|Have you ever not finished a
course of antibiotics prescribed for you? Ever taken the remaining pills
months or perhaps a year later, when similar symptoms occurred? What about
giving leftover medications to a friend or colleague who seemed to have
the same ailment you were diagnosed with? Have you ever called or gone
to your doctor determined to "get something" to alleviate discomfort
or pain, even if it meant overstating your symptoms, or pressured a pediatrician
for medication for a feverish child?
If the answer to any of these questions is yes, you have contributed to a growing, worldwide problem - bacteria that have become resistant to antibiotics. Physicians are also to blame. Their sins include overprescribing the drugs, using a wide-spectrum therapy when a more directed drug would be better, and improper use of them as prophylactics.
None of these germs has a single brain cell, so they aren't technically outwitting us. They are simply behaving in Darwinian fashion, adapting in order to survive. And unlike mutations that may take hundreds of years to evolve in animal species, these are happening much more quickly.
That's because a microbe like E. coli - the source of many intestinal illnesses - reproduces about every 20 minutes. Each time, there is the possibility that the germ's DNA may undergo an alteration that will produce a new strain, one that is able to foil the antibiotic directed against it. Although most of the organisms will be killed by the drug, the mutants will survive, multiply and become the dominant strain.
With molecular typing, scientists are able to keep tabs on these variants, explains Lisa Dever, MD, chief of the infectious disease clinic at the Department of Veterans Affairs Medical Center in East Orange. "They take the DNA, digest it with certain enzymes, embed it in agar and expose it to an electric field. That pulls the DNA apart, and they can look at the molecular weights to identify fragments."
Then the strain is tracked - through a hospital, across a country and over continents. In "The Coming Plague" (Farrar, Strauss and Giroux, 1994), author Laurie Garrett describes the journey of S. pneumoniae, type 19A. It was identified in 1977 in Durban, South Africa - in five small children hospitalized for other reasons. Three of them died. Laboratory tests showed that the microbe was resistant to many antibiotics, including penicillin, ampicillin, cephalothin, streptomycin, methicillin, erythromycin, gentamicin and tetracycline.
It responded to rifampin, but didn't disappear. The following year it resurfaced in a child hospitalized in Johannesburg. The germ spread to dozens of patients and hospital workers, and three died. From South Africa, the bug traveled to Spain, Hungary, England, the U.S. and is now all over the world. Garrett reports that all of these outbreaks can be traced to a single clone, one transformed bacterium.
The organisms causing most U.S. hospital-based infections, says Dever, who is also an assistant professor of medicine at UMDNJ-New Jersey Medical School, are Staphylococcus aureus and enterococci.
Both developed resistance first to penicillin and then to the next drugs of choice: staph to methicillin and enterococcus to vancomycin. In some instances, Enterococcus facium has become so dependent on vancomycin the bug needs it to flourish. Dever reported one such case in the October 1995 issue of the Journal of Clinical Microbiology.
It involved an 82-year-old man, admitted to the VA hospital from a nursing home, whose symptoms included fever, cough and diarrhea. He had been treated with ciprofloxacin and amoxicillin for 10 days prior to being admitted.
The patient was diagnosed with pneumonia and intravenous ceftazidime was given. He was also given oral vancomycin to treat his diarrhea, which was thought to be due to Clostridium difficile, a bacterium that can cause colon infections in people who have received antibiotics.
As part of a surveillance study for resistant enterococci, a stool sample had been obtained upon admission, and a vancomycin-resistant strain of the organism was grown. After a 10-day course of vancomycin, a second strain was recovered - one that required the drug to survive.
Gram-negative bacilli, like psuedomonas, are also a problem. (Staining bacteria is done for identification purposes, and they are classified as gram-negative or gram-positive, depending on whether or not they hold the stain.) Psuedomonas are a likely cause of hospital-acquired pneumonias and patients may then develop acute respiratory distress. "The organisms make toxins," Dever explains, "but it is the inflammatory response to the infection that causes low blood pressure and organ failure. Even with appropriate antibiotics, you're sometimes not able to rescue the patient. If the organisms are resistant to antibiotics, the situation is even worse."
E.coli - the source of many intestinal illnesses - reproduces about every 20 minutes. Each time there is the possibility that the germ's DNA may undergo an alteration that will produce a new strain, one that is able to foil the antibiotic directed against it
The pathogens flourish in these settings because people in a weakened condition are most susceptible to them. "With patients getting more ambulatory care, those in hospitals are usually quite sick," she points out. "They tend to need more extensive therapies and invasive tests - more catheters, IVs, etc. - and that puts them at greater risk for infections."
Dever got interested in enterococci when she came to the VA. "It's now endemic in hospitals in the Northeast," she notes, "particularly those that care for chronically ill patients."
Gut flora is a term for all the bacteria that normally inhabit the intestine. They include enterococci, which become a problem when they get into the blood stream where they can cause septic shock and multiple organ failure. A likely scenario for someone to get the infection would be a case of ruptured appendix or a complicated abdominal surgery in which enterococci leak from the intestine.
The organism is present in feces, and with incontinent patients or those with severe diarrhea it's not hard for contamination to occur. Fecal matter can get on bedclothes or on someone's hand. "It may be only a few bacteria, but that's enough to cause a problem," Dever points out. "The organisms are relatively hardy - they can live on bedside railings, doorknobs, any surface for days to weeks."
She adds that hospital outbreaks of all these bacteria can be stopped by heightening awareness and enforcing strict infection-control measures - stringent cleaning with the appropriate disinfectants, isolating the infected patient and using barrier precautions. Health care workers must wear gloves and gowns when entering the room, the patient needs to have a dedicated stethoscope, thermometer, etc., and everyone must wash their hands carefully before entering and leaving.
The basis of resistance can be: a change in the DNA that alters the antibiotic's target; a major reorganization of a large segment of DNA that alters enzymes, allowing them to degrade an antibiotic or prevent its penetration of the cell; or taking genetic matter that encodes for resistance from another organism, as staphylococci do.
"One of the biggest fears about resistant enterococci is that they will transfer their vancomycin-resistant genes to staphylococci," observes Dever. "If that happens, we'll be left with nothing to treat staph, and it is a much more virulent organism."
Enterococci are very good at transferring genetic material to other organisms, she adds, even to bacilli that are very different from them structurally and genetically. "They mate and they are promiscuous," she says. "It's been accomplished in the lab. That's why there is a big push for new drugs."
The resistant strain is found mainly in people who have been treated with a lot of antibiotics, Dever notes: "Some studies done in Europe have shown it to be more common in people there, and that could be because of higher concentrations of antibiotics in their animal feed." People may get traces of the antibiotic itself or the resistant germ. No matter how high the standards are in processing, it's not a sterile procedure, Dever observes, so some bacteria are present.
Antibiotic resistance has led to the term "reemerging diseases," illnesses that were once under control but are now harder to treat. They include malaria, typhus, some Staphylococcus pneumonias, and the classic example, tuberculosis. (see TB: Still a Potent Threat)
Epidemiologist Stanley H. Weiss, MD, points out that the resistance concept also applies to cancer: "That's why we often use multiple therapies - because we expect that a proportion of malignant cells may develop a mutation that would allow them to counter one of the drugs."
An associate professor of preventive medicine and community health at New Jersey Medical School, he says a debate has raged for over a decade as to whether it's better to sequentially alternate drugs or to use the multiple-drug approach right away in the treatment of cancer. Due to drug toxicities, he adds, how and when to combine them is a key clinical issue.
"Newer data suggest that by giving the combination therapy up front you are preventing the initial emergence of resistance," Weiss notes. "We've seen this phenomenon with some chronic infectious diseases as well, such as TB, and with HIV and AIDS. The point is to think about the issue far enough in advance. Unfortunately, we've often been a step behind the pathogens and have had to play catch up."
Weiss thinks we are ingenious enough to cope with the problem, however, and one way is to find new classes of antimicrobial agents. He is intrigued by those that would involve such fundamental biologic properties that a pathogen would have to do much more than change an enzyme or block a molecule in order to counter a therapy.
He cites the research of Michael Zasloff, MD, PhD, who discovered naturally occurring antibiotic peptides in the skin of a frog in 1987, when he was at the National Institutes of Health. He dubbed the first one a "magainin," which is Hebrew for shield. Zasloff continues his research at Magainin Pharmaceuticals, which he founded in 1992.
"The evolving data suggest that these protective molecules in skin and lungs were an early type of localized defense," notes Weiss. "They are broad-based - protecting against fungi, viruses and bacteria. Maybe we can build on that, since these are the routes that many pathogens take to invade the body."
Novel therapies are very expensive to develop. Until recently modifications in existing antibiotics seemed to handle resistant strains of bugs. But the potential market for a new class of antibiotics is now large enough to give pharmaceutical companies a financial incentive, and they are working on it.
A major concern for epidemiologists like Weiss and Donald Louria, MD, who chairs the Department of Preventive Medicine and Community Health at the medical school, is how easily and quickly disease can spread in a world where international travel is commonplace.
- Newer data suggests that by giving combination therapy up front you
are preventing the initial emergence of resistance.
Concern about antibiotic resistance has prompted the Centers for Disease Control and Prevention to wage a campaign to make physicians and consumers aware of the risks they run in overusing drugs. In conjunction with the American Academy of Pediatrics and the American Society for Microbiology, the CDC published a pamphlet, "Your Child and Antibiotics." A million copies were printed and distributed last spring, according to Scott Dowell, MD, of the CDC's Childhood and Respiratory Diseases Branch.The pamphlet stresses that each course of antibiotics may increase the risk for carrying a resistant strain of the targeted pathogen, and warns that future infections will be harder to treat. Here are a few guiding principles relevant to the five upper-respiratory infections that lead to most visits to doctors and often to requests for antibiotics.
Fall 1997 Table of Contents