Journal of Antimicrobial Chemotherapy最新文献

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.

Objectives: To determine the proportion of patients achieving target attainment of unbound flucloxacillin in blood plasma, evaluate the association between unbound flucloxacillin concentration and toxicity and identify patient subgroups that may benefit from therapeutic drug monitoring (TDM) of unbound flucloxacillin.

Patients and methods: A single-centre retrospective observational study was performed of patients admitted to the Meander Medical Centre between 1 July 2023 and 30 June 2024 who were treated with flucloxacillin and had an unbound flucloxacillin concentration measured ≥48 h after initiation of flucloxacillin treatment. Target attainment was defined as an unbound flucloxacillin concentration within 4-10× the measured MIC (0.25 mg/L in the absence of a positive culture).

Results: For the first measured plasma sample (n = 203), target attainment was achieved in 33% of patients, 35% fell below the target range and 32% exceeded the target range. Threshold concentrations for unbound flucloxacillin were 10.0 mg/L for nephrotoxicity and 21.0 mg/L for neurotoxicity. Above these concentrations, 66.7% and 46.2% of patients developed nephrotoxicity and neurotoxicity, respectively. An unbound flucloxacillin concentration >10 mg/L was observed in 23 (11.3%) patients, 21 of whom had an glomerular filtration rate <50 mL/min/1.73 m2.

Conclusions: Target attainment of unbound flucloxacillin was achieved in one third of patients, while a substantial number of patients had an unbound flucloxacillin concentration >10 mg/L, which was associated with increased toxicity. We advise routine TDM of unbound flucloxacillin for patients with impaired renal function and a high daily dose to mitigate the risk of flucloxacillin-associated nephrotoxicity and neurotoxicity.

Background: Infections caused by XDR Pseudomonas aeruginosa significantly limit treatment options. Although ceftolozane/tazobactam and ceftazidime/avibactam have emerged as promising alternatives, increasing resistance has been reported. This study describes three critically ill patients with ventilator-associated pneumonia caused by OXA-producing XDR P. aeruginosa that developed resistance to both agents during therapy.

Methods: Antibiotic exposure and resistance were monitored clinically and in a hollow-fibre infection model (HFIM) to evaluate different ceftazidime/avibactam and ceftolozane/tazobactam regimens. Drug concentrations, bacterial burden and resistant mutants were assessed. Whole-genome sequencing and resistance profiling were performed on both clinical and HFIM-derived isolates.

Results: Initial patient isolates were susceptible to both antibiotics. One belonged to ST179 (OXA-10 producer), while two were ST235 (OXA-2 or OXA-2 + OXA-10 producers). Resistance emerged during therapy in all cases. In the HFIM, continuous infusion of ceftolozane/tazobactam plus meropenem achieved bacterial eradication for ST179 within 8 h. For ST235 isolates, high-exposure ceftazidime/avibactam regimens (4-h or continuous infusion) achieved bacterial eradication and prevented regrowth. In contrast, low-exposure 2-h infusions allowed bacterial rebound and resistance selection. Mechanisms of resistance were similar across clinical and HFIM isolates, involving overexpression or structural modification of OXA enzymes, except in one ST235 HFIM derived-isolate, in which resistance development was caused by an AmpC Ω-loop mutation. Pharmacokinetic validation confirmed accurate drug exposure in the model.

Conclusions: These findings underscore the importance of optimized dosing strategies, particularly high-concentration and prolonged infusions, in eradicating and preventing resistance development in OXA-producing P. aeruginosa infections.

Objectives: The aim of this retrospective study was to investigate letermovir exposure in allogeneic haematopoietic stem cell transplant (allo-HSCT) recipients under real-world conditions and to evaluate the impact of patient characteristics and comedication on exposure using a population pharmacokinetic (popPK) approach.

Patients and methods: Serum samples from allo-HSCT patients receiving oral letermovir were analysed. A population pharmacokinetic model derived from phase III data was adapted to our real-world population, and was used to assess letermovir pharmacokinetics and identify potential covariates.

Results: Pronounced intra- and interindividual variability was observed across 247 serum samples from 51 allo-HSCT recipients. The medians of observed individual mean minimal letermovir concentrations (Cmin) were 2615 ng/mL in patients receiving LTV 240 mg/day with ciclosporin A (CsA) and 2141 ng/mL in those receiving 480 mg/day without CsA. No correlation was found between Cmin and adverse events. Application of the phase III popPK model yielded considerably higher observed concentrations compared with simulated values. These differences were attributed to a higher systemic availability of letermovir and reduced apparent central volume of distribution in our cohort. Exploratory analyses revealed a 76.5% reduction in relative bioavailability among patients with gastrointestinal graft-versus-host disease (GI GvHD), reflected by a notable decrease in Cmin.

Conclusions: Our findings support the overall tolerability and efficacy of letermovir in allo-HSCT recipients. Discrepancies between observed and simulated Cmin suggest that the phase III model may underestimate letermovir exposure, underscoring the importance of incorporating real-world data to improve characterization of letermovir pharmacokinetics. Conversely, the decreased exposure observed in a small cohort of GI GvHD patients may compromise efficacy and warrants further investigations to elucidate the impact of GI complications on letermovir exposure.

Objective: This study aims to identify spatiotemporal variations in clonal diversity and antimicrobial resistance of methicillin-resistant Staphylococcus pseudintermedius (MRSP).

Materials and methods: A PubMed search (June 2016-December 2023), combined with data from PubMLST and a previous review (September 2007-May 2016), identified 2654 isolates. Multinomial logistic regression (MLR) and Bayesian regression models (BRMs) were used to assess associations between clonal complexes (CCs) and variables (sample type, continent and period), with MLR results feeding into the BRM.

Results: A shift in MRSP clonal structure was observed after 2013. A decline in the prevalence of historically dominant lineages, such as CC71 in Europe, CC68 in North America and CC45 in Asia, coincided with the global emergence of CC551, as well as CC556 and CC1431 in North America, and CC363 and CC1631 in Asia. Resistance to non-β-lactams increased in North America, particularly for chloramphenicol (6%-59%), remained largely stable in Europe except for tetracycline, and decreased in Asia. Striking differences among CCs were observed, with CC71 exhibiting the highest resistance rates and a greater likelihood of being isolated from clinical samples.

Discussion: The observed associations between specific CCs and resistance patterns provide valuable insights into the factors driving these epidemiological changes, including regional antimicrobial use patterns (e.g. chloramphenicol usage in North America) and potential fitness advantages of emerging lineages. These dynamics parallel those seen in methicillin-resistant Staphylococcus aureus.

Conclusion: The evolving MRSP landscape highlights the need for sustained global surveillance to monitor clonal diversity, antimicrobial use and resistance trends.

Background and objectives: Treatment outcomes in Mycobacterium avium complex pulmonary disease may be improved by adding clofazimine, instead of rifampicin, to the azithromycin-ethambutol backbone. Inhalation of clofazimine instead of oral administration has been suggested to increase the antibiotic concentration at the site of infection and to improve its efficacy, while minimizing systemic exposure and adverse effects. We evaluated the efficacy of inhaled clofazimine compared to oral clofazimine with an azithromycin-ethambutol backbone against M. avium.

Methods: We simulated pharmacokinetic exposures to azithromycin, ethambutol and either inhalational or oral clofazimine administration in an in vitro hollow-fiber system during 3 weeks. Intracellular and extracellular Mycobacterium avium ATCC 700898 bacteria were exposed to these antibiotic regimens and bacterial densities were enumerated at day 0, 3, 7, 14 and 21. The development of macrolide resistance was assessed by inoculation of agar plates containing azithromycin. Pharmacokinetic exposures were confirmed on day 0 and 21.

Results: Inhalational administration of clofazimine significantly increased the antimycobacterial effect of the regimen against both intracellular and extracellular bacteria. The inhaled treatment showed an intracellular kill rate of 0.62 (95%C.I. 0.61-0.64) per day, while the oral administration showed a kill rate of 0.55 (95%C.I. 0.54-0.56) per day. For the extracellular fraction, inhaled administration showed a kill rate of 0.56 (95%C.I. 0.55-0.58) per day and the oral administration a kill rate of 0.50 (95%C.I. 0.50-0.51) per day. Inhaled clofazimine exposures reduced and delayed the emergence of macrolide resistance.

Conclusions: Inhalation of clofazimine with an azithromycin-ethambutol backbone increases treatment efficacy and decreases the development of macrolide resistance compared to oral administration in a hollow-fiber system. This calls for a clinical trial of inhaled clofazimine.

Objectives: Antimicrobial resistance (AMR) is an escalating global health concern, driven by multifactorial biological processes not yet fully understood. This study employed network diffusion analysis to dissect the molecular mechanisms driving AMR in Escherichia coli, aiming to identify novel potential drug targets for therapeutic development.

Methods: A systems biology approach was used to identify genes and biological pathways associated with AMR, by mapping known AMR-related genes from the Comprehensive Antibiotic Resistance Database (CARD) and PointFinder database into the E. coli protein interactome. Through a network diffusion algorithm, several network modules were identified, i.e. genes and pathways, in part already known to be involved in AMR mechanisms. We selected gene candidates for performing an in vitro susceptibility validation test, consisting of 13 knockout mutants against nine different antibiotics.

Results: Compared with the WT E. coli BW25113, the AMR of some mutants showed significant shifts of biological relevance: ΔuhpB (S/I) and ΔmdaB (S/R) against ampicillin, ΔrpmG (I/S) and ΔrplA (I/S) against ciprofloxacin, and ΔrplA (I/S) against streptomycin (S, susceptible; I, intermediate; R, resistant). In other cases, only a significant change in inhibition disc diameter was observed, probably deserving further studies.

Conclusions: Network diffusion is an effective tool to infer relevant biological insights related to AMR from microbial biological networks. Our results contribute to a better understanding and characterization of AMR in E. coli. Furthermore, the in vitro validated genes could be considered as new putative drug targets.

Background and objectives: Mycobacterium abscessus can cause severe infections in at-risk patients. Treatment efficacy for M. abscessus infections remains low, and better treatment options are needed. Factors hampering antibiotic potency may include the ability of M. abscessus to form biofilms and to endure in nutrient-deprived environments. These factors are underrepresented in current preclinical drug activity assays. Diversifying preclinical models by incorporating characteristics of these harsh environments may be important to better predict drug efficacy in patients. We aimed to develop a novel tool for studying drug activity against biofilm-embedded M. abscessus. In addition, drug activity was assessed against actively multiplying and nutrient-starved M. abscessus.

Methods: An in-house 3D-printed platform-disc-based biofilm model was developed to study M. abscessus pellicle biofilms. In vitro activity of 16× the MICs of amikacin, bedaquiline, clofazimine, imipenem, rifabutin and tigecycline was assessed using time-kill kinetics assays.

Results: The platform-disc-based model established reliable and reproducible quantification of M. abscessus biofilms. Drug activity against biofilm-embedded and nutrient-starved M. abscessus seemed less pronounced than against actively multiplying mycobacteria. For biofilm-embedded M. abscessus, drug activity was dependent on the developmental stage of the biofilm.

Conclusions: The varying levels of drug activity observed across the different M. abscessus populations highlight their distinct physiological relevance. As such, the platform-disc-based biofilm model could serve as a valuable asset in preclinical drug activity assays for M. abscessus.