Comparison of Antimycotic Activity of Originator and Generics of Voriconazole and Anidulafungin against Clinical Isolates of Candida albicans and Candida glabrata.

BACKGROUND: Concerns have been expressed about the interchangeability of innovator and generic antifungals in their activity and chemical stability. MATERIALS/METHODS: The activity of two different antimycotics was tested, each with one originator and two generics. For voriconazole, the originator VFEND® (Pfizer) and the generics (Ratiopharm and Stada) were used for susceptibility testing (21 clinical isolates of Candida albicans (C. albicans); ATCC-90028 C. albicans) in RPMI growth media in compliance with the EUCAST criteria. Likewise, for anidulafungin, the originator ECALTA® (Pfizer) and the generics (Stada and Pharmore) were used for testing (20 clinical isolates of Candida glabrata (C. glabrata); ATCC-22019 Candida parapsilosis (C. parapsilosis)). Time Kill Curves (TKC) with concentrations above and below the respective MIC were performed for one strain for each antifungal. Stability testing of the antimycotics stored at 4 °C and at room temperature over 24 h was done, and samples were subsequently analyzed with HPLC. RESULTS: MIC results showed no significant difference in activity of generic and innovator antimycotic in all settings, which was also confirmed by TKC. Stability testing revealed no differences between originator and generic drugs. CONCLUSIONS: The present study demonstrates the interchangeability of generic and originator antimycotic in-vitro, potentially leading to broader public acceptance for generic antimycotics.

Human tissue distribution of caspofungin.

Tissue concentrations of caspofungin were determined in nine clinically relevant tissues taken during routine autopsy of 20 patients who had died during caspofungin treatment or within 23 days of cessation. The highest levels were achieved in liver, with concentrations ranging from ≤0.50 to 91.5 µg/g (0.60 µg/g 21 days after the last administration), followed by spleen (<0.25-46.3 µg/g), kidney (<0.25-33.6 µg/g) and lung (<0.25-31.0 µg/g). Intermediate concentrations were found in pancreas, skeletal muscle, thyroid and myocardium. The lowest concentrations were found in brain; caspofungin was only detectable in six of 17 samples. Caspofungin concentrations exceeded the minimum inhibitory concentration values of pathogenic Candida spp. in most of the tissue samples taken from patients who had died during treatment, except in brain samples. These findings warrant clinical outcome studies to establish the optimal treatment for deep-seated candidiasis, and support the current recommendations against echinocandins for treatment of fungal meningoencephalitis.

Pharmacokinetics and Antifungal Activity of Echinocandins in Ascites Fluid of Critically Ill Patients.

The pharmacokinetics and antifungal activity of the echinocandins anidulafungin (AFG), micafungin (MFG), and caspofungin (CAS) were assessed in ascites fluid and plasma of critically ill adults treated for suspected or proven invasive candidiasis. Ascites fluid was obtained from ascites drains or during paracentesis. The antifungal activity of the echinocandins in ascites fluid was assessed by incubation of Candida albicans and Candida glabrata at concentrations of 0.03 to 16.00 µg/ml. In addition, ascites fluid samples obtained from our study patients were inoculated with the same isolates and evaluated for fungal growth. These patient samples had to be spiked with echinocandins to restore the original concentrations because echinocandins had been lost during sterile filtration. In ascites fluid specimens of 29 patients, echinocandin concentrations were below the simultaneous plasma levels. Serial sampling in 20 patients revealed a slower rise and decline of echinocandin concentrations in ascites fluid than in plasma. Proliferation of C. albicans in ascites fluid was slower than in culture medium and growth of C. glabrata was lacking, even in the absence of antifungals. In CAS-spiked ascites fluid samples, fungal CFU counts moderately declined, whereas spiking with AFG or MFG had no relevant effect. In ascites fluid of our study patients, echinocandin concentrations achieved by therapeutic doses did not result in a consistent eradication of C. albicans or C. glabrata. Thus, therapeutic doses of AFG, MFG, or CAS may result in ascites fluid concentrations preventing relevant proliferation of C. albicans and C. glabrata, but do not warrant reliable eradication.

Penetration of echinocandins into wound secretion of critically ill patients.

PURPOSE: Wound infections caused by Candida are life-threatening and difficult to treat. Echinocandins are highly effective against Candida species and recommended for treatment of invasive candidiasis. As penetration of echinocandins into wounds is largely unknown, we measured the concentrations of the echinocandins anidulafungin (AFG), micafungin (MFG), and caspofungin (CAS) in wound secretion (WS) and in plasma of critically ill patients. METHODS: We included critically ill adults with an indwelling wound drainage or undergoing vacuum-assisted closure therapy, who were treated with an echinocandin for suspected or proven invasive fungal infection. Concentrations were measured by liquid chromatography with UV (AFG and MFG) or tandem mass spectrometry detection (CAS). RESULTS: Twenty-one patients were enrolled. From eight patients, serial WS samples and simultaneous plasma samples were obtained within a dosage interval. AFG concentrations in WS amounted to < 0.025-2.25 mg/L, MFG concentrations were 0.025-2.53 mg/L, and CAS achieved concentrations of 0.18-4.04 mg/L. Concentrations in WS were significantly lower than the simultaneous plasma concentrations and below the MIC values of some relevant pathogens. CONCLUSION: Echinocandin penetration into WS displays a high inter-individual variability. In WS of some of the patients, concentrations may be sub-therapeutic. However, the relevance of sub-therapeutic concentrations is unknown as no correlation has been established between concentration data and clinical outcome. Nevertheless, in the absence of clinical outcome studies, our data do not support the use of echinocandins at standard doses for the treatment of fungal wound infections, but underline the pivotal role of surgical debridement.

Human Tissue Distribution of Anidulafungin and Micafungin.

Concentrations of anidulafungin and micafungin were determined in eight different tissues obtained during autopsy of four deceased individuals who had been treated with anidulafungin and of seven who had received micafungin. The largest amounts were recovered from liver, with anidulafungin concentrations of 11.01 to 66.50 µg/g and micafungin levels of 0.36 to 5.53 µg/g (0.65 µg/g 30 days after the last administration). The lowest anidulafungin levels were measured in skeletal muscle, and the lowest micafungin concentrations were in kidneys.

Anidulafungin and Micafungin Concentrations in Cerebrospinal Fluid and in Cerebral Cortex.

Anidulafungin and micafungin were quantified in cerebrospinal fluid (CSF) of critically ill adults and in cerebral cortex of deceased patients. In CSF, anidulafungin levels (<0.01 to 0.66 µg/ml) and micafungin levels (<0.01 to 0.16 µg/ml) were lower than those in plasma concentrations (0.77 to 5.07 and 1.21 to 8.70 µg/ml, respectively) drawn simultaneously. In cerebral cortex, anidulafungin and micafungin levels were 0.21 to 2.34 and 0.18 to 2.88 µg/g, respectively. Thus, MIC values of several pathogenic Candida strains exceed concentrations in CSF and in brain.

Pharmacokinetics of trimethoprim/sulfametrole in critically ill patients on continuous renal replacement therapy.

OBJECTIVES: We investigated the effect of continuous renal replacement therapy (CRRT) on the pharmacokinetics of trimethoprim and sulfametrole. PATIENTS AND METHODS: We enrolled critically ill adults undergoing CRRT and critically ill adults with normal or slightly impaired renal function (plasma creatinine concentration <1.5 mg/dL, control group). All patients received trimethoprim/sulfametrole at standard doses. Pharmacokinetics were determined after the first dose and at steady-state. In addition, a population pharmacokinetic model using plasma data was built. We also assessed the renal clearance (CLR) and the extracorporeal clearance in patients undergoing CRRT. RESULTS: Twelve patients were enrolled in the CRRT group and 12 patients in the control group. There was no statistically significant difference in trimethoprim pharmacokinetics between the two groups. In patients on CRRT, total plasma clearance (CLtot) and V of sulfametrole were significantly higher than in the control group. However, sulfametrole exposure was not significantly altered during CRRT. The population pharmacokinetic analysis indicated that neither CRRT intensity nor residual diuresis were significant covariates on trimethoprim or sulfametrole CL. Median CL by continuous venovenous haemofiltration accounted for about one-third of CLtot of trimethoprim and for about one-half of CLtot of sulfametrole. In patients on CRRT, CLR of trimethoprim and sulfametrole were <5% of CLtot. CONCLUSIONS: During CRRT, standard doses of trimethoprim/sulfametrole appear to be adequate.