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Tips to combat three common drug-resistant infections

From the March ACP-ASIM Observer, copyright © 2003 by the American College of Physicians-American Society of Internal Medicine.

By Margie Patlak

While antibiotic-resistant infections were once confined to hospitals, resistance is increasingly rearing its ugly head in outpatient settings. Drug-resilient bugs are cropping up in a growing number of outpatient practices, and in some parts of the world they are winning the war against antibiotics in diseases like gonorrhea.

Besides disrupting the treatments physicians use for common infections, drug-resistant microbes are bringing medicine closer to the day when some infections simply won't respond to standard drug therapies.

To avoid that worst-case scenario, public health officials are urging physicians to rethink their prescribing practices. The goal is not only to combat the growing threat of antibiotic resistance, but to avoid giving patients drugs that ultimately won't help them fight off infections.

Here's what the experts say you should do about three frequently encountered infections: urinary tract infections, community-acquired pneumonia and gonorrhea.

Urinary tract infections

For the last 20 years, doctors have treated community-acquired urinary tract infections (UTIs) with trimethoprim-sulfamethoxazole (TMP-SMX). This combination quickly tackled the variety of bacteria that cause UTIs—in just three days.

Emerging evidence indicates, however, that you may no longer be able to count on TMP-SMX. Recent research has found that Escherichia coli—the culprit behind most common UTIs—has become increasingly resistant to the therapy.

One study in Washington state, for example, found that the number of TMP-SMX resistant strains of E. coli have doubled in just four years. Another national survey conducted in 2000 found that nearly one in five UTI isolates of E. coli can now fight off the drug.

But the studies don't mean that you can't prescribe TMP-SMX for common UTIs. In fact, researchers, are quick to point out that TMP-SMX may treat a resistant strain of E. coli. That's because doses of the drug typically produce high enough concentrations in patients' urine to overcome resistance.

So how can you tell if drug resistance is a problem in UTI treatment? Recent guidelines from the Infectious Diseases Society of America (IDSA) say you should check local resistance data.

When the prevalence of TMP-SMX resistance reaches 20% in your community, consider alternative treatments. You should also seek other options if local TMP-SMX resistance prevalence reaches 10% and you are treating diabetics or patients with other complications that could hamper recovery from a urinary infection.

The guidelines may not help most doctors, however, because many public health departments do not routinely monitor antibiotic resistance in microbes that cause UTIs. And knowing national resistance levels doesn't help either since rates of resistance vary regionally. Researchers have found significantly more antibiotic-resistant E. coli in the West and Southwest, for instance, than in the Midwest and Northeast.

"This points out a problem for many common community-acquired infections," said Walter E. Stamm, FACP, head of the University of Washington's division of infectious diseases and co-author of the IDSA guidelines. "We really don't know local incidences of resistance."

If you don't have local resistance data, watch for patients who are good candidates for harboring drug-resistant bacteria. They include individuals who currently use or have recently used TMP-SMX or another antibiotic, patients who have recently been hospitalized or individuals who have had a recurrent UTI in the past year.

If you're treating patients with uncomplicated UTIs you think might harbor resistant bacteria, try an antibiotic other than TMP-SMX. Dr. Stamm said good alternatives include a fluoroquinolone (three-day regimen), nitrofurantoin (seven-day regimen) or fosfomycin (single dose). While these alternatives can combat TMP-SMX resistant strains, Dr. Stamm acknowledged that each drug has its own problems.

For example, experts worry that the widespread use of broad-spectrum fluoroquinolones to treat UTIs will foster fluoroquinolone resistance in many other pathogens, including those that cause pneumonia, gonorrhea and skin infections.

To prevent those complications, some doctors avoid prescribing fluoroquinolones, choosing narrow-spectrum antibiotics such as nitrofurantoin and fosfomycin instead. But although these drugs primarily affect the urinary tract, they typically cure only about 75% of UTIs. (Fluoroquinolones, by comparison, usually cure 90% to 95%.)

"It's a difficult decision, because you have to balance the benefits and risks for the patient with the longer term benefits and risks for society," Dr. Stamm explained. "Most practitioners are not too wild about having patients experience treatment failures, even if those incidents could contribute to a greater long-term good."

Infection severity is one factor that should guide your decision-making. "If I saw someone with a lot of cramping and hematuria, then I might go with a fluoroquinolone," said Dr. Stamm. "For a mild case of cystitis, I might use TMP-SMX and switch to a fluoroquinolone only if the infection turned out to be TMP-SMX resistant." And with patients who have severe infections that spread to the kidneys, he added, he's use fluoroquinolones immediately.

Cost is another concern, he pointed out. Nitrofurantoin is the least expensive treatment option, while fluoroquinolones cost the most in terms of purchase price. But Dr. Stamm added that some studies show fluoroquinolones may actually be more cost effective once you factor in repeat office visits and retreatment costs because of treatment failures.

Because such a narrow range of microbes cause UTIs, experts say you can still treat these infections without culture results. When therapy fails, however, you must perform a urine culture and susceptibility testing. You can then use these test results to tailor your antibiotic choices.

Community-acquired pneumonia and meningitis

Streptococcus pneumoniae, the main cause of community-acquired pneumonia in this country, is becoming increasingly resistant to many antibiotics.

According to 2001 CDC surveillance data, about one-quarter of S. pneumoniae strains are now resistant to penicillin, and a somewhat higher percentage resist TMP-SMX. A moderate number (nearly 20% of surveyed strains) are resistant to cefotaxime and erythromycin, while few strains can successfully resist the fluoroquinolone levofloxacin and none are resistant to vancomycin.

Just like with E. coli, data show that S. pneumoniae's ability to fend off treatments varies geographically. The Southeast is again a hotbed area: nearly 50% of all surveyed strains there are drug-resistant.

There is some good news for clinicians. Some of the definitions of resistance are based on clinical effects of various S. pneumoniae strains on meningitis, not pneumonia. Many practitioners may fail to recognize that currently used doses of penicillin and some second- and third-generation cephalosporins will produce high enough concentrations in lung tissue to overcome even resistant strains of S. pneumoniae.

Several recent clinical studies looked at patients with community-acquired pneumonia caused by infections resistant to penicillin or other beta-lactam antibiotics. In some of these studies, researchers found that patients with resistant S. pneumoniae strains fared just as well as those with non-resistant strains. Even more surprising, those results were maintained even when patients were treated with an antibiotic that the bacteria supposedly resisted.

However, most of the studies that found no difference in outcomes focused on patients with infections with low levels of resistance. Other studies that examined patients with highly resistant infections found a link between resistance and poor outcomes.

The important message, according to Daniel M. Musher, FACP, professor of medicine and of molecular virology and microbiology at Baylor College of Medicine in Houston, is that physicians don't necessarily have to change their prescribing patterns for pneumonia based on resistance trends for penicillins and many beta-lactam antibiotics. "Cephalosporin and penicillin resistance as it's been traditionally defined is usually overcome by the dosages we routinely use to treat pneumonia," said Dr. Musher, who is also head of infectious diseases at Houston VA Medical Center. He noted, however, that S. pneumoniae strains that are resistant to erythromycin or other macrolide antibiotics can be more problematic.

So what drugs should you use to treat S. pneumoniae in an outpatient setting? Practice guidelines from the IDSA and a CDC-sponsored report on drug-resistant S. pneumoniae say you can use a wide range of drugs as first-line treatments, including the following:

  • amoxicillin (500 mg three times daily);
  • cefuroxime axetil (500 mg twice daily);
  • azithromycin, clarithromycin, or erythromycin (normal dosages);
  • doxycycline (normal dosages);
  • tetracycline (normal dosages);
  • a fluoroquinolone (normal dosages).

Physicians need to consider the rising rate of resistance to macrolides and doxycycline when selecting therapy for individual patients. "A patient whose story suggests pneumococcal, rather than so-called 'atypical' pneumonia, should probably be treated with amoxicillin, with or without clavulanic acid," Dr. Musher said.

For hospitalized patients with proven pneumococcal pneumonia, experts recommend ampicillin with or without clavulanic acid (1-2 g every six hours), cefotaxime (1 g every six to eight hours), or ceftriaxone (1 g every 12 to 24 hours). For critically ill patients, you should always use a combination of agents.

Vancomycin can combat even resistant strains of S. pneumoniae. To avoid producing vancomycin-resistant strains, however, the report sponsored by the CDC recommends against using it to treat pneumonia. Guidelines from the IDSA suggest reserving it solely to treat pneumococcal pneumonia patients who are critically ill and allergic to beta-lactam antibiotics.

And while newer fluoroquinolones like levofloxacin, gatifloxacin and moxyfloxacin give physicians new weapons to fight S. pneumoniae, many experts worry that strains resistant to these drugs will also emerge. As a result, they suggest using these fluoroquinolones only in the following circumstances:

  • Other regimens have failed.
  • The patient is allergic to other antibiotic choices.
  • The patient has an infection with a highly resistant pneumococci.

Because drug resistance has been growing so quickly, most experts say physicians should test cultured sputum or blood samples from all patients whom they suspect have pneumonia. Such testing should determine not only the cause of the infection, but also the susceptibility of the cultured microbes to common antibiotics. And if a patient isn't responding to therapy, the tests can help you tailor your treatment.

For some resistant strains, consider increasing your dose of beta-lactam antibiotics. Penicillin-resistant pneumococcal infections almost always respond to large doses of amoxicillin or cephalosporins, Dr. Musher said. If patients fail to respond, you should re-evaluate them and retest the sensitivity of the infecting organisms.

Most guidelines recommend boosting beta-lactam antibiotic doses for pneumonia caused by organisms that are penicillin- or cephalosporin-resistant, but they don't give specific dosages. In such cases, Dr. Musher said, physicians must use the "art of medicine." He did note, however, that boosting the dose of macrolides to treat S. pneumoniae strains resistant to them will probably not work.

Resistant S. pneumoniae strains are even more dangerous when they lurk in the cerebral spinal fluid, which has limited immune defenses. In addition, antibiotics usually penetrate the fluid only in low concentrations. Resistance data, therefore, can often accurately predict which drugs will fail to treat meningitis.

Because S. pneumoniae is now the most common cause of bacterial meningitis in North Americans older than one year, you need to treat meningitis carefully. (Successful vaccines have nearly wiped out meningitis caused by Haemophilus influenzae and are also reducing cases caused by S. pneumoniae.)

"Pneumococcal meningitis is a dreadful disease with no margin of error," Dr. Musher said. When you suspect a patient has meningitis, start by assuming that a resistant strain of S. pneumoniae may be the cause. Treat it immediately with maximum doses of vancomycin plus ceftriaxone or cefotaxime.

Gonorrhea

Gonorrhea, the second most common infectious disease reported to the CDC after chlamydia, has a long history of antibiotic resistance. Neisseria gonorrhoeae developed significant resistance to sulfa drugs by 1945, just nine years after the drugs debuted as gonorrhea treatment. While penicillin and similar antibiotics were successfully used for decades, antibiotic-resistant N. gonorrhoeae became commonplace by the 1980s.

Because penicillin- and tetracycline-resistant strains of N. gonorrhoeae have become increasingly common, those antibiotics were abandoned as treatment options. In 1987, ceftriaxone was the only CDC-recommended treatment for gonorrhea, although ciprofloxacin was added in 1989, soon after fluoroquinolones were introduced.

While major problems with fluoroquinolone-resistant strains in the United States are mainly limited to California and Hawaii, infectious diseases experts worry that those strains will spread. CDC data show that the number of fluoroquinolone-resistant N. gonorrhoeae strains detected in their samples doubled in the United States between 2000 and 2001.

Fluoroquinolone resistance is booming in a variety of strains, while resistant strains already dominate in many Asian nations such as the Philippines.

What can you do to make sure your patients get the best treatment that won't spread resistant strains any further?

"Routinely asking about travel history is important," said Susan Wang, MD, coordinator for CDC's antimicrobial surveillance for N. gonorrhoeae. To treat uncomplicated gonorrhea infections acquired where resistant strains are common—Hawaii, California or the Far East—the CDC recommends using cefixime (if available) or ceftriaxone as a first-line treatment. If cefixime is available, use a single 400 mg oral dose. If not, try a single 125 mg intramuscular injection of ceftriaxone.

Unfortunately, the sole manufacturer of cefixime in this country—Wyeth Pharmaceuticals—stopped making the drug last July, and its patent expired in November. That leaves ceftriaxone as the only CDC-recommended option to treat fluoroquinolone-resistant N. gonorrhoeae infections.

Physicians have no oral alternatives to offer patients with resistant infections, since the CDC does not recommend other oral antibiotics such as cefpodoxime, cefuroxime axetil or azithromycin to treat gonorrhea. Officials say these drugs either have not shown sufficient effectiveness in clinical trials or have frequently caused adverse side effects at the dose necessary to treat gonorrhea effectively.

Where fluoroquinolone-resistant strains are uncommon, the CDC recommends treating uncomplicated gonorrhea with the fluoroquinolone drugs ciprofloxacin (a single 500 mg oral dose), ofloxacin (a single 400 mg oral dose) or levofloxacin (a single 250 mg oral dose).

When using recommended regimens to treat patients with uncomplicated gonorrhea, you don't need to test them to confirm they have been cured. You should, however, test patients with persistent symptoms to see if they harbor drug-resistant gonococci, even if their symptoms may be due to reinfection and not a resistant infection. Report all resistant infections to your local public health department and treat them with ceftriaxone or cefixime if available.

Recent troubling reports from Japan indicated that some strains of gonorrhea may be losing susceptibility to some cephalosporins. "That's cause for alarm, because if those strains become widespread, we could lose ceftriaxone or cefixime as options," Dr. Wang said. "We're worried about what will happen if we lose ceftriaxone. We need more drugs available to treat gonorrhea effectively."

It's not only the watchdogs for gonorrhea who are worried. The problem of drug resistance is becoming so widespread and growing so acute that some experts grimly predict an impending "post-antibiotic era" when antibiotics will not be effective against a broad array of infections. Many blame the current overuse of antibiotics to treat suspected bacterial respiratory or ear infections.

"We're held hostage by what's also being used for other infections, not just in American patients, but in agriculture and abroad," Dr. Wang said. "If a person has a sinus infection and also carries some N. gonorrhoeae, that gonorrhea strain will be exposed to several days of whatever the patient gets for the sinus infection, in addition to the antibiotics in food." That exposure boosts the likelihood that resistance will emerge in the gonorrhea strain.

Antibiotics are so heavily used, that "It would be strange not to see the emergence of resistance," Dr. Wang added. "The fact that organisms develop resistance is not necessarily a flaw of the antibiotics, but of the human beings who use them."

Margie Patlak is a freelance science writer in Elkins Park, Pa.

The information included herein should never be used as a substitute for clinical judgment and does not represent an official position of ACP-ASIM.

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For more information

The CDC's new guidelines on using antibiotics for respiratory tract infections are online.

For information on the College's efforts to combat emerging antibiotic resistance, click here.

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Drugs to treat three common infections

Uncomplicated UTIs

  • Trimethoprim-sulfamethoxazole (TMP-SMX)
  • Nitrofurantoin
  • Fosfomycin
  • Fluoroquinolone

Community-acquired pneumococcal pneumonia
For outpatients:

  • Amoxicillin
  • Cefuroxime axetil
  • Azithromycin, clarithromycin or erythromycin
  • Doxycycline
  • Tetracycline
  • Fluoroquinolone

For hospitalized patients:

  • Cefotaxime
  • Ceftriaxone
  • Ampicillin plus a macrolide
  • Vancomycin
  • Newer fluoroquinolones (levofloxacin, gatifloxacin or moxifloxacin)

Gonorrhea

  • Fluoroquinolones (ciprofloxacin, ofloxacin, or levofloxacin)
  • Cefixime (if available)
  • Ceftriaxone

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