Carbapenem-resistant Enterobacterales (CRE) and Pseudomonas aeruginosa (CRPA) carrying multiple targeted carbapenemase genes

Main Points

• Carbapenem-resistant organisms (CROs) are a family of germs that are difficult to treat because they are resistant to nearly all antibiotics. Carbapenems are some of our most powerful drugs. Some of the most common CROs that can cause healthcare-associated infections include carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPA).
• Some CROs carry genes that enable the bacteria to make carbapenemase enzymes that destroy carbapenem antibiotics. These carbapenemase genes can move among bacteria, increasing the likelihood that multidrug resistance will spread. Resistance to carbapenems further reduces patient treatment options.
• The Antimicrobial Resistance Lab Network (AR Lab Network) routinely tests CROs for the presence of five targeted carbapenemase genes: KPC, NDM, OXA-48-like, IMP, and VIM.
• Although most carbapenemase gene-positive CROs (CP-CROs) carry only one of the targeted carbapenemase genes, some were found to carry more than one (i.e., multi-gene).
• Between 2018 and 2021, the AR Lab Network identified 24,364 CP-CROs among all 120,338 CRE and CRPA isolates tested. Of these 24,364 CP-CROs, 440 (1.8%) were multi-CP gene.
  • 414 (1.8%; N=23,251) CP-CRE isolates (or 0.61% of all 68,110 CRE tested) were multi-CP gene.
  • 26 (2.3%; N=1,113) CP-CRPA isolates (or 0.05% of all 52,228 CRPA tested) were multi-CP gene.
• The number of multi-CP gene CROs detected in the AR Lab Network has increased each year, from 70 in 2018 to 169 in 2021.
• Multi-CP gene CROs may pose an even higher risk to patients because antibiotic treatment options may be further limited and the risk of resistance spreading may be higher.
• Recent published literature into multi-CP gene CROs indicate that recent history of international travel, international inpatient healthcare, and solid organ or bone marrow transplantation were possible risk factors for acquiring these resistant bacteria.¹
• Continued testing of CROs in the AR Lab Network will help healthcare facilities and public health departments detect and prevent these and other emerging resistance threats.

Carbapenem-resistant Organisms

Carbapenem-resistant organisms (CROs) are an urgent public health concern.² The most common types of bacteria that can become carbapenem-resistant are Enterobacterales, Pseudomonas and Acinetobacter species. These potentially dangerous bacteria are commonly resistant to all beta-lactam antibiotics including the broad-spectrum carbapenem drugs: meropenem, imipenem, ertapenem, and doripenem. Carbapenems have often been considered the last line of defense in treating multidrug-resistant bacterial infections. Carbapenem resistance may spread at healthcare facilities and is especially dangerous to immunocompromised individuals and medically vulnerable populations.

Carbapenemase Production

One way that a germ becomes resistant to carbapenem drugs is through acquiring a gene that produces a carbapenemase, an enzyme that breaks down carbapenem antibiotics. Examples of genes that produce a carbapenemase enzyme include KPC, NDM, OXA-48, IMP, and VIM. Although most carbapenemase gene-positive CRO (CP-CRO) bacterial isolates were found to carry only one of these targeted genes, it is possible for an organism to acquire multiple genes in one germ. In fact, multi-gene carbapenem-resistant Enterobacterales (CRE) and Pseudomonas aeruginosa (CRPA) have been reported previously in other global settings.

Carbapenemase genes can travel on mobile genetic elements (e.g., plasmids), making it easier for resistance to spread between organisms and among patients, and occasionally leading to the accumulation of multiple carbapenemase genes within a single organism. As new therapies become available with activity against CP-CROs with specific types of carbapenemases but not others, the uptake of multiple carbapenemase genes and the accompanying resistance genes on the plasmids on which they travel may further limit drug treatment options, posing a serious risk for patient safety. Also, the presence of more than one of these genes may present additional risk for onward spread of resistance.

The Antimicrobial Resistance Lab Network

In the United States, antibiotic-resistant bacteria and fungi are monitored through the Antimicrobial Resistance Laboratory Network (AR Lab Network). The AR Lab Network includes labs in 50 states, plus several cities and Puerto Rico. Testing in the AR Lab Network helps us understand these resistant bacteria: their geographic location, antibiotic resistance pattern, and genetic resistance mechanisms. In turn, this information helps public health authorities and healthcare facilities to slow or stop their spread.

Multi-Mechanism Isolates Identified through the AR Lab Network

From 2018 through 2021, the AR Lab Network identified 440 (0.37%, N=120,338) multi-CP gene CRE or CRPA. These isolates carried at least two of the five targeted carbapenemase genes. The most common gene combinations were NDM and OXA-48 (44%; n=186) among CRE isolates and KPC and VIM (35%; n=9) among CRPA isolates. The number and proportion of multi-CP gene CRE isolates detected in the AR lab network increased slightly from 2018 through 2021 but the rates of detection of CP-CROs among CRE and CRPA, as well as the rate of multi-CP gene CRPA, remained more constant.

Detection of CP-CROs and multi-CP gene CROs, by year—AR Lab Network, 2018–2021

The frequency of detection of multi-gene isolates was influenced by a variety of factors, including organism type and geography. Outbreaks of multi-gene organisms have occurred in several states, helping to explain variation in multi-gene prevalence across geographic areas. Patient factors associated with increased risk of a multi-mechanism infection include a recent history of international travel, international inpatient healthcare, and solid organ or bone marrow transplantation.¹

None of the 11,616 isolates of carbapenem-resistant Acinetobacter baumannii tested in the AR Lab Network from 2018 through 2021 were found to carry more than one of the five targeted carbapenemase genes.

In recently published literature¹, the frequency of detection of multi-gene isolates was influenced by a variety of factors, including organism type and geography. Outbreaks of multi-gene organisms have occurred in several states, helping to explain variation in multi-gene prevalence across geographic areas. Patient factors associated with increased risk of a multi-mechanism infection include a recent history of international travel, international inpatient healthcare, and solid organ or bone marrow transplantation.

Continued testing of CROs in the AR Lab Network will help healthcare facilities and public health departments detect and prevent multi-CP gene CROs and other emerging resistance threats.