Challenges in the Design of Antibiotic Equivalency Studies: The Multicenter Equivalency Study of Oral Amoxicillin versus Injectable Penicillin in Children Aged 3–59 Months with Severe Pneumonia
ABSTRACT The World Health Organization (WHO) recommends that children with severe pneumonia (characterized by cough or difficult breathing, as well as lower chest wall indrawing) be hospitalized and treated with parenteral penicillin. Oral amoxicillin, if equally effective for treating severe pneumonia, would address challenges associated with providing parenteral therapy, including risk of transmission of bloodborne pathogens from contaminated needles, exposure to nosocomial pathogens during hospitalization, inadequate access to health care facilities, and cost. The recently completed multicenter international trial of oral amoxicillin versus parenteral penicillin for treatment of severe pneumonia demonstrated the equivalency of these agents in children with severe pneumonia. This article focuses on the challenges of designing an equivalence study and the threats to the validity of the trial results, particularly the implications of the bias toward finding equivalence when subjects are unlikely to respond to either study therapy. These considerations have implications for use of the Amoxicillin Penicillin Pneumonia International Study (APPIS) results in clinical practice and for potential modification of WHO treatment guidelines.
- SourceAvailable from: who.intBulletin of the World Health Organisation 04/2006; 2006(4):269-275. DOI:10.2471/BLT.04.015222 · 5.11 Impact Factor
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ABSTRACT: To determine whether children aged 3-59 months with mild or non-symptomatic human immunodeficiency virus (HIV) infection and WHO-defined severe pneumonia have a higher failure rate than do HIV-uninfected children when treated with the standard WHO treatment of parenteral penicillin or oral amoxicillin. This study was a planned sub-analysis of a randomized trial of 3-59-month-old children presenting with WHO-defined severe pneumonia (the APPIS study). We included two sites with high HIV prevalence in Durban, South Africa and Ndola, Zambia. Primary outcome measures were clinical treatment failure at day 2 and day 14. CLINICALTRIALS.GOV IDENTIFIER: CT00227331http://www.clinicaltrialsgov/show/NCT00227331). Of the 523 children enrolled, HIV status was known for 464 participants; 106 (23%) of these were infected with HIV. By day 2, 57 (12.3%) children had failed treatment and 110 (23.7%) failed by day 14. Twenty (18.9%) HIV-infected children failed by day 2 compared with 37 (10.3%) uninfected children (adjusted odds ratio (OR) 2.07; 95% confidence interval (CI): 1.07-4.00). Thirty-four (32.1%) HIV-infected children failed treatment by day 14 compared with 76 (21.2%) uninfected children (adjusted OR 1.88; 95% CI: 1.11-3.17). Analysis stratified by age showed that the greatest differential in treatment failure at day 2 and day 14 occurred in the children aged 3-5 months. HIV-infected children with severe pneumonia fail WHO-standard treatment with parenteral penicillin or amoxicillin at day 2 and day 14 more often than do HIV-uninfected children, especially young infants. Standard case management of acute respiratory infection (ARI) using WHO treatment guidelines is inadequate in areas of high HIV prevalence and reappraisal of empiric antimicrobial therapy is urgently needed for severe pneumonia associated with HIV-1.Bulletin of the World Health Organisation 05/2006; 84(4):269-75. DOI:10.1590/S0042-96862006000400010 · 5.11 Impact Factor
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ABSTRACT: Since 1986, researchers have noted a syndrome of Klebsiella pneumoniae pyogenic liver abscess that is complicated by endophthalmitis or central nervous system infections. There are limited data regarding the role of bacterial genotype in the pathogenesis of this syndrome. We conducted a retrospective cohort study involving 177 cases of K. pneumoniae pyogenic liver abscess treated during 1997-2005 at a tertiary university hospital in Taiwan. We performed bacterial cps genotyping by polymerase chain reaction detection of serotype-specific alleles at wzy and wzx loci and used an in vitro serum assay to evaluate the virulence of bacterial strains. Septic ocular or central nervous system complications developed in 23 patients (13%). Logistic regression analysis showed that genotype K1 was the only significant risk factor (adjusted odds ratio, 4.8; 95% confidence interval, 1.5-15.7, P=.009). The serum resistance assay indicated that, on average, K1 strains (n=100) were significantly more virulent than were strains of K2 (n=36), K20/K5/K54 (n=21), or other genotypes (n=20) (P<.001 for each comparison). In addition to the serotype-specific cps region, the genomic background of K1 strains also differed significantly from that of non-K1 strains (20-kb kfu/PTS region, 97/100 vs. 13/77; P<.001). Of the 19 cases in which genotype K1 strains caused complications, 8 patients (42%) did not have identifiable underlying medical diseases. K. pneumoniae genotype K1 is an emerging pathogen capable of causing catastrophic septic ocular or central nervous system complications from pyogenic liver abscess independent of underlying diseases in the host.Clinical Infectious Diseases 09/2007; 45(3):284-93. DOI:10.1086/519262 · 9.42 Impact Factor