RESUMO
Cefiderocol, a novel siderophore cephalosporin, demonstrates promising in vitro activity against multidrug-resistant Gram-negative bacteria, including carbapenemase-producing strains. Nonetheless, only a few reports are available regarding the acquisition of resistance in clinical settings, primarily due to its recent usage. This study aimed to investigate cefiderocol resistance using an in vitro resistance development model to gain insights into the underlying molecular resistance mechanisms. Cefiderocol susceptible reference strains (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa) and a clinical Acinetobacter baumannii complex isolate were exposed to increasing cefiderocol concentrations using a high-throughput resistance development model. Cefiderocol susceptibility testing was performed using broth microdilution. Whole-genome sequencing was employed to identify newly acquired resistance mutations. Our in vitro resistance development model led to several clones of strains exhibiting cefiderocol resistance, with MIC values 8-fold to 512-fold higher than initial levels. In total, we found 42 different mutations in 26 genes, of which 35 could be described for the first time. Putative loss-of-function mutations were detected in the envZ, tonB, and cirA genes in 13 out of 17 isolates, leading to a decrease in cefiderocol influx. Other potential resistance mechanisms included multidrug efflux pumps (baeS, czcS, nalC), antibiotic-inactivating enzymes (ampR, dacB), and target mutations in penicillin-binding-protein genes (mrcB). This study reveals new insights into underlying molecular resistance mechanisms against cefiderocol. While mutations leading to reduced influx via iron transporters was the most frequent resistance mechanism, we also detected several other novel resistance mutations causing cefiderocol resistance.
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 200 mg isavuconazole to achieve an assumed steady-state. After the first and final infusion, plasma sampling was conducted over 8 and 12 h, respectively. All subjects underwent one lumbar puncture and bronchoalveolar lavage, at either 2, 6 or 12 h post-infusion of the final dose. PBMCs were collected in six subjects from blood to determine intracellular isavuconazole concentrations at 6, 8 or 12 h. The AUC/MIC was calculated for an MIC value of 1 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±â1.68 mg/L (meanâ±âSD) and 106â±â32.1 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±â17.8 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±â426 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≤â1 mg/L.
Assuntos
Antifúngicos , Voluntários Saudáveis , Nitrilas , Piridinas , Triazóis , Humanos , Triazóis/farmacocinética , Triazóis/administração & dosagem , Piridinas/farmacocinética , Piridinas/administração & dosagem , Antifúngicos/farmacocinética , Antifúngicos/administração & dosagem , Masculino , Adulto , Nitrilas/farmacocinética , Nitrilas/administração & dosagem , Estudos Prospectivos , Feminino , Infusões Intravenosas , Adulto Jovem , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Aspergillus fumigatus/efeitos dos fármacos , Aspergillus flavus/efeitos dos fármacos , Líquido da Lavagem Broncoalveolar/química , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/efeitos dos fármacosRESUMO
BACKGROUND: Linezolid exposure in critically ill patients is associated with high inter-individual variability, potentially resulting in subtherapeutic antibiotic exposure. Linezolid exhibits good penetration into the CSF, but its penetration into cerebral interstitial fluid (ISF) is unknown. OBJECTIVES: To determine linezolid penetration into CSF and cerebral ISF of neurointensive care patients. PATIENTS AND METHODS: Five neurocritical care patients received 600â mg of linezolid IV twice daily for treatment of extracerebral infections. At steady state, blood and CSF samples were collected from arterial and ventricular catheters, and microdialysate was obtained from a cerebral intraparenchymal probe. RESULTS: The median fAUC0-24 was 57.6 (24.9-365)â mg·h/L in plasma, 64.1 (43.5-306.1)â mg·h/L in CSF, and 27.0 (10.7-217.6)â mg·h/L in cerebral ISF. The median penetration ratio (fAUCbrain_or_CSF/fAUCplasma) was 0.5 (0.25-0.81) for cerebral ISF and 0.92 (0.79-1) for CSF. Cerebral ISF concentrations correlated well with plasma (R = 0.93, P < 0.001) and CSF levels (R = 0.93, P < 0.001).The median fAUC0-24/MIC ratio was ≥100 in plasma and CSF for MICs of ≤0.5â mg/L, and in cerebral ISF for MICs of ≤0.25â mg/L. The median fT>MIC was ≥80% of the dosing interval in CSF for MICs of ≤0.5â mg/L, and in plasma and cerebral ISF for MICs of ≤0.25â mg/L. CONCLUSIONS: Linezolid demonstrates a high degree of cerebral penetration, and brain concentrations correlate well with plasma and CSF levels. However, substantial variability in plasma levels, and thus cerebral concentrations, may result in subtherapeutic tissue concentrations in critically ill patients with standard dosing, necessitating therapeutic drug monitoring.