Pharmacology Consult

Pharmacologic advances, opportunities in 
C. difficile infection management

Clostridium difficile infection is an important health care-associated condition marked by severe and prolonged bouts of diarrhea. The risk for developing CDI is strongly associated with antibiotic exposure, and the unique life cycle of C. difficile presents important therapeutic challenges as the pathogen exists in the forms of resilient spores and vegetative bacteria that release exotoxins.

CDI continues to be a significant driver of patient morbidity and mortality, as well as a contributor to increased health care costs, thus substantial strides have been made to broaden the therapeutic options in the management of this infection.

Existing therapies

Oral vancomycin and metronidazole, administered IV or orally, have remained the first-line mainstays of antimicrobial treatment of CDI. Among patients with severe or refractory CDI, alternative dosing strategies of vancomycin have been attempted, such as pulsed dosing or rectal administration. Other treatment modalities described to varying degrees in the literature include rifaximin (Xifaxan, Salix Pharmaceuticals), IV immunoglobulin, nitazoxanide (Alinia, Romark Laboratories) and tigecycline (Tygacil, Wyeth Pharmaceuticals), as described in some case studies.

Fidaxomicin

Fidaxomicin (Dificid, Optimer Pharmaceuticals) is the first new antimicrobial agent to be approved for the treatment of CDI in more than 20 years. Besides an easier administration schedule of 200 mg orally twice daily rather than the four daily doses typically given of other agents, fidaxomicin presents several mechanistic advantages over existing therapeutic options. First, it preserves natural gut microbial flora better than commonly used alternatives. As metronidazole and vancomycin are active against many bacteria commonly found in the gut microbiome of healthy patients, besides C. difficile, these agents have a greater propensity to disrupt the natural and protective intestinal flora, which is a well-described risk factor for CDI. One investigation found significantly reduced the colony counts of Bacteroides species and Prevotella species recovered from fecal samples of patients receiving oral vancomycin vs. minimal differences among patients receiving fidaxomicin.

Whereas only the vegetative form of C. difficile can cause symptomatic infection, the disease is spread through acquisition of highly durable spores that can persist on surfaces for prolonged periods of time. Vancomycin and metronidazole are active against the vegetative bacteria, thus spores are unaffected and can still germinate into viable bacteria to continue causing symptoms.

Fidaxomicin, however, offers activity against both C. difficile vegetative bacteria and spores. When compared with vancomycin and metronidazole, only fidaxomicin and its active metabolite were found to significantly decrease the presence of spores, noted in both in vitro analysis and evaluation of human patient fecal matter. This mechanistic difference contributes to the bactericidal effects of fidaxomicin against C. difficile vs. the bacteriostatic activities of vancomycin and metronidazole.

In clinical phase 3 CDI studies of patients experiencing their first or second occurrence of CDI, fidaxomicin was found to be equally effective as oral vancomycin in achieving clinical cure but offered a significant decrease in disease recurrence. This benefit was seen only, however, among patients who were not infected with a hypervirulent strain of C. difficile, commonly abbreviated as the NAP1/BI/027 strain, which was present in about 35% of study participants. Although encouraging, this finding offers limited practicality because testing to identify this strain is not routinely included in clinical practice, as it historically made no impact on clinical decision making. Another population in which fidaxomicin offered reduction in disease recurrence superior to vancomycin was patients receiving concomitant antimicrobial agents.

Preservation/restoration of normal gastrointestinal flora

The use of probiotics to maintain or restore normal gut flora has been an area of interest. However, both the Infectious Diseases Society of America and the American Academy of Pediatrics discourage use for prevention or treatment of CDI in their guidelines, citing lacking evidence and risk for systemic infection. Meta-analyses exist, however, to suggest that some benefit may exist in the pediatric patients, which has prompted continued evaluation of the practice in this population.

In recent years, the practice of fecal transplantation as a means to replace patient gut flora with that of a donor has gained attention in clinical practice and in the literature. One study has evaluated the long-term (average follow-up time of 17 months) outcomes of patients after undergoing this procedure. On average, patients who underwent fecal transplantation had already failed five courses of antimicrobial therapy. A total of 91% of patients experienced clinical cure without recurrence within 90 days of transplant, and when allowed one further course of oral vancomycin, with or without repeat transplantation, 98% of patients experienced cure with no recurrence through the time of follow-up evaluation.

Another intervention critically important to the maintenance of normal gut flora and the reduction of CDI is the judicious use of antimicrobials, as exposure to these agents has consistently been identified as a significant risk factor for the development of CDI. Although fluoroquinolones and third- and fourth-generation cephalosporins appear to carry the greatest risk for CDI, and should be replaced by lower-risk agents when possible, cumulative antibiotic exposure as a whole is associated with risk for disease and antimicrobial stewardship efforts to minimize unnecessary antibiotic exposure continue to be recommended as a means to prevent CDI.

Future directions

Understanding that germination of the C. difficile spore is needed to cause symptoms of CDI, investigation into the prevention of spore germination is ongoing. The dependence of germination on the interaction of the C. difficile spore with a bile salt, taurocholate, and an amino acid, glycine, has been established and prompted the development of CamSA, a competitive inhibitor of this process. When studied in mice inoculated with large doses of C. difficile, all untreated mice developed severe CDI, whereas mice receiving high doses of CamSA did not experience any symptoms. Although not yet studied in humans, therapies to inhibit spore germination may represent a new therapeutic target for the treatment or prevention of CDI.

As antimicrobial agents target only bacteria and not the toxins integral to CDI pathogenesis, another interesting advancement in drug therapy options is the development of humanized IgG monoclonal antibodies designed to neutralize C. difficile toxins A and B, denoted as TcdA and TcdB. Among hamsters inoculated with quantities of C. difficile sufficient to kill all members of the untreated group within 3 days, and all members of the group receiving vancomycin alone within 11 days, 82% of the hamsters treated with a mixture of anti-TcdA and anti-TcdB monoclonal antibodies survived until the study was completed, 28 days after initial infection.

Although CDI continues to be a highly prevalent disease causing hospital outbreaks and poor patient outcome, advances in the development of new treatment modalities along with judicious use of antimicrobials offer hope for future treatment solutions.

References:

American Academy of Pediatrics Committee on Infectious Diseases. Clin Infect Dis. 2012;55 Suppl 2:S162-169.
Brandt LJ. Am J Gastroenterol. 2012;107:1079-1087.
Davies NL. Clin Vaccine Immunol. 2013;20:377-390.
Herpers BL. Clin Infect Dis. 2009;48:1732-1735.
Howerton A. J Infect Dis. 2013;207:1498-1504.
Johnston BC. Cochrane Database Syst Rev. 2011;11:CD004827.
Koon HW. Antimicrob Agents Chemother. 2013; [Published online ahead of print April 29].
Larson KC. Pharmacother. 2011;45:1005-1010.
Louie TJ. Antimicrob Agents Chemother. 2009;53:261-263.
Louie TJ. Clin Infect Dis. 2012;55 Suppl 2:S132-142.
Louie TJ. N Engl J Med. 2011;364:422-431.
Sorg JA. J Bacteriol. 2008;190:2505-2512.
Stevens V. Clin Infect Dis. 2011;53:42-48.

For more information:

Leah Steinke, PharmD, is a clinical pharmacist, specialist in infectious diseases, at Children’s Hospital of Michigan, Detroit.

Disclosure: Steinke reports no relevant financial disclosures.

Clostridium difficile infection is an important health care-associated condition marked by severe and prolonged bouts of diarrhea. The risk for developing CDI is strongly associated with antibiotic exposure, and the unique life cycle of C. difficile presents important therapeutic challenges as the pathogen exists in the forms of resilient spores and vegetative bacteria that release exotoxins.

CDI continues to be a significant driver of patient morbidity and mortality, as well as a contributor to increased health care costs, thus substantial strides have been made to broaden the therapeutic options in the management of this infection.

Existing therapies

Oral vancomycin and metronidazole, administered IV or orally, have remained the first-line mainstays of antimicrobial treatment of CDI. Among patients with severe or refractory CDI, alternative dosing strategies of vancomycin have been attempted, such as pulsed dosing or rectal administration. Other treatment modalities described to varying degrees in the literature include rifaximin (Xifaxan, Salix Pharmaceuticals), IV immunoglobulin, nitazoxanide (Alinia, Romark Laboratories) and tigecycline (Tygacil, Wyeth Pharmaceuticals), as described in some case studies.

Fidaxomicin

Fidaxomicin (Dificid, Optimer Pharmaceuticals) is the first new antimicrobial agent to be approved for the treatment of CDI in more than 20 years. Besides an easier administration schedule of 200 mg orally twice daily rather than the four daily doses typically given of other agents, fidaxomicin presents several mechanistic advantages over existing therapeutic options. First, it preserves natural gut microbial flora better than commonly used alternatives. As metronidazole and vancomycin are active against many bacteria commonly found in the gut microbiome of healthy patients, besides C. difficile, these agents have a greater propensity to disrupt the natural and protective intestinal flora, which is a well-described risk factor for CDI. One investigation found significantly reduced the colony counts of Bacteroides species and Prevotella species recovered from fecal samples of patients receiving oral vancomycin vs. minimal differences among patients receiving fidaxomicin.

Whereas only the vegetative form of C. difficile can cause symptomatic infection, the disease is spread through acquisition of highly durable spores that can persist on surfaces for prolonged periods of time. Vancomycin and metronidazole are active against the vegetative bacteria, thus spores are unaffected and can still germinate into viable bacteria to continue causing symptoms.

Fidaxomicin, however, offers activity against both C. difficile vegetative bacteria and spores. When compared with vancomycin and metronidazole, only fidaxomicin and its active metabolite were found to significantly decrease the presence of spores, noted in both in vitro analysis and evaluation of human patient fecal matter. This mechanistic difference contributes to the bactericidal effects of fidaxomicin against C. difficile vs. the bacteriostatic activities of vancomycin and metronidazole.

In clinical phase 3 CDI studies of patients experiencing their first or second occurrence of CDI, fidaxomicin was found to be equally effective as oral vancomycin in achieving clinical cure but offered a significant decrease in disease recurrence. This benefit was seen only, however, among patients who were not infected with a hypervirulent strain of C. difficile, commonly abbreviated as the NAP1/BI/027 strain, which was present in about 35% of study participants. Although encouraging, this finding offers limited practicality because testing to identify this strain is not routinely included in clinical practice, as it historically made no impact on clinical decision making. Another population in which fidaxomicin offered reduction in disease recurrence superior to vancomycin was patients receiving concomitant antimicrobial agents.

Preservation/restoration of normal gastrointestinal flora

The use of probiotics to maintain or restore normal gut flora has been an area of interest. However, both the Infectious Diseases Society of America and the American Academy of Pediatrics discourage use for prevention or treatment of CDI in their guidelines, citing lacking evidence and risk for systemic infection. Meta-analyses exist, however, to suggest that some benefit may exist in the pediatric patients, which has prompted continued evaluation of the practice in this population.

In recent years, the practice of fecal transplantation as a means to replace patient gut flora with that of a donor has gained attention in clinical practice and in the literature. One study has evaluated the long-term (average follow-up time of 17 months) outcomes of patients after undergoing this procedure. On average, patients who underwent fecal transplantation had already failed five courses of antimicrobial therapy. A total of 91% of patients experienced clinical cure without recurrence within 90 days of transplant, and when allowed one further course of oral vancomycin, with or without repeat transplantation, 98% of patients experienced cure with no recurrence through the time of follow-up evaluation.

Another intervention critically important to the maintenance of normal gut flora and the reduction of CDI is the judicious use of antimicrobials, as exposure to these agents has consistently been identified as a significant risk factor for the development of CDI. Although fluoroquinolones and third- and fourth-generation cephalosporins appear to carry the greatest risk for CDI, and should be replaced by lower-risk agents when possible, cumulative antibiotic exposure as a whole is associated with risk for disease and antimicrobial stewardship efforts to minimize unnecessary antibiotic exposure continue to be recommended as a means to prevent CDI.

Future directions

Understanding that germination of the C. difficile spore is needed to cause symptoms of CDI, investigation into the prevention of spore germination is ongoing. The dependence of germination on the interaction of the C. difficile spore with a bile salt, taurocholate, and an amino acid, glycine, has been established and prompted the development of CamSA, a competitive inhibitor of this process. When studied in mice inoculated with large doses of C. difficile, all untreated mice developed severe CDI, whereas mice receiving high doses of CamSA did not experience any symptoms. Although not yet studied in humans, therapies to inhibit spore germination may represent a new therapeutic target for the treatment or prevention of CDI.

As antimicrobial agents target only bacteria and not the toxins integral to CDI pathogenesis, another interesting advancement in drug therapy options is the development of humanized IgG monoclonal antibodies designed to neutralize C. difficile toxins A and B, denoted as TcdA and TcdB. Among hamsters inoculated with quantities of C. difficile sufficient to kill all members of the untreated group within 3 days, and all members of the group receiving vancomycin alone within 11 days, 82% of the hamsters treated with a mixture of anti-TcdA and anti-TcdB monoclonal antibodies survived until the study was completed, 28 days after initial infection.

Although CDI continues to be a highly prevalent disease causing hospital outbreaks and poor patient outcome, advances in the development of new treatment modalities along with judicious use of antimicrobials offer hope for future treatment solutions.

References:

American Academy of Pediatrics Committee on Infectious Diseases. Clin Infect Dis. 2012;55 Suppl 2:S162-169.
Brandt LJ. Am J Gastroenterol. 2012;107:1079-1087.
Davies NL. Clin Vaccine Immunol. 2013;20:377-390.
Herpers BL. Clin Infect Dis. 2009;48:1732-1735.
Howerton A. J Infect Dis. 2013;207:1498-1504.
Johnston BC. Cochrane Database Syst Rev. 2011;11:CD004827.
Koon HW. Antimicrob Agents Chemother. 2013; [Published online ahead of print April 29].
Larson KC. Pharmacother. 2011;45:1005-1010.
Louie TJ. Antimicrob Agents Chemother. 2009;53:261-263.
Louie TJ. Clin Infect Dis. 2012;55 Suppl 2:S132-142.
Louie TJ. N Engl J Med. 2011;364:422-431.
Sorg JA. J Bacteriol. 2008;190:2505-2512.
Stevens V. Clin Infect Dis. 2011;53:42-48.

For more information:

Leah Steinke, PharmD, is a clinical pharmacist, specialist in infectious diseases, at Children’s Hospital of Michigan, Detroit.

Disclosure: Steinke reports no relevant financial disclosures.