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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.

Objectives The objective of this study was to evaluate the efficacy of different dosing regimens of ceftazidime/avibactam (CZA) in patients with Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) pulmonary infections. Methods A total of 70 KPC-Kp strains were isolated from sputum and bronchoalveolar lavage samples of patients with pulmonary infections in three hospitals in northern China from April 2015 to October 2015. Monte Carlo simulation (MCS) was performed using population pharmacokinetic parameters of CZA combined with the minimum inhibitory concentration (MIC) distributions gained from antimicrobial susceptibility testing to predict the efficacy of different dosing regimens. Various CZA dosing regimens were modelled using MCS. Results The in vitro study showed potent activity of CZA against KPC-Kp strains with MIC50/90 values of 1/2 mg/L, with a susceptibility rate of 95.7%. The values of cumulative fraction of response (CFR) for bactericidal (50%fT>5 × MIC) target were as follows: for patients with creatinine clearance (CLCr) >51 mL/min, the CFR was 96.01% for 2.5 g CZA every 12 h (q12h) and 97.14% for 2.5 g CZA every 8 h (q8h); and for patients with moderate renal impairment (CLCr >30 to ≤50 mL/min), the CFR was 95.75% for 1.25 g CZA q12h and 97.09% for 1.25 g CZA q8h. Conclusion This study indicated that the recommended dose of CZA can provide adequate pharmacodynamic exposure for treating KPC-Kp pneumonia.

Objectives Ceftazidime-avibactam (CAZ-AVI) is a promising novel agent with activity against carbapenem-resistant Enterobacteriaceae. Here, we describe the dynamic evolution of a Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) infection in a critically ill patient treated with CAZ-AVI-tigecycline combination therapy. Methods Whole-genome sequencing was performed on longitudinal intrapatient KPC-Kp strains isolated from different sites during CAZ-AVI treatment. The pharmacokinetic/pharmacodynamic (PK/PD) analysis was performed on the basis of therapeutic drug monitoring of ceftazidime. Results The development of resistance due to mutations in the blaKPC gene was observed in KPC-Kp strains isolated from bronchoalveolar lavage and blood during CAZ-AVI treatment. PK/PD analysis demonstrated that during the first days of treatment CAZ- AVI blood exposure was suboptimal (steady-state concentration/minimum inhibitory concentration ratio 2.85). Of note, the low antibiotic pressure may have selected hybrid subpopulations harboring blaKPC-3 and T243M mutation in KPC-Kp isolated from bronchoalveolar lavage and D179Y mutation in those isolated from blood. Conclusion These results suggest the high adaptability of KPC to CAZ-AVI due to the rapid evolution of resistance and highlight the importance of identifying the optimal PK/PD target to prevent such an event from occurring again in a critically ill patient with pneumonia due to KPC-Kp.

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

Objectives: Clinical experience with ceftazidime-avibactam (CAZ-AVI) for the treatment of carbapenem-resistant Klebsiella pneumoniae (CR-KP) infections is not well evaluated. The aim of this study was to assess its efficacy in a single-centre cohort of patients infected with CR-KP. Methods: We conducted a retrospective observational study of consecutive patients treated for >72 h with CAZ-AVI or other active antibiotics (OAAs) for CR-KP infections. The primary outcome was 30-d mortality. The secondary outcomes were 14-d clinical failure and 14-d microbiological failure. Multivariate regression and propensity score matching were used to evaluate the relationship between CAZ-AVI treatment and outcomes. Results: Ninety infections caused by CR-KP were documented in our study. Forty-two patients were treated with CAZ-AVI and 48 with OAAs. The crude 30-d mortality (8/42 vs. 22/48, P=0.007), 14-d clinical failure (14/42 vs. 24/48, P=0.046) and 14-d microbiological failure (11/42 vs. 15/48, P=0.034) were significantly lower in patients with CAZ-AVI treatment. The Kaplan–Meier survival curves of 30-d mortality confirmed the findings (logrank=0.004). In the multivariable models, the odds ratio (OR) of 30-d mortality (OR 0.23 95% CI 0.10–0.51, P5, OR 0.13, 95% CI 0.04–0.36, P3, OR 0.15, 95% CI 0.04–0.55, P=0.004). After propensity score matching, 29 cases from each group were well matched. The 30-d mortality remained significantly lower in the CAZ-AVI group (6/29 vs. 13/29, P=0.05). Conclusion: CAZ-AVI may be a more valuable therapeutic option for severe CR-KP infections than for mild cases and further randomized controlled trials are needed to evaluate the efficacy.

Objectives Based on recent pharmacokinetic/pharmacodynamic (PK/PD) evidence, continuous-infusion (CI) β-lactam administration is increasingly recommended for serious infections. Since 2016, the combination ceftazidime/avibactam (CAZ/AVI) is administered as per the manufacturer's instructions as an intermittent infusion of 2.5 g every 8 h. Thus, CI has not yet been evaluated in clinical trials. Methods We aimed to evaluate the use of CI of CAZ/AVI in a retrospective case series from December 2016 to October 2019. All isolates displayed in vitro susceptibility to CAZ/AVI according to EUCAST definitions. Patients were initially given CAZ/AVI as CI of 5 g every 12 h, and dosages were adjusted according to therapeutic drug monitoring of ceftazidime with a therapeutic goal of ≥4–5 × MIC in plasma and/or at the site of infection. Results CAZ/AVI was administered by CI in 10 patients with infections mainly caused by multidrug-resistant Pseudomonas aeruginosa (54.5%) and Klebsiella pneumoniae (36.4%). Bacteraemia occurred in 30% of cases. Sepsis or septic shock was present in 20% of cases. CAZ/AVI was used as monotherapy in 60% of cases. Clinical cure and microbiological eradication were achieved in 80% and 90% of cases, respectively. The 30-day mortality after CAZ/AVI treatment onset was 10%. The therapeutic goals of ≥4–5 × MIC in plasma and/or at the site of infection were achieved in 100% and 87.5% of cases, respectively, without adverse events. Conclusion Despite a limited number of patients, CI of CAZ/AVI provided promising results after optimisation of PK/PD parameters both in plasma and at the site of infection.

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-...

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.

Introduction. Penile cancer (pc) is a rare cancer. The standardized incidence rate of pc in russia is 0.82 cases per 100,000 males. On average, 58 % of patients (20–96 %) with pc have a local infection process: tumor decay, the presence of erosion, tumor ulceration, inflammatory changes in regional lymph nodes, etc. During hospitalization nosocomial pathogens may be possible causes of infection in ulcerative lesions.The aim of the study was to present the results of the treatment of tumor ulcer in a patient with penile cancer infected with multiresistant acinetobacter baumannii and klebsiella pneumoniae.Material and methods. We present a clinical observation of 54-year-old patient diagnosed with penile cancer pt4n3m0, with ulceration of the tumor, localized at the root of the penis and ulceration of metastatic lymph nodes in the left inguinal region and subsequent infection with highly resistant nosocomial microorganisms.Results. The patient received 6 courses of paclitaxel, ifosfamide and cisplatin with clinical effect, such as significant reduction of the tumor and therapeutic pathomorphosis of 3-rd degree. Then ileo-inguinal lymphadenectomy was performed on the left. A few months later the tumor continued to grow in the left groin area. During the 2nd line of chemotherapy (cisplatin, docetaxel and capecitabine), the patient had grade iii–iv neutropenia, febrile neutropenia. High fever and localized infection in the area of tumor ulceration with multiresistant hospital microorganisms was detected. Combined antibiotic therapy had temporary effect. After isolation of multiresistant carbapenemresistant k. Pneumoniae from the ulcer, the patient was prescribed ceftazidim/avibactam 2.5 g 3 times a day. Clinical effect, such as defervescence and significant reduction of the ulceration zone was seen subsequently.Conclusion. Etiotropic antibacterial therapy of the infected tumor ulcer resulted in a significant reduction in the manifestation of the infection process, allowing antitumor therapy to be continued, as well as surgery to be performed.

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.

Worapong Nasomsong,1 Parnrada Nulsopapon,2,3 Dhitiwat Changpradub,1 Manat Pongchaidecha,2 Supanun Pungcharoenkijkul,4 Piraporn Juntanawiwat,5 Waristha Simsiriporn,5 Wichai Santimaleeworagun2,3 1Division of Infectious Diseases, Department of Internal Medicine, Phramongkutklao Hospital and College of Medicine, Bangkok, Thailand; 2Department of Pharmacy, Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, Thailand; 3Pharmaceutical Initiative for Resistant Bacteria and Infectious Diseases Working Group [PIRBIG], Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, Thailand; 4Pharmacy Unit, Nopparat Rajathanee Hospital, Bangkok, Thailand; 5Division of Microbiology, Department of Clinical Pathology, Phramongkutklao Hospital, Bangkok, ThailandCorrespondence: Wichai SantimaleeworagunDepartment of Pharmacy, Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, 73000, ThailandTel +6634 255 800Fax +6634 255 801Email swichai1234@gmail.comPurpose: MBL and OXA-48 genes in carbapenem-resistant Enterobacterales (CRE) have emerged as a major public health problem worldwide, including Thailand. Due to the lack of susceptibility data and dosing regimens of ceftazidime-avibactam (CZA) against CRE in Thailand, especially in colistin-resistant era, we aimed to demonstrate in vitro susceptibility data of CZA and optimal dose based on Monte Carlo simulation of CZA to expand the treatment options.Patients and Methods: We collected 49 carbapenem-resistant Klebsiella pneumoniae (CRKP) clinical isolates from unique patients at Phramongkutklao Hospital (June–October 2020). CZA disk diffusion and E-test testing were performed to obtain minimum inhibitory concentration (MIC). Each drug regimen was simulated using the Monte Carlo technique to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR).Results: The most common genotypes of CRKP were blaOXA-48 (53.1%) and blaOXA-48 +blaNDM (42.8%). CZA showed 47.7% and 90.5% susceptible rate against all genotypes of carbapenemases and OXA-48 type CRKP isolates. The MIC50 and MIC90 of CZA against CRKP were 2 and > 256 μg/mL. The categorical agreement (CA) between disk diffusion and E-test testing of CZA against CRKP was 95.4%. The CZA dosing regimens of 2.5 g infused 2– 3 h every 8 h achieved ≥ 90% of the target of free ceftazidime plasma concentration over MIC (%fTime >MIC) ≥ 50% and 100% against isolates MICs of ≤ 8 and ≤ 8 μg/mL, respectively. The avibactam regimens also provided 100%fTime at 0.5 μg/mL. Based on CFR ≥ 90%, no CZA regimens were effective against all of the studied CRKP isolates except CRKP carrying OXA-48.Conclusion: CZA exhibited a fairly susceptible rate among the OXA-48-positive isolates in Thailand. The current suggested dose of CZA with prolonged infusion appears appropriate to achieve the pharmacokinetic/pharmacodynamic targets of ceftazidime and avibactam against CRKP carrying blaOXA-48.Keywords: CRE, metallo-beta-lactamase, Monte Carlo, oxacillinase

Background . Ceftazidime/Avibactam (C/A) and Ceftolozane/Tazobactam (C/T) are two novel antibacterial agents with a known efficacy on Gram-negative bacteria (GNB). Objectives . We aimed to describe the efficacy and safety of surgical management combined with C/A or C/T treatment for bone and joint infections (BJI). Patients and Methods . We conducted an observational, bi-centric study of patients treated with C/A or C/T for a BJI between May 2016 and June 2019. Failure was defined as a need for an unplanned additional antibiotic treatment or orthopedic surgery or death due to the BJI until the patient's latest visit. Results . Overall, 15 patients were included. Nine patients were treated with C/A, mainly for polymicrobial BJI due to multidrug-resistant (MDR) bacteria (Enterobacteriaceae n=7). Six patients were male; median age was 66 years-old, and median Charlson comorbidity index (CCI) was 5. It was the first septic episode on the site in 3/9 patients. Cure rate was 7/9 (median follow-up: 272 days). Two patients showed C/A-related confusion. Five patients were treated with C/T, for BJI involving MDR-Pseudomonas aeruginosa. Four patients were male; median age was 53 years-old, and median-CCI was 2. All patients had previous septic episodes on infectious site. Cure rate was 3/5 (median follow-up: 350 days). One patient was successfully treated by C/T then C/A for multistage spondylodiscitis. Conclusion . In our experience, C/A and C/T were two effective and safe options, even as salvage treatment of BJI due to MDR GNB despite the absence of label, but more data are warranted.

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.

Qian Zhou,1 Hao Wang,2 Tianxiang Zhan,2 Xiaofeng Yang,1,2 Liang Wen2 1Department of Emergency and Trauma Center, The International Medical Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310003, People’s Republic of China; 2Department of Neurosurgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310003, People’s Republic of ChinaCorrespondence: Liang WenDepartment of Neurosurgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang Province, People’s Republic of ChinaEmail wenliang@zju.edu.cnXiaofeng YangDepartment of Emergency and Trauma Center, The International Medical Center, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang Province, People’s Republic of ChinaEmail zjcswk@zju.edu.cnBackground: Central nervous system (CNS) infections caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacillus, including carbapenem-resistant Enterobacteriaceae (CRE) and Pseudomonas aeruginosa, are associated with high mortality rates. Clinical trials of ceftazidime/avibactam (CAZ/AVI) on infections of other systems indicate that they are effective against these infections. However, clinical studies on the efficacies of CAZ/AVI in the treatment of CNS infections have not been done.Case Presentation: We evaluated 3 patients diagnosed with MDR/XDR Gram-negative bacillus-associated CNS infections, and effectively treated with CAZ/AVI. Moreover, we performed literature reviews. Before the onset of CNS infections, the 3 patients were subjected to neurosurgical operations, treated with mechanical ventilation, long-term intensive care unit therapy, and various antibiotics. By intravenously administering CAZ/AVI, combined with another antibiotic, the MDR/XDR K. pneumoniae and P. aeruginosa associated ventriculitis was effectively treated in the 3 patients.Conclusion: CAZ/AVI is a viable treatment option for CNS infections caused by MDR/XDR Gram-negative bacteria.Keywords: ceftazidime–avibactam, extensively drug-resistant Gram-negative bacillus, Klebsiella pneumoniae, Pseudomonas aeruginosa, ventriculitis infection

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 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...

The spread of metallo-β-lactamase (MBL)-producing Enterobacterales worldwide without the simultaneous increase in active antibiotics makes these organisms an urgent public health threat. This review summarizes recent advancements in diagnostic and treatment strategies for infections caused by MBL-producing Enterobacterales. Adequate treatment of patients infected with MBL-producing Enterobacterales relies on detection of the β-lactamase in the clinic. There are several molecular platforms that are currently available to identify clinically relevant MBLs as well as other important serine-β-lactamases. Once detected, there are several antibiotics that have historically been used for the treatment of MBL-producing Enterobacterales. Antimicrobials such as aminoglycosides, tetracyclines, fosfomycin, and polymyxins often show promising in vitro activity though clinical data are currently lacking to support their widespread use. Ceftazidime-avibactam combined with aztreonam is promising for treatment of infections caused by MBL-producing Enterobacterales and currently has the most clinical data of any available antibiotic to support its use. While cefiderocol has displayed promising activity against MBL-producing Enterobacterales in vitro and in preliminary clinical studies, further clinical studies will better shed light on its place in treatment. Lastly, there are several promising MBL inhibitors in the pipeline, which may further improve the treatment of MBL-producing Enterobacterales.

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.

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.

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.

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.

Infections are a common complication in patients with hematological malignancies, especially during neutropenia. Recently, an increase in multidrug-resistant gram-negative pathogens has been observed in the etiology of infectious complications, including carbapenem-resistant Enterobacteriaceae. However, therapeutic options for treatment of these infections are limited. The review represents treatment options for infections caused by carbapenem-resistant Enterobacteriaceae, including the use of reserve drugs such as polymyxin, carbapenems, tigecycline, as well as a new antibiotic – ceftazidime-avibactam, which contains a new β-lactamase inhibitor with unique properties.

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.

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.

Introduction Ceftazidime–avibactam combines the established anti-pseudomonal cephalosporin, ceftazidime, with the novel non-β-lactam β-lactamase inhibitor, avibactam. Objectives The aim of this study was to evaluate the safety of ceftazidime–avibactam in adults using pooled data from two phase II (NCT00690378, NCT00752219) and five phase III (NCT01499290, NCT01726023, NCT01644643, NCT01808093 and NCT01595438/NCT01599806) clinical studies. Methods Safety data from seven multicentre, randomised, active-comparator studies were pooled by study group at the patient level for descriptive analyses, comprising patients with complicated urinary tract infection (cUTI), including pyelonephritis, complicated intra-abdominal infection (cIAI), or nosocomial pneumonia (NP), including ventilator-associated pneumonia (VAP), treated with ceftazidime–avibactam ± metronidazole or comparator. Results In total, 4050 patients (ceftazidime–avibactam ± metronidazole, n = 2024; comparator, n = 2026) were included in the pooled analysis. Adverse events (AEs) up to the last study visit occurred in 996 (49.2%) and 965 (47.6%) patients treated with ceftazidime–avibactam ± metronidazole and comparator, respectively. The most common AEs across treatment groups were diarrhoea, nausea, headache, vomiting and pyrexia. There were few discontinuations due to AEs (2.5% and 1.7% for ceftazidime–avibactam ± metronidazole and comparators, respectively). Overall rates of serious AEs were 8.7% for ceftazidime–avibactam ± metronidazole and 7.2% for comparators; respective rates of AEs with an outcome of death were 2.0% and 1.8%. AEs considered causally related to the study drug or procedures occurred in 10.7% and 9.6% of patients treated with ceftazidime–avibactam ± metronidazole and comparators; the most common drug-related AEs in both groups were diarrhoea, headache, nausea and increased alanine aminotransferase. No impact to the safety profile of ceftazidime–avibactam ± metronidazole was found with regard to intrinsic factors, such as age or renal function at baseline, or extrinsic factors, such as geographical origin. Potentially clinically significant changes in laboratory parameters were infrequent with no trends or safety concerns identified. Conclusion The observed safety profile of ceftazidime–avibactam across infection types is consistent with the established safety profile of ceftazidime monotherapy and no new safety findings were identified. This analysis supports the use of ceftazidime–avibactam as a treatment option in adults with cUTI, cIAI and NP, including VAP. Electronic supplementary material The online version of this article (10.1007/s40264-020-00934-3) contains supplementary material, which is available to authorized users.

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.

الملخص: أهداف البحث: اختبار حساسية الزائفة الزنجارية للأدوية المستخدمة بشكل روتيني، واثنين من مضادات الميكروبات المتوفرة مؤخرا، سفتازديم افيباكتام وسفتالوزين تازوباكتام اللذين لم يتم تقييمها بعد في المملكة العربية السعودية. طرق البحث: تم تضمين سلالات غير متكررة من الزائفة الزنجارية المعزولة من المرضى الداخليين بين ديسمبر ٢٠١٨ وأبريل ٢٠١٩. تم التعرف عليها باستخدام نظام مخبري آلي كما تم تحديد النمط الظاهري وإجراء اختبار الحساسية الأولية للميكروب. استكملنا هذه الاختبارات بتحديد الحد الأدنى من التركيز المثبط لأربعة مضادات حيوية للميكروب هي الاميبنم والميروبنم وسفتازديم افيباكتام وسفتالوزين تازوباكتام وفقا لأنظمة معهد المعايير السريرية والمخبرية. النتائج: تم الحصول على ما مجموعه ٦٧ سلالة من الزائفة الزنجارية، بما في ذلك ٣٨ سلالة مقاومة للأدوية المتعددة، من عينات مختلفة. تم الحفاظ على القابلية للعديد من الأمينوغليكوزيدات والفلوروكينولونات المختبرة. كانت السلالات عرضة للعوامل التالية بترتيب تصاعدي: سفتازديم (٣٢.٨٪)، سيفيبيم (٣٧.٣٪)، اميبنيم (٣٦٪) وبيبراسلين تازوباكتام (٣٩٪) ثم ميروبينيم (٤٤.٨٪) وسفتازديم افيباكتام (٦١،٢٪) وسفتالوزين تازوباكتام (٦٢.٧٪). كانت معدلات حساسية السلالات المقاومة للأدوية لكل من سفتازديم افيباكتام وسفتالوزين تازوباكتام أقل من ٣٥٪ كما تم اكتشاف مستويات عالية من المقاومة للأدوية الجديدة في ٢١ و٢٢ عزلة بكتيرية. الاستنتاجات: تظهر نتائج الدراسة محدودية الاستخدام التجريبي لسفتازديم افيباكتام وسفتالوزين تازوباكتام كعلاجات للعدوى الخطيرة. علاوة على ذلك، تسلط بياناتنا الضوء على الحاجة إلى اختبار حساسية سريع للميكروبات لتوجيه استخدامها السريري. Abstract: Objectives: We conducted this study to test the susceptibility of P. aeruginosa to the routinely used drugs and to the two recently available antimicrobial agents, ceftazidime-avibactam and ceftolozane-tazobactam. Methods: We isolated the non-replicate strains of P. aeruginosa from inpatients between December 2018 and April 2019. The VITEK® MS system was used for phenotypic identification and VITEK 2 for initial antimicrobial susceptibility testing. We supplemented these tests with determination of the minimum inhibitory concentration (MIC) of four antimicrobials; imipenem, meropenem, ceftazidime-avibactam and ceftolozane-tazobactam. The standards of the Clinical and Laboratory Standards Institute were followed. Results: A total of 67 strains of P. aeruginosa, including 38 multidrug-resistant strains, were obtained from various specimens. Susceptibility to various tested aminoglycosides and fluoroquinolones was maintained in 49.3–56.7% and 40.0–43.3% of the total isolates. Amongst β-lactams, the strains were susceptible to the following agents in an ascending order: ceftazidime (32.8%), cefepime (37.3%), imipenem (36.0%), piperacillin-tazobactam (39.0%), meropenem (44.8%), ceftazidime-avibactam (61.2%) and ceftolozane-tazobactam (62.7%). The susceptibility rates of the multidrug-resistant strains to both ceftazidime-avibactam and ceftolozane-tazobactam were less than 35%. High levels of resistance to the new agents (MIC > 256 ug/ml) were detected in 21 and 22 isolates. Conclusion: Our study shows limitation in the empirical use of ceftazidime-avibactam and ceftolozane-tazobactam as therapeutics in serious infections. Moreover, our data highlights the need for prompt antimicrobial susceptibility testing to guide their clinical usage.

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.

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.

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...

Objectives The objective of this study was to analyse the cost-effectiveness (C-E) of ceftazidime/avibactam (CAZ/AVI)-based therapy versus colistin (COL)-based therapy for pneumonia and bacteraemia caused by carbapenem-resistant enterobacteria (CRE) adjusted to Peruvian context. Methods A Markov decision model was extrapolated from literature to evaluate the clinical and economic consequences of CAZ/AVI-based therapy compared to COL-based therapy for a hypothetical cohort of patients with CRE pneumonia or bacteraemia according to Peruvian context. It was adopted a 5-year time horizon and a Markov-cycle length of 1 year. All patients in the model were assigned to CRE pneumonia or bacteraemia state and may transit through four different health states: home-care, long-term care without dialysis, long-term care with dialysis or death. Key findings Intervention with CAZ/AVI becomes progressively more cost-effective from a threshold of S/ 24,000 or US$ 6666 (equivalent to 1 Gross Domestic Product-per cápita [GDP-pc]). The model simulation allowed to calculate an average total cost of S/ 2’971,582 (US$ 825,440) for CAZ/AVI against S/2’056,488 (US$ 571.247) for COL treatment, yielding an incremental cost of S/ 915,094 (US$ 254,193). The cost/QALY for CAZ/AVI treatment against COL therapy approaches to S/23,154 (US$ 6432), something less than 1 annual GDP-pc. There were additional benefits associated with CAZ/AVI in the 5-year horizon, such as: 21 deaths avoided, 86 hospital days avoided, 1 CRF5 avoided and a NMB of S/6649 (US$ 1847). Conclusions The present transferability model demonstrates the C-E of CAZ/AVI over COL for the treatment of bacteraemia and CRE pneumonia according to peruvian payment thresholds.

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.

Purpose Ceftazidime–avibactam is a novel β-lactam/β-lactamase inhibitor combination recently approved in Europe and the USA for the treatment of adults with hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), among other indications. In the phase III REPROVE trial (NCT01808092), ceftazidime–avibactam demonstrated non-inferiority to meropenem for the treatment of patients with nosocomial pneumonia (NP), including VAP. As ceftazidime–avibactam was not studied in patients with NP prior to REPROVE, selecting an appropriate dosage regimen in the “perfect storm” of NP required careful consideration of potential determinants and confounders of response specific to the NP patient population. Methods This review describes the series of preclinical studies and pharmacokinetic/pharmacodynamic (PK/PD) analyses that supported ceftazidime–avibactam dosage selection for patients with NP/VAP (2000/500 mg by 2-h intravenous infusion every 8 h, adjusted for renal function). In parallel, important considerations for antibiotic dosage selection in patients with NP are highlighted, including adequate drug penetration into the lungs, the suitability of murine-derived plasma PK/PD targets, evaluation of MIC distributions against clinical bacterial isolates from patients with NP, and consideration of PK in patients with NP, who are often critically ill. These analyses also supported the European approval of ceftazidime–avibactam for adults with HAP, including VAP, before the completion of REPROVE. Conclusions This work serves as a successful practical example of dosage design for a new antibacterial drug therapy in the indication of NP, including VAP, where previous drug therapies have failed, possibly as a result of evaluation of too few variables, thereby limiting the accuracy of pharmacodynamic predictions.

Background The rising incidence of resistance to currently available antibiotics among pathogens, particularly Gram-negative pathogens, in complicated intra-abdominal infections (cIAIs) has become a challenge for clinicians. Ceftazidime/avibactam (CAZ-AVI) is a fixed-dose antibiotic approved in Europe and the United States for treating (in combination with metronidazole) cIAI in adult hospitalised patients who have limited or no alternative treatment options. The approval was based on the results of RECLAIM, a Phase III, parallel-group, comparative study (RECLAIM 1 [NCT01499290] and RECLAIM 2 [NCT01500239]). The objective of our study was to assess the cost-effectiveness of CAZ-AVI plus metronidazole compared with 1) ceftolozane/tazobactam plus metronidazole and 2) meropenem, as an empiric treatment for the management of cIAI in Italy. Methods A sequential, patient-level simulation model, with a 5-year time horizon and 3% annual discount rate (applied to both costs and health benefits), was developed using Microsoft Excel® to demonstrate the clinical course of the disease. The impact of resistant pathogens was included as an additional factor. Results In the base-case analysis, the CAZ-AVI sequence (CAZ-AVI plus metronidazole followed by a colistin + tigecycline + high-dose meropenem combination after treatment failure), when compared to sequences for ceftolozane/tazobactam (ceftolozane/tazobactam plus metronidazole followed by colistin + tigecycline + high-dose meropenem after treatment failure) and meropenem (meropenem followed by colistin + tigecycline + high-dose meropenem after treatment failure), had better clinical outcomes with higher cure rates (93.04% vs. 91.52%; 92.98% vs. 90.24%, respectively), shorter hospital stays (∆ = − 0.38 and ∆ = − 1.24 days per patient, respectively), and higher quality-adjusted life years (QALYs) gained per patient (4.021 vs. 3.982; 4.019 vs. 3.960, respectively). The incremental cost effectiveness ratio in the CAZ-AVI sequence was €4099 and €15,574 per QALY gained versus each comparator sequence, respectively, well below the willingness-to-pay threshold of €30,000 per QALY accepted in Italy. Conclusions The model results demonstrated that CAZ-AVI plus metronidazole could be a cost-effective alternative when compared with other antibiotic treatment options, as it is expected to provide better clinical benefits in hospitalised patients with cIAI in Italy.