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Long-acting cabotegravir is approved for pre-exposure prophylaxis and combination HIV treatment, both initiated with optional short-term oral lead-in (OLI). We evaluated the impact of OLI on long-acting cabotegravir pharmacokinetics. Cabotegravir plasma concentrations were compared between HIV-positive participants initiating injections with ( n = 278) or without ( n = 110) OLI in phase III treatment study FLAIR and in HIV-negative participants using OLI ( n = 263) in pivotal pre-exposure prophylaxis studies HPTN 083 and HPTN 084. Cabotegravir pharmacokinetic profiles were simulated in three populations (assigned-male-at-birth, 50%-assigned-female-at-birth, and assigned-female-at-birth) under three scenarios: first injection given (A) 1 or (B) 3 days after final OLI dose (OLI-injection gap) or (C) without OLI. The PK objective was 80% of participants achieving 4× in vitro protein-adjusted 90% maximal inhibitory concentration (PA-IC 90 ) and 50% achieving 8× PA-IC 90 . Observed trough concentrations ( C τ ) were similar with and without OLI ( P > 0.3). With a 3-day OLI-injection gap, simulated pre-injection C τ remained above PK objective. Approximately 1-2 weeks after the first injection, simulated PK profiles became nearly identical among all scenarios. Without OLI, it was predicted that 80% of participants achieve 4× PA-IC 90 in 1.2, 1.8, and 2.8 days after the first injection in each population, respectively, and 50% achieve 8× PA-IC 90 in 1.4, 2.1, and 3.8 days, respectively. Observed long-acting cabotegravir exposure was similar with or without OLI, supporting optional OLI use. Cabotegravir exposure was predicted to remain above PK objective for OLI-injection gaps of ≤3 days and rapidly achieve PK objective after first injection without OLI. Findings are consistent between assigned-male-at-birth and assigned-female-at-birth populations.This study is registered with ClinicalTrials.gov as NCT02720094.

This was an observational study comparing methicillin-resistant Staphylococcus aureus (MRSA) transmission with no decolonization of medical patients to required decolonization of all MRSA carriers during two consecutive periods: baseline with no decolonization of medical patients (16 months) and universal MRSA carrier decolonization (13 months). The setting was a one-hospital, 156-bed facility with 9,200 annual admissions. Regression models were used to compare rates of MRSA acquisition. The chi-square test was used to compare event frequencies. We used rates of MRSA clinical disease as an outcome monitor of the program. Analysis was done on 15,666 patients who had admission and discharge tests; 27.9% of inpatient days were occupied by a MRSA-positive patient (colonized patient-days) who received decolonization while hospitalized during the baseline period (this 27.9% represented those who had planned surgery) compared to 76.0% during the intervention period (P < 0.0001). The rate of MRSA transmission was 97 events (1.0%) for 9,415 admissions (2.0 transmission events/1,000 patient-days) during baseline and was 87 (1.4%) for 6,251 admissions (2.7 transmission events/1,000 patient-days) during intervention (P = 0.06; rate ratio, 0.74; 95% confidence interval [CI], 0.55 to 1.00). The MRSA nosocomial clinical disease rate was 5.9 infections/10,000 patient-days in the baseline period and was 7.2 infections/10,000 patient-days for the intervention period (rate ratio, 0.82; 95% CI, 0.46 to 1.45; P = 0.49). Decolonization of MRSA patients does not add benefit when contact precautions are used for patients colonized with MRSA in acute (hospital) care., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

The plasma and intrapulmonary pharmacokinetics (PK) of intravenous (i.v.) GSK2251052, a novel boron-containing antimicrobial, were evaluated in healthy adult subjects. Thirty subjects underwent bronchoscopy and timed bronchoalveolar lavage (BAL) either following a single dose (cohort 1) or after 5 twice-daily doses (cohort 2) of 1,500 mg GSK2251052 i.v. Serial PK and safety assessments were obtained throughout the study. Bronchoscopy was performed on a single occasion in each subject at 2, 6, or 12 h after start of infusion. Noncompartmental analysis was performed to calculate PK parameters. Thirty subjects completed the study. The mean clearance (CL), volume of distribution at steady state (Vss), and half-life (t1/2) values were 22 liters/h, 231 liters, and 10.7 h, respectively. Approximately 30% of the dose was excreted unchanged in urine. The GSK2251052 concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) were approximately 50% and 500 to 600%, respectively, compared to the concentration in plasma. the GSK2251052 exposures in ELF and AM were comparable following single- and repeat-dose administration. The most frequently reported drug-related adverse event (AE) was mild to moderate infusion site reactions (7 subjects) that occurred primarily in the repeat-dose cohort. No serious drug-related AEs or clinically significant trends in laboratory values, vital signs, or electrocardiograms were observed. GSK2251052 given as a 1,500-mg infusion was generally tolerated following single- or repeat-dose administration. GSK2251052 distributes into both the ELF and AM of healthy volunteers, which supports further study in patients with pneumonia.

Healthy subjects received dolutegravir at 50 mg in a single-dose crossover study while they were in the fasted state or with low-, moderate-, or high-fat meals. Food increased dolutegravir exposure and reduced the rate of absorption. The area under the concentration-time curve from 0 h to infinity (AUC(0-∞)) increased by 33%, 41%, and 66% when administered with low-, moderate-, or high-fat meals, respectively, compared with fasting. This increase in dolutegravir exposure is not anticipated to impact clinical safety, and therefore dolutegravir can be taken with or without food and without regard to fat content.

Dolutegravir (DTG) is an unboosted, once-daily integrase inhibitor currently in phase 3 trials. Two studies evaluated the effects of etravirine (ETR) alone and in combination with ritonavir (RTV)-boosted protease inhibitors (PIs) on DTG pharmacokinetics (PK) in healthy subjects. DTG 50 mg every 24 h (q24h) was administered alone for 5 days in period 1, followed by combination with ETR at 200 mg q12h for 14 days in period 2 (study 1) or with ETR/lopinavir (LPV)/RTV at 200/400/100 mg q12h or ETR/darunavir (DRV)/RTV at 200/600/100 mg q12h for 14 days in period 2 (study 2). PK samples were collected on day 5 in period 1 and day 14 in period 2. All of the treatments were well tolerated. ETR significantly decreased exposures of DTG, with geometric mean ratios of 0.294 (90% confidence intervals, 0.257 to 0.337) for the area under the curve from time zero until the end of the dosage interval (AUC(0-τ)), 0.484 (0.433 to 0.542) for the observed maximum plasma concentration (C(max)), and 0.121 (0.093 to 0.157) for the plasma concentration at the end of the dosage interval (C(τ)). ETR combined with an RTV-boosted PI affected the exposure of DTG to a lesser degree: ETR/LPV/RTV treatment had no effect on the DTG plasma AUC(0-τ) and C(max), whereas the C(τ) increased by 28%. ETR/DRV/RTV modestly decreased the plasma DTG AUC(0-τ), C(max), and C(τ) by 25, 12, and 37%, respectively. Such effects of ETR/LPV/RTV and ETR/DRV/RTV are not considered clinically relevant. The combination of DTG and ETR alone should be avoided; however, DTG may be coadministered with ETR without a dosage adjustment if LPV/RTV or DRV/RTV is concurrently administered.

This study aimed to determine lamivudine disposition in infants and to construct an appropriate dose adjustment for age, given the widespread use of lamivudine for both the prevention of mother-to-child transmission of human immunodeficiency virus (HIV) and the treatment of HIV-infected infants. Using a pooled-population approach, the pharmacokinetics of lamivudine in HIV-exposed or -infected infants from four Pediatric AIDS Clinical Trials Group studies were assessed. Ninety-nine infants provided 559 plasma samples for measurement of lamivudine concentrations. All infants received combination antiretroviral therapy including lamivudine dosed at 2 mg/kg of body weight every 12 h (q12h) for the first 4 to 6 weeks of life and at 4 mg/kg q12h thereafter. Lamivudine's apparent clearance was 0.25 liter/h/kg at birth, doubling by 28 days. In the final model, age and weight were the only significant covariates for lamivudine clearance. While lamivudine is predominantly renally eliminated, the serum creatinine level was not an independent covariate in the final model, possibly because it was confounded by age. Inclusion of interoccasion variability for bioavailability improved the individual subject clearance prediction over the age range studies. Simulations based on the final model predicted that by the age of 4 weeks, 90% of infant lamivudine concentrations with the standard 2 mg/kg dose of lamivudine fell below the adult median concentration. This population pharmacokinetic analysis affirms that adjusting the dose of lamivudine from 2 mg/kg to 4 mg/kg q12 h at the age of 4 weeks for infants with normal maturation of renal function will provide optimal lamivudine exposure, potentially contributing to more successful therapy.

The distribution of abacavir into the cerebrospinal fluid (CSF) was assessed by use of a population pharmacokinetic analysis. Plasma and CSF abacavir concentrations in 54 subjects were determined. The abacavir CSF/plasma ratio averaged 36% and increased throughout the dose interval. Abacavir penetrates into the CSF in adequate concentrations to inhibit local human immunodeficiency virus replication.