Journal of Antimicrobial Chemotherapy最新文献

Background and objective: Stenotrophomonas maltophilia is an emerging multidrug-resistant opportunistic pathogen, frequently recovered from deep sites in immunocompromised or critically ill patients. Its clinical relevance is difficult to distinguish from colonization, particularly in polymicrobial infections. To describe the management of patients with deep-site S. maltophilia isolates and to identify factors associated with 28-day mortality.

Methods: We conducted a bicentric retrospective study including all patients with at least one deep-site S. maltophilia isolates in two Paris academic hospitals between 2018 and 2020. Demographic, clinical, microbiological and therapeutic data were collected. Appropriate therapy was defined upon in vitro susceptibility. Propensity score weighting was applied to adjust for confounding when assessing the association between appropriate therapy and 28-day mortality.

Results: A total of 131 patients were included (67% male; median age 61 years); 63% were immunocompromised and 31% admitted to intensive care. Isolates originated mainly from urine (41%), blood (32%) and respiratory samples (21%); 57% of cultures were polymicrobial. Appropriate therapy was administered to 53% of patients, predominantly trimethoprim/sulfamethoxazole or fluoroquinolones. Overall 28-day mortality was 20%. Mechanical ventilation was independently associated with mortality (HR 4.13, P = 0.001). After propensity score weighting, appropriate therapy was not significantly associated with improved survival.

Conclusion: Targeted therapy against S. maltophilia did not reduce 28-day mortality after adjustment, suggesting that patient condition and infection severity may outweigh the effect of targeted treatment. Given the modest sample size, potential confounding, and the secondary nature of this analysis, these findings should be interpreted with caution. Careful clinical evaluation is warranted before initiating specific S. maltophilia therapy.

Objectives: Perioperative antibiotic prophylaxis is crucial for preventing detrimental postoperative prosthetic joint infections (PJIs). Guidelines aim to prevent infection with methicillin-susceptible staphylococci-in Sweden through administering cloxacillin, at fixed doses with minimal consideration to kidney function or patient weight. Over- and under-dosing could have adverse effects, negative effects on the microbiome, or increase the risk of PJI. We aimed primarily to evaluate whether the current uniform prophylactic regimen of cloxacillin in hip and knee arthroplasty is adequate.

Patients and methods: Patients subjected to elective prosthetic joint surgery (N = 204) were included in a prospective study. Free plasma concentrations of cloxacillin were measured on three occasions throughout arthroplasty surgery. Samples were analysed using a validated HPLC-MS/MS method. A free concentration of <2 mg/L was deemed a theoretically appropriate concentration to suppress growth of methicillin-susceptible staphylococci in bone. A sensitivity analysis with values of 1 and 4 mg/L was included.

Results: Potentially subtherapeutic concentrations (≤2 mg/L) at the end of surgery were found in 31 cases (15%). The corresponding numbers for 1 and 4 mg/L were 3 and 88 (1% and 43%). In multivariable logistic regression analysis, an ASA (American Association of Anesthesiologists physical status) score of I (relatively healthy patients), estimated glomerular filtration rate >90 mL/min/1.73 m2, body weight >100 kg and long duration of surgery significantly predicted suboptimal concentrations.

Conclusions: Current cloxacillin dosing in hip and knee arthroplasty surgery results in a risk for subtherapeutic levels in patients with high body weight and preserved renal function. Therefore, dosing guidelines for cloxacillin prophylaxis in arthroplasty should be reviewed.

Background: Voriconazole is recommended as first-line therapy for invasive fungal infections but exhibits substantial pharmacokinetic (PK) variability and hepatotoxicity. Although CYP2C19 polymorphisms partially explain this variability, evidence regarding additional genetic determinants remains inconsistent. Studies integrating genetic and clinical factors for voriconazole PK and hepatotoxicity are limited.

Objectives: To assess the association between 10 genetic variants and voriconazole trough concentrations in CYP2C19 normal (NM) and intermediate (IM) metabolizers and to identify predictors of PK variability and hepatotoxicity.

Methods: This observational study included 114 adult Chinese patients receiving voriconazole between July 2022 and May 2023. Associations between genetic variants and voriconazole trough concentrations were assessed within CYP2C19 NMs and IMs. Generalized linear models (GLMs) identified predictors of PK variability, and binary logistic regression assessed hepatotoxicity risk.

Results: Voriconazole trough concentrations varied over 40-fold (0.2-9 μg/mL). Nominal associations were observed for CYP3A4 (rs4646437) and NR1I2 (rs7643645, rs3814055) in NMs and for SLCO1B3 (rs4149117), SLCO2B1 (rs3781727) and NR1I2 (rs3814055) in IMs, but none remained significant after Bonferroni correction. GLM analysis identified SLCO1B3 (rs4149117), NR1I2 (rs3814055), albumin, C-reactive protein (CRP) and daily dose as predictors of PK variability. Hepatotoxicity occurred in 27.2% of patients and was associated with higher trough concentrations, whereas the NR1I2 (rs7643645) GG genotype and higher baseline platelet count were associated with reduced risk.

Conclusions: Marked interindividual variability in voriconazole exposure persists among CYP2C19 NMs and IMs. Integrating therapeutic drug monitoring (TDM) with genetic and clinical factors may optimize dosing and reduce hepatotoxicity risk. Larger multicentre studies are still needed.

Background: Teicoplanin exhibits complex pharmacokinetics with substantial inter-patient variability. Therapeutic drug monitoring (TDM) is recommended to ensure adequate exposure, yet contemporary data on real-world prescribing practices are scarce. We evaluated current teicoplanin dosing and monitoring practices across UK and Irish hospitals.

Methods: We conducted a multicentre, retrospective cohort study (Teicoplanin in UK: Study of Hospital Practice; TUcK-SHOP) across 21 hospitals. Adults receiving ≥5 days of intravenous/intramuscular teicoplanin with at least one TDM sample were included. Primary outcome was adherence to local or national dosing guidelines. Secondary outcomes included initial trough level attainment (≥20 mg/L) and laboratory-confirmed toxicity. Multivariable linear regression identified predictors of first trough concentrations.

Results: A total of 391 patients met inclusion criteria (median age 69 years; 57.5% male). Guideline adherence was 66% overall but varied widely between sites (5%-100%). Most patients received three-dose loading (61.3%) with median maintenance dosing of 10.6 mg/kg daily (IQR 7.3-12.1). Median first trough level was 24.6 mg/L (IQR 17.9-33.2); only 40.8% of patients on 6 mg/kg maintenance achieved ≥20 mg/L versus 86.6% on 12 mg/kg (P < 0.001). Independent predictors of higher trough levels included lower creatinine clearance, longer time to TDM sampling, higher loading and maintenance doses, and greater body weight (adjusted R2 = 0.26, P < 0.001). Dose adjustments were required in 30% of patients.

Conclusions: Teicoplanin prescribing demonstrates significant variation across UK and Irish hospitals. Higher maintenance dosing (10-12 mg/kg) predicts therapeutic target attainment. These real-world data support the need for standardized dosing protocols to optimize teicoplanin therapy.

Objectives: The aim of this study was to investigate the fluctuations in isavuconazole concentrations and to identify influencing factors in Chinese patients with haematological malignancies.

Methods: A retrospective analysis was conducted on patients with haematological malignancies who received their first standard dose of isavuconazole treatment in 2024. Statistical analysis of trough concentrations of isavuconazole, demographics and clinical characteristics over 60 days of treatment was performed. A nomogram was constructed based on independent risk factors to predict isavuconazole trough concentrations > 7 mg/L.

Results: A total of 63 patients with a median age of 54 (39-63) years and 390 isavuconazole plasma concentrations with a median value of 5.68 mg/L (range 1.24-16.49 mg/L) were included. The median intra- and inter-individual coefficients of variation were 15.0% and 43.3%, respectively. In univariate and multivariate analysis, isavuconazole levels > 7 mg/L on day 7 were significantly associated with body mass index (BMI) and albumin (ALB). Compared to patients with a BMI > 21.0 kg/m2, those with a BMI ≤ 21.0 kg/m2 exhibited a 15.88-fold increased risk of isavuconazole trough concentrations > 7 mg/L. Similarly, patients with ALB ≥ 36.4 g/L showed a 4.71-fold higher risk of elevated isavuconazole levels than those with ALB < 36.4 g/L. A nomogram model for effectively predicting the risk of isavuconazole concentrations exceeding 7 mg/L based on BMI and ALB results was successfully established.

Conclusions: Patients with haematological malignancies treated with isavuconazole show modest plasma concentration variability. However, for patients with a BMI ≤ 21.0 kg/m2 and/or an ALB ≥ 36.4 g/L, we propose that therapeutic drug monitoring may assist in ensuring medication safety. Additionally, for the first time, a nomogram was developed to predict isavuconazole levels > 7 mg/L using BMI and ALB, though further validation is warranted.

Introduction: Selection and dosing of surgical antimicrobial prophylaxis (SAP) to prevent surgical site infections (SSIs) is variable and often inappropriate in clinical settings resulting in increased risk of SSI. We therefore developed and implemented a novel computer decision-support tool to improve appropriate SAP selection specific to each patient's procedure and clinical context.

Methods: The intervention, performed at a multi-site tertiary hospital network, was a computer decision-support tool programmed within the hospital's electronic health record (EHR) to provide patient-specific SAP recommendations based on four variables: procedure name, patient's beta-lactam allergy status, MRSA status and weight. Safety of cefazolin prophylaxis among patients with self-reported beta-lactam allergy was established in the pre-operative clinic using a validated simple two-item questionnaire. Before each operation, a best practice SAP recommendation alert was provided to the anaesthesiologist based on the inputs from the four aforementioned variables.

Results: In the post-intervention period of 2 years, a total of ∼110 recommendation alerts were logged. A random sample audit of 408 surgical encounters were selected from the pre- and post-intervention periods. Overall, appropriate antibiotic administration rose from 77% (161/208) to 92.5% (185/200) (χ2 = 18.0, P < 0.001) post-intervention. Significant improvements were made for procedure-specific antibiotic selection (80.5% versus 94.5%; χ2 = 19.3, P < 0.001) and weight-based dosing (92.5% versus 98.4%; χ2 = 7.45, P = 0.006). Using National Surgical Quality Improvement Program (NSQIP) auditing of 21 912 surgeries showed a significant decline in SSIs following the implementation of the intervention in June 2022.

Conclusion: In this first-ever intervention designed to direct SAP prescribing based on patient-specific variables, we significantly improved appropriate SAP selection and reduced SSIs across a comprehensive list of surgical procedures.

Objectives: To (1) assess the prevalence and patterns of HIV drug resistance (HIVDR) mutations, (2) identify correlations between different HIVDR mutations within drug classes, and (3) examine the association between resistance mutations and high HIV viral load.

Methods: We conducted a secondary analysis of retrospective data collected through the Population-based HIV Impact Assessment (PHIA) surveys conducted between 2015 and 2019 in 13 African countries. We included participants aged ≥15 years with available HIVDR genotyping. The primary outcomes were (1) prevalence of HIVDR mutations, categorized by drug class into non-nucleoside reverse transcriptase inhibitors (NNRTIs), Nucleoside Reverse Transcriptase Inhibitors (NRTIs), and Protease inhibitors (PIs); (2) high HIV viral load (VL), (HIV RNA ≥1000 copies/mL).

Results: The analysis included 2292 participants, with a median age range between 31 and 41 years. More than one-third of participants were not receiving ART. Of all participants, 1949 (85%) had high VL. Resistance to NNRTIs and NRTIs was the most prevalent in most countries, ranging from 43% to 60%, and 37% to 53%, respectively. Resistance to PI ranges from 0.2% to 5%. Multiple drug resistance mutations across all ART classes were strongly associated with high VL. Among NNRTIs, 16/39 mutations (e.g. K103N, Y181C) and 18/34 NRTI mutations (e.g. M184V, K65R) showed strong associations with high VL in ≥10 countries. For PIs, Q58E and L33F emerged as key mutations strongly associated with high VL across multiple nations.

Conclusions: Strengthening resistance surveillance, optimising ART regimens, and improving adherence are crucial to curb resistance and sustain HIV epidemic control.

Introduction: Risk of transmission of HIV through breastfeeding is minimal in case of maternal viral suppression due to antiretroviral therapy. However, to what extent antiretroviral drugs transfer into breastmilk is not fully understood. Data are especially lacking for relatively newer drugs-such as bictegravir-that only recently was approved to use in pregnancy. Therefore, the aim of this study is to determine infant exposure to bictegravir through breastmilk.

Materials and methods: Concentrations of bictegravir were measured in plasma and breastmilk of healthy, lactating women without HIV after a single dose of bictegravir 50 mg (co-formulated with tenofovir alafenamide 25 mg and emtricitabine 200 mg). Concentrations were measured using validated LC-MS/MS assays and pharmacokinetic parameters were calculated using non-compartmental analysis. Breastmilk to maternal plasma ratio, daily infant dosage and relative infant dose were established to determine infant exposure to bictegravir through breastmilk.

Results: Twelve volunteers participated in the study. The geometric mean (CV%) area under the curve based on the last measured concentration was 52.17 (22.6) mg*h/L in plasma and 0.44 (32.0) mg*h/L in breastmilk, resulting in a geometric mean (CV%) breastmilk to maternal plasma ratio of 0.009 (26.6). The median (IQR) daily infant and relative infant doses with an intake of 150 or 200 mL/kg/day were 0.034 mg/kg/day (0.026-0.060) and 0.046 (0.035-0.080) mg/kg/day and 0.68 (0.53-1.00) % and 0.90% (0.71-1.33), respectively.

Conclusion: Exposure to bictegravir through breastmilk is very low, with a relative infant dose below 1%. Even though metabolizing capacity in newborns is not yet fully developed, it is not expected to cause infant toxicity.

Objectives: Pseudomonas aeruginosa is a common microorganism in chronic infections due to biofilm formation and antibiotic resistance. This study aimed to compare the synergistic effects of antibiotic combinations against carbapenem-resistant P. aeruginosa (CRPA) in planktonic and biofilm-embedded states.

Methods: Twelve CRPA bloodstream isolates from the Asian Bacterial Bank (2016-2018) were analysed. The minimum biofilm eradication concentrations (MBECs) were determined using the peg lid system, and antimicrobial interactions were assessed using biofilm checkerboard assays, testing three double combinations (colistin-rifampin, colistin-imipenem, and rifampin-ceftazidime/avibactam) and two triple combinations (colistin-rifampin-imipenem and colistin-rifampin-ceftazidime/avibactam).

Results: The MBEC values of all four antimicrobial agents (rifampin, colistin, imipenem, and ceftazidime/avibactam) were significantly higher than their corresponding minimum inhibitory concentration values (P < 0.001). Although single agents required markedly elevated concentrations to eradicate CRPA biofilms, approximately half of the double and triple antimicrobial combinations demonstrated synergistic activity. In the biofilm phase, synergism rates were comparable between triple combinations (colistin-rifampin-ceftazidime/avibactam, 50%; colistin-rifampin-imipenem, 66%) and double combinations (colistin-rifampin, 42%; rifampin-ceftazidime/avibactam, 42%; colistin-imipenem, 66%). The triple combinations showed lower FBEC indices (colistin-rifampin-imipenem: median 0.17; colistin-rifampin-ceftazidime/avibactam: 0.34) than the corresponding double combinations (colistin-rifampin: 0.53; colistin-imipenem: 0.20; rifampin-ceftazidime/avibactam: 0.78), although these differences were not statistically significant.

Conclusions: Our study provides experimental evidence that antimicrobial combination therapy may offer advantages over single agents for CRPA biofilm eradication, supporting further investigation into the role of such regimens in biofilm-associated infections.