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No advantage in adding meropenem to colistin for A. baumannii infections
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Adding meropenem to colistin does not result in better outcomes compared with colistin monotherapy in hospital patients with severe infections caused by carbapenem-resistant gram-negative bacteria, according to recently published findings.
Writing in The Lancet Infectious Diseases, researchers said the results of an open-label, randomized controlled trial in three countries contradicted previous in vitro studies that showed “various degrees of synergy and increased bactericidal activity” with polymyxin-carbapenem combinations, especially for Acinetobacter baumannii.
This was not the case among hundreds of hospital patients included in the study by Mical Paul, MD, associate professor and director of infectious diseases at Rambam Health Care Campus in Haifa, Israel, and colleagues.
“We did not observe an advantage to combination therapy with regard to survival, clinical cure, microbiological cure, or development of resistance,” Paul and colleagues wrote, although they noted that the results of their study relate mostly to A. baumannii, the dominant bacterium in their cohort.
They said the study was underpowered to address other bacteria, such as Klebsiella pneumoniae or Pseudomonas aeruginosa.
“Given the potential of carbapenem usage to promote carbapenem resistance, we recommend against the routine use of carbapenems for the treatment of carbapenem-resistant A. baumannii infections,” they wrote. “Although our study cannot provide an answer for K. pneumoniae and P. aeruginosa infections, it points to the necessity of assessing combination therapy in randomized trials before adopting it into clinical use.”
Globally, carbapenem resistance in gram-negative bacteria is increasing, according to Paul and colleagues. In the United States, the CDC has called carbapenem-resistant Enterobacteriaceae a “nightmare bacteria.” There are limited treatment options for patients with these infections, but in most places, two polymyxins — colistin and polymyxin B — are still effective.
However, “clinicians treating patients with carbapenem-resistant gram-negative bacteria express little confidence in polymyxins’ efficacy,” Paul and colleagues wrote. “The high mortality following infections caused by carbapenem-resistant gram-negative bacteria has led to the search for optimal antimicrobial combinations to maximize bacterial killing.”
For their study, Paul and colleagues recruited 406 patients at hospitals in Greece, Israel and Italy with bacteremia, ventilator-associated pneumonia, hospital-acquired pneumonia or urosepsis caused by carbapenem-nonsusceptible gram-negative bacteria. They randomly assigned the participants to receive either colistin monotherapy or colistin with meropenem. Most patients included in the study had pneumonia or bacteremia, and most of the infections were caused by A. baumannii, the researchers said. The study was conducted between Oct. 1, 2013, and Dec. 31, 2016, and the primary outcome was clinical failure at 14 days after randomization.
According to Paul and colleagues, there was no significant difference between colistin monotherapy and combination therapy, with 79% and 73% of patients in each group meeting the criteria for treatment failure, respectively. They said combination therapy increased the incidence of diarrhea and decreased the incidence of mild renal failure.
In a related editorial, Federico Perez, MD, and Robert A. Bonomo, MD, both of the Case VA Center for Antimicrobial Resistance and Epidemiology and Case Western Reserve University School of Medicine, said the results matched findings from two other randomized controlled trials of patients infected with carbapenem-resistant A. baumannii who were treated with colistin in combination with rifampicin vs. colistin alone, and a smaller trial that randomized patients to receive either colistin plus fosfomycin or colistin monotherapy.
Perez and Bonomo said the results do not “close the door on combination therapy for the treatment of all carbapenem-resistant A. baumannii” and that it remains to be seen whether certain genotypes or phenotypes differ in their response to combination therapy. – by Gerard Gallagher
Disclosures: Bonomo reports receiving research grants from Entasis, Merck, Roche, Allergan and Wockhardt. Paul reports no relevant financial disclosures. Perez reports receiving research grants from Pfizer and Merck. Please see the study for all other authors’ relevant financial disclosures.
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