Regional Outbreak of Multidrug-Resistant Klebsiella Pneumoniae Carbapenemase-Producing Pseudomonas Aeruginosa

Abstract

Klebsiella pneumoniae carbapenemase-producing P. aeruginosa (KPC-CRPA) are rare in the U.S. An outbreak of KPC-CRPA was investigated in Texas using molecular and epidemiologic methods and identified 17 cases of KPC-CRPA. The isolates were genetically related and harbored the emerging P. aeruginosa multilocus sequence type 235, the first in the U.S.

Background

Carbapenem resistant-Pseudomonas aeruginosa (CRPA) and Klebsiella pneumoniae carbapenemase (KPC)-producing bacterial infections are rapidly emerging in the U.S.^1,2. Outbreaks of KPC-producing organisms are challenging to control and often spread in acute and long-term care facilities^2,3. KPC-producing organisms are associated with high mortality, attributing to both higher all-cause in-hospital and infection-related mortality ^4,5. Infections caused by KPC-CRPA are extensively resistant to multiple antibiotics ⁶, more difficult to treat, and complicate clinical management of patients^7,8. KPC-producing CRPA is rare in the U.S.⁸. In May and June 2018, cases of KPC-CRPA involving multiple counties in the Houston region of Texas were identified. Due to the unusual nature of such infections, an outbreak investigation was conducted.

Methods

The study utilized surveillance data from health departments in the Houston region and approved by the institutional review board of the University of Texas Health Science Center, Houston, Texas. The Houston Health Department and Texas Department of State Health Services laboratories perform resistance mechanism testing on carbapenemase-producing organisms, including P. aeruginosa, as part of CDC’s antibiotic resistance laboratory network. CRPA clinical isolates showing unusual resistance are submitted to the laboratories by providers or commercial laboratories in the region.

From May 2018 to May 2019, KPC-CRPA outbreak investigation was conducted in the Houston region. Cases were defined as patients or residents with KPC-CRPA from surveillance or clinical cultures. Point prevalence studies (PPS) were conducted at the healthcare facilities where the initial cases had overlapping stays in the previous six months. PPS, contact tracing, and admission screening were conducted using rectal swabs. Repeated PPS were conducted at the facilities until two rounds of KPC-negative results were obtained. The CRPA isolates were initially analyzed by Modified-Hodge test for carbapenemase identification followed by PCR and pulsed-field gel electrophoresis (PFGE), including similarity check by dice comparison. In addition, core-genome multilocus sequence typing (cgMLST) was performed on the KPC-CRPA isolates at the CDC laboratory in Atlanta, Georgia. The clinical data, demographics, and prior laboratory tests were abstracted from medical records. In addition, multiple onsite infection control assessments were conducted at the facilities that had overlapping patient stays.

Results

Four KPC-CRPA cases were identified from different healthcare facilities across the region in May and June 2018. A total of 10 facilities were identified to have been potentially exposed, which included a long-term acute care hospital (LTACH), long-term care facilities (LTCF), three acute care hospitals (ACH), an outpatient wound care centers, and a physician’s office. Average age of the initial cases (3 females and 1 male) identified with KPC-CRPA was 65 years. None of them had a history of international travel in the last 12 months. The first case was identified from the sputum culture of a 65-year-old woman with previous history of admissions to LTACH, LTCF and ACH. The patient died at the time the investigation was undergoing. The second patient was a current nurse who had sought care at an outpatient clinic for skin lesions. This patient declined to provide recent admission history or visit to healthcare facilities in the region. The third case was a 75-year-old man receiving wound care at home and multiple admissions to the LTACH. The fourth case was identified at an ACH from urine culture and had admission to LTACH and LTCF. Overall, the patients were mostly older, had multiple comorbidities, and the majority of them had wound care or debridement and endotracheal tubes at the healthcare facilities. Table 1 shows the number of swabs collected and KPC-CRPA cases identified during the PPS at the LTACH, LTCF, and ACH. Overall, 13 additional cases were identified during PPS and admission screenings at the three facilities. Three KPC-positive patients died during the period of the investigation while five more were reported dead following discharge.

Table 1.

(A) Characteristics of the initial cases of KPC-CRPA, May-June 2018 in Texas and (B) Summary of the findings from the point prevalence studies and admission screenings.

A
Age (years)	Sex	Specimen collection date	Specimen source	Resistant Mechanism	Organism	Resistance	Sensitive	Mcr
65	F	5/26/2018	Sputum	KPC	CRPA	Aztreo, Cefe, Cefta. Imip, Merop, Piper-Tazo	Colistin	MCR-1/2(−)
76	F	6/1/2018	Urine	KPC	CRPA	Aztreo, Cefe, Cefta. Imip, Merop, Piper-Tazo	Colistin	MCR-1(−)
45	F	6/15/2018	Tissue	KPC	CRPA	Aztreo, Cefe, Cefta. Imip, Merop, Piper-Tazo	Colistin	MCR-1/2(−)
75	M	6/15/2018	Blood	KPC	CRPA	Aztreo, Cefe, Cefta. Imip, Merop, Piper-Tazo	Colistin	MCR-1/2(−)
KPC, Klebsiella pneumoniae carbapenemase; CRPA, carbapenem-Resistant Pseudomonas aeruginosa; Mcr. mobile Colistin resistance gene; Aztreo. aztreonam; Cefe, cefepime; Cent, ceftazidime; Imip, imipenem; Merop, meropenem, Piper-Tazo, piperacillin-tazobactam.

B
Healthcare Facilities	Number of PPS conducted	Total number of swabs collected	Number of KPC-CRPA	%
LTACH	5	54	5	9.3
LTCF	2	35	1	2.8
ACH	3	34	5	14.7

The antibiotic resistance mechanisms identified in the bacterial isolates were associated with KPC in all cases. The KPC-CRPA isolates identified showed resistance to aztreonam, cefepime, ceftazidime, imipenem, meropenem, and piperacillin-tazobactam (Table 1). Further analysis at the CDC showed that the CRPA isolates exhibited pan-resistance. PFGE analysis showed distinct patterns with 90% relatedness, and the isolates from all the cases showed 100% similarity by dice comparison. Also, PFGE patterns of the KPC-CRPA isolates identified from the PPS also matched that of the isolates collected from the initial cases. cgMLST analysis revealed that the isolates were genetically related and clustered with the emerging clonally related epidemic multilocus sequence type 235 (ST235) (Figure 1). Core genome single-nucleotide variant phylogenomic analysis indicated that the identified KPC-CRPA isolates were 89.95% related to each other. Interestingly, a unique strain of KPC-CRPA recovered from one of the patients matched the emerging sequence type (ST 298) lineage.

Figure 1.

Phylogenetic tree of healthcare-associated KPC-producing Pseudomonas aeruginosa ST-235 isolates collected from the patients. Core-genome multilocus sequence typing was performed on the KPC-CRPA isolates at the CDC laboratory in Atlanta, Georgia.

Infection control assessments at the LTACH and LTCF found lapses in infection prevention and environmental cleaning, but the sink hygiene assessments revealed no significant shortcomings. At the ACH, serious infection control breaches were identified. These include, not appropriately donning and doffing personal protective equipment like gloves, not performing proper hand hygiene when entering and exiting patient rooms, poor wound care practices, inappropriately touching patient environment while changing dress during wound care, and inadequate high touch surface cleaning in daily and terminal cleaning.

Discussion

We described an emerging threat and regional spread of KPC-CRPA, a rare occurrence in the U.S. Four initial cases of KPC-CRPA were identified from different healthcare facilities through surveillance of clinical isolates. Further investigation uncovered 13 additional cases at three healthcare facilities. The study also revealed an emergence of clonally related KPC-producing Pseudomonas aeruginosa ST235, the first cluster associated with KPC-CRPA in the U.S. A unique case of KPC-CRPA isolates with ST298 was identified. Molecular and genetic analysis of the isolates revealed that the KPC-CRPA were genetically related, suggesting a potential transmission of CRPA within and between the healthcare facilities in the region. The majority of the patients had overlapping stays at LTACH, LTCF, and ACH. The case of the nurse, however, was not epidemiologically linked to any of the other cases. Although, the emergence of carbapenemase-producing Pseudomonas aeruginosa was first reported in Texas in 2001 ⁹ and Florida in 2010 ¹⁰, incidence of KPC-CRPA has generally remained rare in the U.S. ⁸.

Lapses in infection control practices at each facility were noted, suggesting that indirect patient-to-patient transmission through contaminated healthcare workers or medical equipment likely played a role in the outbreak. The genetic relatedness of the isolates also suggests communal exposure and transmission networks. One limitation of this study is that we did not attempt to identify close contacts of the initial cases who were no longer hospitalized or residing at the facilities, and this may have resulted in underestimation of the total number of cases of KPC-CRPA and perhaps the number of potentially exposed facilities. Strengthening implementation of best practices of infection prevention and control in healthcare facilities is critical in containing emerging multidrug-resistant organisms. In addition, our finding highlights the need for increased surveillance targeting CRPA strains.