Stronger, tougher bacteria force antibiotic crisis
March 1, 1999
Stronger, tougher bacteria force antibiotic crisis
Prescription restraint needed
The wonder drugs we’ve all taken at one time or another to eliminate the bacteria that make us ill are now a lot less wonderful than they used to be. Generations of exposure to antibiotics, especially the broad-spectrum variety, have made bacteria so much stronger and tougher that sometimes there’s nothing left in the medicine cabinet that works against a given microbe. The biggest reason for this increase in bacterial power may be overprescription of antibiotics.
According to a study recently published by Moshe Arditi, MD, director, Cedars-Sinai Medical Center Division of Pediatric Infectious Diseases in Los Angeles, controlling antibiotic usage in outpatient settings is now a national priority. Streptococcus pneumoniae, bacteria that can cause life-threatening infections and are a major threat to wound care patients, are rapidly becoming resistant to penicillin and cephalosporins such as ceftriaxone, the most widely used antibiotics currently available to treat bacterial infections.
Resistance rates double and triple in one year
Arditi’s three-year study of children suffering from pneumococcal meningitis covered 180 patients admitted to eight children’s hospitals between Sept. 1, 1993, and Aug. 31, 1996. The study looked at clinical presentation, hospital course, and outcome, taking into consideration the antibiotic resistance patterns of the pneumococci causing the infection. "If you look at each year of the three-year study and look at the percentages, you see a dramatic increase in antibiotic resistance between the second year, for example, and the third year," Arditi says. "In the second year, the penicillin non-susceptible rate [intermediate-susceptible and resistant organisms] was 13%. In the third year of the study, it jumped to 27%. For ceftriaxone, resistance in the first year was 1.7%. In the second year, it became 5%. In the third year, it jumped to 15%. In other words, resistance to ceftriaxone tripled between the second and third year of the study."
The rapid increase in resistance also is obvious when looking at the recent history of penicillin use. For example, 27% of the pneumococci were not susceptible to penicillin in 1996, the final year of this study. That compares to 0.02% reported less than a decade ago, according to Arditi.
There are two crisis-creating forces at work, according to Farrin A. Manian, MD, MPH, FACP, hospital epidemiologist at St. John’s Mercy Medical Center in St. Louis. One is that bacteria, strep pneumoniae chief among them, are becoming resistant in the hospital setting. "In our hospital, strep pneumonia on the adult floors is probably not fully susceptible to penicillin in about 30% to 35% of cases now. In our pediatric wards, over half the cases are not fully susceptible to penicillin anymore."
Manian says strep pneumonia is the most common cause of community-acquired pneumonia and a very common cause of otitis media. He adds that overprescription of antibiotics by community clinicians, often at the insistence of their patients, is the major culprit in the ability of this bacterium to become resistant so rapidly.
The bacterium most commonly present in patients with chronic illness in hospitals and nursing homes is Staphylococcus aureus. This organism, the most common cause of postoperative wound infections, is now resistant to antibiotics in many instances. In the past three years, Manian and his colleagues at St. John’s have seen more and more of these S. aureus isolates from postoperative wounds demonstrate resistance to the typical antibiotics — semisynthetic penicillins and cephalosporins. "In 1996, about 39% of the wound isolates that had Staph aureus in them were resistant to methicillin," Manian says. "In 1998, about 52% of Staph aureus are methicillin-resistant. The other big germ we are very much concerned about is enterococcus, which can cause wound infections and bloodstream infections. We have seen a significant rise in the resistance in these kinds of germs." Manian notes the concomitant rise of vancomycin-resistant enterococci (VRE), which is characteristically resistant to just about every antibiotic available. The incidence of VRE in wound isolates has gone up from 12.5% in 1996 to about 33% in 1998.
Touch control is the first line of defense
Manian says the first step to take in addressing this crisis is to institute appropriate touch control precautions — i.e., private rooms, gloving, strict hand washing, and gowning in the intensive care unit to minimize transmission from colonized patients to noninfected patients.
The second step is treatment of infected patients. "This often requires some creative antibiotic therapy, especially with the vancomycin-resistant enterococci," Manian says. "Only one drug works in the test tube: chloramphenicol. It’s an old drug that fell by the wayside because of its side effects. For many years it was hardly ever used. Now in our hospital we are using it on a quite regular basis because of the emergence of VRE. We have some isolates that have become resistant to chloramphenicol, too.
"I don’t see any immediate solution to the problem," Manian says. "I think it arose for a variety of reasons that are probably going to be staying with us for awhile. We’re taking care of a relatively sicker population than we have in the past. People are living longer, they are more immunosuppressed, they’re older, and so when they come in a hospital the average patient is certainly a lot sicker than they used to be. They are more susceptible to these kinds of infections in the first place, and I don’t see that changing.
"The second factor is the use of antibiotics. Anytime you place a patient on antibiotics, especially the ones who are quite ill and are going to be ill for awhile, you run the risk of having resistant germs emerge."
Michael Rybak, PharmD, professor of pharmacy and medicine and director of anti-infective research at Wayne State University in Detroit, says there are a number of new compounds in clinical trials, but because organisms have a tendency to change their resistance patterns more rapidly than drugs can be developed, new drugs are usually outpaced by the organisms themselves.
"The usual course for a normal drug development that goes from the laboratory bench through animals to humans and eventually to the prescriber is somewhere in the area of eight to 10 years," Rybak says. "There are plenty of drugs in development, but by the time they get to the prescriber so that they can be used on a widespread basis, it may be too late for many patients. There are a few that are pending FDA approval, but I wouldn’t say that they’re the magic bullet. Drugs in themselves will never be the cure-all type of therapy we’re looking for because they are only an adjunct."
Nevertheless, Rybak is looking forward to one drug pending FDA approval. The drug, called Synercid, will be marketed by Rhone-Poulenc-Rorer. "We’ve done quite a bit of research with this drug, both in patients and in the laboratory, and for a number of those resistant organisms, it’s going to be a very useful product," Rybak says.
Synercid initially will be available only for intravenous use, which will effectively restrict its use to the hospitalized infected community. In the future, there may be oral equivalents manufactured. According to Rybak, there is an oral product that has been in use for 25 years in Europe with an action that is somewhat analogous to Synercid, though Synercid has a minimum of two antibiotics in it and the European drug has only one. Resistance to that drug occurs more frequently than it would to two antibiotics.
Rybak says Synercid "will be a very welcomed addition to what we currently have in the face of gram-positive organisms, of which we are more fearful at the moment.
"Antibiotics are adjunctive to your immune system," Rybak observes. "People who come down with the most resistant kinds of organisms are usually quite debilitated, which increases the problem. If you combine [strengthening] the patient’s immune system, antibiotics, and good infection control practices, you really have a powerful type of therapy, but if you try to use only drugs you’re only going at one avenue of it. The spread of resistance is related to hospital personnel and the practice of medicine itself. Isolation of patients, hand washing, and so on are actually the most important tools. Unless you control the thread of resistance patient to patient, you run out of antibiotics too quickly because you can’t develop them fast enough."
The resistant organisms are coming from patients outside the hospital as well as patients in it. Patients put tremendous pressure on physicians to prescribe antibiotics for conditions that otherwise would resolve themselves. Prescribers in the community now have a much larger array of antibiotics than they’ve never had before. "Typically," Rybak says, "in the past the most powerful antibiotics would be prescribed only in a hospital. Patients with moderate to serious infections would normally be hospitalized. Now, many of these people are treated on the outside because community clinicians have such a powerful array of antimicrobials available to them."
Reference
1. Arditi M, et al. Three-year multicenter surveillance of pneumococcal meningitis in children: Clinical characteristics and outcome related to penicillin susceptibility and dexamethasone use. Pediatrics 1998; 102:5.
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