Reply to Raoult and Rolain, and to Echols and Tillotson

To the Editor—We appreciate the letters submitted by Raoult et al [1] and Tillotson et al [2] in response to our article on difficult-to-treat resistance (DTR) in select taxa of Gram-negative bloodstream infection (GNBSI) at US hospitals [3]. DTR was defined as resistance to all first-line (high-efficacy, low-toxicity) agents, which for the study period and chosen GNBSIs meant β-lactams (including carbapenems) and fluoroquinolones. The developers of DTR would like to address a few comments in the letters and reinforce key aspects about this metric.

We agree with Raoult et al [1] that the march of antibiotic resistance has appeared recently to somewhat stabilize [4]. However, complacency induced by this apparent lull would be a major mistake and contrary to the history of antibiotic resistance and our understanding of evolution biology. Furthermore, characterizing DTR as “rare” and “with nonsignificant consequences” is misleading. Although the prevalence of DTR in GNBSI of 1% may seem low, over half of the hospitals distributed across all 9 US census regions displayed at least 1 case. Estimating mortality attributable to resistance is challenging [5, 6] and as we have conceptually shown, varies considerably by site, onset and severity of the infection as well as the calipers used for comparison [7]. Notwithstanding, nearly one in every two patients with DTR GNBSIs died (crude mortality = 43%), which upon risk adjustment still represents a 40% higher adjusted mortality risk compared to those with nonresistant GNBSI (adjusted risk ratio, 1.4; 95% confidence interval [CI], 1.2–1.6; P < .001).

The DTR concept was specifically developed to capture excess mortality attributable to both discordant empirical regimens and subsequent reliance on less effective and/or more toxic “reserve” compounds (eg, colistin, tigecycline and aminoglycosides). Hence, Raoult et al’s suggestion that any increase in mortality due to DTR “should have been corrected with the use of appropriate [reserve] compounds” appears to entirely miss the point of our article. Importantly, injudiciously expanding the empiric use of reserve agents as suggested by Raoult et al would be of questionable benefit and potentially harmful [8].

Tillotson et al raise several important issues that warrant emphasis, including the importance of carbapenem resistance as an epidemiologic designation and the need for the DTR definition to evolve over time. We emphasize in our manuscript [3] that “DTR is not a fixed phenotype but rather a flexible framework.” Much like revision of clinical guidelines and susceptibility breakpoints, the rubric of antibiotics involved in defining DTR will also require periodic revision in order to remain up-to-date. We believe this dynamic quality of DTR, is in fact a strength that enables us to continue to capture how resistance is perceived and confronted at the bedside. The 77-year-long human experiment with antibiotics has taught us that pathogens evolve under antibiotic selective pressure and mobile genetic elements enable strategic co-existence and global dissemination of resistance traits. Consequently, it is unrealistic for any traditional antibiotic to remain perennially and universally active [9]. Furthermore, the influx of new antibiotics, their changing supply, access and cost logistics and evolving evidence regarding their use collectively infuses a dynamic aspect into our armamentarium. These moving parts preclude any static definition of co-resistance from remaining consistently indicative of the same treatment constraints over time. The “carbapenem resistant” label is no exception. Even though it has enabled us to gauge the extent of resistance to this important antibiotic category, carbapenem resistance has a different connotation (relative to “difficult-to-treat”) today than it did a few years ago [10]. Notably, our study [3] demonstrated that carbapenem-resistant isolates of Pseudomonas aeruginosa, a frequent and important healthcare-associated pathogen, are more likely than not to be susceptible to other βlactams and/or fluoroquinolones–a profile that is clearly not DTR.

Importantly, the concept of DTR is scalable to non-bloodstream sites, as well as other bacterial problem-pathogens such as enterococci and even Stenotrophomonas maltophilia as suggested by Tillotson et al. However, there is not one universal definition of DTR that can be applied to all pathogens. Although Stenotrophomonas maltophilia is intrinsically carbapenem resistant, its clinical and epidemiologic implications are substantially different from the bacterial taxa we selected to illustrate the utility of the DTR concept. Intrinsic resistance to carbapenems does pose “difficulty” by virtue of a higher likelihood of inappropriate empiric therapy, yet targeted therapy is generally less challenging given that relatively high levels of susceptibility to trimethoprim-sulfamethoxazole and levofloxacin [11].

Unlike the need of Shadok brains to forgo one concept in order to learn another [1, 12], we suggest parallel adoption and concomitant use of important static definitions like carbapenem resistance and dynamic indices like DTR given that they serve unique and complimentary roles.

Notes

Disclaimer. The comments of the authors do not necessarily represent the official position of the National Institutes of Health, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.

Financial support. This work was supported by the Intramural Research Program of the National Institutes of Health Clinical Center.

Potential conflicts of interest. Both authors: No reported conflicts of interest. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.