Lumefantrine and Desbutyl-Lumefantrine Population Pharmacokinetic-Pharmacodynamic Relationships in Pregnant Women with Uncomplicated Plasmodium falciparum Malaria on the Thailand-Myanmar Border

Artemether-lumefantrine is the most widely used antimalarial artemisinin-based combination treatment. Recent studies have suggested that day 7 plasma concentrations of the potent metabolite desbutyl-lumefantrine correlate better with treatment outcomes than those of lumefantrine. Low cure rates have been reported in pregnant women with uncomplicated falciparum malaria treated with artemether-lumefantrine in northwest Thailand. A simultaneous pharmacokinetic drug-metabolite model was developed based on dense venous and sparse capillary lumefantrine and desbutyl-lumefantrine plasma samples from 116 pregnant patients on the Thailand-Myanmar border. The best model was used to evaluate therapeutic outcomes with a time-to-event approach. Lumefantrine and desbutyl-lumefantrine concentrations, implemented in an E_max model, both predicted treatment outcomes, but lumefantrine provided better predictive power. A combined model including both lumefantrine and desbutyl-lumefantrine did not improve the model further. Simulations suggested that cure rates in pregnant women with falciparum malaria could be increased by prolonging the treatment course. (These trials were registered at controlled-trials.com [ISRCTN 86353884].)     

Genomic Analysis of Reduced Susceptibility to Tigecycline in Enterococcus faecium

Tigecycline (TIG) is approved for use for the treatment of complicated intra-abdominal infections, skin and skin structure infections, as well as pneumonia. Acquired resistance or reduced susceptibility to TIG has been observed in Gram-negative rods, has seldom been reported in Gram-positive organisms, and has not yet been reported in Enterococcus faecium. Using the serial passage method, in vitro mutant AusTig and in vitro mutants HMtig1 and HMtig2 with decreased TIG susceptibility (MICs, 0.25 μg/ml) were obtained from strains E. faecium Aus0004 and HM1070 (MICs, 0.03 μg/ml), respectively. In addition, two vancomycin-resistant E. faecium clinical isolates (EF16 and EF22) with reduced susceptibility to TIG (MICs, 0.5 and 0.25 μg/ml, respectively) were studied. Compared to the wild-type strains, the in vitro mutants also showed an increase in the MICs of other tetracyclines. An efflux mechanism did not seem to be involved in the reduced TIG susceptibility, since the presence of efflux pump inhibitors (reserpine or pantoprazole) did not affect the MICs of TIG. Whole-genome sequencing of AusTig was carried out, and genomic comparison with the Aus0004 genome was performed. Four modifications leading to an amino acid substitution were found. These mutations affected the rpsJ gene (efau004_00094, coding for the S10 protein of the 30S ribosomal subunit), efau004_01228 (encoding a cation transporter), efau004_01636 (coding for a hypothetical protein), and efau004_02455 (encoding the l-lactate oxidase). The four other strains exhibiting reduced TIG susceptibility were screened for the candidate mutations. This analysis revealed that three of them showed an amino acid substitution in the same region of the RpsJ protein. In this study, we characterized for the first time genetic determinants linked to reduced TIG susceptibility in enterococci.