755
Views
12
CrossRef citations to date
0
Altmetric
Review

Developments on antibiotics for multidrug resistant bacterial Gram-negative infections

, &
Pages 387-401 | Received 24 Jan 2019, Accepted 18 Apr 2019, Published online: 27 May 2019

References

  • Vardakas, KZ, Rafailidis PI, Konstantelias AA, et al. Predictors of mortality in patients with infections due to multi-drug resistant Gram negative bacteria: the study, the patient, the bug or the drug? J Infect. 2012;66(5):401–414.
  • Falagas, ME, Tansarli GS, Karageorgopoulos DE, et al. Deaths attributable to carbapenem-resistant Enterobacteriaceae infections. Emerg Infect Dis. 2014;20(7):1170–1175.
  • Falagas, ME, Vouloumanou EK, Samonis G, et al. Fosfomycin. Clin Microbiol Rev. 2016;29(2):321–347.
  • Rafailidis PI, Falagas ME. Options for treating carbapenem-resistant Enterobacteriaceae. Curr Opin Infect Dis. 2014;27(6):479–483.
  • Falagas, ME, Tansarli GS, Ikawa K, et al. Clinical outcomes with extended or continuous versus short-term intravenous infusion of carbapenems and piperacillin/tazobactam: a systematic review and meta-analysis. Clin Infect Dis. 2013;56(2):272–282.
  • Tacconelli, E, Carrara E, Savoldi A, et al. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis. 2018;18(3):318–327.
  • FDA. Establishing a list of qualifying pathogens under the food and drug administration safety and innovation act. final rule. Fed Regist. 2014;79(108):32464–32481.
  • McEwen, A, Lawrence L, Hoover R, et al. Disposition, metabolism and mass balance of delafloxacin in healthy human volunteers following intravenous administration. Xenobiotica. 2015;45(12):1054–1062.
  • Timi Edeki DZ, van Den Berg F, Helen Broadhurst WC, et al. A phase I, 3-part placebo-controlled randomised trial to evaluate the safety, tolerability and pharmacokinetics of aztreonam-avibactam in healthy subjects. 2016. Available from: https://www.escmid.org/escmid_publications/escmid_elibrary/material/?mid=48903
  • Ehmann, DE, Jahić H, Ross PL, et al. Avibactam is a covalent, reversible, non-beta-lactam beta-lactamase inhibitor. Proc Natl Acad Sci U S A. 2012;109(29):11663–11668.
  • Lahiri, SD, Mangani S, Durand-Reville T, et al. Structural insight into potent broad-spectrum inhibition with reversible recyclization mechanism: avibactam in complex with CTX-M-15 and Pseudomonas aeruginosa AmpC beta-lactamases. Antimicrob Agents Chemother. 2013;57(6):2496–2505.
  • Rotschafer JC, Ostergaard BE. Combination beta-lactam and beta-lactamase-inhibitor products: antimicrobial activity and efficiency of enzyme inhibition. Am J Health Syst Pharm. 1995;52(6 Suppl 2):S15–22.
  • Lahiri, SD, Johnstone MR, Ross PL, et al. Avibactam and class C beta-lactamases: mechanism of inhibition, conservation of the binding pocket, and implications for resistance. Antimicrob Agents Chemother. 2014;58(10):5704–5713.
  • Bonnefoy, A, Dupuis-Hamelin C, Steier V, et al. In vitro activity of AVE1330A, an innovative broad-spectrum non-beta-lactam beta-lactamase inhibitor. J Antimicrob Chemother. 2004;54(2):410–417.
  • Aktas Z, Kayacan C, Oncul O. In vitro activity of avibactam (NXL104) in combination with beta-lactams against Gram-negative bacteria, including OXA-48 beta-lactamase-producing Klebsiella pneumoniae. Int J Antimicrob Agents. 2012;39(1):86–89.
  • Ehmann, DE, Jahić H, Ross PL, et al. Kinetics of avibactam inhibition against Class A, C, and D beta-lactamases. J Biol Chem. 2013;288(39):27960–27971.
  • Abboud, MI, Damblon C, Brem J, et al. Interaction of avibactam with Class B metallo-beta-lactamases. Antimicrob Agents Chemother. 2016;60(10):5655–5662.
  • FDA. AVYCAZ (ceftazidime/avibactam) Full Prescribing Information. 2016. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206494s002lbl.pdf
  • EMA. Summary of product characteristics ZAVICEFTA (ceftazidime/avibactam). Available from: https://www.ema.europa.eu/en/documents/product-information/zavicefta-epar-product-information_en.pdf
  • Castanheira, M, Mills JC, Costello SE, et al. Ceftazidime-avibactam activity tested against Enterobacteriaceae isolates from U.S. hospitals (2011 to 2013) and characterization of beta-lactamase-producing strains. Antimicrob Agents Chemother. 2015;59(6):3509–3517.
  • Sader, HS, Castanheira M, Shortridge D, et al. Antimicrobial activity of ceftazidime-avibactam tested against multidrug-resistant Enterobacteriaceae and Pseudomonas aeruginosa isolates from U.S. medical centers, 2013 to 2016. Antimicrob Agents Chemother. 2017; 61(11):e01045-17.
  • Karlowsky, JA, Biedenbach DJ, Kazmierczak KM, et al. Activity of ceftazidime-avibactam against extended-spectrum- and AmpC beta-lactamase-producing Enterobacteriaceae collected in the inform global surveillance study from 2012 to 2014. Antimicrob Agents Chemother. 2016;60(5):2849–2857.
  • Shields, RK, Clancy CJ, Hao B, et al. Effects of Klebsiella pneumoniae carbapenemase subtypes, extended-spectrum beta-lactamases, and porin mutations on the in vitro activity of ceftazidime-avibactam against carbapenem-resistant K. pneumoniae. Antimicrob Agents Chemother. 2015;59(9):5793–5797.
  • Kazmierczak, KM, de Jonge BL, 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(10):2777–2781.
  • Sader, HS, Flamm RK, Carvalhaes CG, et al. Antimicrobial susceptibility of pseudomonas aeruginosa to ceftazidime-avibactam, ceftolozane-tazobactam, piperacillin-tazobactam, and meropenem stratified by U.S. census divisions: results from the 2017 INFORM program. Antimicrob Agents Chemother. 2018;62(12):e01587-18.
  • ECDC. Emergence of resistance to ceftazidime-avibactam in carbapenem-resistant Enterobacteriaceae Stockholm. European Centre for Disease Prevention and Control; 2018. Available from: https://ecdc.europa.eu/sites/portal/files/documents/RRA%20-%20Emergence%20of%20resistance%20to%20CAZ-AVI%20in%20CRE%20Enterobacteriaceae%20-%20final.pdf
  • Nichols, WW, Newell P, Critchley IA, et al. Avibactam pharmacokinetic/pharmacodynamic targets. Antimicrob Agents Chemother. 2018;62(6):e02446-17.
  • Crandon JL, Nicolau DP. Human simulated studies of aztreonam and aztreonam-avibactam to evaluate activity against challenging gram-negative organisms, including metallo-beta-lactamase producers. Antimicrob Agents Chemother. 2013;57(7):3299–3306.
  • Ramsey C, MacGowan AP. A review of the pharmacokinetics and pharmacodynamics of aztreonam. J Antimicrob Chemother. 2016;71(10):2704–2712.
  • 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(7):4239–4248.
  • Karlowsky, JA, Kazmierczak KM, de Jonge BL, 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(9):e00472-17.
  • Sader, HS, Mendes RE, Pfaller MA, et al. Antimicrobial activities of aztreonam-avibactam and comparator agents against contemporary (2016) clinical enterobacteriaceae isolates. Antimicrob Agents Chemother. 2017; 62(1):e01856-17.
  • Castanheira M, RK Flamm HS, Jones RN, et al. Activity of aztreonam combined with the beta-lactamase inhibitor avibactam against metallo-β-lactamase-producing organisms. Escmid Abstr. 2013. Available from: https://www.escmid.org/escmid_publications/escmid_elibrary/material/?mid=9735
  • Singh, R, Kim A, Tanudra MA, et al. Pharmacokinetics/pharmacodynamics of a beta-lactam and beta-lactamase inhibitor combination: a novel approach for aztreonam/avibactam. J Antimicrob Chemother. 2015;70(9):2618–2626.
  • Saxon A. Aztreonam in the management of gram-negative infections in penicillin-allergic patients: a review. Pediatr Infect Dis J. 1989;8(9 Suppl): S124–7; discussion S128-32.
  • James CW, Gurk-Turner C. Cross-reactivity of beta-lactam antibiotics. Proc (Bayl Univ Med Cent). 2001;14(1):106–107.
  • Kishiyama JL, Adelman DC. The cross-reactivity and immunology of beta-lactam antibiotics. Drug Saf. 1994;10(4):318–327.
  • Lohans CT, Brem J, Schofield CJ. New Delhi Metallo-beta-lactamase 1 catalyzes avibactam and aztreonam hydrolysis. Antimicrob Agents Chemother. 2017;61(12).
  • FDA. VABOMRE (meropenem/vaborbactam) Full Prescribing Information. 2018. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209776lbl.pdf
  • EMA. Summary of Product Characteristics VABOMERE (meropenem/vaborbactam). Available from: https://www.ema.europa.eu/documents/product-information/vabomere-epar-product-information_en.pdf
  • Zhanel, GG, Wiebe R, Dilay L, et al. Comparative review of the carbapenems. Drugs. 2007;67(7):1027–1052.
  • Castanheira, M, Rhomberg PR, Flamm RK, et al. Effect of the beta-lactamase inhibitor vaborbactam combined with meropenem against serine carbapenemase-producing enterobacteriaceae. Antimicrob Agents Chemother. 2016;60(9):5454–5458.
  • Hecker, SJ, Reddy KR, Totrov M, et al. Discovery of a cyclic boronic acid beta-lactamase inhibitor (RPX7009) with utility vs class A serine carbapenemases. J Med Chem. 2015;58(9):3682–3692.
  • 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(11):e01443-17.
  • Lapuebla, A, Abdallah M, Olafisoye O, et al. Activity of a Meropenem combined with rpx7009, a novel beta-lactamase inhibitor, against gram-negative clinical isolates in New York City. Antimicrob Agents Chemother. 2015;59(8):4856–4860.
  • 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(12):e01694-17.
  • 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(9):e00567-17.
  • 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(1):e01904-17.
  • Griffith, DC, Sabet M, Tarazi Z, et al. Pharmacokinetics/pharmacodynamics of vaborbactam, a novel beta-lactamase inhibitor, in combination with meropenem. Antimicrob Agents Chemother. 2018;63(1):e01659-18.
  • Griffith, DC, Loutit JS, Morgan EE, et al. Phase 1 study of the safety, tolerability, and pharmacokinetics of the beta-lactamase inhibitor vaborbactam (RPX7009) in healthy adult subjects. Antimicrob Agents Chemother. 2016;60(10):6326–6332.
  • Clissold SP, Todd PA, Campoli-Richards DM. Imipenem/cilastatin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy. Drugs. 1987;33(3):183–241.
  • Blizzard, TA, Chen H, Kim S, et al. Discovery of MK-7655, a beta-lactamase inhibitor for combination with Primaxin(R). Bioorg Med Chem Lett. 2014;24(3):780–785.
  • 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(8):5029–5031.
  • Karlowsky, JA, Lob SH, Young K, et al. Activity of imipenem/relebactam against Pseudomonas aeruginosa with antimicrobial-resistant phenotypes from seven global regions: SMART 2015–2016. J Glob Antimicrob Resist. 2018;15:140–147.
  • 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(6):e02209-16.
  • Livermore DM, Warner M, Mushtaq S. Activity of MK-7655 combined with imipenem against Enterobacteriaceae and Pseudomonas aeruginosa. J Antimicrob Chemother. 2013;68(10):2286–2290.
  • Schmidt-Malan, SM, Mishra AJ, Mushtaq A, et al. In vitro activity of imipenem-relebactam and ceftolozane-tazobactam against resistant gram-negative bacilli. Antimicrob Agents Chemother. 2018;62(8):e00533-18.
  • Wu, J, Racine F, Wismer MK, et al. Exploring the pharmacokinetic/pharmacodynamic relationship of relebactam (MK-7655) in combination with imipenem in a hollow-fiber infection model. Antimicrob Agents Chemother. 2018;62(5):e02323-17.
  • 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(9):2616.
  • 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(10):6234–6243.
  • Rhee, EG, Rizk ML, Calder N, et al. Pharmacokinetics, safety, and tolerability of single and multiple doses of relebactam, a beta-lactamase inhibitor, in combination with imipenem and cilastatin in healthy participants. Antimicrob Agents Chemother. 2018;62(9):e00280-18.
  • Juan, C, Zamorano L, Pérez JL, et al. Activity of a new antipseudomonal cephalosporin, CXA-101 (FR264205), against carbapenem-resistant and multidrug-resistant Pseudomonas aeruginosa clinical strains. Antimicrob Agents Chemother. 2009;54(2):846–851.
  • Zhanel, GG, Chung P, Adam H, et al. Ceftolozane/tazobactam: a novel cephalosporin/beta-lactamase inhibitor combination with activity against multidrug-resistant gram-negative bacilli. Drugs. 2013;74(1):31–51.
  • Livermore DM, Mushtaq S, Ge Y. Chequerboard titration of cephalosporin CXA-101 (FR264205) and tazobactam versus beta-lactamase-producing Enterobacteriaceae. J Antimicrob Chemother. 2010;65(9):1972–1974.
  • Sader, HS, Rhomberg PR, Farrell DJ, et al. Antimicrobial activity of CXA-101, a novel cephalosporin tested in combination with tazobactam against enterobacteriaceae, pseudomonas aeruginosa, and bacteroides fragilis strains having various resistance phenotypes. Antimicrob Agents Chemother. 2011;55(5):2390–2394.
  • Bulik, CC, Tessier PR, Keel RA, et al. In vivo comparison of CXA-101 (FR264205) with and without tazobactam versus piperacillin-tazobactam using human simulated exposures against phenotypically diverse gram-negative organisms. Antimicrob Agents Chemother. 2011;56(1):544–549.
  • VanScoy, B, Mendes RE, Nicasio AM, et al. Pharmacokinetics-pharmacodynamics of tazobactam in combination with ceftolozane in an in vitro infection model. Antimicrob Agents Chemother. 2013;57(6):2809–2814.
  • EMA. Summary of product characteristics ZERBAXA (ceftolozane/tazobactam). Available from: https://www.ema.europa.eu/en/documents/product-information/zerbaxa-epar-product-information_en.pdf
  • FDA. ZERBAXA (ceftolozane/tazobactam) Full Prescribing Information. U.S. Food and Drug Administration; 2014. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206829lbl.pdf
  • Chandorkar, G, Huntington JA, Gotfried MH, et al. Intrapulmonary penetration of ceftolozane/tazobactam and piperacillin/tazobactam in healthy adult subjects. J Antimicrob Chemother. 2012;67(10):2463–2469.
  • Xiao, AJ, Miller BW, Huntington JA, et al. Ceftolozane/tazobactam pharmacokinetic/pharmacodynamic-derived dose justification for phase 3 studies in patients with nosocomial pneumonia. J Clin Pharmacol. 2015;56(1):56–66.
  • Sader, HS, Farrell DJ, Flamm RK, et al. Ceftolozane/tazobactam activity tested against aerobic Gram-negative organisms isolated from intra-abdominal and urinary tract infections in European and United States hospitals (2012). J Infect. 2016;69(3):266–277.
  • Sader, HS, Farrell DJ, Castanheira M, et al. 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(10):2713–2722.
  • Pfaller, MA, Shortridge D, Sader HS, et al. Ceftolozane/tazobactam activity against drug-resistant enterobacteriaceae and pseudomonas aeruginosa causing healthcare-associated infections in the Asia-Pacific region (minus China, Australia and New Zealand): report from an antimicrobial surveillance programme (2013–2015). Int J Antimicrob Agents. 2017;51(2):181–189.
  • Pfaller, MA, Shortridge D, Sader HS, et al. Ceftolozane-tazobactam activity against drug-resistant Enterobacteriaceae and Pseudomonas aeruginosa causing healthcare-associated infections in Latin America: report from an antimicrobial surveillance program (2013–2015). Braz J Infect Dis. 2017;21(6):627–637.
  • Buehrle, DJ, Shields RK, Chen L, et al. Evaluation of the in vitro activity of ceftazidime-avibactam and ceftolozane-tazobactam against meropenem-resistant Pseudomonas aeruginosa isolates. Antimicrob Agents Chemother. 2016;60(5):3227–3231.
  • Pfaller, MA, Bassetti M, Duncan LR, et al. Ceftolozane/tazobactam activity against drug-resistant Enterobacteriaceae and Pseudomonas aeruginosa causing urinary tract and intraabdominal infections in Europe: report from an antimicrobial surveillance programme (2012–15). J Antimicrob Chemother. 2017;72(5):1386–1395.
  • Grupper M, Sutherland C, Nicolau DP. Multicenter evaluation of ceftazidime-avibactam and ceftolozane-tazobactam inhibitory activity against meropenem-nonsusceptible Pseudomonas aeruginosa from blood, respiratory tract, and wounds. Antimicrob Agents Chemother. 2017;61(10):e00875-17.
  • Sutcliffe, JA, O’Brien W, Fyfe C, et al. Antibacterial activity of eravacycline (TP-434), a novel fluorocycline, against hospital and community pathogens. Antimicrob Agents Chemother. 2013;57(11):5548–5558.
  • Zhanel, GG, Cheung D, Adam H, et al. Review of eravacycline, a novel fluorocycline antibacterial agent. Drugs. 2016;76(5):567–588.
  • Grossman, TH, Starosta AL, Fyfe C, et al. Target- and resistance-based mechanistic studies with TP-434, a novel fluorocycline antibiotic. Antimicrob Agents Chemother. 2012;56(5):2559–2564.
  • Zheng, JX, Lin ZW, Sun X, et al. Overexpression of OqxAB and MacAB efflux pumps contributes to eravacycline resistance and heteroresistance in clinical isolates of Klebsiella pneumoniae. Emerg Microbes Infect. 2018;7(1):139.
  • FDA. XERAVA (eravacycline) full prescribing information. 2018. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf
  • EMA. Xerava: product information. 2018. Available from: https://www.ema.europa.eu/documents/product-information/xerava-epar-product-information_en.pdf
  • Zhanel, GG, Baxter MR, Adam HJ, et al. In vitro activity of eravacycline against 2213 Gram-negative and 2424 Gram-positive bacterial pathogens isolated in Canadian hospital laboratories: CANWARD surveillance study 2014–2015. Diagn Microbiol Infect Dis. 2018;91(1):55–62.
  • Abdallah, M, Olafisoye O, Cortes C, et al. Activity of eravacycline against Enterobacteriaceae and Acinetobacter baumannii, including multidrug-resistant isolates, from New York City. Antimicrob Agents Chemother. 2014;59(3):1802–1805.
  • Livermore, DM, Mushtaq S, Warner M, et al. In vitro activity of eravacycline against carbapenem-resistant Enterobacteriaceae and Acinetobacter baumannii. Antimicrob Agents Chemother. 2016;60(6):3840–3844.
  • Seifert, H, Stefanik D, Sutcliffe JA, et al. In-vitro activity of the novel fluorocycline eravacycline against carbapenem non-susceptible Acinetobacter baumannii. Int J Antimicrob Agents. 2017;51(1):62–64.
  • Snydman, DR, McDermott LA, Jacobus NV, et al. Evaluation of the in vitro activity of eravacycline against a broad spectrum of recent clinical anaerobic isolates. Antimicrob Agents Chemother. 2018;62(5):e02206-17.
  • Zhao, M, Lepak AJ, Marchillo K, et al. In vivo pharmacodynamic target assessment of eravacycline against Escherichia coli in a murine thigh infection model. Antimicrob Agents Chemother. 2017;61(7):e00250-17.
  • Newman, JV, Zhou J, Izmailyan S, et al. Randomized, double-blind, placebo-controlled studies of the safety and pharmacokinetics of single and multiple ascending doses of eravacycline. Antimicrob Agents Chemother. 2018;62(11):e01174-18.
  • Newman, JV, Zhou J, Izmailyan S, et al. Mass balance and drug interaction potential of iv eravacycline administered to healthy subjects. Antimicrob Agents Chemother; 2018:e01810-18.
  • Shaeer, KM, Zmarlicka MT, Chahine EB, et al. Plazomicin: a next-generation aminoglycoside. Pharmacotherapy; 2019;39(1):77–93.
  • Armstrong ES, Miller GH. Combating evolution with intelligent design: the neoglycoside ACHN-490. Curr Opin Microbiol. 2010;13(5):565–573.
  • Aggen, JB, Armstrong ES, Goldblum AA, et al. Synthesis and spectrum of the neoglycoside ACHN-490. Antimicrob Agents Chemother. 2010;54(11):4636–4642.
  • Hall D, Shinabarger MT,D, Serio A, et al. Investigating the Post-Antibiotic Effect (PAE) of plazomicin against multidrug-resistant enterobacteriaceae. 2017. Available from: https://static1.squarespace.com/static/51199d96e4b084d1d0b105c3/t/59334fbc2e69cf4f364fbac9/1496534974109/ASM.Hall.Investigating+the+Post-Antibiotic+Effect+of+Plazoagainst+MDR+Enterobacteriaceae.+ASM+2017.pdf
  • Zhanel, GG, Lawson CD, Zelenitsky S, et al. Comparison of the next-generation aminoglycoside plazomicin to gentamicin, tobramycin and amikacin. Expert Rev Anti Infect Ther. 2012;10(4):459–473.
  • FDA. Prescribing information for ZEMDRI. 2018. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210303orig1s000lbl.pdf
  • Walkty, A, Karlowsky JA, Baxter MR, et al. In vitro activity of plazomicin against gram-negative and gram-positive bacterial pathogens isolated from patients in canadian hospitals from 2013 to 2017 as part of the CANWARD surveillance study. Antimicrob Agents Chemother. 2018;63(1):e02068-18.
  • Castanheira, M, Davis AP, Mendes RE, et al. In vitro activity of plazomicin against gram-negative and gram-positive isolates collected from U.S. hospitals and comparative activities of aminoglycosides against carbapenem-resistant enterobacteriaceae and isolates carrying carbapenemase genes. Antimicrob Agents Chemother. 2018; 62(8):e00313-18.
  • European Medicines Agency, E.M.. Xerava: EPAR - product Ιnformation. 2018. Available from: https://www.ema.europa.eu/documents/product-information/xerava-epar-product-information_en.pdf
  • Jacobs MR, Good CE, Abdelhamed AM, et al. In vitro activity of plazomicin, a next-generation aminoglycoside, against carbapenemase-producing Klebsiella pneumoniae. 2018. Available from: https://idsa.confex.com/idsa/2018/webprogram/Paper71246.html
  • Connolly, LE, Riddle V, Cebrik D, et al. A multicenter, randomized, double-blind, phase 2 study of the efficacy and safety of plazomicin compared with levofloxacin in the treatment of complicated urinary tract infection and acute pyelonephritis. Antimicrob Agents Chemother. 2018;62(4):e01989-17.
  • Park, SM, Kim HS, Jeong YM, et al. Impact of intervention by an antimicrobial stewardship team on conversion from intravenous to oral fluoroquinolones. Infect Chemother. 2017;49(1):31–37.
  • Cho, JC., Crotty MP, White BP, et al. What is old is new again: delafloxacin, a modern fluoroquinolone. Pharmacotherapy. 2017;38(1):108–121.
  • FDA. BAXDELA full prescribing information. 2017. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208610s000,208611s000lbl.pdf
  • Kuramoto, Y, Ohshita Y, Yoshida J, et al. A novel antibacterial 8-chloroquinolone with a distorted orientation of the N1-(5-amino-2,4-difluorophenyl) group. J Med Chem. 2003;46(10):1905–1917.
  • So W, Crandon JL, Nicolau DP. Effects of urine matrix and ph on the potency of delafloxacin and ciprofloxacin against urogenic Escherichia coli and Klebsiella pneumoniae. J Urol. 2015;194(2):563–570.
  • Siala, W, Mingeot-Leclercq MP, Tulkens PM, et al. Comparison of the antibiotic activities of daptomycin, vancomycin, and the investigational fluoroquinolone delafloxacin against biofilms from Staphylococcus aureus clinical isolates. Antimicrob Agents Chemother. 2014;58(11):6385–6397.
  • Lemaire S, Tulkens PM, Van Bambeke F. Contrasting effects of acidic pH on the extracellular and intracellular activities of the anti-gram-positive fluoroquinolones moxifloxacin and delafloxacin against Staphylococcus aureus. Antimicrob Agents Chemother. 2010;55(2):649–658.
  • Nilius, AM, Shen LL, Hensey-Rudloff D, et al. In vitro antibacterial potency and spectrum of ABT-492, a new fluoroquinolone. Antimicrob Agents Chemother. 2003;47(10):3260–3269.
  • Hoover, R, Hunt T, Benedict M, et al. Safety, tolerability, and pharmacokinetic properties of intravenous delafloxacin after single and multiple doses in healthy volunteers. Clin Ther. 2015;38(1):53–65.
  • Hoover, RK, Alcorn Jr H, Lawrence L, et al. Delafloxacin pharmacokinetics in subjects with varying degrees of renal function. J Clin Pharmacol. 2017;58(4):514–521.
  • Hoover, R, Marbury TC, Preston RA, et al. Clinical pharmacology of delafloxacin in patients with hepatic impairment. J Clin Pharmacol. 2016;57(3):328–335.
  • Almer, LS, Hoffrage JB, Keller EL, et al. In vitro and bactericidal activities of ABT-492, a novel fluoroquinolone, against Gram-positive and Gram-negative organisms. Antimicrob Agents Chemother. 2004;48(7):2771–2777.
  • McCurdy, S, Lawrence L, Quintas M, et al. In vitro activity of delafloxacin and microbiological response against fluoroquinolone-susceptible and nonsusceptible Staphylococcus aureus isolates from two phase 3 studies of acute bacterial skin and skin structure infections. Antimicrob Agents Chemother. 2017;61(9):e00772-17.
  • Pfaller, MA, Sader HS, Rhomberg PR, et al. In vitro activity of delafloxacin against contemporary bacterial pathogens from the United States and Europe, 2014. Antimicrob Agents Chemother. 2017;61(4):e02609-16.
  • Flamm, RK, Rhomberg PR, Huband MD, et al. In vitro activity of delafloxacin tested against isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Antimicrob Agents Chemother. 2016;60(10):6381–6385.
  • Pullman, J, Gardovskis J, Farley B, et al. Efficacy and safety of delafloxacin compared with vancomycin plus aztreonam for acute bacterial skin and skin structure infections: a phase 3, double-blind, randomized study. J Antimicrob Chemother. 2017;72(12):3471–3480.
  • O‘Riordan, W, McManus A, Teras J, et al. A comparison of the efficacy and safety of intravenous followed by oral delafloxacin with vancomycin plus aztreonam for the treatment of acute bacterial skin and skin structure infections: a phase 3, multinational, double-blind, randomized study. Clin Infect Dis. 2018;67(5):657–666.
  • Kingsley, J, Mehra P, Lawrence LE, et al. A randomized, double-blind, phase 2 study to evaluate subjective and objective outcomes in patients with acute bacterial skin and skin structure infections treated with delafloxacin, linezolid or vancomycin. J Antimicrob Chemother. 2015;71(3):821–829.
  • O‘Riordan, W, Mehra P, Manos P, et al. A randomized phase 2 study comparing two doses of delafloxacin with tigecycline in adults with complicated skin and skin-structure infections. Int J Infect Dis. 2014;30:67–73.
  • Lodise, T, Corey R, Hooper D, et al. Safety of delafloxacin: focus on adverse events of special interest. Open Forum Infect Dis. 2018;5(10):ofy220.
  • Litwin, JS, Benedict MS, Thorn MD, et al. A thorough QT study to evaluate the effects of therapeutic and supratherapeutic doses of delafloxacin on cardiac repolarization. Antimicrob Agents Chemother. 2015;59(6):3469–3473.
  • Kohira, N, West J, Ito A, et al. In vitro antimicrobial activity of a siderophore cephalosporin, S-649266, against Enterobacteriaceae clinical isolates, including carbapenem-resistant strains. Antimicrob Agents Chemother. 2015;60(2):729–734.
  • Mollmann, U, Heinisch L, Bauernfeind A, et al. Siderophores as drug delivery agents: application of the “Trojan Horse” strategy. Biometals. 2009;22(4):615–624.
  • Ito, A, Kohira N, Bouchillon SK, et al. In vitro antimicrobial activity of S-649266, a catechol-substituted siderophore cephalosporin, when tested against non-fermenting Gram-negative bacteria. J Antimicrob Chemother. 2015;71(3):670–677.
  • Monogue, ML, Tsuji M, Yamano Y, et al. Efficacy of humanized exposures of cefiderocol (S-649266) against a diverse population of Gram-negative bacteria in a murine thigh infection model. Antimicrob Agents Chemother. 2017;61(11):e01022-17.
  • Ghazi, IM, Monogue ML, Tsuji M, et al. Pharmacodynamics of cefiderocol, a novel siderophore cephalosporin, in a Pseudomonas aeruginosa neutropenic murine thigh model. Int J Antimicrob Agents. 2017;51(2):206–212.
  • Hackel, MA, Tsuji M, Yamano Y, et al. In vitro activity of the siderophore cephalosporin, cefiderocol, against a recent collection of clinically relevant Gram-negative bacilli from North America and Europe, including carbapenem-nonsusceptible isolates (SIDERO-WT-2014 study). Antimicrob Agents Chemother. 2017;61(9):e00093-17.
  • Dobias, J, Dénervaud-Tendon V, Poirel L, et al. Activity of the novel siderophore cephalosporin cefiderocol against multidrug-resistant Gram-negative pathogens. Eur J Clin Microbiol Infect Dis. 2017;36(12):2319–2327.
  • Matsumoto, S, Singley CM, Hoover J, et al. Efficacy of cefiderocol against carbapenem-resistant gram-negative bacilli in immunocompetent-rat respiratory tract infection models recreating human plasma pharmacokinetics. Antimicrob Agents Chemother. 2017;61(9):e00700-17.
  • Hsueh, SC, Lee YJ, Huang YT, et al. In vitro activities of cefiderocol, ceftolozane/ tazobactam,ceftazidime/avibactam and other comparative drugs against imipenem-resistant Pseudomonas aeruginosa and Acinetobacter baumannii, and Stenotrophomonas maltophilia, all associated with bloodstream infections in Taiwan. J Antimicrob Chemother. 2019;74(2):380–386.
  • Ito-Horiyama, T, Ishii Y, Ito A, et al. Stability of novel siderophore cephalosporin S-649266 against clinically relevant carbapenemases. Antimicrob Agents Chemother. 2016;60(7):4384–4386.
  • Poirel L, Kieffer N, Nordmann P. Stability of cefiderocol against clinically significant broad-spectrum oxacillinases. Int J Antimicrob Agents. 2018;52(6):866–867.
  • Jacobs, MR, Abdelhamed AM, Good CE, et al. ARGONAUT-I: activity of cefiderocol (S-649266), a siderophore cephalosporin, against Gram-negative bacteria, including carbapenem-resistant nonfermenters and Enterobacteriaceae with defined extended-spectrum beta-lactamases and carbapenemases. Antimicrob Agents Chemother. 2018;63(1):e01801-18.
  • Ghazi, IM, Monogue ML, Tsuji M, et al. Humanized exposures of cefiderocol, a siderophore cephalosporin, display sustained in vivo activity against siderophore-resistant Pseudomonas aeruginosa. Pharmacology. 2018;101(5–6):278–284.
  • Falagas, ME, Skalidis T, Vardakas KZ, et al. Activity of cefiderocol (S-649266) against carbapenem-resistant Gram-negative bacteria collected from inpatients in Greek hospitals. J Antimicrob Chemother. 2017;72(6):1704–1708.
  • Kazmierczak, KM, Tsuji M, Wise MG, et al. In vitro activity of cefiderocol, a siderophore cephalosporin, against a recent collection of clinically relevant carbapenem-non-susceptible Gram-negative bacilli, including serine carbapenemase- and metallo-beta-lactamase-producing isolates (SIDERO-WT-2014 Study). Int J Antimicrob Agents. 2018;73(10):2777–2781.
  • Karlowsky, JA, Hackel MA, Tsuji M, et al. In vitro activity of cefiderocol, a siderophore cephalosporin, against Gram-negative bacilli isolated by clinical laboratories in North America and Europe in 2015–2016: SIDERO-WT-2015. Int J Antimicrob Agents. 2019;53(4):456–466.
  • Kanazawa, S, Sato T, Kohira N, et al. Susceptibility of imipenem-susceptible but meropenem-resistant blaIMP-6-carrying enterobacteriaceae to various antibacterials, including the siderophore cephalosporin cefiderocol. Antimicrob Agents Chemother. 2017;61(7):e00576-17.
  • Katsube, T, Wajima T, Ishibashi T, et al. Pharmacokinetic/pharmacodynamic modeling and simulation of cefiderocol, a parenteral siderophore cephalosporin, for dose adjustment based on renal function. Antimicrob Agents Chemother. 2016;61(1):e01381-16.
  • Kawaguchi, N, Katsube T, Echols R, et al. Population pharmacokinetic analysis of cefiderocol, a parenteral siderophore cephalosporin, in healthy subjects, subjects with various degrees of renal function, and patients with complicated urinary tract infection or acute uncomplicated pyelonephritis. Antimicrob Agents Chemother. 2018;62(2):e01391-17.
  • Saisho, Y, Katsube T, White S, et al. Pharmacokinetics, safety, and tolerability of cefiderocol, a novel siderophore cephalosporin for Gram-negative bacteria, in healthy subjects. Antimicrob Agents Chemother. 2018;62(3):e02163-17.
  • Emrich, NC, Heisig A, Stubbings W, et al. Antibacterial activity of finafloxacin under different pH conditions against isogenic strains of Escherichia coli expressing combinations of defined mechanisms of fluoroquinolone resistance. J Antimicrob Chemother. 2010;65(12):2530–2533.
  • Stubbings, W, Leow P, Yong GC, et al. In vitro spectrum of activity of finafloxacin, a novel, pH-activated fluoroquinolone, under standard and acidic conditions. Antimicrob Agents Chemother. 2011;55(9):4394–4397.
  • Higgins, PG, Stubbings W, Wisplinghoff H, et al. Activity of the investigational fluoroquinolone finafloxacin against ciprofloxacin-sensitive and -resistant Acinetobacter baumannii isolates. Antimicrob Agents Chemother. 2010;54(4):1613–1615.
  • Dalhoff A, Schubert S, Vente A. Pharmacodynamics of finafloxacin, ciprofloxacin, and levofloxacin in serum and urine against TEM- and SHV-type extended-spectrum-beta-lactamase-producing enterobacteriaceae isolates from patients with urinary tract infections. Antimicrob Agents Chemother. 2017;61(5):e02446-16.
  • Lyberatos, C, Ladas S, Ladas I, et al. Erythrocyte uroporphyrinogen-I-synthase activity in beta-thalassaemic patients. Eur J Clin Invest. 1983;13(6):461–463.
  • Genzel, GH, Stubbings W, Stingu CS, et al. Activity of the investigational fluoroquinolone finafloxacin and seven other antimicrobial agents against 114 obligately anaerobic bacteria. Int J Antimicrob Agents. 2014;44(5):420–423.
  • Idelevich, EA, Kriegeskorte A, Stubbings W, et al. Comparative in vitro activity of finafloxacin against staphylococci displaying normal and small colony variant phenotypes. J Antimicrob Chemother. 2011;66(12):2809–2813.
  • Patel, H, Andresen A, Vente A, et al. Human pharmacokinetics and safety profile of finafloxacin, a new fluoroquinolone antibiotic, in healthy volunteers. Antimicrob Agents Chemother. 2011;55(9):4386–4393.
  • Taubert, M, Chiesa J, Lückermann M, et al. Pharmacokinetics of intravenous finafloxacin in healthy volunteers. Antimicrob Agents Chemother. 2017;61(10):e01122-17.
  • Vente, A, Bentley C, Lückermann M, et al. Early clinical assessment of the antimicrobial activity of finafloxacin compared to ciprofloxacin in subsets of microbiologically characterized isolates. Antimicrob Agents Chemother. 2018;62(4):e02325-17.
  • Wagenlehner, F, Nowicki M, Bentley C, et al. Explorative randomized Phase II clinical study of the efficacy and safety of finafloxacin versus ciprofloxacin for treatment of complicated urinary tract infections. Antimicrob Agents Chemother. 2018;62(4):e02317-17.
  • Dillon C, Guarascio AJ, Covvey JR. Lefamulin: a promising new pleuromutilin antibiotic in the pipeline. Expert Rev Anti Infect Ther. 2019;17(1):5-15.
  • Veve MP, Wagner JL. Lefamulin: review of a promising novel pleuromutilin antibiotic. Pharmacotherapy. 2018;38(9):935–946.
  • Jacobsson, S, Paukner S, Golparian D, et al. In Vitro activity of the novel pleuromutilin lefamulin (BC-3781) and effect of efflux pump inactivation on multidrug-resistant and extensively drug-resistant Neisseria gonorrhoeae. Antimicrob Agents Chemother. 2017;61(11):e01497-17.
  • Paukner S, Riedl R. Pleuromutilins: potent drugs for resistant bugs-mode of action and resistance. Cold Spring Harb Perspect Med. 2016;7(1).
  • Mittal, J, Szymczak WA, Guo Y, et al. Two for the price of one: emerging carbapenemases in a returning traveller to New York City. BMJ Case Rep. 2018;2018:bcr-2018-225440.
  • Hobson, CA, Bonacorsi S, Fahd M, et al. Successful treatment of a bacteremia due to NDM-1-producing Morganella morganii with Aztreonam and Ceftazidime-avibactam combination in a pediatric patient with hematologic malignancy. Antimicrob Agents Chemother. 2018;63:e02463–18.
  • Barlow G, Morice A. Successful treatment of resistant Burkholderia multivorans infection in a patient with cystic fibrosis using ceftazidime/avibactam plus aztreonam. J Antimicrob Chemother. 2018;73(8):2270–2271.

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.