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Abstract

Clostridium difficile infection (CDI) is the most common infectious cause of nosocomial diarrhea in elderly patients, accounting for 15% to 25% of all cases of antibiotic-induced diarrhea in those patients. Virulent forms of this organism have developed, increasing the associated morbidity, mortality, and complication rates. The average patient undergoing total joint arthroplasty is at particular risk of CDI because of advanced age, the use of prophylactic antibiotic coverage in the perioperative period, multiple comorbid conditions, and length of hospital stay. In addition, patients who have had one CDI are at risk of another; the rate of recurrent CDI (RCDI) is 15% to 30%. To review the available information on RCDI, we conducted an extensive literature search, focusing on its epidemiology and the management strategies for its treatment and prevention. We found the management of RCDI is a controversial topic, with as yet no consensus regarding specific treatment guidelines. Several experienced clinicians have published suggested treatment algorithms, but they are based on anecdotal experience. With regard to the prevention of RCDI, the literature is scarce, and currently, the only effective strategies remain judicious use of perioperative antibiotics and appropriate implementation of infection control procedures. There are several vaccination medications that are currently being studied but are not yet ready for clinical use. We agree with the approach to management of RCDI that has been proposed in several articles, that is, on confirmation of a first recurrence of CDI by a stool toxin assay and clinical symptoms, a 14-day course of metronidazole or vancomycin; for a second recurrence, a tapered-pulsed course of vancomycin; and, for 3 or more recurrences, a repeat course of the tapered-pulsed vancomycin and adjunctive Saccharomyces boulardii or cholestyramine.

Keywords

recurrent infection arthroplasty

Introduction

Over the past decade, the incidence of Clostridium difficile infection (CDI) in the United States has increased. Rates of US hospital discharges with CDI have increased from 3.82/1000 in 2000 to 8.75/1000 in 2008, with the rate 7-fold higher in persons more than 65 years old.¹ The incidence of CDI has increased so much that it has surpassed methicillin-resistant Staphylococcus aureus as the most common cause of health care-associated infection.² In tandem with the rise in incidence, there has also been a substantial rise in mortality rates associated with CDI. Mortality rates have risen from 5.7 deaths per million in 1999 to 23.7 deaths per million in 2004, with CDI reported as the cause of death for more than 20 000 persons during those years.³ There have also been epidemics of CDI, with more aggressive clinical manifestations linked to more virulent strains of the organism such as the NAP1 variant.^4

–8

Recurrent CDI (RCDI), defined as CDI that occurs within 1 month of successfully completing treatment for the primary CDI, has also been reported^9
–11 and is of increasing concern. Currently, the estimated rates of initial recurrence after primary CDI are as high as 20%, with subsequent rates of recurrence approaching 40% to 60%.^10,11 From an economic standpoint, the financial burden associated with cases of RCDI is substantial. A meta-analysis study of the available literature found that the US cost estimates of a case of RCDI ranged from $13 655 to $18 067 and were associated with 4-fold increase in length of stay.⁹

Older age has been recognized as a major risk factor for developing CDI.^12,13 The incidence of disease in hospitalized patients over the age of 65 has been reported as 5 to 10 times that in younger patient populations.^14
–16 In addition, several investigators have identified older age as a significant risk factor for more severe and complicated cases of CDI.^17,18 With the rising incidence and severity of this disease, orthopedic surgeons will increasingly be faced with the management of RCDI in their patients. Most patients undergoing total joint arthroplasty (TJA) and those with hip fracture are at particular risk because age of more than 60 years has been identified as one of the main risk factors for CDI in several studies.^13,19,20

Most current treatment recommendations for RCDI are based on anecdotal evidence or case series reports instead of more comprehensive evidence-based treatment guidelines, as are used for primary CDI treatment recommendations.^21,22 Despite the increase in incidence and severity of this condition, there has been little research conducted into the specific treatment and prevention modalities for it. The purpose of this article is to review the available information on RCDI, focusing on its epidemiology and the management strategies for its treatment and prevention.

Epidemiology

Clostridium difficile is an anaerobic, Gram-positive, spore-forming bacillus that is found widely in nature, particularly in health care settings. These spores are ingested, survive gastric acidity, germinate in the small bowel into their vegetative forms, and colonize the lower intestinal tract. On colonization the organisms produce 2 toxins: toxin A, an enterotoxin, and toxin B, a cytotoxin. These toxins lead to the subsequent clinical manifestation of CDI that range from mild diarrhea to fulminant pseudomembranous colitis with associated toxic megacolon, colonic perforation, and multiorgan failure.²³

The specific mechanism of RCDI is incompletely understood, but several theories have been proposed as explanations for this phenomenon. Some theories suggest that C. difficile forms antibiotic-resistant spores that survive in colonic diverticula and emerge after antibiotics have been stopped²⁴; others propose that reinfection from the external environment occurs through the fecal-oral route.²⁵ The host immune response to C difficile toxin A may dictate the patient’s eventual response to the disease. Higher levels of antitoxin A immunoglobulin G have protected against the development of symptomatic CDI and led to an asymptomatic carrier state.²⁶ One study found that patients who failed to produce an adequate immune response to the initial infection were more likely to relapse after the discontinuation of metronidazole or vancomycin.²⁷ This impairment of the host’s immune system is most likely the result of advanced age, impaired nutrition, and multiple comorbidities, all of which can be concerns in the population of patients with TJA.²⁸

The CDI and Arthroplasty

TJAs of the hip and knee are some of the most commonly performed and successful surgical procedures. The annual number of these procedures is constantly increasing, and it is estimated that by 2030 2.9 million TJAs will be performed.²⁹ Given this dramatic number, it is important that the surgeon focuses attention on the potential complications that can cause substantial morbidity and mortality. CDI is a serious complication after TJA surgery, and the initial infection rate, degree of virulence, and recurrence rate for CDI are increasing.^5

–8,10

In one retrospective case–control study examining CDI after TJA, the authors found an average incidence of 0.17%.³⁰ The mean age of patients with CDI was 75.3 years.³⁰ Additionally, they found a statistically significant increase in CDI in patients who received more than one antibiotic in the postoperative period.³⁰

The authors of a retrospective case–control study of 9880 TJA cases reported a similar incidence (0.16%) of CDI.³¹ They also found that additional risk factors for CDI included using more than 2 antibiotics perioperatively, a hospital stay of more than 4 days, and patients with multiple medical comorbidities (ie, as indicated by an American Society of Anesthesiologists Score of more than 2).³¹

Diagnosis

The diagnostic strategies for CDI have evolved over the past several decades. The cytotoxin assay test is considered the “gold standard” because it is both highly sensitive and specific; however, it has fallen out of favor because of the slow and labor-intensive process associated with it.³² The development of the toxin A and B enzyme immunoassay (EIA) provided a much easier and rapid test that could provide same-day results; this test emerged as the test of choice for many centers, but despite its high specificity of 97% to 98%, it is limited by a low sensitivity of 75% to 80%.^33,34 The subsequent development of the glutamine dehydrogenase EIA has provided a highly sensitive test that, when used in combination with the toxin A/B EIA, can provide a reliable algorithm for laboratory diagnosis. This 2-step approach for the diagnosis of CDI has been described in recently published clinical practice guidelines.²¹ If both tests are positive, the specimen can be interpreted as being positive, and if both tests are negative, it can be interpreted as negative. If the glutamine dehydrogenase EIA and toxin A/B EIA are discordant, then alternative testing, such as the cytotoxin assay, must be used.³⁵

Over recent years, other technologies have also emerged such as the polymerase chain reaction assays for detection of C difficile toxin B. This test is both highly sensitive and specific.³⁶ As it gains in use and availability it may replace the 2-step EIA strategy as the standard test.

Treatment Modalities

Current modalities used for the management of RCDI are standard antibiotic regimens, tapered-pulsed antibiotic therapy, probiotics, immunomodulation therapies, anion-binding resins, and novel treatments such as toxin receptor decoys and vaccination.

Antibiotic Regimens

The administration of vancomycin or metronidazole as the first choice for antibiotic therapy for CDI is a subject of controversy in the literature. Zar et al³⁷ stratified 172 patients according to disease severity and randomly assigned them to treatment with metronidazole or vancomycin. These medications were found to be equivalent in terms of cure rate for mild CDI; however, for severe CDI, vancomycin therapy had a significantly higher cure rate than did metronidazole.³⁷ Based on the theory that antibiotic-resistant spores of C difficile lead to RCDI, many clinicians now use a tapered-pulsed vancomycin regimen. The medication is given on alternate days and in progressively decreasing doses so that the resistant spores of C difficile are converted to antibiotic-sensitive vegetative forms. In 2 published case series, this method of treatment has shown promising results.^38,39 The recommended dose was 125 mg of vancomycin 4 times daily for the first week, 3 times daily for the second week, once daily for the third week, every other day for the following 2 weeks, and every third day for the final 2 weeks.

In addition to the standard antibiotic treatment regimens that use metronidazole or vancomycin, recent studies have examined the effectiveness of other agents such as rifaximin and fidaxomicin. Rifaximin is an antibiotic that has been used by some in the treatment of RCDI. Some small case series studies have shown success when rifaximin is given as adjunctive therapy after the completion of a course of vancomycin.^33,34 It should be noted that rifaximin is not a widely accepted treatment modality and that there are concerns regarding the development of resistance to the medication.^40,41 Another antibiotic that holds promise for the treatment of RCDI is fidaxomicin (OPT-80). Studies using fidaxomicin as a treatment agent have shown equivalence to vancomycin in the treatment of primary CDI but with less alteration of the normal gut flora.^35,36 Larger studies using fidaxomicin as a primary treatment modality are currently being conducted.^42,43

Probiotics

Probiotics have been marketed for the treatment of CDI because they aid in the restoration of the normal gut flora. The most studied microorganism has been Saccharomyces boulardii, which has shown mixed results in the treatment of CDI.^38,44,45 In one study, which included 60 patients with RCDI, the recurrence rate for 26 patients treated with S. boulardii and antibiotics was 35% (9 patients), whereas that for the 34 patients treated with antibiotics only was 65% (22 patients).⁴⁴ Although treatment with S boulardii resulted in a significantly lower RCDI rate, there was no significant improvement in terms of primary disease response.

Fecal bacteriotherapy, or “stool transplantation”, is the restoration of the colonic flora by the administration of normal freeze-dried human feces via colonoscopy or enema. In the 1980s, published case studies showed promising outcomes of this treatment for patients with RCDI.^46,47 In the past several years, 2 other case series have shown success with this treatment method,^48,49 but additional clinical research and strategies are needed to overcome the patient’s own reluctance to undergo this treatment.

Immunomodulation Therapies

Immunoglobulin therapy has emerged as a treatment modality based on the theory of an impaired host immune response to the C difficile toxin, which leads to more severe and recurrent disease. The concept behind this treatment is the administration of preformed antitoxin. In one recent study, 14 adult patients with RCDI were given an oral preparation of bovine antibody-enriched whey concentrate that was prepared after immunizing the cows with C difficile toxoid.⁵⁰ Nine patients had complete resolution of their symptoms within 26 days (range 2–26 days). Another case study of intravenous immunoglobulin therapy has shown promising results,¹⁰ but conclusive randomized clinical studies are still lacking.

Anion-Binding Resins

Anion-binding resins act by binding to intraluminal C difficile toxins and preventing the toxins from binding to membrane receptors on the surface of colonic cells. These agents do not interfere with the binding of normal colonic cells. Cholestyramine and colestipol have been given in the management of primary CDI and in recurrent disease.¹⁰ Despite less than promising results when used as the only treatment, anion-binding resins have shown promise when given as an adjunct to primary antibiotic therapy.^10,51 Tedesco⁵¹ successfully treated 11 patients with RCDI using a tapered-pulsed regimen of vancomycin in conjunction with colestipol hydrochloride at a dose of 5 g twice daily, beginning the second week of vancomycin treatment and continuing for 2 weeks after its cessation.

Novel Treatments

Several other treatment modalities remain in experimental phases but have shown promise for the management of RCDI. The C. difficile toxin receptor decoys act by binding to the toxins in the gut lumen, strongly inhibiting their cytotoxicity and enterotoxicity.⁵² A phase III study evaluating the safety and efficacy of a particular receptor decoy (tolevamer) was recently discontinued because of lack of noninferiority.⁵² Other experimental approaches to the prevention of RCDI include a toxoid vaccine and monoclonal antibodies to the C difficile toxins.^{10,11,39,53,54} A recently published phase II clinical trial of 200 patients with CDI found promising results with monoclonal antibodies to C difficile toxins.⁵³ Those who received monoclonal antibodies had a lower rate of CDI recurrence than those who received a placebo (7% vs 25%, P < .001).⁵³ For patients with more than one previous episode of CDI, patients receiving the monoclonal antibodies also had lower recurrence rates than those receiving the placebo (7% vs. 38%, respectively; P < .006).⁵³

Potential vaccines against CDI, including specific vaccines to the C difficile toxins and bovine anti-Clostridium antibody-enriched whey protein, are currently under investigation. These experimental modalities have shown promising results in very limited human trials studies but remain in early phases and are currently unavailable commercially.^55
–57

Prevention of RCDI

A patient with TJA who previously had CDI is generally fearful of a second bout of the disease, which can complicate his or her decision making regarding whether to proceed with surgery. The risk of a second infection after a subsequent surgery has been reported to be as high as 30%.¹¹ Therefore, an evidence-based strategy to reduce the risk of RCDI would seem prudent. Currently, the only effective strategies are judicious use of perioperative antibiotics and appropriate implementation of infection control procedures.

The judicious use of perioperative antibiotics can be more specifically examined by recognizing that different antimicrobial agents have varying propensities for increasing the risk of CDI. The highest risk agents have been shown in the literature to be broad-spectrum agents with antianaerobic activity. More specifically, second- and third-generation cephalosporins and fluoroquinolones have been associated with recent epidemics of virulent CDI. In the perioperative setting, the use of first-generation cephalosporins, considered a low-risk agent for CDI, is routine for surgical-site infection prophylaxis. Avoidance of broader spectrum agents when possible would be considered ideal.

Furthermore, there appears to be consensus that minimizing the number of antimicrobial agents used and limiting the duration of antibiotic therapy also decreases the risk of CDI.^58

–62 It is therefore also important that, for the perioperative patient, the managing physician maintains a high index of suspicion regarding noninfectious causes of low-grade fevers and completes an appropriate workup before initiating any antimicrobial agents.

With regard to prophylactic management of patients at high risk of RCDI, the literature is scarce. Several vaccination medications are currently being studied, but they are not yet ready for clinical use.^53,55
–57

Discussion

It is important to understand the potential morbidity caused by CDI and to try to prevent its recurrence. Preoperative evaluation should include questions about the history of previous CDI. If the history is positive, there should be a discussion in advance with the patient’s primary care doctor and/or with a gastrointestinal specialist to plan for the optimal treatment strategy in the event of RCDI. Many patients undergoing TJA are at increased risk of developing CDI because of their advanced age, length of inpatient hospital stay, and the use of perioperative antibiotics. If a patient who has had a joint replacement does develop CDI, as should be suspected in patients with diarrhea after surgery, a gastrointestinal consultation should be arranged to optimize medical management.

The Infectious Diseases Society of America recently published updated practice guidelines for the management of primary CDI²¹; however, there are no clear guidelines and no strong, evidence-based algorithm for the treatment protocol of RCDI, although experienced clinicians have published some suggested algorithms.^10,11,63,64 We agree with the approach to management that has been proposed in previously published articles:^10,63 on confirmation of a first recurrence of CDI by a stool toxin assay and clinical symptoms, the patient should be started on a 14-day course of metronidazole or vancomycin; for a second recurrence, the patient should be placed on a tapered-pulsed course of vancomycin; and, for 3 or more recurrences, the patient should be treated with a repeat course of the tapered-pulsed vancomycin and adjunctive S. boulardii or cholestyramine (Table 1).

Table 1.

Suggested Treatment Plan for Recurrent Clostridium Difficile-Associated Disease.^a

Recurrence	Treatment	Supporting Literature and Level of Evidence
Initial	Diagnosed with positive stool toxin assay: 14-day course of metronidazole 250, 3 times daily or vancomycin 250, 3 times daily (Note that for severe disease, vancomycin is preferred.)	Zar et al³⁷ level I
Second	Tapered-pulsed vancomycin: 125 mg 4 times daily for 1 week 125 mg 3 times daily for 1 week 125 mg every day for 1 week 125 mg every other day for 2 weeks 125 mg every third day for 2 weeks	Surawicz³⁸ level II McFarland et al⁶⁵ level II Tedesco et al³⁹ level IV
Third or subsequent	Tapered-pulsed vancomycin	Surawicz³⁸ level II McFarland et al⁶⁵ level II Tedesco et al³⁹ level IV
Third or subsequent	Plus Saccharomyces boulardii (Florastor, Biocodex, Inc, San Bruno, California), 500 mg (2 × 250 mg caps) twice daily for 30 days started during the last 2 weeks of the tapered-pulsed vancomycin regimen (above)	Tannock et al⁴³ level I Surawicz et al⁶⁶ level I

^aModified with permission from Maroo S, Lamont JT. Recurrent Clostridium difficile. Gastroenterology. 2006;130:1311-1316.

There are several promising treatment options on the horizon, including novel antibiotic therapies and immune-modulating medications; however, substantially more research needs to be conducted with regard to these management strategies for RCDI. Many patients undergoing TJA are at particular risk of this disease, and prospective studies to analyze treatment modalities and to solidify an evidence-based treatment algorithm are needed.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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Management and Prevention of Recurrent Clostridium Difficile Infection in Patients After Total Joint Arthroplasty

Abstract

Keywords

Introduction

Epidemiology

The CDI and Arthroplasty

Diagnosis

Treatment Modalities

Antibiotic Regimens

Probiotics

Immunomodulation Therapies

Anion-Binding Resins

Novel Treatments

Prevention of RCDI

Discussion

Footnotes

Declaration of Conflicting Interests

Funding

References