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Combination Therapy For CRE Offers No Advantages Over Monotherapy

These deadly infections are often treated with combination therapy, but a new study finds no significant difference in outcomes when using a 2-drug regimen versus a single-drug regimen.

Thousands of infections occurring in hospital patients every year are due to carbapenem-resistant Enterobacteriaceae (CRE). These gram-negative bacteria are so deadly that the World Health Organization (WHO) recently issued the first ever set of guidelines for preventing and controlling their spread; in fact, it categorized these infections as among those that cause the greatest risk to human health. Recognizing the severity of CRE, a team of scientists in Israel, Greece, and Italy conducted a study testing a combination therapy in humans after seeing that it performed well in in vitro studies.

Between 2013 and 2016, 406 patients in Israel, Greece, and Italy were enrolled in the study. Almost all suffered from either hospital-acquired pneumonia, ventilator-associated pneumonia, or bacteremia, as CRE typically does not manifest in healthy people. One-hundred ninety-eight patients were randomly assigned to take colistin, and 208 were randomly assigned to take a combination of colistin and meropenem. The study’s primary outcome was clinical success after 14 days of treatment, with clinical success defined as the patient remaining alive, hemodynamically stable, and with a stable or improved Sequential Organ Failure Assessment score, among other factors.

After 2 weeks of treatment, 79% of the patients treated with colistin saw clinical failure compared with 73% of patients treated with the colistin-meropenem combination, a statistically insignificant difference. By the end of the study, 33% of the patients had died. Most of the rest saw no improvement in their SOFA scores, or had experienced a decline.

Although the clinical failure rates were essentially the same between the 2 groups, they did have somewhat different experiences while on the drug regimens. Patients taking combination therapy were weaned more quickly from a ventilator than patients taking colistin only. Those in intensive care who survived were discharged more quickly in the colistin-only cohort. Few medication side effects were reported, but patients taking combination therapy reported significantly more instances of diarrhea (27% in the combination group versus 16% in the colistin-only group). Patients on the combination therapy also experienced lower rates of renal failure than those in the colistin-only group.

“Carbapenems cause Clostridium difficile (C. difficile) [infections],” Mical Paul, MD, director of infectious diseases at Rambam Medical Center in Haifa, Israel, and an author of the study, told Contagion® when asked why 1 group was disproportionately affected by diarrhea. “These cases might represent undiagnosed C. difficile or just antibiotic-associated diarrhea related to carbapenems. We do not have a plausible explanation for the difference in renal failure. Colistin is nephrotoxic, but the same dosing of colistin was used in both study arms.”

The scientists were motivated to address the question of whether combination therapy is superior to monotherapy in light of its popularity. “People use this combination therapy very frequently in the belief that the combination is more effective than colistin monotherapy,” Dr. Paul said, referring to numerous positive results in in vitro studies. Because most of the patients in this study had Acinetobacter infections, “we do not provide a solid answer to the question of colistin-meropenem versus colistin alone for CRE. However, we show how important it is to test these interventions in a randomized design before implementing them for clinical use.”

According to Dr. Paul, CRE is particularly common in Spain, Italy, Eastern Europe, Greece, the Middle East, India, China, and parts of the United States. She recommends that health care providers’ first move should be to treat CRE with colistin only: “[They should] reserv[e] carbapenems for carbapenem-susceptible bacteria that are resistant to other narrower-spectrum antibiotics. Unnecessary use of carbapenems leads to more carbapenem-resistance development.”

Laurie Saloman, MS, is a health writer with more than 20 years of experience working for both consumer- and physician-focused publications. She is a graduate of Brandeis University and the Medill School of Journalism at Northwestern University. She lives in New Jersey with her family.