Journal of Antimicrobial Chemotherapy最新文献

Background: Klebsiella pneumoniae producing KPC variants conferring resistance to ceftazidime-avibactam often remain susceptible to meropenem, suggesting a potential therapeutic use of this antibiotic.

Objectives: In this study, the efficacy of clinically relevant concentrations of meropenem was evaluated against high-risk clones of ceftazidime-avibactam-resistant K. pneumoniae strains producing KPC variants, in a tandem in vitro time-kill/in vivo Galleria mellonella survival model.

Methods: In vitro/in vivo efficacy of meropenem against ceftazidime-avibactam-resistant K. pneumoniae of CG16, CG25 and CG258, producing KPC-31, KPC-33, KPC-90, KPC-106 and KPC-114 variants, was evaluated using EUCAST dosing recommendation adjusted to the G. mellonella model. For in vivo assays, untreated, meropenem (40 mg/kg × 1)-treated and ceftazidime-avibactam (40 mg/kg ceftazidime-10 mg/kg avibactam × 1)-treated groups were established, with 60 larvae per group. Kaplan-Meier curves, log-rank tests, univariate Cox regression and hazard ratios (HR) were used to assess treatment effects (P < 0.05).

Results: For all KPC-variant producers, time-kill assays showed >3 log-kills reduction (-6.91 ± 1.28 SD) after 6 h interaction when exposed to 8-32 mg/L meropenem MIC values (i.e.  ≥  × 4 MIC). In the assessment of in vivo efficacy of meropenem, at the 4-day follow-up, mortality rates were 96.7% (untreated), 83.3% (ceftazidime-avibactam-treated) and 13.3% (meropenem-treated) (P < 0.05). Univariate Cox regression analysis showed significantly lower risk in the meropenem group compared to untreated group [HR 0.02 (95% CI: 0.01-0.05)].

Conclusions: These pre-clinical results might support use of meropenem as a potential alternative for treatment of infections due to KPC-variant producers displaying in vitro susceptibility to meropenem.

Objectives: Vancomycin is commonly used in neonates with the same pharmacokinetics/pharmacodynamics (PK/PD) target as adults. However, no evidence supports this practice, and the association between trough concentrations and treatment outcomes has been widely questioned. This study aimed to identify the optimal PK/PD predictor and assess the correlation between AUC/MIC, trough concentration and the vancomycin efficacy in neonates.

Methods: This study retrospectively collected neonates who used vancomycin and constructed a population pharmacokinetic (PPK) model to estimate the AUC. Logistic analyses were used to identify the variables related to efficacy. Classification and regression tree analysis was used to explore thresholds. The correlation between trough concentration and AUC/MIC on the first day was analysed using a linear regression model.

Results: PPK modelling involved 131 neonates. Postmenstrual age and current weight were included in the covariate analysis. Forty-eight patients were included in the efficacy analysis, 13 of whom were infected with MRSA. The best-performance PK/PD target for efficacy was AUC0-24  h/MIC ≥ 331. The trough concentration was correlated with AUC0-24  h/MIC (r2 = 0.32), but individual differences existed. AUC0-24  h/MIC ranged up to 2.5-fold for a given trough concentration.

Conclusions: AUC0-24  h/MIC ≥ 331 was the optimal target of vancomycin efficacy in neonates. The trough concentration was not a reliable predictor of efficacy and AUC0-24  h/MIC. AUC-guided dosage adjustments are more valuable in clinical applications.

Objectives: To evaluate the synergistic effect of a ceftibuten and polymyxin B combination and to determine its capacity to overcome polymyxin B resistance in polymyxin/carbapenem-resistant (PC-R) Klebsiella pneumoniae.

Methods: To investigate the combination's antibacterial efficacy, antimicrobial susceptibility tests using broth microdilution methods, chequerboard assays and time-kill testing were performed. Antibiofilm activity was also assessed. The treatment's effect on the bacterial cell membrane was examined by quantifying intracellular protein leakage and conducting scanning electron microscopy. Haemocompatibility tests were conducted to evaluate toxicity. Additionally, an infection model was established using Swiss mice to assess in vivo antimicrobial activity.

Results: The ceftibuten/polymyxin B combination demonstrated synergistic effects against several PC-R strains of K. pneumoniae, as determined by the FIC index (FICI) values, which ranged from 0.15 to 0.37. This combination was efficacious, exhibiting bactericidal activity at twice the MIC. Ceftibuten/polymyxin B also demonstrated antibiofilm activity. Additionally, ceftibuten/polymyxin B neither damaged the bacterial membrane nor exhibited haemolytic activity. Based on these findings, the in vivo therapeutic potential was investigated and it was found that ceftibuten/polymyxin B significantly decreased the bacterial load in the peritoneal lavage fluid of mice, revealing its effectiveness in treating infections caused by PC-R K. pneumoniae.

Conclusions: The ceftibuten/polymyxin B combination exhibited synergistic effects in vitro and in vivo, and thus might be a promising therapeutic alternative for treating PC-R K. pneumoniae infections. As the combination was efficacious in preclinical models, researchers may further investigate its potential in clinical studies.

Background: The role of integrase strand transfer inhibitors (INSTI) in the cardiovascular risk of people with HIV is controversial.

Objectives: To assess the association of INSTI to subclinical atherosclerosis progression measured with the carotid intima-media thickness (cIMT).

Methods: Prospective study in virologically suppressed people with HIV receiving INSTI- or NNRTI-based regimens. cIMT was measured at baseline, 48 and 96 weeks. cIMT progression was analysed both as a continuous and categorical variable, defined as cIMT increase ≥ 10% and/or new carotid plaque. Adjustments through Cox proportional hazard regression and linear mixed models, and propensity score matching were conducted.

Results: 190 participants were recruited and 173 completed the 96 week follow-up. 107 (56.3%) were receiving an INSTI-containing, 128 (67.4%) a NNRTI-containing and 45 (23.7%) a NNRTI plus an INSTI-containing regimen. The overall median (IQR) 2-year change of cIMT was 0.029 (-0.041 to 0.124) mm; 87 (45.8%) participants experienced a cIMT increase ≥ 10%, of whom 54 (28.4%) developed a new carotid plaque. Adjusted Cox regression showed no differences between INSTI and NNRTI groups in the categorical 2-year progression of cIMT, both including or excluding participants receiving INSTI + NNRTI. Similar results were observed for the continuous cIMT increase through adjusted linear mixed models. Propensity score matching showed no significant differences in the 2 year cIMT change between treatment groups [0.049 mm (-0.031-0.103) in the INSTI group versus 0.047 mm (-0.023-0.115) in the NNRTI group; P = 0.647]. cIMT progression was associated with traditional cardiovascular risk factors.

Conclusions: INSTI-based regimens are not associated with increased progression of subclinical atherosclerosis when compared to NNRTI.

Background and objectives: In Belgium, monitoring antibiotic consumption relies on reimbursement data, which is obtained with a time delay and does not account for over-the-counter or nonreimbursed products. This study aims to bridge this gap by comparing reimbursement and retail data for primary care to understand variations and assess the accuracy of current surveillance methods.

Method: Reimbursement data were obtained from the National Institute for Health and Disability Insurance, and retail data were obtained from IQVIA for the period 2013-22. The community consumption of systemic antibiotics was expressed in defined daily doses (DDD-WHO ATC/DDD Index 2023) per inhabitants per day (DID). Relative differences in DID (RDs) based on the two data sets were computed and validated through Bland-Altman plots and correlation analysis.

Results: The sales of antibiotics declined from 22.89 DID (2013) to 20.50 (2022), with a steep drop during the COVID-19 pandemic-from 21.31 DID in 2019 to 16.55 DID in 2020-and a subsequent rebound. Reimbursement data slightly underestimated consumption compared to retail data, with RDs ranging from 2% (2013) to 9% (2022) when including quinolones and from 2% to 4% when excluding them. Bland-Altman plots showed high agreement between reimbursement and retail estimates, identifying quinolones as outliers.

Conclusion: Our findings suggest that reimbursement data are generally reliable for monitoring antibiotic consumption, but incorporating retail data is crucial for accurate assessments. The use of retail data can facilitate timely interventions and inform public health strategies to effectively address antimicrobial resistance.

Background: Bacterial persistence is a phenomenon whereby a subpopulation of bacteria survive high concentrations of an active antibiotic in the absence of phenotypic alterations. Persisters are associated with chronic and recurrent infections for pathogens including Pseudomonas aeruginosa. Understanding persister profiles of newer antibiotics such as cefiderocol and ceftolozane/tazobactam against P. aeruginosa is warranted as these agents generally target difficult-to-treat infections.

Methods: Persister formation was assessed using in vitro assays against nine clinical P. aeruginosa isolates exposed to cefiderocol or ceftolozane/tazobactam. Quantitative persister assays were performed using a stationary phase of bacteria challenged with 10-fold MIC drug concentrations. Persisters were quantitated as the percent persisters at 24 h and the log ratio (LR) difference in AUC for cfu for each antibiotic alone compared with growth control. The tolerance disc test (TDtest) was used to qualitatively detect persisters.

Results: Percent persisters at 24 h was lower with cefiderocol compared with ceftolozane/tazobactam for six of the nine tested isolates. Eight of the nine isolates had higher reduction in LR for cefiderocol groups, suggesting an overall higher and more rapid bacterial reduction in cefiderocol groups. For cefiderocol, five of the nine tested isolates lacked regrowth after replacement with glucose disc, suggesting no persistence via the TDtest. For ceftolozane/tazobactam, three isolates lacked persister formation.

Conclusions: Cefiderocol resulted in less bacterial persistence relative to ceftolozane/tazobactam against nine clinical P. aeruginosa isolates. Cefiderocol's siderophore mechanism may be advantageous over ceftolozane/tazobactam through enhanced anti-persister effects. Clinical correlation of these findings is warranted as persisters can lead to antibiotic resistance and treatment failure.

Background: We previously reported a cross-sectional analysis of online pharmacy practices and processes. Since then, the demand for and context of online healthcare has changed. However, the current state of access to and usage of antibiotics obtained online remains poorly understood.

Objectives: This study aimed to: (i) determine the legality of online pharmacies selling antibiotics in the UK; (ii) describe processes for obtaining antibiotics online; (iii) identify antimicrobial stewardship (AMS) and patient safety issues; and (iv) compare data with those obtained in 2016 to understand changes in context, and set priorities for targeted research in antibiotic access and usage.

Methods: Searches for 'buy antibiotics online' were conducted using 'Google' and 'Yahoo'. The first 10 websites with unique URL addresses for each were reviewed. Analyses were conducted on evidence of pharmacy registration, prescription requirement, whether choice was 'prescriber-driven' or 'consumer-driven', and whether information was required (allergies, comorbidities, pregnancy) or given (adverse effects) prior to purchase.

Results: Twenty unique URL addresses were analysed. Those evidencing UK location (n = 20; 100%) required a prescription and were appropriately registered. For 11 (55%) online pharmacies, decisions were initially consumer-driven for antibiotic choice, but not for dose or duration; contrasting with 2016 when for most (n = 16; 80%), decisions were consumer-driven for antibiotic choice, dose and quantity.

Conclusions: Variation continues to exist in relation to antibiotic practices online. We make several key recommendations for lawmakers and stakeholders. Targeted research, improved public engagement, professional education and new best practice guidelines are urgently needed for online UK antibiotic suppliers.

Background: The emergence of β-lactamase-producing bacteria has led to the use of β-lactam (BL) antibiotic and β-lactamase inhibitor (BLI) drug combinations. Despite therapeutic drug monitoring (TDM) being endorsed for BLs, the impact of TDM on BLIs remains unclear.

Objectives: Evaluate whether BLIs are available in effective exposures at the site of infection and assess if TDM of BLIs could be of interest.

Methods: Population pharmacokinetic models for 9 BL and BLI compounds were used to simulate drug concentrations at infection sites following EMA-approved dose regimens, considering plasma protein binding and tissue penetration. Predicted target site concentrations were used for probability of target attainment (PTA) analysis.

Results: Using EUCAST targets, satisfactory (≥90%) PTA was observed for BLs in patients with typical renal clearance (CrCL of 80 mL/min) across various sites of infection. However, results varied for BLIs. Avibactam achieved satisfactory PTA only in plasma, with reduced PTAs in abdomen (78%), lung (73%) and prostate (23%). Similarly, tazobactam resulted in unsatisfactory PTAs in intra-abdominal infections (79%), urinary tract infections (64%) and prostatitis (34%). Imipenem-relebactam and meropenem-vaborbactam achieved overall satisfactory PTAs, except in prostatitis and high-MIC infections for the latter combination.

Conclusions: This study highlights the risk of solely relying on TDM of BLs, as this can indicate acceptable exposures of the BL while the BLI concentration, and consequently the combination, can result in suboptimal performance in terms of bacterial killing. Thus, dose adjustments also based on plasma concentration measurements of BLIs, in particular for avibactam and tazobactam, can be valuable in clinical practice to obtain effective exposures at the target site.

Introduction: Cefiderocol is a siderophore cephalosporin active in vitro against carbapenemase-producing Enterobacterales, including New Delhi metallo-β-lactamases (NDM-1). A significant impact of the size of bacterial inoculum on its efficacy has been described in vitro, the clinical impact of which is unclear. Here, we analyse the inoculum effect of cefiderocol against E. coli-NDM-1 in vitro and in a murine peritonitis model.

Materials and methods: Escherichia coli 62-pTOPO and its isogenic variant expressing NDM-1, 62-pTOPO-NDM, were constructed from a clinical strain. MICs and bactericidal kinetics were determined at standard (105 cfu/mL) and high inoculum (107 cfu/mL). The in vivo effect was assessed in a severe murine peritonitis model, comparing low (106 cfu/mL) and high (108 cfu/mL) inoculum. Survival rates, organ sterilization and bacterial counts in spleen and peritoneal fluid were compared.

Results: Cefiderocol MICs for 62-pTOPO and 62-pTOPO-NDM at standard and high inoculum were 0.008, 2, 2 and 1024 mg/L, respectively. Bactericidal activity was not achieved in vitro for 62-pTOPO-NDM at high inoculum with high cefiderocol concentrations (16 mg/L). In vivo, for 62-pTOPO-NDM, no difference was found in survival, organ sterilization or bacterial counts between low and high inoculum. For 62-pTOPO, no difference was observed in survival, despite less organ sterilization and higher bacterial counts in organs with the high inoculum.

Conclusion: A significant inoculum effect of cefiderocol was observed in vitro for 62-pTOPO and 62-pTOPO-NDM. However, the effectiveness of cefiderocol was not reduced in vivo with a high bacterial inoculum. In vitro inoculum effect of cefiderocol may not be clinically significant.