High ceftazidime-avibactam resistance among carbapenem-resistant Enterobacter species: Data from the Antimicrobial Testing Leadership and Surveillance (ATLAS) programme, 2014-2021.

OBJECTIVES: Trends in the susceptibility to ceftazidime-avibactam (CZA) and tigecycline (TGC) among Enterobacter species from different geographic areas are unknown.This study aimed to analyse the trends in CZA and TGC susceptibility changes across different continents from 2014 to 2021 utilizing Antimicrobial Testing Leadership and Surveillance (ATLAS) data. METHODS: A total of 23 669 isolates of Enterobacter species were collected over an 8-y period. RESULTS: The overall non-susceptibility rate of Enterobacter isolates to both CZA and TGC was 3.2%. India (16.5%), Guatemala (15.4%), and the Philippines (13.1%) exhibited the highest resistance to CZA. The increase in CZA resistance rates was particularly evident in Asia, with an increase from 4.0% to 8.3%, and in Latin America, from 1.5% to 5%. The non-susceptibility rate for TGC mildly increased in Africa/Middle East but decreased in other continents during the study period. The overall rate of carbapenem resistance increased from 2.9% in 2014-2017 to 4.3% in 2018-2021. Among carbapenem-resistant Enterobacter isolates, the CZA resistance rate was highest in Asia (87.4%), followed by Europe (69.2%) and Africa/Middle East (60.8%). Among the 380 Enterobacter isolates resistant to CZA and carbapenem, the most common genotype of carbapenemase genes was blaNDM (59.2%), followed by blaVIM (24.2%), blaOXA (4.2%), blaIMP (1.1%), and blaKPC (1.1%). The susceptibility of carbapenem-resistant Enterobacter to TGC remained high, with an overall susceptibility rate of 90%. CONCLUSIONS: The heterogeneous distribution of CZA resistance rates among different geographical regions highlights the divergent therapeutic options for drug-resistant Enterobacter species.

The pharmacokinetics/pharmacodynamics of ceftazidime/avibactam for central nervous system infections caused by carbapenem-resistant Gram-negatives: a prospective study.

OBJECTIVES: To describe the pharmacokinetics/pharmacodynamics (PK/PD) of ceftazidime/avibactam in critically ill patients with CNS infections. METHODS: A prospective study of critically ill patients with CNS infections who were treated with ceftazidime/avibactam and the steady-state concentration (Css) of ceftazidime/avibactam in serum and/or CSF was conducted between August 2020 and May 2023. The relationship between PK/PD goal achievement, microbial eradication and the clinical efficacy of ceftazidime/avibactam was evaluated. RESULTS: Seven patients were finally included. The ceftazidime/avibactam target attainment in plasma was optimal for three, quasi-optimal for one and suboptimal for three. In three patients with CSF drug concentrations measured, ceftazidime/avibactam target attainment in CSF was 100% (3/3), which was optimal. The AUCCSF/serum values were 0.59, 0.44 and 0.35 for ceftazidime and 0.57, 0.53 and 0.51 for avibactam. Of the seven patients, 100% (7/7) were treated effectively, 71.4% (5/7) achieved microbiological eradication, 85.7% (6/7) survived and 14.3% (1/7) did not survive. CONCLUSIONS: The limited clinical data suggest that ceftazidime/avibactam is effective in the treatment of CNS infections caused by MDR Gram-negative bacilli (MDR-GNB), can achieve the ideal drug concentration of CSF, and has good blood-brain barrier penetration.

Concomitant Resistance to Cefiderocol and Ceftazidime/Avibactam in Two Carbapenemase-Producing Klebsiella pneumoniae Isolates from Two Lung Transplant Patients.

In this study, we present two cases of Klebsiella pneumoniae, one KPC-33- and one NDM-1-producing, showing resistance to cefiderocol and ceftazidime/avibactam, collected in the intensive care unit of a hospital in Northern Italy from two patients who had recently undergone lung transplantation. Whole-genome sequencing was performed to investigate the molecular features of these strains.

Clinical efficacy of ceftazidime/avibactam combination therapy for severe hospital-acquired pulmonary infections caused by carbapenem-resistant and difficult-to-treat Pseudomonas aeruginosa.

OBJECTIVES: This retrospective study aimed to identify the effectiveness of ceftazidime/avibactam (CAZ/AVI) and its optimisation programs for severe hospital-acquired pulmonary infections (sHAPi) caused by carbapenem-resistant and difficult-to-treat Pseudomonas aeruginosa (CRPA and DTR-P. aeruginosa). METHODS: We retrospectively analysed observational data on treatment and outcomes of CAZ/AVI for sHAPi caused by CRPA or DTR-P. aeruginosa. The primary study outcomes were to evaluate the clinical and microbiology efficacy of CAZ/AVI. RESULTS: The cohort consisted of 84 in-patients with sHAPi caused by CRPA (n = 39) and DTR-P. aeruginosa (n = 45) who received at least 72 h of CAZ/AVI therapy. The clinical cure rate was 63.1% in total. There was no significant difference in study outcomes between patients treated with CAZ/AVI monotherapy and those managed with combination regimens. CAZ/AVI as first-line therapy possessed prominent clinical benefits regarding infections caused by DTR-P. aeruginosa. The clinical cure rate was positively relevant with loading dose for CAZ/AVI (odds ratio [OR] 0.03; 95% confidence interval [CI] 0.004-0.19; P < 0.001) and with CAZ/AVI administration by prolonged infusion (odds ratio 0.15; 95% confidence interval 0.03-0.77; P = 0.002). APACHE II score>15 (P = 0.013), septic shock at infection onset (P = 0.001), and CAZ/AVI dose adjustment for renal dysfunction (P = 0.003) were negative predictors of clinical cure. CONCLUSION: CAZ/AVI is a valid alternative for sHAPi caused by CPRA and DTR-P. aeruginosa, even when used alone. Optimisations of the treatment with CAZ/AVI in critically ill patients, including loading dose, adequate maintenance dose and prolonged infusion, were positively associated with potential clinical benefits.

Emergence of cefiderocol resistance during ceftazidime/avibactam treatment caused by a large genomic deletion, including ampD and piuCD genes, in Pseudomonas aeruginosa.

We report the emergence of cefiderocol resistance during the treatment of a ST312 Pseudomonas aeruginosa respiratory infection with ceftazidime/avibactam. whole genome sequencing (WGS) revealed that resistance was caused by a large genomic deletion, including PiuDC (iron transport system) and AmpD (ampC negative regulator), driven by the integration of phage DNA. Thus, our findings alert that this type of deletion could be an efficient (two mechanisms in one step) specific cefiderocol resistance mechanism that might occur nonspecifically upon treatment with ß-lactams that select for AmpC overexpression.

Moving towards a standardized definition of antimicrobial resistance: a comparison of the antimicrobial susceptibility profile of difficult-to-treat resistance (DTR) versus multidrug-resistant (MDR) Pseudomonas aeruginosa clinical isolates (CANWARD, 2016-2021).

Pseudomonas aeruginosa clinical isolates demonstrating difficult-to-treat resistance (DTR) and multidrug-resistant (MDR) phenotypes were evaluated by broth microdilution. Susceptibility was lower for all antimicrobials versus DTR relative to MDR isolates. Ceftazidime-avibactam, ceftolozane-tazobactam, and imipenem-relebactam susceptibility was 35.9%, 64.5%, and 47.0% for DTR isolates and 60.5%, 80.6%, and 71.5% for MDR isolates.

A descriptive pharmacokinetic/pharmacodynamic analysis of ceftazidime-avibactam in a case series of critically ill patients with augmented renal clearance.

To describe the pharmacokinetics/pharmacodynamics (PK/PD) of a 2 h infusion of ceftazidime-avibactam (CAZ-AVI) in critically ill patients with augmented renal clearance (ARC). A retrospective review of all critically ill patients with ARC who were treated with CAZ-AVI between August 2020 and May 2023 was conducted. Patients whose 12-h creatinine clearance prior to CAZ-AVI treatment and steady-state concentration (Css) of CAZ-AVI were both monitored were enrolled. The free fraction (fCss) of CAZ-AVI was calculated from Css. The joint PK/PD targets of CAZ-AVI were considered optimal when a Css/minimum inhibitory concentration (MIC) ratio for CAZ ≥4 (equivalent to 100% fT > 4 MIC) and a Css/CT ratio of AVI >1 (equivalent to 100% fT > CT 4.0 mg/L) were reached simultaneously, quasioptimal when only one of the two targets was reached, and suboptimal when neither target was reached. The relationship between PK/PD goal achievement, microbial eradication and the clinical efficacy of CAZ-AVI was evaluated. Four patients were included. Only one patient achieved optimal joint PK/PD targets, while the other three reached suboptimal targets. The patient with optimal PK/PD targets achieved microbiological eradication, while the other three patients did not, but all four patients achieved good clinical efficacy. Standard dosages may not enable most critically ill patients with ARC to reach the optimal joint PK/PD targets of CAZ-AVI. Optimal drug dose adjustment of CAZ-AVI in ARC patients requires dynamic drug concentration monitoring.

Looking for Stenotrophomonas maltophilia treatment: in vitro activity of ceftazidime/avibactam alone and in combination with aztreonam.

During the Sars-Cov-2 pandemic, Stenotrophomonas maltophilia (S.maltophilia) 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 in vitro activity of ceftazidime/avibactam (CZA) alone and in combination with aztreonam (ATM) against S. maltophilia 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.

Mortality in KPC-producing Klebsiella pneumoniae bloodstream infections: a changing landscape.

OBJECTIVES: To assess the impact of carbapenem resistance on mortality in Klebsiella pneumoniae bloodstream infection (BSI) in the era of novel ß-lactam/ß-lactamase inhibitor combinations. MATERIAL AND METHODS: Retrospective study of patients with K. pneumoniae BSI between January and August 2020 in 16 centres (CARBANEW study within the MULTI-SITA project). RESULTS: Overall, 426 patients were included: 107/426 (25%) had carbapenem-resistant K. pneumoniae (CR-Kp) BSI and 319/426 (75%) had carbapenem-susceptible K. pneumoniae (CS-Kp) BSI. Crude cumulative 30 day mortality was 33.8% and 20.7% in patients with, respectively, CR-Kp BSI and CS-Kp BSI (P = 0.027). Carbapenemase production or carbapenemase-encoding genes were detected in 84/98 tested CR-Kp isolates (85.7%), mainly KPC (78/84; 92.9%). Ceftazidime/avibactam was the most frequently used appropriate therapy for CR-Kp BSI (80/107; 74.7%). In multivariable analyses, variables showing an unfavourable association with mortality after correction for multiple testing were age-adjusted Charlson comorbidity index (HR 1.20; 95% CI 1.10-1.31, P < 0.001) and Pitt score (HR 1.33; 95% CI 1.15-1.55, P < 0.001), but not carbapenem resistance (HR 1.28, 95% CI 0.74-2.22, P = 0.410). In a propensity score-matched analysis, there was no difference in mortality between patients appropriately treated with ceftazidime/avibactam for CR-Kp BSI and patients appropriately treated with other agents (mainly meropenem monotherapy or piperacillin/tazobactam monotherapy) for CS-Kp BSI (HR 1.07; 95% CI 0.50-2.29, P = 0.866). CONCLUSIONS: Our results suggest that the increased mortality in CR-Kp BSI compared with CS-Kp BSI is not (or no longer) dependent on the type of therapy in areas where ceftazidime/avibactam-susceptible KPC-producing isolates are the most prevalent type of CR-Kp.

Case Commentary: Successful Use of Cefepime/Zidebactam (WCK 5222) as a Salvage Therapy for the Treatment of Disseminated Extensively Drug-Resistant New Delhi Metallo-ß-Lactamase-Producing Pseudomonas aeruginosa Infection in an Adult Patient with Acute T-Cell Leukemia.

Multidrug-resistant/extensively drug-resistant (MDR/XDR) Pseudomonas aeruginosa (PA) are critical antimicrobial resistance threats. Despite their increasing prevalence, treatment options for metallo-ß-lactamase (MBL)-producing PA are limited, especially for New Delhi metallo-ß-lactamase (NDM) producers. Pending further clinical studies, this case provides support for limited-scope use of cefepime-zidebactam for treating disseminated infections secondary to NDM-producing XDR PA. Susceptibilities should be tested and/or alternative regimens considered when treating isolates with alternative MBLs or increased efflux pump expression because some in vitro data suggest associated loss of cefepime-zidebactam susceptibility.

Ceftolozane-Tazobactam Versus Ceftazidime-Avibactam for the Treatment of Infections Caused by Multidrug-Resistant Pseudomonas aeruginosa: a Multicenter Cohort Study.

Ceftolozane-tazobactam (C-T) and ceftazidime-avibactam (CAZ-AVI) are two novel antimicrobials that retain activity against resistant Pseudomonas aeruginosa. The comparative effectiveness and safety of C-T versus CAZ-AVI remain unknown. A retrospective, multicenter cohort study was performed in six tertiary centers in Saudi Arabia and included patients who received either C-T or CAZ-AVI for infections due to multidrug-resistant (MDR) P. aeruginosa. Overall in-hospital mortality, 30-day mortality, and clinical cure were the main study outcomes. Safety outcomes were also evaluated. A multivariate analysis using logistic regression was used to determine the independent impact of treatment on the main outcomes of interest. We enrolled 200 patients in the study (100 in each treatment arm). A total of 56% were in the intensive care unit, 48% were mechanically ventilated, and 37% were in septic shock. Approximately 19% of patients had bacteremia. Combination therapy was administered to 41% of the patients. The differences between the C-T and CAZ-AVI groups did not reach statistical significance in the overall in-hospital mortality (44% versus 37%; P = 0.314; OR, 1.34; 95% CI, 0.76 to 2.36), 30-day mortality (27% versus 23%; P = 0.514; OR, 1.24; 95% CI, 0.65 to 2.35), clinical cure (61% versus 66%; P = 0.463; OR, 0.81; 95% CI, 0.43 to 1.49), or acute kidney injury (23% versus 17%; P = 0.289; OR, 1.46; 95% CI, 0.69 to 3.14), even after adjusting for differences between the two groups. C-T and CAZ-AVI did not significantly differ in terms of safety and effectiveness, and they serve as potential options for the treatment of infections caused by MDR P. aeruginosa.

Successful Use of Cefepime-Zidebactam (WCK 5222) as a Salvage Therapy for the Treatment of Disseminated Extensively Drug-Resistant New Delhi Metallo-ß-Lactamase-Producing Pseudomonas aeruginosa Infection in an Adult Patient with Acute T-Cell Leukemia.

With limited and often toxic treatment options, carbapenem-resistant Gram-negative infections are associated with significant mortality. Cefepime-zidebactam is a promising antibiotic option undergoing a phase 3 trial that has activity against diverse antibiotic-resistant mechanisms in Gram-negative pathogens due to its ß-lactam enhancer mechanism, mediating multiple PBP binding. We report a case of disseminated infection caused by a New Delhi metallo-ß-lactamase-producing, extensively drug-resistant Pseudomonas aeruginosa isolate in a patient with acute T-cell leukemia, successfully managed with cefepime-zidebactam as a salvage therapy.

Assessing the in vivo efficacy of rational antibiotics and combinations against difficult-to-treat Pseudomonas aeruginosa producing GES ß-lactamases.

OBJECTIVES: We evaluated the in vivo efficacy of human-simulated regimens (HSRs) of cefiderocol, ceftazidime/avibactam, meropenem and ceftazidime/avibactam/meropenem combination against Guiana-extended spectrum (GES)-producing Pseudomonas aeruginosa isolates. METHODS: Eighteen P. aeruginosa isolates producing GES-1 (n = 5), GES-5 (n = 5) or miscellaneous GESs (combinations of GES-19, GES-20 and/or GES-26; n = 8) were evaluated. In vitro MIC testing was determined using broth microdilution. In a validated murine thigh infection model, HSRs of cefiderocol 2 g q8h as a 3 h IV infusion, ceftazidime/avibactam 2.5 g q8h as a 2 h IV infusion, meropenem 2 g q8h as a 3 h IV infusion or ceftazidime/avibactam/meropenem were administered. Change in bacterial burden relative to baseline and the proportion of isolates in each genotypic group meeting 1-log10 kill endpoint were assessed. RESULTS: Modal MICs (mg/L) ranged from 0.125 to 1 for cefiderocol, 4 to >64 for ceftazidime/avibactam and 2 to >64 for meropenem. Cefiderocol produced >1-log10 of kill against all 18 tested isolates. Meropenem was active against all GES-1 isolates whereas activity against GES-5 and miscellaneous GESs was lacking, consistent with the MICs. Ceftazidime/avibactam was active against all GES-1 and GES-5 isolates and retained activity against 62.5% of miscellaneous GESs including isolates with elevated MICs. For isolates where ceftazidime/avibactam failed, the addition of meropenem restored the in vivo efficacy. CONCLUSIONS: As monotherapy, cefiderocol was active in vivo against all tested isolates. The activities of meropenem or ceftazidime/avibactam alone were variable; however, a combination of both was active against all isolates. Cefiderocol and ceftazidime/avibactam/meropenem could be valuable therapeutic options for GES-producing P. aeruginosa infections. Clinical confirmatory data are warranted.

Comparing novel antibiotics and carbapenems for complicated intra-abdominal infections: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Carbapenem-sparing antibiotics are needed urgently for patients with complicated intra-abdominal infections (cIAIs). Although several novel antibiotics - novel ß-lactam/ß-lactamase inhibitor combinations (e.g. ceftolozane-tazobactam and ceftazidime-avibactam) and a novel tetracycline derivative (eravacycline) - have been developed for cIAIs, it remains unclear whether these antibiotics are comparable to carbapenems for the treatment of cIAIs. METHODS: A comprehensive search of PubMed, Embase, Cochrane Library and ClinicalTrials.gov was conducted until 1 October 2022. Only randomized controlled trials (RCTs) that compared the clinical efficacy and safety of novel antibiotics against carbapenems for patients with cIAIs were included. RESULTS: Among the 11 selected RCTs, no significant differences in clinical cure rate at the test-of-cure visit were observed between the study group and the control group on analysis of the clinically evaluable population [93.6% vs 93.7%, risk ratio (RR) 1.00, 95% confidence interval (CI) 0.98-1.01; P=0.84], microbiologically evaluable population (93.0% vs 94.5%, RR 0.98, 95% CI 0.96-1.00; P=0.10) and modified intention-to-treat population (85.9% vs 87.7%, RR 0.98, 95% CI 0.95-1.01; P=0.13). All findings were consistent across the subgroup analyses and sensitivity tests. Similarly, no significant difference in microbiological eradication was observed between the study group and the control group (87.8% vs 89.7%, RR 0.98, 95% CI 0.96-1.01; P=0.18). The risk of adverse events was similar in both groups. CONCLUSIONS: Clinical efficacy, microbiological response and safety of the novel antibiotics, including ceftazidime-avibactam, ceftolozane-tazobactam and eravacycline, are comparable to carbapenems for the treatment of patients with cIAIs. These agents can be potential therapeutic options as carbapenem-sparing antibiotics for cIAIs.

Real-world effectiveness of ceftazidime/avibactam versus polymyxin B in treating patients with carbapenem-resistant Gram-negative bacterial infections.

OBJECTIVES: To compare the effectiveness of ceftazidime/avibactam (CAZ/AVI) and polymyxin B against carbapenem-resistant Gram-negative bacteria (CRGNB) infections in western China. METHODS: The medical records of patients with CRGNB infections in this hospital from 2018-2022 were retrospectively reviewed. The data included demographic characteristics, laboratory results, antibiotic strategies and clinical outcomes. RESULTS: A total of 378 patients with CRGNB infections were enrolled, including 112 patients in the CAZ/AVI group and 266 patients in the polymyxin B group. The most common pathogen was carbapenem-resistant Klebsiella pneumoniae (44.44%). The rates of treatment failure at 28 days (65.04% vs. 45.54%; P = 0.000) and 28-day in-hospital mortality (20.30% vs. 9.82%; P = 0.014) in the polymyxin B group were higher than those in the CAZ/AVI group. Multivariable analysis revealed that multiple organ dysfunction syndrome (OR 2.730; P = 0.017), acute renal failure (OR 2.595; P = 0.020), higher Charlson comorbidity index (CCI) (OR 1.184; P = 0.011) and Acute Physiology And Chronic Health Evaluation (APACHE) Ⅱ scores (OR 1.149; P = 0.000) were independent risk factors for treatment failure, whereas CAZ/AVI therapy (OR 0.333; P = 0.002) had a protective effect. Multivariate Cox regression analysis revealed that CCI ≥ 5 and APACHE II score ≥ 15 were associated with a higher 28-day in-hospital mortality rate (P < 0.001). CONCLUSION: CAZ/AVI therapy was associated with treatment success among patients with CRGNB infection. However, CAZ/AVI therapy did not improve 28-day in-hospital survival compared with polymyxin B. The CCI ≥ 5 and APACHE II score ≥ 15 affected 28-day in-hospital mortality of CRGNB-infected patients.

Occurrence, resistance patterns, and management of carbapenemase-producing bacteria in war-wounded refugees from Ukraine.

We analyzed consecutive clinical cases of infections due to carbapenemase-producing gram-negative bacteria detected in war-wounded patients from Ukraine who were treated at one university medical center in southwest Germany between June and December 2022. The isolates of multiresistant gram-negative bacteria were subjected to a thorough microbiological characterization and whole genome sequencing (WGS). We identified five war-wounded Ukrainian patients who developed infections with New Delhi metallo-ß-lactamase 1-positive Klebsiella pneumoniae. Two isolates also carried OXA-48 carbapenemases. The bacteria were resistant to novel antibiotics, such as ceftazidime/avibactam and cefiderocol. The used treatment strategies included combinations of ceftazidime/avibactam + aztreonam, colistin, or tigecycline. WGS suggested transmission during primary care in Ukraine. We conclude that there is an urgent need for thorough surveillance of multiresistant pathogens in patients from war zones.

A therapeutic regimen of ceftazidime-avibactam for a critical patient receiving prolonged intermittent renal replacement therapy.

The present report firstly described a critically ill patient receiving a dosing regimen of ceftazidime-avibactam (CAZ-AVI) (1.875g q24h) to eliminate multidrug-resistant Klebsiella pneumoniae and a scheduled time for prolonged intermittent renal replacement therapy (PIRRT) every 48h (6h-session beginning 12h after the previous dosage on hemodialysis day). This dosing regimen for CAZ-AVI and a scheduled time for PIRRT allowed pharmacodynamic parameters of ceftazidime and avibactam to have little difference on hemodialysis and non-hemodialysis days so that we can maintain a relatively stable drug concentration. Our report highlighted not only the importance of dosing regimens in patients with PIRRT but also the significance of hemodialysis time points during the dosing interval. The innovative therapeutic plan proved to be suitable for patients infected with Klebsiella pneumoniae when on PIRRT according to the trough plasma concentrations of ceftazidime and avibactam which were maintained above the minimum inhibitory concentration during the dosing interval.