Elimination of Doripenem during Dialysis and Pharmacokinetic Evaluation of Posthemodialysis Dosing for Patients Undergoing Intermittent Renal Replacement Therapy.

Doripenem is a broad-spectrum parenteral carbapenem with enhanced activity against Pseudomonas aeruginosa and Enterobacteriaceae Current dosing regimens recommend the administration of 0.25 to 0.5 g once daily in patients undergoing intermittent renal replacement therapy. As patients are usually dialyzed thrice weekly, we aimed to investigate a 1-g posthemodialysis regimen, thus reducing treatment costs and enhancing patient compliance. A second objective of this trial was to describe the pharmacokinetics of intradialytic doripenem. Ten oliguric or anuric patients in need of intermittent renal replacement therapy were included in this trial. All patients suffered from a septic episode. The mean hemofilter clearance was 123.46 ± 42.03 ml/min, and the total body clearance between hemodialysis sessions was 16.79 ± 6.02 ml/min. The average prehemodialysis trough concentration was 2.4 ± 1.3 mg/liter, while the EUCAST resistance breakpoint for Enterobacteriaceae is set at 2 mg/liter. The interpatient variability was considerably higher than the intrapatient variability. Apart from one patient who suffered an allergic reaction, doripenem was tolerated well by all patients. Our data indicate that posthemodialysis administration of 1 g of doripenem results in sufficient plasma levels in anuric but not oliguric patients during the entire dosing interval. (This trial was registered with EudraCT under registration no. 2009-018010-18 and at ClinicalTrials.gov under registration no. NCT02018939.).

Translational Pharmacometric Evaluation of Typical Antibiotic Broad-Spectrum Combination Therapies Against Staphylococcus Aureus Exploiting In Vitro Information.

Broad-spectrum antibiotic combination therapy is frequently applied due to increasing resistance development of infective pathogens. The objective of the present study was to evaluate two common empiric broad-spectrum combination therapies consisting of either linezolid (LZD) or vancomycin (VAN) combined with meropenem (MER) against Staphylococcus aureus (S. aureus) as the most frequent causative pathogen of severe infections. A semimechanistic pharmacokinetic-pharmacodynamic (PK-PD) model mimicking a simplified bacterial life-cycle of S. aureus was developed upon time-kill curve data to describe the effects of LZD, VAN, and MER alone and in dual combinations. The PK-PD model was successfully (i) evaluated with external data from two clinical S. aureus isolates and further drug combinations and (ii) challenged to predict common clinical PK-PD indices and breakpoints. Finally, clinical trial simulations were performed that revealed that the combination of VAN-MER might be favorable over LZD-MER due to an unfavorable antagonistic interaction between LZD and MER.

In vivo efficacy and pharmacokinetics of voriconazole in an animal model of dermatophytosis.

The standard treatment for tinea capitis caused by Microsporum species for many years has been oral griseofulvin, which is no longer universally marketed. Voriconazole has been demonstrated to inhibit growth of Microsporum canis in vitro. We evaluated the efficacy and tissue pharmacokinetics of oral voriconazole in a guinea pig model of dermatophytosis. Guinea pigs (n = 16) were inoculated with M. canis conidia on razed skin. Voriconazole was dosed orally at 20 mg/kg/day for 12 days (days 3 to 14). The guinea pigs were scored clinically (redness and lesion severity) and mycologically (microscopy and culture) until day 17. Voriconazole concentrations were measured day 14 in blood, skin biopsy specimens, and interstitial fluid obtained by microdialysis in selected animals. Clinically, the voriconazole-treated animals had significantly less redness and lower lesion scores than untreated animals from days 7 and 10, respectively (P < 0.05). Skin scrapings from seven of eight animals in the voriconazole-treated group were microscopy and culture negative in contrast to zero of eight animals from the untreated group at day 14. The colony counts per specimen were significantly higher in samples from untreated animals (mean colony count of 28) than in the voriconazole-treated animals (<1 in the voriconazole group [P < 0.0001]). The voriconazole concentration in microdialysate (unbound) ranged from 0.9 to 2.0 microg/ml and in the skin biopsy specimens total from 9.1 to 35.9 microg/g. In conclusion, orally administered voriconazole leads to skin concentrations greater than the necessary MICs for Microsporum and was shown to be highly efficacious in an animal model of dermatophytosis. Voriconazole may be a future alternative for treatment of tinea capitis in humans.