Pub Date : 2025-02-01DOI: 10.1016/j.ijantimicag.2024.107417
Alessandra Oliva , Lorenzo Volpicelli , Antonietta Gigante
{"title":"Assessment of actual renal function in critically ill patients with severe infections: Moving towards a personalized approach","authors":"Alessandra Oliva , Lorenzo Volpicelli , Antonietta Gigante","doi":"10.1016/j.ijantimicag.2024.107417","DOIUrl":"10.1016/j.ijantimicag.2024.107417","url":null,"abstract":"","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"65 2","pages":"Article 107417"},"PeriodicalIF":4.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.ijantimicag.2024.107423
Jelmer Raaijmakers , Mike M. Ruth , Jodie A. Schildkraut , Erik van den Hombergh , Rob E. Aarnoutse , Elin M. Svensson , Heiman F.L. Wertheim , Wouter Hoefsloot , Jakko van Ingen
Objective
Mycobacterium avium complex bacteria cause chronic pulmonary disease (MAC-PD) in susceptible patients. The recommended treatment regimen (rifampicin, ethambutol and azithromycin) achieves 65% cure rates but with considerable toxicity and drug-drug interactions [[2], [3]]. Minocycline proved active in monotherapy experiments using the hollow-fibre model [4]. We compared the efficacy of the recommended regimen with a minocycline, ethambutol and azithromycin regimen using this model.
Methods
Epithelial lining fluid pharmacokinetic (PK) profiles of the recommended regimen and minocycline, ethambutol, azithromycin regimen were simulated. THP-1 cells infected with M. avium ATCC 700898 were exposed to these regimens for 21 d. PK profiles were determined at d 0 and d 21. The pharmacodynamic effect was measured by determining bacterial densities at d 0, 3, 7, 14 and 21 for intra- and extracellular fractions. Emergence of macrolide-resistance was monitored by inoculating azithromycin-containing agar, MIC measurements and resistance mutation analysis.
Results
The minocycline-containing regimen exhibited a 1.5 log10 CFU/mL lower bacterial burden than the recommended regimen at d 7, though both regimens lost effectiveness over time. Treatment failure in both arms was not linked to the emergence macrolide-resistance. PK profiles simulated in the model matched those in MAC-PD patients.
Conclusions
Replacing rifampicin with minocycline increased the antimycobacterial activity of the MAC-PD treatment regimen in the hollow-fibre model, without jeopardizing the prevention of macrolide-resistance. This promising minocycline-containing regimen is a candidate for inclusion in clinical trials.
{"title":"Replacing rifampicin with minocycline increases the activity of the treatment regimen for Mycobacterium avium complex pulmonary disease in a dynamic hollow-fibre system","authors":"Jelmer Raaijmakers , Mike M. Ruth , Jodie A. Schildkraut , Erik van den Hombergh , Rob E. Aarnoutse , Elin M. Svensson , Heiman F.L. Wertheim , Wouter Hoefsloot , Jakko van Ingen","doi":"10.1016/j.ijantimicag.2024.107423","DOIUrl":"10.1016/j.ijantimicag.2024.107423","url":null,"abstract":"<div><h3>Objective</h3><div><em>Mycobacterium avium</em> complex bacteria cause chronic pulmonary disease (MAC-PD) in susceptible patients. The recommended treatment regimen (rifampicin, ethambutol and azithromycin) achieves 65% cure rates but with considerable toxicity and drug-drug interactions [<span><span>[2]</span></span>, <span><span>[3]</span></span>]. Minocycline proved active in monotherapy experiments using the hollow-fibre model [<span><span>4</span></span>]. We compared the efficacy of the recommended regimen with a minocycline, ethambutol and azithromycin regimen using this model.</div></div><div><h3>Methods</h3><div>Epithelial lining fluid pharmacokinetic (PK) profiles of the recommended regimen and minocycline, ethambutol, azithromycin regimen were simulated. THP-1 cells infected with <em>M. avium</em> ATCC 700898 were exposed to these regimens for 21 d. PK profiles were determined at d 0 and d 21. The pharmacodynamic effect was measured by determining bacterial densities at d 0, 3, 7, 14 and 21 for intra- and extracellular fractions. Emergence of macrolide-resistance was monitored by inoculating azithromycin-containing agar, MIC measurements and resistance mutation analysis.</div></div><div><h3>Results</h3><div>The minocycline-containing regimen exhibited a 1.5 log10 CFU/mL lower bacterial burden than the recommended regimen at d 7, though both regimens lost effectiveness over time. Treatment failure in both arms was not linked to the emergence macrolide-resistance. PK profiles simulated in the model matched those in MAC-PD patients.</div></div><div><h3>Conclusions</h3><div>Replacing rifampicin with minocycline increased the antimycobacterial activity of the MAC-PD treatment regimen in the hollow-fibre model, without jeopardizing the prevention of macrolide-resistance. This promising minocycline-containing regimen is a candidate for inclusion in clinical trials.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"65 2","pages":"Article 107423"},"PeriodicalIF":4.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142903160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.ijantimicag.2024.107404
Suzanne M. Dufault , Geraint R. Davies , Elin M. Svensson , Derek J. Sloan , Andrew D. McCallum , Anu Patel , Pieter Van Brantegem , Paolo Denti , Patrick P.J. Phillips
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 (ULOQM) 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 ULOQMs 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.
{"title":"Analysis of time-to-positivity data in tuberculosis treatment studies: Identifying a new limit of quantification","authors":"Suzanne M. Dufault , Geraint R. Davies , Elin M. Svensson , Derek J. Sloan , Andrew D. McCallum , Anu Patel , Pieter Van Brantegem , Paolo Denti , Patrick P.J. Phillips","doi":"10.1016/j.ijantimicag.2024.107404","DOIUrl":"10.1016/j.ijantimicag.2024.107404","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>We explored whether there is evidence to suggest setting an upper limit of quantification for modeling purposes (ULOQ<em><sub>M</sub></em>) lower than the diagnostic limit of detection (LOD) using data from several TB-PACTS randomized clinical trials and PanACEA MAMS-TB.</div></div><div><h3>Results</h3><div>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<em><sub>M</sub></em>s 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.</div></div><div><h3>Conclusions</h3><div>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.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"65 2","pages":"Article 107404"},"PeriodicalIF":4.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142800553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"Prophylactic phage aerosols for nosocomial infection control in an extracorporeal membrane oxygenation unit: A 4-year prospective study of temporospatially designed phage cocktails","authors":"Chun-Chieh Tseng , Li-Kuang Chen , Hsiu-Tzu Chu , Yi-Ting Chen , Hui-Li Jiang , Hui-Hua Yang , Chin-Cheng Chang , Sankhla Debangana , Lee-Mei Ponge , Min-Xiu Li , Ying-Hao Chin , Jui-Chih Chang","doi":"10.1016/j.ijantimicag.2024.107413","DOIUrl":"10.1016/j.ijantimicag.2024.107413","url":null,"abstract":"<div><div>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 <em>Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa</em>, and <em>Stenotrophomonas maltophilia</em>. 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 (<em>P</em> = 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.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"65 2","pages":"Article 107413"},"PeriodicalIF":4.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.ijantimicag.2024.107415
Liqin Shi , Haitao Yuan , Jie Xu , Jinzhao Long , Fang Liu , Yuefei Jin , Shuaiyin Chen , Jingyuan Zhu , Guangcai Duan , Haiyan Yang
{"title":"The longitudinal trend and driving factors of antimicrobial resistance among Streptococcus pneumoniae worldwide","authors":"Liqin Shi , Haitao Yuan , Jie Xu , Jinzhao Long , Fang Liu , Yuefei Jin , Shuaiyin Chen , Jingyuan Zhu , Guangcai Duan , Haiyan Yang","doi":"10.1016/j.ijantimicag.2024.107415","DOIUrl":"10.1016/j.ijantimicag.2024.107415","url":null,"abstract":"","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"65 2","pages":"Article 107415"},"PeriodicalIF":4.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"Toxicokinetic profiling of VRP-034: Evaluating its potential in mitigating polymyxin-B-associated nephrotoxicity","authors":"Kamlesh Vishwakarma, Anmol Bisht, Parveen Kumar, Satish Kumar, Jawed Akhter, Anurag Payasi, Saransh Chaudhary, Anmol Aggarwal","doi":"10.1016/j.ijantimicag.2024.107393","DOIUrl":"10.1016/j.ijantimicag.2024.107393","url":null,"abstract":"<div><div>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.</div><div>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.</div><div>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.</div><div>In conclusion, VRP-034 demonstrated reduced nephrotoxicity compared with marketed PMB, suggesting its potential as a safer alternative.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"65 2","pages":"Article 107393"},"PeriodicalIF":4.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"Clarithromycin for improved clinical outcomes in community-acquired pneumonia: A subgroup analysis of the ACCESS trial","authors":"Karolina Akinosoglou , Konstantinos Leventogiannis , Elisavet Tasouli , Nikolaos Kakavoulis , Georgios Niotis , Sarantia Doulou , Lamprini Skorda , Konstantina Iliopoulou , Anna Papailiou , Paraskevi Katsaounou , Vassiliki Rapti , George Chrysos , Theodoros Seferlis , Styliani Gerakari , Konstantina Dakou , Ilias C. Papanikolaou , Haralampos Milionis , Samantha Kewitz , Sara Georgiadou , Theano Kontopoulou , Evangelos J. Giamarellos-Bourboulis","doi":"10.1016/j.ijantimicag.2024.107406","DOIUrl":"10.1016/j.ijantimicag.2024.107406","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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 (<em>P</em><0.0001), whereas MV was required in 18.8% and 7.4% of patients, respectively (<em>P</em>=0.022). The addition of corticosteroids alone was not as clinically advantageous as the use of clarithromycin alone, when added to SoC.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"65 2","pages":"Article 107406"},"PeriodicalIF":4.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.ijantimicag.2024.107414
Zhili Tan , Yani Lin , Junsheng Fan , Yaping Jia , Shansong Zheng , Xinmei Wang , Cong Gao , Zhemin Zhang , Bing Li , Haiqing Chu
Background
β-lactams are crucial for anti-Mycobacterium abscessus complex (MABC) therapy. Treating infections is challenging since MABC produces a class A β-lactamase (BlaMab), which is capable of hydrolyzing β-lactams thus causing drug resistance. Diazabicyclooctane (DBO) β-lactamase inhibitors (BLIs) can inhibit BlaMab. 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 BlaMab mutations in clinical isolates were analyzed using sequence alignment to determine whether BlaMab 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 BlaMab 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.
{"title":"FL058, a novel β-lactamase inhibitor, increases the anti-Mycobacterium abscessus activity of imipenem","authors":"Zhili Tan , Yani Lin , Junsheng Fan , Yaping Jia , Shansong Zheng , Xinmei Wang , Cong Gao , Zhemin Zhang , Bing Li , Haiqing Chu","doi":"10.1016/j.ijantimicag.2024.107414","DOIUrl":"10.1016/j.ijantimicag.2024.107414","url":null,"abstract":"<div><h3>Background</h3><div><em>β</em>-lactams are crucial for anti-<em>Mycobacterium abscessus</em> complex (MABC) therapy. Treating infections is challenging since MABC produces a class A <em>β</em>-lactamase (Bla<sub>Mab)</sub>, which is capable of hydrolyzing <em>β</em>-lactams thus causing drug resistance. Diazabicyclooctane (DBO) <em>β</em>-lactamase inhibitors (BLIs) can inhibit Bla<sub>Mab</sub>. FL058 is a novel DBO BLI; the anti-MABC activity of FL058 combined with <em>β</em>-lactams remains unknown.</div></div><div><h3>Methods</h3><div>The activities of ten <em>β</em>-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<sub>Mab</sub> mutations in clinical isolates were analyzed using sequence alignment to determine whether Bla<sub>Mab</sub> mutations are associated with DBO BLIs sensitivity.</div></div><div><h3>Results</h3><div>FL058, avibactam and relebactam significantly increased the anti-MABC activity of <em>β</em>-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<sub>Mab</sub> T141A mutation may reduce the susceptibility of MABC to imipenem-BLIs.</div></div><div><h3>Conclusion</h3><div>The elevated anti-MABC activity exhibited by imipenem combined with FL058 suggests a potential new approach to treating MABC infections.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"65 2","pages":"Article 107414"},"PeriodicalIF":4.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.ijantimicag.2024.107422
Md. Kaisar Rahman, Howard Rodriguez-Mori, Guy Loneragan, Babafela Awosile
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 (blaCMY-2, blaCTX-M-(1, 2, 9, 14, 15, 27, 32, 65), blaFOX-5, blaIMP-27, blaKPC-2, blaNDM-(1, 5), blaOXA-(1, 48), blaPSE-1, blaSHV-(1, 12), blaTEM-(1, 1A, 1B)) have been reported across animals, humans, and environment. Notably, blaCTX-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, blaCMY-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 blaCTX-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.
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