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Clostridium difficile: An intestinal infection on the rise

JUN 2010

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When you're admitted to a hospital, you expect to receive tests and treatments that will make you feel better. When you get antibiotics in the hospital, you expect that the drugs will treat or prevent infection. But it doesn't always work that way. A distressing number of patients acquire infections while they are in the hospital. And antibiotic therapy can actually increase the odds of coming down with a hospital-acquired infection, particularly when the cause is a bacterium named Clostridium difficile. Although doctors are working hard to control intestinal infections caused by the bug commonly (if not fondly) known as C. diff, the problem is rapidly becoming more common, more serious, and harder to treat.

Intestinal fortitude

No man is truly alone. Instead, the human body is teeming with bacteria. Each person's body is made up of about 10 trillion cells — and each of us plays host to about 100 trillion bacterial cells. Most are harmless, and even the potentially bad actors usually behave themselves, especially if they stay put on tissues that have learned to accommodate them. And some of the body's resident bacteria are actually quite helpful.

The gastrointestinal (GI) tract is a prime example of the co-existence between humans and their germs. The average GI tract harbors 500 to 1,000 different microbial species that take up residence in infancy and call the GI tract home throughout life. The vast majority of these critters reside in the lowest part of the GI tract, the colon, or large intestine. In fact, fecal material is composed largely of wall-to-wall bacteria.

The most numerous bacteria go by fierce names such as E. coli, Proteus, Klebsiella, Enterococcus, and Bacteroides. Each of these germs can cause disastrous illnesses if it works its way into the bloodstream or invades various tissues. But in the colon, these bacteria are harmless. In fact, the normal colonic bacteria make important contributions to health. They produce vitamin K, stimulate the immune system and help establish the proper balance between its components, and detoxify various chemicals that might otherwise be harmful. And another vital role of normal bacteria is to crowd out and suppress would-be pathogens, including C. diff.

A bit player takes center stage

C. diff is the most important cause of infectious diarrhea in the United States, but it's a bit player on the long roster of intestinal bacteria. In fact, only 1% to 3% of healthy adults harbor C. diff among their normal intestinal bacteria, and, even then, C. diff is present in tiny numbers and is usually harmless.

What has turned a bit player into a major pathogen that is wreaking havoc on a rapidly growing number of Americans? Surprisingly, perhaps, the culprits are antibiotics. It sounds paradoxical, but it's not. Antibiotics are supposed to inhibit or kill bacteria, and they do. When used properly, they target aggressive bacteria that are causing infections. But even when they succeed at that task, they inevitably cause collateral damage to bacteria that are innocent bystanders in the human body. When normal intestinal bacteria are bumped off by friendly fire, a void is created. With increasing frequency, C. diff seizes the opportunity to fill the void — especially in hospitalized patients, many of whom are already weakened and ill-prepared to withstand the stress of diarrhea and fever.

C. diff: Up close and personal

Scientists discovered C. diff in 1935, but they didn't recognize it as the major cause of antibiotic-associated diarrhea until 1978. The rise of C. diff in the 1970s was triggered by the widespread use of the antibiotic clindamycin. Over the next 20 years, broad-spectrum antibiotics in the penicillin and cephalosporin families fueled the C. diff epidemic, and in the early years of this century, fluoroquinolone antibiotics were linked to a new and more dangerous hypervirulent strain of C. diff.

C. diff is classified as an anaerobic bacterium because it thrives in the absence of oxygen. Like its cousins, the Clostridia that cause tetanus, botulism, and gas gangrene, C. diff passes through a life cycle in which the actively dividing form transforms itself into the spore stage. Spores are inert and metabolically inactive, so they don't cause disease. At the same time, though, spores are very tough and sturdy; they are hard to kill with disinfectants, and they shrug off even the most powerful antibiotics.

Here's how C. diff causes trouble. Patients with C. diff shed spores into their feces. Without strict precautions, spores are inadvertently transmitted to hands, utensils, and foods, and then swallowed by someone else. The spores come to life in the second person's GI tract, but in the best of circumstances, the normal bacteria keep C. diff in check and illness does not develop. But if the "good" GI bacteria have been knocked down by antibiotics, C. diff gets the upper hand. As C. diff multiplies and grows, it produces toxins that injure the lining of the colon, producing diarrhea, inflammation, and sometimes worse. Ordinary strains of C. diff produce two toxins, called toxins A and B, but the new, worrisome hypervirulent strains produce up to 16 times more toxin A and 23 times more toxin B.

Who gets C. diff?

Although C. diff can occasionally crop up without rhyme or reason, the vast majority of its victims are patients in hospitals or long-term care facilities — and the great majority of them have received antibiotics. Virtually any antibiotic can pave the way for C. diff, but the most frequent offenders are the drugs that are most likely to alter the GI bacteria; in addition to clindamycin, common offenders include broad-spectrum penicillins, cephalosporins, and fluroquinolones. Patients with serious illnesses and prolonged hospitalizations are at particular risk, as are people above 65 years of age. Because stomach acid helps fight off C. diff, powerful anti-ulcer medications in the proton-pump inhibitor family may also increase vulnerability.

Symptoms

Healthy people can harbor C. diff without knowing it. In some cases, it's because they have a mutant strain of C. diff that doesn't produce toxins; in others, only tiny numbers of C. diff are present; and in still others, people have blood antibodies that neutralize toxins A and B.

When C. diff causes problems, symptoms range from mild to severe, even life-threatening. With their insatiable love of acronyms, doctors call the wide range of symptoms CDAD for Clostridium difficile–associated disease.

In its mildest form, CDAD produces watery diarrhea at least three times a day, usually accompanied by lower abdominal cramps. Bleeding and fever are absent, and patients have a normal number of white blood cells.

Patients with moderate CDAD have profuse diarrhea, abdominal pain, and fever. Nausea is common. The diarrhea does not usually look bloody, but tests may reveal traces of intestinal bleeding. Blood tests show a high white blood cell count.

In severe CDAD, the temperature and white blood cell count are very high, and the patient's blood pressure may be low, sometimes dangerously so, as severe diarrhea leads to dehydration. Intestinal bleeding may be dramatic. In its most critical form, CDAD leads to a complication called toxic megacolon, in which the colon is dilated and at risk for perforation.

Diagnosis

An experienced nurse may suspect CDAD because of the diarrhea's foul odor. But even with this clue, more precise testing is mandatory.

Although microbiologists can culture C. diff from the fecal specimens of patients with CDAD, the test is rarely employed because it's slow, cumbersome, and expensive. Instead of identifying the bacterium itself, the standard way to diagnose CDAD is to detect C. diff toxins in the patient's feces. The first tests were based on the fact that C. diff toxins produce visible damage to cells maintained in tissue culture. This cytotoxicity assay is a more sensitive and specific test for C. diff, but many labs have abandoned it because it takes 48 hours and is expensive.

The newer immunologic tests can identify C. diff toxin in a matter of hours. Most labs rely on these simple tests, but since a relatively large amount of toxin must be present to register positive, the enzyme immunoassays can miss a substantial minority of CDAD cases. If a doctor still suspects CDAD despite a negative immunoassay, he can order a repeat test or send a specimen to a lab that performs the cytotoxicity assay. And in the near future polymerase chain reaction tests may combine the sensitivity of cytotoxicity assays with the speed and simplicity of immunoassays.

If a patient's toxin test is positive, doctors need look no further to establish the diagnosis of CDAD. But if the assay is negative, they can sometimes make the diagnosis by looking a foot or two farther — in this case by inspecting the lining of the patient's colon through a sigmoidoscope or colonoscope. Expert technique and care are required, but in moderate to severe CDAD, the colon lining often displays a telltale series of yellowish plaques called pseudomembranous colitis. In such cases, CT scans often demonstrate thickening of the colon wall. And although imaging tests are not necessary in milder cases of CDAD, they are important in patients with moderate to severe disease who are at risk for toxic megacolon.

Standard treatment

The first step is to stop the antibiotic that triggered CDAD in the first place. It sounds simple, but it can be tricky in patients with an ongoing need for antibiotic therapy.

Although an antibiotic may have sparked CDAD, the next step in treatment is to fight fire with fire, in this case by administering an antibiotic that will kill C. diff. The best drugs are metronidazole (Flagyl) and vancomycin (Vancocin). Most experts recommend metronidazole for mild cases, vancomycin for moderate to severe disease. Since C. diff resides in the intestinal tract, these medications are best administered by mouth. However, patients with severe CDAD may benefit from intravenous metronidazole along with oral vancomycin (if the patient is able to take oral medication).

Ancillary measures may be helpful. Although it may seem paradoxical, most authorities caution against giving medication to slow diarrhea; in theory, at least, these medications may hamper the body's attempt to expel C. diff. On the other hand, cholestyramine (Questran) or colestipol (Colestid), orally administered resin medications ordinarily used to lower cholesterol levels, may help lessen symptoms in a helpful way, by binding the toxins themselves. Unfortunately, the resins also bind vancomycin, so they should never be administered with this antibiotic.

Severe CDAD may require an additional dramatic intervention. Because toxic megacolon is life-threatening, patients with this complication of CDAD require urgent surgery, which entails complete removal of the colon.

Alternative and experimental treatments

In most cases, mild to moderate C. diff. infections respond well to vancomycin or metronidazole. But some patients are slow to recover, and many others relapse. As a result, doctors are exploring new treatment strategies.

Since C. diff thrives when normal intestinal bacteria are suppressed, a logical approach is to crowd out the culprit by administrating harmless microbes called probiotics. In the case of C. diff, there is mixed evidence that certain probiotics (Saccharomyces and Lactobacillus species) may reduce the risk of developing CDAD, but there is little evidence that they can speed recovery once the process is underway.

Another approach is to develop newer drugs to treat CDAD. Rifaximin (Xifaxan) is an oral nonabsorbable antibiotic that is FDA approved for use in so-called traveler's diarrhea. Small studies suggest it may be effective for CDAD. A still-experimental toxin-binding resin, tolevamer, has also shown promise in mild to moderate CDAD.

Other experimental approaches testify to just how troublesome CDAD can be. Scientists are investigating intravenous immunoglobulin (IVIG) with the hope that these proteins from healthy blood donors may contain antibodies that can neutralize C. diff toxins. A 2010 study found monoclonal antibodies that specifically target C. diff toxins to be particularly helpful. Other trials involve giving vancomycin by enema to patients who are too ill to take the antibiotic by mouth. And intrepid investigators are also testing fecal bacteriotherapy, in which intestinal bacteria in normal fecal material are administered to CDAD patients by enema; if nothing else, it emphasizes the value of prevention (see below).

Round 2: Relapsing CDAD

Most patients with mild to moderate CDAD improve nicely with 10 to 14 days of metronidazole or vancomycin. If CDAD were an ordinary infection, that would be the end of the story. Unfortunately, though, about 20% of patients relapse after treatment stops. Metronidazole and vancomycin kill the active form of C. diff, so toxin production halts and diarrhea resolves. But the spore form of C. diff survives, and when therapy stops, the spores can spring to life and resume toxin production. If a patient remains clinically well after a course of treatment, it is not necessary to check his stool for C. diff toxins — but if diarrhea returns, such testing is mandatory.

In many infections, antibiotic failure suggests that the bacterial pathogen has become resistant to the antibiotics that have been administered. But C. diff breaks this rule, too, since the bacterium almost always remains susceptible to vancomycin and metronidazole. One approach to a first relapse is straightforward: another 10 to 14 days of one of the first-line antibiotics. Patients who respond and stay well can be considered a success — but a surprising number of patients relapse yet again.

Most experts recommend prolonged therapy with vancomycin for the second recurrence. One plan calls for tapering the dose over a one-month period; another calls for intermittent therapy.

There is less agreement about the best management for additional relapses. One option is vancomycin followed by rifaximin. But some experts turn to experimental treatment with IVIG, probiotics, or fecal bacteriotherapy. And in all cases, measures to prevent the spread of C. diff are essential.

Contain and control

C. diff is a preventable infection. Prevention begins with a prompt diagnosis of CDAD so control measures can take effect before C. diff spreads. Contact precautions are essential for CDAD patients who are in hospitals or other care facilities. Whenever possible, the patient should be moved to a private room with a private bathroom or commode. All medical, nursing, and ancillary personnel should cleanse their hands and then don gloves and a gown before coming in contact with the patient. The gown and gloves should be placed in appropriate receptacles as caregivers leave the room.

Nearly all hospitals rely on alcohol-based hand cleansers for hand hygiene and infection control. But C. diff breaks that rule, too, as its spores resist alcohol. So in addition to alcohol disinfectant, people who come into contact with C. diff should use good old-fashioned soap and running water with vigorous scrubbing and thorough rinsing. Soap doesn't kill the spores, either, but scrubbing can physically remove many of them.

Because C. diff spores can survive on dry surfaces for weeks and months, environmental surfaces in a patient's room also require special care. Hypochlorite-based solutions appear best.

When CDAD strikes at home, precautions can help protect household contacts. Hand hygiene with frequent soap and water scrubbing is essential, both for the patient and his contacts. Patients with diarrhea should not prepare food for others, and if possible, they should use separate utensils and a separate toilet. Kitchen and bathroom surfaces and fixtures should be cleansed with a bleach solution, diluted one part bleach to 10 parts water.

Turn back to move ahead

C. diff is an old bacterium, but the CDAD epidemic is relatively new. What turned a medical curiosity into a major threat? In a word, antibiotics.

Antibiotics are marvelous medications, and they are obviously here to stay. But doctors must use them wisely. That means prescribing an antibiotic only when it's truly necessary, choosing the simplest, most narrowly focused drug that will do the job, and stopping treatment as soon as the job is done. Patients can help by resisting the temptation to demand an antibiotic for every potential infection.

When it comes to using antibiotics properly, less can be more.