Antimicrobial susceptibility of enterobacterales causing bloodstream infection in United States medical centres: comparison of aztreonam-avibactam with beta-lactams active against carbapenem-resistant enterobacterales.

BACKGROUND: Bloodstream infection (BSI) is associated with poor outcomes especially when effective antimicrobial therapy and control of infection source are delayed. As the frequency of Enterobacterales producing metallo-ß-lactamases (MBL) and/or OXA-48-like carbapenemases is increasing in some United States (US) medical centres, effective antimicrobials to treat the infections caused by these organisms are urgently needed. Aztreonam-avibactam is under clinical development for treatment of infections caused by Gram-negative bacteria, including MBL producers. OBJECTIVES: To evaluate the antimicrobial susceptibility of Enterobacterales causing BSI in US medical centres and compare the activity of aztreonam-avibactam with ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, cefiderocol, and other antimicrobials used to treat BSI. METHODS: 4,802 Enterobacterales were consecutively collected (1/patient) from 72 US medical centres in 2020-2022 and susceptibility tested by broth microdilution. Aztreonam-avibactam was tested with avibactam at a fixed concentration of 4 mg/L. A pharmacokinetic/pharmacodynamic susceptible breakpoint of ≤ 8 mg/L was applied for aztreonam-avibactam for comparison. Carbapenem-resistant Enterobacterales (CRE) isolates were tested for ß-lactamase-encoding genes using Next-generation sequencing. RESULTS: Aztreonam-avibactam was highly active against Enterobacterales; only 2 isolates showed aztreonam-avibactam MICs > 8 mg/L: 1 meropenem-susceptible E. coli and 1 K. aerogenes (CRE). All carbapenemase producers and 98.0% of CRE were inhibited at an aztreonam-avibactam MIC of ≤ 8 mg/L. CRE susceptibility rates were 81.6% for ceftazidime-avibactam, 65.3% for meropenem-vaborbactam, 61.2% for imipenem-relebactam, and 87.8% for cefiderocol. Aztreonam-avibactam retained activity (MIC, ≤ 8 mg/L) against all (100.0%) meropenem-vaborbactam nonsusceptible (n = 17), 99.5% of imipenem-relebactam nonsusceptible (n = 206), and 90.0% of ceftazidime-avibactam nonsusceptible (n = 10) isolates. The most common carbapenemases were KPC-2/3 (57.1% of CREs), OXA-48-like (16.3%), and NDM (14.3%). A carbapenemase gene was not observed in 12.3% of CREs. Ceftazidime-avibactam and meropenem-vaborbactam were active against 100.0% of KPC producers, but ceftazidime-avibactam showed limited activity against MBL producers and meropenem-vaborbactam showed limited activity against OXA-48-like and MBL producers. The most active non-ß-lactam comparators against CRE were gentamicin (49.0% susceptible) and amikacin (44.9% susceptible). CONCLUSIONS: Aztreonam-avibactam demonstrated potent activity against a large collection of Enterobacterales isolated from patients with BSI in US hospitals, including CRE, MBL producers, and isolates resistant to recently approved ß-lactamase inhibitor combinations.

Overexpression of blaSHV-12 caused by tandem amplification contributed to ceftazidime/avibactam resistance in hypervirulent and carbapenem-resistant Klebsiella pneumoniae.

AbstractWe identified a novel ceftazidime/avibactam (CAZ/AVI) resistance mechanism in endemic sequence type 11 hypervirulent and carbapenem-resistant Klebsiella pneumoniae isolated from a patient who had not been exposed CAZ/AVI. Overexpression of blaSHV-12 caused by tandem gene amplification contributed to CAZ/AVI resistance instead of the carriage of blaKPC-2. Enhanced genomic surveillance is essential to identify emerging variants.

In vivo emergence of resistance to ceftazidime/avibactam through modification of chromosomal AmpC ß-lactamase in Klebsiella aerogenes.

We describe the in vivo emergence of resistance to ceftazidime/avibactam via modification of AmpC in a clinical Klebsiella aerogenes isolate during therapy with this combination. Paired ceftazidime/avibactam-susceptible/resistant isolates were obtained before and during ceftazidime/avibactam treatment. Whole genome sequencing revealed a differential mutation in AmpC (R148W) in the ceftazidime/avibactam-resistant isolate. Molecular cloning and structural studies confirmed the impact of this substitution, which affects the architecture of the H10 helix, on the evolved resistant phenotype.

Ceftazidime with avibactam for treating severe aerobic Gram-negative bacterial infections: technology evaluation to inform a novel subscription-style payment model.

Background: To limit the use of antimicrobials without disincentivising the development of novel antimicrobials, there is interest in establishing innovative models that fund antimicrobials based on an evaluation of their value as opposed to the volumes used. The aim of this project was to evaluate the population-level health benefit of ceftazidime-avibactam in the NHS in England, for the treatment of severe aerobic Gram-negative bacterial infections when used within its licensed indications. The results were used to inform National Institute for Health and Care Excellence guidance in support of commercial discussions regarding contract value between the manufacturer and NHS England. Methods: The health benefit of ceftazidime-avibactam was first derived for a series of high-value clinical scenarios. These represented uses that were expected to have a significant impact on patients' mortality risks and health-related quality of life. Patient-level costs and health-related quality of life of ceftazidime-avibactam under various usage scenarios compared with alternative management strategies in the high-value clinical scenarios were quantified using decision modelling. Results were reported as incremental net health effects expressed in quality-adjusted life-years, which were scaled to 20-year population in quality-adjusted life-years using infection number forecasts based on data from Public Health England. The outcomes estimated for the high-value clinical scenarios were extrapolated to other expected uses for ceftazidime-avibactam. Results: The clinical effectiveness of ceftazidime-avibactam relative to its comparators was estimated by synthesising evidence on susceptibility of the pathogens of interest to the antimicrobials in a network meta-analysis. In the base case, ceftazidime-avibactam was associated with a statistically significantly higher susceptibility relative to colistin (odds ratio 7.24, 95% credible interval 2.58 to 20.94). The remainder of the treatments were associated with lower susceptibility than colistin (odds ratio < 1). The results were sensitive to the definition of resistance and the studies included in the analysis. In the base case, patient-level benefit of ceftazidime-avibactam was between 0.08 and 0.16 quality-adjusted life-years, depending on the site of infection and the usage scenario. There was a high degree of uncertainty surrounding the benefits of ceftazidime-avibactam across all subgroups, and the results were sensitive to assumptions in the meta-analysis used to estimate susceptibility. There was substantial uncertainty in the number of infections that are suitable for treatment with ceftazidime-avibactam, so population-level results are presented for a range of scenarios for the current infection numbers, the expected increases in infections over time, and rates of emergence of resistance. The population-level benefit varied substantially across the scenarios, from 531 to 2342 quality-adjusted life-years over 20 years. Conclusion: This work has provided quantitative estimates of the value of ceftazidime-avibactam within its areas of expected usage within the NHS. Limitations: Given existing evidence, the estimates of the value of ceftazidime-avibactam are highly uncertain. Future work: Future evaluations of antimicrobials would benefit from improvements to NHS data linkages, research to support appropriate synthesis of susceptibility studies, and application of routine data and decision modelling to assess enablement value. Study registration: No registration of this study was undertaken. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Policy Research Programme (NIHR award ref: NIHR135592), conducted through the Policy Research Unit in Economic Methods of Evaluation in Health and Social Care Interventions, PR-PRU-1217-20401, and is published in full in Health Technology Assessment; Vol. 28, No. 73. See the NIHR Funding and Awards website for further award information.

This project tested new methods for estimating the value to the NHS of an antimicrobial, ceftazidime-avibactam (CAZ-AVI), so its manufacturer could be paid fairly even if very little drug is used in order to reduce the risk of bacteria becoming resistant to the product. Clinicians said that the greatest benefit of CAZ-AVI is when used for complicated urinary tract infections (cUTI) and pneumonia acquired within hospitals caused by bacteria called Enterobacterales, with a resistance mechanism called OXA-48. Because there were no relevant clinical trial data, we estimated how effective CAZ-AVI and alternative treatments were by doing a systematic literature review of studies that grew bacteria from infections in the laboratory and tested the drugs on them. We linked this to data estimating the long-term health and survival of patients. Some evidence was obtained by asking clinicians detailed questions about what they thought the effects would be based on their experience and the available evidence. We included the side effects of the alternative treatments, some of which can cause kidney damage. We estimated how many infections there would be in the UK, whether they would increase over time and how resistance to treatments may change over time. Clinicians told us that they would also use CAZ-AVI to treat intra-abdominal and bloodstream infections. We estimated how many of these infections there would be, and assumed the same health benefits as for cUTI and HAP/VAP, respectively. The total value to the NHS was calculated using these estimates. We also considered whether we had missed any additional elements of value. We estimated that the value to the NHS was £11 million to £47 million over 20 years. This reflects the maximum the NHS could pay for use of CAZ-AVI if the health lost as a result of making these payments rather than funding other NHS services is not to exceed the health benefits of using this antimicrobial. However, these estimates are uncertain due to limitations with the evidence used to produce them and assumptions that had to be made.

Multicenter evaluation of ceftazidime-avibactam use in carbapenem-resistant Klebsiella pneumoniae bloodstream infections in OXA-48 endemic regions.

Data in the literature on the use of ceftazidime-avibactam (CAZ-AVI) in carbapenem-resistant Klebsiella pneumoniae bloodstream infections (CRKP-BSIs) are limited especially in OXA-48 (Oxacillinase-48) predominant regions. Our study aimed to evaluate the effect of CAZ-AVI use on outcomes in CRKP-BSIs in Turkey, where OXA-48 is endemic. A multicenter retrospective observational study was conducted between January 2017 and September 2021. The effects of clinical and treatment characteristics on 30-day mortality and relapse in CRKP-BSIs were analyzed. Predictors of outcomes were detected using a Cox regression model. The study enrolled 106 adults with CAZ-AVI-sensitive CRKP-BSIs who received CAZ-AVI for at least 72 h. Patients who received CAZ-AVI as initial therapy had lower mortality rates when compared to those who switched from last resort regimens [14.3% (n = 3/21) vs. 37.7% (n = 32/85), p = 0.04]. In multivariate analysis, older age and severe neutropenia were detected to be associated with higher mortality, significantly. Initiation of CAZ-AVI on the day of blood culture was obtained, was found to be significantly associated with lower mortality (HR: 0.25, CI: 0.07-0.84, p = 0.025). CAZ-AVI monotherapy is an important treatment option for CRKP-BSIs in OXA-48 endemic areas. Early initiation of CAZ-AVI should be preferred rather than switching from a last-resort regimen as it profoundly improves the survival rates.

Personalized CZA-ATM dosing against an XDR E. coli in liver transplant patients; the application of the in vitro hollow fiber system.

BACKGROUND: A patient with an extensively drug-resistant (XDR) New Delhi metallo-ß-lactamase (NDM) and oxacillinase (OXA-48) producing Escherichia coli (E. coli) infection was awaiting orthotopic liver transplant. There is no standardized antibiotic prophylaxis regimen; however, in line with the Infectious Diseases Society of America guidance, an antibiotic prophylactic regimen of ceftazidime-avibactam 2.5 g TDS with aztreonam 2 g three times a day (TDS) IV was proposed. METHODS: The hollow fiber system (HFS) was applied to inform the individualized pharmacodynamic outcome likelihood prior to prophylaxis. RESULTS: A 4-log reduction in CFU/mL in the first 10 h of the regimen exposure was observed; however, the killing dynamics were slow and six 8-hourly infusions were required to reduce bacterial cells to below the limit of quantification. Thus, the HFS supported the use of the regimen for infection clearance; however, it highlighted the need for several infusions. Standard local practice is to administer prophylaxis antibiotics at induction of orthotopic liver transplantation (OLT); however, the HFS provided data to rationalize earlier dosing. Therefore, the patient was dosed at 24 h prior to their OLT induction and subsequently discharged 8 days after surgery. CONCLUSION: The HFS provides a dynamic culture solution for informing individualized medicine by testing antibiotic combinations and exposures against the bacterial isolates cultured from the patient's infection. .

Clinical experience with ceftazidime/avibactam for the treatment of extensively drug-resistant or pandrug-resistant Klebsiella pneumoniae in neonates and children.

PURPOSE: Klebsiella pneumoniae is a significant cause of healthcare-associated infections, resulting in high morbidity and mortality rates due to limited treatment options. In this study, we aimed to evaluate the treatment outcomes and the safety of Ceftazidime-avibactam in infections caused by extensively drug-resistant or pandrug-resistant Klebsiella pneumoniae in pediatric patients. METHODS: This study included pediatric patients who received ceftazidime-avibactam treatment due to extensively drug-resistant or pandrug-resistant Klebsiella pneumoniae infections, monitored in the pediatric intensive care, neonatal intensive care, and pediatric wards of Cukurova University Faculty of Medicine between 2022 and 2023. Patients' microbiological responses, clinical responses, medication side effects, and 30-day survival rates were evaluated. RESULTS: Eleven pediatric patients were included in the study, of whom nine were male (81.8%). The median age at the initiation of ceftazidime-avibactam treatment was 15 months (range: 14 days-183 months). Sepsis was diagnosed in 9 patients (81.8%). Two premature infants (27 and 35 weeks) were admitted to the neonatal ICU. Regarding the Klebsiella pneumoniae strains, 10 (91%) were extensively drug-resistant (XDR), and 1 (9%) was pandrug-resistant (PDR). Eight strains (72.7%) were carbapenem-resistant, and 9 (81.8%) were colistin-resistant. Microbiological response was noted in 8 patients (72.7%), clinical response was evident in 6 patients (54.5%). The 30-day survival rate was 54.5%, with six patients surviving. CONCLUSION: In our study, ceftazidime-avibactam has been identified as a significant treatment option for resistant Klebsiella pneumoniae infection in critically ill children and premature infants with sepsis and organ failure, and it has been found to be well tolerated.

Insights into the Rising Threat of Carbapenem-Resistant Enterobacterales and Pseudomonas aeruginosa Epidemic Infections in Eastern Europe: A Systematic Literature Review.

BACKGROUND: Antimicrobial resistance is a major global public health challenge, particularly with the rise of carbapenem-resistant Enterobacterales (CRE) and Pseudomonas aeruginosa (CRPA). This study aimed to describe the characteristics of CRE and CRPA infections in Eastern Europe, focusing on Bulgaria, Croatia, Czechia, Greece, Hungary, Poland, Romania, Serbia, Slovakia, and Slovenia. METHODS: Following MOOSE and PRISMA guidelines, a systematic literature review of articles published between 1 November 2017 and 1 November 2023 was conducted using the MEDLINE, Embase, Web of Science, CDSR, DARE, and CENTRAL databases. The search strategy used a combination of free text and subject headings to gather pertinent literature regarding the incidence and treatment patterns of CRE and CRPA infections. A total of 104 studies focusing on infections in both children and adults were included in this review. RESULTS: This review revealed a significant prevalence of carbapenem-resistant Gram-negative isolates and underscored the effectiveness of imipenem/relebactam and ceftazidime/avibactam (CAZ/AVI) against Klebsiella pneumoniae carbapenemase-producing Enterobacterales and of ceftolozane/tazobactam, imipenem/relebactam and ceftazidime/avibactam against non-metallo-ß-lactamase-producing CRPA strains. CONCLUSIONS: This study highlights the urgent need for comprehensive measures to combat the escalating threat of CRE and CRPA infections in Eastern European countries. At the same time, it shows the activity of the standard of care and new antimicrobials against carbapenem-resistant Gram-negative pathogens in Eastern Europe. Clinical real-world data on the treatment of carbapenem-resistant infections in Eastern Europe are needed.

Ceftazidime-Avibactam Versus Polymyxin-Based Combination Therapies: A Study on 30-Day Mortality in Carbapenem-Resistant Enterobacterales Bloodstream Infections in an OXA-48-Endemic Region.

Background: Ceftazidime-avibactam (CAZ-AVI) is recommended as first-line treatment for Oxacillinase-48 (OXA-48) ß-Lactamase-producing carbapenem-resistant Enterobacterales (CRE) infections, while polymyxin-based combination therapies (PBCTs) are used as a last resort when CAZ-AVI is unavailable. Research comparing the effectiveness of CAZ-AVI and PBCT in CRE blood stream infections (CRE-BSIs) is limited, mostly focusing on Klebsiella pneumoniae carbapenemase (KPC)-producing isolates. In Turkey, OXA-48 is endemic and OXA-48-Like is common. Therefore, our study aimed to compare the impact of these treatments on 30-day mortality in patients with CRE-BSIs in endemic regions. Methods: Retrospective data from January 2019 to May 2023 were collected from four tertiary healthcare centers in Istanbul. Demographic, clinical, and outcome data of ICU patients treated with CAZ-AVI monotherapy or PBCT for CRE-BSIs were analyzed. The effect on 30-day survival was evaluated using Cox regression analysis post propensity score matching (PSM). Results: Out of 151 patients, 44.4% (n: 67) received CAZ-AVI and 55.6% (n: 84) received PBCT. All-cause mortality rates were 20% (n: 13) with CAZ-AVI and 36.9% (n: 31) with PBCT. Cox regression analysis post PSM indicated CAZ-AVI monotherapy significantly reduced the mortality risk compared to PBCT (HR: 0.16, 95%CI: 0.07-0.37, p < 0.001), while age increased the risk (HR: 1.02 per year, 95% CI 1.0-1.04, p: 0.01). Conclusions: In OXA-48-predominant areas, CAZ-AVI demonstrated significantly lower mortality in patients with CRE-BSIs compared to PBCT. The results were attributed to the pharmacokinetic and pharmacodynamic disadvantages of polymyxins compared to CAZ-AVI, and the impact of age-related physical conditions. Therefore, CAZ-AVI should be the preferred treatment for CRE-BSIs in OXA-48-endemic regions.

Geographic differences in susceptibility profiles of potential non-class B carbapenemase-producing Enterobacterales isolates against ceftazidime-avibactam, meropenem-vaborbactam, colistin, amikacin, gentamicin, and tigecycline: Data from the Antimicrobial Testing Leadership and Surveillance, 2018-2022.

To evaluate the susceptibility profiles of regional meropenem-resistant (MEM-R) potential non-class B carbapenemase-producing Enterobacterales (CPE) isolates (without confirmation by phenotypic tests) against important antibiotics, we extracted data from the 2018-2022 Antimicrobial Testing Leadership and Surveillance. This data included susceptibility information of MEM-R potential non-class B CPE isolates against indicated antibiotics - amikacin [AMK], gentamicin [GM], ceftazidime-avibactam [CZA], colistin [CST], meropenem-vaborbactam [MVB], and tigecycline [TGC] - from sepsis patients hospitalized in ICUs across six major regions. Carbapenemase-encoding genes of the tested CPE isolates, determined by multiplex PCR and Sanger sequencing, were also analyzed. Susceptibility breakpoints recommended by CLSI 2024 and US FDA criteria (for TGC only) against Enterobacterales were employed. A total of 1,500 potential non-class B CPE isolates (89% of which were Klebsiella pneumoniae) were tested globally. Resistance rates to AMK and GM against the evaluated isolates were statistically higher in Africa/the Middle East, Europe, and India compared to other regions. A similar pattern was observed in the susceptibility of these potential CPE isolates to CZA and MVB. High CST resistance rates were noted in Asia, Latin America, and Europe (29%-35%). Furthermore, the proportions of potential CPE isolates carrying genes encoding blaOXA variants were notably higher among the tested CPE isolates in India, Europe, and Africa/the Middle East regions (99.2%, 53.3%, and 96.7%, respectively) compared to other regions. Trends in resistance to important antibiotics among potential non-class B CPE isolates warrant close monitoring.

Navigating the Current Treatment Landscape of Metallo-ß-Lactamase-Producing Gram-Negative Infections: What are the Limitations?

The spread of carbapenemase-producing gram-negative pathogens, especially those producing metallo-ß-lactamases (MBLs), has become a major health concern. MBLs are molecularly the most diverse carbapenemases, produced by a wide spectrum of gram-negative organisms, including the Enterobacterales, Pseudomonas spp., Acinetobacter baumannii, and Stenotrophomonas maltophilia, and can hydrolyze most ß-lactams using metal ion cofactors in their active sites. Over the years, the prevalence of MBL-carrying isolates has increased globally, particularly in Asia. MBL infections are associated with adverse clinical outcomes including longer length of hospital stay, ICU admission, and increased mortality across the globe. The optimal treatment for MBL infections not only depends on the pathogen but also on the underlying resistance mechanisms. Currently, there are only few drugs or drug combinations that can efficiently offset MBL-mediated resistance, which makes the treatment of MBL infections challenging. The rising concern of MBLs along with the limited treatment options has led to the need and development of drugs that are specifically targeted towards MBLs. This review discusses the prevalence of MBLs, their clinical impact, and the current treatment options for MBL infections and their limitations. Furthermore, this review will discuss agents currently in the pipeline for treatment of MBL infections.

Ceftazidime/avibactam combined with colistimethate sodium successfully cures carbapenem-resistant Pseudomonas aeruginosa-induced brain abscess in a child post-craniotomy: a case report.

The treatment of brain abscess induced by carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a clinical challenge around the world. Apart from novel ß-lactam/ß-lactamase inhibitors and polymyxins, there are few sufficiently powerful antibiotics that are effective against CRPA-induced infections. Considering the blood-brain barrier factor, there are even fewer drugs that can be used to treat intracranial CRPA-induced infections. In this article, we reported a case of CRPA-induced brain abscess that was successfully treated with intravenous ceftazidime/avibactam and intrathecal colistimethate sodium in a child after intracranial tumor resection.

Real-World Evidence on Use of Ceftazidime-Avibactam in the Management of Gram-Negative Infections: A Retrospective Analysis.

There is limited real-world data from India examining the treatment characteristics, safety, and efficacy of ceftazidime-avibactam against Gram-negative organisms especially multidrug-resistant pathogens including carbapenem-resistant Enterobacterales and carbapenem-resistant Pseudomonas. In this retrospective study, the real-world treatment patterns, effectiveness, and safety of ceftazidime-avibactam in treating Gram-negative infections were assessed. Data was extracted from electronic health records of adult patients admitted to the hospital with documented Gram-negative infection who had received treatment for at least 48 hours with ceftazidime-avibactam as a part of routine clinical management. Among the 189 patients, on Day 3, clinical symptom improvement was recorded in 79.6% of patients who received ceftazidime-avibactam within 72 hours of hospital admission. Clinical success was achieved in 79.5% and 76.3% of assessed patients on Day 7 and Day 14/end-of-treatment (EOT), respectively. Microbiological success was reported in 76% of patients on Day 7 and in 60.3% of patients on Day 14 or EOT. The mean treatment duration of ceftazidime-avibactam therapy was 6.92 (± 4.1) days. No new safety concerns were identified. In conclusion, this study provides real-world evidence on treatment patterns and clinical outcomes associated with ceftazidime-avibactam in India, complementing the previously reported literature. The results suggest ceftazidime-avibactam is an effective and tolerable option for the management of multidrug-resistant (MDR) Gram-negative infections in critically ill patients.

Activity of polymyxin B combined with cefepime-avibactam against the biofilms of polymyxin B-resistant Pseudomonas aeruginosa and Klebsiella pneumoniae in in vitro and in vivo models.

Bacterial biofilms, often forming on medical devices, can lead to treatment failure due to their increased antimicrobial resistance. Cefepime-avibactam (CFP-AVI) exhibits potent activities against Pseudomonas aeruginosa (P. aeruginosa) and Klebsiella pneumoniae (K. pneumoniae) when used with polymyxin B (PMB). However, its efficacy in biofilm-related infections is unknown. The present study aimed to evaluate the activity of PMB combined with CFP-AVI against the biofilms of PMB-resistant Gram-negative bacteria. Five K. pneumoniae strains and three P. aeruginosa strains known to be PMB-resistant and prone to biofilm formation were selected and evaluated. Antimicrobial susceptibility assays demonstrated that the minimal biofilm inhibitory and eradication concentrations of PMB and CFP-AVI for biofilms formed by the eight strains were significantly higher than the minimal inhibitory concentrations of the antibiotics for planktonic cells. The biofilm formation inhibition and eradication assays showed that PMB combined with CFP-AVI cannot only suppress the formation of biofilm but also effectively eradicate the preformed mature biofilms. In a modified in vitro pharmacokinetic/pharmacodynamic biofilm model, CFP-AVI monotherapy exhibited a bacteriostatic or effective activity against the biofilms of seven strains, whereas PMB monotherapy did not have any activity at 72 h. However, PMB combined with CFP-AVI demonstrated bactericidal activity against the biofilms of all strains at 72 h. In an in vivo Galleria mellonella infection model, the 7-day survival rates of larvae infected with biofilm implants of K. pneumoniae or P. aeruginosa were 0-6.7%, 40.0-63.3%, and 46.7-90.0%, respectively, for PMB alone, CFP-AVI alone, and PMB combined with CFP-AVI; the combination therapy increased the rate by 6.7-33.3% (P < 0.05, n = 6), compared to CFP-AVI monotherapy. It is concluded that PMB combined with CFP-AVI exhibits effective anti-biofilm activities against PMB-resistant K. pneumoniae and P. aeruginosa both in vitro and in vivo, and thus may be a promising therapeutic strategy to treat biofilm-related infections.

Mechanisms leading to in vivo ceftazidime/avibactam resistance development during treatment of GES-5-producing Pseudomonas aeruginosa infections.

The mechanisms underlying ceftazidime/avibactam resistance development in four ceftazidime/avibactam susceptible/resistant pairs of GES-5-producing ST235 Pseudomonas aeruginosa clinical isolates were investigated. In three of the cases, ceftazidime/avibactam resistance was driven by a single mutation leading to GES-27 (P162Q), GES-29 (P162A), or the novel GES-60 (N136S), as confirmed through cloning experiments. Moreover, these mutations were associated with increased cefiderocol MICs but reduced carbapenem, particularly imipenem/relebactam, resistance. Understanding the complexity of resistance mechanisms to the growing repertoire of antipseudomonal ß-lactams is crucial to guide optimized treatments and antimicrobial stewardship measures.

Pharmacodynamic Target Attainment at Infection Site during Treatment of Post-Neurosurgical Ventriculitis Caused by Carbapenem-Resistant Klebsiella pneumoniae with Ceftazidime-Avibactam-Based Regimens: a case report.

A patient developed a post-neurosurgical ventriculitis with carbapenem-resistant Klebsiella pneumoniae and mold, initially treated with ceftazidime/avibactam and voriconazole. A Klebsiella pneumoniae carbapenemase mutation led to therapy adjustment to ceftazidime/avibactam and polymyxin B, achieving cure. Pharmacokinetic/pharmacodynamic analysis highlights effective ceftazidime/avibactam's brain penetration and bacterial clearance efficacy.

Renal function and its impact on the concentration of ceftazidime-avibactam: A cross-sectional study.

OBJECTIVE: This study measured the effect of renal function on the plasma concentrations of ceftazidime and avibactam in critically ill patients. We also sought to measure the concentration ratio of ceftazidime to avibactam. METHODS: This was a cohort study at a tertiary referral centre in Italy, on patients treated with continuous infusion of ceftazidime-avibactam (CAZ-AVI) between November 2019 and December 2023. The association between creatine clearance (CrCl) and free plasma ceftazidime and avibactam concentration, as well as CAZ-AVI ratio was explored to assess correlation and potential risk to fail to achieve target therapeutic concentration. RESULTS: Fifty-two patients, predominantly male (75%), with a median age of 68.5 y were included. Our analyses provided strong evidence for inverse correlation between CrCl and both free-CAZ (r = -0.627; R2 = 0.3936; P < 0.001) and free-AVI plasma concentration (r = -0.619; R2 = 0.3832; P < 0.001). Overall CrCl alone could explain about 40% of overall variation of either free-CAZ and free-AVI. Linear models suggest that free-CAZ and free-AVI concentration drop of about 7.31% and 9.23% for each 10 point increase of CrCl, respectively. Assessment of the CAZ-AVI ratio supports a direct linear association with CrCl suggesting that free-AVI concentration is more affected by CrCl variation than free-CAZ concentration. Patients with CrCl ≥130 mL/min showed a significantly higher risk of suboptimal drug exposure (i.e., less than 4 times the MIC) both to CAZ and AVI. CONCLUSION: The findings emphasise the need for individualised dosing strategies of CAZ-AVI based on renal function, for antibiotics used in critically ill patients. The study suggests that underdosing in patients with high CrCl is likely to be common and as such could affect drug effectiveness.

In vitro activity of cefepime-enmetazobactam on carbapenem-resistant gram negatives.

OBJECTIVES: Cefepime-enmetazobactam is a new ß-lactam/ßlactamase inhibitor combination with broad-spectrum activity against multidrug-resistant Enterobacterales, including extended-spectrum ß-lactamase producers. This study evaluated the in vitro activity of cefepime-enmetazobactam towards a collection of carbapenem-resistant Enterobacterales (CRE), Pseudomonas aeruginosa and Acinetobacter baumannii compared to the other ß-lactam/ß-lactamase inhibitor combinations. METHODS: The MIC of cefepime, cefepime-enmetazobactam, ceftazidime, ceftazidime-avibactam, meropenem, meropenem-vaborbactam, imipenem, imipenem-relebactam, and ertapenem were determined by broth microdilution on 2212 CRE, including 2089 carbapenemase producers (1000 OXA-48-like, 49 KPC, 697 NDM, 180 VIM, 1 IMP, 9 IMI, and 158 multiple carbapenemases) and 123 CRE that do not produce carbapenemase received at the French National Reference Centre (from March 1, 2023 to August 31, 2023), 50 P. aeruginosa, and 30 A. baumannii. All strains were fully sequenced. RESULTS: We confirmed the absence of inhibitory activity of enmetazobactam towards metallo-ß-lactamases. Cefepime-enmetazobactam and ceftazidime-avibactam exhibited a similar susceptibility (96.7% vs. 99.5%, respectively) on OXA-48-producers. Cefepime-enmetazobactam exhibited 66.9% and 63.3% susceptibility for CRE non-EPC and KPC, whereas those rates rose to 96.7%/95.9%, 93.4%/95.9%, and 95.9%/98.0% for ceftazidime-avibactam, imipenem-relebactam, and meropenem-vaborbactam, respectively. Low MICs (≤0.25 mg/L) were obtained for ceftazidime-avibactam-resistant KPC variants. Cefepime-enmetazobactam did not display a significant added value when compared with cefepime alone on Pseudomonas aeruginosa and Acinetobacter baumannii. DISCUSSION: OXA-48 producers displayed high susceptibility to cefepime-enmetazobactam, which is similar to ceftazidime-avibactam, including for OXA-48 producers that coproduce a ceftazidime hydrolyzing enzyme (extended-spectrum ß-lactamases or AmpC). In vivo experiments have to be implemented to confirm if cefepime-enmetazobactam might be a relevant alternative to ceftazidime-avibactam for the treatment of infections caused by OXA-48 producers.

Impact of porin deficiency on the synergistic potential of colistin in combination with ß-lactam/ß-lactamase inhibitors against ESBL- and carbapenemase-producing Klebsiella pneumoniae.

Combinations of colistin and ß-lactam/ß-lactamase inhibitors (BLBLIs) have shown in vitro synergy against ß-lactamase-producing strains. However, data are limited and conflicting, potentially attributed to variations among the examined strains. This study investigated whether loss of porins OmpK35 and OmpK36 impacts the synergistic potential of colistin in combination with ceftazidime-avibactam or meropenem-avibactam against ß-lactamase-producing Klebsiella pneumoniae. Genetically modified strains were constructed by introducing blaCTX-M-15, blaKPC-2, and blaOXA-48 chromosomally into K. pneumoniae ATCC 35657, in which the major porin-encoding genes (ompK35, ompK36) were either intact or knocked out. The in vitro activity of colistin in combination with ceftazidime-avibactam or meropenem-avibactam was evaluated by time-lapse microscopy screening and in static time-kill experiments. The deletion of porins in the ß-lactamase-producing strains resulted in 2- to 128-fold increases in MICs for the ß-lactams and BLBLIs. The activity of avibactam was concentration-dependent, and 4- to 16-fold higher concentrations were required to achieve similar inhibition of the ß-lactamases in strains with porin loss. In the screening, synergy was observed for colistin and ceftazidime-avibactam against the CTX-M-15-producing strains and colistin and meropenem-avibactam against the KPC-2- and OXA-48-producing strains. The combination effects were less pronounced in the time-kill experiments, where synergy was rarely detected. No apparent associations were found between the loss of OmpK35 and OmpK36 and combination effects with colistin and BLBLIs, indicating that additional factors determine the synergistic potential of such combinations.