Journal of Antimicrobial Chemotherapy最新文献

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 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: 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: 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.

Aims: Ciprofloxacin has been demonstrated to prolong QT intervals at higher doses beyond those used in conventional practice. We investigated the effect of ciprofloxacin on the QT interval by examining the difference between mean QT intervals (raw and corrected) at baseline and after theoretical achievement of steady state levels in 88 patients receiving oral ciprofloxacin therapy. The utility of a nomogram to decide the cut point for QT interval prolongation was also examined.

Patients and methods: A retrospective study examined serial surface 12-lead ECGs in a sample of patents prescribed oral ciprofloxacin by physicians in the Department of Ambulatory Care and Hospital in the Home Service at Liverpool Hospital, a tertiary referral hospital in Sydney, Australia. All patients had a baseline ECG and a follow-up ECG after achievement of theoretical steady state.

Results: A total of 88 patients were included. No significant difference in either raw QT or corrected QT using Bazett's formula was observed. Two methods were used to measure the QT interval, one using the median of six observations and one using a single lead. Poor inter-rater reliability for raw measures was observed. A high level of agreement for the cut point for QT prolongation was observed using a nomogram.

Conclusion: QT and QTc prolongation in a standard 12 lead ECG would not be expected after oral administration of ciprofloxacin at conventional doses. We recommend ECG monitoring to be undertaken only with increased clinical risk.

Objectives: Mutations in the 3'-polypurine tract (3'PPT) of HIV-1 have been observed under pressure with two integrase strand transfer inhibitors, dolutegravir and cabotegravir. In the DOMONO randomized clinical trial, 3'PPT mutations emerged in a participant who experienced treatment failure under dolutegravir monotherapy. To understand the basis for this rare mutational pathway, we examined baseline viral sequences and identified the K156N natural polymorphism. Given the role of K156 in viral DNA binding, the potential relationship between K156N and 3'PPT mutations was further investigated.

Methods: We assessed the impact of K156N on integrase using in silico modelling and biochemical assays with recombinant proteins. Infectivity, replicative capacity, and drug susceptibility of viruses carrying K156N, 3'PPT mutations, or both were measured. Viral evolution was assessed in cell culture.

Results: Structural models indicated that K156N altered viral DNA binding. K156N reduced strand transfer activity through decreased affinity for the LTR but increased 3'-processing. The K156N virus had normal infectivity, whereas the 3'PPT mutations decreased infectiousness sixfold and lowered maximal infectivity. K156N partially compensated for this defect, but maximal infectivity remained diminished. K156N also partially compensated for defects in replicative capacity imposed by 3'PPT mutations. K156N alone did not confer resistance against dolutegravir, nor did it increase the modest (2.5-fold) resistance conferred by the 3'PPT mutations. K156N alone promoted the spontaneous emergence of 3'PPT mutations distinct from those seen in DOMONO.

Conclusions: These findings establish a direct functional relationship between natural variation in HIV-1 integrase and the emergence of 3'PPT mutations. People harbouring a virus with the K156N natural polymorphism may be predisposed to developing 3'PPT mutations upon failure with DTG. However, the clinical relevance of this association remains to be established.

Background: Critically ill patients are exposed to important pharmacokinetic alteration that can lead to under- or over-exposure. In addition, children and neonates undergo physical growth and organ maturation that alter drug pharmacokinetics, especially children with sickle cell disease who frequently experience organ dysfunctions. The aim of the study was to describe cefotaxime and desacetyl-cefotaxime pharmacokinetics and optimize dosing regimens in this population.

Methods: We performed a pharmacokinetic analysis of cefotaxime and its metabolite desacetyl-cefotaxime via a population approach. Trough concentrations and steady-state concentrations were then simulated using several doses and were compared to pharmacological targets: 100% fT > 4 × MIC and Cτ or CSS < 60 mg/L.

Results: A total of 797 cefotaxime and desacetyl-cefotaxime observations were collected from 242 children and neonates, including 50 with sickle cell disease (SCD). Cefotaxime data was best described by a two-compartment model with first-order absorption and elimination. A supplemental compartment was linked to the cefotaxime central compartment to describe desacetyl-cefotaxime pharmacokinetics. Allometric scaling with bodyweight, eGFR and Sickle cell status turned out to be significant in the model. Post-menstrual age was used to describe organ maturation functions for neonates. Simulations showed that probability of attaining targets was systematically better through continuous perfusion. Doses were suggested up to 300 mg/kg/day according to covariates.

Conclusion: We identified bodyweight, SCD status and eGFR as significant covariate that influence cefotaxime PK. Continuous infusion was the most performant way to achieve the pharmacological target in critically ill children and neonates, making a first necessary step towards individualized prescription in this fragile population.

Objectives: VRE resistant to potential therapeutic agents such as linezolid are an increasing concern in Canada and worldwide. Infections produced by these isolates have limited treatment options and are associated with poor clinical outcomes. We report an isolate of vancomycin-resistant Enterococcus faecium (VREfm); identified through the Canadian surveillance program, CANWARD, which exhibited linezolid resistance (LVREfm); and carried the optrA and cfr(D) genes on a linear plasmid.

Methods: Antimicrobial susceptibility testing was performed by broth microdilution and MICs were interpreted by 2025 CLSI breakpoints. WGS was performed to characterize resistance determinants and the associated plasmid.

Results: In 2021, a single LVREfm isolate was recovered from a blood culture of a 67-year-old male patient admitted to an ICU. The isolate was XDR but remained susceptible dose dependent to daptomycin (MIC = 2 mg/L). MLST identified the isolate as ST817, a sequence type not commonly found in our national collection.Vancomycin resistance was mediated by the vanA gene cluster, while linezolid resistance determinants included optrA, cfr(D) and the 23S rRNA gene mutation, G2576T. Vancomycin and linezolid resistance genes were co-located on a linear plasmid that exhibited over 94% sequence identity to previously described linear plasmids from India and the USA. Notably, the plasmid also encoded four toxin-antitoxin systems, potentially contributing to its stability and persistence.

Conclusions: This case highlights the appearance of linezolid resistance in VRE mediated by linear plasmids in Canada and underscores the importance of ongoing genomic surveillance to track the dissemination of MDR determinants in clinical settings.

Background: Pluralibacter gergoviae is a gram-negative bacillus in the Enterobacteriaceae family. Although rarely associated with human infections, its resistance to preservatives and presence in hospital-use products raise concerns about nosocomial transmission.

Objectives: To describe the clinical and microbiological profiles of P. gergoviae infections.

Methods: A comprehensive search was conducted in multiple databases and grey literature without time restrictions. Eligibility criteria included: (1) studies reporting human infections by P. gergoviae and (2) patients with confirmed infections. Data were synthesized narratively and summarized as frequencies and proportions. Univariate and multivariate analyses assessed risk factors for multidrug resistance (MDR) and mortality.

Results: Of 371 articles retrieved, 16 met the inclusion criteria, and 18 additional studies were identified through grey literature and manual search, totalling 34 studies. Three described outbreaks, two in neonatal intensive care units (NICUs). Overall, 196 patients were identified, predominantly male (59%), with 66% of infections being healthcare-associated. Most were admitted to ICUs (74%), especially NICUs (70%). Bloodstream infections were most common, followed by periodontitis and urinary tract infections. Phenotypic methods were primarily used for identification. MDR was reported in 33% of strains; ESBL and carbapenemase production in 35% and 23% of cases, respectively. The most frequent carbapenemase genes were blaKPC, blaNDM, and blaIMP. Mortality occurred in 11% of cases, and all MDR-related deaths were associated with blaKPC. Prior antibiotic use was significantly associated with mortality (P = 0.039; OR: 13).

Conclusions: Pluralibacter gergoviae is rare but clinically relevant, with MDR potential and impact on vulnerable populations, particularly in NICU settings.

Objectives: Gepotidacin is a novel triazaacenaphthylene topoisomerase inhibitor that has demonstrated non-inferiority to 500 mg of intramuscular ceftriaxone plus 1 g of oral azithromycin for the treatment of uncomplicated urogenital gonorrhoea. We evaluated gepotidacin in vitro activity against a panel of ceftriaxone-resistant Neisseria gonorrhoeae isolates that were referred to the UK Health Security Agency between 2015 and 2023.

Methods: Gepotidacin and comparator antimicrobials were tested against 23 ceftriaxone-resistant (MIC ≥0.25 mg/L) N. gonorrhoeae isolates by agar dilution. Genomic sequences were examined for known resistance determinants and sequence types.

Results: Gepotidacin inhibited the majority (96%) of isolates at ≤2 mg/L, with MIC range, MIC50 and MIC90 values of 0.25-4, 0.5 and 2 mg/L, respectively. All 23 isolates had amino-acid modifications associated with ciprofloxacin resistance, including the rare GyrA A92P alteration in 10 isolates, none of which are believed to effect gepotidacin binding. All isolates had mutations causing the overexpression of the MtrCDE efflux pump and 10 isolates had mutations causing the overexpression of the NorM efflux pump. Nine different MLSTs were subdivided into 16 and 14 NG-MAST and NG-STAR types, respectively. MLST ST8123 was the most prevalent MLST and the gepotidacin MIC range against this sequence type was similar to the overall distribution.

Conclusion: Overall, gepotidacin was active in vitro against this challenging panel of ceftriaxone-resistant gonococcal clinical isolates. Gepotidacin activity does not seem to be affected in this ceftriaxone-resistant set of strains. A structural analysis suggests that the rare GyrA A92P alteration identified in this study does not affect gepotidacin binding.