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Review

Emerging Gram negative resistance to last-line antimicrobial agents fosfomycin, colistin and ceftazidime-avibactam – epidemiology, laboratory detection and treatment implications

ORCID Icon & ORCID Icon
Pages 289-306 | Received 05 Jan 2018, Accepted 14 Mar 2018, Published online: 21 Mar 2018

References

  • World Health Organization. Global action plan on antimicrobial resistance. Geneva: WHO; 2015.
  • 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.
  • Falagas ME, Vouloumanou EK, Samonis G, et al. Fosfomycin. Clin Microbiol Rev. 2016;29(2):321–347.
  • Silver LL. Fosfomycin: mechanism and resistance. Cold Spring Harbor Perspect Med. 2017;7(2):a025262.
  • Walsh CC, McIntosh MP, Peleg AY, et al. In vitro pharmacodynamics of fosfomycin against clinical isolates of Pseudomonas aeruginosa. J Antimicrob Chemother. 2015;70(11):3042–3050.
  • Michalopoulos AS, Livaditis IG, Gougoutas V. The revival of fosfomycin. Int J Infect Dis. 2011;15(11):e732–e739.
  • Benzerara Y, Gallah S, Hommeril B, et al. Emergence of plasmid-mediated fosfomycin-resistance genes among Escherichia coli isolates, France. Emerg Infect Dis. 2017;23(9):1564–1567.
  • Shorr AF, Pogue JM, Mohr JF. Intravenous fosfomycin for the treatment of hospitalized patients with serious infections. Expert Rev Anti-Infect Ther. 2017;15(10):935–945.
  • Vardakas KZ, Legakis NJ, Triarides N, et al. Susceptibility of contemporary isolates to fosfomycin: a systematic review of the literature. Int J Antimicrob Agents. 2016;47(4):269–285.
  • European Committee on Antimicrobial Susceptibility Testing (EUCAST). Breakpoint tables for interpretation of MICs and zone diameters (version 7.1). 2017 [cited 2011 Dec 1]. Available from: http://www.eucast.org.
  • Clinical & Laboratory Standards Institute, Performance standards for antimicrobial susceptibility testing. 27th ed.. ( CLSI supplement M100). CLSI: Wayne, PA, 2017.
  • Matuschek E, Wootton M, Ahman J, et al. EUCAST zone diameter breakpoints for fosfomycin and Escherichia coli. 27th ECCMID; 2017 April 22–25; Vienna, Austria.
  • de Cueto M, Lopez L, Hernandez JR, et al. In vitro activity of fosfomycin against extended-spectrum-beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae: comparison of susceptibility testing procedures. Antimicrob Agents Chemother. 2006;50(1):368–370.
  • Diez-Aguilar M, Morosini MI, del Campo R, et al. In vitro activity of fosfomycin against a collection of clinical Pseudomonas aeruginosa isolates from 16 Spanish hospitals: establishing the validity of standard broth microdilution as susceptibility testing method. Antimicrob Agents Chemother. 2013;57(11):5701–5703.
  • Perdigao-Neto LV, Oliveira MS, Rizek CF, et al. Susceptibility of multiresistant Gram-negative bacteria to fosfomycin and performance of different susceptibility testing methods. Antimicrob Agents Chemother. 2014;58(3):1763–1767.
  • Qiao LD, Chen S, Yang Y, et al. Characteristics of urinary tract infection pathogens and their in vitro susceptibility to antimicrobial agents in China: data from a multicenter study. BMJ Open. 2013;3(12):e004152.
  • Jiang Y, Shen P, Wei Z, et al. Dissemination of a clone carrying a fosA3-harbouring plasmid mediates high fosfomycin resistance rate of KPC-producing Klebsiella pneumoniae in China. Int J Antimicrob Agents. 2015;45(1):66–70.
  • Li -J-J, Sheng Z-K, Deng M, et al. Epidemic of Klebsiella pneumoniae ST11 clone coproducing KPC-2 and 16S rRNA methylase RmtB in a Chinese university hospital. BMC Infect Dis. 2012;12(1):373.
  • Yu W, Shen P, Bao Z, et al. In vitro antibacterial activity of fosfomycin combined with other antimicrobials against KPC-producing Klebsiella pneumoniae. Int J Antimicrob Agents. 2017;50(2):237–241.
  • Livermore DM, Warner M, Mushtaq S, et al. What remains against carbapenem-resistant Enterobacteriaceae? Evaluation of chloramphenicol, ciprofloxacin, colistin, fosfomycin, minocycline, nitrofurantoin, temocillin and tigecycline. Int J Antimicrob Agents. 2011;37(5):415–419.
  • Falagas ME, Kastoris AC, Karageorgopoulos DE, et al. Fosfomycin for the treatment of infections caused by multidrug-resistant non-fermenting Gram-negative bacilli: a systematic review of microbiological, animal and clinical studies. Int J Antimicrob Agents. 2009;34(2):111–120.
  • Castaneda-Garcia A, Blazquez J, Rodriguez-Rojas A. Molecular mechanisms and clinical impact of acquired and intrinsic fosfomycin resistance. Antibiotics. 2013;2(2):217–236.
  • Nilsson AI, Berg OG, Aspevall O, et al. Biological costs and mechanisms of fosfomycin resistance in Escherichia coli. Antimicrob Agents Chemother. 2003;47(9):2850–2858.
  • Takahata S, Ida T, Hiraishi T, et al. Molecular mechanisms of fosfomycin resistance in clinical isolates of Escherichia coli. Int J Antimicrob Agents. 2010;35(4):333–337.
  • Klontz EH, Tomich AD, Gunther S, et al. Structure and dynamics of FosA-mediated fosfomycin resistance in Klebsiella pneumoniae and Escherichia coli. Antimicrob Agents Chemother. 2017;61(11):e01572–17.
  • Ito R, Mustapha MM, Tomich AD, et al. Widespread fosfomycin resistance in Gram-negative bacteria attributable to the chromosomal fosA gene. mBio. 2017;8(4):e00749–17.
  • Cao XL, Shen H, Xu YY, et al. High prevalence of fosfomycin resistance gene fosA3 in blaCTX-M-harbouring Escherichia coli from urine in a Chinese tertiary hospital during 2010–2014. Epidemiol Infect. 2017;145(4):818–824.
  • Guo Q, Tomich AD, McElheny CL, et al. Glutathione-S-transferase FosA6 of Klebsiella pneumoniae origin conferring fosfomycin resistance in ESBL-producing Escherichia coli. J Antimicrob Chemother. 2016;71(9):2460–2465.
  • Rehman MA, Yin X, Persaud-Lachhman MG, et al. First detection of a fosfomycin resistance gene fosA7 in Salmonella enterica serovar Heidelberg isolated from broiler chickens. Antimicrob Agents Chemother. 2017;61(8):e00410–17.
  • White BP, Stover KR, Barber KE, et al. Mechanisms of fosfomycin resistance in carbapenem-resistant Enterobacter spp. Int J Antimicrob Agents. 2017;50(5):690–692.
  • Sato N, Kawamura K, Nakane K, et al. First detection of fosfomycin resistance gene fosA3 in CTX-M-producing Escherichia coli isolates from healthy individuals in Japan. Microb Drug Resist. 2013;19(6):477–482.
  • He D, Liu L, Guo B, et al. Chromosomal location of the fosA3 and blaCTX-M genes in Proteus mirabilis and clonal spread of Escherichia coli ST117 carrying fosA3-positive IncHI2/ST3 or F2: A-:B-plasmids in a chicken farm. Int J Antimicrob Agents. 2017;49(4):443–448.
  • Ho PL, Chan J, Lo WU, et al. Prevalence and molecular epidemiology of plasmid-mediated fosfomycin resistance genes among blood and urinary Escherichia coli isolates. J Med Microbiol. 2013;62(11):1707–1713.
  • Huang L, Hu YY, Zhang R. Prevalence of fosfomycin resistance and plasmid-mediated fosfomycin-modifying enzymes among carbapenem-resistant Enterobacteriaceae in Zhejiang, China. J Med Microbiol. 2017;66(9):1332–1334.
  • Liu X, Li R, Zheng Z, et al. Molecular characterization of Escherichia coli isolates carrying mcr-1, fosA3, and extended-spectrum-beta-lactamase genes from food samples in China. Antimicrob Agents Chemother. 2017;61(6):e00064–17.
  • Tseng SP, Wang SF, Ma L, et al. The plasmid-mediated fosfomycin resistance determinants and synergy of fosfomycin and meropenem in carbapenem-resistant Klebsiella pneumoniae isolates in Taiwan. J Microbiol Immunol Infect. 2017;50(5):653–661.
  • Wang XM, Dong Z, Schwarz S, et al. Plasmids of diverse Inc groups disseminate the fosfomycin resistance gene fosA3 among Escherichia coli isolates from pigs, chickens, and dairy cows in Northeast China. Antimicrob Agents Chemother. 2017;61(9):e00859–17.
  • Ballestero-Tellez M, Docobo-Perez F, Rodriguez-Martinez JM, et al. Role of inoculum and mutant frequency on fosfomycin MIC discrepancies by agar dilution and broth microdilution methods in Enterobacteriaceae. Clin Microbiol Infect. 2017;23(5):325–331.
  • Ballestero-Tellez M, Docobo-Perez F, Portillo-Calderon I, et al. Molecular insights into fosfomycin resistance in Escherichia coli. J Antimicrob Chemother. 2017;72(5):1303–1309.
  • Karageorgopoulos DE, Miriagou V, Tzouvelekis LS, et al. Emergence of resistance to fosfomycin used as adjunct therapy in KPC Klebsiella pneumoniae bacteraemia: report of three cases. J Antimicrob Chemother. 2012;67(11):2777–2779.
  • Zhao M, Bulman ZP, Lenhard JR, et al. Pharmacodynamics of colistin and fosfomycin: a ‘treasure trove’ combination combats KPC-producing Klebsiella pneumoniae. J Antimicrob Chemother. 2017;72(7):1985–1990.
  • Walsh CC, Landersdorfer CB, McIntosh MP, et al. Clinically relevant concentrations of fosfomycin combined with polymyxin B, tobramycin or ciprofloxacin enhance bacterial killing of Pseudomonas aeruginosa, but do not suppress the emergence of fosfomycin resistance. J Antimicrob Chemother. 2016;71(8):2218–2229.
  • VanScoy BD, McCauley J, Ellis-Grosse EJ, et al. Exploration of the pharmacokinetic-pharmacodynamic relationships for fosfomycin efficacy using an in vitro infection model. Antimicrob Agents Chemother. 2015;59(12):7170–7177.
  • Sastry S, Doi Y. Fosfomycin: resurgence of an old companion. J Infect Chemother. 2016;22(5):273–280.
  • Karaiskos I, Giamarellou H. Multidrug-resistant and extensively drug-resistant Gram-negative pathogens: current and emerging therapeutic approaches. Expert Opin Pharmacother. 2014;15(10):1351–1370.
  • Grabein B, Graninger W, Rodriguez Bano J, et al. Intravenous fosfomycin-back to the future. Systematic review and meta-analysis of the clinical literature. Clin Microbiol Infect. 2017;23(6):363–372.
  • Hickman RA, Hughes D, Cars T, et al. Cell‐wall‐inhibiting antibiotic combinations with activity against multidrug‐resistant Klebsiella pneumoniae and Escherichia coli. Clin Microbiol Infect. 2014;20(4):O267–O273.
  • Souli M, Galani I, Boukovalas S, et al. In vitro interactions of antimicrobial combinations with fosfomycin against KPC-2-producing Klebsiella pneumoniae and protection of resistance development. Antimicrob Agents Chemother. 2011;55(5):2395–2397.
  • Sirijatuphat R, Thamlikitkul V. Preliminary study of colistin versus colistin plus fosfomycin for treatment of carbapenem-resistant Acinetobacter baumannii infections. Antimicrob Agents Chemother. 2014;58(9):5598–5601.
  • Pontikis K, Karaiskos I, Bastani S, et al. Outcomes of critically ill intensive care unit patients treated with fosfomycin for infections due to pandrug-resistant and extensively drug-resistant carbapenemase-producing Gram-negative bacteria. Int J Antimicrob Agents. 2014;43(1):52–59.
  • Jeannot K, Bolard A, Plesiat P. Resistance to polymyxins in Gram-negative organisms. Int J Antimicrob Agents. 2017;49(5):526–535.
  • Lim LM, Ly N, Anderson D, et al. Resurgence of colistin: a review of resistance, toxicity, pharmacodynamics, and dosing. Pharmacotherapy. 2010;30(12):1279–1291.
  • Poirel L, Jayol A, Nordmann P. Polymyxins: antibacterial activity, susceptibility testing, and resistance mechanisms encoded by plasmids or chromosomes. Clin Microbiol Rev. 2017;30(2):557–596.
  • Poudyal A, Howden BP, Bell JM, et al. In vitro pharmacodynamics of colistin against multidrug-resistant Klebsiella pneumoniae. J Antimicrob Chemother. 2008;62(6):1311–1318.
  • Nation RL, Li J, Cars O, et al. Framework for optimisation of the clinical use of colistin and polymyxin B: the Prato polymyxin consensus. Lancet Infect Dis. 2015;15(2):225–234.
  • European Committee on Antimicrobial Susceptibility Testing (EUCAST). EUCAST warnings concerning antimicrobial susceptibility testing products or procedures: antimicrobial susceptibility testing of colistin – problems detected with several commercially available products 2017 [updated 2017 Jun 20; cited 2017 Nov 22]. Available from: http://www.eucast.org/ast_of_bacteria/warnings/#c13111.
  • Clinical & Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing; twenty-fourth informational supplement (M100-S24). Wayne, PA: CLSI; 2014.
  • Jayol A, Poirel L, Dortet L, et al. National survey of colistin resistance among carbapenemase-producing Enterobacteriaceae and outbreak caused by colistin-resistant OXA-48-producing Klebsiella pneumoniae, France, 2014. Eurosurveillance. 2016;21(37):30339.
  • Guerin F, Isnard C, Sinel C, et al. Cluster-dependent colistin hetero-resistance in Enterobacter cloacae complex. J Antimicrob Chemother. 2016;71(11):3058–3061.
  • Landman D, Salamera J, Quale J. Irreproducible and uninterpretable polymyxin B MICs for Enterobacter cloacae and Enterobacter aerogenes. J Clin Microbiol. 2013;51(12):4106–4111.
  • Cai Y, Chai D, Wang R, et al. Colistin resistance of Acinetobacter baumannii: clinical reports, mechanisms and antimicrobial strategies. J Antimicrob Chemother. 2012;67(7):1607–1615.
  • Li J, Rayner CR, Nation RL, et al. Heteroresistance to colistin in multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 2006;50(9):2946–2950.
  • Schurek KN, Sampaio JL, Kiffer CR, et al. Involvement of pmrAB and phoPQ in polymyxin B adaptation and inducible resistance in non-cystic fibrosis clinical isolates of Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2009;53(10):4345–4351.
  • Lo-Ten-Foe JR, De Smet AM, Diederen BM, et al. Comparative evaluation of the VITEK 2, disk diffusion, etest, broth microdilution, and agar dilution susceptibility testing methods for colistin in clinical isolates, including heteroresistant Enterobacter cloacae and Acinetobacter baumannii strains. Antimicrob Agents Chemother. 2007;51(10):3726–3730.
  • Jayol A, Nordmann P, Lehours P, et al. Comparison of methods for detection of plasmid-mediated and chromosomally encoded colistin resistance in Enterobacteriaceae. Clin Microbiol Infect. 2018;24(2):175–179.
  • CLSI-EUCAST Polymyxin Breakpoints Working Group. Recommendations for MIC determination of colistin (polymyxin E). EUCAST; 2016 March 22 cited 2018 Jan 4. Available from: www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/General_documents/Recommendations_for_MIC_determination_of_colistin_March_2016.pdf
  • Matuschek E, Ahman J, Webster C, et al. Evaluation of five commercial MIC methods for colistin antimicrobial susceptibility testing for Gram-negative bacteria. 27th ECCMID; 2017 April 22–25; Vienna, Austria.
  • Hindler JA, Humphries RM. Colistin MIC variability by method for contemporary clinical isolates of multidrug-resistant Gram-negative bacilli. J Clin Microbiol. 2013;51(6):1678–1684.
  • Moskowitz SM, Garber E, Chen Y, et al. Colistin susceptibility testing: evaluation of reliability for cystic fibrosis isolates of Pseudomonas aeruginosa and Stenotrophomonas maltophilia. J Antimicrob Chemother. 2010;65:1416–1423.
  • Hogardt M, Schmoldt S, Gotzfried M, et al. Pitfalls of polymyxin antimicrobial susceptibility testing of Pseudomonas aeruginosa isolated from cystic fibrosis patients. J Antimicrob Chemother. 2004;54(6):1057–1061.
  • Lee SY, Shin JH, Lee K, et al. Comparison of the Vitek 2, MicroScan, and Etest methods with the agar dilution method in assessing colistin susceptibility of bloodstream isolates of Acinetobacter species from a Korean university hospital. J Clin Microbiol. 2013;51(6):1924–1926.
  • Nordmann P, Jayol A, Poirel L. Rapid detection of polymyxin resistance in Enterobacteriaceae. Emerg Infect Dis. 2016;22(6):1038.
  • Simar S, Sibley D, Ashcraft D, et al. Evaluation of the rapid polymyxin NP test for polymyxin B resistance detection using Enterobacter cloacae and Enterobacter aerogenes isolates. J Clin Microbiol. 2017;55(10):3016–3020.
  • Nordmann P, Jayol A, Poirel L. A universal culture medium for screening polymyxin-resistant Gram-negative isolates. J Clin Microbiol. 2016;54(5):1395–1399.
  • Cannatelli A, D’Andrea MM, Giani T, et al. In vivo emergence of colistin resistance in Klebsiella pneumoniae producing KPC-type carbapenemases mediated by insertional inactivation of the PhoQ/PhoP mgrB regulator. Antimicrob Agents Chemother. 2013;57(11):5521–5526.
  • Jayol A, Nordmann P, Brink A, et al. High-level resistance to colistin mediated by various mutation in the ccrB gene among carbapenemase-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2017;61(11):e01423–17.
  • Olaitan AO, Morand S, Rolain JM. Mechanisms of polymyxin resistance: acquired and intrinsic resistance in bacteria. Front Microbiol. 2014;5:643.
  • Regenbogen B, Willmann M, Steglich M, et al. Rapid and consistent evolution of colistin resistance in XDR Pseudomonas aeruginosa during morbidostat culture. Antimicrob Agents Chemother. 2017;61(9):e00043–17.
  • Liu YY, Wang Y, Walsh TR, et al. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis. 2015;16(2):161–168.
  • Zhao F, Feng Y, Lu X, et al. Remarkable diversity of Escherichia coli carrying mcr-1 from hospital sewage with the identification of two new mcr-1 variants. Front Microbiol. 2017;8:2094.
  • Lu X, Hu Y, Luo M, et al. MCR-1.6, a new MCR variant carried by an IncP plasmid in a colistin-resistant Salmonella enterica serovar Typhimurium isolate from a healthy individual. Antimicrob Agents Chemother. 2017;61(5):e02632–16.
  • Zeng KJ, Doi Y, Patil S, et al. Emergence of the plasmid-mediated mcr-1 gene in colistin-resistant Enterobacter aerogenes and Enterobacter cloacae. Antimicrob Agents Chemother. 2016;60(6):3862–3863.
  • Zhang J, Wang J, Chen L, et al. Housefly (Musca domestica) and blow fly (Protophormia terraenovae) as vectors of colistin resistance genes-carrying bacteria. Appl Environ Microbiol. 2018;84(1):e01736–17.
  • Zhou HW, Zhang T, Ma JH, et al. Occurrence of plasmid- and chromosome-encoded mcr-1 in waterborne Enterobacteriaceae in China. Antimicrob Agents Chemother. 2017;61(8):e00017.
  • AbuOun M, Stubberfield EJ, Duggett NA, et al. mcr-1 and mcr-2 variant genes identified in Moraxella species isolated from pigs in Great Britain from 2014 to 2015. J Antimicrob Chemother. 2017;72(10):2745–2749.
  • Garcia-Graells C, De Keersmaecker SC, Vanneste K, et al. Detection of plasmid-mediated colistin resistance, mcr-1 and mcr-2 genes, in Salmonella spp. isolated from food at retail in Belgium from 2012 to 2015. Foodborne Pathog Dis. 2018;15(2):114–117.
  • Xavier BB, Lammens C, Ruhal R, et al. Identification of a novel plasmid-mediated colistin-resistance gene, mcr-2, in Escherichia coli, Belgium, June 2016. Eurosurveillance. 2016;21(27):30280.
  • Litrup E, Kiil K, Hammerum AM, et al. Plasmid-borne colistin resistance gene mcr-3 in Salmonella isolates from human infections, Denmark, 2009–17. Eurosurveillance. 2017;22(31):30587.
  • Yin W, Li H, Shen Y, et al. Novel plasmid-mediated colistin resistance gene mcr-3 in Escherichia coli. mBio. 2017;8(3):e00543–17.
  • Hernandez M, Iglesias MR, Rodriguez-Lazaro D, et al. Co-occurrence of colistin-resistance genes mcr-1 and mcr-3 among multidrug-resistant Escherichia coli isolated from cattle, Spain, September 2015. Eurosurveillance. 2017;22(31):30586.
  • Carattoli A, Villa L, Feudi C, et al. Novel plasmid-mediated colistin resistance mcr-4 gene in Salmonella and Escherichia coli, Italy 2013, Spain and Belgium, 2015 to 2016. Eurosurveillance. 2017;22(31):30589.
  • Fukuda A, Sato T, Shinagawa M, et al. High prevalence of mcr-1, mcr-3, and mcr-5 in Escherichia coli derived from diseased pigs in Japan. Int J Antimicrob Agents. 2017;51(1):163–164.
  • Hammerl JA, Borowiak M, Schmoger S, et al. mcr-5 and a novel mcr-5.2 variant in Escherichia coli isolates from food and food-producing animals, Germany, 2010 to 2017. J Antimicrob Chemother. 2018. DOI:10.1093/jac/dky020.
  • Carretto E, Brovarone F, Nardini P, et al. Detection of mcr-4 positive Salmonella enterica serovar Typhimurium in clinical isolates of human origin, Italy, October to November 2016. Eurosurveillance. 2018;23(2):17–00821.
  • Poirel L, Kieffer N, Fernandez-Garayzabal JF, et al. MCR-2-mediated plasmid-borne polymyxin resistance most likely originates from Moraxella pluranimalium. J Antimicrob Chemother. 2017;72(10):2947–2949.
  • Borowiak M, Fischer J, Hammerl JA, et al. Identification of a novel transposon-associated phosphoethanolamine transferase gene, mcr-5, conferring colistin resistance in d-tartrate fermenting Salmonella enterica subsp. enterica serovar Paratyphi B. J Antimicrob Chemother. 2017;72(12):3317–3324.
  • 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.
  • Ip M, Lai CK, Fung KSC, et al. Activity of temocillin and 15 other agents, including fosfomycin and colistin, against Enterobacteriaceae in Hong Kong. Eur J Clin Microbiol Infect Dis. 2017;36(12):2491–2494.
  • Sader HS, Castanheira M, Flamm RK, et al. Ceftazidime/avibactam tested against Gram-negative bacteria from intensive care unit (ICU) and non-ICU patients, including those with ventilator-associated pneumonia. Int J Antimicrob Agents. 2015;46(1):53–59.
  • Oteo J, Ortega A, Bartolome R, et al. Prospective multicenter study of carbapenemase-producing Enterobacteriaceae from 83 hospitals in Spain reveals high in vitro susceptibility to colistin and meropenem. Antimicrob Agents Chemother. 2015;59(6):3406–3412.
  • Sader HS, Farrell DJ, Flamm RK, et al. Antimicrobial susceptibility of Gram-negative organisms isolated from patients hospitalised with pneumonia in US and European hospitals: results from the SENTRY Antimicrobial Surveillance Program, 2009–2012. Int J Antimicrob Agents. 2014;43(4):328–334.
  • Halaby T, Kucukkose E, Janssen AB, et al. Genomic characterization of colistin heteroresistance in Klebsiella pneumoniae during a nosocomial outbreak. Antimicrob Agents Chemother. 2016;60(11):6837–6843.
  • Sader HS, Castanheira M, Flamm RK, et al. Antimicrobial activity of ceftazidime-avibactam against Gram-negative organisms collected from US medical centers in 2012. Antimicrob Agents Chemother. 2014;58(3):1684–1692.
  • Sader HS, Castanheira M, Mendes RE, et al. Ceftazidime-avibactam activity against multidrug-resistant Pseudomonas aeruginosa isolated in U.S. medical centers in 2012 and 2013. Antimicrob Agents Chemother. 2015;59(6):3656–3659.
  • Bradford PA, Kazmierczak KM, Biedenbach DJ, et al. Correlation of beta-lactamase production and colistin resistance among Enterobacteriaceae isolates from a global surveillance program. Antimicrob Agents Chemother. 2015;60(3):1385–1392.
  • Castanheira M, Mendes RE, Jones RN, et al. Changes in the frequencies of beta-lactamase genes among Enterobacteriaceae isolates in U.S. hospitals, 2012 to 2014: activity of ceftazidime-avibactam tested against beta-lactamase-producing isolates. Antimicrob Agents Chemother. 2016;60(8):4770–4777.
  • Sader HS, Castanheira M, Flamm RK, et al. Antimicrobial activities of ceftazidime-avibactam and comparator agents against Gram-negative organisms isolated from patients with urinary tract infections in U.S. medical centers, 2012 to 2014. Antimicrob Agents Chemother. 2016;60(7):4355–4360.
  • European Centre for Disease Prevention and Control. Antimicrobial resistance surveillance in Europe 2016. Stockholm: ECDC; 2017.
  • Sader HS, Castanheira M, Shortridge D, et al. Antimicrobial activity of ceftazidime-avibactam tested against multidrug-resistant Enterobacteriaceae and Pseudomonas aeruginosa isolates from United States medical centers (2013–2016). Antimicrob Agents Chemother. 2017;61(11):w01045-17.
  • Ah YM, Kim AJ, Lee JY. Colistin resistance in Klebsiella pneumoniae. Int J Antimicrob Agents. 2014;44(1):8–15.
  • de Maio Carrillho CM, Gaudereto JJ, Martins RC, et al. Colistin-resistant Enterobacteriaceae infections: clinical and molecular characterization and analysis of in vitro synergy. Diagn Microbiol Infect Dis. 2017;87(3):253–257.
  • Giani T, Arena F, Vaggelli G, et al. Large nosocomial outbreak of colistin-resistant, carbapenemase-producing Klebsiella pneumoniae traced to clonal expansion of an mgrB deletion mutant. J Clin Microbiol. 2015;53(10):3341–3344.
  • Pena I, Picazo JJ, Rodriguez-Avial C, et al. Carbapenemase-producing Enterobacteriaceae in a tertiary hospital in Madrid, Spain: high percentage of colistin resistance among VIM-1-producing Klebsiella pneumoniae ST11 isolates. Int J Antimicrob Agents. 2014;43(5):460–464.
  • Papadimitriou-Olivgeris M, Christofidou M, Fligou F, et al. The role of colonization pressure in the dissemination of colistin or tigecycline resistant KPC-producing Klebsiella pneumoniae in critically ill patients. Infection. 2014;42(5):883–890.
  • Xu A, Zheng B, Xu YC, et al. National epidemiology of carbapenem-resistant and extensively drug-resistant Gram-negative bacteria isolated from blood samples in China in 2013. Clin Microbiol Infect. 2016;22(Suppl 1):S1–S8.
  • Castanheira M, Griffin MA, Deshpande LM, et al. Detection of mcr-1 among Escherichia coli clinical isolates collected worldwide as part of the SENTRY Antimicrobial Surveillance Program in 2014 and 2015. Antimicrob Agents Chemother. 2016;60(9):5623–5624.
  • Prim N, Turbau M, Rivera A, et al. Prevalence of colistin resistance in clinical isolates of Enterobacteriaceae: a four-year cross-sectional study. J Infect. 2017;75(6):493–498.
  • Beyrouthy R, Robin F, Lessene A, et al. MCR-1 and OXA-48 in vivo acquisition in KPC-producing Escherichia coli after colistin treatment. Antimicrob Agents Chemother. 2017;61(8):e02540-16.
  • Falgenhauer L, Waezsada S-E, Yao Y, et al. Colistin resistance gene mcr-1 in extended-spectrum β-lactamase-producing and carbapenemase-producing Gram-negative bacteria in Germany. Lancet Infect Dis. 2016;16(3):282–283.
  • Huang L, Wang X, Feng Y, et al. First identification of an IMI-1 carbapenemase-producing colistin-resistant Enterobacter cloacae in China. Ann Clin Microbiol Antimicrob. 2015;14:51.
  • Huang TD, Bogaerts P, Berhin C, et al. Increasing proportion of carbapenemase-producing Enterobacteriaceae and emergence of a MCR-1 producer through a multicentric study among hospital-based and private laboratories in Belgium from September to November 2015. Eurosurveillance. 2017;22(19):30530.
  • Wang Y, Zhang R, Li J, et al. Comprehensive resistome analysis reveals the prevalence of NDM and MCR-1 in Chinese poultry production. Nat Microbiol. 2017;2:16260.
  • Lenhard JR, Thamlikitkul V, Silveira FP, et al. Polymyxin-resistant, carbapenem-resistant Acinetobacter baumannii is eradicated by a triple combination of agents that lack individual activity. J Antimicrob Chemother. 2017;72(5):1415–1420.
  • van Belkum A, Halimi D, Bonetti EJ, et al. Meropenem/colistin synergy testing for multidrug-resistant Acinetobacter baumannii strains by a two-dimensional gradient technique applicable in routine microbiology. J Antimicrob Chemother. 2015;70(1):167–172.
  • Wei WJ, Yang HF. Synergy against extensively drug-resistant Acinetobacter baumannii in vitro by two old antibiotics: colistin and chloramphenicol. Int J Antimicrob Agents. 2017;49(3):321–326.
  • Abdul Rahim N, Cheah SE, Johnson MD, et al. Synergistic killing of NDM-producing MDR Klebsiella pneumoniae by two ‘old’ antibiotics – polymyxin B and chloramphenicol. J Antimicrob Chemother. 2015;70(9):2589–2597.
  • Tumbarello M, Viale P, Viscoli C, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin Infect Dis. 2012;55(7):943–950.
  • Zarkotou O, Pournaras S, Tselioti P, et al. Predictors of mortality in patients with bloodstream infections caused by KPC-producing Klebsiella pneumoniae and impact of appropriate antimicrobial treatment. Clin Microbiol Infect. 2011;1798-1803.
  • Zavascki AP, Bulitta JB, Landersdorfer CB. Combination therapy for carbapenem-resistant Gram-negative bacteria. Exp Rev Anti-Infect Ther. 2013 Dec;11(12):1333–1353.
  • Durante-Mangoni E, Utili R, Zarrilli R. Combination therapy in severe Acinetobacter baumannii infections: an update on the evidence to date. Fut Microbiol. 2014;9(6):773–789.
  • Zusman O, Altunin S, Koppel F, et al. Polymyxin monotherapy or in combination against carbapenem-resistant bacteria: systematic review and meta-analysis. J Antimicrob Chemother. 2017;72(1):29–39.
  • Zasowski EJ, Rybak JM, Rybak MJ. The beta-lactams strike back: ceftazidime-avibactam. Pharmacother. 2015;35(8):755–770.
  • Zhanel GG, Lawson CD, Adam H, et al. Ceftazidime-avibactam: a novel cephalosporin/beta-lactamase inhibitor combination. Drugs. 2013 Feb;73(2):159–177.
  • J-M P, Peslier S, Keating TA, et al. Role of the outer membrane and porins in susceptibility of β-lactamase-producing Enterobacteriaceae to ceftazidime-avibactam. Antimicrob Agents Chemother. 2016;60(3):1349–1359.
  • Gardiner BJ, Golan Y. Ceftazidime-avibactam (CTZ-AVI) as a treatment for hospitalized adult patients with complicated intra-abdominal infections. Expert Rev Anti-Infect Ther. 2016;14(5):451–463.
  • European Medicines Agency. Zavicefta (ceftazidime/avibactam): European public assessment report 2017 [cited 2017 Dec 1]. Available from: www.ema.europa.eu/ema/index
  • Federal Drug Agency (FDA). AVYCAZ (ceftazidime-avibactam) prescribing information 2015 [cited 2017 Dec 1]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206494s000lbl.pdf
  • Crandon JL, Schuck VJ, Banevicius MA, et al. Comparative in vitro and in vivo efficacies of human simulated doses of ceftazidime and ceftazidime-avibactam against Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2012;56(12):6137–6146.
  • Dallow J, Otterson LG, Huband MD, et al. Microbiological interaction studies between ceftazidime-avibactam and pulmonary surfactant and between ceftazidime-avibactam and antibacterial agents of other classes. Int J Antimicrob Agents. 2014 Dec;44(6):552–556.
  • Falcone M, Paterson D. Spotlight on ceftazidime/avibactam: a new option for MDR Gram-negative infections. J Antimicrob Chemother. 2016 Oct;71(10):2713–2722.
  • Evans BA, Amyes SG. OXA beta-lactamases. Clin Microbiol Rev. 2014 Apr;27(2):241–263.
  • Castanheira M, Farrell SE, Krause KM, et al. 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. 2014;58(2):833–838.
  • Mutters NT, Zimmermann S, Kaase M, et al. Activity of temocillin, mecillinam, ceftazidime, and ceftazidime/avibactam against carbapenem-non-susceptible Enterobacteriaceae without carbapenemase production. Eur J Clin Microbiol Infect Dis. 2015;34(12):2429–2437.
  • Dupont H, Gaillot O, Goetgheluck AS, et al. Molecular characterization of carbapenem-nonsusceptible Enterobacterial isolates collected during a prospective interregional survey in France and susceptibility to the novel ceftazidime-avibactam and aztreonam-avibactam combinations. Antimicrob Agents Chemother. 2015;60(1):215–221.
  • Flamm RK, Farrell DJ, Sader HS, et al. Ceftazidime/avibactam activity tested against Gram-negative bacteria isolated from bloodstream, pneumonia, intra-abdominal and urinary tract infections in US medical centres (2012). J Antimicrob Chemother. 2014;69(6):1589–1598.
  • Walkty A, DeCorby M, Lagace-Wiens PR, et al. In vitro activity of ceftazidime combined with NXL104 versus Pseudomonas aeruginosa isolates obtained from patients in Canadian hospitals (CANWARD 2009 study). Antimicrob Agents Chemother. 2011;55(6):2992–2994.
  • 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.
  • Yoshizumi A, Ishii Y, Aoki K, et al. In vitro susceptibility of characterized beta-lactamase-producing Gram-negative bacteria isolated in Japan to ceftazidime-, ceftaroline-, and aztreonam-avibactam combinations. J Infect Chemother. 2015;21(2):148–151.
  • Sader HS, Castanheira M, Farrell DJ, et al. Ceftazidime-avibactam activity when tested against ceftazidime-nonsusceptible Citrobacter spp., Enterobacter spp., Serratia marcescens, and Pseudomonas aeruginosa from Unites States medical centers (2011–2014). Diagn Microbiol Infect Dis. 2015;83(4):389–394.
  • Lahiri S, Johnstone M, Ross P, 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(10):5704–5713.
  • 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.
  • Lagace-Wiens PR, Tailor F, Simner P, et al. Activity of NXL104 in combination with beta-lactams against genetically characterized Escherichia coli and Klebsiella pneumoniae isolates producing class A extended-spectrum beta-lactamases and class C beta-lactamases. Antimicrob Agents Chemother. 2011;55(5):2434–2437.
  • De Jonge BL, Karlowsky JA, Kazmierczak KM, et al. In vitro susceptibility to ceftazidime-avibactam of carbapenem-nonsusceptible Enterobacteriaceae isolates collected during the INFORM global surveillance study (2012 to 2014). Antimicrob Agents Chemother. 2016;60(5):3163–3169.
  • Endimiani A, Choudhary Y, Bonomo RA. In vitro activity of NXL104 in combination with beta-lactams against Klebsiella pneumoniae isolates producing KPC carbapenemases. Antimicrob Agents Chemother. 2009;53(8):3599–3601.
  • Kazmierczak KM, Biedenbach DJ, Hackel M, et al. Global dissemination of blaKPC into bacterial species beyond Klebsiella pneumoniae and in vitro susceptibility to ceftazidime-avibactam and aztreonam-avibactam. Antimicrob Agents Chemother. 2016;60(8):4490–4500.
  • Vasoo S, Cunningham SA, Cole NC, et al. In vitro activities of ceftazidime-avibactam, aztreonam-avibactam, and a panel of older and contemporary antimicrobial agents against carbapenemase-producing Gram-negative bacilli. Antimicrob Agents Chemother. 2015;59(12):7842–7846.
  • Levasseur P, Girard AM, Miossec C, et al. In vitro antibacterial activity of the ceftazidime-avibactam combination against Enterobacteriaceae, including strains with well-characterized beta-lactamases. Antimicrob Agents Chemother. 2015;59(4):1931–1934.
  • Li H, Estabrook M, Jacoby GA, et al. In vitro susceptibility of characterized beta-lactamase-producing strains tested with avibactam combinations. Antimicrob Agents Chemother. 2015;59(3):1789–1793.
  • 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.
  • Mushtaq S, Warner M, Livermore DM. In vitro activity of ceftazidime+NXL104 against Pseudomonas aeruginosa and other non-fermenters. J Antimicrob Chemother. 2010;65(11):2376–2381.
  • Lahiri SD, Alm RA. Identification of novel VEB beta-lactamase enzymes and their impact on avibactam inhibition. Antimicrob Agents Chemother. 2016;60(5):3183–3186.
  • Lahiri SD, Giacobbe RA, Johnstone MR, et al. Activity of avibactam against Enterobacter cloacae producing an extended-spectrum class C beta-lactamase enzyme. J Antimicrob Chemother. 2014;69(11):2942–2946.
  • Mushtaq S, Warner M, Williams G, et al. Activity of chequerboard combinations of ceftaroline and NXL104 versus beta-lactamase-producing Enterobacteriaceae. J Antimicrob Chemother. 2010;65(7):1428–1432.
  • Shields RK, Clancy CJ, Hao B, et al. Effects of Klebsiella pneumoniae carbapenemase subtypes, extended-spectrum β-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.
  • Flamm RK, Nichols WW, Sader HS, et al. In vitro activity of ceftazidime/avibactam against Gram-negative pathogens isolated from pneumonia in hospitalised patients, including ventilated patients. Int J Antimicrob Agents. 2016 Mar;47(3):235–242.
  • Singh R, Saxena A, Singh H. Identification of group specific motifs in beta-lactamase family of proteins. J Biomed Sci. 2009;16:109.
  • Canton R, Morosini MI, de la Maza OM, et al. IRT and CMT beta-lactamases and inhibitor resistance. Clin Microbiol Infect. 2008;14(Suppl 1):53–62.
  • Livermore DM, Warner M, Jamrozy D, et al. In vitro selection of ceftazidime-avibactam resistance in Enterobacteriaceae with KPC-3 carbapenemase. Antimicrob Agents Chemother. 2015 Sep;59(9):5324–5330.
  • Lahiri SD, Walkup GK, Whiteaker JD, et al. Selection and molecular characterization of ceftazidime/avibactam-resistant mutants in Pseudomonas aeruginosa strains containing derepressed AmpC. J Antimicrob Chemother. 2015;70(6):1650–1658.
  • Winkler ML, Papp-Wallace KM, Taracila MA, et al. Avibactam and inhibitor-resistant SHV β-lactamases. Antimicrob Agents Chemother. 2015;59(7):3700–3709.
  • Papp-Wallace KM, Winkler ML, Taracila MA, et al. Variants of β-lactamase KPC-2 that are resistant to inhibition by avibactam. Antimicrob Agents Chemother. 2015;59(7):3710–3717.
  • Haidar G, Clancy CJ, Shields RK, et al. Mutations in blaKPC-3 that confer ceftazidime-avibactam resistance encode novel KPC-3 variants that function as extended-spectrum beta-lactamases. Antimicrob Agents Chemother. 2017;61(5):e02534–16.
  • Levitt PS, Papp-Wallace KM, Taracila MA, et al. Exploring the role of a conserved class A residue in the omega-Loop of KPC-2 beta-lactamase: a mechanism for ceftazidime hydrolysis. J Biol Chem. 2012;287(38):31783–31793.
  • MacVane SH, Crandon JL, Nichols WW, et al. In vivo efficacy of humanized exposures of ceftazidime-avibactam in comparison with ceftazidime against contemporary Enterobacteriaceae isolates. Antimicrob Agents Chemother. 2014;58(11):6913–6919.
  • Livermore DM, Mushtaq S, Warner M, et al. Activities of NXL104 combinations with ceftazidime and aztreonam against carbapenemase-producing Enterobacteriaceae. Antimicrob Agents Chemother. 2011;55(1):390–394.
  • Winkler ML, Papp-Wallace KM, Hujer AM, et al. Unexpected challenges in treating multidrug-resistant Gram-negative bacteria: resistance to ceftazidime-avibactam in archived isolates of Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2015;59(2):1020–1029.
  • Nelson K, Hemarajata P, Sun D, 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(10):e00989–17.
  • Marshall S, Hujer AM, Rojas LJ, et al. Can ceftazidime-avibactam and aztreonam overcome beta-lactam resistance conferred by metallo-beta-lactamases in Enterobacteriaceae? Antimicrob Agents Chemother. 2017;61(4):e02243–16.
  • Wang X, Zhang F, Zhao C, et al. In vitro activities of ceftazidime-avibactam and aztreonam-avibactam against 372 Gram-negative bacilli collected in 2011 and 2012 from 11 teaching hospitals in China. Antimicrob Agents Chemother. 2014;58(3):1774–1778.
  • 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.
  • ClinicalTrials.gov. Determine the PK and safety and tolerability of ATM-AVI for the treatment of cIAIs in hospitalized adults (REJUVENATE): National Institutes of Health; 2017 cited 2017 Nov 11. Available from: https://clinicaltrials.gov/ct2/show/NCT02655419?term=aztreonam-avibactam&rank=2
  • Mojica MF, Ouellette CP, Leber A, et al. Successful treatment of bloodstream infection due to metallo-beta-lactamase-producing Stenotrophomonas maltophilia in a renal transplant patient. Antimicrob Agents Chemother. 2016;60(9):5130–5134.
  • Davido B, Fellous L, Lawrence C, et al. Ceftazidime-avibactam and aztreonam, an interesting strategy to overcome beta-lactam resistance conferred by metallo-beta-lactamases in Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2017;61(9):e01008-17.
  • Sibley D, Simar S, Ashcraft D, et al. In vitro synergy of ceftazidime-avibactam plus rifampin against Pseudomonas aeruginosa. ID Week 2016 Oct 26–30; New Orleans, LA, USA.
  • Gaibani P, Lewis RE, Volpe SL, et al. In vitro interaction of ceftazidime-avibactam in combination with different antimicrobials against KPC-producing Klebsiella pneumoniae clinical isolates. Int J Infect Dis. 2017;65:1–3.
  • Manning N, Balabanian G, Rose M, et al. Activity of ceftazidime-avibactam against clinical isolates of Klebsiella pneumoniae, including KPC-carrying isolates, endemic to New York City. Microb Drug Res. 2018;24(1):35–39.
  • 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(12):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(2):e01964–16.

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