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Cochrane Database of Systematic Reviews Protocol - Intervention

Oral antibiotics versus parenteral antibiotics for severe pneumonia in children

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

Primary objective
(1) Determine the equivalence in effectiveness and safety of oral antibiotic and the parenteral antibiotic therapies in the treatment of severe pneumonia in children between three months and five years (59 months old).

Secondary objectives
(1) Describe the proportion of children with severe pneumonia that fail to recover or clinically deteriorate with oral antibiotic therapy compared to parenteral antibiotic therapy.
(2) Determine the relative risk of side effects and deaths with oral antibiotic therapy compared to parenteral antibiotic therapy.
(3) Determine the mean time for recovery with oral antibiotic therapy compared to parenteral antibiotic therapy.
(4) Determine the mean days of hospitalisation with oral antibiotic therapy compared to parenteral antibiotic therapy.
(5) Describe the costs associated with oral antibiotic therapy compared to parenteral antibiotic therapy.

Background

Acute respiratory infection (ARI) is one of the leading causes of morbidity and mortality in children under five years of age in developing countries (Garenne 1992; WB 1993). It is estimated that 4.3 million children under the age of five die of ARIs each year. In Colombia, ARI is the most frequent reason to attend an outpatient clinic, the most frequent cause of hospitalisation in children less than five years old, and the second most frequent cause of mortality in this age group after diarrhoea. Present evidence indicates that bacterial infection plays a far greater role as a cause of pneumonia in children in developing countries than it does in developed countries. Bacterial pathogens have been isolated using lung aspirates in up to 74% of patients with pneumonia in developing countries. The primary pathogenic organisms are Streptococcus pneumoniae (S. pneumoniae) and Haemophilus influenzae (H. influenzae) (WHO 1991).

The ARI control programme was developed by the World Health Organization (WHO) in response to the high mortality rate of this illness. Its principal purpose was to reduce mortality and to support the rational use of antibiotics. The recommendations have also been incorporated into the WHO/UNICEF Integrated Management of Childhood Illness (IMCI) programme. These simple strategies advise that children with a cough and normal respiratory rate (cough or cold) should not be treated with antibiotics or be hospitalised. Children who have rapid breathing and no chest in‐drawing (pneumonia), should receive antibiotics as outpatients. Children who have chest in‐drawing with or without rapid breathing (severe pneumonia) should be hospitalised and treated with penicillin or parenteral ampicillin every six hours for at least three days. After the child recovers, treatment should be changed to oral ampicillin or amoxicillin or intramuscular procaine penicillin. Treatment should continue for at least five days. If the child does not recover within 48 hours of starting treatment with penicillin, or if the child's clinical condition deteriorates, antibiotic treatment should be changed to chloramphenicol every six hours. This strategy has resulted in a reduction of mortality when used in developing countries (WHO 1991).

Hospitalisation required for the administration of injectable therapy has several drawbacks. Firstly, the routine use of injectable antibiotics, either intravenously or intramuscularly, is associated with an increase risk of significant morbidity such as abscess formation, transmission of HIV, hepatitis or other pathogens associated with use of contaminated needles. Secondly, in some settings needles for injection and equipment are in short supply or periodically unavailable. Thirdly, hospitalisation can substantially increase the cost of health care. Fourthly, children who must be referred for admission and injectable therapy may not be able to get to the hospital. Finally, and very importantly, we must keep in mind the discomfort and pain caused to children when using injectable therapy.

Recent studies conducted in outpatients (CSG 2002; MASCOT 2002) have demonstrated that oral antibiotics (amoxicillin, co‐trimazole) are effective and safe treatments in non‐severe pneumonia in children from developing countries. Harris (MASCOT 2002) found that azithromycin is equally effective as amoxicillin‐clavulanate or erythromycin estolate in the treatment of community acquired pneumonia in children between six months to 16 years of age. Clinical success (complete recovery of symptoms) was 94% in the azithromycin group and 96.2% in the control treatment group.

Less evidence was found about the use of oral antibiotics in treatment of severe pneumonia in hospitalized children. Mulholland (Mulholland 1998) studied 144 malnourished children younger than five years old admitted to the General Hospital in Fajara (Gambia) with clinical or radiographic diagnosis of pneumonia. Children were randomly assigned to received either oral chloramphenicol or oral TMP/SMX. This study showed that a change therapy required (Mulholland 1998). However this study has several methodological limitations. These include unclear classification and diagnosis criteria,

exclusion of patients from the analysis after randomisation, and non specific outcome measurements. Another randomised clinical trial conducted in a large urban American pediatric hospital evaluated 170 outpatient children with a radiographic diagnosistic of pneumonia; patients were randomised to receive: amoxicillin 50 mg/kg/day or procaine penicillin G 50.000U/kg. Treatment failures were 40% (27/68) in the amoxicillin group and 33% (29/86) in the intramuscular penicillin group (p = 0.053). The authors suggest that there was not a significant difference between oral amoxicillin and intramuscular penicillin in the early treatment of paediatric outpatients with pneumonia (Thesaurus 2001).

Whether oral antibiotic treatment strategies can be used effectively and safely in children with severe pneumonia is unclear.

If oral antibiotics are shown to be as effective as injectable antibiotics in the treatment of severe pneumonia, substantial improvements in access to appropriate care could be achieved. Children would benefit from less pain and discomfort; the risk of certain adverse treatment events could be reduced (i.e., nosocomial infections, iatrogenic complications); and lower treatment costs would result.

This review will also contribute to the rational use of antibiotics, avoidance of antibiotic overuse, and appropriate prescriptions.

Objectives

Primary objective
(1) Determine the equivalence in effectiveness and safety of oral antibiotic and the parenteral antibiotic therapies in the treatment of severe pneumonia in children between three months and five years (59 months old).

Secondary objectives
(1) Describe the proportion of children with severe pneumonia that fail to recover or clinically deteriorate with oral antibiotic therapy compared to parenteral antibiotic therapy.
(2) Determine the relative risk of side effects and deaths with oral antibiotic therapy compared to parenteral antibiotic therapy.
(3) Determine the mean time for recovery with oral antibiotic therapy compared to parenteral antibiotic therapy.
(4) Determine the mean days of hospitalisation with oral antibiotic therapy compared to parenteral antibiotic therapy.
(5) Describe the costs associated with oral antibiotic therapy compared to parenteral antibiotic therapy.

Methods

Criteria for considering studies for this review

Types of studies

Published or unpublished randomised controlled trials, comparing oral and parenteral antibiotic therapy for the treatment of severe pneumonia in children from three months to five years old. Studies reported in any languages will be included.

Studies where children had received treatment within 15 days before the date of recruitment and studies that started before 1960 will be excluded.

Studies that include patients with chronic pulmonary disease such as asthma, bronchopulmonary dysplasia, pulmonary hypertension, recurrent pneumonia, or patients with other diseases such as immunodeficiency, metabolic disorders, neurological pathologies affecting pulmonary functions, or cardiac problems, will be excluded.

Types of participants

Children from three to 59 months old who are diagnosed as having severe pneumonia as defined by WHO:
‐ cough for less than two weeks;
‐ rapid breathing (defined as a respiratory rate of more than 50 breaths /min in children three months to 12 months old, and more than 40 breaths/min in children 12 to 59 months old);
‐ subcostal in‐drawing;
‐ absence of laryngeal stridor, somnolence, lethargy, difficulty in drinking liquids, convulsions or more than three vepisodes of vomiting per hour.

Studies that use a different but consistent definition for pneumonia will be included. The effect that this might have on the outcomes will be assessed by sensitivity analysis.

Types of interventions

Any oral antibiotic compared with any parenteral antibiotic for treatment of severe pneumonia. Treatments will not be restricted by type of antibiotics, dose or duration of therapy.

Types of outcome measures

The primary outcome measures will be:
(1) Absence of respiratory signs consistent with sever pneumonia (subcostal in‐drawings and rapid breathing)
(2) Time for recovery of respiratory symptoms for each antibiotic therapy group.
(3) Death during the acute episode.

The secondary outcome measures will be:
(1) Change of antibiotic therapy during the first 48 hours of treatment due to clinical deterioration.
(2) Rate of infectious complications (such as empyema or sepsis).
(3) Need for ventilation due to respiratory distress.
(4) Side effects of the therapy.
(5) Days of hospitalisation.
(6) Total cost of resources associated with treating severe pneumonia in children
(7) Episodes of recurrence requiring re‐treatment within 28 days

Search methods for identification of studies

The following electronic databases will be searched for trials:
The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, latest issue)
MEDLINE (January 1966 to present)
EMBASE ( January 1990 to present)
LILACS
Bandolier (University of Oxford)
Drugdex
Poisondex

MEDLINE will be searched using the highly sensitive search strategies designed by the Cochrane Collaboration for identifying randomised controlled trials (Dickersin 1994) in combination with the following specific terms:

(exp Pneumonia/ OR pneumonia)
AND
(exp Anti‐bacterial agents OR antibiotic*)
AND
(exp Administration, oral/ OR oral* OR exp Infusions, parenteral/ OR
parenteral* OR exp Injections/ OR injection* OR injectable therapy OR
exp Infusions, intravenous/ OR intravenous OR exp Injections,
Intramuscular/ OR intramuscular)

*There are several MESH headings in MEDLINE that are used to describe parenteral or injectable therapy. The full text of the articles identified with the search strategy as "potentially eligible", will be obtained through:
‐ PubMed
‐ Freemedicaljournals
‐ Hinari
‐ University medical libraries from Bogotá.
‐ Sent from the different search engines, or authors.
‐ Cochrane's research support

The age will be limited from three months to five years. Appropriate modifications in search terms will be made for each database. The reference lists of relevant articles will be checked for additional studies. To avoid publication bias, the strategy planned to identify unpublished studies is to do a search on the following web pages:
(1) Medical and scientific associations:
‐ American College of Chest Physician www.chestnet.org
‐ American Medical Association www.ama.org
‐ American Academy of Paediatrics www.apa.org
‐ Sociedad Española de Neumopediatría www.neumoped.org
‐ American Association of Respiratory Care www.aarc.org
‐ American Lung Association www.lungusa.org
‐ American Thoracic Society www.thoracic.org
‐ European Respiratory Society
‐ The Canadian Lung Association, respiratory review from ERS and the Topical reviews of current respiratory literature.
‐ The Canadian Society of Respiratory Therapists Journal

(2) Other Latin‐American health information services:
‐ SCIELO
‐ HINARI

(3) Relevant conference abstracts will be searched in:
‐ ACID‐FREE Official Journal Of The American Thoracic Society
‐ PRIMARILY Publications European Respiratory
‐ Trial registers managed by the British Association for Lung research.

Data collection and analysis

Trial identification
Two reviewers (MXR and CG) will independently scan the titles identified by electronic searching. Potential relevant studies will be retrieved in full text to be evaluated for inclusion. Once the article is obtained a research assistant, will mask the information about article authors and data of study publication, before the article being evaluated by reviewers. Using a check list designed in advance, all full text articles will be reviewed blinded and independently by MXR and CG to identify if it meets the inclusion criteria.

Quality assessment
Methodological quality assessment of the trials that meet eligibility criteria will be done using Guyatt´s guidelines (User's Guides to Medical Literature, JAMA 2002). If disagreement in the assessment of quality occurs, the study will be assessed by a third person, and differences resolved by consensus. The level of agreement between the two primary reviewers will be reported using the Kappa statistics.

The methodological quality of randomisation concealment, blinding and follow‐up will be described.

Data extraction
From each study, the following information will be extracted and recorded on the data collection form:
‐ Randomisation details
‐ Number of patients enrolled
‐ Number of patients analyzed
‐ Details of therapies
‐ Demographic characteristics from the population studied (sex, age, severity of illness and any other relevant baseline characteristics)
‐ Country were the study was carried out
‐ Treatment (types of antibiotics, total days of treatment, side effects and complications reported)
‐ Method of assessment
‐ Follow‐up (time of follow‐up, dropouts)
‐ Outcome measure used
‐ Total treatment failures( details of treatment failure definition)
‐ Number of deaths

Data analysis
Quantitative analysis of outcomes will be based on the intention to treat principle. Each trial will be analysed individually to determine the relative risk and absolute risk difference between treatments for the predetermined categorical outcomes. The weighted mean difference will be used for our continuous outcomes (days of hospitalisation and costs). The results of each study will be described. The consistency of these results and any clinical heterogeneity between studies will be reported. Statistical heterogeneity between studies will be assessed using the chi squared test and heterogeneity statistic. In the case of significant clinical heterogeneity, no statistical analysis will be performed to pool the results. If the results of individual studies are sufficiently homogeneous, meta‐analysis using a random effects model will be used to pool the results of the individual studies for each outcome. In addition to combining all oral antibiotic therapies and parenteral antibiotic therapies, antibiotics will be classified as follows: cephalosporins, penicillins, macrolides, aminoglycoside and other. Planned subgroup analysis will be conducted according to the category of antibiotic used.