- Letter to the Editor
- Open Access
Ecological effects of cefepime use during antibiotic cycling on the Gram-negative enteric flora of ICU patients
© The Author(s). 2018
- Received: 17 April 2018
- Accepted: 9 July 2018
- Published: 27 July 2018
This study examines the impact of cefepime and APP-β (antipseudomonal penicillin/ β-lactamase inhibitor combinations) on Gram-negative bacterial colonization and resistance in two Australian ICUs. While resistance did not cumulatively increase, cefepime (but not APP-β treatment) was associated with acquisition of antibiotic resistant Enterobacteriaceae, consistent with an ecological effect. Analysis of the resident gut E. coli population in a subset of patients showed an increase in markers of horizontal gene transfer after cefepime exposure that helps explain the increase in APP-β resistance and reminds us that unmeasured impacts on the microbiome are key outcome determinants that need to be fully explored.
To the Editor,
Effect of antibiotic on gain and loss of resistance in Enterobacteriaceae after 72 h in ICU
Timentin and/or gentamicin
p = 0.610
p = 0.34
p = 0.004a
p = 0.07
p = 0.550
p = 0.20
p = 0.002a
p = 0.10
p = 0.456
p = 0.16
p = 0.014a
p = 0.06
Our analysis showed that high-level homogeneity of β-lactam antibiotics within cycles was not associated with overall increased resistance, in agreement with other studies on antibiotic cycling in which Gram-negative bacterial susceptibility was not significantly altered [2, 6, 7]. The apparent ecological effects that we describe are consistent with our own data regarding MRSA and P. aeruginosa , challenging antimicrobial homogeneity as a driver of resistance per se , an idea that was premised on a mathematical model which was recently disputed . Antibiotic use is recognized as the single most powerful selective pressure for the emergence of resistance particularly in environments where usage is high (ICU). However, the different strategies implemented to curb the rise of resistance in hospitals, including cycling, have had variable outcomes due to the complex relationship between use of specific drugs and resistance patterns in bacterial populations . In our study, despite stable overall resistance rates, treatment with cefepime was a significant independent predictor of acquisition of antibiotic-resistant Gram-negative organisms and was also strongly associated with increased resistance to APP-β, but not to cefepime or extended-spectrum β-lactams (Table 1), in agreement with other studies on cefepime use in hospitalized patients [6, 11].
Antimicrobial resistance (AR) profiles of isolated E. coli representatives
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In animal models, a proteobacterial bloom that accompanies colitis was associated with accelerated plasmid transfer between species , and a similar proteobacterial bloom is relatively prolonged after third-generation cephalosporins compared to penicillins [13, 14], providing a potential biological explanation for our findings (Fig. 2). Antibiotic treatment modifies the microbial community structure in the gut by shifting the competitive balance between sensitive bacteria and resistant/pathogenic subpopulations . These subpopulations carry different resistant determinants that may come to predominate both by amplification of the original carriers and/or spread to other species. In Gram-negative enterobacteria, antibiotic resistance develops mainly via horizontal transfer of resistance genes that often cluster together in the same genetic locus, either on the chromosome or on plasmids, giving rise to multiple resistant types. Use of one antibiotic may drive selection of resistance to an entirely different class of drugs due to both cross-resistance mechanisms and co-localization of genetic elements. Perhaps more importantly resistance determinants are also associated with diverse mobile genetic elements (transposons, insertion sequences, plasmids) that allow for the movement of multidrug resistance loci between bacterial cells .
Even though selection and spread of specific resistance might be constrained by fitness requirements, antibiotic activity itself is known to promote horizontal gene transfer by triggering recombination and conjugation events, which will affect population-level resistance patterns , and by acceleration of gene transfer during population expansion events . Together, these data indicate that cefepime exposure differentially drives antibiotic resistance in the microflora other than by direct phenotypic selection and are consistent with descriptions of enhanced plasmid transfer in other gut dysbioses . This provides a potential explanation for resistance (e.g., to extended-spectrum β-lactam antibiotics) in Enterobacteriaceae that has been linked to exposure to late-generation cephalosporins, such as cefepime , and seems likely generalizable to third-generation cephalosporins, which have similar activities, gut penetration and associations with antibiotic resistance. It appears unlikely from (narrower-spectrum) first-generation cephalosporins, but reminds us that unmeasured impacts on the microbiome are key outcome determinants that have yet to be fully explored.
The authors acknowledge Agnieszka M Wiklendt for her technical support.
This work was supported by grants from the Australian National Health and Medical Research Council (NHMRC) to JI (1001020; 1046889).
Availability of data and materials
The datasets supporting the conclusions of this article are included within the article (and its additional files).
CV designed and performed all analyses for the E. coli characterization study, participated in the analysis of clinical data, and wrote the manuscript. ANG performed the initial culture work for resistance data from the clinical specimens and analysis of clinical data and participated in clinical study design and manuscript preparation. BEW performed the analysis of clinical data. GT supported the bioinformatic screening of sequencing data for resistance, mobile element, and plasmid markers. IP participated in the study design. SRP participated in the study design and analysis of sequence data and created the plasmid marker database. JRI designed the study, supervised all analysis, and wrote the manuscript. All authors approved the final version of the manuscript.
Ethics approval and consent to participate
The previously published clinical component in the parent study (Ginn et al. 2012 ) was conducted under a waiver of consent, under the auspices of the relevant Human Research Ethics Committees of the Sydney West Area Health Service and the Royal Brisbane and Women’s Hospital.
Consent for publication
The authors declare that they have no competing interests.
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