Another organism that has more recently become problematic is Clostridium difficile. Usually, normal gut flora resist overgrowth and colonization by this organism. However, antibiotic use that suppresses the normal gut flora, allows proliferation of C. difficile. The organism releases toxins that cause inflammation and damage to the mucosal lining of the colon, leading to severe diarrhea. An antibiotic-resistant strain has developed that can result in colitis, sepsis, and death. Elderly patients, patients with severe underlying illness, and patients undergoing immunosuppressive therapy are at higher risk of becoming infected since their immune response to the bacteria and its toxins is diminished.
Staphylococci are non-motile, non-spore-forming, gram-positive organisms occurring singly, in pairs, tetrads or in clusters resembling grapes. More than 20 species have been identified; three species are significant in their interactions with humans - S. aureus, S. epidermidis and S. saprophyticus.The staphylococci are members of the normal flora of the skin and mucous membranes of humans and warm-blooded animals. Colonization of the nares (nostrils) and skin can provide large reservoirs of organisms for transmission. Approximately 25-30% of the general population are colonized by Staphylococcus aureus, mainly in the nasal passages, but the organism can be found in most anatomical sites including the skin, oral cavity and GI tract.Infections are frequently acquired when the colonizing strain gains access to a normally sterile site as a result of trauma or abrasion to skin or mucosal surface. S. aureus infections range from superficial, localized skin infections, such as folliculitis, to deeper, more serious skin lesions and the more serious toxin mediated conditions – scalded skin syndrome and toxic shock syndrome.
|Staphylococcus aureus Virulence Factors|
S. aureus is the most pathogenic member of the genus Staphylococcus; it possesses several factors that contribute to its virulence: Structural components of its cell wall function as a protective barrier, aid in adherence to mucous membranes, and allow the organism to resist phagocytosis. The production of several different toxins Enterotoxins A, D, F (TSST1) Exfoliative toxin ( causing scalded skin syndrome Cytolytic toxins (causing cell & tissue damage). Production of enzymes Catalase – distinguishes staphylococci from streptococci Coagulase – distinguishes S. aureus from other staphylococci Hyaluronidase & lipase – aid in skin colonization/infection spread Beta-lactamase – breaks down the beta-lactam antibiotics, e.g., penicillins, cephalosporins, carbapenems and monobactams.
|The pathogenicity of Staphylococcus aureus, as well as the frequency with which this organism produces infections, can be attributed to:||View Page|
|Enzyme Immunoassay Methods|
The most common laboratory tests for detection of C. difficile are enzyme immunoassays (EIA) for detection of C. difficile Toxin A and Toxin B. The immunoassays are simple to perform and provide rapid results. However the sensitivities of these tests are not as good as culture, CCNA, or molecular methods. Only liquid stool samples should be processed. Due to the fact that the colonization rate is high, a positive result with a normal stool sample proves that the patient is colonized with C. difficile but not necessarily infected. There are many test kits available commercially for detection of C. difficile toxins. Results are available in 15 minutes to 2 hours, depending on assay. Initially Toxin A was thought to be the toxin responsible for the majority of the effects of C.difficile disease. Therefore, most early test kits only detected Toxin A, based on monoclonal anti-Toxin A antibodies. With the discovery that there are strains that cause infection and produce aberrant or no Toxin A (A-), it is now recommended that a kit is used that detects both toxins.
|Treatment of Clostridium difficile Infection (CDI) and C. difficile Associated Disease (CDAD)|
The first step in treating patients with CDAD is to discontinue the causative agent wherever possible. The choice for initial antibiotic therapy depends on the severity of disease. Oral vancomycin or metronidazole remain the mainstays of therapy for CDI, with vancomycin reserved for patients with more severe disease and/or those who have not responded to metronidazole. Metronidazole is currently favored in guidelines from the Centers for Disease Control and Prevention (CDC) on the basis of cost and concern that oral vancomycin promotes colonization with vancomycin-resistant Enterococcus. Oral fluids (water and electrolytes) may be necessary to counteract fluid loss as a result of excessive diarrhea, which can quickly lead to dehydration. Patients with fulminant disease and toxic megacolon may require colectomy. Recurrence of CDI is becoming an increasing problem. Most recurrences happen 7-14 days after completion of therapy, suggesting relapse rather than re-infection. If a patient develops a second episode of CDI following initial successful treatment, it is recommended that if possible, the same drug be used to treat the second episode. Contributing factors to recurrent CDI include:Continuing exposure to organisms either through re-infection (via contaminated environment or poor hand hygiene) or an endogenous source, such as C. difficile spores in GI tract. An inability to mount an adequate anti-Toxin A IgM and/or IgG antibody response (i.e., poor host immune response); a likely reason why CDI affects an increasingly elderly population. Unfortunately a vicious cycle can arise whereby the initial treatment prescribed, vancomycin or metronidazole, significally disrupts normal colonic flora reducing colonization resistance and leaving the patient vulnerable to the next recurrent episode.Other treatments, including the use of probiotics or anion-exchange resins to absorb toxins, may work in some cases but none work in every case.The goal of all treatment is to reestablish normal colonic flora so as to control C. difficile (over)growth.
|C. difficile Toxin A and Toxin B|
Clostridial toxins are among the largest bacterial toxins reported to date and C. difficile produces two potent toxins: Toxin A ((TcdA), an enterotoxin and Toxin B (TcdB), a cytotoxin. It is the production of these toxins in the gastrointestinal tract that ultimately leads to disease. There is a relationship between toxin levels, the development of pseudomembranous colitis (PMC), and the duration of diarrhea. Levels of Immunoglobulin G against TcdA correlate directly with protection from disease following colonization, suggesting that a robust immune response is sufficient for protection from C. difficle-associated diarrhea (CDAD). The role of TcdB is not as well understood. Naturally occurring Toxin A negative/Toxin B positive (TcdA-TcdB+) strains have been identified from clinical isolates, which are capable of causing disease, even extensive PMC, suggesting a role for TcdB in CDAD. Toxin A had always been regarded as more important than Toxin B in infection. However, recent work utilizing mutant C. difficile, strains which did not, or could not produce Toxin A, and which were capable of producing very serious disease has led researchers to completely rethink the roles of Toxin A and Toxin B in CDAD. Toxin B was found to be responsible for the more serious damage to intestinal cells. In addition to the primary virulence factors (Toxin A and Toxin B ), Clostridium difficile also produces a third toxin, binary toxin (CDT). The prevalence of CDT in clinical isolates varies widely and its clinical relevance and role in pathogenicity are still not well defined.
|Pathogenisis of C. Difficile-Associated Diarrhea|
Clostridium difficile is the leading cause of hospital-acquired diarrhea in the United States, with the number of cases rising annually over the last three decades. This is largely due to the increased frequency of antibiotic usage, the development of better detection methods, and the fact that hospital environments are increasingly contaminated with spores of C. difficile. The definition of C. difficile diarrhea includes > 6 episodes of non-formed diarrheic stool per 24 hours, along with prior antibiotic treatment. At least three events must occur in the pathogenesis of C. difficile-associated diarrhea (CDAD): Alteration of the normal fecal flora Colonic colonization with toxigenic C. difficile Growth of the organism with elaboration of its toxins"Colonization resistance" is the term used to describe the mechanism by which indigenous flora control overgrowth of C. difficile. This resistance may be compromised by the use of antimicrobial compounds, underlying illness, or therapeutic procedures. Infection begins with the ingestion of either the organism itself or spores, usually via the fecal-oral route. Spores in particular are able to survive the acidity of the stomach and germinate in the colon to produce vegetative organisms. Toxinogenic strains subsequently produce Toxin A, Toxin B, and/or the Binary Toxin leading to colitis, pseudomembrane formation, and watery diarrhea. Significant complications of the clinical disease associated with infection are hypoalbuminemia, toxic megacolon (acute toxic colitis with dilatation of colon), and pseudomembranous colitis (PMC).
|Clostridium difficile-associated Diarrhea|
Clostridium difficile-associated diarrhea (CDAD) is a unique hospital infection that occurs almost entirely in patients who have received previous antimicrobial treatment. Anaerobic gut flora are crucial to colonization resistance, so any disruption of the normal colonic flora (through illness, therapeutic procedures or, most commonly, antibiotic use) is essential to the pathogenesis of C. difficile infection. The association of CDAD with antibiotic use is significant. Early attention (1970s) focused on clindamycin but later on (1980s,1990s & continuing today) the cephalosporins, especially third generation, and broad spectrum penicillins (e.g., amoxycillin/ampicillin) were also implicated. The risk of CDAD is increased if C. difficile is resistant to the particular antimicrobial. In the case of clindamycin, C. difficile resistance is variable. Risk of infection due to a clindamycin-resistant strain increases with use of the drug. For the third generation cephalosporins, C. difficile is universally resistant; thus, any toxigenic strain is capable of causing CDAD during cephalosporin use. Other less commonly implicated antibiotics are the macrolides, e.g., erythromycin, azithromycin, clarithromycin. However, prolonged courses of any antibiotics will increase the risk of disease. Even those antibiotics used to treat colitis (metronidazole, for example) have sometimes been reported to cause CDAD.The fluoroquinolones have been in use since the 1980s. Ciprofloxacin was approved in 1987, but it is only in recent years with the emergence of the epidemic strain 027/NAP1/BI, which is resistant to the fluoroquinolones, that this class of drugs has been implicated in Clostridium difficile disease. The fluoroquinolones were initially considered to be low risk but their use has been increasing, both with hospital inpatients and in the community, and fluoroquinolones are now implicated as a risk factor for C. difficile infection. The newer fluoroquinolones, e.g., gatifloxacin, moxifloxacin, have better activity against anaerobes, but poor in vitro activity against C. difficile, thus increasing the likelihood of CDAD. The CDC now recommends that all fluoroquinolones, as a class, be used sparingly as each poses an increased risk for CDAD.
|C. difficile disease is more likely to occur when:||View Page|