WASHINGTON — The United States may be poised on the brink of the next drug-resistant infection epidemic, with outbreaks of Acinetobacter baumannii already appearing in hospitals here, according to experts speaking at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy. Ventilator-dependent patients are among the most vulnerable. Central nervous system infections also are common.
The spread of the bacteria has already reached epidemic proportions in Israeli and Latin American hospitals, and is a serious problem in Europe as well. In fact, “Acinetobacter has been designated as the gram-negative MRSA [methicillin-resistant Staphylococcus aureus],” said Dr. Harald Seifert, a professor at the University of Cologne's Institute of Medical Microbiology and Hygiene.
“We're not only dealing with an increasing incidence of multiresistant Acinetobacter, but we seem to be dealing with an increasing absolute incidence of Acinetobacter,” said Dr. Anthony D. Harris, an epidemiologist for the University of Maryland Medical System, Baltimore.
Acinetobacter baumannii is a nonmotile, gram-negative bacterium that affects mainly immunocompromised patients, particularly patients in the ICU setting or those who have been hospitalized for long periods, Dr. Seifert said at the meeting sponsored by the American Society for Microbiology.
In particular, it is the most important pathogen causing pneumonia in patients who are on a ventilator, he said.
About half of Acinetobacter infections are sepsis- or ventilator-associated pneumonias, based on data from several series, said Dr. Yehuda Carmeli, head of the division of epidemiology at the Tel Aviv Sourasky Medical Center. Central nervous system infections following neurosurgery are also common.
Acinetobacter outbreaks also have occurred after manmade and natural disasters, including the 1999 earthquake in Turkey, the 2002 terrorist bombing in Bali, and the 2004 tsunami in the Pacific. The U.S. military has also reported an increasing number of Acinetobacter bloodstream infections in soldiers injured in Iraq, Kuwait, and Afghanistan.
Rates Nearly Double
Between 1986 and 2002, the rate of nosocomial pneumonia infections caused by Acinetobacter almost doubled in the United States, from 4% to 7%, Dr. Seifert said. In an analysis of data from the Surveillance and Control of Pathogens of Epidemiologic Importance (SCOPE) program, Acinetobacter ranked 10th among causes of 24,179 nosocomial bloodstream infections in U.S. hospitals from 1995 to 2002. In non-ICU wards, the pathogen accounted for up to 1% of these infections; in ICU wards, Acinetobacter accounts for 0.6% of these infections.
“We've had more than 15 hospitals in Maryland in the last 11/2–2 years that have reported multiresistant Acinetobacter,” Dr. Harris said. Outbreaks have also been reported in New York and among soldiers returning from Iraq and Afghanistan.
In Europe, Acinetobacter accounts for 2.5% of all bloodstream infections, earning a number 10 ranking there as well, according to the SENTRY Antimicrobial Surveillance Program, which monitors the predominant pathogens and antimicrobial resistance for both nosocomial and community-acquired infections.
In the United States, Acinetobacter accounts for 7% of respiratory tract infections in ICUs alone, Dr. Seifert said.
Resistance Is Rising
Of particular concern is Acinetobacter resistance to an increasing number of antimicrobial agents and developing pan-resistant strains, Dr. Seifert said. Strains that are resistant to every antimicrobial class on the market are now common in some parts of the world.
“Antibiotic-resistant Acinetobacter has had a sharp increase in the last decade basically worldwide,” Dr. Harris said. Resistance has been reported for aminopenicillins, first- and second-generation cephalosporins, cephamycins, most aminoglycosides, and tetracyclines, among others. In addition, unique clones have been reported that are resistant to several drugs. The likelihood of mismatch between chosen therapy and drug susceptibility is very high—almost 100%—because many Acinetobacter strains are multidrug resistant.
“In many cases, we don't have any effective treatment,” Dr. Carmeli said. He related trying as many as five antibiotics at the same time to treat patients.
“[W]e desperately need new antibiotics for gram-negative bacteria. Few are in the pipeline,” Dr. Harris said. Those that are under investigation are related to currently approved drugs for gram-negative organisms and “are unlikely to solve some of our major, resistant, gram-negative bacterial problems, including Acinetobacter.”
Mortality can be high for patients with Acinetobacter infections. According to one study of three Israeli hospitals, fatality rates for bloodstream infections caused by multidrug-resistant Acinetobacter averaged about 50% (J. Hosp. Infect. 2005;60:256–60).
Dr. Carmeli and his colleagues performed a matched case-control study of 118 patients with a positive culture for multidrug-resistant Acinetobacter (susceptibility to carbapenems, colistin, and ampicillin-sulbactam) during a 6-month period. Mortality in patients was 36%, compared with 21% in controls, for an adjusted odds ratio of 6.23.
Average length of stay for patients with Acinetobacter was 28 days, compared with 17 days for controls, but the difference was not statistically significant.
“Most of the mortality, in my experience, is concentrated in patients who have either sepsis or pneumonia,” Dr. Carmeli said.
Eludes Eradication Efforts
“Another characteristic feature of Acinetobacter baumannii is the propensity for epidemic spread,” Dr. Seifert said. The organism is easily transmitted by person-to-person contact.
“Once it's established in your hospital, it's very difficult to get rid of it,” said Dr. Carmeli, who is also a research staff member at Beth Israel Deaconess Medical Center and Harvard Medical School in Boston. He noted that in one ICU ward in Israel, the staff was able to eliminate Clostridium difficile and MRSA through strict infection control measures, “but did not make any change in Acinetobacter at all.” More worrying, environmental contamination may play a role in the spread of the bacterium. Acinetobacter can live on a dry surface for a month or longer. Contamination times of 3 months have even been reported.
Based on the current epidemiology of Acinetobacter in Israeli hospitals, Dr. Carmeli estimates that at the peak of a U.S. epidemic, physicians here could expect to see 280,000 cases each year, including 120,000 cases of pneumonia or sepsis and 30,000 cases of attributable mortality.
Double Therapy May Thwart Resistance
“My inclination is that double therapy in fact might prevent the evolution of resistance, but that is a question that has been in the literature for a long time and never proven,” said Dr. James J. Rahal.
Research involving other organisms has shown that resistance is less likely when therapy involves two or more classes of antibiotics. Combination therapy has a synergistic effect that lowers the risk for resistance, compared with monotherapy, said Dr. Rahal, director of the infectious disease section at New York Hospital Queens and a professor of medicine at Weill Medical College of Cornell University, New York.
Findings from his own research suggest that the most active combinations are those that add either imipenem or rifampin or both to polymyxin B, he said.
For now, Dr. Rahal advised:
▸ Cephalosporins should probably be avoided for the treatment of Acinetobacter, with the possible exception of use in combination with an aminoglycoside.
▸ For susceptible Acinetobacter strains, trimethoprim-sulfamethoxazole, quinolones, and ampicillin-sulbactam may be effective as single therapies.
▸ Carbapenems remain the drugs of choice. It's unclear whether combination therapy with another drug might prevent the development of resistance to the carbapenems.
▸ Colistin and polymyxin B have been shown to be effective clinically. “From my review, I have concluded that the efficacy is clearly less in serious pulmonary infection … so higher-than-usual doses should be considered,” said Dr. Rahal.
▸ The addition of rifampin to single-drug therapy should be considered. “The contribution of rifampin to anti-gram-negative therapy has been demonstrated both clinically and in vitro for many years,” said Dr. Rahal.
Another interesting aspect that has emerged is dosage, said Dr. Rahal. The usual dosage of colistin is 5 mg/kg per day, but researchers have experimented with dosages as high as 15 mg/kg per day.
In 2005, the Food and Drug Administration approved Tygacil (tigecycline), a novel antibiotic with a broad spectrum of antimicrobial activity, including activity against the drug-resistant bacteria methicillin-resistant Staphylococcus aureus. The drug shows activity in vitro against multidrug-resistant Acinetobacter, but what effect the drug will have clinically is unknown, said Dr. Rahal.
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