Ceftazidime-avibactam Research Articles

Evaluation of the In vitro efficacy of ceftazidime-avibactam against Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa isolates from respiratory tract cultures in intensive care units

Aims: Worldwide, an increase in multidrug resistance is observed in Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumoniae), and Pseudomonas aeruginosa (P. aeruginosa) isolates, leading to challenges in the treatment of infections caused by these pathogens. This study aims to investigate the in vitro efficacy of ceftazidime-avibactam (CZA) against isolates containing K. pneumoniae, E. coli, and P. aeruginosa strains obtained from respiratory tract samples sent from intensive care units. Methods: A retrospective analysis was conducted on 653 Enterobacterales (E. coli, K. pneumoniae) and P. aeruginosa isolates obtained from respiratory tract cultures, including sputum, tracheal aspirates, and bronchial lavage, from patients over 18 years old admitted to the intensive care units of Ordu University Training and Research Hospital between May 1, 2021, and May 1, 2024. Automated systems were used to identify the pathogens and perform antibiotic susceptibility testing. Discriptive data analysis was conducted using SPSS version 24.0. Results: A total of 653 isolates from respiratory tract samples were included in the study, consisting of 368 Enterobacteriaceae [61 E. coli (9.3%) and 307 K. pneumoniae (47%)] and 285 P. aeruginosa (43.7%). These samples were isolated from endotracheal aspirate (69.5%), sputum (27.9%), and bronchoalveolar lavage (2.6%). Among all isolates, 364 (55.7%) were found to be sensitive to carbapenems, while 289 (44.3%) were carbapenem-resistant. Of the samples, 631 (96.6%) were sensitive to CZA, while 22 (3.4%) were resistant. Although resistance to CZA was detected in 3.6% of K. pneumoniae isolates and 3.9% of P. aeruginosa isolates, no resistance was detected in E. coli. Colistin resistance was observed in 15.3% of K. pneumoniae and 5.6% of P. aeruginosa isolates, but was absent in E. coli isolates. Resistance rates to other antibiotics were as follows for E. coli, K. pneumoniae, and P. aeruginosa isolates, respectively: amikacin (3.3%, 46.6%, 8.1%), ciprofloxacin (73.8%, 73.6%, 85.9%), ceftazidime (67.2%, 77.8%, 35.8%), piperacillin-tazobactam (26.2%, 70%, 37.2%), and trimethoprim-sulfamethoxazole (52.5%, 66.4%, 0%). Conclusion: In our study, CZA was found to be the most effective antibiotic against multidrug-resistant Enterobacterales and P. aeruginosa isolates, followed by colistin.

Investigating Gram-negative bacilli isolates’ sensitivity to ceftazidime/avibactam

ABSTRACT Background: Multidrug resistant (MDR) Gram negative organisms are becoming increasingly common. Carbapenem resistant Enterobacterales (CRE) pose a major threat and necessitate the development of new antibiotics. MDR and carbapenem resistant infections, which are common in intensive care units and hospitals, lead to increased morbidity, mortality, prolonged hospital stays, and higher healthcare costs. New antimicrobials such as ceftazidime avibactam offer potential alternatives to conventional treatments such as tigecycline and colistin, which have significant side effects and limitations. Aim: This study focuses on the antibiotic susceptibility of ceftazidime/ avibactam to Gram negative bacilli found in a large number of clinical samples collected from a tertiary care facility in Netaji Subhas Medical University and Hospital, Bihta, India. Methodology: The study included 81 Gram negative bacteria isolated from patient samples. Based on the Clinical Laboratory Standards Institute guidelines mentioned in the Kirby Bauer disc diffusion method. Result and Conclusion: the results showed that ceftazidime avibactam inhibited 89.9% of the Enterobacteriaceae isolates, which was higher than the 80.3% of amikacin and the 85.1% of meropenem. Ceftazidime avibactam was effective against CRE isolates in 69.9% of cases and against MDR isolates in urine in 94% of cases, which was higher than the 40% of ceftriaxone and 94% of nitrofurantoin. The results show that ceftazidime avibactam can cure MDR and CRE infections, especially urinary tract infections, better than conventional antibiotics, which is a great help in the fight against increasing antibiotic resistance.

Ceftazidime-avibactam (CAZ-AVI) pharmacokinetics in critically ill patients undergoing continuous venovenous hemodiafiltration (CVVHDF)

PurposeTo investigate the pharmacokinetics (PK) of ceftazidime-avibactam (CAZ-AVI) in critically ill patients undergoing continuous venovenous hemodiafiltration (CVVHDF), and compare with a general phase III trial population. MethodsA prospective PK study was conducted in critically ill patients who received CVVHDF for acute kidney injury, treated with CAZ-AVI (1000/250 mg or 2000/500 mg q8h). Plasma and CVVHDF-circuit samples were collected to determine CAZ-AVI concentrations. Individual PK parameters at steady-state were estimated using non-compartmental analysis. For visual comparison, plasma concentrations from CVVHDF patients were overlaid with simulated data from patients not receiving CVVHDF based on previously developed population PK models. ResultsA total of 35 plasma samples and 16 CVVHDF-circuit samples were obtained from four patients, with two patients sampled on two separate occasions. Median total clearance and volume of distribution were 4.54 L/h and 73.2 L for CAZ and 10.5 L/h and 102 L for AVI, respectively. Median contribution of CVVHDF to total clearance was 19.8% for CAZ and 5.3% for AVI. Observed CAZ-AVI PK profiles were generally within the 90% confidence interval of model predictions, but the observed concentrations were notably lower early (0-2 h) and higher later (4-8 h) in the dosing interval, suggesting a higher volume of distribution. ConclusionsThese results suggest that the CAZ-AVI dose regimens used in this study can be applicable in critically ill patients undergoing CVVHDF, despite the different shape of the PK profiles observed in this population. Further research with a larger patient cohort is warranted to validate and refine these findings.

Ceftazidime-avibactam for the treatment of febrile neutropenia in HSCT recipients and acute leukemia patients post induction chemotherapy

Febrile neutropenia is a major complication in patients with acute leukemia or those undergoing hematopoietic stem cell transplantation (HSCT). Understanding patient characteristics and susceptibility patterns in febrile neutropenia is essential for appropriate antimicrobial therapy. First-line agents should have Pseudomonas aeruginosa coverage, but with the increase in multi-drug resistant organisms, ceftazidime-avibactam has emerged as a new therapeutic option. This retrospective case–control study included 300 admissions (143 patients) between January 2009 and December 2022. Patients with hematologic neoplasms and patients that underwent HSCT, satisfying the criteria of febrile neutropenia and treated with ceftazidime-avibactam (CAZAVI) were included and compared to controls who received the best available therapy (BAT). A bivariate regression model explored independent predictors of septic shock and mortality. Patients who received CAZAVI were more likely to have a microbiologically documented infection (59.0% vs. 28.3%). Complications were significantly more frequent in the CAZAVI group, with sepsis being the most common (59.0%). Multivariable logistic regression analysis showed that receiving CAZAVI was an independent risk factor for both sepsis and mortality (aOR 6.33 [95% CI 2.81–14.30] and 7.82 [2.63–23.26], respectively). Knowing common organisms and patterns of resistance, with an understanding of risk factors for morbidity and mortality, is crucial for the antimicrobial management of febrile neutropenia. Further studies on the effectiveness of CAZAVI in this population are needed.

The in vitro synergistic and antibiofilm activity of Ceftazidime/avibactam against Achromobacter species recovered from respiratory samples of cystic fibrosis patients.

Achromobacter spp. may form biofilm in patients' respiratory tracts and cause serious infections. This research examined the bactericidal and synergistic effects of ceftazidime/avibactam (CZA) alone and in combination with different antibiotics against Achromobacter spp. MICs of 52 Achromobacter spp. were determined by broth microdilution. In-vitro time-kill curve experiments assessed CZA's bactericidal and synergistic properties alone and in combination with other antibiotics. Moreover, the antibiofilm activity of CZA alone or in combination with the antibiotics was assessed with using microplate method. Based on MIC90 values, CZA exhibited four times greater in-vitro activity against tested strains than ceftazidime. The most effective agent was meropenem, with a 92% susceptibility level on the tested strains. On the other hand, ciprofloxacin was found to be bactericidal at both 1 × and 4xMIC concentrations. CZA, chloramphenicol and meropenem were observed to have bactericidal effects alone at 4xMIC concentrations against the tested isolates. CZA + CS and CZA + MEM showed synergy in three out of five and two out of five strains tested at 1xMIC, respectively. Furthermore, the pairing of CZA with colistin, CZA with meropenem and CZA with ciprofloxacin exhibited a synergistic impact at 4xMIC. Moreover, combination therapy CZA with the tested antibiotics showed reduced biofilm formation in a concentration-dependent manner at 24h. The outcomes of this research also suggest that CZA plus colistin, meropenem, or ciprofloxacin were more productive against Achromobacter strains. To our knowledge, this is the first article to evaluate the synergistic and antibiofilm activities of CZA alone or in combination with different agents against Achromobacter species.

Comparing ceftazidime/avibactam and polymyxin B for treating carbapenem-resistant organisms infections: a propensity score-matched retrospective cohort study.

Comparative studies of Ceftazidime/avibactam(CAZ/AVI) versus polymyxin B (PMB) for carbapenem-resistant organisms (CRO) infections are limited. We aims to compare the efficacy and safety of CAZ/AVI and PMB in treating CRO infections. This single-center, propensity score-matched (PSM) retrospective cohort study involved adult patients with CRO infections. Patients who received a CAZ/AVI-based regimen were included in the cohort group, while those prescribed with a PMB-based regimen were in the control group. The primary outcome was 28-day all-cause mortality. Among 298 eligible patients, 96 patients in each group were included in the PSM cohort. The CAZ/AVI group showed no improvement in 28-day or 14-day all-cause mortality, nor in 14-day clinical response, compared to the PMB group. However, the CAZ/AVI-based regimen showed higher 14-day clinical response rates than PMB-based regimen in subgroups of carbapenem-resistant Pseudomonas aeruginosa (CRPA) infections and monotherapy. The CAZ/AVI group achieved more CRO eradication than the PMB group (crude OR 1.658; 95% CI, 1.108-2.480; P=0.014; adjusted OR 1.718; 95% CI, 1.055-2.798; P=0.030). This advantage in CRO eradication with CAZ/AVI was consistent in most subgroups including septic shock, bloodstream infection and lower respiratory tract infection. The CAZ/AVI and PMB groups had comparable nephrotoxicity (crude OR 0.577; 95% CI, 0.306-1.089; P=0.090, adjusted OR, 0.741; 95% CI, 0.361-1.521; P= 0.414). CAZ/AVI-based and PMB-based regimens demonstrated similar clinical efficacy and nephrotoxicity in treating CRO infections. However, CAZ/AVI was superior to PMB in CRO eradication and treating CRPA infections. CAZ/AVI monotherapy was more effective than PMB monotherapy for CRO infections. ChiCTR2300078790 prospectively registered on Dec 19, 2023 (https://www.chictr.org.cn).

In-vitro activity of the novel β-lactam/β-lactamase inhibitor combinations and cefiderocol against carbapenem-resistant Pseudomonas spp. clinical isolates collected in Switzerland in 2022.

To evaluate the in-vitro activity of the novel commercially-available drugs, including meropenem-vaborbactam (MEV), ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T), imipenem-relebactam (IPR) as well as cefiderocol (FDC), against carbapenem-resistant Pseudomonas spp. (CRP) isolates. All CRP isolates collected at the Swiss National Reference Laboratory (NARA) over the year 2022 (n = 170) have been included. Most of these isolates (n = 121) were non-carbapenemase producers. Among the 49 carbapenemase producers, 47 isolates produced metallo-β-lactamases (MBL) including NDM-1 (n = 11), VIM-like (n = 28), IMP-like (n = 7), and both NDM-1 and VIM-2 (n = 1) and two isolates produced the class A carbapenemase GES-5. Susceptibility testing was determined by broth microdilution method (BMD), or disk diffusion test, and results interpreted following EUCAST guidelines. The susceptibility rates for MEV, CZA, C/T and IPR were found to be 41%, 45%, 59% and 58%, respectively, for the whole set of isolates tested. Among non-carbapenemase producers, susceptibility rates for these β-lactam/β-lactamase inhibitors (BL/BLI) combinations were higher, determined at 55%, 61%, 83%, and 82%, respectively. The overall susceptibility of carbapenemase-producing Pseudomonas spp. to novel BL/BLI was relatively low, while 80% of these isolates demonstrated susceptibility to FDC, with a similar proportion (79%) observed among MBL producers. A total of 10 MBL-producing isolates (6%), mainly NDM-1, were found to exhibit resistance to all drugs tested, with the exception of colistin. FDC exhibited an excellent in-vitro activity against this collection of CRP recovered from Switzerland in 2022, including MBL producers. The new BL/BLI combinations displayed significant activity against non-carbapenemase CRP, with IPR and C/T showing the highest susceptibility rates.

Characterization of a Novel KPC-2 Variant, KPC-228, Conferring Resistance to Ceftazidime-Avibactam in an ST11-KL64 Hypervirulent Klebsiella pneumoniae.

With the widespread clinical use of ceftazidime-avibactam (CZA), reports of resistance have increased continuously, posing immense threats to public health worldwide. In this study, we explored the underlying mechanisms leading to the development of CZA resistance in an ST11-KL64 hypervirulent Klebsiella pneumoniae CRE146 that harbored the blaKPC-228 gene. Twelve carbapenem-resistant Klebsiella pneumoniae (CRKP) strains were isolated from the same patient, including K. pneumoniae CRE146. Whole genome sequencing (WGS), phylogenetic analysis, blaKPC gene cloning and pACYC-KPC construction assays were conducted to further explore the molecular mechanisms of CZA resistance. Quantitative siderophore production assay, string test, capsule quantification and Galleria mellonella in vivo infection model were applied to verify the level of pathogenicity of K. pneumoniae CRE146. This strain carried key virulence factors, iutA-iucABCD operon and rmpA gene. Compared to the wild-type KPC-2 carbapenemase, the novel KPC-228 enzyme exhibited a deletion of four amino acids in the Ω-loop (del_167-170_ELNS). In addition, the emergence of CZA resistance appeared to be associated with drug exposure, and we observed the in vivo evolution of wild-type KPC-2 to KPC-228 and then the reversion to its original wild-type KPC-2. The blaKPC-228 gene was located within the double IS26 flanking the ISKpn6-blaKPC-228-ISKpn27 core structure and carried on an IncFII/IncR-type plasmid. Notably, CRE146 exhibited high-level resistance to CZA (64/4 mg/L) but increased susceptibility to meropenem (1 mg/L) and imipenem (0.5 mg/L) respectively. PACYC-KPC plasmids were constructed and expressed in K. pneumoniae ATCC13883. Compared to K. pneumoniae ATCC13883 harboring blaKPC-2, K. pneumoniae ATCC13883 harboring blaKPC-228 exhibited a high-level resistance to CZA (32/4 mg/L) and increased susceptibility to meropenem (1 mg/L) and imipenem (0.5 mg/L). Interestingly, K. pneumoniae ATCC13883 harboring blaKPC-228 showed a significant decrease in their resistance to all β-lactamases tested except CZA and ceftazidime. In conclusion, we reported a novel KPC variant, KPC-228, in a clinical ST11-KL64 hypervirulent K. pneumoniae strain, which conferred CZA resistance, possibly through enhancing ceftazidime affinity and reducing avibactam binding. The blaKPC-228 can mutate back to blaKPC-2 under carbapenem pressure, which was very detrimental to clinical treatment. This strain carried both resistance and virulence genes, posing a major challenge in clinical management.

Investigation of the synergistic effect ofceftazidime-avibactam and aztreonam combination on carbapenem-resistant Klebsiella pneumoniae isolates with 3 different methods.

Treatment options are limited for infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) isolates due to the production of metallo-β-lactamase (MBL). The ceftazidime-avibactam (CZA)/ aztreonam (ATM) combination represents a new therapeutic approach in MBL-positive isolates. Our study aims to determine distribution of carbapenemase genes in CRKP isolates and to investigate the in vitro synergistic effect of the CZA/ATM combination.Our study included 48 CRKP strains isolated from various clinical samples. Identification was performed using MALDI-TOF MS (bioMérieux, France), and susceptibility was tested with Vitek-2 (bioMérieux). The susceptibility to CZA and ATM was determined using CZA 30/20 µg and ATM 30 µg (Oxoid™,UK) disks. Carbapenemase genes VIM, NDM, IMP, KPC, OXA-23, OXA-58, OXA-48, and OXA-51 were investigated in only 44 isolates using the Bio-Speedy Carbapenem resistance qPCR (Bioexen, Turkiye) kit. Synergy testing was evaluated with double disk diffusion, gradient strip (bioMérieux)/disk diffusion, and broth disk elution methods.Out of 48 carbapenem-resistant isolates, 40 (83.3%) isolates showed resistance to CZA and 46 (95.8%) to aztreonam. Synergy was detected with all three methods in all isolates identified as resistant to CZA, CZA-sensitive isolates were not included in this evaluation. The most frequently detected carbapenemase genes were NDM+OXA-48, found in 28 (63.6%) of the isolates.Although the NDM+OXA-48 coexistence predominates in our center, in vitro synergy between CZA and ATM was detected in all of CZA-resistant isolates. Performing the CZA+ATM synergy test and reporting the result is crucial for choosing appropriate treatment in CRKP infection.

Overexpression of KPC contributes to ceftazidime-avibactam heteroresistance in clinical isolates of carbapenem-resistant Klebsiella pneumoniae.

Ceftazidime-avibactam (CZA) is one of the effective antibiotics used for the treatment of carbapenem-resistant Klebsiella pneumoniae (CRKP) infections, but its resistance rate has increased recently. Previous studies have focused on the mechanisms of CZA resistance, while its heteroresistance in CRKP remains poorly understood. This study aimed to investigate the characteristics and mechanisms of CZA heteroresistance in CRKP isolates. A total of 311 CRKP clinical strains were collected in China from 2020 to 2022. The MICs of CZA and other antibiotics against K. pneumoniae were determined by broth microdilution method. The occurrence of CZA heteroresistance in CRKP was evaluated with population analysis profiling (PAP) and their characteristics were detected by polymerase chain reaction (PCR). The underlying mechanism of CZA heteroresistance in CRKP strains was investigated by molecular sequencing, whole genome sequencing (WGS), quantitative real-time PCR (qRT-PCR), and in vitro functional experiments. Strategies for preventing the emergence of CZA heteroresistance and alternative treatment options for strains exhibiting CZA heteroresistance were further explored. Thirty-four (12.4%) CZA-susceptible CRKP isolates were found to exhibit heteroresistance to CZA. All heteroresistant strains belonged to KPC-2 (97.1%) or KPC-3 (2.9%). The dominant multilocus sequence typing (MLST) was ST11 (64.7%) and the prevalent capsular serotypes were KL47 (38.2%) and KL64 (32.4%). Imipenem-relebactam and meropenem-vaborbactam still exhibited excellent antimicrobial activity against the resistant subpopulations of CZA heteroresistant strains. No significant mutations were found in KPC, OmpK35/36, PBP2/3, and LamB in resistant subpopulations. The relative expression and copy number of bla KPC were significantly upregulated in 47.1% and 35.3% of the resistant subpopulations compared with their parental strains, respectively. Silencing bla KPC expression significantly decreased the CZA MIC in resistant subpopulations with high bla KPC expression and hindered the emergence of CZA heteroresistance in their parental strains. Moreover, increasing the avibactam concentration to 8 or 16 mg/L or combining CZA with 0.5 × MIC tigecycline significantly suppressed the formation of CZA heteroresistance (P<0.05). In conclusion, we identified the occurrence of CZA heteroresistance in CRKP in China, which was attributed to the overexpression of KPC. Increasing the concentration of avibactam or combining CZA with tigecycline could effectively prevent the development of CZA heteroresistance in CRKP isolates. Besides, imipenem-relebactam and meropenem-vaborbactam may serve as alternative therapeutic options when clinical isolates with CZA heteroresistance are detected.

Susceptibility pattern of Ceftazidime-Avibactam against multi drug resistant gram-negative rods

This study was conducted to evaluate the susceptibility pattern of ceftazidime avibactam against multi drug resistant gram negative rods. This prospective study cross sectional study conducted in Microbiology Section of Dow Diagnostic Reference and Research Laboratory, Dow University of Health Sciences, Karachi, Pakistan. Identification of isolates was done in accordance with the standard bacteriological technique, and were distinguished based on gram staining, colony morphology and biochemical tests. Antibiotic susceptibility testing (AST) was performed on Muller-Hinton agar by Kirby-Bauer Disk Diffusion method in accordance with the Clinical Laboratory Standard Institute (CLSI) guidelines. Good sensitivity of Lactose fermenters (Escherichia coli, Klebsiella pneumoniae and Enterobacter) were observed against Ceftazidime avibactam. Pseudomonas aeruginosa exhibited 42% resistance in all clinical samples. Proteus species and Serratia have shown high resistance in our study. Our observations showed the persistence of high ceftazidime avibactam activity against pathogenic and multi drug resistant strains of Enterobacterales and Non lactose fermenting bacteria.

Ceftazidime-Avibactam for the Treatment of Carbapenem-Resistant Klebsiella Pneumoniae Infection: A Retrospective, Single Center Study.

Ceftazidime-avibactam (CZA), a novel beta-lactam/beta-lactamase inhibitor, plays an important role in the threat of emerging carbapenem-resistant Enterobacterales (CRE) infection. The study aims to analyze the clinical effectiveness and factors influencing treatment response to CZA for carbapenem-resistant Klebsiella pneumoniae (CRKP) infections. From February 2020 to December 2021, patients with CRKP infection treated with CZA were enrolled in this retrospective, single-center cohort study in northern Taiwan. The primary outcome was 28-day survival rate. The secondary outcomes were clinical success, and microbiological cure. Multivariate regression analysis was used to evaluate factors associated with 28-day survival. A total of 142 patients treated with CZA alone (n=82) or in combination therapy (n=60) were included. We found 28-day survival rate, microbiological cure, and clinical success rate were 78% (111/142), 86% (87/101), and 48% (63/132), respectively. In multivariate analysis, there were no significant differences in 28-day survival between monotherapy group and combination therapy group (P=0.424). A relative lower microbiological cure rate can be observed in lower respiratory tract infection from univariate analysis (P=0.07). In addition, significantly better survival was observed in patients with creatinine clearance rate (CCr) ≥50 mL/min than CCr <50 mL/min (P=0.005). CZA is an effective and important treatment option for CRKP infection even when it is treated as monotherapy. In patients with impaired renal function, a potential impact of CZA dose adjustments on poor survival outcomes has been observed, indicating the need for further research to determine optimal renal dose adjustment strategies.

Ceftazidime-avibactam versus other antimicrobial agents for treatment of Multidrug-resistant Pseudomonas aeruginosa: a systematic review and meta-analysis.

Multidrug-resistant Pseudomonas aeruginosa (MDR-PA) is a life-threatening infection with limited treatment options. This is the first meta-analysis of recently published data to compare the clinical outcomes of ceftazidime-avibactam (CAZ-AVI) with other antimicrobial agents in treating MDR-PA infections. Systematic review and meta-analysis. PubMed, Embase and the Cochrane Library have been systematically reviewed, for publications in the English language, from database inception to July 2023. Studies comparing CAZ-AVI outcomes with other antimicrobial agents were included. In-hospital mortality & 30-day mortality were assessed as the main outcomes. Literature screening, data extraction, and the quality evaluation of studies were conducted by two researchers independently, with disagreements resolved by another researcher. The Newcastle-Ottawa Scale was used to assess the bias risk for the included studies. Review Manager V.5.4 was employed for the meta-analysis. The meta-analysis included four retrospective studies, enrolling 1934 patients. The CAZ-AVI group demonstrated significantly lower in-hospital mortality (risk ratio (RR) = 0.60, 95% CI:0.37-0.97, I2 = 74%, p = 0.04) in three studies with 1444 patients and lower 30-day mortality, in 438 patients from three studies (RR = 0.54, 95% CI:0.28-1.05, I2 = 67%, p = 0.07). No significant difference in clinical success, microbiological success, length of hospital, and ICU stay was observed. This meta-analysis demonstrated that CAZ-AVI treatment significantly lowered in-hospital mortality compared with other antimicrobial agents in MDR-PA infections. However, the analysis only included a few observational studies and high-quality, randomized controlled trials are needed to investigate further the scope of CAZ-AVI in MDR-PA infections.

Safety evaluation of ceftazidime/avibactam based on FAERS database.

To explore adverse event (AE) signals of Ceftazidime/avibactam (CZA) based on the FDA Adverse Event Reporting System (FAERS) database. AE reports primarily associated with CZA were retrieved from the FAERS database from the second quarter of 2015 to the second quarter of 2023. Signal detection was conducted using the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS) methods. A total of 750 AEs reports with CZA as the preferred suspected drug were obtained, identifying 66 preferred terms (PTs) involving 24 system organ classes (SOCs). Besides, the AEs already mentioned in the drug label, this study also revealed some new, clinically valuable potential AEsignals, such as Cholestasis (n = 14, ROR 29.39, PRR 29.15, IC 3.34, EBGM 29.11), Drug-induced liver injury (n = 8, ROR 9.05, PRR 9.01, IC 2.25, EBGM 9.01), Hepatocellular injury (n = 7, ROR 13.90, PRR 13.84, IC 2.41, EBGM 13.63), Haemolytic anaemia (n = 5, ROR 24.29, PRR 24.22, IC 2.42, EBGM 40.53), etc. Additionally, AE signals with higher intensity were identified, such as Hypernatraemia (n = 5, ROR 40.73, PRR 40.61, IC 2.31, EBGM 24.19), Toxic epidermal necrolysis (n = 4, ROR 11.58, PRR 11.55, IC 1.89, EBGM 11.54). Therefore, special vigilance for these potential AEs is warranted when using CZA clinically. This study highlights the potential AEs and risks associated with the clinical use of CZA, particularly the risks related to Cholestasis, Drug-induced liver injury, Haemolytic anaemia, Hypernatraemia, and Toxic epidermal necrolysis.

Clinical characteristics and mortality risk factors of premature infants with carbapenem-resistant Klebsiella pneumoniae bloodstream infection

Due to the resistance of carbapenem-resistant Klebsiella pneumoniae (CRKP) to most antibiotics, CRKP treatment is challenging, which results a high mortality rate. CRKP infection poses a significant challenge for infection management and treatment, especially among neonates and premature infants. Therefore, it is important to understand the clinical characteristics of CRKP bloodstream infection (BSI) in premature infants and identify the related risk factors for death. This study aims to explore and analyze the clinical characteristics and risk factors affecting mortality of BSI caused by CRKP in premature infants. A retrospective study was conducted in a Children’s Hospital in Henan to analyze clinical data of premature infants with CRKP BSI admitted from January 2015 to December 2022. Univariate and multivariate logistic regression models were utilized to investigate risk factors affecting mortality. Receiver operating characteristic curves were employed to evaluate the predictive value of different indicators on mortality, and differences in area under the curve (AUC) were compared using Stata 17 SE. A total of 96 premature infants with CRKP BSI were enrolled, including 70 patients in the survival group and 26 in the death group. At the onset of infection, 69 (71.9%) patients exhibited persistent tachycardia (heart rate > 180 beats/min), 61 (63.5%) had fever, and 59 (61.4%) experienced apnea episodes. Concurrent meningitis (OR 9.588, 95% CI 1.401–57.613, P = 0.021), concurrent necrotizing enterocolitis (NEC) (OR 7.881, 95% CI 1.672–73.842, P = 0.032), and the maximum vasoactive-inotropic score (VIS) value within 48 h of onset (OR 1.467, 95% CI 1.021–1.782, P = 0.001) were identified as independent risk factors for mortality. The univariate analysis showed that ceftazidime-avibactam (CAZ/AVI) treatment and appropriate early antimicrobial treatment were significantly associated with survival (P < 0.05). The combined predictive AUC for mortality in premature infants with CRKP BSI using the maximum VIS value ≥ 52.5 points within 48 h of onset, concurrent NEC, and purulent meningitis was 0.931 (95% CI 0.856–1.000) with a sensitivity of 92% and specificity of 85.7%. CRKP BSI was a significant mortality risk in premature infants. It is crucial to administer proper antimicrobial therapy in order to increase survival rates of the patients. CAZ/AVI has the potential to improve outcomes in this particular population; however, further research is required to evaluate the effectiveness of specific treatment in premature infants.

National Multicenter Study on the Prevalence of Carbapenemase-Producing Enterobacteriaceae in the Post-COVID-19 Era in Argentina: The RECAPT-AR Study.

A total of 182 hospitals participated by submitting Enterobacterales clinical isolates to the National Reference Laboratory (NRL) during the first three weeks of November 2021. Inclusion criteria were defined as an ertapenem MIC ≥ 0.5 mg/L, a zone diameter ≤ 22 mm. Carbapenemase genes and those coding for major extended-spectrum β-lactamases were molecularly characterized using multiplex PCR at the NRL. Antibiotic susceptibility testing followed international standards (CLSI and EUCAST). The NRL analyzed 821 Enterobacterales isolates. Metallo-β-lactamase (MBL, 42.0%) and KPC (39.8%) accounted for 81.8% of carbapenemases, followed by OXA-163 (7.4%), a variant of OXA-48 with additional activity against extended-spectrum cephalosporins, and enzyme combinations (8.3%). These combinations included NDM plus KPC (3.4%), OXA-163 plus KPC (2.4%), and OXA-163 plus NDM (2.1%). Klebsiella pneumoniae was the main species recovered, representing 76% of the isolates. According to the carbapenemase classes or combinations, tigecycline exhibited a susceptibility range of 33-83%, fosfomycin 59-81%, colistin 27-78%, and amikacin 17-81%. Ceftazidime-avibactam (CZA) and imipenem-relebactam (IMR) showed 92% and 98% susceptibility against serine carbapenemases, respectively. Meanwhile, aztreonam-avibactam (AZA) exhibited 96-98% susceptibility against all carbapenemase classes. A new epidemiological landscape has emerged, characterized by the equivalent circulation of NDM and KPC. K. pneumoniae remains the primary species responsible for their dissemination. The co-production of carbapenemase combinations, particularly KPC plus NDM, was confirmed, mainly in K. pneumoniae. High activity was observed for AZA against MBLs and for CZA and IMR against KPC and OXA-163 carbapenemases.

Ceftazidime–avibactam for the Treatment of Intra-abdominal Sepsis and Urosepsis: A Retrospective Hospital-based Study in India

Abstract Background: In India, microbial susceptibility to antibiotics has been gradually decreasing, thus making treatment of multidrug-resistant bacterial infections challenging. We aimed to assess the effectiveness of ceftazidime–avibactam in patients with intra-abdominal sepsis or urosepsis. Methods: This hospital-based, single-center retrospective study was conducted between April 2020 and March 2022 using data from inpatient records. Outcomes included inpatient mortality, clinical success/failure, and microbiological cure/failure measured on day 14/end of treatment, length of hospitalization and intensive care unit (ICU) admission, treatment and infection characteristics, recurrence within 30 days, and healthcare resource utilization. Descriptive statistics were used for data analysis. Results: Data from 46 patients (mean age = 65.2 ± 14.5 years, 73.9% male) were included. Ceftazidime–avibactam treatment was initiated within 5 days of hospitalization in 51.2% of patients. The median (range) duration of treatment was 8 (1, 20) days, and the average daily dose was 4.6 g. Inpatient and 30-day all-cause mortality rates were 41.5% and 17.1%, respectively. We observed clinical success, defined a priori, by day 14 in 58.5% of patients and microbiological cure in 61.3%. Most patients (97.0%) did not have recurrent infections. The median (range) length of hospitalization and ICU admission was 15.5 (3, 63) days and 11 (2, 63) days, respectively. Most patients (85.7%) utilized various healthcare resources during hospitalization. Conclusion: Among patients with available data, most showed clinical success (58.5%) and microbiological cure (61.3%) within 14 days of treatment initiation with ceftazidime–avibactam, with nearly no recurrence of infection, indicating treatment effectiveness in patients with intra-abdominal sepsis or urosepsis in an Indian hospital setting.

Analysis of the virulence of a lethal, carbapenem-resistant hypervirulent KPC-33-producing Klebsiella pneumoniae: Emergence of ST11-KL64 hv-CRKP in ICU

ObjectiveHypervirulent and carbapenem-resistant Klebsiella pneumoniae (hv-CRKP) poses a serious threat to public health. Here, we analyse a case of systemic infection caused by a hv-CRKP, which ultimately led to the patient's death from sepsis. And a total of 30 CRKPs were analyzed to elucidate the molecular epidemiological features of CRKPs in the hospital, and to provide a basis for clinical anti-infective therapy. MethodsIn this case, a total of 7 K. pneumoniae strains were isolated from the blood, sputum, urine, and feces of the patient. The Vitek-2 compact system was used to identify the strains and perform antimicrobial susceptibility testing. Biofilm formation, siderophore production assays and Galleria mellonella infection model were used to verify the virulence phenotypes of the strains in the case. Whole-genome sequencing was conducted on the four hv-CRKP isolated from different samples in the case and 26 other CRKP collected in our hospital from September to November in 2022, using the Illumina Hiseq 6000 high-throughput sequencing platform to analyse the resistance and virulence genes. ResultsIn the case, after 7 days of treatment with ceftazidime-avibactam (CZA), the resistance profile of the strains changed. The strain that was initially sensitive to CZA developed to resistant, resistant to imipenem (IPM) developed to sensitive, and resistant to meropenem (MEM) developed to intermediate. Whole-genome sequencing revealed that the four strains in the case were all ST11-KL64 K. pneumoniae, and the change in resistance phenotype was due to the mutation from blaKPC-2 to blaKPC-33. KPN7 had a total of six plasmids, with siderophore-related genes iucABCD and iutA, and mucoid phenotype-related gene rmpA2 located on plasmid p4-KPN7; resistance genes blaKPC-33, blaTEM-1B, and blaCTX-M-65 located on plasmid p5-KPN7; and virulence genes fim, irp, iutA, and ybt located on the chromosome. Biofilm formation and siderophore production assays confirmed that the seven K. pneumoniae strains isolated in this case had strong biofilm formation and siderophore production capabilities. Galleria mellonella Infection Model showed that KPN4 and KPN7 was phenotypically highly virulent and KPN7 performed lower virulence compared to KPN4. Apart from the 4 hv-CRKP strains, other 26 CRKP strains all carried blaKPC-2, and 69.2% (18/26) were ST-11 and 30.8%(8/26) were ST-15. And 83.3% (15/18) were ST11-KL64 strains, followed by ST11-KL25 strains 11.1%(2/18) and ST11-KL47 strain 5.6%(1/18). All the eight ST-15 strains were KL-19. ConclusionThe ST11-KL64 hv-CRKP clone spread widely in ICU carried numerous resistance and virulence genes, and under antibiotic pressure, they easily underwent mutations resulting in changes in resistance phenotypes, especially in mutations of blaKPC-2 gene in acquiring resistance to CZA. Therefore, clinical attention should be paid to such strains, and the use of antibiotics should be adjusted promptly based on the susceptibility of the strains to antimicrobial agents.

Efficacy of ceftazidime-avibactam with or without polymyxin for carbapenem-resistant Klebsiella pneumoniae infections after initial treatment with polymyxin.

Although polymyxins are a suboptimal option for difficult-to-treat resistant infections, they are still preferred as the first-line treatment, especially in low- and middle-income countries. This study assesses the efficacy of ceftazidime-avibactam (CAZ-AVI) following polymyxin B failure in patients with carbapenem-resistant Klebsiella pneumoniae (CRKP) infections. We retrospectively reviewed cases of infections caused by CRKP in adults who received CAZ-AVI as salvage therapy. Clinical features and outcomes were described, and a logistic regression model was used to assess the risk factors associated with in-hospital crude mortality. One hundred and six patients were included in this study. The median age was 56 years. The most common infectious sites were lung. The patients received CAZ-AVI as salvage therapy for a median duration of 9 days following initial treatment with polymyxin B (median, 12.5 days). Also, 91 (85.8%) patients received CAZ-AVI combination therapy, and 34 (32.1%) patients received CAZ-AVI in combination with polymyxin B. The rate of in-hospital crude mortality was 25.5% (27/106), with the highest rate observed in patients treated with regimens containing polymyxin B (41.2%; 14/34). Therapeutic response was observed in 81 (76.4%) patients, with microbiological eradication achieved in 77.1% (74/96) of cases. Multivariable analysis identified that the length of intensive care unit stays, the sequential organ failure assessment (SOFA) score at CAZ-AVI withdrawal, and regimens containing polymyxin B were independently associated with in-hospital mortality, whereas the duration of CAZ-AVI treatment was independently associated with survival. CAZ-AVI salvage therapy demonstrated improved survival outcomes in patients who experienced failure with polymyxin B therapy.IMPORTANCEFor patients with carbapenem-resistant Klebsiella pneumoniae (CRKP) infections, published experience with salvage therapy is limited after the failure of polymyxin-based initial therapy. Here, we found that ceftazidime-avibactam salvage therapy for patients with CRKP infections offers benefit in mortality.

Ceftazidime-avibactam treatment dilemma of blaKPC−2-containing Klebsiella pneumoniae due to the development of co-existence of mixed strains carrying blaKPC−2 or blaKPC−33 in lung transplant recipients

BackgroundCarbapenem-resistant Klebsiella pneumoniae (CRKP) poses a significant threat to immunocompromised populations, including lung transplant recipients. This study investigates mixed CRKP strains carrying either blaKPC−2 or blaKPC−33 following ceftazidime-avibactam (CAZ/AVI) exposure, particularly in the context of lung transplantation. Mixed CRKP strains with shifting resistance phenotypes were frequently identified in patients exposed to CAZ/AVI. We aimed to elucidate the transitional state of blaKPC variants by selecting CAZ/AVI-sensitive and -resistant CRKP strains from a lung transplantation patient.MethodsThe blaKPC-variant-carrying CRKP strains were collected from lung transplant recipients exposed to CAZ/AVI in less than two years. Antibiotic susceptibility testing (AST) was conducted using microbroth dilution, and whole-genome sequencing (WGS) was used to identify genotypes and resistance mechanisms. Limiting dilution, drop-plate, and in vitro induction experiments determined blaKPC-variant changes during CAZ/AVI administration. qPCR primers/probes were designed to identify blaKPC−2 mutations.ResultsAmong 104 lung transplant recipients infected by blaKPC-harboring CRKP strains and receiving CAZ/AVI, 10 (9.6%) experienced changing resistance phenotypes. The limiting dilution method found that Patient 10’s CRKP strains carried either blaKPC−2 or blaKPC−33. The drop-plate experiment showed differing growth patterns on CAZ/AVI mediums. The in vitro induction experiment demonstrated shifting from blaKPC−2 to blaKPC−33.ConclusionsThe study identified a “transitional state” of the mixed CRKP strains carrying either blaKPC−2 or blaKPC−33 in CAZ/AVI-exposed patients. Molecular diagnostics are crucial for identifying mixed strains and the transitional state of blaKPC variants, guiding treatment decisions in this complex landscape.