In the War on Antibiotic Resistance, There May Be No Clear Winner
As gram-negative resistance continues to grow, it limits our treatment options for many infections, and providers are increasingly being forced to consider antibiotics that have long been locked away and nearly forgotten. As we await novel compounds from a relatively apathetic industry, we are resurrecting antibiotics of which we have an outdated understanding. and that carry the potential for substantial side effects: polymyxins.
To further complicate matters, there is an intriguing debate developing within the infectious diseases arena: the use of polymyxin B versus polymyxin E (colistin). Colistin has been called into question as a drug of choice for multi-drug resistant (MDR) infections, while a recent spotlight on polymyxin B is bringing it back onto the MDR treatment stage. Colistin’s historically unattractive properties have incentivized providers to reevaluate other potential options, reopening the door for polymyxin B with its potentially more appealing profile. Many clinicians are aware of colistin’s nephrotoxity and the ambiguity surrounding dosing, particularly in renal insufficiency, but most are largely unfamiliar with polymyxin B. We start the debate by delineating the benefits of polymyxin B and follow it up with an explanation of why hospitals continue to use colistin.
TEAM POLYMYXIN B
Although structurally similar to colistin, polymyxin B offers multiple pharmacokinetic advantages in the treatment of systemic infections. Polymyxin B achieves therapeutic concentrations rapidly, provides more predictable serum concentrations, does not require renal dose adjustments and may not require a loading dose. In comparison, colistin’s peak serum concentration may not be reached for up to 7 hours, serum concentrations are unpredictable due to significant interpatient variability, renal dose adjustments must be considered, and a loading dose is required.
What accounts for these prominent differences in two structurally similar drugs? Colistin is administered as an inactive prodrug, colistimethate (CMS), while polymyxin B is already in its active form. In patients with moderate to good renal function, studies suggest only 20% to 25% of CMS is converted to its active form, with the majority of the dose being renally excreted prior to conversion.1
Because of this, larger doses of CMS are required to achieve therapeutic systemic colistin concentrations. Polymyxin B is mainly eliminated via nonrenal pathways, accounting for little interpatient variability across a wide range of creatinine clearance, whereas CMS clearance is variable even at a given creatinine clearance (eg, two patients with the same creatinine clearance will clear CMS at different rates). Although nephrotoxicity has been a point of contention, recent studies have found lower rates of nephrotoxicity with polymyxin B compared with colistin.2,3
The need for higher doses and extensive renal excretion of CMS leading to increased renal exposure have been offered as the rationale for this difference.
A recent study assessing the pharmacokinetic differences on bacterial killing and resistance emergence in Acinetobacter baumanii
found that rapid attainment of target concentrations was critical for polymyxin-induced bacterial killing.4
The gradual rise in colistin concentrations lead to faster development of polymyxin resistance, contributing to little bacterial killing over the treatment period. Conversely, polymyxin B demonstrated good early bacterial killing, which the authors attributed to rapid attainment of bactericidal concentrations that overtook the onset of polymyxin resistance. However, resistance eventually developed following treatment with either agent, despite significant differences in the magnitude of bacterial killing. This supports the importance of using both polymyxins only in combination with additional antibiotics and (almost) never as monotherapy.