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C. difficile: Microbial emergency across US hospitals without effective therapy
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The rate of Clostridium difficile infection has tripled during the past 15 years, and the increase continues.
Reasons for the rise in rates of CDI across our hospitals are multiple and include a minimum of four factors in addition to increasing virulence of the organism. First, we are seeing an increasing number of elderly and infirm patients who represent perfect hosts for CDI.
Herbert L. DuPont
Second, hospitals are being asked to efficiently prepare rooms after a patient is discharged to receive a new patient. Methods being used may not successfully remove the C. difficile spores from the environment because of incomplete cleaning methods, including failure to use sodium hypochlorite in the cleaning of rooms of infected patients.
Third, most hospital diagnostic laboratories are moving to the very sensitive fecal polymerase chain reaction methods for detecting toxin genes of the organism. This approach is finding patients who with other methods may not be identified. Finally, inadequate therapy of patients with CDI is encouraging the persistence of the organism in hospital environments. This review focuses on the problem of inadequate therapy of CDI. Each of the other topics, the host, environmental contamination and the method of diagnosis of CDI are equally worthy of an expanded analysis and review.
Commonly used therapies
Currently, most infectious disease physicians are using metronidazole, which is not an FDA-approved medication, for the therapy of milder cases of CDI and assigning the approved oral vancomycin for more severe cases. The recurrence rate after either of these therapies is approximately 25%. A newly licensed drug, fidaxomicin (Dificid, Optimer Pharmaceuticals), has been shown to be as effective as oral vancomycin in leading to clinical cure and reduces the reoccurrence rate of CDI to approximately 15% for non-NAP1 strains (for this strain, both fidaxomicin and vancomycin cause the same rate of recurrence).
Figure 1. This micrograph depicts gram-positive C. difficile bacteria stool sample culture obtained using a .1mcm filter.
Source: CDC
The recommended duration of therapy with each of the three drugs is 10 to 14 days. Recurrent CDI (RCDI) is a serious problem seen by all infectious disease specialists involved with management of patients with CDI. Some patients with RCDI experience a series of recurrences that lead to literally years of intermittent illness and antibiotic treatments. This setting is among the most complex for us to manage. A high priority in our field is finding a management strategy that prevents recurrences.
Successful therapy
The four objectives of successful CDI therapy are:
1.Concentration of biologically active drug in the colon.
2.Intestinal reduction of vegetative cells and, eventually, spores of C. difficile.
3.Preservation and re-establishment of colonic microflora.
4.Facilitation of antibody development against the toxins of the organism.
These factors will each be considered.
- Objective 1: Metronidazole is pharmacokinetically flawed as an anti-CDI therapy. It is so well absorbed from the upper gut that little drug can be found in the colon where infection is found. Metronidazole works against the initial infection because the short gut transit time in active diarrhea drives the drug into the colon. Also, there is likely to be a serum drug component diffusing across the inflamed gut mucosa. After diarrhea and colitis decrease, however, the lack of metronidazole in the colon is unlikely to be sufficient to eradicate luminal bacteria.
- Objective 2: It is doubtful that 10 or 14 days of therapy is sufficient to reduce the gut burden of C. difficile, the second objective above. Some investigators have gone to chaser treatment after a conventional course of therapy of CDI with rifaximin (Xifaxan, Salix Pharmaceuticals), vancomycin or Saccharomyces boulardii to continue the antibacterial effect. Studies are needed to see whether prolonging the initial therapy may be all that is needed. Supporting that idea, we successfully treat another spore-forming infection, anthrax, with 2 months of antibiotics.
- Objective 3: Two drugs that seem to preserve colonic microflora the best are rifaximin and fidaxomicin, which may help to explain the value of the two drugs. One way clinicians have attempted to improve the microenvironment of the colon after a bout of CDI is to administer a probiotic such as S. boulardii.
- Objective 4: We have found that some patients do not mount an antibody to the toxins of C. difficile because of a genetic factor related to presence of a polymorphism in the interleukin-8 promoter gene. These patients show a very high rate of CDI recurrence. To assure the development of protective antibodies to the toxin, vaccines and humanized monoclonal antibodies to the two toxins are in development and appear likely to help reduce recurrence.
As infectious diseases specialists, we should not accept the high rate of recurrence of this disease. We need to perform well-controlled studies to determine the best way to accomplish a successful clinical response. There is reason to believe that we have the tools at hand now for successful therapy.