To the Editor—We thank Macesic and colleagues for their interest in our work. The additional data that they present in their letter adds to the growing body of knowledge regarding polymyxin resistance in multidrug-resistant gram- negative bacteria

Bonomo R.A.

van Duin D.

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Reply to Macesic et alTo the Editor—We thank Macesic and colleagues for their interest in our work. The additional data that they pres-ent in their letter adds to the growing body of knowledge regarding polymyxin resistance in multidrug-resistant gram- negative bacteria.Carbapenem-resistant Klebsiella pneu-moniae (CRKp)—or any pathogen that displays an antibiotic-resistant pheno-type—can be recovered from a patient as a result of a variety of clinical circum-stances. The most direct and intuitive way is that exposure to polymyxins will inev-itably lead to resistance to polymyxins in a certain number of cases. This is high-lighted by the experience summarized by Macesic and colleagues, in which about half of patients were treated with a poly-myxin before the detection of polymyxin resistance in CRKp. This circumstantial link between polymyxin exposure and subsequent resistance was also shown in cases of colistin resistance in Acinetobacter baumannii [1]. We agree that for a certain proportion of patients in our study, this is likely the mechanism by which polymyxin resistance arose. We also agree that evalu-ation for a period of time beyond 14 days before the index culture would have uncovered more cases with colistin expo-sure. As we reported, we were able to col-lect such data in a small subset of patients. In these 27 patients, 6 (22%) were exposed to colistin. However, even assuming that all patients with documented polymyxin exposure are examples of de novo poly-myxin resistance development, the data presented in the letter by Macesic et al and our data still leave between 51% and 78% of patients without documented exposure. Undoubtedly, limitations in electronic medical records and clinical research data collection may be at fault. Nonetheless, alternative mechanisms of spread of colis-tin resistance should be considered as well.As importantly, polymyxin-resistant CRKp may be transmitted from one patient to another or from the environment to a patient. A striking example of this mech-anism is seen in China, where polymyx-ins have not been available for clinical use. However, agricultural application presumably resulted in a favorable envi-ronment for the dissemination of plas-mid-borne mcr-1–mediated colistin resistance, which subsequently found its way into clinical isolates [2]. While we did not find any genetic evidence for mcr-1–mediated resistance. CRKp with chro-mosomally encoded polymyxin resistance may obviously also be transmitted from person to person. Furthermore, for sev-eral antibiotics, exposure to one antibiotic leads to increased resistance to another antibiotic [3].Ongoing work in the Consortium on Resistance against Carbapenems in Klebsiella pneumoniae and other Enterobacteriaceae (CRACKLE) study will hopefully shed some light on the relative contributions of resistance devel-oping within bacterial strains of antibi-otic-exposed patients vs transmission of resistant strains from one patient to the next [4]. Data such as this and the data that is being generated by Macesic and colleagues will be crucial to stem not only the rise of polymyxin resistance but more importantly of resistance to more novel anti-CRKp agents as well.NotePotential conflicts of interest. Both authors: No reported conflicts. The authors have submit-ted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manu-script have been disclosed.David van Duin1 and Robert A. Bonomo2–71Division of Infectious Diseases, University of North Carolina, Chapel Hill; Departments of  2Medicine and 3Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, 4Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, 5Division of Infectious Diseases and HIV Medicine, Department of Medicine, Departments of  6Molecular Biology and Microbiology, and  7Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OhioReferences1. Qureshi ZA, Hittle LE, O’Hara JA, et al. Colistin-resistant Acinetobacter baumannii: beyond carbap-enem resistance. Clin Infect Dis 2015; 60:1295–303.2. Liu YY, Wang Y, Walsh TR, et  al. Emergence ofplasmid-mediated colistin resistance mechanismMCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis 2016; 16:161–8.3. Tacconelli E, De Angelis G, Cataldo MA, et  al.Antibiotic usage and risk of colonization andinfection with antibiotic-resistant bacteria: a hos-pital population-based study. Antimicrob AgentsChemother 2009; 53:4264–9.4. van Duin D, Perez F, Rudin SD, et al. Surveillance of carbapenem-resistant Klebsiella pneumoniae: track-ing molecular epidemiology and outcomes through a regional network. Antimicrob Agents Chemother 2014; 58:4035–41.C O R R E S P O N D E N C ECorrespondence: D. van Duin, Division of Infectious Diseases, CB 7030, University of North Carolina, 130 Mason Farm Road, Chapel Hill, North Carolina 27599 (david_vanduin@med.unc. edu).Clinical Infectious Diseases®  2017;65(4):703–4 DOI: 10.1093/cid/cix394

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