Clinical and Microbiologic Practice Patterns for Inducible AmpC-Producing Enterobacterales

Study Overview and Clinical Context for AmpC-Producing Enterobacterales

This research, titled "Battle of the Mnemonics, SPACE versus HECK-Yes!", presents a cross-sectional, nationwide survey objective of evaluating clinical and microbiologic practice patterns among infectious diseases (ID) clinicians. The study addresses the management of Enterobacterales at risk of inducible AmpC production. While traditional mnemonics like SPACE and SPICE have been used for decades to identify these organisms, they often fail to account for the significant variability in AmpC induction potential among different species. This variability leads to inconsistent antibiotic selection and susceptibility reporting across various healthcare institutions. The study was conducted by a multidisciplinary team from the Medical University of South Carolina (MUSC) and published in the journal JAC-Antimicrobial Resistance (JACAMR) in 2026.

Pathophysiology of AmpC β\beta-lactamases and Induction Mechanisms

AmpC β\beta-lactamases are enzymes produced at basal levels by various gram-negative organisms, primarily for the purpose of bacterial cell wall recycling. In most wild-type Enterobacterales, the chromosomal $ampC$ expression is maintained at very low levels by a regulatory protein known as $ampR$, which limits the transcription of the $ampC$ gene. Inducible AmpC production occurs when bacterial exposure to certain β\beta-lactam antibiotics disrupts cell wall synthesis. This disruption leads to the accumulation of specific degradation products that bind to the $ampR$ protein, alleviating its repression of $ampC$ and significantly increasing enzyme production. The clinical significance of this induction is determined by the substrate affinity for the enzyme. Strong inducers, such as ampicillin and first-generation cephalosporins, are also good substrates for AmpC, resulting in high levels of hydrolysis and resistance. In contrast, agents like piperacillin and ceftriaxone are considered weak inducers but remain good substrates, making them vulnerable to hydrolysis if the enzyme is produced. Cefepime and certain carbapenems are both weak inducers and poor substrates, which generally allows them to withstand AmpC-mediated hydrolysis, positioning them as preferred therapeutic options.

Evolution of Mnemonics and IDSA Risk Stratification

Historical mnemonics such as SPACE (Serratia spp., Pseudomonas aeruginosa, Acinetobacter spp., Citrobacter spp., and Enterobacter spp.), SPICE, MYSPACE, and ESCPM have served as learning tools to identify pathogens with inducible AmpC potential. However, the Infectious Diseases Society of America (IDSA) has raised concerns that these acronyms are overly simplistic. To address this, the IDSA 2024 guidance classifies organisms based on the likelihood of clinically significant AmpC production. Enterobacter cloacae complex, Klebsiella aerogenes, and Citrobacter freundii (along with less common species like Hafnia alvei and Yersinia enterocolitica) are classified as moderate risk. A new mnemonic, HECK-Yes!, was coined to highlight these moderate-risk organisms. Conversely, other members such as Serratia marcescens, Morganella morganii, and Providencia species are considered low risk because they are less likely to overexpress $ampC$. The IDSA suggests that using cefepime is reasonable for low-risk organisms in high-burden clinical scenarios, yet definitive therapy choice remains a subject of investigation.

Survey Methodology and Participant Demographics

The study utilized a cross-sectional, investigator-developed electronic survey distributed via REDCap. It was sent to members of the American College of Clinical Pharmacy (ACCP) ID Practice and Research Network, IDSA Exchange, and the Pediatric Infectious Diseases Society (PIDS) listservs between Nov 5, 2024, and Dec 16, 2024. A total of 9494 complete responses were analyzed from U.S.-based participants. The demographics revealed that the majority of respondents were pharmacists (58.5\text{%}) and ID-trained physicians (38.3\text{%}). Most participants (78.7\text{%}) had completed formal ID residency or fellowship training. Institutional settings were primarily adult academic medical centers (39.4\text{%}) or adult community hospitals (37.2\text{%}). In terms of size, 36.2\text{%} of institutions had between 251251 and 500500 beds, while 22.3\text{%} had between 751751 and 10001000 beds. Familiarity with the SPICE/SPACE mnemonic (90.4\text{%}) was higher than familiarity with the newer HECK-Yes! mnemonic (81.9\text{%}).

Clinical Practice Patterns and Antibiotic Preferences

The survey identified distinct preferences for definitive β\beta-lactam therapy based on the organism's risk level and the invasiveness of the infection. For moderate-risk organisms, cefepime was the preferred option for both invasive infections (87.2\text{%}) and non-invasive infections (68.1\text{%}). For low-risk organisms, ceftriaxone was the most common choice for both invasive infections (57.4\text{%}) and non-invasive infections (60.7\text{%}). Subgroup analysis indicated that for invasive moderate-risk infections, pharmacists were more likely to select cefepime (96.4\text{%}) compared to physicians (72.2\text{%}). Physicians more frequently favored meropenem (22.2\text{%}) compared to pharmacists (1.8\text{%}). Despite these preferences, some variability existed as some clinicians opted for meropenem (9.6\text{%}) or ceftriaxone (16.0\text{%}) for certain moderate-risk scenarios, and cefepime was still used by some for low-risk invasive (27.7\text{%}) or non-invasive (10.6\text{%})$ infections.

Institutional Microbiologic Reporting Practices

Microbiologic reporting patterns generally aligned with clinical preferences but showed some concerning trends regarding older antibiotics. For non-urinary isolates of moderate-risk Enterobacterales, common antibiogram reports included cefepime (98.8\text{%}), meropenem (85.5\text{%}), piperacillin/tazobactam (72.3\text{%}), and ceftriaxone (67.5\text{%}). For low-risk organisms, the reports were similar but with higher ceftriaxone inclusion at 94.0\text{%}. Interestingly, strong inducers such as aminopenicillins and cefazolin were reported on antibiograms at approximately 50\text{%} or more of the surveyed institutions, which may not align with antimicrobial stewardship goals given their high induction and hydrolysis potential. The survey noted that susceptibility reporting and antibiogram reporting were generally similar in their patterns of included antibiotics.

Comparative In Vitro Data and Clinical Outcomes

The rationale for stratification is supported by in vitro mutation rate analyses. Research by Kohlmann and colleagues determined the species-specific mutation rates for $ampC$ derepression following exposure to cefotaxime. The highest mutation rates were found in Citrobacter freundii complex (3.3×10−83.3 \times 10^{-8}), Enterobacter cloacae complex (2.7×10−82.7 \times 10^{-8}), and Klebsiella aerogenes (2.1×10−82.1 \times 10^{-8}). These rates were significantly higher than those for Serratia marcescens (2.4×10−102.4 \times 10^{-10}) and Morganella morganii (5.1×10−115.1 \times 10^{-11}). Clinical outcomes data remain conflicting. A study by Mulbah et al. found no significant difference in 30-day all-cause mortality or clinical failure (21.1\text{%} versus 9.3\text{%}, P=0.059P = 0.059) when comparing ceftriaxone to AmpC-stable therapies for low-risk bloodstream infections. However, a larger multicenter study by Maillard et al. reported that AmpC-related treatment failure was significantly more common with 3rd generation cephalosporins in both high-risk species (Hazard Ratio 7.07.0, 95\text{%} CI 3.03.0-6.46.4) and low-risk species (Hazard Ratio 15.315.3, 95\text{%} CI 1.91.9-125.9125.9). This highlights the ongoing need for standardized, evidence-based antimicrobial stewardship approaches to optimize patient care and mitigate resistance.