Journal of Antimicrobial Chemotherapy最新文献

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: Antibiotic resistance complicates treatment of urinary infections, particularly when these ascend above the bladder, with few oral options remaining. New oral β-lactamase inhibitor combinations present a potential answer, with ceftibuten/avibactam-now undergoing clinical trials-widely active against strains with ESBLs and serine carbapenemases. To inform its development we undertook mutant selection studies.

Methods: Single-step mutants were sought from Enterobacterales (n = 24) with AmpC, ESBL, OXA-48 and KPC β-lactamases. MICs were determined by CLSI agar dilution. Illumina WGS of selected mutants (n = 50) was performed.

Results: Even at low MIC multiples, mutant frequencies were mostly only c. 10-8. β-Lactamase structural mutants were obtained only from KPC and AmpC enzymes. The KPC mutants had Trp105Arg or Ser130Thr substitutions, causing only small MIC shifts; the AmpC mutant had an Asn346Trp replacement, as previously selected with other avibactam combinations. No ESBL mutants were obtained. Rather, from Escherichia coli, we predominantly selected mutants with modifications to ftsI, encoding penicillin-binding protein (PBP) 3. From Klebsiella pneumoniae and Enterobacter cloacae we predominantly obtained variants with modification of uptake and efflux components or their regulators. ftsI mutants lacked cross-resistance to other avibactam combinations; uptake mutants had broader MIC rises. A few putative mutants had other lesion(s) of uncertain significance, or grew as small, stressed colonies lacking detectable lesions.

Conclusions: There seems little risk of ESBLs mutating to confer ceftibuten/avibactam resistance, though some risk may apply for KPC and AmpC enzymes. The propensity to select E. coli ftsI/PBP3 mutants is notable and was not seen with other avibactam combinations.

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.

Background: Model-informed precision dosing (MIPD) combines population pharmacokinetic knowledge with therapeutic drug monitoring (TDM) to optimize dosage adjustment. It could improve target concentration attainment over empirical TDM, still widely practised for broad-spectrum antibiotics.

Objectives: To evaluate the respective performance of TDM and MIPD in achieving target piperacillin exposure.

Methods: Measurements from 80 courses of intermittent piperacillin infusions, each with two TDM samples, were retrospectively submitted to our MIPD software TUCUXI. We considered six dosage adjustment strategies: identical dosage for all (4000 mg q8h), actual initial dosage (chart-based), actual empirical adjustment following first TDM, a priori MIPD-based dosage, a posteriori MIPD-based adjustment after first TDM and MIPD including both TDM measurements. Dosing strategies were compared regarding daily dosage, trough levels distribution and PTA (with target trough 8-32 mg/L).

Results: Median trough concentration fell within 8-32 mg/L for all strategies except a priori MIPD-based dosage (42 mg/L). Distributions of trough concentrations predicted with the six dosage adjustment strategies showed significant differences, with both a posteriori MIPD-based strategies best reducing their standard deviation (P < 0.001). PTA of 32%, 32%, 55%, 29%, 83% and 94% were estimated, respectively for the six strategies (P < 0.001). Poor performance of a priori MIPD-based dosage did not hinder a posteriori MIPD-based strategies from significantly improving target attainment.

Conclusions: Whilst empirical TDM improves exposure standardization and target attainment compared with no TDM, MIPD can still bring further improvement. Prospective trials remain warranted to confirm MIPD benefits not only on target attainment but also on clinical endpoints.

Background: Coccidioidomycosis (Valley Fever) is a dimorphic fungal infection endemic to the southwest United States, Mexico, Central and South America, which can lead to chronic debilitating illness and death.

Objectives: This qualitative study was conducted to develop a bespoke patient-reported outcome measure for patients with chronic disseminated coccidioidomycosis to assess health-related quality of life (HRQoL) impacts.

Patients and methods: Online, first-person narratives of patient experiences of disseminated coccidioidomycosis were used to create a patient-centred conceptual model of symptoms and impacts of the condition. Interviews were conducted with expert clinicians, followed by concept elicitation interviews with patients, to generate key symptom and impact concepts from which an initial patient-reported outcome measure was developed. The draft measure was reviewed with clinicians for clinical relevance and further assessed in cognitive debriefing interviews with patients to refine the measure and establish content validity.

Results: A total of 25 patients were interviewed, which identified impacts relating to physical function, activities of daily living, cognitive function, social/role function and emotional function of disseminated coccidioidomycosis. Twenty items were developed simultaneously in English and Spanish to capture the main impacts across these 5 areas. In general, items were clear and well understood by patients, and clinicians found the measure clinically relevant and appropriate for assessing the burden of disseminated coccidioidomycosis on HRQoL.

Conclusions: Once fully validated, the Valley Fever-Patient Reported Outcome measure may be used in interventional studies to assess HRQoL outcomes, and in clinical practice to monitor patients' HRQoL.

Background: The prevention of invasive fungal infections (IFIs) is crucial for paediatric haemato-oncological patients. This study evaluates the clinical efficacy and side-effects of posaconazole and liposomal amphotericin B (L-AmB) as primary prophylaxis.

Materials and methods: This cohort study included patients aged 3 months to 21 years who received posaconazole or L-AmB (5 mg/kg twice weekly) as prophylaxis from January 2017 to March 2022 at the Hemato-oncological Pediatric Unit, University Hospital of Padua, Italy. Outcomes included adverse events and IFI diagnoses after the start of prophylaxis. Separate analyses were performed for patients with ALL and non-ALL diagnoses, and high-risk and low-risk groups. Cumulative incidence was calculated using the Kaplan-Meier estimator, with significant differences assessed using the log-rank test. Hazard ratios (HR) were estimated using Cox regression.

Results: Fifty-one patients received posaconazole, and 37 received L-AmB. Adverse events occurred in 26% of L-AmB patients and 5.6% of posaconazole patients. IFI breakthrough events were similar in both groups (four events each). In ALL patients, 41% experienced adverse events with L-AmB, compared to 5% with posaconazole. After 1 year, the probability of adverse events was lower in the posaconazole group (54% versus 65%, P < 0.001). Overall, posaconazole was associated with a 91% lower risk of adverse events (HR: 0.07, P < 0.001). Among high-risk patients, IFI breakthrough rates were similar between groups (P = 0.964).

Conclusions: Posaconazole was associated with fewer adverse events than L-AmB, and both drugs showed similar efficacy in preventing IFI breakthroughs, making posaconazole a viable alternative for primary prophylaxis.

Background: NOSO-5O2 is the first clinical candidate of a new antimicrobial class-the odilorhabdins. The pharmacodynamics of NOSO-502 were studied in vitro and in vivo to establish the pharmacodynamic index (PDI) driver.

Methods: A dilutional pharmacokinetic system was used for in vitro experiments. In vivo experiments were conducted in the neutropenic murine thigh infection model. Three Escherichia coli and two Klebsiella pneumoniae strains were used. NOSO-502 pharmacokinetics (PK) in mice were described in a population PK model. Dose fractionation and escalation exposures were performed and bacteriostatic and 1 log10 and 2 log10 kill effects were determined using an Emax model. The coefficient of determination (R2) was used to estimate the variance that might be due to regression with various PDIs (fAUC/MIC, fCmax/MIC, %fT>MIC and fAUC/MIC per length of dosing interval fAUC/MIC·1/tau).

Results: Exposure fractionation in both in vitro and in vivo studies indicated that 6-hourly dosing resulted in a greater reduction in K. pneumoniae bacterial burden compared with either 12- or 24-hourly dosing. Similar observations were made with three E. coli strains in vitro and a single strain of E. coli in vivo. For K. pneumoniae, R2 for fAUC/MIC·1/tau was 0.8376 in vitro and 0.6001 in vivo, which was greater than R2 with other PDIs. Analysis of pooled in vitro data from three strains of E. coli produced an R2 of 0.7073 for fAUC/MIC and 0.6100 for fAUC/MIC·1/tau.

Conclusions: NOSO-502 exhibits both dose- and time-dependent in vitro and in vivo activity against both E. coli and K. pneumoniae.