Brigham and Women's Hospital is a 779-bed academic hospital with general medical and surgical services and a large oncology patient population. Cases were defined as B cereus blood or CNS isolates obtained from an AML patient with fever, neurological symptoms, and radiological evidence of acute CNS disease occurring >48 hours after admission. After the initial 5 cases were identified, we reviewed medical records of patients with B cereus isolated from any source from January 2011 through February 2014 and AML patients with unexpected deaths in 2013 to assess for other potential cases. We reviewed records of case-patients to collect information relevant to possible risk factors including room locations, medical staff contacts, procedures, medications, blood products, and dietary exposures. Multiple medication samples, environmental swabs, and air samples from areas shared by AML patients were sent for microbiologic culture. Pharmacy, interventional radiology, blood bank, nursing, and kitchen practices were observed.

A matched case-control study was performed to assess risk factors, including medications, procedures, and dietary exposures. Controls were randomly selected among patients hospitalized for AML treatment within the same month for an equal or longer duration than the time to onset of illness for each case (defined as the start of recurrent fever before B cereus bacteremia and/or neurological deterioration). The number of controls per case depended upon the availability of medication (4 controls), procedures (4 controls), and dietary (1–4 controls) exposure data. Odds ratios and P values were calculated using Fisher's exact test. Due to the small number of cases, the analysis focused only on exposures that were common to 4 or more case-patients. Some 2-by-2 tables contained cells with a value of zero; for these exposures, odds ratios and P values were calculated by adding .5 to each cell. There were too few case-patients to construct a multivariable regression model.

These 5 cases of B cereus infection highlight the risk of nosocomial infection from this organism and the potential for devastating neurologic sequelae in immunocompromised patients. Although there were few cases, the investigation was performed with urgency because of the high associated mortality (80% in our series) and the unusual nature of this cluster, as supported by the absence of other cases in the preceding 3 years at BWH. Clinical and pathologic review suggests gastrointestinal translocation as the likely route of infection for some or all of the case-patients, because all had notable gastrointestinal symptoms and 2 had colonic ulcers with evidence of Bacillus infection on autopsy.

Multilocus sequence typing demonstrated that the cluster was not the result of a single B cereus strain. Rather, the infections appear to have been attributable to multiple distinct strains within at least 2 distinct genotypic clusters. Although this is less consistent with a point-source outbreak, a common environmental or food exposure is still possible, particularly if the exposure was due to intermittent environmental contamination of a common food. All 5 case-patients had consumed bananas, 1 of only 2 dietary items significantly associated with infection in the case-control analysis. Bacillus cereus was recovered from the shelf where the bananas were stored in the kitchen, and B cereus was also cultured from a banana peel. The timing of the cluster with multiple hospital renovation and construction projects, some of which were proximate to the kitchen storage area, raises the possibility of environmental contamination of foods stored in the kitchen or direct inoculation of patients, although no breaches were identified in construction containment practices.

Nosocomial B cereus outbreaks at other institutions have been reported with various suspected sources, including construction work, contaminated linen and towels, intravenous catheters, infusion fluids, ventilator equipment, air ventilation systems, tea bags, gloves, and hands of staff [4–10]. However, definitively establishing the source of an outbreak is complicated by the fact that B cereus is a ubiquitous organism (including in food), and so the significance of isolating low colony counts from environmental cultures is often unclear. When outbreaks do occur, obtaining control can be difficult because Bacillus is able to survive long periods in the environment and is resistant to many commonly used cleaning products [11].

Bacillus cereus is typically disregarded as a contaminant when isolated from blood cultures, but patients receiving chemotherapy for hematological malignancies have been noted to be at disproportionately high risk for CNS infection, with substantial associated mortality [12–15]. The pathogenicity of B cereus (both intestinal and extraintestinal) is associated with the production of a wide range of tissue-destructive exotoxins and enterotoxins [16–18]. Central nervous system infection in immunocompromised patients may result from bloodstream seeding from gastrointestinal infection (particularly in the setting of mucosal injury from chemotherapy), or from central venous catheters with subsequent CNS invasion, or possibly from direct introduction via intrathecal administration of chemotherapy [14, 19, 20]. It is important to note that our first 2 case-patients never had positive blood cultures, and none received lumbar punctures or intrathecal chemotherapy before onset of disease. All 5 case-patients shared risk factors for poor prognosis, including acute leukemia, an absolute neutrophil count approaching zero, neurological symptoms at the time of febrile episodes, and active receipt of induction or reinduction chemotherapy [1]. It is interesting to note that the 1 case-patient who received a lumbar puncture had a normal number of total nucleated cells on CSF analysis. Bacillus cereus meningitis has been reported to be associated with a relatively bland CSF profile in patients with hematological malignancies. This may be a reflection of underlying host immunosuppression and possibly an intrinsic lack of inflammatory response by the organism [7, 13, 21]. Neuropathology in our cases demonstrated areas of acute infarction, cerebritis, abscesses, hemorrhage, and meningitis, reflecting the wide range of potential CNS manifestations of this organism [12–14, 20, 22–27].

Several control measures were instituted as a result of this investigation, including enhanced environmental cleaning and exclusion of bananas and fresh fruits, vegetables, and rice from the diets of AML patients undergoing induction chemotherapy. Our hospital's empiric antibiotic recommendations were also modified to include the addition of ciprofloxacin for recurrent neutropenic fever to optimize B cereus coverage, given that susceptibility testing on the isolates revealed low minimum inhibitory concentrations for ciprofloxacin. No additional cases have been found in the year after the last case.

In summary, this cluster of neuroinvasive B cereus infections in 5 AML patients prompted an extensive epidemiologic and genomic investigation that ultimately did not support the hypothesis of a single point source, but it did suggest the possibility of a dietary exposure to B cereus. Our experience underscores the potential virulence of this organism in susceptible hosts. Clinicians should not automatically disregard Bacillus in blood cultures as being contaminants and B cereus should be considered in febrile immunocompromised patients with neurological symptoms, even without positive blood cultures. It is possible that the responsible organisms share a transferable virulence-conferring factor, and comparative microbial genomic and biological efforts are underway that may identify bacterial and host factors that induce heightened virulence.