Journal of Antimicrobial Chemotherapy最新文献

Objectives: To determine the PK of the pro-drug colistimethate sodium (CMS) and colistin in adult patients admitted to a South African critical care unit and to compare the PK with historical data.

Materials and methods: We conducted a prospective, observational, PK study in critically ill adult patients receiving intravenous colistin as part of standard of care. CMS was administered as a loading dose of either 9 million units (MU) or 12 MU followed by maintenance doses dependent on creatinine clearance (CrCl) at either 12- or 8-hourly. PK samples were collected at 1, 2, 4, 8, 12, 24 and 48 hours post-loading dose. CMS and colistin concentrations were analysed using liquid chromatography-tandem mass spectrometry. The PK of CMS and colistin were described using non-compartmental analysis in Phoenix WinNonlin.

Results: We enrolled 24 participants, 50% (12/24) were admitted with burns. Mean age was 42 years (SD ± 16.3) and mean CrCl was 140 mL/min (SD ± 58.7). The PK parameters following a loading dose of 9 MU were comparable to published data. Colistin AUC showed a negative correlation with white cell count (r = -0.63) and eGFR (r = -0.44). Probability of target attainment was acceptable at Acinetobacter baumannii minimum inhibitory concentrations <1 mg/L.

Conclusion: Our results are comparable to previously published literature. Notably, increasing eGFR and WCC decreased colistin AUC. Future work will adopt a population pharmacokinetic modelling approach to quantify and account for sources of variability, with the aim of informing individualized dosing strategies for this South African population.

Objectives: This study assessed the real-world clinical impact of rapid antimicrobial susceptibility testing (RAST) compared with conventional susceptibility testing (AST) in critically ill patients with Gram-negative bloodstream infections (GNB BSIs), focusing on early optimization of therapy and clinical outcomes in a high multidrug-resistant (MDR) setting.

Methods: We conducted a retrospective, observational study including adult patients with GNB BSIs who were stratified according to the susceptibility testing strategy used (RAST or conventional AST). The primary outcome was 30-day all-cause mortality. Secondary outcomes included administration of early active antimicrobial therapy, clinical failure and length of both intensive care unit (ICU) and hospital stay.

Results: A total of 133 patients were included (RAST: 37; AST: 96). Thirty-day mortality was observed in 4/37 patients (10.8%) in the RAST group and in 30/96 (31.3%) in the AST group (P = 0.015). Early active therapy was administered to 32/37 (86.5%) RAST patients versus 44/96 (45.8%) in the AST group (P < 0.001). Clinical failure occurred in 0/37 RAST patients versus 20/96 (20.8%) AST patients (P = 0.003). Mean ICU stay was 30.3 ± 22.9 days (RAST) versus 36.9 ± 25.6 days (AST), P = 0.17. In Cox regression analysis, RAST-guided management (HR = 0.16, 95% CI 0.04-0.62) and early active therapy (HR = 0.51, 95% CI 0.19-0.94) were independently associated with survival.

Conclusions: RAST may represent a valuable tool to optimize antimicrobial therapy in critically ill patients with GNB BSIs, particularly considering the increasing prevalence of MDR pathogens.

Therapeutic drug monitoring (TDM) is essential for optimizing systemic antifungal therapy, particularly for agents with narrow therapeutic windows, variable pharmacokinetics (PK) or established exposure-response relationships. By enabling individualized dosing, TDM improves efficacy, reduces toxicity and helps prevent resistance. This review synthesizes current evidence and recommendations for antifungal TDM across available and emerging agents, including triazoles, flucytosine, echinocandins, amphotericin B, and novel therapies such as ibrexafungerp, olorofim and fosmanogepix. Voriconazole, posaconazole and itraconazole exhibit substantial interpatient variability and concentration-dependent toxicity, supporting routine TDM. Fluconazole is generally predictable but may warrant monitoring in critically ill patients, those on renal replacement therapy, or with central nervous system infections, though empiric dose escalation is often more practical. Isavuconazole has more stable PK, limiting TDM to select high-risk scenarios. Flucytosine requires TDM due to its narrow therapeutic index and resistance risk, particularly in renal impairment. Echinocandins are safe, but critically ill or obese patients may be underexposed, warranting empiric dose adjustments over routine TDM. Liposomal amphotericin B exhibits complex PK with plasma concentrations poorly reflecting active drug, precluding reliable TDM. Emerging antifungals lack sufficient data to support routine TDM. Despite strong justification, real-world utilization remains inconsistent, constrained by access, logistics and interpretive challenges. Expanding timely access, standardizing protocols and developing consensus-driven guidance, while using empiric dosing strategies where appropriate, are essential to ensure safe, effective and individualized antifungal therapy.

Background: People with HIV have a greater risk of cardiovascular disease than the general population. Current literature suggests that some ARTs may exacerbate this risk.

Objectives: To estimate the risk of hypertension in treatment-naïve people with HIV receiving integrase strand transfer inhibitor (INSTI)/tenofovir alafenamide (TAF) or INSTI/non-TAF versus NNRTI/non-TAF regimens.

Methods: Post hoc pooled analysis evaluating data from US participants in five Phase 3 randomized studies. Adjusted prevalence of Stage 1 and 2 hypertension (American College of Cardiology/American Heart Association criteria) and conditional odds of higher blood pressure ratios were estimated using proportional odds mixed-effect regression through 108 weeks after ART initiation. Time to incident hypertension through 96 weeks was modelled using Cox proportional-hazards regression.

Results: In total, 2411 participants were included (528, 749 and 1134 received NNRTI/non-TAF, INSTI/non-TAF and INSTI/TAF regimens, respectively). Nearly half of participants had hypertension (Stage ≥1) at baseline. The Week 96 adjusted estimates of risk of hypertension (95% CI) were 1.06 (0.99, 1.13) and 1.12 (0.98, 1.27) for Stages ≥1 and ≥2 hypertension, respectively, for NNRTI/non-TAF versus INSTI/non-TAF, and 1.01 (0.95, 1.08) and 1.02 (0.91, 1.17) for Stages ≥1 and ≥2 hypertension, respectively, for NNRTI/non-TAF versus INSTI/TAF. There were no significant differences in conditional odds of high blood pressure between treatment groups. No significant differences were identified in time to incident composite hypertension for INSTI/non-TAF and INSTI/TAF versus NNRTI/non-TAF regimens; estimated hazard ratios (approximate 95% CI) were 0.88 (0.66, 1.17) and 0.98 (0.75, 1.28), respectively.

Conclusions: Results suggest the risk of hypertension is not significantly different across INSTI/TAF, INSTI/non-TAF and NNRTI/non-TAF regimens.

Objectives: To clarify the relationship between acute kidney injury (AKI) and vancomycin use in patients with renal impairment and to establish a risk score for AKI.

Methods: In this retrospective, multicentre, observational cohort study, trough and peak blood samples were collected from patients who initiated vancomycin therapy. The cumulative incidence of AKI within 14 days was compared among three groups classified according to renal function (estimated glomerular filtration rate ≥ 60, 30-59 and <30 mL/min/1.73 m2). The risk score and predicted probability of AKI incidence were calculated. AKI was defined in accordance with the Kidney Disease Improving Global Outcomes criteria.

Results: The incidence of AKI was 11.7% (99/847). No statistically significant difference was detected in the cumulative incidence of AKI among the three groups (P = 0.103). Cox proportional hazard analysis showed that the use of tazobactam/piperacillin [HR: 3.3, 95% CI (2.18-4.99), 2 points], vasopressors/inotropes [HR: 3.0, 95% CI (2.02-4.51), 2 points] and area under the concentration-time curve (AUC) on Day 2 [500-600 µg·h/mL: HR, 2.4, 95% CI (1.50-3.89), 1 point; >600 µg·h/mL: HR, 4.4, 95% CI (2.62-7.37), 3 points] were significantly related to the development of AKI. The predicted probabilities of AKI incidence were <5% (low-risk), 5% to <20% (moderate-risk), 20% to <40% (high-risk) and 40% to 67% (very high-risk), with total points of 0, 1-2, 3-4 and ≥5, respectively.

Conclusions: A risk prediction model was developed for AKI based on AUC exposure and concomitant medications, and no difference in AKI risk was observed across renal function categories.

Background: Emergence and spread of carbapenem-resistant Acinetobacter baumannii (CRAB) producing metallo-β-lactamases (MBLs), especially New Delhi MBLs (NDMs), are concerning due to resistance to last-resort antibiotics.

Methods: PubMed and Scopus were queried for studies published between 2020 and 2024 reporting MBL prevalence in CRAB isolates. Risk of bias was assessed across the population, setting and measurement domains. Binomial-Normal mixed-effects models were applied to estimate regional and country-specific weighted MBL and NDM prevalence proportions in CRAB. Subgroup and meta-regression analyses were performed to investigate heterogeneity.

Results: Two hundred thirty-three studies reporting 58 676 CRAB isolates were analysed. The global MBL prevalence in CRAB was 5.3% [95% confidence interval CI), 3.3%-8.2%]. Regional variability explained a substantial portion of heterogeneity in meta-regression (R2 = 35%). MBL prevalence in CRAB was highest in the Eastern Mediterranean (42.1%; 95% CI, 28.7%-56.8%) and African (36.1%; 95% CI, 12.2%-69.8%) regions, moderately high in South-East Asia (17.9%; 95% CI, 9.6%-30.9%), and low (<1%) in Europe, the Americas and the Western Pacific region. MBL prevalence in CRAB was higher in studies conducted during 2020-2024 than during 2012-2019 (7.2% versus 4.2%; adjusted odds ratio 2.3, P = 0.024). NDM was the dominant MBL in CRAB, with a global prevalence of 1.7% (95% CI, 1.1%-2.7%) in 218 studies.

Conclusions: Although its global prevalence is low, MBL-producing CRAB is common in specific regions and countries, threatening the utility of new antibiotics. Sustained surveillance, rigorous infection control and antimicrobial stewardship are required to preserve the activity of last-resort antimicrobials.