From the Department of Pediatrics, King George’s Medical College, Lucknow (U.P.) 226 003, India.Reprint requests: Dr. Shally Awasthi, C-4, Officer’s Colony, Niralanagar, Lucknow (U.P.) 226 020, India. E-mail: [email protected] in

Manuscript received: July 8, 1999;
Initial review completed: August 10, 1999;
Revision accepted: September 1, 1999

Pneumonia is a common cause of childhood morbidity(1). For the standard case management of non-severe pneumonia, co-trimoxazole has been recommended as the antibiotic of choice (2-5) and is being used in India. However, there are reports from India as well as other countries about rising resistance of two most common bacteria, Streptcoccus pneumoniae and Haemo-philus influenzae, against co-trimoxazole(6-10). This has made it necessary to find alternative antibodies for the community-based treatment of non-severe pneumonia. The preferred alter-native is amoxycillin(9,11,12). The use of amoxycillin instead of co-trimoxazole would substantially increase the cost of treatment of non-severe pneumonia. Since workers have reported that shorter duration of treatment of non-severe pneumonia does result in clinical cure(13) and since there is meager data on the clinical efficacy of amoxycillin for the treatment of non-severe pneumonia, the current study was conducted to assess the clinical response to amoxycillin after 2 days of a five day course of antibiotic therapy.

The study was conducted in the Outpatient Division of Department of Pediatrics of King George’s Medical College, Lucknow, India, from August to October 1997 after obtaining institutional ethical clearance. The objectives were to determine the clinical responses of children 2 to 59 months of age with cough and fast breathing, with or without wheezing, but no evidence of WHO defined severe illness(3-5), after 48 hours of therapy when treated with amoxycillin. WHO defines "severe pneumonia" as lower chest wall indrawing and "very severe disease" if there is any one of the following: cyanosis, inability to drink, convul-sions, drowsiness, stridor at rest, or severe malnutrition(3-5).

A fixed sample size of 100 cases was taken based on the calculations that if 100 cases of non-severe pneumonia are recruited and all followed up then ³50% improvement can be detected with 1% precision, for an alpha level of 0.05. With a <10% and 10-20% losses to follow-up the precision will be 2% and 5%, respectively, for the same alpha level for the same response rates.

The main outcome measure was clinical cure after 2 days of treatment. Clinical cure was defined as respiratory rate <40 per minute and <50 per minute in children between 12-59 months and between 2-11 months of age, respectively, and absence of any of the follow-ing signs of treatment failure: (i) clinical deterioration as indicated by the occurrence of any sign of WHO defined "very severe disease" or "severe pneumonia", (ii) increase in respira-tory rate by >10 breaths per minute above baseline and (iii) respiratory rate >70 per minute for children 2 to 11 months of age or >60 per minute for children 12 to 59 months.

Included were children aged 2 to 59 months attending the outpatient’s clinics with written informed consent by a parent or legal guardian and having: (a) WHO criteria for non-severe pneumonia (3-5), which are cough and difficult breathing of less than 30 days duration, with respiratory rate ³ 50 per minute in children 2 to 11 months and ³ 40 per minute in children 12-59 months of age counted in a calm child, preferably without fever, and (b) Accessibility for follow-up.

Children were excluded if they had any of the following: (i) WHO signs of very severe disease/pneumonia (3-5); (ii) Other clinical findings of severe pneumonia-nasal flaring or grunting; (iii) Previous history of wheezing including asthma, or who have been prescribed corticosteroids along with bronchodilators for the treatment of wheeze; (iv) Known or clinically recognizable congenital heart disease: (v) Known or clinically recognizable acute/chronic organ system disorders; (vi) Immuno-deficiency (congenital/acquired), including suspected HIV infection; (vii) Other infectious conditions requiring antibiotic therapy at the day of contact; (viii) Respiratory rate >60 per minute in children 12 months of age or older, and >70 per minute in children less than 12 months of age; (ix) A history of antibiotic use in the previous 2 days. Evidence of oral antibiotic use included any one of the following: parent reported that an antibiotic was consumed, parent had prescription for antibiotics and parent had bottle containing antibiotic pills or liquid medicine; (x) A history of hospitalization in the past 2 weeks; (xi) Measles or a history of measles within the last month; (xii) Prior enrolment in the current study; and (xiii) Known penicillin allergy, including a history of rash, urticaria, or anaphylactic symptoms.

One para-medical research assistant was trained to count respiratory rate and recognize lower chest retraction, cyanosis, drowsiness and stridor. During the study period, the respiratory rate and physical examination findings of a random 20% sample of included cases were verified on the spot by the investigator.

Data was collected on the age, sex and weight. History of cough, breathlessness, noisy respiration and fever was noted with the duration of each symptom. The chest of the child was bared and the respiratory rate was counted by a para-medical research staff for 1 minute. After a gap of 5 minutes or longer the respiratory rate was counted again for 1 minute. The average of these two rates was considered for assessing the suitability of including the child in the study.

The child was examined for the presence of exclusion criteria and ausculated by the investigator. Included children were given amoxycillin (15 mg/kg/dose) eight hourly. Medications for 48 hours were dispensed. Scored, 125-mg amoxycillin dispersible tablets were used. The parents were requested to come back after 48 hours for outcome assessment. Those who cured or who did not have any sign of treatment failure were given another 3 days of amoxycillin supply. Those who were identified as treatment failures were shown to the investigator or another consultant and treated according to their advice. Children with wheeze were given either theophylline (5 mg/kg/dose) in six hourly or salbutamol (0.2 mg/kg/24 h) in eight hourly doses or both as prescribed by the consultant. Children with pyrexia were provided with paracetamol. Nebulization was given in the inpatient facilities only to those who were advised for this by the treating physician.

The outcome assessment and follow-up was done after 48 hours of treatment at which time respiratory rate twice was counted as before and the child was examined for signs of treatment failure.

Univariate distribution of age, sex and weight was calculated. The presence of various symptoms along with its mean duration was analyzed. The presence of auscultatory wheeze and crepitations at enrolment was assessed among children between 2-11 months and 12-59 months of age. The number of treatment failures and clinical cures at the end of 2 days were calculated in the two age categories and stratified for the presence or absence of wheeze at enrolment.

Results

Of 1992 new cass in the eligible age group that registered in the Outpatient’s Department, 236 were of non-severe pneumonia from whom one hundred cases, who had no exclusion criteria, were recruited in the study. The mean age at recruitment was 20.41 ± 14.18 months. Twenty-nine children were between 2-11 months and 71 between 12-59 months of age. Two thirds of children were males. The duration of various symptoms and signs at enrolment are given in Table I. The mean respiratory rate at enrolment and at day 3 follow-up for children in the two age categories is given in Table I. All the symptoms were present on an average for a mean duration of 5 days prior to hospital consultation. At enrolment 11% (95% CI: 5.9-18.3) had wheeze on auscultation, of which 2 (6.9%) were in the 2-11 month age and 8 (11.3%) in the older age category. There were just 2 children with auscultatory crepitations. Only 61% children were pyrexic with measured axillary temperature >99 degrees Farenhiet at the time of presentation.

The overall loss to follow-up on day 3 was 15%. The number of doses was counted on day 3. Five (5.9%) had taken 5 out of six recom-mended doses while all the rest had taken complete six doses. There were no treatment failures on day 3 and in entire cohort, 77.7% (95% CI: 67.9-85.9) children were clinical cures. In the 2-11 month age category, 91.3% children had respiratory rate <50/minute and in the 12-59 month age category 67.7% had respiratory rate <40/minute. Of those who were not clinically cured in the 12-59 month age category (n = 20), 25% had wheeze at enrolment and also on day 2 follow-up (p value = 0.08).

This study was conducted in the ambulatory care setting. It was found that after 48 hours of treatment with oral amoxycillin about three-fourth of cases of non-severe pneumonia had clinical cure, meaning thereby return of respiratory rate below age specific cutoff in absence of signs of treatment failure. In all cases, however, treatment with amoxycillin was provided for further 3 days.

The current study had included children with and without wheeze as the community health worker will not be able to distinguish between them and also because there is a lot of variability in physician reported auscultatory signs(5). To simulate field conditions no radiological investigation was done at baseline. The pill count was taken as a surrogate measure for compliance and no follow-up was done beyond day 3 as all the children were provided with the conventional dose of the antibiotic. Hence there is no information on deterioration following initial improvement or subsequent relapse. At enrolment there were similar proportion of wheezers in both the groups. However, 25% of those who were not cured clinically in the 12-59 month age category had wheeze at enrolment as well as on day 3. It is possible that these were cases with hyper reactive airways who were recruited due to generic inclusion criteria.

An observational study from Bangladesh reported that three-fourths of the cases of non-severe pneumonia were cured with just three days of co-trimoxazole and thereafter dis-continued the medication by themselves(13). Our study shows that three-fourths of the cases do have clinical cure as early as within 2 days of treatment. The clinical cure rate of 77.6% found in this study is similar to 82% cure rates found with 5 days treatment with single or double dose co-trimoxazole(14). However, the 77.6% clinical cure found with 2 days in the current study is less than 88% cure rate with amoxycillin in a randomized trial among cases of non-severe pneumonia from Pakistan(9). Observations from the current study as well as other workers(15) suggest the need to institute studies to identify shorter than conventional duration of therapy for non-severe pneumonia.

Protocol was developed as a part WHO-ARCH-INCLEN funded workshop in Canberra, Australia, in June 1997.

Contributors: SA conducted the study, analyzed the data and drafted the manuscript; she will act as the guarantor for the paper.
Funding: Natco Pharmaceuticals and Aristo Pharmaceuticals donated the drugs. Computing facilities provided by INCLEN Inc., Philadelphia, USA, were used.
Competing interests: None stated.

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