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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 [1]. 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)[18]/46, XY[2] 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 [6]. A five-year review of
Cleveland hospitals revealed 38 patients with significant
infections caused by Bacillus species [5]. Fourteen of the
15 isolates in this study were found to be B. cereus [5].
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 [5].
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 [7]. 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 [7]. 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 [1]. 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 [1]. Indeed, B. cereus can give rise to systemic
syndromes including endocarditis, meningitis, pneumonia, bacteremia, and septicemia [1]. 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 [5]. 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 [8]. 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. [12], 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 [5]. 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 [4]. 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 [14]. 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 [8]. 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. [18], 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 [18]. 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.
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