Abstract
Background
Enterobacterales considered at risk of inducible AmpC production are denoted by mnemonics including SPACE and HECK-Yes! However, these mnemonics may fail to account for the variability in AmpC induction potential, which lends to variation in antibiotics chosen for management of associated infections and susceptibility reporting. This study aimed to evaluate clinical and microbiologic practice patterns for the management of infections caused by Enterobacterales at risk of inducible AmpC production.
Methods
This cross-sectional survey was developed by a multidisciplinary infectious diseases (ID) team and distributed via ID-related listservs (November-December 2024). The survey assessed institutional demographics, β-lactam of choice, and microbiologic reporting for Enterobacterales with a moderate risk (Enterobacter cloacae complex, Klebsiella aerogenes, Citrobacter freundii) and low risk (Serratia marcescens, Morganella morganii, Providencia spp.) of inducible AmpC production.
Results
Of 94 complete responses, most were from pharmacists (58.5%) and physicians (38.3%) working in adult academic medical centres (39.4%) or community hospitals (37.2%). Cefepime was the preferred β-lactam for invasive (87.2%) and non-invasive (68.1%) infections caused by moderate-risk inducible AmpC producers, while ceftriaxone was preferred for invasive (57.4%) and non-invasive (60.7%) infections caused by low-risk inducible AmpC Inducers. Cefepime (98.8% versus 98.8%), meropenem (85.5% versus 83.1%), piperacillin/tazobactam (72.3% versus 83.1%), and ceftriaxone (67.5% versus 94.0%) were commonly reported antibiotics on non-urinary antibiograms for moderate risk and low risk Enterobacterales, respectively. The beta-lactams reported in institutional antibiograms and microbiology susceptibility reporting were generally similar.
Conclusions
This survey highlights differences in practice patterns for management of infections caused by inducible AmpC-producing Enterobacterales. These results emphasize the importance of standardized, evidence-based antimicrobial stewardship approaches and continued clinical investigation to better optimize therapy for infections caused by Enterobacterales capable of inducible AmpC production.
Background
AmpC β-lactamases are enzymes produced at basal levels by various gram-negative organisms, primarily functioning in bacterial cell wall recycling. Increased AmpC production resulting from inducible ampC expression varies by species and exposure to specific β-lactam antibiotics. Meanwhile, associated β-lactam hydrolysis is dependent on substrate affinity for AmpC.1–5 In most wild-type Enterobacterales, chromosomal AmpC expression is maintained at low levels by the regulatory protein AmpR, which limits AmpC transcription. Induction occurs when β-lactam exposure disrupts cell wall synthesis, leading to the accumulation of certain degradation products that bind to the AmpR protein, alleviating its repression of ampC and thereby increasing enzyme production. Specifically, strong inducers such as ampicillin and first generation cephalosporins are also good substrates for AmpC, resulting in sufficient hydrolysis. In contrast, agents such as piperacillin and ceftriaxone, while weak inducers, are good substrates and therefore remain vulnerable to AmpC-mediated hydrolysis. Cefepime and some carbapenems, however, are weak inducers and poor substrates and thus can generally withstand AmpC-mediated hydrolysis, making them the preferred options for treating infections caused by organisms at risk for inducible ampC expression.1–5
Several mnemonics have been used to denote organisms at increased risk of inducible AmpC production (i.e. ‘SPACE,’ ‘SPICE,’ ‘MYSPACE,’ ‘ESCPM’). The ‘SPACE’ organisms, Serratia spp., Pseudomonas aeruginosa, Acinetobacter spp., Citrobacter spp., and Enterobacter spp., are among the most commonly cited in clinical teaching.1,4,6 Despite the use of these historical learning tools, there is no established consensus surrounding which mnemonic(s) best describe those pathogens at most risk of inducible AmpC production. Importantly, overreliance on these acronyms may potentially complicate treatment strategies and microbiological decision-making. Guidance on the Treatment of Antimicrobial Resistant (AMR) Gram-Negative Infections from the Infectious Diseases Society of America (IDSA) identifies concerns that these traditionally used mnemonics may be overly simplistic, leading to variability in assessing the likelihood of clinically significant AmpC production. Specifically, this guidance classifies Enterobacter cloacae complex, Klebsiella aerogenes, and Citrobacter freundii as moderate risk for inducible AmpC production. Other Enterobacterales members such as Hafnei alvei and Yersinia enterocolitica, are less frequently encountered in clinical practice, but are still considered moderate risk for inducible AmpC production.4,7 To highlight these organisms, a new mnemonic—HECK-Yes!—was coined based on data reflecting their moderate risk of inducible AmpC production.2,4,8 Other Enterobacterales known to carry an inducible, chromosomal ampC gene, such as Serratia marcescens, Morganella morganii, and Providencia species, are less likely to overexpress ampC and are considered low risk.2,4 Notably, IDSA Guidance indicates that the use of a weak inducer and poor AmpC substrate (e.g. cefepime) remains reasonable for infections caused by these lower-risk organisms in clinical scenarios involving high bacterial burden and limited source control.4
Importantly, there is limited evidence evaluating clinical outcomes with the use of various β-lactams for treating Enterobacterales infections based on risk of inducible AmpC production.7,9–12 One report found that definitive therapy with ceftriaxone versus AmpC-stable therapies resulted in no significant differences in 30-day all-cause mortality, overall clinical failure, or relapse in patients with bloodstream infections caused by Enterobacterales at low-risk of inducible AmpC production.9 Conversely, another study associated treatment failure with the use of 3rd generation cephalosporins for management of bloodstream infections or pneumonia caused by Enterobacterales at risk of inducible AmpC production, regardless of risk stratification.10
Based on conflicting clinical outcomes data and release of the IDSA Guidance on the Treatment of AMR Gram-Negative Infections, we hypothesized that there is variation in clinical and microbiologic practice patterns for management of infections caused by Enterobacterales at risk of inducible AmpC production.4,9,10 Therefore, the objective of this study was to evaluate these potential practice variations based on invasiveness of infection and risk stratification for inducible AmpC production within Enterobacterales.
Methods
General study design
This was a cross-sectional, investigator-developed, electronic survey that assessed institutional demographics, β-lactam of choice, and microbiologic reporting practices for the management of infections caused by Enterobacterales at risk of inducible AmpC production based on risk stratification. The survey was distributed by email to the American College of Clinical Pharmacy (ACCP) Infectious Diseases (ID) Practice and Research Network, IDSA Exchange, and Pediatric Infectious Diseases Society listservs between November 5, 2024, and December 16, 2024. In addition, two reminder emails were sent during the open survey period. A fully completed survey from United States respondents were required for participant response inclusion. Multiple responses from the same institution were assessed for clinical practices but duplicates were omitted for microbiologic-based questions (i.e. antibiogram reporting, microbiology culture reporting) based on random selection. The study protocol was reviewed by the Institutional Review Board at the Medical University of South Carolina (MUSC), determined to be exempt from Human Research Subject Regulations, and respondents were made aware that their participation in this research was voluntary. The survey was created and distributed electronically using the Research Electronic Data Capture (REDCap)® application hosted at MUSC.13 Furthermore, if required, each listserv approved the survey instrument prior to distribution.
Survey development
Survey items were developed by a multidisciplinary group of ID and antimicrobial stewardship pharmacists and physicians. The survey consisted of 23 potential questions organized into three sections. The first section gathered institutional demographic information including geographic location, institution type and size, and respondent role with associated training in ID practice. The second section focused on clinical practice management for infections caused by Enterobacterales at risk of inducible AmpC production, classified as either moderate risk or low risk according to IDSA guidance. Within our study, commonly encountered organisms with a risk of inducible AmpC production defined as moderate risk included Enterobacter cloacae complex, K. aerogenes, and C. freundii while those defined as low risk included S. marcescens, M. morganii, and Providencia spp.2,4 Clinicians were then asked to specify their β-lactam of choice for managing both invasive (e.g. bloodstream infections, severe pneumonia) and non-invasive infections (e.g. urinary tract infections, lower-risk intra-abdominal infections with source control) with antibiotic selection further stratified based on organism risk level. The third section examined institutional microbiologic reporting practices including susceptibility reporting for relevant isolates and antibiogram reporting based on risk stratification and culture source (e.g. non-urine versus urine isolates). In cases where respondents indicated that their institution did not distinguish between urinary and non-urinary antibiograms, and had not already duplicated the data themselves, this was accounted for in the analysis by duplicating the reported susceptibility data across both categories.
Respondents were required to answer each survey item before proceeding to the next section, and branching logic was utilized based on answers entered on pertinent questions. Free-text comments were enabled for each question, and a final comment was included to elaborate on any other items of importance. Following survey build, pilot testing was performed by a subset of the study investigators to assess interpretability, identify errors, and estimate time to completion.
Data analysis
Proportions were used to describe categorical variables. Free-text comments and responses were abstracted and grouped based on similar concepts or phrasing. Subgroups for definitive β-lactam of choice were delineated between adult and paediatric institutions, as well as clinician type. No statistical analyses were planned or performed based on the exploratory nature of this study, which precluded meaningful statistical inference. Data wrangling and graphical visualization were performed using Microsoft Excel (version 2502; Microsoft Corporation, Redmond, Washington).
Results
The survey was fully completed in 94 of 124 responses, predominately by pharmacists (58.5%) and ID-trained physicians (38.3%). Overall, formal ID residency and/or fellowship training was common (78.7%). Most pharmacists (n = 55) reported postgraduate year 2 ID training (67.3%) while most physicians (n = 36) reported ID medical fellowship training (97.2%). The institution types were primarily adult academic medical centres (39.4%) or adult community hospitals (37.2%). Institution size was determined by reported licensed bed size, and most institutions represented between 251–500 beds (36.2%) or 751–1000 beds (22.3%). Respondents were more familiar with the SPICE/SPACE mnemonic (90.4%) compared with HECK-Yes! (81.9%). All demographics are reported in Table 1.
Table 1.
Baseline characteristics
| Characteristic | n = 94 |
|---|---|
| Institution type | — |
| Academic Medical Center | 37 (39.4) |
| Community Hospital | 35 (37.2) |
| Pediatric Academic Medical Center | 16 (17.0) |
| Pediatric Community Hospital | 2 (2.1) |
| Veterans Affairs or Federal Hospital | 3 (3.2) |
| Specialty Hospital | 1 (1.1) |
| Hospital size (number of beds) | — |
| <100 | 2 (2.1) |
| 101–250 | 11 (11.7) |
| 251–500 | 34 (36.2) |
| 501–750 | 20 (21.3) |
| 751–1000 | 21 (22.3) |
| >1000 | 6 (6.4) |
| United States Census Region | — |
| Northeast | 17 (18.1) |
| Midwest | 31 (33.0) |
| South | 30 (31.9) |
| West | 16 (17.0) |
| Clinical role | — |
| Pharmacist | 55 (58.5) |
| Physician | 36 (38.3) |
| Infectious diseases medical fellow | 2 (2.1) |
| Other | 1 (1.1) |
| Infectious diseases training a | — |
| Infectious diseases pharmacy residency | 37 (39.4) |
| Infectious diseases pharmacy fellowship | 2 (2.1) |
| Infectious diseases medical fellowship | 35 (37.2) |
| Antimicrobial stewardship certificate | 24 (25.5) |
| Other | 2 (2.1) |
| None | 8 (8.5) |
| Clinician with primary responsibility for ID management (i.e. >50% of time spent on ID activities) | 92 (97.9) |
Data reported as n (%).
ID, infectious diseases.
a>94 as some individuals may have pursued multiple training avenues.
There were differences noted in definitive β-lactam of choice that were dependent on invasiveness of infection and organism risk level (Figure 1). Specifically, cefepime was most reported to be the respondent’s preferred option for moderate-risk organisms causing invasive (87.2%) and non-invasive (68.1%) infections while ceftriaxone was most reported to be the respondent’s preferred option for low-risk organisms causing invasive (57.4%) and non-invasive (60.7%) infections. Responses were analysed separately by clinician type (pharmacists, n = 55; physicians, n = 36) and by institution type (adult, n = 76; paediatric, n = 18) for definitive β-lactam selection. Overall, no major clinically relevant differences were observed. However, notable exceptions occurred by clinician type in the preferred β-lactam of choice for moderate-risk organisms causing invasive infections (cefepime, pharmacists: 96.4% versus physicians: 72.2%; meropenem, pharmacists: 1.8% versus physicians: 22.2%; other data not reported).
Figure 1.
Definitive β-lactam of choice for invasive and non-invasive Enterobacterales infections with potential for inducible AmpC production from all institutions. a: Definitive β-lactam for moderate-risk invasive infection; b: Definitive β-lactam for moderate-risk non-invasive infection; c: Definitive β-lactam for low-risk invasive infection; d: Definitive β-lactam for low-risk non-invasive infection.
Eleven responses received were duplicative based on the associated institution and were excluded to review 83 responses for assessment of microbiology practice patterns. For urinary isolate antibiogram reporting, cefepime (97.6%), meropenem (85.5%), ceftriaxone (72.3%), and piperacillin/tazobactam (72.3%) were commonly reported antibiotics for moderate risk Enterobacterales while cefepime (96.4%), ceftriaxone (95.2%), meropenem (81.9%), piperacillin/tazobactam (83.1%) were commonly reported antibiotics for low risk Enterobacterales. For non-urinary isolate antibiogram reporting, cefepime (98.8%), meropenem (85.5%), piperacillin/tazobactam (72.3%), and ceftriaxone (67.5%) were commonly reported antibiotics moderate risk Enterobacterales while cefepime (98.8%), ceftriaxone (94.0%), meropenem (83.1%), and piperacillin/tazobactam (83.1%) were commonly reported antibiotics for low risk Enterobacterales. Microbiology susceptibility reporting followed relatively similar patterns (Figure 2).
Figure 2.
Agents reported for Enterobacterales with clinically relevant moderate- and low-risk of inducible AmpC production on institutions antibiograms and microbiology susceptibility results for urinary and non-urinary isolates. a: β-lactams reported from institutional antibiograms; b: a: β-lactams reported from institutional microbiology susceptibility results.
Discussion
In this cross-sectional, multicentre, electronic survey, clinical and microbiologic practice patterns were described for the management of infections caused by Enterobacterales with a risk of inducible AmpC β-lactamase production. Of the included 94 fully completed participant responses, the most common β-lactam of choice was cefepime and ceftriaxone for organisms at moderate risk and low risk, respectively. However, it is important to note that variations in practice patterns were recognized, as some respondents chose meropenem (9.6%) and ceftriaxone (16.0%) for moderate risk invasive and non-invasive infections, respectively. Furthermore, there was also variability noted for low-risk organisms with some respondents choosing cefepime for invasive (27.7%) and non-invasive (10.6%) infections. We also compared responses from adult and paediatric institutions, as well as pharmacists and physicians, to assess whether clinicians’ β-lactam of choice preferences varied based on patient population or profession. Though there were more responses from clinicians at adult institutions (80.9%), there were no major clinically relevant differences in the definitive β-lactam of choice, regardless of risk level. However, for invasive infections caused by moderate-risk organisms, pharmacists predominately selected cefepime as their preferred β-lactam (96.4% versus 72.2%), whereas physicians more frequently favoured meropenem (22.2% versus 1.8%).
Commonly reported antibiotics in institutional antibiograms and microbiology susceptibility reports were cefepime, meropenem, piperacillin/tazobactam, and ceftriaxone for both moderate and low risk organisms. As cefepime and meropenem are weak inducers of ampC and poor substrates of AmpC β-lactamase hydrolysis, releasing these antibiotics within these reports is consistent with existing pharmacologic principles as they are likely to be efficacious in most instances, regardless of organism risk level. Although piperacillin/tazobactam and ceftriaxone are considered weak inducers of ampC, they are good substrates for AmpC hydrolysis; therefore, some clinicians may use caution in utilizing these agents, particularly in moderate-risk organisms causing invasive infections. Important to note, aminopenicillins and cefazolin which are considered strong inducers of ampC and good substrates for AmpC hydrolysis were reported on antibiograms and antimicrobial susceptibility reports at approximately 50% (or greater) of institutions.1 To better align with current treatment recommendations, institutions could consider utilizing antimicrobial stewardship interventions to optimize the use of β-lactams dependent on organism risk level, the invasiveness of infection, and/or patient- and other clinical-specific scenarios.4
The propensity for organisms to be at risk for clinically significant ampC induction is not equally common amongst the Enterobacterales with the potential for inducible AmpC production.2,4 Kohlmann and colleagues conducted an in vitro mutation rate analysis in 237 Enterobacterales with potential inducible AmpC production to determine species-specific mutation rates for ampC derepression.2 Of note, the isolates must have demonstrated initial in vitro susceptibility to oxyimino-cephalosporins. Of the most clinically relevant organisms, mean mutation rates were highest with E. cloacae complex (2.7 × 10−8), K. aerogenes (2.1 × 10−8), and C. freundii complex (3.3 × 10−8), and lowest with S. marcescens (2.4 × 10−10) and M. morganii (5.1 × 10−11) following exposure to cefotaxime.2 This in vitro analysis is also consistent with some clinical data reporting presumed ampC expression following antibiotic treatment, most reported with E. cloacae, K. aerogenes, and C. freundii.7,14–16
There is currently limited data evaluating the clinical outcomes of patients treated with various β-lactams (i.e. cefepime versus ceftriaxone) with infections caused by AmpC-producing organisms exhibiting different risks of ampC induction potential.7,9–12 Mulbah and colleagues conducted a retrospective, single-centre cohort of hospitalized adults receiving ceftriaxone versus AmpC-stable therapy (i.e. cefepime or carbapenems) for low-risk AmpC-harbouring Enterobacterales bloodstream infections.9 Importantly, the definitions for low-risk organisms in this study were consistent with those used in the present study. Of the 163 patients included, AmpC-stable therapy was used more commonly than ceftriaxone (66.9% versus 33.1%) and most patients had a genitourinary (37.4%), intra-abdominal (17.2%), or skin and soft tissue (15.3%) infectious sources. There were no differences in clinical failure rates (21.1% versus 9.3%; P = 0.059) or infection relapse (9.3% versus 5.6%; P = 0.55) between patients treated with AmpC-stable therapy or ceftriaxone, and definitive therapy with ceftriaxone was not associated with 30-day all-cause mortality (adjusted odds ratio, 0.79; 95% CI, 0.23–2.3).9
In contrast, another retrospective, multicentre study conducted by Maillard and colleagues evaluated 575 patients with pneumonia (52.5%) and bloodstream infections (47.5%) due to wild-type AmpC-producing Enterobacterales treated with either cefepime (39.8%), carbapenems (7.3%), third generation cephalosporins (20.9%), or piperacillin +/− tazobactam (32.0%) as definitive therapy.10 Most isolated organisms (70.1%) were deemed to have a high mutation rate for ampC derepression (E. cloacae, K. aerogenes, C. freundii, and H. alvei), while the remaining isolates (29.9%) were deemed to have a low mutation rate (S. marcescens, M. morganii, and ‘other species’). There were no differences noted in 30-day in-hospital mortality between the high and low mutation rate groups following multivariable logistic regression and there were also no statistically significant differences between any of the definitive therapeutic groups. However, AmpC-related treatment failure was more common in patients receiving third generation cephalosporins and piperacillin/tazobactam for species with both high mutation rates (third generation cephalosporins: 22% versus 4%; HR, 7.0 [95% CI, 3.0–6.4]; piperacillin/tazobactam: 12% versus 4%; HR, 3.2 [95% CI, 1.4–7.4] and low mutation rates (third generation cephalosporins: 15% versus 1%; HR, 15.3 [95% CI, 1.9–125.9]; piperacillin/tazobactam: 6% versus 1%; HR, 6.4 [95% CI, 0.6–63.6]) compared to those treated with reference therapy.10 It is noteworthy that the cohort examined by Maillard and colleagues (in comparison to Mulbah and colleagues) may have included a higher proportion of patients with more invasive, high inoculum infections which may have led to the differences in treatment outcomes.9,10 The variations in clinical practice identified in this survey, along with inconsistent clinical outcomes reported in prior studies, highlight the need for further research. Such work is essential to draw more definitive conclusions and optimize therapy for invasive and non-invasive infections caused by moderate- and low-risk organisms.9,10
Though this survey aids in defining the current national trends of definitive therapy selection, antibiogram reporting, and microbiology susceptibility reporting, it did not evaluate the clinical outcomes of any types of antimicrobial stewardship interventions when treating low risk and moderate risk organisms causing invasive and/or non-invasive infections. Despite the inclusion of examples for ‘invasive’ and ‘non-invasive’ infections, the lack of an explicit, standardized definition also represents a limitation as it allowed for variability in respondent interpretation. Given the nature of research surveys and that some questions were also opinion-based, selection bias and response bias are apparent limitations. Additionally, the use of cascade reporting noted by some institution respondents may have contributed to variability and responses to microbiology reporting questions, potentially contributing to inter-respondent variability.
Despite these limitations, this was the first survey conducted nationwide to evaluate the clinical and microbiologic practice patterns for the management of infections caused by Enterobacterales with a risk of inducible AmpC β-lactamase production. Given that this survey was distributed across multiple ID listservs, there was a broad sample of clinicians assessed, enhancing the generalizability of the findings. Furthermore, this survey was validated by a multidisciplinary antimicrobial stewardship and ID team which likely improved the relevance and clarity of questions and was assessed for any potential bias. Finally, this survey captured both clinical decision-making and operational microbiology laboratory practices, offering a comprehensive view of clinician and institutional behaviour.
The results of this national survey highlight variability in treatment choices and reporting practices. These findings underscore the need for standardized evidence-based antimicrobial stewardship strategies and future clinical research to optimize the treatment of infections caused by Enterobacterales with inducible AmpC potential, ensuring both effective therapy and the mitigation of antimicrobial resistance.
Contributor Information
Sarah Hughes, Department of Pharmacy, Medical University of South Carolina Health, Charleston, SC, USA.
Rachel B Colven, Department of Pharmacy, Medical University of South Carolina Health, Charleston, SC, USA.
Gustavo R Alvira-Arill, Department of Pharmacy, Medical University of South Carolina Health, Charleston, SC, USA; Department of Clinical Pharmacy & Outcomes Sciences, Medical University of South Carolina College of Pharmacy, Charleston, SC, USA.
Zachary Gruss, Department of Pharmacy, Medical University of South Carolina Health, Charleston, SC, USA.
Aaron Hamby, Department of Pharmacy, Medical University of South Carolina Health, Charleston, SC, USA.
Richard Lueking, Department of Medicine, Division of Infectious Diseases, Medical University of South Carolina Health, Charleston, SC, USA.
Logan Patterson, Department of Pathology and Laboratory Medicine, Medical University of South Carolina Health, Charleston, SC, USA.
Alexandra Mills, Department of Medicine, Division of Infectious Diseases, Medical University of South Carolina Health, Charleston, SC, USA.
Stephen A Thacker, Department of Pediatrics, Division of Infectious Diseases, Medical University of South Carolina Health, Charleston, SC, USA.
Krutika Mediwala Hornback, Department of Pharmacy, Medical University of South Carolina Health, Charleston, SC, USA.
Taylor Morrisette, Department of Pharmacy, Medical University of South Carolina Health, Charleston, SC, USA; Department of Clinical Pharmacy & Outcomes Sciences, Medical University of South Carolina College of Pharmacy, Charleston, SC, USA.
Funding
This study was carried out as part of our routine work.
Transparency declarations
KMH has received research and travel grant funding from BioMérieux and Merck Sharp & Dohme, has participated in scientific advisory boards for Invivyd, and is on the Cepheid Diagnostics speaker’s bureau. TM is currently receiving grant funding through Stellus Rx, AbbVie Inc., and Merck Sharp & Dohme, has participated in scientific advisory boards for AbbVie Inc., Shionogi Inc., and Pfizer, has provided expert witness testimony to Copeland, Stair Valz & Lovell and Huff, Powell & Bailey, and has received honoraria from Shionogi Inc., Infectious Diseases Special Edition, and Managed Healthcare Executive. All other authors have no conflicts to disclose.
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