Ceftazidime

Infections due to carbapenemase-producing Gram-negative pathogens are associated with limited treatment options and consequently lead to increased mortality and morbidity. In response, combinations of existing β-lactams and novel β-lactamase inhibitors, such as ceftazidime-avibactam (CAZ-AVI), have been developed as alternative treatment options. To understand the development of resistance and evolutionary trajectories under CAZ-AVI exposure, we studied the effects of ceftazidime (CAZ) and CAZ-AVI on the carbapenemase OXA-48 and the epidemic OXA-48 plasmid in Escherichia coli Exposure of CAZ and CAZ-AVI resulted in single (P68A) and double (P68A,Y211S) amino acid substitutions in OXA-48, respectively. The antimicrobial susceptibility data and enzyme kinetics showed that the P68A substitution was responsible for an increased activity toward CAZ, whereas P68A,Y211S led to a decrease in the inhibitory activity of AVI. X-ray crystallography and molecular modeling of the mutants demonstrated increased flexibility within the active site, which could explain the elevated CAZ hydrolysis and reduced inhibitory activity of AVI. Interestingly, these substitutions resulted in collateral effects compromising the activity of OXA-48 toward carbapenems and penicillins. Moreover, exposure to CAZ-AVI selected for mutations within the OXA-48-encoding plasmid that severely reduced fitness in the absence of antimicrobial selection. These evolutionary trade-offs may contribute to limit the evolution of OXA-48-mediated CAZ and CAZ-AVI resistance, as well as potentially resensitize isolates toward other therapeutic alternatives.IMPORTANCE The recent introduction of novel β-lactam/β-lactamase inhibitor combinations like ceftazidime-avibactam has increased our ability to treat infections caused by multidrug-resistant Gram-negative bacteria, including carbapenemase-producing Enterobacterales However, the increasing number of cases of reported resistance to ceftazidime-avibactam is a concern. OXA-48 is a carbapenemase that has no significant effect on ceftazidime, but is inhibited by avibactam. Since isolates with OXA-48 frequently harbor extended-spectrum β-lactamases that are inhibited by avibactam, it is likely that ceftazidime-avibactam will be used to treat infections caused by OXA-48-producing Enterobacterales. Our data show that exposure to ceftazidime-avibactam can lead to changes in OXA-48, resulting in increased ability to hydrolyze ceftazidime and withstand the inhibitory effect of avibactam. Thus, resistance toward ceftazidime-avibactam among OXA-48-producing Enterobacterales should be monitored. Interestingly, the compromising effect of the amino acid substitutions in OXA-48 on other β-lactams and the effect of ceftazidime-avibactam exposure on the epidemic OXA-48 plasmid indicate that the evolution of ceftazidime-avibactam resistance comes with collateral effects.

BackgroundCarbapenem-resistant Enterobacteriaceae (CRE) represent an important global threat. The aim of this study is to describe the clinical course and outcomes of patients with CRE infections treated with ceftazidime-avibactam (CAZ-AVI) compared to patients treated with other agents.MethodsA retrospective cohort study of patients with established CRE infections from January 2017 until August 2018 was conducted. All patients who received CAZ-AVI and all cultures with carbapenem-resistant isolates were screened. We compared patients who received CAZ-AVI for CRE infections with patients who received other agents.ResultsA total of 38 consecutive patients with CRE infections were identified. Age and baseline comorbidities were similar between the two groups. The median time from admission to isolation of CRE culture was 22.5 days in the CAZ-AVI group and 17 days in the comparative group (P = 0.7). The incidence of CRE bacteremia was similar between the two groups: 7 patients (70%) in the CAZ-AVI group and 15 patients (53.6%) in the comparative group (P = 0.47). The most common type of CRE infections in both groups was hospital acquired pneumonia (HAP). Klebsiella pneumoniae was the predominant pathogen in both groups. A carbapenemase gene was detected in 35 (92%) patients; the OXA-48 gene was the predominant gene identified in 28 (74%) isolates. Eight out of ten patients in the CAZ-AVI group and fifteen out of twenty-eight in the comparative group achieved clinical remission (P = 0.14). After thirty days, all-cause mortality was observed in five patients in the CAZ-AVI group and 16 patients in the comparative group, accounting for 50 and 57% respectively.ConclusionsIn patients with established OXA-48-type CRE infection, CAZ-AVI is a reasonable alternative to standard therapy. These findings need to be confirmed in prospective studies.

Resolution is an active process that protects the host damage from inflammation responses induced by infections. Simultaneously resolving inflammation and eliminating pathogens may be effective to treat infectious diseases, but it is required to deliver therapeutics to infectious sites. Here, we proposed a strategy to incorporate RvD1 and an antibiotic (ceftazidime) in human neutrophil-membrane derived nanovesicles that can specifically target inflamed vasculature for treatment of lung infection caused by P. aeruginosa. Using the nitrogen cavitation method, we generated liposome-like nanovesicles from human neutrophil membrane. The results showed that nanovesicles loaded with RvD1 decreased cytokine levels and neutrophil lung infiltration, thus shortening the resolution intervals of lung inflammation. When RvD1 and ceftazidime were co-loaded in nanovesicles, they alleviated both inflammation and bacterial growth in the mouse lung. The studies reveal a new strategy to treat infectious diseases by designing nanoparticles to simultanesouly target host inflammatory pathways and pathogens.

BackgroundCeftolozane-tazobactam and ceftazidime-avibactam are considered first-line treatment for multidrug-resistant (MDR) and/or difficult-to-treat resistant (DTR) Pseudomonas aeruginosa infections. Conflicting results in terms of clinical outcome and resistance development emerged from real-world comparative studies. We performed a systematic review with meta-analysis to compare ceftolozane-tazobactam and ceftazidime-avibactam in the treatment of MDR/DTR P. aeruginosa infections.MethodsTwo authors independently searched PubMed-MEDLINE and Scopus databases from inception to 18 November 2025 to retrieve studies comparing ceftolozane-tazobactam versus ceftazidime-avibactam in the management of MDR/DTR P. aeruginosa infections. Clinical cure was set as the primary outcome, whereas 90-day resistance development, microbiological failure, and the 30-day mortality rate were set as the secondary outcomes. Meta-analysis was performed by pooling the odds ratios (ORs) retrieved from studies providing adjustment for confounders by means of a random-effects model with the inverse variance method. The risk of bias in the included studies was independently assessed using the RoB 2.0 and the ROBINS-I tools.ResultsAmong a total of 1193 articles screened, 6 observational studies were retrieved and included (n = 1161; 644 receiving ceftolozane-tazobactam vs 517 receiving ceftazidime-avibactam). Ceftolozane-tazobactam showed a higher clinical cure rate than ceftazidime-avibactam (n = 4; OR, 1.82 [95% confidence interval, 1.10-2.99]; I2 = 25.3%). No difference emerged in terms of microbiological failure (n = 2; OR, 0.66 [95% confidence interval, .36-1.19]; I2 = 21.9%), 90-day resistance development (n = 3; OR, 1.11 [.51-2.42]; I2 = 50.0%), or 30-day mortality rate (n = 4; OR, 1.00 [.89-1.12]; I2 = 0.0%).ConclusionsOur meta-analysis showed that, after appropriate adjustment for confounders, ceftolozane-tazobactam could grant a higher clinical cure rate than ceftazidime-avibactam in the treatment of MDR/DTR P. aeruginosa infections.