The OVERCOME trial (Colistin Monotherapy Versus Combination Therapy for Carbapenem-Resistant Organisms), published in NEJM Evidence, is an international, randomized, double-blind, placebo-controlled trial that aimed to assess whether the combination therapy of colistin and meropenem was superior to colistin monotherapy for the treatment of pneumonia and bloodstream infections (BSI) caused by extensively drug-resistant (XDR) Acinetobacter baumannii, XDR Pseudomonas aeruginosa, and carbapenem-resistant Enterobacterales (CRE).
From 2012 to 2020, 464 participants were randomly assigned to treatment, and 423 patients were included in the modified intention-to-treat population. The trial found no significant difference in 28-day mortality, clinical failure, microbiologic cure, or adverse events between the colistin monotherapy and combination therapy groups. In conclusion, the combination therapy of colistin and meropenem was not found to be superior to colistin monotherapy for the treatment of pneumonia or BSI caused by these pathogens.
Polymyxins, including colistin, were discovered in the 1940s and played an essential role in treating resistant gram-negative bacterial infections. However, as newer and less toxic antibiotics became available, their use declined. Due to the rise in antimicrobial resistance (AMR), polymyxins have experienced a resurgence in recent years. Polymyxins have a narrow therapeutic window, and colistin is administered as an inactive prodrug, colistin methanesulfonate. This leads to several challenges in its use:
Slow rise in plasma concentration of active drug: The conversion of colistin methanesulfonate to the active drug colistin takes time, which can delay the drug's therapeutic effect.
Interindividual variability in steady-state plasma concentrations: Different patients may have widely varying levels of the active drug in their bloodstream, which makes it difficult to predict the optimal dosage for each individual.
Difficulty achieving or maintaining effective drug concentrations: Due to dose-limiting nephrotoxicity (kidney damage caused by the drug), it can be challenging to achieve or maintain effective concentrations of the active drug in some patients.
Despite these limitations, polymyxins, including colistin, continue to be important therapeutic options for treating resistant gram-negative bacterial infections, especially as AMR becomes an increasing concern. However, their pharmacokinetic properties and potential side effects must be carefully considered when prescribing these drugs.
As of a 2021 WHO report, there are several promising antibacterial agents in the drug development pipeline with potential to treat CRAB, CRE, and carbapenem-resistant P. aeruginosa. In phase I development, there are 9 agents for CRAB, 14 for CRE, and 8 for carbapenem-resistant P. aeruginosa. However, no drugs are actively being developed in phase II. In phase III, taniborbactam+cefepime shows potential activity against CRE and carbapenem-resistant P. aeruginosa, while durlobactam+sulbactam (SUL-DUR) is being developed for CRAB.
The results of a phase III multicenter randomized noninferiority trial (NCT03894046) comparing imipenem+colistin with imipenem+SUL-DUR for patients with hospital-acquired pneumonia or bloodstream infection caused by A. baumannii are promising. The SUL-DUR group showed lower 28-day mortality and higher clinical cure rates.
It is important to note that the historical likelihood of approval for infectious disease investigational drugs from phase I has been around 17%. The development of new antibacterial agents is essential in the fight against antibiotic-resistant bacteria. However, it is crucial to remember that the development process is lengthy and uncertain, and not all drugs in the pipeline will ultimately be approved or successful in treating these challenging infections.
The study underscores the urgent need for better therapeutics for infections caused by resistant gram-negative bacteria. The use of polymyxins, such as colistin, should be limited to cases where no other active agents are available. Emphasizing antimicrobial stewardship is critical to slowing the emergence of Antimicrobial resistance and preserving the efficacy of new drugs.
In a world where microbes fight and resist,
Antibiotics struggle, a challenging twist.
A study was conducted to see what's best,
Colistin monotherapy or combo, the test.
With XDR bacteria lurking around,
Effective treatments need to be found.
A. baumannii, P. aeruginosa, and CRE,
All battled by doctors with fervency.
The trial revealed no difference in fate,
Between colistin alone and its combo mate.
A question arises, should colistin stand tall,
Or be replaced by better drugs for all?
Polymyxins, once stars in the fight,
Now show limitations, their future not bright.
Guidelines have shifted, recommending a change,
Polymyxin B over colistin, a more suitable range.
New antibacterial agents emerge with potential,
Treating resistant foes, their power essential.
Durlobactam and sulbactam, a promising pair,
In a phase III trial, results quite fair.
So let's raise awareness, with stewardship we strive,
To slow resistance and keep patients alive.
For in this battle against the microbial swarm,
Innovation and prudence will become the new norm.