LETTERS

Letters that report new clinical or laboratory observations, cases of unusual importance, and new developments in medical care will be considered for publication in this section. Manuscripts must be typed double-spaced. Text length must not exceed 750 words; no more than five references and one figure or table can be used. See "Information for Authors" on page 1-6 for form of references. Manuscripts should include an abstract of length not exceeding 100 words. Letters will be reviewed by consultants when, in the opinion of the editors, such review is needed. The Editor reserves the right to shorten letters and to make changes that accord with our style. Outbreak of Clindamycin-Associated Colitis C LINDAMYCIN-ASSOCIATED COLITIS has been reported by

the manufacturer to occur once m 50 000 to 100 000 treatment courses ( 1 ) . Tedesco, Barton, and Alpers (2) reported a 10% incidence in a prospective study in St. Louis. Ramirez-Ronda (3) in a retrospective analysis reported an incidence of 1 in 5000 to 10 000 in the Dallas area. In addition, a feature that defies explanation has been a marked geographic variability in the distribution of cases (personal communication from G. L. Royer, Jr., M.D., The Upjohn Company, Kalamazoo, Michigan). We report an outbreak of clindamycin-associated colitis affecting 9 patients during a 2-month period and occurring for unknown reasons after 20 months of uneventful prior use of the antibiotic. Therefore, in addition to variation in regional incidence of colitis, there appears to be significant variation in incidence of colitis in a single institution from one period of time to another. In September and October 1974, the Infectious Disease ser-

vice saw 8 patients, 4 of whom died with clindamycin-associated colitis (Patients 1 through 8, Table 1). As a consequence of the outbreak, we sharply curtailed the use of clindamycin in our hospital. During the second week of November 1974, we surveyed 600 adult hospitalized patients and found 2 additional cases. One, (Patient 9) is recorded in the table; the other patient received oral lincomycin. Surveys conducted in December 1974 and January 1975 did not show any cases of colitis among the 8 patients who received clindamycin or lincomycin. During the first 20 months of clindamycin phosphate use at Michael Reese Hospital, we were unaware of any episodes of colitis even though the infectious disease service saw the majority of patients treated with clindamycin phosphate. Survey of the attending staff for cases that we may have missed during this 20-month period showed protracted diarrhea in one patient who received oral clindamycin hydrochloride and none in those who received clindamycin phosphate. Stronger support for our contention that we encountered a sudden outbreak of clindamycin associated pseudomembranous colitis came from the review of autopsy data. Three instances of pseudomembranous colitis were found among the 61 autopsies done during September and October 1974. Careful review of the 627 autopsies done during the 20-month period that preceded the outbreak did not disclose a single instance of clindamycin associated colitis. During this 20-month period there was a progressive increase in purchases of clindamycin phosphate from 230 to 850 grams per month. We estimated that 488 patients were treated with clindamycin phosphate before September 1974 without apparent colitis. Then 17% of the patients treated with clindamycin phosphate in September and October 1974 developed colitis. Eight percent had documented pseudomembranous colitis, which is remarkably similar to the 10% incidence of pseudomembranous colitis reported by Tedesco, Barton, and Alpers (2). Although treatment with clindamycin was the "common

Table 1. Details of Clindamycin Therapy and Colitis* Patient

Age/Sex

Reason for Use

Daily Dose

Route

70/F

2

78/M

3

66/F

4

77/M

5 6

52/F 73/M

7 8

57/M 75/F

9

24/M

Fever of undetermined origin Mediastinitis Prophylaxis postbowel surgery Aspiration pneumonia Cellulitis Infected decubitus Peritonitis Aspiration pneumonia Infected ulcer of foot

Associated Antibiotics

Date

Onset of Colitis

Proctoscopic Findings

Outcome

PMC

Died; entire colon PMC

ND

days\

days

g 1

Duration

2.7

IV

4

Am, Be

9/4/74

13

2.7

IV

17

Am, Be

9/7/74 J

None

3.6

IV

8

Am

9/28/74

15

PMC

2.7

IV

5

Am,

10/23/74

15

NS

2.4 2.7 0.9 2.7 2.7

IV IV PO IV IV

2 3 6 8 4

Be Am

10/12/74 9/15/74

7 3

NS PMC

Died; focal PMC Died; entire colon PMC Died; no autopsy Resolved Resolved

Be Am, Be

10/4/74 10/14/74

17 10

PMC ND

Resolved Resolved

0.3

PO

9

None

10/19/74

7

PMC

Resolved

Chlor

* F = female; M = male; IV = intravenous; PO = by mouth; Am == an aminoglycoside antibiotic (gentamicin, kanamycin) ; Be = a betalactam antibiotic (a penicillin or cephalosporin) ; Chlor = chloramphenicol; PMC = pseudomembranous colitis; N D = not done; NS = nonspecific. t Number of days from start of clindamycin therapy. t Date of onset unknown. Patient did not have diarrhea. 830

December 1975 • Annals of Internal Medicine • Volume 83 • Number 6

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denominator" in the patients with colitis, we do not believe that it was solely responsible for this outbreak. Otherwise, we cannot explain the peculiarity of the abrupt change in its incidence at our hospital. Additional factors may be involved. Most of our patients were over 60 years of age, received a large daily dose of clindamycin, were on other antibiotics, and had other predisposing causes for colitis. The cause may be multifactorial. The high mortality rate ( 4 4 % ) observed during this outbreak is unusual and its explanation must remain conjectural. In only two patients (Patients 1 and 3) could we be reasonably sure that colitis was the cause of death. Tedesco noted that severe colitis related to diarrhea which occurred in the face of continued clindamycin therapy or which began after the administration of clindamycin was stopped. In six of our patients, symptoms of colitis began after clindamycin was stopped and in two, clindamycin was continued in the face of diarrhea. It is of interest that one patient (Patient 2) had no diarrhea, yet focal pseudomembranous colitis was found at autopsy. The use of clindamycin should be restricted to patients with Bacteroides fragilis infections or to penicillin-allergic patients with severe staphylococcal infection. With the earliest evidence of diarrhea, the patient should be proctoscoped. If pseudomembranous colitis is found or if it should develop, clindamycin should be stopped. Prompt institution of cholestyramine may be of benefit ( 4 ) . The authors appreciate the valuable advice of Sidney Cohen, M.D., and thank Martin Swerdlow, M.D., and Khalid Ahmed, M.D., for their review of the autopsy records. SHERWIN A. KABINS, M.D., F.A.C.P.

Department of Medicine Michael Reese Hospital and Medical Center Chicago, Illinois 60616 THOMAS J. SPIRA, M.D.

Pritzker School of Medicine University of Chicago Chicago, Illinois 60637 Received 27 June 1975. REFERENCES

1. THE UPJOHN COMPANY: Letter to Physicians. 16 August 1974 2. TEDESCO FJ, BARTON RW, ALPERS DH: Clindamycin-associated

colitis: a prospective study. Ann Intern Med 81:429-433, 1974 3. RAMIREZ-RONDA CH: Incidence of clindamycin-associated colitis. Ann Intern Med 81:860, 1974 4. BURLUGE EJ, MILLIGAN FD: Pseudomembranous colitis: association with antibiotics and therapy with cholestyramine. JAMA 231:1157-1158, 1975

The Use of Ampicillin in Acute Pancreatitis T H E SUGGESTION that bacteria may be involved pathophysiologically in acute pancreatitis has been supported by the efficacy of antibiotics in diminishing the mortality of experimental pancreatitis ( 1 ) , and the possibly lower incidence of pancreatic abscesses since the use of antibiotics in pancreatitis ( 2 ) . However, a recent retrospective review showed that the incidence of infectious complications in acute pancreatitis was similar in those given and not given prophylactic antibiotics ( 3 ) . As there have been heretofore no published controlled studies, our investigation was designed to help answer this question, by comparing pro-

phylactic ampicillin with placebo in the management of acute pancreatitis. All of the subjects selected for this study were clinically diagnosed as having acute pancreatitis. Each had constant upper abdominal pain for 24 hours or more, and an elevated serum amylase (normal, 60 to 160 amylase U/dl), except one who had an elevated urinary amylase. None had been taking anticholinergics or other antibiotics, and each denied penicillin or ampicillin allergy. There was no evidence of infection other than that possibly related to pancreatitis except for one patient undergoing antituberculous therapy. After signed informed consent, the subjects were randomized by one of us (LM) by a standard randomization table, blind to the others (RMC, ED), into ampicillin and placebo treatment groups, and started on the trial within 24 hours of admission to the hospital. Each subject was placed on nasogastric suction and intravenous fluids until he was asymptomatic for 48 hours. Ampicillin, 1 g, or placebo was given intravenously every 6 hours until the nasogastric tube was removed and clear liquids were begun. Then two 500-mg ampicillin capsules or two identically appearing lactose placebo capsules were administered orally every 6 hours to complete a 7-day course of therapy. Anticholinergics and additional antibiotics were not given except: two patients to whom sulfisoxazole was administered late in their courses for urinary tract infections; one who received penicillin on the sixth day of therapy for a possible pneumonitis; one maintained on ethambutal and isoniazide for pulmonary tuberculosis; and one treated with cephalothin for a positive blood culture on the fifth study day. The subjects were evaluated daily by one of us (RMC) for pain, tenderness, leukocytosis, serum amylase, and fever. Urine cultures and chest X-rays were obtained in each case and blood cultures were obtained daily for fever greater than 38.3 °C [101 °F] rectally. Thirty-nine men with 47 episodes of acute pancreatitis entered the study. Sixteen placebo- and 15 ampicillin-treated subjects had experienced similar abdominal pain. The protocol was completed in each case except for: one removed from the study because his nasogastric tube was prematurely withdrawn; one patient who had an anaphylactic reaction to ampicillin; one who had his medication inadvertantly stopped on day 5, and one who had his medication stopped on day 7 because of suspected bacterial endocarditis. The treatment code was not broken before the termination of the investigation except for the patient with ampicillin anaphylaxis and the patient with suspected endocarditis. The ampicillin and placebo groups each comprised 23 episodes of pancreatitis. The average ages for the placebo and ampicillin groups were 40 years and 41 years respectively; the average initial serum amylases for the placebo and ampicillin groups were 340 U / d l and 325 U/dl, respectively. Forty-three episodes were probably alcoholic pancreatitis, on the basis of a history of heavy ethanol use and no other predisposing etiology. Two subjects had choledocholithiasis and one had presumed idiopathic pancreatitis. There was no difference between the groups regarding duration or severity of abdominal pain, leukocytosis, hyperamylasemia, or fever (Table 1 ) . One patient, receiving ampicillin, had three positive blood cultures for Escherichia coli resistant to ampicillin that required intravenous cephalothin on the fifth study day. Two patients, each receiving placebo, had pericardial friction rubs during the earlier part of their illnesses. There were no other serious complications of acute pancreatitis. Every patient survived his illness and was discharged symptomatically well. The only complication of the ampicillin treatment was one anaphylactic reaction, with subsequent full recovery. Letters

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831

Table 1 . Indices of Therapeutic Response in Treatment Groups

Mean Number Subjects with of Days 8 or More Days of with Findings* Finding P value Leukocytosis f Ampicillin Placebo Pain or tenderness Ampicillin Placebo Elevated serum amylase Ampicillin Placebo Fever Ampicillin Placebo

1.8 2.3

3 3

0.2

3.0 3.0

1 2

0.5

6.0 5.0

10 9

0.3

3.0 3.0

1

0.6

* Those with 8 or more days with thefindingwere considered as 8 days for statistical evaluation. t Leukocytosis: absolute leukocyte count greater than 10 000. It should be stressed that the present negative results in patients with alcoholic pancreatitis need not be extrapolated to include all forms of pancreatitis. Most subjects with alcoholic pancreatitis experience complete resolution of the acute process and have a very low mortality rate, in the range 0 to 4% ( 4 ) , as confirmed by our study. In contradistinction, a recent study of the use of Aprotinin® in acute pancreatitis in Great Britain showed an untreated mortality rate in excess of 20%, probably due to the larger numbers of pancreatitis due to choledocholithiasis ( 5 ) . A study of the use of antibiotics in this group of patients would be of interest. In conclusion, ampicillin has been found ineffective as prophylactic therapy in patients in a Veterans Administration Hospital with primarily alcoholrelated acute pancreatitis. The authors thank Bristol Laboratories, Syracuse, New York, for furnishing blank polycillin capsules; and Arnold Kravitz, B.S., R.Ph., for technical assistance. ROBERT M. CRAIG, M.D. ERL DORDAL, M.D., F.A.C.P. LEWIS MYLES, M.S., R.PH.

Veterans Administration Research Hospital; and Gastroenterology Department Northwestern University School of Medicine Chicago, Illinois 60611 Received 2 July 1975. REFERENCES

1. PERSKY L, SCHWEINBERG FB, JACOB S, et al: Aureomycin in

experimental acute pancreatitis of dogs. Surgery 30:652-656, 1951 2. EVANS FC: Pancreatic abscess. Am J Surg 117:537, 1969 3. KODESCH R, Du PONT HL: Infectious complications of acute pancreatitis. Surg Gynecol Obstet 136:763-768, 1973 4. SWITZ DM: Acute alcoholic pancreatitis: effect of clinical presentation and therapies on outcome at a V.A. Hospital (abstract). Ann Intern Med 78:816-817, 1973 5. TRAPNELL JE, RIGBY CC, TALBOT CH, et al: A controlled trial

of Trasylol in the treatment of acute pancreatitis. Br J Surg 61:177-182, 1974

Acute Pancreatitis Due to Procainamide-lnduced Lupus Erythematosus ALTHOUGH Blomgren, Condemi, and Vaughan (1) reported abdominal pain in 4 of 44 patients with drug-related lupus 832

December

erythematosus, no patients with the drug-induced lupus erythematosus syndrome have been described with acute pancreatitis. We report here a case of the procainamide-induced lupus erythematosus syndrome manifested clinically only by acute pancreatitis. A 65-year-old white man was admitted to our hospital after 2 days of abdominal pain, nausea, and vomiting. He had been taking procainamide, 500 mg three times a day, for 7 months for a cardiac arrhythmia, and nitroglycerin for angina pectoris. He denied any alcohol intake, history of gall bladder disease, weight loss, congestive heart failure, arthralgias, myalgias, pleuritic chest pain, rash, or fever. This elderly muscular man complained of abdominal pain. Blood pressure was 116/70 mmHg; respirations, 18/min; pulse, 100/min; and oral temperature, 37.5 °C. The chest and cardiac examinations were normal except for an S4 gallop. There was moderate epigastric tenderness, and bowel sounds were absent. Stool guaiac was negative. The remainder of the physical examination was normal. Initial laboratory data were as follows: hematocrit, 48%; leukocyte count, 12 000/mm3 with 84% polymorphonuclear leukocytes; blood urea nitrogen, 29 mg/dl; creatinine, 1.3 mg/dl. Serum glutamic oxalacetic transaminase level was 100 Karmen units/ml (normal, < 4 0 Karmen units/ml); serum glutamic pyruvic transaminase level was 130 Karmen units/ml (normal, < 4 0 Karmen units/ml). Results of the following tests were normal: serum sodium, potassium, chloride, calcium, inorganic phosphorus, fasting glucose, cholesterol, triglyceride, bilirubin, alkaline phosphatase, and protein electrophoresis. Serum amylase level was 2010 Somogyi units/dl (normal,

Letter: Acute pancreatitis due to procainamide-induced lupus erythematosus.

LETTERS Letters that report new clinical or laboratory observations, cases of unusual importance, and new developments in medical care will be consid...
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