WASHINGTON, D.C. The 1990s may be remembered as the decade of resistance.
Organisms are developing strong resistances to many antibiotics, and researchers at several recent conferences expect those numbers to increase.
Among the reasons for this microscopic rebellion are the overprescribing of antibiotics by doctors and the misuse of these medications by their patients.
Some of the organisms found to have developed resistance to multidrug therapies are Staphylococcus aureus, Enterococcus, Klebsiella, Enterobacter, Escherichia coli, Pseudomonas, Acinetobacter, pneumococcus, gonococcus and Mycobacterium tuberculosis.
New antibacterials are in the process of, or already have been, deployed against the resistant organisms; cefepime (Maxipime, Bristol-Myers Squibb), meropenem (Merren, Zeneca), levofloxacin (Levaquin), sparfloxacin (Zagam) and the experimental drug Synercid (quinupristin/ dalfopristin) which Rhone-Poulenc Rorer is rushing to complete and submit for approval. (Levofloxacin and sparfloxacin are quinolones, which are not indicated for children.)
Antibiotic resistance is a global problem, confronting hospitals, communities and nations worldwide. "[Bacteria] that consistently have been susceptible to all antimicrobial agents for decades now have developed resistance not only to the classic therapies but to the newer agents as well," said John E. McGowen Jr., MD, professor of epidemiology at Emory University School of Medicine in Atlanta, one of many epidemiologists tracking antimicrobial resistance. "It's important that the proper use of antibiotics and the problems associated with their misuse be conveyed to everyone."
The first signs of bacterial resistance appeared more than 50 years ago. In 1940, scientists had already identified the presence of an enzyme that inactivated the effects of penicillin in E. coli Then, just four years later, a similar type of enzyme was found by epidemiologists in S. aureus.
"Even before penicillin came into widespread use, resistance was already cropping up in both gram-positive and gram-negative organisms," he said.
Then, in the 1970s, there were reports of organisms resistant not only to penicillin-type drugs, but other classes of antimicrobial agents, such as aminoglycosides, chloramphenicol and tetracycline.
It has only been in the last few years that a handful of organisms have become resistant to all known antimicrobial agents. Several strains of enterococci, Acinetobactor and Pseudomonas aeruginosa are now virtually impregnable to the effects of antibiotics. Fortunately for the public, these organisms remain the rare exceptions, but, McGowen said, the conditions favoring the development and spread of such organisms are abundant.
Several studies have found a higher prevalence of antimicrobial resistance in hospitals especially among intensive care units (ICUs). Recent information indicates that the rate of resistance to vancomycin in hospital-acquired Enterococcus is increasing. Since December 1993, 14% of all enterococci associated with nosocomial infections in ICU patients were vancomycin-resistant. But antimicrobial resistance is not limited to the hospital setting. Streptococcus pneumoniae infections have been leading causes of morbidity and mortality in children, people with previous medical conditions and the elderly. Multidrug-resistant strains of this organism are surfacing throughout the country. Methicillin-resistant S. aureus, traditionally thought to be hospital-acquired, has been found in several communities in large numbers.
One of the greatest nightmares confronting the infectious disease community would be if vancomycin, currently the last line of defense against these drug-resistant bacteria, falls victim to resistance.
"We are not powerless to reverse this process, we simply have to begin using antibiotics intelligently again," said Craig Wood, MD, associate professor of medicine in the division of infectious diseases at Allegheny University of the Health Sciences. "Because if we lose vancomycin, we could be living like we did 50 years ago; all the [antibiotic] drugs we have now will be no good."
Over the last decade, antibiotic-resistant pneumococci have emerged to pose major threats to communities. Pneumococcal infections cause more than 1 million deaths worldwide.
There are several consequences to the spread of drug-resistant pneumococci, researchers said. Death or long-term sequelae may result from ineffective treatment of meningitis. Chronic or recurrent infections also may occur; for children with ear infections, this may result in hearing loss, developmental delay and the need for tympanostomy tubes. Ear and sinus infections may also spread to the bloodstream or central nervous system. The result of all of this has been more expensive antibiotic therapy, prolonged hospitalization and recurrent infection with a $4 billion annual price tag.
Benjamin Schwartz, MD, chief of the Childhood and Vaccine Preventable Diseases Epidemiology Section at the Centers for Disease Control and Prevention, said the bacteria resistance currently witnessed by the medical community is being encouraged by the widespread overuse of antibiotics.
"By killing susceptible organisms, antibiotic therapy provides a selective advantage to resistant organisms facilitating their spread," Schwartz said at a conference in Washington recently. "To reverse the spread of pneumococcal resistance we have to decrease the unnecessary use of antibiotics."
Schwartz said in this country alone more than 120 million courses of outpatient antibiotics are prescribed each year, of which about three-quarters are written for respiratory infections. He added that controlling the spread of resistance will require patients and doctors working together to limit the overprescribing and overuse of antibiotics.
"The course of action must change from one where antibiotics are expected and prescribed just to be safe to one where the safest course of action is not to prescribe an antibiotic unnecessarily," Schwartz said.
"Bacteria want to live and we want to kill them," Schwartz said. Bacteria are very adaptable and are known to share information with other bacteria, so we are now playing catch-up developing the new gram-negative antibacterials."
Increasing in the United States since the mid-1980s, drug resistant pneumococci are estimated to have caused more than 500 cases of meningitis, 5,000 cases of sepsis/bacteremia, 50,000 cases of pneumonia and 1 million cases of otitis media. Between 10% to 40% of all pneumococcal illness is due to drug-resistant strains. The groups most at risk are children younger than 2 years of age, blacks, American Indians, HIV-infected patients and people with immune system problems and children with sickle cell anemia.
Several steps are needed to deal with these new resistant organisms. The problem will not be solved until the entire health care system becomes involved. Among the most important measures will be improving the use of antibiotics.
"Using antibiotics conservatively is critical if they are to maintain their effectiveness," McGowen said, "be cause we have come as far as we can go with antibiotics."
For more information:
- McGowen JE, Tenover FC. Reasons for the emergence of antibiotic resistance. Am J Med Sci 1996:311.9-15.
- Schwartz B. Drug-resistant pneumococcus A challenge to the nation's health. Richard J. Duma/NFID Annual Press Conference and Symposium on Infectious Diseases. April 1997. Washington, D.C.
- Wood CA. New antibacterials. Presented at the American College of Physicians Annual Session. March 1997. Philadelphia.
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