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Antimicrobial (Drug) Resistance

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In recent years, antimicrobial (drug) resistance has become an increasingly important health issue, forcing healthcare providers to rely on a dwindling selection of drugs to fight infection among patients. Gram-negative bacteria, which include Escherichia coli. E. coli, Acinetobacter baumanni, Pseudomonas aeruginosa, Klebsiella pneumonia, and Enterobacter sp., are an especially dangerous group of pathogens because they are difficult to treat and have become increasingly resistant to currently available antimicrobial drugs.

In situations where commonly used antibiotics are no longer effective, healthcare providers are turning to some older antibiotics to treat drug-resistant bacterial infections. Colistin, an antibiotic approved in the late 1950s for the treatment of acute and chronic infections caused by certain sensitive strains of Gram-negative bacteria, is one of these older antibiotics that is getting a second look.

Background

Healthcare providers had largely stopped using colistin in the 1970s because of its toxicity. However, with antibacterial resistance on the rise, colistin is increasingly being used today to treat severe, multidrug-resistant Gram-negative bacterial infections, particularly among intensive care-based patients.

The problem with re-introducing an older drug, such as colistin, though, is that techniques for evaluating new drugs have evolved since the 1950s, and therefore, little is known about the dose needed to effectively fight infection while limiting the potential emergence of antimicrobial resistance and reducing potentially toxic side effects. More data are needed to guide optimal use of these older medications.

An international team of NIAID-funded researchers is making progress in obtaining better dosing information about colistin and how best to use the antibiotic to treat Gram-negative bacterial infections.

Microscopic image of Acinetobacter baumanii
Acinetobacter baumanii, one of the most common multi-drug resistant organisms that colistin effectively treats.
Credit: F. Silveira.

Specifically, the research team began in 2009 an ongoing study in the United States and Thailand among critically ill, hospitalized patients with varying degrees of kidney function. The scientists are collecting data on how colistin methanesulfonate (CMS)—an inactive drug that converts to colistin once inside the body—is processed by the human body (the drug’s pharmacokinetics), how the drug affects the body (pharmacodynamics) and causes side effects (toxicodynamics). In a paper published in the July 2011 Antimicrobial Agents and Chemotherapy, the researchers described early pharmacokinetic results and dosing recommendations for the first 105 critically ill patients enrolled in the study. A total of roughly 238 patients are expected to participate.

At the time the study began, participants were undergoing treatment for infection by a strain of Gram-negative bacteria resistant to at least four classes of antibiotic drugs. Each participant received CMS treatment intravenously. The size and frequency of their doses varied, averaging roughly 200 mg per day.

The researchers took blood samples from all participants, as well as dialysis solution samples from the 12 participants receiving dialysis and continuous renal replacement therapy for significant kidney function impairment. They built two mathematical models based on the sample data: one for patients who were on dialysis and renal replacement therapy and one for those who were not. Next, they used the models to find each patient’s ideal blood-based colistin concentration, and finally, worked to find the daily dose of CMS needed to maintain that ideal. Because it takes the body some time to process CMS, the researchers recommended starting CMS treatment with a larger initial, or loading, dose.

Results and Significance

The researchers’ analysis showed that renal function affects colistin levels in the body. This is because the human renal system effectively clears foreign chemicals, such as colistin. Study participants with better renal function cleared colistin more quickly, leaving less of the drug in the body to fight infection. These patients would need a larger daily dose of CMS in order to maintain the ideal drug concentration, the researchers concluded.

However, they cautioned against exceeding the recommended dose, which could increase the risk of kidney damage. Instead, they suggested using CMS in combination with other antibacterial therapies to safely and effectively treat the infection.

The study’s preliminary results provide the first science-based CMS dosing recommendations for critically ill patients, which will help healthcare providers determine the appropriate dose for patients with adequate renal function as well as those with impaired renal function.

Next Steps

As these results are only preliminary, the researchers plan to continue enrolling participants until they reach the target 238 participants and will update their analysis with the larger sample. They also plan to expand the CMS dosing model to include the drug’s pharmacodynamics and toxicodynamics.

Reference

Garonzik SM, Li J, Thamlikitkul V, Paterson DL, Shoham S, Jacob J, Silviera FP, Forrest A, Nation RL. Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically-ill patients from a multi-center study provide dosing suggestions for various categories of patients. Antimicrobial Agents and Chemotherapy. 2011 Jul;55(7):3284-94. Epub 2011 May 9.

Last Updated March 07, 2012

Last Reviewed March 07, 2012