Short‐course versus long‐course antibiotic therapy for non‐severe community‐acquired pneumonia in children aged 2 months to 59 months
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To evaluate the efficacy of short‐course versus long‐course therapy with the same antibiotic for non‐severe community‐acquired pneumonia in children aged 2 to 59 months.
Background
Pneumonia is an infection of the lungs (Gaston 2002). Community‐acquired pneumonia (CAP) refers to pneumonia in a previously healthy person who has acquired the infection from outside a hospital. Pneumonia can be caused by organisms such as bacteria and viruses; in children the organisms which cause pneumonia vary with the age of the child (McIntosh 2002). Group B streptococcus and gram‐negative enteric bacteria are the most common pathogens in neonates (from birth to 20 days after birth); whereas in infants aged three weeks to three months Streptococcus pneumoniae (S. pneumoniae) is the most common pathogen. In infants older than four months and in preschool‐aged children, viruses are a frequent cause and S. pneumoniae is the most common bacterial pathogen (Ostapchuk 2004). Staphylococcus aureus (S. aureus) and Haemophilus influenzae (H. influenzae), including non‐typable, are also common causes of childhood pneumonia in developing countries (McIntosh 2002).
Acute lower respiratory tract infections (ALRI) are among the leading causes of mortality in children under five years of age (Williams 2002). They account for nearly two million deaths each year with most of the deaths occurring in the developing countries. Pneumonia is the largest killer, accounting for 18% of all child deaths in developing countries (WHO 2003). Interventions that affect mortality due to pneumonia are thus of great importance for any effort to improve child survival.
Definitions of pneumonia vary widely. Some require evidence of the presence of infiltrates on a chest radiograph whereas others require certain respiratory signs or symptoms (McIntosh 2002). The World Health Organization (WHO) has defined pneumonia solely on the basis of clinical findings obtained by visual inspection and setting respiratory rate cut offs (WHO 1981). To reduce the number of people dying from pneumonia, the WHO developed standard guidelines for the management of acute respiratory infections (WHO 1990). These guidelines were developed using evidence from studies on etiology, clinical aspects and susceptibility (WHO 1991). Because S. pneumoniae and H. influenzae are the most common causes of childhood pneumonia in developing countries, the WHO recommends using oral cotrimoxazole or amoxicillin as the first‐line drugs for the treatment of non‐severe pneumonia at first level health facilities (WHO 1990; WHO 1991). These guidelines have effectively reduced death from pneumonia in less‐developed countries (Sazawal 2003).
Treatment of pneumonia requires the use of an effective antibiotic given in adequate doses and for an appropriate duration. Recommendations for antibiotic therapy for pneumonia are based, in general, on etiological diagnosis (Prober 2000). Identification of the causative organism in routine clinical care is rare and is not usually attempted. Because of these diagnostic problems empirical antibiotic therapy is the commonly accepted practice worldwide (McIntosh 2002). In most cases the duration of treatment ranges between 7 to 14 days, which is not based on any empirical evidence. Rather this treatment duration seems to be the result of initial treatment studies of tonsillo‐pharyngitis, which was treated for 10 to 14 days (Pichichero 2000).
Optimum duration of therapy for pneumonia is especially important in resource‐poor settings where there is a high risk of death, poor access to medicines and health care, and limited budgets for medicines (Campbell 1995). Important aspects of a shorter course of antibiotic therapy, if found to be effective without an increase in morbidity and mortality, include improved adherence to therapy, reduced antimicrobial resistance, and lowered cost.
The aim of this review is to evaluate the efficacy of short‐course versus long‐course therapy using the same antibiotic for non‐severe community‐acquired pneumonia in children aged 2 months to 59 months.
Objectives
To evaluate the efficacy of short‐course versus long‐course therapy with the same antibiotic for non‐severe community‐acquired pneumonia in children aged 2 to 59 months.
Methods
Criteria for considering studies for this review
Types of studies
All randomized controlled trials (RCTs) evaluating the efficacy of short‐course versus long‐course therapy using the same antibiotic for non‐severe community‐acquired pneumonia in children. Studies using a standard WHO algorithm for ARIs (WHO 1991) which defines non‐severe pneumonia as cough or difficult and fast breathing (respiratory rate of 50 breaths per minute or more for children aged 2 months to 11 months; or respiratory rate of 40 breaths per minute or more for children aged 12 months to 59 months) will be considered for this review. Trials published in languages other than English will also be included after translation into English. Non‐randomized (quasi‐randomized) trials will be excluded.
Types of participants
Children aged 2 months to 59 months with non‐severe community‐acquired pneumonia will be included. Studies including children with severe or very severe pneumonia (defined on the basis of chest in‐drawing, inability to drink, convulsions, abnormally sleepy or difficult to wake), any chronic illness, or those who have received antibiotics in the past 48 hours will be excluded.
Types of interventions
Short‐course versus long‐course therapy using the same antibiotic for non‐severe community‐acquired pneumonia in children. A comparison of duration of antibiotic therapies (less than versus more than between three to seven days) will be performed.
Types of outcome measures
Primary outcome
Clinical cure rate defined as return of respiratory rate to the normal age‐specific range.
Secondary outcomes
1. Treatment failure: defined as development of chest in‐drawing, convulsions, drowsiness, or inability to drink at any time; respiratory rate above the age‐specific cut‐off on completion of treatment; or oxygen saturation, measured by pulse oximetry, of less than 90% after completion of the treatment; loss to follow up or withdrawal from the study.
2. Relapse rate: defined as development of any sign of pneumonia within seven days after fast breathing had returned to normal.
3. Additional interventions used.
4. Mortality in one month.
Search methods for identification of studies
We will search the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library latest issue); MEDLINE (1966 to present); EMBASE (1974 to present); LILACS (all years).
The following search terms will be combined with the highly sensitive search strategy devised by Dickersin et al (Dickersin 1994) and run over MEDLINE and CENTRAL. The terms will be adapted to search EMBASE and LILACS.
((exp Pneumonia/ AND exp Community‐Acquired Infections/) OR pneumonia OR community acquired pneumonia OR CAP OR lower respiratory tract infection$ OR LRTI OR lower respiratory infection$)
AND
(exp Anti‐Bacterial Agents/ OR antibiotic$ OR exp Anti‐Infective Agents/ OR exp Amoxicillin/ OR exp Penicillins/ OR exp Ampicillin/ OR exp Trimethoprim‐Sulfamethoxazole Combination/ OR exp Macrolides/ OR exp Erythromycin/ OR exp Azithromycin/ OR exp Clarithromycin/ OR penicillin$ or amoxicillin or ampicillin or cotrimoxazole or macrolide$ or erythromycin OR azithromycin OR clarithromycin)
AND
(exp Child/ OR child OR children OR exp Infant/ OR infant OR infants OR paediatric OR pediatric)
Searches will be limited to human studies. There will be no language or publication restrictions (published, unpublished, in press, and in progress). We will also search the related conference proceedings for relevant abstracts. We will contact organizations and researchers in the field and pharmaceutical companies for information on unpublished and ongoing trials. We will also check the reference list of all trials identified by the above methods.
Data collection and analysis
Study selection and eligibility
Eligibility of the trials will be assessed independently by two authors. Authors will select studies as being potentially relevant by screening the titles and abstracts, if available. If the relevance cannot be ascertained by screening the title and the abstract the full text of the article will be retrieved and reviewed. Authors will retrieve full texts of all potentially relevant articles and will independently assess the eligibility by filling out eligibility forms designed in accordance with the specified inclusion criteria. Any disagreements, if found, will be resolved by discussion and consensus will be reached. If unable to reach a consensus about the eligibility of a trial the authors concerned will be contacted for clarification. Studies excluded from the review will be displayed in a table along with the reasons for exclusion.
Assessment of methodological quality
Two authors will assess the methodological quality of the selected trials by independently filling out methodological assessment quality forms. Quality assessment of the trials will be undertaken using the standard criteria of allocation concealment in categories of adequate, inadequate and unclear. Assessment of random allocation sequence will include both randomization and evaluation of whether it is secure or not. Evaluation of blinding of caregivers and outcome assessors will also be undertaken for quality assessment of the trials and will be divided into categories of yes, no and unclear. Information on differential loss to follow up of participants and analysis of participants in their respective randomized groups will also be obtained. Any disagreements found between the two authors will be resolved by discussion. If consensus cannot be reached regarding methodology, study authors will be contacted for clarification
Data extraction
Data extraction will be done using a data extraction form which will be designed and pilot tested by the review authors. The form will extract information regarding:
1. study setting (for example country, type of population and socioeconomic status);
2. description of antibiotic used (including type of drug, dose, duration and frequency);
3. sample size;
4. length of follow up;
5. randomization procedure;
6. outcomes as listed above.
For dichotomous outcomes, we will extract the total number of participants for each group and the number of participants experiencing an event. For continuous outcomes, we will extract the mean, standard deviation (or data required to calculate this) and the total number of participants for each group.
Data analysis
Data analysis will be undertaken using Review Manager Version 4.2. Analysis of the outcome will be based on the intention‐to‐treat principle. For dichotomous outcome we will use the odds ratio (or relative risk) and for continuous outcomes we will use the weighted mean difference.
A sensitivity analysis will be performed for studies of varying methodological quality. Heterogeneity among the trials will be measured by the visual inspection of forest plots and by calculating the I2 statistic. If I2 exceeds 50% and visual inspection of forest plots is indicative, heterogeneity will be considered to be substantial and reasons for it will be sought, such as differences in:
1. dosage and frequency of antibiotics used;
2. different durations of short‐course versus long‐course of antibiotic therapy used;
3. high baseline infant mortality;
4. bacterial or viral aetiology;
5. differences in the half lives of the antibiotics used;
6. characteristics of the study population;
7. differences in the diagnosing technique of pneumonia.
