Antimicrobial Agents and Chemotherapy最新文献

Candidemia and invasive candidiasis persist as significant causes of morbidity and mortality. As fluconazole resistance rates rise, alternative means of treatment are necessary, either via mold-active azoles or extended durations of echinocandins. These come with the potential for undesirable side effects for triazoles or choosing between prolonged hospitalization or outpatient parenteral antimicrobial therapy in the case of echinocandins. Rezafungin offers an opportunity to manage extended treatment durations with shorter hospital stays and no extended parenteral access. Herein, we review the most recent published data pertaining to rezafungin including anti-fungal activity, pharmacokinetics, and clinical data relating to the treatment of invasive candidiasis. Given its prolonged half-life allowing for once-weekly dosing, rezafungin has the potential as an anti-fungal prophylactic agent in high-risk patients, and studies to examine this potential role are ongoing.

Persons with CF (pwCF) present altered pharmacokinetics (PK) and are often infected with multidrug-resistant (MDR) bacteria. Herein, we describe the PK of cefiderocol, a siderophore cephalosporin with potent activity against MDR Gram-negative rods, in hospitalized adult pwCF with acute pulmonary exacerbation (APE). PwCF received ≥3 doses of 2 g cefiderocol (3 h infusion) with frequency determined according to their estimated glomerular filtration rate (eGFR). Blood sampling collected at steady state. Concentrations were fitted using the non-parametric adaptive grid algorithm in Pmetrics for R. Ten pwCF were enrolled; nine completed the study with six receiving 2 g q8 h and three 2 g q6 h. A two-compartment model best fitted the data. Mean (SD) PK parameters were clearance, 5.66 (1.28) L/h; volume of central compartment, 5.81 (3.52) L, and intercompartment transfer constants, k12, 4.29 (3.46) and k21, 2.25 (2.76) h^-1. Protein binding was 48% (35-57). The 2 g q8 h regimen achieved a mean free time above the MIC (fT >MIC) of 99% (94-99), 90% (69-100), and 64% (41-81) at MICs of 4 (susceptible), 8 (intermediate), and 16 (resistant) mg/L, respectively, with AUC_24h of 1,191 (781-1,496) mg/L*h. In pwCF with eGFR >120 mL/min, 2 g q6 h attained 100% fT >MIC up to 8 mg/L and 87% (83-92) at 16 mg/L, with AUC_24h of 1,279 (1,054-1,590) mg/L*h. Among these nine pwCF with APE with normal or augmented renal clearance, cefiderocol using label prescribed dosing regimens according to eGFR was well tolerated and achieved optimal fT >MIC exposure for pathogens up to MICs of 8 mg/L and AUC_24h estimates similar to previously reported estimates in non-CF patients.

We evaluated the in vitro activity of olorofim against Coccidioides species. Olorofim demonstrated potent in vitro activity against all isolates tested with a minimum inhibitory concentration (MIC) range ≤0.008-0.06 µg/mL and geometric mean MIC of 0.010 µg/mL. This activity was also maintained against isolates with elevated fluconazole MICs (≥16 µg/mL), including strains with MICs ≥32 µg/mL (olorofim MIC range ≤0.008-0.06 µg/mL and geometric mean MICs of ≤0.009 and ≤0.013 µg/mL, respectively).

The multidrug-resistant Acinetobacter baumannii clonal complex 92 is spreading worldwide due to its high-frequency gene mutation and recombination, posing a significant threat to global medical and health safety. Between November 2021 and April 2022, a total of 132 clinical A. baumannii isolates were collected from a tertiary hospital in China. Their growth ability and virulence of these isolates were assessed using growth curve analyses and the Galleria mellonella infection model. The genetic characteristics of the isolates were further examined through whole-genome sequencing. ST1791^O/ST2^P isolates represented the largest proportion of isolates in our collection and exhibited the highest growth rate and strongest virulence among all sequence types (STs) analyzed. Whole-genome sequences from 14,159 clinical isolates were collected from the National Center for Biotechnology Information database, and only nine ST1791^O/ST2^P isolates were detected. Comparative genomic analysis revealed that ST1791^O/ST2^P carried 11 unique genes, 5 of which were located within the capsular polysaccharide synthesis (cps) gene cluster. Single nucleotide polymorphisms (SNPs) between ST1791^O/ST2^P and other isolates were primarily found in the cps gene cluster. Among the other isolates, ST195^O/ST2^P and ST208^O/ST2^P exhibited the smallest SNP differences from ST1791^O/ST2^P, while ST195^O/ST2^P and ST1486^O/ST2^P had high homology. The ST1791^O/ST2^P strain in Anhui, China, displayed significant homology with ST195^O/ST2^P, ST208^O/ST2^P, and ST1486^O/ST2^P isolates. Compared to other isolates in this study, ST1791^O/ST2^P exhibited strong growth ability and virulence. Therefore, preventing the further spread of ST1791^O/ST2^P should be a top public health priority.

BRII-693 is a next-generation intravenous (IV)-administered synthetic macrocyclic peptide antibiotic for infections caused by drug-resistant gram-negative pathogens. This single-center, randomized, double-blind, placebo-controlled phase 1 study investigated the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending doses of BRII-693 in 104 healthy participants. In single-dose cohorts, 10-400 mg of BRII-693 was evaluated in eight participants (six active; two placebo) per cohort. In the 7-day repeat-dose cohorts, 100-200 mg of BRII-693 was evaluated in eight participants (six active; two placebo) per cohort. In two 14-day repeat-dose cohorts, 150 mg of BRII-693 was evaluated in 12 participants (10 active, two placebo) each of non-Chinese and Chinese descent. No participant reported a severe or serious adverse event (AE) or an AE leading to death. Across all cohorts and for non-Chinese and Chinese participants, most AEs were mild. C_max and area under the concentration-time curve (AUC) increased in a dose-proportional manner over the dose range of single- and repeat-dosing. Mean t_1/2 was 2.58-4.37 hours and generally similar across single doses. An accumulation of exposure was observed following multiple doses with an accumulation ratio of 1.5 to 1.7 which was within the expected 1.3 to 2.5 range at steady state. Mean total clearance (CL) was similar between single and multiple dose administration, suggesting time-independent pharmacokinetics (PK). PK exposure was statistically equivalent between non-Chinese and Chinese participants. This phase 1 study demonstrates a favorable safety, tolerability, and PK profile of BRII-693 in healthy non-Chinese and Chinese participants.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04808414.

Antibiotic resistance has become a critical concern in recent years, and antimicrobial peptides may function as innovative antibacterial agents to address this issue. In this work, we identified a novel antimicrobial peptide, LC-AMP-I1, derived from the venom of Lycosa coelestis, demonstrating substantial antibacterial properties and minimal hemolytic activity. LC-AMP-I1 was subjected to additional assessment for antibacterial efficacy, anti-biofilm properties, drug resistance, stability, and cytotoxicity in vitro. It exhibited comparable antibacterial efficacy to melittin against six common clinical multidrug-resistant bacteria, effectively inhibiting biofilm formation and disrupting established biofilms. Additionally, LC-AMP-I1 demonstrated minimal bacterial resistance, excellent stability, negligible mammalian cell toxicity, low hemolytic activity, and appropriate selectivity for both normal and tumor cells. When combined with traditional antibiotics, LC-AMP-I1 exhibited additive or synergistic therapeutic effects. In a neutropenic mouse thigh infection model, LC-AMP-I1 exhibited a therapeutic effect in inhibiting bacterial proliferation in vivo. The mechanistic investigation indicated that LC-AMP-I1 could influence bacterial cell membrane permeability at low concentrations and directly disrupt structure-function at high concentrations. The results of this work indicate that LC-AMP-I1 may function as a viable alternative to traditional antibiotics in addressing multidrug-resistant bacteria.

Sulbactam-durlobactam is a β-lactam/β-lactamase inhibitor combination approved in the United States for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus in adults. A population pharmacokinetic (PK) model of sulbactam-durlobactam in plasma was developed using data from eight Phase 1-3 studies. A total of 432 subjects and 8,100 plasma concentrations were available for the population PK data set. The combined model was a four-compartment (two compartments per drug) model with linear kinetics. Both renal clearance and nonrenal clearance were estimated, and total clearance was calculated as the sum of renal and nonrenal clearance. Individual renal clearances were scaled by baseline creatinine clearance. The sampling-importance-resampling analysis indicated that the parameters were estimated reliably with adequate precision. Hemodialysis (HD) and epithelial lining fluid (ELF) sub-models were developed for each analyte separately. Intermittent HD resulted in an approximately 30% decrease in the daily area under the concentration-time curve (AUC_0-24) when HD was started 1 hour after the end of the infusion. Assuming protein binding estimates of 10% and 38% for durlobactam and sulbactam, respectively, ELF penetration ratios were found to be 41.3% for durlobactam and 86.0% for sulbactam. Of the statistically significant covariates of PK identified, which included body weight, body mass index, infection type, and region of origin, renal function was the only clinically relevant covariate. Overall, a robust description of the plasma PK of sulbactam and durlobactam was achieved. The resultant population PK model was expected to be appropriate for model-based simulations and assessment of pharmacokinetic-pharmacodynamic relationships.

Sulbactam-durlobactam is approved for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex. Patients with serious Acinetobacter infections may require support with continuous renal replacement therapy (CRRT), which presents challenges for optimal dosing of antibiotics. Sulbactam-durlobactam dosing regimens were derived for this population using an ex vivo CRRT model and Monte Carlo simulation (MCS). Transmembrane clearance (CL_TM) was determined in hemofiltration (CVVH) and hemodialysis (CVVHD) modes using the Prismaflex M100 and HF1400 hemofilter sets and with effluent rates of 1, 2, and 3 L/h. Pre-filter, post-filter blood, and effluent samples were collected over 60 min to calculate sieving (SC) and saturation (SA) coefficients for CVVH and CVVHD, respectively. An established population pharmacokinetic model was integrated with the CL_TM; then, a 1,000 patient MCS was conducted to determine exposures of potential dosing regimens. Adsorption and degradation in the ex vivo CRRT model were negligible. The overall mean ± standard deviation SC/SA was 1.14 ± 0.12 and 0.93 ± 0.08 for sulbactam and durlobactam, respectively. In multivariable regression analyses, effluent rate was the primary driver of CL_TM for both drugs. For effluent rates <3 L/h, sulbactam-durlobactam 1 g-1g q8h as 3 h infusion achieved a high probability of pharmacodynamic target attainment while retaining area under the curve exposures consistent with the standard dose in non-CRRT patients. For effluent rates ≥3 to 5 L/h, the optimal regimen was 1 g-1g q6h 3 h infusion. Sulbactam-durlobactam regimens that provide optimum drug exposures for efficacy and safety were identified for CRRT based on the prescribed effluent rate.

The global rise of carbapenem-resistant Klebsiella pneumoniae, including strains producing K. pneumoniae carbapenemase (KPC) types, poses a significant public health challenge due to their resistance to critical antibiotics. Treatment options for infections caused by KPC-producing K. pneumoniae (KPC-KP) are increasingly limited, particularly as these strains develop resistance to last-line antibiotics such as ceftazidime/avibactam and colistin. This study investigates the evolution of antibiotic resistance and persistence in a series of clonally related ST11 KPC-KP strains isolated from a single patient undergoing extended antimicrobial treatment. The patient, a 47-year-old male with a history of kidney transplantation, developed multiple KPC-KP lung infections during his hospital stay. Resistance to colistin and ceftazidime/avibactam emerged during treatment with these antibiotics. Key resistance mechanisms identified included the integration of ISKpn26 into mgrB gene, leading to mgrB inactivation and colistin resistance, and the emergence of novel bla_KPC-2 variants (bla_KPC-71 and bla_KPC-179) that confer resistance to ceftazidime/avibactam. Despite the development of colistin resistance in a ceftazidime/avibactam-resistant KPC-KP strain following combination therapy, the patient's clinical condition significantly improved. Phenotypic assays showed that mgrB disruption in KPC-KP resulted in increased biofilm formation and higher susceptibility to phagocytosis. In mouse models, KPC-KP strains with mgrB disruption showed reduced virulence, increased lung colonization and persistence, and a lower inflammatory response, suggesting that mgrB disruption facilitates the transition from acute infection to colonization. This study highlights the complex interplay between antibiotic resistance and bacterial fitness, offering insights into why some patients experience clinical improvement despite severe drug resistance and incomplete bacterial clearance.

Plasmids containing the wild-type (WT) or mutant type A blaZ (blaZ_A) gene (mutations at codons 226, 229, or both 226 and 229) were constructed and transformed into Staphylococcus aureus RN4220, yielding the strains WT-blaZ, M226-blaZ, M229-blaZ, and MB-blaZ. The high-inoculum cefazolin MIC was significantly lower in MB-blaZ and M226-blaZ than in WT-blaZ but not in M229-blaZ, suggesting that the single nucleotide polymorphism at codon 226 in blaZ_A contributes to the cefazolin inoculum effect.