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.
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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: Encapsulated Klebsiella pneumoniae is the predominant causative agent of pyogenic liver abscess, an emerging infectious disease that often complicates metastatic meningitis or endophthalmitis. The capsular polysaccharide on K. pneumoniae surface was determined as the key to virulence. Although the regulation of capsular polysaccharide biosynthesis is largely unclear, it was found that protein-tyrosine kinases and phosphatases are involved. Therefore, the identification and characterization of such kinases, phosphatases, and their substrates would advance our knowledge of the underlying mechanism in capsule formation and could contribute to the development of new therapeutic strategies. Here, we analyzed the phosphoproteome of K. pneumoniae NTUH-K2044 with a shotgun approach and identified 117 unique phosphopeptides along with 93 in vivo phosphorylated sites corresponding to 81 proteins. Interestingly, three of the identified tyrosine phosphorylated proteins, namely protein-tyrosine kinase (Wzc), phosphomannomutase (ManB), and undecaprenyl-phosphate glycosyltransferase (WcaJ), were found to be distributed in the cps locus and thus were speculated to be involved in the converging signal transduction of capsule biosynthesis. Consequently, we decided to focus on the lesser studied ManB and WcaJ for mutation analysis. The capsular polysaccharides of WcaJ mutant (WcaJY5F) were dramatically reduced quantitatively, and the LD(50) increased by 200-fold in a mouse peritonitis model compared with the wild-type strain. However, the capsular polysaccharides of ManB mutant (ManBY26F) showed no difference in quantity, and the LD(50) increased by merely 6-fold in mice test. Our study provided a clear trend that WcaJ tyrosine phosphorylation can regulate the biosynthesis of capsular polysaccharides and result in the pathogenicity of K. pneumoniae NTUH-K2044.Molecular & Cellular Proteomics 09/2009; 8(12):2613-23. DOI:10.1074/mcp.M900276-MCP200 · 7.25 Impact Factor
Bulletin of the World Health Organisation 04/2006; 2006(4):269-275. DOI:10.2471/BLT.04.015222 · 5.11 Impact Factor