Can Ceftazidime-Avibactam and Aztreonam Overcome β-Lactam Resistance Conferred by Metallo-β-Lactamases in Enterobacteriaceae?
United States Department of Veterans Affairs1, Case Western Reserve University2, University of California, Los Angeles3, LAC+USC Medical Center4, University of Queensland5, National University of Rosario6, University of North Carolina at Chapel Hill7, Public Health Research Institute8, University of California, San Francisco9, Duke University10, University of North Texas Health Science Center11
01 Apr 2017-Antimicrobial Agents and Chemotherapy (American Society for Microbiology)-Vol. 61, Iss: 4
TL;DR: In vitro activity of CAZ-AVI in combination with ATM against diverse Enterobacteriaceae possessing MBLs was demonstrated, and the data presented herein require us to carefully consider this new therapeutic combination to treat infections caused by MBL-producing Enterobacteria.
Abstract: Based upon knowledge of the hydrolytic profile of major β-lactamases found in Gram-negative bacteria, we tested the efficacy of the combination of ceftazidime-avibactam (CAZ-AVI) with aztreonam (ATM) against carbapenem-resistant enteric bacteria possessing metallo-β-lactamases (MBLs). Disk diffusion and agar-based antimicrobial susceptibility testing were initially performed to determine the in vitro efficacy of a unique combination of CAZ-AVI and ATM against 21 representative Enterobacteriaceae isolates with a complex molecular background that included blaIMP, blaNDM, blaOXA-48, blaCTX-M, blaAmpC, and combinations thereof. Time-kill assays were conducted, and the in vivo efficacy of this combination was assessed in a murine neutropenic thigh infection model. By disk diffusion assay, all 21 isolates were resistant to CAZ-AVI alone, and 19/21 were resistant to ATM. The in vitro activity of CAZ-AVI in combination with ATM against diverse Enterobacteriaceae possessing MBLs was demonstrated in 17/21 isolates, where the zone of inhibition was ≥21 mm. All isolates demonstrated a reduction in CAZ-AVI agar dilution MICs with the addition of ATM. At 2 h, time-kill assays demonstrated a ≥4-log10-CFU decrease for all groups that had CAZ-AVI with ATM (8 μg/ml) added, compared to the group treated with CAZ-AVI alone. In the murine neutropenic thigh infection model, an almost 4-log10-CFU reduction was noted at 24 h for CAZ-AVI (32 mg/kg every 8 h [q8h]) plus ATM (32 mg/kg q8h) versus CAZ-AVI (32 mg/kg q8h) alone. The data presented herein require us to carefully consider this new therapeutic combination to treat infections caused by MBL-producing Enterobacteriaceae.
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TL;DR: Overall, therapy of MDR-E infection must be individualized according to the susceptibility profile, type, and severity of infection and the features of the patient.
Abstract: Therapy of invasive infections due to multidrug-resistant Enterobacteriaceae (MDR-E) is challenging, and some of the few active drugs are not available in many countries For extended-spectrum β-lactamase and AmpC producers, carbapenems are the drugs of choice, but alternatives are needed because the rate of carbapenem resistance is rising Potential active drugs include classic and newer β-lactam-β-lactamase inhibitor combinations, cephamycins, temocillin, aminoglycosides, tigecycline, fosfomycin, and, rarely, fluoroquinolones or trimethoprim-sulfamethoxazole These drugs might be considered in some specific situations AmpC producers are resistant to cephamycins, but cefepime is an option In the case of carbapenemase-producing Enterobacteriaceae (CPE), only some "second-line" drugs, such as polymyxins, tigecycline, aminoglycosides, and fosfomycin, may be active; double carbapenems can also be considered in specific situations Combination therapy is associated with better outcomes for high-risk patients, such as those in septic shock or with pneumonia Ceftazidime-avibactam was recently approved and is active against KPC and OXA-48 producers; the available experience is scarce but promising, although development of resistance is a concern New drugs active against some CPE isolates are in different stages of development, including meropenem-vaborbactam, imipenem-relebactam, plazomicin, cefiderocol, eravacycline, and aztreonam-avibactam Overall, therapy of MDR-E infection must be individualized according to the susceptibility profile, type, and severity of infection and the features of the patient
480 citations
TL;DR: New Delhi metallo-β-lactamase will remain a severe challenge in health care settings, and more studies on appropriate countermeasures are required, as commonly used phenotypic tests cannot specifically identify NDM.
Abstract: SUMMARY New Delhi metallo-β-lactamase (NDM) is a metallo-β-lactamase able to hydrolyze almost all β-lactams. Twenty-four NDM variants have been identified in >60 species of 11 bacterial families, and several variants have enhanced carbapenemase activity. Klebsiella pneumoniae and Escherichia coli are the predominant carriers of blaNDM, with certain sequence types (STs) (for K. pneumoniae, ST11, ST14, ST15, or ST147; for E. coli, ST167, ST410, or ST617) being the most prevalent. NDM-positive strains have been identified worldwide, with the highest prevalence in the Indian subcontinent, the Middle East, and the Balkans. Most blaNDM-carrying plasmids belong to limited replicon types (IncX3, IncFII, or IncC). Commonly used phenotypic tests cannot specifically identify NDM. Lateral flow immunoassays specifically detect NDM, and molecular approaches remain the reference methods for detecting blaNDM. Polymyxins combined with other agents remain the mainstream options of antimicrobial treatment. Compounds able to inhibit NDM have been found, but none have been approved for clinical use. Outbreaks caused by NDM-positive strains have been reported worldwide, attributable to sources such as contaminated devices. Evidence-based guidelines on prevention and control of carbapenem-resistant Gram-negative bacteria are available, although none are specific for NDM-positive strains. NDM will remain a severe challenge in health care settings, and more studies on appropriate countermeasures are required.
336 citations
TL;DR: The current understanding of issues related to CRE is described and combination therapeutic strategies for CRE infections, including high-dose tigecycline, high- dose prolonged-infusion of carbapenem, and double carbapENem therapy are reviewed.
Abstract: Carbapenems are considered as last-resort antibiotics for the treatment of infections caused by multidrug-resistant Gram-negative bacteria. With the increasing use of carbapenems in clinical practice, the emergence of carbapenem-resistant pathogens now poses a great threat to human health. Currently, antibiotic options for the treatment of carbapenem-resistant Enterobacteriaceae (CRE) are very limited, with polymyxins, tigecycline, fosfomycin, and aminoglycosides as the mainstays of therapy. The need for new and effective anti-CRE therapies is urgent. Here, we describe the current understanding of issues related to CRE and review combination therapeutic strategies for CRE infections, including high-dose tigecycline, high-dose prolonged-infusion of carbapenem, and double carbapenem therapy. We also review the newly available antibiotics which have potential in the future treatment of CRE infections: ceftazidime/avibactam, which is active against KPC and OXA-48 producers; meropenem/vaborbactam, which is active against KPC producers; plazomicin, which is a next-generation aminoglycoside with in vitro activity against CRE; and eravacycline, which is a tetracycline class antibacterial with in vitro activity against CRE. Although direct evidence for CRE treatment is still lacking and the development of resistance is a concern, these new antibiotics provide additional therapeutic options for CRE infections. Finally, we review other potential anti-CRE antibiotics in development: imipenem/relebactam and cefiderocol. Currently, high-dose and combination strategies that may include the new β-lactam/β-lactamase inhibitors should be considered in severe CRE infections to maximize treatment success. In the future, when more treatment options are available, therapy for CRE infections should be individualized and based on molecular phenotypes of resistance, susceptibility profiles, disease severity, and patient characteristics. More high-quality studies are needed to guide effective treatment for infections caused by CRE.
271 citations
TL;DR: This review aims to provide a summary of the existing evidence on efficacy, spectrum of activity and the development of resistance of new agents that have been licensed or have completed advanced clinical trials and that possess activity against resistant Gram-negative organisms.
211 citations
TL;DR: CAZ-AVI/ATM combination offers therapeutic advantage compared to OAAs for patients with BSI due to MBLs-producing Enterobacterales, and a matched analysis confirmed these findings.
Abstract: Background In vitro data support the use of combination of aztreonam (ATM) with ceftazidime-avibactam (CAZ-AVI), but clinical studies are lacking. The aim of our study was to compare the outcome of patients with bloodstream infections (BSIs) due to metallo-β-lactamase (MBL)-producing Enterobacterales treated either with CAZ-AVI plus ATM or other active antibiotics (OAAs). Methods This was a prospective observational study including patients admitted to 3 hospitals in Italy and Greece. The primary outcome measure was 30-day all-cause mortality. Secondary outcomes were clinical failure at day 14 and length of stay after BSI diagnosis. Cox regression analysis including a propensity score (PS) for receiving CAZ-AVI + ATM was performed to evaluate primary and secondary outcomes. A PS-based matched analysis was also performed. Results We enrolled 102 patients with BSI; 82 had infections caused by NDM-producing (79 Klebsiella pneumoniae and 3 Escherichia coli) and 20 by VIM-producing (14 K. pneumoniae, 5 Enterobacter species, 1 Morganella morganii) strains. The 30-day mortality rate was 19.2% in the CAZ-AVI + ATM group vs 44% in the OAA group (P = .007). The PS-adjusted analysis showed that the use of CAZ-AVI + ATM was associated with lower 30-day mortality (hazard ratio [HR], 0.37 [95% confidence interval {CI}, .13-.74]; P = .01), lower clinical failure at day 14 (HR, 0.30 [95% CI, .14-.65]; P = .002), and shorter length of stay (subdistributional HR, 0.49 [95% CI, .30-.82]; P = .007). The PS-matched analysis confirmed these findings. Conclusions The CAZ-AVI + ATM combination offers a therapeutic advantage compared to OAAs for patients with BSI due to MBL-producing Enterobacterales. Further studies are warranted.
155 citations
References
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01 Jan 2008
1,541 citations
Journal Article•
TL;DR: Carbapenem resistance among common Enterobacteriaceae has increased over the past decade; most CRE are associated with health-care exposures; Implications for Public Health Interventions exist that could slow the dissemination of CRE.
Abstract: Background
Enterobacteriaceae are a family of bacteria that commonly cause infections in health-care settings as well as in the community. Among Enterobacteriaceae, resistance to broad-spectrum carbapenem antimicrobials has been uncommon. Over the past decade, however, carbapenem-resistant Enterobacteriaceae (CRE) have been recognized in health-care settings as a cause of difficult-to-treat infections associated with high mortality.
457 citations
TL;DR: Ceftolozane/tazobactam and ceftazidime/avibactam are 2 new second-generation cephalosporin/β-lactamase inhibitor combinations and may prove useful in the treatment of MDR GNB infections.
Abstract: Ceftolozane/tazobactam and ceftazidime/avibactam are 2 novel β-lactam/β-lactamase combination antibiotics. The antimicrobial spectrum of activity of these antibiotics includes multidrug-resistant (MDR) gram-negative bacteria (GNB), including Pseudomonas aeruginosa. Ceftazidime/avibactam is also active against carbapenem-resistant Enterobacteriaceae that produce Klebsiella pneumoniae carbapenemases. However, avibactam does not inactivate metallo-β-lactamases such as New Delhi metallo-β-lactamases. Both ceftolozane/tazobactam and ceftazidime/avibactam are only available as intravenous formulations and are dosed 3 times daily in patients with normal renal function. Clinical trials showed noninferiority to comparators of both agents when used in the treatment of complicated urinary tract infections and complicated intra-abdominal infections (when used with metronidazole). Results from pneumonia studies have not yet been reported. In summary, ceftolozane/tazobactam and ceftazidime/avibactam are 2 new second-generation cephalosporin/β-lactamase inhibitor combinations. After appropriate trials are conducted, they may prove useful in the treatment of MDR GNB infections. Antimicrobial stewardship will be essential to preserve the activity of these agents.
414 citations
"Can Ceftazidime-Avibactam and Aztre..." refers background in this paper
...The monobactam antibiotic aztreonam (ATM) remains stable against MBLs but is not a therapeutic option in many cases because it is inactivated by ESBLs, KPCs, and other cephalosporinases frequently found in the background of MBL-producing bacteria (2, 3)....
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...In response, the “antibiotic pipeline” has delivered an important -lactam– lactamase inhibitor combination, ceftazidime-avibactam (CAZ-AVI) (2)....
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TL;DR: Exposure to duodenoscopes with bacterial contamination was associated with apparent transmission of NDM-producing E coli among patients at 1 hospital and facilities should be aware of the potential for transmission of bacteria including antimicrobial-resistant organisms via this route.
Abstract: Importance Carbapenem-resistant Enterobacteriaceae (CRE) producing the New Delhi metallo-β-lactamase (NDM) are rare in the United States, but have the potential to add to the increasing CRE burden. Previous NDM-producing CRE clusters have been attributed to person-to-person transmission in health care facilities. Objective To identify a source for, and interrupt transmission of, NDM-producing CRE in a northeastern Illinois hospital. Design, Setting, and Participants Outbreak investigation among 39 case patients at a tertiary care hospital in northeastern Illinois, including a case-control study, infection control assessment, and collection of environmental and device cultures; patient and environmental isolate relatedness was evaluated with pulsed-field gel electrophoresis (PFGE). Following identification of a likely source, targeted patient notification and CRE screening cultures were performed. Main Outcomes and Measures Association between exposure and acquisition of NDM-producing CRE; results of environmental cultures and organism typing. Results In total, 39 case patients were identified from January 2013 through December 2013, 35 with duodenoscope exposure in 1 hospital. No lapses in duodenoscope reprocessing were identified; however, NDM-producingEscherichia coliwas recovered from a reprocessed duodenoscope and shared more than 92% similarity to all case patient isolates by PFGE. Based on the case-control study, case patients had significantly higher odds of being exposed to a duodenoscope (odds ratio [OR], 78 [95% CI, 6.0-1008],P Conclusions and Relevance In this investigation, exposure to duodenoscopes with bacterial contamination was associated with apparent transmission of NDM-producingE coliamong patients at 1 hospital. Bacterial contamination of duodenoscopes appeared to persist despite the absence of recognized reprocessing lapses. Facilities should be aware of the potential for transmission of bacteria including antimicrobial-resistant organisms via this route and should conduct regular reviews of their duodenoscope reprocessing procedures to ensure optimal manual cleaning and disinfection.
341 citations
"Can Ceftazidime-Avibactam and Aztre..." refers background in this paper
...Additionally, MBLs are a worldwide problem, with outbreaks reported in the United States in numbers that were previously unanticipated (6, 7)....
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TL;DR: This “renaissance” of β-lactamase inhibitors offers new hope in a world plagued by multidrug-resistant (MDR) Gram-negative bacteria.
Abstract: As the incidence of Gram-negative bacterial infections for which few effective treatments remain increases, so does the contribution of drug-hydrolyzing β-lactamase enzymes to this serious clinical problem. This review highlights recent advances in β-lactamase inhibitors and focuses on agents with novel mechanisms of action against a wide range of enzymes. To this end, we review the β-lactamase inhibitors currently in clinical trials, select agents still in preclinical development, and older therapeutic approaches that are being revisited. Particular emphasis is placed on the activity of compounds at the forefront of the developmental pipeline, including the diazabicyclooctane inhibitors (avibactam and MK-7655) and the boronate RPX7009. With its novel reversible mechanism, avibactam stands to be the first new β-lactamase inhibitor brought into clinical use in the past 2 decades. Our discussion includes the importance of selecting the appropriate partner β-lactam and dosing regimens for these promising agents. This "renaissance" of β-lactamase inhibitors offers new hope in a world plagued by multidrug-resistant (MDR) Gram-negative bacteria.
255 citations
"Can Ceftazidime-Avibactam and Aztre..." refers background in this paper
...An unexpected benefit from using CAZ and ATM may arise by the simultaneous inhibition of multiple penicillin-binding proteins (PBPs)....
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...For CAZ and ATM, zones of inhibition were interpreted according to the Clinical and Laboratory Standards Institute (CLSI) guidelines (9)....
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...possess class C enzymes and possibly some class A ESBLs, we reasoned that AVI would prevent the hydrolysis of CAZ and ATM (10)....
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...AVI is a very potent -lactamase inhibitor of class A and C enzymes, and since most strains of Enterobacter spp. possess class C enzymes and possibly some class A ESBLs, we reasoned that AVI would prevent the hydrolysis of CAZ and ATM (10)....
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