Ceftazidime-avibactam Combination Research Articles

The Use of Ceftazidime–Avibactam in a Pediatric Intensive Care Unit—An Observational Prospective Study

Background/objectives: Infections caused by carbapenem-resistant Enterobacterales (CRE) are progressively increasing in Pediatric Intensive Care Units (PICUs). Its treatment is challenging due to the lack of pediatric trials. CRE infections are associated with significantly poor outcomes, but ceftazidime–avibactam (CAZ-AVI) has been reported to be successful in their treatment. This study aimed to describe the use and outcome of CAZ-AVI in a PICU. Results: Ten patients were included, with 12 episodes of clinical suspicion or confirmed multidrug-resistant (MDR) bacterial infections treated with CAZ-AVI for surgical prophylaxis, suspicion of sepsis, pneumonia, and surgical wound infection. Of these patients, 80% received empirical treatment because of previous MDR bacterial colonization, and 60% were administrated combination therapy with aztreonam for Metallo-β-Lactamases (MBL)strains. No bacteria were resistant to CAZ-AVI. The average duration of the treatment was 3 days when cultures turned negative and 7 days when MDR bacteria were isolated. Methods: This was an observational prospective study of children treated with CAZ-AVI in the PICU of a tertiary hospital in 2022. Epidemiological, clinical, microbiological, and outcome data were collected. Conclusions: The most frequent use of CAZ-AVI in our PICU was the short-term empirical treatment for patients with previous MDR bacterial colonization and clinical suspicion of bacteremia or sepsis. Furthermore, the combination of CAZ-AVI plus aztreonam could be more effective for CRE infections, especially type Ambler class B as MBL strains.

Testing new waters in management of Stenotrophomonas maltophilia blood stream infection in a post cardiac surgery patient

Hospital acquired infections are the most common non-cardiac complications after cardiac surgery. Organisms commonly found in this cohort of patients include Klebsiella spp, Escherichia coli, Pseudomonas spp, Staphylococcus aureus, Coagulase negative Staphylococcus and Enterococcus spp etc. We hereby present a case of post cardiac surgery patient presenting with Stenotrophomonas maltophilia bloodstream infection. Combination of ceftazidime-avibactam (CZA) and aztreonam(AT) was used as inactivity was exhibited to primary panel of drugs. Broth disc elution testing was done to exhibit synergy between CZA and AT. This case highlights the growing need for active interaction between the treating physician and the microbiologist.

Investigation of Citrobacter freundii clinical isolates in a Chinese hospital during 2020-2022 revealed genomic characterization of an extremely drug-resistant C. freundii ST257 clinical strain GMU8049 co-carrying blaNDM-1 and a novel blaCMY variant.

The emergence of multidrug-resistant Citrobacter freundii poses a significant threat to public health. C. freundii isolates were collected from clinical patients in a Chinese hospital during 2020-2022. An unusual strain, GMU8049, was not susceptible to any of the antibiotics tested, including the novel β-lactam/β-lactamase inhibitor combination ceftazidime-avibactam. Whole-genome sequencing (WGS) revealed that GMU8049 harbors a circular chromosome belonging to the rare ST257 and an IncX3 resistance plasmid. Genomic analysis revealed the coexistence of two β-lactamase genes, including plasmid-mediated blaNDM-1 and chromosomal blaCMY encoding a novel CMY variant, combined with an outer membrane porin deficiency, which may account for the extreme resistance to β-lactams. Conjugation experiment confirmed that the blaNDM-1 resistance gene located on pGMU8049 could be successfully transferred to Escherichia coli EC600. The novel CMY variant had an amino acid substitution at position 106 (N106S) compared to the closely related CMY-51. Additionally, a GMU8049-specific truncation in an OmpK37 variant that produces a premature stop codon. Moreover, a variety of chromosome-located efflux pump coding genes and virulence-related genes were also identified. Analysis of strain GMU8049 in the context of other C. freundii strains reveals an open pan-genome and the presence of mobile genetic elements that can mediate horizontal gene transfer of antimicrobial resistance and virulence genes. Our work provides comprehensive insights into the genetic mechanisms of highly resistant C. freundii, highlighting the importance of genomic surveillance of this opportunistic pathogen as a high-risk population for emerging resistance and pathogenicity.IMPORTANCEEmerging pathogens exhibiting multi-, extremely, and pan-drug resistance are a major concern for hospitalized patients and the healthcare community due to limited antimicrobial treatment options and the potential for spread. Genomic technologies have enabled clinical surveillance of emerging pathogens and modeling of the evolution and transmission of antimicrobial resistance and virulence. Here, we report the genomic characterization of an extremely drug-resistant ST257 Citrobacter freundii clinical isolate. Genomic analysis of GMU8049 with a rare ST type and unusual phenotypes can provide information on how this extremely resistant clinical isolate has evolved, including the acquisition of blaNDM-1 via the IncX3 plasmid and accumulation through chromosomal mutations leading to a novel CMY variant and deficiency of the outer membrane porin OmpK37. Our work highlights that the emergence of extremely resistant C. freundii poses a significant challenge to the treatment of clinical infections. Therefore, great efforts must be made to specifically monitor this opportunistic pathogen.

Practical Application of Aztreonam-Avibactam as a Treatment Strategy for Ambler Class B Metallo-β-Lactamase Producing Enterobacteriaceae.

Carbapenem-resistant Enterobacteriaceae infections are a considerable challenge for clinicians. In recent years, novel antibiotic options have resulted in a tremendous advance in medical therapy; however, current treatment options are primarily effective for resistance derived from serine-based carbapenemases. The Ambler class B metallo-β-lactamases (MBLs) remain a critical challenge with decidedly fewer effective options. One intriguing option for these MBL pathogens is the combination of ceftazidime-avibactam with aztreonam. While clinical experience with this regimen is limited, in vitro studies are promising, and limited case reports describe success with this regimen; however, significant challenges preclude widespread adoption of this novel treatment regimen. A systemic literature review was performed to offer recommendations based on current evidence for a practical strategy on how to best integrate the use of aztreonam with avibactam combination therapy.

Drug utilization evaluation of ceftazidime-avibactam in a tertiary care hospital

Background: The World Health Organization considers antimicrobial resistance a major global threat, and ceftazidime-avibactam (CAZ-AVI) is a treatment for multidrug-resistant Gram-negative infections. The FDA approved its use in 2015 for infections with limited treatment options. Methods: A retrospective study was conducted in a hospital in India to analyse the use of CAZ-AVI formulation in patients. Data was collected from electronic records and included information on patient demographics, clinical and microbiological profiles, antibiotic treatment, and patient outcomes for those in the ICU. Results: A total of 110 patients were included in the study. On assessing the results of this study, it was found that, the median age of population who received CAZ-AVI was 63 years and hypertension, diabetes mellitus were the common comorbidities present in the patients. Out of 110 subjects, 66 (60%) patients were started with a high-end antibiotic as an empirical therapy. While analysing the resistance pattern, it was found that 22 (20%) were resistant and 84 (76%) of the study subjects were sensitive to ceftazidime-avibactam. There was higher clinical success for BSI, CUTI, VAP amongst the indications of CAZ-AVI and combination of CAZ-AVI with aztreonam has given the most successful treatment outcome. The combination of CAZ-AVI with one or two high end antibiotics was observed as a common clinical practice. Conclusions: The analysis of results showed encouraging clinical cure rates. Our study results suggest that ceftazidime-avibactam could be an effective standard therapy for managing MDR Gram -negative organisms.

Ceftazidime-avibactam combination therapy versus monotherapy for treating carbapenem-resistant gram-negative infection: a systemic review and meta-analysis.

This meta-analysis was conducted to compare the efficacy of ceftazidime-avibactam combination therapy with that of monotherapy in the treatment of carbapenem-resistant Gram-negative bacterial (CR-GNB). A literature search of PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov was conducted until September 1, 2023. Only studies that compared CZA combination therapy with monotherapy for CR-GNB infections were included. A total of 25 studies (23 retrospective observational studies and 2 prospective studies) involving 2676 patients were included. There was no significant difference in 30-day mortality between the study group receiving combination therapy and the control group receiving monotherapy (risk ratio [RR] 0.91; 95% confidence interval [CI] 0.71-1.18). In addition, no significant differences were observed between the study and the control group in terms of in-hospital mortality (RR 1.00; 95% CI 0.79-1.27), 14-day mortality (RR 1.54; 95% CI 0.24-9.91), 90-day mortality (RR 1.18; 95% CI 0.62-2.22), and clinical cure rate (RR 0.95; 95% CI 0.84-1.08). However, the combination group had a borderline higher microbiological eradication rate than the control group (RR 1.15; 95% CI 1.00-1.32). Compared to monotherapy, CZA combination therapy did not yield additional clinical benefits. However, combination therapy may be associated with favorable microbiological outcomes.

PAM-1: an antimicrobial peptide with promise against ceftazidime-avibactam resistant Escherichia coli infection.

Antibiotic misuse and overuse have led to the emergence of carbapenem-resistant bacteria. The global spread of resistance to the novel antibiotic combination ceftazidime-avibactam (CZA) is becoming a severe problem. Antimicrobial peptide PAM-1 offers a novel approach for treating infections caused by antibiotic-resistant bacteria. This study explores its antibacterial and anti-biofilm activities and mechanisms against CZA-resistant Escherichia. Coli (E. coli), evaluating its stability and biosafety as well. The broth microdilution method, growth curve analysis, crystal violet staining, scanning electron microscopy, and propidium iodide staining/N-phenyl-1-naphthylamine uptake experiments were performed to explore the antibacterial action and potential mechanism of PAM-1 against CZA-resistant E. coli. The biosafety in diverse environments of PAM-1 was evaluated by red blood cell hemolysis, and cytotoxicity tests. Its stability was further assessed under different temperatures, serum concentrations, and ionic conditions using the broth microdilution method to determine its minimum inhibitory concentration (MIC). Galleria mellonella infection model and RT-qPCR were used to investigate the in vivo antibacterial and anti-inflammatory effects. In vitro antibacterial experiments demonstrated that the MICs of PAM-1 ranged from 2 to 8 μg/mL, with its effectiveness sustained for a duration of 24 h. PAM-1 exhibited significant antibiofilm activities against CZA-resistant E. coli (p < 0.05). Furthermore, Membrane permeability test revealed that PAM-1 may exert its antibacterial effect by disrupting membrane integrity by forming transmembrane pores (p < 0.05). Red blood cell hemolysis and cytotoxicity tests revealed that PAM-1 exerts no adverse effects at experimental concentrations (p < 0.05). Moreover, stability tests revealed its effectiveness in serum and at room temperature. The Galleria mellonella infection model revealed that PAM-1 can significantly improve the survival rate of Galleria mellonella (>50%)for in vivo treatment. Lastly, RT-qPCR revealed that PAM-1 downregulates the expression of inflammatory cytokines (p < 0.05). Overall, our study findings highlight the potential of PAM-1 as a therapeutic agent for CZA-resistant E. coli infections, offering new avenues for research and alternative antimicrobial therapy strategies.

Activities of aztreonam in combination with several novel β-lactam-β-lactamase inhibitor combinations against carbapenem-resistant Klebsiella pneumoniae strains coproducing KPC and NDM.

Isolates coproducing serine/metallo-carbapenems are a serious emerging public health threat, given their rapid dissemination and the limited number of treatment options. The purposes of this study were to evaluate the in vitro antibacterial activity of novel β-lactam-β-lactamase inhibitor combinations (BLBLIs) against carbapenem-resistant Klebsiella pneumoniae (CRKP) coproducing metallo-β-lactamase and serine-β-lactamase, and to explore their effects in combination with aztreonam, meropenem, or polymyxin in order to identify the best therapeutic options. Four CRKP isolates coproducing K. pneumoniae carbapenemase (KPC) and New Delhi metallo-β-lactamase (NDM) were selected, and a microdilution broth method was used to determine their susceptibility to antibiotics. Time-kill assay was used to detect the bactericidal effects of the combinations of antibiotics. The minimum inhibitory concentration (MIC) values for imipenem and meropenem in three isolates did not decrease after the addition of relebactam or varbobactam, but the addition of avibactam to aztreonam reduced the MIC by more than 64-fold. Time-kill assay demonstrated that imipenem-cilastatin/relebactam (ICR) alone exerted a bacteriostatic effect against three isolates (average reduction: 1.88 log10 CFU/mL) and ICR combined with aztreonam exerted an additive effect. Aztreonam combined with meropenem/varbobactam (MEV) or ceftazidime/avibactam (CZA) showed synergistic effects, while the effect of aztreonam combined with CZA was inferior to that of MEV. Compared with the same concentration of aztreonam plus CZA combination, aztreonam/avibactam had a better bactericidal effect (24 h bacterial count reduction >3 log10CFU/mL). These data indicate that the combination of ATM with several new BLBLIs exerts powerful bactericidal activity, which suggests that these double β-lactam combinations might provide potential alternative treatments for infections caused by pathogens coproducing-serine/metallo-carbapenems.

A multi-species outbreak of VIM-producing carbapenem-resistant bacteria in a burn unit and subsequent investigation of rapid development of cefiderocol resistance.

Carbapenem resistance due to metallo-β-lactamases (MBLs) such as the Verona integron-encoded metallo-β-lactamase (VIM) is particularly problematic due to the limited treatment options. We describe a case series of bacterial infections in a tertiary care hospital due to multi-species acquisition of a VIM gene along with our experience using novel β-lactam antibiotics and antibiotic combinations to treat these infections. Four patients were treated with the combination of ceftazidime-avibactam and aztreonam, with no resistance to the combination detected. However, cefiderocol-resistant Klebsiella pneumoniae isolates were detected in two out of the five patients who received cefiderocol within 3 weeks of having started the antibiotic. Strain pairs of sequential susceptible and resistant isolates from both patients were analyzed using whole-genome sequencing. This analysis revealed that the pairs of isolates independently acquired point mutations in both the cirA and fiu genes, which encode siderophore receptors. These point mutations were remade in a laboratory strain of K. pneumoniae and resulted in a significant increase in the MIC of cefiderocol, even in the absence of a beta-lactamase enzyme or a penicillin-binding protein 3 (PBP3) mutation. While newer β-lactam antibiotics remain an exciting addition to the antibiotic armamentarium, their use must be accompanied by diligent monitoring for the rapid development of resistance.

Evaluation of the MTS™ aztreonam-avibactam strip (Liofilchem) on New Delhi metallo-β-lactamase-producing Enterobacterales.

The combination of ceftazidime-avibactam (CAZ-AVI) and aztreonam (ATM) is used to treat MBL-producing Enterobacterales-related infections. The new combination aztreonam-avibactam (AZA) is currently in development. We compared results obtained with the new MIC test strip (MTS) AZA (Liofilchem) with broth microdilution method (BMD) on 41 MBL-producing Enterobacterales from 41 clinical samples. The MTS AZA was also compared to combination testing method using CAZ-AVI and ATM strips. Compared to BMD, categorical agreement (CA) was 100%. Compared with combination testing method, CA was 97.6%. The MTS AZA can be used to determine MICs levels of AZA or CAZ-AVI/ATM combinations.

Etiological structure of infections in patients of the surgical intensive care unit in the post-covid era

Objective. To determine etiological structure of infections in the surgical intensive care unit (ICU), identify the most common mechanisms of antibiotic resistance of leading pathogens, and develop recommendations for optimizing antimicrobial therapy in the ICU at the present stage. Materials and Methods. A prospective observational study was conducted in the surgical ICU of the Moscow City Clinical Center «Kommunarka» from September 2022 to February 2024. The subjects of observation were 2120 patients treated in the unit. Microbiological examination of patients’ biological fluids was carried out in accordance with approved methodological guidelines. The results of determining the susceptibility of isolated pathogens were interpreted based on the EUCAST v14.0 criteria. Automatic bacteriological analyzers, MALDI-TOF mass spectrometry for pathogen identification, PCR and immunochromatographic methods for determining resistance mechanisms were used. To determine the etiological structure of infections in hospitalized patients, only original isolates were considered, following the principle of «one patient – one microbe.» Results. A total of 1213 bacterial and 53 fungal pathogens were isolated from 394 patients. The leading pathogens were Klebsiella pneumoniae (18.5%), Acinetobacter baumannii (13.4%), and Pseudomonas aeruginosa (9.5%). Resistance to meropenem was 83.0% for K. pneumoniae, 97.4% for A. baumannii, and 81.5% for P. aeruginosa. The highest in vitro activity against Enterobacterales was exhibited by ceftazidime-avibactam (79.2% of susceptible isolates), while against A. baumannii and P. aeruginosa, it was colistin (98.6% and 90.6% of susceptible isolates, respectively). The genetic mechanisms of carbapenem resistance in Enterobacterales were identified: production of NDM (26.3%), OXA-48 (29.6%), and KPC (44.1%) carbapenemases. Conclusions. The predominant pathogens of infections in surgical ICU patients are gram-negative bacteria with a high level of antibiotic resistance, including carbapenem-resistant Enterobacterales, whose resistance is due to the production of carbapenemases of various molecular classes. An increase in the prevalence of the serine carbapenemase KPC, previously atypical for the Russian Federation, has been noted. Currently, for infections caused by Enterobacterales producing serine carbapenemases, ceftazidime-avibactam can be recommended, and in the case of metallo-beta-lactamase production by Enterobacterales, a combination of ceftazidime-avibactam with aztreonam. For infections caused by A. baumannii and P. aeruginosa, regimens including polymyxins are indicated.

Ceftazidime-avibactam/aztreonam combination synergy against carbapenem-resistant Gram-negative isolates: In vitro study

ABSTRACT Background: The ceftazidime-avibactam combination is able to inhibit ESBLs, AmpCs and Class A carbapenemases and has been recommended for the treatment of complicated UTIs and ventilator-associated bacterial pneumonia. Aims: The present study was undertaken to evaluate the in vitro activity of ceftazidime-avibactam and to determine the synergistic activity of aztreonam/ceftazidime-avibactam combination against carbapenem-resistant Gram-negative bacilli. Materials and Methods: Gram-negative isolates that exhibited resistance to at least one of the carbapenems (imipenem or meropenem) by the Kirby–Bauer disc diffusion method were subjected to phenotypic characterisation by the Vitek-2 automated method. Phenotypically confirmed isolates were subjected to ceftazidime/avibactam-aztreonam synergy testing by disc diffusion method. Results: Twenty-two carbapenem-resistant isolates showed a minimum inhibitory concentration of 4–64 μg/mL for imipenem and 8–64 μg/mL for meropenem. Out of 22 carbapenem-resistant isolates, 18 (81.82%) isolates showed resistance to ceftazidime-avibactam and aztreonam, and 2 (9.09%) isolates showed intermediate resistance to aztreonam. Nine (40.91%) isolates showed synergy to ceftazidime-avibactam/aztreonam combination by disc diffusion method. An increase in zone diameter of 5–23 mm and 5–16 mm was observed with the ceftazidime-avibactam/aztreonam combination for Klebsiella pneumoniae and Escherichia coli, respectively, when compared to ceftazidime-avibactam and aztreonam disc tested alone. Out of 21 Enterobacterales studied, 21 (100%) isolates showed resistance to amoxicillin-clavulanate (≥32 μg/mL) and piperacillin-tazobactam (128 μg/mL), 12 (57.14%) isolates showed resistance to gentamicin (≥16 μg/mL), 5 (23.81%) isolates were resistant to amikacin (≥64 μg/mL), 21 (100%) isolates were resistant to ciprofloxacin (≥4 μg/mL), 19 (90.48%) isolates were resistant to cotrimoxazole (≥320 μg/mL), 21 (100%) isolates were resistant to cefepime (≥16 μg/mL) and 6 (28.57%) isolates were resistant to tigecycline (2 μg/mL). Conclusion: In the present study, 42.86% of Enterobacterales isolates showed synergism to the ceftazidime-avibactam/aztreonam combination. The optimal dosing strategy and in vivo efficacy of this combination need to be evaluated.

In vitro effectiveness of ceftazidime-avibactam in combination with aztreonam on carbapenemase-producing Enterobacterales

ObjectiveThis work aimed to describe the in vitro performance of the combined activity of ceftazidime-avibactam (CZA) plus aztreonam (ATM) against carbapenemase-producing Enterobacterales (CPE). MethodsWe studied 44 CPE clinical isolates: NDM-1 (31), KPC-2 (5), KPC-3 (3), VIM-2 (2), NDM-1+KPC-2 (2), and OXA-48 (1). The efficacy of CZA in combination with were determined by two methods: (i) Kirby-Bauer's double disk synergy test and; (ii) Determination of the minimum inhibitory concentration to CZA by E-test, in either Mueller-Hinton agar alone or, supplemented with ATM 4 mg/L. Additionally, the Fractional inhibitory concentration index (FICI) was determined; values of ≤ 0.5 were interpreted as synergistic, while FICI > 0.5 were considered indifferent. ResultsAll isolates were carbapenem-resistant, 14 were resistant to CZA and ATM, 15 were only CZA resistant, 12 were only ATM resistant, and three were susceptible to both. 34/44 isolates presented positive double disk synergy tests between CZA and ATM regardless of their susceptibility profile, the isolates with negative synergy tests were susceptible to at least one of the agents. On the other hand, the 21 isolates selected to compare the MIC to CZA alone and CZA plus 4 mg/L ATM of exhibited FICI values between 0.016 and 0.125, indicating a synergistic effect. ConclusionsThis method is available to clinical laboratories and would provide valuable information to guide the treatment of infections with CZA and ATM. In this sense, the use of CZA together with ATM is a potentially suitable combination for the treatment of carbapenemase-producing microorganisms.

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

During the Sars-Cov-2 pandemic, Stenotrophomonas maltophilia (S.maltophilia) secondary pulmonary infections have increased, especially in critically ill patients, highlighting the need for new therapeutic options. Trimethoprim-sulfamethoxazole (SXT) is the treatment of choice but the increase of resistant strains or adverse drug reactions limited its clinical use. Recently ceftazidime/avibactam (CZA) has been approved for the treatment of multi drug resistant (MDR) Gram-negative bacteria infections, including hospital acquired pneumonia. The aim of this study was to evaluate the in vitro activity of ceftazidime/avibactam (CZA) alone and in combination with aztreonam (ATM) against S. maltophilia clinical isolates by E-test method. Susceptibility of SXT and levofloxacin (LEV) was also investigated. Our results showed 22% of resistance to CZA, 2% to SXT and 26% to LEV. CZA in combination with ATM demonstrated synergistic activity against 86% of the strains, including all those resistant to CZA. The combination of CZA with ATM provides a new therapeutic option for the treatment of severe respiratory infections in critically ill patients.

Evaluation of Aztreonam and Ceftazidime/Avibactam Synergism against Klebsiella pneumoniae by MALDI-TOF MS.

Resistance to carbapenems due to the co-production of NDM and ESBL or NDM and KPC is increasing. Therefore, combined therapy with aztreonam (ATM) plus ceftazidime/avibactam (CZA) has been recommended. Then, it is necessary to develop and evaluate fast and simple methods to determine synergism in vitro in microbiology laboratories. To develop a method to determine the synergism of ATM and CZA by MALDI-TOF MS (SynMALDI). Klebsiella pneumoniae (n = 22) isolates with blaNDM and/or blaKPC genes were tested. The time-kill curve assay was performed for four isolates (three positives for blaNDM and blaKPC and one positive for blaNDM only). For SynMALDI, each isolate was incubated for 3 h in 4 tubes containing brain-heart infusion broth with the following: (1) no antibiotic; (2) ATM at 64 mg/L; (3) CZA at 10/4 mg/L; and (4) ATM at 64 mg/L plus CZA at 10/4 mg/L. After incubation, the bacterial protein extract was analyzed by MALDI-TOF MS, and the relative growth (RG) was determined for each isolate, considering intensities of the peaks of the bacterium incubated with antibiotic (tubes 2, 3, and 4) to the same bacterium incubated without antibiotic (tube 1), as follows: RG = IntensityWith antibiotic/IntensityWithout antibiotic. The combination was determined as synergistic when there was an RG decrease of 0.3 in the antibiotic combination in relation to the RG of the most active antibiotic alone. The combination of ATM plus CZA proved to be synergic by time-kill curve assay. All isolates tested with the SynMALDI method also presented synergism. Detection of synergism for ATM plus CZA combination can be determined by MALDI-TOF MS, providing fast results in order to improve patient treatment.

Aktifitas Antibiotik Ceftazidime-Avibactam Dan Ceftaroline Secara In Vitro Terhadap Isolat Klinis Di Pekanbaru

Ceftaroline and Ceftazidime–avibactam are relatively new antibiotics that show good effectiveness against antibiotic-resistant pathogens. Both of these antibiotics are now available worldwide, but reports of resistance to them are also starting to emerge. This study aimed to evaluate the in vitro activity of the antibiotic Ceftazidime-avibactam combination of 100 clinical isolates consisting of Enterobacteriaceae and Pseudomonas aeruginosa bacteria and to evaluate the antibiotic effect of Ceftaroline against 100 clinical isolates of Enterobacteriaceae and Staphylococcus sp. This study is observational with cross-sectional study design. The study was conducted at the microbiology laboratory of a private hospital at Pekanbaru Riau in Januari-June 2021. There were 100 clinical isolates tested with Ceftaroline and Ceftazidime-avibactam. The sensitivity to Ceftaroline and Ceftazidime-avibactam were reported as a number isolate and percentage. The results showed the sensitivity of bacteria K. pneumoniae, E. coli, Enterobacter sp, and P. aeruginosa, to Ceftazidime-Avibactam were 87%, 90%, 66%, and 82%, respectively. The sensitivity of the antibiotic Ceftaroline to the bacteria K. pneumoniae, E. coli, Enterobacter sp and Staphylococcus sp. were 39%, 54%, 36.4%, 67% and 75%, respectively. Based on these results, the antibiotic ceftazidime avibactam can be used for the treatment of suitable pathogenic infections because of its fairly good sensitivity (&gt;80%) to Enterobacteriaceae and P. aeruginosa bacteria. Ceftaroline antibiotics are not recommended to be used as a therapeutic option, because of the high resistance to Enterobacteriaceae and Staphylococcus sp. Further research is needed to determine the molecular mechanism of resistance to Ceftaroline antibiotics

Enhanced bacterial killing with a combination of sulbactam/minocycline against dual carbapenemase-producing Acinetobacter baumannii

Carbapenem-resistant Acinetobacter baumannii (CRAB) is often difficult to treat. Considering the current circumstances, there is an unquestionable need for new therapeutic options to treat CRAB infections. In the present study, the synergistic activity of sulbactam-based combination was determined against genetically characterized CRAB isolates. Non-duplicate CRAB isolates (n = 150) recovered from blood culture and endotracheal aspirates were included in this study. The minimum inhibitory concentrations (MICs) of tetracyclines (minocycline, tigecycline, eravacycline) and their comparators (meropenem, sulbactam, cefoperazone/sulbactam, ceftazidime/avibactam, and colistin) were determined using the microbroth dilution method. Six isolates were tested for the synergistic activity of various sulbactam-based combinations using time-kill experiments. Tigecycline and minocycline showed a wide spread of MICs with most isolates in the range of1 to 16mg/L. The MIC90 of eravacycline (0.5mg/L) was four dilutions lower than that of tigecycline (8mg/L). Minocycline with sulbactam was the most active dual combination against OXA-23 like (n = 2) and NDM with OXA-23 like producers (n = 1), which resulted in ≥ 2 log10 kill. The combination of ceftazidime-avibactam with sulbactam showed ≥ 3 log10 kill against all the three tested OXA-23 like producing CRAB isolates, but showed no activity against dual carbapenemase producers. Sulbactam with meropenem showed ≥ 2 log10 kill against one OXA-23 like producing CRAB isolate. The findings suggest that sulbactam-based combination may confer therapeutic benefits against CRAB infections.

In vitro and in vivo Antimicrobial Activities of Ceftazidime/Avibactam Alone or in Combination with Aztreonam Against Carbapenem-Resistant Enterobacterales.

To examine the in vitro and in vivo antimicrobial activities of ceftazidime/avibactam (CZA) alone or in combination with aztreonam (ATM) against KPC-, NDM-, IMP-, KPC+IMP-, KPC+NDM-producing strains. A total of 67 clinical non-repetitive carbapenem-resistant Enterobacterales (CRE) strains were selected for the microdilution broth method that was performed to analyze the minimal inhibitory concentration (MIC) and the combination antimicrobial susceptibility test using checkerboard titration method. The fractional inhibitory concentration (FIC) was calculated to determine the antimicrobial effect. The time-kill assays and the mouse infection model were used to study the bactericidal effect and therapeutic effect of CZA alone or in combination with ATM. The CZA minimal inhibitory concentration (MIC) values of CZA revealed that 29 KPC-producing strains and 1 OXA-producing strain were ≤4µg/mL. The CZA MIC values of 37 metal-β-lactamase (MBLs)-producing strains such as NDM-, IMP-, KPC+IMP-, KPC+NDM-producing strains were ≥128µg/mL, after combining with ATM, the FIC values were all below 0.51. The time-kill assays revealed that CZA at various concentrations of 2, 4 and 8 MIC showed significant bactericidal efficiency to the KPC-producing strains. For NDM-, IMP-producing strains, no colony growth was detected after 8 hours of incubation with CZA in combination with ATM. Six percent of the mice in the treatment group and 58% of the mice in the infection group died within 3 days. Our in vitro results showed that CZA had a good antimicrobial effect on the KPC-producing and OXA-producing strains. CZA combined with ATM showed synergistic bacteriostatic or bactericidal activity against NDM-, IMP-, KPC+IMP-, KPC+NDM-producing strains. The combination of CZA and ATM reduced mortality and prolonged lifespan of mice infected with NDM-, IMP-, KPC+IMP-, and KPC+NDM-producing strains, which provides fundamental knowledge for improving treatment strategies and initializing clinical trials.

Outbreak of Klebsiella pneumoniae ST11 Resistant To Ceftazidime-Avibactam Producing KPC-31 and the Novel Variant KPC-115 during COVID-19 Pandemic in Argentina.

We describe an outbreak of Klebsiella pneumoniae sequence type 11 (ST11) producing KPC variants resistant to ceftazidime-avibactam. Six patients hospitalized in the intensive care unit (mostly due to critical COVID pneumonia) presented infection or colonization by this bacterium. They had several comorbidities and required mechanical ventilation, central venous catheters, and urinary catheters. All 6 patients had a history of fecal colonization with KPC-producing Enterobacterales (KPC-E). Three of them had previous episodes of infection with ceftazidime-avibactam-susceptible KPC-producing K. pneumoniae, which were treated with ceftazidime-avibactam. Several phenotypic methods failed to detect carbapenemase production in these 6 ceftazidime-avibactam-resistant isolates, and they showed in vitro susceptibility to imipenem and meropenem. All of them rendered positive results for blaKPC by PCR, and amplicon sequencing identified blaKPC-31 variant in 5 isolates and a novel variant, named blaKPC-115, in the other. Moreover, matrix-assisted laser desorption ionization-time of flight mass spectrometry was able to detect KPC in all isolates. Ceftazidime-avibactam-resistant isolates, as well as those recovered from previous infection episodes (KPC-3-producing K. pneumoniae, ceftazidime-avibactam susceptible), displayed a unique pulse type and belonged to ST11. Based on whole-genome sequencing results of selected isolates, less than 7 single-nucleotide polymorphisms were identified among them, which was indicative of the presence of a unique clone. Both in vivo selection and horizontal transmission seemed to have occurred in our hospital. Detection of these strains is challenging for the laboratory. History of previous KPC-E infections or colonization and systematic testing for resistance to ceftazidime-avibactam might help raise awareness of this possibility. IMPORTANCE Klebsiella pneumoniae is one of the main bacteria that cause infections in health care settings. This pathogen has developed a high level of resistance to many antibiotics. Some K. pneumoniae isolates can produce an enzyme known as carbapenemase KPC, making carbapenems (considered the last line for therapy) not effective to treat their infections. The combination ceftazidime-avibactam, approved by FDA in 2015, is useful to treat infections caused by KPC-producing K. pneumoniae. This study describes the emergence, in one hospital in Argentina, of K. pneumoniae isolates that produce KPC variants (KPC-31 and KPC-115) resistant to ceftazidime-avibactam. The ceftazidime-avibactam-resistant bacteria were isolated in inpatients, including some that previously received this combination as treatment. Transmission of this strain to other patients also occurred in the studied period. Detection of these bacteria is challenging for the laboratory. The knowledge and awareness of the emergence of this pathogen in our region are highly valuable.

Emergence of KPC-31, a KPC-3 Variant Associated with Ceftazidime-Avibactam Resistance, in an Extensively Drug-Resistant ST235 Pseudomonas aeruginosa Clinical Isolate.

A ceftazidime-avibactam-resistant KPC-producing Pseudomonas aeruginosa strain was isolated in Argentina from a tracheal aspirate. The patient was treated with ceftazidime-avibactam in combination with other agents for 130 days. Whole-genome sequencing of P. aeruginosa identified a D179Y substitution in the Ω loop of KPC-3, corresponding to KPC-31, integrated at the chromosome. The strain belonged to the sequence type 235/O11 (ST235/O11) high-risk clone. Evaluation of carbapenemase detection assays most used by clinical laboratories failed to identify the isolate as a KPC producer.