Journal of Antimicrobial Chemotherapy最新文献

Background and objectives: An allometric miltefosine regimen dosed based on fat-free mass (FFM) is effective and safe in treating children with visceral leishmaniasis (VL). However, its complexity hinders successful implementation in endemic areas. We aimed to develop a simplified dosing based on weight bands (WBs) that achieves equivalent miltefosine exposure in a paediatric VL population using a simulation-based approach.

Methods: Utilizing demographic data from 9379 Eastern African paediatric VL patients, WHO-CDC growth curves were adjusted to create a realistic virtual paediatric VL population. The virtual children were given either an allometric FFM-based, a WB-based or a 2.5 mg/kg dosing of miltefosine per day. To compare the regimens, two pharmacokinetic metrics were derived from the simulated patient population receiving the allometric FFM-based regimen: the 5th percentile of the time above the concentration associated with 90% in vitro intracellular parasite killing for efficacy and the 95th percentile of the AUC for safety. The performance of the dosing regimens was evaluated for both 14- and 28-day regimens.

Results: A virtual population was constructed that closely resembled real-world paediatric Eastern African VL patients' height- and weight-for-age distributions. Target attainment rates for the two pharmacokinetic metrics tested differed by less than 1.5% between the final WB- and FFM-based dosing regimens. The final doses in mg were 20 for children under 6 kg, 30 for 6.0-9.9 kg, 50 for 10.0-14.9 kg, 60 for 15.0-19.9 kg, 70 for 20.0-24.9 kg and 80 for 25.0-29.9 kg, for both 14- and 28-day regimens.

Conclusions: Our simplified WB-based dosing strategy offers a practical alternative for allometric miltefosine dosing in children, yielding satisfactory exposure levels.

Background: Salmonella enterica serovar Typhi results in >160 000 deaths annually. In endemic regions, infections disproportionately affect infants and children. Current diagnostics rely on culture-based approaches that lack sensitivity and require infrastructure and skills that are not always possible in developing regions.

Objectives: We developed a suite of rapid, sensitive and specific molecular diagnostic tools to detect S. Typhi, and markers of extensive antimicrobial resistance (AMR), with the capacity to be used in low- and middle-income countries (LMIC).

Methods: Singleplex and multiplex PCR assays, recombinase polymerase amplification with lateral flow detection (RPA-LF) assays and loop-mediated isothermal amplification (LAMP) assays were developed, targeting markers consistent with Salmonella Typhi and makers of extensive AMR (blaCTX-M-15 and qnrS1). Assays were tested across four banks of samples (n = 115 total) to assess sensitivity, specificity and limit of detection.

Results: Singleplex and multiplex PCR assays demonstrated excellent sensitivity (100%) and specificity (96%-100%) for detection of XDR S. Typhi and extensive AMR, particularly the H58 clade deletion and STY4669 genes of S. Typhi. Similarly, sensitivity and specificity were also observed for RPA-LF assays (100% sensitivity, 96%-100% specificity) and LAMP assays (100% sensitivity, 87.5%-100% specificity) for all targets.

Conclusions: These tools are timely, providing a range of options for targeted detection of XDR S. Typhi in the laboratory or nearer to the point of care. These assays have the potential to improve resistance-guided therapy for S. Typhi, which is important given the increasing prevalence of XDR S. Typhi in endemic regions of Pakistan, and increasing case reports globally.

Background: Isavuconazole is widely used in children. It has a favourable safety profile, fewer drug-drug interactions, predictable pharmacokinetics and broad spectrum of action compared with alternative triazoles.

Objectives: To assess its place in therapy in a real-world setting, and investigate the achieved exposure.

Methods: This cohort study reports isavuconazole usage in children between 2018 and 2023 in the Princess Máxima Center, the Netherlands. Clinical data, toxicity data and isavuconazole plasma concentrations were extracted from patient records. Exposure was estimated post hoc using nonlinear mixed-effects modelling.

Results: In total, 77 patients (median age 8.0 years) received isavuconazole during 92 episodes. Isavuconazole was primarily prescribed as second-line therapy. Out of 77 patients, 72 had a haematological malignancy and 34/77 underwent stem cell transplantation. Median episode duration was 75.5 (IQR, 44-144) days. Treatment was discontinued in 29.1% unrelated to confirmed drug side effects. 958 concentrations were available. Median Ctrough was 3.3 (range, 0.04-12.6) mg/L. The intra-patient coefficient of variation was 30.6% (IQR, 21.1%-42.8%). Predicted exposure during the first week was 79.2 (range, 35.2-95.8) mg·h/L, 81.8% > 60 mg·h/L, the 25th percentile from a pivotal trial. Median maintenance dosage for patients <18 kg, 18-32 kg and ≥32 kg was 6.4, 5.2 and 4.6 mg/kg/day.

Conclusion: We think that isavuconazole merits a place for treatment of invasive fungal infections in children. Isavuconazole was generally well tolerated with exposures in line with the pivotal trial. Lower-weight children required higher dosage per kg of bodyweight to achieve equivalent exposures to their older peers. Considerable inter/intra-patient variability supports the need for therapeutic drug monitoring.

Background: Hypoalbuminaemia in patients with MSSA bacteraemia is associated with a delayed time to blood culture sterilization and increased mortality. Although this phenomenon has been postulated to be due to suboptimal antimicrobial exposure, the albumin thresholds that predispose patients to worse outcomes remain unclear.

Methods: This was a multicentre, retrospective study of adult patients with MSSA-positive blood cultures for at least 48 h despite treatment with in vitro active antimicrobials. To determine the precise cut-off for defining hypoalbuminaemia, we applied a bootstrap resampling approach in combination with Cox proportional hazards models. A range of candidate albumin thresholds was evaluated to identify the optimal value that maximized the partial log-likelihood of the Cox model, with time from target therapy to negative blood cultures as the outcome.

Results: Among the 461 patients screened, 285 patients met the inclusion criteria; 34% (97/285) were people who inject drugs and 45% (130/285) had definite endocarditis. The median (IQR) albumin level was 2.4 (2-2.9) g/dL. The albumin threshold that corresponded to the highest mean bootstrapped log-likelihood was ≤3.0 g/dL. After propensity score weighting, patients with an albumin level of ≤3.0 g/dL had a significantly slower time to blood culture sterilization compared with patients with albumin levels >3 g/dL (HR = 0.6; 95% CI: 0.44-0.81; P < 0.01).

Conclusions: In the largest study to evaluate the impact of hypoalbuminaemia on the outcomes of patients with MSSA bacteraemia, we identified a cut-off value of albumin ≤3 g/dL to be associated with an increased risk for a delayed blood culture sterilization.

Background: Macrolide resistance in Mycoplasma pneumoniae is an increasing concern worldwide.

Objectives: To investigate the prevalence of macrolide resistance in M. pneumoniae in The Netherlands.

Methods: All non-duplicate consecutive specimens with a positive M. pneumoniae PCR were prospectively collected by four hospital laboratories during the outbreak of M. pneumoniae infection in 2023/2024 in The Netherlands. The two most common mutations in the 23S rRNA gene that are known to cause macrolide resistance, A2063G and A2064G, were detected by PCR with melting curve analysis.

Results: PCR-positive specimens were identified in 268 patients. Of the 268 PCR-positive specimens, 238 were available for analysis of which 235 could be amplified for mutational analysis. Mutations were detected in 7 of 235 specimens (3%).

Conclusions: The low resistance rate of 3% still supports the use of macrolides for empirical treatment of M. pneumoniae infections in The Netherlands, but macrolide non-responsive infections should lead to the suspicion of resistant M. pneumoniae. Regular surveillance studies are important as clonal spread may cause rapid changes in resistance rates.

Objectives: To develop a population pharmacokinetic (popPK) model to understand factors affecting the broadly neutralizing HIV antibody (bNAb) VR07-523LS disposition and infant predicted serum neutralization 80% inhibitory dilution titre ratio (PT80) and its potential relationship to antiviral effects.

Methods: PK data from two studies were used: infants exposed to HIV initiating therapy ≤5 days of age (IMPAACT P1112, n = 21) and healthy adults (VRC605, n = 25). The infant study implemented fixed subcutaneous (s.c.) dosing whereas the adult study implemented weight-based dosing, via both intravenous (i.v.) and s.c. routes. Monte Carlo simulation assessed two doses (80 mg followed by 100 mg at 12 weeks) to determine the maintenance of levels >10 µg/mL in virtual infants. The broadly neutralizing antibodies (bNAbs) concentration/IC80 ratio (PT80) was calculated on the basis of simulated concentrations from the popPK model and VRC07-523LS HIV-1 sensitivity (IC80) distribution.

Results: This model predicts typical infant CL/F and t1/2 of 159 mL/day/70 kg and 39 days. Comparatively, predicted adult typical CL/F and t1/2 were 269 mL/day/70 kg and 31 days. Concentrations were >10 µg/mL in >87% of virtual infants at 12 weeks following one dose and >98% at 24 weeks following two doses. Median (90% predictive interval) PT80 was 163 (71-383), 116 (51-274) and 61 (26-144) at 6, 8 and 12 weeks, respectively. Significant model covariates included age (infant versus adult) and multiple dosing.

Conclusions: Age and repeat dosing influence VRC07-523LS PK. An 80-mg dose followed by 100 mg at 12 weeks rapidly achieves and maintains concentrations >10 µg/mL for >24 weeks. This dosing strategy is expected to result in antiviral effects in patients with sensitive viruses and supports further evaluation of VRC07-523LS.

Objectives: Notwithstanding the wide uptake of outpatient antimicrobial therapy (OPAT) in the UK, there is a paucity of data on antimicrobial exposure. We aimed to assess antimicrobial pharmacokinetic-pharmacodynamics (PK-PD) for several agents in our service with a view to understanding a potential role for therapeutic drug monitoring (TDM) and precision antimicrobial therapy in this setting.

Methods: The study was a prospective, observational, pilot PK-PD study. Adult patients receiving intravenous ceftazidime, ceftriaxone, daptomycin, ertapenem, flucloxacillin or teicoplanin, or oral treatment with linezolid were enrolled. Peak and trough blood samples were obtained. Total and unbound antibacterial concentrations were measured. Clinical details, laboratory findings and UK OPAT good practice recommendation metrics were extracted from the medical record. PK-PD was interpreted according to EUCAST rationale documents and other published guidance. Doses were not adjusted except for linezolid and teicoplanin.

Results: In total, 39 patients were recruited to the study, predominantly on ceftriaxone (21/39, 54%) or ertapenem (6/39, 15%). Four patients received (10%) teicoplanin, three (8%) ceftazidime, three (8%) flucloxacillin, one (3%) linezolid and one (3%) daptomycin. The most common reason for OPAT was bacteraemia and endocarditis (6/39; 15% each). PK-PD target attainment was acceptable for all drugs and dose regimens, and all β-lactam-based treatments met conservative PK-PD targets.

Conclusions: We have demonstrated that drug monitoring is practicable in the OPAT setting of a large institution with no on-site analytical capability. Current dosage regimens result in acceptable PK-PD target attainment. Our findings provide an initial step towards supporting TDM in OPAT.

Objectives: Understand how mutations upstream of pvdS and fecI in Pseudomonas aeruginosa PAO1 lead to reduced susceptibility to cefiderocol, a siderophore cephalosporin.

Materials and methods: Whole-genome sequencing, gene complementation and inactivation, mRNA expression, siderophore quantification and supplementation were carried out with mutants that showed reduced susceptibility to cefiderocol.

Results: Whole-genome sequencing, combined with gene complementation studies, with isolated mutants that showed 4-fold reduced susceptibility to cefiderocol identified mutations within the Fur-box of promoter regions upstream of pvdS and fecI. The pvdS promoter mutation led to increased pvdS transcription, resulting in increased pyoverdine production, as well as reduced transcription of other iron transport-related genes, including piuA an iron transporter responsible for cefiderocol uptake. The down-regulation of piuA, rather than competition for iron between pyoverdine and cefiderocol, was responsible for the decreased cefiderocol susceptibility. The fecI mutant demonstrated increased transcription of fecI and fecA, and the expression level of piuA in the fecI mutant was not related to reduced cefiderocol susceptibility, indicating a different mechanism for the reduced cefiderocol susceptibility in this mutant. Sequence analyses of over 35 000 clinical P. aeruginosa isolates did not identify isolates with the pvdS mutation, and only one isolate with the fecI mutation.

Conclusions: These data highlight different mechanisms by which P. aeruginosa attempts to evade the action of cefiderocol by exploiting the complexities of iron haemostasis in bacteria. The absence of such mutants in the clinic suggests that such mutations may be detrimental for P. aeruginosa to survive in the clinical environment.