Vaborbactam: Spectrum of beta-lactamase inhibition and impact of resistance mechanisms on activity in enterobacteriaceae

Antimicrobial Agents and Chemotherapy

Volumn 61, Issue 11, 2017, Pages

  Lomovskaya, Olga ^a   Sun, Dongxu ^a   Rubio Aparicio, Debora ^a   Nelson, Kirk ^a   Tsivkovski, Ruslan ^a   Griffith, David C ^a   Dudley, Michael N ^a  

^a Medicines Company   (United States)

Author keywords

KEYWORDS vaborbactam; KPC; Major porins OmpK35; Meropenem vaborbactam; OmpK36

Indexed keywords

BETA LACTAMASE; EXTENDED SPECTRUM BETA LACTAMASE; MEROPENEM; PORIN; VABORBACTAM; ANTIINFECTIVE AGENT; BACTERIAL PROTEIN; BETA LACTAMASE INHIBITOR; BETA-LACTAMASE KPC-2, KLEBSIELLA PNEUMONIAE; BETA-LACTAMASE KPC-3, KLEBSIELLA PNEUMONIAE; BORONIC ACID DERIVATIVE; CARBAPENEM DERIVATIVE; OMPK35 PORIN, KLEBSIELLA PNEUMONIAE; OMPK36 PROTEIN, KLEBSIELLA PNEUMONIAE; THIENAMYCIN DERIVATIVE;

ANTIBIOTIC RESISTANCE; ARTICLE; BACTERIAL OUTER MEMBRANE; BACTERIAL STRAIN; CONTROLLED STUDY; DRUG MECHANISM; DRUG POTENCY; ENTEROBACTERIACEAE; ENZYME INHIBITION; ESCHERICHIA COLI; KLEBSIELLA PNEUMONIAE; LOSS OF FUNCTION MUTATION; MINIMUM INHIBITORY CONCENTRATION; NONHUMAN; PRIORITY JOURNAL; BACTERIUM CONJUGATION; BETA-LACTAM RESISTANCE; COMBINATION DRUG THERAPY; DRUG EFFECT; GENE EXPRESSION REGULATION; GENETICS; METABOLISM; MICROBIAL SENSITIVITY TEST; MUTATION;

ANTI-BACTERIAL AGENTS; BACTERIAL PROTEINS; BETA-LACTAM RESISTANCE; BETA-LACTAMASE INHIBITORS; BETA-LACTAMASES; BORONIC ACIDS; CARBAPENEMS; CONJUGATION, GENETIC; DRUG THERAPY, COMBINATION; ENTEROBACTERIACEAE; ESCHERICHIA COLI; GENE EXPRESSION REGULATION, BACTERIAL; MICROBIAL SENSITIVITY TESTS; MUTATION; PORINS; THIENAMYCINS;

EID: 85032476113     PISSN: 00664804     EISSN: 10986596     Source Type: Journal    
DOI: 10.1128/AAC.01443-17     Document Type: Article

References (54)

1. Ambler RP, Coulson AF, Frere JM, Ghuysen JM, Joris B, Forsman M, Levesque RC, Tiraby G, Waley SG. 1991. A standard numbering scheme for the class A beta-lactamases. Biochem J 276:269–270. https://doi.org/10.1042/bj2760269.
2. Queenan AM, Bush K. 2007. Carbapenemases: the versatile beta-lactamases. Clin Microbiol Rev 20:440–458. https://doi.org/10.1128/CMR.00001-07.
3. Nordmann P, Dortet L, Poirel L. 2012. Carbapenem resistance in Enterobacteriaceae: here is the storm! Trends Mol Med 18:263–272. https://doi.org/10.1016/j.molmed.2012.03.003.
4. Grundmann H, Glasner C, Albiger B, Aanensen DM, Tomlinson CT, An-drasevic AT, Canton R, Carmeli Y, Friedrich AW, Giske CG, Glupczynski Y, Gniadkowski M, Livermore DM, Nordmann P, Poirel L, Rossolini GM, Seifert H, Vatopoulos A, Walsh T, Woodford N, Monnet DL, European Survey of Carbapenemase-Producing Enterobacteriaceae (EuSCAPE) Working Group. 2017. Occurrence of carbapenemase-producing Klebsiella pneumoniae and Escherichia coli in the European Survey of Carbapenemase-Producing Enterobacteriaceae (EuSCAPE): a prospective, multinational study. Lancet Infect Dis 17:153–163. https://doi.org/10.1016/S1473-3099(16)30257-2.
5. Satlin MJ, Chen L, Patel G, Gomez-Simmonds A, Weston G, Kim AC, Seo SK, Rosenthal ME, Sperber SJ, Jenkins SG, Hamula CL, Uhlemann AC, Levi MH, Fries BC, Tang YW, Juretschko S, Rojtman AD, Hong T, Mathema B, Jacobs MR, Walsh TJ, Bonomo RA, Kreiswirth BN. 2017. Multicenter clinical and molecular epidemiological analysis of bacteremia due to carbapenem-resistant Enterobacteriaceae (CRE) in the CRE epicenter of the United States. Antimicrob Agents Chemother 61:e02349-16. https://doi.org/10.1128/AAC.02349-16.
6. Zhang R, Liu L, Zhou H, Chan EW, Li J, Fang Y, Li Y, Liao K, Chen S. 2017. Nationwide surveillance of clinical carbapenem-resistant Enterobacteriaceae (CRE) strains in China. EBioMedicine 19:98–106. https://doi.org/10.1016/j.ebiom.2017.04.032.
7. Tumbarello M, Trecarichi EM, De Rosa FG, Giannella M, Giacobbe DR, Bassetti M, Losito AR, Bartoletti M, Del Bono V, Corcione S, Maiuro G, Tedeschi S, Celani L, Cardellino CS, Spanu T, Marchese A, Ambretti S, Cauda R, Viscoli C, Viale P, Isgri S. 2015. Infections caused by KPC-producing Klebsiella pneumoniae: differences in therapy and mortality in a multicentre study. J Antimicrob Chemother 70:2133–2143. https://doi.org/10.1093/jac/dkv086.
8. Borer A, Saidel-Odes L, Riesenberg K, Eskira S, Peled N, Nativ R, Schlaeffer F, Sherf M. 2009. Attributable mortality rate for carbapenem-resistant Klebsiella pneumoniae bacteremia. Infect Control Hosp Epidemiol 30: 972–976. https://doi.org/10.1086/605922.
9. Alexander EL, Loutit J, Tumbarello M, Wunderink R, Felton T, Daikos G, Fusaro K, White D, Zhang S, Dudley MN. 2017. Carbapenem-resistant Enterobacteriaceae infections: results from a retrospective series and implications for the design of prospective clinical trials. Open Forum Infect Dis 4:ofx063. https://doi.org/10.1093/ofid/ofx063.
10. Kitchel B, Rasheed JK, Endimiani A, Hujer AM, Anderson KF, Bonomo RA, Patel JB. 2010. Genetic factors associated with elevated carbapenem resistance in KPC-producing Klebsiella pneumoniae. Antimicrob Agents Chemother 54:4201–4207. https://doi.org/10.1128/AAC.00008-10.
11. Landman D, Bratu S, Quale J. 2009. Contribution of OmpK36 to carbapenem susceptibility in KPC-producing Klebsiella pneumoniae. J Med Microbiol 58:1303–1308. https://doi.org/10.1099/jmm.0.012575-0.
12. Clancy CJ, Chen L, Hong JH, Cheng S, Hao B, Shields RK, Farrell AN, Doi Y, Zhao Y, Perlin DS, Kreiswirth BN, Nguyen MH. 2013. Mutations of the ompK36 porin gene and promoter impact responses of sequence type 258, KPC-2-producing Klebsiella pneumoniae strains to doripenem and doripenem-colistin. Antimicrob Agents Chemother 57:5258–5265. https://doi.org/10.1128/AAC.01069-13.
13. Shields RK, Nguyen MH, Potoski BA, Press EG, Chen L, Kreiswirth BN, Clarke LG, Eschenauer GA, Clancy CJ. 2015. Doripenem MICs and ompK36 porin genotypes of sequence type 258, KPC-producing Klebsiella pneumoniae may predict responses to carbapenem-colistin combination therapy among patients with bacteremia. Antimicrob Agents Chemother 59:1797–1801. https://doi.org/10.1128/AAC.03894-14.
14. Humphries RM, Hemarajata P. 2017. Resistance to ceftazidime-avibactam in Klebsiella pneumoniae due to porin mutations and the increased expression of KPC-3. Antimicrob Agents Chemother 61:e00537 -17. https://doi.org/10.1128/AAC.00537-17.
15. Drawz SM, Bonomo RA. 2010. Three decades of beta-lactamase inhibitors. Clin Microbiol Rev 23:160–201. https://doi.org/10.1128/CMR.00037-09.
16. Ehmann DE, Jahic H, Ross PL, Gu RF, Hu J, Durand-Reville TF, Lahiri S, Thresher J, Livchak S, Gao N, Palmer T, Walkup GK, Fisher SL. 2013. Kinetics of avibactam inhibition against class A, C, and D beta-lactamases. J Biol Chem 288:27960–27971. https://doi.org/10.1074/jbc.M113.485979.
17. Ehmann DE, Jahic H, Ross PL, Gu RF, Hu J, Kern G, Walkup GK, Fisher SL. 2012. Avibactam is a covalent, reversible, non-beta-lactam beta-lactamase inhibitor. Proc Natl Acad Sci U S A 109:11663–11668. https://doi.org/10.1073/pnas.1205073109.
18. Bassetti M, Righi E, Viscoli C. 2008. Novel beta-lactam antibiotics and inhibitor combinations. Expert Opin Investig Drugs 17:285–296. https://doi.org/10.1517/13543784.17.3.285.
19. Stachyra T, Levasseur P, Pechereau MC, Girard AM, Claudon M, Miossec C, Black MT. 2009. In vitro activity of the -lactamase inhibitor NXL104 against KPC-2 carbapenemase and Enterobacteriaceae expressing KPC carbapenemases. J Antimicrob Chemother 64:326–329. https://doi.org/10.1093/jac/dkp197.
20. Castanheira M, Mills JC, Costello SE, Jones RN, Sader HS. 2015. Ceftazidime-avibactam activity tested against Enterobacteriaceae isolates from U.S. hospitals (2011 to 2013) and characterization of beta-lactamase-producing strains. Antimicrob Agents Chemother 59: 3509–3517. https://doi.org/10.1128/AAC.00163-15.
21. de Jonge BL, Karlowsky JA, Kazmierczak KM, Biedenbach DJ, Sahm DF, Nichols WW. 2016. In vitro susceptibility to ceftazidime-avibactam of carbapenem-nonsusceptible Enterobacteriaceae isolates collected during the INFORM Global Surveillance Study (2012 to 2014). Antimicrob Agents Chemother 60:3163–3169. https://doi.org/10.1128/ AAC.03042-15.
22. Shields RK, Nguyen MH, Chen L, Press EG, Potoski BA, Marini RV, Doi Y, Kreiswirth BN, Clancy CJ. 2017. Ceftazidime-avibactam is superior to other treatment regimens against carbapenem-resistant Klebsiella pneumoniae bacteremia. Antimicrob Agents Chemother 61:e00883-17. https://doi.org/10.1128/aac.00883-17.
23. Krapp F, Grant JL, Sutton SH, Ozer EA, Barr VO. 2017. Treating complicated carbapenem-resistant Enterobacteriaceae infections with ceftazidime/avibactam: a retrospective study with molecular strain char-acterisation. Int J Antimicrob Agents 49:770–773. https://doi.org/10.1016/j.ijantimicag.2017.01.018.
24. Shields RK, Potoski BA, Haidar G, Hao B, Doi Y, Chen L, Press EG, Kreiswirth BN, Clancy CJ, Nguyen MH. 2016. Clinical outcomes, drug toxicity, and emergence of ceftazidime-avibactam resistance among patients treated for carbapenem-resistant Enterobacteriaceae infections. Clin Infect Dis 63:1615–1618. https://doi.org/10.1093/cid/ciw636.
25. Shields RK, Chen L, Cheng S, Chavda KD, Press EG, Snyder A, Pandey R, Doi Y, Kreiswirth BN, Nguyen MH, Clancy CJ. 2017. Emergence of ceftazidime-avibactam resistance due to plasmid-borne blaKPC-3 mutations during treatment of carbapenem-resistant Klebsiella pneumoniae infections. Antimicrob Agents Chemother 61:e02097-16. https://doi.org/10.1128/aac.02097-16.
26. Hecker SJ, Reddy KR, Totrov M, Hirst GC, Lomovskaya O, Griffith DC, King P, Tsivkovski R, Sun D, Sabet M, Tarazi Z, Clifton MC, Atkins K, Raymond A, Potts KT, Abendroth J, Boyer SH, Loutit JS, Morgan EE, Durso S, Dudley MN. 2015. Discovery of a cyclic boronic acid beta-lactamase inhibitor (RPX7009) with utility versus class A serine carbapenemases. J Med Chem 58:3682–3692. https://doi.org/10.1021/acs.jmedchem.5b00127.
27. Wozniak A, Villagra NA, Undabarrena A, Gallardo N, Keller N, Moraga M, Roman JC, Mora GC, Garcia P. 2012. Porin alterations present in non-carbapenemase-producing Enterobacteriaceae with high and intermediate levels of carbapenem resistance in Chile. J Med Microbiol 61: 1270–1279. https://doi.org/10.1099/jmm.0.045799-0.
28. Crowley B, Benedi VJ, Domenech-Sanchez A. 2002. Expression of SHV-2 beta-lactamase and of reduced amounts of OmpK36 porin in Klebsiella pneumoniae results in increased resistance to cephalosporins and carbapenems. Antimicrob Agents Chemother 46:3679–3682. https://doi.org/10.1128/AAC.46.11.3679-3682.2002.
29. Garcia-Fernandez A, Villa L, Carta C, Venditti C, Giordano A, Venditti M, Mancini C, Carattoli A. 2012. Klebsiella pneumoniae ST258 producing KPC-3 identified in Italy carries novel plasmids and OmpK36/OmpK35 porin variants. Antimicrob Agents Chemother 56:2143–2145. https://doi.org/10.1128/AAC.05308-11.
30. Agyekum A, Fajardo-Lubian A, Ai X, Ginn AN, Zong Z, Guo X, Turnidge J, Partridge SR, Iredell JR. 2016. Predictability of phenotype in relation to common beta-lactam resistance mechanisms in Escherichia coli and Klebsiella pneumoniae. J Clin Microbiol 54:1243–1250. https://doi.org/10.1128/JCM.02153-15.
31. Castanheira M, Huband MD, Mendes RE, Flamm RK. 2017. 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 61:e00567-17. https://doi.org/10.1128/aac.00567-17.
32. Munoz-Price LS, Poirel L, Bonomo RA, Schwaber MJ, Daikos GL, Cormican M, Cornaglia G, Garau J, Gniadkowski M, Hayden MK, Kumarasamy K, Livermore DM, Maya JJ, Nordmann P, Patel JB, Paterson DL, Pitout J, Villegas MV, Wang H, Woodford N, Quinn JP. 2013. Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. Lancet Infect Dis 13:785–796. https://doi.org/10.1016/S1473-3099(13)70190-7.
33. Chen L, Mathema B, Chavda KD, DeLeo FR, Bonomo RA, Kreiswirth BN. 2014. Carbapenemase-producing Klebsiella pneumoniae: molecular and genetic decoding. Trends Microbiol 22:686–696. https://doi.org/10.1016/j.tim.2014.09.003.
34. Deleo FR, Chen L, Porcella SF, Martens CA, Kobayashi SD, Porter AR, Chavda KD, Jacobs MR, Mathema B, Olsen RJ, Bonomo RA, Musser JM, Kreiswirth BN. 2014. Molecular dissection of the evolution of carbapenem-resistant multilocus sequence type 258 Klebsiella pneumoniae. Proc Natl Acad Sci U S A 111:4988–4993. https://doi.org/10.1073/pnas.1321364111.
35. Kitchel B, Rasheed JK, Patel JB, Srinivasan A, Navon-Venezia S, Carmeli Y, Brolund A, Giske CG. 2009. Molecular epidemiology of KPC-producing Klebsiella pneumoniae isolates in the United States: clonal expansion of multilocus sequence type 258. Antimicrob Agents Chemother 53: 3365–3370. https://doi.org/10.1128/AAC.00126-09.
36. Mehta SC, Rice K, Palzkill T. 2015. Natural variants of the KPC-2 carbapenemase have evolved increased catalytic efficiency for ceftazidime hydrolysis at the cost of enzyme stability. PLoS Pathog 11:e1004949. https://doi.org/10.1371/journal.ppat.1004949.
37. Alba J, Ishii Y, Thomson K, Moland ES, Yamaguchi K. 2005. Kinetics study of KPC-3, a plasmid-encoded class A carbapenem-hydrolyzing beta-lactamase. Antimicrob Agents Chemother 49:4760–4762. https://doi.org/10.1128/AAC.49.11.4760-4762.2005.
38. Shields RK, Clancy CJ, Hao B, Chen L, Press EG, Iovine NM, Kreiswirth BN, Nguyen MH. 2015. 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 59:5793–5797. https://doi.org/10.1128/AAC.00548-15.
39. Lapuebla A, Abdallah M, Olafisoye O, Cortes C, Urban C, Quale J, Landman D. 2015. Activity of meropenem combined with RPX7009, a novel beta-lactamase inhibitor, against gram-negative clinical isolates in New York City. Antimicrob Agents Chemother 59:4856–4860. https://doi.org/10.1128/AAC.00843-15.
40. Castanheira M, Rhomberg PR, Flamm RK, Jones RN. 2016. Effect of the beta-lactamase inhibitor vaborbactam combined with meropenem against serine carbapenemase-producing Enterobacteriaceae. Antimicrob Agents Chemother 60:5454–5458. https://doi.org/10.1128/AAC.00711-16.
41. Tsivkovski R, Griffith DC, Hecker SJ, Dudley MN, Lomovskaya O. 2012. Biochemical characterization of the beta-lactamase inhibitor RPX7009, abstr F-849. Abstr 52nd Intersci Conf Antimicrob Agents Chemother, San Francisco, CA. American Society for Microbiology, Washington, DC.
42. Castanheira M, Farrell SE, Krause KM, Jones RN, Sader HS. 2014. Contemporary diversity of beta-lactamases among Enterobacteriaceae in the nine U.S. census regions and ceftazidime-avibactam activity tested against isolates producing the most prevalent beta-lactamase groups. Antimicrob Agents Chemother 58:833– 838. https://doi.org/10.1128/AAC.01896-13.
43. Hernandez-Alles S, Alberti S, Alvarez D, Domenech-Sanchez A, Martinez-Martinez L, Gil J, Tomas JM, Benedi VJ. 1999. Porin expression in clinical isolates of Klebsiella pneumoniae. Microbiology 145(Pt 3):673–679.
44. Sho T, Muratani T, Hamasuna R, Yakushiji H, Fujimoto N, Matsumoto T. 2013. The mechanism of high-level carbapenem resistance in Klebsiella pneumoniae: underlying Ompk36-deficient strains represent a threat of emerging high-level carbapenem-resistant K. pneumoniae with IMP-1 beta-lactamase production in Japan. Microb Drug Resist 19:274–281. https://doi.org/10.1089/mdr.2012.0248.
45. Szabó D, Silveira F, Hujer AM, Bonomo RA, Hujer KM, Marsh JW, Bethel CR, Doi Y, Deeley K, Paterson DL. 2006. Outer membrane protein changes and efflux pump expression together may confer resistance to ertapenem in Enterobacter cloacae. Antimicrob Agents Chemother 50: 2833–2835. https://doi.org/10.1128/AAC.01591-05.
46. Davies TA, Marie Queenan A, Morrow BJ, Shang W, Amsler K, He W, Lynch AS, Pillar C, Flamm RK. 2011. Longitudinal survey of carbapenem resistance and resistance mechanisms in Enterobacteriaceae and non-fermenters from the USA in 2007-09. J Antimicrob Chemother 66: 2298–2307. https://doi.org/10.1093/jac/dkr290.
47. Griffith DC, Loutit JS, Morgan EE, Durso S, Dudley MN. 2016. Phase 1 study of the safety, tolerability, and pharmacokinetics of the beta-lactamase inhibitor vaborbactam (RPX7009) in healthy adult subjects. Antimicrob Agents Chemother 60:6326–6332. https://doi.org/10.1128/AAC.00568-16.
48. Bhavnani SM, Hammel JP, Rubino CM, Tran J, Loutit JS, Griffin DC, Lomovskaya O, Dudley MN, Ambrose PG. 2017. Meropenem-vaborbactam pharmacokinetic-pharmacodynamic analyses for efficacy based on data from patients enrolled in phase 3 studies, abstr Sunday-193. Abstr ASM Microbe, New Orleans, LA. American Society for Microbiology, Washington, DC.
49. West SE, Schweizer HP, Dall C, Sample AK, Runyen-Janecky LJ. 1994. Construction of improved Escherichia-Pseudomonas shuttle vectors derived from pUC18/19 and sequence of the region required for their replication in Pseudomonas aeruginosa. Gene 148:81– 86. https://doi.org/10.1016/0378-1119(94)90237-2.
50. Broberg CA, Wu W, Cavalcoli JD, Miller VL, Bachman MA. 2014. Complete genome sequence of Klebsiella pneumoniae strain ATCC 43816 KPPR1, a rifampin-resistant mutant commonly used in animal, genetic, and molecular biology studies. Genome Announc 2(5):e00924-14. https://doi .org/10.1128/genomeA.00924-14.
51. Leavitt A, Chmelnitsky I, Carmeli Y, Navon-Venezia S. 2010. Complete nucleotide sequence of KPC-3-encoding plasmid pKpQIL in the epidemic Klebsiella pneumoniae sequence type 258. Antimicrob Agents Chemother 54:4493–4496. https://doi.org/10.1128/AAC.00175-10.
52. Datsenko KA, Wanner BL. 2000. One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products. Proc Natl Acad Sci U S A 97:6640 – 6645. https://doi.org/10.1073/pnas.120163297.
53. Clinical and Laboratory Standards Institute. 2015. M07-A10. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard: ninth edition. Clinical and Laboratory Standards Institute, Wayne, PA.
54. Moody J. 2007. Synergism testing: broth microdilution checkerboard, p 12. In Garcia L (ed), Clinical microbiology procedures handbook, 3rd ed and 2007 update. ASM Press, Washington, DC.