Recrudescence, Reinfection, or Relapse? A More Rigorous Framework to Assess Chloroquine Efficacy for Plasmodium vivax Malaria.

Background: Plasmodium vivax resistance to chloroquine (CQ) has been reported worldwide, although the World Health Organization clinical drug efficacy studies protocol does not permit classification of patient outcomes. Methods: We enrolled 40 patients with P. vivax malaria in northeastern Cambodia, where >17% treatment failures were previously reported. Patients were treated with CQ (30 mg/kg) and followed for 2 months, with frequent clinical examination and capillary blood sample collection for microscopy, molecular parasite detection and genotyping, and drug concentration measurements. Reinfections were prevented by relocating patients to a transmission-free area. Results: P. vivax parasites were eliminated in all patients by day 3. Genomic analyses revealed that all clones in polyclonal infections were cleared at the same rate, indicating their equal susceptibility to CQ. CQ blood concentrations were below the therapeutic level in all recurrent infections (24 of 40 patients), which were efficiently cleared by a second course of CQ treatment. Genotyping (128 SNPs barcode) and sequences of entire parasite genome (Whole-Genome Sequencing, Illumina) indicated that two thirds (6 of 8) of the recurrent parasites resulted from heterologous relapses whose 50% are from by sibling/recombinant clones. Conclusions: No evidence of CQ resistance was observed. Our data suggest that P. vivax antimalarial drug resistance is likely overestimated and that the current guidelines for clinical drug studies of P. vivax malaria need to be revised.

Post-hemodialysis dosing of 1 vs. 2 g of ceftazidime in anuric end-stage renal disease patients on low-flux dialysis and its pharmacodynamic implications on clinical use.

Ceftazidime is a cost-effective antimicrobial against Gram-negative pathogens associated with sepsis in end-stage renal disease (ESRD) hemodialysis patients with potential for wider use with the advent of ceftazidime-avibactam. Dosing ceftazidime post-hemodialysis appears attractive and convenient, but limited in vivo data on pharmacodynamic efficacy (PE) attainment, defined as >70% of the interdialytic period drug concentrations exceed susceptible pathogens minimal inhibitory concentrations (MICs) (%TMIC), warrants further assessment. We therefore evaluated PE and tolerability of 1 against 2 g regime in anuric ESRD patients on low-flux hemodialysis. Two doses of 1 or 2 g ceftazidime were administered post-hemodialysis prior to 48- and 72-hour interdialytic intervals in ESRD inpatients without active infections. Peak and trough concentrations (mg/L) were assayed using a validated liquid chromatography-tandem mass spectrometry method. Proportion of patients achieving PE for known pathogens with MICs ≤ 8 mg/L and adverse effects were assessed. Six (43%) and eight (57%) adult patients received 1 and 2 g dose, respectively. Median (25th-75th percentile), peak, 48- and 72-hour trough ceftazidime concentrations were 78 (60-98) vs. 158 (128-196), 37 (23-37) vs. 49 (39-71), and 13 (12-20) vs. 26 (21-41) mg/L, respectively, resulting in 100% TMIC for both doses. One patient on the 1-g dose experienced mild pruritus. Reliable and safe PE attainment over both 48- and 72-hour interdialytic interval was achievable with 1 g of ceftazidime dosed post-hemodialysis. The 2 g dose was equally effective and well tolerated but may not be necessary. These findings need validation in non-anuric patients, high-flux hemodialysis, and during avibactam co-administration.