Gram-Negative Bacteria Harboring Multiple Carbapenemase Genes, United States, 2012–2019

Reports of organisms harboring multiple carbapenemase genes have increased since 2010. During October 2012–April 2019, the Centers for Disease Control and Prevention documented 151 of these isolates from 100 patients in the United States. Possible risk factors included recent history of international travel, international inpatient healthcare, and solid organ or bone marrow transplantation.

As part of routine public health investigations, health departments reviewed medical records and laboratory reports for patient demographic data and risk factors for exposure. We conducted descriptive analyses using SAS version 9.4 (https://www.sas. com) and calculated Pearson χ 2 score using SPSS Statistics 21.0 (IBM, https://www.ibm.com).
During January 2010-April 2019, a total of 151 multi-CPO isolates, including those from 105 incident cases, were identifi ed in 100 unique patients; the fi rst case was identifi ed in October 2012 (Table 1; Appendix Tables 1,2 WGS was conducted on 46 isolates from incident cases, identifying 6 sequence types of Enterobacter cloacae, 9 of Escherichia coli, and 11 of K. pneumoniae. WGS identified 21 isolates harboring bla NDM-1 , 16 harboring bla NDM-5 , 16 harboring bla OXA-181 , and 11 harboring bla KPC-3 (Appendix Table 2). In total, 8 incident cases were associated with 2 separate clusters at acute care hospitals.
The median age of patients at the time of multi-CPO identification was 63 years (range 2-94 years). Among 93 incident cases with available data, 62 (66.7%) occurred in patients who had traveled internationally in the 12 months before their incident culture. Among patients with a history of international travel, most (89.5%) had received inpatient healthcare while abroad. Association with international travel varied by carbapenemase combination; among 59 incident cases with available data that harbored bla NDM and bla OXA-48-like , 47 (79.7%) occurred in patients who reported international travel; only 5/19 (26.3%; p<0.01) incident cases that harbored bla KPC and bla NDM occurred in patients who reported international travel. Among the 80 incident cases with available data, 14 (17.5%) occurred in patients with a history of solid organ or bone marrow transplantation before their incident culture ( Table 2).
Multi-CPOs in this convenience sample were identified in many states and included diverse organisms, sequence types, and carbapenemase gene combinations and variants, suggesting that clonal spread is not responsible for their emergence. Variants harboring bla KPC-4 and bla NDM-4 , which are uncommon in the United States, were identified (9)(10)(11). Most incident cases of CROs harboring multiple carbapenemase genes occurred in patients who had a recent history of international travel and inpatient healthcare outside the United States; we also identified history of solid organ or bone marrow transplant as a potential risk factor.
Receiving healthcare abroad and, more recently, international travel without medical care are risk factors for acquiring carbapenemase-producing organisms among patients in the United States (9). However, in this study, one third of cases occurred in persons without known recent travel outside the United States. For some carbapenemase combinations, such as isolates harboring bla KPC and bla NDM, most cases occurred in patients who had not recently traveled internationally. In addition, identifying facility clusters raises further concerns about dissemination of these multidrug-resistant organisms among healthcare facilities in the United States.
The emergence of multi-CPOs has clinical, laboratory testing, and public health implications. The ceftazidime/avibactam, meropenem/vaborbactam, and imipenem/cilastatin/relebactam combination therapies have increased treatment options for CREs that produce KPC and OXA-48-like carbapenemases; growth in the proportion of isolates that co-harbor   bla NDM jeopardizes the usefulness of these therapies. We noted 1 P. aeruginosa isolate harboring bla NDM-1 and bla IMP-1 ; this isolate was panresistant to all antimicrobial drugs tested (12). A high proportion (17.5%) of cases occurred among patients with history of solid organ or bone marrow transplantation before their index culture, a population for whom CRO infections are associated with worse outcomes than patients without transplants (13,14). The first limitation of our analysis is that these data represent a passively reported convenience sample during a period in which multiple changes in testing practices, including the establishment of the AR Lab Network, occurred. For this reason, we cannot determine whether multi-CPOs became more common during the evaluation period. Second, CROs from patients with a history of healthcare abroad might have been selected for mechanism testing, biasing detection toward this risk factor; bias might have been more influential early in the investigation period, when testing resources were limited. Finally, this analysis did not systematically document outpatient healthcare exposures and residence in long-term care facilities, which also might be relevant sources of exposure; 1 case in this analysis was associated with invasive urologic procedures abroad (7).

Conclusions
Multi-CPOs in healthcare facilities are an emerging concern in the United States. Although hospitalization outside the United States was the most common risk factor, we found a substantial proportion of cases that were probably acquired in healthcare facilities in the United States. Several measures might slow further spread. First, screening patients who were recently hospitalized outside the United States can help prevent additional introductions of carbapenemase genes not commonly found in the United States. Second, molecular testing to identify carbapenemase genes should not use hierarchical algorithms. Finally, when a multi-CPO is identified, public health officials should assess for potential transmission (https://www.cdc.gov/ hai/containment/guidelines.html).