Presentation and Clinical Manifestation of Clostridium difficile-associated disease (CDAD)
Clostridium difficile is a spore-forming, gram-positive anaerobic bacillus that was first recognized as a major cause of antibiotic-associated diarrhea in 1977.1 Some strains of the bacterium (so called "toxigenic strains") produce two toxins, toxin A, an enterotoxin, and toxin B, a cytotoxin. Infection with toxin-producing C. difficile may result in a wide spectrum of clinical illness ranging in severity from diarrhea to inflammation of the colon and pseudomembranous colitis, to toxic megacolon, and death.2 Symptoms can occur within a few days of starting antibiotic therapy or a few months following a course of antibiotic therapy.
C. difficile is shed in feces as a highly contagious and easily spread spore.3 The organism survives on any surface, device, or material (e.g., commodes, bathing tubs, and electronic rectal thermometers) that becomes contaminated with feces. These surfaces may serve as a reservoir for the C. difficile spores and spores can be spread from patient to patient, patient to health-care worker to patient, or patient to inanimate object to patient.4
Diagnosis of CDAD can be confirmed by a number of different tests including culture of C. difficile, a cytotoxicity assay or detection of one of the toxins.5 Diagnosis can also be made by endoscopy and biopsy.5
Toxigenic C. difficile is now recognized as a frequent cause of antibiotic-associated diarrhea and colitis. It is implicated in up to 20% of patients with antibiotic-associated diarrhea and in more than 90% of those with antibiotic associated pseudomembranous colitis.6 VANCOCIN® HCl Capsules (vancomycin hydrochloride capsules, USP) can be used to treat antibiotic-associated pseudomembranous colitis caused by C. difficile.
CDAD occurs most commonly in patients who are hospitalized or in longterm care facilities.7 Most patients have been exposed to an antimicrobial agent (the most commonly implicated agents include third-generation cephalosporins, ampicillin or amoxicillin, and clindamycin).8 Later studies have linked flouroquinolones to CDAD and implicated these antimicrobial agents as important risk factors for CDAD.9 Other non-antimicrobial agents (such as doxorubicin, cisplatin, cyclophosphamide, and proton-pump inhibitors) have also been implicated as potential triggers for C. difficile disease.10,11 The exposure to an antimicrobial agent alters the microecology of the gut,4 making patients more susceptible to C. difficile acquisition and overgrowth. This, in addition to other risk factors, are likely to determine whether or not a patient develops C. difficile infection and what severity of disease ultimately presents.
The incidence of CDAD is generally higher in the winter months, probably associated with the increased incidence of infections such as community-acquired pneumonia requiring hospitalization and the use of broad-spectrum antibiotics. The overall incidence of CDAD is increasing,12 as the major risk factors for development of CDAD, namely increased age, antimicrobial use, increased severity of underlying illness, and surgical manipulation of the gastrointestinal tract, are more prevalent in hospitalized patients. Figure 1 shows age-specific growth in CDAD incidence in adults from 2000-2005.13
Figure 1. Changes in the age-specific Clostridium difficile–associated disease incidence rate per 10,000 population in the United States, 2000–2005.
Community acquired CDAD has been seen with increasing frequency in populations considered low risk such as non-hospitalized patients and peripartum woman.14,15 Diagnosis of CDAD in this population could be challenging because patients do not necessarily have traditional risk factors (eg, old age, recent microbial exposure, or recent hospitalization).14
The severity of disease may also be increasing due to the emergence of a highly virulent strain of Clostridium difficile (NAP1) expressing changes in susceptibility to antimicrobials (clindamycin-resistance16 and flouroquinolone-resistance), a variation in a gene that downregulates toxin production, and productivity of a "binary toxin" , the significance of which is unknown.17,18 As of October 2008, this strain has been reported in 40 states in the United States (Figure 2).
ref. http://www.cdc.gov/ncidod/dhqp/id_Cdiff_data.html
Figure 2. The States with the North American Pulsed Field Type 1 (NAP1) strain of C.difficile, October 2008.
In addition to the increased severity of disease a review of US deaths for the period 1999 – 2004 indicates an increase in the annual number of C. difficile related deaths.13 Clostridium difficile is an underecognized cause of severe illness and death.19 An epidemiologic study reported mortality rates from Clostridium difficile disease in the US increased from 5.7 per million population in 1999 to 23.7 per million population in 2004 (Fig. 3)19 The authors postulated that the increased rate of mortality may be due to the emergence of the highly virulent strain (NAP1) of Clostridium difficile.19
Figure 3. Yearly Clostridium difficile–related mortality rates per million population, United States, 1999–2004.
Recent reports of this more virulent and possibly more resistant strain of Clostridium difficile causing epidemics in both the US and Canada have heightened clinicians' awareness of CDAD emphasizing the importance of early recognition and appropriate treatment.9
Although the majority of patients will require specific drug therapy, discontinuation of antimicrobial therapy may be the only intervention necessary in 15% to 23% of patients.5, 20, 21 A number of antibiotics have been shown to have some activity against C. difficile, but the most effective and most widely used are oral vancomycin (the only FDA-approved treatment) and metronidazole.5
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VANCOCIN® HCl Capsules may be administered orally for treatment of enterocolitis caused by Staphylococcus aureus (including methicillin-resistant strains) and antibiotic-associated pseudomembranous colitis caused by Clostridium difficile. Parenteral administration of vancomycin is not effective for the above indications; therefore, VANCOCIN HCl Capsules must be given orally for these indications. Orally administered VANCOCIN HCl Capsules are not effective for other types of infection.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of VANCOCIN HCl Capsules and other antibacterial drugs, VANCOCIN HCl Capsules should only be used to treat or prevent infections that are proven or strongly suspected to be caused by a susceptible bacteria. When culture and sensitivity are available, they should be considered in selecting or modifying antibacterial therapy.
Adverse events include nephrotoxicity, ototoxicity, reversible neutropenia, thrombocytopenia, and "Red Man's Syndrome." In patients with renal dysfunction or those receiving concomitant therapy with an aminoglycoside, serial renal function testing should be performed. In patients receiving concomitant therapy with another ototoxic agent, serial tests of auditory function may be helpful in order to minimize the risk of ototoxicity. Infrequently allergic reaction, including anaphylaxis, and exfoliative dermatitis have been reported.
Clinically significant serum concentrations of vancomycin have been reported in some patients treated with VANCOCIN HCl Capsules for pseudomembranous colitis caused by Clostridium difficile. It is noteworthy that total systemic and renal clearance of vancomycin are reduced in the elderly. Monitoring of serum concentrations may be appropriate in patients with renal insufficiency and/or colitis.
VANCOCIN HCl Capsules are contraindicated in patients with a known hypersensitivity to vancomycin.
References
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