Journal of Antimicrobial Chemotherapy最新文献

Objectives: The objective of this study was to identify and analyse the distribution characteristics, toxin genotyping and antimicrobial susceptibility of Clostridium perfringens and to investigate its resistance mechanisms and genetic characteristics.

Methods: The MICs of various antibiotics against C. perfringens were determined using the agar dilution method, and resistance genes and toxin genotypes were detected by PCR. Genetic relationships were analysed using MLST. WGS was conducted on the DNB system and PacBio platforms.

Results: Analysis of 36 strains of C. perfringens revealed that the major toxin types were types C and F, with 86.1% of the strains isolated from bile samples. Of these, 30.6% of the strains exhibited MDR, with resistance rates of 75.0%, 52.8% and 52.8% for penicillin, clindamycin and ampicillin, respectively; however, no resistance to metronidazole and carbapenems was observed. MLST analysis identified 29 STs, including 14 novel types. ST221 and ST498 were the dominant types. The WGS revealed that the most prevalent virulence factors are plc (100.0%), nagH (100.0%), colA (100.0%), nanJ (100.0%), entB (100%), nanH (97.0%), entA (97.0%) and nanI (90.9%). Among these factors, the primary determinants of tetracycline resistance are tetA (66.7%) and tetB (78.8%), which represent the most frequently detected antibiotic resistance genes.

Conclusions: This study indicates that the infection rate of C. perfringens is relatively high, with the majority of isolated strains exhibiting MDR. The observed high levels of antibiotic resistance, combined with the significant genetic diversity of these strains, suggest a potential public health risk.

Background: Scedosporium/Lomentospora species are ranked as the second most frequently isolated filamentous fungi from cystic fibrosis (CF) patients. Previously, we demonstrated that the minimum inhibitory concentration (MIC) for voriconazole and posaconazole increased when performed on a mucin-containing synthetic CF sputum medium (SCFM) compared to the standard medium, RPMI-1640. In this study, we have expanded the MIC comparison to four additional azoles and investigated characteristics linked to azole resistance in Scedosporium apiospermum, Scedosporium minutisporum, Scedosporium aurantiacum and Lomentospora prolificans.

Methods: MIC was assayed by CLSI protocol, efflux pump activity was assessed by rhodamine 6G and sterols were analysed by gas chromatography-mass spectrometry (GC-MS).

Results: Overall, MICs for fluconazole, itraconazole, voriconazole, posaconazole, miconazole and ketoconazole increased by least 2-fold when susceptibility tests were performed using SCFM compared to RPMI. The activity of efflux pumps was similar in both media; however, in RPMI, but not in SCFM, the activity was induced by voriconazole and fluconazole. Additionally, MICs for those antifungals decreased more noticeably in SCFM than in RPMI in the presence of the efflux pump inhibitor PaβN. The SCFM-grown cells presented fewer sterols in their composition, and consequently higher membrane fluidity, than RPMI-grown cells. GC-MS analysis demonstrated a remodulation in the sterol profile in SCFM- compared to RPMI-grown cells. Accordingly, when the MIC assay was performed in the presence of the membrane stressor NaCl (3%), the susceptibility to voriconazole and fluconazole increased more in SCFM- than RPMI-grown cells.

Conclusions: Scedosporium/Lomentospora species undergo cellular adaptations in SCFM that favours their growth in face of the challenges imposed by azole antifungals.

Objectives: To evaluate clinical impact of ceftazidime/avibactam on treating infections due to MDR Gram-negative bacteria in patients with haematological malignancies (HMs).

Methods: We conducted a retrospective, observational study at 17 Italian haematological wards that included patients with HMs receiving ceftazidime/avibactam for the treatment of suspected or proven infections. The primary endpoint was all-cause mortality 30 days after infection onset. Secondary endpoints included the development of in vitro ceftazidime/avibactam resistance, adverse reactions and infection relapse.

Results: Of 198 patients enrolled, 66 had fever of unknown origin and 132 had microbiologically proven infections (MPIs). Enterobacterales were responsible for 98 MPIs, with KPC producers accounting for 75% of these, and carbapenem-resistant Pseudomonas aeruginosa caused 25% of MPIs. The overall 30-day mortality rate was 17.7%. Infection relapse occurred in four patients with MPI. Patients who died within 30 days of infection onset tended to have pre-existing cerebrovascular diseases, a Charlson Comorbidity Index > 4 and septic shock at infection onset and had received inadequate initial antibiotic therapy. Thirty-day mortality was independently associated with septic shock at infection onset and inappropriate initial antibiotic therapy.

Conclusions: Our study provides further evidence about the effectiveness of ceftazidime/avibactam in treating infections in patients with HMs.

Echinocandin drugs are the current first-line therapy for fungal infections caused by Candida spp. Most patients require once-daily intravenous (IV) administration in a hospital or outpatient setting for treatment, which may negatively impact their quality of life and stress healthcare resources. Similar to other echinocandins, the novel FDA-, EMA-, and Medical and Healthcare Products Regulatory Agency-approved echinocandin, rezafungin (CD101), exhibited strong antifungal activity against several fungal pathogens and a low drug-drug interaction liability, which are important for medically complex patients. A pharmacometric-based approach has been adopted throughout the development of rezafungin, which contrasts with older echinocandins where dosing regimens were largely derived empirically, and only recently based on pharmacometric guidance. This state-of-the-art approach used model-based simulations incorporating pre-clinical and clinical data as it became available to optimize the dosing regimen for rezafungin. The enhanced stability of the molecular structure and the safety profile of rezafungin allow for the administration of once-weekly IV doses, compared to the daily dosing requirement for other echinocandin drugs, with this distinctive pharmacokinetic profile of rezafungin resulting in a front-loaded dosing regimen with high exposures early in therapy for enhanced fungal killing. The long shelf-life of rezafungin makes this echinocandin more flexible in terms of storage and manufacturing. Demonstrated across clinical development, rezafungin may provide patients with next-generation first-line antifungal treatment for the treatment of candidaemia and invasive candidiasis.

Objective: To explore whether vancomycin plus piperacillin/tazobactam actually increases nephrotoxicity compared with other anti-pseudomonal beta-lactams (BLs).

Methods: PubMed, Embase, Web of Science, Cochrane, CNKI, Wanfang and VIP were searched from inception to October 2023. The primary outcomes were acute kidney injury (AKI) as defined as acute increase in serum creatinine of 0.3 mg/dL or 50% and severe Stage 2-3 AKI.

Results: We included 70 studies (76 638 patients). Network meta-analysis indicated that vancomycin plus piperacillin/tazobactam was associated with significantly higher AKI risk than vancomycin plus cefepime (OR 2.55, 95% CI 2-3.28), vancomycin plus meropenem (OR 2.26, 95% CI 1.71-3.02) and vancomycin plus other uncommonly used BLs (OR 2.47, 95% CI 1.87-3.29). Also, vancomycin + piperacillin/tazobactam was associated with significantly higher Stage 2-3 AKI risk than vancomycin + cefepime (OR 2.22, 95% CI 1.34-3.62), vancomycin + meropenem (OR1.96, 95% CI 1.22-3.25) and vancomycin + uncommonly used BLs (OR 2.81, 95% CI 1.66-4.91). Vancomycin plus piperacillin/tazobactam did not result in a significant difference in the incidence of receiving dialysis treatment, mortality, length of stay and time to AKI. Subgroup analyses of studies conducting propensity score matching demonstrated vancomycin + piperacillin/tazobactam was associated with significantly higher AKI rates than vancomycin + cefepime (OR 2.19, 95% CI 1.38-3.47) and vancomycin + meropenem (OR 1.38, 95% CI. 1.18-1.60). Subgroup analysis of critically ill patients and children indicated that vancomycin + piperacillin/tazobactam was associated with significantly higher AKI rates.

Conclusions: Vancomycin + piperacillin/tazobactam significantly increased the risk of AKI and severe Stage 2-3 AKI compared with vancomycin plus other BLs. More prospective studies are needed.

Background: Pneumocystis jirovecii pneumonia (PcP) is an opportunistic infection for which the standard of care is co-trimoxazole. However, safety concerns and intolerance may compromise its utility.

Objectives: To evaluate the safety and efficacy of the combination of echinocandins and clindamycin to treat PcP.

Patients and methods: We investigated 14 patients treated with a co-trimoxazole-free combined regimen that included echinocandins and clindamycin.

Results: Clinical cure was achieved in 8 out of 14 patients, while 5 had a fatal outcome due to their primary disease; however, only one patient died due to PcP.

Conclusions: Echinocandin and clindamycin may be a safe and effective alternative treatment for patients who cannot be given co-trimoxazole for PcP.

Background: To date, no research has compared longer-term outcomes (antibiotic provision; re-consultations; hospital admissions for quinsy; cost-effectiveness) following presentation with acute sore throat at general practice (GP) versus newer, pharmacy-led services.

Methods: A retrospective, longitudinal cohort study of sore throat consultations between 1 November 2018 and 28 February 2020 either with the Wales pharmacy-led sore throat test and treat (STTT) service or with a healthcare professional at GP. Individual-level pharmacy consultation data from the national Choose Pharmacy IT application were securely uploaded to the Secure Anonymised Information Linkage Databank and linked to routinely collected, anonymized, population-scale, individual-level, anonymized health and administrative data.

Results: Of 72 736 index consultations, 6495 (8.9%) were with STTT and 66 241 (91.1%) with GP. Antibiotic provision at the index consultation was 1382 (21%) with STTT and 25 506 (39%) with GP [adjusted odds ratio (AOR), 0.30; 95% CI, 0.27 to 0.32]. Antibiotic provision within 28 days of index occurred in 1820 (28%) STTT and 26 369 (40%) GP consultations (AOR, 0.44; 95% CI, 0.41 to 0.47). GP re-consultation rate within 28 days of index date was 21% (n = 1389) with STTT compared with 7.4% (n = 4916) with GP (AOR, 3.8; 95% CI, 3.5 to 4.1). Coding limitations may lead to overestimates of GP re-consultations rates in the STTT group. Hospital admissions for quinsy were rare in both STTT (n = 20, 0.31%) and GP (n = 274, 0.41%) (AOR, 0.68; 95% CI, 0.43 to 1.1). STTT was less costly than consultation with GP.

Conclusions: The pharmacy-led STTT service is safe, cost-effective, and contributes to antimicrobial stewardship.

Background: Subcutaneous delivery of antibiotics is a practical alternative to IV administration. Meropenem is commonly used to treat infections caused by resistant Gram-negative organisms.

Methods: This was a prospective, crossover self-controlled study in 11 stable inpatients established on meropenem. Participants received a single dose of subcutaneous meropenem, in 50 mL normal saline via gravity feed. Venous blood sampling was performed at baseline, 0.5, 1, 2, 4 and 8 h following the subcutaneous and IV doses. Antibiotic concentrations were measured using UPLC-MS/MS. Pharmacokinetic data were analysed using a non-linear mixed-effects modelling approach. Pain scores and infusion site reactions (oedema/erythema) were assessed.

Results: Subcutaneous meropenem was well tolerated. The bioavailability of subcutaneous administration was 81.5% (95% CI 71.6%-93.2%). Increasing BMI was associated with slower absorption from subcutaneous tissue. Compared with IV, subcutaneous administration resulted in lower peak and higher trough concentrations. Despite the lower bioavailability observed, the PTA for free drug concentrations greater than the MIC for more than 40% of the time between doses was higher for subcutaneous than IV administration at MIC values between 0.03 and 8 mg/L. Simulated subcutaneous doses of 1.5 g twice daily, or 3 g continuous 24 h infusion had improved PTA relative to standard IV dosing of 1 g three times daily.

Conclusions: Subcutaneous meropenem appears to be well tolerated and has a favourable pharmacokinetic profile. Either 1.5 g twice daily or 3 g as a 24 h subcutaneous infusion could be considered for future evaluation.

Objectives: The co-resistance between bedaquiline and clofazimine raises significant concerns, as they are commonly co-administered as core drugs in drug-resistant TB regimens. The present study aimed to monitor drug resistance-associated gene mutations and the phenotypic change in Mycobacterium tuberculosis (Mtb) under a stepwise drug resistance induction in vitro using bedaquiline, clofazimine or combined drugs.

Methods: Drug-resistant Mtb strains were gradually induced in vitro on a drug-containing solid medium with a 2-fold increasing concentration of bedaquiline, clofazimine and their combination. The MIC of the induced drug-resistant Mtb strains was determined. The drug resistance-associated genes, including Rv0678, Rv1979c, atpE and pepQ, were sequenced and analysed.

Results: Unlike exposure to bedaquiline alone or the combination of these two drugs, clofazimine alone resulted in drug resistance gene mutations occurring later, specifically in the fourth round of induction as opposed to the second round of induction. Besides, nucleotide deletion or insertion in Rv0678 was the main mutation type for induction under the two-drug combination, while single-nucleotide polymorphisms (SNPs) in Rv0678 were the major mutation types when induced by bedaquiline or clofazimine alone. Rv0678 mutation happened at a relatively lower bedaquiline concentration exposure alone, while atpE mutation occurred at a higher bedaquiline concentration. Regardless of the drug exposure manner, a strong correlation between bedaquiline MICs and clofazimine MICs was observed in all drug resistance strains.

Conclusions: Combined exposure to bedaquiline and clofazimine developed Rv0678 mutation as early as exposure to bedaquiline alone. However, rather than SNPs, deletion and insertion were the dominant mutation types in dual-drug exposure strain.