International Journal of Antimicrobial Agents最新文献

Background: The BACTEC Mycobacteria Growth Indicator Tube (MGIT) machine is the standard globally for detecting viable mycobacteria in patients' sputum. Samples are observed for no longer than 42 days, at which point the sample is declared 'negative' for tuberculosis (TB). This time to detection of bacterial growth, referred to as time-to-positivity (TTP), is increasingly of interest, not solely as a diagnostic tool but also as a continuous biomarker wherein change in TTP can be used for comparing the bactericidal activity of different TB treatments. However, as a continuous measure, there are oddities in the distribution of TTP values observed, particularly at higher values.

Methods: We explored whether there is evidence to suggest setting an upper limit of quantification for modeling purposes (ULOQ_M) lower than the diagnostic limit of detection (LOD) using data from several TB-PACTS randomized clinical trials and PanACEA MAMS-TB.

Results: Across all trials, less than 7.1% of weekly samples returned TTP measurements between 25 and 42 days. Further, the relative absolute prediction error (%) was highest in this range. When modelling with ULOQ_Ms of 25 and 30 days, estimator precision improved for 23 of 25 regimen-level slopes compared to models using the LOD. Discrimination between regimens based on Bayesian posteriors also improved.

Conclusions: Although TTP measurements between 25 days and the diagnostic LOD may be important for diagnostic purposes, TTP values in this range may not contribute meaningfully to its use as a quantitative measure, particularly when assessing treatment response, and may lead to underpowered clinical trials.

Phage-based decontamination has rarely been explored in real-world settings, particularly in the environments of patients undergoing extracorporeal membrane oxygenation (ECMO). This four-year prospective study aimed to evaluate the effectiveness of aerosolized phage cocktails tailored to combat target antibiotic-resistant species of Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia. The decontamination procedure with phage aerosols was proactively implemented before the admission of ECMO patients based on a thorough analysis of phage typing results from bacterial species isolated from prospective patient areas during the preceding two months. The phage cocktail formulation design also accounted for phage resistance development, phage families, and plaque characteristics. Throughout the study, 85 ECMO patients were monitored, with the environments of 22 patients undergoing phage decontamination. Fifty phage cocktails were prepared to target the identified species. Respiratory infections were most common among ECMO patients, accounting for 71.4 %. The ECMO duration for patients infected with the targeted species was significantly longer than that for noninfected patients (P = 0.019), with peak infection incidence occurring between 3 and 7 days of ECMO treatment (67.1 per 1000 ECMO days). Notably, none of the patients in phage-treated environments contracted infections from the targeted species. However, the overall incidence of bacterial infections did not significantly correlate with phage decontamination efforts, as phages are effective only against their specific hosts. This study demonstrates the potential of prophylactic phage decontamination to prevent specific infections, aligning with One Health principles by offering a sustainable alternative to antibiotics, potentially significantly reducing antibiotic use.

This study assessed the nephrotoxicity and toxicokinetic profile of VRP-034 [a novel formulation of polymyxin B (PMB)] compared with marketed PMB over a 7-day repeat-dose regimen. Three objectives were pursued: evaluating PMB pharmacokinetics in both groups, alongside assessing the impact of VRP-034 on mitigating PMB-associated kidney injury; analysing the reversibility of kidney injury; and validating novel kidney injury biomarkers against traditional markers using histopathological scoring. Sixty-eight Sprague-Dawley rats were divided into three groups: 30 in each of the marketed PMB and VRP-034 groups, and eight in the control group. Rats received drugs at 6 mg/kg subcutaneously every 8 h (human equivalent dose ∼3 mg/kg/day). Toxicokinetic evaluations were conducted on selected animals on days 1, 2, 4, and 7 (after 3rd, 6th, 12th and 21st dose), while the remaining animals were observed for an additional 7 days without treatment. Samples were collected up to 12 h post-administration, followed by necropsy and histopathological examination. Plasma PMB concentrations were quantified; and kidney injury biomarkers, oxidative stress and anti-inflammatory markers were evaluated. Receiver operating characteristic curve analysis was performed to validate kidney injury biomarkers against histopathological grading. Similar plasma PMB concentrations and pharmacokinetic parameters were found in the two treatment groups. However, the VRP-034 group exhibited significantly lower nephrotoxicity, with reduced levels of kidney injury biomarkers, and diminished oxidative stress and inflammation levels compared with the marketed PMB group. Histopathological examination confirmed reduced renal damage in the VRP-034 group. Novel kidney injury biomarkers demonstrated superior sensitivity, specificity and early detection capability over traditional markers. In conclusion, VRP-034 demonstrated reduced nephrotoxicity compared with marketed PMB, suggesting its potential as a safer alternative.

Background: In the ACCESS trial, the addition of clarithromycin to standard-of-care antibiotics (SoC) enhanced early clinical response and attenuated the inflammatory burden in adults with community-acquired pneumonia (CAP) requiring hospitalisation. A post-hoc analysis was performed to investigate the benefit in specific subgroups.

Methods: The primary endpoint comprised two conditions to be met during the first 72 h: ≥50% decrease in respiratory symptom severity score; and any of ≥30% decrease in sequential organ failure assessment score and favourable change in the kinetics of procalcitonin (PCT, defined as ≥80% PCT decrease or PCT <0.25 ng/mL). In this exploratory post-hoc analysis, achievement of the study composite primary endpoint was compared between the two treatment groups within subsets differentiated by demographic characteristics, comorbidities, CAP severity, baseline laboratory findings and corticosteroid co-administration. The impact of clarithromycin treatment on the need for mechanical ventilation (MV) in all subgroups was also analysed.

Results: The addition of clarithromycin significantly increased the proportion of patients achieving the primary endpoint across all subgroups and decreased the need for MV in 19 out of the 37 subgroups studied. For instance, the primary endpoint was attained in 32.7% of placebo-treated patients and in 67% of clarithromycin-treated patients with CURB-65 score ≥2 (P<0.0001), whereas MV was required in 18.8% and 7.4% of patients, respectively (P=0.022). The addition of corticosteroids alone was not as clinically advantageous as the use of clarithromycin alone, when added to SoC.

Conclusion: Adding clarithromycin to SoC in the ACCESS trial achieved early clinical anti-inflammatory responses and decreased the need for MV in subgroups of hospitalised patients with CAP.

Background: β-lactams are crucial for anti-Mycobacterium abscessus complex (MABC) therapy. Treating infections is challenging since MABC produces a class A β-lactamase (Bla_Mab), which is capable of hydrolyzing β-lactams thus causing drug resistance. Diazabicyclooctane (DBO) β-lactamase inhibitors (BLIs) can inhibit Bla_Mab. FL058 is a novel DBO BLI; the anti-MABC activity of FL058 combined with β-lactams remains unknown.

Methods: The activities of ten β-lactams (imipenem, meropenem, faropenem, tebipenem, cefoxitin, cefepime, ceftazidime, cefdinir, cefuroxime, and amoxicillin) combined with three DBO BLIs (FL058, avibactam, and relebactam) toward two MABC reference strains were determined by broth microdilution assay. The anti-MABC activities of imipenem combined with three BLIs against 193 clinical isolates were also evaluated. The activity of imipenem combined with FL058 was also tested against intracellular MABC residing in macrophages and in a mouse model. Finally, the Bla_Mab mutations in clinical isolates were analyzed using sequence alignment to determine whether Bla_Mab mutations are associated with DBO BLIs sensitivity.

Results: FL058, avibactam and relebactam significantly increased the anti-MABC activity of β-lactams, especially imipenem, against reference strains and clinical isolates. The anti-MABC activity of imipenem combined with FL058 was superior to its activity when combined with either avibactam or relebactam. The combination of imipenem and FL058 significantly reduced the numbers of intracellular organisms in cultured macrophages, and of viable bacteria in the lungs of MABC-infected mice. Rough morphotypes tended to be more resistant than smooth morphotype. A Bla_Mab T141A mutation may reduce the susceptibility of MABC to imipenem-BLIs.

Conclusion: The elevated anti-MABC activity exhibited by imipenem combined with FL058 suggests a potential new approach to treating MABC infections.

Background: The study aimed to review the beta-lactamase resistance genes detected in Enterobacterales from humans, animals, and the environment in the United States.

Methods: We conducted a comprehensive search on PubMed, Web of Science, and Google Scholar for articles reporting beta-lactamase genes in the United States from 1981 to 22 April 2022, following the PRISMA protocol. Studies were evaluated based on predefined eligibility criteria, and both qualitative and quantitative analyses were conducted on the selected studies.

Results: Of the 335 articles, a total of 169 different beta-lactamase genes, including narrow-spectrum, extended-spectrum, AmpC, and carbapenemase have been detected and reported in the United States, with human (137), animal (53), and environment (47). 22 genes (bla_CMY-2, bla_{CTX-M-(1, 2, 9, 14, 15, 27, 32, 65)}, bla_FOX-5, bla_IMP-27, bla_KPC-2, bla_{NDM-(1, 5)}, bla_{OXA-(1, 48)}, bla_PSE-1, bla_{SHV-(1, 12)}, bla_{TEM-(1, 1A, 1B)}) have been reported across animals, humans, and environment. Notably, bla_CTX-M-15 was prevalent in E. coli isolates, with an overall pooled proportion of 10.7 %, varying between animals (8.6 %), humans (13.1 %), and the environment (0.8 %). Similarly, bla_CMY-2 in E. coli isolates had an overall pooled proportion of 10.6 %, with distinctions in proportion among animals (1.6 %), humans (41.3 %), and the environment (16.2 %). The sequence type (ST131) was detected as the predominant, mainly associated with the bla_CTX-M-15, with a pooled proportion of 56.9 %, varying from 14.3 % to 90 % across studies.

Conclusion: This study highlights the distribution of beta-lactamases in the United States, essential for understanding One Health and the molecular epidemiology of key beta-lactamases, especially extended-spectrum beta-lactamases and carbapenemases.

In vitro time-kill curve (TKC) experiments are an important part of the pharmacokinetic- pharmacodynamic (PKPD) characterisation of antibiotics. Traditional TKCs use Mueller-Hinton broth (MHB), which lacks specific plasma components that could potentially influence the bacterial growth and killing dynamics, and affect translation to in vivo. This study aimed to evaluate the impact of plasma on the PKPD characterisation of two antibiotics; cefazolin and clindamycin. TKC experiments were conducted in pure MHB, and MHB spiked with 20% and 70% human plasma. Plasma protein binding (PPB) data were available, and a linear model described cefazolin's PPB, while clindamycin's PPB was best described by a second-order polynomial model. PKPD models were developed based on pure MHB and described drug effects using an E_max model, with consideration of adaptive resistance for cefazolin. The observed bacterial growth and killing in the plasma-spiked MHB TKC data was insufficiently described when applying the developed PPB and PKPD models. In plasma spiked MHB, a growth delay was observed, estimated to 0.25 h (20% plasma), or 2.90 h (70% plasma) for cefazolin, and 0.64 h (20% plasma), or 1.40 h (70% plasma) for clindamycin. Furthermore, the drug effect was higher than expected in plasma-spiked MHB, with bacterial stasis and/or killing at unbound concentrations below MIC, necessitating drug effect parameter scaling (C₅₀ for cefazolin, Hill coefficient for clindamycin). The findings highlight significant differences in bacterial growth and killing dynamics between pure MHB and plasma-spiked MHB and exemplify how PKPD modelling may be used to improve the translation of in vitro results.

Background: Combination therapy offers a promising option to enhance efficacy and prevent resistance. A comprehensive and quantitative assessment of the last-resort combination of ceftazidime/avibactam and tigecycline is not available.

Objective: This study systematically investigated the pharmacodynamic interaction between ceftazidime/avibactam and tigecycline in clinical and isogenic Escherichia coli and Klebsiella pneumoniae strains harbouring genes that encode various carbapenemases or ESBLs.

Methods: An adaptive in vitro 'dynamic' checkerboard design and pharmacometric modelling were employed for the evaluation of pharmacodynamic interactions in fifteen bacterial isolates. Additionally, time-kill assays and metabolomic analyses were used to provide mechanistic insights.

Results: Antagonistic drug interactions between ceftazidime/avibactam and tigecycline were identified in the majority of tested strains. Time-kill assays confirmed antagonistic interactions, with tigecycline limiting ceftazidime/avibactam total killing. Metabolomic analyses of mono and combined drug exposure to bacteria revealed matching metabolomes in tigecycline alone and the combination with ceftazidime/avibactam, corroborating the identified antagonism between these drugs.

Conclusions: Our study reveals that the antagonistic interaction between ceftazidime/avibactam and tigecycline can undermine ceftazidime/avibactam's efficacy, suggesting limited clinical benefit in combining these antibiotics. Therefore, further research is encouraged to explore this and alternative combinations or approaches that may offer better clinical outcomes.

Background: Antibiotics have been among the drugs most affected by shortages over the last two decades, with harmful consequences that may persist over years. This position paper was designed by the Alliance for the Prudent Use of Antibiotics (APUA), an international multidisciplinary consortium of experts dedicated to combating antimicrobial resistance.

Methods: We performed a narrative review to examine the main causes and impacts of antibiotics shortages, and to identify the solutions that may be proposed to prevent and mitigate this public health threat.

Results: The main causes of antibiotic shortages are failure to comply with good manufacturing practices, regulatory issues, unavailability of essential components, unanticipated discontinuation of production by a major supplier, unexpected surges in demand, and other logistical challenges. The main consequences include delays in appropriate treatment administration, overuse of broad-spectrum antibiotics with an increased risk of resistance, reduced efficacy, and increased toxicity due to sub-optimal antibiotics use, increased costs, medication errors, and prolonged or repeated hospital stays. Proposed potential solutions for antibiotic shortages include multidisciplinary international initiatives to foster market entry rewards, specific solutions for low-and-middle income countries (LMICs), strengthening supply chains, encouraging local production, implementing market entry incentives and facilitating the registration process for novel antibiotics and vaccines.

Conclusions: Antibiotics shortage severely impacts patient care and public health worldwide. The sustainability of both current and future antibiotics depends on the implementation of effective global health strategies and ongoing financial commitment. Immediate and decisive action is necessary to protect global health for future generations.