Role of surgery in antibiotic-induced pseudomembranous enterocolitis

REVIEW

Role of Surgery in Antibiotic-Induced Pseudomembranous Enterocolitis Jon B. Morris,

MD,

Robert M. Zollinger,

Jr., MD,

With the increased use of prophylactic and broadspectrum antibiotics, pseudomembranous colitis has emerged as a significant clinical problem. Management with specific anti-Clostridium difficile therapy (vancomycin or metronidazole) has reduced mortality to less than 2%. Nevertheless, the disease may progress to a fulminant toxic colitis or colonic perforation. Additionally, another subset of patients will present with a dramatic clinical picture, suggesting acute peritonitis, eventuating in unnecessary laparotomy. This report reviews both the medical and surgical literature during the past 15 years of patients treated for pseudomembranous colitis. Analysis of this clinical data has provided us with the opportunity to both define the role of surgery in this disorder and illustrate the necessity for a combined medical and surgical cooperative approach in the early management of this iatrogenic disease.

he pathogenesis and treatment of pseudomembranous colitis have gained substantial interest over the T past two decades, but the entity has been known for almost 100 years. The first case of pseudomembranous colitis in the English literature was reported in 1893 by Dr. Finny who described a 22-year-old woman with obstructive peptic ulcer disease [I]. A gastroenterostomy was performed without complication, and the initial postoperative course was uneventful. On the 10th postoperative day, the patient developed bloody diarrhea, which worsened, resulting in death on postoperative day 15. Dr. Flexner's autopsy report of the colon is as follows: "The caecum is intensely reddened, its mucous membrane is swollen, there are more extensive losses of substance, appearing gray in contrast with the haemorrhagic mucous membrane about it, and a coating of what is apparently fibrin (and blood) can be scraped from the surface. The rest of the large intestine is similar but less extensively affected, excepting particular patches in the sigmoid flexure where the condition is equal to the caecum." From the Department of Surgery, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, Ohio. Requests for reprints should be addressed to Thomas A. Stellato, M D, 2074 Abington Road, Cleveland, Ohio 44106. Manuscript submitted August 28, 1989, and accepted October 4, 1989.

Thomas A. Stellato,

MD,

Cleveland, Ohio

A variety of clinical conditions have historically been implicated in the pathogenesis of pseudomembranous colitis, including heavy metal poisoning, ischemic heart disease, uremia, and intestinal obstruction [2]. In a Mayo Clinic study, between 1925 and 1952, 107 cases of pseudomembranous colitis following a surgical procedure were identified, of which 72% included intestinal procedures [3]. No significant correlation with antibiotic use could be demonstrated in this series. However, over the past 30 years, antibiotic-induced change in intestinal flora has clearly emerged as the single greatest risk factor [2]. Some clinical reports in the late 1950s and early 1960s implicated Staphylococcus aureus as the etiologic agent from evidence based on stool cultures [4]. The correlation between clindamycin (an effective anti-staphylococcal agent) and pseudomembranous colitis in the 1970s suggested that S. aureus was probably not an important etiologic agent. Experimental work by Bartlett et al [5], utilizing a hamster model of clindamycin-induced pseudomembranous colitis, constituted a major breakthrough in the understanding of this disease. The observation that a toxin-producing species of Clostridium difficile could cause pseudomembranous colitis was confirmed in humans [6], leading to the current understanding of the pathophysiology of this disease: antibiotic exposure (oral or parental) ---- alteration in colonic flora ---- overgrowth of C. difficile --, C. difficile toxin production ---- pseudomembraneous colitis. With the exception of vancomycin, all antibiotics (particularly ampicillin, clindamycin, and the cephalosporins) have been implicated in the pathogenesis of pseudomembranous colitis [7]. DIAGNOSIS AND CURRENT MEDICAL MANAGEMENT Patients most commonly present within 1 week after having received antibiotics with a clinical tetrad of watery diarrhea (90% to 95%), fever (80%), crampy abdominal pain (80% to 90%), and leukocytosis (80%) [2]. Up to 40% of patients will develop pseudomembranous colitis 2 to 10 weeks after antibiotic therapy [2]. Sigmoidoscopy will typically demonstrate multiple elevated yellow-white or green plaques ("pseudomembranes") between which the mucosa may be edematous or quite hyperemic [8]. Proctosigmoidoscopy may be completely negative [9], and colonoscopy has been recommended by some authors [10]. Histologically, each plaque represents a pseudomembrane of mucous, inflammatory cells, and fibrin exudate, which may be overlying normal mucosa [11]. Aircontrast barium roentgenograms may suggest plaque-like lesions over the mucosa [12], and recently, computed tomography has been reported to elucidate characteristic findings of a diffusely thickened colonic wall [13]. Currently, the gold standards for diagnosis are

THE AMERICAN JOURNAL OF SURGERY

VOLUME 160 NOVEMBER 1990

535

MORRIS ET AL

stool anaerobic C. difficile culture and C. difficile toxin assays, which have been shown to be positive in pseudomembranous colitis in 95% and 97% to 100% of cases, respectively [7]. Treatment for the disorder has traditionally included discontinuance of the offending antibiotics, bowel rest, and general supportive measures. Of historical interest, therapeutic maneuvers have included oral administration of cholestyramine resins, which are capable of binding the C. difficile toxin [14], and donor fecal enemas, the rationale here being to restore the normal colonic flora [15]. Currently, the treatment modality of choice is to eradicate C. difficile from the gastrointestinal tract. Oral

vancomycin [16] and metronidazole [17] are the drugs of choice, with the clinical response usually being prompt and unequivocal, and resolution of the abdominal pain, diarrhea, and fever occurring within 2 to 4 days [2]. In this country, the prognosis is quite good for pseudomembranous colitis, with a mortality rate reported by Bartlett [18] in a series of 272 cases collected between 1977 and 1980 of 1.1%. TOXIC MEGACOLON COMPLICATING PSEUDOMEMBRANOUS COLITIS Elucidation of the pathophysiology of pseudomembranous colitis has significantly reduced the morbidity

TABLE I

Results of Surgery for Pseudomembranous Colitis (PMC) Complicated by Toxic Megacolon Indications for Antibiotics

Author (year) Keeffe et al [ 19] (1974)

Diagnosis of PMC

Foot ulcer

Sigmoidoscopy Histology Sigmoidoscopy Histology Histology

Gastroenteritis Hiatal herniogrhaphy Axelrod et al [22] (1975) Gibson et al [23] (1975) Tedesco et al [24] (1975) Boyd and DenBesten [25] (1976) Cammerer et al [26] (1976) Saylor et al [27] (1976) Smart et al [28] (1976) Hoogland et al [29] (1977)

Eye infection Hip prosthesis Urinary tract infection Cellulitis Postoperative fever Upper respiratory infection Fever Diarrhea Pneumonia Elbow arthroplasty Urinary tract infection

Proctoscopy Histology

Hip prosthesis

Proctoscopy Histology

Lazar et al [30] (1978) Cone and Wetzel [20] (1982)

Closure of colostomy

Histology

Peri-rectal abscess

Proctoscopy Histology

Schnitt et al [31] (1983)

Urinary tract infection

Sigmoidoscopy Stool titer Sigmoidoscopy Histology Sigmoidoscopy Stool titer Sigmoidoscopy Stool titer Histology Proctoscopy Stool titer Colonoscopy Stool titer Sigmoidoscopy

Urinary tract infection Diverticulitis Haaga et al [32] (1987)

Malignant histocytoma

VanNess and Caftan [21] (1987) Bradley et al [33] (1988)

Urinary tract infection Urinary tract infection Fever

536

Sigmoidoscopy Histology Sigmoidoscopy Histology Sigmoidoscopy Proctoscopy Histology Sigmoidoscopy Histology Sigmoidoscopy Histology Proctoscopy Histology Sigmoidoscopy Histology Histology

THE AMERICAN JOURNAL OF SURGERY

VOLUME 160

Operation

Outcome

Subtotal colectomy

Death

Subtotal colectomy

Survived

Ileostomy Cecostomy Subtotal colectomy Ileostomy Colectomy

Death

Death

Subtotal colectomy Diverting ileostomy

Survived Survived

Subtotal colectomy Ileostomy Subtotal colectomy Ileostomy Colectomy

Survived Survived

Ileostomy

Survived

Total colectomy Ileostomy Transverse colostomy Loop ileostomy Ascending and transverse colostomies Ascending colostomy Laparotomy; subtotal colectomy Ileostomy Subtotal colectomy

Survived

Survived

Death

Death

Death

Death Survived

Survived

Subtotal colectomy

Survived

Sigmoid colectomy

Survived

Laparotomy; cecostomy; subtotal colectomy; Subtotal colectomy

Survived

Survived

Subtotal colectomy

Survived

Diverting ileostomy; subtotal colectomy

Death

NOVEMBER 1990

SURGERY IN ANTIBIOTIC-INDUCED PSEUDOMEMBRANOUS ENTEROCOLITIS

and mortality of the disease, and correspondingly has reduced the role of surgery in its management. In a collective review of pseudomembranous colitis, prior to the introduction of therapy specifically aimed toward C. dtfficile, medical therapy failed in 22% of patients, resulting in the need for surgical intervention [19]. More recently, aggressive early medical management with vancomycin or metronidazole has made pseudomembranous colitis essentially a "medical" disease. Nevertheless, surgeons will occasionally be confronted with cases that have progressed to a fulminant colitis with characteristics very similar to those of toxic megacolon, i.e., massive dilatation of the entire colon in the face of a progressive septic clinical picture. In recent reports, between 65% and 71% of patients with toxic megacolon complicating pseudomembranous colitis required operative intervention [20,21]. Table I presents the results of surgery for pseudomembranous colitis complicated by toxic megacolon [19-33]. The patients ranged in age from 1.5 to 83 years (mean: 55.5 years) with a male/female ratio of 1.2:1. Twenty-six percent received antibiotics for perioperative prophylaxis, and clindamycin was the most commonly used, being involved in 57% of all presented cases [1933]. The diagnosis of pseudomembranous colitis was made by proctosigmoidoscopy in 87% of cases. Colectomy was performed in 73% of patients, with an operative mortality of 24%. Diversion of the fecal stream by either ileostomy, cecostomy, or decompressive colostomy was performed in 26% of patients, with an operative mortality of 66%. It is possible that this later group of patients was too ill to tolerate an extensive surgical procedure, but it would seem that colectomy with removal of the septic focus is the procedure of choice in fulminant toxic megacolon associated with pseudomembranous colitis. Septicemia with severe pseudomembranous colitis has been reported [34]. The high overall mortality of this collected series (35%) presumably reflects the dismal state of these patients by the time surgery is considered. Since toxic megacolon complicating pseudomembranous colitis will resolve with medical therapy in only approximately two thirds of patients [20,21], a more aggressive, earlier surgical intervention may improve survival.

COLONIC PERFORATION COMPLICATING PSEUDOMEMBRANOUS COLITIS Rarely, pseudomembranous colitis will progress to involve full-thickness colonic necrosis with resultant perforation. Table II summarizes these reported cases [19,28,35-38]. The ages ranged from 2 to 80 years (median: 60 years), with a male/female ratio of 1:1. Two thirds of patients received antibiotics for perioperative prophylaxis, with a cephalosporin used in 67% of all reported cases [19,28,35-38]. There appeared to be two patterns of perforation. When a large portion of the colon was involved with multiple perforations [28,35,36], operative mortality was 66%. However, if there was a single perforation, mortality was reduced to 33% [19,37,38]. In two cases, where the disease was focal, segmental resection was successful [36,38]. The remainder of patients underwent colectomy with an operative mortality of 75%. UNNECESSARY LAPAROTOMY FOR PSEUDOMEMBRANOUS COLITIS The clinical presentation of severe pseudomembranous colitis, characterized by diarrhea, fever, abdominal pain, and leukocytosis, as well as by a tender abdomen on physical examination, may certainly be consistent with a "surgical" abdomen. Tedesco and co-workers [24] reported 8 of 42 patients (19%) with pseudomembranous colitis in a 1-year period who presented with an acute abdomen. Proctoscopy allowed for the diagnosis of pseudomembranous colitis in seven of these patients, who were then treated conservatively by discontinuance of the antibiotics and generalized supportive measures. Unnecessary ]aparotomy was avoided in seven patients, while one worsened and required appropriate operative intervention. More recently, Drapkin and co-workers [39] described five patients with pseudomembranous colitis who had received either penicillin or a cephalosporin and subsequently developed fever, leukocytosis, right lower quadrant pain, and tenderness. Only one patient presented with diarrhea. All underwent exploratory surgery, and none had acute appendicitis. A common finding was edema or erythema involving the right colon. These authors noted that 5% of all C. difficile colitis patients in their institution presented with an acute abdomen. Three addi-

T A B L E II

Results of Surgery for Pseudomembranous Colitis (PMC) Complicated by Colonic Perforation Author (year) Keeffe et a l [ 19] (1974) Fee et al [35] (1975) Smart et al [28] (1976)

Indications for Antibiotics

Diagnosis of PMC

Femoral-femoral bypass

Histology

Fever Diarrhea Knee arthroplasty

Sigmoidoscopy Histology

Klinger et al [35] (1984)

Hip prosthesis

Snooks et al [37] (1984) Osier et al [38] (1985)

Open tibia fracture

Sigmoidoscopy Histology Stool titer Histology

Hip prosthesis Urinary tract infection

Histology Stool titer

Operative Findings Single perforation Multiple perforations Colon edema; multiple perforations Multiple perforations Single perforation Single perforation

THE A M E R I C A N J O U R N A L OF SURGERY

Operation

Outcome

Subtotal colectomy

Survived

Total protocolectomy

Death

Laparotomy, total colectomy

Death

Left colectomy Colostomy

Survived

Hartmann's procedure

Death

Sigmoid resection

Survived

VOLUME 160

NOVEMBER 1990

537

MORRIS ET AL

tional examples of unnecessary laparotomy for pseudomembranous colitis can be seen in this review in Table I [20,32] and Table II [28]. Utilization of computed tomography in the management of patients with an acute abdomen m a y suggest the diagnosis of pseudomembranous colitis [13,40-43]. Mukai and Janower [13] reported two patients with abdominal pain and tenderness who underwent computed tomographic scanning to rule out an intra-abdominal abscess. In both patients, the scan was highly suggestive of pseudomembranous colitis, and improvement occurred with anti-C, difficile therapy. Computed tomographic findings in pseudomembranous colitis appear to be diffuse colonic wall thickening, with a doughnut-like appearance of the ascending and descending colons, and colonic dilatation. This finding appears to be a sensitive indicator for pseudomembranous colitis, but is certainly not specific for this entity. Nevertheless, recognition of this sign, in the appropriate clinical setting, m a y help to avoid unnecessary laparotomy. SUMMARY In an era of increased use of prophylactic and broadspectrum antibiotics, pseudomembranous colitis has emerged essentially as an iatrogenic disease. Because the clinical presentation invariably includes abdominal pain of varying severity, surgical consultation should be obtained whenever the diagnosis is entertained, although surgical intervention will be infrequent. Moreover, since 26% and 66% of patients with toxic megacolon and colonic perforation, respectively, had received perioperative antibiotics, it is mandatory that surgeons be familiar with the natural history of this disease. In order to achieve the best results, fulminant toxic colitis should be aggressively approached early in its course with total colectomy. CoIonic perforation obviously must be addressed surgically. In cases in which the perforation and disease are localized, segmental resection appears to be adequate. Widespread multiple perforations in a diffusely diseased colon suggest a grim prognosis. Finally, in patients with an "acute abdomen" who have received prior antibiotics, consideration must always be given to the diagnosis of pseudomembranous colitis. A thorough history and a low threshold for colonoscopy and computed tomography m a y help to avoid unnecessary laparotomy. REFERENCES 1. Finny JMT. Gastroenterostomy for cicatrizing ulcer of the pyloris. Bull Johns Hopkins Hosp 1893; 4: 53-5. 2. Tedesco FJ. Pseudomembranous colitis: pathogenesis and therapy. Med Clin North Am 1982; 66: 655-65. 3. Pettet JD, Baggenstoss AH, Dearing WH, Judd ES. Postoperative pseudomembranous enterocolitis. Surg Gynecol Obstet 1954; 98: 546-52. 4. Altemeier WA, Hummel RD, Hill EO. Staphylococcal enterocolitis following antibiotic therapy. Ann Surg 1963; 157: 847-58. 5. Bartlett JG, Onderdonk AB, Cisneros RL, et al. Clindamycinassociated colitis in hamsters due to a toxin-producing clostridial species. J Infect Dis 1977; 136: 701-5. 6. Bartlett JG, Chang TW, Gurwith M, Gorbach SL, Onderdonk AB. Antibiotic-associated pseudomembranous colitis due to toxinproducing elostridia. N Engl J Med 1978; 298: 531-4. 538

7. Trnka YM, Lamont JT. Clostridiurn difficile colitis. Adv Intern Med 1984; 29: 85-107. 8. Bartlett JG. Pseudomembranous colitis and antibiotic-associated colitis. In: Bouchier lAD, Allan RN, Hodgson HJF, Keighley MRB, eds. Textbook of gastroenterology. Philadelphia: Bailliere Tindall, 1984; 1091-7. 9. Tedesco FJ. Antibiotic-associated pseudomembranous colitis with negative proctosigmoidoscopic examination. Gastroenterology 1979; 77: 295-7. 10. Seppals K, Hjelt L, Sipponen P. Colonscopy in the diagnosis of antibiotic-associated colitis: a prospective study. Scand J Gastroenterol 1981; 16: 465-8. 11. Price AB, Davies DR. Pseudomembranous colitis. J Clin Pathol 1977; 30: 1-12. 12. Stanley R J, Melson GL, Tedesco FJ. The spectrum of radiographic findings in antibiotic-related pseudomembranous colitis. Radiology 1974; 111:519-24. 13. Mukai JK, Janower ML. Diagnosis of pseudomembranous colitis by computed tomography: a report of two patients. J Can Assoc Radiol 1987; 38: 62-3. 14. Kreutzer EW, Milligan FD. Treatment of antibiotic-associated pseudomembranous colitis with cholestyramine resin. Johns Hopkins Med 1978; 143: 67-72. 15. Bowden TA, Mansberger AR, Lykins LE. Pseudomembranous enterocolitis: mechanism of restoring floral homeostasis. Am Surg 1981; 47: 178-83. 16. Tedesco FJ, Markham R, Gurwith M, Christie D, Bartlett JG. Oral vancomycin for antibiotic-associated pseudomembranous colitis. Lancet 1978; 2: 226-8. 17. Pashby NL, Bolton RP, Sherriff RJ. Oral metronidazole in Clostridium difficile colitis. Br Med J 1979; 1: 1605-6. 18. Bartlett JG. Treatment of antibiotic-associated pseudomembranous colitis. Rev Infect Dis 1984; 6: $235-41. 19. Keeffe EB, Katon RM, Chan TT, Melnyk CS, Benson JA. Pseudomembranous enterocolitis: resurgence related to newer antibiotic therapy. West J Med 1974; 121: 462-72. 20. Cone JB, Wetzel W. Toxic megacolon secondary to pseudomembranous colitis. Dis Colon Rectum 1982; 25: 478-82. 21. VanNess MM, Cattau EL. Fulminant colitis complicating antibiotic-associated pseudomembranous colitis: case report and review of the clinical manifestations and treatment. Am J Gastroenterol 1987; 82: 374-7. 2 2 . Axelrod M, Allon O, Felton M, Goldfinger M. Clindamycinassociated colitis with toxic megacolon. JAMA 1975; 233: 419-20. 23. Gibson GE, Rowland R, Hecker R. Diarrhoea and colitis associated with antibiotic treatment. Aust N Z J Med 1975; 5: 3407. 24. Tedesco FJ, Anderson CB, Ballinger WF. Drug-induced colitis mimicking an acute surgical condition of the abdomen. Arch Surg 1975; 110: 481-4. 25. Boyd WC, DenBesten L. Subtotal colectomy for refractory pseudomembranous enterocolitis. JAMA 1976; 235:181. 26. Cammerer RC, Anderson DC, Boyce HW, Burdick GE. Clinical spectrum of pseudomembranous colitis. JAMA 1976; 235: 2502-5. 27. Saylor JL, Anderson CB, Tedesco FJ. Pseudomembranous colitis treated with completely diverting ileostomy. Arch Surg 1976; 111: 596-8. 28. Smart RF, Ramsden DA, Gear MWL, Nicol A, Lennox WM. Severe pseudomembranous colitis after lincomycin and clindamycin. Br J Surg 1976; 63: 25-9. 29. Hoogland T, Cooperman AM, Farmer RG, Faxio VW. Toxic megacolon-unusual complication of pseudomembranous colitis. Cleve Clin J Med 1977; 44: 149-55. 30. Lazar HL, Wesley JR, Weintraub WH, Coran AG. Pseudomembranous colitis associated with antibiotic therapy in a child: report of a case and review of the literature. J Pediatr Surg 1978; 13: 488-91. 31. Schnitt SJ, Antonioli DA, Goldman H. Massive mural edema in severe pseudomembranous colitis. Arch Pathol Lab Med 1983;

THE AMERICAN JOURNAL OF SURGERY VOLUME 160 NOVEMBER 1990

SURGERY IN ANTIBIOTIC-INDUCED PSEUDOMEMBRANOUS ENTEROCOLITIS

107:211-3. 32. Haaga JR, Bick R J, Zollinger RM Jr. CT-guided percutaneous catheter cecostomy. Gastrointest Radiol 1987; 12: 166-8. 33. Bradley SJ, Weaver DW, Maxwell NT, Bouwman DL. Surgical management of pseudomembranous colitis. Am Surg 1988; 54: 329-32. 34. Neville L, Noone P. Bacteraemia secondary to pseudomembranous colitis. J Clin Pathol 1985; 38: 1314-5. 35. Fee H J, Kearney JP, Ament ME, Fonkalsrud EW. Fatal outcome in a Child with pseudomembranous colitis. J Pediatr Surg 1975; 10: 959-63. 36. Klinger D, Radford P, Collin J. Pneumoperitoneum without faecal peritonitis in a patient with pseudomembranous colitis. Br Med J 1984; 288: 1271-2. 37. Snooks SJ, Hughes A, Horsburgh AG. Perforated colon complicating pseudomembranous colitis. Br J Surg 1984; 21: 291-2.

38. Osler T, Lott D, Bordley J, Lynch F, Ellsworth C, Kozak A. Cefazolin-induced pseudomembranous colitis resulting in perforation of the sigmoid colon. Dis Colon Rectum 1986; 29: 140-3. 39. Drapkin MS, Worthington MG, Chang TW, Razvi SA. Clostridium difficile colitis mimicking acute peritonitis. Arch Surg 1985; 120: 1321-2. 40. Goodman PC, Federle MP. Pseudomembranous colitis. J Comput Assist Tomogr 1980; 4: 403-4. 41. Brunner D, Feifarek C, McNeely D, Haney P. CT of pseudomembranous colitis. Gastrointest Radiol 1984; 9: 73-5. 42. Megibow AJ, Streiter ML, Balthazar E J, Bosniak MA. Pseudomembranous colitis:diagnosis by computed tomography. J Comput Assist Tomogr 1984; 8: 281-3. 43. Letourneau JG, Day DL, Steely JW, Goldberg ME. CT appearance of antibiotic-induced colitis. Gastrointest Radiol 1987; 12: 257-61.

THE AMERICAN JOURNAL OF SURGERY VOLUME 160 NOVEMBER 1990 5 3 9