In this article inducible drug resistance in AmpC harboring bacteria are discussed using the acronym HECK Yes.
Authored by: Brandon Garcia, Pharm.D.
Article Mentor: Madeline King, Pharm.D., BCIDP
Article Posted 25 January 2022
AmpC β-lactamases are Ambler class C enzymes that can be divided into three categories: (1) inducible resistance (e.g., Enterobacter cloacae, Citrobacter freundii), (2) non-inducible chromosomal resistance due to mutations (e.g., Escherichia coli, Shigella spp., Acinetobacter baumannii), and (3) plasmid-mediated resistance (e.g., Klebsiella pneumoniae, E. coli, Salmonella spp.) . In non-inducible chromosomal resistance and plasmid-mediated resistance, AmpC production is constitutive, thus initial susceptibility testing to these organisms are expected to display resistance to third-generation cephalosporins such as ceftriaxone and ceftazidime. In inducible expression, exposure to certain antibiotics triggers increased production of AmpC enzymes and development of de-repressed mutants. As a result, Enterobacterales that initially tested susceptible to ceftriaxone or ceftazidime may subsequently exhibit non-susceptibility to these agents when inappropriate antimicrobial therapy is initiated [1,2].
Inducible resistance occurs via reduced activity in the AmpR regulatory protein that normally represses AmpC production . Some β-lactams induce the production of cell-wall degradation products that bind to AmpR that then causes a conformational change [1,3]. This conformational change in AmpR causes the protein to lose its function, causing a de-repression of AmpC (therefore increased production of AmpC β-lactamases) and decreased susceptibility to β-lactams cleaved by these enzymes.1 Antibiotics vary in their capacity to induce AmpC production and their affinity as substrates for AmpC :
Adapted from MacDougall. J Pediatr Pharmacol Ther. 2011;16(1):23-30.
Isolates capable of this inducible resistance pose a greater dilemma when treating patients compared to isolates that constitutively express AmpC enzymes and test non-susceptible to ceftriaxone prior to antibiotic exposure . Therefore, the recent Infectious Diseases Society of America (IDSA) guidance document on the treatment of antimicrobial-resistant Gram negative infections focus on these organisms when providing suggestions on how to treat AmpC β-lactamase-producing Enterobacterales .
The commonly used “SPACE” or “SPICE” (Serratia, Providencia/Pseudomonas, Acinetobacter/indole-positive Proteus, Citrobacter, and Enterobacter) acronyms are used to convey the Gram negative organisms at risk for inducible AmpC production. However, these mnemonics do not address the range of inducibility amongst the organisms included, as well as the differences among species of the same genus [2,3]. Additionally, organisms like Pseudomonas aeruginosa possess additional resistance mechanisms (including efflux pumps and porin channel loss) that confer resistance to β-lactams.
Within the IDSA guidance, Enterobacterales identified as “at moderate to high risk” of clinically significant AmpC production include Enterobacter cloacae, Klebsiella aerogenes (formerly Enterobacter aerogenes), and Citrobacter freundii . The authors note that these three organisms have been most often implicated in reports of clinically relevant AmpC expression, with inducible resistance after exposure to an antibiotic like ceftriaxone occurring in approximately 8-40% of these infections. In an in vitro study calculating the mutation rates for AmpC de-repressed mutants of various Enterobacterales, a mean mutation rate of 3×10-8 was calculated for E. cloacae complex, E. aerogenes, C. freundii complex, and Hafnia alvei . This rate was 15-fold higher than Serratia liquefaciens, 50- to 150-fold higher than Providencia spp. and Serratia marcescens, and 600-fold higher than Morganella morganii, reflecting what has been seen in clinical reports [2,4]. Organisms such as H. alvei, Citrobacter youngae, and Yersinia enterocolitica carry chromosomal AmpC genes but are not reported in many clinical reports, limiting the ability to interpret the clinical relevance of inducible AmpC expression.
As a result of the in vitro and clinical data highlighting the deficiencies of the “SPACE/SPICE” mnemonic, there has been a movement within #IDTwitter (amongst other infectious diseases enthusiasts) to change the mnemonic commonly used to teach learners about inducible AmpC organisms to “HECK Yes” – Hafnia alvei, Enterobacter cloacae, Citrobacter freundii, Klebsiella aerogenes, and Yersinia enterocolitica.
There are limited data comparing clinical outcomes for these organisms when treated with a third-generation cephalosporin versus an agent predicted to be more active (i.e. cefepime or a carbapenem). One descriptive study comparing empiric therapy with piperacillin-tazobactam or an oxyimino cephalosporin (ceftriaxone, ceftazidime, or cefotaxime) versus agents expected to retain activity against AmpC β-lactamases in Enterobacterales bloodstream infections found no difference in mortality between groups, although only one of the 458 cases reported utilized a third-generation cephalosporin as definitive treatment .
A multicenter observational cohort study looking at bloodstream infections caused by Enterbocater spp., Citrobacter spp., and Serratia spp., found no statistical difference in overall treatment failure with third-generation cephalosporins as definite therapy, albeit in a population with a lower severity of illness and fewer respiratory sources of infection .
While these studies may suggest a niche role for third-generation cephalosporins in the treatment of some AmpC producing Enteobacterales, the risk for the emergence of resistance while on treatment leads the authors of the IDSA guidance to recommend avoidance of ceftriaxone unless treating an uncomplicated cystitis.
With the IDSA guidance published in November, at least the “ECK” portion of the “HECK Yes” acronym may gain more traction. Nevertheless, for some organisms now thought to have lower rates of inducible AmpC production than previously thought (i.e., Serratia marcescens, Morganella morganii) and the organisms where we lack clinical data (Yersinia enterocolitica, Hafnia alvei), it is still reasonable to avoid ceftriaxone in cases with high bacterial burden and limited source control.2 If you are ready to throw out “SPACE/SPICE” and embrace “HECK Yes”, remember there remains a grey area with a number of exceptions – like nearly all things in infectious diseases.
1. Tamma PD, Doi Y, Bonomo RA, Johnson JK, Simner PJ; Antibacterial Resistance Leadership Group. A primer on AmpC β-lactamases: necessary knowledge for an increasingly multidrug-resistant world. Clin Infect Dis. 2019;69:1446–55.
2. Tamma PD, Aitken SL, Bonomo RA, et al. Infectious Diseases Society of America Guidance on the treatment of AmpC β-lactamase-producing Enterobacterales, carbapenem-resistant Acinetobacter baumannii, and Stenotrophomonas maltophilia infections. Clin Infect Dis. 2021 Dec 5:ciab1013. doi: 10.1093/cid/ciab1013. Epub ahead of print. PMID: 34864936.
3. MacDougall C. Beyond susceptible and resistant, part I: treatment of infections due to gram-negative organisms with inducible β-lactamases. J Pediatr Pharmacol Ther. 2011;16(1):23-30.
4. Kohlmann R, Bahr T, Gatermann SG. Species-specific mutation rates for ampC derepression in Enterobacterales with chromosomally encoded inducible AmpC beta-lactamase. J Antimicrob Chemother. 2018;73(6):1530-6.
5. Chaubey VP, Pitout JD, Dalton B, et al. Clinical and microbiological characteristics of bloodstream infections due to AmpC beta-lactamase producing Enterobacteriaceae: an active surveillance cohort in a large centralized Canadian region. BMC Infect Dis. 2014;14:647.
6. Derrick C, Bookstaver PB, Lu ZK, et al. Multicenter, Observational Cohort Study Evaluating Third-Generation Cephalosporin Therapy for Bloodstream Infections Secondary to Enterobacter, Serratia, and Citrobacter Species. Antibiotics (Basel) 2020; 9(5).
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