Dosing in obese critically ill patients is challenging due to pathophysiological changes derived from obesity and/or critical illness, and it remains fully unexplored. This study estimated the micafungin probability of reaching adequate 24-h area under the curve (AUC0–24h)/minimum inhibitory concentration (MIC) values against Candida spp. for an obese/nonobese, critically ill/noncritically ill, large population. Blood samples for pharmacokinetic analyses were collected from 10 critically ill nonobese patients, 10 noncritically ill obese patients, and 11 critically ill morbidly obese patients under empirical/directed micafungin treatment. Patients received once daily 100–150 mg micafungin at the discretion of the treating physician following the prescribing information and hospital guidelines. Total micafungin concentrations were determined by high-performance liquid chromatography (HPLC). Monte-Carlo simulations were performed and the probability of target attainment (PTA) was calculated using the AUC0–24/MIC cut-offs 285 (C. parapsilosis), 3000 (all Candida spp.), and 5000 (nonparapsilosis Candida spp.). Intravenous once-daily 100-mg, 150-mg, and 200-mg doses were simulated at different body weights (45, 80, 115, 150, and 185 kg) and age (30, 50, 70 and 90 years old). PTAs ≥ 90% were considered optimal. Fractional target attainment (FTA) was calculated using published MIC distributions. A dosing regimen was considered successful if the FTA was ≥ 90%. Overall, 100 mg of micafungin was once-daily administered for nonobese and obese patients with body mass index (BMI) ≤ 45 kg/m2 and 150 mg for morbidly obese patients with BMI > 45 kg/m2 (except two noncritically ill obese patients with BMI ~ 35 kg/m2 receiving 150 mg, and one critically ill patient with BMI > 45 kg/m2 receiving 100 mg). Micafungin concentrations in plasma were best described using a two-compartment model. Weight and age (but not severity score) were significant covariates and improved the model. FTAs > 90% were obtained against C. albicans with the 200 mg/24 h dose for all body weights (up to 185 kg), and with the 150 mg/24 h for body weights < 115 kg, and against C. glabrata with the 200 mg/24 h dose for body weights < 115 kg. The lack of adequacy for the 100 mg/24 h dose suggested the need to increase the dose to 150 mg/24 h for C. albicans infections. Further pharmacokinetic/pharmacodynamic studies should address optimization of micafungin dosing for nonalbicans Candida infections.

Objectives: In order to explore the pharmacodynamic need for continuous versus intermittent (three times a day) administration of ceftazidime in critically ill patients, a pharmacokinetic computerized device was used to simulate concentrations of ceftazidime in human serum after 6 g/day. Methods: Efficacy was measured as the capability of simulated concentrations over time to reduce initial inoculum against four strains of Pseudomonas aeruginosa. MICs of the strains matched NCCLS breakpoints: one susceptible strain (MIC=8 mg/L), two intermediate strains (MIC=16 mg/L) and one resistant strain (MIC=32 mg/L). C_max was 119.97±2.53 mg/L for intermittent bolus and C_ss (steady-state concentration) was 40.38±0.16 mg/L for continuous infusion. AUC_0–24 was similar for both regimens (∼950 mg·h/L). Inhibitory quotients were three times higher for the intermittent administration whereas t > MIC was higher for continuous infusion (100%) versus intermittent administration (99.8%, 69% and 47.6% for the susceptible, intermediate and resistant strains, respectively). Results: Against the susceptible and intermediate strains, no differences were found between both regimens with ≥ 3 log₁₀ reduction from 8 to 24 h. Against the resistant strain, only the continuous infusion achieved this bactericidal activity in the same time period, minimizing the differences between resistant and susceptible strains. Significantly higher initial inoculum reduction at 32 h was obtained for the continuous versus the intermittent administration (83.35% versus 38.40%, respectively). Conclusions: These results stress the importance of optimizing t >MIC, even at peri-MIC concentrations, of ceftazidime against resistant strains. Local prevalence of resistance justifies, on a pharmacodynamic basis, electing for continuous infusion versus intermittent administration.

Objectives: To compare different methods for the identification and determination of susceptibility to penicillin and methicillin of Staphylococcus lugdunensis. Methods: Seventeen clinical isolates of S. lugdunensis (identified by PCR amplification and sequencing of the rpoB gene) were studied using the ATB32-Staph, Crystal, Vitek 2 and Wider commercial systems. The clumping factor test and the tube coagulase test were also performed. β-Lactamase production was studied by chromogenic methods. Methicillin resistance was phenotypically studied by the MRSA slide latex agglutination test, growth in MRSA agar, and the Vitek 2 and Wider systems (based on oxacillin MIC), and genotypically studied by detection of the mecA gene by PCR. Results: The clumping factor test was negative in 35.3% of strains. All isolates were correctly identified to species level by the ATB32-Staph system. Species misidentification rates were 5.9%, 23.5% and 29.4% with the Crystal, the Vitek 2 and the Wider systems, respectively, mostly as Staphylococcus haemolyticus. β-Lactamase was present in 11.8% of strains. Whereas 76.5% and 47.1% of strains exhibited oxacillin resistance (MIC range 0.5–2 mg/L) by the Vitek 2 system and the Wider system, respectively, none of the strains was positive in the MRSA slide latex agglutination test or grew in MRSA agar. All strains lacked the mecA gene. Conclusions: The clumping factor test and some commercial systems may misidentify S. lugdunensis. Oxacillin resistance detected by commercial systems is not indicative of the presence of the mecA gene. These facts, together with β-lactamase production, may preclude adequate treatment of infections by this virulent coagulase-negative Staphylococcus.