By Karen Blum

Hospital clinicians face several challenges in helping manage antibiotic-resistant, gram-negative superbugs that produce carbapenemases. One of the most worrisome is Klebsiella pneumoniae (KPC).

A report in the March issue of Infection Control and Hospital Epidemiology (2013;34:259-268) found that the proportion of K. pneumoniae cases resistant to carbapenems increased from 0.1% in 2001 to 4.5% in 2010. “That is huge,” said Robert Rapp, PharmD, professor of pharmacy and surgery emeritus at the University of Kentucky Medical Center in Lexington, one of many pharmacists concerned about KPC.

Those concerns were compounded by the Centers for Disease Control and Prevention’s own report on the rising prevalence of carbapenem-resistant enterobacteriaceae (CRE). According to the report, in the last decade, hospitals have seen a fourfold increase in CRE, with most of the increase attributable to Klebsiella species (MMWR 2013;62:1-6).

The fact that these superbugs are making their presence most felt in hospitals is not surprising: In healthy patients, KPC may colonize the intestines without causing disease, but in patients whose immune system is impaired—a common occurrence during a hospital stay—it can turn deadly. KPC can spread through human-to-human contact and has been found to live on equipment such as catheters. In the past, K. pneumoniae typically had been treated with cephalosporins or carbapenems antibiotics, but the bacteria are becoming increasingly resistant. Thus, drugs used to treat the organism, including colistin, polymyxin B and tigecyline are not always effective alone, so they have to be combined. “But there’s no real, solid data on the drugs of choice,” Dr. Rapp noted, and medical staff “are just kind of flying by the seat of their pants.”

With no new antibiotics in the pipeline, “we really have a problem,” he stressed. “If you come down with one of these [superbug infections], your chances of dying are high—probably 40% to 50%,” a figure echoed in the March CDC report.

KPC is “definitely something that’s on our radar,” said Claudine El-Beyrouty, PharmD, BCPS, an infectious disease pharmacist at Thomas Jefferson University Hospital in Philadelphia. Although KPC was detected first in New York, in 2000, most hospitals in the Northeast region of the country have encountered it. At Jefferson, several patients per quarter carry the organism or show signs of being infected, Dr. El-Beyrouty noted. KPC most often is found among critically ill patients hospitalized for extended stays or in patients who go in and out of the hospital frequently, she said.

The hospital manages the infections through a multitiered approach, Dr. El-Beyrouty noted. Infection control personnel track cases; once the organism is detected in a patient, the person is isolated and the chart is flagged. If the patient is discharged and later returns, the flag is reactivated and the person is isolated again. Caregivers treating these patients wear gowns and gloves and employ handwashing techniques. Pharmacists participating in the hospital’s antibiotic stewardship program try to reserve agents like colistin, tigecycline and amikacin specifically for KPC patients.


A Deadly Outbreak

One of the most difficult Klebsiella outbreaks to control occurred in 2011, at the National Institutes of Health (NIH) Clinical Center in Bethesda, Md., where the organism infected 19 patients, seven of whom died. That June, a 43-year-old woman with lung disease was transferred to the medical center from a New York hospital. Medical staff knew the patient was colonized with KPC, so they isolated her and wore gowns, gloves and masks while treating her. Three weeks after that patient left the hospital, a cancer patient who had no contact with the infected patient developed KPC. Ten days later, a patient with an immune disease also became infected.

NIH epidemiologists and infection control specialists scrutinizing the problem found that the organism had been transmitted from the first patient despite following all infection control protocols. They implemented additional procedures to prevent further transmission, including more invasive testing of ICU patients; using rectal swabs to check for KPC carriers; building a wall to create a specific unit to care for and isolate KPC patients; paying monitors to ensure everyone followed infection control procedures; and spraying hydrogen peroxide in rooms and on equipment. They reported their efforts in the journal Science Translational Medicine (2012;4:148ra116). The last carrier was identified in December 2011, but patients still are swabbed to check for KPC when they arrive and before they leave the facility.

The pharmacy faced several challenges during that time, said Timothy Jancel, PharmD, BCPS, a clinical pharmacy specialist in infectious diseases at the hospital. The isolation unit was created overnight, he said, so pharmacists had to quickly install a new drug-dispensing unit and decide how emergency medicines would be delivered. They educated staff on handwashing and isolation protocols. Because some isolated patients took their own medicines, pillboxes leaving the unit had to be sterilized.

Infectious disease experts worked with with staff to come up with antibiotic regimens to treat and monitor KPC, which involved educating a lot of people, Dr. Jancel said. Medications like colistin have “been around for decades, but we never had to use it because we always had other options.” Devising accurate dosing was challenging because labeling requirements were less stringent when colistin was approved, and the pharmacokinetics of the antibiotic still are not well understood, he added. They had to combine colistin with gentamicin and tigecycline for some patients, and then monitor them for side effects including renal toxicity, pancreatitis, nausea and vomiting.

“We were using drug combinations typically not used on a daily basis,” Dr. Jancel said.

Investigational antibiotics were also pursued. Although one agent was acquired and administered to one patient, it was too late: The person died a few days after starting therapy.

Dr. Jancel said he has helped thwart other types of antibiotic-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), but MRSA still had treatment options such as linezolid (Zyvox, Pfizer), trimethoprim/sulfamethoxazole or clindamycin. “With gram-negative bacteria [like KPC], we’re getting to the point where we don’t have other options.”

More From the CDC Report

As daunting as Klebsiella is to eradicate in the nation’s hospitals, it isn’t the only superbug that poses a public health threat, the CDC report stressed; the authors also cited the emergence of resistant Enterobacter and Escherichia species. By releasing these findings, the agency succeeded in getting a long-standing problem quite a bit of media attention. News articles in The Wall Street Journal, The New York Times and television news outlets covered the report in seemingly alarmist terms. Most quoted one health official who termed these resistant organisms “nightmare bacteria,” and the CDC’s Arjun Srinivasan, MD, got a lot of coverage when he called these superbugs “a major threat emerging in our hospitals.”

That statement is not surprising, given the 40% mortality associated with some of the superbug infections. Moreover, many of the bacteria have a kind of “panresistance” that renders them, in some cases, unresponsive to most available antimicrobials, which makes even combination treatments problematic, the CDC researchers reported.

“Make no mistake, this is a public health crisis,” Dr. Rapp said. With the pipeline for new drugs looking dismal right now, “I don’t see much hope for a savior coming from Pharma.”

Dr. Rapp urged hospitals to take the same types of proactive approaches detailed in the Science Translational Medicine report.

“We have several tools to prevent transmission and improve patient outcomes, including better infection control practices, strong antimicrobial stewardship programs and optimization of the pharmacokinetic/pharmacodynamics of our presently available agents to enhance the killing of these bacteria,” he said. “So we are certainly not powerless in this fight. But it’s going to be a long battle.”