CASE REPORTS
Clostridium difficile Toxin–Induced Colitis After Use of
Clindamycin Phosphate Vaginal Cream
Amy M Meadowcroft, Philip R Diaz, and Georgia S Latham
OBJECTIVE: To report a case of toxin-positive Clostridium difficile–
induced colitis (CDIC) after use of clindamycin phosphate vaginal
cream.
CASE SUMMARY: A 25-year-old postpartum white woman developed
multiple watery stools and abdominal cramping on day 6 of therapy
with clindamycin vaginal cream for bacterial vaginosis. She
received no other concomitant medications. The patient’s stool
sample was found to be positive for the C. difficile toxin. Due to the
costs and risks of standard therapy, we decided to manage the
patient supportively. Complete resolution of the diarrhea occurred
shortly thereafter.
DISCUSSION: No published clinical studies in patients receiving
clindamycin vaginal cream for bacterial vaginosis have documented
C. difficile toxin in stool samples of patients with diarrhea.
Approximately 5–6% of intravaginal clindamycin is absorbed in the
bloodstream, making systemic effects possible.
CONCLUSIONS: This report indicates clindamycin phosphate vaginal
cream as the most probable cause of CDIC due to the temporal
relationship between the occurrence of diarrhea and clindamycin
administration, lack of concomitant medications, and documentation
of C. difficile toxin.
KEY WORDS: Clostridium difficile, clindamycin phosphate, vaginal
cream.
Ann Pharmacother 1998;32:309-11.
ORAL, PARENTERAL, AND TOPICAL (dermal) formulations of
clindamycin have been associated with Clostridium diffi-
Amy M Meadowcroft PharmD BCPS, at time of writing, PharmD Student, School of
Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC; now,
Drug Development Fellow and Clinical Instructor, School of Pharmacy, Uni-
versity of North Carolina, Chapel Hill
Philip R Diaz PharmD BCPS, at time of writing, Associate Director of Pharmacy
Research, Pharmacotherapy and Pharmacy Education, Greensboro Area Health
Education Center, The Moses Cone Hospital Family Practice Center, Greens-
boro, NC; and Assistant Professor, Pharmacy Practice, School of Pharmacy,
and Assistant Instructor, Family Medicine School of Medicine, University of
North Carolina
Georgia S Latham MD, at time of writing, Family Practice Resident, Greensboro
Area Health Education Center, The Moses Cone Hospital Family Practice Cen-
ter; now, Family Physician, Sparta, NC
Reprints: Amy M Meadowcroft PharmD BCPS, School of Pharmacy, University of
North Carolina, CB# 7360 Beard Hall, Chapel Hill, NC 27599, FAX 919/870-
7549
The Annals of Pharmacotherapy
cile–induced colitis (CDIC).1-4 Severity ranges from mild,
self-limiting diarrhea to fulminant, life-threatening pseudo-
membranous colitis in some cases. Relevant clinical studies
in patients receiving clindamycin vaginal cream for bacterial
vaginosis as identified through MEDLINE searches (Janu-
ary 1966–June 1997) have failed to document C. difficile
in the stool of patients with diarrhea.2-9 However, approxi-
mately 5–6% of the intravaginal clindamycin is absorbed
in the bloodstream, so systemic effects are possible.1,10 We
report a case of CDIC in which clindamycin phosphate
vaginal cream was a probable cause.
CASE REPORT
A 25-year-old white woman was seen in the family practice clin-
ic for follow-up of mastitis and evaluation of malformations of
the labia minora secondary to trauma of childbirth. The malfor-
mations resulted in painful sexual intercourse. She also reported
persistent vaginal itching unrelated to sexual intercourse. Bacteri-
al vaginosis was diagnosed after a vaginal wet mount showed a
few clue cells (vaginal epithelial cells covered with bacteria),
more than 20 white blood cells, 4+ bacteria, no yeast, and no Tri-
chomonas per high-power field. Clindamycin phosphate vaginal
cream 2% was prescribed as one applicatorful in the vagina night-
ly for 7 days.
On day 6 of therapy, the patient experienced diarrhea. The last
dose of clindamycin was not administered. The patient received
no concomitant medications during or around this time. On day
12, she presented to the clinic and reported multiple watery stools
and abdominal cramping. These began on day 6 of therapy, per-
sisted for 4 days, ceased for about 24 hours, and then recurred the
day prior to this clinic visit. No blood or mucus was noted at any
time in her stools and the presence of a fever was not assessed.
The patient further reported taking kaolin–pectin mixture for di-
arrhea and was using a homemade rehydration solution contain-
ing water, sugar, and salt, as well as plenty of other liquids, to
maintain good hydration. A vaginal wet mount at this time showed
no clue cells, 0–3 white blood cells, and 1+ bacteria per high-
power field. No further treatment was prescribed for the resolved
bacterial vaginosis, and a stool sample was obtained to confirm
C. difficile and to rule out a gastrointestinal viral infection.
The patient’s stool sample was positive for the C. difficile tox-
in (2 d after the sample was collected) and contained numerous
white blood cells on examination. Metronidazole was ruled out
for treatment since it is secreted in the breast milk and the patient
■ 1998 March, Volume 32 ■ 309
 was breastfeeding11; vancomycin 250 mg po qid for 10 days was
prescribed but not obtained by the patient due to its cost. The pa-
tient was told that if the diarrhea was under control or at least di-
minishing and she remained well hydrated, her condition could
be managed without antibiotic therapy. Cholestyramine was con-
sidered for residual diarrhea; however, when contacted by phone
the following day, the patient reported complete resolution of the
diarrhea. She was not rechallenged with clindamycin phosphate
vaginal cream.
Discussion
C. difficile is a gram-positive, spore-forming anaerobic
bacillus known to produce exotoxins known as toxin A,
primarily an enterotoxin, and toxin B, a cytotoxin.12 CDIC
is the gastrointestinal disorder ensuing from colonization
and overgrowth of C. difficile.12-16 The four critical require-
ments for diagnosis are: (1) having a readily available
source of C. difficile, accomplished from either endoge-
nous flora (approximately 3–5% of healthy adults and
15– 46% of hospitalized adult patients harbor the organ-
ism) or from an exogenous source, typically the hospital
environment where isolates of C. difficile have been found
in areas housing patients colonized with the bacteria or
through transmission from caregivers who fail to wash
their hands12,13,15; (2) exposure to drugs such as antibiotics
that disrupt the preservation of a normal colonic microflora
in the bowel and promotes overgrowth of C. difficile and
elaboration of the toxin13,15,16; (3) the production of cytotox-
ins by the C. difficile strain that colonizes the colon; and
(4) advanced age, as well as other risk factors such as se-
vere underlying illness and a prolonged hospital stay.13-15
Diarrhea is the predominant and often sole manifestation
of CDIC. In more than 90% of patients, the stools are brown
or clear and watery in composition, and bloody in 5–10%
of patients.15,17 In more severe cases, fever and leukocytosis
are also present. The formation of pseudomembranous
plaques in the colon occurs infrequently and indicates se-
vere cases in which mucus usually is present in the feces.
Presumptive diagnosis often is based on a positive cytotox-
in assay, in addition to ruling out other potential causes of
colitis such as viral gastrointestinal infections.12,15
Management of CDIC requires discontinuation of the
offending antimicrobial, supportive care, and oral metroni-
dazole or vancomycin therapy.12,18 These agents treat the
overgrowth of toxin-producing C. difficile and their use is
dictated by the condition of the patient. Patients who re-
spond to discontinuation of the inciting drug should not be
subjected to indiscriminant treatment with antimicrobials.
Those requiring treatment should, in most cases, receive
oral metronidazole rather than oral vancomycin, due to
lower cost and proven efficacy.19 Other drugs such as oral
bacitracin, anion–exchange resins that bind the toxin (i.e.,
cholestyramine, colestipol), rifampin, ciprofloxacin, and
various agents still under investigation have also been use-
ful treatments of CDIC.12,18 Severe cases may require re-
peat treatment, a prolonged course of vancomycin therapy
in tapering doses, or pulsed (every-other-day) or cycled
antimicrobial administration. Combination therapies with
metronidazole or vancomycin and the aforementioned al-
ternative therapies have also been used in resistant cases.
310 ■ The Annals of Pharmacotherapy ■ 1998 March, Volume 32
Clindamycin is among those antibiotics most likely to
produce changes in the normal gastrointestinal flora.1,20
The development of CDIC is not known to be dose-related
and occurs a few days or weeks following the initiation of
antibiotic therapy; it is most commonly seen 3–10 days af-
ter therapy begins.1,21 Clindamycin-induced changes in
bowel flora have been hypothesized to cause CDIC by ei-
ther accumulation of bile acids within the gut leading to
catharsis from enhanced sodium secretion from the colon,22
or by a colloid osmotic effect of large molecules (200–500
Da) resulting in increased quantities of water in the fe-
ces.22,23 This alteration of the normal ecology of the gut
could then promote viral invasion of gut mucosa, contribut-
ing to an already-damaged gut mucosa secondary to in-
creased permeability; local inflammation with necrosis and
pseudomembranous colitis may ensue.22
The incidence of CDIC with clindamycin is difficult to
assess. The most frequent adverse effect of clindamycin re-
mains the development of diarrhea, but the toxin-produc-
ing C. difficile is not often documented. Diarrhea occurs in
up to 20% of patients receiving systemic therapy,20 and in
less than 1% with clindamycin vaginal cream.1,20 Other
topical clindamycin formulations implicated in causing
CDIC may be systemically absorbed (maximum of 10%
for topical acne products)24; clindamycin vaginal cream also
can undergo systemic absorption and thus could cause
CDIC.10
Summary
This is the first documentation that clindamycin vaginal
cream can cause CDIC. The temporal relationship between
the treatment and diarrhea, the lack of concomitant medi-
cations, and the isolation of C. difficile toxin 6 days after
the start of clindamycin vaginal cream therapy support
clindamycin phosphate vaginal cream as the probable cause
of CDIC.
References
1. Package insert. Cleocin Vaginal Cream 2% (clindamycin). Kalamazoo,
MI: Upjohn Co., November 1992.
2. Becker LE, Bergstresser PR, Whiting DA, Clendenning WE, Dobson RL,
Jordan WP, et al. Topical clindamycin therapy for acne vulgaris: a coop-
erative clinical study. Arch Dermatol 1981;117:482-5.
3. Cohen LE, McNeill CJ, Wells RF. Clindamycin-associated colitis. JAMA
1973;223:1379-80.
4. Gurwith MJ, Rabin HR, Love K. Diarrhea associated with clindamycin
and ampicillin therapy: preliminary results of a cooperative study. J In-
fect Dis 1977;135(suppl):S104-10.
5. Dhar J, Arya OP, Timmins DJ, Moss S, Mukembo S, Alawattegama AB,
et al. Treatment of bacterial vaginosis with a three day course of 2% clin-
damycin vaginal cream: a pilot study. Genitourin Med 1994;70:121-3.
6. Fischbach F, Petersen EE, Weissenbacher ER, Martius J, Hosmann J,
Mayer H. Efficacy of clindamycin vaginal cream versus oral metronida-
zole in the treatment of bacterial vaginosis. Obstet Gynecol 1993;82:
405-10.
7. Schmitt C, Sobel JD, Meriwether C. Bacterial vaginosis: treatment with
clindamycin cream versus oral metronidazole. Obstet Gynecol 1992;79:
1020-3.
8. Greaves WL, Chungafund J, Morris B, Haile A, Townsend JL. Clinda-
mycin versus metronidazole in the treatment of bacterial vaginosis. Ob-
stet Gynecol 1988;72:799-802.
9. Stein GE, Christensen SL, Mummaw NL, Soper DE. Placebo-controlled
trial of intravaginal clindamycin 2% cream for the treatment of bacterial
vaginosis. Ann Pharmacother 1993;27:1343-5.

10. Borin MT. Systemic absorption of clindamycin following intravaginal
application of clindamycin phosphate 1% cream. J Clin Pharmacol 1990;
30:33-8.
11. Package insert. Flagyl (metronidazole). Skokie, IL: GD Searle & Co.,
July 1990.
12. Gerding DN, Johnson S, Peterson LR, Mulligan ME, Silva J. Clostridi-
um difficile–associated diarrhea and colitis. Infect Control Hosp Epi-
demiol 1995;16:459-77.
13. Bartlett JG. Clostridium difficile: clinical considerations. Rev Infect Dis
1990;12(suppl 2):S243-51.
14. Borriello SP. Pathogenesis of Clostridium difficile infection of the gut.
J Med Microbiol 1990;33:207-15.
15. Reinke CM, Messick CR. Update on Clostridium difficile–induced coli-
tis, part 1. Am J Hosp Pharm 1994;51:1771-81.
16. Wilson KH. The microecology of Clostridium difficile. Clin Infect Dis
1993;16(suppl 4):S214-8.
17. Knoop FC, Owens M, Crocker IC. Clostridium difficile: clinical disease
and diagnosis. Clin Microbiol Rev 1993;6:251-65.
18. Reinke CM, Messick CR. Update on Clostridium difficile–induced coli-
tis, part 2. Am J Hosp Pharm 1994;51:1892-901.
19. Delmee M, Melin P, Peetermans W, Verbist L, Verschraegen G. Treat-
ment of Clostridium difficile colitis. Acta Clinica Belg 1995;50:114-6.
20. Soper DE. Clindamycin. Obstet Gynecol Clin North Am 1992;19:483-96.
21. Stroehlein JR, Sedlack RE, Hoffman HN, Newcomer AD. Clindamycin-
associated colitis. Mayo Clin Proc 1976;49:240-3.
22. Hofman AF. Bile acids, diarrhea, and antibiotics: data, speculation, and a
unifying hypothesis. J Infect Dis 1977;135(suppl):126-32.
23. Loeschke K, Kautz U, Lohrs U. Effects of antibiotics on caecal electro-
lytes transfer and morphology in rats: contribution to the pathogenesis of
antibiotic-associated diarrhea. Klin Wochenchr 1980;58:383-5.
24. Milstone EB, McDonald AJ, Scholhamer CF. Pseudomembranous colitis
after topical application of clindamycin. Arch Dermatol 1981;117:154-5.
EXTRACTO
OBJETIVO: Describir el caso de una colitis inducida por Clostridium
difficile con toxina positiva luego del uso de fosfato de clindamicina en
crema vaginal.
RESUMEN DEL CASO: Una paciente de 25 años de edad, desarrolló diarrea
acuosa y dolor abdominal el sexto día de terapia con clindamicina en
crema vaginal para una vaginosis bacteriana post-parto. La paciente no
recibió otros fármacos concurrentes. Las muestras de excreta de la
paciente resultaron positivas para la toxina de C. difficile. Debido a los
costos y riesgos de la terapia estándar, se decidió continuar manejando la
The Annals of Pharmacotherapy
Case Reports
paciente con terapia de apoyo. La diarrea resolvió completamente poco
tiempo después.
DISCUSIÓN: No existen estudios clínicos de pacientes recibiendo
clindamicina en crema vaginal para vaginosis bacteriana que
documenten toxina de C. difficile en muestras de excreta de pacientes
con diarrea. Aproximadamente 5–6% de clindamicina intravaginal es
absorbido en el torrente sanguíneo, lo que hace posible que ocurran
efectos sistémicos.
CONCLUSIONES: Este caso indica que el fosfato de clindamicina en crema
vaginal es la causa más probable para la colitis inducida por C. difficile
debido a la relación de tiempo entre la aparición de la diarrea y la
administración de clindamicina, la ausencia de otros medicamentos
concurrentes y la documentación de toxina de C. difficile.
GISELLE C RIVERA-MIRANDA
RÉSUMÉ
OBJECTIF: Décrire le cas d’une patient ayant développé une colite
pseudomembraneuse causée par le Clostridium difficile suite à
l’administration d’une crème vaginale de clindamycine.
RÉSUMÉ: Une jeune patiente de 25 ans se présente à la clinique pour un
suivi postpartum se plaignant de prurit vaginal. Le diagnostic d’une
vaginite bactérienne est posé et la patiente se voit prescrire une crème
vaginale de clindamycine 2% pour 7 jours. A la sixième journée de
traitement, la patiente développe de multiples épisodes de selles liquides
et de crampes abdominales et la dernière dose de clindamycine n’est pas
administrée. Six jours plus tard, ces effets indésirables se poursuivent et
la patiente consulte. L’analyse de selles révèle une présence positive de
toxines produites par le C. difficile. Considérant qu’aucune autre
médication n’a été prise par la patiente durant ce temps, le
développement de cette colite pseudomembraneuse causée par le C.
difficile semble fortement relié à la prise de clindamycine vaginale.
DISCUSSION: Aucune étude publiée ne rapporte à ce jour des cas
similaires de colite pseudomembraneuse causée par le C. difficile suite à
l’administration vaginale de clindamycine. Par contre, il est estimé
qu’environ 5–6% de la clindamycine vaginale est absorbée au niveau
sanguin pouvant ainsi rendre possibles les effets indésirables
systémiques.
CONCLUSIONS: Ce cas décrit la relation possible entre l’administration
vaginale de clindamycine et le développement d’une colite
pseudomembraneuse causée par le C. difficile.
SYLVIE ROBERT
■ 1998 March, Volume 32 ■ 311