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Tam Explores Benefits and Outcomes of Highly Effective, Yet Nephrotoxic Antibacterial Agent in Combinatorial Regimen

With the clock ticking for patients with bloodstream infections, clinicians often have to weigh the risks and benefits of strict interpretation of their Hippocratic Oath of "first, do no harm," when it comes to initiating therapies with known nephrotoxicity risks.

Vincent TamUH College of Pharmacy Professor Vincent H. Tam, Pharm.D., has launched a project to evaluate the benefits and adverse events associated with the common clinical practice of initiating a "double-shot" combination therapy that includes an effective, yet potentially kidney-damaging antimicrobial, to patients with bacteremia.

With results from the clinical microbiology laboratory often taking up to days to identify the specific species and susceptibility profiles of the pathogens in patients with bacteremia, clinicians typically have little choice but to start the patient on an "educated guess" antimicrobial regimen as lost time can mean lost lives.

Standard practice for unknown or unconfirmed infections often involves an empiric combinatorial regimen with an aminoglycoside component, based on the assumption that one or both of the agents will buy the patient valuable time until the clinician has sufficient data to support a more informed decision about the most appropriate therapy.

Aminoglycosides are highly effective in treating infections caused by gram-negative bacteria, from the relatively harmless Escherichia coli and Salmonella species to the more dangerous bugs such as Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii.

"Aminoglycosides are fairly well preserved from a stewardship standpoint because of toxicity concerns, when they are used, people generally don’t use them for long-term therapy because of the well-known nephrotoxicity risk," Tam said.

Yet, Tam wonders whether the well-intending clinician may not be unwittingly initiating a functional aminoglycoside monotherapy – and unnecessarily increasing the risk of nephrotoxicity, even with short-term use – if the secondary component of the combinatorial therapy is in fact ineffective against the given species, which in his study is focused on P. aeruginosa infections. 

"We’re trying to determine the outcomes associated with this practice of empiric aminoglycoside combination therapy," Tam said. "About 90 percent of the anticipated bacterial pathogens are susceptible to aminoglycosides, but does that translate into something that is clinically relevant? We don’t know."

Due to the complex inclusion screening criteria, Tam said it’s unknown at this time how many patients will be included in the final retrospective study, but he is aiming to screen a sample size of approximately 400 cases. The project is being supported by a $130,000 research grant from Merck & Co., which is not currently marketing an aminoglycoside agent.