New β-lactam-β-lactamase inhibitor combinations represent last-resort antibiotics to treat infections caused by multidrug-resistant Pseudomonas aeruginosa. Carbapenemase gene acquisition can limit their spectrum of activity, and reports of resistance toward these new molecules are increasing. In this multi-center study, we evaluated the prevalence of resistance to ceftazidime-avibactam (CZA) and comparators among P. aeruginosa clinical isolates from bloodstream infections, hospital-acquired or ventilator-associated pneumonia, and urinary tract infections, circulating in Southern Italy. We also investigated the clonality and content of relevant β-lactam resistance mechanisms of CZA-resistant (CZAR) isolates. A total of 120 P. aeruginosa isolates were collected. CZA was among the most active β-lactams, retaining susceptibility in the 81.7% of cases, preceded by cefiderocol (95.8%) and followed by ceftolozane-tazobactam (79.2%), meropenem-vaborbactam (76.1%), imipenem-relebactam (75%), and aztreonam (69.6%). Among non-β-lactams, colistin and amikacin were active against 100% and 85.8% of isolates respectively. In CZAR strains subjected to whole-genome sequencing (n = 18), resistance was mainly due to the expression of metallo-β-lactamases (66.6% VIM-type and 5.5% FIM-1), followed by PER-1 (16.6%) and GES-1 (5.5%) extended-spectrum β-lactamases, mostly carried by international high-risk clones (ST111 and ST235). Of note, two strains producing the PER-1 enzyme were resistant to all β-lactams, including cefiderocol. In conclusion, the CZA resistance rate among P. aeruginosa clinical isolates in Southern Italy remained low. CZAR isolates were mostly metallo-β-lactamases producers and belonging to ST111 and ST253 epidemic clones. It is important to implement robust surveillance systems to monitor emergence of new resistance mechanisms and to limit the spread of P. aeruginosa high-risk clones.
OBJECTIVE: Multidrug-resistant Pseudomonas aeruginosa infections are a growing threat due to the limited therapeutic options available. Ceftazidime-avibactam (CZA) is among the last-resort antibiotics for the treatment of difficult-to-treat P. aeruginosa infections, although resistance due to the acquisition of transferable β-lactamase genes is increasing. With this work, we report that CZA represents a highly active antipseudomonal β-lactam compound (after cefiderocol), and that metallo-β-lactamases (VIM-type) and extended-spectrum β-lactamases (GES and PER-type) production is the major factor underlying CZA resistance in isolates from Southern Italian hospitals. In addition, we reported that such resistance mechanisms were mainly carried by the international high-risk clones ST111 and ST235.

UNASSIGNED: Ceftazidime-avibactam is a treatment option for carbapenem-resistant gram-negative bacilli (CR-GNB) infections. However, the risk factors associated with ceftazidime-avibactam (CAZ-AVI) treatment failure in kidney transplant (KT) recipients and the need for CAZ-AVI-based combination therapy remain unclear.
UNASSIGNED: From June 2019 to December 2023, a retrospective observational study of KT recipients with CR-GNB infection treated with CAZ-AVI was conducted, with the primary outcome being 30-day mortality and secondary outcomes being clinical cure, microbiological cure, and safety. Risk factors for 30-day mortality and clinical failure were also investigated.
UNASSIGNED: A total of 81 KT recipients treated with CAZ-AVI were included in this study. Forty recipients (49.4%) received CAZ-AVI monotherapy, with a 30-day mortality of 22.2%. The clinical cure and microbiological cure rates of CAZ/AVI therapy were 72.8% and 66.7%, respectively. CAZ-AVI alone or in combination with other medications had no effect on clinical cure or 30-day mortality. Multivariate logistic regression analysis revealed that a higher Acute Physiology and Chronic Health Evaluation (APACHE) II score (odds ratio [OR]: 4.517; 95% confidence interval [CI]: 1.397-14.607; P = 0.012) was an independent risk factor for 30-day mortality. Clinical cure was positively associated with the administration of CAZ-AVI within 48 hours of infection onset (OR: 11.009; 95% CI: 1.344-90.197; P=0.025) and negatively associated with higher APACHE II scores (OR: 0.700; 95% CI: 0.555-0.882; P=0.002). Four (4.9%) recipients experienced recurrence within 90 days after the initial infection, 3 (3.7%) recipients experienced CAZ-AVI-related adverse events, and no CAZ-AVI resistance was identified.
UNASSIGNED: CAZ-AVI is an effective medication for treating CR-GNB infections following kidney transplantation, even as monotherapy. Optimization of CAZ/AVI therapy (used within 48 hours of infection onset) is positively associated with potential clinical benefit. Further larger-scale studies are needed to validate these findings.

The main aim of this study was to compare and analyze the effectiveness of treatment regimens using ceftazidime/avibactam (CAZ/AVI) versus fosfomycin plus meropenem (FOS/MER) for managing bloodstream infections (BSI) or ventilator-associated pneumonia (VAP) caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) in critically ill patients. Between 4 January 2019, and 16 July 2023, adult patients (≥18 years old) diagnosed with BSI or VAP due to culture confirmed CRKP in ICU of a tertiary care hospital were investigated retrospectively. A total of 71 patients were categorized into two groups: 30 patients in CAZ/AVI-based, and 41 patients in FOS/MER-based group. No substantial disparities were found in the total duration of ICU hospitalization, as well as the 14- and 30-day mortality rates, between patients treated with CAZ/AVI-based and FOS/MER-based therapeutic regimens. We consider that our study provides for the first time a comprehensive understanding of treatment outcomes and associated risk factors among patients with CRKP-related infections.

UNASSIGNED: Since the introduction of ceftazidime-avibactam (CZA) in the Chinese market, accumulating clinical evidence has substantiated its efficacy in the treatment of infections caused by carbapenem-resistant gram-negative bacteria (CR-GNB). Nevertheless, an ongoing debate persists concerning the choice between monotherapy and combination therapy when devising clinical anti-infection protocols.
UNASSIGNED: This retrospective, single-center observational study enrolled patients with CR-GNB infections who received CZA treatment between December 2019 and August 2023. The primary outcome assessed was 30-day mortality, and the secondary outcome measured was 14-day bacterial clearance. A multivariate Cox regression model was used to identify variables that were independently associated with 30-day mortality rate.
UNASSIGNED: Eighty-three patients were enrolled in the study; of which, 45 received CZA monotherapy, whereas 38 received combination therapy. The overall 30-day mortality rate was 31.3%, and no significant difference was observed in the 30-day mortality rates between the CZA combination therapy and monotherapy groups (31.6% vs 31.1%, p=0.963). After adjustment by propensity score matching, the 30-day mortality rate was not significantly different between the two groups (28.6% vs 31.4%, p=0.794). Multivariate COX analysis revealed that age and SOFA score were independent predictors of 30-day mortality.
UNASSIGNED: Combination therapy with CZA and other antimicrobials was not found to have an advantage over monotherapy in reducing the 30-day mortality rate.

OBJECTIVE: The incidences of nosocomial pneumonia in intensive care units (ICUs) in India have been reported to range from 9% to 58% and are associated with a mortality rate of 30-70%. Ceftazidime-avibactam has activity against OXA-48-like carbapenem-resistant Enterobacterales (CRE) and has a safer adverse effect profile as compared to the nephrotoxic colistin. The current study aimed to assess the effectiveness and usage pattern of ceftazidime-avibactam in gram-negative hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) in real-world settings in India.
METHODS: Electronic medical records of hospitalized patients in three prominent medical centers in India (Fortis Memorial Research Centre, Gurugram, S L Raheja Hospital, Mumbai, and Fortis Hospital, Anandapur, Kolkata) with nosocomial pneumonia and documented gram-negative Klebsiella pneumoniae (KP)-confirmed infection were collected. This study assessed the effectiveness, usage pattern of ceftazidime-avibactam, and clinical and microbiological cure rates.
RESULTS: Among the 116 patients included, 78.45% (91/116) showed clinical cure. Microbiological cure was observed in nine out of 13 (69.23%) patients. In the subset analysis, a clinical cure rate of 84.85% (28/33) and microbiological recovery rate of 62.50% (5/8) were observed when ceftazidime-avibactam was initiated within 72 hours of diagnosis. Ceftazidime-avibactam was administered for a mean (±SD) duration of 7.79 ± 4.43 days, with improvement in signs and symptoms reported among 91.38% (106/116). Ceftazidime-avibactam showed a susceptibility of 56% (28/56) in the study.
CONCLUSIONS: The current study showed a better clinical and microbiological cure rate with a safer tolerability profile of ceftazidime-avibactam in carbapenem-resistant KP nosocomial pneumonia and VAP. This study has further demonstrated that ceftazidime-avibactam may be used as one of the viable treatment choices in carbapenem-resistant KP with favorable clinical outcomes.

UNASSIGNED: Extensively drug-resistant Pseudomonas aeruginosa (XDR-PA) is a growing concern due to its increasing incidence, limited therapeutic options, limited data on the optimal treatment, and high mortality rates. The study aimed to characterize the population, the outcome and the microbiological characteristics of XDR-PA identified in a Portuguese university hospital center.
UNASSIGNED: All XDR-PA isolates between January 2019 and December 2021 were identified. XDR-PA was defined as resistance to piperacillin-tazobactam, third and fourth generation cephalosporins, carbapenems, aminoglycosides and fluoroquinolones. A retrospective analysis of the medical records was performed.
UNASSIGNED: One hundred seventy-eight individual episodes among 130 patients with XDR-PA detection were identified. The most common sources of infection were respiratory (32%) and urinary tracts (30%), although skin and soft tissue infections (18%) and primary bacteremia (14%) were also prevalent. Colonization was admitted in 64 cases. Several patients had risk factors for complicated infections, most notably immunosuppression, structural lung abnormalities, major surgery, hemodialysis or foreign intravascular or urinary devices. XDR-PA identification was more frequent in male patients with an average age of 64.3 ± 17.5 years. One non-susceptibility to colistin was reported. Only 12.4% were susceptible to aztreonam. Ceftazidime-avibactam (CZA) was susceptible in 71.5% of the tested isolates. Ceftolozane-tazobactam (C/T) was susceptible in 77.5% of the tested isolates. Antibiotic regimens with XDR-PA coverage were reserved for patients with declared infection, except to cystic fibrosis. The most frequently administered antibiotics were colistin (41 cases), CZA (39 cases), and C/T (16 cases). When combination therapy was used, CZA plus colistin was preferred. The global mortality rate among infected patients was 35.1%, significantly higher in those with hematologic malignancy (50.0%, p < 0.05), followed by the ones with bacteremia (44.4%, p < 0.05) and those medicated with colistin (39.0%, p < 0.05), especially the ones with respiratory infections (60.0%). Among patients treated with CZA or C/T, the mortality rate seemed to be lower.
UNASSIGNED: XDR-PA infections can be severe and difficult to treat, with a high mortality rate. Even though colistin seems to be a viable option, it is likely less safe and efficient than CZA and C/T. To the best of the authors\' knowledge, this is the first description of the clinical infection characteristics and treatment of XDR-PA in Portugal.

UNASSIGNED: Carbapenem-Resistant Klebsiella pneumoniae (CRKP) is a significant public health threat, because it is associated with substantial morbidity and mortality. However, the risk factors associated with treatment failure of ceftazidime-avibactam (CAZ-AVI) and the need for CAZ-AVI-based combination remain unclear.
UNASSIGNED: We conducted a retrospective study of critically ill patients (age: > 18 years) diagnosed with CRKP infections and treated with CAZ-AVI for at least 24 h between June 2020 and December 2022 at Henan Provincial People\'s Hospital.
UNASSIGNED: This study included a total of 103 patients who received CAZ-AVI. Of these, 91 (88.3%) patients received the standard dosage of 2.5 g every q8h, while only 20 (19.4%) received monotherapy. The Kaplan-Meier curves showed that the all-cause 30-day mortality was significantly higher among patients who experienced septic shock than those who did not. There was no significant difference in mortality between monotherapy and combination therapy. Dose reduction of CAZ-AVI was associated with a significantly increased mortality rate. Independent risk factors for the 30-day mortality included higher APACHE II score (HR: 1.084, 95% CI: 1.024-1.147, p = 0.005) and lower lymphocyte count (HR: 0.247, 95% CI: 0.093-0.655, p = 0.005). Conversely, a combination therapy regimen containing carbapenems was associated with lower mortality (HR: 0.273, 95% CI: 0.086-0.869, p = 0.028).
UNASSIGNED: Our study suggests that CAZ-AVI provides clinical benefits in terms of survival and clinical response in critically ill patients with CRKP infection. A higher APACHE II score and lower lymphocyte count were associated with 30-day mortality, while the combination therapy regimen containing carbapenems was the only protective factor. CAZ-AVI dose reduction was associated with an increased mortality rate. Futher large-scale studies are needed to validate these findings.

UNASSIGNED: The incidence of carbapenem-resistant organism (CRO) infections is increasing in children. However, pediatric-specific treatment strategies present unique challenges. Ceftazidime/avibactam is a β-lactam/β-lactamase inhibitor combination, showing adequate efficiency against CRO isolates. However, clinical data on the efficacy of ceftazidime/avibactam in children are still lacking.
UNASSIGNED: This was a retrospective study of children (aged <18 years) infected with confirmed or suspected carbapenem-resistant pathogens and treated with ceftazidime-avibactam at the First Affiliated Hospital of Zhengzhou University between 2020 and 2022.
UNASSIGNED: We identified 38 children aged 14 (5.0-16.3) years; 20 (52.6%) had hematologic malignancies. 25 children with confirmed CRO infections were administered ceftazidime-avibactam as targeted therapy. The median treatment was 10 (6.0-16.5) days. Among them, 24 had infections caused by carbapenem-resistant Enterobacterales (CRE) (18 carbapenem-resistant Klebsiella pneumoniae and six carbapenem-resistant Escherichia coli species) and one with carbapenem-resistant Pseudomonas aeruginosa strains. The source of infection was the bloodstream in 60.0% of the cases (15/25). The clinical response rate was 84.0% (21/25), and 30-day mortality rate was 20% (5/25). 13 children were administered ceftazidime-avibactam as empiric therapy for suspected infections. The median treatment was 8 (6.0-13.0) days. No deaths occurred and clinical response was achieved in 12 of the 13 patients (92.3%) who empirically treated with ceftazidime-avibactam.
UNASSIGNED: Ceftazidime-avibactam is important for improving survival, and clinical response in children with infections caused by CRO.

In a propensity-score-weighted cohort of 183 adults with carbapenem-resistant Enterobacterales bacteremia at 24 US hospitals, patients receiving short courses of active therapy (7-10 days, median 9 days) experienced similar odds of recurrent bacteremia or death within 30 days as those receiving prolonged courses of active therapy (14-21 days, median 14 days).

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