IMI/REL Effective Against Multidrug-Resistant P aeruginosa and Enterobacteriaceae, Including Carbapenem-Resistant K pneumoniae

A quartet of posters presented at the 2018 ASM Microbe Meeting has firmly established the prowess of imipenem in combination with relebactam (IMI/REL) against isolates of multidrug-resistant (MDR) non-Proteeae Enterobacteriaceae, including Klebsiella pneumoniae carbapenemase (KPC)-positive Enterobacteriaceae, and supports the continued development of the drug combination for MDR Pseudomonas aeruginosa. IMI/REL was effective against isolates from the United States and Europe.

“Data from the SMART presentations at ASM Microbe collectively highlight the potent in vitro activity of IMI/REL against MDR P aeruginosa and MDR and KPC-positive Enterobacteriaceae in both the United States and in Europe. Although many clinicians and researchers have expressed their excitement about the in vitro activity of IMI/REL versus KPC-producing Enterobacteriaceae, they are equally excited about the in vitro activity against MDR P aeruginosa,” said Daryl DePestel, PharmD, research scientific director, Infectious Diseases/Vaccines, Merck Research Laboratories, Grand Rapids, Michigan.

The presenter of the 4 posters was Sibylle Lob, MD, MPH, of IHMA, Inc. The posters included findings of isolates collected from 2015 through 2017 as part of the Study for Monitoring Antimicrobial Resistance Trends (SMART) surveillance program.

The data were collected from 25 US and 50 European hospitals. Each hospital collected up to 250 consecutive gram-negative pathogens each year for 3 years. The tally comprised 100 lower respiratory tract isolates all 3 years, 100 isolates from intra-abdominal infections (IAIs) in 2015 and 2016, with 75 in 2017, and 50 isolates from urinary tract infections (UTIs) in 2015 and 2016, with 75 in 2017.

Minimal inhibitory concentrations were determined for 9,296 and 21,258 Enterobacteriaceae isolates from the United States and Europe, respectively, and for 2,733 and 4,107 P aeruginosa US and European isolates, respectively. An IMI susceptible breakpoint of 1 µg/mL was applied to the antibiotic combination for Enterobacteriaceae and K pneumoniae, with 2 µg/mL used for P aeruginosa. REL was always tested at 4 µg/mL in the drug combination.

An isolate resistant to 3 or more of 8 sentinel drugs—amikacin, aztreonam, cefepime, ceftazidime, ciprofloxacin, colistin, IMI, and piperacillin-tazbactum—was deemed MDR.

In the US isolates, the most common non-Proteeae Enterobacteriaceae were Escherichia coli followed by K pneumoniae and Enterobacter cloacae. Their overall susceptibility to IMI/REL was 98.8%, followed by amikacin (99.3%), imipenem (95.7%), and colistin (92.1%). The remainder displayed <90% susceptibility.

The overall susceptibility of IMI/REL to MDR non-Proteeae Enterobacteriaceae was 97.3%, followed by amikacin (95.7%) and colistin (91.5%), with the remainder <90%. The overall susceptibility of the KPC-positive Enterobacteriaceae to IMI/REL was 92.9%, followed by colistin (84.7%) and amikacin (83.7%). The next, ciprofloxacin, displayed only 20.4% susceptibility.

Switching to Europe, the most common non-Proteeae Enterobacteriaceae were also E coli followed by K pneumoniae and E cloacae. Their overall susceptibility to IMI/REL was 96.6%, followed by amikacin (97.3%), imipenem (93.7%), and colistin (92.5%), with the remainder <90%. The overall susceptibility of IMI/REL to MDR non-Proteeae Enterobacteriaceae was 88.3%, which was comparable to amikacin (88.4%). Both trailed colistin (89.6%). After imipenem (80.5%), susceptibility was markedly less. The overall susceptibility of the KPC-positive Enterobacteriaceae to IMI/REL was 96.8%, followed by colistin (67.1%) and amikacin (47.0%). The remainder, including imipenem, were inactive.

Considering next the MDR isolates, about one-quarter of the US isolates were resistant to 5 of the 8 sentinel drugs and 20% of the European isolates were resistant to 6 of the 8 drugs, compared to 96% of the KPC-positive Enterobacteriaceae isolates in both geographic locales. The IMI/REL combination was active against >90% of the US MDR isolates, except those resistant to 7 or all of the sentinel drugs, and against >95% of the European isolates, except those resistant to 6 or more of the sentinel drugs.

For P aeruginosa US isolates, the overall susceptibility to IMI/REL was 93.7%, compared with <77% to the β-lactam comparator antibiotics. IMI/REL activity against MDR P aeruginosa was 80.5%, which was exceeded only by colistin (98.9%) and amikacin (89.1%). Susceptibility to imipenem alone was only 36.6%, with the other β-lactam comparators being <26%. IMI/REL displayed >90% activity against isolates resistant to 3 or 4 of the 8 sentinel drugs, and >80% activity against those resistant to 5 drugs. The activity of the comparators was approximately 20-80% less, depending on the MDR level.

For P aeruginosa isolates from Europe, the overall susceptibility to IMI/REL was 89.6%, compared with <73% to the β-lactam comparator antibiotics. IMI/REL activity against MDR P aeruginosa was 68.7%, similar to amikacin (69.8%). Colistin ranked first (98.5%). Susceptibility to imipenem was only 25.2%. Susceptibility to the other β-lactam comparators was<18%. IMI/REL displayed >80% activity against isolates resistant to 3 to 5 of the 8 sentinel drugs, with the comparators displaying approximately 20% to 80% less activity, depending on the MDR level.

The 4 poster presentations provide ample evidence of the potential of IMI/REL as a therapeutic option for treating patients with infections caused by multidrug-resistant P aeruginosa and MDR Enterobacteriaceae, especially against those producing KPC enzymes.

“IMI/REL has demonstrated broad-spectrum Gram-negative in vitro activity; however, it offers the most promise for multidrug-resistant Gram-negative pathogens, such as carbapenem-resistant P aeruginosa and CRE, including KPC-producing K pneumoniae, while still providing in vitro activity against extended-spectrum β-lactamase-producing Gram-negatives as well. All 3 pathogens have been designated as urgent (CRE) or serious (MDR P aeruginosa and ESBLs) threats by the US Centers for Disease Control and Prevention and designated as priority 1, critical on the World Health Organization priority pathogens list for R&D of new antibiotics,” said Dr. DePestel.

Merck initiated SMART, one of the world’s largest antimicrobial resistance surveillance studies, in 2002, with the aim to determine the in vitro antibiotic resistance of gram-negative clinical isolates, initially from IAIs and subsequently including IAIs and UTIs, with a particular focus on carbapenems and ESBLs. SMART consists of 217 sites in 63 countries encompassing all major global regions.

Funding was provided by Merck & Co, Inc.

DISCLOSURES

Daryl DePestel is an employee of Merck & Co., Inc, and Sibylle Lob is an employee of IHMA, Inc.

PRESENTATIONS

SATURDAY-650 Activity of Imipenem-Relebactam against Multidrug-Resistant and KPC-positive Enterobacteriaceae from the United States — SMART 2015-2017. S. Lob1, K. Kazmierczak1, M. Hackel1, K. Young2, M. Motyl2, D. Sahm1; 1IHMA, Inc., Schaumburg, IL, 2Merck & Co., Inc., Kenilworth, NJ

SATURDAY-651 Activity of Imipenem-Relebactam against Multidrug-Resistant P. Aeruginosa from Europe -Smart 2015-2017. S. Lob1, M. Hackel1, K. Young2, M. Motyl2, S. Hawser3, S. Magnet3, M. Gueny3, D. Sahm1; 1IHMA, Inc., Schaumburg, IL, 2Merck & Co., Inc., Kenilworth, NJ, 3IHMA Europe Sàrl, Monthey, Switzerland

SATURDAY-653 Activity of Imipenem-Relebactam against Multidrug-Resistant and Kpc-Positive Enterobacteriaceae from Europe -Smart 2015-2017. S. Lob1, K. Kazmierczak1, K. Young2, M. Motyl3, S. Hawser4, S. Magnet4, V. Di Lorenzo4, D. Sahm1; 1IHMA, Inc., Schaumburg, IL, 2Merck & Co., Inc., Kenilworth, NJ, 3Merck & Co., Inc., Kenilworth, IL,

4IHMA Europe Sàrl, Monthey, Switzerland

SATURDAY-654 Activity of Imipenem-Relebactam against Multidrug-Resistant P. Aeruginosa from the U.S. -Smart 2015-2017S. Lob1, M. Hackel1, K. Kazmierczak1, K. Young2, M. Motyl2, D. Sahm1; 1IHMA,Inc., Schaumburg, IL, 2Merck & Co., Inc., Kenilworth, NJ

Brian Hoyle, PhD, is a medical and science writer and editor from Halifax, Nova Scotia, Canada. He has been a full-time freelance writer/editor for over 15 years. Prior to that, he was a research microbiologist and lab manager of a provincial government water testing lab. He can be reached at hoyle@square-rainbow.com.