BETHESDA, MD 19 September 2012—Last year's spread of deadly carbapenemase-producing Klebsiella pneumoniae (KPC) bacteria at the National Institutes of Health (NIH) Clinical Center in Bethesda, Maryland, posed complex pharmacotherapy issues for the research hospital's pharmacy staff.
The outbreak at the 243-bed Clinical Center began after the arrival of a 43-year-old lung transplant recipient from a New York hospital. According to NIH, the patient was known shortly before her arrival in June 2011 to be colonized with KPC, and contact isolation procedures were implemented to prevent the spread of the bacterium to others at the hospital.
As described in a report in the August 22 issue of Science Translational Medicine, the containment plan failed. Molecular analysis confirmed that over the course of several months, resistant bacteria originating from the New York patient spread to 17 other patients.
By the time the outbreak ended last December, six people had died from their infection and five died of an underlying disease while harboring the bacteria.
Multidrug-resistant strains of K. pneumonia are increasingly becoming a problem in health care settings, according to the Centers for Disease Control and Prevention (CDC).
In healthy patients, Klebsiella bacteria typically colonize the intestines without causing disease. But in patients whose immune system is impaired by cancer, an immune deficiency syndrome, or immunosuppressive therapy, the bacteria can become deadly.
At the NIH Clinical Center, "the patients that were infected with KPC almost all had either immunodeficiency or immunosuppression," said Timothy Jancel, clinical pharmacy specialist in infectious diseases at the hospital.
Drug therapy. Jancel said medical literature suggests that KPC strains in hospitals are likely to be susceptible to the polymyxin drug colistin, as well as gentamicin and tigecycline. Susceptibility test results confirmed this to be the case, at least initially, for the bacteria that spread among Clinical Center patients.
Jancel said that the patients who were under his care during the outbreak received all three antimicrobials in an effort to stem their infection.
An injectable formulation of colistimethate sodium, a prodrug of colistin, was approved by FDA in 1970, according to agency documents. But the drug reportedly fell into disfavor because of its nephrotoxicity.
"We don't know much about its pharmacokinetics and pharmacodynamics today, even though the drug has been around for decades," Jancel said. "We've only had to use it in the last few years, because it's one of the last agents we have left" to target carbapenem-resistant organisms.
The i.v. formulation of colistimethate is currently labeled for the treatment of infection with Pseudomonas aeruginosa, K. pneumoniae, and other susceptible gram-negative organisms. The labeling advises clinicians to exercise "the greatest caution" when using the drug in patients with kidney impairment.
Gentamicin is also nephrotoxic, and Jancel said simultaneous use of the aminoglycoside and colistimethate increases the risk of kidney damage.
Because the KPC-infected patients were seriously ill even before they encountered the bacterium, drug-related adverse events were a special concern.
"Pharmacists [are] on board to help dose medications, monitor renal function, adjust the dosing of the medications," he said. "You're there as part of a team, [and] especially with a very complex medication regimen and complex patients, pharmacy input is incredibly important."
Jancel said little definitive data exist to guide clinicians in selecting the colistimethate dosage appropriate for patients with systemic infections.
In addition, dosage and administration instructions in the U.S. labeling for the drug refer to the amount of colistin base activity, in milligrams, contained in each vial. But some reports in the medical literature describe dosing in terms of units or milligrams of the prodrug.
The Institute for Safe Medication Practices issued an alert last year about the risk of serious or deadly medication errors resulting from confusion about how much drug each vial contains and whether dosage calculations are based on colistin or its prodrug.
Jancel said the pharmacy staff issued reminders to others on the health care team to always calculate dosages on the basis of colistin base activity.
He said tigecycline dosage calculations also presented challenges, because the drug is not indicated for the treatment of bacteremia. The dosage instructions in the FDA-approved labeling are thus geared toward achieving adequate levels of the drug in tissues but not in the bloodstream.
"We've been using tigecycline a lot in these patients . . . at a higher dose than the approved dosing," Jancel said.
He said the Clinical Center used the results of in vitro susceptibility tests to guide decisions on which antimicrobial dosages could produce adequate bloodstream levels of the medications.
"As pharmacists, our knowledge of the pharmacokinetics and pharmacodynamics of drugs will help guide optimal dosing and our
recommendations," Jancel noted.
Resistance. According to the report in Science Translational Medicine, resistance to all three antimicrobial agents developed during the course of the outbreak, leaving some patients with "no effective therapeutic options."
The report focused on resistance to colistin, and the authors determined that bacteria from the index patient had evolved to the verge of colistin resistance when she arrived at the Clinical Center.
According to the report on the 18 cases at the Clinical Center, one patient's initial KPC isolate was already colistin resistant when it was first identified, and another patient's isolate developed resistance during colistin treatment.
"Unfortunately, the more you treat, you run the risk of the organisms becoming resistant," Jancel said.
He said there is optimism that antimicrobial agents now in clinical trials may eventually be used to treat carbapenem-resistant organisms. But infectious-diseases experts have long lamented the need for a robust antimicrobial drug pipeline.
"This is an area that people have been talking about for a long time—that we're going to get to the point where we're not going to have any other options left," Jancel said.
The Infectious Diseases Society of America in early 2010 called for a global commitment to the development of 10 new antimicrobial drugs by 2020 as a way to avert what the society calls a looming crisis in infection control.
A CDC action plan to combat antimicrobial resistance was released in 2001 and revised in 2011. A progress report on federal efforts to meet the plan's goal, including support for the development of new antimicrobial drugs, was scheduled for release during the first half of this year but had not been published at presstime.