Carbapenem-resistant Enterobacteriaceae (CRE), Acinetobacter baumannii (CRA), and Pseudomonas aeruginosa (CRPA), 2018

Carbapenem-resistant Enterobacteriaceae (CRE), Acinetobacter baumannii (CRA), and Pseudomonas aeruginosa (CRPA) are Gram-negative bacilli that most commonly occur among patients with significant healthcare exposures, co-morbid conditions, invasive devices, and those who have received extended courses of antibiotics. Invasive infections caused by CRE, such as carbapenem-resistant Klebsiella pneumoniae, are associated with higher morbidity and mortality than those caused by carbapenem-susceptible Enterobacteriaceae. Carbapenem-resistant A. baumannii (CRA) is recognized as one of the leading causes of healthcare-associated infections worldwide, and is associated with high mortality rates and unfavorable clinical outcomes. Invasive infections caused by CRPA are associated with higher morbidity and mortality than those caused by carbapenem-susceptible P. aeruginosa. Carbapenem resistance can be acquired through a variety of mechanisms including transmissible genetic elements. Some CRE, CRA, and CRPA carry resistance genes that produce enzymes called carbapenemases. Certain carbapenemase genes (e.g., K. pneumoniae carbapenemase [KPC]) can easily spread between bacteria of similar species. KPC is the predominant carbapenemase in the United States.

MDH first identified a KPC-producing CRE in February 2009, and began voluntary reporting, including isolate submission. In 2012, we used standardized CRE and CRA definitions developed by the EIP Multi-site Gram-negative Surveillance Initiative (MuGSI), and initiated active laboratory- and population-based surveillance in Hennepin and Ramsey Counties. This surveillance includes all isolates of A. baumannii, Escherichia coli, Enterobacter spp., or Klebsiella spp. from normally sterile sites or urine that are resistant to imipenem, meropenem, doripenem, or ertapenem using current Clinical and Laboratory Standards Institute (CLSI) breakpoints (ertapenem excluded for Acinetobacter isolates). An incident case is defined as the first eligible isolate of each species collected from a Hennepin or Ramsey County resident in 30 days. Statewide CRE surveillance was initiated in 2016 and includes Citrobacter spp. as well as E. coli, Enterobacter spp. and Klebsiella spp. The PHL tested all isolates for carbapenemase production using either a phenotypic assay (carbapenem inactivation method [CIM], modified carbapenem inactivation method [mCIM], or CarbaNP), or a PCR targeting KPC and NDM genes.

Other carbapenemases (e.g., New Delhi metallo-β-lactamase [NDM], Verona integron-encoded metallo-β- lactamase [VIM oxacillinase-48 [OXA- 48]) are more frequently identified in other countries. Resistance can also be acquired through the production of a β-lactamase effective against third generation cephalosporins (e.g., AmpC β-lactamases or extended-spectrum β-lactamases [ESBLs]) when combined with porin mutations that prevent carbapenem antibiotics from entering the cell.

MDH first identified a KPC-producing CRE in February 2009, and began voluntary reporting, including isolate submission for all Enterobacteriaceae and A. baumannii resistant to imipenem, meropenem, doripenem, or ertapenem using Clinical and Laboratory Standards Institute (CLSI) breakpoints (ertapenem excluded for Acinetobacter isolates). In 2012, MDH used standardized EIP CRE and CRA definitions and initiated active laboratory- and population-based surveillance in Hennepin and Ramsey Counties. As a subset of statewide reporting, this surveillance includes all isolates from normally sterile sites or urine of the three most common types of CRE (Escherichia coli, Enterobacter spp., or Klebsiella spp.) and A. baumannii that are resistant to imipenem, meropenem, or doripenem. An incident case is defined as the first eligible isolate of each species collected from a Hennepin or Ramsey County resident in 30 days. In 2016, MDH initiated statewide CRE surveillance. MDH also tracks other Enterobacteriaceae including, but not limited to Morganella spp., Proteus spp., and Providencia spp. The PHL tests all CRE isolates for carbapenemase production using a phenotypic assay (modified carbapenem inactivation method [mCIM] or CarbaNP), and conducts PCR on isolates with a positive phenotypic test for KPC, NDM, OXA-48-like, VIM, and IMP genes. All CRA isolates are tested by PCR for KPC, NDM, OXA- 48, VIM, and IMP genes, along with Acinetobacter-specific OXA genes (OXA-23, OXA-24, and OXA-58).

In 2018, 517 CRE incident cases representing 486 patients were identified from Minnesota residents; the most common cases were Enterobacter spp. (239) and Klebsiella spp. (124), followed by E. coli (70), Citrobacter spp. (32), Serratia spp. (23), Proteus spp. (11), Providencia spp. (7), Morganella spp. (5), and other Enterobacteriaceae (6). Among 517 incident cases, there were 122 CRE incident cases (representing 118 patients) reported among residents of Hennepin and Ramsey Counties. Among these 122, 62 (51%) were Enterobacter spp., 35 (29%) Klebsiella spp., and 25 (20%) were E. coli. KPC was identified in 4 (3%); all were E. cloacae. CRE was most frequently isolated from urine (116), followed by blood (2) and other sites (4). We identified 10 additional surveillance cases (from 9 patients) through colonization screening. Among surveillance cases, there were 4 K. pneumoniae, 2 E. cloacae, and 2 E. coli isolates harboring carbapenemases (NDM [5], KPC [3], and OXA-48 [1]).

Among the 517 incident cases, 44 (9%) were carbapenemase-producing organisms. Twenty-seven (61%) cases (from 23 patients) were KPC positive (E. cloacae [13], K. pneumoniae [7], K. oxytoca [1], C. freundii [5], and E. coli [1]). Of note, 1 case was positive for 2 different organisms producing KPC in the same calendar year. Five incident cases (from 5 patients) were NDM positive (E. coli [3], K. pneumoniae [1], and K. aerogenes [1]). Two NDM-positive cases had healthcare exposure outside of the United States (India). Seven cases (from 7 patients) were OXA-48 positive (E. coli [5] and K. pneumoniae [2]) and 5 cases (from 5 patients) were IMP positive (P. rettgeri [3], P. vulgaris [1], and M. morgannii [1]). For colonization screening, 7 cases (78%) had healthcare exposure outside of the United States or from an area in the United States where carbapenemases are more common.

Among 40 Minnesota residents with carbapenemase-producing isolates, the median age was 61 years (range, 3 to 94); 21 (53%) were female; 16 (40%) were residents of Hennepin or Ramsey County, 4 were residents of Anoka County, and 2 residents each were of Dakota, Scott, and Washington Counties. Seventeen (43%) were inpatients at the time of specimen collection, 13 (33%) were in outpatient settings, 7 (18%) were in long-term acute care hospitals, and 3 (8%) were in long-term care facilities. Urine (27) was the most common isolate source followed by sputum (4), wound (3), blood (3), and other sites (3).

Detection of NDM and OXA-48 serve as a reminder to clinicians that assessing travel history to identify receipt of healthcare outside the United States is a critical component of early detection of CRE isolates with carbapenemases that are less common in the United States. In April 2019, MDH released recommendations for admission colonization screening to detect carbapenemase-producing organisms (CPO). In line with CDC recommendations, MDH strongly recommends that Minnesota hospitals screen on admission patients who received healthcare abroad in the last 12 months; healthcare abroad includes ambulatory surgery, hemodialysis, or an overnight stay. Furthermore, MDH recommends Minnesota hospitals consider screening patients on admission who received healthcare in the U.S. regions of Chicago, New Jersey, and New York City where CPO are more common.

In 2018, CDC released the Containment Strategy which provides guidance when responding to cases of novel or rare multidrug-resistant organisms (MDROs) including CPOs. Novel or rare MDROs are epidemiologically important because these organisms cause severe, difficult-to-treat infections, and have the potential to spread within healthcare settings. MDH utilizes the Containment Strategy in response to all single cases of carbapenemase-producing CRE, CRA, and CRPA. This rapid and aggressive action includes prompt identification of the organism, notification and investigation with healthcare facilities, and response or “containing the spread” in an effort to slow the spread of novel or rare MDROs in Minnesota.

In 2018, 20 CRA incident cases representing 15 patients were identified from clinical cultures among Minnesota residents. Urine (7) was the most common isolate source followed by wound (5), sputum (4), other sites (3), and blood (1). Eleven (55%) were hospitalized at the time of culture collection. Other CRA isolates were collected from patients in longterm care facilities (4), outpatient settings (3), and long-term acute care hospitals (2). Three CRA isolates possessed genes for carbapenemase production (2 OXA-23, 1 OXA-24). Of 20 CRA incident cases, 7 incident cases were reported for MuGSI and isolated from urine (5), wound (1), and blood (1). None were found to harbor a carbapenemase.

Active laboratory- and population based surveillance for CRPA was initiated August 1, 2016 in Hennepin and Ramsey Counties as part of MuGSI and ended July 31, 2018. This surveillance included all CRPA isolates collected from normally sterile sites, wounds, urine, sputum, throat cultures from cystic fibrosis (CF) patients, or other lower respiratory sites that are resistant to imipenem, meropenem, or doripenem using current CLSI breakpoints. An incident case was defined as the first report of CRPA, or a subsequent report of CRPA ≥ 30 days after the last incident report. The PHL tested all isolates submitted in the 2018 surveillance year (August 1, 2017-July 31, 2018) for carbapenemase production. Only 7 CRPA isolates (from 4 patients) were carbapenemase-producers (IMP [1], VIM [1]); 2 isolates were found, by whole genome sequencing, to be carrying potentially inducible genes (OXA-50 and OXA-2/OXA-50/PDC-7) capable of hydrolyzing carbapenems. Since there is an extremely low percentage (<1%) of CRPA isolates found to be carbapenemase-producers, the PHL has discontinued surveillance testing of CRPA isolates for carbapenemase production, but will perform testing on submitted isolates upon request of the submitting facility or clinical laboratory.

In the 2018 surveillance year, 801 CRPA incident cases representing 568 patients were identified from clinical cultures among Minnesota residents. Of 801 incident cases, 440 cases from 279 unique patients were reported in Hennepin and Ramsey County residents. Urine (268) was the most common source, followed by sputum (52), wounds (18), and lower respiratory sites (14). Among the 279 patients, median age was 58 years (range, <1 to 98); 210 (75%) were white, 31 (11%) were black, 8 (3%) were Asian/Pacific Islander, and 30 (11%) were of unknown race. Ninety-six (34%) were inpatient at the time of specimen collection including 36 patients who had their culture collected in the intensive care unit, 105 (38%) were outpatient, 34 (12%) were in the emergency department, 25 (9%) were in a long-term acute care hospital, and 19 (7%) were in a longterm care facility. More than half (144) were hospitalized within 30 days

• For up to date information see>> Carbapenem-resistant Enterobacteriaceae (CRE), Carbapenem Resistant Pseudomonas aeruginosa (CRPA)
• Full issue>> Annual Summary of Communicable Diseases Reported to the Minnesota Department of Health, 2018