MDRO, DTR, WTF? Defining drug-resistance in Gram Negative Organisms

Gram negatives are a nightmare. Or at least, they are becoming a nightmare with all new patterns of resistance, beta-lactamases and carbapenamases, and plasmid-encoded resistances bringing forth the new generation of beta-lactam and beta-lactamase combinations that I find difficult to keep up with. The definitions of multi-drug resistant organisms tend to be more geared towards epidemiological studies rather than for a clinical application.

The definition for MDR was proposed in 2012 (1), and looking at the second page of the paper, you can see the following: “It is important to note that these definitions are meant for public health use and epidemiological purposes only. They are not intended to replace clinical judgement, to contribute to therapeutic decision-making, or to offer guidance.”  Acquired resistance, rather than intrinsic, was the only type of resistance taken into consideration. Here, the authors define MDR as “non-susceptibility to at least one agent in three or more antimicrobial categories.” XDR is defined as “non-susceptibility to at least one agent in all but two or fewer antimicrobial categories.”

You can see that you may be able to use a BL/BLI combination, or another beta-lactam (i.e. carbapenem) and still be labeled as an MDRO if you have an R next to cephalosporins, fluoroquinolones, or penicillins. Why does this matter? Partly, because it doesn’t really give you the full scope of what is not available for you to use. It has been argued that using this definition implies that all antibiotics in a certain category are of equal efficacy and toxicity, limiting its applicability in clinical practice (2). As a result, a new definition, difficult-to-treat resistance (DTR) has been proposed, which states these organisms are resistant to ALL beta-lactams (including beta-lactam/beta-lactamase inhibitors and carbapenems) and fluoroquinolones. This may be more treatment and prognostic implications than the standard MDRO definition, because now you are forced to use things like aminoglycosides, colistin, or another novel antibiotic that may have lower efficacy/higher toxicity. The initial paper on this topic evaluated the 5-year prevalence of DTR in gram negative infections in a retrospective cohort (2). Over 46,000 isolates were evaluated with 471 displaying DTR for a prevalence of 1%. This is significantly lower for the other definitions in this paper, which included carbapenem-resistant (2.3%), extended-cephalosporin resistance (9%) and fluoroquinolone resistance (22%). Across different classifications, DTR had the lowest prevalence overall and within each category:

Moreover, those who had DTR isolates were more likely to be in the ICU, require ventilator use, and have a higher unadjusted death rates. Adjusted risk of mortality for DTR was 1.4 (95% CI 1.2-1.6), compared for CR 1.2 (95% CI 1.0-1.4), ECR (1.2, 95% CI 1.1-1.4), or FQ-R (1.2, 95% CI 1.0-1.4):

DTR patients also had longer hospital stays, and were more likely to be administered colistin/polymyxin-B, tigecycline, or any aminoglycoside. These data have been validated in three different cohorts. In a cohort of 17,677 gram negative isolates (3), 1.3% of these met DTR criteria, with the highest proportion being in A. baumannii complex compared to E. coli, or even pseudomonas:

Mortality for all resistance phenotypes was higher when compared to susceptible strains, however DTR displayed higher mortality when compared to other resistance definitions (aRR vs carbapenem-resistant 1.35, 95% CI 1.02-1.78, vs extended cephalosporin resistance 1.39, 95% CI 1.11-1.73, vs FQ resistance 1.55, 95% CI 1.24-1.93). The same effect was not see for enterobacteriace and pseudomonas, perhaps due to the relative low numbers seen:

In a Korean retrospective cohort, 147/1167 patients were classified as having DTR (12.6%), which was higher than other cohorts (4). Compared to other resistance profiles, DTR still had a lower overall prevalence:

Not surprisingly, the DTR cohort had higher rates of ICU stay and ventilator use, with the vast majority of the strains belonging to the Acinetobacter spp and Pseudomonas. They also tended to be less likely to receive appropriate empiric antibiotics (OR 0.20, 95% CI 0.14-0.28) with multivariate analysis showing that recent antibiotic use (aOR 2.18, 95% CI 1.22-3.91) steroid use (aOR 5.56, 95% CI 1.94-15.94), health-care associated infection (aOR 1.91, 95% CI 0.98-3.71) and mechanical ventilation aOR 4.46, 95% CI 2.3-8.66) being associated with DTR gram negative infections. Multiple logistic regression analysis found that DTR compared to other resistant profiles was independently associated with mortality, which was also seen after propensity score matching:

Other factors associated with mortality included higher Charlson comorbidity index, recent hospitalization, renal failure, poor baseline performance, and higher Pitt bacteremia score. 

DTR has also served as a fairly good prognostication tool. An Italian single-center retrospective study found an overall prevalence of DTR 11%, with the higher percentage seen in A. baumanii (5):

All 3 types of resistance-definitions (the original Magiorakos, or MDR; carbapenem resistance, and DTR) seem to perform well in terms of prognostication when added to the multivariate model for predicting 30-day mortality:

It seems the reason why DTR patients tend to have higher mortality comes from the lack of appropriate empiric therapy against these. Due to the definition, all beta-lactams and FQs tend to be unavailable with certain exceptions, so you are always forced to use more toxic agents, so this may be a more apt classification to use in clinical practice, as it has greater treatment and prognostic implications. For instance, in one retrospective cohort study (6) compared the susceptibility of DTR and MDR organisms against 2 BL/BLI combination, ceftolozane/tazobactam and imipenem/relebactam 10516 enterobacteriaceae and 2732 pseudomonas organisms were evaluated. For enterobacteriaceae, imipenem/relebactam was susceptible in 82% of DTR and 92% of MDR isolates, while ceftolozane/tazobactam was only susceptible in 1.5% of DTR and 66% of MDR isolates. Indeed, saying “this organism is DTR” tells you a bit more than “this organism is an MDR” though both sound terrifying. 

References:

1. Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, Harbarth S, Hindler JF, Kahlmeter G, Olsson-Liljequist B, Paterson DL, Rice LB, Stelling J, Struelens MJ, Vatopoulos A, Weber JT, Monnet DL. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2012 Mar;18(3):268-81. doi: 10.1111/j.1469-0691.2011.03570.x. Epub 2011 Jul 27. PMID: 21793988.
2. Kadri SS, Adjemian J, Lai YL, Spaulding AB, Ricotta E, Prevots DR, Palmore TN, Rhee C, Klompas M, Dekker JP, Powers JH 3rd, Suffredini AF, Hooper DC, Fridkin S, Danner RL; National Institutes of Health Antimicrobial Resistance Outcomes Research Initiative (NIH–ARORI). Difficult-to-Treat Resistance in Gram-negative Bacteremia at 173 US Hospitals: Retrospective Cohort Analysis of Prevalence, Predictors, and Outcome of Resistance to All First-line Agents. Clin Infect Dis. 2018 Nov 28;67(12):1803-1814. doi: 10.1093/cid/ciy378. PMID: 30052813; PMCID: PMC6260171.
3. Kadri SS, Lai YLE, Ricotta EE, Strich JR, Babiker A, Rhee C, Klompas M, Dekker JP, Powers JH 3rd, Danner RL, Adjemian J; NIH Antimicrobial Resistance Outcomes Research Initiative (NIH-ARORI). External Validation of Difficult-to-Treat Resistance Prevalence and Mortality Risk in Gram-Negative Bloodstream Infection Using Electronic Health Record Data From 140 US Hospitals. Open Forum Infect Dis. 2019 Feb 28;6(4):ofz110. doi: 10.1093/ofid/ofz110. PMID: 31240236; PMCID: PMC6441782.
4. Huh K, Chung DR, Ha YE, Ko JH, Kim SH, Kim MJ, Huh HJ, Lee NY, Cho SY, Kang CI, Peck KR, Song JH; Korean Antimicrobial Resistance Surveillance Network (KARS-Net) Investigators. Impact of Difficult-to-Treat Resistance in Gram-negative Bacteremia on Mortality: Retrospective Analysis of Nationwide Surveillance Data. Clin Infect Dis. 2020 Dec 3;71(9):e487-e496. doi: 10.1093/cid/ciaa084. PMID: 31994704.
5. Giannella M, Bussini L, Pascale R, Bartoletti M, Malagrinò M, Pancaldi L, Toschi A, Ferraro G, Marconi L, Ambretti S, Lewis R, Viale P. Prognostic Utility of the New Definition of Difficult-to-Treat Resistance Among Patients With Gram-Negative Bloodstream Infections. Open Forum Infect Dis. 2019 Dec 12;6(12):ofz505. doi: 10.1093/ofid/ofz505. PMID: 31858018; PMCID: PMC6916520.
6. Karlowsky JA, Lob SH, Raddatz J, DePestel DD, Young K, Motyl MR, Sahm DF. In Vitro Activity of Imipenem/Relebactam and Ceftolozane/Tazobactam Against Clinical Isolates of Gram-negative Bacilli With Difficult-to-Treat Resistance and Multidrug-resistant Phenotypes-Study for Monitoring Antimicrobial Resistance Trends, United States 2015-2017. Clin Infect Dis. 2021 Jun 15;72(12):2112-2120. doi: 10.1093/cid/ciaa381. PMID: 32246147.