Journal of Antimicrobial Chemotherapy最新文献

Background and objectives: Treatment outcomes in Mycobacterium avium complex pulmonary disease may be improved by adding clofazimine, instead of rifampicin, to the azithromycin-ethambutol backbone. Inhalation of clofazimine instead of oral administration has been suggested to increase the antibiotic concentration at the site of infection and to improve its efficacy, while minimizing systemic exposure and adverse effects. We evaluated the efficacy of inhaled clofazimine compared to oral clofazimine with an azithromycin-ethambutol backbone against M. avium.

Methods: We simulated pharmacokinetic exposures to azithromycin, ethambutol and either inhalational or oral clofazimine administration in an in vitro hollow-fiber system during 3 weeks. Intracellular and extracellular Mycobacterium avium ATCC 700898 bacteria were exposed to these antibiotic regimens and bacterial densities were enumerated at day 0, 3, 7, 14 and 21. The development of macrolide resistance was assessed by inoculation of agar plates containing azithromycin. Pharmacokinetic exposures were confirmed on day 0 and 21.

Results: Inhalational administration of clofazimine significantly increased the antimycobacterial effect of the regimen against both intracellular and extracellular bacteria. The inhaled treatment showed an intracellular kill rate of 0.62 (95%C.I. 0.61-0.64) per day, while the oral administration showed a kill rate of 0.55 (95%C.I. 0.54-0.56) per day. For the extracellular fraction, inhaled administration showed a kill rate of 0.56 (95%C.I. 0.55-0.58) per day and the oral administration a kill rate of 0.50 (95%C.I. 0.50-0.51) per day. Inhaled clofazimine exposures reduced and delayed the emergence of macrolide resistance.

Conclusions: Inhalation of clofazimine with an azithromycin-ethambutol backbone increases treatment efficacy and decreases the development of macrolide resistance compared to oral administration in a hollow-fiber system. This calls for a clinical trial of inhaled clofazimine.

Objectives: Antimicrobial resistance (AMR) is an escalating global health concern, driven by multifactorial biological processes not yet fully understood. This study employed network diffusion analysis to dissect the molecular mechanisms driving AMR in Escherichia coli, aiming to identify novel potential drug targets for therapeutic development.

Methods: A systems biology approach was used to identify genes and biological pathways associated with AMR, by mapping known AMR-related genes from the Comprehensive Antibiotic Resistance Database (CARD) and PointFinder database into the E. coli protein interactome. Through a network diffusion algorithm, several network modules were identified, i.e. genes and pathways, in part already known to be involved in AMR mechanisms. We selected gene candidates for performing an in vitro susceptibility validation test, consisting of 13 knockout mutants against nine different antibiotics.

Results: Compared with the WT E. coli BW25113, the AMR of some mutants showed significant shifts of biological relevance: ΔuhpB (S/I) and ΔmdaB (S/R) against ampicillin, ΔrpmG (I/S) and ΔrplA (I/S) against ciprofloxacin, and ΔrplA (I/S) against streptomycin (S, susceptible; I, intermediate; R, resistant). In other cases, only a significant change in inhibition disc diameter was observed, probably deserving further studies.

Conclusions: Network diffusion is an effective tool to infer relevant biological insights related to AMR from microbial biological networks. Our results contribute to a better understanding and characterization of AMR in E. coli. Furthermore, the in vitro validated genes could be considered as new putative drug targets.

Background and objectives: Mycobacterium abscessus can cause severe infections in at-risk patients. Treatment efficacy for M. abscessus infections remains low, and better treatment options are needed. Factors hampering antibiotic potency may include the ability of M. abscessus to form biofilms and to endure in nutrient-deprived environments. These factors are underrepresented in current preclinical drug activity assays. Diversifying preclinical models by incorporating characteristics of these harsh environments may be important to better predict drug efficacy in patients. We aimed to develop a novel tool for studying drug activity against biofilm-embedded M. abscessus. In addition, drug activity was assessed against actively multiplying and nutrient-starved M. abscessus.

Methods: An in-house 3D-printed platform-disc-based biofilm model was developed to study M. abscessus pellicle biofilms. In vitro activity of 16× the MICs of amikacin, bedaquiline, clofazimine, imipenem, rifabutin and tigecycline was assessed using time-kill kinetics assays.

Results: The platform-disc-based model established reliable and reproducible quantification of M. abscessus biofilms. Drug activity against biofilm-embedded and nutrient-starved M. abscessus seemed less pronounced than against actively multiplying mycobacteria. For biofilm-embedded M. abscessus, drug activity was dependent on the developmental stage of the biofilm.

Conclusions: The varying levels of drug activity observed across the different M. abscessus populations highlight their distinct physiological relevance. As such, the platform-disc-based biofilm model could serve as a valuable asset in preclinical drug activity assays for M. abscessus.

Objective: To investigate the epidemiology and outcomes of patients with non-Serratia Enterobacterales endocarditis.

Methods: Adult patients were identified at 14 hospitals between January 2000 and December 2024 with definite non-Serratia Enterobacterales endocarditis. Combination therapy was defined as receipt of ≥2 antimicrobial agents with documented in vitro activity against the primary pathogen for ≥72 hours. Clinical failure was defined as a composite of all-cause 42-day mortality or treatment-emergent resistance.

Results: Seventy-five patients were included. The median (IQR) age was 67 (51-78) years, and 16% (12/75) were patients who inject drugs. The most common pathogens were E. coli [41% (31/75)] and Klebsiella spp. [37% (28/75)]. Klebsiella spp. were most commonly associated with septic emboli. Patients who experienced clinical failure were more likely to have a higher median (IQR) age [71 (66-79) versus 62 (43-76); P = 0.031], higher median (IQR) Charlson comorbidity index [4 (2-7) versus 3 (1-4); P = 0.026] and were less likely to receive surgery despite an indication [59% (10/17) versus 21% (10/47); P = 0.007]. After propensity score weighting, patients with valvular endocarditis treated with a combination regimen had a trend towards a lower 90-day mortality (HR = 0.39; 95% CI: 0.13-1.19; P = 0.098). However, patients who received combination therapy also had a proportionally higher rate of adverse events [33% (7/21) versus 13% (7/47); P = 0.054].

Conclusions: Use of combination treatment may improve mortality in patients with non-Serratia Enterobacterales endocarditis; however, larger studies are required. Adverse effects among patients who received combination therapy were common.

Background and objectives: Isavuconazole (ISA) has been recently approved for the treatment of invasive aspergillosis and mucormycosis in patients aged >1 year. Prior to this approval, it was used in paediatric patients under compassionate use. The objective of this study is to describe the experience with ISA use in children.

Patients and methods: A descriptive, retrospective, multicentre study conducted in nine Spanish hospitals, including patients aged ≤18 years who received ≥7 days of ISA between 2018 and 2023. Therapeutic drug monitoring (TDM) was performed with pre-dose [trough concentration (Ctrough)] levels measured according to local protocols. A therapeutic range of 2.5-5 mg/L was used for analysis.

Results: A total of 107 patients (median age: 11 years, 56% male) were included. ISA was used as a treatment (95 patients), mostly as second-line therapy (64 patients, 67%), due to toxicity from previous antifungals (27 patients, 42%). Of 53 patients with proven/probable invasive fungal disease (IFD), 32 (60%) showed a favourable response and 21 (40%) died, 13 due to IFD. Twelve patients received ISA as prophylaxis and none developed breakthrough IFD. Overall, 27/107 (25%) patients experienced adverse effects, the most common being hepatotoxicity, with 10 requiring discontinuation. TDM was performed in 76/95 patients (80%), revealing 59% of Ctrough values outside the therapeutic range.

Conclusions: ISA appears to be a safe and effective option for treating IFD in children, especially when first-line agents have failed or caused excessive toxicity. Although no correlation between Ctrough and clinical outcomes was observed, the significant proportion of patients with out-of-range Ctrough emphasizes the need for TDM in paediatrics.

Background: Amoxicillin/clavulanic acid (AMX/CLV) is commonly prescribed in older adults. Because oral and intravenous (IV) routes may be compromised by swallowing disorders or poor venous access, subcutaneous (SC) administration of AMX/CLV could be an alternative. The main objective of this study was to compare the bioavailability of AMX and CLV after IV and SC administration in older patients.

Patients and methods: This prospective multicentre study enrolled patients aged over 65 y receiving SC or IV AMX/CLV (1 g/0.2 g/8 h). At steady state, AMX and CLV concentrations were measured just before and after the infusion, at 2 h (in the SC group only) and at 5 h using liquid chromatography coupled to tandem mass spectrometry. Population PK analysis estimated SC AMX/CLV bioavailability in comparison to IV administration and tolerance was assessed.

Results: Seventeen patients (mean age 85.1 ± 4.8 y) were enrolled (14 in the IV group and three in the SC group). SC bioavailability of AMX and CLV was estimated at 78% and 82%, respectively. Although Cmax values were ∼45% lower with SC administration, unbound AMX concentrations remained above thresholds for common pathogens (i.e. Streptococcus pneumoniae, Enterococci and Enterobacterales) and trough concentrations were close to those observed after IV administration. On the basis of safety assessment after 122 IV and SC infusions, no serious adverse event related to the treatment occurred and local SC adverse events were transient oedema, erythema and pain.

Conclusions: The present study provides data supporting the use of SC administration of AMX/CLV in the older population.

Objectives: This study investigated CYP3A4-mediated pharmacokinetic interactions between ruxolitinib (JAK1/2 inhibitor for steroid-refractory acute and chronic graft-versus-host disease) and posaconazole (antifungal prophylaxis in haematological malignancies) to inform clinical dosing strategies.

Methods: In this open-label, fixed-sequence trial, eight Chinese patients with haematological malignancies received ruxolitinib 5 mg once daily (Day 1: monotherapy) followed by ruxolitinib 5 mg plus posaconazole 200 mg three times daily (Days 2-6: combination). Plasma concentrations of ruxolitinib and posaconazole were analysed using validated LC-MS/MS. Geometric mean ratios (GMRs) with 90% CIs for PK parameters were calculated to assess PK interactions.

Results: All patients completed the study. Co-administration with posaconazole increased ruxolitinib AUC0-24h by 58% (GMR: 1.58; 90% CI: 1.32-1.88). Geometric mean AUC0-24h values were 179.80 μg·h/L [monotherapy, coefficient of variation (CV) 39.26%] versus 283.60 μg·h/L (combination, CV 41.42%). No significant change in Cmax was observed (GMR: 1.10; 90% CI: 0.90-1.36). Geometric mean of the maximum plasma concentration at steady state (Cmax,ss) and AUC0-24h of posaconazole were 1543.52 μg/L (CV 41.81%) and 31 404.37 μg·h/L (CV 32.14%). There was no significant correlation between the systemic exposure of posaconazole (AUC or Cmax,ss) and the ratio of ruxolitinib AUC0-24h when co-administered versus administered alone.

Conclusions: Although co-administration of posaconazole with ruxolitinib resulted in a statistically significant increase in ruxolitinib systemic exposure, the magnitude of this interaction was clinically moderate. Although ruxolitinib dose adjustment may not be routinely required when used concomitantly with posaconazole, close monitoring for ruxolitinib-related adverse effects is recommended under this combination therapy setting.

Background: The fixed-dose combination of aztreonam/avibactam is administered with a loading dose (LD), resulting in systematic drug wastage in patients with preserved renal function. Whether the LD can be reduced remains unclear.

Objectives: To evaluate in silico the pharmacokinetic (PK) and pharmacodynamic (PD) consequences of reducing the current LD in patients with normal renal function, using a population PK model and Monte Carlo simulations.

Methods: A published two-compartment population PK model was implemented. We performed 10 000 Monte Carlo simulations of virtual patients with normal renal function (creatinine clearance > 80 mL/min), receiving the standard LD (2 g/0.67 g over 3 h) or a reduced LD (1.5 g/0.5 g over 3 h), followed by standard maintenance doses every 6 h. PK metrics (C0, AUC) and probability of target attainment were compared between the two regimens.

Results: Reducing the LD decreased early exposure (AUC0-24 h) from 1281 ± 497 to 1200 ± 464 mg h/L for aztreonam and from 276 ± 118 to 258 ± 110 mg h/L for avibactam, but steady-state AUC24-48 h was identical between regimens. PTA differences for intermediate PD thresholds were modest and transient.

Conclusions: Lowering the LD in patients with preserved renal function had only a short-lived impact on early exposure and did not compromise PK/PD performance. These results support dose adaptation to reduce unnecessary drug waste.

Objectives: To assess the feasibility of lot quality assurance sampling (LQAS) for defining high prevalence of antibiotic-resistant (ABR) uropathogens in Dutch nursing homes.

Methods: In this cross-sectional study, we constructed 'lots' of residents with urinary tract infections (UTIs) across three Dutch nursing home organizations (21 locations, 2095 beds) between February and July 2023. Resistance thresholds for common antibiotics used in empirical antibiotic therapy (EAT) were set at 20% (upper) and 5% (lower). Per organization ≥44 strains of E. coli/Klebsiella spp. were consecutively sampled;  ≥ 5 resistant strains indicated 'high' ABR prevalence. Aggregate data were used in an adapted, meta-regression model to identify structural ABR determinants. Three multidisciplinary focus groups were conducted to identify implementation requirements for LQAS-based ABR surveillance.

Results: From 298 urine specimens 132 E. coli/Klebsiella strains were identified. Across all three organizations, amoxicillin-clavulanic acid (first-choice EAT for pyelonephritis) was classified as 'high', while seven other antibiotics, including three EAT agents, had varying classifications. Higher ABR was associated with higher proportions of rehabilitation/short-stay care beds, higher number of shared bathrooms, higher hospital admission rates and higher antibiotic usage. Focus groups revealed that defining a ABR upper threshold for LQAS was difficult, that multiple factors influenced the choice of EAT (e.g. side effects), and that the role of ABR prevalence in EAT-related decision making was unclear.

Conclusions: Using LQAS to classify E. coli/Klebsiella ABR in nursing homes was feasible within 4 months. To effectively inform local EAT, consensus is needed on the threshold of maximum acceptable level of ABR.