Introduction
Empiric antibiotics are the main pillar of sepsis treatment in the intensive care unit (ICU). There is a 10–42% absolute increase in sepsis mortality when initial empiric antibiotics fail to appropriately treat infecting organisms [
1‐
3]. Clinical guidelines recommend that broad-spectrum, empiric antibiotics be initiated as part of a treatment bundle within 1 h of presentation with sepsis [
4], and studies suggest that outcomes may improve when antibiotics are given as quickly as possible [
5].
Balanced against the imperative for early, broad-spectrum antibiotics is the mandate for antibiotic stewardship. Using fewer or more narrow-spectrum antibiotics avoids drug-drug interactions, avoids antibiotic side effects, and furthers the stewardship goal of minimizing the emergence of antimicrobial resistance [
6].
Long courses of antibiotics in the ICU are associated with increased gastrointestinal antimicrobial resistance [
7]. The impact of short-course antibiotics on antimicrobial resistance in the ICU is less certain. Large structural microbiome changes can be seen within 72 h after oral antibiotic intake in healthy, antibiotic-naïve volunteers [
8]. Whether antimicrobial resistance can emerge so quickly following intravenous antibiotics in the ICU is not known.
This study gathered rectal swabs from ICU patients immediately at the time of ICU admission and 72 h later, and compared changes in gastrointestinal antimicrobial resistance in those who did or did not receive antibiotics among different classes. The goal of the study was to determine if short-term antibiotics adversely impact gastrointestinal antimicrobial resistance in the ICU.
Discussion
In this study of 48 critically ill patients, there was no association between receipt of short-course antibiotics and change in antimicrobial resistance phenotype or genotype during the 72 h following ICU admission. Initial patient-level ICU antimicrobial resistance pattern was the best predictor of antimicrobial resistance after 72 h, and significant interim changes were rare. Opioids, which have traditionally been associated with poor ICU outcomes, were associated with modestly reduced overall resistance in antimicrobial genotype.
This study addressed the question of short-term resistance dynamics within the gut microbiome of ICU patients. Clinically, the imperative for early broad-spectrum antibiotics in the ICU is balanced against the desire for antibiotic stewardship. Decisions regarding use of antibiotics for sepsis are usually made before diagnostic microbiology results are available [
18,
19]. Can intensivists reasonably give and continue empiric broad-spectrum antibiotics for 72 h without excessive concern that they are promoting antimicrobial resistance? Our results are reassuring but must be interpreted with caution. Prior studies clearly establish that antimicrobial resistance arises within colonizing gut bacteria during long-term antibiotic treatment in the ICU. The question is not
if resistance develops but
when. The 72-h treatment window in this study parallels the 3-day interval after which antibiotic discontinuation is sometimes considered in the ICU [
4,
20]. The results suggest that 72 h is not long enough for the development of new gastrointestinal antimicrobial resistance within a given individual. Longer antibiotic treatment window periods would almost certainly have led to different study results.
These findings regarding the dynamics of resistance contrast sharply with in vitro studies. When bacterial isolates are exposed to selective pressure in culture, mutations that confer antimicrobial resistance are rapidly selected [
21,
22]. Compared to in vitro systems, the gut microbiome of ICU patients has many competing selection pressures. This dense network of interactions may delay selection for antimicrobial resistance genes [
23]. In ICU patients, collapse of the pre-existing gut microbiome and emergence of a pathobiome enriched in resistance may require 11–14 days of antibiotic treatment [
24,
25]. Other studies suggest that resistance does emerge, but does so slowly. In allogeneic stem cell transplant patients, emergence of new resistance within multiple VRE clones was seen after 7 days of selective antibiotics, with most new resistance observed after 3 weeks or more [
26]. In an infant treated with multiple antibiotics, 2 months were required before antimicrobial resistance emerged within specific bacterial lineages [
27,
28]. In a similar study, novel plasmid-mediated ampicillin resistance was acquired after 16–32 days in the absence of antibiotic treatment [
29]. The implication is that resistance within complex human systems such as the gut arises over weeks instead of days [
7].
Multiple factors probably contributed to the relatively modest changes observed in antimicrobial resistance. The antibiotics received were 93% intravenous. Intravenous antibiotics do penetrate into the gut [
30], but luminal concentrations and pharmacodynamics may matter [
31]. Another possibility is that patients were already too enriched in antimicrobial resistance at the time of ICU admission because of past antibiotic exposures to detect a meaningful change in resistance over 72 h. Prior studies support such a conclusion. Willmann et al. found surprisingly little gains in fluoroquinolone resistance during prophylaxis of neutropenic patients, perhaps because of past exposures [
32].
This study has limitations. It did not seek to correlate antimicrobial resistance with specific bacterial lineages and cannot state whether “new” antimicrobial resistance was acquired from the environment, from horizontal gene transfer, or vertically within bacterial lineages. Such correlations are technically challenging [
33]. Rather, a standard clinical culture-based approach was used to identify resistance within the primarily Gram-negative bacteria that cause most serious ICU infections [
34]. Then quantitative PCR was added to determine resistance genotype. Alternative methodologies could have been used for genotyping [
35], but qPCR was selected for ease of performance and high sensitivity [
36]. The ICUs involved were high-acuity regional referral centers, and results may not generalize perfectly to other ICUs. Last, the study was relatively small. While there were within-individual increases in antibiotic resistance based on culture (see Fig.
2), the study was not powered to detect weak relationships between antibiotics and antimicrobial resistance, especially for certain antibiotic class categories where few patients were unexposed. Given the large historical benefits attributed to antibiotics, a modest effect on antimicrobial resistance is unlikely to significantly alter the clinical risk-benefit calculation.
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