Journal of Antimicrobial Chemotherapy最新文献

Objectives: Bloodstream infections (BSIs) due to vancomycin-resistant Enterococcus spp. (VRE) are considered a predictor of mortality among frail patients. The aim of this study was to evaluate the risk factors associated with 30 day mortality and relapse of infection in enterococcal BSI caused by VRE and to evaluate the impact of antibiotic regimens in targeted therapy.

Methods: We conducted a retrospective study of consecutive hospitalized patients in six teaching hospitals from August 2016 to August 2022 in Italy. All adult patients with a documented VRE BSI were included.

Results: We enrolled 517 consecutive hospitalized patients with VRE BSI; of these BSIs 496 (96.5%) were caused by Enterococcus faecium and 26 (5.1%) by Enterococcus faecalis. The most frequently used antibiotics as backbone were linezolid (48.1%) and daptomycin (43.7%). Overall, the 30 day mortality was 32.1%. Upon Cox regression analysis, the risk factor independently associated with 30 day mortality was Charlson comorbidity index >3 points (P < 0.001), whereas a Pitt score <4 points (P = 0.031), surgery for source control of infection (P = 0.016) and time to targeted therapy <24 h (P = 0.006) were associated with survival. After propensity score adjustment, a daptomycin-based regimen (P = 0.003) was associated with 30 day survival.

Conclusions: VRE BSI is an important cause of mortality in frail/critically ill patients. Our data highlighted the role of daptomycin as backbone agent for the treatment of enterococcal BSI caused by vancomycin-resistant strains.

Background: Tenofovir diphosphate concentration in red blood cells is an objective measure of long-term oral pre-exposure prophylaxis (PrEP) or antiretroviral therapy (ART) adherence. However, current methods for measuring tenofovir diphosphate are equipment and capital intensive, limiting widespread adoption.

Objectives: Low cost, rapid diagnostics for measuring tenofovir diphosphate may drive clinical adoption of routine drug level measurement as a tool for adherence monitoring of tenofovir disoproxil fumarate-based PrEP or ART. We validate a simple and accessible enzymatic assay [REverSe TRanscrIptase Chain Termination (RESTRICT)] for measuring tenofovir diphosphate in dried blood spots (DBS) obtained from a directly observed therapy study of individuals on PrEP.

Methods: We performed RESTRICT measurements on 74 DBS samples from individuals on tenofovir disoproxil fumarate/emtricitabine regimens. We compared RESTRICT measurements with those from a gold-standard method of liquid chromatography tandem mass spectrometry (LC-MS/MS). The ability of RESTRICT to correctly classify DBS tenofovir diphosphate concentrations to established steady-state adherence benchmark concentrations was determined using area under receiver operating characteristic curves (AUCs).

Results: The RESTRICT measurements of DBS samples were highly correlated with LC-MS/MS measurements of tenofovir diphosphate from DBS (r = -0.90; P < 0.0001). The RESTRICT assay correctly classified DBS samples as above or below established steady-state adherence benchmark concentrations corresponding to low (AUC = 0.974), moderate (AUC = 0.936) and high (AUC = 0.955) levels of adherence.

Conclusions: The enzymatic RESTRICT assay can accurately measure tenofovir diphosphate concentrations in DBS specimens using simple procedures and readily available laboratory equipment, offering accessible objective adherence monitoring for persons receiving tenofovir disoproxil fumarate-based PrEP or ART.

Background: Cefepime/enmetazobactam is a newly approved β-lactam/β-lactamase inhibitor combination with promising activity against MDR Gram-negative Enterobacterales, particularly ESBL- and OXA-48-producing isolates. Reliable susceptibility testing methods are essential to guide its clinical use.

Objectives: To evaluate the performance of two commercial cefepime/enmetazobactam susceptibility testing methods, disc diffusion and Liofilchem™ MTS gradient strips, using broth microdilution (BMD) as the gold standard.

Methods: A total of 291 carbapenem-resistant Enterobacterales isolates, including 194 carbapenemase producers, were included. Susceptibility testing was performed using BMD, disc diffusion and Liofilchem™ MTS strips. Results were interpreted following EUCAST and FDA 2025 breakpoints. Essential agreement (EA) and bias were calculated for gradient strip methods according to the ISO 20776-2021 guideline, whereas categorical agreement (CA), very major errors (VMEs) and major errors (MEs) were determined for disc diffusion according to the ISO 20776-2:2007 guideline.

Results: The disc diffusion method demonstrated high CA (93.8% EUCAST, 95.9% FDA). VME rates exceeded acceptable thresholds using EUCAST breakpoints (20.8%) but were within limits for FDA (1.9%). Liofilchem™ MTS strips achieved 88.3% (95% CI: 84.1%-91.5%) EA and a bias of -8.9%. Both methods accurately detected susceptibility in OXA-48-producing isolates but showed limitations for isolates close to the MIC breakpoints.

Conclusions: Disc diffusion and Liofilchem™ MTS strips represent reliable alternatives to BMD for routine cefepime/enmetazobactam testing.

Background: The rise in fungal infections caused by multidrug-resistant pathogens like Candida haemulonii sensu stricto presents a significant global health challenge. The common resistance to current treatments underscores the urgency to explore alternative therapeutic strategies, including drug repurposing.

Objectives: To assess the potential of repurposing tafenoquine, an antimalarial agent, for antifungal use against C. haemulonii sensu stricto.

Methods: The efficacy of tafenoquine was tested using in vitro assays for minimum inhibitory concentration (MIC), minimum fungicidal concentration, biofilm inhibition, cell damage, cell membrane integrity, nucleotide leakage, sorbitol protection assay, and efflux pump inhibition. The compound's cytotoxicity was assessed through a haemolysis assay, and in vivo safety and efficacy were tested using Tenebrio molitor larvae.

Results: Tafenoquine exhibited potent fungicidal activity against C. haemulonii sensu stricto with an MIC of 4 mg/L and significantly inhibited biofilm formation by 60.63%. Tafenoquine also impaired mitochondrial functionality, leading to compromised cellular respiration. Despite these effects, tafenoquine did not cause significant protein leakage, indicating a distinct mechanism from membrane-targeting agents. In vivo study confirmed tafenoquine's non-toxic profile with no observed haemolysis or acute toxicity in the T. molitor model. During antifungal treatment with tafenoquine, a survival rate of approximately 60% was observed after 3 days.

Conclusions: The findings of this study highlight tafenoquine's potential as a promising candidate for antifungal drug repurposing, especially against C. haemulonii sensu stricto. Its effectiveness in inhibiting fungal growth and biofilm formation underscores its viability for further clinical development as a novel antifungal therapy.

Background: Well-established side effects of trimethoprim/sulfamethoxazole include cutaneous and liver toxicity, hypersensitivity syndrome and blood dyscrasias. Trimethoprim/sulfamethoxazole has also been associated with severe lung toxicity (LT) but reports are scarce.

Methods: We investigated pharmacovigilance data and reviewed spontaneous reports of trimethoprim/sulfamethoxazole-related LT recorded in the French national pharmacovigilance database (FPVD) and the WHO global database of adverse events (VigiBase®) up to 31 December 2023. We performed disproportionality analysis to detect a possible pharmacovigilance signal.

Results: A total of 755 patients with trimethoprim/sulfamethoxazole-related LT were reported in VigiBase®, 17 of which were from the FPVD. In VigiBase®, interstitial lung disease was the most frequent LT pattern (30.5%). A fatal outcome was reported in 197 patients (26.1%). Significant reporting ORs were observed for the following trimethoprim/sulfamethoxazole-related LT patterns: interstitial lung disease 1.5 (95% CI: 1.3-1.7); acute respiratory distress syndrome 2.9 (95% CI: 2.5-3.5); eosinophilic pneumonia 4.1 (95% CI: 3.2-5.2); diffuse alveolar damage 3.7 (95% CI: 2.6-5.3); organizing pneumonia 2.1 (95% CI: 1.4-3.1); pulmonary toxicity 1.9 (95% CI: 1.3-2.9); acute lung injury 7.5 (95% CI: 4.9-11.6) and hypersensitivity pneumonitis 2.7 (95% CI: 1.7-4.2).

Conclusions: We highlight statistically significant disproportionality for several trimethoprim/sulfamethoxazole-related LT patterns, which constitutes a pharmacovigilance signal. Trimethoprim/sulfamethoxazole-related LT is rare, but may be critical and even life-threatening. Physicians should be aware of potential trimethoprim/sulfamethoxazole-related LT and should inform their patients, since early intervention could prevent severe outcome.

Background: Respiratory syncytial virus (RSV) may contribute to a substantial volume of antibiotic prescriptions in primary care. However, data on the type of antibiotics prescribed for such infections are only available for children <5 years in the UK. Understanding the contribution of RSV to antibiotic prescribing would facilitate predicting the impact of RSV preventative measures on antibiotic use and resistance. The objective of this study was to estimate the proportion of antibiotic prescriptions in English general practice attributable to RSV by age and antibiotic class.

Methods: Generalized additive models examined associations between weekly counts of general practice antibiotic prescriptions and laboratory-confirmed respiratory infections from 2015 to 2018, adjusting for temperature, practice holidays and remaining seasonal confounders. We used general practice records from the Clinical Practice Research Datalink and microbiology tests for RSV, influenza, rhinovirus, adenovirus, parainfluenza, human metapneumovirus, Mycoplasma pneumoniae and Streptococcus pneumoniae from England's Second Generation Surveillance System.

Results: An estimated 2.1% of antibiotics were attributable to RSV, equating to an average of 640 000 prescriptions annually. Of these, adults ≥75 years contributed to the greatest volume, with an annual average of 149 078 (95% credible interval: 93 733-206 045). Infants 6-23 months had the highest average annual rate at 6580 prescriptions per 100 000 individuals (95% credible interval: 4522-8651). Most RSV-attributable antibiotic prescriptions were penicillins, macrolides or tetracyclines. Adults ≥65 years had a wider range of antibiotic classes associated with RSV compared with younger age groups.

Conclusions: Interventions to reduce the burden of RSV, particularly in older adults, could complement current strategies to reduce antibiotic use in England.

Background: A drawback of vancomycin use is the need for therapeutic drug monitoring and renal function monitoring. Traditional blood sampling involves drawing blood through a venepuncture. An alternative method, dried blood spot (DBS) sampling allows for self-sampling at home.

Objectives: To clinically validate a DBS method for simultaneous monitoring of vancomycin and creatinine.

Methods: Hospitalized adults treated with intravenous vancomycin were included (trial registration NCT05257070). Blood sampling consisted of one venepuncture and one finger prick. Whole-blood DBS samples from patients were obtained by applying one drop of whole blood onto Whatman 903 filtrate paper. Bland-Altman analyses were used to assess the agreement and bias between the two measurements. Patients were asked to state their preferences for one of the two sampling methods.

Results: The study involved a final analysis of 39 patient samples for the clinical validation of vancomycin and 46 patient samples for the clinical validation of creatinine. The difference between plasma and DBS concentrations was ≤20% for 77% of the vancomycin samples, the mean bias was -0.1379% (95% limit of agreement -5.899-5.623). The difference between plasma and DBS concentrations was ≤20% for 89% of the creatinine samples, the mean bias was 2.656% (95% limit of agreement -26.16-31.47). Most patients (18 out of 31) preferred a finger prick over a venepuncture and 12 patients indicated no preference.

Conclusions: This is the first study that successfully clinically validated a DBS sampling method for simultaneous measurement of vancomycin and creatinine, allowing for direct use in (outpatient) practice.