Background
Antibiotic use is increasing worldwide and has been implicated in the dramatic rise of antimicrobial resistance, which in turn threatens to reverse historical reductions in mortality for infectious diseases [
1]. Few treatment options remain, for example, for Enterobacteriaceae, which are increasingly resistant to beta-lactam antibiotics due to production of extended spectrum beta-lactamase (ESBL), AmpC, and carbapenemases. Infections with drug-resistant Enterobacteriaceae, such as those producing ESBL, have been associated with increased mortality [
2].
The gut serves as a reservoir for drug-resistant Enterobacteriaceae [
3]. Antibiotic administration increases drug-resistant Enterobacteriaceae colonization through selection pressure and disruption of protective normal microbiota [
3,
4]. Animal models show a disruption to the gut microbiome within 12 h and emergence of drug resistance genes within 3 days of antibiotic administration [
5,
6]. Patients colonized with ESBL-producing Enterobacteriaceae are at greater risk for clinical infections with ESBL-producing Enterobacteriaceae than those who are not colonized [
7].
In resource-limited settings, colonization with drug-resistant Enterobacteriaceae is common in adults, and, in community-based populations, associated with antibiotic use [
8‐
10]. However, risk factors for inpatient acquisition of colonization with drug-resistant Enterobacteriaceae have not been clearly defined. As the world’s largest consumer of antibiotics [
11], India has among the highest burdens of antimicrobial resistance worldwide [
12‐
14]. Travelers from high income countries to India return home colonized with ESBL-producing Enterobacteriaceae more frequently than travelers to other countries, suggesting that India has a heavier burden of drug-resistant Enterobacteriaceae colonization compared to other low and middle income countries [
15,
16].
In this study, we sought to assess the clinical factors associated with ceftriaxone- and carbapenem-resistant Enterobacteriaceae colonization among adults and children admitted to a tertiary care hospital in Pune, India. Given prior work suggesting an association with antibiotic use, we enrolled patients with acute febrile illness, a group likely to be treated with antibiotics [
17].
Discussion
Our study has several key findings. First, we identified a 10% prevalence of community-acquired ceftriaxone-resistant GNR colonization and 1.6% colonization with CPRE among Indian adults and children admitted with acute febrile illness. Second, we observed that healthcare contact was associated with increased odds of admission CTRE colonization. Third, we found that participants without baseline CTRE colonization who received empiric third generation cephalosporins had almost three-fold higher odds of follow up detection of CTRE colonization, and were more likely to acquire CPRE colonization if admitted to the ICU.
The 10% rate of community-acquired CTRE colonization reported in this study is comparable to rates of 10–15% reported in studies that used rectal and perirectal swabs to detect colonization [
27,
28], and to another study of children in India showing 13% of children to have ceftriaxone-resistant
E. coli colonization [
29]. The rate was lower than the 23–69% ESBL-Enterobacteriaceae colonization rate reported among healthy adults from other resource limited Asian settings that determined colonization using higher inoculum stool samples [
8,
9]. While obtaining a stool specimen from healthy volunteers at a time of convenience may be practical for community surveillance studies, in order to assess dynamic colonization during hospitalization, perirectal swab collection at specific time intervals is more practical than stool culture.
Admission CTRE colonization was no longer detected at follow-up for almost two-thirds of CTRE colonized participants, a higher than expected proportion. Although some studies have shown persistence of multidrug-resistant Enterobacteriaceae for months after acquisition, others have shown that with daily screening, more than half of patients demonstrate intermittent colonization [
25,
30,
31]. As we only performed one follow-up culture, it is possible that further follow-up cultures may have revealed persistence of colonization in additional participants. However, because third-generation cephalosporin use was not associated with loss of detectable ceftriaxone-resistant GNR colonization, limitations in the CTRE colonization detection modality were not impacted by third-generation cephalosporin use.
Use of empiric third generation cephalosporins was associated with detection of CTRE colonization among participants not found to be colonized at admission, even when adjusted for other factors. Empiric aminoglycosides use was associated with acquisition of carbapenem-resistant Enterobacteriaceae colonization, but was likely confounded by ICU admission. From this study, we cannot determine if follow-up detection of drug-resistant Enterobacteriaceae colonization among participants without baseline colonization was due to nosocomial transmission or overgrowth of minority drug-resistant colonies in the presence of selection pressure from administered antibiotics. Most nosocomial acquisition of drug-resistant Enterobacteriaceae in studies conducted in resource-rich settings is not attributed to transmission from other hospitalized patients [
32,
33]. However, a study in a resource-limited setting showed genetic similarities among acquired isolates suggesting nosocomial cross-transmission [
34].
Previous work in a resource-rich ICU setting has shown an association between drug-resistant Enterobacteriaceae colonization and mortality [
35], but similar data from resource-limited settings describing clinical associations with colonization is limited. We found that participants with CTRE colonization at follow-up were more likely to die in an unadjusted analysis. After adjusting for ICU admission and age, the association no longer remained statistically significant. Any association of CTRE colonization and mortality does not necessarily signify causality, as there may be unmeasured risk factors common to both CTRE colonization acquisition and mortality.
Unfettered antibiotic use has been implicated as one of the key factors driving global increasing antimicrobial resistance [
1]. Studies in other settings have demonstrated that antibiotic administration and ICU admission are associated with development of antibiotic-resistant bacterial stool colonization during the course of a hospitalization, but used longer intervals between enrollment and follow-up [
28,
36]. The finding that initial empiric antibiotic choice can also significantly impact this process is concerning, especially given how commonly third generation cephalosporins are used in India and elsewhere.
Antimicrobial use may be tempered by antimicrobial stewardship policies, which were not yet in place at the time of this study. Guidelines offer two general antimicrobial stewardship approaches: preauthorization of antibiotics and auditing of antibiotic prescriptions after treatment initiation [
37,
38]. De-escalation of antibiotic therapy was associated in a meta-analysis with decreased mortality risk [
39]. However, it remains unclear how quickly antibiotics should be de-escalated. Rapid acquisition of detectable resistant Enterobacteriaceae colonization, as noted in our study, may result in a narrow window of opportunity for prevention of drug-resistant organism colonization. A recent study notably failed to show a reduction in the emergence of multidrug-resistant Gram-negative infections after de-escalation of anti-pseudomonal beta-lactams [
40]. Our study design required participants to remain hospitalized through Day 3 or Day 4, which excluded both those with early mortality, and those with mild illness who were quickly discharged. However, among patients who do remain hospitalized through the third or fourth day of admission, the contribution of empiric antibiotics to drug-resistant Enterobacteriaceae colonization poses an antimicrobial stewardship concern.
Conclusions
In conclusion, colonization with drug-resistant Enterobacteriaceae is common among patients admitted with fever in Pune, India. Our study highlights the need for improved antimicrobial stewardship and infection control measures, which the World Health Organization acknowledges in its Global Action Plan on Antimicrobial Resistance [
41]. Physicians and governing bodies in India have recognized the threat of antimicrobial resistance responding with newly introduced legislation which requires a prescription for the sale of many advanced antibiotics including third and fourth generation cephalosporins [
12,
42]. Continued surveillance of drug-resistant Enterobacteriaceae colonization in India and other resource-limited settings is warranted.
Acknowledgments
We thank the study participants and staff for their immense contribution.