RESUMO
BACKGROUND: Invasive aspergillosis is a severe fungal infection that affects multiple organ systems including the CNS and the lungs. Isavuconazole, a novel triazole antifungal agent, has demonstrated promising activity against Aspergillus spp. However, data on the penetration of isavuconazole into the CNS and ELF and intracellular accumulation remain limited. MATERIALS AND METHODS: We conducted a prospective single-centre pharmacokinetic (PK) study in 12 healthy volunteers. Subjects received seven doses of 200â mg isavuconazole to achieve an assumed steady-state. After the first and final infusion, plasma sampling was conducted over 8 and 12â h, respectively. All subjects underwent one lumbar puncture and bronchoalveolar lavage, at either 2, 6 or 12â h post-infusion of the final dose. PBMCs were collected in six subjects from blood to determine intracellular isavuconazole concentrations at 6, 8 or 12â h. The AUC/MIC was calculated for an MIC value of 1â mg/L, which marks the EUCAST susceptibility breakpoint for Aspergillus fumigatus and Aspergillus flavus. RESULTS: C max and AUC0-24h of isavuconazole in plasma under assumed steady-state conditions were 6.57â±â1.68â mg/L (meanâ±âSD) and 106â±â32.1â h·mg/L, respectively. The average concentrations measured in CSF, ELF and in PBMCs were 0.07â±â0.03, 0.94â±â0.46 and 27.1â±â17.8â mg/L, respectively. The AUC/MIC in plasma, CSF, ELF and in PBMCs under steady-state conditions were 106â±â32.1, 1.68â±â0.72, 22.6â±â11.0 and 650â±â426â mg·h/L, respectively. CONCLUSION: Isavuconazole demonstrated moderate penetration into ELF, low penetrability into CSF and high accumulation in PBMCs. Current dosing regimens resulted in sufficient plasma exposure in all subjects to treat isolates with MICsâ≤â1â mg/L.
RESUMO
Invasive Staphylococcus aureus infections are associated with a high burden of disease, case fatality rate and healthcare costs. Oxazolidinones such as linezolid and tedizolid are considered potential treatment choices for conditions involving methicillin resistance or penicillin allergies. Additionally, they are being investigated as potential inhibitors of toxins in toxin-mediated diseases. In this study, linezolid and tedizolid were evaluated in an in vitro resistance development model for induction of resistance in S. aureus. Whole genome sequencing was conducted to elucidate resistance mechanisms through the identification of causal mutations. After inducing resistance to both linezolid and tedizolid, several partially novel single nucleotide variants (SNVs) were detected in the rplC gene, which encodes the 50S ribosome protein L3 in S. aureus. These SNVs were found to decrease the binding affinity, potentially serving as the underlying cause for oxazolidinone resistance. Furthermore, in opposite to linezolid we were able to induce phenotypically small colony variants of S. aureus after induction of resistance with tedizolid for the first time in literature. In summary, even if different antibiotic concentrations were required and SNVs were detected, the principal capacity of S. aureus to develop resistance to oxazolidinones seems to differ between linezolid and tedizolid in-vivo but not in vitro. Stepwise induction of resistance seems to be a time and cost-effective tool for assessing resistance evolution. Inducted-resistant strains should be examined and documented for epidemiological reasons, if MICs start to rise or oxazolidinone-resistant S. aureus outbreaks become more frequent.