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Norelle Sherry, Benjamin Howden
Multidrug-resistant (MDR) and extensively-drug-resistant (XDR) Gram-negative bacteria have emerged as a major threat to human health globally. This has resulted in the "re-discovery" of some older antimicrobials and development of new agents, however resistance has also rapidly emerged to these agents. Areas Covered: Here we describe recent developments in resistance to three of the most important last-line antimicrobials for treatment of MDR and XDR Gram negatives: fosfomycin, colistin and ceftazidime-avibactam...
March 15, 2018: Expert Review of Anti-infective Therapy
Marguerite L Monogue, George Sakoulas, Victor Nizet, David P Nicolau
β-lactam-β-lactamase inhibitors (BLIs) have previously demonstrated antimicrobial activity against Acinetobacter baumannii (AB). Colistin retains the highest susceptibility rate against A. baumannii, and has demonstrated synergy with other antimicrobials, including β-lactam-BLIs. Therefore, we assessed the potential individual activity and synergistic combinations in vivo against carbapenem-susceptible (CS) and multidrug-resistant (MDR) A. baumannii isolates in neutropenic thigh and lung infection models...
March 13, 2018: Pharmacology
David P Nicolau, Brittany A Rodrigueza, Jennifer E Girottoa
The rise in multidrug-resistant (MDR) infections has become a significant problem in both the developing countries and in the United States (U.S.). Specifically, MDR gram-negative infections are emerging, affecting not only adults but children as well. The specific gram-negative organisms that have been most concerning within the pediatric population include MDR P. aeruginosa, Enterobacteriaceae, and Acinetobacter spp. The increase in antimicrobial resistance rates are associated with various mechanisms, with, one of the most common being the production of beta-lactamases...
March 8, 2018: Current Pediatric Reviews
Ryan K Shields, M Hong Nguyen, Liang Chen, Ellen G Press, Barry N Kreiswirth, Cornelius J Clancy
Ceftazidime-avibactam was used to treat 77 patients with carbapenem-resistant Enterobacteriaceae (CRE) infections at our center. Thirty- and 90-day survival rates were 81% and 69%, respectively; rates were higher than predicted by SAPS II and SOFA scores at the onset of infection. Clinical success was achieved in 55% of patients, but varied by site of infection. Success rates were lowest for pneumonia (36%) and higher for bacteremia (75%) and urinary tract infections (88%). By multivariate analysis, pneumonia ( P =0...
March 5, 2018: Antimicrobial Agents and Chemotherapy
Norelle L Sherry, Sarah L Baines, Benjamin P Howden
Avibactam is a novel β-lactamase inhibitor active against classes A, C and some class D β-lactamases. In combination with ceftazidime, it may be useful for the treatment of infections due to carbapenemase-producing Gram negative (CPGN) bacteria from these classes; however, susceptibility data for some of the less-common carbapenemases are limited. To assess the in vitro activity of ceftazidime-avibactam (CZA), we tested a panel of fifty diverse CPGN collected from clinical isolates in Victoria, Australia, containing KPC, GES, SME, OXA-23 and OXA-48-like carbapenemases for CZA susceptibility using broth microdilution (BMD), E-tests and disc diffusion...
February 27, 2018: International Journal of Antimicrobial Agents
Jesús Rodríguez-Baño, Belén Gutiérrez-Gutiérrez, Isabel Machuca, Alvaro Pascual
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...
April 2018: Clinical Microbiology Reviews
Michiyoshi Nukaga, Krisztina M Papp-Wallace, Tyuji Hoshino, Scott T Lefurgy, Christopher R Bethel, Melissa D Barnes, Elise T Zeiser, J Kristie Johnson, Robert A Bonomo
Ceftazidime-avibactam is a "second generation" β-lactam-β-lactamase inhibitor combination that is effective against Enterobacteriaceae expressing class A extended-spectrum β-lactamases, class A carbapenemases and/or class C cephalosporinases. Knowledge of the interactions of avibactam, a diazabicyclooctane with different β-lactamases is required to anticipate future resistance threats. FOX family β-lactamases possess unique hydrolytic properties with a broadened substrate profile to include cephamycins, partly as a result of an isoleucine at position 346, instead of the conserved asparagine found in most AmpCs...
February 12, 2018: Antimicrobial Agents and Chemotherapy
Sherwin K B Sy, Luning Zhuang, Huiming Xia, Marie-Eve Beaudoin, Virna J Schuck, Wright W Nichols, Hartmut Derendorf
Objectives: To characterize quantitatively the effect of avibactam in potentiating ceftazidime against MDR Pseudomonas aeruginosa by developing a mathematical model to describe the bacterial response to constant concentration time-kill information and validating it using both constant and time-varying concentration-effect data from in vitro and in vivo infection systems. Methods: The time course of the bacterial population dynamics in the presence of static concentrations of ceftazidime and avibactam was modelled using a two-state pharmacokinetic/pharmacodynamic (PK/PD) model, consisting of active and resting states, to account for bactericidal activities, bacteria-mediated ceftazidime degradation and inhibition of degradation by avibactam...
February 3, 2018: Journal of Antimicrobial Chemotherapy
Barbara A Santevecchi, Tiffeny T Smith, Shawn H MacVane
BACKGROUND: Ceftazidime/avibactam is a newly approved β-lactam/β-lactamase inhibitor combination with activity against antibiotic-resistant gram-negative organisms, including many carbapenem-resistant strains. While this agent may offer a promising treatment option for serious infections with limited alternatives available, clinical experience with ceftazidime/avibactam in treatment of infections caused by multidrug-resistant gram-negative organisms outside of Klebsiella pneumoniae is limited...
February 2, 2018: International Journal of Antimicrobial Agents
Chau-Chyun Sheu, Shang-Yi Lin, Ya-Ting Chang, Chun-Yuan Lee, Yen-Hsu Chen, Po-Ren Hsueh
The spread of extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae has become a major public health threat worldwide. Area covered: A thorough systematic literature review describing the current evidence and future prospects of therapeutic options for infections caused by ESBL-producing Enterobacteriaceae. Expert commentary: The methods of detecting ESBLs have been evolving. The Clinical and Laboratory Standards Institute and the European Committee on Antimicrobial Susceptibility Testing lowered the MIC breakpoints of cephalosporins against ESBL-producing Enterobacteriaceae in 2010...
March 2018: Expert Review of Anti-infective Therapy
Marco Falcone, Pierluigi Viale, Giusy Tiseo, Manjunath Pai
Ceftazidime-avibactam (CAZ-AVI) is a combination of a third-generation cephalosporin and a non-β-lactam, β-lactamase inhibitor, recently approved for urinary tract infections and complicated abdominal infections. Moreover, it represents a treatment option for patients with hospital acquired pneumonia (HAP), especially when caused by multidrug-resistant (MDR) bacteria. Areas covered: The review focuses on the pharmacokinetics (PK) of CAZ-AVI in HAP and on preclinical and clinical studies evaluating PK/pharmacodynamics (PD) in this field...
January 31, 2018: Expert Opinion on Drug Metabolism & Toxicology
María García-Castillo, Sergio García-Fernández, Rosa Gómez-Gil, Cristina Pitart, Marina Oviaño, Irene Gracia-Ahufinger, Jazmín Díaz-Regañón, Marta Tato, Rafael Cantón
The increasing rates of carbapenemase-producing Enterobacteriaceae (CPE) represent an important threat to health care systems and make treatment of CPE infections a challenge. The aim of the infection-carbapenem resistance evaluation surveillance trial (iCREST) was to determinate the prevalence of CPE in urine specimens in Spain and to evaluate the in vitro activity of ceftazidime-avibactam. Urine specimens (n=11,826) were included and activity of ceftazidime-avibactam and comparators were investigated by broth microdilution in CPE...
January 22, 2018: International Journal of Antimicrobial Agents
Eris Cani, Farzad Moussavi, Eric Ocheretyaner, Roopali Sharma, Clinton Brown, Brandon Eilertson
Ceftazidime-avibactam (CAZ-AVI) is a novel cephalosporin beta lactamase inhibitor combination that has shown activity against carbapenem-resistant Enterobactericeae. Data are limited on its utilization in the treatment of carbapenem-resistant Klebsiella pneumoniae osteomyelitis in solid organ transplant patients. We describe a case report on the use of CAZ-AVI in the treatment of vertebral osteomyelitis in a renal transplant recipient. This article is protected by copyright. All rights reserved.
January 23, 2018: Transplant Infectious Disease: An Official Journal of the Transplantation Society
Sundus Akhter, Bjarte Aarmo Lund, Aya Ismael, Manuel Langer, Johan Isaksson, Tony Christopeit, Hanna-Kirsti S Leiros, Annette Bayer
β-Lactam antibiotics are of utmost importance when treating bacterial infections in the medical community. However, currently their utility is threatened by the emergence and spread of β-lactam resistance. The most prevalent resistance mechanism to β-lactam antibiotics is expression of β-lactamase enzymes. One way to overcome resistance caused by β-lactamases, is the development of β-lactamase inhibitors and today several β-lactamase inhibitors e.g. avibactam, are approved in the clinic. Our focus is the oxacillinase-48 (OXA-48), an enzyme reported to spread rapidly across the world and commonly identified in Escherichia coli and Klebsiella pneumoniae...
December 30, 2017: European Journal of Medicinal Chemistry
Matteo Bassetti, Antionio Vena, Nadia Castaldo, Elda Righi, Maddalena Peghin
PURPOSE OF REVIEW: Ventilator-associated pneumonia (VAP) caused by multidrug-resistant (MDR) bacteria represents a global emerging problem. Delayed prescription of an adequate treatment for VAP has been associated with higher morbidity and mortality. New molecules have been developed to face the need of compounds that are active against resistant Gram-positive and Gram-negative pathogens. The aim of this review is to summarize the current scenario of new therapeutic options for the treatment of VAP...
April 2018: Current Opinion in Infectious Diseases
Novella Carannante, Carlo Pallotto, Mariano Bernardo, Giovanni Di Caprio, Carlo Tascini
KPC-producing Klebsiella pneumoniae (KPC-Kp) is nowadays a global concern. Ceftazidime/avibactam is the most promising novel antibiotic combination available at the moment. We describe the case of a migrant with no risk factors for an infection due to multidrug resistant bacteria. He suffered from a KPC-Kp cellulitis and was treated with a ceftazidime/avibactam-meropenem-fosfomycin combination that not only eradicated the infection but also decontaminated his gut. Ceftazidime/avibactam-based treatment can be useful also in decontamination procedures...
January 16, 2018: Journal of Chemotherapy
Karen Bush
Recent regulatory approvals for the β-lactam inhibitor combinations of ceftazidime-avibactam and meropenem-vaborbactam have provided two novel therapeutic options for the treatment of multidrug-resistant infections caused by Gram-negative bacteria. Most importantly, these combination agents have satisfied an important medical need related to antibiotic-resistant Klebsiella pneumoniae that produce serine carbapenemases, especially the Klebsiella pneumoniae carbapenemase (KPC) enzymes. Both combinations contain non-β-lactam β-lactamase inhibitors of novel chemical classes not previously developed as antibacterial agents, the diazabicyclooctanes and cyclic boronic acid derivatives...
December 12, 2017: ACS Infectious Diseases
George G Zhanel, Courtney K Lawrence, Heather Adam, Frank Schweizer, Sheryl Zelenitsky, Michael Zhanel, Philippe R S Lagacé-Wiens, Andrew Walkty, Andrew Denisuik, Alyssa Golden, Alfred S Gin, Daryl J Hoban, Joseph P Lynch, James A Karlowsky
Relebactam (formerly known as MK-7655) is a non-β-lactam, bicyclic diazabicyclooctane, β-lactamase inhibitor that is structurally related to avibactam, differing by the addition of a piperidine ring to the 2-position carbonyl group. Vaborbactam (formerly known as RPX7009) is a non-β-lactam, cyclic, boronic acid-based, β-lactamase inhibitor. The structure of vaborbactam is unlike any other currently marketed β-lactamase inhibitor. Both inhibitors display activity against Ambler class A [including extended-spectrum β-lactamases (ESBLs), Klebsiella pneumoniae carbapenemases (KPCs)] and class C β-lactamases (AmpC)...
January 2018: Drugs
David M Livermore, Danièle Meunier, Katie L Hopkins, Michel Doumith, Robert Hill, Rachel Pike, Peter Staves, Neil Woodford
Background: Ceftazidime/avibactam combines an established oxyimino-cephalosporin with the first diazabicyclooctane β-lactamase inhibitor to enter clinical use. We reviewed its activity against Gram-negative isolates, predominantly from the UK, referred for resistance investigation in the first year of routine testing, beginning in July 2015. Methods: Isolates were as received from referring laboratories; there is a bias to submit those with suspected carbapenem resistance...
December 8, 2017: Journal of Antimicrobial Chemotherapy
Helio S Sader, Michael D Huband, Leonard R Duncan, Robert K Flamm
BACKGROUND: Ceftazidime-avibactam was approved by the US Food and Drug Administration in 2015 to treat complicated intra-abdominal and urinary tract infections in adults, and is under clinical development for treating pediatric patients. METHODS: Among 53,381 gram-negative organisms (1 per patient) collected in 2011-2015, 8,461 (15.9%) were from pediatric (≤17 years-old [yo]) patients. The isolates were collected from 82 US medical centers and susceptibility tested against ceftazidime-avibactam (avibactam at fixed 4 µg/mL) and comparators by reference broth microdilution methods...
December 4, 2017: Pediatric Infectious Disease Journal
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