Journal of Antimicrobial Chemotherapy最新文献

Objectives: To develop a population pharmacokinetic (popPK) model to understand factors affecting the broadly neutralizing HIV antibody (bNAb) VR07-523LS disposition and infant predicted serum neutralization 80% inhibitory dilution titre ratio (PT80) and its potential relationship to antiviral effects.

Methods: PK data from two studies were used: infants exposed to HIV initiating therapy ≤5 days of age (IMPAACT P1112, n = 21) and healthy adults (VRC605, n = 25). The infant study implemented fixed subcutaneous (s.c.) dosing whereas the adult study implemented weight-based dosing, via both intravenous (i.v.) and s.c. routes. Monte Carlo simulation assessed two doses (80 mg followed by 100 mg at 12 weeks) to determine the maintenance of levels >10 µg/mL in virtual infants. The broadly neutralizing antibodies (bNAbs) concentration/IC80 ratio (PT80) was calculated on the basis of simulated concentrations from the popPK model and VRC07-523LS HIV-1 sensitivity (IC80) distribution.

Results: This model predicts typical infant CL/F and t1/2 of 159 mL/day/70 kg and 39 days. Comparatively, predicted adult typical CL/F and t1/2 were 269 mL/day/70 kg and 31 days. Concentrations were >10 µg/mL in >87% of virtual infants at 12 weeks following one dose and >98% at 24 weeks following two doses. Median (90% predictive interval) PT80 was 163 (71-383), 116 (51-274) and 61 (26-144) at 6, 8 and 12 weeks, respectively. Significant model covariates included age (infant versus adult) and multiple dosing.

Conclusions: Age and repeat dosing influence VRC07-523LS PK. An 80-mg dose followed by 100 mg at 12 weeks rapidly achieves and maintains concentrations >10 µg/mL for >24 weeks. This dosing strategy is expected to result in antiviral effects in patients with sensitive viruses and supports further evaluation of VRC07-523LS.

Objectives: Understand how mutations upstream of pvdS and fecI in Pseudomonas aeruginosa PAO1 lead to reduced susceptibility to cefiderocol, a siderophore cephalosporin.

Materials and methods: Whole-genome sequencing, gene complementation and inactivation, mRNA expression, siderophore quantification and supplementation were carried out with mutants that showed reduced susceptibility to cefiderocol.

Results: Whole-genome sequencing, combined with gene complementation studies, with isolated mutants that showed 4-fold reduced susceptibility to cefiderocol identified mutations within the Fur-box of promoter regions upstream of pvdS and fecI. The pvdS promoter mutation led to increased pvdS transcription, resulting in increased pyoverdine production, as well as reduced transcription of other iron transport-related genes, including piuA an iron transporter responsible for cefiderocol uptake. The down-regulation of piuA, rather than competition for iron between pyoverdine and cefiderocol, was responsible for the decreased cefiderocol susceptibility. The fecI mutant demonstrated increased transcription of fecI and fecA, and the expression level of piuA in the fecI mutant was not related to reduced cefiderocol susceptibility, indicating a different mechanism for the reduced cefiderocol susceptibility in this mutant. Sequence analyses of over 35 000 clinical P. aeruginosa isolates did not identify isolates with the pvdS mutation, and only one isolate with the fecI mutation.

Conclusions: These data highlight different mechanisms by which P. aeruginosa attempts to evade the action of cefiderocol by exploiting the complexities of iron haemostasis in bacteria. The absence of such mutants in the clinic suggests that such mutations may be detrimental for P. aeruginosa to survive in the clinical environment.

Background: Macrolide resistance in Mycoplasma pneumoniae is an increasing concern worldwide.

Objectives: To investigate the prevalence of macrolide resistance in M. pneumoniae in The Netherlands.

Methods: All non-duplicate consecutive specimens with a positive M. pneumoniae PCR were prospectively collected by four hospital laboratories during the outbreak of M. pneumoniae infection in 2023/2024 in The Netherlands. The two most common mutations in the 23S rRNA gene that are known to cause macrolide resistance, A2063G and A2064G, were detected by PCR with melting curve analysis.

Results: PCR-positive specimens were identified in 268 patients. Of the 268 PCR-positive specimens, 238 were available for analysis of which 235 could be amplified for mutational analysis. Mutations were detected in 7 of 235 specimens (3%).

Conclusions: The low resistance rate of 3% still supports the use of macrolides for empirical treatment of M. pneumoniae infections in The Netherlands, but macrolide non-responsive infections should lead to the suspicion of resistant M. pneumoniae. Regular surveillance studies are important as clonal spread may cause rapid changes in resistance rates.

Objectives: Notwithstanding the wide uptake of outpatient antimicrobial therapy (OPAT) in the UK, there is a paucity of data on antimicrobial exposure. We aimed to assess antimicrobial pharmacokinetic-pharmacodynamics (PK-PD) for several agents in our service with a view to understanding a potential role for therapeutic drug monitoring (TDM) and precision antimicrobial therapy in this setting.

Methods: The study was a prospective, observational, pilot PK-PD study. Adult patients receiving intravenous ceftazidime, ceftriaxone, daptomycin, ertapenem, flucloxacillin or teicoplanin, or oral treatment with linezolid were enrolled. Peak and trough blood samples were obtained. Total and unbound antibacterial concentrations were measured. Clinical details, laboratory findings and UK OPAT good practice recommendation metrics were extracted from the medical record. PK-PD was interpreted according to EUCAST rationale documents and other published guidance. Doses were not adjusted except for linezolid and teicoplanin.

Results: In total, 39 patients were recruited to the study, predominantly on ceftriaxone (21/39, 54%) or ertapenem (6/39, 15%). Four patients received (10%) teicoplanin, three (8%) ceftazidime, three (8%) flucloxacillin, one (3%) linezolid and one (3%) daptomycin. The most common reason for OPAT was bacteraemia and endocarditis (6/39; 15% each). PK-PD target attainment was acceptable for all drugs and dose regimens, and all β-lactam-based treatments met conservative PK-PD targets.

Conclusions: We have demonstrated that drug monitoring is practicable in the OPAT setting of a large institution with no on-site analytical capability. Current dosage regimens result in acceptable PK-PD target attainment. Our findings provide an initial step towards supporting TDM in OPAT.

Bacillus cereus is a common foodborne pathogen closely related to various foodborne diseases. The diarrhoea-type enterotoxins and vomiting-type enterotoxins it produces can lead to local or systemic infections. In recent years, resistance in B. cereus has been increasing, and multidrug-resistant bacteria have emerged. Therefore, understanding the drug resistance mechanism of B. cereus has become a matter of considerable concern in scientific research. In addition, this review explores the main resistance mechanisms of B. cereus to antibacterial drugs and discusses the detection and control strategies for the drug resistance of this bacterium. In addition, the purpose of this article is to deeply explore the drug resistance mechanism of B. cereus, with the aim of providing scientific basis and practical guidance for rational clinical drug use. Meanwhile, this article also provides innovative ideas for exploring new research approaches and screening safe and efficient antibacterial candidate drugs, with the aim of providing practical assistance for improving the current clinical cure rate.

Background: Pneumococcal 21-valent conjugate vaccine (PCV21) was developed specifically for adults. It contains 21 serotypes [3, 6A, 7F, 8, 9N, 10A, 11A, 12F, 15A, 15C (de-O-acetylated 15B), 16F, 17F, 19A, 20A, 22F, 23A, 23B, 24F, 31, 33F, 35B]. In October 2024, the US Advisory Committee on Immunization Practices recommended PCV21 for adults aged ≥50 years and those aged 19-49 years with underlying diseases or risk factors. PCV21 provides serotype coverage for approximately 83% of invasive pneumococcal disease (IPD) in the USA. We evaluated serotype distribution and antimicrobial susceptibility of Streptococcus pneumoniae obtained from adult patients (≥18 years) with a positive blood and/or respiratory culture during 2022-2023.

Methods: S. pneumoniae (n = 675) was obtained from IPD (n = 112) and non-IPD isolates (n = 563) in adults at each of 30 US sites in 19 states, between 2022 and 2023. Serotype was determined using PneumoCat, and isolates were tested for susceptibility by CLSI reference broth microdilution.

Results: Of 675 S. pneumoniae isolates, 29%, 36% and 35% were from patients aged 18-49 years, 50-64 years and  ≥ 65 years, respectively. For adults aged ≥50 years, IPD and non IPD cases attributable to PCV21 serotypes were 82% compared with 50% for PCV20. Serotypes unique to PCV21 showed the lowest susceptibility rates when compared with PCV20-unique serotypes: for azithromycin (49.5% versus 92%), oral penicillin (52.0% versus 81.3%) and clindamycin (83.3% versus 94.7%).

Conclusions: Based on surveillance data from the SENTRY Antimicrobial Surveillance Program, PCV21 serotypes were associated with 82% of IPD and non-IPD cases in adults although PCV21-unique serotypes had lower rates of susceptibility to commonly used antibiotics. Continued surveillance is crucial to track serotype and resistance trends.

Background: An unprecedented surge in chronic, recalcitrant, and resistant dermatophytosis has been observed, predominantly caused by Trichophyton indotineae. While terbinafine resistance is usually linked to squalene epoxide gene (SE) mutations, azole-resistance involves CYP51B overexpression and target gene mutations.

Objective: To investigate the role of multidrug efflux-transporters and Erg1 in terbinafine and fluconazole-resistant T. indotineae. The secondary aim was to examine a similar mechanism in T. rubrum.

Methods: Quantitative real-time PCR assessed ABC-transporters, major facilitator superfamily (MFS)-transporters, and Erg1 expression in 63 Trichophyton spp. isolates to explore antifungal resistance mechanisms. For the terbinafine exposure experiment, 39 isolates were tested, while 26 isolates were used for the fluconazole exposure experiment, giving a combined total of 65. Additionally, mutation analysis of the SE and Erg11A genes was performed.

Results: In T. indotineae, terbinafine exposure induced significant expression of MDR1 and MDR2 in terbinafine-resistance wild-type (TiTR-WT; P < 0.0001), with lower gene-expression for MDR1 and MDR2 noted in terbinafine-resistance with F397L-mutation (TiTR-M) and terbinafine-sensitive wild type. MFS1 gene-expression was significantly higher in TiTR-WT (P < 0.001). In T. rubrum, significant MDR1 induction was found in TrTR-WT isolates (3.88-fold; P < 0.0462). Fluconazole exposure showed significant MDR1, MDR2 and MDR3 expression in T. indotineae resistant isolates. Similarly, fluconazole-resistant T. rubrum isolates showed higher expression of MDR1, MDR2, MDR3, MDR5, MFS1 and SE genes.

Conclusions: Our study provides valuable insights into the expression patterns of efflux-pump genes in Trichophyton spp. and their role in antifungal resistance. TiTR-WT predominantly upregulate MDR1, MDR2, MFS1, while SE-mutant strains compensate via SE gene overexpression in T. indotineae.

Background: All triazoles decrease the metabolism of calcineurin inhibitors (CNIs) and mammalian target of rapamycin (mTOR) inhibitors through CYP3A4 and P-glycoprotein inhibition leading to increased exposure and the potential for serious adverse events (SAEs).

Objectives: We sought to describe triazoles and CNI and mTOR inhibitor use in solid organ transplantation (SOT) recipients hospitalized for invasive aspergillosis (IA).

Patients and methods: We included adults with ≥1 claim for an IA admission in a US claims database from October 2015 to November 2022 who received systemic antifungal therapy for ≥3 days during the stay. This cohort was limited to patients with a history of SOT (defined as ≥1 diagnosis code for post-transplant status and/or complication) between January 2010 and IA admission. Triazoles and CNI or mTOR inhibitor co-administration in newly admitted IA patients were described.

Results: We identified 173 admitted IA patients with SOT. Kidney and lung transplant were most prevalent (>42% for both). Triazoles were used in 170 (98.3%) of patients (mean duration,  116 ± 184 post-admission days). Voriconazole (71.1%) and isavuconazole (41.0%) were most prescribed, and triazoles were co-administered with a CNI or mTOR inhibitor in 139 (81.8%) of patients. Tacrolimus was the predominantly used (89.9%) immunosuppressant.

Conclusions: Voriconazole was used nearly twice as frequently as isavuconazole, despite isavuconazole having more predictable pharmacokinetics and a lower propensity for severe drug-drug interactions versus voriconazole. The still-frequent use of isavuconazole may reflect its lower inhibition of CNIs and mTOR inhibitors. Resulting drug-drug interactions may be serious and dose adjustment and therapeutic drug monitoring are needed to reduce SAEs.