Multi-site Gram-negative Surveillance Initiative

Overview

Gram-negative bacteria cause infections including pneumonia, bloodstream infections, wound or surgical site infections, and meningitis in healthcare and community settings. Selected gram-negative bacteria are becoming resistant to all or nearly all antibiotics, meaning that patients with infections from these bacteria might have few or no treatment options. Infections due to highly resistant bacteria, such as carbapenem-resistant Enterobacterales (CRE), carbapenem-resistant Acinetobacter baumannii (CRAB), and carbapenem-resistant Pseudomonas aeruginosa (CRPA), are mainly associated with healthcare settings and have high death rates, but some resistant bacteria, such as extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales, have reportedly increased as a cause of human infection in the community. Data from this tracking project will help scientists understand illness caused by these bacteria and help shape prevention strategies to contain and prevent the spread of resistant bacteria.

In response to growing concerns about resistant gram-negative bacteria, the Emerging Infections Program’s (EIP) Healthcare-Associated Infections Community Interface (HAIC) activity started the Multi-site Gram-negative Surveillance Initiative (MuGSI) in 2011 to:

• Determine the extent of selected resistant gram-negative bacteria in the United States
• Measure trends of disease over time
• Identify people most at risk for illness from these bacteria
• In addition, the project provides infrastructure that allows future research to be done on these and other Gram-negative bacteria.

Background

MuGSI initially conducted active population- and laboratory-based surveillance for CRE and CRAB; however, recent history has shown that new resistant bacteria emerge when new antimicrobials are developed. Therefore, public health surveillance for these resistant bacteria must be dynamic. Consequently, MuGSI expanded the bacteria under surveillance to include CRPA from August 2016 through July 2018; and, starting in July 2019, ESBL-producing Enterobacterales.

Surveillance Objectives

1. To evaluate the incidence of selected resistant gram-negative bacteria, and to describe changes in incidence over time.
2. To characterize the epidemiologic characteristics and risk factors associated with selected resistant gram-negative bacteria.
3. To describe resistance mechanisms and strain types among selected resistant gram-negative bacteria.

Methods:

Case Definition

Cases are defined as follows:

• CRE: carbapenem-resistant E. coli, Enterobacter cloacae complex species (i.e., E. cloacae, E. asburiae, E. bugandensis, E. cancerogenus, E. hormaechei, E. kobei, E. ludwigii, and E. nimipressuralis), and Klebsiella species (i.e., K. aerogenes, K. oxytoca, K. pneumoniae, and K. variicola) isolated from normally sterile sites or urine (Table 1) from a resident of the surveillance area.
• CRAB: carbapenem-resistant Acinetobacter baumannii complex (A. baumannii, A. baumannii complex, and A. calcoaceticus-baumannii complex [including A. calcoaceticus]) isolated from normally sterile sites or urine (Table 1) from a resident of the surveillance area. Starting in 2021, CRAB surveillance expanded at selected EIP sites to include specimens from the lower respiratory tract and wounds.
• CRPA: carbapenem-resistant P. aeruginosa isolated from normally sterile sites, urine, lower respiratory tract (LRT) specimens, wounds, or cystic fibrosis patient throat swabs from a resident of the surveillance area. HAIC CRPA surveillance ended mid-2018.
• ESBL-producing Enterobacterales: extended-spectrum cephalosporin-resistant E. coli, Klebsiella pneumoniae, Klebsiella variicola, or Klebsiella oxytoca isolated from normally sterile sites or urine (Table 1) from a resident of the surveillance area.

Table 1. Specimen sources that meet the case definition, by organism

^*Normally sterile site include the following: Blood, cerebrospinal fluid, pleural fluid, pericardial fluid, peritoneal fluid, joint/synovial fluid, bone, internal body site (lymph node, brain, heart, liver spleen, vitreous fluid, kidney, pancreas, or ovary), muscle, deep tissue or other normally sterile site

^§Lower respiratory tract specimens include: Bronchoalveolar lavage, sputum, tracheal aspirate, or other lower respiratory site

†Throat swab specimens include: CRPA cystic fibrosis patient only

¶Lower respiratory tract and wound cultures added for CRAB surveillance at selected EIP sites in 2021

Phenotypic case definitions: The minimum inhibitory concentration (MIC) and zone diameter interpretive criteria produced by the local clinical laboratory’s primary antibiotic testing methodology are used to classify isolates.

• For CRE surveillance, carbapenem resistance is defined as resistance to one or more carbapenems (doripenem, imipenem, meropenem, or ertapenem).
• For CRAB surveillance, carbapenem resistance is defined as resistance to one or more carbapenems (doripenem, imipenem, or meropenem).
• For CRPA surveillance, carbapenem resistance was defined as resistance to one or more carbapenems (doripenem, imipenem, or meropenem).
• For ESBL-producing Enterobacterales surveillance, resistance is defined as resistance to at least one extended-spectrum cephalosporin (ceftazidime, cefotaxime, or ceftriaxone) and non-resistant (i.e., susceptible or intermediate) to all carbapenems tested. The exclusion of carbapenem-resistant isolates ensures lack of duplication with existing MuGSI CRE surveillance.
• The minimum inhibitory concentration (MIC) and zone diameter interpretive criteria produced by the local clinical laboratory’s primary antibiotic testing methodology is used to classify isolates.

Case Ascertainment

Cases are identified based on the local clinical laboratory’s antibiotic susceptibility testing data. Most local clinical laboratories conduct antibiotic testing using an Automated Testing Instrument (ATI). Many of the clinical laboratories within the surveillance catchment area identify the specimen results meeting the MuGSI case definitions directly from these ATI systems.

Surveillance Areas

The MuGSI surveillance catchment area consists of selected counties in the following states: California, Colorado, Connecticut, Georgia, Maryland, Minnesota, New Mexico, New York, Oregon, and Tennessee.

Table 2. MuGSI surveillance area, by state and county, 2011-2022

¶CRPA surveillance began in August 2016 and ended in July 2018

*California started CRE surveillance in August 2017 and does not participate in CRAB surveillance

†California and Connecticut did not participate in CRPA surveillance

‡CRPA surveillance catchment area in Tennessee only included Davidson county

#ESBL surveillance began in July 2019

Surveillance strategy

The first carbapenem-resistant Enterobacterales of each species, first carbapenem-resistant Acinetobacter baumannii complex, first extended-spectrum cephalosporin-resistant Enterobacterales of each species, and first carbapenem-resistant Pseudomonas aeruginosa per patient in a 30-day period is eligible for inclusion as an incident case. The date of incident specimen collection is the date the first specimen was obtained for each organism in the 30-day period. If a new specimen meeting the case definition is collected more than 30 days after the patient’s last incident case of the same organism, it is reported as an incident case and a case report form is completed, according to the procedures described in Table 3. If a specimen was collected less than 30 days after the patient’s last incident case of the same organism, the case is categorized as a “non-incident” case and a case report form is not completed.

The process for completing case report forms may differ across the EIP sites but primarily consists of trained surveillance epidemiologists reviewing the patient’s medical records to gather information, such as patient demographic characteristics, location of specimen collection, types of infections associated with the positive specimen, underlying medical conditions, and healthcare exposures.

Table 3. Procedures for completing case report forms, by organism

*CRPA surveillance ended on July 31, 2018

Laboratory Characterization

As part of MuGSI, isolates of selected resistant gram-negative bacteria that meet the MuGSI surveillance definitions will be collected by sites and submitted to CDC in order to:

• Characterize antibiotic resistance mechanisms (i.e. phenotypic carbapenemase production, phenotypic ESBL production, and the presence of antibiotic resistance genes) associated with the bacteria under surveillance
• Evaluate antimicrobial susceptibility testing results using a reference method
• Characterize the molecular epidemiology of selected resistant gram-negative bacteria

Additionally, CDC contributes some MuGSI isolates to the AR Isolate Bank.

Publications

• Karlsson M, Lutgring JD, Ansari U, Lawsin A, Albrecht V, McAllister G, Daniels J, Lonsway D, McKay S, Beldavs Z, Bower C, Dumyati G, Gross A, Jacob J, Janelle S, Kainer MA, Lynfield R, Phipps EC, Schutz K, Wilson L, Witwer ML, Bulens SN, Walters MS, Duffy N, Kallen AJ, Elkins CA, Rasheed JK. Molecular Characterization of Carbapenem-Resistant Enterobacterales Collected in the United States. Microb. Drug Resist. 2022; ahead of print.
• Duffy N, Karlsson M, Reses HE, Campbell D, Daniels J, Stanton RA, Janelle SJ, Schutz K, Bamberg W, Rebolledo PA, Bower C, Blakney R, Jacob JT, Phipps EC, Flores KG, Dumyati G, Kopin H, Tsay R, Kainer MA, Muleta D, Byrd-Warner B, Grass JE, Lutgring JD, Rasheed JK, Elkins CA, Magill SS, See I. Epidemiology of extended-spectrum β-lactamase–producing Enterobacterales in five US sites participating in the Emerging Infections Program, 2017. Infect Control Hosp Epidemiol. 2022:1-9. doi:10.1017/ice.2021.496.
• Cameron A, Mangat R, Mostafa HH, Taffner S, Wang J, Dumyati G, Stanton RA, Daniels JB, Campbell D, Lutgring JD, Pecora ND. Detection of CTX-M-27 β-Lactamase Genes on Two Distinct Plasmid Types in ST38 Escherichia coli from Three U.S. States. Antimicrob. Agents Chemother. 2021;65 (7):e00825-21. doi:10.1128/AAC.00825-21.
• Bower CW, Fridkin DW, Wolford HM, Slayton RB, Kubes JN, Jacob JT, Ray SM, Fridkin SK. Evaluating Movement of Patients With Carbapenem-resistant Enterobacteriaceae Infections in the Greater Atlanta Metropolitan Area Using Social Network Analysis. Clin Infect Dis. 2020 Jan 1;70(1):75-81. doi: 10.1093/cid/ciz154.
• Walters MS, Grass JE, Bulens SN, Hancock EB, Phipps EC, Muleta D, Mounsey J, Kainer MA, Concannon C, Dumyati G, Bower C, Jacob J, Cassidy PM, Beldavs Z, Culbreath K, Phillips WE Jr, Hardy DJ, Vargas RL, Oethinger M, Ansari U, Stanton R, Albrecht V, Halpin AL, Karlsson M, Rasheed JK, Kallen A. Carbapenem-Resistant Pseudomonas aeruginosa at US Emerging Infections Program Sites, 2015. Emerg Infec Dis. 2019 Jul;25(7):1281-1288. doi: 10.3201/eid2507.181200.
• Karlsson M, Stanton RA, Ansari U, McAllister G, Chan MY, Sula E, Grass JE, Duffy N, Anacker ML, Witwer ML, Rasheed JK, Elkins CA, Halpin AL. Identification of a Carbapenemase-Producing Hypervirulent Klebsiella pneumoniae Isolate in the United States. Antimicrob Agents Chemother. 2019 Jun 24;63(7):e00519-19. doi: 10.1128/AAC.00519-19.
• Bulens SN, Yi SH, Walters MS, Jacob JT, Bower C, Reno J, Wilson L, Vaeth E, Bamberg W, Janelle SJ, Lynfield R, Vagnone PS, Shaw K, Kainer M, Muleta D, Mounsey J, Dumyati G, Concannon C, Beldavs Z, Cassidy PM, Phipps EC, Kenslow N, Hancock EB, Kallen AJ. Carbapenem-Nonsusceptible Acinetobacter baumannii, 8 US Metropolitan Areas, 2012-2015. Emerg Infec Dis. 2018 Apr;24(4):727-34. doi: 10.3201/eid2404.171461.
• Guh A, Bulens SN, Mu Y, Jacob JT, Reno J, Scott J, Wilson LE, Vaeth E, Lynfield R, Shaw KM, Vagnone PM, Bamberg WM, Janelle SJ, Dumyati G, Concannon C, Beldavs Z, Cunningham M, Cassidy PM, Phipp EC, Kenslow N, Travis T, Lonsway D, Rasheed JK, Limbago BM, Kallen AJ. Epidemiology of Carbapenem-Resistant Enterobacteriaceae in 7 US Communities, 2012-2013. JAMA. 2015 Oct 13;314(14):1479-87. doi: 10.1001/jama.2015.12480.
• Chea N, Bulens SN, Kongphet-Tran T, Lynfield R, Shaw KM, Vagnone PS, Kainer MA, Muleta DB, Wilson L, Vaeth E, Dumyati G, Concannon C, Phipps EC, Culbreath K, Janelle SJ, Bamberg WM, Guh AY, Limbago B, Kallen AJ. Improved Phenotype-Based Definition for Identifying Carbapenemase Producers among Carbapenem-Resistant Enterobacteriaceae. Emerg Infect Dis. 2015 Sep;21(9):1611-1615. doi: https://dx.doi.org/10.3201/eid2109.150198.
• Reno J, Schenck C, Scott J, Clark LA, Wang YF, Ray S, Vagnone P, Jacob JT. Querying automated antibiotic susceptibility testing instruments: a novel population-based active surveillance method for multidrug-resistant gram-negative bacilli. Infect Control Hosp Epidemiol. 2014 Apr;35(4):336-41. doi: 10.1086/675608.
• Shaw KM, Harper JE, Vagnone PS, Lynfield R. Establishing Surveillance for Carbapenem-resistant Enterobacteriaceae in Minnesota, 2012. Infect Control Hosp Epidemiol. 2014 Apr;35(4):451-3. doi: 10.1086/675615.
• Pereira EC, Shaw KM, Vagnone PM, Harper JE, Kallen AJ, Limbago BM, Lynfield R. Thirty-day laboratory-based surveillance for carbapenem-resistant Enterobacteriaceae in the Minneapolis-St. Paul metropolitan area. Infect Control Hosp Epidemiol. 2014 Apr;35(4):423-5. doi: 10.1086/675602.
• Pfeiffer CD, Cunningham MC, Poissant T, Furuno JP, Townes JM, Leitz A, Thomas A, Buser GL, Arao RF, Beldavs ZG. Establishment of a statewide network for carbapenem-resistant Enterobacteriaceae prevention in a low-incidence region. Infect Control Hosp Epidemiol. 2014 Apr;35(4):356-61. doi: 10.1086/675605.
• CDC. Vital signs: Carbapenem-Resistant Enterobacteriaceae. Morb Mortal Wkly Rep. 2013 Mar 5;62(9):1-6.

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