Clinical population pharmacokinetics and toxicodynamics of linezolid.

Thrombocytopenia is a common side effect of linezolid, an oxazolidinone antibiotic often used to treat multidrug-resistant Gram-positive bacterial infections. Various risk factors have been suggested, including linezolid dose and duration of therapy, baseline platelet counts, and renal dysfunction; still, the mechanisms behind this potentially treatment-limiting toxicity are largely unknown. A clinical study was conducted to investigate the relationship between linezolid pharmacokinetics and toxicodynamics and inform strategies to prevent and manage linezolid-associated toxicity. Forty-one patients received 42 separate treatment courses of linezolid (600 mg every 12 h). A new mechanism-based, population pharmacokinetic/toxicodynamic model was developed to describe the time course of plasma linezolid concentrations and platelets. A linezolid concentration of 8.06 mg/liter (101% between-patient variability) inhibited the synthesis of platelet precursor cells by 50%. Simulations predicted treatment durations of 5 and 7 days to carry a substantially lower risk than 10- to 28-day therapy for platelet nadirs of <100 ×10(9)/liter. The risk for toxicity did not differ noticeably between 14 and 28 days of therapy and was significantly higher for patients with lower baseline platelet counts. Due to the increased risk of toxicity after longer durations of linezolid therapy and large between-patient variability, close monitoring of patients for development of toxicity is important. Dose individualization based on plasma linezolid concentration profiles and platelet counts should be considered to minimize linezolid-associated thrombocytopenia. Overall, oxazolidinone therapy over 5 to 7 days even at relatively high doses was predicted to be as safe as 10-day therapy of 600 mg linezolid every 12 h.

Population pharmacokinetics of oseltamivir when coadministered with probenecid.

Oseltamivir is a potent, selective, oral neuraminidase inhibitor for the treatment and prophylaxis of influenza. Plasma concentrations of the active metabolite, oseltamivir carboxylate, are increased in the presence of probenecid, suggesting that the combination could allow for the use of reduced doses of oseltamivir. To investigate this proposal, we developed a population pharmacokinetic model and simulated the pharmacokinetics of candidate combination regimens of oral oseltamivir (45 mg and 30 mg twice a day) plus oral probenecid (500 mg/6 hourly). Probenecid plus oseltamivir 45 mg achieved all the pharmacokinetic parameters expected of oseltamivir alone, but combination with oseltamivir 30 mg and dose interval extension approaches did not. An oseltamivir-probenecid combination may compromise tolerability and enhance the potential for drug interactions. In addition, increased dosing requirements may affect compliance and attainment of optimal oseltamivir exposure, potentially facilitating the emergence of viral strains with reduced susceptibility to oseltamivir. These factors, set alongside increased capacity for oseltamivir production, should be carefully considered before an oseltamivir-probenecid combination is used.

Pharmacokinetic/pharmacodynamic factors influencing emergence of resistance to linezolid in an in vitro model.

Emerging resistance threatens the usefulness of linezolid for the treatment of severe infections caused by multidrug-resistant gram-positive bacteria. Optimal pharmacokinetic (PK)/pharmacodynamic (PD) indices have been described for the antimicrobial efficacy of linezolid (area under the concentration-time curve over 24 h at steady state divided by the MIC, >100; the cumulative percentage of a 24-h period that the drug concentration exceeds the MIC under steady-state PK conditions, >85). The aim of this study was to investigate the influence of these PK/PD indices on the development of resistance to linezolid by using an in vitro PK/PD model. Four dosage regimens were simulated over 72 h (two intermittent bolus regimens of 600 mg every 12 h [q12h] and 120 mg q12h and two continuous-infusion regimens of 120 mg/24 h and 30 mg/24 h) against four reference strains: methicillin-resistant Staphylococcus aureus (MRSA), heteroresistant vancomycin-intermediate S. aureus (hVISA), vancomycin-intermediate S. aureus (VISA), and vancomycin-resistant Enterococcus faecium (VRE). Linezolid concentrations were measured by high-performance liquid chromatography. Changes in susceptibility were characterized by pre- and posttreatment MIC measurements and population analysis profiles (PAPs). The linezolid concentrations that were achieved closely matched those that were targeted. The simulation with 600 mg q12h provided a >3-log10 reduction in the number of CFU/ml for all four strains, as did the 120-mg-q12h regimen for hVISA and VISA and the 30-mg/24-h continuous infusion for VRE and VISA. After 72 h of exposure to the 120-mg/24-h continuous-infusion simulation, the area under the PAP curve for all strains increased substantially (40 to 178%); increases in the MICs for the MRSA and hVISA strains were observed. The results demonstrate that PK/PD considerations are important in optimizing both antibacterial activity and the development of resistance to linezolid. The potential for resistance development appears to be higher when a constant concentration is maintained in the vicinity of the MIC of the bacteria.

High-performance liquid chromatographic method for simple and rapid determination of linezolid in human plasma.

A simple high-performance liquid chromatographic (HPLC) method was developed and validated for rapid quantification of linezolid in human plasma. Protein precipitation using a mixture of 5% trichloroacetic acid and methanol (3:1, v/v) provided a straightforward method of sample preparation and the internal standard eperezolid was employed. A concentration range from 0.20 to 40.0 mg/L was utilized to construct calibration curves, and analysis of low- (0.40 mg/L), medium- (7.50 mg/L) and high-quality (25.0 mg/L) control samples revealed excellent reproducibility (

Successful treatment and cerebrospinal fluid penetration of oral linezolid in a patient with coagulase-negative Staphylococcus ventriculitis.

OBJECTIVE: To describe a case of coagulase-negative Staphylococcus ventriculitis successfully treated with oral linezolid, for which good cerebrospinal fluid (CSF) penetration was observed. CASE SUMMARY: A 69-year-old man had an extraventricular drain inserted following a right cerebellar infarct. On day 6, the CSF culture was positive for coagulase-negative staphylococci; intravenous vancomycin 1 g daily was initiated to treat ventriculitis. A ventriculoperitoneal shunt, inserted on day 35 to manage communicating hydrocephalus, was subsequently removed as symptoms suggesting infection presented. Coagulase-negative Staphylococcus was isolated from shunt reservoir aspirate, and intrathecal vancomycin 10 mg daily was added to the treatment regimen. On day 61, vancomycin was stopped and oral linezolid 600 mg twice daily was started. Linezolid was discontinued 22 days later, with no evidence of ongoing infection. Four blood samples were collected around the seventh dose of linezolid and 5 CSF samples were collected on separate days during treatment. Linezolid concentrations were measured in plasma and CSF by HPLC. Using an ADAPT II maximum a priori Bayesian estimator module, a 2 compartment pharmacokinetic model was fitted to the plasma linezolid concentration data and CSF:predicted plasma concentration ratios (ranging from 0.27 to 1.02) were derived. All CSF concentrations exceeded the reported 90% minimum inhibitory concentration of 2 mg/L for linezolid against coagulase-negative staphylococci. DISCUSSION: Evidence of the effectiveness of linezolid against central nervous system infections is growing; however, limited data exist describing its CSF penetration. Oral linezolid exhibited good CSF penetration in this patient, which corresponded to positive clinical response. CONCLUSIONS: Oral linezolid may play a valuable role in the treatment of multiresistant gram-positive central nervous system infections.

Responses to neither exogenous nor endogenous endothelin-1 are altered in patients with hypercholesterolemia.

There is some controversy regarding whether vascular responses to endothelin are altered in hypercholesterolemia. Studies performed to date have been compromised by the use of endothelin antagonists at inappropriate concentrations. In the current study, we examine the role of endothelin-1 in hypercholesterolemic patients using lower, more selective doses of specific endothelin antagonists. Twenty-two patients with hypercholesterolemia (total plasma cholesterol > 6.0 mmol/l) and 17 healthy controls were recruited. Forearm vascular responses to endothelin-1 (5 pmol/min), the endothelin A antagonist BQ-123 (10 nmol/min), and the endothelin B antagonist BQ-788 (1 nmol/min) were obtained. Endothelin-1 caused a significant vasoconstriction in both hypercholesterolemic and control subjects, an effect that was not significantly different between the two groups (P = 0.784). BQ-123 caused a significant vasodilatation that was not significantly different between the two groups (P = 0.899). Similarly, responses to BQ-788 (P = 0.774) and mean plasma endothelin-1 levels were not different (control vs. hypercholesterolemia, 1.16 +/- 0.18 vs. 1.06 +/- 0.15 fmol/ml; P = 0.64). Responses to neither exogenous nor endogenous endothelin are influenced by plasma cholesterol levels in humans. It is thus unlikely that the endothelin system contributes to early vascular disease pathology in patients with hypercholesterolemia.