The main purpose of this article is to review recent developments in the management of acute and recurrent Clostridium difficile-associated disease, with consideration of existing and new antibiotic and non-antibiotic agents for treatment. Details of the current developmental stage of new agents are provided and the role of surgery in the management of severe disease is discussed. Infection control measures considered comprise prudent use of antimicrobials, prevention of cross-infection and surveillance. Other topics that are covered include the recent emergence of an epidemic hypervirulent strain, pathogenesis, clinical presentation and approaches to rapid diagnosis and assessment of the colonic disease.
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Clostridium difficile is a Gram-positive, anaerobic, spore-forming bacillus that was identified as an aetiological agent of antibiotic-associated pseudomembranous colitis in the late 1970s.1,2 It is believed to be responsible for 15–20% of antibiotic-related cases of diarrhoea and nearly all cases of pseudomembranous colitis.3 Over the last decade, the incidence of C difficile-associated disease has progressively increased and is now a significant clinical problem in North America and Europe.
Key points 1
Clostridium difficile-associated disease (CDAD) is an important healthcare-associated infection.
CDAD may recur in 15–30% of patients.
A virulent strain of C difficile has been responsible for recent outbreaks.
Control measures are based on prudent use of antimicrobials, prevention of cross-infection and active surveillance of cases.
In the United Kingdom, the Health Protection Agency’s data for voluntary reporting of positive stool samples show that C difficile infection has been an increasing clinical problem since the early 1990s.4 5 Whilst some of the increase may be due to improved reporting, it is widely accepted that there has also been an increase in the number of cases. Mandatory reporting of Clostridium difficile-associated disease (CDAD) in people aged 65 years and over has been included in the healthcare-associated infection surveillance system for acute hospital trusts in England since January 2004. There were 51 681 reports of CDAD in people aged 65 years and over in 2006, a 26.2% increase on 2004.6
There have also been reports of more cases of CDAD in North America, which have been associated with the use of fluoroquinolones and more severe disease than that seen previously, especially in those over the age of 65 years.7–9 Molecular studies in C difficile isolates from a number of US and Canadian healthcare facilities suggest that a more virulent strain of C difficile is responsible for outbreaks of CDAD and also more severe disease.10 11 Characteristics of the epidemic strain, designated NAP1/027, are discussed below. In one report, the NAP1/027 strain was isolated from 67% with healthcare-associated disease and 37% associated with community-acquired disease.12 The same genotype as NAP1/027 (also known as type BI) has been found in historic isolates obtained before 2001 but was not previously reported to cause either severe disease or outbreaks.12
C difficile infection may induce a relapse in patients with inflammatory bowel disease.13,14 Two retrospective studies have recently reported a 2- to 3-fold increase in the frequency of C difficile infection in patients with inflammatory bowel disease over a 5- to 6-year period.15,16
Another recent trend has been the reporting of more severe disease in non-traditional hosts such as young seemingly healthy adults and children in the community and some without antimicrobial exposure.17 18 Potential sources of C difficile in the community include domestic (dogs, cats) and farm animals (horses, pigs, cows).19–21 There have also been recent reports of a marked overlap between isolates from calves and humans, including the predominant type 027.22 23 In a recent Canadian study, C difficile spores were identified in 20% of retail ground meat (beef and veal) samples.24 Moreover, a toxigenic strain of C difficile has been isolated from raw turkey-based food for dogs and cats.25 Further studies are required to determine the clinical relevance of these findings but they raise the possibility that C difficile could also be transmitted via food contaminated with spores.
In addition to microbial virulence determinants, it is likely that host factors contribute to the increase in the incidence of CDAD. Those over the age of 65 years are particularly susceptible and numbers in this age group have progressively increased over the last century and are predicted to continue to do so.26 Disruption of the protective colonic flora (designated colonisation resistance) by broad-spectrum antibiotics is the commonest predisposing factor to CDAD and different antibiotics may have distinct effects on not only the gut microbiota but also C difficile.27 Immunosuppression has also been shown to be an independent risk factor for developing Clostridium difficile infection. Particularly susceptible patients include those exposed to chemotherapeutic or immunosuppressant agents on nephrology, haematology and oncology wards.28–30
An association between acid suppression and increased risk of C difficile infection has been reported in a number of studies. In a recent systematic review,31 there was an increased risk of taking antisecretory therapy in those infected with C difficile [pooled odds ratio (OR), 1.94; 95% confidence interval (CI), 1.37 to 2.75]. The association was greater for proton pump inhibitor use (OR, 1.96; 95% CI, 1.28 to 3.00) compared with the use of H2 receptor antagonists (OR, 1.40; 95% CI, 0.85 to 2.29). Whilst further studies are required to determine whether the association is causal, a potential mechanism could be survival of vegetative forms of C difficile in gastric contents with proton pump inhibitor-induced raised pH.32
Diarrhoea and colonic inflammation following infection with toxigenic strains of C difficile are believed to be due to two large molecular weight secreted toxins, designated toxin A and B. Some strains of toxigenic C difficile (such as the epidemic NAP1/027 strain) also secrete binary toxin, but its role in disease pathogenesis remains to be determined. The NAP1/027 strain has been reported to produce more toxin A and B than other strains of C difficile,12 which may be due to deletion in the tcdC gene that negatively regulates toxin expression. Both of the two large molecular weight toxins (A and B) are cytotoxic to mammalian cells and the role of toxin A in disease pathogenesis has been better characterised than that of toxin B.33 Initial effects of toxin A on intestinal epithelial cells include induction of the expression of cytokines such as interleukin 8 (IL-8) (potent chemoattractant for neutrophils) and loss of barrier function, with subsequent cell death by apoptosis34–37 (fig 1). Epithelial cells and monocytes are more sensitive to C difficile toxin A-induced cell death than lymphocytes,35 38 39 implying differential effects of the toxin on cells of the innate and adaptive immune system.
Histologically, the disease is characterised by focal epithelial ulceration associated with an inflammatory exudate40 that appears as a characteristic pseudomembrane on endoscopic examination. Reasons for the focal nature of the colonic inflammation remain unknown but could be due to high concentrations of toxins secreted by bacteria in close vicinity to the affected epithelium, resulting in high expression of IL-8 and rapid epithelial cell death. The ensuing focal epithelial ulceration would enable the toxins access to a blood vessel in the superficial lamina propria, leading to migration of neutrophils through the breach in the epithelial barrier. By contrast, epithelial cells distant to the bacteria would be exposed to lower concentrations of the toxins and the subsequent induction of transforming growth factor-β, which has been shown to not only protect against loss of barrier function, but also facilitates epithelial restitution.36
Following colonisation with toxigenic C difficile, individuals may become asymptomatic carriers41–43 or develop colonic disease. In those who develop C difficile-associated disease, clinical features can range from mild diarrhoea to life-threatening pseudomembranous colitis. Severe disease is characterised by abdominal pain, profuse diarrhoea (which is often non-bloody) and systemic symptoms such as fever, anorexia, nausea and malaise.
In severe CDAD, leukocytosis, raised C-reactive protein and low albumin levels are frequently seen. In one recent report, of those patients with severe CDAD who required admission to the intensive care unit, independent predictors of 30-day mortality were leukocytosis ⩾50×109/l, lactate level ⩾5 mmol/l, age ⩾75 years, immunosuppression and shock requiring vasopressor treatment.44 Some patients with severe pseudomembranous colitis may have little or no diarrhoea as a result of toxic megacolon and paralytic ileus. In these patients, abdominal distension, marked leukocytosis and dilated and inflamed colon on abdominal x ray and computed tomography scan may provide important clues regarding the diagnosis.
C difficile-associated disease is usually diagnosed following the demonstration of toxins A and/or B in stool samples. Demonstration of the presence of C difficile toxins by the characteristic cytopathic effect on a monolayer of cells is considered by many to be the “gold standard”.50,51 The main disadvantage of this assay is that it takes 24–48 h to obtain a result. Many laboratories now use enzyme-linked immunosorbent assays (ELISAs) for toxin A or toxins A and B. Since toxin A-negative, toxin B-positive strains have been reported to cause disease,52 assays that test for the presence of both toxins are preferable. A number of studies have shown that false negative rates can be high for both assays.16,48,51,53 In some patients with pseudomembranous colitis, repeat stool test may also be negative.48 Reasons for false negative rates are not fully understood, but may include inappropriate handling or storage of stool samples prior to testing.
In view of the characteristic appearance of pseudomembranous colitis at endoscopy and also on histological examination of biopsies, flexible sigmoidoscopy (with biopsies) has been proposed in those patients suspected to have C difficile-associated diarrhoea but who have a negative stool test for C difficile toxins.48 The identification of pseudomembranous colitis at the endoscopic examination enables a rapid diagnosis to be made and appropriate clinical management to be initiated. In those patients with non-specific changes in the colonic mucosa, a second stool sample can be collected during the endoscopic examination and further management could be guided by the results of the repeat stool test and histological examination of biopsies. For patients suspected to have CDAD, flexible sigmoidoscopy by the bedside, without any bowel preparation, has been shown to be safe and well tolerated.48 Avoidance of moving the patient to the endoscopy unit minimises the risk of contamination of other sites with C difficile spores. Flexible sigmoidoscopy may also facilitate the identification of other causes of diarrhoea, such as ischaemic colitis and inflammatory bowel disease. It should be noted that in patients with relapse of ulcerative colitis due to C difficile infection pseudomembranes may not be seen at endoscopy, nor the characteristic histological changes (of pseudomembranous colitis) on biopsy.16 Colonoscopy may be required to diagnose the predominantly right-sided antibiotic-associated haemorrhagic colitis, which has recently been shown to be due to Klebsiella oxytoca.54
Stool samples may also be cultured on selective medium for C difficile. However, further tests would be required on the cultured C difficile to confirm that it is a toxigenic strain by demonstration of its ability to express toxin A and/or B. Thus, it would take 3–4 days to obtain a result and this test is not routinely undertaken in most hospitals for diagnostic purposes. However, culture is useful for investigating outbreaks of C difficile infection as isolates can be genotyped, and for measuring the antimicrobial susceptibility of C difficile strains.
Stool enzyme immunoassays for glutamate dehydrogenase antigen are available for the diagnosis of C difficile-associated disease but are not widely used55 and have not been as extensively evaluated as cytotoxicity assays and ELISAs for C difficile toxins.
INFECTION PREVENTION AND CONTROL
Whilst infection with C difficile may occur in both the hospital and community setting, the majority of these infections now occur in relation to healthcare. C difficile is fast becoming one of the most important healthcare-associated infections and the prevention and control of this infection is posing a significant challenge. Control measures are based on three main strategies: (1) prudent use of antimicrobials, (2) prevention of cross-infection, and (3) active surveillance of cases.
Prudent use of antimicrobials
The principal risk factor for C difficile-associated disease is prior antimicrobial therapy, especially with broad-spectrum antibiotics. Some antibiotics appear to have a much higher propensity to cause disease than others (see table 1), although this may change over time. For instance the fluoroquinolone antibiotics have previously been shown to have a low risk for causing C difficile-associated disease compared to cephalosporins.56 57 However, high-level fluoroquinolone resistance has now emerged in some strains of C difficile, including ribotypes 027 and 106, and fluoroquinolones have recently been shown to be a major risk factor for infection with the hypervirulent strain NAP1/027.58
It is now accepted that the prudent use of antibiotics is an essential component of C difficile control measures, particularly within high risk areas of healthcare. Components of a good antimicrobial control programme include: prescribing short durations of antibiotics including one-dose prophylaxis, avoiding broad-spectrum antibiotics where possible, restricting intravenous antibiotics, using automatic stop dates, monitoring antibiotic use by specialty and employing antibiotic pharmacists.59 Most of the published interventions on antibiotic prescribing as a method of C difficile control have looked at the benefits of reducing broad-spectrum antibiotics in favour of restrictive or narrow-spectrum antibiotic policies. There are now a number of reported studies demonstrating that a significant reduction in C difficile infections can be achieved by introducing new antibiotic policies (see table 2).
Prevention of cross-infection
The basic infection prevention and control measures for patients with C difficile are well established. The mode of spread is via the faecal–oral route. The principal factor that makes the control of C difficile particularly difficult within the healthcare setting is that the organism is capable of producing highly resistant spores. These survive readily within the hospital environment for long periods and there can be widespread contamination of the environment, including mattresses, bed frames, commodes, toilets, radiators and medical equipment in the vicinity of symptomatic patients.60
Patients with suspected CDAD should be isolated as soon as possible, preferably in a room with an en-suite toilet or else with a dedicated commode. During outbreaks, patients may be cohort nursed together if there are insufficient single rooms, and consideration should be given to a dedicated C difficile isolation ward for institutions with hyperendemic C difficile. Failure to isolate symptomatic patients promptly was one of the principal contributory factors in the outbreaks at Stoke Mandeville Hospital, UK.61
Enhanced environmental and equipment cleaning is necessary for symptomatic patients. C difficile spores are relatively resistant to a wide range of disinfectants, with perhaps chlorine-containing agents retaining at least some sporicidal activity.8 62 There is now interest in the use of vaporised hydrogen peroxide as a reliable sporicidal method for environmental disinfection of C difficile spores,63 although this type of technology cannot be used in the same room as patients or staff.
Staff looking after symptomatic patients, or who are in direct contact with their immediate environment or equipment should wear the appropriate protective clothing (gloves, aprons). Strict hand hygiene should be observed with soap and water. Alcohol rinses or gels are much less effective against C difficile spores compared with other organisms causing healthcare associated infections, eg, methicillin-resistant Staphyloccocus aureus (MRSA).64 Each healthcare organisation should have policies in place to support the control of C difficile infection, reinforced through adequate programmes of teaching, training and audit.
Active surveillance for cases of C difficile infection should be undertaken to monitor local, regional and national rates of infection, to provide timely feedback to clinicians and other healthcare professionals, to detect outbreaks, and to monitor the effectiveness of particular interventions. Mandatory reporting of all cases of C difficile infection in the over 65s was introduced for all UK NHS Trusts in 2004. This has been supplemented by a planned national programme of culturing for C difficile isolates, and submitting isolates to the Anaerobic Reference Laboratory of the National Public Health Service, Wales, for molecular typing and antibiotic susceptibility testing.
Local surveillance programmes should aim to provide timely feedback on C difficile rates, especially to high-risk areas of secondary care including elderly care, general and renal medicine and clinical haematology. It is also recommended that NHS Trusts regard outbreaks of C difficile as serious untoward incidents associated with infection, and that investigation of these outbreaks should include a root-cause analysis.
In susceptible patients, prophylaxis against the development of CDAD, administered at the same time as antibiotics (eg, for pneumonia) is an attractive concept. Probiotics are live micro-organisms that confer a health benefit on the host and have been of interest for a number of years. They may provide protection against colonisation by C difficile, and may also act via other mechanisms that remain to be fully characterised. Most of the studies to date have investigated the effect of probiotics on antibiotic associated diarrhoea, of which (as outlined above) 15–20% will be due to C difficile infection.
A recent meta-analysis concluded that Saccharomyces boulardii, Lactobacillus rhamnosus GG, and probiotic mixtures significantly reduced the development of antibiotic-associated diarrhoea.65 S boulardii is a non-pathogenic yeast, which has also been shown to be effective in preventing the recurrence of CDAD (see below). Recently, a randomised, double-blind, placebo-controlled trial involving older patients in hospital who were receiving antibiotics, has reported that a commercially available probiotic yoghurt preparation led to a significant reduction in both the incidence of antibiotic-associated diarrhoea and C difficile-associated diarrhoea.66 The probiotic yoghurt drink contained Lactobacillus casei DN-114 001 (L casei imunitass) (1.0×108 colony forming units/ml), S thermophilus (1.0×108 cfu/ml), and L bulgaricus (1.0×107 cfu/ml). Further studies are expected to determine the role of probiotic treatment in prophylaxis against CDAD in routine clinical practice.
Prophylactic intragastric administration of bovine immunoglobulin G (IgG) concentrated from colostrum has been reported to protect hamsters against CDAD.67 However, diarrhoea developed when the IgG was stopped, implying the additional requirement for reconstitution of the normal colonic flora for continuing protection. Orally administered anti-toxin A avian antibody has also been shown to protect hamsters against CDAD68 and appropriate clinical studies are awaited.
Treatment of an acute episode
Stopping offending antibiotics
Early studies suggested that in those with mild disease, discontinuation of the offending antibiotics may lead to resolution of CDAD. In the prospective randomised trial of metronidazole versus vancomycin, in 22.8% of patients with CDAD, the diarrhoea resolved during 48–72 h observation period before recruitment into the study.69 In another early randomised controlled trial,70 diarrhoea resolved or improved in two patients with pseudomembranous colitis on placebo. In our more recent prospective study, diarrhoea resolved in 30% of patients over median 4.0 days, after discontinuing the offending antibiotics.48 Out of those who had had flexible sigmoidoscopy, diarrhoea in four patients without pseudomembranous colitis resolved within 24 h of discontinuing the offending antibiotics.48 Thus, in mild CDAD, specific antimicrobial treatment may not be required if the offending antibiotics can be discontinued and flexible sigmoidoscopy may facilitate the identification of such patients. For those requiring treatment, established and new agents for management of acute CDAD are listed in table 3.
Antimicrobial treatment of CDAD
Previous controlled clinical trials have demonstrated efficacy of vancomycin, metronidazole, bacitracin and fusidic acid in the treatment of CDAD.71 Metronidazole and vancomycin are widely used in clinical practice. Many guidelines recommend the use of metronidazole in those deemed to require treatment.3 50 72 This guidance is based on (1) reported equivalent efficacy of metronidazole and vancomycin in controlled clinical trials, (2) risk of colonisation with vancomycin-resistant enterococci,73 and (3) the cost of vancomycin. However, in a retrospective study, the mean duration of symptoms was significantly shorter with vancomycin than with metronidazole.74 Moreover, recent studies have reported high failure rates of metronidazole.75 76 Although resistance to metronidazole has been reported,77 78 clinical CDAD treatment failures with this antibiotic may not be attributable to decreased susceptibility of the causative C difficile isolate to metronidazole.79
Metronidazole is not detected in faeces of healthy subjects80 81 and in asymptomatic carriers of C difficile.82 By contrast, metronidazole has been detected in watery and semiformed stool samples of patients with C difficile-associated colitis83 and in Crohn’s disease patients with colonic inflammation.81 Metronidazole has also been detected in stool samples of patients with C difficile-associated disease who have received the antibiotic intravenously.83 Thus, it is likely that metronidazole is secreted only by the inflamed colonic mucosa.
In a small retrospective case series, the use of intracolonic vancomycin therapy has been reported to be an effective adjunctive treatment in patients with severe Clostridium difficile-associated colitis.84
A recent Cochrane review71 concluded that, in terms of symptomatic cure (defined as initial symptomatic resolution without symptomatic recurrence at any time during the follow-up period that ranged from 2 to 6 weeks), teicoplanin may be slightly more effective than vancomycin with a relative risk of 1.21 (95% CI, 1.00 to 1.46; p = 0.06). For initial symptomatic resolution (described as cessation of diarrhoea as defined by each individual study during the treatment period ranging from 7 to 10 days), teicoplanin was as effective as vancomycin.71 Teicoplanin may not currently be available in all countries.
New antimicrobial agents for CDAD
The search for new antimicrobial agents against C difficile (either newly developed antibiotics or established antimicrobial drugs investigated for their use in patients with CDAD) is driven by the desire to find an alternative to metronidazole and vancomycin. Thus, the new agents may be active against both C difficile and vancomycin-resistant enterococci (eg, ramoplanin85), and/or be predicted to reduce the risk of recurrence because of a narrow spectrum of activity (eg, PAR-101/OPT-8086), in anticipation of the maintenance of colonisation resistance. These new agents are initially tested for their in vitro activity against clinical isolates of C difficile87 and include nitazoxanide, rifaximin, tinidazole, PAR-101 (also known as OPT-80, tiacumicin B) and ramoplanin. Some of these agents have also been tested in the hamster model of C difficile-associated colitis,88 89 prior to clinical trials.
Nitazoxanide is a nitrothiazole benzamide compound that is active against many intestinal parasites, including Giardia lamblia, Entamoeba histolytica, Cryptosporidium parvum, Encephalitozoon intestinalis, Isospora belli, Blastocystis hominis, Balantidium coli, Enterocytozoon bieneusi, Ascaris lumbricoides and Trichuris trichura.90 After oral administration, a significant proportion (approximately 66%) of the drug is excreted in faeces in its deacetylated form designated tizoxanide,91 which is active against C difficile.92 In a recent, randomised, double-blind study, nitazoxanide (500 mg every 12 h) was shown to be as effective as metronidazole (250 mg every 6 h) in the treatment of CDAD.93 In an open-label study, nitazoxanide was given to 35 patients who failed treatment with metronidazole for C difficile colitis, and 26 (74%) responded, of whom seven later had recurrent disease.94
Rifaximin is a semi-synthetic derivative of rifamycin, which is very poorly absorbed from the gastrointestinal tract. It has been available in Italy for many years and more recently has been approved by the US Food and Drug Administration for use in non-dysenteric traveller’s diarrhoea.95 Rifaximin has been used in combination with ciprofloxacin in patients with treatment-resistant pouchitis96 and has also been studied in patients with diverticular disease97 and hepatic encephalopathy.98 These studies have shown that this antibiotic is generally well tolerated. Rifaximin has good in vitro activity against C difficile87 99 and has been reported to be as effective as vancomycin in initial resolution of symptoms in CDAD.71
PAR-101 (formerly OPT-80), also known as tiacumicin b, is an 18-membered macrocyclic antibiotic that was originally isolated from fermentation broth of Dactylosporangium aurantiacum subsp. Hamdenensis.100 101 It has high in vitro activity against C difficile, but poor activity against eubacteria and anaerobic Gram-negative rods,86 102 suggesting that it may disrupt the colonic flora to a lesser degree than current antibiotic treatment of CDAD. Orally administered tiacumicin b was effective in the treatment of C difficile-induced colitis in hamsters.88 Poor absorption of this antibiotic was illustrated by lack of detectable levels in the serum of treated hamsters but it was present in their caeca. In an open-label, phase IIa, clinical trial,103 PAR-101 demonstrated therapeutic efficacy against CDAD. Phase III studies consisting of randomised, double-blind comparisons of PAR-101 and vancomycin for the treatment of CDAD were commenced in 2006.103
Ramoplanin is a novel lipoglycodepsipeptide antibiotic with bactericidal activity against aerobic and anaerobic Gram-positive bacteria (including C difficile, vancomycin-resistant enterococci and methicillin-resistant S aureus) but has no activity against Gram-negative organisms.85 Ramoplanin acts by inhibiting the assembly of bacterial peptidoglycan cell walls and its activity against C difficile did not change when the level of susceptibility to either vancomycin or metronidazole was reduced.104 In the hamster model of C difficile-induced colitis, ramoplanin demonstrated comparable therapeutic efficacy to vancomycin.89 Following oral administration, ramoplanin does not appear to be absorbed, with significant concentrations of the drug detected in faeces.85 It has been reported to be safe and effective in temporarily suppressing asymptomatic gastrointestinal carriage of vancomycin-resistant enterococci.105 In a phase II study, similarity in response rates of ramoplanin compared with vancomycin for treatment of CDAD has been reported at a scientific meeting.85
Non-antimicrobial treatment of CDAD
These treatments are based on the concept that interference with C difficile toxin–host cell interactions lead to therapeutic efficacy. Colestipol and cholestyramine are anion-exchange resins that have been shown to bind C difficile toxins but have not been deemed clinically efficacious.72 Synthetic oligosaccharide sequences attached to an inert support (SYNSORB) have been shown to bind and neutralise the activities of C difficile toxin A106 107 but clinical studies have not been reported.
Tolevamer is the salt of a soluble, high molecular weight anionic polymer which non-covalently binds C difficile toxins A and B, but has no significant antimicrobial activity.108 It has been shown to have therapeutic efficacy in the hamster model of CDAD.109 The results of a multicentre, randomised, double-blind, phase II, clinical trial were recently reported.110 A total 289 patients with a first ever or recurrent episode of CDAD were randomised to tolevamer monotherapy (3 g or 6 g/day) or vancomycin (125 mg every 6 h). Tolevamer at a dose of 6 g/day demonstrated non-inferiority to vancomycin with a trend towards reduced recurrence (p = 0.05). There was an increased risk of hypokalaemia in patients treated with tolevamer, thought to be due to the binding of potassium in the intestinal lumen. A current phase III trial is investigating the therapeutic effect of 9 g/day of tolevamer, the formulation of which has been changed to minimise the risk of hypokalaemia.108
In case reports, intravenous human immune globulin has been reported to be beneficial in patients with severe CDAD,111 112 but a recent retrospective analysis does not support the use of this treatment outside of a controlled clinical trial.113
Intraperitoneal administration of a human monoclonal antibody to toxin A led to significant reduction in mortality in the hamster model of CDAD but combination treatment with the addition of anti-toxin B antibody provided greater protection.114 Phase II clinical trials using these human monoclonal antibodies are currently being undertaken.114
Oral administration of avian antibodies to toxin A and B has also been reported to provide full protection against CDAD in hamsters, when administration was initiated 8 h after challenge with C difficile (and continued for 4 days).68 Thus clinical studies in which anti-toxin antibodies are administered orally, for treatment of CDAD, will also be of interest.
Treatment of recurrent CDAD
Recurrent disease occurs in 15–35% of patients with CDAD,45–47 115 which may reflect relapse of infection due to the original strain or by re-infection with a new strain of C difficile. The risk of recurrent disease is higher in those that have previously had more than one episode of CDAD116 and has been shown to be related to the host immune response.49 117 Whilst persistence of spores of the original strain may germinate and lead to relapse after treatment, in many patients disease recurrence may be due to re-infection by a different strain of C difficile.118 119 Treatment for recurrent CDAD is summarised in table 4.
Tapered and pulsed regimens of vancomycin have been reported to be beneficial in the treatment of recurrent CDAD.115 120 The rationale for such treatment is that antibiotic-resistant spores may convert to antibiotic-sensitive vegetative forms during gradual withdrawal of antibiotics (tapered) and given on alternate days (pulsed).47
In an uncontrolled study, rifaximin administered for 2 weeks and given immediately after vancomycin (before recurrence of symptoms) was effective in preventing predictable recurrences in seven out of eight patients.121 The one patient with further recurrence responded to a second course of rifaximin but resistant C difficile was recovered after treatment. A controlled trial is awaited.
In an effort to restore the disrupted colonic microflora in patients with recurrent CDAD, several case reports describe the use of faecal enemas prepared from healthy donor stools.122 123 Most of these patients reported no further C difficile recurrence. In a study in five patients in whom a mixture of different facultative aerobic and anaerobic bacteria were administered123 Bacteroides species in the normal bowel flora appeared to provide protection against colonisation by C difficile.
In a more recent retrospective review, donor stool (provided by healthy family members) was administered via nasogastric infusion in 18 patients with recurrent CDAD, over a 9 year period.124 Ninety days after receipt of the “stool transplant”, 15 of the 18 patients remained relapse free.
Key points 2
Rapid diagnosis of Clostridium difficile-associated disease (CDAD) will facilitate infection control measures and early treatment.
Significant false negative rates for stool C difficile toxin assays have been reported.
Flexible sigmoidoscopy enables rapid diagnosis of C difficile-associated pseudomembranous colitis.
Patients with mild CDAD may respond to discontinuation of offending antibiotics, without the need for specific treatment.
Those with severe CDAD may require admission to the intensive care unit and a combined medical and surgical approach to management.
Vancomycin and metronidazole are widely used for the treatment of CDAD.
A number of new antimicrobial and non-antimicrobial agents are currently under investigation for the treatment of acute and recurrent CDAD.
Probiotics and prebiotics
In a double-blind, randomised, placebo-controlled trial, the addition of the probiotic yeast S boulardii to standard antibiotics significantly reduced the rate of recurrent CDAD.116 When vancomycin is combined with S boulardii, recurrent CDAD may respond better to a short course of high-dose vancomycin, compared to high-dose vancomycin alone.125 It should be noted that although S boulardii is generally well tolerated, fatal fungaemia has been reported during treatment.126
Prebiotics are non-digestible oligosaccharides which selectively stimulate the growth, activity, or both, of probiotic-like bacteria normally present in the gut. A randomised trial of 142 CDAD cases treated with standard antibiotics, with or without an adjunctive prebiotic (oligofructose), showed that significantly fewer patients in the prebiotic group experienced a recurrence within 60 days compared with those on placebo.127 However, there was no difference between the two groups in the stool culture rate for C difficile at days 30 and 60. Thus the mechanism for the reduction in recurrence rate with oligofructose remains to be determined.
A small, double-blind, placebo-controlled, multicentre trial comparing metronidazole and L plantarum v metronidazole and placebo in patients with recurrent C difficile-associated diarrhoea reported no statistically significant differences between the groups.128 Since persistent disruption of the colonic flora appears to be an important determinant of recurrent CDAD, further studies investigating the role of probiotics, prebiotics and synbiotics (combination of probiotics and prebiotics) in the management of patients with relapsing CDAD are likely.
Rationale for intravenous gamma globulin treatment in recurrent CDAD is that these patients may have an impaired antibody response to C difficile toxins and that anti-toxin specific antibodies may be present in the gamma globulin preparations administered.129 130 Controlled clinical trials investigating the role of intravenous gamma globulin in recurrent CDAD are awaited.
In a small, open-label, pilot study, nine adults with relapsing CDAD were treated orally with anti-C difficile whey protein concentrate daily for 2 weeks, following completion of a course of metronidazole and/or vancomycin.131 During a median follow-up period of 333 days (range, 35 days to 12 months), there were no further episodes of CDAD. Anti-C difficile whey protein concentrate was prepared from mature milk (not colostrum) of cows immunised with C difficile-inactivated toxins and killed whole-cell C difficile to generate mainly secretory IgA against C difficile, toxin A and toxin B.132
In an open-label study, three patients with multiple episodes of recurrent CDAD received C difficile vaccine containing toxoids A and B.133 After vaccination, none of the subjects had any further episodes of CDAD over the subsequent 6 months. Two of the three subjects showed an increase in levels of anti-toxin A and anti-toxin B IgG, compared to baseline values.
The role of surgery for treatment of severe CDAD has been recognised for many years.134 Indications for surgery include toxic dilatation of the colon, bowel perforation, systemic toxicity and failure to respond to medical treatment. However, post-operative mortality is often high.135 136 Compared to partial resection, total colectomy is reported to be associated with lower mortality rate.137 In a recent retrospective observational cohort study of 165 cases of CDAD that required admission to intensive care unit, emergency colectomy seemed more beneficial in patients aged 65 years or more, those who were immunocompetent, those with leukocytosis ⩾20×109/l or lactate level between 2.2 and 4.9 mmol/l.44 A combined medical and surgical cooperative approach in the early management of patients with severe CDAD is likely to improve outcome.134 135
Recent changes in the epidemiology of C difficile infection and the emergence of an epidemic hypervirulent strain serve to emphasise the need for greater attention to infection control, early diagnosis of CDAD, and more effective treatments for those with severe and recurrent disease.
A significant proportion of patients with mild disease may not require any further treatment, if the offending antibiotics can be discontinued. Currently, a number of therapeutic avenues are being pursued for treatment of acute and recurrent CDAD. It is anticipated that the results of a number of recent and currently ongoing clinical trials will provide a robust evidence base for future recommendations for the management of patients with C difficile infection. Surgical resection of the inflamed colon is a therapeutic option in those with severe CDAD and a combined medical and surgical approach is recommended for such patients.
Competing interests: None.
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