Changing C. difficile-associated disease

Clostridium difficile shares an important identification with the pediatric population, as this anaerobic bacterium was first isolated from healthy infants’ stools 75 years ago. Its name, in part, relates to the difficulty (original species name of difficilis) originally encountered in culturing this organism. C. difficile is now known to be an important pathogenic cause of diarrheal disease. Most recently, newer data have suggested that the epidemiology and risk factors for developing illness from this pathogen in infants and children may be changing.

Traditionally, C. difficile-associated disease (CDAD) had occurred mostly in children and adults who had significant exposure to a health care institution (eg, hospitalized for another illness) or antibiotic therapy.

Older adults are also believed to be at greater risk of developing CDAD. In the pediatric population, it is known that gastrointestinal colonization by toxin-producing stains of C. difficile in asymptomatic infants less than 1 year is common. Although development of CDAD has been known to occur in previously healthy children without recent antibiotic exposure, this is generally uncommon.

These characteristics and risk factors may be changing, however. Newer data from 2000 and later have demonstrated significant increases in CDAD in acute care facilities. Data describing several outbreaks of CDAD during 2000-2005 have been published, yielding a nearly threefold increase in the incidence of CDAD (84 CDAD cases/100,000 in 2005).

CDAD illness severity and mortality rate have also increased during this time.

Additional data specific to the pediatric population have also recently become available. In a retrospective study of hospitalized children at 22 U.S. children’s hospitals during 2001-2006, researchers reported an increase in the annual incidence of CDAD from 2.6 to 4 cases/1,000 admissions, or a 54% increase. Twenty-six percent of children with CDAD were less than 1 year of age. The all-cause mortality rate among children with CDAD did not increase.

In another retrospective study, researchers examined the incidence of hospitalization of U.S. infants less than 1 year of age with CDAD during 2000-2005, using data from the National Inpatient Sample (Agency for Healthcare Research and Quality).

The number of infants discharged from U.S. hospitals with a CDAD diagnosis increased by 91.3%. In 2005, the CDC reported on cases of severe CDAD, where the infected individuals had characteristics previously believed to be at low-risk for developing CDAD. In this report, 33 individuals from four states are described, 23 with community exposure and 10 with peripartum exposure. Of the community-acquired cases, 11 were aged 18 years or younger. Eight individuals (five were children) did not report use of an antibiotic within 3 months of CDAD onset.

An additional change in the epidemiology of CDAD is the potential increasing role of a specific C. difficile strain in the data described above. This strain, NAP-1/027, has been identified to be a common cause of CDAD in these reports. The NAP-1/027 strain is unique for its increased production of toxins A and B, production of a binary toxin, and resistance to fluoroquinolone antibiotics. Although the identification of this hypervirulent strain in CDAD cases is concerning, its exact role and contribution to changing CDAD epidemiology is not clear, and requires further study.

Treatment

The initial treatment strategy recommended for children and adults with CDAD is discontinuance of the causative antibiotic.

Nearly every antibiotic has been implicated as a causative agent in CDAD, although clindamycin, third-generation cephalosporins, and penicillins are classically described as the most likely to cause CDAD. More recent data have also implicated fluoroquinolones as potentially more likely to cause CDAD.

Antibiotic restriction programs with clindamycin and third-generation cephalosporins have been demonstrated to reduce CDAD incidence. Discontinuing the offending antibiotic may be effective in up to 23% of individuals with CDAD.

In May, the Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America published evidence-based guidelines on the management of C. difficile infection in adults.

These comprehensive guidelines recommend metronidazole as the drug of choice for initial treatment of mild-moderate disease. Vancomycin is recommended initially for severe disease. Several controlled trials have shown metronidazole and vancomycin to be similarly effective. However, more recent adult data have demonstrated that vancomycin is more effective for more severe disease. In a recently published controlled trial, metronidazole and vancomycin demonstrated equivalent efficacy rates in subjects with mild CDAD. In patients with severe disease, vancomycin demonstrated superior efficacy.

The 2009 Red Book lists similar recommendations to these adult guidelines. If discontinuance of the offending antibiotic is not effective, metronidazole is initially recommended (30 mg/kg/day, divided in 4 doses). Vancomycin given orally (40 mg/kg/day, divided in 4 doses) is recommended initially for severe disease (hospitalized in an intensive care unit, pseudomembranous colitis on endoscopy, or underlying intestinal tract disease). Considerations for assessing severe disease in adults include advanced age, leukocytosis, and increased serum creatinine.

Metronidazole and vancomycin are most commonly administered orally for CDAD. Both of these antibiotics are commercially available as oral dosage forms (generic tablets and capsules for metronidazole, trade product capsules only for vancomycin). A commercially available liquid oral dosage form is not available for either agent, although a published recipe is available for metronidazole (50 mg/ml). Some institutions administer the intravenous vancomycin dosage form orally. Vancomycin is not appreciably absorbed from the gastrointestinal tract when given orally, and thus it is more likely to achieve high fecal levels. A clinical benefit of this, however, is not well defined. Vancomycin ($500 for 20 x 125 mg capsules) is significantly more expensive than metronidazole ($16 for 90 x 250 mg tablets). Resistance by C. difficile to metronidazole or vancomycin is rare.

As with nearly all infectious diseases, proper hand hygiene is a very important tool to prevent the spread of infectious pathogens and disease. Although alcohol-based hand gels and antiseptic products can prove useful and easy to use when striving to limit the spread of infectious pathogens, the ability of C. difficile to exist as spores is important to consider. C. difficile spores have been demonstrated to resist alcohol as an antiseptic agent. No evidence exists, however, that use of alcohol-based antiseptics for hand hygiene increases risk of transmitting C. difficile spores (via displacing spores over the hands). The newly published adult guidelines described above recommend, among other infection control precautions, that visitors and health care workers use soap and water for hand washing after contacting or caring for individuals with CDAD. The 2009 Red Book also recommends use of soap and water for hand washing, and not alcohol-based antiseptics, as a more effective strategy to remove C. difficile spores from contaminated hands.

As newer data are suggesting that the epidemiology of CDAD is changing, pediatric clinicians should demonstrate increased awareness for clinical illness due to C. difficile in infants and children, especially in children not previously considered to be at high risk. As has been stated in this

Pharmacology Consult column on numerous occasions, antibiotic use can result in significant adverse effects, and thus judicious use of these medications is important to consider.

Edward Bell, PharmD, BCPS, is a Professor of Clinical Sciences at Drake University College of Pharmacy, Blank Children’s Hospital and Clinics in Des Moines, Iowa.

For more information:

• CDC. MMWR. 2005; 54:1201-1205.
• Cohen SH. Infection Control and Hospital Epidemiol. 2010;31:431-455.
• Kelly CP. NEJM. 2009;359:1932-1940.
• Kim J. Pediatrics. 2008;122:1266-1270.
• Zar FA. Clin Infect Dis. 2007;45:302-307.
• Zilberberg. Pediatr Infect Dis J. 2008; 27:1111-1113.