Four new β lactam-β lactamase inhibitor (BL-BLI) combinations, namely ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam and imipenem-cilastatin-relebactam are currently approved by the Food and Drug Administration for complicated urinary tract infections (cUTIs), complicated intra-abdominal infections (cIAIs) and two of them for hospital-acquired pneumonia/ventilator-associated pneumonia. The clinical trials of these antibiotics have shown them to be non-inferior to comparator antibiotics. These antibiotics have action against extended-spectrum beta-lactamase enterobacterales and Klebsiella pneumoniae carbapenemase producers. Some have action against OXA-48 producing Gram-negative bacilli. However, all the above BL-BLI antibiotics have no action against metallo-β lactamase-producing organisms. These are currently being used for the treatment of cUTI and cIAI caused by multidrug-resistant (MDR) Enterobacterales and MDR Pseudomonas aeruginosa.
Tacconelli E, Carrara E, Savoldi A, Harbarth S, Mendelson M, Monnet DL, et al. Discovery, research, and development of new antibiotics: The WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis 2018;18:318-27.
Karlowsky JA, Biedenbach DJ, Kazmierczak KM, Stone GG, Sahm DF. Activity of ceftazidime-avibactam against extended-spectrum- and ampc β-lactamase-producing enterobacteriaceae collected in the INFORM global surveillance study from 2012 to 2014. Antimicrob Agents Chemother 2016;60:2849-57.
Spiliopoulou I, Kazmierczak K, Stone GG. In vitro activity of ceftazidime/avibactam against isolates of carbapenem-non-susceptible Enterobacteriaceae collected during the INFORM global surveillance programme (2015-17). J Antimicrob Chemother 2020;75:384-91.
Nelson K, Hemarajata P, Sun D, Rubio-Aparicio D, Tsivkovski R, Yang S, et al. Resistance to ceftazidime-avibactam is due to transposition of KPC in a porin-deficient strain of Klebsiella pneumoniae with increased efflux activity. Antimicrob Agents Chemother 2017;61:e00989-17.
Humphries RM, Hemarajata P. Resistance to ceftazidime-avibactam in Klebsiella pneumoniae due to porin mutations and the increased expression of KPC-3. Antimicrob Agents Chemother 2017;61:e00537-17.
Yahav D, Giske CG, Grāmatniece A, Abodakpi H, Tam VH, Leibovici L. New β-lactam-β-lactamase inhibitor combinations. Clin Microbiol Rev 2020;34:e00115-20.
Sternbach N, Leibovici Weissman Y, Avni T, Yahav D. Efficacy and safety of ceftazidime/avibactam: A systematic review and meta-analysis. J Antimicrob Chemother 2018;73:2021-9.
Zhang Y, Tao LN, Qu XY, Niu JQ, Ding YH, Zhang SX. Efficacy and safety of ceftazidime-avibactam in the treatment of complicated intra-abdominal infections (CIAIs) and complicated urinary tract infections (CUTIs): A meta-analysis of randomized controlled trials. Rev Assoc Med Bras (1992) 2018;64:253-63.
Jorgensen SC, Trinh TD, Zasowski EJ, Lagnf AM, Bhatia S, Melvin SM, et al. Real-World experience with ceftazidime-avibactam for multidrug-resistant gram-negative bacterial infections. Open Forum Infect Dis 2019;6:ofz522.
Zhong H, Zhao XY, Zhang ZL, Gu ZC, Zhang C, Gao Y, et al. Evaluation of the efficacy and safety of ceftazidime/avibactam in the treatment of Gram-negative bacterial infections: A systematic review and meta-analysis. Int J Antimicrob Agents 2018;52:443-50.
Onorato L, Di Caprio G, Signoriello S, Coppola N. Efficacy of ceftazidime/avibactam in monotherapy or combination therapy against carbapenem-resistant Gram-negative bacteria: A meta-analysis. Int J Antimicrob Agents 2019;54:735-40.
Bradley JS, Broadhurst H, Cheng K, Mendez M, Newell P, Prchlik M, et al. Safety and efficacy of ceftazidime-avibactam plus metronidazole in the treatment of children 3 months to 18 years with complicated intra-abdominal infection: Results from a phase 2, randomized, controlled trial. Pediatr Infect Dis J 2019;38:816-24.
Bradley JS, Roilides E, Broadhurst H, Cheng K, Huang LM, MasCasullo V, et al. Safety and efficacy of ceftazidime-avibactam in the treatment of children 3 months to 18 years with complicated urinary tract infection: Results from a phase 2 randomized, controlled trial. Pediatr Infect Dis J 2019;38:920-8.
Mazuski JE, Gasink LB, Armstrong J, Broadhurst H, Stone GG, Rank D, 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;62:1380-9.
Qin X, Tran BG, Kim MJ, Wang L, Nguyen DA, Chen Q, 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;49:579-88.
Wagenlehner FM, Sobel JD, Newell P, Armstrong J, Huang X, Stone GG, 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;63:754-62.
Shields RK, Chen L, Cheng S, Chavda KD, Press EG, Snyder A, et al. Emergence of ceftazidime-avibactam resistance due to plasmid-borne blaKPC-3 mutations during treatment of carbapenem-resistant Klebsiella pneumoniae infections. Antimicrob Agents Chemother 2017;61:e02097-16.
Iannaccone M, Boattini M, Bianco G, Corcione S, Cavallo R, Costa C. Ceftazidime-avibactam susceptible to resistant KPC-producing Enterobacterales bloodstream infections: an observational study. J Chemother 2020;32:160-2.
Moyá B, Zamorano L, Juan C, Ge Y, Oliver A. Affinity of the new cephalosporin CXA-101 to penicillin-binding proteins of Pseudomonas aeruginosa. Antimicrob Agents Chemother 2010;54:3933-7.
Carvalhaes CG, Castanheira M, Sader HS, Flamm RK, Shortridge D. Antimicrobial activity of ceftolozane-tazobactam tested against gram-negative contemporary (2015-2017) isolates from hospitalized patients with pneumonia in US medical centers. Diagn Microbiol Infect Dis 2019;94:93-102.
Shortridge D, Duncan LR, Pfaller MA, Flamm RK. Activity of ceftolozane-tazobactam and comparators when tested against Gram-negative isolates collected from paediatric patients in the USA and Europe between 2012 and 2016 as part of a global surveillance programme. Int J Antimicrob Agents 2019;53:637-43.
Tato M, García-Castillo M, Bofarull AM, Cantón R, CENIT Study Group. In vitro activity of ceftolozane/tazobactam against clinical isolates of pseudomonas aeruginosa and Enterobacteriaceae recovered in Spanish medical centres: Results of the CENIT study. Int J Antimicrob Agents 2015;46:502-10.
Pazzini C, Ahmad-Nejad P, Ghebremedhin B. Ceftolozane/tazobactam susceptibility testing in extended-spectrum betalactamase- and carbapenemase-producing Gram-negative bacteria of various clonal lineages. Eur J Microbiol Immunol (Bp) 2019;9:1-4.
Barnes MD, Taracila MA, Rutter JD, Bethel CR, Galdadas I, Hujer AM, et al. Deciphering the evolution of cephalosporin resistance to ceftolozane-tazobactam in pseudomonas aeruginosa. mBio 2018;9:e02085-18.
Sader HS, Farrell DJ, Castanheira M, Flamm RK, Jones RN. Antimicrobial activity of ceftolozane/tazobactam tested against Pseudomonas aeruginosa and Enterobacteriaceae with various resistance patterns isolated in European hospitals (2011-12). J Antimicrob Chemother 2014;69:2713-22.
Haidar G, Philips NJ, Shields RK, Snyder D, Cheng S, Potoski BA, et al. Ceftolozane-tazobactam for the treatment of multidrug-resistant Pseudomonas aeruginosa infections: Clinical effectiveness and evolution of resistance. Clin Infect Dis 2017;65:110-20.
Jorgensen SC, Trinh TD, Zasowski EJ, Lagnf AM, Simon SP, Bhatia S, et al. Real-world experience with ceftolozane-tazobactam for multidrug-resistant Gram-negative bacterial infections. Antimicrob Agents Chemother 2020;64:e02291-19.
Cheng IL, Chen YH, Lai CC, Tang HJ. The use of ceftolozane-tazobactam in the treatment of complicated intra-abdominal infections and complicated urinary tract infections-A meta-analysis of randomized controlled trials. Int J Antimicrob Agents 2020;55:105858.
Kollef MH, Nováček M, Kivistik Ü, Réa-Neto Á, Shime N, Martin-Loeches I, et al. Ceftolozane-tazobactam versus meropenem for treatment of nosocomial pneumonia (ASPECT-NP): A randomised, controlled, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis 2019;19:1299-311.
Pogue JM, Kaye KS, Veve MP, Patel TS, Gerlach AT, Davis SL, et al. Ceftolozane/tazobactam vs. polymyxin or aminoglycoside-based regimens for the treatment of drug-resistant Pseudomonas aeruginosa. Clin Infect Dis 2020;71:304-10.
Vena A, Giacobbe DR, Mussini C, Cattelan A, Bassetti M, Ceftabuse Study Group. Clinical Efficacy of ceftolozane-tazobactam versus other active agents for the treatment of bacteremia and nosocomial pneumonia due to drug-resistant Pseudomonas aeruginosa. Clin Infect Dis 2020;71:1799-801.
Huntington JA, Sakoulas G, Umeh O, Cloutier DJ, Steenbergen JN, Bliss C, et al. Efficacy of ceftolozane/tazobactam versus levofloxacin in the treatment of complicated urinary tract infections (cUTIs) caused by levofloxacin-resistant pathogens: Results from the ASPECT-cUTI trial. J Antimicrob Chemother 2016;71:2014-21.
Bradley JS, Ang JY, Arrieta AC, Larson KB, Rizk ML, Caro L, et al. Pharmacokinetics and safety of single intravenous doses of ceftolozane/tazobactam in children with proven or suspected Gram-negative infection. Pediatr Infect Dis J 2018;37:1130-6.
Kullar R, Wagenlehner FM, Popejoy MW, Long J, Yu B, Goldstein EJ. Does moderate renal impairment affect clinical outcomes in complicated intra-abdominal and complicated urinary tract infections? Analysis of two randomized controlled trials with ceftolozane/tazobactam. J Antimicrob Chemother 2017;72:900-5.
Popejoy MW, Long J, Huntington JA. Analysis of patients with diabetes and complicated intra-abdominal infection or complicated urinary tract infection in phase 3 trials of ceftolozane/tazobactam. BMC Infect Dis 2017;17:316.
Solomkin J, Hershberger E, Miller B, Popejoy M, Friedland I, Steenbergen J, et al. Ceftolozane/tazobactam plus metronidazole for complicated intra-abdominal infections in an era of multidrug resistance: Results from a randomized, double-blind, phase 3 trial (ASPECT-cIAI). Clin Infect Dis 2015;60:1462-71.
Wagenlehner FM, Umeh O, Steenbergen J, Yuan G, Darouiche RO. Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: A randomised, double-blind, phase 3 trial (ASPECT-cUTI). Lancet 2015;385:1949-56.
Bassetti M, Castaldo N, Cattelan A, Mussini C, Righi E, Tascini C, et al. Ceftolozane/tazobactam for the treatment of serious Pseudomonas aeruginosa infections: A multicentre nationwide clinical experience. Int J Antimicrob Agents 2019;53:408-15.
Xipell M, Paredes S, Fresco L, Bodro M, Marco F, Martínez JA, et al. Clinical experience with ceftolozane/tazobactam in patients with serious infections due to resistant Pseudomonas aeruginosa. J Glob Antimicrob Resist 2018;13:165-70.
Hecker SJ, Reddy KR, Totrov M, Hirst GC, Lomovskaya O, Griffith DC, et al. Discovery of a cyclic boronic acid β-lactamase inhibitor (RPX7009) with utility vs. class A serine carbapenemases. J Med Chem 2015;58:3682-92.
Pfaller MA, Huband MD, Mendes RE, Flamm RK, Castanheira M. In vitro activity of meropenem/vaborbactam and characterisation of carbapenem resistance mechanisms among carbapenem-resistant Enterobacteriaceae from the 2015 meropenem/vaborbactam surveillance programme. Int J Antimicrob Agents 2018;52:144-50.
Kinn PM, Chen DJ, Gihring TM, Schulz LT, Fox BC, McCreary EK, et al. In vitro evaluation of meropenem-vaborbactam against clinical CRE isolates at a tertiary care center with low KPC-mediated carbapenem resistance. Diagn Microbiol Infect Dis 2019;93:258-60.
Athans V, Neuner EA, Hassouna H, Richter SS, Keller G, Castanheira M, et al. Meropenem-Vaborbactam as salvage therapy for ceftazidime-avibactam-resistant Klebsiella pneumoniae Bacteremia and abscess in a liver transplant recipient. Antimicrob Agents Chemother 2019;63:e01551-18.
Castanheira M, Rhomberg PR, Flamm RK, Jones RN. Effect of the β-Lactamase inhibitor vaborbactam combined with meropenem against serine carbapenemase-producing Enterobacteriaceae. Antimicrob Agents Chemother 2016;60:5454-8.
Kaye KS, Bhowmick T, Metallidis S, Bleasdale SC, Sagan OS, Stus V, 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;319:788-99.
Viale P. Meropenem-vaborbactam versus best-available therapy for carbapenem-resistant Enterobacteriaceae infections in TANGO II: Outcomes in patients with cancer, abstract P0285. Madrid, Spain: 28th European Society of Clinical Microbiology and Infectious Diseases; 2018.
Wunderink RG, Giamarellos-Bourboulis EJ, Rahav G, Mathers AJ, Bassetti M, Vazquez J, et al. Effect and safety of meropenem-vaborbactam versus best-available therapy in patients with carbapenem-resistant Enterobacteriaceae infections: The TANGO II randomized clinical trial. Infect Dis Ther 2018;7:439-55.
Bassetti M, Giacobbe DR, Patel N, Tillotson G, Massey J. Efficacy and safety of meropenem-vaborbactam versus best available therapy for the treatment of carbapenem-resistant enterobacteriaceae infections in patients without prior antimicrobial failure: A post hoc analysis. Adv Ther 2019;36:1771-7.
Sun D, Rubio-Aparicio D, Nelson K, Dudley MN, Lomovskaya O. Meropenem-vaborbactam resistance selection, resistance prevention, and molecular mechanisms in mutants of KPC-Producing Klebsiella pneumoniae. Antimicrob Agents Chemother 2017;61:e01694-17.
Shields RK, McCreary EK, Marini RV, Kline EG, Jones CE, Hao B, et al. Early experience with meropenem-vaborbactam for treatment of carbapenem-resistant Enterobacteriaceae infections. Clin Infect Dis 2020;71:667-71.
Karlowsky JA, Lob SH, Kazmierczak KM, Young K, Motyl MR, Sahm DF. In-vitro activity of imipenem/relebactam and key β-lactam agents against Gram-negative bacilli isolated from lower respiratory tract infection samples of intensive care unit patients – SMART surveillance United States 2015-2017. Int J Antimicrob Agents 2020;55:105841.
Livermore DM, Warner M, Mushtaq S. Activity of MK-7655 combined with imipenem against Enterobacteriaceae and Pseudomonas aeruginosa. J Antimicrob Chemother 2013;68:2286-90.
Papp-Wallace KM, Barnes MD, Alsop J, Taracila MA, Bethel CR, Becka SA, et al. Relebactam is a potent inhibitor of the KPC-2 β-Lactamase and restores imipenem susceptibility in kpc-producing Enterobacteriaceae. Antimicrob Agents Chemother 2018;62:e00174-18.
Fraile-Ribot PA, Zamorano L, Orellana R, Del Barrio-Tofiño E, Sánchez-Diener I, Cortes-Lara S, et al. Activity of imipenem-relebactam against a large collection of Pseudomonas aeruginosa clinical isolates and isogenic β-Lactam-Resistant Mutants. Antimicrob Agents Chemother 2020;64:e02165-19.
Haidar G, Clancy CJ, Chen L, Samanta P, Shields RK, Kreiswirth BN, et al. Identifying spectra of activity and therapeutic niches for ceftazidime-avibactam and imipenem-relebactam against carbapenem-resistant Enterobacteriaceae. Antimicrob Agents Chemother 2017;61:e00642-17.
Sims M, Mariyanovski V, McLeroth P, Akers W, Lee YC, Brown ML, 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;72:2616-26.
Lucasti C, Vasile L, Sandesc D, Venskutonis D, McLeroth P, Lala M, et al. Phase 2, dose-ranging study of relebactam with imipenem-cilastatin in subjects with complicated intra-abdominal infection. Antimicrob Agents Chemother 2016;60:6234-43.
Motsch J, Murta de Oliveira C, Stus V, Köksal I, Lyulko O, Boucher HW, et al. RESTORE-IMI 1: A Multicenter, randomized, double-blind trial comparing efficacy and safety of imipenem/relebactam vs. Colistin plus imipenem in patients with imipenem-nonsusceptible bacterial infections. Clin Infect Dis 2020;70:1799-808.
Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. Infectious diseases society of america guidance on the treatment of extended-spectrum β-lactamase producing enterobacterales (esbl-e), carbapenem-resistant enterobacterales (CRE), and pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. Aeruginosa). Clin Infect Dis 2021;72:e169-83.
