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AmpC β-lactamase-producing Enterobacterales: what a clinician should know

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Abstract

Background

Enterobacterales are among the most common causes of bacterial infections in the community and among hospitalized patients, and multidrug-resistant (MDR) strains have emerged as a major threat to human health. Resistance to third-generation cephalosporins is typical of MDRs, being mainly due to the production of extended spectrum β-lactamases or AmpC-type β-lactamases.

Objective

The objective of this paper is to review the epidemiological impact, diagnostic issues and treatment options with AmpC producers.

Findings

AmpC enzymes encoded by resident chromosomal genes (cAmpCs) are produced by some species (e.g., Enterobacter spp., Citrobacter freundii, Serratia marcescens), while plasmid-encoded AmpCs (pAmpCs) can be encountered also in species that normally do not produce cAmpCs (e.g., Salmonella enterica, Proteus mirabilis, Klebsiella pneumoniae and Klebsiella oxytoca) or produce them at negligible levels (e.g., Escherichia coli). Production of AmpCs can be either inducible or constitutive, resulting in different resistance phenotypes. Strains producing cAmpCs in an inducible manner (e.g., Enterobacter spp.) usually appear susceptible to third-generation cephalosporins, which are poor inducers, but can easily yield mutants constitutively producing the enzyme which are resistant to these drugs (which are good substrates), resulting in treatment failures. pAmpCs are usually constitutively expressed. Production of pAmpCs is common in community-acquired infections, while cAmpC producers are mainly involved in healthcare-associated infections.

Conclusions

To date, there is no conclusive evidence about the most appropriate treatment for AmpC-producing Enterobacterales. Carbapenems are often the preferred option, especially for severe infections in which adequate source control is not achieved, but cefepime is also supported by substantial clinical evidences as an effective carbapenem-sparing option.

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References

  1. Giani T, Antonelli A, Caltagirone M, Mauri C, Nicchi J, Arena F, et al. The AMCLI-CoSA survey participants. Evolving beta-lactamase epidemiology in Enterobacteriaceae from Italian nationwide surveillance, October 2013: KPC-carbapenemase spreading among outpatients. Euro Surveill. 2017;22:30583.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Jacoby GA, Munoz-Price LS. The new beta-lactamases. N Engl J Med. 2005;352:380–91.

    Article  CAS  PubMed  Google Scholar 

  3. Hall BG, Barlow M. Evolution of the serine beta-lactamases: past, present and future. Drug Resist Updat. 2004;7:111–23.

    Article  CAS  PubMed  Google Scholar 

  4. Abraham EP, Chain E. An enzyme from bacteria able to destroy penicillin. Nature. 1940;146:837.

    Article  CAS  Google Scholar 

  5. Jacoby GA. AmpC beta-lactamases. Clin Microbiol Rev. 2009;22:161–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bush K, Jacoby GA. Updated functional classification of beta-lactamases. Antimicrob Agents Chemother. 2010;54:969–76.

    Article  CAS  PubMed  Google Scholar 

  7. Chaubey VP, Pitout JD, Dalton B, Gregson DB, Ross T, Laupland KB. Clinical and microbiological characteristics of bloodstream infections due to AmpC β-lactamase producing Enterobacteriaceae: an active surveillance cohort in a large centralized Canadian region. BMC Infect Dis. 2014;14:647.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Hilty M, Sendi P, Seiffert SN, Droz S, Perreten V, Hujer AM, et al. Characterisation and clinical features of Enterobacter cloacae bloodstream infections occurring at a tertiary care university hospital in Switzerland: is cefepime adequate therapy? Int J Antimicrob Agents. 2013;41:236–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Alexandre K, Fantin B. Pharmacokinetics and Pharmacodynamics of Temocillin. Clin Pharmacokinet. 2018;57:287–96.

    Article  CAS  PubMed  Google Scholar 

  10. Mammeri H, Nordmann P, Berkani A, Eb F. Contribution of extended-spectrum AmpC (ESAC) beta-lactamases to carbapenem resistance in Escherichia coli. FEMS Microbiol Lett. 2008;282:238–40.

    Article  CAS  PubMed  Google Scholar 

  11. D’Angelo RG, Johnson JK, Bork JT, Heil EL. Treatment options for extended-spectrum beta-lactamase (ESBL) and AmpC-producing bacteria. Expert Opin Pharmacother. 2016;17:953–67.

    Article  CAS  PubMed  Google Scholar 

  12. Chow JW, Fine MJ, Shlaes DM, Quinn JP, Hooper DC, Johnson MP, et al. Enterobacter bacteremia: clinical features and emergence of antibiotic resistance during therapy. Ann Intern Med. 1991;115:585–90.

    Article  CAS  PubMed  Google Scholar 

  13. Choi SH, Lee JE, Park SJ, Choi SH, Lee SO, Jeong JY, et al. Emergence of antibiotic resistance during therapy for infections caused by Enterobacteriaceae producing AmpC beta-lactamase: implications for antibiotic use. Antimicrob Agents Chemother. 2008;52:995–1000.

    Article  CAS  PubMed  Google Scholar 

  14. Peter-Getzlaff S, Polsfuss S, Poledica M, Hombach M, Giger J, Böttger EC, et al. Detection of AmpC beta-lactamase in Escherichia coli: comparison of three phenotypic confirmation assays and genetic analysis. J Clin Microbiol. 2011;49:2924–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Pascual V, Alonso N, Simó M, Ortiz G, Garcia MC, Xercavins M, et al. Bloodstream infections caused by Escherichia coli producing AmpC β-lactamases: epidemiology and clinical features. Eur J Clin Microbiol Infect Dis. 2016;35:1997–2003.

    Article  CAS  PubMed  Google Scholar 

  16. den Drijver E, Verweij JJ, Verhulst C, Oome S, Soer J, Willemsen I, et al. Decline in AmpC β-lactamase-producing Escherichia coli in a Dutch teaching hospital (2013–2016). PLoS One. 2018;13:e0204864.

    Article  CAS  Google Scholar 

  17. Leclercq R, Cantón R, Brown DF, Giske CG, Heisig P, MacGowan AP, et al. EUCAST expert rules in antimicrobial susceptibility testing. Clin Microbiol Infect. 2013;19:141–60.

    Article  CAS  PubMed  Google Scholar 

  18. Harris PN, Ferguson JK. Antibiotic therapy for inducible AmpC β-lactamase-producing Gram-negative bacilli: what are the alternatives to carbapenems, quinolones and aminoglycosides? Int J Antimicrob Agents. 2012;40:297–305.

    Article  CAS  PubMed  Google Scholar 

  19. Bauernfeind A, Chong Y, Schweighart S. Extended broad spectrum beta-lactamase in Klebsiella pneumoniae including resistance to cephamycins. Infection. 1989;17:316–21.

    Article  CAS  PubMed  Google Scholar 

  20. The European Committee on Antimicrobial Susceptibility Testing. EUCAST guidelines for detection of resistance mechanisms and specific resistances of clinical and/or epidemiological importance. Version 2.01 July (2017). http://www.eucast.org.

  21. Drinkovic D, Morris AJ, Dyet K, Bakker S, Heffernan H. Plasmid-mediated AmpC beta-lactamase-producing Escherichia coli causing urinary tract infection in the Auckland community likely to be resistant to commonly prescribed antimicrobials. N Z Med J. 2015;128:50–9.

    PubMed  Google Scholar 

  22. Harris PNA, Ben Zakour NL, Roberts LW, Wailan AM, Zowawi HM, Tambyah PA, et al. MERINO Trial investigators. Whole genome analysis of cephalosporin-resistant Escherichia coli from bloodstream infections in Australia, New Zealand and Singapore: high prevalence of CMY-2 producers and ST131 carrying blaCTX-M-15 and blaCTX-M-27. J Antimicrob Chemother. 2018;73:634–42.

    Article  CAS  Google Scholar 

  23. Conen A, Frei R, Adler H, Dangel M, Fux CA, Widmer AF. Microbiological screening is necessary to distinguish carriers of plasmid-mediated AmpC beta-lactamase-producing Enterobacteriaceae and extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae because of clinical similarity. PLoS One. 2015;10:e0120688.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Arena F, Giani T, Becucci E, Conte V, Zanelli G, D’Andrea MM, et al. Large oligoclonal outbreak due to Klebsiella pneumoniae ST14 and ST26 producing the FOX-7 AmpC β-lactamase in a neonatal intensive care unit. J Clin Microbiol. 2013;51:4067–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. D’Andrea MM, Nucleo E, Luzzaro F, Giani T, Migliavacca R, Vailati F, et al. CMY-16, a novel acquired AmpC-type beta-lactamase of the CMY/LAT lineage in multifocal monophyletic isolates of Proteus mirabilis from northern Italy. Antimicrob Agents Chemother. 2006;50:618–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Luzzaro F, Brigante G, D’Andrea MM, Pini B, Giani T, Mantengoli E, et al. Spread of multidrug-resistant Proteus mirabilis isolates producing an AmpC-type beta-lactamase: epidemiology and clinical management. Int J Antimicrob Agents. 2009;33:328–33.

    Article  CAS  PubMed  Google Scholar 

  27. Kaye KS, Cosgrove S, Harris A, Eliopoulos GM, Carmeli Y. Risk factors for emergence of resistance to broad-spectrum cephalosporins among Enterobacter spp. Antimicrob Agents Chemother. 2001;45:2628–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rodríguez-Baño J, Gutiérrez-Gutiérrez B, Machuca I, Pascual A. Treatment of infections caused by extended-spectrum-beta-lactamase-, AmpC-, and carbapenemase-producing Enterobacteriaceae. Clin Microbiol Rev. 2018;31:e00079-17.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Tamma PD, Girdwood SC, Gopaul R, Tekle T, Roberts AA, Harris AD, et al. The use of cefepime for treating AmpC β-lactamase-producing Enterobacteriaceae. Clin Infect Dis. 2013;57:781–8.

    Article  CAS  PubMed  Google Scholar 

  30. Siedner MJ, Galar A, Guzmán-Suarez BB, Kubiak DW, Baghdady N, Ferraro MJ, et al. Cefepime vs other antibacterial agents for the treatment of Enterobacter species bacteremia. Clin Infect Dis. 2014;58:1554–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lee NY, Lee CC, Li CW, Li MC, Chen PL, Chang CM, Ko WC. Cefepime therapy for monomicrobial Enterobacter cloacae bacteremia: unfavorable outcomes in patients infected by cefepime-susceptible dose-dependent isolates. Antimicrob Agents Chemother. 2015;59:7558–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Blanchette LM, Kuti JL, Nicolau DP, Nailor MD. Clinical comparison of ertapenem and cefepime for treatment of infections caused by AmpC beta-lactamase-producing Enterobacteriaceae. Scand J Infect Dis. 2014;46:803–8.

    Article  CAS  PubMed  Google Scholar 

  33. Harris PN, Wei JY, Shen AW, Abdile AA, Paynter S, Huxley RR, et al. Carbapenems versus alternative antibiotics for the treatment of bloodstream infections caused by Enterobacter, Citrobacter or Serratia species: a systematic review with meta-analysis. J Antimicrob Chemother. 2016;71:296–306.

    Article  CAS  PubMed  Google Scholar 

  34. Hawkey PM, Warren RE, Livermore DM, McNulty CAM, Enoch DA, Otter JA, Wilson APR. Treatment of infections caused by multidrug-resistant Gram-negative bacteria: report of the British Society for Antimicrobial Chemotherapy/Healthcare Infection Society/British Infection Association Joint Working Party. J Antimicrob Chemother. 2018;73:2–78.

    Article  CAS  Google Scholar 

  35. Robin F, Auzou M, Bonnet R, Lebreuilly R, Isnard C, Cattoir V, Guérin F. In vitro activity of ceftolozane-tazobactam against Enterobacter cloacae complex clinical isolates with different β-lactam resistance phenotypes. Antimicrob Agents Chemother. 2018;62:e00675-18.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Paterson D, Harris P. Pilot RCT of Meropenem Versus Piperacillin-Tazobactam for Definitive Treatment of Bloodstream Infections Caused by AmpC Beta-lactamase Producing Enterobacter spp., Citrobacter freundii, Morganella morganii, Providencia spp. or Serratia Marcescens in Low-risk Patients. ClinicalTrials.gov Identifier NCT02437045. http://clinicaltrials.gov.

  37. Hammer KL, Stoessel A, Justo JA, Bookstaver PB, Kohn J, Derrick CB, et al. Association between chronic hemodialysis and bloodstream infections caused by chromosomally mediated AmpC-producing Enterobacteriaceae. Am J Infect Control. 2016;44:1611–6.

    Article  PubMed  Google Scholar 

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Funding

This work was performed as part of our routine work. No external funding was required for the project.

Author information

Authors and Affiliations

  1. Internal Medicine Unit, Santa Maria Annunziata Hospital, Florence, Italy

    Simone Meini

  2. First Division of Infectious Diseases, Cotugno Hospital, Naples, Italy

    Carlo Tascini

  3. Internal Medicine Unit, Cecina Hospital, Cecina, Italy

    Marco Cei

  4. Emergency Department, North-West District Tuscany Health Care, Spedali Riuniti, Leghorn, Italy

    Emanuela Sozio

  5. Clinical Microbiology and Virology Unit, Florence Careggi University Hospital, Florence, Italy

    Gian Maria Rossolini

  6. Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

    Gian Maria Rossolini

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  1. Simone Meini
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Correspondence to Simone Meini.

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On behalf of all authors, the corresponding author states that there is no conflict of interest.

Transparency declarations

In the past 2 years, C.T. has been paid for lectures on behalf of Pfizer, Novartis, Merck, Angelini, Gilead, and Astellas. G.M.R. has received research grants from Angelini, Basilea, Menarini, Merck, Nordic Pharma, Pfizer, Rempex, Shionogi, VenatorX, Zambon; has received congress lecture fees from Angelini, Basilea, Merck, Pfizer, Zambon; has received consultancy fees from Angelini, Menarini, Merck, Nordic Pharma, Pfizer, Rempex, Shionogi, Zambon. The other authors have nothing to declare. All authors read and approved the final manuscript.

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Meini, S., Tascini, C., Cei, M. et al. AmpC β-lactamase-producing Enterobacterales: what a clinician should know. Infection 47, 363–375 (2019). https://doi.org/10.1007/s15010-019-01291-9

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  • DOI: https://doi.org/10.1007/s15010-019-01291-9

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