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Objectives: Treatment options are limited for melioidosis patients who develop nosocomial infections due to extensively drug-resistant (XDR) Gram-negative bacilli. Ceftolozane/tazobactam (C/T) and ceftazidime/avibactam (CZA), which have activity against XDR Gram-negative bacteria, are two potential options. Data regarding the susceptibility of Burkholderia pseudomallei to these agents are limited, especially from Thailand, which is an endemic area for melioidosis. Methods: A total of 28 B. pseudomallei isolates from melioidosis patients in northeast Thailand were tested for susceptibility to C/T and CZA by Etest and the disk diffusion method. Minimum inhibitory concentrations (MICs) for other antibiotics commonly used in melioidosis, including trimethoprim/sulfamethoxazole (SXT), ceftazidime (CAZ), imipenem (IPM) and meropenem, were also determined. Results: The MIC of C/T was very low for all isolates, ranging from 0.75 μg/mL to 1.0 μg/mL. For CZA, wide inhibitory zones ranging from 34–35 mm and MICs at 0.5 μg/mL were found. All isolates were also susceptible to SXT, CAZ and IPM based on Clinical and Laboratory Standards Institute (CLSI) breakpoints. Conclusion: C/T and CZA exhibited excellent in vitro activity against B. pseudomallei. Further studies are required to prove efficacy in human subjects.

Background & Objective:: Our goal was to compare the in vitro activities of ceftazidime/avibactam (CZA) to those observed in response to other drugs used to treat carbapenem-resistant Enterobacteriaceae (CRE). Methods:: Bacterial isolates collected from intensive care unit patients with hospital-acquired infections were identified using the VITEK 2TMCompact 15. Susceptibility testing for Escherichia coli and Klebsiella spp. was performed using Kirby- Bauer disk diffusion and the VITEK2 system. Minimum inhibitory concentration (MIC) E-test strips were used to examine susceptibility to fosfomycin, colistin, and CZA. Detection of carbapenemase in isolates of Enterobacteriaceae was performed using the modified carbapenem inactivation method (mCIM) and multiplex polymerase chain reaction. Results:: A full 62.5% of the Enterobacteriaceae isolates were CRE. The sensitivity and specificity of mCIM were 98.3% and 100%, respectively, with positive predictive and negative predictive values and accuracy at 100%, 97.3%, and 98.96%, respectively. The most prevalent of the carbapenemase genes was blaKPC which was detected in 46.7% of all isolates and in 83.3% of those identified as Klebsiella pneumoniae. CRE were most sensitive to colistin (96.7%), CZA (80%) and tigecycline (71.7%) (p Conclusions:: mCIM is sensitive, specific, inexpensive and easy to perform; as such, it an ideal method for identification of carbapenem-resistant strains. Our results suggest that CZA may be a good choice for treating infections with CRE if therapeutic options are limited.

Background The increase in carbapenem-resistant Klebsiella pneumoniae (CRKP) infections is of great concern because of limited treatment options. New antimicrobials were recently approved for clinical therapy. This study evaluated the epidemiology of carbapenemase-producing K. pneumoniae isolates collected at a Greek university hospital during 2017-2020, and their susceptibilities to ceftazidime-avibactam (CAZ/AVI), meropenem-vaborbactam (M/V), imipenem-relebactam (I/R), eravacycline, plazomicin, and comparators. Methods Minimum inhibitory concentrations (MICs) were evaluated by Etest. Only colistin MICs were determined by the broth microdilution method. Carbapenemase genes were detected by PCR. Selected isolates were typed by multilocus sequence typing (MLST). Results A total of 266 carbapenemase-producing K. pneumoniae strains were isolated during the 4-year study period. Among them, KPC was the most prevalent (75.6%), followed by NDM (11.7%), VIM (5.6%), and OXA-48 (4.1%). KPC-producing isolates belonged mainly to ST258 and NDM producers belonged to ST11, whereas OXA-48- and VIM producers were polyclonal. Susceptibility to tigecycline, fosfomycin, and colistin was 80.5%, 83.8%, and 65.8%, respectively. Of the novel agents tested, plazomicin was the most active inhibiting 94% of the isolates at ≤ 1.5 μg/ml. CAZ/AVI and M/V inhibited all KPC producers and I/R 98.5% of them. All OXA-48 producers were susceptible to CAZ/AVI and plazomicin. The novel β-lactam/β-lactamase inhibitors (BLBLIs) tested were inactive against MBL-positive isolates, while eravacycline inhibited 61.3% and 66.7% of the NDM and VIM producers, respectively. Conclusions KPC remains the predominant carbapenemase among K. pneumoniae, followed by NDM. Novel BLBLIs, eravacycline, and plazomicin are promising agents for combating infections by carbapenemase-producing K. pneumoniae. However, the emergence of resistance to these agents highlights the need for continuous surveillance and application of enhanced antimicrobial stewardship.

Aim: Infections by Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae represent a major challenge because of limited treatment strategies. New β-lactam/β-lactamase inhibitor associations may help to deal with this challenge. The aim of this study is to evaluate the in vitro susceptibility of KPC-producing K. pneumoniae for meropenem/vaborbactam in comparison with ceftazidime/avibactam against. Materials and methods: Twenty-eight strains isolated from blood cultures were evaluated. Testing for susceptibility to meropenem/vaborbactam and ceftazidime/avibactam was performed by E-test gradient strip. Results: All the clinical isolates were susceptible to meropenem/vaborbactam, while one strain was resistant to ceftazidime/avibactam with a MIC of 32 μg/ml. The median MIC of ceftazidime/avibactam evaluated after standardization was higher compared with that of meropenem/vaborbactam. Conclusion: Meropenem/vaborbactam could be an important turning point in the treatment of KPC-producing K. pneumoniae infections, especially considering the emergence of ceftazidime/avibactam resistance.

The wide spread of carbapenemases among gram-negative bacteria of the Enterobacterales order in hospitals around the world, including Russia, creates great difficulties in the effective use of antibiotics for these infections in the ICU. Ceftazidime-avibactam is the first antibiotic developed and studied for the treatment of infections caused by carbapenem-resistant enterobacteria. Ceftazidime-avibactam shows high activity against producers of class A and D serine carbapenemases (KPC and OXA-48). In combination with aztreonam it is effective in infections caused by producers of class B metallo-beta-lactamases (NDM and VIM). The review analyzes the results of 19 non-comparative and 10 comparative studies of ceftazidime-avibactam in infections caused by carbapenem-resistant Enterobacterales, as well as case reports. According to the data of non- comparative studies, the clinical efficacy of ceftazidime-avibactam ranged from 45.0 to 87.2%, on average 71.7±11.3%, and the eradication rate of KPC or OXA-48 carbapenemase producers ranged from 40.0 to 100%, on average 65.5±18.6%. The effectiveness of ceftazidime-avibactam in comparative studies was 67.9±17.3%, which was significantly higher compared to other antibiotics (44.3±14.4%,P=0.012). Treatment with ceftazidime-avibactam was accompanied by a significantly lower 30-day mortality in contrast to other antibiotics – 23.8±13.5% and 41.0±13.6%, respectively,P=0.001. The development of resistance in Enterobacterales species to ceftazidime-avibactam during therapy is rarely observed, on average 5.4±4.4%, which characterizes a rather low potential of the antibiotic in resistance selection. Early administration of ceftazidime-avibactam is accompanied by better treatment results as opposed to delayed therapy. Treatment of infections caused by carbapenem-resistant enterobacteria with ceftazidime-avibactam is associated with a significantly higher recovery rate and a lower mortality compared to other regimens of antibacterial therapy.

Pseudomonas aeruginosa isolates were consecutively collected from patients with pneumonia in 29 medical centers in 2020 and susceptibility tested by broth microdilution method. Ceftazidime-avibactam (95.5% susceptible), imipenem-relebactam (94.3% susceptible), and ceftolozane-tazobactam (93.3% susceptible) were the most active compounds after colistin (99.5% susceptible). Susceptibility rates for the β-lactam/β-lactamase inhibitor combinations (BL/BLIs) varied against isolates resistant to piperacillin-tazobactam, meropenem, imipenem, and/or ceftazidime. Ceftazidime-avibactam was the most active BL/BLI against resistant subsets from Western Europe, whereas imipenem-relebactam was slightly more active than other BL/BLIs against resistant subsets from Eastern Europe. Susceptibility rates were markedly lower in Eastern Europe than Western Europe.

Introduction The aim of the present study was to assess the safety profile and outcomes of a ceftazidime–avibactam (CAZ-AVI)-based regimen and compare them with those of a tigecycline (TGC)-based regimen in intensive care unit (ICU) for the treatment of carbapenem-resistant Klebsiella pneumoniae (CRKP), which is classified into hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP). Methods Clinical and microbiological cure rates, 28-day survival rates, and safety evaluation findings were compared between patients treated with CAZ-AVI-based regimen and those treated with TGC-based regimen in this retrospective study. Conventional multivariate logistic regression analysis and regression adjustment analysis with propensity score (PS) were performed to control for confounding variables. Results A total of 105 cases of critically ill ICU patients with CRKP-induced HAP or VAP were included in the present study from July 2019 to September 2020; 62 patients (59%) received TGC-based regimen and 43 patients (41%) received CAZ-AVI-based regimen. The most common concomitant agent in the CAZ-AVI group and TGC group was carbapenem (44.2% versus 62.9%, P = 0.058), while only a small proportion of the study population received CAZ-AVI and TGC monotherapy (20.9% versus 6.5%, P = 0.027). The clinical and microbiological cure rates of the CAZ-AVI group were superior to those of the TGC group [51.2% versus 29.0% (P = 0.022) and 74.4% versus 33.9% (P

To assess the in vitro activity of cefiderocol (CFDC) against a collection of both ceftazidime-avibactam (CZA) susceptible and resistant KPC-producing Enterobacterales (KPC-EB) isolates. Secondly, to assess its synergistic activity in combination with different antibiotics. One hundred KPC-EB isolates were tested: 60 CZA susceptible and 40 CZA resistant. Among them, 17 pairs of CZA susceptible and resistant KPC-producing Klebsiella pneumoniae (KPC-Kp) isolates were collected from 17 distinct patients before and after CZA treatment, respectively. CFDC susceptibility was evaluated by both broth microdilution (lyophilized panels; Sensititre; Thermo Fisher) and disk diffusion testing. Results were interpreted using EUCAST breakpoints. Synergistic activity of CFDC in combination with CZA, meropenem-vaborbactam, imipenem, and amikacin against six characterized KPC-Kp strains, before and after acquisition of CZA resistance, was evaluated using gradient diffusion strip crossing method. CFDC resistance rate was significantly higher in CZA resistant EB subset than in the susceptible one (p

Ceftazidime-Avibactam (CAZ-AVI) is a new antimicrobial against carbapenem-resistant Klebsiella pneumoniae. The aim of the study is to examine the cost-effectiveness of CAZ-AVI compared to colistin-...

Ceftazidime is a semi synthetic, broad-spectrum, beta-lactam, third-generation cephalosporin antibiotic useful for the treatment of many bacterial infections like joint infections, meningitis, pneumonia, sepsis, urinary tract infections, malignant otitis externa, and vibrio infection. It is synthesized chemically using ethyl acetoacetate, sodium nitrite and hydrochloric acid. The Structural analogues of Ceftazidime are better in terms of activity, potency and stability. Cefmenoxime has increased stability to beta-lactamases, the syn isomer of Ceftizoxime is more potent, Moxalactam has enhanced activity against Pseudomonas, Ceftriaxone has higher serum peak level and a prolonged half-life. Ceftazidime acts by inhibiting bacterial transpeptidases and preventing the synthesis of bacterial cell wall. It is assayed by Infrared spectroscopy. Stability studies showed that the drug degrades extensively on reconstitution in aqueous solution on exposures to heating at 45ºC and UV/Visible radiation, while the drug in solid state is stable. The drug is identified by carbonate or sodium tests and tested for its pH, clarity of solution, loss on drying and bacterial endotoxins. In 2015, USFDA approved a combination of Ceftazidime with Avibactam, a non-β-lactam β-lactamase inhibitor which protects ceftazidime from hydrolysis by a wide range of serine β-lactamases and expands its spectrum of activity to Enterobacteriaceae resistant to ceftazidime, and is used for the treatment of complicated urinary tract infections and intra-abdominal infections. Five new ceftazidime derivatives have improved acid stability and increased spectrum of ceftazidime. All the Schiff bases showed good antimicrobial activity especially against G(+) bacteria. Compounds 2 and 3 showed broader antibacterial spectrum against both G(+) and G(-) bacteria.

Introduction Antimicrobial treatments for carbapenem-resistant Enterobacteriaceae (CRE) bacteremia are limited, with colistin-based regimens being a primary therapy. Ceftazidime-avibactam is an emerging treatment for various CRE infections. This study aimed to assess ceftazidime-avibactam effectiveness compared to colistin in patients with CRE bacteremia. Methods This retrospective, multi-centre study included adult patients with CRE bacteremia treated with ceftazidime-avibactam or colistin, from 01 September 2017 until 01 December 2020, at two tertiary centres in Saudi Arabia. The risk of 14-day mortality was compared between recipients of ceftazidime-avibactam versus colistin, using Cox multivariable regression, adjusted for Pitt score, Charlson Comorbidity Index score, and treatment with chemotherapy and immunosuppressive agents. Results We enrolled 61 patients; 32 received ceftazidime-avibactam, and 29 received colistin. The adjusted risk of 14-day mortality was lower in the ceftazidime-avibactam group than the colistin group (hazard ratio [HR] 0.32; 95% confidence interval [CI] 0.10 – 0.99;P = 0.049), while the crude 14-day mortality was not different between the two antibiotics (HR, 0.59; 95% CI 0.21-1.66; P = 0.32). The clinical success rate was higher with the use of ceftazidime-avibactam versus colistin (46.8% versus 20.4%, respectively; P = 0.047). Conclusion Ceftazidime-avibactam was associated with a lower risk of 14-day mortality than colistin in patients with CRE bacteremia.

Increasing cases of carbapenem-resistant Klebsiella pneumoniae (CR-KP) infections have been observed globally where multi-drug resistance to CR-KP can make the infection difficult to treat. In recent years, the β-lactam/β-lactamase inhibitor, ceftazidime-avibactam (CAZ-AVI), has been developed to treat complicated urinary tract infections and complicated intra-abdominal infections. CAZ-AVI is approved for children over 3-month old but has yet to be investigated for cases of osteomyelitis. Only three case reports exist in literature on the use of CAZ-AVI for CR-KP osteomyelitis in adults. In this report, we present an infant with primary hematogenous osteomyelitis and septic arthritis in the right shoulder following surgical treatment for a heart murmur. Bacterial isolation revealed a strain of CR-KP, which was successfully treated with CAZ-AVI after initial administration of imipenem-based treatments.

Aims Klebsiella pneumoniae has been reported to develop increased antibiotic resistance. Ceftazidime-avibactam (CZA) is a novel antibiotic with activity against serine-lactamase. Here, we investigated the sensitivity of carbapenem-resistant K. pneumoniae (CRKP) to CZA and the mechanisms of drug resistance in our hospital. Methods and results Patient characteristics were obtained from medical records. K. pneumoniae and its antibiotic susceptibility were determined using the Vitek-2 Compact instrument. The antibiotic resistance genes KPC, NDM, OXA-48, VIM, IMP, CIM, SPM, TMB, SMB, SIM, AIM and DIM were detected using real-time PCR. Multilocus sequence typing was used for genetic RELATEDNESS analysis. In total, 121 CRKP strains were isolated from patients in the intensive care unit (51·2%), senior ward (12·4%) and neurosurgery department (10%). With an average age of 72·5 years, most patients were in care for respiratory (34·7%), brain (20·7%), digestive tract (13·2%) and cardiovascular (8·3%) diseases. Specimens were predominantly obtained from sputum (39·67%), urine (29·75%) and blood (6·61%). Conclusion Of 23 CZA-resistant CRKP strains (19·01%), ST11 being the most common at 56·52%, 11 NDM-1-positive (47·83%) and four NDM-5-positive (17·39%) strains were detected. Significance and impact of the study Our study indicates that CZA resistance occurs in ~19·01% CRKP strains and that blaNDM-1 and blaNDM-5 might be critical for resistance.

Introduction. So far there has been no clear protocol on the treatment of bacterial infections in hematopoietic cancer patients undergoing polychemotherapy (PCT) and hematopoietic stem cell transplantation (HSCT). Guidelines available from antibiotic therapy panels such as EMBT, NCCN, ECIL, Sepsis-3 often fail to cover the entire spectrum of clinical risk factors of severe complications caused specifically by multiresistant Klebsiella pneumoniae.The aim of the study — is to showcase the clinical experience of demonstration of the experience of the Research Institute of Pediatric Oncology and Hematology at N.N. Blokhin Russian Cancer Research Center with respect to adjusting antibacterial therapy for the spectrum of microorganisms found in the patient before the onset of antitumor therapy, and for the multiresistant microorganism findings in patients with blood cancers and febrile neutropenia (FN) undergoing PCT and HSCT.Materials and methods. The study involved five patients undergoing either PCT or HSCT for hematopoietic cancers at Research Institute of Pediatric Oncology and Hematology in October 2019 — October 2020, multiresistant Klebsiella pneumonia colonies found in each case. Results. Five patients with hematopoietic cancers and induced bone marrow aplasia were found to have multiresistant Klebsiella pneumoniae colonies on top of post-PCT/HSCT immunosuppression. Given high risk of death, these patients need early antibacterial therapy with reserve antibiotics outside standard empirical antibacterial treatment protocols should they develop FN. The Center's practices have shown that baseline protocols are often inadequate to the severity of these patients' conditions in a certain timeframe.Conclusions. To sum up the Center's limited experience, the finding is that additional research is required into the factors of risk of severe multiresistant Klebsiella pneumoniae infections in patients undergoing PCT and HSCT; algorithms must be developed for the treatment of patients in such a critical condition.

Introduction Carbapenem-resistant Enterobacteriaceae (CRE) infections have a major effect on mortality as well as healthcare cost. Intensive care units (ICUs) in India, the epicenters for multidrug-resistant organisms, are facing a “postantibiotic era” because of very limited treatment options. A latest beta-lactam/beta-lactamase inhibitor ceftazidime–avibactam (CZA) new has a broad-spectrum antibacterial activity. CZA inhibits class-A and class-C beta-lactamases (as well Klebsiella pneumoniae carbapenemase (KPC)), along with some class-D carbapenems such as OXA-48-like enzymes that are seen in Enterobacteriaceae has recently become available. The current study aimed to assess and present the clinical response and patient outcome with infections due to CRE when treated with CZA alone or in combination with other drugs. Materials and methods This retrospective study reviews the experience recorded and analyzed at two tertiary care centers including only adult patients with CRE infection who had received CZA alone or in combination with other antibiotics over a period between February 2019 and January 2020. Results In the period from February 2019 to January 2020, 119 culture-confirmed CRE isolates were tested for Xpert Carba-R. The predominant genetic mechanism was a combination of NDM+OXA-48 in 45/119 (37.81%). Total 40/57 patients received CZA+aztreonam alone or in combination with other drugs with an overall cure rate of 77.5% while the rest 17 received CZA alone in combination with the cure rate of 82.35%. 41/57 (71.92%) patients were in ICU. Conclusion With overall mortality of 21%, these data suggest that CZA is a viable option for patients with CRE infections. To our knowledge, this is the first Indian study reporting CZA data in CRE infections. How to cite this article Nagvekar V, Shah A, Unadkat VP, Chavan A, Kohli R, Hodgar S, et al. Clinical Outcome of Patients on Ceftazidime–Avibactam and Combination Therapy in Carbapenem-resistant Enterobacteriaceae. Indian J Crit Care Med 2021;25(7):780–784.

The efficacy and safety of Ceftazidime-Avibactam (CAZ-AVI) as compared to meropenem for nosocomial pneumonia was established in a randomized, phase-III, non-inferiority trial REPROVE, which included Indian patients. We determined if the results for the Indian patients were in-line with the results of overall population. Descriptive analysis of efficacy and safety demonstrated ceftazidime-avibactam was comparable to meropenem in the management of nosocomial pneumonia in Indian patients and it may be a useful addition to the armamentarium of antibiotics for management of such infections with Enterobacterales and Pseudomonas.

Background The limited armamentarium against multidrug-resistant Gram-negative bacilli led to the development of a new generation of β-lactam/β-lactamase inhibitor combinations (BL/BLI). Objectives To evaluate the in vitro activity of ceftazidime/avibactam, ceftolozane/tazobactam, meropenem/vaborbactam, and imipenem/relebactam against Pseudomonas aeruginosa isolates recovered from patients hospitalized with skin and soft tissue infections (SSTIs) in several countries around the world. Methods A total of 360 P. aeruginosa isolates were consecutively collected from 47 medical centers located in Western Europe, Eastern Europe, the Asia-Pacific region, and Latin America. Susceptibility testing was performed by broth microdilution method at a monitoring laboratory. EUCAST breakpoints were applied. Results Ceftazidime/avibactam (98.3% susceptible), ceftolozane/tazobactam (98.6% susceptible), and imipenem/relebactam (98.3% susceptible) were the most active compounds after colistin (100.0% susceptible) and retained activity against isolates nonsusceptible to piperacillin/tazobactam, meropenem, imipenem, and/or ceftazidime. Meropenem-vaborbactam was active against 94.2% of isolates. Ceftazidime/avibactam was the most active BL/BLI against meropenem-nonsusceptible (92.6% susceptible) and imipenem-resistant (93.8% susceptible) isolates, whereas ceftolozane/tazobactam was the most active BL/BLI against piperacillin/tazobactam-resistant (91.1% susceptible) and ceftazidime-resistant (91.7% susceptible) isolates. Conclusions The recently approved BL/BLIs demonstrated potent activity and broad coverage against contemporary P. aeruginosa isolates from patients with SSTIs.

ObjectivesTo investigate the susceptibility of imipenem-non-susceptible Escherichia coli (INS-EC), Klebsiella pneumoniae (INS-KP), Acinetobacter baumannii (INS-AB) and Pseudomonas aeruginosa (INS-PA) to novel antibiotics.MethodsMICs were determined using the broth microdilution method. Carbapenemase and ESBL phenotypic testing and PCR for genes encoding ESBLs, AmpCs and carbapenemases were performed.ResultsZidebactam, avibactam and relebactam increased the respective susceptibility rates to cefepime, ceftazidime and imipenem of 17 INS-EC by 58.8%, 58.8% and 70.6%, of 163 INS-KP by 77.9%, 88.3% and 76.1% and of 81 INS-PA by 45.7%, 38.3% and 85.2%, respectively. Vaborbactam increased the meropenem susceptibility of INS-EC by 41.2% and of INS-KP by 54%. Combinations of β-lactams and novel β-lactamase inhibitors or β-lactam enhancers (BLI-BLE) were inactive against 136 INS-AB. In 58 INS-EC and INS-KP with exclusively blaKPC-like genes, zidebactam, avibactam, relebactam and vaborbactam increased the susceptibility of the partner β-lactams by 100%, 96.6%, 84.5% and 75.9%, respectively. In the presence of avibactam, ceftazidime was active in an additional 85% of 20 INS-EC and INS-KP with exclusively blaOXA-48-like genes while with zidebactam, cefepime was active in an additional 75%. INS-EC and INS-KP with MBL genes were susceptible only to cefepime/zidebactam. The β-lactam/BLI-BLE combinations were active against INS-EC and INS-KP without detectable carbapenemases. For INS-EC, INS-KP and INS-AB, tigecycline was more active than omadacycline and eravacycline but eravacycline had a lower MIC distribution. Lascufloxacin and delafloxacin were active in Conclusionsβ-Lactam/BLI-BLE combinations were active in a higher proportion of INS-EC, INS-KP and INS-PA. The susceptibility of novel fluoroquinolones and tetracyclines was not superior to that of old ones.

Debao Li,1,* Keyang Li,2,* Hongliang Dong,2 Dongmei Ren,1 Dandan Gong,2 Fuguo Jiang,1 Chunhua Shi,1 Junmin Li,1 Qi Zhang,3 Wenjuan Yan,3 Yi Li3 1Department of Clinical Laboratory, Jiaozuo People’s Hospital, Jiaozuo, Henan, People’s Republic of China; 2Department of Clinical Pharmacy, Jiaozuo People’s Hospital, Jiaozuo, Henan, People’s Republic of China; 3Department of Clinical Laboratory, Henan Provincial People’s Hospital, Zhengzhou, Henan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenjuan Yan; Yi LiDepartment of Clinical Laboratory, Henan Provincial People’s Hospital, Weiwu Road 7#, Jinshui District, Zhengzhou, 450003, Henan, People’s Republic of ChinaTel +86 15225061830; +86 15939039006Email yanwenjuan2008@126.com; liyilabmed@henu.edu.cnPurpose: Carbapenem-resistant Klebsiella pneumoniae (CRKP) represents a serious problem worldwide. Herein, we describe the evolution of ceftazidime–avibactam (CZA) resistance by sequencing clinical isolates from a patient with CRKP infection undergoing CZA treatment.Patients and Methods: In this study, six CRKP strains were isolated from sputum and blood samples of a patient with CRKP infection after intracerebral hemorrhage. Two strains were selected for whole-genome analysis.Results: Drug susceptibility testing showed that the MIC of CZA for CRKP strains isolated after 6 days of CZA treatment was 64-fold higher than that for three CRKP strains isolated before CZA treatment (4 vs > 256 μg/mL), whereas the MIC of imipenem and meropenem was 128-fold (> 32 vs 0.25 μg/mL) and 16-fold (> 32 vs 2 μg/mL) lower relatively, respectively. Multilocus sequence typing showed that all six CRKP strains isolated from the patient were ST11 and pulsed-field gel electrophoresis confirmed that they were of the same clone. Two strains were selected for whole-genome analysis. The aspartic acid residue at position 179 in the Ω loop was replaced by a tyrosine residue in the resistant strain, and the plasmid carried a blaKPC-2 to blaKPC-33 mutation. The results of the modified carbapenem inactivation method and the carbapenemase inhibitor enhancement and colloidal gold enzyme immunochromatographic assays for blaKPC-33 were negative.Conclusion: This is the first report from Henan to show that treatment with CZA for 6 days can cause mutations and change the phenotype from CZA sensitive to resistant. Therefore, routine testing for drug susceptibility and carbapenemase phenotypes should be conducted during treatment with CZA, and genotype determination is essential.Keywords: ceftazidime–avibactam, drug resistance, carbapenem-resistant Klebsiella pneumoniae, K. pneumoniae carbapenemase-2, ST11

Aims: Colistin became the critical treatment option for multidrug-resistant Gram-negative bacteria (GNB); however, resistance to colistin is increasingly being reported among clinical isolates. New...

Very few antimicrobial agents remain active against Pseudomonas aeruginosa and Klebsiella pneumoniae in some geographic regions. We evaluated the in vitro activity of ceftazidime-avibactam, ceftolozane-tazobactam, and comparator agents against 6,210 P. aeruginosa and 6,041 K. pneumoniae isolates consecutively collected from 85 U.S. medical centers across 37 states in 2016-2018. Antimicrobial susceptibility was determined by reference broth microdilution method. K. pneumoniae isolates found to have elevated MICs for broad-spectrum cephalosporins were submitted to whole-genome sequencing analysis to detect resistance genes. Ceftazidime-avibactam (97.1% susceptible [S]) and ceftolozane-tazobactam (97.0%S) were the most active compounds against P. aeruginosa and retained activity against meropenem-nonsusceptible (88.5-89.0%S), piperacillin-tazobactam-nonsusceptible (86.6-87.0%S), and other resistant subsets of isolates. The most active agents against K. pneumoniae per CLSI criteria were ceftazidime-avibactam (>99.9%S), amikacin (98.4%S), and meropenem (97.1%S). Ceftolozane-tazobactam was active against 95.3% of K. pneumoniae but showed limited activity against extended-spectrum β-lactamase and carbapenemase producers (82.9% and 0.0%S, respectively).

The continuous spread of carbapenem-resistant Klebsiella pneumoniae (CP-Kp) strains presents a severe challenge to the healthcare system due to limited therapeutic options and high mortality. Since its availability, ceftazidime/avibactam (C/A) has become a first-line option against KPC-Kp, but C/A-resistant strains have been reported increasingly, especially with pneumonia or prior suboptimal blood exposure to C/A treatment. A retrospective, observational study was conducted with all patients admitted to the Intensive Care Unit (ICU) dedicated to COVID-19 patients at the City of Health & Sciences in Turin, between 1 May 2021 and 31 January 2022, with the primary endpoint to study strains with resistance to C/A, and secondly to describe the characteristics of this population, with or without previous exposure to C/A. Seventeen patients with colonization or invasive infection due to Klebsiella pneumoniae, C/A resistance, and susceptibility to meropenem (MIC = 2 µg/L) were included; the blaKPC genotype was detected in all isolates revealing D179Y mutation in the blaKPC-2 (blaKPC-33) gene. Cluster analysis showed that 16 out of the 17 C/A-resistant KPC-Kp isolates belonged to a single clone. Thirteen strains (76.5%) were isolated in a 60-day period. Only some patients had a previous infection with non-mutant KPC at other sites (5; 29.4%). Eight patients (47.1%) underwent previous large-spectrum antibiotic treatment, and four patients (23.5%) had prior treatment with C/A. The secondary spread of the D179Y mutation in the blaKPC-2 during the COVID-19 pandemic needs to be addressed constantly by an interdisciplinary interaction between microbiologists, infection control personnel, clinicians, and infectious diseases consultants to properly diagnose and treat patients.

The case of a female who had an accident that caused an open fracture is reported. During hospitalisation, Verona integron-encoded metallo-β-lactamase (VIM)-producing Klebsiella pneumoniae was isolated. Antimicrobial susceptibility testing revealed resistance to β-lactam antibiotics, quinolones, trimethoprim/sulfamethoxazole, and susceptibility to tigecycline, colistin, fosfomycin and aminoglycosides. Synergistic activity of ceftazidime-avibactam and aztreonam was proved in vitro and a combined therapy with tigecycline was started. Combination with aminoglycosides was ruled out as it was not described in the literature and also in order to avoid side effects. Colistin was rejected because of its nephrotoxicity profile. The antibiotic treatment was assessed by a multidisciplinary team with a pharmacist who closely monitored adverse effects and interactions with other drugs. The total duration of this combination was 25 days, without any adverse events reported. Fourteen weeks after the accident the patient was discharged. After 2 months of follow-up neither relapses nor reinfections have been reported.

To the Editor, In this journal attempts to circumvent carbapenem resistance of Pseudomonas aeruginosa were recently reported [1]. Among 28 clinical carbapenem-resistant isolates of P. aeruginosa, 1...

Background Antibacterial activity of ceftazidime-avibactam (CAZ-AVI) was evaluated against bacterial isolates from children in the United States with a urinary tract infection (UTI) or intra-abdominal infection (IAI) during the 2016-2019 International Network for Optimal Resistance Monitoring program. Prevalence of isolates and susceptibility to CAZ-AVI in pediatric and adult patients were compared. Methods Bacterial isolates were collected from children with a UTI or IAI at 70 US medical centers from 2016 to 2019. The antimicrobial activity of CAZ-AVI and comparator agents was tested by broth microdilution methods. Results The most prevalent Enterobacterales pathogens in children with UTIs were Escherichia coli (62.5%), Klebsiella pneumoniae (12.1%) and Proteus mirabilis (6.2%). Minimum inhibitory concentration 90% values for CAZ-AVI against Enterobacterales (0.25 μg/mL) and Pseudomonas aeruginosa (4 μg/mL) were identical for children and adults. The most prevalent Enterobacterales pathogens in children with IAIs were E. coli (57.4%), K. pneumoniae (11.1%) and Enterobacter cloacae species complex (9.3%). All isolates of Enterobacterales from pediatric patients with UTI and IAI were susceptible to CAZ-AVI, including extended-spectrum β-lactamase phenotypes. Susceptibility of P. aeruginosa isolates to CAZ-AVI was 96.2% in children and 98.4% in adults with a UTI: for IAI it was 100% and 97.2%, respectively. Conclusions Contemporary UTI and IAI pathogens collected from US children from 2016 to 2019 exhibited similar prevalence and susceptibilities as isolates collected from adult patients. CAZ-AVI exhibited potent activity against these pathogens.

Increasing prevalence of infections caused by antimicrobial-resistant gram-negative bacteria represents a global health crisis, and while several novel therapies that target various aspects of antimicrobial resistance have been introduced in recent years, few are currently approved for children. Ceftazidime-avibactam is a novel β-lactam β-lactamase inhibitor combination approved for adults and children 3months and older with complicated intra-abdominal infection, and complicated urinary tract infection or hospital-acquired ventilator-associated pneumonia (adults only in the United States) caused by susceptible gram-negative bacteria. Extensive population pharmacokinetic (PK) data sets for ceftazidime and avibactam obtained during the adult clinical development program were used to iteratively select, modify, and validate the approved adult dosage regimen (2,000-500mg by 2-hour intravenous (IV) infusion every 8hours (q8h), with adjustments for renal function). Following the completion of one phase I (NCT01893346) and two phase II ceftazidime-avibactam studies (NCT02475733 and NCT02497781) in children, adult PK data sets were updated with pediatric PK data. This paper describes the development of updated combined adult and pediatric population PK models and their application in characterizing the population PK of ceftazidime and avibactam in children, and in dose selection for further pediatric evaluation. The updated models supported the approval of ceftazidime-avibactam pediatric dosage regimens (all by 2-hour IV infusion) of 50-12.5mg/kg (maximum 2,000-500mg) q8h for those ≥6months to 18years old, and 40-10mg/kg q8h for those ≥3 to 6months old with creatinine clearance > 50mL/min/1.73 m2 .

Background Infections caused by KPC-producing Klebsiella pneumoniae (Kp) are associated with high mortality. Therefore, new treatment options are urgently required. Objectives To assess the outcomes and predictors of mortality in patients with KPC- or OXA-48-Kp infections treated with ceftazidime/avibactam with an emphasis on KPC-Kp bloodstream infections (BSIs). Methods A multicentre prospective observational study was conducted between January 2018 and March 2019. Patients with KPC- or OXA-48-Kp infections treated with ceftazidime/avibactam were included in the analysis. The subgroup of patients with KPC-Kp BSIs treated with ceftazidime/avibactam was matched by propensity score with a cohort of patients whose KPC-Kp BSIs had been treated with agents other than ceftazidime/avibactam with in vitro activity. Results One hundred and forty-seven patients were identified; 140 were infected with KPC producers and 7 with OXA-48 producers. For targeted therapy, 68 (46.3%) patients received monotherapy with ceftazidime/avibactam and 79 (53.7%) patients received ceftazidime/avibactam in combination with at least another active agent. The 14 and 28 day mortality rates were 9% and 20%, respectively. The 28 day mortality among the 71 patients with KPC-Kp BSIs treated with ceftazidime/avibactam was significantly lower than that observed in the 71 matched patients, whose KPC-Kp BSIs had been treated with agents other than ceftazidime/avibactam (18.3% versus 40.8%; P = 0.005). In the Cox proportional hazards model, ultimately fatal disease, rapidly fatal disease and Charlson comorbidity index ≥2 were independent predictors of death, whereas treatment with ceftazidime/avibactam-containing regimens was the only independent predictor of survival. Conclusions Ceftazidime/avibactam appears to be an effective treatment against serious infections caused by KPC-Kp.

Pseudomonas aeruginosa is a common gram-negative bacillus in nosocomial settings. Consideration of this organism is important due to its potential to acquire multi-drug resistance through various mechanisms causing severe infections, particularly in immunocompromised hosts. Here, we present a challenging case of a blood stream infection caused by a drug-resistant strain of P. aeruginosa in a debilitated young patient. A 31-year-old male patient with a complex history of multiple trauma following a vehicle accident that required several surgical interventions, is plagued by persistent bacteremia. An extensively drug-resistant strain of P. aeruginosa was repeatedly isolated that continued to grow in the patient's blood cultures despite treatment with meropenem and colistin for an extended period. In addition to phenotypic characterization, the complete genome of the strain was sequenced and a genomic view was provided regarding its antimicrobial resistance (AMR) patterns, efflux pump genes, virulence determinants, phageomic signals, and genomic islands. The strain belongs to sequence type ST357 with dominant Class A (VEB), Class B, Class C (PDC-11) and D (OXA-10, OXA-50) β-lactamases, and injectosomes (type III secretion system) known to mediate high virulence. The pool of extended spectrum β-lactamases genes and the upregulated chromosomal efflux system are likely to account for the extended resistance pattern in this strain. In light of the global spread of ST357 isolates, it is essential to continue monitoring their resistance patterns and evaluate effective epidemiological tools to define the genetic determinants of emerging resistance. Intensified infection control measures are continuously required to stop dissemination of such strains in an institution where susceptible hosts are at risk of acquiring them.

Purpose Post-neurosurgical infection caused by extensively drug resistant Pseudomonas aeruginosa (XDR-PA) are becoming a matter of great concern due to limited therapeutic options. Although not approved for these indications, the new BetaLactam-BetaLactamase Inhibitor combinations (BLBLIs) could represent a valid salvage treatment. We describe one nosocomial meningitis and two cervical osteomyelitis due to an XDR-PA who were treated with ceftazidime/avibactam (CZA) and ceftolozane/tazobactam (C/T) and review the literature. Methods The first and the third patients developed an osteomyelitis following cervical stabilization surgery due to an XDR-PA. Although the first patient started treatment with a high dose of C/T, resistance to C/T occurred, so therapy was switched to CZA plus aztreonam. The third patient switched to aztreonam plus CZA due to development of acute kidney injury during therapy with colistin. The second patient had an XDR-PA meningitis following the insertion of an external ventricular catheter and he was treated with C/T plus meropenem and amikacin. Results All three cases reported were successfully conservatively treated thanks to the use of the new BLBLIs with different combinations. Only few experiences demonstrated an equally favorable outcome: one patient treated with C/T plus fosfomycin for otogenic meningitis caused by an XDR-PA and another case of XDR-PA post-surgical meningitis with CZA in combination with colistin. Finally, the combination of CZA plus aztreonam has proven to be effective on XDR-PA only in limited mostly in vitro studies. Conclusion These recently developed antibiotics, C/T and CZA are promising and complementary therapy options against post-neurosurgical hard-to-treat P. aeruginosa infections. Further prospective real-life studies are required to validate these findings in this special setting.

Purpose To assess the antimicrobial activities of ceftazidime/avibactam (CAZ/AVI) and aztreonam/avibactam (ATM/AVI) against carbapenem-resistant Enterobacteriaceae (CRE) isolates collected from three secondary hospitals in Southwest China between 2018 and 2019. Materials and methods A total of 120 unique CRE clinical isolates were collected and carbapenemase genes were detected using PCR. Antimicrobial susceptibility was determined using standard broth microdilution method and the results were interpreted according to CLSI breakpoints. Results The 120 carbapenem-resistant strains included 92 Klebsiella pneumoniae, 10 Escherichia coli, 10 Enterobacter cloacae, five Klebsiella aerogenes, and three Klebsiella oxytoca isolates. Seventy-four percent of these 120 CRE isolates were collected from patients located in non-ICUs; 65.0% of these CRE isolates were collected from male patients; and 34.2% of these isolates were isolated from respiratory tracts. Four different carbapenemase genes were identified among 103 carbapenemase-producing Enterobacteriaceae (CPE) isolates, including bla KPC-2 (n=77), bla NDM-1 (n=16), bla NDM-5 (n=12) and bla IMP-4 (n=2). Overall, 21.7%, 37.5%, 40.8%, 75.0%, and 100% of the CRE strains were susceptible to levofloxacin, trimethoprim/sulfamethoxazole, amikacin, CAZ/AVI, and ATM/AVI, respectively. In addition, antimicrobial susceptibility testing showed that 96.7% isolates (n=116) were resistant to aztreonam, and the addition of avibactam (4 mg/L) significantly reduced the MICs of those aztreonam-resistant isolates by more than 128-fold (range: ≤0.125-4 mg/L), and 90.0% (n=108) of total 120 isolates were inhibited at ATM/AVI concentration ≤1 mg/L. Conclusion Our study revealed significant antimicrobial resistance among the CRE isolates against some commonly used antibiotics in three secondary Chinese hospitals. ATM/AVI exhibited potent activity against CRE isolates, including double carbapenemase-producing isolates, whereas CAZ/AVI was active against all KPC producers.

A rapid colorimetric method, the Andrade screening antimicrobial test, was compared with the E-test method to detect ceftazidime/avibactam (CZA) resistance in carbapenem resistant Enterobacterales clinical isolates. A 106 non-duplicated isolates (86 susceptible and 20 resistant to CZA) were chosen for validation. The sensitivity and specificity were 100%. This method investigates CZA resistance regardless of the resistance mechanism involved. It represents an economical and easy technique that can be applied to routine microbiology laboratories. It allows the detection of CZA resistance at 3 hours of incubation and consequently, the early implementation of accurate therapeutic interventions.

Objectives The aim of this study was to investigate the molecular mechanisms of imipenem resistance in Enterobacteriaceae and to assess the antimicrobial activities of ceftazidime/avibactam (CAZ/AVI) and aztreonam/avibactam (ATM/AVI) against imipenem-resistant clinical isolates in a tertiary hospital in China. Methods A total of 91 imipenem-resistant Enterobacteriaceae were collected and genes encoding carbapenemases, ESBLs, AmpC β-lactamases and porins were detected using PCR. MICs and susceptibility were determined using in-house-prepared broth microdilution panels and were interpreted according to CLSI breakpoints. Results Imipenem-resistant isolates comprising 54 Klebsiella pneumoniae, 18 Escherichia coli, 8 Enterobacter cloacae, 6 Serratia marcescens, 3 Klebsiella oxytoca and 2 Klebsiella aerogenes were collected independently. Five different carbapenemase genes were identified, namely blaKPC-2 (n = 60), blaNDM-5 (n = 14), blaNDM-1 (n = 11), blaKPC-3 (n = 4) and blaIMP-4 (n = 1). Among the 91 carbapenem-resistant Enterobacteriaceae (CRE), 85 isolates harboured at least one ESBL and/or AmpC gene, including 5 strains without carbapenemase-encoding genes. Moreover, 31 K. pneumoniae carried ompK35 and/or ompK36 mutations. MLST results showed that the K. pneumoniae belonged to 12 different STs, with ST11 being predominant (29/54; 53.7%). Overall, 17.6%, 25.3%, 41.8%, 65.9% and 100% of the CRE strains were susceptible to amikacin, trimethoprim/sulfamethoxazole, tetracycline, CAZ/AVI and ATM/AVI, respectively. Conclusion This study revealed that CRE isolates differ significantly in their species, STs, porins and carbapenemase genes in a single Chinese hospital. ATM/AVI exhibited potent activity against CRE isolates, even for the most notorious double-carbapenemase-producers with porin defects, whereas CAZ/AVI was active against all the non-metallo-β-lactamase-producing isolates.

The resistance of Enterobacterales to carbapenems can be realized by different mechanisms, but the most common one is enzymatic, associated with the production of carbapenemases. Carbapenemases of enterobacteria are characterized by a wide variety;they are represented in three classes of beta-lactamases. The most well-known carbapenemases belong to classes A (KPC, GESenzymes), D (OXA-48), and B (metalloenzymes — NDM, VIM, IMP). Detailed clinical and microbiological characteristics of carbapenemases are given, as well as recommendations for their detection. Carbapenemases are widespread, and the paper discusses the geographical distribution of carbapenemases in different regions of the world; OXA-48 and NDM are the most widelydistributed enzymes in Russia. The clinical significance of carbapenemases and risk factors for these infections are discussed,including the following: 1) previous carbapenem therapy; 2) high levels of carbapenemases in the Department; 3) colonization of theintestine with carbapenemase-producing enterobacteria; 4) traveling to regions with a high prevalence of carbapenemases (4th and5th epidemiological levels). The possibilities of antibacterial therapy of infections caused by carbapenem-resistant enterobacteriaare discussed, the clinical and pharmacological characteristics of different antibiotics (ceftazidime/avibactam, aztreonam, carbapenems, polymyxins, tigecycline, fosfomycin), their effectiveness and treatment options are analyzed in detail. Current clinicaldata showing the effectiveness of ceftazidime/avibactam monotherapy for infections caused by carbapenemase producers OXA-48and KPC are presented. Practical issues of management of such patients are discussed. Algorithms for empirical and targeted therapy of infections caused by carbapenem-resistant enterobacteria are presented.

Introduction Carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) is increasingly reported worldwide, but ceftazidime/avibactam (CAZ/AVI)-resistant hvKP isolates have rarely been observed. We attempted to characterize them in clinical CRKP isolates collected from a university hospital in China from March 2016 to March 2018. Methods All isolates were analyzed by antimicrobial susceptibility testing, molecular detection of antibiotic resistance determinants, multilocus sequence typing (MLST), SDS-PAGE, and pulsed-field gel electrophoresis (PFGE). The pLVPK-related genetic loci (rmpA2, terW, iutA, and silS) were screened in all CAZ/AVI-resistant CRKP isolates for the presence of virulence plasmids by PCR. Capsule typing, serum killing assay, Galleria mellonella lethality experiments, and mouse lethality assay were conducted to identify CAZ/AVI-resistant hvKP among isolates that carried all four virulence genes. Results A total of 232 CRKP isolates were collected. Overall, CAZ/AVI-resistance was found in 8.2% (19/232) CRKP isolates isolated from patients with no history of previous CAZ/AVI-based treatment. Among these, 63.2% (12/19) were metallo-β-lactamase-producing K. pneumoniae (MBL-KP), 52.6% (10/19) were Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-KP), and 26.3% (5/19) produced both MBL and KPC. The presence of carbapenemase promoted a very high increase in CAZ/AVI minimum inhibitory concentration only when ompk35 and ompk36 were absent. Alarmingly, nine isolates had all four virulence genes for the presence of virulence plasmids. All nine isolates were considered to be CAZ/AVI-resistant hvKP according to the G. mellonella infection model and mouse lethality assay, with ST23 being the most common type (55.6%, 5/9). Conclusion The newly emerged hypervirulent CAZ/AVI-resistant KP strain might cause a serious threat to public health, suggesting an urgent need for enhanced clinical awareness and epidemiologic surveillance.

Background Ceftazidime/avibactam (CZA)-resistant carbapenem-resistant Klebsiella pneumoniae (CRKP) infections occur in adults worldwide but are rarely observed in neonates. We evaluated the activities of CZA against CRKP and described the clinical and molecular epidemiology of CZA-resistant CRKP in a NICU prior to CZA approval in China. Methods A laboratory-based surveillance of CRKP was conducted from July 2017 to June 2018. Clinical data were initially reviewed. Antimicrobial susceptibility was determined by the broth microdilution method. CZA-resistant CRKP isolates were submitted to carbapenemase types screening and multilocus sequence typing. Results Over 23.3% (10/43) of CRKP strains were resistant to CZA, MIC50 and MIC90 values being 0.5 μg/mL and >32μg/mL, respectively. Most neonates shared similar clinical features with cesarean (n=8), preterm birth (n=6), low birth weight (n=5), and exposure to carbapenems/β-lactam (n=8). All CZA-resistant CRKP isolates were highly resistant to most tested drugs except for polymyxin B (POL) and tigecycline (TGC). CZA-resistant CRKP isolates showed greater sensitivity to amikacin (AMK), nitrofurantoin (NIT), levofloxacin (LVX) and ciprofloxacin (CIP), compared with CZA-sensitive CRKP. All CZA-resistant CRKP isolates harbored carbapenemase genes, blakpc-2 (n=5) being predominant, followed by blaNDM-1 (n=4) and blaNDM-5 (n=2). Among these CZA-resistant CRKP isolates, a total of eight different STs were identified. CRKP harboring KPC belonged to ST1419, ST37 and ST11, while NDM types were assigned to ST784, ST1710, ST37 and ST324. Furthermore, other β-lactamase genes including blaSHV and blaCTX-M were also found. Conclusion Over 23.3% of CRKP strains isolated from neonates were resistant to CZA. Cesarean, preterm birth, low birth weight, and exposure to carbapenems/β-lactam were similar clinical features of most neonates with CZA-resistant CRKP. The predominant carbapenemases of CZA-resistant CRKP were KPC-2 and NDM-1, and KPC-2 producing K. pneumoniae assigned into 3 STs, which indicate the genetic diversity of clinical CZA-resistant CRKP isolates.

Introduction. The therapeutic options to treat Acinetobacter baumannii infections are very limited. Aim. Our aim was to evaluate the activity of sulbactam combined directly with avibactam or the ampicillin-sulbactam/ceftazidime-avibactam combination against extensively drug-resistant A. baumannii isolates. Methodology. Extensively drug-resistant A. baumannii isolates (n=127) collected at several South American hospitals were studied. Synergy with the sulbactam/avibactam combination was assessed in all isolates using the agar dilution method. Avibactam was used at a fixed concentration of 4 mg l−1. A disc diffusion synergy test was also performed. Synergy by a time-kill experiment was performed in a selected isolate. Results. Synergy with sulbactam/avibactam was demonstrated in 124 isolates and it showed MIC values ≤4 mg l−1. This synergy was not detected in the three New Delhi metallo-β-lactamase-harbouring isolates. Similar results were observed with the disc diffusion synergy test of ampicillin-sulbactam/ceftazidime-avibactam. In the time-kill experiments, sulbactam/avibactam showed a rapid synergistic and bactericidal activity in ampicillin-sulbactam-resistant isolates. Conclusions. This study demonstrated that the sulbactam/avibactam combination displayed synergistic activity against A. baumannii isolates. This synergy was observed when both inhibitors were also used as part of the commercially available combinations: ampicillin-sulbactam and ceftazidime-avibactam.

Objective: To provide a review of 3 novel antimicrobial agents—ceftazidime-avibactam, meropenem-vaborbactam, and imipenem/cilastatin-relebactam—regarding treatment of Klebsiella pneumoniae carbapenemase-producing Enterobacterales (KPC). Data Sources: A literature search of PubMed and OVID (MEDLINE) was performed up to March 2020 using the following search terms: Vabomere, meropenem-vaborbactam, vaborbactam, RPX7009, Klebsiella pneumoniae carbapenemase, KPC, carbapenem-resistant Enterobacteriaceae, CRE, relebactam, imipenem-relebactam, MK-7655, ceftazidime-avibactam. Abstracts from conferences, article bibliographies, and product information were also reviewed. Study Selection and Data Extraction: Articles were first screened by English language, then title, then abstract, and finally by review of the full article. Fifty-five clinical and preclinical studies were included. Data Synthesis: These 3 novel β-lactam/β-lactamase inhibitor combinations have shown considerable improvement in safety and efficacy as compared with traditional polymyxin-based combination therapy for the treatment of KPC infections. While meropenem-vaborbactam has not shown improved activity against Pseudomonas aeruginosa, it has shown decreased rates of resistance to KPC versus ceftazidime-avibactam. Conclusions: With increasing incidence of KPC infections on a global scale, pharmacists should be aware of the notable similarities and differences between these 3 agents, and the current data supporting their use. Pharmacists may want to consider meropenem-vaborbactam over ceftazidime-avibactam for KPC infections due to decreased likelihood of resistance.

Antimicrobial resistance poses a substantial threat to global public health. The pursuit of new antibiotics has decreased and very few options have been investigated for the treatment of complicated multidrug-resistant Gram-negative (MDR-GN) infections in adult population and even less in pediatric patients. Ceftazidime-avibactam (CAZ-AVI) is novel cephalosporin/β-lactamase inhibitor (BL-BLI) combination with broad antibacterial spectrum. The aim of this review is to describe the current and future role CAZ-AVI in the pediatric population with suspected or confirmed MDR-GN infections.

Ceftazidime-avibactam is a novel combination of a known cephalosporin and a non-β-lactam/β-lactamase inhibitor that has been approved for the treatment of complicated intra-abdominal and urinary tract infections, hospital-acquired pneumonia as well as Gram-negative infections with limited treatment options in Europe. Since its approval, it has been used in patients with infections due to carbapenem-resistant bacteria, in many occasions as off-label indication or salvage therapy, with promising clinical and microbiological cure rates. Emergence of resistance during therapy to this new combination has already been described, which is a matter of concern. A rational use of these new therapeutic options is critical in the multidrug resistance era. The current review focuses on the clinical experience in real life of ceftazidime-avibactam use in the treatment of carbapenemase-producing Enterobacterales.

Objectives We report the in vitro activity of ceftazidime/avibactam and comparators against 7729 Enterobacterales isolates and 2053 Pseudomonas aeruginosa isolates collected from six Latin American countries between 2015 and 2017. Methods A central reference laboratory performed antimicrobial susceptibility testing using broth microdilution panels according to CLSI guidelines. The presence of β-lactamases was confirmed using multiplex PCR assays. Results Susceptibility rates among Enterobacterales were highest for ceftazidime/avibactam (99.3%, MIC90 = 0.5 mg/L), meropenem (95.4%, MIC90 = 0.12 mg/L) and amikacin (93.5%, MIC90 = 8 mg/L). High susceptibility rates were observed for ceftazidime/avibactam in all six countries. The majority of carbapenemase-positive isolates among Enterobacterales (N = 366, 4.7%) were susceptible to ceftazidime/avibactam (86.9%), colistin (76.8%) and amikacin (60.9%); MBL-positive isolates (N = 49, 0.6%) were susceptible only to colistin (79.6%), with a minority susceptible to amikacin (49.0%), aztreonam and levofloxacin (both 30.6%). Highest rates of susceptibility among P. aeruginosa isolates were for colistin (99.2%) and ceftazidime/avibactam (86.6%), with rates of susceptibility to all other agents being Conclusions Ceftazidime/avibactam susceptibility rates in Latin American countries are stable and high; ceftazidime/avibactam can be an appropriate treatment for patients with infections caused by Enterobacterales or P. aeruginosa and for whom treatment options may be limited.

Aim: Escherichia coli is one of the Gram-negative bacteria, known to cause many nosocomial infections. Multi-drug (MDR) and extensively-drug resistant (XDR). E. coli are of particular note, due to significant limitations in antibiotic therapy. Ceftolozane-tazobactam and ceftazidime-avibactam are novel therapeutic options against Gram-negative bacteria; hence the aim of this study was to evaluate and compare the in vitro activity of ceftolozane-tazobactam and ceftazidime-avibactam against MDR and XDR clinical E. coli isolates. Material/Methods: The study included 100 non-replicate E. coli isolates derived from clinical samples of patients hospitalized in teaching hospitals. Bacteria were identified by applying mass spectrometry in the MALDI Biotyper system (Bruker). ESBL (blaCTX-M-1group, blaCTX-M-9group) and carbapenemase (blaKPC, blaVIM, blaNDM, blaOXA-48, blaOXA-181) genes were detected using the eazyplex® SuperBug CRE test, based on a loop-mediated isothermal amplification (LAMP). The in vitro susceptibility to ceftolozane-tazobactam and ceftazidime-avibactam was tested using validated MIC Test strips (Liofilchem). Results: All 84 extended-spectrum β-lactamase-producing (ESBL) E. coli isolates were susceptible to ceftazidime-avibactam and 83 to ceftolozane-tazobactam. Among 17 E. coli isolates with resistance to at least one of the carbapenems, three (17.6%) were susceptible to ceftolozane-tazobactam and ceftazidime-avibactam. All 14 blaVIM gene-positive E. coli isolates were resistant to both ceftolozane-tazobactam and ceftazidime-avibactam. Both antibiotics were active against blaCTX-M-9group and blaOXA-48 gene-positive E. coli isolates, but they were not active against blaCTX-M-1group and blaVIM gene-positive isolates. Conclusions: Ceftolozane-tazobactam and ceftazidime-avibactam are alternative, non-carbapenem therapeutic options for ESBL-positive E. coli strains, and they are promising in the treatment of carbapenem-resistant E. coli strains, but not for those carrying the metallo-β-lactamase enzymes. Both drug combinations have comparable activity against ESBL, however, lower MIC values were found for ceftazidime-avibactam.

Objectives This study aimed to compare the activity of ceftazidime–avibactam (C/A), ceftolozane–tazobactam (C/T) and three anti-pseudomonal β-lactams (piperacillin–tazobactam, ceftazidime and cefepime) against a collection of meropenem-non-susceptible Pseudomonas aeruginosa (P. aeruginosa) clinical isolates recovered from two centres in Turkey. Methods A total of 102 unique patient isolates of meropenem-non-susceptible P. aeruginosa were included in the study. MICs of antimicrobials were determined by the gradient diffusion method. Results Overall susceptibility rates for C/A and C/T were 83.3% and 82.4%, respectively. Both C/A and C/T had better activity than any one of the three anti-pseudomonal β-lactams. According to the MIC50 values, C/T was the most potent agent against isolates. Although the susceptibility rates of isolates to C/T and C/A were similar, C/T (MIC50, 1 μg/mL) was four-fold more potent than C/A (MIC50, 4 μg/mL). The MIC50 values of C/A and C/T for the isolates that were non-susceptible to three β-lactams were significantly higher than those for isolates that were non-susceptible to zero, one or two β-lactams. Also, the C/A MIC50 value for the isolates that were non-susceptible to two β-lactams was higher than that for isolates which were non-susceptible to one β-lactam. Conclusions C/A and C/T showed good activity against meropenem-non-susceptible P. aeruginosa isolates. However, resistance to these agents was not uncommon among these isolates. The overall β-lactam susceptibility profile of isolates seems to have an effect on the probability of susceptibility to C/A and C/T. Antimicrobial susceptibility testing should be performed for C/A and C/T if these agents are considered for treatment of infections caused by meropenem-non-susceptible P. aeruginosa.

Background Ceftazidime-avibactam has in vitro activity against some carbapenem-resistant gram-negative infections (GNIs), and therefore may be a useful alternative to more toxic antibiotics such as colistin. Understanding ceftazidime-avibactam uptake and usage patterns would inform hospital formularies, stewardship, and antibiotic development. Methods A retrospective cohort study assessed inpatient encounters in the Vizient database. Ceftazidime-avibactam and colistin administrations were categorized into presumed empiric (3 consecutive days of therapy or less with qualifying exclusions) versus targeted therapy (≥4 consecutive days of therapy) for presumed carbapenem-resistant GNIs. Quarterly percentage change (QPC) using modified Poisson regression and relative change in frequency of targeted ceftazidime-avibactam to colistin encounters was calculated. Factors associated with preferentially receiving targeted ceftazidime-avibactam versus colistin were identified using generalized estimating equations. Results Between 2015 quarter (q) 1 and 2017q4, ceftazidime-avibactam was administered 21 215 times across 1901 encounters. Inpatient prescriptions for ceftazidime-avibactam increased from 0.44/10 000 hospitalizations in 2015q1 to 7.7/10 000 in 2017q4 (QPC, +11%; 95% CI, 10–13%; P < .01), while conversely colistin prescriptions decreased quarterly by 5% (95% CI, 4–6%; P < .01). Ceftazidime-avibactam therapy was categorized as empiric 25% of the time, targeted 65% of the time, and indeterminate 10% of the time. Patients with chronic kidney disease were twice as likely to receive targeted ceftazidime-avibactam versus colistin (RR, 2.02; 95% CI, 1.82–2.25), whereas those on dialysis were less likely to receive ceftazidime-avibactam than colistin (RR, 0.71; 95% CI, .61–.83). Conclusions Since approval in 2015, ceftazidime-avibactam use has grown for presumed carbapenem-resistant GNIs, while colistin has correspondingly declined. Renal function drove the choice between ceftazidime-avibactam and colistin as targeted therapy.

Purpose Pseudomonas aeruginosa causes complicated and/or nosocomial UTI. These infections are usually associated with severe and multi-drug resistant P. aeruginosa isolates. As there is no study about the activity of novel antibiotics ceftazidime-avibactam (CZA) and ceftolozane-tazobactam (C/T) against P. aeruginosa isolates in Iran, we aimed to evaluate for the first time the efficacy of these agents against P. aeruginosa isolated from patients with UTI in Iran. Then, the genetic diversity of the resistant isolates was assayed. Methods In this study, a total of 200 P. aeruginosa isolates were collected from patients with UTI in Tehran, Iran. Disk diffusion and Minimum Inhibitory Concentration (MIC) methods were applied to determine the resistance of the isolates to CZA, C/T, and the other antibiotics. Extended-spectrum β-lactamases (ESBLs) and Metallo Beta Lactamase (MBL) production were assayed by Combination disk diffusion test (CDDT). Polymerase chain reaction (PCR) was carried out to detect the resistance genes, including beta-lactamases and carbapenemases genes. Finally, genomic analysis of the isolates was performed using the Pulse field gel electrophoresis (PFGE). Results Among the isolates, 16 (8%) were resistant to CZA and C/T that MIC confirmed it. The resistant isolates showed high resistance to the other classes of antibiotics. Among the resistant isolates, 31.2% and 75% were ESBL and MBL producers, respectively. The prevalence of blaOXA10, blaVIM, blaOXA48, blaOXA2 , and blaCTX-M was 100%, 50%, 31.2%, 25%, and 12.5%. Furthermore, two isolates (12.5%) harbored blaPER and blaNDM genes. The resistant isolates were grouped into 14 distinct pulsotypes and two shared pulsotypes were found. Conclusion Ceftazidime-avibactam and ceftolozane-tazobactam showed high activity against the P. aeruginosa isolated from patients with UTI in Iran. The low rate of resistance to the antibiotics is also alarming and should be considered to avoid further spreading of the antibiotic resistance among the P. aeruginosa and the other bacteria.

During 2014–2016, a total of 248 carbapenem-resistant Klebsiella pneumoniae (CARB-R Kp) were recovered in a Greek intensive care unit (ICU), the colistin resistance (COL-R) rates among CARB-R Kp fr...

Introduction.The most common mechanism for the resistance of gram-negative bacteria to various classes of antimicrobial agents, including carbapenems, is the production of beta-lactamases, enzymes that destroy the beta-lactam ring.Purpose of the study.To analyze the activity of ceftazidime/avibactam against pseudomonads and Klebsiella isolated in patients with severe thermal injury.Materials and methods.We analyzed 2553 isolates – pathogens of wound burn infection in patients with thermal injury treated in 2018–2019. Results and discussion. Phenotypically, 72,8% of the analyzed P. aeruginosa were resistant to carbapenems, while 56,3% of carbapenemresistant strains produce group Vim metal-beta-lactamases. Analysis of the effectiveness of ceftazidime/avibactam against P. aeruginosa showed its high efficiency, more than half of the strains (55,3%) were sensitive to the drug. The studied K. pneumoniae phenotypically in 63,1% were carbapenem-resistant. Among K. pneumoniae resistant to carbapenems, 89,3% of the strains revealed genes of serine KPC or OXA-48 like carbapenemases. In vitro ceftazidime/avibactam was active against two-thirds (72,7%) of K. pneumoniae strains.Сonclusions.1. Gram-negative microorganisms occupy 30,2% of the etiological structure of a wound burn infection. 2. Phenotypically 72,8% of Pseudomonas aeruginosa are resistant to carbapenems, 56,3% of them produce metal beta-lactamases. 3. 63,1% of Klebsiella pneumoniae isolated in patients with thermal injury are resistant to carbapenems, 89,3% of them carry cattle or OXA-48 genes like carbapenemases. 4. Ceftazidime / avibactam in vitro showed activity against P. aeruginosa and K. pneumoniae, with 55,3% and 72,7% of the strains, respectively, being sensitive.

In an infection with an Enterobacter sp. isolate producing Klebsiella pneumoniae Carbapenemase–4 and New Delhi Metallo-β-Lactamase–1 in the United States, recognition of the molecular basis of carbapenem resistance allowed for successful treatment by combining ceftazidime-avibactam and aztreonam. Antimicrobial synergy testing and therapeutic drug monitoring assessed treatment adequacy.