Population pharmacokinetics of colistin and the relation to survival in critically ill patients infected with colistin susceptible and carbapenem-resistant bacteria.

OBJECTIVES: The aim was to analyse the population pharmacokinetics of colistin and to explore the relationship between colistin exposure and time to death. METHODS: Patients included in the AIDA randomized controlled trial were treated with colistin for severe infections caused by carbapenem-resistant Gram-negative bacteria. All subjects received a 9 million units (MU) loading dose, followed by a 4.5 MU twice daily maintenance dose, with dose reduction if creatinine clearance (CrCL) < 50 mL/min. Individual colistin exposures were estimated from the developed population pharmacokinetic model and an optimized two-sample per patient sampling design. Time to death was evaluated in a parametric survival analysis. RESULTS: Out of 406 randomized patients, 349 contributed pharmacokinetic data. The median (90% range) colistin plasma concentration was 0.44 (0.14-1.59) mg/L at 15 minutes after the end of first infusion. In samples drawn 10 hr after a maintenance dose, concentrations were >2 mg/L in 94% (195/208) and 44% (38/87) of patients with CrCL ≤120 mL/min, and >120 mL/min, respectively. Colistin methanesulfonate sodium (CMS) and colistin clearances were strongly dependent on CrCL. High colistin exposure to MIC ratio was associated with increased hazard of death in the multivariate analysis (adjusted hazard ratio (95% CI): 1.07 (1.03-1.12)). Other significant predictors included SOFA score at baseline (HR 1.24 (1.19-1.30) per score increase), age and Acinetobacter or Pseudomonas as index pathogen. DISCUSSION: The population pharmacokinetic model predicted that >90% of the patients had colistin concentrations >2 mg/L at steady state, but only 66% at 4 hr after start of treatment. High colistin exposure was associated with poor kidney function, and was not related to a prolonged survival.

Management of carbapenem-resistant Enterobacteriaceae infections.

BACKGROUND: Carbapenem resistance is defined as in vitro non-susceptibility to any carbapenem and/or documented production of a carbapenemase. This feature has rapidly spread worldwide among clinical isolates of Enterobacteriaceae, mostly Klebsiella spp., and is associated with diverse molecular mechanisms. Carbapenem resistance is often associated with resistance to all traditional ß-lactams and other classes of antibiotics, denoting a typical example of an extensively drug-resistant phenotype. OBJECTIVES: To summarize and interpret in a balanced manner the most clinically relevant data in terms of carbapenem-resistant Enterobacteriaceae (CRE) infection management. SOURCES: Data were extracted by PubMed and clinicaltrials.gov search and manual scrutiny among references of analysed articles. CONTENT: Features of newer and older, rediscovered antimicrobial options for CRE are described. Observational studies and randomized clinical trials (RCT) of CRE treatment are summarized, with a specific focus on the effects of monotherapy compared with combination treatment. IMPLICATIONS: The available evidence on the current management of CRE mostly comes from observational, non-comparative, retrospective, small studies, with a high risk of selection bias. Very little evidence comes from RCT. Conflicting results of RCT and observational studies call for caution before combination therapies are deemed superior to monotherapy. Data on newer agents have spurred enthusiasm but remain limited as concerns severe CRE infections. A balanced approach should guide the clinician in the choice of old or new drugs, and of monotherapies or combination regimens. Efforts should be made to perform adequately sized clinical trials answering well-defined research questions.

Acute kidney injury during colistin therapy: a prospective study in patients with extensively-drug resistant Acinetobacter baumannii infections.

The study aimed to prospectively assess incidence and risk factors for colistin-associated nephrotoxicity. This is a secondary analysis of a multicentre, randomized clinical trial, comparing efficacy and safety of colistin versus the combination of colistin plus rifampicin in severe infections due to extensively drug-resistant (XDR) Acinetobacter baumannii. The primary end point was acute kidney injury (AKI) during colistin treatment, assessed using the AKI Network Criteria, and considering death as a competing risk. A total of 166 adult patients without baseline kidney disease on renal replacement therapy were studied. All had life-threatening infections due to colistin-susceptible XDR A. baumannii. Patients received colistin intravenously at the same initial dose (2 million international units (MIU) every 8 h) with predefined dose adjustments according to the actual renal function. Serum creatinine was measured at baseline and at days 4, 7, 11, 14 and 21 (or last day of therapy when discontinued earlier). Outcomes assessed were 'time to any kidney injury' (AKI stages 1-3) and 'time to severe kidney injury' (considering only AKI stages 2-3 as events). When evaluating overall mortality, AKI occurrence was modelled as a time-dependent variable. AKI was observed in 84 patients (50.6%, stage 1 in 40.4%), with an incidence rate of 5/100 person-days (95% CI 4-6.2). Risk estimates of AKI at 7 and 14 days were 30.6% and 58.8%. Age and previous chronic kidney disease were significantly associated with any AKI in multivariable analysis. Neither 'any' nor 'severe AKI' were associated with on-treatment mortality (p 0.32 and p 0.54, respectively). AKI occurs in one-third to one-half of colistin-treated patients and is more likely in elderly patients and in patients with kidney disease. As no impact of colistin-associated AKI on mortality was found, this adverse event should not represent a reason for withholding colistin therapy, whenever indicated.

Efficacy and safety of tenofovir, entecavir, and telbivudine for chronic hepatitis B in heart transplant recipients.

BACKGROUND: Treatment of chronic hepatitis B (CHB) with polymerase inhibitors is key to prevent disease flares and progression toward advanced liver disease. Efficacy and tolerability of newer agents has been reported anecdotally in transplant recipients. METHODS: In this prospective, observational study, we assessed outcomes of therapy with tenofovir (TDF), entecavir (ETV), and telbivudine (LdT) in 13 heart transplant recipients (HTR) with CHB. RESULTS: Most patients were hepatitis B e antigen negative, had low baseline hepatitis B virus (HBV) DNA, and normal aminotransferases. Liver biopsy showed a median fibrosis score of 1.5 (range 0-4). Glomerular filtration rate (GFR) was <50 mL/min in 7 patients (54%). Two patients were started on de novo ETV before transplant. Eleven previously treated patients were switched to TDF (n = 9) or LdT (n = 2). Median treatment duration was 33 months (range 1-71). HBV DNA remained suppressed in 6 patients and became undetectable in 5. Aminotransferases went down to the normal range in all patients, with a single flare in 1 patient. One patient lost hepatitis B surface antigen. No cases occurred of hepatic decompensation, hepatocellular carcinoma, or liver-related death. The GFR remained largely stable, and no cases of TDF-related hyper-phosphaturia were observed. CONCLUSIONS: This study indicates that newer antivirals are effective and safe in HTR with CHB.

Treatment options for methicillin-resistant Staphylococcus aureus (MRSA) infection: Where are we now?

Methicillin-resistant Staphylococcus aureus (MRSA) infection continues to be a substantial global problem with significant associated morbidity and mortality. This review summarises the discussions that took place at the 4th MRSA Consensus Conference in relation to the current treatment options for serious MRSA infections and how to optimise whichever therapy is embarked upon. It highlights the many challenges faced by both the laboratory and clinicians in the diagnosis and treatment of MRSA infections.