Robert Fekety

The Search for a Better Treatment for Recurrent Clostridium difficile Disease: Use of High-Dose Vancomycin Combined with Saccharomyces boulardii

Recurrent Clostridium difficile disease (CDD) is a difficult clinical problem because antibiotic therapy often does not prevent further recurrences. In a previous study, the biotherapeutic agent Saccharomyces boulardii was used in combination with standard antibiotics and was found to be effective in reducing subsequent recurrences of CDD. In an effort to further refine a standard regimen, we tested patients receiving a regimen of a standard antibiotic for 10 days and then added either S. boulardii (1 g/day for 28 days) or placebo. A significant decrease in recurrences was observed only in patients treated with high-dose vancomycin (2 g/day) and S. boulardii (16.7%), compared with those who received high-dose vancomycin and placebo (50%; P=.05). No serious adverse reactions were observed in these patients. Comparison of data from this trial with data from previous studies indicates that recurrent CDD may respond to a short course of high-dose vancomycin or to longer courses of low-dose vancomycin when either is combined with S. boulardii.

RECURRENT CLOSTRIDIUM DIFFICILE DISEASE: EPIDEMIOLOGY AND CLINICAL CHARACTERISTICS

OBJECTIVE To describe the epidemiology, diagnosis, risk factors, patient impact, and treatment strategies for recurrent Clostridium difficile-associated disease (CDAD). DESIGN Data were collected as part of a blinded, placebo-controlled clinical trial testing a new combination treatment for recurrent CDAD. Retrospective data regarding prior CDAD episodes were collected from interviews and medical-chart review. Prospective data on the current CDAD episode, risk factors, and recurrence rates were collected during a 2-month follow-up. SETTINGS National referral study. PARTICIPANTS Patients with recurrent CDAD. INTERVENTIONS Treatment with a 10-day course of low-dose (500 mg/d) or high-dose (2 g/d) vancomycin or metronidazole (1 g/d). RESULTS Recurrent CDAD was found to have a lengthy course involving multiple episodes of diarrhea, abdominal cramping, nausea, and fever. CDAD may recur over several years despite frequent treatment with antibiotics. Recurrence rates were similar regardless of the choice or dose of antibiotic. Recurrent CDAD is not a trivial disease: patients may have multiple episodes (as many as 14), may require hospitalization, and the mean lifetime cost of direct medical care was

Epidemiology of antibiotic-associated colitis: Isolation of clostridium difficile from the hospital environment☆

10,970 per patient. Fortunately, the disease does not become progressively more severe as the number of episodes increase. Two risk factors predictive for recurrent CDAD were found: increasing age and a decreased quality-of-life score at enrollment. CONCLUSIONS Recurrent CDAD is a persistent disease that may result in prolonged hospital stays, additional medical costs, and rare serious complications.

Therapy of relapsing Clostridium difficile-associated diarrhea and colitis with the combination of vancomycin and rifampin.

Clostridium difficile is the most important cause of antibiotic-associated colitis. Using selective media, it was found that contamination with this organism was common in the environment of patients in the hospital with the disease. It was often found on floors, hoppers, toilets, bedding, mops, scales and furniture. This organism was also present on these items, but less often, in areas in which patients known to carry this hardy spore-forming organism had not been detected. Air, food and walls were negative. The organism was isolated from the hands and stools of asymptomatic hospital personnel. It was also found on surfaces in a patients home. The importance of the various sources of the organism in its spread in the hospital is not known, and further studies are needed. It is suggested that enteric isolation precautions, and careful handwashing and cleansing of potentially contaminated surfaces and objects may be worthwhile when cases of antibiotic-associated colitis are identified.

Treatment of Clostridium difficile colitis and diarrhea with vancomycin

Seven patients with multiple bacteriologic and symptomatic relapses of Clostridium difficile-associated diarrhea and/or colitis were treated with vancomycin and rifampin in combination. Diarrhea and abdominal pain promptly resolved in all, and neither C. difficile nor its toxin could be recovered from their stools shortly after therapy. However, stools of all patients subsequently became culture-positive for C. difficile and occasionally had demonstrable cytotoxin. Except in one instance following oral antibiotic use, all patients remained free of symptoms. Resistance to either vancomycin or rifampin was not encountered. Biotyping of isolates with clostridial bacteriophages and bacteriocins suggested true relapse with the same organism in all patients studied, rather than reinfection with another strain. Vancomycin and rifampin in combination appear to be useful in the therapy of relapsing antibiotic-associated diarrhea due to C. difficile.

Studies on the epidemiology of antibiotic-associated Clostridium difficile colitis.

Toxigenic Clostridium difficle is the major cause of antibiotic-associated colitis and is susceptible to vancomycin at fecal concentrations achieved with oral therapy. The effect of oral vancomycin was studied in 16 patients with C. difficile-related diarrhea or colitis, 12 of whom had colitis documented by endoscopy, biopsy, and/or barium enema. Four patients had antibiotic-associated diarrhea and possibly antibiotic-associated colitis, because sigmoidoscopy either showed normal results (two patients) or was not performed (two patients). Nineteen episodes of diarrhea were treated with oral vancomycin in two dosage regimens for three to 14 days. Twelve patients received 2 g daily, and four patients initially received 1 g or less per day. Within 48 hours of the start of vancomycin therapy, 14 of 16 patients (87 percent) showed a decrease in temperature, abdominal pain and diarrhea. Diarrhea ceased completely within two days of the start of vancomycin in nine episodes, within three to seven days in six episodes, and within eight to 14 days in the remaining four episodes, and within eight to 14 days in the remaining four episodes. Diarrhea recurred in two of these patients (12 percent) when the drug inciting the initial episode of colitis was given again 42 days or more after vancomycin therapy was stopped; both patients responded again to retreatment with vancomycin. Oral vancomycin is an effective treatment of C. difficile-related colitis and diarrhea.

Treatment with ganciclovir of adenovirus pneumonia in a cardiac transplant patient

Vancomycin protects hamsters from the development of Clostridium difficile colitis after treatment with clindamycin, and vancomycin is useful in treatment of humans with the disease. Relapses have occurred in both hamsters and humans when vancomycin is discontinued. Vancomycin appears to enhance susceptibility to colonization with C. difficile by eliminating competing intestinal organisms. The nature of these organisms is not known, but various tools are now available to aid in identifying them. Cancer chemotherapeutic agents should be added to the list of factors such as surgery and antibiotics that may predispose to emergence of C. difficile. The number of organisms required for colonization of antibiotic-treated hamsters is low and cross-infection seems to play a role in the disease in hamster colonies. The organism can be detected on surfaces in rooms of patients with the disease, and on the hands of personnel caring for them. Outbreaks of the disease have been recognized. Our results suggest isolation precautions should be used to prevent spread of the organism from patients with the disease to others being treated with antibiotics.

Ciprofloxacin versus vancomycin in the therapy of experimental methicillin-resistant Staphylococcus aureus endocarditis.

/ 2213 5138 Mp 439 Wednesday Oct 22 11:39 AM EL–AJM (v. 103, no. 4) 5202 REFERENCES 1. Demarmels Biasiutti F, Lammle B. Thrombophilieabklarung: Indikation und Durchfuhrung. Therapeutische Umschau. 1992;49:850–858. 2. Dahlback B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA. 1993;90:1004–1008. 3. Bertina RM, Koeleman BPC, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994;369:64–67. 4. Kreiter H, Fink U. Ein Fall von Leberschadigung nach Coumarin-Medikation. Med Klin. 1967;62:12–15. 5. Den Boer W, Loeliger EA. Phenprocoumon-induced jaundice. Lancet. 1976;i:912. 6. Slagboom G, Loeliger EA. Coumarin-associated hepatitis. Report of two cases. Arch Intern Med. 1980;140:1028–1029. 7. de Man RA, Wilson JHP, Schalm SW, et al. Phenprocoumon-induced hepatitis mimicking non-A, non-B hepatitis. J Hepatology. 1990;11:318–321. 8. Hohler T, Schnutgen M, Helmreich-Becker I, et al. Drug-induced hepatitis: a rare complication of oral anticoagulants. J Hepatology. 1994;21:447–449. 9. Ehrenforth S, Scharrer I, Herrmann G. Phenprocoumon-induzierte nekrotisierende Hepatitis. Dtsch Med Wschr. 1995;120:1529–1530. 10. Wolley S, Burger HR, Zellweger U. Phenprocoumon-induzierte cholestatische Hepatitis. Dtsch Med Wschr. 1995;120:1507–1510. 11. Gondocs C, Szalay L, Balo-Banga JM, Feher J. Syncumar induced toxic liver damage. Orv Hetil. 1990;131:1477–1479. 12. Rehnqvist N. Intrahepatic jaundice due to warfarin therapy. Acta Med Scand. 1978;204:335–336. 13. Matsukawa R, Uemura S, Fukuchi S, et al. Thrombosed St. Jude medical prosthesis with drug induced hepatitis due to warfarin potassium—a case report. Nippon Kyobu Geka Gakkai Zasshi. 1994;42:413–415. 14. Esmon CT. The protein C anticoagulant pathway. Arterioscler Thromb. 1992;12:135–145.

Ampicillin-induced enterocolitis: implication of toxigenic Clostridium perfringens type C.

We compared the efficacy of ciprofloxacin with that of vancomycin by using the rabbit model of methicillin-resistant Staphylococcus aureus endocarditis. Endocarditis was treated with ciprofloxacin (25 mg/kg [body weight] intravenously every 8 h) or vancomycin (17.5 mg/kg intravenously every 6 h) for 3 days. Vancomycin and ciprofloxacin were equally efficacious in clearing bacteremia. Both reduced vegetation bacterial counts by 5 log10 CFU/g and renal and splenic bacterial counts by more than 3 log10 CFU/g as compared with untreated control rabbits after 26 h of infection (P less than 0.001). Both antimicrobial agents were able to eradicate the infectious process in an equivalent proportion of animals. No methicillin-resistant S. aureus that was recovered from ciprofloxacin-treated rabbits developed resistance to ciprofloxacin during therapy. Peak concentrations of ciprofloxacin in the sera of rabbits with endocarditis were significantly higher than those predicted by single-dose studies in uninfected rabbits. This finding was likely due to changes in the pharmacokinetics of the drug with multiple dosing and in infected versus uninfected rabbits. This study demonstrated that intravenously administered ciprofloxacin is as efficacious as vancomycin is in an in vivo model of a serious systemic methicillin-resistant S. aureus infection.

Effects of topical clindamycin on intestinal microflora in patients with acne

THE MOST IMPORTANT CAUSE of ant ibiot ic-associated p s e u d o m e m b r a n o u s colitis is toxigenic Clostridium difficile. M a n y cases s tudied a few decades ago seemed a t t r ibutable to Staphylococcus aureus. 1. 2 Both types of the disease appea red responsive to oral t r ea tment with vancomycin. It is not known Whether o ther microbes are capable of induc ing this syndrome, bu t it is known that most of the d iar rhea associated with antibiotics and in which there is no evident colitis is of u n k n o w n cause. We recent ly encounte red a pa t ient with severe ant ibioticinduced d iar rhea and enterocolitis in whom Clostridium perfringens type C appeared responsible for the disease. Vancomycin was successful in t rea tment . We are writing this report to call a t ten t ion to this organism in cases of severe ant ibiot ic-associated d iar rhea in which C. difficile and its toxin canno t be identified.