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Higher colistin doses do not improve mortality rates
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Higher doses of colistin did not reduce 28-day mortality rates compared with lower doses administered to patients with infections caused by carbapenem-resistant gram-negative bacteria, according to recent findings. Researchers, however, found that higher colistin dosing was associated with an increased risk for nephrotoxicity.
“Previous studies show that higher dosing might have some benefit in early microbiological and non-mortality-related clinical outcomes on day 7,” Yael Dishon Benattar, PhD student from the Infectious Diseases Institute, Rambam Health Care Campus, and the Cheryl Spencer Department of Nursing at the University of Haifa, Israel, and colleagues wrote in Clinical Infectious Diseases. “However, both in our study and the previous studies, overall for the patient this does not seem to matter since 1-month mortality rates are not different with high or low dosing.”
The researchers examined data from two prospective cohort studies conducted in Israel from April 2006 to August 2009 and August 2012 to July 2015 to assess the effects of colistin at a lower dose of 3 to 6 million international units (MIU), and a higher dose (according to the European Medicines Agency) of 9 MIU followed by a 4.5 MIU dose every 12 hours. Their analysis included 530 patients treated at a tertiary care university-affiliated hospital for invasive infections, including bloodstream infections, hospital-associated pneumonia, ventilator-associated pneumonia, urinary tract infections, deep skin, soft tissue, joint and bone infections.
According to the results, 28-day, all-cause mortality was 34.7% in the high dosing group (n = 144) vs. 42.9% in the low dosing group (n = 385; P = .09). High-dose colistin was not significantly associated with mortality in a multivariate analysis adjusted for the propensity score (OR = 1.07; 95% CI, 0.63-1.83) or a propensity-matched analysis for mortality (36% vs. 33.7%; OR = 1.11; 95% CI, 0.67-1.82). Similarly, there was no significant difference in mortality regardless of study period or among patients with bacteremia (n = 207; 43.8% vs. 52%). However, patients who received the higher dose were more likely to develop nephrotoxicity, defined as a RIFLE score of injury or higher (OR = 2.12; 95% CI, 1.29-3.48), and seizures (P = .01).
Although the results do not support the use of a higher colistin dose, the findings are “significantly complicated” by many factors, including diverse patient populations, organisms and site of infections treated, combined therapies, actual colistin dosage, renal dosing adjustments, minimum inhibitory concentrations of organisms, illness severity and delays to therapy, according to Jason M. Pogue, PharmD, of the department of pharmacy services at Sinai-Grace Hospital, Detroit Medical Center, and colleagues.
In an accompanying editorial, Pogue and colleagues wrote that, “In spite of the negative findings of this study, given the limitations described above, it is still reasonable and appropriate to continue to utilize ‘high dose’ regimens of colistin (either 9 MIU/day or 5 mg/kg [colistin base activity]/day).”
Pogue and colleagues noted that there are two ongoing randomized controlled trials in Europe and the United States comparing colistin monotherapy with combination therapy with meropenem, which may help clarify clinical pharmacokinetic/pharmacodynamic guidance. Researchers from the trials are using colistin serum concentrations to correlate pharmacokinetic exposures to pharmacodynamic and toxicodynamic outcomes.
“Hopefully, findings from these studies will lead to recommendations for clinically relevant target colistin concentrations and a potential opportunity for both optimizing future empiric dosing regimens and therapeutic drug monitoring strategies,” they concluded. – by Stephanie Viguers
Disclosures: The researchers report no relevant financial disclosures.
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