacterial agents like Streptococcus pneumoniae are still at large (Forgie 1991; Rudan 2013). The incidence of Haemophilus influenzae (H. influenzae) pneumonia has reduced considerably since the advent of immunisations, however in some parts of the world these immunisation practices are still not used or have been recently introduced (Morris 2008; Naeem 2011; Rudan 2013). Studies have shown that vaccination against streptococcal pneumonia decreases the incidence by as much as 20% in certain cases (Cutts 2005), although it does not completely eradicate the risk. The recent Lancet series on childhood pneumonia and diarrhoea estimates an 18% and 29% reduction in radiologically confirmed pneumonia with use of Hib (H. influenzae type B) and pneumococcal vaccines respectively (Bhutta 2013). With limited options and resources to diagnose rapidly the agent responsible for pneumonia, particularly in low- and middle-income countries, the empirical use of an antibiotic can be supported by a number of facts. Viral and bacterial infections can clearly coexist and even a positive diagnostic test for a viral aetiology does not exclude a bacterial infection. Secondly, viral pneumonia predisposes to a secondary bacterial infection that can be much more severe and lead to complications. Lastly, there is no clear or standard diagnostic test to differentiate between the two pathogens.

We do not currently have evidence to support or challenge the continued use of antibiotics for the treatment of non-severe pneumonia, as suggested by the World Health Organization (WHO) guidelines.

Implications for research

The results of our review provide a number of implications for future research. Firstly, trials should be carried out to assess the differences between treatment with antibiotics and no antibiotics for non-severe pneumonia with wheeze in children. These trials should not be limited to low- and middle-income countries but should also extend to high-income countries. Secondly, antibiotics other than amoxicillin, which are commonly used to treat non-severe pneumonia, should be compared with no antibiotics.

Acknowledgements

As part of the pre-publication editorial process, the title of this review has been commented on by ARI Group Editors: Allen Cheng, Mieke van Driel, Anca Zalmanovici Trestioreanu, Roger Damoiseaux, John Holden and Chris del Mar. We would like to thank the following people for commenting on the draft protocol: Amy Zelmer, Sushil Kabra, Rakesh Lodha, Mark Jones and Roger Damoiseaux. We would like to thank the following people for commenting on the draft review: Rakesh Lodha, U Hla Htay, Sushil Kabra and Roger Damoiseaux.

Data and analyses

Download statistical data

This review has no analyses.

Appendices

Appendix 1. MEDLINE (Ovid) search strategy

1 exp Pneumonia/ (66207)
2 (pneumon* or bronchopneumon* or pleuropneumon*).tw. (115710)
3 1 or 2 (140936)
4 exp Anti-Bacterial Agents/ (1110397)
5 antibiotic*.tw,nm. (207586)
6 (azithromycin* or erythromycin* or ampicillin* or clarithromycin* or amoxicillin* or amoxycillin*).tw,nm. (56284)
7 (cotrimoxazole* or co-trimoxazole* or co trimoxazole*).tw,nm. (3918)
8 Trimethoprim-Sulfamethoxazole Combination/ (5262)
9 (trimethoprim* adj1 sulfamethoxazole*).tw,nm. (8959)
10 Amoxicillin-Potassium Clavulanate Combination/ (1813)
11 (coamoxyclav* or coamoxiclav* or co-amoxyclav* or co-amoxiclav* or co amoxyclav* or co amoxiclav* or augmentin*).tw,nm. (7609)
12 or/4-11 (1207989)
13 3 and 12 (50371)
14 exp Infant/ (855216)
15 (infant* or infancy or newborn* or baby* or babies or neonat* or preterm* or prematur*).tw. (544718)
16 exp Child/ (1402530)
17 (child* or schoolchild* or school age* or preschool* or kid or kids or toddler*).tw. (835934)
18 Minors/ (2068)
19 (minor* or boy* or girl*).tw. (315036)
20 exp Pediatrics/ (38717)
21 (pediatric* or paediatric*).tw. (170926)
22 (nursery school* or kindergar*).tw. (4131)
23 or/14-22 (2391733)
24 13 and 23 (14045)

Appendix 2. EMBASE (Elsevier) search strategy

#28. 'pneumonia'/de OR 'infectious pneumonia'/exp OR 'bronchopneumonia'/de AND [embase]/lim OR (pneumon*:ab,ti OR bronchopneumon*:ab,ti OR pleuropneumon*:ab,ti AND [embase]/lim) AND
('antibiotic agent'/exp AND [embase]/lim OR (antibiotic*:ab,ti AND [embase]/lim) OR (azithromycin*:ab,ti OR erythromycin*:ab,ti OR ampicillin*:ab,ti OR amoxycillin*:ab,ti OR amoxicillin*:ab,ti OR cotrimoxazole*:ab,ti OR 'co-trimoxazole':ab,ti OR 'co trimoxazole':ab,ti AND [embase]/lim) OR ('cotrimoxazole'/de AND [embase]/lim) OR ((trimethoprim* NEAR/1 sulfamethoxazol*):ab,ti AND [embase]/lim) OR (((amoxycillin* OR amoxicillin*) NEAR/1 clavulan*):ab,ti AND [embase]/lim) OR (coamoxyclav*:ab,ti OR coamoxiclav*:ab,ti OR (co* NEAR/1 (amoxyclav* OR amoxiclav*)):ab,ti OR augmentin*:ab,ti AND [embase]/lim)) AND ('infant'/exp AND [embase]/lim OR infant*:ab,ti OR infancy:ab,ti OR newborn*:ab,ti OR baby*:ab,ti OR babies:ab,ti OR neonat*:ab,ti OR preterm*:ab,ti OR prematur*:ab,ti OR ('child'/exp AND [embase]/lim) OR (child*:ab,ti OR schoolchild*:ab,ti OR (school NEXT/1 age*):ab,ti OR preschool*:ab,ti OR kid OR kids OR toddler*:ab,ti AND [embase]/lim) OR ('juvenile'/de AND [embase]/lim) OR (minor*:ab,ti OR boy*:ab,ti OR girl*:ab,ti OR juvenile*:ab,ti AND [embase]/lim) OR ('pediatrics'/de OR 'neonatology'/exp AND [embase]/lim) OR (pediatric*:ab,ti OR paediatric*:ab,ti AND [embase]/lim) OR ((nursery NEXT/1 school*):ab,ti OR kindergar*:ab,ti AND [embase]/lim)) AND ('randomized controlled trial'/de OR 'single blind procedure'/de OR 'double blind procedure'/exp OR 'crossover procedure'/exp AND [embase]/lim OR (random*:ab,ti OR placebo*:ab,ti OR factorial*:ab,ti OR crossover*:ab,ti OR 'cross over':ab,ti OR 'cross-over':ab,ti OR volunteer*:ab,ti OR assign*:ab,ti OR allocat*:ab,ti OR ((singl* OR doubl*) NEXT/1 blind*):ab,ti AND [embase]/lim)) AND [embase]/lim AND [1-1-2010]/sd NOT [23-1-2012]/sd 157 22 Jan 2012
#27. 'pneumonia'/de OR 'infectious pneumonia'/exp OR 'bronchopneumonia'/de AND [embase]/lim OR (pneumon*:ab,ti OR bronchopneumon*:ab,ti OR pleuropneumon*:ab,ti AND [embase]/lim) AND ('antibiotic agent'/exp AND [embase]/lim OR (antibiotic*:ab,ti AND [embase]/lim) OR (azithromycin*:ab,ti OR erythromycin*:ab,ti OR ampicillin*:ab,ti OR amoxycillin*:ab,ti OR amoxicillin*:ab,ti OR cotrimoxazole*:ab,ti OR
'co-trimoxazole':ab,ti OR 'co trimoxazole':ab,ti AND [embase]/lim) OR ('cotrimoxazole'/de AND [embase]/lim) OR ((trimethoprim* NEAR/1 sulfamethoxazol*):ab,ti AND [embase]/lim) OR (((amoxycillin* OR amoxicillin*) NEAR/1 clavulan*):ab,ti AND [embase]/lim) OR (coamoxyclav*:ab,ti OR coamoxiclav*:ab,ti OR (co* NEAR/1 (amoxyclav* OR amoxiclav*)):ab,ti OR augmentin*:ab,ti AND [embase]/lim)) AND ('infant'/exp AND [embase]/lim OR infant*:ab,ti OR infancy:ab,ti OR newborn*:ab,ti OR baby*:ab,ti OR babies:ab,ti OR neonat*:ab,ti OR preterm*:ab,ti OR prematur*:ab,ti OR ('child'/exp AND [embase]/lim) OR (child*:ab,ti OR schoolchild*:ab,ti OR (school NEXT/1 age*):ab,ti OR preschool*:ab,ti OR kid OR kids OR toddler*:ab,ti AND [embase]/lim) OR ('juvenile'/de AND [embase]/lim) OR (minor*:ab,ti OR boy*:ab,ti OR girl*:ab,ti OR juvenile*:ab,ti AND [embase]/lim) OR ('pediatrics'/de OR 'neonatology'/exp AND [embase]/lim) OR (pediatric*:ab,ti OR paediatric*:ab,ti AND [embase]/lim) OR ((nursery NEXT/1 school*):ab,ti OR kindergar*:ab,ti AND [embase]/lim)) AND ('randomized controlled trial'/de OR 'single blind procedure'/de OR 'double blind procedure'/exp OR 'crossover procedure'/exp AND [embase]/lim OR (random*:ab,ti OR placebo*:ab,ti OR factorial*:ab,ti OR crossover*:ab,ti OR 'cross over':ab,ti OR 'cross-over':ab,ti OR volunteer*:ab,ti OR assign*:ab,ti OR allocat*:ab,ti OR ((singl* OR doubl*) NEXT/1 blind*):ab,ti
#26. 'randomized controlled trial'/de OR 'single blind procedure'/de OR 'double blind procedure'/exp OR 'crossover procedure'/exp AND [embase]/lim OR (random*:ab,ti OR placebo*:ab,ti OR factorial*:ab,ti OR crossover*:ab,ti OR 'cross over':ab,ti OR 'cross-over':ab,ti OR volunteer*:ab,ti OR assign*:ab,ti OR allocat*:ab,ti OR ((singl* OR doubl*) NEXT/1 blind*):ab,ti AND [embase]/lim) 925,562 22 Jan 2012
#25. random*:ab,ti OR placebo*:ab,ti OR factorial*:ab,ti OR crossover*:ab,ti OR 'cross over':ab,ti OR 'cross-over':ab,ti OR volunteer*:ab,ti OR assign*:ab,ti OR allocat*:ab,ti OR ((singl* OR doubl*) NEXT/1
blind*):ab,ti
#24. 'randomized controlled trial'/de OR 'single blind procedure'/de OR 'double blind procedure'/exp OR 'crossover procedure'/exp
#23. 'pneumonia'/de OR 'infectious pneumonia'/exp OR 'bronchopneumonia'/de AND [embase]/lim OR (pneumon*:ab,ti OR bronchopneumon*:ab,ti OR pleuropneumon*:ab,ti AND [embase]/lim) AND ('antibiotic agent'/exp AND [embase]/lim OR (antibiotic*:ab,ti AND [embase]/lim) OR (azithromycin*:ab,ti OR erythromycin*:ab,ti OR ampicillin*:ab,ti OR amoxycillin*:ab,ti OR amoxicillin*:ab,ti OR cotrimoxazole*:ab,ti OR
'co-trimoxazole':ab,ti OR 'co trimoxazole':ab,ti AND [embase]/lim) OR ('cotrimoxazole'/de AND [embase]/lim) OR ((trimethoprim* NEAR/1 sulfamethoxazol*):ab,ti AND [embase]/lim) OR (((amoxycillin* OR amoxicillin*) NEAR/1 clavulan*):ab,ti AND [embase]/lim) OR (coamoxyclav*:ab,ti OR coamoxiclav*:ab,ti OR (co* NEAR/1 (amoxyclav* OR amoxiclav*)):ab,ti OR augmentin*:ab,ti AND [embase]/lim)) AND ('infant'/exp AND [embase]/lim OR infant*:ab,ti OR infancy:ab,ti OR newborn*:ab,ti OR baby*:ab,ti OR babies:ab,ti OR neonat*:ab,ti OR preterm*:ab,ti OR prematur*:ab,ti OR ('child'/exp AND [embase]/lim) OR (child*:ab,ti OR schoolchild*:ab,ti OR (school NEXT/1 age*):ab,ti OR preschool*:ab,ti OR kid OR kids OR toddler*:ab,ti AND [embase]/lim) OR ('juvenile'/de AND [embase]/lim) OR (minor*:ab,ti OR boy*:ab,ti OR girl*:ab,ti OR juvenile*:ab,ti AND [embase]/lim) OR ('pediatrics'/de OR 'neonatology'/exp AND [embase]/lim) OR (pediatric*:ab,ti OR paediatric*:ab,ti AND [embase]/lim) OR ((nursery NEXT/1 school*):ab,ti OR kindergar*:ab,ti
#22. 'infant'/exp AND [embase]/lim OR infant*:ab,ti OR infancy:ab,ti OR newborn*:ab,ti OR baby*:ab,ti OR babies:ab,ti OR neonat*:ab,ti OR preterm*:ab,ti OR prematur*:ab,ti OR ('child'/exp AND [embase]/lim) OR (child*:ab,ti OR schoolchild*:ab,ti OR (school NEXT/1 age*):ab,ti OR preschool*:ab,ti OR kid OR kids OR toddler*:ab,ti AND [embase]/lim) OR ('juvenile'/de AND [embase]/lim) OR (minor*:ab,ti OR boy*:ab,ti OR girl*:ab,ti OR juvenile*:ab,ti AND [embase]/lim) OR ('pediatrics'/de OR 'neonatology'/exp AND [embase]/lim) OR (pediatric*:ab,ti OR paediatric*:ab,ti AND [embase]/lim) OR ((nursery NEXT/1 school*):ab,ti OR kindergar*:ab,ti
#21. (nursery NEXT/1 school*):ab,ti OR kindergar*:ab,ti
#20. pediatric*:ab,ti OR paediatric*:ab,ti
#19. 'pediatrics'/de OR 'neonatology'/exp
#18. minor*:ab,ti OR boy*:ab,ti OR girl*:ab,ti OR juvenile*:ab,ti
#17. 'juvenile'/de
#16. child*:ab,ti OR schoolchild*:ab,ti OR (school NEXT/1 age*):ab,ti OR preschool*:ab,ti OR kid OR kids OR toddler*:ab,ti
#15. 'child'/exp
#14. infant*:ab,ti OR infancy:ab,ti OR newborn*:ab,ti OR baby*:ab,ti OR babies:ab,ti OR neonat*:ab,ti OR preterm*:ab,ti OR prematur*:ab,ti
#13. 'infant'/exp
#12. 'pneumonia'/de OR 'infectious pneumonia'/exp OR 'bronchopneumonia'/de AND [embase]/lim OR (pneumon*:ab,ti OR bronchopneumon*:ab,ti OR pleuropneumon*:ab,ti AND [embase]/lim) AND
('antibiotic agent'/exp AND [embase]/lim OR (antibiotic*:ab,ti AND [embase]/lim) OR (azithromycin*:ab,ti OR erythromycin*:ab,ti OR ampicillin*:ab,ti OR amoxycillin*:ab,ti OR amoxicillin*:ab,ti OR cotrimoxazole*:ab,ti OR 'co-trimoxazole':ab,ti OR 'co trimoxazole':ab,ti AND [embase]/lim) OR ('cotrimoxazole'/de AND [embase]/lim) OR ((trimethoprim* NEAR/1 sulfamethoxazol*):ab,ti AND [embase]/lim) OR (((amoxycillin* OR amoxicillin*) NEAR/1 clavulan*):ab,ti AND [embase]/lim) OR (coamoxyclav*:ab,ti OR coamoxiclav*:ab,ti OR (co* NEAR/1 (amoxyclav* OR amoxiclav*)):ab,ti OR augmentin*:ab,ti
#11. 'antibiotic agent'/exp AND [embase]/lim OR (antibiotic*:ab,ti AND [embase]/lim) OR (azithromycin*:ab,ti OR erythromycin*:ab,ti OR ampicillin*:ab,ti OR amoxycillin*:ab,ti OR amoxicillin*:ab,ti OR cotrimoxazole*:ab,ti OR 'co-trimoxazole':ab,ti OR 'co trimoxazole':ab,ti AND [embase]/lim) OR ('cotrimoxazole'/de AND [embase]/lim) OR ((trimethoprim* NEAR/1 sulfamethoxazol*):ab,ti AND [embase]/lim) OR (((amoxycillin* OR amoxicillin*) NEAR/1 clavulan*):ab,ti AND [embase]/lim) OR (coamoxyclav*:ab,ti OR coamoxiclav*:ab,ti OR (co* NEAR/1 (amoxyclav* OR amoxiclav*)):ab,ti OR augmentin*:ab,ti
#10. coamoxyclav*:ab,ti OR coamoxiclav*:ab,ti OR (co* NEAR/1 (amoxyclav* OR amoxiclav*)):ab,ti OR augmentin*:ab,ti
#9. ((amoxycillin* OR amoxicillin*) NEAR/1 clavulan*):ab,ti
#8. (trimethoprim* NEAR/1 sulfamethoxazol*):ab,ti
#7. 'cotrimoxazole'/de AND [embase]/lim 51,669
#6. azithromycin*:ab,ti OR erythromycin*:ab,ti OR ampicillin*:ab,ti OR amoxycillin*:ab,ti OR amoxicillin*:ab,ti OR cotrimoxazole*:ab,ti OR 'co-trimoxazole':ab,ti OR 'co trimoxazole':ab,ti
#5. antibiotic*:ab,ti AND [embase]/lim 186,969
#4. 'antibiotic agent'/exp AND [embase]/lim 738,968
#3. 'pneumonia'/de OR 'infectious pneumonia'/exp OR 'bronchopneumonia'/de OR pneumon*:ab,ti OR bronchopneumon*:ab,ti OR pleuropneumon*:ab,ti
#2. pneumon*:ab,ti OR bronchopneumon*:ab,ti OR pleuropneumon*:ab,ti
#1. 'pneumonia'/de OR 'infectious pneumonia'/exp OR 'bronchopneumonia'/de

Appendix 3. CINAHL (EBSCO) search strategy

S33 S22 and S32 105
S32 S23 or S24 or S25 or S26 or S27 or S28 or S29 or S30 or S31 169815
S31 (MH "Quantitative Studies") 7264
S30 TI placebo* OR AB placebo* 18383
S29 (MH "Placebos") 6148
S28 TI random* OR AB random* 90149
S27 (MH "Random Assignment") 26932
S26 TI ((singl* or doubl* or tripl* or trebl*) W1 (blind* or mask*)) OR AB ((singl* or doubl* or tripl* or trebl*) W1 (blind* or mask*)) 13386
S25 TI clinic* W1 trial* OR AB clinic* W1 trial* 24723
S24 PT clinical trial 49565
S23 (MH "Clinical Trials+") 101080
S22 S12 and S21 640
S21 S13 or S14 or S15 or S16 or S17 or S18 or S19 or S20 338980
S20 TI (nursery school* or kindergar*) OR AB (nursery school* or kindergar*) 859
S19 TI (pediatric* or paediatric*) OR AB (pediatric* or paediatric*) 37641
S18 TI (minor* or boy* or girl*) OR AB (minor* or boy* or girl*) 34008
S17 TI (child* or schoolchild* or school age* or preschool* or kid or kids or toddler*) OR AB (child* or schoolchild* or school age* or preschool* or kid or kids or toddler*) 155546
S16 TI (infant* or infancy or newborn* or baby* or babies or neonat* or preterm* or prematur*) OR AB (infant* or infancy or newborn* or baby* or babies or neonat* or preterm* or prematur*) 67273
S15 (MH "Pediatrics+") 5280
S14 (MH "Child+") 249936
S13 (MH "Infant+") 101518
S12 S3 and S11 2773
S11 S4 or S5 or S6 or S7 or S8 or S9 or S10 29892
S10 TI (coamoxyclav* or coamoxiclav* or co-amoxyclav* or co-amoxiclav* or co amoxyclav* or co amoxiclav* or augmentin*) OR AB (coamoxyclav* or coamoxiclav* or co-amoxyclav* or co-amoxiclav* or co amoxyclav* or co amoxiclav* or augmentin*) 500
S9 TI trimethoprim* W1 sulfamethoxazole* OR AB trimethoprim* W1 sulfamethoxazole* 334
S8 (MH "Trimethoprim-Sulfamethoxazole Combination") 421
S7 TI (cotrimoxazole* or co-trimoxazole* or co trimoxazole*) OR AB (cotrimoxazole* or co-trimoxazole* or co trimoxazole*) 183
S6 TI (azithromycin* or erythromycin* or ampicillin* or amoxycillin* or amoxycillin* or clarithromycin*) OR AB (azithromycin* or erythromycin* or ampicillin* or amoxicillin* or amoxycillin* or clarithromycin*) 1768
S5 TI antibiotic* OR AB antibiotic* 12983
S4 (MH "Antibiotics+") 22785
S3 S1 or S2 12414
S2 TI (pneumon* or bronchopneumon* or pleuropneumon*) OR AB (pneumon* or bronchopneumon* or pleuropneumon*) 9246
S1 (MH "Pneumonia+") 8012

Appendix 4. LILACS (BIREME - virtual health library) search strategy

(MH:pneumonia OR Neumonía OR pneumon$ OR Pulmonía OR MH:C08.381.677$ OR MH:C08.730.610$ OR bronconeumonía OR pleuropneumon$ OR Pleuroneumonía) AND (MH:"Anti-Bacterial Agents" OR "Agentes antibacterianos" OR "Agentes Antibacterianos" OR antibiotic$ OR Antibióticos OR "Medicamentos Antibióticos" OR Antibacterianos OR "Medicamentos Antibióticos" OR MH:azithromycin OR Azitromicina OR Azitromicina OR azithromycin$ OR MH:Erythromycin OR Eritromicina OR Eritromicina OR erythromycin OR MH:Clarithromycin OR Claritromicina OR Claritromicina OR Clarithromycin OR MH:Amoxicillin OR Amoxicilina OR Amoxicilina OR amoxicillin OR amoxycillin OR MH:Ampicillin OR Ampicilina OR Ampicilina OR ampicillin OR MH:"Trimethoprim-Sulfamethoxazole combination" OR "Combinación Trimetoprim-Sulfametoxazol" OR "Combinação trimetoprima- Sulfametoxazol" OR cotrimoxazole OR Cotrimoxazol OR MH:"Amoxicillin-Potassium Clavulanate Combination" OR "Combinación Amoxicilina-Clavulanato de Potasio" OR "Combinação Amoxicilina-clavulanato de Potássio" OR "Amoxicillin-Clavulanic Acid" OR "Potassium Clavulanate-Amoxicillin Combination" OR "Amoxicilina-Ácido Clavulánico" OR "Combinación Clavulanato de Potasio-Amoxicilina" OR "amoxicilina-Ácido Clavulânico" OR "Combinação Clavulanato de Potássio-Amoxicilina" OR coamoxyclav OR coamoxiclav OR "co-amoxyclav" or "co-amoxiclav" OR "co amoxyclav" OR "co amoxiclav" OR augmentin) AND (MH:infant OR lactante OR Lactente OR MH:M01.060.703$ OR infant$ OR infancy OR newborn$ OR baby$ OR babies OR neonat$ OR preterm$ OR prematur$ OR MH:child OR Niño OR Criança OR MH:M01.060.406$ OR MH:SP4.011.127.413.654$ OR child$ OR schoolchild$ OR preschool$ OR kid OR kids OR toddler$ OR MH:minors OR Menores OR "Menores de Idade" OR minor$ OR boy$ OR girl$ OR MH:Pediatrics OR pediatric$ OR paediatric$ OR Pediatría OR pediatria OR MH:H02.403.670$ OR "nursery school" OR kindergar$) > clinical_trials

Appendix 5. Web of Science (Thomson ISI) search strategy

Topic=(pneumon* or bronchopneumon* or pleuropneumon*) AND Topic=(antibiotic* or azithromycin or erythromycin or ampicillin or clarithromycin or amoxicillin or amoxycillin or cotrimoxazole or "co-trimoxazole" or "co trimoxazole" or "trimethoprim-sulfamethoxazole" or augmentin* or coamoxyclav or "co amoxyclav" or coamoxiclav or "co amoxiclav" or "co-amoxyclav" or "co-amoxiclav" or (amoxycillin NEAR/2 clavulanate) or (amoxicillin NEAR/2 clavulanate)) AND Topic=(child* or infant* or infancy or newborn* or baby* or babies or neonat* or preterm* or prematur* or schoolchild* or "school age" or "school aged" or "school ages" or preschool* or kid or kids or toddler* or minors or juvenile* or boy* or girl* or pediatric* or paediatric* or kindergar* or "nursery school" or "nursery schools")

Refined by: Topic=(random* or placebo* or (clinic* NEAR/1 trial*) or (singl* NEAR/1 blind*) or (doubl* NEAR/1 blind*))

Timespan=1985-2012. Databases=SCI-EXPANDED, CPCI-S, CCR-EXPANDED, IC.

Lemmatization=On  

Appendix 6. Networked digital library of thesis and dissertations (NDLTD) search strategy

Subject: pneumonia or bronchopneumonia or pleuropneumonia AND Subject: antibiotic or antibiotics or azithromycin or amoxycillin or amoxicillin or ampicillin or erythromycin or clarithromycin or cotrimoxazole or trimethoprim or coamoxyclav or coamoxiclav or co-amoxyclav or co-amoxiclav or augmentin

Title: pneumonia or bronchopneumonia or pleuropneumonia AND Title: antibiotic or antibiotics or azithromycin or amoxycillin or amoxicillin or ampicillin or erythromycin or clarithromycin or cotrimoxazole or trimethoprim or coamoxyclav or coamoxiclav or co-amoxyclav or co-amoxiclav or augmentin

Contributions of authors

The review has been written by Zohra S Lassi (ZSL) and Rohail Kumar (RK) and supervised by Zulfiqar A Bhutta (ZAB). Rehana A Salam (RAS), Jai K Das (JKD), ZSL and RK contributed to the screening of studies and data extraction.

Declarations of interest

Zohra S Lassi: no conflicts of interest.
Rohail Kumar: no conflicts of interest.
Jai K Das: no conflicts of interest.
Rehana A Salam: no conflicts of interest.
Zulfiqar A Bhutta: no conflicts of interest.

Sources of support

Internal sources

  • Aga Khan University, Pakistan.

External sources

  • No sources of support supplied

Characteristics of studies

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Agarwal 2004This study compared the efficacy of 3 days versus 5 days of treatment with oral amoxicillin for curing non-severe pneumonia in children aged 2 to 59 months. A no treatment arm was not included in the study and therefore it was excluded
Awasthi 2008Children with non-severe pneumonia and wheeze who did not show improvement on a bronchodilator and had a normal chest X-ray were enrolled in the study
Fontoura 2010This study was not a randomised controlled trial. A prospective study design was used to estimate clinical failure and adverse events in children with non-severe pneumonia receiving amoxicillin
Hazir 2007This study compared a standard dose of amoxicillin with a double dose for the management of children aged 2 to 59 months with non-severe pneumonia. A no treatment arm was not included in the study and therefore it was excluded
MASCTM Pakistan 2002This study compared the efficacy of 3 days versus 5 days of treatment with oral amoxicillin for curing non-severe pneumonia in children aged 2 to 59 months. A no treatment arm was not included in the study and therefore it was excluded

Characteristics of studies awaiting assessment [ordered by study ID]

Hazir 2011

  1. a

    ARI: acute respiratory infections
    h: hour
    WHO: World Health Organization

MethodsThis was a double-blind, randomised, placebo-controlled trial performed in 4 hospitals in 3 cities in Pakistan (Islamabad, Lahore and Rawalpindi). The objective was to compare clinical outcomes in children aged 2 to 59 months diagnosed with WHO-defined non-severe pneumonia treated with or without antibiotics. Enrolled children were randomly assigned to receive either oral amoxicillin or placebo. The randomisation scheme was generated by a computer program at ARI Research Cell, Islamabad, with uneven blocks of 4, 6 and 8. Drug assignment was concealed from patients, parents and study personnel. The code was broken after the data analysis
Participants

Inclusion criteria: 2103 children aged 2 to 59 months with cough, difficult breathing, or both, were screened for fast breathing. Children were classified using standard WHO algorithm for ARI. 900 children classified as having non-severe pneumonia were included in this study

Exclusion criteria: children who had underlying chronic illness, had a history of more than 3 episodes of wheeze or acute bronchial asthma and had used any antibiotic in appropriate doses during the previous 48 h were excluded

Interventions

Enrolled children were randomly assigned to receive either oral amoxicillin (n = 450) (15 mg/kg every 8 h) or a placebo (n = 450)

with a similar colour and consistency and in the same volume, masked with regard to taste and smell to the greatest extent possible, for 3 days. Oral amoxicillin was changed (or started in the placebo group) to oral chloramphenicol if the child was declared as a treatment failure by day 3, day 5 or at relapse. Children who developed severe pneumonia or very severe pneumonia and/or disease or who did not improve after 48 h of oral chloramphenicol therapy were referred for inpatient treatment with the appropriate injectable antibiotic. Oral cefixime was used for 7 days when injectable therapy was not possible. Children were followed for a total of 14 days

OutcomesThe study outcome was treatment failure by day 3. The secondary outcomes were treatment failure by day 5 (cumulative treatment failure) and relapse. Relapse of disease was defined as development of any sign of pneumonia 6 to 14 days after fast breathing had initially returned to normal. Clinical resolution was defined as either return of respiratory rate to the normal age-specific range or an improvement by day 3
Notes54.5% and 50% of the children in the antibiotic and no antibiotic group respectively had wheeze

Ancillary