Comparison of oral amoxicillin with placebo for the treatment of world health organization-defined nonsevere pneumonia in children aged 2-59 months: a multicenter, double-blind, randomized, placebo-controlled trial in pakistan.

BACKGROUND: world Health Organization (WHO) acute respiratory illness case management guidelines classify children with fast breathing as having pneumonia and recommend treatment with an antibiotic. There is concern that many of these children may not have pneumonia and are receiving antibiotics unnecessarily. This could increase antibiotic resistance in the community. The aim was to compare the clinical outcome at 72 h in children with WHO-defined nonsevere pneumonia when treated with amoxicillin, compared with placebo. METHODS: we performed a double-blind, randomized, equivalence trial in 4 tertiary hospitals in Pakistan. Nine hundred children aged 2-59 months with WHO defined nonsevere pneumonia were randomized to receive either 3 days of oral amoxicillin (45mg/kg/day) or placebo; 873 children completed the study. All children were followed up on days 3, 5, and 14. The primary outcome was therapy failure defined a priori at 72 h. RESULTS: in per-protocol analysis at day 3, 31 (7.2%) of the 431 children in the amoxicillin arm and 37 (8.3%) of the 442 in placebo group had therapy failure. This difference was not statistically significant (odds ratio [OR], .85; 95%CI, .50-1.43; P = .60). The multivariate analysis identified history of difficult breathing (OR, 2.86; 95% CI, 1.29-7.23; P = .027) and temperature >37.5°C 100°F at presentation (OR, 1.99; 95% CI, 1.37-2.90; P = .0001) as risk factors for treatment failure by day 5. CONCLUSION: clinical outcome in children aged 2-59 months with WHO-defined nonsevere pneumonia is not different when treated with an antibiotic or placebo. Similar trials are needed in countries with a high burden of pneumonia to rationalize the use of antibiotics in these communities.

Ambulatory short-course high-dose oral amoxicillin for treatment of severe pneumonia in children: a randomised equivalency trial.

BACKGROUND: WHO case management guidelines for severe pneumonia involve referral to hospital for treatment with parenteral antibiotics. If equally as effective as parenteral treatment, home-based oral antibiotic treatment could reduce referral, admission, and treatment costs. Our aim was to determine whether home treatment with high-dose oral amoxicillin and inpatient treatment with parenteral ampicillin were equivalent for the treatment of severe pneumonia in children. METHODS: This randomised, open-label equivalency trial was done at seven study sites in Pakistan. 2037 children aged 3-59 months with severe pneumonia were randomly allocated to either initial hospitalisation and parenteral ampicillin (100 mg/kg per day in four doses) for 48 h, followed by 3 days of oral amoxicillin (80-90 mg/kg per day; n=1012) or to home-based treatment for 5 days with oral amoxicillin (80-90 mg/kg per day in two doses; n=1025). Follow-up assessments were done at 1, 3, 6, and 14 days after enrollment. The primary outcome was treatment failure (clinical deterioration) by day 6. Analyses were done per protocol and by intention to treat. This trial is registered, ISRCTN95821329. FINDINGS: In the per-protocol population, 36 individuals were excluded from the hospitalised group and 37 from the ambulatory group, mainly because of protocol violations or loss to follow-up. There were 87 (8.6%) treatment failures in the hospitalised group and 77 (7.5%) in the ambulatory group (risk difference 1.1%; 95% CI -1.3 to 3.5) by day 6. Five (0.2%) children died within 14 days of enrollment, one in the ambulatory group and four in the hospitalised group. In each case, treatment failure was declared before death and the antibiotic had been changed. None of the deaths were considered to be associated with treatment allocation; there were no serious adverse events reported in the trial. INTERPRETATION: Home treatment with high-dose oral amoxicillin is equivalent to currently recommended hospitalisation and parenteral ampicillin for treatment of severe pneumonia without underlying complications, suggesting that WHO recommendations for treatment of severe pneumonia need to be revised.

Nosocomial bloodstream infection in a tertiary care paediatric intensive care unit.

OBJECTIVE: To determine the frequency, causative organisms and susceptibility pattern of nosocomial bloodstream infections in children. STUDY DESIGN: Observational study. PLACE AND DURATION OF STUDY: Paediatric Intensive Care Unit of the Children's Hospital, Lahore, from January to December 2004. PATIENTS AND METHODS: All children admitted to the unit during the study period were daily evaluated for features suggestive of nosocomial infection. In addition to other investigations, blood cultures were done in all suspected cases for the confirmation of nosocomial bloodstream infection (BSI). Nosocomial infection was defined according to the criteria set by Centre for Disease Control and Prevention. Demographic, microbiological and other variables were carefully studied to analyze frequency, incidence rate, spectrum of isolates and susceptibility pattern. Children with and without nosocomial BSI were compared with regard to age, duration of stay in hospital, need and duration of ventilation and the outcome. RESULTS: Of the total 406 admissions, 134 children were suspected to have nosocomial infection on at least 214 occasions (episodes). Blood cultures yielded growth of pathological organisms in 62 of these episodes, giving the frequency of nosocomial BSI as 15.2 per 100 admissions (62/406 episodes). Children with nosocomial bloodstream infection were found to have younger mean age (2.1 vs. 4.1 years), longer average duration of stay (13.1 vs. 6.6 days), more frequent need for ventilation (64% vs. 34%) and longer duration of ventilation (9.7 vs. 4.8 days). Majority of isolates (77%) were gram-negative bacteria; Klebsiella being the most common isolate (n= 23). Aztreonam, Ceftiazidime, Ceforuxime and Ciprofloxacin showed high resistance pattern (33-50%). Isolates showed good sensitivity to Vancomycin (100%), Imipenem (80%), Meropenem (100%) and Co-amoxiclav (88%). CONCLUSION: The frequency of nosocomial BSI in the observed setting was quite high, having marked impact on the duration of stay and outcome. Emergence of resistant pathogens is alarming.

Comparison of standard versus double dose of amoxicillin in the treatment of non-severe pneumonia in children aged 2-59 months: a multi-centre, double blind, randomised controlled trial in Pakistan.

INTRODUCTION: WHO pneumonia case management guidelines recommend oral amoxicillin as first line treatment for non-severe pneumonia. Increasing treatment failure rates have been reported over a period of time, which could possibly be due to increasing minimum inhibitory concentrations of Streptococcus pneumoniae and Haemophilus influenzae for amoxicillin. Microbiological data show that this resistance can be overcome by increasing amoxicillin dosage. Based on this data, we examined whether we can improve the clinical outcome in non-severe pneumonia by doubling the dose of amoxicillin. METHODS: A double blind randomised controlled trial was conducted in the outpatient departments of four large hospitals in Pakistan. Children aged 2-59 months with non-severe pneumonia were randomised to receive either standard (45 mg/kg/day) or double dose (90 mg/kg/day) oral amoxicillin for 3 days and then followed up for 14 days. Final outcome was treatment failure by day 5. RESULTS: From September 2003 to June 2004, 876 children completed the study. 437 were randomised to standard and 439 to double dose oral amoxicillin. 20 (4.5%) children in the standard and 25 (5.7%) in the double dose group had therapy failure by day 5. Including the relapses, by day 14 there were 26 (5.9%) cumulative therapy failures with standard and 35 (7.9%) with double dose amoxicillin. These differences were not statistically significant (p = 0.55 and p = 0.29, respectively). CONCLUSION: Clinical outcome in children aged 2-59 months with non-severe pneumonia is the same with standard and double dose oral amoxicillin. Non-severe pneumonia can be treated effectively and safely with a 3 day course of a standard dose.

Efficacy and safety of halofantrine in Pakistani children and adults with malaria caused by P. falciparum and P. vivax.

One hundred two patients aged 2-43 years diagnosed with acute malaria due to P. falciparum or P. vivax were treated with 3 doses of halofantrine (500 mg for > or = 18 year old patients and 8 mg/kg of patient body weight for 2-17 year olds), with each dose administered once in 6 hours and followed up for 28 days. Out of 102 patients 63 had P. falciparum, 36 had P. vivax and 3 had unidentified species. Following three dose therapy, 96.1% (98/102) of patients were cured, 0.98% (1/102) showed improvement from baseline, 1.96% (2/102) did not respond and were considered as treatment failures and one patient had indeterminate data. The lone patient, who relapsed after 120 hours post dose 1, was cured following re-treatment on day 7. The median parasite clearance and fever clearance times, from the first dose, were 26 hours and 30 hours, respectively. Eleven point eight percent (12/102) of patients reported adverse events, of which abdominal pain, reported by one subject, was considered to be probably related to the drug and required corrective therapy. There were no serious adverse events or fatalities and none of the patients had a change in QTc interval greater than 10%. Thirteen point seven percent (14/102) of patients had abnormal clinical laboratory parameters that normalized later.

Does early referral to tertiary care decrease the mortality related to birth asphyxia?

OBJECTIVE: To find the association of time of referral of asphyxiated newborns with the outcome. DESIGN: Observational study. PLACE AND DURATION OF STUDY: Neonatal Unit of Children's Hospital, Lahore, from August to December 2000. PATIENTS AND METHODS: One hundred fifty newborns with birth asphyxia were studied, who fulfilled four out of six Levene criteria. Exclusion criteria included age more than 48 hours at the time of admission, respiratory depression due to other causes, birth weight less than 1500 grams, gestational age less than 34 weeks, major congenital malformations, dysmorphism, severe hyperbilirubinemia, meningitis and bleeding disorders. Newborns were divided into two groups. Group A (n=78,52%) comprised of those newborns who reached our hospital within 12 hours after birth and group B (n=7, 48%) were those newborns who reached between 12-48 hours. Outcome was described either good outcome (newborns discharged from hospital in good clinical condition having normal vital signs, taking oral feed and not requiring medicine) or poor outcome (newborns expired during stay in neonatal unit). Chi-square test was applied and p-value was calculated. RESULTS: One hundred and seventeen (117) newborns (78%) were males and 33 (22%) were females. Thirty-five (35) mothers (23%) had proper antenatal visits to trained medical professionals. Majority of mothers (n=59, 39%) had their visits to untrained midwives, 56 mothers (37%) to semi-trained persons like a midwife, LHV or nurse. Majority (n =93, 61%) of study population were home delivered. Thirty-six newborns (24%) were delivered at private clinics and maternity homes while only 21 newborns (14%) came from tertiary care centers. Mortality was 24% in group A as compared to 76% in group B (p-value < 0.001). CONCLUSION: Those asphyxiated newborns who reached to a tertiary care hospital earlier had significantly better outcome as compared to those who arrived late. Early recognition of birth asphyxia and referral, therefore, reduces morbidity and mortality.

Immunogenicity of a recombinant, yeast-derived, anti-hepatitis-B vaccine after alternative dosage and schedule vaccination in Pakistani children.

A controlled, randomized trial was conducted in urban areas of Karachi and Lahore with the aim to look for ways to improve the cost-effectiveness of hepatitis B vaccination. Children under 15 years old (including neonates) were selected and screened for immunization by three regimens according to the frequency and doses of the recombinant vaccine used (Heberbiovac HB, Heber Biotec, Havana). Group A received 10 microg at 0, 1 months; group B (control) received 10 microg at 0, 1 and 2 months (standard regime), and group C received 5 microg at 0, 1 and 2 months. Antibody levels were titrated 2 months after the last dose. Cut-off for seroprotection and hyperresponse were taken as 10 and 100 IU/L, respectively. Nine hundred and ninety children were included and evaluated after discarding those positive for serological hepatitis virus infection markers. Seroprotection rates were 100, 99.7 and 99.7%, and hyperresponse was achieved by 92.7, 99.4, and 97% of the vaccinees in groups A, B, and C, respectively. The same good result was obtained in extreme ages subgroups (< or =1 year and > or =10 years old). The 1-year follow up of the children from Karachi showed good persistence of seroprotection (98, 100, and 99.4%) and hyperresponse (79.7, 96.7, and 87.4%). It is concluded that it is feasible to improve the cost-benefit ratio and compliance of hepatitis B vaccination by means of a two-shots or reduced dose schedule of the vaccine employed in the trial.

Acute poisoning in children.

OBJECTIVE: To determine the frequency, etiology, clinical presentation and outcome of acute poisoning in children presenting to a tertiary care hospital. DESIGN: Descriptive and observational study. PLACE AND DURATION OF STUDY: Emergency Department of the Children's Hospital and the Institute of Child Health, Lahore. Over five years from September 1998 to August 2003. MATERIAL AND METHODS: All cases of suspected or confirmed acute poisoning in children (1 month to 15 years) were retrospectively analyzed by retrieving data from hospital records and from patients files where possible. Variables like demographic data, season of presentation, type of agent, route of exposure and outcome were studied for all cases. Detailed files were available for 90 patients in whom place of exposure, risk factors and clinical features were also studied. RESULTS: Three hundred and forty-six cases of acute poisoning were registered during the study period, which constitute 0.93% of all ER admission. Most (59%) were less than 2 years of age with median age of 18 months (SD+ 32.6). Majority (80%) belonged to urban areas and presented during summer and monsoon season (57%). Pharmaceutical products were the leading cause (51%) followed by petroleum products (23%), chemicals (8.4%), household substances (7.6%) and unidentifiable agents in 10% cases. Anti-diarrhoeal drugs and kerosene oil were the two most frequent agents involved and ingestion remained the primary route of exposure. Gastrointestinal system was primarily involved in 40% patients. Eighty percent patients were discharged, 6% with residual damage while 11% patients died of poisoning or its complications. CONCLUSION: Acute poisoning carries a significant impact as regards morbidity and mortality. Awareness and education about the potential toxicity of commonly used drugs and household substances may help in reducing the burden of acute poisoning in children.

Brain abscess in children.

OBJECTIVE: To find out the clinical presentation, radiological characteristics, various underlying predisposing conditions and causative organisms of brain abscess in children in our setup. DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: The Children's Hospital and the Institute of Child Health, Lahore, over two years from September 2001 to August 2003. PATIENTS AND METHODS: All children (< 16 years) presenting with brain abscess were included to study demographic, clinical and radiological features. In addition, attempts were made to find out underlying predisposing conditions and causative organisms. RESULTS: Twenty-five children with brain abscess were managed over 2 years. The mean age was 7.8 years (range 9 months to 16 years). Male to female ratio was 2.1:1. Most patients (43%) presented with 4 weeks history of illness, with mean duration of illness at presentation of 29.3 days. Main presenting complaints were fever (72%), vomiting (48%), headache (44%) and convulsions (32%). Five patients (20%) had papilledema at presentation, another 4 (16%) had paresis/paralysis and 3 (12%) had cranial nerve palsies. Majority (64%) had solitary abscess, located in parietal, temporal, frontal and occipital lobes in order of frequency. No underlying predisposing condition was identified in 8 (32%) cases; while 8 (32%) had cyanotic congenital heart disease, 5 (20%) patients had otic infection (mastoiditis), 2 (8%) were postoperative cases and one each developed brain abscess secondary to ventriculo-peritoneal (VP) shunt infection and pulmonary tuberculosis. Causative organisms were isolated in 40% cases, which included staphylococcus aureus, Staphylococcus epidermidis, Streptococcal species, Klebsiella, E. coli and Proteus. CONCLUSION: Awareness of predisposing factors, early recognition of clinical features and understanding of the prevalent microbial profile is imperative for better management of children with brain abscess.

Clinical utility and accuracy of a blood glucose meter for the detection of neonatal hypoglycemia.

OBJECTIVE: To determine the accuracy and reliability of a glucometer in comparison to hexokinase method in detecting neonatal hypoglycemia. DESIGN: Comparative analytical study. PLACE AND DURATION OF STUDY: Neonatal Unit of the Children ' Hospital, Lahore from August 2001 to February 2002. SUBJECTS AND METHODS: All neonates presenting with known risk factors or suggestive clinical features were screened for hypoglycemia by using capillary blood on Accutrend alpha glucometer. Simultaneously the venous blood glucose values were done on Hitachi 902 autoanalyser by hexokinase method. A level of 40 mg/dl or less was taken as neonatal hypoglycemia. RESULTS: A total of 292-paired samples were taken from 223 neonates. Hypoglycemia was detected in 112 samples (38.4%). Correlation of glucometer values with laboratory values of blood glucose levels was excellent throughout the range with coefficient of correlation (r) of 0.976 (p-value < 0.001). For blood glucose values < 40 mg/dl, r was 0.547 (p-value < 0.001). The instrument used showed a sensitivity of 98% and specificity of 93% to detect neonatal hypoglycemia (< 40 mg/dl) with a positive predictive value of 88% and negative predictive value 99%. CONCLUSION: The blood glucose reflectance meter can be a useful and accurate instrument for screening and detecting neonatal hypoglycemia in symptomatic babies under stress. All low values by glucometer should be promptly analyzed and confirmed by chemical laboratory.

The etiology of neonatal sepsis and patterns of antibiotic resistance.

OBJECTIVE: To study the patterns of causative bacteria and antibiotic resistance in neonatal sepsis. DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Department of Neonatology, The Children s Hospital and the Institute of Child Health, Lahore from July 2000 to December 2000. SUBJECTS AND METHODS: Two hundred and twenty-eight neonates (age 0-28 days) with clinical sepsis and positive blood cultures were selected. Blood cultures were taken before antibiotics (intravenous cefotaxime and amikacin) administration. The clinical and birth records were thoroughly analyzed. Blood culture reports (n=233) were analyzed for bacterial isolates and pattern of resistance to cefotaxime, ceftazidime, amikacin and ciprofloxacin were compared as percentage of reports showing resistance to the above antibiotics. RESULTS: Among 228 cases included in the study, the male to female ratio was 2.1 to 1. The gestational age was less than 36 weeks in 68 (30%) cases and low birth weight babies were 143 (62.6%). History of birth asphyxia was present in 103 (45%) cases. There were 142 (62.3%) cases of early onset (< 7 days) sepsis and 86 (37.7%) cases of late onset (>7 days). Out of 233 positive blood cultures Escherichia coli was found to be commonest (47.8%, n=111, p <0.05) both in early onset (47.8%, n=68, p <0.05) and late onset sepsis (47.3%, n=43, p<0.05). Staphylococcus aureus was the most common among gram positive organism. Resistance to cefotaxime, ceftazidime and amikacin was 34% to 80% and to ciprofloxacin 13% to 72%. A total of 64 cases (28%) died. Mortality was four times higher in early onset sepsis (n=53 vs 11, 47% vs 12%). CONCLUSION: Gram negative bacteria are the commonest cause of neonatal sepsis. The resistance to the commonly used antibiotics is alarmingly high. Mortality is four times higher in early onset sespis.