1,279
Views
61
CrossRef citations to date
0
Altmetric
Review

Novel β-lactam-β-lactamase inhibitor combinations: expectations for the treatment of carbapenem-resistant Gram-negative pathogens

ORCID Icon, ORCID Icon, ORCID Icon & ORCID Icon
Pages 133-149 | Received 21 Sep 2018, Accepted 20 Dec 2018, Published online: 10 Jan 2019

References

  • Tängdén T, Giske CG. Global dissemination of extensively drug-resistant carbapenemase-producing Enterobacteriaceae: clinical perspectives on detection, treatment and infection control. J Intern Med. 2015;277:501–512.
  • Karaiskos I, Antoniadou A, Giamarellou H. Combination therapy for extensively-drug resistant gram-negative bacteria. Expert Rev Anti Infect Ther. 2017;15:1123–1140.
  • Tzouvelekis LS, Markogiannakis A, Piperaki E, et al. Treating infections caused by carbapenemase-producing Enterobacteriaceae. Clin Microbiol Infect. 2014;20:862–872.
  • Karaiskos I, Giamarellou H. Multidrug-resistant and extensively drug-resistant Gram-negative pathogens: current and emerging therapeutic approaches. Expert Opin Pharmacother. 2014;15:1351–1370.
  • Karaiskos I, Souli M, Galani I, et al. Colistin: still a lifesaver for the 21st century? Expert Opin Drug Metab Toxicol. 2017 Jan;13(59–71).
  • Summary of the latest data on antibiotic resistance in the European Union. EARS-Net surveillance data November. 2017. Available from: https://ecdc.europa.eu/en/publications-data/summary-latest-data-antibiotic-resistance-european-union
  • World Health Organization: Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. 2017. Available from: http://www.who.int/medicines/publications/WHO-PPL-Short_Summary_25FebET_NM_WHO.pdf.
  • Boucher HW, Talbot GH, Benjamin BDK Jr, et al. 10 x ‘20 progress–development of new drugs active against gram-negative bacilli: an update from the infectious diseases society of America. Clin Infect Dis. 2013;56:1685–1694.
  • Magiorakos AP, Srinivasan A, Carey RB, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2012;18:268–281.
  • Docquier JD, Mangani S. An update on β-lactamase inhibitor discovery and development. Drug Resist Updat. 2018;36:13–29.
  • Queenan AM, Bush K. Carbapenemases BK. the versatile beta-lactamases. Clin Microbiol Rev. 2007;20:440–458.
  • Bush K. Past and present perspectives on β-Lactamases. Antimicrob Agents Chemother. 2018;DOI:10.1128/AAC.01076-18
  • National Center for Biotechnology Information. PubChem compound database. CID=56649692, Available from: https://pubchem.ncbi.nlm.nih.gov/compound/56649692 [ cited 2018 Sept].
  • Papp-Wallace KM, Bonomo RA. New β-lactamase inhibitors in the clinic. Infect Dis Clin North Am. 2016;30:441–464.
  • Lomovskaya O, Sun D, Rubio-Aparicio D, et al. Vaborbactam: spectrum of beta-lactamase inhibition and impact of resistance mechanisms on activity in enterobacteriaceae. Antimicrob Agents Chemother. 2017;61:e 01443–17.
  • Bonnefoy A, Dupuis-Hamelin C, Steier V, et al. In vitro activity of AVE1330A, an innovative broad-spectrum non-β-lactam β-lactamase inhibitor. J Antimicrob Chemother. 2004;54:410–417.
  • Zhanel GG, Lawson CD, Adam H, et al. Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. Drugs. 2013;73:159–177.
  • Flamm RK, Stone GG, Sader HS, et al. Avibactam reverts the ceftazidime MIC90 of European Gram-negative bacterial clinical isolates to the epidemiological cut-off value. J Chemother. 2014;26:333–338.
  • Ehmann DE, Jahic H, Ross PL, et al. Avibactam is a covalent, reversible, non-beta-lactam beta-lactamase inhibitor. Proc Natl Acad Sci USA. 2012;109:11663–11668.
  • Lahiri SD, Johnstone MR, Ross PL, et al. Avibactam and class C β-lactamases: mechanism of inhibition, conservation of the binding pocket, and implications for resistance. Antimicrob Agents Chemother. 2014;58:5704–5713.
  • Blizzard TA, Chen H, Kim S, et al. Discovery of MK-7655, a β-lactamase inhibitor for combination with Primaxin®. Bioorg Med Chem Lett. 2014;24:780–785.
  • Bush K, Bradford PA. β-Lactams and β-Lactamase inhibitors: an overview. Cold Spring Harb Perspect Med. 2016;6:a025247.
  • Papp-Wallace KM, Nguyen NQ, Jacobs MR, et al. Strategic approaches to overcome resistance against gram-negative pathogens using β-lactamase inhibitors and β-lactam enhancers: activity of three novel diazabicyclooctanes WCK 5153, Zidebactam (WCK 5107), and WCK 4234. J Med Chem. 2018;61:4067–4086.
  • Sader HS, Rhomberg PR, Flamm RK, et al. WCK 5222 (cefepime/zidebactam) antimicrobial activity tested against Gram-negative organisms producing clinically relevant β-lactamases. J Antimicrob Chemother. 2017;72:1696–1703.
  • Bush K. A resurgence of β-lactamase inhibitor combinations effective against multidrug-resistant Gram-negative pathogens. Int J Antimicrob Agents. 2015;46:483–493.
  • Monogue ML, Giovagnoli S, Bissantz C, et al. In vivo efficacy of meropenem with a novel non-β-Lactam-β-lactamase inhibitor, nacubactam, against gram-negative organisms exhibiting various resistance mechanisms in a murine complicated urinary tract infection model. Antimicrob Agents Chemother. 2018A;62:e 02596–17.
  • Daigle D, Hamrick J, Chatwin C, et al. Open forum. Infect Dis. 2018;5(Suppl 1):S419–S420.
  • Petersen PJ, Jones CH, Venkatesan AM, et al. Efficacy of piperacillin combined with the Penem beta-lactamase inhibitor BLI-489 in murine models of systemic infection. Antimicrob Agents Chemother. 2009;53(4):1698–1700.
  • Durand-Réville TF, Guler S, Comita-Prevoir J, et al. ETX2514 is a broad-spectrum β-lactamase inhibitor for the treatment of drug-resistant Gram-negative bacteria including acinetobacter baumannii. Nat Microbiol. 2017;2:17104.
  • Hackel MA, Lomovskaya O, Dudley MN, et al. In vitro activity of meropenem-vaborbactam against clinical isolates of KPC-positive enterobacteriaceae. Antimicrob Agents Chemother. 2017;62:e 01904–17.
  • AVYCAZ (ceftazidime and avibactam) for injection, for intravenous use. FDA. 2016. Available from: www.accessdata.fda.gov/drugsatfda_docs/lab11el/2016/206494s002lbl.pdf
  • European Medicines Agency. Zavicefta: summary of product characteristics. 2018. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/004027/WC500210234.pdf
  • Shirley M. Ceftazidime-avibactam: a review in the treatment of serious gram-negative bacterial infections. Drugs. 2018;78:675–692.
  • Clinical Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing. 28th Informational Supplement M100. Wayne, PA, USA: CLSI; 2018
  • The European Committee on Antimicrobial Susceptibility Testing-EUCAST. Clinical breakpoints. 2018. Available from: http://www.eucast.org/
  • Stone GG, Newell P, Bradford PA. In vitro activity of ceftazidime-avibactam against isolates from patients in a phase 3 clinical trial for treatment of complicated intra-abdominal infections. Antimicrob Agents Chemother. 2018;62:e 02584–17.
  • Stone GG, Bradford PA, Yates K, et al. In vitro activity of ceftazidime/avibactam against urinary isolates from patients in a Phase 3 clinical trial programme for the treatment of complicated urinary tract infections. J Antimicrob Chemother. 2017;72:1396–1399.
  • Stone GG, Bradford PA, Newell P, et al. In vitro activity of ceftazidime-avibactam against isolates in a phase 3 open-label clinical trial for complicated intra-abdominal and urinary tract infections caused by ceftazidime-nonsusceptible gram-negative pathogens. Antimicrob Agents Chemother. 2017;61(2):e 01820–16.
  • Kazmierczak KM, de Jonge BLM, Stone GG, et al. In vitro activity of ceftazidime/avibactam against isolates of Enterobacteriaceae collected in European countries: INFORM global surveillance 2012–15. J Antimicrob Chemother. 2018;73:2782–2788.
  • Kazmierczak KM, de Jonge BLM, Stone GG, et al. In vitro activity of ceftazidime/avibactam against isolates of Pseudomonas aeruginosa collected in European countries: INFORM global surveillance 2012–15. J Antimicrob Chemother. 2018;73:2777–2781.
  • Sader HS, Castanheira M, Duncan LR, et al. Antimicrobial susceptibility of enterobacteriaceae and pseudomonas aeruginosa isolates from United States medical centers stratified by infection type: results from the International Network for Optimal Resistance Monitoring (INFORM) surveillance program, 2015–2016. Diagn Microbiol Infect Dis. 2018;92:69–74.
  • Merdjan H, Rangaraju M, Tarral A. Safety and pharmacokinetics of single and multiple ascending doses of avibactam alone and in combination with ceftazidime in healthy male volunteers: results of two randomized, placebo-controlled studies. Clin Drug Investig. 2015;35:307–317.
  • Das S, Li J, Armstrong J, et al. Randomized pharmacokinetic and drug-drug interaction studies of ceftazidime, avibactam, and metronidazole in healthy subjects. Pharmacol Res Perspect. 2015;3:e00172.
  • Nicolau DP, Siew L, Armstrong J, et al. Phase 1 study assessing the steady-state concentration of ceftazidime and avibactam in plasma and epithelial lining fluid following two dosing regimens. J Antimicrob Chemother. 2015;70:2862–2869.
  • Merdjan H, Tarral A, Das S, et al. Phase 1 study assessing the pharmacokinetic profile and safety of avibactam in patients with renal impairment. J Clin Pharmacol. 2017;57:211–218.
  • Mazuski JE, Gasink LB, Armstrong J, et al. Efficacy and safety of ceftazidime-avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infection: results from a randomized, controlled, double-blind, phase 3 program. Clin Infect Dis. 2016;62:1380–1389.
  • Qin X, Tran BG, Kim MJ, et al. A randomised, double-blind, phase 3 study comparing the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem for complicated intra-abdominal infections in hospitalised adults in Asia. Int J Antimicrob Agents. 2017;49:579–588.
  • Wagenlehner FM, Sobel JD, Newell P, et al. Ceftazidime-avibactam versus doripenem for the treatment of complicated urinary tract infections, including acute pyelonephritis: RECAPTURE, a Phase 3 randomized trial program. Clin Infect Dis. 2016;63:754–762.
  • Torres A, Zhong N, Pachl J, et al. Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial. Lancet Infect Dis. 2018;18:285–295.
  • Carmeli Y, Armstrong J, Laud PJ, et al. Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study. Lancet Infect Dis. 2016;16:661–673.
  • Shields RK, Potoski BA, Haidar G, et al. Clinical outcomes, drug toxicity, and emergence of ceftazidime-avibactam resistance among patients treated for carbapenem-resistant Enterobacteriaceae infections. Clin Infect Dis. 2016;63:1615–1618.
  • Temkin E, Torre-Cisneros J, Beovic B, et al. Ceftazidime-avibactam as salvage therapy for infections caused by carbapenem-resistant organisms. Antimicrob Agents Chemother. 2017;61:e 01964–16.
  • King M, Heil E, Kuriakose S, et al. Multicenter study of outcomes with ceftazidime-avibactam in patients with carbapenem-resistant Enterobacteriaceae infections. Antimicrob Agents Chemother. 2017;61:e 00449–17.
  • Shields RK, Nguyen MH, Chen L, et al. Pneumonia and renal replacement therapy are risk factors for ceftazidime-avibactam treatment failures and resistance among patients with carbapenem-resistant Enterobacteriaceae infections. Antimicrob Agents Chemother. 2018;62:e 02497–17.
  • Shields RK, Nguyen MH, Chen L, et al. Ceftazidime-avibactam is superior to other treatment regimens against carbapenem-resistant Klebsiella pneumoniae bacteremia. Antimicrob Agents Chemother. 2017;61:e 00883–17.
  • Castón JJ, Lacort-Peralta I, Martín-Dávila P, et al. Clinical efficacy of ceftazidime/avibactam versus other active agents for the treatment of bacteremia due to carbapenemase-producing Enterobacteriaceae in hematologic patients. Int J Infect Dis. 2017;59:118–123.
  • Tumbarello M, Trecarichi EM, Corona A, et al. Efficacy of Ceftazidime-avibactam salvage therapy in patients with infections caused by KPC-producing Klebsiella pneumoniae. Clin Infect Dis. 2018 Jun 9. DOI:10.1093/cid/ciy492
  • van Duin D, Lok JJ, Earley M, et al. Colistin versus ceftazidime-avibactam in the treatment of infections due to carbapenem-resistant Enterobacteriaceae. Clin Infect Dis. 2018;66:163–171.
  • Sousa A, Pérez-Rodríguez MT, Soto A, et al. Effectiveness of ceftazidime/avibactam as salvage therapy for treatment of infections due to OXA-48 carbapenemase-producing Enterobacteriaceae. J Antimicrob Chemother. 2018;73:3170–3175.
  • Wright H, Bonomo RA, Paterson DL. New agents for the treatment of infections with Gram-negative bacteria: restoring the miracle or false dawn? Clin Microbiol Infect. 2017;23:704–712.
  • Marshall S, Hujer AM, Rojas LJ, et al. Can ceftazidime-avibactam and aztreonam overcome β-lactam resistance conferred by metallo-β-lactamases in enterobacteriaceae? Antimicrob Agents Chemother. 2017;61:e 02243–16.
  • Galani I, Karaiskos I, Karantani I, et al. Epidemiology and resistance phenotypes of carbapenemase-producing Klebsiella pneumoniae in Greece, 2014 to 2016. Euro Surveill. 2018;23. DOI:10.2807/1560-7917.ES.2018.23.30.1700775
  • Albiger B, Glasner C, Struelens MJ, et al. Carbapenemase-producing Enterobacteriaceae in Europe: assessment by national experts from 38 countries, May 2015. Euro Surveill. 2015;20. DOI:10.2807/1560-7917.ES.2015.20.45.30062
  • Dortet L, Poirel L, Nordmann P. Worldwide dissemination of the NDM-type carbapenemases in Gram-negative bacteria. Biomed Res Int. 2014;2014:249856.
  • Biedenbach DJ, Kazmierczak K, Bouchillon SK, et al. In vitro activity of aztreonam-avibactam against a global collection of Gram-negative pathogens from 2012 and 2013. Antimicrob Agents Chemother. 2015;59:4239–4248.
  • Karlowsky JA, Kazmierczak KM, Blm DJ, et al. In vitro activity of aztreonam-avibactam against Enterobacteriaceae and Pseudomonas aeruginosa isolated by clinical laboratories in 40 countries from 2012 to 2015. Antimicrob Agents Chemother. 2017;61:e 00472–17.
  • Alm RA, Johnstone MR, Lahiri SD. Characterization of Escherichia coli NDM isolates with decreased susceptibility to aztreonam/avibactam: role of a novel insertion in PBP3. J Antimicrob Chemother. 2015;70:1420–1428.
  • Avery LM, Nicolau DP. Assessing the in vitro activity of ceftazidime/avibactam and aztreonam among carbapenemase-producing enterobacteriaceae: defining the zone of hope. Int J Antimicrob Agents. 2018;S0924–8579(18):30202–4. DOI:10.1016/j.ijantimicag.2018.07.011.
  • Sy SK, Beaudoin ME, Zhuang L, et al. In vitro pharmacokinetics/pharmacodynamics of the combination of avibactam and aztreonam against MDR organisms. J Antimicrob Chemother. 2016;71:1866–1880.
  • Singh R, Kim A, Tanudra MA, et al. Pharmacokinetics/pharmacodynamics of a β-lactam and β-lactamase inhibitor combination: a novel approach for aztreonam/avibactam. J Antimicrob Chemother. 2015;70:2618–2626.
  • Davido B, Fellous L, Lawrence C, et al. Ceftazidime-avibactam and aztreonam, an interesting strategy to overcome β-lactam resistance conferred by metallo-β-lactamases in Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2017;61:e 01008–17.
  • Shaw E, Rombauts A, Tubau F, et al. Clinical outcomes after combination treatment with ceftazidime/avibactam and aztreonam for NDM-1/OXA-48/CTX-M-15-producing Klebsiella pneumoniae infection. J Antimicrob Chemother. 2018;73:1104–1106.
  • Edeki T, Zhou D, van Den Berg F, et al. A phase I, 3-part placebo-controlled randomised trial to evaluate the safety, tolerability and pharmacokinetics of aztreonam-avibactam in healthy subjects (EV0643). 26th Amsterdam, Netherlands: ECCMID; 2016 April 9 – 12.
  • Scott LJ. Ceftaroline fosamil: a review in complicated skin and soft tissue infections and community-acquired pneumonia. Drugs. 2016;76:1659–1674.
  • Testa R, Cantón R, Giani T, et al. In vitro activity of ceftazidime, ceftaroline and aztreonam alone and in combination with avibactam against European Gram-negative and Gram-positive clinical isolates. Int J Antimicrob Agents. 2015;45:641–646.
  • Papp-Wallace KM, Bajaksouzian S, Abdelhamed AM, et al. Activities of ceftazidime, ceftaroline, and aztreonam alone and combined with avibactam against isogenic Escherichia coli strains expressing selected single β-lactamases. Diagn Microbiol Infect Dis. 2015;82:65–69.
  • Riccobene TA, Su SF, Rank D. Single- and multiple-dose study to determine the safety, tolerability, and pharmacokinetics of ceftaroline fosamil in combination with avibactam in healthy subjects. Antimicrob Agents Chemother. 2013;57:1496–1504.
  • Vabomere® (meropenem/vaborbactam for injection) [prescribing information]. FDA. 2017. Available from: www.accessdata.fda.gov/drugsatfda_docs/label/2017/209776lbl.pdf
  • Castanheira M, Huband MD, Mendes RE, et al. Meropenem-vaborbactam tested against contemporary Gram-negative isolates collected worldwide during 2014, including carbapenem-resistant, KPC-producing, multidrug resistant, and extensively drug-resistant Enterobacteriaceae. Antimicrob Agents Chemother. 2017;61:e 00567–17.
  • Castanheira M, Rhomberg PR, Flamm RK, et al. Effect of the β-lactamase inhibitor vaborbactam combined with meropenem against serine carbapenemase-producing Enterobacteriaceae. Antimicrob Agents Chemother. 2016;60:5454–5458.
  • Griffith DC, Loutit JS, Morgan EE, et al. Phase 1 study of the safety, tolerability, and pharmacokinetics of the β-lactamase inhibitor vaborbactam (RPX7009) in healthy adult subjects. Antimicrob Agents Chemother. 2016;60:6326–6332.
  • Wenzler E, Gotfried MH, Loutit JS, et al. Meropenem-RPX7009 concentrations in plasma, epithelial lining fluid, and alveolar macrophages of healthy adult subjects. Antimicrob Agents Chemother. 2015;59:7232–7239.
  • Mathers A, Hope W, Kaye KS, et al. Meropenem-vaborbactam (Vabomere): outcomes in subjects with renal impairment in phase 3 studies TANGO I and II. [abstract 1879]. Poster presented at: ID Week 2017; 2017 Oct 4 – 8; San Diego, CA.
  • Sime FB, Pandey S, Karamuji N, et al. Ex vivo. Antimicrob Agents Chemother. 2018;DOI:10.1128/AAC.01306-18
  • Kaye KS, Bhowmick T, Metallidis S, et al. Effect of meropenem-vaborbactam vs piperacillin-tazobactam on clinical cure or improvement and microbial eradication in complicated urinary tract infection. The TANGO I randomized clinical trial. JAMA. 2018;319:788–799.
  • Kaye KS, Vazquez J, Mathers A, et al. Meropenem/vaborbactam (Vabomere) vs. best available therapy for CRE infections: TANGO II randomized, controlled phase 3 study results. [abstract 1862]. Poster presented at: ID Week 2017; 2017 Oct 4 – 8; San Diego, CA.
  • Wunderink R, Giamarellos-Bourboulis EJ, Rahav G, et al. Meropenem-vaborbactam (Vabomere) vs. best available therapy for carbapenem-resistant Enterobacteriaceae infections in TANGO II: primary outcomes by site of infection. [abstract 1867]. Poster presented at: ID Week; 2017; Oct 4 – 8; San Diego, CA.
  • Paterson D, Kwak EJ, Bhowmick T, et al. Meropenem/vaborbactam (Vabomere) vs. best available therapy for carbapenem-resistant Enterobactericeae in TANGO II: outcomes in immunocompromised patients. [abstract 1868]. Poster presented at: ID Week 2017; 2017 Oct 4 – 8; San Diego, CA.
  • Sabet M, Tarazi Z, Rubio-Aparicio D, et al. Activity of simulated human dosage regimens of meropenem and vaborbactam against carbapenem-resistant enterobacteriaceae in an in vitro hollow-fiber model. Antimicrob Agents Chemother. 2018;62:e 01969–17.
  • Sun D, Rubio-Aparicio D, Nelson K, et al. Meropenem-vaborbactam resistance selection, resistance prevention, and molecular mechanisms in mutants of KPC-producing klebsiella pneumoniae. Antimicrob Agents Chemother. 2017;61:e 01694–17.
  • Lomovskaya O, Castanheira M, Vazquez J, et al. Assessment of MIC increases with meropenem-vaborbactam and ceftaizdime-avibactam in tango II (a phase 3 study of the treatment of CRE infections). [ abstract 1874]. Presented at ID week; 2017, Oct 4 – 8, San Diego, CA.
  • Olsen I. New promising β-lactamase inhibitors for clinical use. Eur J Clin Microbiol Infect Dis. 2015;34:1303–1308.
  • Livermore DM, Warner M, Mushtaq S. Activity of MK-7655 combined with imipenem against Enterobacteriaceae and Pseudomonas aeruginosa. J Antimicrob Chemother. 2013;68:2286–2290.
  • Lapuebla A, Abdallah M, Olafisoye O, et al. Activity of imipenem with relebactam against gram-negative pathogens from New York City. Antimicrob Agents Chemother. 2015;59:5029–5031.
  • Zhanel GG, Lawrence CK, Adam H, et al. Imipenem-relebactam and meropenem-vaborbactam: two novel carbapenem-β-lactamase inhibitor combinations. Drugs. 2018;78:65–98.
  • Mavridou E, Melchers RJ, van Mil AC, et al. Pharmacodynamics of imipenem in combination with β-lactamase inhibitor MK7655 in a murine thigh model. Antimicrob Agents Chemother. 2015;59:790–795.
  • Karlowsky JA, Lob SH, Kazmierczak KM, et al. In vitro activity of imipenem/relebactam against Gram-negative ESKAPE pathogens isolated in 17 European countries: 2015 SMART surveillance programme. J Antimicrob Chemother . 2018. DOI:10.1093/jac/dky107
  • Lob SH, Hackel MA, Kazmierczak KM, et al. In vitro activity of imipenem-relebactam against gram-negative ESKAPE pathogens isolated by clinical laboratories in the United States in 2015 (results from the SMART global surveillance program). Antimicrob Agents Chemother. 2017;61:e 02209–16.
  • Bhagunde P, Chang KT, Hirsch EB, et al. Novel modeling framework to guide design of optimal dosing strategies for β-lactamase inhibitors. Antimicrob Agents Chemother. 2012;56:2237–2240.
  • Rhee EG, Rizk ML, Calder N, et al. Pharmacokinetics, safety, and tolerability of single and multiple doses of relebactam, a β-lactamase inhibitor, in combination with imipenem and cilastatin in healthy participants. Antimicrob Agents Chemother. 2018;DOI: 10.1128/AAC.00280-18
  • Rizk ML, Rhee EG, Jumes PA, et al. Intrapulmonary pharmacokinetics of relebactam, a novel β-lactamase inhibitor, dosed in combination with imipenem-cilastatin in healthy subjects. Antimicrob Agents Chemother. 2018;62:e 01411–17.
  • Lucasti C, Vasile L, Sandesc D, et al. Phase 2, dose-ranging study of relebactam with imipenem-cilastatin in subjects with complicated intra-abdominal infection. Antimicrob Agents Chemother. 2016;60:6234–6243.
  • Sims M, Mariyanovski V, McLeroth P, et al. Prospective, randomized, double-blind, Phase 2 dose-ranging study comparing efficacy and safety of imipenem/cilastatin plus relebactam with imipenem/cilastatin alone in patients with complicated urinary tract infections. J Antimicrob Chemother. 2017;72:2616–2626.
  • Motsch J, de Oliveira C, Stus V, et al. RESTORE-IMI 1: A multicenter, randomized, double-blind, comparator controlled trial comparing the efficacy and safety of imipenem/relebactam versus colistin plus imipenem in patients with imipenem-non-susceptible bacterial infections.[abstract O0427].Presented in 28th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID); 2018 April 21–24, Madrid, Spain.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.