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Repurposed drugs fight antimicrobial resistance crisis
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SAN DIEGO —Physicians have been forced to resurrect older drug classes with known toxicities due to a lack of new agents in the pipeline fighting against multiresistant pathogens, according to a speaker here at ID Week.
In order to obtain the highest likelihood of a positive clinical response while maintaining the lowest probability of concentration-driven toxicity, clinicians need the proper dosing information for a drug or class of drugs.
In the past 2 to 3 decades, researchers have developed additional dosing information for aminoglycosides.
“The duration of therapy has a major impact on the likelihood of your patient getting aminoglycosides nephrotoxicity,” said George L. Drusano, MD, FIDSA, co-director of the Ordway Research Institute in Albany, N.Y.
But two patients with the same 5 mg/kg a day dose of aminoglycosides would likely have completely different concentration time profiles. The same dose of a drug will act differently according to each patient and their individual pharmacokinetics, according to Drusano.
Plazomicin (Achaogen Inc.) is a new aminoglycoside currently in clinical trial. It must be given once daily to limit toxicity. Therapy should not exceed 10 days. Because of this, Drusano recommended a dosage increase.
“Because the uptake in the proximal renal tubule cells is saturable, you can get much larger doses in 7 to 10 days without running into increased risk of aminoglycoside toxicity,” he said.
The proposed dose for plazomicin is 15 mg/kg per day instead of the 5 mg/kg per day for gentamicin.
Polymyxin E (colistin) is a polypeptide that has been available since the 1960s. Previous clinical trials have found that the antibiotic has a relatively high rate of nephrotoxicity. But, similar to aminoglycosides, it has the ability to treat resistant infections in various patient settings.
“With colistin and polymyxin, we are on the cusp of being where we were with aminoglycosides 15 or 20 years ago,” Drusano said. “We need to sort out the dosing a little better. Can we find a way to safely increase the dose?”
Aminoglycosides have shown to be safe and effective for use against serious infection.
“For colistin, we are not quite there, but we are getting there,” Drusano concluded.
For more information:
Drusano GL. Abstract #23. Presented at: ID Week; Oct. 17-21, 2012; San Diego.
Disclosure: Drusano is a consultant and grant investigator for Achaogen and has received salary from a BARDA contract to Achaogen.
Perspective
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Sujata Bhavnani, PharmD
Everyone is talking about the shortage of new antimicrobials, and there are a lot of actions being taken to correct that, such as providing incentives for those who are developing drugs. We hope that part of the equation will push us forward and that we will see new drugs. Repurposing old drugs is very important because we learned so much about pharmacokinetics and pharmacodynamics in the last 30 years. We are using all of these principles now to develop new drugs. Going back to repurpose old drugs is such a good idea. It is efficient and makes use of a resource that we may have looked over in the past. We can go back and evaluate if the doses were appropriate. We have new techniques to better understand drug penetration. If we manage safety issues, maybe we can increase dosage. We have learned so much and we can use new information to help us identify better results.
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