Journal of Antimicrobial Chemotherapy最新文献

Objectives: Oral second- and third-generation cephalosporins are increasingly used as transitional therapy for Escherichia coli bloodstream infection, particularly in patients with resistance and intolerance to first-line agents. However, many automated antimicrobial susceptibility testing (AST) systems only assess parenteral cephalosporins, potentially delaying transitions of care. Limited data exist on the correlation and surrogacy between parenteral and oral cephalosporin AST. We aimed to determine whether AST for parenteral cefazolin, ceftriaxone or cefotaxime can serve as surrogates to predict susceptibility for oral cephalosporins.

Methods: E. coli blood isolates susceptible to parenteral third-generation cephalosporins were consecutively collected from unique patients from two health systems in Phoenix, AZ, USA from January 2021 to 2023. Broth microdilution was performed according to CLSI. Categorical agreement (CA) rates were calculated using cefazolin, ceftriaxone, or cefotaxime as the surrogate antibiotic for oral cephalosporins (cefuroxime, cefaclor, cefprozil, cefdinir, cefpodoxime, cefixime). Discrepancies were classified as minor errors (mE), major errors (ME), or very major errors (VME) per CLSI.

Results: Among 200 isolates, susceptibility to cefazolin at MIC ≤2 mg/L, cefazolin at MIC ≤16 mg/L, ceftriaxone and cefotaxime at MIC ≤1 mg/L were 43%, 91.5% and 100%, respectively. Cefazolin MIC ≤2 mg/L provided high CA across oral cephalosporins but excessive mE (25%-37%) and ME (20%-40%) rates. Ceftriaxone and cefotaxime achieved 100% CA for oral third-generation cephalosporins with mE rates within acceptable limits; however, CA was suboptimal for oral second-generation agents (83%-88%). No surrogate antibiotic met acceptable CLSI criteria due to lack of CA, however, ceftriaxone/cefotaxime achieved acceptable limits in CA, mE, ME and VME.

Conclusions: Prediction of oral second-generation cephalosporins may warrant cefazolin MIC ≤2 mg/L, despite limitations regarding false resistance and susceptibility discordant. Ceftriaxone/cefotaxime demonstrates a more reliable surrogate for predicting oral third-generation cephalosporins susceptibility. Future investigations are necessary to clinically corroborate these findings.

Objectives: To evaluate the long-term sustainability and impact of an integrated electronic medical record-driven antimicrobial stewardship (AMS) ward round in an ICU at a tertiary referral hospital. The study assessed antimicrobial prescribing patterns, acceptance of stewardship recommendations, and antimicrobial consumption over 7 years.

Methods: A prospective review commenced with implementation of the ICU-AMS ward round at Austin Health in 2017. When AMS recommendations were given, data were collected including patient demographics, antimicrobial prescribing, classification of recommendation, and acceptance. Antimicrobial use was assessed via DDDs per occupied bed day per month and analysed using interrupted time series analysis. Logistic regression examined patient and clinician factors associated with recommendation acceptance.

Results: Over 7 years, 9163 AMS recommendations were made for 4610 patients. Recommendation acceptance was high, with antibiotic escalation the most accepted (95%) and discontinuation least accepted (82%). Recommendations were more likely to be accepted in immunocompromised (OR 1.31, P = 0.003) and non-surgical patients (OR 1.31, P < 0.001). Recommendations provided by AMS physicians who identified as men were more likely to be accepted (OR 1.23, P = 0.003). Antimicrobial consumption trends showed significant decreases in piperacillin/tazobactam, meropenem, ciprofloxacin and vancomycin use post-implementation. Amoxicillin/clavulanate use increased, suggesting potential compensatory prescribing.

Conclusions: This study demonstrates the long-term effectiveness and sustainability of an ICU-AMS programme, achieving high recommendation acceptance and sustained reductions in broad-spectrum antimicrobial use. Continued efforts should focus on optimizing stewardship practices, addressing barriers to acceptance, and evaluating compensatory prescribing patterns.

Background: The plasmid-mediated tigecycline resistance gene tmexCD-toprJ has emerged in clinical and animal isolates, but its epidemiological spread and plasmid adaptation mechanisms remain unclear.

Methods: We characterized tmexCD-toprJ-carrying plasmids from the PLSDB database through comprehensive bioinformatic analyses, revealing their genetic features and potential inter-species transmission routes.

Results: Genomic analysis of 197 tmexCD-toprJ-carrying plasmids revealed significant backbone diversity, clustering into 18 groups and 12 singletons. The 30 identified host species were predominantly Klebsiella pneumoniae (K. pneumoniae) (53.3%), followed by Pseudomonas aeruginosa (P. aeruginosa) (16.8%) and Klebsiella quasipneumoniae (K. quasipneumoniae) (4.1%). MOB-suite typing classified 53.8% as conjugative, 5.6% mobilizable and 40.61% non-mobilizable. Over half of the tmexCD-toprJ-carrying plasmids were predicted to contain the MOBH family. Among the identified variants, tmexCD1-toprJ1, tmexCD2-toprJ2 and tmexCD3-toprJ1 representing the predominant forms. TmexCD1-toprJ1 was linked to IncFIB/IncHI1B/rep_cluster_1254 plasmids, while tmexCD2-toprJ2 associated with diverse replicons, enabling cross-species spread. A total of 14 plasmids co-localized tmexCD-toprJ with carbapenemase (blaNDM/KPC) and mcr genes, forming high-risk resistance platforms. Notably, a 36 483 bp insertion in IncP/rep_cluster_1115 plasmids disrupted tmexC6D6-toprJ1b and carried heavy metal resistance genes.

Conclusions: These findings enhance our understanding of the diversity of tmexCD-toprJ-carrying plasmids. The convergence of tmexCD-toprJ with carbapenemase and polymyxin resistance genes in clinically prevalent plasmids underscores an urgent need for enhanced surveillance targeting complete genetic environments.

Introduction: Aligning national standard treatment guidelines (STGs) with WHO AWaRe Book recommendations where appropriate is a key antimicrobial stewardship goal. Antibiotic recommendations in national STGs vary significantly, creating gaps that require evaluation to help address rising AMR rates.

Methods: We analysed adult STGs from 24 countries in six WHO regions for 11 infections commonly seen across countries in the primary care section of the WHO AWaRe Book. These included acute otitis media (AOM), pharyngitis, sinusitis, community-acquired pneumonia (CAP), chronic obstructive pulmonary disease, lower urinary tract infections, gastroenteritis (bloody and non-bloody), oral and dental infections, skin and soft tissue infections and enteric fever. National STGs were compared with WHO AWaRe recommendations to assess alignment of first-line antibiotic recommendations.

Results: 522 different first-line oral antibiotic regimens were collected from the different STGs in 24 countries across 6 WHO regions. Access antibiotics were recommended in 65.7% of the regimens, while Watch antibiotics accounted for 34.3% of first-line recommendations globally, with limited recommendations of Reserve antibiotics. The Western Pacific Region (76.4%), showed the highest proportions of Access group antibiotic recommendations. Infection-specific analysis showed significant variation in alignment, with a higher alignment for enteric fever, non-bloody gastroenteritis and cystitis, and a lower alignment for CAP, oral and dental infections, and AOM (P = 0.0089).

Conclusion: First-line antibiotic recommendations in adult STGs showed moderate alignment with WHO AWaRe Book treatment guidance, with regional variability. Aligning first-line recommendations with the WHO AWaRe Book guidance in primary care would assist stewardship programmes.

Background and objectives: Bone and joint infections (BJIs) due to third-generation cephalosporin-resistant (3GC-R) Enterobacterales are particularly challenging-to-treat infections, and their treatment often relies on carbapenems. Due to its stability towards various beta-lactamases, as well as its limited spectrum of activity, temocillin could be a promising alternative. This study evaluated the in vitro activity of temocillin against a collection of 3GC-R Enterobacterales isolates from BJIs and modelled the probability of PK/PD target attainment according to the dosage regimen used.

Methods: MICs of temocillin and seven comparators (ertapenem, imipenem, meropenem, levofloxacin, delafloxacin, doxycycline and tigecycline) were determined using gradient strips for 104 3GC-R Enterobacterales isolates from BJIs in three French hospitals. Isolates were characterized about their mechanism of resistance to 3GC (ESBL or hyperproduced cephalosporinase). PK/PD simulations were performed with six dosage regimens and different stages of renal function in order to calculate PTA according to temocillin MIC.

Results: Temocillin showed a susceptibility rate of 92.3% (96/104) in 3GC-R isolates from BJIs: 95.3% (61/64) in ESBL producers and 87.5% (35/40) in AmpC hyperproducers. Temocillin was the only alternative to carbapenems for 25% (26/104) of isolates. PTA values increased with declining renal function. In normorenal patients, none of the tested regimen achieved adequate PTA up to the Enterobacterales breakpoint (16 mg/L).

Conclusions: This study demonstrated the high in vitro efficacy of temocillin against 3GC-R Enterobacterales from BJIs, regardless of the underlying resistance mechanism. However, dosage adjustments based on the strain's MIC and the patient's renal function are crucial for optimal efficacy.

Objectives: This study aims to elucidate the molecular mechanism of enhanced florfenicol resistance mediated by the resistance-enhanced RE-CmeABC in Campylobacter, with a focus on the evolution of its efflux function.

Materials and methods: The complex models of FFC with wild-type CmeB and RE-CmeB are constructed by molecular modelling methods, and the efflux channels and corresponding bottleneck residues are predicted by CAVER program. Then mutants are constructed on the basis of predicted amino acid residues by natural transformation and functional confirmation is performed by antimicrobial susceptibility testing and accumulation assay.

Results: Channel P1 is identified as the optimal FFC efflux channel, and the specific residues composed are illustrated. The corresponding bottleneck residues are S615, S616, Q87, T614, K89, S47 and S84. Among them, mutations of Q87 and K89 are non-conserved, having a particularly pronounced effect on efflux function. Decreased (8-fold) MIC and increased FFC accumulation were observed in MU-11168-RE-CmeABC (with mutated RE-CmeB) compared with that in 11168-RE-CmeABC (with RE-CmeB), respectively, which verifies the predicted FFC efflux tunnel is reliable. This demonstrates that the P1 channel in RE-CmeB has evolved into a dominant and specialized extrusion pathway with minimal functional redundancy, fundamentally underpinning its enhanced resistance.

Conclusions: Our findings reveal that the enhanced resistance is primarily due to a functional specialization of the P1 efflux channel in RE-CmeB. This elucidation, strongly supported by the concordance between computational predictions and experimental data, provides a mechanistic basis and high-value targets (Q87/K89) for the development of efflux pump inhibitors against multidrug-resistant Campylobacter.

Continuous infusion (CI) of linezolid has been proposed to stabilize exposure and improve pharmacokinetic/pharmacodynamic (PK/PD) target attainment compared with conventional intermittent dosing. By maintaining concentrations above inhibitory thresholds, CI may optimize antibacterial efficacy and reduce inter- and intra-patient variability. However, this 'new way of dosing' revisits 'old risks' associated with linezolid, including nonlinear PK, metabolic saturation, and concentration-dependent toxicities such as lactic acidosis, myelosuppression and neurotoxicity. Rather than eliminating these concerns, CI may accentuate them by prolonging exposure near toxic thresholds, particularly in patients with impaired elimination. Current evidence is predominantly PK; robust clinical outcome data remain limited. Our review synthesizes pharmacometric, observational and trial data and outlines how therapeutic drug monitoring and model-informed precision dosing can be used to individualize CI while surveilling for toxicity. We propose a pragmatic framework for candidate selection, regimen design aligned to PK/PD goals, early therapeutic drug monitoring with adaptive adjustments and vigilant safety monitoring. Overall, CI of linezolid is mechanistically attractive but is not established as standard of care; its use should remain individualized, safety-conscious and evidence-generating pending randomized controlled trials.