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The Journal of Antimicrobial... Dec 2023Ceftaroline is a novel cephalosporin active against MDR Gram-positive (GP) bacteria. For β-lactam antibiotics, such as ceftaroline, prolonged infusions and therapeutic...
Real-world experience of therapeutic drug monitoring and PK/PD achievement of ceftaroline administered by different infusion regimens in patients with confirmed infections caused by Gram-positive bacteria.
BACKGROUND
Ceftaroline is a novel cephalosporin active against MDR Gram-positive (GP) bacteria. For β-lactam antibiotics, such as ceftaroline, prolonged infusions and therapeutic drug monitoring (TDM) are used for dosage optimization based on their pharmacokinetics/pharmacodynamics (PK/PD).
OBJECTIVES
To describe our experience with TDM and PK/PD target attainment of ceftaroline administered by intermittent and prolonged infusion in a cohort of patients with MDR-GP bacterial infections.
METHODS
Patients treated with ceftaroline administered by continuous (24 h), extended (3 h/6 h) and intermittent infusion (1 h) and undergoing TDM of plasma concentrations were included. A 100%fT>4×MIC was the pre-specified PK/PD target and 100%fT>10×MIC was considered overexposure. Dose recommendations were made based on TDM results and each patient's clinical condition.
RESULTS
Twelve patients [83.3% male, median age of 73 (38-83) years] were included. Nine patients (75%) achieved 100%fT>4×MIC, all under prolonged infusions. In one patient, the 100%fT was >10×MIC but no toxicity was observed. Based on TDM results, initial doses were recommended to be maintained in eight patients, decreased in three and increased in one.
CONCLUSIONS
The administration of ceftaroline by prolonged infusion together with TDM may be a useful strategy for achieving the desired PK/PD target in these patients. However, more studies evaluating the relationship between PK/PD attainment and clinical outcomes are needed.
Topics: Humans; Male; Aged; Aged, 80 and over; Female; Anti-Bacterial Agents; Drug Monitoring; Cephalosporins; Infusions, Parenteral; Monobactams; Ceftaroline
PubMed: 37823445
DOI: 10.1093/jac/dkad296 -
Journal of Chemotherapy (Florence,... Nov 2023During the Sars-Cov-2 pandemic, secondary pulmonary infections have increased, especially in critically ill patients, highlighting the need for new therapeutic options....
During the Sars-Cov-2 pandemic, secondary pulmonary infections have increased, especially in critically ill patients, highlighting the need for new therapeutic options. Trimethoprim-sulfamethoxazole (SXT) is the treatment of choice but the increase of resistant strains or adverse drug reactions limited its clinical use. Recently ceftazidime/avibactam (CZA) has been approved for the treatment of multi drug resistant (MDR) Gram-negative bacteria infections, including hospital acquired pneumonia. The aim of this study was to evaluate the activity of ceftazidime/avibactam (CZA) alone and in combination with aztreonam (ATM) against clinical isolates by E-test method. Susceptibility of SXT and levofloxacin (LEV) was also investigated. Our results showed 22% of resistance to CZA, 2% to SXT and 26% to LEV. CZA in combination with ATM demonstrated synergistic activity against 86% of the strains, including all those resistant to CZA. The combination of CZA with ATM provides a new therapeutic option for the treatment of severe respiratory infections in critically ill patients.
Topics: Humans; Aztreonam; Ceftazidime; Stenotrophomonas maltophilia; Critical Illness; Drug Combinations; Azabicyclo Compounds; Levofloxacin; Microbial Sensitivity Tests; Anti-Bacterial Agents
PubMed: 37615040
DOI: 10.1080/1120009X.2023.2247199 -
PLoS Biology Dec 2023The emerging and global spread of a novel plasmid-mediated colistin resistance gene, mcr-1, threatens human health. Expression of the MCR-1 protein affects bacterial...
The emerging and global spread of a novel plasmid-mediated colistin resistance gene, mcr-1, threatens human health. Expression of the MCR-1 protein affects bacterial fitness and this cost correlates with lipid A perturbation. However, the exact molecular mechanism remains unclear. Here, we identified the MCR-1 M6 variant carrying two-point mutations that conferred co-resistance to β-lactam antibiotics. Compared to wild-type (WT) MCR-1, this variant caused severe disturbance in lipid A, resulting in up-regulation of L, D-transpeptidases (LDTs) pathway, which explains co-resistance to β-lactams. Moreover, we show that a lipid A loading pocket is localized at the linker domain of MCR-1 where these 2 mutations are located. This pocket governs colistin resistance and bacterial membrane permeability, and the mutated pocket in M6 enhances the binding affinity towards lipid A. Based on this new information, we also designed synthetic peptides derived from M6 that exhibit broad-spectrum antimicrobial activity, exposing a potential vulnerability that could be exploited for future antimicrobial drug design.
Topics: Humans; Colistin; Anti-Bacterial Agents; beta Lactam Antibiotics; Lipid A; Antimicrobial Peptides; Monobactams; Plasmids; Drug Resistance, Bacterial; Escherichia coli Proteins; Microbial Sensitivity Tests
PubMed: 38091366
DOI: 10.1371/journal.pbio.3002433 -
European Journal of Clinical... Mar 2024Relebactam is a novel β-lactamase inhibitor, which, when combined with imipenem/cilastatin, is active against both class A and class C β-lactamases. To evaluate in...
PURPOSE
Relebactam is a novel β-lactamase inhibitor, which, when combined with imipenem/cilastatin, is active against both class A and class C β-lactamases. To evaluate in vitro antimicrobial activity of imipenem/relebactam against a collection of recent clinical isolates of carbapenem-non-susceptible P. aeruginosa and K. pneumoniae ST258 and ST512 KPC producers belonging to different lineages from hospitals in Southern Spain.
METHODS
Six hundred and seventy-eight isolates were tested: 265 K. pneumoniae (230 ST512/KPC-3 and 35 ST258/KPC-3) and 413 carbapenem-non-susceptible P. aeruginosa. Imipenem, piperacillin/tazobactam, ceftazidime, cefepime, aztreonam, ceftolozane/tazobactam, meropenem, amikacin, ciprofloxacin, colistin, and ceftazidime/avibactam were used as comparators against P. aeruginosa. Against K. pneumoniae ceftazidime, cefepime, aztreonam, and ceftolozane/tazobactam were not tested, and tigecycline was studied instead. MICs were determined in duplicate by broth microdilution according to EUCAST guidelines.
RESULTS
Imipenem/relebactam displayed potent in vitro activity against both sequence types of KPC-3-producing K. pneumoniae. MIC and MIC values were 0.25 mg/L and 1 mg/L, respectively, with percent of susceptible isolates >97%. Only three K. pneumoniae ST512/KPC-3 isolates and one ST258/KPC-3 were resistant to imipenem/relebactam. Relebactam sensitized 98.5% of K. pneumoniae isolates resistant to imipenem. The activity of imipenem/relebactam against P. aeruginosa was moderate (susceptibility rate: 62.7%). Analysis of the acquired and mutational resistome of isolates with high levels of resistance to imipenem/relebactam has not shown a clear association between them.
CONCLUSION
Imipenem/relebactam showed excellent activity against K. pneumoniae KPC-3. The activity of imipenem/relebactam against imipenem-resistant P. aeruginosa was moderate.
Topics: Humans; Imipenem; Ceftazidime; Pseudomonas aeruginosa; Klebsiella pneumoniae; Cefepime; Aztreonam; Anti-Bacterial Agents; Pseudomonas Infections; Tazobactam; beta-Lactamases; Drug Combinations; Microbial Sensitivity Tests; Cephalosporins; Azabicyclo Compounds
PubMed: 38157139
DOI: 10.1007/s10096-023-04735-1 -
European Journal of Clinical... Feb 2024To evaluate the different present and future therapeutic β-lactam/β-lactamase inhibitor (BL/BLI) alternatives, namely aztreonam-avibactam, imipenem-relebactam,...
PURPOSE
To evaluate the different present and future therapeutic β-lactam/β-lactamase inhibitor (BL/BLI) alternatives, namely aztreonam-avibactam, imipenem-relebactam, meropenem-vaborbactam, cefepime-zidebactam, cefepime-taniborbactam, meropenem-nacubactam, and sulbactam-durlobactam against clinical isolates showing reduced susceptibility or resistance to cefiderocol in Enterobacterales, Acinetobacter baumannii, and Pseudomonas aeruginosa.
METHODS
MIC values of aztreonam, aztreonam-avibactam, cefepime, cefepime-taniborbactam, cefepime-zidebactam, imipenem, imipenem-relebactam, meropenem, meropenem-vaborbactam, meropenem-nacubactam, sulbactam-durlobactam, and cefiderocol combined with a BLI were determined for 67, 9, and 11 clinical Enterobacterales, P. aeruginosa or A. baumannii isolates, respectively, showing MIC values of cefiderocol being ≥1 mg/L. If unavailable, the respective β-lactam breakpoints according to EUCAST were used for BL/BLI combinations.
RESULTS
For Enterobacterales, the susceptibility rates for aztreonam, cefepime, imipenem, and meropenem were 7.5%, 0%, 10.4%, and 10.4%, respectively, while they were much higher for cefepime-zidebactam (91%), cefiderocol-zidebactam (91%), meropenem-nacubactam (71.6%), cefiderocol-nacubactam (74.6%), and cefiderocol-taniborbactam (76.1%), as expected. For P. aeruginosa isolates, the higher susceptibility rates were observed for imipenem-relebactam, cefiderocol-zidebactam, and meropenem-vaborbactam (56% for all combinations). For A. baumannii isolates, lower susceptibility rates were observed with commercially or under development BL/BLI combos; however, a high susceptibility rate (70%) was found for sulbactam-durlobactam and when cefiderocol was associated to some BLIs.
CONCLUSIONS
Zidebactam- and nacubactam-containing combinations showed a significant in vitro activity against multidrug-resistant Enterobacterales clinical isolates with reduced susceptibility to cefiderocol. On the other hand, imipenem-relebactam and meropenem-vaborbactam showed the highest susceptibility rates against P. aeruginosa isolates. Finally, sulbactam-durlobactam and cefiderocol combined with a BLI were the only effective options against A. baumannii tested isolates.
Topics: Humans; Cefiderocol; Meropenem; Cefepime; Aztreonam; Anti-Bacterial Agents; Cephalosporins; Imipenem; beta-Lactamase Inhibitors; Microbial Sensitivity Tests; beta-Lactamases; Carboxylic Acids; Piperidines; Lactams; Boronic Acids; Cyclooctanes; Azabicyclo Compounds; Borinic Acids
PubMed: 38095831
DOI: 10.1007/s10096-023-04732-4 -
Journal of Endourology Dec 2023Updated in 2019, the American Urological Association's (AUA) Best Practice Statement on Urologic Procedures and Antimicrobial Prophylaxis outlines prophylaxis for...
Updated in 2019, the American Urological Association's (AUA) Best Practice Statement on Urologic Procedures and Antimicrobial Prophylaxis outlines prophylaxis for percutaneous nephrolithotomy (PCNL). Recent studies have challenged these recommendations. We hypothesized that endourologists do not routinely follow the AUA's statement on antibiotic use during PCNL and assessed their prescribing patterns. A 24-question survey was distributed to members of the Endourological Society. The primary outcome was adherence to the AUA's recommendations. Two multiple logistic regression analyses were performed with demographics and antibiotic preference as predictors of following the AUA. A total of 51.4% of endourologists follow the AUA Best Practice Statement for antimicrobial prophylaxis of uncomplicated PCNL. No demographic data were predictive of following the AUA. 90.9% and 83.6% reported they have "never" used the first-line recommendation options of metronidazole and aztreonam, respectively. Preferred antibiotics were cephalosporins (uncomplicated 60%, complicated 52.6%), fluoroquinolones (13.3%, 7.2%), aminoglycosides (12.7%, 17.8%), penicillins (7.9%, 11.2%), carbapenems (0.6%, 0.7%), trimethoprim-sulfamethoxazole (2.4%, 5.9%), fosfomycin (0.6%, 0.7%), nitrofurantoin (2.4%, 2.6%), aztreonam (0%, 0.7%), and clindamycin (0%, 0.7%). For uncomplicated PCNL, 63.1% prescribe ≤24 hours of perioperative antibiotics. For complicated PCNL, 16.2% prescribe ≤24 hours of perioperative antibiotics, while 20.4% begin antibiotics 7 or more days prior. Nearly half of respondents do not follow the AUA's recommendations for antibiotic choice for PCNL. Few endourologists prescribe 7 days of preoperative antibiotics for complicated PCNL despite supporting data. Metronidazole and aztreonam are rarely used as a first-line antibiotic choice for PCNL and their roles needs to be further evaluated as first-line prophylaxis recommendations. Updates on antibiotic recommendations for PCNL are needed based on current literature, antimicrobial stewardship, and contemporary practice patterns.
Topics: Humans; Nephrolithotomy, Percutaneous; Aztreonam; Metronidazole; Anti-Bacterial Agents; Urology; Antibiotic Prophylaxis
PubMed: 37830181
DOI: 10.1089/end.2023.0254 -
ACS Infectious Diseases Sep 2023Carbapenem-resistant () was designated as a critical priority pathogen by the World Health Organization for which new therapeutic solutions are required. With the rapid...
Carbapenem-resistant () was designated as a critical priority pathogen by the World Health Organization for which new therapeutic solutions are required. With the rapid dissemination of β-lactamases in , β-lactam (BL) antibiotics are used in conjunction with β-lactamase inhibitors (BLI). The effectiveness of the BL/BLI combination could be further enhanced with the inclusion of an outer membrane (OM) permeabilizer, such as aminoglycosides and aminoglycoside-based adjuvants. Thus, the development of seven tobramycin derivatives reported herein focused on improving OM permeabilizing capabilities and reducing associated toxicity. The structure-activity relationship studies emphasized the effects of the nature of the cationic group; the number of polar head groups and positive charges; and flexibility, length, and steric bulk of the hydrophobic moiety. The optimized guanidinylated tobramycin-biphenyl derivative was noncytotoxic and demonstrated the ability to potentiate ceftazidime and aztreonam monotherapy and in dual combinations with avibactam against multidrug-resistant (MDR) and β-lactamase harboring isolates of . The triple combination of ceftazidime/avibactam plus guanidinylated tobramycin-biphenyl resulted in rapid bactericidal activity within 4-8 h of treatment, demonstrating the potential application of these guanidinylated amphiphilic tobramycin derivatives in augmenting BL/BLI combinations.
Topics: Lactams; Tobramycin; Pseudomonas aeruginosa; beta-Lactamase Inhibitors; Ceftazidime; Monobactams; Anti-Bacterial Agents; Aminoglycosides
PubMed: 37603592
DOI: 10.1021/acsinfecdis.3c00217 -
Journal of Clinical Microbiology Apr 2024Traditionally, cephalothin susceptibility results were used to predict the susceptibility of additional cephalosporins; however, in 2013-2014, the Clinical and... (Review)
Review
Traditionally, cephalothin susceptibility results were used to predict the susceptibility of additional cephalosporins; however, in 2013-2014, the Clinical and Laboratory Standards Institute (CLSI) revisited this practice and determined that cefazolin is a more accurate proxy than cephalothin for uncomplicated urinary tract infections (uUTIs). Therefore, a cefazolin surrogacy breakpoint was established to predict the susceptibility of seven oral cephalosporins for , , and in the context of uUTIs. Clinical microbiology laboratories face several operational challenges when implementing the cefazolin surrogacy breakpoint, which may lead to confusion for the best path forward. Here, we review the historical context and data behind the surrogacy breakpoints, review PK/PD profiles for oral cephalosporins, discuss challenges in deploying the breakpoint, and highlight the limited clinical outcome data in this space.
Topics: Humans; Cefazolin; Cephalosporins; Cephalothin; Anti-Bacterial Agents; Microbial Sensitivity Tests; Urinary Tract Infections; Escherichia coli; Monobactams
PubMed: 38457194
DOI: 10.1128/jcm.00788-21 -
Annals of Clinical Microbiology and... Jul 2023Infections in critically-ill patients caused by extensively-drug-resistant (XDR)-Pseudomonas aeruginosa are challenging to manage due to paucity of effective treatment...
Compassionate use of a novel β-lactam enhancer-based investigational antibiotic cefepime/zidebactam (WCK 5222) for the treatment of extensively-drug-resistant NDM-expressing Pseudomonas aeruginosa infection in an intra-abdominal infection-induced sepsis patient: a case report.
Infections in critically-ill patients caused by extensively-drug-resistant (XDR)-Pseudomonas aeruginosa are challenging to manage due to paucity of effective treatment options. Cefepime/zidebactam, which is currently in global Phase 3 clinical development (Clinical Trials Identifier: NCT04979806, registered on July 28, 2021) is a novel mechanism of action based β-lactam/ β-lactam-enhancer combination with a promising activity against a broad-range of Gram-negative pathogens including XDR P. aeruginosa. We present a case report of an intra-abdominal infection-induced sepsis patient infected with XDR P. aeruginosa and successfully treated with cefepime/zidebactam under compassionate use. The 50 year old female patient with past-history of bariatric surgery and recent elective abdominoplasty and liposuction developed secondary pneumonia and failed a prolonged course of polymyxins. The organism repeatedly isolated from the patient was a New-Delhi metallo β-lactamase-producing XDR P. aeruginosa resistant to ceftazidime/avibactam, imipenem/relebactam and ceftolozane/tazobactam, susceptible only to cefepime/zidebactam. As polymyxins failed to rescue the patient, cefepime/zidebactam was administered under compassionate grounds leading to discharge of patient in stable condition. The present case highlights the prevailing precarious scenario of antimicrobial resistance and the need for novel antibiotics to tackle infections caused by XDR phenotype pathogens.
Topics: Humans; Cefepime; Pseudomonas Infections; Compassionate Use Trials; Cephalosporins; Anti-Bacterial Agents; Monobactams; Pseudomonas aeruginosa; beta-Lactamases; Sepsis; Intraabdominal Infections; Polymyxins; Microbial Sensitivity Tests
PubMed: 37408075
DOI: 10.1186/s12941-023-00606-x -
Scientific Reports Feb 2024Antimicrobial resistance has emerged as one of the leading public health threats of the twenty-first century. Gram-negative pathogens have been a major contributor to...
Antimicrobial resistance has emerged as one of the leading public health threats of the twenty-first century. Gram-negative pathogens have been a major contributor to the declining efficacy of antibiotics through both acquired resistance and tolerance. In this study, a pan-drug resistant (PDR), NDM-1 and CTX-M-15 co-producing isolate of K. pneumoniae, CDC Nevada, (Kp Nevada) was exposed to the clinical combination of aztreonam + ceftazidime/avibactam (ATM/CAZ/AVI) to overcome metallo-β-lactamases. Unexpectedly, the β-lactam combination resulted in long filamentous cell formation induced by PBP3 inhibition over 168 h in the hollow fiber infection model experiments with eventual reversion of the total population upon drug removal. However, the addition of imipenem to the two drug β-lactam combination was highly synergistic with suppression of all drug resistant subpopulations over 5 days. Scanning electron microscopy and fluorescence microscopy for all imipenem combinations in time kill studies suggested a role for imipenem in suppression of long filamentous persisters, via the formation of metabolically active spheroplasts. To complement the imaging studies, salient transcriptomic changes were quantified using RT-PCR and novel cassette assay evaluated β-lactam permeability. This showed significant upregulation of both spheroplast protein Y (SPY), a periplasmic chaperone protein that has been shown to be related to spheroplast formation, and penicillin binding proteins (PBP1, PBP2, PBP3) for all combinations involving imipenem. However, with aztreonam alone, pbp1, pbp3 and spy remained unchanged while pbp2 levels were downregulated by > 25%. Imipenem displayed 207-fold higher permeability as compared with aztreonam (mean permeability coefficient of 17,200 nm/s). Although the clinical combination of aztreonam/avibactam and ceftazidime has been proposed as an important treatment of MBL Gram-negatives, we report the first occurrence of long filamentous persister formation. To our knowledge, this is the first study that defines novel β-lactam combinations involving imipenem via maximal suppression of filamentous persisters to combat PDR CDC Nevada K. pneumoniae.
Topics: Ceftazidime; Klebsiella pneumoniae; Aztreonam; Anti-Bacterial Agents; Imipenem; beta-Lactamases; Drug Combinations; Microbial Sensitivity Tests; Azabicyclo Compounds
PubMed: 38326428
DOI: 10.1038/s41598-024-53130-z