Significant absorption of oral vancomycin in a patient with Clostridium difficile colitis and normal renal function.

Abstract: Orally-administered vancomycin is poorly absorbed in most patients, usually producing minimal or subtherapeutic serum concentrations. Bowel inflammation may enhance absorption of oral vancomycin, particularly in those with renal failure. A 77-year-old female with Clostridium difficile (C difficile) colitis and normal renal function was treated with high doses of oral vancomycin and achieved serum concentrations in the therapeutic range. To our knowledge, this is the first report of a patient with C difficile colitis and normal renal function to develop therapeutic serum concentrations following oral administration of vancomycin.

Key Words: Clostridium difficile colitis, normal renal function, vancomycin, oral administration, leukopenia 

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With the widespread use of broad-spectrum antibiotics and the increasing number of immunocompromised patients, the incidence of Clostridium difficile (C difficile) associated disease has risen dramatically during the past two decades. (1-6) In nonepidemic periods, the incidence of C difficile associated disease is estimated to be 0.1 to 30 cases per 1,000 patients in hospital settings and 8 to 12 cases per 100,000 patient years in community settings. (1-6) C difficile has been associated with 96 to 100% of cases of pseudomembranous colitis, 60 to 75% of cases of antibiotic-related colitis and 11 to 33% of cases of diarrhea occurring with antibiotic therapy. (1-6) With recent evidence suggesting increased resistance to metronidazole in such patients, oral administration of vancomycin is currently regarded as standard therapy for C difficile colitis. (7-9)

Vancomycin is poorly absorbed after oral administration. However, presence of bowel inflammation may increase its absorption. (10,11) Prior reports have documented that oral vancomycin therapy may produce therapeutic serum concentrations in patients with pseudomembranous colitis and renal failure. (9,11) Even so, most patients with impaired renal function develop undetectable or subtherapeutic serum vancomycin concentrations after oral administration. (10-13) To date, there are no reports of therapeutic serum concentrations following oral administration of vancomycin in patients with normal renal function. We describe herein the case of a patient with C difficile colitis and normal renal function who achieved therapeutic serum vancomycin concentrations following high-dose oral therapy with the antibiotic.

Case Report

A 77-year-old female who had previously been treated with levofloxacin and azithromycin for acute bacterial bronchitis and bacterial cystitis was admitted to our hospital on April 19, 2005, with a three-week history of abdominal pain, intermittent abdominal cramping, nausea, vomiting and brown-colored, watery, explosive diarrhea. She had a history of hypertension, hypercholesterolemia, diverticulosis, gastric metaplasia and lactose intolerance. Cholecystectomy and appendectomy had been performed > 10 years before this presentation. She had no history of renal disease or hematologic disorders.

At admission her blood hemoglobin was 11.6 g/dL, her hematocrit was 35.2%, her blood leukocyte count was 6,400 cells/[mm.sup.3] and her platelet count was 220,000 cells/[micro]mol. Her blood urea nitrogen was 23 mg/dL, her serum creatinine was 1.2 mg/dL, her serum calcium was 8.4 mg/dL and her serum TSH level was 2.06 [micro]mol/nL. A C difficile stool assay (ELISA) was positive. A computed tomogram of her abdomen suggested pancolitis and sigmoid diverticulosis. Flexible sigmoidoscopy showed extensive pseudomembranous colitis. Following IV volume repletion her blood urea nitrogen decreased to 12 mg/dL and her serum creatinine level decreased to 1.0 mg/dL. Both remained normal throughout the remainder of her hospitalization.

Beginning on April 21, 2005, she was treated with oral metronidazole 500 mg three times per day and oral vancomycin 125 mg four times per day. The oral dose of vancomycin was increased to 250 mg four times per day on April 23, and to 500 mg four times per day on May 1. Vancomycin enemas (1-2 g in 500 mL of sterile water) were administered daily from April 25 through May 2. In addition, oral cholestyramine and IV infusions of immunoglobulin were administered daily from May 1 through May 4. Flexible sigmoidoscopy was repeated nine days after the initiation of antibiotic therapy and showed persistent pseudomembranous colitis. A repeat computed tomogram on May 3 showed diffuse colonic wall thickening and inflammatory changes. Her blood leukocyte count at admission (April 8, 2005) was 4,800 cells/[mm.sup.3]. It rose steadily reaching a peak of 20,100 cells/[mm.sup.3] on April 20. By April 29, 11 days after initiation of antibiotic therapy, the blood leukocyte count had decreased to 3,600 cells/[mm.sup.3] and continued to decline thereafter reaching a nadir of 1,600 on May 3. Serum vancomycin concentrations (Fig. 1) were obtained daily from May 1 through May 5, and ranged from 6.3 to 7.9 [micro]g/mL (therapeutic range is 5.0-10.0 [micro]g/mL). Peak serum vancomycin concentrations obtained two hours after ingestion of 500 mg of vancomycin (6.6 [micro]g/mL) were nearly identical with trough levels (6.3 [micro]g/mL). No cause for her leukopenia was found other than vancomycin toxicity. Her blood leukocyte count rose to a peak of 30,000 cells/[mm.sup.3] following a short course of filgrastim before eventually normalizing on May 12, 2005. Due to the recalcitrant nature of her diarrhea, oral vancomycin therapy was continued. Her diarrhea resolved one month after the initiation of oral vancomycin. Serum vancomycin concentrations decreased progressively as her colitis improved, eventually reaching undetectable levels.

[FIGURE 1 OMITTED]

Discussion

Vancomycin is poorly absorbed after oral administration, usually generating serum concentrations that are minimal or undetectable. (10-17) A recent study however, suggests that bowel inflammation may enhance absorption of orally administered vancomycin. (4) Two case reports have documented that patients with pseudomembranous colitis and renal failure may achieve clinically-important serum vancomycin concentrations after oral administration. (9,11) Thomson et al described the case of a 14-year-old female with pseudomembranous colitis and severe renal failure who developed serum vancomycin concentration ranging from 13.5 to 34.0 [micro]g/mL while receiving vancomycin orally 250 mg every six hours. (9) Spitzer and Eliopoulos (11) reported the case of a 62-year-old male with pseudomembranous colitis and renal failure who achieved serum vancomycin levels ranging from 11.4 to 20.3 [micro]g/mL while receiving 250 mg of oral vancomycin every six hours. In patients with pseudomembranous colitis and normal renal function, oral administration of vancomycin 500 mg every six hours produced serum concentrations ranging from 2.4 to 3.0 [micro]g/mL. (18,19) To our knowledge, our case is the first to document serum vancomycin concentrations in the therapeutic range in a patient with pseudomembranous colitis and normal renal function.

We hypothesize that the clinically significant serum vancomycin concentrations observed in our patient resulted from increased absorption of vancomycin through the highly inflamed colonic mucosa. While it is possible that the vancomycin enemas may have contributed to such absorption before May 3, 2005, the persistence of serum vancomycin concentrations >6.0 [micro]g/mL after discontinuation of the enemas suggests that oral administration was primarily responsible for this observation. The nearly identical trough and peak serum vancomycin concentrations following oral administration of 500 mg every six hours suggest that absorption did not occur in the stomach or small intestine, but rather through the inflamed colonic mucosa.

Our patient developed leukopenia 11 days after the initiation of oral vancomycin therapy. She did not receive other drugs that are known to depress the blood leukocyte count, nor did she have a history or current evidence of comorbidities that produce leukopenia. Leukopenia is a well-known complication of IV vancomycin therapy, even when serum concentrations are within the therapeutic range. (10,13,20,21) We believe that the serum vancomycin concentrations achieved in our patient produced leukopenia, suggesting that systemic toxicity may occur following oral vancomycin administration. Whether such toxicity is related to dosage or duration of therapy or both is uncertain.

Our findings raise several important questions concerning oral vancomycin therapy in patients with C difficile colitis. Should high dose oral vancomycin therapy (500 mg every six hours) be abandoned in favor of lower dose therapy (125 mg every 6 h) in patients with normal renal function? Fekety et al (22) have demonstrated that the 125 mg dose is as effective as the 500 mg dose in such patients. Should we routinely monitor serum vancomycin concentrations in patients receiving high-dose oral therapy regardless of renal function? And finally, should we monitor for adverse systemic effects in all patients receiving high-dose oral vancomycin therapy?

Conclusion

In conclusion, this case demonstrated that clinically significant serum vancomycin concentrations may be achieved following high-dose oral administration of vancomycin in patients with C difficile colitis and normal renal function. Such patients may be at risk for adverse effects of vancomycin therapy such as leukopenia.

References

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Sangita Aradhyula, MD, Farrin A. Manian, MD, Saad A.S. Hafidh, MD, Saqib S. Bhutto, MD, and Martin A. Alpert, MD

From the Department of Medicine, St. John's Mercy Medical Center, St. Louis, MO.

Reprint requests to Martin A. Alpert, MD, Suite 3019-B. St. John's Mercy Medical Center, 621 S. New Ballas Road., St. Louis, MO 63141. Email: [e-mail]

Accepted January 26, 2006.

RELATED ARTICLE: Key Points

* Clostridium difficile colitis may be associated with increased absorption of oral vancomycin via an inflamed colon.

* Therapeutic serum vancomycin concentrations may be achieved in patients with C difficile colitis and normal renal function during high-dose oral administration of the drug.

* Adverse effects of vancomycin therapy such as leukopenia may occur during high dose oral vancomycin therapy in such patients.