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Journal ArticleDOI

The β-Lactams Strike Back: Ceftazidime-Avibactam.

TL;DR: The current body of evidence suggests that ceftazidime‐avibactam is a promising addition to the therapeutic armamentarium with potential to answer an urgent unmet medical need.
Abstract: Gram-negative resistance has reached a crucial point, with emergence of pathogens resistant to most or all available antibiotics. Ceftazidime-avibactam is a newly approved agent combining ceftazidime and a novel β-lactamase inhibitor with activity against multidrug-resistant gram-negative bacteria. Avibactam has increased potency and expanded spectrum of inhibition of class A and C β-lactamases relative to available β-lactamase inhibitors, including extended-spectrum β-lactamases, AmpC, and Klebsiella pneumoniae carbapenemase (KPC) enzymes. Avibactam expands ceftazidime's spectrum of activity to include many ceftazidime- and carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa. Early clinical data indicate that ceftazidime-avibactam is effective and well tolerated in patients with complicated urinary tract infections (cUTIs) and complicated intraabdominal infections (cIAI). In a phase II trial of patients with cUTIs, ceftazidime-avibactam produced similar rates of clinical and microbiologic success compared with imipenem-cilastatin (70.5% and 71.4% microbiologic success rates, respectively). Likewise, patients receiving ceftazidime-avibactam plus metronidazole in a phase II study of patients with cIAI had similar response rates to those receiving meropenem (91.2% and 93.4% clinical success rates, respectively). Based on available in vitro, in vivo, and phase II trial data, as well as preliminary phase III trial results in ceftazidime-resistant, gram-negative cUTI and cIAI, ceftazidime-avibactam received U.S. Food and Drug Administration approval for treatment of cUTI, including pyelonephritis, and cIAI, in combination with metronidazole, in adult patients with limited or no alternative treatment options. The approved dosage, ceftazidime 2 g-avibactam 0.5 g administered as a 2-hour infusion every 8 hours, was selected based on pharmacodynamic analysis and available clinical data. This dosage is under further investigation in patients with cUTI, cIAI, and nosocomial or ventilator-associated pneumonia. The current body of evidence suggests that ceftazidime-avibactam is a promising addition to our therapeutic armamentarium with potential to answer an urgent unmet medical need. Further data in highly resistant gram-negative infections, particularly those caused by KPC-producing Enterobacteriaceae, are needed. As it is introduced into clinical use, careful stewardship and rational use are essential to preserve ceftazidime-avibactam's potential utility.
Citations
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Journal ArticleDOI
01 Feb 2016
TL;DR: Important key points related to carbapenem resistance are reviewed and future perspectives are discussed.
Abstract: Carbapenem resistance, mainly among Gram-negative pathogens, is an ongoing public-health problem of global dimensions. This type of antimicrobial resistance, especially when mediated by transferable carbapenemase-encoding genes, is spreading rapidly causing serious outbreaks and dramatically limiting treatment options. In this article, important key points related to carbapenem resistance are reviewed and future perspectives are discussed.

412 citations


Cites background or methods from "The β-Lactams Strike Back: Ceftazid..."

  • ...ceftazidime-avibactam has been made available recently [Zasowski et al. 2015]....

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  • ...Despite the difficulties though, a new compound, ceftazidime-avibactam has been made available recently [Zasowski et al. 2015]....

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Journal ArticleDOI
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


Cites background from "The β-Lactams Strike Back: Ceftazid..."

  • ...However, relebactam cannot inhibit Class D OXA-48 like avibactam (Petty et al., 2018; Zhanel et al., 2018)....

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  • ...One in vitro study reported variable synergistic patterns among KPC and OXA-48 producers, while no synergism was observed for the NDM-producing strain (Poirel et al., 2016)....

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  • ...Some carbapenem-producing Enterobacteriaceae (CPE) are even susceptible to carbapenems themselves and this is particularly observed in OXA-48 producers (Dautzenberg et al., 2014; Navarro-San Francisco et al., 2013)....

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  • ...Avibactam inhibits both Class A KPC and Class D OXA-48 (Zasowski et al., 2015), while vaborbactam and relebactam inhibits only Class A KPC (Petty et al., 2018; Zhanel et al., 2018) (Table 1)....

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  • ...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....

    [...]

Journal ArticleDOI
TL;DR: The different classes of beta-lactam antibiotics (penicillins, cephalosporins, carbapenems, monobactams and penems) are discussed in light of their stability, sensitivity to β- lactamases, mechanism of action and spectrum of antimicrobial activity.

154 citations

Journal ArticleDOI
TL;DR: Observational studies and randomized clinical trials of CRE treatment are summarized, with a specific focus on the effects of monotherapy compared with combination treatment and a high risk of selection bias.

138 citations

Journal ArticleDOI
TL;DR: Microbiological surveillance studies, in vivo animal models of infection and pharmacokinetic/pharmacodynamic target attainment analyses are discussed, to assess the potential role of this new drug in the treatment of infections caused by MDR GNB.
Abstract: During the last decade infections caused by MDR Gram-negative bacteria (GNB) have become increasingly prevalent. Because of their high morbidity and mortality rates, these infections constitute a serious threat to public health worldwide. Ceftazidime/avibactam is a new approved agent combining ceftazidime and a novel β-lactamase inhibitor with activity against various β-lactamases produced by MDR GNB. Avibactam has a spectrum of inhibition of class A and C β-lactamases, including ESBLs, AmpC and Klebsiella pneumoniae carbapenemase (KPC) enzymes. Thus, combination with this inhibitor expands ceftazidime's spectrum of activity to MDR Enterobacteriaceae and Pseudomonas aeruginosa strains. In Phase II clinical trials of patients with complicated intra-abdominal infections and complicated urinary tract infections ceftazidime/avibactam exhibited clinical efficacy comparable to those of meropenem and imipenem/cilastatin, respectively. A Phase III clinical trial confirmed the efficacy of ceftazidime/avibactam in patients with MDR Enterobacteriaceae and P. aeruginosa infections. Microbiological surveillance studies, in vivo animal models of infection and pharmacokinetic/pharmacodynamic target attainment analyses are also discussed, to assess the potential role of this new drug in the treatment of infections caused by MDR GNB.

136 citations

References
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Journal Article
TL;DR: The physician's role in this effort to prevent and controlling resistance is singularly important and requires the engagement of many different sectors of society.
Abstract: Preventing and controlling resistance requires the engagement of many different sectors of society. However, the physician's role in this effort is singularly important.

2,189 citations


"The β-Lactams Strike Back: Ceftazid..." refers background or methods in this paper

  • ...” Gram-negative resistance is at the forefront of the discussion, with the Centers for Disease Control and Prevention’s list of top antibiotic resistance threats dominated by gram-negative organisms.(1) This includes the major gram-negative nosocomial pathogens such as multidrug-resistant (MDR) Acinetobacter species and Pseudomonas aeruginosa, extended-spectrum b-lactamase (ESBL)-producing Enterobacteriaceae, and carbapenem-resistant Enterobacteriaceae (CRE)....

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  • ...According to the Centers for Disease Control and Prevention, CRE are the most urgent unmet medical need that can potentially be addressed by ceftazidime-avibactam.(1) Through potential improvements in clinical efficacy and spared use of more toxic treatment alternatives, such as polymyxin-containing regimens, ceftazidime-avibactam may have a profound impact on the outcomes of patients with CRE infections....

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Journal ArticleDOI
TL;DR: In this paper, the authors review the catalytic mechanisms of each β-lactamase class and discuss approaches for circumventing β-latamase-mediated resistance, including properties and characteristics of mechanism-based inactivators.
Abstract: Summary: Since the introduction of penicillin, β-lactam antibiotics have been the antimicrobial agents of choice. Unfortunately, the efficacy of these life-saving antibiotics is significantly threatened by bacterial β-lactamases. β-Lactamases are now responsible for resistance to penicillins, extended-spectrum cephalosporins, monobactams, and carbapenems. In order to overcome β-lactamase-mediated resistance, β-lactamase inhibitors (clavulanate, sulbactam, and tazobactam) were introduced into clinical practice. These inhibitors greatly enhance the efficacy of their partner β-lactams (amoxicillin, ampicillin, piperacillin, and ticarcillin) in the treatment of serious Enterobacteriaceae and penicillin-resistant staphylococcal infections. However, selective pressure from excess antibiotic use accelerated the emergence of resistance to β-lactam-β-lactamase inhibitor combinations. Furthermore, the prevalence of clinically relevant β-lactamases from other classes that are resistant to inhibition is rapidly increasing. There is an urgent need for effective inhibitors that can restore the activity of β-lactams. Here, we review the catalytic mechanisms of each β-lactamase class. We then discuss approaches for circumventing β-lactamase-mediated resistance, including properties and characteristics of mechanism-based inactivators. We next highlight the mechanisms of action and salient clinical and microbiological features of β-lactamase inhibitors. We also emphasize their therapeutic applications. We close by focusing on novel compounds and the chemical features of these agents that may contribute to a “second generation” of inhibitors. The goal for the next 3 decades will be to design inhibitors that will be effective for more than a single class of β-lactamases.

1,225 citations

Journal ArticleDOI
TL;DR: This survey demonstrates some progress in development of new antibacterial drugs that target infections caused by resistant GNB, but progress remains alarmingly elusive.
Abstract: Infections caused by antibiotic-resistant bacteria, especially the “ESKAPE” pathogens, continue to increase in frequency and cause significant morbidity and mortality. New antimicrobial agents are greatly needed to treat infections caused by gram-negative bacilli (GNB) resistant to currently available agents. The Infectious Diseases Society of America (IDSA) continues to propose legislative, regulatory, and funding solutions to this continuing crisis. The current report updates the status of development and approval of systemic antibiotics in the United States as of early 2013. Only 2 new antibiotics have been approved since IDSA's 2009 pipeline status report, and the number of new antibiotics annually approved for marketing in the United States continues to decline. We identified 7 drugs in clinical development for treatment of infections caused by resistant GNB. None of these agents was included in our 2009 list of antibacterial compounds in phase 2 or later development, but unfortunately none addresses the entire spectrum of clinically relevant GNB resistance. Our survey demonstrates some progress in development of new antibacterial drugs that target infections caused by resistant GNB, but progress remains alarmingly elusive. IDSA stresses our conviction that the antibiotic pipeline problem can be solved by the collaboration of global leaders to develop creative incentives that will stimulate new antibacterial research and development. Our aim is the creation of a sustainable global antibacterial drug research and development enterprise with the power in the short term to develop 10 new, safe, and efficacious systemically administered antibiotics by 2020 as called for in IDSA's “10 × '20 Initiative.”

649 citations

Journal ArticleDOI
TL;DR: It is shown that avibactam is a covalent, slowly reversible inhibitor, which is a unique mechanism of inhibition among β-lactamase inhibitors.
Abstract: Avibactam is a β-lactamase inhibitor that is in clinical development, combined with β-lactam partners, for the treatment of bacterial infections comprising Gram-negative organisms. Avibactam is a structural class of inhibitor that does not contain a β-lactam core but maintains the capacity to covalently acylate its β-lactamase targets. Using the TEM-1 enzyme, we characterized avibactam inhibition by measuring the on-rate for acylation and the off-rate for deacylation. The deacylation off-rate was 0.045 min−1, which allowed investigation of the deacylation route from TEM-1. Using NMR and MS, we showed that deacylation proceeds through regeneration of intact avibactam and not hydrolysis. Other than TEM-1, four additional clinically relevant β-lactamases were shown to release intact avibactam after being acylated. We showed that avibactam is a covalent, slowly reversible inhibitor, which is a unique mechanism of inhibition among β-lactamase inhibitors.

415 citations

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