Bacillus cereus, a Volatile Human Pathogen
SUMMARY
Bacillus cereus is a Gram-positive aerobic or facultatively anaerobic, motile, spore-forming, rod-shaped bacterium that is widely distributed environmentally. While B. cereus is associated mainly with food poisoning, it is being increasingly reported to be a cause of serious and potentially fatal non-gastrointestinal-tract infections. The pathogenicity of B. cereus, whether intestinal or nonintestinal, is intimately associated with the production of tissue-destructive exoenzymes. Among these secreted toxins are four hemolysins, three distinct phospholipases, an emesis-inducing toxin, and proteases. The major hurdle in evaluating B. cereus when isolated from a clinical specimen is overcoming its stigma as an insignificant contaminant. Outside its notoriety in association with food poisoning and severe eye infections, this bacterium has been incriminated in a multitude of other clinical conditions such as anthrax-like progressive pneumonia, fulminant sepsis, and devastating central nervous system infections, particularly in immunosuppressed individuals, intravenous drug abusers, and neonates. Its role in nosocomial acquired bacteremia and wound infections in postsurgical patients has also been well defined, especially when intravascular devices such as catheters are inserted. Primary cutaneous infections mimicking clostridial gas gangrene induced subsequent to trauma have also been well documented. B. cereus produces a potent β-lactamase conferring marked resistance to β-lactam antibiotics. Antimicrobials noted to be effective in the empirical management of a B. cereus infection while awaiting antimicrobial susceptibility results for the isolate include ciprofloxacin and vancomycin.
INTRODUCTION
In 1993, Drobniewski (40) published a major review in this journal, entitled Bacillus cereus and Other Related Species, which followed “Farrar's landmark review” published 30 years earlier (45). Continuing on the “shoulders of these giants” and reviewing and dissecting the expanding horizon of publications on B. cereus non-gastrointestinal-tract infection, one becomes truly fascinated by the diligence of the author's depiction of the evolving spectrum of human infections associated with this bacterium, which has heretofore been regarded as a “contaminant” when isolated from a clinical specimen. Furthermore, immersion into the details of the infectious process and uncovering potential routes of pathogenesis even when not specifically elucidated by the authors afforded a wonderful opportunity to integrate concepts derived in part from the numerous publications reviewed in a Sherlock Holmes manner to arrive at a rationale for the infectious process described. In those instances scenarios were interjected based upon new-found knowledge and personal experiences where relevant. In the end, it is hoped that the reader would become enlightened and intrigued with the kaleidoscopic nature of this volatile bacterial species.
The joy in the undertaking of this topic resides in reviewing and appreciating the insights of early investigators who recognized the pathogenic potential of “Bacillus species” other than B. anthracis. Their determined endeavors sought to alert the medical community to the biphasic contaminant-pathogen differentiation of B. cereus. Such a distinction is critical in order to embark on the correct therapeutic approach prior to having to backtrack because of misconceptions regarding the significance of a B. cereus isolate from a patient specimen. To this end, this review, which focuses mainly on non-food-borne infections, will reemphasize the plea of past authors who sought to give B. cereus a well-earned pathogenic status worthy of serious clinical evaluation when encountered. The reader is referred to a comprehensive review of B. cereus food poisoning by Arnesen et al. (7).
Bacillus cereus is a Gram-positive, aerobic-to-facultative, spore-forming rod widely distributed environmentally and bearing a close phenotypic and genetic (16S rRNA) relationships to several other Bacillus species, especially B. anthracis (8).
The bacterium exists as a spore former and vegetative cell in nature and as a vegetative cell when colonizing the human body (see Epidemiology below). Transmission electron microscopy of the vegetative cell reveals a cytoplasmic membrane surrounding the cellular content (79, 80). In addition, some strains contain an outermost crystalline surface protein (S layer) (79, 80). The core of the spore is surrounded by the inner membrane, cortex, and inner and outer coats. While devoid of metabolic activity, the B. cereus spore is refractory to extreme environmental conditions inclusive of heat, freezing, drying, and radiation and may be regarded as the infective agent for this bacterium.
In keeping with its close relationship to B. anthracis, the surface antigens of the spore share epitopes with B. anthracis spores as determined serologically by cross-agglutination (17). In the food industry the spores of B. cereus are particularly troublesome because spores can be refractory to pasteurization and gamma radiation, and their hydrophobic nature allows them to adhere to surfaces (5, 79, 111).
EPIDEMIOLOGY
The natural environmental reservoir for B. cereus consists of decaying organic matter, fresh and marine waters, vegetables and fomites, and the intestinal tract of invertebrates (71), from which soil and food products may become contaminated, leading to the transient colonization of the human intestine (53). Spores germinate when they come into contact with organic matter or within an insect or animal host (7). A multicellular filamentous growth pattern containing refractile inclusions, termed arthromitus (rooted), has been observed in the guts of certain arthropods, which is regarded as the normal intestinal stage in soil-dwelling insects (95). In this setting, as long rod-shaped bacteria, the bacilli lose their flagella, attach to the arthropod intestinal epithelium, and sporulate (95). B. cereus also has a saprophytic life cycle in which spores germinate in soil, with the production of a vegetative bacillus, which could then sporulate, maintaining the life cycle (7). Defecation by or death of the host releases cells and spores into the soil, where vegetative cells may sporulate and survive until their uptake by another host (71, 135). Furthermore, when B. cereus grows in soil, it undergoes a switching from a single-cell to a multicellular phenotype, which allows it to translocate through the soil (135). This morphogenic phase is analogous to B. cereus swarming on agar media (118).
B. cereus may be the most common aerobic spore bearer in many types of soil and in sediments, dust, and plants (107). B. cereus is also frequently present in food production environments due to the adhesive nature of its endospores (7). This characteristic enables the bacterium to spread to all kinds of food.
Because of the ubiquitous distribution of B. cereus in food products, the bacterium is ingested in small numbers and becomes part of the transitory human intestinal flora (71, 130). It is unclear, however, if the recovery of B. cereus in cultures of stool specimens is a function of germinating spores or the growth of vegetative cells.
MICROBIOLOGY
Bacterial Morphology
Microbiologically, members of the B. cereus group exclusive of B. anthracis display a range of morphological forms depending upon the milieu in which they are observed. In Gram-stained smears of body fluids such as anterior-chamber aspirates or broth cultures, B. cereus presents as straight or slightly curved slender bacilli with square ends singly or in short chains (Fig. 1). Clear-cut junctions separating members of the chain are distinctly displayed. Gram-stained smears prepared from agar growth will show more uniform bacillary morphology with oval, centrally situated spores, which do not distort the bacillary form. In tissue sections such as those shown in Fig. 2, long, slender, bacillary forms may predominate, with some clearly displaying polyhydroxybutyrate vacuoles, which may be confused with spores. Long filamentous forms characterized as filamentation may also show beading, which may preclude identification as a Bacillus species (Fig. 3). In wet preparations of body fluids or broth cultures, the peritrichous bacilli are motile, displaying a leisurely gait rather than darting motility.
Colony Morphology
When grown under aerobic conditions on 5% sheep blood agar at 37°C, B. cereus colonies are dull gray and opaque with a rough matted surface (Fig. 4). Colony perimeters are irregular and represent the configuration of swarming from the site of initial inoculation, perhaps due to B. cereus swarming motility (118). Zones of beta-hemolysis surround and conform to the colony morphology (131). In some instances smooth colonies develop either alone or in the midst of rough colonies (Fig. 4). When grown apart from the initial inoculum, smooth colonies are surrounded by a uniform zone of beta-hemolysis framing the centrally situated colony (Fig. 5). Interestingly, smears prepared from the distal and frontal (spreading) advancing perimeters of a mature colony may reveal two distinct morphological presentations. Smears prepared from the distal edge show uniform bacillary forms with prominent centrally situated spores admixed with chains of Gram-positive bacilli, while smears from the advancing edge are comprised predominately of masses of entangled bacillary chains traversing the microscopic field and a remarkable absence of spore-containing bacilli. Perhaps, as the colony spreads forward from the initial inoculum site, it leaves behind a trail of metabolic end products, which alters the pH and oxygen content of the growth environment, thereby inducing spore formation. B. cereus grows anaerobically and at 45°C. Biochemical characterization can be achieved through the use of the API 20 Enterobacteriaceae (API 20 E) and API 50 Carbohydrate (50 CH) kits (bioMerieux, France), used together (88).
PATHOGENESIS
The pathogenicity of B. cereus, whether intestinal or nonintestinal, is intimately associated with tissue-destructive/reactive exoenzyme production. Among these secreted toxins are four hemolysins (56), three distinct phospholipases, an emesis-inducing toxin, and three pore-forming enterotoxins: hemolysin BL (HBL), nonhemolytic enterotoxin (NHE), and cytotoxin K (91, 92, 114). In the gastrointestinal tract (small intestine), vegetative cells, ingested as viable cells or spores, produce and secrete a protein enterotoxin and induce a diarrheal syndrome, whereas emetic toxin, a plasmid-encoded cyclic peptide (cereulide), is produced in food products and ingested preformed. In rabbit ligated ileal-loop assays, culture filtrates of enterotoxigenic strains induce fluid accumulation and hemolytic, cytotoxic, dermonecrotic, and vascular permeability activities in rabbit skin (13).
This tripartite enterotoxin is composed of a binding component (B) and two hemolytic components, designated HBL (13). Also diarrheagenic in the gastrointestinal tract is a nonhemolytic three-component enterotoxin, designated NHE (91). The emetic toxin, which induces a vomiting syndrome, is synthesized in the contaminated food product, e.g., milk, rice, and pasta, in which B. cereus is growing and may represent a metabolic product of growth.
NONGASTROINTESTINAL INFECTIONS
In addition to food poisoning, B. cereus causes a number of systemic and local infections in both immunologically compromised and immunocompetent individuals. Among those most commonly infected are neonates, intravenous drug abusers, patients sustaining traumatic or surgical wounds, and those with indwelling catheters. The spectrum of infections include fulminant bacteremia, central nervous system (CNS) involvement (meningitis and brain abscesses), endophthalmitis, pneumonia, and gas gangrene-like cutaneous infections, to name a few.
Respiratory Tract Infections
Bacillus anthracis possesses two plasmids, pX01 and pX02, which encode the lethal toxin and the poly-d-glutamic acid capsule, respectively, which would normally distinguish this bacterium from the closely related B. cereus. Although these two species differ in phenotypes and disease spectra produced, reports of pulmonary infections mimicking anthrax have been attributed to B. cereus strains harboring B. anthracis toxin genes (67).
In 1997, Miller et al. (99) described rapidly progressive pneumonia and bacteremia in two previously healthy welders aged 46 and 41 years, respectively, without any enjoining epidemiological link. Patient 1 was a resident of central Louisiana who was healthy 5 days prior to hospital admission, while patient 2 lived in South Louisiana and was healthy until 3 days prior to hospitalization. According to these authors, the overwhelming sepsis and pulmonary infiltrates in the two patients resembled those produced by Bacillus anthracis respiratory disease. It was postulated that welders acquired their infection by the inhalation of B. cereus spores from contaminated dust. While these two case presentations paralleled pulmonary infection by B. anthracis, the two isolates were not initially tested for the presence of B. anthracis toxin genes. However, a later publication by Hoffmaster et al. (67) stated that the Miller isolates did not contain the B. anthracis pagA-like genes carried on the pXO1 phage. Seven years later, Hoffmaster and colleagues (68), working with B. cereus strain G9241, isolated from the sputum and blood of a nonimmunosuppressed patient with an illness resembling pulmonary anthrax, showed that the B. cereus isolate harbored a plasmid homologue of the B. anthracis pXO1-carried PA toxin gene pagA but not the pXO2 glutamic acid capsule gene. The patient was well until 2 days before the onset of symptoms and, analogous to the two patients reported by Miller et al. (99), did not abuse drugs or alcohol and was a nonsmoker without underlying disease. He received intensive care, including a partial lobectomy, and was discharged 44 days postadmission.
More recently, in 2007, Avashia et al. (10) reported two metal workers with fatal B. cereus pneumonia and sepsis. Neither patient, aged 39 and 56 years, respectively, had any significant predisposing comorbidities, both worked as metal workers grinding metal for polishing, and, while both were residents of Texas, they were substantially separated geographically. Both patient isolates tested positive for the pXO1-specific virulence plasmid but not the pXO2 plasmid by PCR.
Interestingly, while the B. cereus isolates reported by Miller et al. (99) were lacking B. anthracis genes (67), the clinical presentation and occupation of the two patients who succumbed to the infection remarkably resembled the clinical presentation and occupation of patients subsequently reported by Avashia et al. (10) and Hoffmaster et al. (68). Perhaps, the Miller isolate lost the B. anthracis genes during the 7-year interval between initial isolation and testing by Hoffmaster et al. (68). Alternatively, plasmids carrying B. anthracis genes may not be required for severe pulmonary infections, as other isolates from severe cases have been negative for plasmids (A. Hoffmaster, personal communication).
Regarding the upper respiratory tract, invasion of the oral cavity in immunosuppressed patients may be more prevalent than previously documented, as the oral cavity may become colonized with B. cereus either through the inhalation of spores or by vegetative bacteria passing through in B. cereus-contaminated food (31, 44). Foci can be established by the entrapment of bacteria in furrows in the oral cavity in which the bacterium may develop locally and elaborate toxins, which can spread to adjacent tissues, or the bacterium can disseminate to other body sites. A report by Strauss et al. (124) of the development of pseudomembranous tracheobronchitis in a 52-year-old female patient with aplastic anemia suggests that treatment-mediated damage to the buccal mucosa may expedite spore/vegetative cell adherence and colonization. Fiber-optic bronchoscopy of the patient revealed a severely inflamed tracheal and bronchial mucosa accompanied by white diphtheria-like membranes obstructing the lower lobe bronchi on the left side. Over an 8-h period, the membranes spread and obstructed the entire visible bronchial system. B. cereus was recovered from blood and bronchoalveolar lavage cultures and the membrane biopsy specimen. As this patient's initial symptoms included chest pain, yellowish sputum, and a rapid progression of the infection, the authors likened her infection to pulmonary anthrax. B. cereus colonization of the oral cavity, as noted here and elsewhere (31, 44), may well be an underappreciated first stage in the pathogenesis of pulmonary as well as systemic infections in immunocompromised individuals.
Bacillus cereus spores, which are hydrophobic and have projecting appendages, adhere to Caco-2 and small-intestine epithelial cells (5) and HeLa cells (110). In these studies, spores adhered in aggregates, which, when germinating, released high concentrations of tissue-destructive toxins. Contact adherence of spores in aggregates to epithelial cells triggers the germination of spores, enterotoxin production, and disintegration of the Caco-2 tissue monolayer. Interestingly, bacteria continue to adhere to membrane debris (110). While these studies emphasized the adherence of B. cereus spores mainly to colonic epithelia, the ingestion of spores with binding capability in the setting of potentially disrupted respiratory mucosa could lead to cytotoxicity in the respiratory tract, as exemplified by the development of diphtheria-like membranes in addition to pulmonary infection and systemic dissemination.
Nosocomial Infections
Due to the widespread distribution of Bacillus spores in soil, dust, water, and the hospital environment, B. cereus is usually considered a contaminant when isolated from clinical specimens of various origins (blood, wounds, and sputum, etc.). Bacillus species, however, are gaining notoriety as causing definitive nosocomial outbreaks among immunosuppressed hospitalized patients (106, 108; reviewed in Table 1). Environmental reservoirs identified for this species include contaminated air filtration and ventilation equipment (23), fiber-optic bronchoscopy equipment (55, 109), linen (12), gloves (139), hands of staff (101), intravenous catheters (64), alcohol-based hand wash solutions (69), specimen collection tubes, balloons used in manual ventilation (134), linens (10, 11), and reused towels in Japan (38). Furthermore, a 17-year-old neutropenic patient with acute lymphoblastic leukemia developed B. cereus bacteremia traced to drinking lukewarm tea prior to her bacteremic episode (44). A thorough investigation by those authors showed a high prevalence (17 of 19 tea bags) of contamination by B. cereus.
As noted previously, outbreaks of B. cereus pseudoinfections among hospitalized patients have been well documented, especially with regard to pseudobacteremias (16, 69, 139). A pseudo-outbreak has been defined as a situation in which an organism is recovered in culture at a rate that is greater than expected and that cannot be correlated clinically with the supposed infection implied by the culture results (94). There is no question that spores of B. cereus (as with other Bacillus species) permeate hospital environments and contribute to nosocomial and pseudonosocomial infections. Pseudo-outbreaks of bacteremia and respiratory tract infections have been traced to contaminated ethyl alcohol (69) and fiber-optic bronchoscopy equipment (55, 109), respectively.
Because most Bacillus species (except B. anthracis) isolated from blood cultures and even from open wounds are often regarded as contaminants, it becomes critical for the clinical microbiology laboratory to alert infection control practitioners if a sudden increase in the isolation of this bacterial species is noted. If such a scenario arises, B. cereus isolates should be forwarded to a reference center for serotyping and/or subjected to genotypic fingerprinting (86) to determine if isolates are clonal, which could lead to a point source of contamination.
Catheter-related B. cereus bloodstream infections have been well documented, especially among immunosuppressed patients and those with hematological malignancies (82, 106). It was previously shown that B. cereus can produce biofilms (9, 82), which can play a major role in attachment to catheters. When examined by scanning electron microscopy after growth on inoculated coverslips, B. cereus isolates associated with nosocomial bacteremia formed aggregates of bacilli, which could easily attach to the surface of catheters, resulting in persistent infection until catheter removal. Biofilm formation can result from cell-to-cell and cell-surface contact, which leads to the formation of microcolonies. The release of planktonic bacteria from the biofilm can result in the formation of additional biofilms, thereby maintaining persistence (33). While antibiotic therapy may arrest planktonic invasion, sessile bacteria in the biofilm are spared, resulting in recurrent or protracted bacteremia. Biofilm formation, because of their protected mode of growth on inert surfaces, may also contribute to B. cereus persistence in the hospital environment in settings wherein replication can take place, in addition to the survival of spores.
ENDOPHTHALMITIS
Case Vignette
A 45-year-old patient with a history of insulin-dependent diabetes mellitus presented with redness and worsening pain in his left eye 3 days post-cataract surgery. A rapid diagnosis of endophthalmitis was made by Gram staining of vitreous fluid, which showed numerous Gram-positive bacilli (Fig. 6). Wet preparation of the vitreous fluid showed motile bacilli. Despite the administration of intravitreal and systemic vancomycin and ceftazidime on the day of admission, the infection progressed, requiring the enucleation of the eye on the same day. Cultures of vitreous fluid and blood grew B. cereus.
Endophthalmitis is a vision-threatening eye infection resulting from traumatic or systemic microbial infection of the interior of the eye (24). The outcome of the infection varies with the microbial agent involved and the rapidity of and response to treatment. The hallmark of the ophthalmic lesion is a corneal ring abscess accompanied by rapid progression of pain, chemosis, proptosis, retinal hemorrhage, and perivasculitis. Systemic manifestations include fever, leukocytosis, and general malaise (97).
With regard to B. cereus, as exemplified in the case described above, endophthalmitis caused by this bacterium is a devastating malignant eye infection because of the rapidity with which the infection progresses and the bacterium's elaboration of a multitude of extracellular tissue-destructive virulence factors (14). In his exceptional review of B. cereus infections, Drobniewski (40) detailed the results of 35 cases of B. cereus endophthalmitis “reported during this century,” of which 20 eyes were lost to enucleation and 1 was lost to blindness. In their review of B. cereus endophthalmitis, Callegan et al. (28) noted a 70% loss of total vision resulting from enucleation or evisceration. It is noteworthy that during the first half of the 20th century, bacilli isolated from cases of endophthalmitis were not identified to the species level and subsequently were all grouped as Bacillus subtilis (36). In 1952, Davenport and Smith (36) described a patient with B. cereus endophthalmitis based on identification criteria of their isolate published 4 years earlier in Bergey's Manual of Determinative Bacteriology (68a). As their patient's clinical presentation closely mimicked those of earlier reports of endophthalmitis attributed to B. subtilis, Davenport and Smith raised the thought that those earlier reports of endophthalmitis attributed to B. subtilis were actually “an error of taxonomy.”
B. cereus endophthalmitis can be divided into two categories: exogenous, attributable to globe-penetrating eye trauma, and endogenous, originating through the hematogenous seeding of the posterior segment of the eye from a distant site or through direct intravenous acquisition through blood transfusion (75), indwelling devices, or contaminated needles or injection paraphernalia or illicit drugs (59, 98, 119, 127) or by iatrogenic administration of medications such as B vitamins (21) and insulin (101). Bouza et al. (21) reported a case of severe suppurative endogenous panophthalmitis caused by B. cereus in a 43-year-old man, which resulted from the intravenous administration of B vitamins obtained from three multidose vitamin- and mineral-containing vials, which, when cultured, grew pure cultures of B. cereus. The patient received twice-weekly intravenous injections by his private physician for several weeks. The last injection was administered less than 24 h prior to the onset of the patient's ocular symptoms, which consisted of a 12-h history of pain, swelling, and severe loss of vision in the right eye.
In 1953, Kerkenezov (75) described a patient who had developed B. cereus endogenous panophthalmitis following a blood transfusion, although the blood was not cultured. In this instance, it is conceivable that other items, e.g., alcohol sponges and gloves, etc., could have been contaminated with B. cereus spores, which ultimately led to bacteremia and endophthalmitis.
Hematogenous invasion of the eye among intravenous drug abusers, attributable to contaminated heroin (138), cocaine (98), and injection equipment (128) has been documented. Shamsuddin et al. (119) cultured 59 samples of heroin and injection paraphernalia, of which 20 cultures were positive. Bacillus species were recovered from 13 of the 20 samples, 5 (38%) of which were B. cereus. In their earlier study (127), these investigators recovered Bacillus species from 47 of 89 paraphernalia cultures and 32 of 68 heroin cultures. B. cereus was the species most commonly isolated. Furthermore, B. cereus keratitis or more significant eye infections in contact lens wearers has been associated with acquiring the microorganism from contaminated contact lens care systems (39). Donzis et al. (39) pointed out that Bacillus spores can survive multiple heat disinfection treatments as well as chemical disinfection systems used for the minimum recommended lens care techniques.
Suspicion of the presence of B. cereus in a penetrating eye infection may be related to occupation, e.g., metal workers (97), and if the injury occurred in a rural area or agricultural setting (37) or following cataract extraction surgery (case history). Regarding the latter, Simini (120) reported an outbreak of B. cereus necrotizing endophthalmitis secondary to surgery for senile cataract. Within a day of surgery, all four patients lost vision in the affected eye. Although a single ophthalmologist was a member on all of the surgical teams operating on the four patients in the same operating room (OR) on the same day, no source of infection could be identified, as a bacteriological investigation was not undertaken until 3 days postsurgery. Based upon previous reports of B. cereus nosocomial infections, as outlined in Table 1, contaminated fomites such as gauze, linens, and ventilators, etc., in addition to health care workers' hands, may have served as the source of the B. cereus outbreak.
Diagnosis of endogenous and exogenous B. cereus endophthalmitis should be attempted by immediate anterior-chamber paracentesis. If microorganisms are not detected, this should be followed by a second vitreous aspiration after a short interval (98), along with blood culture collection (57).
Because of the rapidity with which B. cereus can destroy an infected eye, especially in cases of penetrating trauma with a soil-contaminated foreign body, rapid therapeutic intervention is mandatory irrespective of results of immediate diagnostic testing (37). Early studies suggested the efficacy of intravitreal antibiotics, namely, 1,000 μg of vancomycin in combination with 400 μg of amikacin (133). Factors contributing to the outcome of B. cereus endophthalmitis include duration between injury and treatment therapy chosen and condition of the eye upon presentation (26, 49). Systemic antibiotics have been used in concert with intravitreal antibiotics, but it is noteworthy that vancomycin and aminoglycosides do not readily penetrate into the vitreous fluid (46) due to the protective effect of the blood-ocular fluid barrier (26).
Using B. cereus to induce endophthalmitis in a rabbit model, Liu and Kwok (87) injected 20 rabbit eyes intravitreally with 0.1 ml of an isotonic sodium chloride solution containing 1 × 106 CFU of B. cereus. After 24 h, 1 mg of vancomycin alone in 0.1 ml of saline was administered intravitreally, and in a second group of rabbit eyes infected with B. cereus, 1 mg of vancomycin and 0.4 mg of dexamethasone were simultaneously administered intravitreally. Eyes treated with vancomycin and dexamethasone examined at 7 and 14 days expressed significantly less inflammation over the conjunctiva and vitreous fluid at 7 days and over the iris and vitreous fluid than did eyes treated with vancomycin treatment alone. In reviewing reports of naturally acquired B. cereus as well as experimentally induced endophthalmitis, ocular entrance of the bacterium results in a massive destruction of the eye within 12 to 18 h (26), and in many instances, vision loss occurs regardless of the therapeutic and surgical intervention, largely because of the delayed administration of antibiotics, toxin production of the infecting strain, and migration and sequestration of the motile bacillus out of antibiotic reach (27). For instance, in experimental rabbit studies conducted by Callegan et al. (24), 100 CFU of B. cereus was inoculated into rabbit eyes. Inflammation was observed at as early as 3 h, and from 12 to 18 h, inflammatory symptoms were severe, with anterior-chamber hyphema, severe iritis, and peripheral ring abscesses present. The B. cereus strain used in their experiments was recovered from a pediatric posttraumatic endophthalmitis case that progressed to enucleation. In contrast, no information was given regarding the source of the B. cereus strain used by Liu and Kwok (87) in their studies. This raises the possibility that the strain used was of potentially reduced virulence, since one would expect substantial damage to the eye during the 24-h interval from the inoculation and administration of vancomycin and dexamethasone. Perhaps, further studies with a clinically isolated, fully toxigenic B. cereus strain will confirm or temper the results obtained by Liu and Kwok (87).
Endophthalmitis Pathogenesis
It is well established that B. cereus elaborates a host of tissue-destructive exotoxins that contribute to the devastating outcomes in endophthalmitis (14). However, recent investigations into the pathogenesis of B. cereus-induced endophthalmitis have identified several other factors that also contribute to the poor outcome of B. cereus endophthalmitis.
Initially, Beecher et al. (14) suggested that the poor outcome of antibiotic treatment of B. cereus endophthalmitis was actually a consequence of continued tissue-destructive activity independent of antibiotic bacterial killing. Among the elaborated exotoxins incriminated in an experimental rabbit model of destructive endophthalmitis conducted by Beecher et al. (14, 15) were hemolysin BL (a tripartite dermonecrotic vascular permeability factor), a crude exotoxin (CET) derived from cell-free B. cereus culture filtrates, phosphatidylcholine-preferring phospholipase C (PC-PLC), and collagenase. The contribution of these factors individually or in concert could account for retinal toxicity, necrosis, and blindness in experimentally infected rabbit eyes. The toxicity of PC-PLC was a direct result of the propensity of the secreted enzyme for the phospholipids in retinal tissue, which may also act similarly in human eye retinal tissue, which also contains a significant amount of phospholipids (18). In a separate study, Callegan et al. (25) showed that the role of BL toxin in intraocular B. cereus infection was minimal, “making a detectable contribution only very early in experimental B. cereus endophthalmitis but did not effect the overall course of infection.” Intraocular inflammation and retinal toxicity occurred irrespective of the presence of hemolysin BL, implying the contribution of other factors to pathogenesis.
In an experimental rabbit eye study of the pathogenesis of bacterial endophthalmitis caused by the Gram-positive ocular pathogens Staphylococcus aureus, Enterococcus faecalis, and Bacillus cereus, Callegan et al. (24) concluded that B. cereus endophthalmitis followed a more rapid and virulent course than the other two bacterial species. Additionally, B. cereus intraocular growth was significantly greater than those of S. aureus and E. faecalis. Analysis of bacterial location within the eye showed that the motile B. cereus rapidly migrates from posterior to anterior segments during infection. This phenomenon was confirmed in a subsequent study (27) using wild-type motile and nonmotile B. cereus strains, which confirmed that while both strains grew to a similar number in the vitreous fluid, the motile swarming strain migrated to the anterior segment during infection, causing more severe anterior segment disease than the nonswarming strain.
Bacterial swarming is a specialized form of surface translocation undertaken by flagellated bacterial species. Swarm cells in a population undergo a morphological differentiation from short bacillary forms to filamentous, multinucleate, and hyperflagellated swarm cells with nucleoids evenly distributed along the lengths of the filaments (43, 52, 118). The differentiated cells do not replicate but rapidly migrate away from the colony in organized groups, which comprise the advancing rim of growing colonies (43, 61, 118).
Swarming motility collectively stops, and swarm cells differentiate back into the short bacillary forms. Swarming is thought to be a mechanism by which flagellated microorganisms traverse environmental niches or colonize host mucosal surfaces (4). Moreover, swarming can play a role in host-pathogen interactions by leading to an increase in the production of specific virulence factors (4, 52).
Regarding B. cereus, Ghelardi et al. (52) showed a correlation between swarming and hemolysin BL secretion in a collection of 42 B. cereus isolates. The highest levels of toxin were detected in swarmers, which suggested that swarming B. cereus strains may have a higher virulence potential than nonswarming strains.
Blood-Ocular Barrier
The eye is protected from inflammatory cells and blood constituents by the blood-ocular barrier systems (102). The barrier system separates the interior portion of the eye from blood entering the eye and maintains the transparency and function of the interior portion of the eye. There are two main blood-ocular barriers, the blood aqueous barrier and the blood retinal barrier, a barrier to the free diffusion of molecules formed by tight junctions (18, 30). During experimental B. cereus endophthalmitis, Moyer et al. (102) showed that the bacterium causes a permeability of the blood-retinal barrier as early as 4 h postinfection by the disruption of tight junctions between endothelial cells and the basement membrane of retinal capillaries and retinal pericytes. Such changes in the blood-ocular barrier during endophthalmitis contribute to the loss of retinal structure and function (78, 102). These authors speculated that a group of B. cereus toxins might have contributed to the loss of barrier function in experimental B. cereus endophthalmitis.
CENTRAL NERVOUS SYSTEM INFECTIONS
Case Vignette
A 28-year-old male presented with a complaint of bruising and bleeding of the gums and nose and a 2-week history of watery nonbloody diarrhea. Through the examination of a bone marrow biopsy specimen, the patient was diagnosed with T-cell acute lymphocytic leukemia, for which induction chemotherapy was administered. Seven days later, the patient developed chills, which was followed by a febrile episode 2 days later. Blood cultures were obtained, which grew B. cereus bacteria. That night, the patient expired. Autopsy revealed bilateral hemorrhagic necrosis of the brain (Fig. 7), with numerous Gram-positive bacilli embedded in the necrotic areas (Fig. 2).
Central nervous system (CNS) invasion by B. cereus includes meningitis (83, 129), meningoencephalitis (96), subarachnoid hemorrhage (3, 50, 74), and brain abscesses (70, 114, 125) occurring in pediatric (51, 102a) and adult (114) patients generally in the setting of immunosuppression due to leukemia and other malignancies. In reviewing these various reports, CNS infections occur secondarily to B. cereus bacteremia or following induction chemotherapy (6, 51, 72, 74, 96). In a very dramatic presentation, two patients developed fulminant sepsis and massive intravascular hemolysis subsequent to induction chemotherapy. Both patients had abdominal symptoms prior to bacteremia (6).
The pathogenesis of B. cereus CNS infection in most cases is obscure, although several risk factors are worthy of consideration. A substantial number of patients developed necrotizing brain lesions following intrathecal induction chemotherapy (51, 72, 74, 96). Presumably, in addition to promoting neutropenia, this procedure could introduce ubiquitous B. cereus spores from a multitude of environmental sources and fomites (see “Nosocomial Infections”). Other routes of acquisition include bacteremia from a distal site and infected central venous catheters (51) and other catheters used for the periodic administration of remission induction chemotherapy.
In a series of 12 patients described by Gaur et al. (51) from whom B. cereus was isolated from blood cultures, 4 had leukemia and underwent a lumbar puncture with the intrathecal administration of chemotherapy in the week preceding CNS infection. The introduction of B. cereus into the CNS during this procedure is conceivable. Further support for the intrathecal route of acquisition of B. cereus is the absence of positive blood cultures for some patients who developed CNS infection following the intrathecal administration of chemotherapy.
Several authors have advanced the possibility of the gastrointestinal tract as a potential source of the B. cereus strain involved in CNS infections, as patients either presented with gastrointestinal symptoms (nausea, vomiting, epigastric pain, or diarrhea) suggestive of food poisoning prior to CNS involvement (3, 50, 51, 101) or developed gastrointestinal symptoms concomitant with CNS involvement (3, 96). The concept underscores the acquisition of B. cereus from an exogenous source, e.g., food and water, etc., with gastric invasion, mucosal necrosis, and spread to the liver and CNS via blood circulation (3, 50). Support for this premise can be acquired at autopsy, which may reveal liver involvement (abscesses and infarcts) (3, 50, 51, 96, 140). Furthermore, Gaur et al. (51) reported the recovery of B. cereus from rectal swabs of three of four patients with B. cereus bacteremia and meningitis within 72 h of hospital presentation. Similarly, Funada et al. (50) isolated B. cereus in surveillance stool cultures of a leukemic patient who developed fatal bacteremia with a clinical syndrome of acute gastroenteritis, meningoencephalitis with subarachnoid hemorrhage, and multiple liver abscesses and liver infarcts replete with B. cereus infiltration. In an unrelated survey, Ghosh (53) isolated B. cereus from 14% of healthy adults in the general population and from a similar percentage of laboratory workers. Excretion rates persisted for 2 weeks. Ghosh concluded that the colonization represented the intake of B. cereus in an individual's diet.
While the above-described speculations on B. cereus origins from the gastrointestinal tract are indeed intriguing, two separate reports by Girsch and colleagues (54) and Le Scanff et al. (85) may well have advanced these concepts. Girsch et al. (54) described a premature, cesarean-section-delivered infant who developed multiple small-bowel necrotic perforations and abdominal peritonitis 3 days postbirth. Culture of the abdominal cavity grew only B. cereus. These authors attributed the necrotic areas of the small intestine to B. cereus enterotoxins (91, 129). One may draw a parallel between the infant's gastrointestinal pathology and that of leukemic patients whose immune system is markedly compromised by chemotherapy and who may have acquired B. cereus intestinal colonization/infection due to chemotherapy-induced mucosal insult (85).
Le Scanff et al. (85) described a 37-year-old woman with acute myeloblastic anemia who developed sudden severe nonradiating epigastric pain accompanied by massive hematemesis 2 months after induction chemotherapy. Upper gastrointestinal endoscopy showed a narrowed gastric lumen with severely inflamed gastric mucosa with hemorrhagic, erosive, and necrotic areas extending from the corpus to the antral region. Gastric mucosa and blood culture grew only B. cereus. Histological examination of biopsy specimens revealed extensive necrosis and a large number of bacteria (bacilli) in the gastric mucosa. Those authors hypothesized that neutropenia, immunosuppressive treatment, and gastric mucosal injury due to chemotherapy may have facilitated B. cereus colonization of the gastric mucosa, leading to the onset of acute necrotizing gastritis. The source of B. cereus could have been food, swallowing respiratory secretions containing B. cereus colonizing the throat (31), or hematological spread, although in this case, it was not clear if bacteremia preceded gastric invasion or was a consequence of erosive gastric disease.
Two unusual cases of B. cereus meningitis were described by overlapping authors at the University Hospital of Leiden, in which 19-year-old and, 4 years later, 18-year-old leukemia patients developed B. cereus bacteremia and meningitis subsequent to chemotherapy-induced neutropenia. In the first instance (31), the 19-year-old patient who was being treated for active myelomonocytic leukemia under gnotobiotic conditions in a laminar-airflow isolation room was noted by throat culture to be colonized with B. cereus a week prior to the spread of the bacterium to the meninges, which resulted in the death of the patient within 48 h. Those authors stated that B. cereus contamination of the isolated decontaminated patient was not surprising since food fed to the patient “is allowed to contain a small quantity of it” (B. cereus). The authors' comment suggests that food for patients under gnotobiotic isolation is treated to reduce bacterial concentrations and is cultured prior to feeding of the patient. In this regard, the recovery of even a few colonies of B. cereus was regarded as harmless until the bacterium was “cultured from other than routine sites.”
The second case (60), involving the 18-year-old leukemic patient, was indeed tragic, as the patient, on his last day of treatment prior to being placed in protective isolation, was allowed to take a short walk on the hospital grounds. By accident, he fell, which resulted in a minor abrasion on his forearm, which was washed and cleansed and regarded as unimportant. Over a 2-day period, the patient became febrile and complained of malaise, and his arm was not swollen but tender, with a demarcated erythematous area above the wound. Gram staining of a serous exudate revealed “large Gram-positive rods thought to be Clostridium species because of his ‘street injury,’” and the patient was treated with penicillin. Concomitantly, but unrelated to his infection, his leukocyte count dropped. Despite additional broad-spectrum antibiotic therapy, blood and wound cultures grew B. cereus, and a computed-tomography scan revealed signs of a damaged blood-brain barrier potentially compatible with toxic encephalitis. Three days after the initial injury, the patient died due to respiratory arrest. In the first case, the isolation of B. cereus from a throat culture was not considered serious, while in the second case, the visualization of “large Gram-positive rods on smear of the wound exudate” was interpreted as a Clostridium species, and penicillin was administered to the patient, which the authors later realized was ineffective against the prodigious β-lactamase-producing B. cereus. In a scenario somewhat reminiscent of the case described above, Gröschel et al. (58) reported a case of a 35-year-old patient with a histocytic lymphoma in remission receiving chemotherapy who developed a fulminant gas gangrene-like infection of the hand. The hand infection developed a few hours after the patient hit his right hand with a wrench while working on his car. His white blood cell (WBC) count was 1,200 cells/mm3 at the time of the injury. Upon admission to the hospital, he was febrile, and his right hand was diffusely swollen with purplish discoloration of the fingers and the dorsal and palmar surfaces. On the dorsum, there were several bullae with serosanguinous drainage. Gram staining of the exudate showed Gram-positive rods (which later proved to be B. cereus) with no leukocytes. The patient was initially treated with penicillin for suspected Clostridium perfringens infection. Incision and drainage were undertaken, and when B. cereus was identified, penicillin was discontinued and lincomycin treatment was started, which resulted in clinical improvement. Nevertheless, because of extensive necrosis, the third, fourth, and fifth fingers were removed.
GAS GANGRENE-LIKE INFECTIONS
The second meningitis case described above introduces the capacity of B. cereus to produce a clinical syndrome resembling clostridial myonecrosis.
Johnson et al. (73) also presented a case of presumed clostridial myonecrosis in a 20-year-old marine who endured a crush injury to his left arm when he caught it between two train cars and sustained an incomplete amputation and a commuted fracture of the radius and ulna. Three days postsurgery, the patient appeared septic, and his left arm was notably increased in size, with slight crepitance and a brown watery fluid oozing from the wound. Gram staining of superficial tissue revealed numerous Gram-positive and Gram-variable rods without spores and a few WBCs, suggesting C. perfringens myonecrosis. The patient was taken to surgery, where an above-the-elbow open amputation was performed because of a deteriorating clinical condition. Penicillin was administered, and the patient was begun on a hyperbaric-oxygen protocol for presumed C. perfringens- induced gangrene. When cultures grew B. cereus, antimicrobial therapy was changed, and the hyperbaric protocol was discontinued. An analogous case was described by Sada et al. (113), that of a diabetic patient with alcoholic hepatopathy who developed B. cereus fasciitis and myonecrosis. The patient was initially treated with penicillin on the basis of the presence of Gram-positive bacilli in smears of the lesion. After extensive debridement twice, on the third hospital day, a culture of the lesion grew B. cereus (“despite the initial expectation”), which prompted an immediate switch from penicillin to vancomycin, with gradual improvement. The patient was discharged on the 94th hospital day after several debridement and skin graft operations. Perhaps, the takeaway lesson here is that one should render antibiotic coverage that would include activity against B. cereus (e.g., vancomycin, clindamycin, and gentamicin) as well as against Clostridium species until the identification of the Gram-positive bacillus is achieved. To further stress the necessity for an early differentiation of the two bacillary species, Darbar et al. (35) described a gas gangrene-like necrotizing infection due to B. cereus in an 8-year-old boy after a small tree branch pierced the child's left leg. Blistering developed above the wound, and crepitus was detected. The potential for B. cereus to mimic clostridial myonecrosis or even streptococcal necrotizing fasciitis should be considered when a patient presents with either of these suspected soft-tissue infections. The mimicry of B. cereus myonecrosis compared to that caused by C. perfringens may in part be attributed to phospholipase activity, which in C. perfringens accounts for increased capillary permeability, platelet aggregation, hemolysis, and myonecrosis (48), all attributes described for B. cereus-induced myonecrosis (58).
In reviewing B. cereus gas gangrene-like infections, I was troubled by the fact that B. cereus, in contrast to C. perfringens (which ferments carbohydrates in muscle tissue and produces gases, CO2 and H2 [93]), is anaerogenic with regard to fermentable carbohydrates (89; my unpublished data). This troubling dilemma, however, may have been solved by an intensive literature search, which uncovered a reported Fitzpatrick et al. (47), which also included P. C. B. Turnbull, a renowned expert on microorganisms of the family Bacillaceae, especially B. cereus, as an author (129, 130, 131, 132). In this report of two gas gangrene-like infections due to B. cereus from 1979, those authors also recognized that B. cereus “does not produce gas to any obvious extent in routine laboratory tests.” The authors offered, however, “that the production of gas during anaerobic reduction of nitrate is a characteristic of B. cereus.” It was suspected that the gas was nitrogen, and I undertook another search under the definition of denitrification, which rendered the following finding: the formation of the gases nitrogen and/or other oxides of nitrogen from nitrate to nitrite by certain bacteria during anaerobic respiration. Denitrification occurs only under anaerobic or microaerophilic conditions, when there is a sufficient amount of organic carbons to support the reaction. From personal experience, this concept may be relevant, as mixed B. cereus and C. perfringens infection may occur following traumatic accidents involving soil and water contamination. A review by Bessman and Wagner (19) described 48 cases of nonclostridial “gas infection” in diabetic patients with or without gangrene caused by members of the family Enterobacteriaceae alone or in combination with anaerobes (Bacteroides fragilis) and Enterococcus species. There again, those authors stressed that rapid diagnosis is critical since appropriate antibiotic therapy and surgery can result in low mortality rates.
DIFFERENTIATION OF B. CEREUS FROM C. PERFRINGENS
Case Vignette
Several years ago a 21-year-old patient was transferred to the Mount Sinai Hospital (New York, NY) with a diagnosis of gas gangrene subsequent to an automobile accident in which he was trapped under his vehicle in a body of muddy water. Gram-stained smears of the involved leg revealed Gram-positive rods (Fig. 8), which grew beta-hemolytic colonies aerobically and anaerobically upon culture and when isolated and identified proved to be those of B. cereus and C. perfringens. As the patient's course did not improve despite hyperbaric therapy and antibiotic treatment, he was taken to the operating room for disarticulation of the infected leg. Prior to surgery, however, the surgeons submitted a piece of necrotic tissue to determine if “Clostridium perfringens was still present in the wound.” A Gram stain smear of a touch imprint of the tissue specimen showed Gram-positive bacilli. In view of the presence of two morphologically similar bacilli in the original smears and cultures, the issue of answering the surgeon's question was daunting. To differentiate between the two bacillary forms, an India ink preparation (as outlined in the legend of Fig. 9) was performed, which revealed the presence of encapsulated bacilli consistent with C. perfringens. This information was relayed to the surgeons awaiting a response in the operating room, who then undertook their surgical procedure. The following day, a culture of the necrotic tissue grew only C. perfringens. A rapid differentiation between B. cereus gangrene-like myonecrosis from C. perfringens myonecrosis can be achieved initially by performing an India ink test directly with a tissue sample from the wound. The absence of capsules suggests infection with B. cereus or perhaps a non-C. perfringens clostridial species, which nevertheless should indicate antibiotic coverage for B. cereus while awaiting culture results.
CUTANEOUS INFECTIONS DUE TO TRAUMA
For patients who suffer bodily trauma, whether by penetrating objects or as a consequence of burns or motor vehicle-related trauma, infection remains a leading cause of death. Depending upon the environment in which the trauma takes place, e.g., fresh or salt water or soil, recognized microbial species such as Pseudomonas aeruginosa or Aeromonas or Vibrio species predominate (107), whereas Bacillus species isolated from trauma-induced wounds, whether water related or not, are usually regarded as contaminants and basically ignored until a more dramatic complication such as, for example, sepsis or necrotizing fasciitis occurs and is attributed to the bacillary species. In recent years, however, the recognition of B. cereus as a major pathogen infecting individuals who sustain traumatic injuries is being well documented (2, 22, 42, 81, 107). Because of the wide environmental distribution of B. cereus spores, especially in soil, they can easily disseminate through dust, water, and food. A consequence of this widespread dispersion is open-wound infections, whether postsurgical (2) or posttraumatic, e.g., gun shot wounds (81), injection drug abuse (22), ground-contracted open-wound fractures (138), and severe war wounds (65), which may occur in both immunocompetent and immunosuppressed individuals, while infections resulting from hematogenous dissemination are more likely to occur in the setting of immunosuppression. Risk factors for these cases include mainly articulation with soil and water in addition to contaminated medicinals such as insulin (100) and heroin (22) in the setting of drug abuse among other injection-administered medicinals. Wound contamination with B. cereus can take place at the time of initial trauma due to the ubiquitous presence of B. cereus spores in the environment. Alternatively, the capacity of B. cereus spores to persist in plaster-impregnated gauze (112), incontinence pads, and hospital linen (11, 12) as well as in many antiseptics such as chlorhexidine, povodone iodine, and alcohol (42, 69) facilitates this bacterium's capacity to function as a secondary nosocomial invader of sites of traumatic injury (Table 1).
PRIMARY CUTANEOUS INFECTIONS
From the data reviewed above, it is apparent that B. cereus infections predominate in immunosuppressed patients, while primary cutaneous infections may occur in both immunosuppressed (58, 63, 76) and nonimmunosuppressed individuals, with the latter usually being associated with traumatic incidents (2, 22, 42, 65).
In a review of culture reports for children with neutropenic cancer treated at St. Jude Children's Research Hospital from 1983 to 1988, Henrickson et al. (62) reported 10 cases of B. cereus primary cutaneous infections in the absence of positive blood culture results. The lesions, which developed mainly on the extremities, e.g., finger, toe, and limb, were initially vesicular and then became purulent with rapidly spreading cellulitis. In no instance did the affected patients have signs of or history of injury to the skin. The review revealed that all 10 infections occurred during the spring and summer months, drawing an analogy to B. anthracis cutaneous infections of children in the Gambia (West Africa), which have a predominance in the dry (November to May) season and persist through the rainy months of June, July, and August (66). B. anthracis spores survive in uncultivated soil and at ambient temperatures above 15°C, similar to conditions of the lower Mississippi valley. Those authors then speculated that B. cereus spores, which are widespread in soil, may be common in the hospital (Memphis, TN) environment. Spores of B. cereus may enter the skin of hands and feet, which are often in contact with the environment through microscopic skin abrasions (Fig. 10), as do spores of B. anthracis (63, 66). Clinically, the evolving skin lesions of B. anthracis infection start with a papule, which becomes serous or serosanguinous and develops a black eschar that is similar to some of the B. cereus skin lesions described by Henrickson et al. (62). The elaboration of the various B. cereus exotoxins, including dermonecrotic toxin, may well account for eschar production in B. cereus cutaneous infections (13).
On the heels of the publication by Henrickson was a report by Dryden and Kramer (41), who described primary cutaneous infections among 21 healthy individuals, 18 to 27 years of age, undertaking an expedition in a remote rain forest in Costa Rica, Central America. Infections developed almost exclusively on the extremities following multiple lacerations from injury by rocks, thorns, machetes, and mosquito and tick bites and one following an attack by a wild peccary (pugnacious hog-like ungulate). Of 36 wound specimens cultured, B. cereus was isolated from 30 cultures, 24 of which resulted in heavy growth. Altogether, 14 of 18 expedition members developed B. cereus infections, while the remaining 3 patients developed Streptococcus pyogenes cutaneous infections. B. cereus was also recovered from 15 nose swabs and five throat swabs, which is most likely due to the fact that “expedition members were continuously covered in dust and dirt throughout the 6 weeks in the jungle.” Sixteen of the strains were prodigious producers of one or more exotoxins having necrotic activity, a finding correlating with the clinical presentation of pyoderma with surrounding cellulitis.
ENDOCARDITIS
The rarity of a B. cereus infection of the heart of a drug addict was documented in an almost obscure letter by Craig et al. (34), who vividly penned the course of endocarditis in an 18-year-old girl who was a heroin addict and had an atrial septal defect. Upon admission, numerous needle tracks were present, but no petechiae or retinal hemorrhage was apparent. Because of abnormal cardiac sounds and elevated leukocyte counts, blood cultures were drawn upon admission, and during the next 4 days, all of them grew B. cereus. Those authors suspected that tricuspid-valve endocarditis was induced during self-administration of drugs. Despite some early setbacks with inappropriate antibiotic treatment, e.g., penicillin, the patient responded well to intravenous clindamycin. Later studies of bacteremia in drug addicts incriminated heroin and contaminated injection paraphernalia (84, 127, 137) as risk factors in addition to cardiac anomalies.
Since that early description, B. cereus endocarditis in drug addicts and in patients with an intravascular device has been well recognized. In a review of B. cereus by Steen et al. (123), they noted that the rates of morbidity and mortality associated with B. cereus endocarditis were high among patients with valvular heart disease (20, 29, 105, 121). In the course of their review, those authors noted that 10 cases of endocarditis had been previously reported: 6 were drug addicts (including that reported by Craig et al.), 1 had a pacemaker, and the remaining cases had valvular disease. Since that review was published, several more case reports of B. cereus endocarditis in the setting of patients with pacemakers (1, 121), two cases of infection of a prosthetic mitral valve (20, 29), and two cases under remarkable circumstances (32, 126) have surfaced. The first case (126) was that of a 12-month-old girl with no past medical history who presented with bloody diarrhea attributable to ulcerative colitis that was later complicated by B. cereus endocarditis and cerebral infarctions (not necessarily related to endocarditis). In this instance, there were two factors that may have contributed to B. cereus sepsis and endocarditis. Initially, colonic endoscopy and biopsy specimens showed a swollen reddened mucosa with multiple erosions and a prodigious infiltration of inflammatory cells and microabscesses in the crypts. Although the presence of microorganisms was not commented upon in that report, invasion of B. cereus through the disrupted mucosa could have taken place, with food as the source of the bacterium. The second risk factor was the administration of betamethasone suppositories, which was followed by high fever and marked leukocytosis.
The second case, reported by Cone et al. (32), is noteworthy in that it possessed many of the above-described issues associated with B. cereus infections in immunosuppressed individuals. The patient was a 38-year-old male farm worker (risk 1) with relapsing acute lymphoblastic leukemia (risk 2) who developed spontaneously an ulcerating ulcer on his anterior thigh, which was surrounded by a nontender area of erythema from which B. cereus was isolated concomitant with a positive blood culture. After 2 weeks of intravenous therapy (penicillin and vancomycin) and, later, therapy with gatifloxacin orally, the patient received chemotherapy (risk 3), which a day later led to neutropenic B. cereus bacteremia. The patient expired 3 days later. At autopsy, the patient was found to have acute mitral-valve endocarditis and bilateral brain abscesses. Because the development of his cutaneous lesion was followed by sepsis, those authors likened his infection to that of B. anthracis.
With the exception of intravenous drug abuse-associated B. cereus endocarditis, the source of the microorganism in many cases is somewhat occult. In patients with an inserted pacemaker or prosthetic valve in place, one may speculate that asymptomatic B. cereus bacteremia could induce endocarditis. Alternatively, the repeated use of a venipuncture site for heparin injections could be the venue for introducing B. cereus into the bloodstream. In one instance the site was reported to be swollen and tender, which was attributable to the development of thrombophlebitis (29). Other possibilities include B. cereus invasion of the gastrointestinal tract under appropriate conditions, as outlined above, and, through hematological spread, colonization of a susceptible cardiac valve.
OSTEOMYELITIS
Bone infections by B. cereus are somewhat rare, and as of 1994, only nine cases were uncovered by Schricker et al. (117) in their review of this topic. Most of the cases were not reported individually but, rather, were included as part of reviews of the spectrum of B. cereus infections (45, 121, 128). B. cereus osteomyelitis in these patients was associated with intravenous drug addiction and surgical trauma, in addition to two individuals not included in the review who had sustained motor vehicle trauma prior to developing B. cereus osteomyelitis (138). Infections were either monobacterial or mixed with another copathogen, e.g., Staphylococcus aureus (117). In no instance was a case of B. cereus osteomyelitis documented in the absence of one or more of the above-described risk factors, e.g., in addition to alcohol abuse or sickle cell-thalassemia disease (122).
URINARY TRACT INFECTIONS
A PubMed search of the literature revealed one documented case of B. cereus urinary tract infection in a 71-year-old woman with invasive bladder cancer (115). The patient underwent radical cystectomy and percutaneous left ureterostomy, after which an indwelling urethral catheter was placed, along with treatment with cephalosporin and other antibiotics. Five weeks postoperatively, she presented with fever, shaking chills, and pyuria and was diagnosed with pyelonephritis of the left kidney. A urine culture grew B. cereus, which those authors suspected colonized the catheter and ascended into the urinary system through ureterostomy irrigation, which was performed several times daily. Among the virulence mechanisms of B. cereus pathogenesis, adherence to catheters via biofilm formation and motility could have easily accounted for the ascension of the bacterium into the urinary tract. Occult listings of B. cereus urinary tract infections have also cited instrumentation as a prelude to infection (128).
ANTIBIOTIC SUSCEPTIBILITY
The clinical spectrum of B. cereus infections is multifaceted, and therapeutic options usually revolve around the antibiotic susceptibility pattern of the isolated strain. In general, most B. cereus isolates are resistant to penicillins and cephalosporins as a consequence of β-lactamase production. In the setting of a suspected B. cereus infection, empirical therapy may be necessary while awaiting the antibiotic susceptibility testing profile. Resistance of B. cereus to erythromycin, tetracycline, and carbapenem has been reported (77, 116), which may complicate the selection of an empirical treatment choice. To address this issue, several investigators have undertaken in vitro susceptibility studies utilizing various methodologies to provide some guidance while awaiting isolate-specific susceptibility data.
An early study of 54 B. cereus strains isolated from blood cultures (15 judged significant [23 possibly significant]) conducted in 1988 by Weber et al. (136) showed that all strains tested by microdilution were susceptible to imipenem, vancomycin, chloramphenicol, gentamicin, and ciprofloxacin. Most strains were resistant to clindamycin, cefazolin, and cefotaxime. Many strains were susceptible to erythromycin and tetracycline. Using National Committee for Clinical Laboratory Standards (NCCLS) breakpoints for aerobic bacteria (103, 104), microdilution and disk diffusion susceptibility testing showed that data collected by disk diffusion correlated with microdilution results showing that all B. cereus isolates were resistant to penicillins (except mezlocillin), oxacillin, and cephalosporins. Clavulanic acid combined with ticarcillin did not lead to increased activity. Based on their data, those authors stated that “the drug of choice for B. cereus infections appears to be vancomycin” and that broad-spectrum cephalosporins and ticarcillin-clavulanate should be avoided in the empirical treatment of patients with suspected B. cereus infection.
With the advent of the Etest, in 2004, Turnbull et al. (132) reported their results for MICs of selected antibiotics against 67 B. cereus strains implicated in nongastrointestinal infections (21) and food poisoning (15) and from the environment (31). With this selection of isolates, those authors thought the results would give the greatest guidance for initial empirical therapy of B. cereus infections. For comparison, 15 of the B. cereus strains were also tested by using an agar dilution method. An analysis of the results for the different categories of B. cereus isolates did not reveal any group trends. From the authors' data, and quoting many case reports of B. cereus infections, they concluded that resistance to penicillin, ampicillin, cephalosporins, and trimethoprim is constant, while susceptibility to clindamycin, erythromycin, chloramphenicol, vancomycin, the aminoglycosides, and tetracycline is usually observed. Susceptibility to ciprofloxacin was uniform, and it has been shown to be highly effective in the treatment of B. cereus wound infections (132).
Luna et al. (90) tested 42 B. cereus isolates by Sensititre and Etest methods and reported results similar to those reported above (132, 136). In the final analysis in each of the reported studies, small populations of B. cereus isolates showed resistance to clindamycin, erythromycin, and trimethoprim-sulfamethoxazole. Regarding newer antibiotics, Luna et al. (90) extended their spectrum of therapeutic/prophylactic antimicrobials, which included gatifloxacin, levofloxacin, moxifloxacin, rifampin, daptomycin, and linezolid, to which all 42 isolates were 100% susceptible.
CONCLUSIONS
There is no conclusion to the saga of human infections due to B. cereus. Despite their supposed “rare occurrence,” the recognition of this seemingly stealth, environmentally pervasive bacterium coexisting with human flora is indeed a “Tale of Two Cities.” On the one hand, the bacterium has evolved a panoply of virulence-related attributes such as adhesins and toxins that enable its entry and survival within the human host and, under appropriate circumstances, enable it to breach barriers to produce disease in various anatomical compartments.
The major hurdle in evaluating its presence when isolated from a clinical specimen is overcoming its nagging stigmata as an “insignificant contaminant,” which is still in vogue despite a globally ongoing documentation of extraintestinal infections.
Indeed, outside the notoriety of B. cereus in association with food poisoning and eye infection, recognition and appreciation for the multitude of other serious infections such as fulminant sepsis and devastating central nervous system infections are lacking. The suspicion of the association of B. cereus with these mounting infectious complications moves with a fatal lethargy in its recognition as a bona fide human pathogen. Clinicians and clinical microbiologists must both give serious consideration to the significance of a B. cereus isolate from a clinical specimen, especially if the patient is immunosuppressed.
B. cereus, by virtue of its extensive exoenzyme armamentarium, is centrally situated between B. anthracis and, although anaerobic, C. perfringens, forming a formidable link enjoining these spore-forming bacterial species. B. cereus can acquire and harbor B. anthracis genes producing anthrax-like pulmonary infections and, through its exoenzyme profile, some of which overlaps with that of C. perfringens, causing gas gangrene-like cutaneous infections.
While B. cereus engenders clinical presentations that coincide with those of its close bacterial relatives, its extraintestinal spectrum of human infections, as noted herein, exceeds those attributed to the two more-renowned bacterial species. One can envision B. cereus as a biblical Sampson, arms spread between two pillars, embracing rather than undoing a common bond! Perhaps, by the time a new review of B. cereus is penned, the bacterium would have acquired its acceptance as a volatile human pathogen, quiescent in nature yet a formidable human adversary!
FIG. 1.
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FIG. 3.
FIG. 4.
FIG. 5.
FIG. 6.
FIG. 7.
FIG. 8.
FIG. 9.
FIG. 10.
TABLE 1.
| Yr | Reference(s) | No. of patients | Infection risk factor(s) | Source(s) of infection | Outcome |
|---|---|---|---|---|---|
| 1993 | 23 | 16 ventilated patients in medical/surgical ICU | Ventilation/ICU, bacteremia, pneumonia | Ventilation equipment | 1 died |
| 1994 | 10, 11 | 2 | Meningitis postneurosurgery | Contaminated hospital linen in OR | Expired |
| 2000 | 134 | 3 neonates | Bacteremia, meningitis, preterm (neonates immunosuppressed) | Balloons used in manual ventilation, hands of nursing staff | 1 died |
| 2000-2005 | 38 | 16, 5 studied in detail | Bacteremia, cecal cancer, esophageal cancer, chronic kidney failure, cholangitis, ALL | Catheters, reused dried and steamed towels, washing machines in hospital linen rooms | 5 case vignettes presented; antibiotics administered, outcomes not given |
| 2003 | 64 | 1 | Bacteremia cholecystectomy | Nutrition via central catheter | Survived |
| 2004 | 44 | 1 (ALL) | Bacteremia (ALL) | Contaminated tea bags | Not given, survived(?) |
| 2006 | 106 | 3 (AML) | Bacteremia (AML), pneumonia (AML), bacteremia (AML), pneumonia (AML), septicemia (AML) | Nonsterile cotton wool used for skin disinfection | Died (ventilation-associated pneumonia) |
| 2009 | 82 | 18 | Bacteremia, malignancy, COPD, CVA | Gauze, catheter tip, hospital environment, steamed towel, and alcoholic cotton pot | Not given |
a
ICU, intensive care unit; ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; CVA, cardiovascular accident; COPD, chronic obstructive pulmonary disease.
Acknowledgments
I extend my sincere gratitude to Dipankar Jyoti Dutta, James Viskochil, and Christopher Marro for their computer expertise in assisting me with the formatting of the manuscript.
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Author Bios
Edward J. Bottone, Ph.D., was born and raised in East Harlem in New York City. He received his B.S. degree in biology from the City College of New York, his master's degree in public health and bacteriology from Wagner College, Staten Island, NY, and his Ph.D. from St. John's University, Queens, NY. Dr. Bottone's career in microbiology began when he was drafted into the U.S. Army in 1957 and was sent to Fort Sam Houston in San Antonio, TX, where he was selected to attend the Army Medical Service School course in Medical Technology. Upon completion of his training as a medical technologist, Dr. Bottone was assigned to the 34th General Hospital in La Chapelle, France, where he was assigned to the Bacteriology Section of the laboratory. Upon completion of his Army tour in 1959, he joined the microbiology staff of the Mount Sinai Hospital in New York City, where, over a course of 16 years, he rose from the status of a Junior Technician to Director of the Microbiology Department en route to earning his bachelor's, master's, and doctoral degrees as a part-time evening student. Dr. Bottone's career has been highlighted by receiving several of Mount Sinai's most prestigious awards in addition to earning his American Board of Medical Microbiology (ABMM) certification and diplomate status of the ABMM. He was honored for Distinguished Achievements in Clinical Microbiology by the American Society for Microbiology, New York City Branch (1995), and was the recipient of the bioMerieux-Vitek Sonnenwirth Memorial Award by the American Society for Microbiology (1996) and the Professional Recognition Award by the American Academy of Microbiology (2002). Presently, Dr. Bottone is Professor Emeritus of Medicine/Infectious Disease, Mount Sinai School of Medicine, and Professor of Medicine (Infectious Diseases), New York Medical College, Valhalla, NY.Information & Contributors
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Published online: 1 April 2010
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Bacillus cereus, a Volatile Human Pathogen. Clin Microbiol Rev
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