Journal of Antimicrobial Chemotherapy最新文献

Background: Antibiotic consumption is considered an important risk factor for Clostridioides difficile infection (CDI). This ecological analysis investigates the influence of outpatient antibiotic prescriptions in statutory health insurance (SHI) on the admission prevalence of CDI in German hospitals participating in voluntary CDI surveillance through the hospital infection surveillance system (Krankenhaus-Infektions-Surveillance-System; KISS).

Methods: The annual CDI admission prevalence of a hospital at the federal state level was associated with the outpatient antibiotic consumption of the corresponding federal state. The quantification of outpatient antibiotic prescriptions was determined as the average DDD per 1000 insured persons per day. The risk factors for CDI on hospital admission included the annual consumption of the eight substance groups aminopenicillin combinations/staphylococcal penicillins, basic penicillins, cephalosporins, quinolones, lincosamides/macrolides, nitrofurantoin/fosfomycin/nitroxoline, sulphonamides/trimethoprim and tetracyclines, the type of care provided by the hospital, and the calendar year, and were examined using multivariable regression analyses (generalized estimating equations models).

Results: Between 2011 and 2019, the number of outpatient antibiotic prescriptions decreased from 13.9 to 10.4 DDD per 1000 insured persons per day (-25%), and the CDI admission prevalence decreased from 0.22 to 0.12 per 100 patients (-45%). Basic penicillins and cephalosporins were identified as risk factors for increased CDI admission prevalence, while nitrofurantoin/fosfomycin/nitroxoline and sulphonamides/trimethoprim were associated with decreased CDI admission prevalence.

Conclusions: A decrease in outpatient antibiotic prescriptions with known risk of developing CDI was associated with a decrease in hospital CDI admission prevalence. Our ecological analysis indicates that rational and restrained antibiotic use in the outpatient setting may reduce the incidence of CDI in the population requiring inpatient treatment.

Background: Doravirine is licensed in patients living with HIV (PWH) harbouring no prior resistance to any NNRTIs. We aimed to evaluate in real life the efficacy of doravirine with prior NNRTI virological failure and NNRTI resistance-associated mutations (RAMs).

Methods: This observational study included PWH switched to a doravirine-containing regimen between 30 September 2019 and 1 May 2022, with an HIV-1 RNA of ≤50 copies/mL and past NNRTI-RAMs. The main outcome was the proportion of participants with virological failure at Week 48 and Week 96. Secondary outcomes evaluated the rate of viral suppression and transient virological blip, RAMs in the case of virological failure and side effects.

Results: A total of 102 patients were analysed, mostly men (63%), with a median age of 59 years (IQR 51-63). The median time since HIV-1 diagnosis was 26 years (IQR 16-31), on ART for 22 years (IQR 14-26) and virally suppressed for 7 years (IQR 1-11).Of the patients analysed, 25/102 (25%) had documented historical RAMs to doravirine, 9/25 (36%) showing possible resistance and 16/25 (64%) showing major resistance. The resistance profile primarily (21/23) consisted of the K103N, Y181C and/or G190A/E reverse transcriptase substitutions. Median time since the last detection of NNRTI-RAMs was 12 years (5-17). Over 2 years follow-up, no virological failure occurred, neither at Week 48 (0/87; 0%) nor Week 96 (0/86; 0%).

Conclusions: This is the first real-world study to provide new insight about the use of doravirine-containing regimens as a treatment in long-term suppressed patients whose viruses harboured specific NNRTI-RAMs in their history.

Background: Posaconazole is used to prevent and treat invasive fungal infections (IFIs) in immunocompromised children, including those undergoing cancer treatment or HSCT. Despite differences in pharmacokinetics and IFI epidemiology between children and adults, therapeutic targets established in adult studies are often applied to children.

Objectives: This systematic review evaluated the correlation between serum posaconazole concentrations and clinical outcomes of IFI prophylaxis and treatment in children with malignancies or HSCT recipients.

Methods: Four databases (Cochrane, Embase, MEDLINE and PubMed) were searched for studies involving children (≤18 years old) receiving cancer treatment or HSCT that reported posaconazole serum concentrations and treatment outcomes. Animal studies, those primarily in adult (>18 years old) populations, non-malignant conditions (excluding HSCT), case reports, letters, editorials, conference abstracts and narrative reviews were excluded. Bias was assessed using the Newcastle-Ottawa scale.

Results: Nineteen studies were included: 12 reported outcomes of posaconazole prophylaxis; two of treatment; and five of both. For prophylaxis, breakthrough IFIs occurred in 1%-12% of children. All but one occurred with serum concentrations of ≤0.7 mg/L. For treatment, no clear association was observed between a trough concentration of >1.0 mg/L and treatment efficacy, with poor outcomes reported for serum concentrations ranging between 0.2 and 4.8 mg/L. Overall, quality of evidence was poor (medium to high risk of bias for 18 papers, low risk for 1 paper) and there was variation in IFI definitions across studies.

Conclusions: This review supports current recommendations for posaconazole prophylaxis in paediatric oncology and HSCT recipients. The absence of a clear correlation found between serum trough concentrations and treatment efficacy highlights the need for further studies to determine optimal therapeutic targets for treatment.

Objectives: To study the population structure and genomic characteristics, including antimicrobial resistance genes, plasmid types and surface polysaccharide type, of the globally distributed Acinetobacter baumannii belonging to ST32 (Institut Pasteur scheme).

Methods: Antibiotic resistance phenotype for 19 antibiotics was determined using Vitek 2. Whole-genome sequencing was performed using the Illumina MiSeq platform. Genomes were assembled using Newbler. Phylogenetic analysis was done by determining the core-genome alignments using Panaroo v1.3, analysed in IQ-Tree2 v2.2.0.3 to construct Maximum Likelihood trees using the RaxML software. Resistance genes and IS were identified using the Abricate programme, and ISFinder databases.

Results: One hundred and thirty-three (n = 133) ST32 A. baumannii isolates were analysed in this study. These genomes originated mainly from US military treatment facilities (n = 113), but also included additional publicly available genomes in GenBank (n = 20) recovered from a broad geographic distribution extending to Asia and South America. Phylogenetic analysis of all 133 genomes revealed at least four clades, with over 80 genomes forming a tightly clustered branch, suggesting they are likely to represent outbreak strains. Analysis of the ampC region showed that ST32 strains played a significant role in the formation of the widely distributed ampC transposon, Tn6168, and supplying DNA segments containing an ISAba1-ampC from ST32s via homologous recombination.

Conclusions: ST32 strains played a significant role in the evolution of antibiotic resistance in several widely distributed sequence types including ST1 (global clone 1) and ST3.

Background: Our research aimed to investigate the potential of in vitro triple antimicrobial synergism against carbapenem-resistant Pseudomonas aeruginosa (CRPA) as a strategy to overcome antimicrobial resistance.

Methods: We used 12 CRPA blood isolates stocked in the Asian Bacterial Bank between 2016 and 2018. All isolates were tested by multi-locus sequencing and carbapenemase multiplex PCR. To assess the antimicrobial interactions, we performed time-kill assays using double or triple combination regimens. These regimens included CST and/or rifampin combined with IPM, MEM, or CZA. The assay was conducted at 1× and 0.5× MICs.

Results: Among the 12 CRPA isolates, nine produced metallo-beta-lactamases (6 IMP-6, 2 VIM-2 and 1 NDM-1). In the time-kill assay, the median viable bacterial count for CST-rifampin was the lowest among double combinations after 24 h incubation (2.25 log cfu/mL at 1× MIC and 3.71 log cfu/mL at 0.5× MIC). In contrast, all triple combinations achieved 0 log cfu/mL at both 1× MIC and 0.5× MIC. Compared with CST-rifampin (synergism: 25% at 1× MIC, 42% at 0.5× MIC; bactericidal: 50% at 1× MIC, 42% at 0.5× MIC), all triple combinations showed greater synergism and bactericidal activity at both 1× MIC (50%-75% for synergism, 75%-83% for bactericidal activity) and 0.5× MIC (58%-75% for both).

Conclusions: Our findings suggest that CST-rifampin-based triple antimicrobial combinations exhibit greater synergy and bactericidal activity in eradicating CRPA compared with double antimicrobial combinations.

Background: In cases of maternal primary infection with cytomegalovirus (CMV-MPI) maternal treatment with oral valaciclovir 8 g/day has been shown to reduce the risk of fetal infection. The pharmacological profile of this high dosage during pregnancy is not yet known.

Objectives: To quantify maternal-fetal exposure to valaciclovir 8 g/day in a population pharmacokinetic (popPK) study.

Methods: Between October 2019 and April 2023, pregnant women referred for CMV-MPI were offered to participate following: (i) CMV-MPI <14 weeks of gestation; (ii) acceptance of valaciclovir 8 g/day; and (iii) consent for amniocentesis. Amniotic fluid was tested for (i) CMV PCR for prenatal diagnosis; and (ii) dosage of aciclovir concentration (the active form of valaciclovir). Maternal serum levels of aciclovir were also measured. Aciclovir assays in both compartments were used for popPK analysis. Pharmacokinetics were described using non-linear mixed-effect modelling.

Results: We prospectively included 119 women with their 122 fetuses. CMV-MPI occurred at a median of 3.0 (range: -12; + 14) weeks of gestation. CMV-infected pregnant women were treated at a median of 12.3 (range: 4.6-21.4) weeks of gestation for a median duration of 35 days (range: 7-90 days). Median pharmacokinetic parameters (Cmin, Cmax and AUC0-24) were all successfully defined in both maternal blood and amniotic fluid compartments. No differences in aciclovir exposure were observed between infected (n = 12, 9.8%) and non-infected fetuses. Simulations showed that after a last maternal dose, aciclovir concentration would be undetectable in the amniotic fluid after 43-47 h.

Conclusions: In this popPK study, maternal and fetal pharmacokinetics were established using in vivo data. The results provide a better understanding of how this fetal therapy works.

Background: AUC-based dosing with validated Bayesian software is recommended as a good approach to guide bedside vancomycin dosing.

Objectives: To compare treatment and vancomycin-associated acute kidney injury (AKI) costs between Bayesian AUC-based dosing and conventional therapeutic drug monitoring (TDM) using steady-state plasma concentrations of vancomycin administered as continuous infusion in hospitalized non-critically ill patients with severe Gram-positive infection.

Methods: A cost-benefit analysis presented as a return on investment (ROI) analysis from a hospital perspective was conducted using a decision tree model (TDM versus AUC-based dosing) to simulate treatment cost (personnel, serum sampling and drug cost), vancomycin-associated AKI risk and cost up to 14 days. ROI was calculated against AUC-based software cost. One-way and probabilistic sensitivity analyses (respectively OWSA and PSA) were performed to check for robustness.

Results: In base case, an overall cost per patient of €621.0 with TDM and €543.6 with AUC-based dosing resulted in a treatment saving of €77.4 per patient when applying AUC-based dosing. This saving against the software cost (€26.9/patient) generated an ROI per patient of €1.9 per invested € in software [€1.9 (95% CI 1.6-2.2) in PSA]. Enrolling 900 AUC-based dosed patients annually translated to a net saving of €45 469. Software break-even was reached after 313 patients. In OWSA, a higher AKI risk with TDM strongly contributed to a positive ROI.

Conclusions: AUC-based dosing appeared a cost-saving strategy compared with conventional TDM when applying base-case settings of vancomycin-associated AKI risk, treatment and AKI costs.

Objectives: We assessed HIV-1 drug resistance profiles among people living with HIV (PLWH) with detectable viral load (VL) and on dolutegravir-based antiretroviral therapy (ART) in Botswana.

Methods: The study utilised available 100 residual HIV-1 VL samples from unique PLWH in Francistown who had viraemia at-least 6 months after initiating ART in Botswana's national ART program from November 2023 to January 2024. Viraemia was categorized as low-level viraemia (LLV) (VL: 200-999 copies/mL) or virologic failure (VF) (VL ≥1000 copies/mL). HIV-1 protease, reverse transcriptase and integrase genes were sequenced using an in-house next-generation sequencing Oxford nanopore technology. HIV-1 drug resistance mutations (DRMs) were identified using the HIVdb Program in the Stanford HIV drug resistance database and compared between VL groups.

Results: Among 100 participants, 83.0% were on dolutegravir-based, 10.0% were on non-dolutegravir-based ART and 7.0% had unknown/undocumented ART regimens. Thirty (30%) participants had LLV and 70 (70%) had VF. Among 58 successfully sequenced, 32.8% [95% Confidence Interval (CI): 21.8-46.0] had DRMs to any drug class, 33.3% (4/12) in the LLV group and 32.6% (15/46) in the VF group. Among individuals on dolutegravir-based ART, the overall HIV DRMs were 34.8% (95% CI: 22.7-49.2). By VL groups, 40.0% (95% CI: 16.8-68.7) and 33.3% (95% CI: 20.2-50.0) had DRMs at LLV and VF, respectively.

Conclusions: A high but similar prevalence of any DRMs was observed among individuals with LLV and those with VF on dolutegravir-based therapy. Monitoring DRMs in individuals with detectable VL is crucial for preserving dolutegravir-based ART.

Objectives: To develop a scoring system to predict resistance to ceftolozane/tazobactam in Pseudomonas aeruginosa strains isolated from respiratory specimens.

Methods: A case-control study was conducted to evaluate the risk factors associated with resistance to ceftolozane/tazobactam. Patients with P. aeruginosa were defined as cases if they had ceftolozane/tazobactam-resistant strains, whereas those with ceftolozane/tazobactam-susceptible strains were defined as test-negative controls. A predictive scoring system based on binary logistic regression coefficients was formulated to predict resistance to ceftolozane/tazobactam. The score's performance was assessed using ROC curves and AUC. The sensitivity, specificity and predictive values of the score were determined on the basis of a cut-off point, using the Youden index.

Results: Ceftolozane/tazobactam resistance was detected in 18.4% of P. aeruginosa isolates from 473 patients. In multivariate analysis, a history of bronchoscopy [OR (95% CI) = 2.1 (1.1-4.3), P = 0.035], invasive mechanical ventilation [OR (95% CI) = 2.4 (1.2-4.5), P = 0.009], colistin/polymyxin B use [OR (95% CI) = 3.2 (1.8-5.7), P < 0.001] and fluoroquinolone use [OR (95% CI) = 2.3 (1.1-4.8), P = 0.024] in the preceding month prior to P. aeruginosa isolation were significantly associated with ceftolozane/tazobactam resistance. The AUC (95% CI) of the score was 0.734 (0.675-0.794), with a sensitivity of 69%, specificity of 71.8%, positive predictive value of 35.5% and negative predictive value of 91.1% at the cut-off point of 2, out of a range of 0-5.

Conclusions: In respiratory tract infections caused by P. aeruginosa, use of the proposed scoring system may reduce inappropriate use of ceftolozane/tazobactam in empirical treatment.

Background: Vancomycin remains the treatment-of-choice in MRSA bacteraemia (MRSAB) despite significant limitations.

Objective: To compare the effectiveness of ceftaroline and vancomycin monotherapy as the initial targeted therapy for MRSAB.

Methods: We conducted a retrospective matched cohort study. Consecutive adult patients treated with ceftaroline in the years 2019-2021 were matched in a 1:2 ratio with patients who received vancomycin. Controls were matched for performance of trans-oesophageal echocardiography, Charlson comorbidity index and age. The primary outcome was a composite of treatment failure, defined as 90-day mortality or microbiological failure. Descriptive statistics were used to compare the ceftaroline and vancomycin-treated groups. Univariate and multivariable binary logistic regression models were created using ceftaroline treatment as the exposure variable.

Results: Forty-five patients treated with ceftaroline for MRSAB were matched with 83 patients who received vancomycin. The groups were well balanced with regards to demographics and clinical characteristics. The primary outcome of treatment failure occurred at a similar rate in patients treated with ceftaroline or vancomycin (51.1%, 23/45% versus 57.8%, 48/83, respectively, P = 0.47). In the multivariable analysis, only age (aOR 1.06, 95% CI 1.01-1.1, P = 0.02) was associated with treatment failure. Acute kidney injury was more common among patients treated with ceftaroline (51.1%, 23/45% versus 18.1%, 15/83, P < 0.001).

Conclusions: Ceftaroline was not associated with improved outcomes compared to vancomycin when given as initial treatment for MRSAB, however, it appears to be a viable alternative to vancomycin. Larger studies are needed to provide definitive results and to elucidate the risk of nephrotoxicity.