Journal of Antimicrobial Chemotherapy最新文献

Background: Integrase mutations associated with dolutegravir resistance have been well characterized, but based on limited data from non-B subtypes.

Objectives: We aim to identify potential integrase mutations not currently classified as integrase strand transfer inhibitor (INSTI) resistance mutations (DRMs) in individuals with viremia on dolutegravir-based regimens.

Methods: We included integrase sequences from DTG RESIST study sites in African countries. These were interpreted using Stanford HIVdb v9.8. We used a viral genome-wide association study-like approach restricted to the integrase region (INT-WAS) to identify mutations not classified as major or accessory INSTI DRMs but occurring more frequently in sequences carrying major INSTI DRMs than in those without major INSTI DRMs. We performed the same INT-WAS analysis with drug-naïve sequences from the Los Alamos HIV-1 database to test whether these identified mutations were enriched among sequences from individuals with viraemia whilst receiving DTG-based treatment.

Results: Among 382 sequences, 104 (27.2%) showed at least intermediate dolutegravir resistance. Twelve integrase mutations not classified as major or accessory DRMs (S39R, L45I, I72L, L74I, V79I, I113V, S119R, K156N, I208M, T218M, A265V, and R284G) were significantly associated with predicted DTG resistance. Among them, V79I [adjusted odds ratio (aOR) 167.1, 95% credible interval (CrI) 17.9-2947.6] and I72L (aOR 65.6, 95% CrI 6.6-1273.7) were strongly associated. S39R, L45I, V79I, S119R, and K156N were linked to established INSTI resistance pathways, and I72L, L74I, V79I, K156N, I208M, and R284G were overrepresented in sequences from viraemic individuals on DTG-based treatment relative to drug-naïve sequences.

Conclusions: We identified several amino acid substitutions outside the established DRMs that are strongly associated with predicted dolutegravir resistance. Dolutegravir resistance evolution is complex and likely involves mutations not currently classified as DRMs.

Background: NOSO-5O2 is the first clinical candidate of a new antimicrobial class, the odilorhabdins. The pharmacodynamics of NOSO-502 was studied to establish the magnitude of the pharmacodynamic index (PDI) and make human dose predictions.

Methods: In vitro experiments using different types of media were performed in time-kill curves and a pharmacokinetic model. In vivo experiments were conducted in the neutropenic murine thigh infection model. Six E. coli (MIC 1-8 mg/L) and two K. pneumoniae (MIC 1-2 mg/L) strains were used. 24 h bacteriostatic and 1- and 2-log10 kill effects were related to fAUC0-24/MIC and fAUC0-24/MIC per length of dosing interval (fAUC0-24/MIC·1/tau). Human pharmacokinetic parameters were predicted using interspecies allometric scaling and used to simulate the dose needed to reach the bacteriostatic PDI target for E. coli.

Results: The in vitro activity of NOSO-502 was dependent on the media and the strength of Mueller-Hinton Broth II (MHBII) used such that fAUC0-24/MIC ratios were higher when measured in 100% MHBII than 50% MHBII. In vivo for E. coli, the fAUC0-24/MIC for bacteriostatic effect and 1-log10 reduction in bacterial count were 10.7 ± 10.9 and 18.2 ± 16.5, respectively. The final human predicted parameters of the model had CV values of <20%. The human dose required to achieve the bacteriostatic fAUC0-24/MIC for each E. coli strain varied from 149 to 1717 mg/day.

Conclusions: A combination of the use of PDI targets and prediction of human pharmacokinetics allowed effective doses of NOSO-502 in man to be estimated.

Background and objectives: Fluoroquinolones are linked with increased risk of CNS adverse events, such as anxiety and depression. Recently, case reports have linked fluoroquinolone use and panic attacks. However, current evidence exploring the link between fluoroquinolone use and panic attacks remains limited and requires investigation for safe use. To systematically review the literature on fluoroquinolone use and the risk of panic attacks, and to study this association by comparing fluoroquinolones with other antibiotics using the FDA Adverse Event Reporting System (FAERS) database.

Methods: MEDLINE and Embase databases were searched to identify relevant studies for systematic review. Active-comparator restricted disproportionality analyses using FAERS (2004Q1-2024Q4) were performed for ciprofloxacin, levofloxacin, and moxifloxacin compared to azithromycin and trimethoprim/sulfamethoxazole. Reporting odds ratios (ROR), proportional reporting ratios, adjusted ROR for potential confounders, and Bayesian analyses were conducted to detect safety signals for MedDRA term 'panic attack'.

Results: The systematic review identified 12 studies (4 clinical trials, 8 publications describing 11 case reports), with the prevalence of panic attacks ranging between 0.46% and 1.76% in trials. Disproportionality analysis showed that, compared to azithromycin, fluoroquinolones were associated with a 6-fold increase in reports of panic attacks and a 12-fold increase compared to trimethoprim/sulfamethoxazole. Results were consistent across Bayesian analyses.

Conclusion: The findings suggest an association between fluoroquinolones and increased risk of panic attacks, underscoring the need for validation through pharmacoepidemiological studies. Due to reliance on spontaneous reports, causal relationships cannot be determined for clinical recommendations. These results offer insights for research on CNS safety profiles of fluoroquinolones.

Background and objective: Cefepime-induced neurotoxicity (CIN) is a recognized side effect of excessive cefepime exposure and high plasma concentrations in adults. However, the relationship between cefepime concentrations and neurotoxic symptoms in paediatric patients is unknown. The objective of this paper is to explore the relationship between cefepime pharmacokinetics and CIN in a paediatric intensive care unit (PICU) cohort.

Patients and methods: PICU patients with cefepime concentrations measured for a previous PK study were chosen for this cohort. CIN symptoms and related testing were evaluated by retrospective chart review and likelihood of causal association was determined using blinded adjudicators via the Naranjo adverse drug reaction probability scale.

Results: Among 73 patients with complete data, 43 patients (59%) had either no neurotoxicity or neurotoxicity doubtful to be CIN, while 25 (34%) patients had possible CIN and five (7%) had probable CIN. Symptoms of neurotoxicity included irritability, altered mental status, depressed level of consciousness, myoclonus, seizures and delirium. There were no differences in age, sex, severity of illness or renal dysfunction among groups. Patients with probable CIN had higher cefepime area under the curve (2250 versus 1107 mg*h/L, P = 0.03) and peak concentrations (232 versus 172 mg/L, P < 0.001).

Conclusions: This investigation presents a paediatric cohort analysis of CIN and provides preliminary evidence supporting the hypothesis that neurotoxicity risk is probably concentration dependent in this age group and presents with similar spectrum of symptoms as those described in adults.

Objectives: To report on clinical outcomes associated with vancomycin-resistant Enterococcus faecium (VRE) Bloodstream infections (BSIs) observed during a 6-year period at a hospital from an area of high VRE endemicity.

Material and methods: Retrospective study of patients with VRE and/or vancomycin-susceptible E. faecium (VSE) BSI in an Italian tertiary care hospital from January 2018 to December 2023.

Results: The cohort included 116 VRE and 225 VSE BSIs. The baseline characteristics were comparable in both populations. Almost half VRE population (53/116, 46%) received no or ineffective empiric therapy against VRE. A targeted effective therapy was initiated with a mean delay of 2.2,  ± 0.4 days in the VRE patients and of 1.2 ± 0.1 days (P < 0.01) in the VSE patients. The univariate analysis showed higher rates of septic shock in the VRE group (60% versus 40%, P < 0.01), and the 30-day mortality rate was 29% and 46% in VSE and VRE BSIs, respectively (P < 0.01). By multivariate analysis, Sequential Organ Failure Assessment score (HR 1.25; 95% CI 1.19-1.31, P < 0.001), Charlson Comorbidity Index (HR 1.14; 95% CI 1.06-1.22, P = 0.001) and vancomycin resistance (HR 1.93; 95% CI 1.33-2.82, P = 0.001) resulted as independent predictors of mortality. The statistical association was confirmed in a sensitive analysis after removing polymicrobial BSI.

Conclusions: E. faecium BSIs confirmed to be associated with high mortality rate, especially in fragile patients. Moreover, vancomycin resistance is an independent mortality factor. Further studies are needed to identify patients at higher risk for E. faecium BSI.

Objectives: Polymyxin B has been used for many years to treat Acinetobacter baumannii, but little is known about its pharmacodynamics (PD). We aimed to describe the PD of polymyxin B in treating A. baumannii infections.

Methods: Using the murine neutropenic thigh and lung infection models we determined the magnitude of the pharmacokinetic (PK)/PD index correlating with efficacy for eight A. baumannii strains. PD was analysed using the Emax model to determine PD targets. Using published human PK data the PTAs were calculated.

Results: In the thigh infection model, stasis, 1-log10 and 2-log10 kill were reached for all strains. Median (range) fAUC/MIC (area under the unbound concentration-time curve divided by the MIC) targets for stasis, 1-log10 kill and 2-log10 kill were 2.1 (1.0-11), 2.9 (1.0-15) and 4.0 (1.1-20), respectively. In contrast, in the lung model, 2-log10 kill was reached in 2/8 strains only, and there was insufficient killing at tolerated exposures to determine PD fAUC/MIC targets. For the standard human dosing regimen, PTAs derived from the thigh model were inadequate at the USCAST (United States Committee on Antimicrobial Susceptibility Testing) clinical breakpoint and a protein binding of 90%.

Conclusions: Whereas polymyxin B treatment had good efficacy in the murine thigh infection model, in the lung infection model its effect was limited. PD targets, with MICs of circulating A. baumannii isolates of ≤2 mg/L, are not reached with a standard human dosing regimen and will probably exceed threshold values for toxicity. These data suggest that the efficacy of polymyxin B as monotherapy for A. baumannii infections is questionable.