Monday, March 11, 2013

KPC Treatment Strategies

The threat of multi-drug resistant pathogens is nothing new. Over the years, as we’ve developed antimicrobial agents to attack these pathogens, they’ve responded by evolving and mounting resistance mechanisms to stay alive.  Either alone or in combination, the mechanism are typically altering the binding site for the antimicrobial drug, reducing the intracellular antimicrobial concentration through efflux pumps, modifying the antimicrobial agent itself or altering one or more metabolic pathways to circumvent the action of the antimicrobial.

From drug resistant strep to MRSA to extended-spectrum beta-lactamases (ESBL) and now to Klebsiella pneumonia carbapenemases (KPC), these pathogens are outsmarting us.

Since there has been little production from that “20 new antimicrobials by 2020” campaign, astute clinicians have repurposed antimicrobial agents that have gone out of favor; pulling them “off the shelf,” so to speak. Specifically for carbapenemase producing enterobacteriaceae, that “throwback” drug is polymyxin b.

The polymyxins consist of polymyxin b and colistin (aka polymyxin e, a common pimping question for pharmacy students). These drugs function as cationic detergents, interacting strongly with the bacterial cell membrane thereby disputing its structure and leading to changes in permeability.  This destabilized membrane permits passage of various proteins and molecules, and other antimicrobials, all promoting cell death. With a spectrum covering the enterobacteriaceae (except for Proteus and Serratia species), the polymyxins have seen a resurrection in their clinical utility.  Though polymyxins are doses to take advantage of their concentration dependent killing effects (high dose), one must remember the reason why they fell out of favor: a 10-20% risk of nephrotoxicity. An excellent review of colistin (the most extensively studied polymyxin) can be found in Lancet Infect Dis. 2006 Sep;6(9):589-601.

Going beyond simple “double coverage,” combining polymyxins with other agents could potentially increase the likelihood of successful treatment and minimize toxicity. Careful consideration of both spectrum and pharmacokinetic (distribution) of the antimicrobials is crucial. For instance, tigecycline is a glycylcycline, similar to tetracyclines, can be used to treat KPC organisms. However, because of its large volume of distribution and distribution kinetics, its usefulness in treating bacteremia or urosepsis is limited at normal doses. Alternative dosing strategies (200mg IV load, 100mg IV q12 à double the normal dose) have been used in case reports to treat KPC organisms causing urosepsis. (Elemam A, Rahimian J, Mandell W. Infection with panresistant Klebsiella pneumoniae: a report of 2 cases and a brief review of the literature. Clin Infect Dis 2009; 49: 271–4)

Other combinations include the addition of aminoglycosides or using carbapenems. Successful use of carbapenems in this scenario depends, again, on optimizing the pharmacokinetics and pharmacodynamics of these agents. Being time-dependent killers, continuous infusions of carbapenems increase the likelihood of achieving a 4-5x MIC concentration for the maximum amount of time.  Similarly to tigecycline, there is limited data to support this theory. Case reports and small studies back up these theories, but (shameless plug for pharmacists) experienced pharmacists can help in these situations.

While empiric therapy should likely not differ in the ED, consideration for expanded/additive coverage should take place if a patient has a history of infection resulting from a KPC organism. The kitchen sink would also be thrown in if it wasn’t also covered in MDR pathogens. 

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