American Journal of Hematology 72:204–208 (2003) Fatal Bacillus cereus Sepsis Following Resolving Neutropenic Enterocolitis During the Treatment of Acute Leukemia Amy S. Ginsburg,1 Lupe G. Salazar,1 Lawrence D. True,2 and Mary L. Disis1* 1 Department of Internal Medicine, University of Washington, Seattle, Washington 2 Department of Pathology, University of Washington, Seattle, Washington Bacillus cereus is increasingly being acknowledged as a serious bacterial pathogen in immunosuppressed hosts. We report a case of fatal B. cereus sepsis in a patient with newly diagnosed acute leukemia following resolving neutropenic enterocolitis. Gastrointestinal complaints are common during induction chemotherapy, yet some antimicrobial coverage suitable for generalized neutropenia is not optimal for the eradication of B. cereus. This case demonstrates that, in the neutropenic patient with gastrointestinal complaints or in the setting of resolving neutropenic enterocolitis, it is important to anticipate possible B. cereus infection and sepsis. Am. J. Hematol. 72:204–208, 2003. © 2003 Wiley-Liss, Inc. Key words: Bacillus cereus; gastrointestinal; leukemia; neutropenic INTRODUCTION Bacillus cereus is an aerobic Gram-positive sporeforming rod that is ubiquitous in the environment. This microorganism is widely distributed in the air, water, soil, and feces, with some species being a part of the normal flora particularly in patients with prolonged hospitalization [1,2]. Therefore, isolation of the Bacillus species in blood cultures is common, and the organism is usually considered a contaminant and not clinically relevant. While B. cereus is a well-known cause of food poisoning, which is usually benign and self-limiting in the normal host, it is increasingly being identified as the cause of serious or life-threatening infections in neutropenic and immunosuppressed patients [2–5]. B. cereus has been implicated in systemic infections that include bacteremia and septicemia, central nervous infections such as meningitis and abscesses, respiratory infections, endocarditis, as well as local wound, burn, and ocular infections . The pathogenicity and virulence of B. cereus in these infections are related to several toxins and enzymes produced by the organism. These include a necrotizing enterotoxin, emetic toxin, hemolysins, and phospholipases [1,4]. We report a case of fatal B. cereus sepsis in a patient with acute leukemia following resolving neutropenic enterocolitis. In addition to demonstrating the fulminant clinical course of B. cereus sepsis in the © 2003 Wiley-Liss, Inc. neutropenic patient, this case highlights the importance of anticipating possible B. cereus sepsis in the neutropenic patient with gastrointestinal complaints. CASE REPORT The patient was a 22-year-old male who presented with left facial swelling and tenderness secondary to an odontogenic infection and newly diagnosed acute myelogenous leukemia. His past medical history was significant for an appendectomy and herniorraphy, and he had a history of marijuana use. Recent medical history was significant for recurrent left facial swelling starting 3 months prior to admission with intermittent treatment with oral clindamycin. The patient presented at an emergency room, where he was noted to have a white blood *Correspondence to: Mary L. Disis, Box 356527, Oncology, University of Washington, Seattle, WA 98195-6527. E-mail: [email protected] Received for publication 27 September 2001; Accepted 15 November 2002 Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ajh.10272 Case Report: Fatal B. cereus Sepsis in Acute Leukemia cell count of 131.6 × 103/L with 86% circulating blasts. His hematocrit was 23%, and platelet count was 83 × 103/L. The lactate dehydrogenase (LDH) was 689 IU/L, and other liver function tests were within normal limits. On admission, the patient was afebrile with severe left facial swelling and extensive cervical lymphadenopathy. Serologies for hepatitis A, B, and C, herpes simplex viruses 1 and 2, and cytomegalovirus were negative. A neck CT revealed no evidence of abscess, and consultation with otolaryngology, oralmaxillofacial surgery, and infectious diseases services determined that the patient had an odontogenic infection secondary to an impacted wisdom tooth. Antibiotic therapy with ticarcillinclavulanic acid, 3 g IV every 4 hr, was initiated, and the facial swelling improved dramatically over 48 hr. Consensus by the consulting services was to have the patient’s wisdom tooth extracted when he became more stable. A diagnostic bone marrow revealed acute myelogenous leukemia (AML), 61% myeloid blasts by flow cytometry (CD33+, CD13+, CD34+, and HLA-DR+). The absence of significant myeloperoxidase and non-specific esterase staining coupled with the absence of megakaryocytic antigens, CD41 and CD61 favored FAB classification M 0 . Cytogenetics demonstrated 46 XY, t(2: 13)(p21:q12)/46, XY consistent with a reciprocal translocation; however, it was not associated with any particular type of subtype of leukemia. On the second hospital day, the patient began a standard induction chemotherapy regimen with idarubicin, 12 mg/m2 on days 1–3, and cytosine arabinoside (Ara-C), 200 mg/m2 on days 1–7. In addition, due to jaw pain, the patient was only intermittently taking food or fluids by mouth. On initial presentation he was malnourished at 76% of his ideal body weight. Total parenteral nutrition was instituted after completion of his induction regimen. The patient became both febrile and neutropenic on the fifth hospital day (Fig. 1A). Although ticarcillinclavulanic acid was adequate for the odontogenic infection, in light of the patient’s neutropenia and new fever, the antibiotic regimen was changed to imipenem, 1 g IV every 8 hr, for broad-spectrum coverage. On the eighth hospital day, the patient developed right lower quadrant pain with bright red blood in his stools. Abdominal CT demonstrated marked thickening of the colon from the cecum to the colosigmoid junction with a small amount of pneumatosis and fluid consistent with neutropenic enterocolitis. After review by general surgery, the patient was placed on bowel rest and managed medically with antibiotics which included the addition of oral vancomycin, 125 mg PO every 6 hr, intravenous metronidazole 500 mg every 8 hr, and ciprofloxacin 400 mg IV every 12 hr, to the imipenem. Over the following days, the patient improved symptomatically, and by the fourteenth hospital day he denied abdominal pain and able to tolerate liquids by mouth. 205 Fig. 1. Clinical course of AML. (A) Temperature curve during hospitalization as related to chemotherapy and infection. (B) Progression of AST (IU/L) and ALT (IU/L) over the time course of hospitalization. (C) Progressive increase in bilirubin (mg/dL) over time. 206 Case Report: Ginsburg et al. Stool testing for Clostridium difficile toxin was negative. The ciprofloxacin and vancomycin were discontinued, while the metronidazole was continued to complete a fourteen-day course, and the imipenem was planned to continue until the patient was no longer neutropenic. Although the LDH normalized with treatment for AML, the bone marrow examination performed 14 days after initiation of induction chemotherapy revealed persistent leukemic blasts, 50%, with the same phenotypic markers present on the blasts as the original analysis. Although he still had low-grade fever at this time (Fig. 1A), given his known nidus of infection in the jaw and his clinical improvement, amphotericin was not initiated; rather, he continued treatment with broad spectrum antibiotics as described and debridement of the odontogenic infection after his hemotologic parameters stabilized was planned. Subsequently, the patient underwent a second induction with idarubicin and Ara-C at the same doses as described above. On the sixth day of his second induction, a followup CT of the abdomen and pelvis showed interval improvement of the diffuse colonic wall thickening consistent with clinical resolution of neutropenic enterocolitis. Six days later, the patient complained of abdominal pain, in both the right upper and right lower quadrants. The patient was febrile (Fig. 1A), and metronidazole was added back to the empiric neutropenic coverage with imipenum. Blood cultures were positive for large aerobic hemolytic Gram-positive rods, and due to the marked change in the patient’s clinical status, vancomycin and ampicillin were also added to the antibiotic regimen. The patient was once again put on bowel rest due to the abdominal pain. Over the next 24 hr he developed a steadily rising alkaline phosphatase, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) (Fig. 1B) as well as jaundice (Fig. 1C), and was transferred to the intensive care unit. Bone marrow evaluation revealed persistent leukemic blasts. He became increasingly jaundiced and febrile with decreasing mental status and liver function over the next 48 hr (Fig. 1B,C). Evaluation included a contrast head CT that demonstrated no pathologic findings and a contrast CT of chest, abdomen, and pelvis that revealed mild thickening of the ascending colon and cecum consistent with possible early recurrence of colitis as well as multiple hypodense hepatic lesions. B. cereus was identified in the blood cultures and was sensitive to vancomycin and imipenum. The patient’s condition continued to deteriorate rapidly despite maximal antibiotic coverage. He remained unresponsive and died on the thirty-fourth hospital day. There were no other cases of B. cereus septicemia or patients with blood cultures positive for B. cereus in the hospital during this time. At autopsy, the patient had multiple well-circumscribed non-inflammatory microabscesses scattered over the surface of the liver (Fig. 2). Most were 1–2 mm, Fig. 2. Non-inflammatory microabscesses present in the liver of this neutropenic patient (Hematoxylin and Eosin stain, original magnification 20×). [Color figure can be viewed in the online issue, which is available at www. interscience.wiley.com.] Fig. 3. Bacillary forms in microabscesses found scattered throughout the liver (tissue Gram stain, original magnification 1,000×). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.] although there was a 2.5-cm region where the abscesses became confluent on the left lobe. Bacillary forms were present within the microabscesses (Fig. 3). In addition, the patient had evidence of pancolitis and typhlitis with a cecal ulcer. Evaluation of bone marrow demonstrated persistent leukemic blasts. The patient’s lungs and heart revealed no pathologic changes. DISCUSSION B. cereus is a Gram-positive aerobic, spore-forming rod-shaped bacterium, ubiquitous in the environment, that was once considered a contaminant and nonpathogenic. Blood cultures positive for Bacillus are common; yet, in the past have been only infrequently associated with actual clinical infection. In one large hospital Case Report: Fatal B. cereus Sepsis in Acute Leukemia study, over a 4-year period 78 patients were found to have cultures positive for Bacillus that resulted in clinically significant infections in only 6% of cases; the majority of those were B. cereus . A five-year review of Cleveland hospitals revealed 38 patients with significant infections caused by Bacillus species . Fourteen of the 15 isolates in this study were found to be B. cereus . Importantly, B. cereus is increasingly being acknowledged as a bacterial pathogen serious for immunosuppressed hosts, including those with histories of intravenous drug abuse, trauma, an intravascular device, sickle cell disease, acquired immune deficiency syndrome, an underlying malignancy, and granulocytopenia . B. cereus can be a significant cause of food poisoning, provoking a diarrheal and/or emetic syndrome. The diarrheal syndrome is secondary to enterotoxins, hemolysin BL, and non-hemolytic enterotoxin, that induce a self-limited profuse diarrhea with abdominal pain and cramps, and, rarely, vomiting or fever . The emetic syndrome is due to the effects of an emetic toxin, cereulide, that causes self-limited nausea, vomiting, abdominal cramps, and, in about one-third of patients, diarrhea . Food poisoning caused by B. cereus is generally limited and requires little supportive therapy and no antimicrobial therapy. The diarrheal syndrome most commonly results from ingestion of meat-based foods, and the emetic syndrome occurs following intake of rice- and pasta-based dishes . In addition to these toxins, B. cereus also elaborates phospholipases, proteases, hemolysins, their production, and the subsequent tissue invasion by bacteria, and bacterial multiplication is a cause of the multi-organ damage seen with B. cereus sepsis . Indeed, B. cereus can give rise to systemic syndromes including endocarditis, meningitis, pneumonia, bacteremia, and septicemia . In general, the enterotoxins and emetic toxins are associated with the gastrointestinal syndromes, and the phospholipases, hemolysins, and proteases are associated with nongastrointestinal infections. Patients with acute leukemia are particularly susceptible to bacteremia resulting from B. cereus [8–11]. Over the past two decades there has been a clear shift from Gram-negative bacteria to Gram-positive and resistant bacteria being responsible for 60–70% of bacteremias identified in patients with neutropenia and cancer . B. cereus has emerged as one of the “new” Gram-positive pathogens to cause serious infection in patients with neutropenia [3,4]. There have been 16 reported cases of B. cereus septicemia in leukemic patients with only three recoveries . While fulminant B. cereus sepsis remains rare, the outcome is usually fatal. In the setting of nosocomial sepsis, isolation of Bacillus from the blood may suggest an intravascular device as the source of continuing infection. Banerjee et al. , reported a study of 24 Bacillus bacteremias, 12 of which were clinically signifi- 207 cant. Seven of the 12 bacteremic episodes were associated with infected Hickman catheters and 4 of the 7 required removal of the catheter for adequate management of the infection. However, neutropenic patients are particularly prone to B. cereus, even if no central line is in place . As intravascular devices predispose to persistent Bacillus bacteremia, prompt removal of infected or potentially infected catheters should be considered [5,12,13] and appropriate antibiotic coverage instituted. B. cereus produces ␤-lactamases and is resistant to penicillins, cephalosporins, and trimethoprim-sulfamethoxazole yet susceptible to aminoglycosides, clindamycin, vancomycin, chloramphenicol, imipenem, and erythromycin [3,5]. More recently there have been reported cases of “refractory” B. cereus bacteremia and/or persistent evolving fulminant meningeal infection in immunocompromised hosts, despite optimal antibiotic treatment with vancomycin and amikacin. Musa and colleagues reported three fatal cases of fulminant B. cereus sepsis in neutropenic AML patients despite early treatment with aminoglycosides . In addition, fatal B. cereus infection has been reported in an immunocompromised neonate despite treatment with a multi-drug antibiotic regimen including vancomycin, gentamicin, imipenem, and clindamycin . These observations demonstrate a lack of efficacy of antimicrobials of choice in certain cases in spite of repeated observed in vitro efficacy against B. cereus isolates. Whether the failure of adequate therapy is due to true drug-resistant organisms or difficult-to-eradicate tissue-based infections is not known. In the case presented here, the patient was treated with an appropriate antibiotic, imipenem. There may be some degree of antibiotic tolerance or possibly poor penetration of the blood brain barrier when treating meningeal infections or of deep-seated tissue infections such as hepatic abscesses [4,14,15]. There are only three reported cases in the literature of fatal B. cereus bacteremia in an adult with acute leukemia that revealed evidence of coagulation necrosis in the liver. Patients in these reports all demonstrated gastrointestinal symptoms immediately preceding death . It is not known whether the inflamed gastrointestinal tract in this patient served as a nidus for seeding B. cereus systemically. The patient reported here had neutropenic enterocolitis, a necrotizing inflammatory process that occurs predominantly in neutropenic patients. Pathological findings usually include transmural inflammation of the bowel with mucosal ulceration, wall edema, necrosis, and formation of intramural hematomas. Recent studies have reported the incidence of neutropenic enterocolitis to be approximately 6% in patients with AML [16,17]. In a study by Hogan et al. , neutropenic enterocolitis was observed in 15% of patients with AML who received idarubicin and arabinoside combination therapy, as in our patient. Furthermore, the mortality rate of neutropenic 208 Case Report: Ginsburg et al. enterocolitis was shown to be 40% in these patients, suggesting that neutropenic enterocolitis was a frequent and serious complication of this intensive chemotherapy regimen . B. cereus can cause fulminant septicemia with multiorgan involvement and frequently death in the neutropenic patient, and it is important to consider antibiotic coverage of the organism early in the clinical course. Therefore, in the neutropenic patient with gastrointestinal complaints or in the setting of resolving neutropenic enterocolitis, it is important to anticipate possible B. cereus sepsis and to have a low threshold for instituting appropriate therapy; addition of an aminoglycoside to broadspectrum coverage or the preferred use of imipenem as a single agent in the setting of neutropenia and gastrointestinal symptoms. ACKNOWLEDGMENTS Our heartfelt thanks to the family members of the patient described in this report for allowing us to perform an autopsy. REFERENCES 1. Drobniewski FA. Bacillus cereus and related species. Clin Microbiol Rev 1993;6:324–338. 2. Thuler LC, Velasco E, de Souza Martins CA, et al. An outbreak of Bacillus species in a cancer hospital. Infect Control Hosp Epidemiol 1998;19:856–858. 3. Zinner SH. Changing epidemiology of infections in patients with neutropenia and cancer: emphasis on Gram-positive and resistant bacteria. Clin Infect Dis 1999;29:490–494. 4. Musa MO, Al Douri M, Khan S, et al. Fulminant septicaemic syndrome of Bacillus cereus: three case reports. J Infect 1999;39:154– 156. 5. Sliman R, Rehm S, Shales DM, et al. Serious infections caused by Bacillus species. Medicine (Baltimore) 1987;66:218–223. 6. Weber DJ, Saviteer SM, Rutala WA, et al. Clinical significance of Bacillus species isolated from blood cultures. South Med J 1989;82: 705–709. 7. Kotiranta A, Lounatmaa K, Haapasalo M, et al. Epidemiology and pathogenesis of Bacillus cereus infections. Microbes Infect 2000;2: 189–198. 8. Akiyama N, Mitani K, Tanaka Y, et al. Fulminant septicemic syndrome of Bacillus cereus in a leukemic patient. Intern Med 1997;36: 221–226. 9. Funada H, Uotani C, Machi T, et al. Bacillus cereus bacteremia in an adult with acute leukemia. Jpn J Clin Oncol 1988;18:69–74. 10. Ihde DC, Armstrong D. Clinical spectrum of infection due to Bacillus species. Am J Med 1973;55:839–845. 11. Motoi N, Ishida T, Nakano I, et al. Necrotizing Bacillus cereus infection of the meninges without inflammatory reaction in a patient with acute myelogenous leukemia: a case report. Acta Neuropathol (Berlin) 1997;93:301–305. 12. Banerjee C, Bustamante CI, Wharton R, et al. Bacillus infections in patients with cancer. Arch Intern Med 1988;148:1769–1774. 13. Cotton DJ, Gill VJ, Marshall DJ, et al. Clinical features and therapeutic interventions in 17 cases of Bacillus bacteremia in an immunosuppressed patient population. J Clin Microbiol 1987;25:672–674. 14. Tuladhar R, Patole SK, Koh TH, et al. Refractory Bacillus cereus infection in a neonate. Int J Clin Pract 2000;54:345–347. 15. Carretto E, Barbarini D, Poletti F, et al. Bacillus cereus fatal bacteremia and apparent association with nosocomial transmission in an intensive care unit. Scand J Infect Dis 2000;32:98–100. 16. Gorschluter M, Marklein G, Hofling K, et al. Abdominal infections in patients with acute leukaemia: a prospective study applying ultrasonography and microbiology. Br J Hematol 2002;117:351–358. 17. Cartoni C, Dragoni F, Micozzi A, et al. Neutropenic enterocolitis in patients with acute leukemia: prognostic significance of bowel wall thickening detected by ultrasonography. J Clin Oncol 2001;19:756– 761. 18. Hogan W, Letendre L, Litzow M, et al. Neutropenic colitis after treatment of acute myelogenous leukemia with idarubicin and cytosine arabinoside. Mayo Clin Proc 2002;77:760–762.
© Copyright 2018