Antimicrobial agents and chemotherapy
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Antimicrob. Agents Chemother. · Aug 2015
Incidence, Predictors, and Impact on Hospital Mortality of Amphotericin B Nephrotoxicity Defined Using Newer Acute Kidney Injury Diagnostic Criteria.
Studies on amphotericin B (AmB) nephrotoxicity use diverse definitions of acute kidney injury (AKI). Here, we used the new Kidney Disease Improving Global Outcome (KDIGO) system to describe the incidence, predictors, and impact of AmB-induced AKI on hospital mortality in 162 patients treated with AmB (120 with deoxycholate preparation and 42 with liposomal preparation). KDIGO stage 1 requires an absolute increase of ≥0.3 mg/dl or ≥1.5× over baseline serum creatinine (SCr), while stage 2 requires ≥2×, and stage 3 requires ≥3×. ⋯ However, only traditional criteria were associated with intensive care unit (ICU) admission, mechanical ventilation, and mortality. In conclusion, the increase in sensitivity of KDIGObin is accompanied by a loss of specificity and ability to predict outcomes. Prospective studies are required to weigh the potential gain from early AKI detection against the potential loss from undue changes in management in patients with subtle elevations in SCr.
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Antimicrob. Agents Chemother. · Aug 2015
Multicenter Study Clinical Trial Observational StudyAltered Micafungin Pharmacokinetics in Intensive Care Unit Patients.
Micafungin is considered an important agent for the treatment of invasive fungal infections in the intensive care unit (ICU). Little is known on the pharmacokinetics of micafungin. We investigated micafungin pharmacokinetics (PK) in ICU patients and set out to explore the parameters that influence micafungin plasma concentrations. ⋯ Strikingly, micafungin exposure in our cohort of ICU patients was lower than that in healthy volunteers but not significantly different from that of other reference populations. The clinical consequence of these findings must be investigated in a pharmacokinetic-pharmacodynamic (PK-PD) study incorporating outcome in a larger cohort. (This study is registered at ClinicalTrials.gov under registration no. NCT01783379.).
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Antimicrob. Agents Chemother. · Aug 2015
A Simulation Study Reveals Lack of Pharmacokinetic/Pharmacodynamic Target Attainment in De-escalated Antibiotic Therapy in Critically Ill Patients.
De-escalation of empirical antibiotic therapy is often included in antimicrobial stewardship programs in critically ill patients, but differences in target attainment when antibiotics are switched are rarely considered. The primary objective of this study was to compare the fractional target attainments of contemporary dosing of empirical broad-spectrum β-lactam antibiotics and narrower-spectrum antibiotics for a number pathogens for which de-escalation may be considered. The secondary objective was to determine whether alternative dosing strategies improve target attainment. ⋯ EUCAST MIC distribution data were used to calculate fractional target attainment. The probability that therapeutic exposure will be achieved was lower for the narrower-spectrum antibiotics with conventional dosing than for the broad-spectrum alternatives and could drastically be improved with higher dosages and different modes of administrations. For a selection of microorganisms, the probability that therapeutic exposure will be achieved was overall lower for the narrower-spectrum antibiotics using conventional dosing than for the broad-spectrum antibiotics.
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Antimicrob. Agents Chemother. · Aug 2015
Mode of Action of Clofazimine and Combination Therapy with Benzothiazinones against Mycobacterium tuberculosis.
Clofazimine (CZM) is an antileprosy drug that was recently repurposed for treatment of multidrug-resistant tuberculosis. In Mycobacterium tuberculosis, CZM appears to act as a prodrug, which is reduced by NADH dehydrogenase (NDH-2), to release reactive oxygen species upon reoxidation by O2. CZM presumably competes with menaquinone (MK-4), a key cofactor in the mycobacterial electron transfer chain, for its reduction by NDH-2. ⋯ The synergy between CZM and PBTZ169 was lost in an MK-4-rich medium, indicating that MK-4 is the probable link between their activities. The efficacy of the dual combination of CZM and PBTZ169 was tested in vivo, where a great reduction in bacterial load was obtained in a murine model of chronic tuberculosis. Taken together, these data confirm the potential of CZM in association with PBTZ169 as the basis for a new regimen against drug-resistant strains of M. tuberculosis.
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Antimicrob. Agents Chemother. · Jul 2015
Clinical TrialFluconazole population pharmacokinetics and dosing for prevention and treatment of invasive Candidiasis in children supported with extracorporeal membrane oxygenation.
Candida infections are a leading cause of infectious disease-related death in children supported by extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics (PK); thus, standard fluconazole dosing may result in suboptimal drug exposures. The objective of our study was to determine the PK of fluconazole in children on ECMO. ⋯ The final model included the effect of serum creatinine (SCR) level on CL and the effect of ECMO on V as follows: CL (in liters per hour) = 0.019 × weight × (SCR/0.4)(-0.29) × exp(ηCL) and V (in liters) = 0.93 × weight × 1.4(ECMO) × exp(ηV). The fluconazole V was increased in children supported by ECMO. Consequently, children on ECMO require a higher fluconazole loading dose for prophylaxis (12 mg/kg of body weight) and treatment (35 mg/kg) paired with standard maintenance doses to achieve exposures similar to those of children not on ECMO.