Journal of Antimicrobial Chemotherapy最新文献

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: The S147G mutation is associated with high-level resistance to the integrase strand transfer inhibitor (INSTI) elvitegravir. In several poorly documented cases, it was also selected in patients on dolutegravir. Given the widespread use of dolutegravir, further studies of S147G are required.

Methods: We consulted the HIV-1 resistance databases of French laboratories to identify all cases of S147G emergence. We collected immunological and virological parameters, history of treatment and INSTI resistance mutations. Mann-Whitney and Fisher's exact tests were performed.

Results: We retrospectively identified 88 cases of S147G selection, from 2015 to 2022, in 22 laboratories. The most frequent HIV-1 subtypes were Clade B (55.7%) and CRF02_AG (21.6%). At the time of resistance genotyping, the median viral load was 5860 copies/mL (IQR 1011-24  525) and the median CD4 cell count was 412 cells/mm3 (228-560). S147G emerged on dolutegravir (48%), elvitegravir (36%) and raltegravir (10%) treatments. S147G was associated with a larger median number of other INSTI mutations on dolutegravir than on elvitegravir [3.0 (2.0-4.0) versus 2.0 (1.0-2.0); P = 0.0002] and was never observed with G148H or G118R. On dolutegravir, S147G was associated principally with T97A (62%), N155H (59%), E138K (50%), L74I/M (38%) and Q148R (33%).

Conclusions: In this French study, S147G emerged principally in patients on dolutegravir regimens, in association with up to five other INSTI resistance mutations. This accumulation of mutations suggests a replicative advantage on HIV strains under dolutegravir selection pressure, suggesting that caution is required when interpreting dolutegravir resistance in the presence of such S147G resistance patterns, even in patients prescribed dolutegravir twice daily.

Background: Major adverse cardiovascular events (MACEs) may contribute to the high morbidity in people with four-class drug-resistant HIV (4DR-PWH).

Objectives: To explore the probability of MACEs in 4DR-PWH compared with non-4DR controls.

Methods: This was a retrospective, propensity score-matched cohort study on 4DR-PWH (cases) and non-4DR-PWH (controls), on ART, without previous MACEs. Controls were matched with cases in a 4:1 ratio for age, sex-assigned-at-birth and ART duration. Incidence rates (IRs) and incidence rate ratio (IRR) of MACEs with 95% CIs were modelled by Poisson regression. Cumulative probabilities of the first incident MACE were estimated by Kaplan-Meier curves. A multivariable stepwise Cox proportional hazards model estimated predictors of incident MACEs among covariates with univariable P < 0.100.

Results: Overall, 223 4DR-PWH and 797 non-4DR-PWH were evaluated. During a median (IQR) follow-up of 8.2 (5.4-11.1) years [1833 person-years of follow-up (PY)], 23/223 (10.3%) 4DR-PWH developed 29 MACEs, IR = 1.6 (95% CI = 1.1-2.3)/100 PY. During a median follow-up of 8.4 (5.2-11.0) years (6450 PY), 42/797 (5.3%) non-4DR controls had 45 MACEs, IR = 0.7 (95% CI = 0.5-0.9)/100 PY, IRR (4DR/non-4DR) = 2.3 (95% CI = 1.4-3.6). The cumulative probabilities of the first MACE were more than doubled in 4DR-PWH (P = 0.006). At multivariable analysis, an increased risk of MACEs was associated with 4DR status [adjusted hazard ratio (aHR) = 1.9; 95% CI = 1.0-3.4], after adjusting for age, sex-assigned-at-birth, HIV load, CD4+ nadir, total cholesterol, HDL cholesterol, diabetes mellitus, statin use and baseline HCV serostatus.

Conclusions: In PWH, MDR is significantly associated with a higher risk of cardiovascular events. Prompt implementation of prevention strategies is mandatory in this fragile population.

Background: MDR Gram-negative bacteria, such as ESBL-producing and carbapenemase-producing Klebsiella pneumoniae, represent major global health threats. Treatment options are limited due to increasing resistance and slowed development of novel antimicrobials, making it necessary to apply effective combination therapies based on approved antibiotics.

Objectives: To quantitatively evaluate the synergistic potential of meropenem and fosfomycin against carbapenem-resistant K. pneumoniae strains isolated from clinics.

Methods: We evaluated four MDR K. pneumoniae strains, each expressing KPC-2 or KPC-3, using static time-kill assays that accounted for measured meropenem degradation. This was followed by pharmacokinetic/pharmacodynamic (PK/PD) interaction modelling, which estimated meropenem degradation rate constants and identified perpetrator-victim relationships in PD interactions. Dynamic hollow-fibre infection model (HFIM) experiments were used to confirm synergy.

Results: Static time-kill assays demonstrated high killing effects and suppressed regrowth for the combination of meropenem and fosfomycin, compared with the failure of monotherapy. Meropenem degradation was significantly higher in the presence of bacteria, attributable to carbapenemase activity. Pharmacometric models indicated a synergistic interaction primarily driven by meropenem as the perpetrator, enhancing the potency of fosfomycin. HFIM experiments confirmed in vitro synergy, demonstrating continuous bacterial suppression of the combination therapy.

Conclusions: Meropenem and fosfomycin exhibited additive or synergistic potential against carbapenemase-expressing single- or double-resistant K. pneumoniae at clinically achievable concentrations. This combination therapy may offer a strategy against MDR infections, possibly improving clinical treatment outcomes. Further in vivo research is needed to translate these findings into clinical practice, emphasizing the importance of PK/PD modelling in rationalizing antibiotic use.

Objectives: To describe the pharmacokinetics (PK) of linezolid in plasma and pleural fluid (PF) in critically ill patients with proven or suspected Gram-positive bacterial infections.

Patients and methods: Observational PK study in 14 critically ill patients treated with linezolid at standard doses. Blood and PF samples were collected and analysed by HPLC. The ratio between PF and plasma concentrations was calculated. The PK/pharmacodynamic (PD) target of linezolid in plasma was defined as 100% of the duration of the dosing interval in which concentrations were above the MIC (%100 T > MIC).

Results: The median (5th and 95th percentiles) linezolid concentration values for plasma pre-dose at steady state (Cmin,ss) and at the end of the 1-h infusion at steady state (Cmax,ss) were 1.1 (0.02-28.3) and 13.8 mg/L (2.9-38.1), respectively, and the PF pre-dose concentration (PF0 h) and PF concentration at the end of the 1-h intravenous infusion (PF1 h) were 2.8 (0.1-31.6) and 4.2 mg/L (0.1-45.2), respectively. At both times (pre-dose and post-infusion), a strong positive correlation was observed between PF and plasma linezolid concentrations (Spearman's rho coefficients = 0.8 and 0.9, with P < 0.001 for both). The defined PK/PD target in plasma was achieved in 8 (57.1%), 4 (28.6%) and 3 (21.4%) patients assuming an MIC of 1, 2 and 4 mg/L, respectively.

Conclusions: Linezolid seems to penetrate well into the PF, with concentrations exceeding those in plasma. However, high inter-individual variability, both in plasma and PF concentrations, was observed. A high proportion of patients did not achieve the PK/PD target in plasma, especially in the presence of high MIC strains.

Objectives: To evaluate the long-term effectiveness, persistence and tolerability of dolutegravir (DTG)/lamivudine (3TC), compared with the most frequently prescribed first-line treatment regimens, among antiretroviral-naive people with HIV from CoRIS, a multicentre cohort in Spain, in 2018-23.

Methods: We used multivariable regression models to compare viral suppression (VS) (HIV RNA viral load <50 copies/mL), change in CD4 cell counts, persistence and treatment discontinuations due to adverse events (AEs), at 96 (±24) weeks after treatment initiation.

Results: Of 2359 participants, DTG/3TC was prescribed in 472 (20.0%), bictegravir/tenofovir alafenamide (TAF)/emtricitabine (FTC) in 1134 (48.1%), DTG + tenofovir disoproxil fumarate/FTC in 300 (12.7%), DTG/abacavir/3TC in 273 (11.6%) and darunavir/cobicistat/TAF/FTC in 180 (7.6%). At 96 weeks from treatment initiation, 94.0% of participants initiating with DTG/3TC achieved VS, and the mean increase in CD4 cell counts was 295.5 cells/μL (95% CI: 269.9-321.1). During the first 96 weeks after DTG/3TC initiation, 9.8% and 1.3% discontinued their initial regimen, overall and due to AEs, respectively. In multivariable analyses, we did not find significant differences in VS or increase in CD4 cell counts among participants initiating with DTG/3TC compared with other regimens. Initiating ART with a regimen other than DTG/3TC was associated with a higher risk of treatment discontinuation, overall and due to AEs.

Conclusions: Among treatment-naive people with HIV from this large multicentre cohort, DTG/3TC had similar effectiveness and better persistence and tolerability than those of the most frequently prescribed first-line regimens at 96 weeks.

Background and objectives: Cefiderocol approved dosages are based on a prolonged infusion (PI) of 3 h that may not be adequate in all settings The objective of this study was to identify alternative cefiderocol dosage regimens based on short infusion (SI) or continuous infusion (CI).

Methods: We performed 1000-patient pharmacokinetic/pharmacodynamic (PK/PD) simulations based on a reference population model. Drug penetration into the epithelial lining fluid (ELF) was considered for pneumonia. For various stages of creatinine clearance (CLCR), we simulated the recommended PI as well as various SI (1 h-infusion) and CI regimens. The PK/PD targets were set at 75% or 100% of the dosing interval during which the free concentration of cefiderocol was above the MIC (fT > MIC) in plasma and ELF. The PTAs were computed considering the cefiderocol MIC breakpoint (2 mg/L).

Results: In plasma, all recommended PI regimens were associated with a PTA  ≥ 90%. Some SI regimens also showed acceptable PTAs. CI regimens were associated with high PTAs, even for doses as low as 2 g over 24 h and in patients with high CLCR. Recommended dosages failed to achieve acceptable PTAs in ELF for the 100% fT > MIC target in patients with CLCR  ≥ 90 mL/min. CI regimens showed the highest PTAs for the high target, but high doses of 6 to 8 g over 24 h were required in patients with CLCR  ≥ 90 mL/min.

Conclusions: We identified SI and CI regimens of cefiderocol that may be useful alternatives to the PI regimens in some patients. Continuous administration of cefiderocol may be especially relevant for patients with pneumonia. However, further clinical evaluation is necessary.

Introduction: Temocillin is a semi-synthetic β-lactam with a narrow spectrum but high stability against hydrolysis by β-lactamases, including AmpC. Despite its favourable properties, data regarding its clinical value in the treatment of AmpC β-lactamase-producing Enterobacterales (ABPE) infections are scarce. Most recent guidelines do not include temocillin in the therapeutic strategy for ABPE infection.

Objectives: This study investigated (i) the proportion of ABPE isolates susceptible to temocillin and (ii) the clinical outcomes of patients treated with temocillin for ABPE infections.

Materials and methods: This retrospective multicentre (Bordeaux and Reunion Island) study was performed in two parts. First, all the antimicrobial susceptibility test (AST) results of ABPE isolated from May 2021 to August 2023 were included in the analysis. Second, all patients who had received at least one dose of temocillin for ABPE infection between 2017 and 2023 were analysed. The electronic clinical records of these patients were reviewed to determine their treatment outcomes. Therapeutic success was defined as the absence of relapse one month after the end of temocillin treatment (3 months in the case of bone and joint infection) and the absence of treatment modification following an unfavourable outcome.

Results: During the microbiologic period of investigation (2021-23), 5166 ABPE strains were included. Of these, 4253 (82%) were susceptible to temocillin, whereas 4564 (88%) were susceptible to cefepime. After restriction to third-generation cephalosporin-resistant (3GCR) ABPE strains (n = 1446), the proportion of strains susceptible to temocillin was 66% (n = 1227) versus 59% (n = 1092) for cefepime. Temocillin treatment was initiated in 67 patients with ABPE infection during the study period (2017-23). The main infections were complicated urinary tract infections (n = 32, 48%) and bone and joint infections (n = 15, 22%). The estimated overall success rate for patients who underwent complete follow-up was 89% (n = 56/63).

Conclusions: Temocillin appears to be reliable for ABPE infections. Our data showed a high therapeutic success rate. Its high tolerability, narrow spectrum and ease of administration could make temocillin a relevant alternative to cefepime, the current standard for ABPE infection.