Do we need to combine meropenem with colistin in multidrug-resistant infections?

Colistin is often used as combination therapy in multidrug-resistant infections. The antibiotics used in combination with colistin include meropenem, rifampicin, and minocycline. Combination therapy is favored for several theoretical reasons. Colistin levels in the lung have often resulted in subtherapeutic levels in animal models. Heteroresistance, a phenomenon by which subsets of bacteria may be resistant, even though in vitro testing suggests otherwise, may occur with colistin monotherapy. Heteroresistance may lead to the proliferation of a fully resistant strain during the course of treatment. Antibiotic synergism has also been proposed to explain the benefits of combination therapy with colistin. Furthermore, some studies suggest poor rates of clinical cure with colistin monotherapy. (1)

Paul et al. in a multicenter randomized controlled trial, compared combination therapy with colistin and meropenem with monotherapy using colistin alone in carbapenem-resistant gram-negative infections. (2) A total of 406 patients were included, with 198 in the monotherapy group and 208 with combination therapy. The groups were well matched at baseline; 65% of patients were ventilated, while 18% required hemodynamic support, and 6.4% required renal replacement therapy. The median SOFA score was 6, with an overall mortality of 44%. The most common infection was ventilator-associated pneumonia (VAP), followed by bacteremia, and urosepsis. About 36% of infections were ICU-acquired. The most common pathogen, by far, was Acinetobacter Baumannii.

The primary outcome was “clinical success” of therapy at 14 days, which required all the following criteria: 1. Survival; 2. Systolic blood pressure > 90 mm Hg without vasopressors; 3. Improved or stable SOFA score; 4. Stable or improved P/F ratio in patients with VAP; 5. No growth in blood culture on day 14 for patients with bacteremia. Clinical failure rates were high and similar in both groups; failure of therapy was seen in 156/198 (79%) of patients with monotherapy and 152/208 (73%) with combination therapy. There was no difference in all-cause mortality between groups at 14 and 28 days. There was a lower incidence of AKI on day 14 with combination therapy, in patients with “injury” and “failure” on the RIFLE classification. Clinical failure was lower in ventilator-associated pneumonia, hospital-acquired pneumonia, and bloodstream infection, although the difference was not statistically significant.

This study aimed to answer an important question that we ask in patients with multidrug-resistant infections with in vitro sensitivity to colistin and resistance to meropenem. Hitherto, the general policy in most units has been to combine both, although there was no robust evidence to support the efficacy of such a combination. This study had several limitations, including the use of a composite outcome with short-term (14-day) mortality as one of the components. The overwhelming majority of infections were caused by A.Baumannii, which naturally raises a question about applicability to other organisms. There was considerable heterogeneity in the site of infections. Would the results apply to specific infections such as VAP, given that colistin has poor penetration into lung tissue? Therapeutic drug monitoring was not performed; it may have been interesting to know if adequate drug levels were achieved, especially with colistin.

However, based on this study, I feel that we should strongly consider using colistin as monotherapy if in vitro resistance to meropenem is noted. Antibiotic synergism is at best, hypothetical, especially when resistance has been demonstrated in vitro. Furthermore, in our setting, the manifold escalation of the cost of care with combination therapy should also be a deterrent. The findings of a retrospective observational study from an oncological unit in India, that showed no change in crude mortality with a carbapenem-colistin combination compared to colistin alone, lends further support to monotherapy. (3)

References:

1. Parchem NL, Bauer KA, Cook CH, Mangino JE, Jones CD, Porter K, et al. Colistin combination therapy improves microbiologic cure in critically ill patients with multi-drug resistant gram-negative pneumonia. Eur J Clin Microbiol Infect Dis. 2016 Sep;35(9):1433–9.
2. Paul M, Daikos GL, Durante-Mangoni E, Yahav D, Carmeli Y, Benattar YD, et al. Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial. Lancet Infect Dis. 2018 Apr;18(4):391–400.
3. Ghafur A, Devarajan V, Raja T, Easow J, Raja MA, Sreenivas S, et al. Monotherapy versus combination therapy against nonbacteremic carbapenem-resistant gram-negative infections: a retrospective observational study. Indian J Crit Care Med. 2017 Dec 1;21(12):825.