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This complication ranges from mild diarrhea to pseudomembranous colitis. ... antibiotic-associated diarrhea (AAD) may also occur in healthcare settings, usually ...
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Antibiotic-associated diarrhea: epidemiology, trends and treatment Lynne V McFarland Department of Health Services Research & Development, Puget Sound Veterans Administration, Healthcare System, S-152, 1100 Olive Way, #1400 Seattle, WA 98101, USA Tel.: +1 206 277 1095; Fax: +1 206 764 2935; [email protected]

Keywords: antibioticassociated diarrhea, antibiotic complications, Clostridium difficile, colitis, diarrhea, epidemiology, probiotics, risk factors part of

A common complication of antibiotic use is the development of gastrointestinal disease. This complication ranges from mild diarrhea to pseudomembranous colitis. Outbreaks of antibiotic-associated diarrhea (AAD) may also occur in healthcare settings, usually caused by Clostridium difficile. AAD typically occurs in 5–35% of patients taking antibiotics and varies depending upon the specific type of antibiotic, the health of the host and exposure to pathogens. The pathogenesis of AAD may be mediated through the disruption of the normal microbiota resulting in pathogen overgrowth or metabolic imbalances. The key to addressing AAD is prompt diagnosis followed by effective treatment and institution of control measures. Areas of active research include the search for other etiologies and more effective treatments.

Antibiotics are an effective available treatment for numerous infectious diseases, but their use is not without clinical complications. Concerns include the overuse or inappropriate use of antibiotics, the emergence of antibiotic-resistant strains of pathogens, poor compliance and the increasing rates of disease related to antibiotic use [1–4]. The most common intestinal complication of antibiotic use arises when antibiotics disrupt the ecology of the normal intestinal microbiota, resulting in antibiotic-associated diarrhea (AAD). AAD is a broad disease designation that has historically lacked a standard definition in the literature, but generally encompasses people exposed to antibiotics who develop diarrhea within 8 weeks. For nearly two-thirds of the AAD cases, the etiology is not known, but Clostridium difficile accounts for nearly one-third of all cases. Unless otherwise designated in this review, the term ‘AAD’ will refer to studies where the etiologic agent was unknown or not diagnosed. The term ‘C. difficile AAD’ will refer to studies focused specifically on this etiology only. AAD has been reported in a wide variety of populations including outpatients, hospitalized patients and residents of long-term care facilities [5]. The clinical presentation of AAD may range from mild, uncomplicated diarrhea to more severe colitis, and may result in toxic megacolon or death [6,7]. Consequences of AAD may result in extended hospital stays, increased medical care costs and increased diagnostic procedures [8–12]. The objective of this review is to summarize the current state-of-the-art on the epidemiology and risk factors for AAD and suggest recommendations for treatment and control.

10.2217/17460913.3.5.563 © 2008 Future Medicine Ltd ISSN 1746-0913

History

AAD became a recognized clinical concern in the 1950s when the use of broad-spectrum antibiotics (tetracycline and chloramphenicol) increased. However, little attention was given to this seemingly benign complication until the frequency of a relatively rare but serious disease, pseudomembranous colitis (PMC), was reported in 10% of patients receiving clindamycin [13]. Attempts to uncover the etiologic agent remained elusive until 1977/1978 when the link between AAD and an opportunistic anaerobe, C. difficile, was discovered [14]. In the 1980s, much of the attention centered on nosocomial outbreaks that were due to C. difficile, even though C. difficile was only implicated in about one-quarter of the outbreaks [15,16]. Research during the 1990s was focused on unraveling the pathogenesis, risk factors and transmission of C. difficile disease [17–19]. The 21st century has brought greater understanding of the risk factors for AAD, mechanisms, other possible etiologies, diagnostic assays, treatment strategies and methods of control. Although much has been discovered about AAD, it continues to persist, especially with the development of newer broad-spectrum antibiotics. The search for other etiologies of AAD has been expanded, although C. difficile remains the leading known cause of AAD. AAD has been shown to be a risk for the individual (in whom AAD may lead to serious complications), but also a risk for the medical community (reflected by the increased frequency of hospital outbreaks). As current treatment regimes are not always successful, AAD will be a continuing medical concern. Future Microbiol. (2008) 3(5), 563–578

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Incidence of AAD

The reported incidence of AAD ranges from 12 per 100,000 person-years to 34 per 100 outpatient visits (Table 1), depending upon the type of antibiotic, host factors (age, health status, and so on), etiology, hospitalization status and presence of a nosocomial outbreak [20–34]. Rates of AAD are similar in pediatric and adult populations (Table 1). The highest frequency of AAD is found during healthcare-associated outbreaks, when susceptible patients are clustered by time, exposure and proximity. Healthcare-associated (in hospitals, longterm care facilities, nursing homes, and so on) outbreaks of AAD are to be expected because inciting agents (antibiotics), infectious agents and a susceptible patient population are intermixed. Historically, most cases of AAD were reported in hospitalized patients [5]. More recently, although AAD still occurs in hospital settings, high rates have been reported in outpatient pediatric populations (6–33 out of 100 admissions) [21,22] and lower rates (12 out of 100,000 person-years to 14 out of 100 persons) in nonhospitalized adults [23,30]. Lower rates observed in outpatients may be due to their generally higher health status compared to hospitalized patients and also to the lack of exposure to nosocomial pathogens that

commonly contaminate hospital environments. Higher incidences are still found in healthcareassociated pediatric and adult patients (ranging from 5–34 out of 100 patients) [20,24–26,29]. Secular trends of AAD are only available for C. difficile AAD, and data from several sources show that these types of infections are increasing over time. The National Nosocomial Infections Surveillance reports increasing rates of C. difficile AAD from 1987 to 2000 in US hospitals (from 2.7 out of 10,000 up to 5.5 out of 10,000 discharges) and other reports reflect this increasing trend in Canada and the UK [35–37]. Incidence of C. difficile AAD from a large Veterans Administration Healthcare System in Seattle, WA, USA shows a trend for increasing rates (Figure 1), which reflects the national experience in other Veterans Administration centers [33,201]. Clinical presentation

AAD has a spectrum of severity including uncomplicated diarrhea, colitis and PMC. Epidemiologic studies are limited to the clinical description of non-C. difficile-associated cases, but C. difficile AAD has also been well described. In the general healthcare-associated population, most of the cases of C. difficile AAD are

Table 1. Incidence of antibiotic-associated diarrhea by population. Population

Age/group

Country

No. studied

Frequency of AAD

Ref.

Sweden

2462

4.9%

[20]

Population studies of AAD Inpatient

>12 years

Outpatient

1 month–15 years

France

650

11%

[21]

Outpatient

4 months–14.5 years

Thailand

225

6.2%

[22]

Ambulatory

Adults

USA

358,389

12/100,000 py

[23]

Clinical trials (placebo group rates) of AAD Inpatient

>50 years

UK

56

33.9%

[24]

Inpatient

1–36 months

Poland

36

33.3%

[25]

Inpatient

6–36 months

Brazil

77

31%

[26]

Inpatient

>18 years

USA

134

29.9%

[27]

In and outpatient

6 months–14 years

Poland

127

23%

[28]

Inpatient

Children

Japan

455

22.6%

[29]

Outpatient

>1 year

UK

120

14%

[30]

Clostridium difficile AAD Inpatient

Adults

France

38

18.5%

[31]

Inpatient

Adults

Ireland

60

21/1000 pd

[32]

Inpatient veteran

Adults

USA

60,590

29.2/10,000 pd

[33]

Inpatient

Oregon residents

USA

381,721

3.5/10,000

[34]

AAD: Antibiotic-associated diarrhea; pd: Person-days; py: Person-years.

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Figure 1. Secular trend for Clostridium difficile infections at Puget Sound Veterans Administration Health Care System, Seattle, WA, USA, from 1998–2006.

Incidence of CDAD/100,000 admissions

500

400

300

200

100

0 1998

1999

2000

2001

2002

2003

2004

2005

2006

CDAD: Clostridium difficile-associated disease.

uncomplicated diarrhea (10–30 out of 100 patients), while colitis is less frequent (5–10 out of 100 patients) and PMC is infrequent (0.1–1 out of 100 patients) [5]. Incubation time

The incubation time (defined as the time between antibiotic initiation and the onset of diarrhea) falls into two groups: early onset, occurring during antibiotic treatment and delayed onset, which may occur from 2–8 weeks after the antibiotics have been discontinued [5,20]. In 225 outpatient children given antibiotics, the mean onset after antibiotics was 2.3 ± 1.1 days and all cases of AAD occurred while the children were taking the antibiotics [22]. Of 157 inpatient children (aged 6–36 months), the mean onset was 4.0 ± 4.3 days and most cases occurred during antibiotic exposure (92%), while only 8% occurred within 15 days of discontinuing the antibiotics [26]. The time of onset is similar for outpatients (ranging from 2.3 to 7 days) [21,22,38] and for inpatients (ranging from 4 to 19 days) [20,26,39]. The incubation time for severe disease is also similar for milder forms of AAD. Most patients with AAD and PMC become symptomatic within 1 week following antibiotic exposure, but symptoms may be delayed in as many as 40% of patients with PMC for 2–8 weeks after antibiotics have been discontinued [24]. future science group

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Antibiotic-associated diarrhea

Diarrhea is defined as a change in the normal stool frequency with at least three loose or watery stools per day for several days [40–42,202]. The duration of AAD typically ranges from 1 to 7 days in both pediatric and adult populations [21,22,38,43]. Of 225 outpatient children on a variety of different types of antibiotics, the mean duration of AAD was found to be 2.6 ± 1.1 days [22]. Hsu et al. reported a longer mean duration of AAD in 42 hospitalized elderly patients (26.2 ± 56.1 days) [43]. Antibiotic-associated colitis

If colitis develops, the diarrhea is usually more severe and is associated with abdominal pain/cramping, fever that exceeds 40°C, hypoalbuminemia and leukocytosis [19,44]. Colitis can be diagnosed by colonoscopy when inflammatory changes (erythema, friability or edema) are noted by biopsy, but no pseudomembranes are present. Histologic examination for C. difficile colitis may reveal ‘summit lesions’ or ‘volcano lesions’ where inflammatory cells and debris are ejected into the colonic lumen. Sigmoidoscopy of patients with Klebsiella oxytoca usually reveals diffuse or segmental left colitis. Severe AAD

At the extreme end of the spectrum of severity is PMC, which is almost always associated with C. difficile. PMC may have a prolonged duration (>1–3 weeks) [45,46]. The symptoms of PMC 565

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include watery diarrhea (90–95%), abdominal cramping (80–90%), fever (80%), leukocytosis (80%) and, rarely, vomiting [47]. Lee et al. determined that patients over 70 years of age and patients with lengthy hospitalizations (>20 days) had significantly increased risk of developing PMC compared with AAD (adjusted odds ratio [aOR]: 2.7; 95% confidence interval [CI]: 1.2–6.1 and aOR: 5.1; 95% CI: 2.1–12.2, respectively) [48]. Complications of PMC may include hypokalamia (37%), renal failure (27%) and hypoproteinema (50%). Less frequently, complications of PMC may include toxic megacolon, perforation of the colon and shock [49]. Recurrent AAD

In approximately 15–60% of the patients who develop C. difficile AAD, a recurrent form of the disease may develop, despite repeated antibiotic treatments [37,50,51]. The clinical disease may be more severe in patients with recurrent C. difficile AAD compared to patients with an initial episode. Fekety compared 60 patients with recurrent C. difficile AAD with 64 nonrecurrent disease and found more patients reported fever (43 and 13%, respectively), abdominal cramping (83 and 32%, respectively) and colitis (60 and 40%, respectively) [19]. This recurrent form of AAD leads to increased use and cost of antibiotics, especially vancomycin, additional hospitalizations and medical complications [50]. Patients with recurrent episodes of C. difficile AAD do not show an increase in the severity of disease as the number of episodes progress [5]. Diagnosis of AAD

AAD should be suspected in persons exhibiting continuing diarrhea and who have had a recent exposure to either antibiotics or recent hospitalization (within 8 weeks) (Table 2). If a specific pathogen is not detected, the diagnosis may have to rest on the exposure to antibiotics and the exclusion of other causes of diarrhea (other medications, chronic intestinal conditions, such as inflammatory bowel disease or irritable bowel syndrome, and food intolerances). If the patient has had a recent hospitalization, C. difficile should be suspected and appropriate assays performed. The diagnosis of C. difficile disease must fulfill all of the following criteria: a positive C. difficile assay (culture, toxin A or toxin B), presence of diarrhea associated with antibiotic use and exclusion of other causes of diarrhea [33,41]. Diagnosis must rely on the combination of laboratory assays and the clinical presentation 566

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of the patient owing to the multiplicity of etiologies of diarrhea and the high frequency of asymptomatic carriers of C. difficile in hospitalized patients. Although enzyme immunoassays (EIAs) are more frequently used in healthcare facilities due to the rapid availability of results and low cost, tissue cell-culture with neutralization is considered the ‘gold standard’ for the detection of C. difficile toxin B as it is very sensitive to even low levels of stool toxin B [52]. However, a negative stool toxin B test should not be relied upon to rule out C. difficile. EIAs for C. difficile toxins A and B have been shown to have 48–99% sensitivity and 75–100% specificity [52–54]. Although few local microbiology laboratories perform cultures for C. difficile, up to 32–35% of cases may be missed if cultures are not done [33,53]. Examination of the stools for leukocytes may not be sufficiently specific to diagnose C. difficile infections by itself, but may be clinically useful to identify inflammatory diarrhea. Newer technologies including real-time PCR assays have acceptable sensitivity and specificity (86 and 97%, respectively) [52]. Endoscopic examination should be reserved for patients who are seriously ill or whose diagnosis is in doubt due to negative cultures, or when other possible intestinal conditions are suspected. PMC is diagnosed when sigmoidoscopic examination reveals multiple yellow-tan or green raised plaques (pseudomembranes) that can be dislodged from the mucosa during biopsy. These pseudomembranes may range in size from small (1–2 mm) distinct nodules to a confluent layer of pseudomembrane overlying the mucosa. Proctosigmoidoscopy may be completely negative and some clinicians recommend colonoscopy. Histologically, each plaque consists of mucous, inflammatory cells and fibrin excavate typically overlaying normal appearing mucosa. Computerized tomography may be useful to detect fulminant C. difficile AAD, or infrequent cases of right-sided colitis or acute abdomen syndrome [41,52]. The differential diagnosis of AAD includes acute or chronic diarrhea caused by enteric pathogens not associated with antibiotic exposure (Giardia, Vibrio, Staphylococcal food poisoning and Shigella), chronic gastrointestinal conditions (inflammatory bowel disease, irritable bowel syndrome, ischemic colitis, collagenous colitis and colon cancer), side effects of nonantibiotic medications (laxatives, cancer chemotherapeutic agents, antiviral therapy, antacids and nonsteroidal anti-inflammatory drugs), or other infections (intra-abdominal sepsis). future science group

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Table 2. Diagnosis of antibiotic-associated diarrhea and Clostridium difficile antibiotic-associated diarrhea. General

Check for

Medical history

History of recent antibiotics (15 out of 10,000 patient-days) were reported in over 30 hospitals, which were over four-times higher than expected rates and cases had five-times the expected mortality rates. A hypervirulent strain (BI/NAP1/027) of C. difficile was associated with this increase and this strain was also found to produce more toxin A and B than other C. difficile strains owing to a mutation in a toxin downregulator gene [3,9]. Although C. difficile appears to cause approximately onethird of all cases of AAD and has been the most thoroughly studied, other possible etiologies need to be examined to further understand AAD. Clostridium perfringens

The association between Clostridium perfringens and AAD has been reported in a few small studies. In 89 inpatients with AAD, only five (6%) 568

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were positive for C. perfringens [60]. In 52 fecal samples in hospitalized patients with diarrhea, 11% were positive for C. perfringens only, 44% were positive for C. difficile only and 31% were positive for both bacteria. [65]. Another study of 4659 consecutive inpatients from June 2001 to April 2002, of which 94% had diarrhea and 85% had taken antibiotics within the past 28 days, a positive etiologic agent was only found in 16.2% of the cases [8]. C. difficile cytotoxin was found in 591 patients (12.7%), C. perfringens enterotoxin was found in 155 (3.3%) and methicillin-resistant Staphylococcus aureus was found in 10 (0.2%). Usually, only one etiologic agent was found in a patient at the same time, but 21 (2.9%) were co-infected with two agents (usually both C. difficile and C. perfringens). Although C. perfringens is less frequently isolated in patients with AAD, it appears to contribute as an etiologic agent. Klebsiella oxytoca

Another potential candidate that has been investigated is K. oxytoca, which produces a cytotoxin and has been studied in rabbit intestinal loop models. A recent case report of amoxicillin-associated hemorrhagic colitis was caused by K. oxytoca [66]. Högenauer et al. reported cytotoxic K. oxytoca was more frequently isolated in patients with antibiotic-associated hemorrhagic colitis (22.7% of 22 cases) compared with healthy controls (6 out of 385, 1.6%, p 65 years • Female • Co-morbidity • Reduced immune response • Prior AAD history

Pathogen exposure • Prolonged hospitalization • Infected roommate • Type of institution • Prior admissions • Colonization pressure

Procedures • Surgery • Nasogastric tube • Enemas? • Diagnostic endoscopy?

AAD: Antibiotic-associated diarrhea.

Use of penicillin V or G was significantly protective against C. difficile AAD (OR: 0.13; 95% CI: 0.07–0.18). By contrast, only one risk factor for C. perfringens AAD was found: antacid use (OR: 2.79; 95% CI: 2.03–3.55). Use of broadspectrum pencillins was significantly protective against C. perfringens AAD (OR: 0.26; 95% CI: 0.16–0.31). Hsu et al. did not find any significant differences in risk factors between C. difficile AAD and non-C. difficile AAD [43]. Proton pump inhibitors

Other medications that can alter colonic microbiota may also increase or decrease the risk of AAD or C. difficile AAD. One area that is hotly debated is whether proton pump inhibitors (PPIs) increase the risk of C. difficile AAD. Some studies have found a significant effect, while others have not [33,44,77,78]. The role of PPIs in C. difficile AAD has yet to be resolved. Host factors

The frequency of AAD shows a distinctive curve with increased frequencies found in children under 6 years, a nadir in frequency for ages 7–50 and an increase in adults aged over 50 years [5]. In hospitalized adults, the mean age of patients with AAD was significantly older (mean: 70.2 ± 14.6) than patients with no AAD (mean: 58.5 ± 21.0) [15]. Higher rates of C. difficile AAD are typically reported for patients over 65 years old [6,76]. There is no evidence that comorbidity plays a role in non-C. difficile AAD. By contrast, comorbidity has been significantly associated with

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C. difficile AAD in several studies [6,76,79]. The risk of comorbidity may be due, in part, to additional antibiotic exposure used to treat the concurrent infection. However, the risk is significant even for illnesses not treated with additional antibiotics and thus the comorbidity may be an indictor of a patient in poor health who cannot mount an effective immune response to challenge by bacterial overgrowth. There may be an immune component to the pathogenesis of AAD, but this role needs further investigation. Depressed immune response has been associated with an increased risk of C. difficile AAD. Munoz et al. found the rate of C. difficile AAD was significantly higher in 141 hypogammaglobulinemic heart transplant patients (29 cases, 20.6%) compared with 6 out of 94 (6.4%) heart transplant patients treated with γ-globulin [80]. In addition, symptomatic C. difficile AAD patients have been found to have lower IgG antitoxin A levels than healthy controls or asymptomatic carriers of C. difficile [81]. Pathogen exposure

Being susceptible owing to antibiotic exposure is not sufficient to cause AAD – exposure to a pathogen is also involved. To date, most of the etiologic agents are not culturable, but as hospitalized patients have higher rates of AAD, it may be assumed that the pathogens are present in the healthcare setting. The best example of this is C. difficile AAD. Nonhospitalized adults and outpatients have lower rates of AAD, even when exposed to similar types of broad-spectrum

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antibiotics. The lower rates are probably associated with a lower risk of exposure to pathogens able to cause AAD. For inpatients, the length of hospitalization before AAD develops has been found to be a significant risk factor. Asha et al. compared 503 C. difficile AAD cases to 254 ageand gender-matched controls and determined that the risk of C. difficile AAD increases by each day of hospitalization (aOR: 1.03; 95% CI: 1.01–1.04) [8]. Admittedly, this factor may be confounded by multiple in-hospital exposures that increase the risk of AAD, such as exposure to other infected patients, additional antibiotic exposures, medical procedures, and so on. Colonization pressure, or proximity to a C. difficile AAD case, increases the risk of acquiring C. difficile AAD in patients who are nearby [11,82]. Procedures

Healthcare-associated procedures, such as intestinal surgery or endoscopy, can also disrupt colonic microbiota and have been found to increase the risk of AAD [5,73]. Asha et al. found the use of nasogastric tubes increased the risk of C. difficile AAD (aOR: 5.63; 95% CI: 4.52–6.41) even after adjusting for age, gender, length of stay and antibiotic use [8]. Multivariate risk factor analyses

Many of the above risk factors are closely correlated and the individual risk estimates of AAD attributable to each factor are thus difficult to quantitate. Multivariate models allow the assessment of the risk for each factor, while simultaneously adjusting for the influences of the other risk factors in the model. Unfortunately, the majority of studies utilizing multivariate modeling have focused on just one etiology of AAD (C. difficile), so the risk factors for other etiologies of AAD need to be studied using this method of analysis. Multivariate analyses indicate that antibiotics and exposures that perturb colonic microbiota are consistently predictive of C. difficile AAD. Most multivariate models for C. difficile AAD have found age over 65 years, exposure to antibiotics, comorbidities and length of hospitalization to be common risk factors for this type of AAD [33,64,78,79,83,84]. Treatments for AAD Discontinuation of inciting antibiotic

For uncomplicated cases of AAD, the most prudent measure is to discontinue or change the inciting antibiotic if possible, as shown in Figure 3 future science group

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[8,37,85].

However, for more serious cases of AAD and C. difficile AAD, more active treatment is required.

Antibiotic treatment

In instances where the etiologic agent for AAD is known, specific antibiotics targeted against these pathogens is recommended. For C. difficile, two antibiotics are recommended: oral vancomycin and metronidazole [3,85]. Vancomycin has been shown to be more effective in reducing the time until diarrhea is cured and the patient has less than three loose stools per day (a mean of 3 days) compared with metronidazole (a mean of 5 days) [3,85]. Currently, however, oral vancomycin is not given as a first-line treatment for patients with initial C. difficile AAD owing to its expense and the possibility of increased rates of vancomycinresistant enterococci. Vancomycin should be used in patients whose use of metronidazole is contraindicated (previously failed on metronidazole, allergic or pregnant) or who have severe C. difficile disease or toxic megacolon, or when the AAD is caused by S. aureus [85,86]. If symptoms persist, if vancomycin cannot be given orally, or if ileus is present, vancomycin may be given via nasogastric tube or by enema. In similar cases, metronidazole may be delivered intravenously [85]. Intravenous immunoglobulin as an adjunct to vancomycin has been helpful in a few cases, but controlled randomized trials are lacking. The higher rate of metronidazole treatment failures associated with the BI/NAP1/027 C. difficile strain raises the concern that the two most replied upon antibiotics may not be effective in the future. Other antibiotics under investigation for C. difficile AAD include nitrazoxanide, tiacumicin B and rifampin [87–89], but other treatments for non-C. difficile AAD are urgently needed. Another difficult treatment problem is recurrent C. difficile AAD. This form of C. difficileassociated AAD has been noted in 20% of patients after their initial episode of C. difficile AAD has been treated, and recurrent episodes may persist for up to 4 years, despite multiple treatments with antibiotics [49,90]. Strategies of antibiotic treatment for recurrent C. difficile AAD include a repeat course of antibiotic using a prolonged, tapering dose schedule or a pulsed (every other day) scheme [90]. The need to find an effective treatment that would not further perturb the colon microbiota (as with an additional course of antibiotics) has generated interest in nonantibiotic-dependent treatments. The 571

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Figure 3. Treatment algorithm for antibiotic-associated diarrhea and Clostridium difficile antibiotic-associated diarrhea.

AAD diagnosed

No known etiology • Stop inciting antibiotic • Switch to lower-risk antibiotic

Clostridium difficile-positive •Toxin or culture-positive • Rule out other etiologies for diarrhea

Asymptomatic carrier • No treatment

Primary episode of C. difficile AAD • Stop inciting antibiotic if possible • Treat with oral metronidazole (500 mg t.i.d., 10–15 days) • Treat with oral vancomycin (125–250 mg q.i.d., 10 days)

Initial resolution of symptoms

Persistence of symptoms or development of serious colitis • Intravenous metronidazole or vancomycin enema • Intravenous immunoglobulin • Last resort: colectomy

First recurrence of C. difficile AAD • Retreat with metronidazole or vancomycin

Repeated C. difficile recurrences • Pulsed or tapering course of vancomycin • Adjunctive treatment with probiotics • Fecal replacement therapy

Other etiology found • Appropriate antibiotic or antifungal

If no response, consider investigational therapies • Intravenous immunoglobulin • Toxin-binding polymers • Investigational antibiotics

AAD: Antibiotic-associated diarrhea; q.i.d.: Four-times daily; t.i.d.: Three-times daily.

rationale is to find a treatment strategy that would allow the re-establishment of normal microbiota (and colonization resistance) or decrease bowel motility while limiting the use of additional antibiotics. One tactic has been to use toxin-binders instead of targeting the pathogen directly with antibiotics. One investigational drug, tolevamer, is a good example of using a toxin binder and Phase III trials are ongoing [91]. Probiotic therapy

Use of living organisms as a treatment or prophylaxis for AAD has been tried using several species, and probiotics are widely used in Europe for diarrhea therapy [6,92]. Probiotics are defined as ‘living microorganisms, which administered in adequate amounts, confer health benefits to the host’ [93]. Although the evidence is strong for 572

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some bacterial and yeast strains as probiotics for the prevention of AAD, the evidence for C. difficile AAD is weaker. The advantages of using living microbes is that they are effective while minimizing the impact on normal intestinal microbiota and, unlike antibiotic treatments, have not been associated with serious adverse effects. Other types of treatments

As it has been shown in several studies that patients with recurrent C. difficile AAD may be immunosuppressed, use of pooled immunoglobulin as a treatment strategy has been reported in several case reports and series, but there are no controlled trials to date [94,95]. Other types of treatments under investigation include colonization with nontoxigenic strains of C. difficile and fecal replacement therapy using donor stool infusions [85]. future science group

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Surgery should be considered the last resort for some patients with severe or fulminant cases of C. difficile AAD and intractable PMC. Although the rate of colectomy has ranged from 3.4 out of 1000 to 23% in C. difficile AAD patients [55,96], the rate of mortality is high in these patients (44–47%) [55,97]. Patients with severe disease treated with emergency colectomies (soon after C. difficile AAD diagnosis) have a significantly lower mortality rate (34%) than patients treated with metronidazole or vancomycin before surgery was performed (58%) [55]. Prevention

Because AAD is a direct effect of the use of antibiotics, simultaneous use of a probiotic which is not sensitive to the prescribed antibiotic (such as a yeast probiotic) may be an effective prophylactic strategy. Another recommendation is to limit the abuse and overuse of antibiotics. Antibiotics are overprescribed for viral respiratory infections and bronchitis and the overuse of antibiotics has been shown to be associated with an increase in antibiotic-associated complications, such as AAD and antibiotic resistance [1,98]. Kardas et al. analyzed data from 46 studies and found that the mean compliance with a course of antibiotic was only 62%, part of which may be due to the development of AAD [2]. Rational use of antibiotics may well be the best preventive in our arsenal. There are several lines of evidence that probiotics may be effective for preventing AAD. Beausoleil et al. conducted a double-blind randomized study of hospitalized patients for the prevention of AAD using fermented milk with a mixture of two lactobacilli strains (Lactobacillus casei and Lactobacillus acidophilus CI1285) compared with placebo milk [99]. Of 89 enrolled patients, AAD occurred in 7 out of 44 (15.9%) of the probiotic milk group, and significantly more (16 out of 45, 35.6%) of the placebo group developed AAD. There were no adverse effects of either treatment in this study. Wenus et al. also found a significant protection of probiotic fermented milk in their study of 87 adult inpatients receiving antibiotics [100]. Patients were randomized to either a probiotic fermented milk (Lactobacillus rhamnosus GG, Lactobacillus acidophilus La-5 and Bifidobacterium bifidus Bb-12) or a control group with heat-killed bacteria. Significantly fewer patients (2 out of 46, 5.9%) given the probiotic milk developed AAD compared with the patients receiving the control milk (8 out of 41, 27.6%). future science group

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A meta-analysis of 25 randomized controlled trials (involving 2810 patients) found that probiotics have an overall protective efficacy for AAD (pooled RR: 0.43, 95% CI: 0.31–0.58) [101]. Another meta-analysis limited the trials to those done with children and pooled results from six randomized, controlled trials (involving 766 children) and found a protective effect (pooled RR: 0.44; 95% CI: 0.25–0.77) [102]. The efficacy was most pronounced for L. rhamnosus GG, Saccharomyces cerevisiae variant boulardii and a mixture of Bifidobacterium lactis and Streptococcus thermophilus. In another study, Szajewska et al. limited their meta-analysis to randomized, controlled trials of one type of probiotic (S. cerevisiae boulardii) [103]. Pooling the results from five trials (involving 1076 subjects), a significantly protective effect was found (pooled RR: 0.43; 95% CI: 0.23–0.78). However, most of the protective effect was due to two studies with S. cerevisiae boulardii. Although these results show promise, more clinical trials testing different types of probiotics are needed for C. difficile AAD and other types of AAD. In addition, it is important to note that the therapeutic effect is specific to the probiotic strain, so clinical efficacy found for one strain does not guarantee efficacy for another type of probiotic. Prebiotics are ‘nondigestible food ingredients that benefically affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the intestine’ [104]. Lewis et al. randomized 435 elderly inpatients (>65 years old) taking broad spectrum antibiotics to either a prebiotic (oligofructose, 12 g/d) or placebo [105]. Patients were treated during the duration of the antibiotics and for an additional 7 days. Patients given the prebiotic developed AAD at a similar rate (36 out of 215, 17%) to the control patients (37 out of 220, 16.8%). Control of AAD

The prevention of AAD and C. difficile AAD that is associated with healthcare facilities has been easier to control than trying to reduce inappropriate antibiotic use. Several studies have shown positive results when focused efforts have been taken on several levels. The first step is to promptly diagnosis and treat cases (when appropriate), which limits the spread of the organism into the hospital environment. The second step is to limit the transmission of pathogens through increased enteric precautions, use of disposable gloves and thermometers, increased room disinfection and increased educational programs for 573

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hospital personnel [3]. Hospital wide restriction of high-risk antibiotics (clindamycin and second or third-generation cephalosporins) and controlling inappropriate antibiotic prophylaxis has been shown to be effective in reducing nosocomial rates of C. difficile AAD [3,98]. Integrated, multidisciplinary multilevel infection control programs have been shown to be effective in reducing outbreaks of C. difficile AAD and may well be effective even in cases where the etiology is not known, but is amenable to the same infection control practices as C. difficile AAD [32,106].

Conclusion

AAD continues to become more frequent due to the increase in broad spectrum antibiotics, the aging of the population and the increasing frequency of healthcare-associated outbreaks. Four major factors increase the risk of AAD and C. difficile AAD: host characteristics (age, comorbidity), exposure to fomites (shared hospital rooms, prolonged hospital stays), medications (antibiotics, chemotherapy, motility altering drugs, antacids) and medical procedures (surgery, enemas). AAD may result in increased costs

Executive summary Incidence • A lower incidence of antibiotic-associated diarrhea (AAD) is found in outpatients and community populations. • Higher incidences of AAD are found in healthcare-associated settings. • Secular trends show a continued increase in incidence over time. Clinical presentation • • • •

AAD ranges from mild diarrhea to inflammatory colitis to pseudomembranous colitis (PMC). AAD may occur while taking antibiotics, or develop as much as 8 weeks afterwards. Duration of AAD ranges from 1 day to several months. Colitis and PMC are associated with fever, leukocytosis and abdominal cramping.

Consequences • AAD may cause extended hospital stays and increased healthcare costs. • Recurrent AAD may occur in 20–50% of patients. • Mortality is increased in severe cases of AAD. Pathogenesis • Disruption of normal intestinal microbiota is the key step that causes susceptibility. • Overgrowth of opportunistic pathogens or altered fermentation results in the development of symptoms. • Etiologic agents for AAD include Clostridium difficile, Clostridium perfringens, Klebsiella oxytoca and Staphylococcus aureus. Risk factors • • • • •

High-risk antibiotics (especially clindamycin, cephalosporins and penicillins). Low-risk antibiotics (fluoroquinolones and macrolides). Host factors (advanced age, immunosuppression and co-morbidities). Exposure to pathogens (hospitalization, shared rooms and outbreaks). Procedures (nasogastric tube feeding and surgery).

Treatment • • • •

Discontinue inciting antibiotic or switch to a lower risk antibiotic if possible. If C. difficile AAD, treat with metronidazole or vancomycin. Consider probiotics for recurrent C. difficile AAD or to prevent AAD. Colectomy for nonresponsive cases.

Prevention • Rational use of antibiotics. • Prompt diagnosis and treatment. • Infection control programs for inpatients.

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of medical care and has infrequent, but serious complications, especially if the etiology is C. difficile. Further research into treatments and preventive measures are required. Limitations in the literature on AAD include a lack of standardized definitions for AAD. Studies often report different etiologies or do not fully diagnose them, have a variety of incubation period definitions, follow patients for varying times and use different diagnostic procedures. In addition, treatment or prevention clinical trials are needed with consistant inclusion and exclusion criteria, using standardized study drug doses and durations and intention to treat analyses. Future perspective

As C. difficile AAD continues to plague healthcare settings and rates continue to increase, effective control programs and newer treatments will be the focus of future research. The development of technologically advanced molecular probes are beginning to characterize new, previously unculturable species of intestinal microbes. A greater

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Affiliation • Lynne V McFarland, PhD Department of Health Services Research & Development, Puget Sound Veterans Administration, Healthcare System, S-152, 1100 Olive Way, #1400 Seattle, WA 98101, USA Tel.: +1 206 277 1095; Fax: +1 206 764 2935; [email protected] and, Department of Medicinal Chemistry, Box 357610, School of Pharmacy, University of Washington, Seattle, WA 98101, USA

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