Journal of Antimicrobial Chemotherapy最新文献

Mycobacterium abscessus complex is a group of rapidly growing non-tuberculous mycobacteria (NTM), increasingly emerging as opportunistic pathogens. Current treatment options for these microorganisms are limited and associated with a high rate of treatment failure, toxicity and recurrence. In search of new therapeutic strategies, interest has grown in dual β-lactam (DBL) therapy, as research recently discovered that M. abscessus cell wall synthesis is mainly regulated by two types of enzymes (d,d-transpeptidases and l,d-transpeptidases) differently susceptible to inhibition by distinct β-lactams. In vitro studies testing several DBL combinations have shown synergy in extracellular broth cultures as well as in the intracellular setting: cefoxitin/imipenem, ceftaroline/imipenem, ceftazidime/ceftaroline and ceftazidime/imipenem. The addition of specific β-lactamase inhibitors (BLIs) targeting M. abscessus β-lactamase did not significantly enhance the activity of DBL combinations. However, in vivo data are lacking. We reviewed the literature on DBL/DBL-BLI-based therapies for M. abscessus infections to raise greater attention on this promising yet overlooked treatment option and to guide future preclinical and clinical studies.

Objectives: Bacterial persistence is a significant cause of the intractability of chronic and relapsing infections. Despite its importance, many of the underlying mechanisms are still not well understood.

Methods: Antibiotic-tolerant mutants of Burkholderia thailandensis were isolated through exposure to lethal doses of AMP or MEM, followed by whole-genome sequencing to identify mutations. Subsequently, these mutants underwent comprehensive characterization via killing curves, growth curves, and persistence-fraction plots. Northern blot analysis was employed to detect uncharged tRNA, while the generation of relA and spoT null mutations served to confirm the involvement of the stringent response in this persistence mechanism. Phenotypic reversion of the persistence mutation was demonstrated by incubating the mutants without antibiotics for 2 weeks.

Results: We have discovered a novel mechanism of persistence triggered by specific mutations at positions 32 or 38 within the anticodon loop of tRNAAsp. This leads to heightened persistence through a RelA-dependent stringent response. Notably, this persistence can be easily reverted to wild-type physiology by losing the mutant tRNA allele within the tRNA gene cluster when persistence is no longer essential for survival.

Conclusions: This distinct form of persistence underscores the novel function of tRNA mutations at positions 32 or 38 within the anticodon loop, as well as the significance of the tRNA gene cluster in conferring adaptability to regulate persistence for enhanced survival.

Background: Darunavir is a potent HIV protease inhibitor with a high barrier to resistance. We conducted a nested pharmacokinetic sub-study within CHAPAS-4 to evaluate darunavir exposure in African children with HIV, taking once-daily darunavir/ritonavir for second-line treatment.

Methods: We used data from the CHAPAS-4 pharmacokinetic sub-study treating children with once-daily darunavir/ritonavir (600/100 mg if 14-24.9 kg and 800/100 mg if ≥25 kg) with either tenofovir alafenamide fumarate (TAF)/emtricitabine (FTC), abacavir/lamivudine or zidovudine/lamivudine. Steady-state pharmacokinetic sampling was done at 0, 1, 2, 4, 6, 8, 12 and 24 hours after observed darunavir/ritonavir intake. Non-compartmental and population pharmacokinetic analyses were used to describe the data and identify significant covariates. Reference adult pharmacokinetic data were used for comparison. We simulated the World Health Organization (WHO) recommended 600/100 mg darunavir/ritonavir dose for the 25-34.9 kg weight band.

Results: Data from 59 children with median age and weight 10.9 (range 3.8-14.7) years and 26.0 (14.5-47.0) kg, respectively, were available. A two-compartment disposition model with transit absorption compartments and weight-based allometric scaling of clearance and volume best described darunavir data. Our population achieved geometric mean (%CV) darunavir AUC0-24h, 94.3(50) mg·h/L and Cmax, 9.1(35) mg/L, above adult reference values and Ctrough, 1.5(111) mg/L, like adult values. The nucleoside reverse-transcriptase inhibitor backbone was not found to affect darunavir concentrations. Simulated WHO-recommended darunavir/ritonavir doses showed exposures equivalent to adults. Higher alpha-1-acid glycoprotein increased binding to darunavir and decreased apparent clearance of darunavir.

Conclusions: Darunavir exposures achieved in our trial are within safe range. Darunavir/ritonavir can safely be co-administered with TAF/FTC. Both WHO-recommended 600/100 mg and CHAPAS-4 800/100 mg darunavir/ritonavir doses for the 25-34.9 kg weight band offer favourable exposures. The choice between them can depend on tablet availability.

Background: Teicoplanin has been widely used in patients with infections caused by Staphylococcus aureus, especially for critically ill patients. The pharmacokinetics (PK) of teicoplanin vary between individuals and within the same individual. We aim to establish a prediction model via a combination of machine learning and population PK (PPK) to support personalized medication decisions for critically ill patients.

Methods: A retrospective study was performed incorporating 33 variables, including PPK parameters (clearance and volume of distribution). Multiple algorithms and Shapley additive explanations were employed for feature selection of variables to determine the strongest driving factors.

Results: The performance of each algorithm with PPK parameters was superior to that without PPK parameters. The composition of support vector regression, categorical boosting and a backpropagation neural network (7:2:1) with the highest R2 (0.809) was determined as the final ensemble model. The model included 15 variables after feature selection, of which the predictive performance was superior to that of models considering all variables or using only PPK. The R2, mean absolute error, mean squared error, absolute accuracy (±5 mg/L) and relative accuracy (±30%) of external validation were 0.649, 3.913, 28.347, 76.12% and 76.12%, respectively.

Conclusions: Our study offers a non-invasive, fast and cost-effective prediction model of teicoplanin plasma concentration in critically ill patients. The model serves as a fundamental tool for clinicians to determine the effective plasma concentration range of teicoplanin and formulate individualized dosing regimens accordingly.

Objectives: To determine the association of adequate empirical combination therapy (AECT) with 30-day all-cause mortality in patients with septic shock due to Pseudomonas aeruginosa bloodstream infections (BSI).

Methods: This multicentre, retrospective cohort study analysed data from 14 public hospitals in Italy, including all consecutive adult patients admitted during 2021-2022 with septic shock due to P. aeruginosa BSI. We compared the outcomes of patients receiving AECT to those on adequate empirical monotherapy (AEMT) using Cox regression analyses.

Results: Of the 98 patients who received adequate empirical antibiotic treatment for septic shock due to P. aeruginosa BSI, 24 underwent AECT and 74 were given AEMT. AECT was associated with a lower 30-day all-cause mortality (25%, six out of 24) compared to AEMT (56.8%, 42 out of 74; P = 0.007). Multivariate Cox regression analysis indicated AECT as the only factor significantly associated with improved survival (aHR 0.30; 95% CI 0.12-0.71; P = 0.006). By contrast, the use of monotherapy or combination therapy in the definitive regimen did not influence mortality (aHR 0.73; 95% CI 0.25-2.14; P = 0.568).

Conclusions: AECT may be associated with reduced mortality compared to monotherapy in septic shock patients due to P. aeruginosa BSI. However, the administration of definitive adequate monotherapy or combination therapy yields similar outcomes, suggesting that once susceptibility is documented, switching to a single active in vitro drug is safe and feasible. Further studies are recommended to validate these findings.

Background: Despite improvements in treatment and oral pre-exposure prophylaxis (PrEP) access, 1.3 million people acquired HIV in 2022. Six-monthly lenacapavir PrEP could benefit tens of millions of people at high risk of infection. However, prices are currently up to $44 819 per person per year (pppy).

Objectives: We projected minimum lenacapavir pricing based on generic mass production and a Cost-Plus (Cost+) model.

Methods: Current active pharmaceutical ingredient (API) and key starting materials (KSMs) costs were obtained from export databases. The routes of synthesis (ROS) were analysed to project a cost of goods (COGs). Formulation, vials and profit margin costs were included using standardized algorithms and Cost+ pricing. We estimated prices with scale-up to supply 1 million then 10 million treatment-years, comparing this with national list prices.

Results: The lenacapavir API is currently exported from India for $64 480/kg on 1 kg scale. Based on the ROS and KSMs, API COGs of $25 000/kg and $10 000/kg are achievable for a committed demand of 1 million (2 million tonnes/annum of API) and 10 million treatment-years, respectively. Including formulation steps, injectable lenacapavir could be mass produced for approximately $94 pppy for 1 million and $41 for 10 million treatment-years, if voluntary licences are in place and competition between generic suppliers substantially improves. Greater scale-up with improvements in manufacturers' ROS could reduce prices further. Currently lenacapavir costs $25 395-44 819 pppy.

Conclusions: Lenacapavir could be mass produced for <$100 pppy at launch. Voluntary licensing and multiple suppliers are required to achieve these low prices. This mechanism is already in place for other antiretrovirals. To date, Gilead has not agreed lenacapavir voluntary licences with the Medicines Patent Pool.