avibactam and Critical-Illness

The objective of this pharmacokinetic (PK)/pharmacodynamic (PD) analysis was to evaluate the efficacy of different dosing regimens of ceftazidime/avibactam (CZA) for the treatment of pulmonary infections by extensively drug-resistant (XDR) Pseudomonas aeruginosa using optimized two-step administration therapy (OTAT) and traditional infusion (TI). We used Monte Carlo simulations (MCS) to integrate PK parameters with PD parameters to assess the adequacy of CZA dosing in critically ill patients with XDR P. aeruginosa pulmonary infections. Dosing models were as follows: 2.5 g q8h, 2.5 g q6h, 4 g q8h, 4 g q6h, 1.25 g q8h, 1.25 g q6h, and 0.94 g q12h. MCS showed that the cumulative fraction of response of all dosing regimens of OTAT was higher than 90%. The probability of target attainment of all dosing regimens of OTAT at MICs (minimal inhibitory concentrations) between 16 mg/L and 32 mg/L was higher than that of TI. Based on these models, PK/PD goals were met with OTAT regimens, even with high MICs (>16 mg/L) compared to traditional infusion (TI) intervals. Thus, this study indicates that OTAT with sufficient PK exposure could improve the efficacy of CZA in critically ill patients with XDR P. aeruginosa pulmonary infections.

Topics: Anti-Bacterial Agents; Ceftazidime; Critical Illness; Humans; Microbial Sensitivity Tests; Pharmaceutical Preparations; Pseudomonas aeruginosa; Pseudomonas Infections

Ceftazidime-avibactam (CAZ-AVI)-based treatments have been associated with the emergence of resistance in KPC-producing Klebsiella pneumoniae (KPC-Kp) isolates after antimicrobial exposure. Here, we evaluated the CAZ-AVI resistance development in KPC-Kp isolated from patients treated with CAZ-AVI-based therapy.. We enrolled adult patients treated with CAZ-AVI-based regimens between January 2020 and January 2021. Carbapenemase-producing isolates collected from clinical samples and rectal swabs were evaluated for CAZ-AVI resistance development after antimicrobial exposure. KPC-Kp developing CAZ-AVI resistance and parental susceptible strains were genomically characterized. Whole genome sequencing was performed by using the Illumina iSeq100 platform and genomes were analyzed for antimicrobial-resistance genes, plasmid and porins sequences.. We enrolled 90 patients treated with CAZ-AVI-based therapy and 62.2% (56/90) of them were colonized by KPC-producers before CAZ-AVI-based treatment and 6.6% acquired colonization during therapy. Six (6.6%) patients developed infections because of resistant KPC-Kp after CAZ-AVI exposure and 3 (3.3%) of them developed CAZ-AVI resistance in the rectum. Development of resistance among KPC in the rectum occurred after 32 (IQR, 9-35) days of therapy and after 30 (IQR, 22-40) days in clinical specimens. Genetic analysis demonstrated that the development of CAZ-AVI resistance was associated with mutated bla. Antimicrobial exposure induce a higher incidence of CAZ-AVI resistance development in the blood and respiratory tract than in the rectum (6.7% vs. 3.3%) of CAZ-AVI-treated patients and genome analysis showed that resistance was associated with mutated bla

Topics: Adult; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Ceftazidime; Critical Illness; Drug Combinations; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Phylogeny

This study aimed to assess the efficacy of ceftazidime/avibactam (C/A) in the treatment of infections due to Gram-negative bacteria (GNB) in critically ill patients. A multicentre, retrospective, observational study was conducted in critically ill patients receiving C/A for GNB infections. We evaluated demographic data, localisation and severity of infection, clinical and microbiological outcomes, and mortality. A total of 68 patients received C/A for serious GNB infections. The main infections were respiratory (33.8%), intra-abdominal (22.1%) and urinary tract infections (10.3%); bacteraemia was found in 22 cases (32.4%). Most infections were complicated by septic shock (58.8%) or sepsis (36.8%) and most of them required life-supporting therapies. Enterobacterales (79.4%) and Pseudomonas aeruginosa (19.1%) were the most frequently isolated bacteria; 84.2% of isolates were carbapenem-resistant. Thirty-four patients (50.0%) received C/A in combination with other antimicrobials. Fifty patients (73.5%) presented a favourable clinical response. Microbiological eradication was documented in 25 cases (36.8%). No significant differences were found in clinical response between patients treated with monotherapy or combined therapy (79.4% vs. 67.6%; P = 0.27). Overall intensive care unit (ICU) mortality was 41.2%. Univariate analysis showed that 30-day all-cause mortality was significantly (P < 0.05) associated with bacteraemia, previous corticosteroid use and the need of life-supporting therapies. C/A appears to be an effective therapy for severe infections due to GNB, including carbapenem-resistant isolates, in critically ill patients. C/A combination therapy was not associated with a higher clinical response. Mortality correlated significantly with the presence of bacteraemia, previous corticosteroid use and the need for life-supporting therapies.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Ceftazidime; Critical Illness; Drug Combinations; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Retrospective Studies

Rising antimicrobial resistance is a pressing public health concern. An increase in carbapenem-resistant organisms has led to increased use of novel antibiotics, such as ceftazidime/avibactam (CZ/AV). However, recent studies have shown increasing treatment failures and resistance rates associated with ceftazidime/avibactam use. The efficacy of CZ/AV has not been studied in patients with thermal or inhalation injuries, where pharmacokinetic derangements are common and patients are often subject to longer lengths of stay and several antimicrobial courses that may lead to higher resistance rates. The objective of this study was to evaluate the outcomes of patients with thermal and inhalation injuries including clinical success, the frequency of adverse effects, and emergence of resistance. In the 17 courses of CZ/AV evaluated, clinical success occurred in 71% (12/17) of courses. Enterobacter cloacae was the most commonly treated pathogen. Resistance developed in 18% (3/17) of courses, but follow-up sensitivities were not evaluable for every case. Although lower than desired, clinical success rates in this sample were similar to other reported populations treated with CZ/AV. However, the emergence of resistance occurred more frequently and was likely underreported in this sample. Although limited by its small sample size, this study emphasizes the concern of growing antimicrobial resistance among even novel antibiotics. Resistance can develop during the initial course, stressing the importance of infection prevention and antimicrobial stewardship. Furthermore, attention and resources should be given to proper pharmacokinetic analysis of medications given in severely ill, hypermetabolic populations.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Burns; Carbapenems; Ceftazidime; Critical Illness; Drug Combinations; Drug Resistance, Multiple, Bacterial; Humans; Microbial Sensitivity Tests

Carbapenemase-producing Enterobacterales (CPE) represent a public health concern. The limited antimicrobial options against CPE have led to the development of novel antimicrobial molecules. In the present study, we characterized the genetic determinants associated with the resistance to ceftazidime/avibactam (CAZ-AVI), meropenem/vaborbactam (MER-VAB), imipenem/relebactam (IMI-REL) and cefiderocol (CFD) in a carbapenemase-producing Klebsiella pneumoniae strain isolated from a critically ill patient.. Genomic DNA was sequenced using Illumina iSeq 100 and Minion Oxford Nanopore platforms. Assemblies were performed with a de novo approach using short-read, hybrid and long-lead assembly approaches. Final assembly was manually curated and carefully verified. Circular elements were screened for antimicrobial-resistance genes, porins, virulence factors and prophage regions.. KPC-Kp (KPC-producing Klebsiella pneumoniae) BO743 was resistant to all novel β-lactams including CAZ-AVI, MER-VAB, IMI-REL and CFD. The genome of strain BO743 is composed of a single chromosome of 5 347 606 bp and three circular plasmids of 363 634 bp (pBO743-363Kb), 120 290 bp (pBO743-120Kb) and 54 339 bp (pBO743-54Kb). Sequence analysis demonstrated that KPC-Kp BO743 co-harboured bla. The description of the genome of KPC-Kp cross-resistant to novel βL-βLICs and cefiderocol reveals the presence of numerous antimicrobial resistance genes including bla

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Boronic Acids; Cefiderocol; Ceftazidime; Cephalosporins; Critical Illness; Humans; Imipenem; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests