Search

Gentamicin is known to have concentration-dependent bactericidal activity, and its nephrotoxic effect is well described. We developed a population pharmacokinetic/pharmacodynamic model to optimize gentamicin dosing in pediatrics. Data were retrospectively collected for pediatric patients 1 month to 12 years of age, admitted to general pediatric wards or intensive care units and received gentamicin for suspected or proven Gram-negative infections at King Saud University Medical City, Riyadh, Saudi Arabia. A total of 306 gentamicin peak and trough concentrations sets from 107 patients were analyzed with mean (±standard deviation) patient age and weight of 4.5 ± 3.5 years and 16.7 ± 10.8 kg, respectively. Gentamicin pharmacokinetics were adequately described with a one compartment system (R = 0.82, bias = 1.75% and precision = 88% for population predictions and R = 0.94, bias = 5% and precision = 29% for individual predictions). The gentamicin pharmacokinetic parameters were as follows: volume of distribution = 8.9 L, total body clearance = 2.8 L/h for a 20-kg patient. Monte Carlo simulations showed that doses of 5-6 mg/kg/dose once daily are adequate only to treat infections with Gram-negative organisms having minimal inhibitory concentration less than 1 µg/mL. While, at minimal inhibitory concentration of 1 µg/mL, higher doses (7-8 mg/kg/dose once daily) are needed to maximize the efficacy of gentamicin. However, at minimal inhibitory concentration of 2 µg/mL, even a 10 mg/kg dose showed poor target attainment (52%). The finding of this study highlights the need to reevaluate the current breakpoints of gentamicin and also to assess the safety of higher doses of gentamicin in pediatrics.

In adults, nucleoside reverse transcriptase inhibitor-only antiretroviral regimens (NOARs) with ≥3 nucleoside reverse transcriptase inhibitors are less potent than highly active antiretroviral therapy (HAART). Published pediatric experience with NOARs is limited; thus, we wished to better define the virological, immunological and toxicological effects of NOARs in children and adolescents.We analyzed data from NOAR-treated participants in LEGACY, a multicenter observational cohort study of HIV-infected children and adolescents. NOAR-treated case-participants were matched to participants without prior NOAR who initiated HAART during the same year for comparison.Of 575 participants with data from time of HIV diagnosis through 2006, 67 (12%) received NOARs for at least 24 weeks; most (46%) received the fixed dose combination of zidovudine/lamivudine/abacavir. NOAR use peaked in 2001 to 2002. NOAR-treated participants were significantly older and more treatment experienced than HAART-treated participants. Virologic outcomes, including the percentage of participants with a plasma HIV RNA viral load400 copies/mL at week 24 (47% versus 34%) and the mean 24-week change in log10 plasma HIV RNA viral load from baseline (-0.63 versus -1.02), were similar between NOAR- and HAART-treated participants, but virologic rebound was more likely in NOAR-treated participants (77% versus 54%, P = 0.02). Increase in CD4 percentage points from baseline to 24 weeks was negligible in NOAR-treated participants compared with HAART-treated participants (0.95% versus 10.1%, P0.001). Anemia and leukopenia were more commonly reported with NOARs than HAART.Week 24 virologic outcomes were similar between NOAR- and HAART-treated participants, but NOAR durability was poorer and their use was associated with less immunologic reconstitution. NOARs should play a limited role in pediatric and adolescent antiretroviral therapy.