Antimicrobial Agents and Chemotherapy最新文献

{"title":"Bacteriophage treatment is effective against carbapenem-resistant <i>Klebsiella pneumoniae</i> (KPC) in a neutropenic murine model of gastrointestinal translocation and renal infection.","authors":"Panagiotis Zagaliotis, Jordyn Michalik-Provasek, Eleftheria Mavridou, Ethan Naing, Ioannis S Vizirianakis, Dimitrios Chatzidimitriou, Jason J Gill, Thomas J Walsh","doi":"10.1128/aac.00919-24","DOIUrl":"https://doi.org/10.1128/aac.00919-24","url":null,"abstract":"<p><p>Carbapenemase-producing <i>Klebsiella pneumoniae</i> (KPC) are globally emerging pathogens that cause life-threatening infections. Novel treatment alternatives are urgently needed. We therefore investigated the effectiveness of three novel bacteriophages (Spivey, Pharr, and Soft) in a neutropenic murine model of KPC gastrointestinal colonization, translocation, and disseminated infection. Bacteriophage efficacy was determined by residual bacterial burden of KPC (CFU/g) in kidneys. Parallel studies were conducted of bacteriophage pharmacokinetics and resistance. Treatment of mice with 5 × 10⁹ PFU of phage cocktail via intraperitoneal injection was effective in significantly reducing renal KPC CFU by 100-fold (<i>P</i> < 0.01) when administered every 24 h and 1000-fold (<i>P</i> < 0.01) every 12 h. Moreover, a combination of bacteriophage and ceftazidime-avibactam produced a synergistic effect, resulting in a 10⁵-fold reduction in bacterial burden in cecum and kidney (<i>P</i> < 0.001 in both tissues). Prophylactic administration of bacteriophages via oral gavage did not prevent KPC translocation to the kidneys. Bacteriophage decay determined by linear regression of the ln of mean concentrations demonstrated R² values in plasma of 0.941, kidney 0.976, and cecum 0.918, with half-lives of t_1/2 = 2.5 h. Furthermore, a phage-resistant mutant displayed increased sensitivity to serum killing <i>in vitro</i>, but did not show significant defects in renal infection <i>in vivo</i>. A combination of bacteriophages demonstrated significant efficacy alone and synergy with ceftazidime/avibactam in the treatment of experimental disseminated KPC infection in neutropenic mice.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0091924"},"PeriodicalIF":4.1,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862907","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}

{"title":"<i>In vitro</i> resensitization of multidrug-resistant clinical isolates of <i>Enterococcus faecium</i> and <i>E. faecalis</i> through phage-antibiotic synergy.","authors":"Pooja Ghatbale, Govind Prasad Sah, Sage Dunham, Ethan Khong, Alisha Blanc, Alisha Monsibais, Andrew Garcia, Robert T Schooley, Ana G Cobián Güemes, Katrine Whiteson, David T Pride","doi":"10.1128/aac.00740-24","DOIUrl":"https://doi.org/10.1128/aac.00740-24","url":null,"abstract":"<p><p>Bacteriophages are an increasingly attractive option for the treatment of antibiotic-resistant infections, but their efficacy is difficult to discern due to the confounding effects of antibiotics. Phages are generally delivered in conjunction with antibiotics, and thus, when patients improve, it is unclear whether the phages, antibiotics, or both are responsible. This question is particularly relevant for enterococcus infections, as limited data suggest phages might restore antibiotic efficacy against resistant strains. Enterococci can develop high-level resistance to vancomycin, a primary treatment. We assessed clinical and laboratory isolates of <i>Enterococcus faecium</i> and <i>Enterococcus faecalis</i> to determine whether we could observe synergistic interactions between phages and antibiotics. We identified synergy between multiple phages and antibiotics including linezolid, ampicillin, and vancomycin. Notably, antibiotic susceptibility did not predict synergistic interactions with phages. Vancomycin-resistant isolates (<i>n</i> = 6) were eradicated by the vancomycin-phage combination as effectively as vancomycin-susceptible isolates (<i>n</i> = 2). Transcriptome analysis revealed significant gene expression changes under antibiotic-phage conditions, especially for linezolid and vancomycin, with upregulated genes involved in nucleotide and protein biosynthesis and downregulated stress response and prophage-related genes. While our results do not conclusively determine the mechanism of the observed synergistic interactions between antibiotics and phages, they do confirm and build upon previous research that observed these synergistic interactions. Our work highlights how using phages can restore the effectiveness of vancomycin against resistant isolates. This finding provides a promising, although unexpected, strategy for moving forward with phage treatments for vancomycin-resistant <i>Enterococcus</i> infections.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0074024"},"PeriodicalIF":4.1,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852231","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}

{"title":"The gene <i>MAB_2362</i> is responsible for intrinsic resistance to various drugs and virulence in <i>Mycobacterium abscessus</i> by regulating cell division.","authors":"Yanan Ju, Lijie Li, Jingran Zhang, Buhari Yusuf, Sanshan Zeng, Cuiting Fang, Xirong Tian, Xingli Han, Jie Ding, Han Zhang, Wanli Ma, Shuai Wang, Xinwen Chen, Tianyu Zhang","doi":"10.1128/aac.00433-24","DOIUrl":"https://doi.org/10.1128/aac.00433-24","url":null,"abstract":"<p><p><i>Mycobacterium abscessus</i> exhibits intrinsic resistance to most antibiotics, hence leading to infections that are difficult to treat. To address this issue, the identification of new molecular targets is essential for the development or repositioning of therapeutic agents. This study demonstrated that the <i>MAB_2362</i>-knockout strain, Mab^Δ2362, became significantly susceptible to a range of antibiotics, not only <i>in vitro</i> but also exhibited susceptibility to rifabutin, bedaquiline, and linezolid <i>in vivo</i>. While the bacterial burden of the wild-type <i>M. abscessus</i> (Mab^Wt) increased by over 1 log₁₀ CFU/lung in a murine infection model 16 days post-infection, that of Mab^Δ2362 strain decreased by more than 1 log₁₀ CFU/lung, which suggests that the disruption leads to attenuation. Bioinformatics analysis revealed that MAB_2362 shares the highest similarity (41.35%) with SteA, a protein known to influence cell division in <i>Corynebacterium glutamicum</i>, suggesting that MAB_2362 might be involved in cell division. Mab^Δ2362 cells exhibited a median length of 2.62 µm, which was substantially longer than the 1.44 µm recorded for Mab^Wt cells. Additionally, multiple cell division septa were observed in 42% of Mab^Δ2362 cells, whereas none were seen in Mab^Wt cells. An ethidium bromide uptake assay further suggested a higher cell envelope permeability in Mab^Δ2362 compared to Mab^Wt. Collectively, these findings underscore the role of <i>MAB_2362</i> in intrinsic resistance and virulence of <i>M. abscessus</i> possibly through the regulation of cell division. Thus, MAB_2362 emerges as a promising candidate for targeted interventions in the pursuit of novel antimicrobials against <i>M. abscessus</i>.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0043324"},"PeriodicalIF":4.1,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851782","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}

{"title":"Impact of the inoculum size on the <i>in vivo</i> activity of the aztreonam-avibactam combination in a murine model of peritonitis due to <i>Escherichia coli</i> expressing CTX-M-15 and NDM-1.","authors":"Ariane Amoura, Laura Benchetrit, Sophie Magréault, Samuel Chosidow, Alice Le Menestrel, Vincent Jullien, Victoire de Lastours, Françoise Chau, Sara Dion, Laurent Massias, Bruno Fantin, Agnès Lefort","doi":"10.1128/aac.01288-22","DOIUrl":"https://doi.org/10.1128/aac.01288-22","url":null,"abstract":"<p><p>The combination of aztreonam (ATM) and avibactam (AVI) is an attractive option to treat infections caused by extended spectrum β-lactamase plus NDM-1-producing <i>Enterobacteriaceae</i>. Since ATM activity was shown to be severely impacted by an increase in the inoculum size <i>in vitro</i>, we wondered whether ATM-AVI activity could be impaired in high-inoculum infections. We analyzed the impact of the inoculum size on ATM-AVI activity <i>in vitro</i> and in a murine model of peritonitis due to susceptible <i>Escherichia coli</i> CFT073-pTOPO and its isogenic derivatives producing NDM-1 (<i>E. coli</i> CFT073-NDM1) and CTX-M-15 plus NDM-1 (<i>E. coli</i> CFT073-CTXM15-NDM1). The impact of the inoculum size on bacterial morphology was studied by microscopic examination. <i>In vitro</i>, at standard (10⁵) inoculum, <i>E. coli</i> CFT073-CTXM15-NDM1 was resistant to ATM but susceptible to the ATM-AVI combination. At high (10⁷) inoculum, MICs of ATM alone and of the ATM-AVI combination reached >512 and 64 mg/L, respectively, against all tested strains. ATM led to bacterial filamentation when active against the bacteria, i.e., in monotherapy or in combination with AVI against susceptible <i>E. coli</i> CFT073-pTOPO and only in combination with AVI against <i>E. coli</i> CFT073-CTXM15-NDM1. <i>In vivo</i>, increase in the inoculum led to a drastic decrease in the activity of ATM alone against <i>E. coli</i> CFT073-pTOPO and ATM-AVI against <i>E. coli</i> CFT073-CTXM15-NDM1. Our results suggest a high <i>in vivo</i> impact of the inoculum increase on the activity of ATM alone against ATM-susceptible <i>E. coli</i> and of ATM-AVI against CTX-M-15 plus NDM-1 producing <i>E. coli</i>. Clinicians must be aware of the risk of failures when using ATM-AVI in high-inoculum infections.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0128822"},"PeriodicalIF":4.1,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852194","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}

{"title":"Population pharmacokinetics of piperacillin-tazobactam in the plasma and cerebrospinal fluid of critically ill patients.","authors":"Nilesh Kumta, Aaron J Heffernan, Menino Osbert Cotta, Xin Liu, Suzanne Parker, Steven Wallis, Amelia Livermore, Therese Starr, Wai Tat Wong, Gavin M Joynt, Jeffrey Lipman, Jason A Roberts","doi":"10.1128/aac.00601-24","DOIUrl":"https://doi.org/10.1128/aac.00601-24","url":null,"abstract":"<p><p>Ventriculitis in neurocritical care patients leads to significant morbidity and mortality. Antibiotic dose optimization targeting pharmacokinetic/pharmacodynamic (PK/PD) exposures associated with improved bacterial killing may improve therapeutic outcomes. We sought to develop and apply a population PK model in infected critically ill patients to determine optimal piperacillin-tazobactam (PTZ) dosing regimens to achieve target cerebrospinal fluid (CSF) exposures. Neurosurgical patients with external ventricular drains and receiving PTZ treatment were recruited and had plasma and CSF samples collected and assayed. A population PK model was developed using plasma and CSF piperacillin and tazobactam concentrations. Eight patients were recruited. Median age was 59 years, median weight was 70 kg, and five patients were female. The median creatinine clearance was 84 mL/min/1.73 m² (range 52-163). Substantial inter-individual PK variability was apparent, particularly in CSF. Piperacillin penetration into CSF had a median of 3.73% (range 0.73%-7.66%), and tazobactam CSF penetration was not predictable. Dosing recommendations to optimize CSF exposures for the treatment of ventriculitis were not possible due to substantial PK variability and very low drug penetration. High plasma PTZ exposures may not translate to effective exposures in CSF.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0060124"},"PeriodicalIF":4.1,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852200","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}

{"title":"Efficacy and safety of praziquantel plus artemisinin-based combinations versus praziquantel in the treatment of Kenyan children with <i>Schistosoma mansoni</i> infection: open-label, randomized, head-to-head, non-inferiority trial.","authors":"Charles O Obonyo, Vincent O Were, Peter Wamae, Erick M O Muok","doi":"10.1128/aac.00739-24","DOIUrl":"https://doi.org/10.1128/aac.00739-24","url":null,"abstract":"<p><p>Praziquantel alone is insufficient for the control of schistosomiasis due to poor efficacy against juvenile worms and increasing concerns about the risk of drug resistance. We compared the efficacy and safety of praziquantel combined with four different artemisinin-based combinations to praziquantel alone in treating <i>Schistosoma mansoni</i> infection in Kenyan children. In this randomized, open-label, five-arm, head-to-head, non-inferiority trial, children (aged 9-15 years) with <i>S. mansoni</i> infection according to duplicate Kato Katz thick smears from a stool sample in the Mwea irrigation scheme of central Kenya, were enrolled. Participants were randomly assigned (1:1:1:1:1) via a computer-generated block randomization procedure to receive a single oral dose of praziquantel (PZQ) (40 mg/kg/day) alone or in combination with a 3-day course (4 mg/kg of artesunate) of artesunate plus sulfalene-pyrimethamine (As + SP), artesunate plus amodiaquine (As + AQ), artesunate plus mefloquine (As + MQ) or dihydroartemisinin-piperaquine (DHAP). Laboratory technicians were masked to treatment allocation, but participants, clinicians, and study nurses were not. The primary outcomes were the cure rate and frequency of adverse events, which were assessed 6 weeks after treatment in the available case population using a per-protocol analysis. The non-inferiority margin was set at -10% for the risk difference in cure rates between combination therapy and PZQ alone. Between 12 September 2018 and 11 January 2019, 540 participants were assigned to receive PZQ alone (<i>n</i> = 108), PZQ plus As + SP (<i>n</i> = 108), PZQ plus As + AQ (<i>n</i> = 108), PZQ plus As + MQ (<i>n</i> = 108), or PZQ plus DHAP (<i>n</i> = 108). Primary outcome data were available for 523 (96.9%) participants. The cure rate was 82.5% (85/103) in PZQ alone, 81.7% (85/104) in PZQ plus As + SP, 76.2% (80/105) in PZQ plus As + AQ, 88.7% (94/106) in PZQ plus As + MQ, and 85.7% (90/105) in PZQ plus DHAP arm. Non-inferiority was declared for PZQ plus As + MQ (difference 6.2 [95% confidence interval: -3.3 to 15.6]) and PZQ plus DHAP (3.2 [-6.7 to 13.1]) but not for PZQ plus As + SP (-0.8 [-11.2 to 9.6]) or PZQ plus As + AQ (-6.3 [-17.3 to 4.6]). Adverse events were reported by 26% (138/540) of participants, including abdominal pain, headache, and vomiting. There were no serious adverse events. Alternatives to praziquantel should include praziquantel plus artesunate-mefloquine or praziquantel plus dihydroartemisinin-piperaquine. However, further multicentre trials are needed in different epidemiological settings and population groups to confirm these findings.CLINICAL TRIALSThis study is registered with the Pan-African Clinical Trials Registry under PACTR202001919442161.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0073924"},"PeriodicalIF":4.1,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852236","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}

{"title":"SARS-CoV-2 resistance analyses from the Phase 3 PINETREE study of remdesivir treatment in nonhospitalized participants.","authors":"Lauren Rodriguez, Hery W Lee, Jiani Li, Ross Martin, Dong Han, Simin Xu, Jasmine Moshiri, Nadine Peinovich, Gregory Camus, Jason K Perry, Robert H Hyland, Danielle P Porter, Mazin Abdelghany, Matthias Götte, Charlotte Hedskog","doi":"10.1128/aac.01238-24","DOIUrl":"https://doi.org/10.1128/aac.01238-24","url":null,"abstract":"<p><p>Remdesivir inhibits the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp; Nsp12). Here, we conducted viral resistance analyses from the Phase 3 PINETREE trial of remdesivir in nonhospitalized participants at risk of severe COVID-19. Nasopharyngeal swabs (collected at baseline [Day 1], Days 2, 3, 7, and 14) were eligible for analysis if their viral load was above the lower limit of quantification for the RT-qPCR assay (2228 copies/mL). The SARS-CoV-2 genome was sequenced for all remdesivir participants and 50% of placebo participants (baseline, Days 3, 7, and 14) and for participants who progressed to COVID-19-related hospitalization or all-cause death (all time points). Emergent substitutions in Nsp12 and other replication complex proteins were phenotyped using site-directed mutagenesis in a SARS-CoV-2 subgenomic replicon system. Overall, emergent Nsp12 substitutions were detected in 8/115 (7.0%) remdesivir participants and 7/129 (5.4%) placebo participants (1 substitution overlap between groups). Based on a structural analysis, none of the emergent Nsp12 substitutions were in direct contact with the incoming nucleoside triphosphate substrate, the RNA, or the RNA template 5' overhang. One substitution (A376V) showed reduced susceptibility to remdesivir (12.6-fold change in remdesivir half-maximal concentration [EC₅₀]); it also showed reduced fitness when introduced in the SARS-CoV-2 replicon and virus <i>in vitro</i>. Other substitutions had <1.1-fold change in remdesivir EC₅₀. None of the emergent substitutions in Nsp8, Nsp10, Nsp13, or Nsp14 (remdesivir, 10/115 [8.7%]; placebo, 10/129 [7.8%]) showed reduced remdesivir susceptibility. In conclusion, emergent substitutions in the SARS-CoV-2 RdRp complex with reduced remdesivir susceptibility were uncommon, indicating a high barrier to remdesivir resistance.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04501952.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0123824"},"PeriodicalIF":4.1,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851760","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}

{"title":"<i>TAC1b</i> mutation in <i>Candida auris</i> decreases manogepix susceptibility owing to increased <i>CDR1</i> expression.","authors":"Tatsuro Hirayama, Taiga Miyazaki, Rina Tanaka, Natsume Kitahori, Masataka Yoshida, Kazuaki Takeda, Shotaro Ide, Naoki Iwanaga, Masato Tashiro, Takahiro Takazono, Koichi Izumikawa, Katsunori Yanagihara, Koichi Makimura, Kazuhiro Tsukamoto, Hiroshi Mukae","doi":"10.1128/aac.01508-24","DOIUrl":"https://doi.org/10.1128/aac.01508-24","url":null,"abstract":"<p><p><i>Candida auris</i> is an emerging pathogenic fungus that is highly resistant to existing antifungal drugs. Manogepix is a novel antifungal agent that exerts antifungal activity by inhibiting glycosylphosphatidylinositol anchor biosynthesis. Although the mechanisms of resistance of <i>Candida</i> species to manogepix have been reported previously, those of <i>C. auris</i> are yet to be studied. To investigate the resistance mechanisms of <i>C. auris</i>, we exposed a clinical isolate (clade I) to manogepix <i>in vitro</i> and generated strains with reduced susceptibility to manogepix. A search for gain-of-function mutations that upregulate efflux pump expression confirmed the presence of the D865N amino acid mutation in <i>TAC1b</i>. We used the clustered regularly interspaced short palindromic repeats-Cas9 system to create a recovery strain (N865D) in which only this single nucleotide mutation was returned to the wild-type sequence. We generated a mutant strain by introducing only the D865N mutation into the parent strain and a different clade strain (clade III). The D865N mutant strains were clearly less susceptible to manogepix than the parental strains and exhibited high <i>CDR1</i> expression. Moreover, we generated a strain deficient in <i>CDR1</i> and confirmed that this strain had significantly increased susceptibility to manogepix. Thus, the present study demonstrated that the <i>TAC1b</i> mutation in <i>C. auris</i> upregulates <i>CDR1</i> expression and decreases its susceptibility to manogepix.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0150824"},"PeriodicalIF":4.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845680","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}

{"title":"Performance of a broth microdilution assay for routine minimum inhibitory concentration determination of 14 anti-tuberculous drugs against the <i>Mycobacterium tuberculosis</i> complex based on the EUCAST reference protocol.","authors":"Mikael Mansjö, Carmen Espinosa-Gongora, Ishak Samanci, Ramona Groenheit, Jim Werngren","doi":"10.1128/aac.00946-24","DOIUrl":"https://doi.org/10.1128/aac.00946-24","url":null,"abstract":"<p><p>This comparative study aimed at qualifying a broth microdilution (BMD) assay for phenotypic drug susceptibility testing (pDST) of <i>Mycobacterium tuberculosis</i> complex (MTBC) strains for implementation in a routine DST workflow. The assay was developed based on the EUCAST (European Committee on Antimicrobial Susceptibility Testing) reference protocol for determination of the minimum inhibitory concentration (MIC) of 14 anti-tuberculous drugs (isoniazid [INH], rifampicin [RIF], ethambutol [EMB], amikacin [AMI], moxifloxacin [MFX], levofloxacin [LFX], bedaquiline [BDQ], clofazimine [CFZ], delamanid [DLM], pretomanid [PA], para-aminosalicylic acid [PAS], linezolid [LZD], ethionamide [ETH], and cycloserine [CS]). Forty MTBC strains with various drug resistance profiles were tested to determine the agreement between MIC results and genotypic drug susceptibility testing (gDST) results derived from whole-genome sequencing (WGS). The agreement between the BMD and gDST results was solid for the majority of the drugs (average agreement 98%, range 90%-100%), including key drugs such as INH, RIF, MFX, LFX, BDQ, DLM, and PA. Ten discrepancies were identified (corresponding to 1.8% of the total number of MIC determinations) and most (8/10) were characterized by MICs equal or close to the potential critical concentration (pCC) applied in the BMD assay. Importantly, the assay can be adjusted to new drug recommendations and concentrations, tailored to local needs. We conclude that the BMD assay provides reliable results, and its implementation in our MTBC routine workflow will produce valuable data that improve our understanding and management of MTBC drug resistance.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0094624"},"PeriodicalIF":4.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845682","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}

{"title":"Population pharmacokinetics of caspofungin in critically ill patients receiving extracorporeal membrane oxygenation-an ASAP ECMO study.","authors":"Mohd H Abdul-Aziz, Arne Diehl, Xin Liu, Vesa Cheng, Amanda Corley, Eileen Gilder, Bianca Levkovich, Shay McGuinness, Jenny Ordonez, Rachael Parke, Vincent Pellegrino, Steven C Wallis, John F Fraser, Kiran Shekar, Jason A Roberts","doi":"10.1128/aac.01435-24","DOIUrl":"https://doi.org/10.1128/aac.01435-24","url":null,"abstract":"<p><p>This study aimed to describe the population pharmacokinetics of caspofungin in critically ill patients receiving extracorporeal membrane oxygenation (ECMO) and to identify dosing regimens with a high likelihood of achieving effective exposures. Serial blood samples were collected over a single-dosing interval during ECMO. Total plasma concentrations were measured by a validated chromatographic assay. A population pharmacokinetic model was built and Monte Carlo dosing simulations were performed using Monolix. The probability of target attainment (PTA) and fractional target attainment (FTA) rates were simulated for various caspofungin dosing regimens against <i>Candida albicans</i>, <i>Candida glabrata</i>, and <i>Candida parapsilosis</i>. In all, 64 plasma concentration-time points were obtained from 8 critically ill patients receiving ECMO. Plasma concentration-time data for caspofungin were best described by a one-compartment model with first-order elimination. Lean body weight was identified as a significant covariate of volume of distribution. The typical volume of distribution and clearance of caspofungin in this cohort were 8.13 L and 0.55 L/h, respectively. The licensed caspofungin dosing regimen (a loading dose of 70 mg on day 1 followed by a maintenance dose of either 50 mg/day or 70 mg/day) demonstrated optimal PTA rates (≥90%) against <i>C. albicans</i> with an MIC of ≤0.064 mg/L, <i>C. glabrata</i> with an MIC of ≤0.125 mg/L, and <i>C. parapsilosis</i> with an MIC of ≤0.064 mg/L. The FTA analysis suggested that the licensed dosing regimen is only optimal (≥95%) against <i>Candida glabrata</i>, regardless of lean body weight. A higher-than-standard empirical dosing regimen (e.g., a loading dose of 100 mg on day 1, followed by a maintenance dose of 100 mg daily) is likely advantageous for critically ill patients receiving ECMO.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0143524"},"PeriodicalIF":4.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845683","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}