A Case of Staphylococcus aureus Enterocolitis

First recognized almost 70 years ago,¹ enterocolitis due to Staphylococcus aureus has been described as both a complication of antibiotic therapy and as occurring in individuals with predisposing conditions but no previous antibiotic treatment. Sporadic cases and outbreaks have been reported in infants since the 1940s, with prematurity and low birth weight as the major predisposing factors. In adults and noninfant children, staphylococcal enterocolitis is usually associated with prior use of antimicrobials (particularly fluoroquinolones), recent abdominal surgery, prior proton pump inhibitor therapy, and immune-compromising conditions such as advanced age, immunosuppressive therapy, and HIV infection.

However, following the identification of Clostridium difficile and its toxins as the primary cause of pseudomembranous colitis in the 1970s, the role of S. aureus in antibiotic-associated colitis has been downplayed. As a result, awareness of staphylococcal enterocolitis has diminished in the medical community, to the extent that S. aureus is not universally considered to be a potential etiology of nosocomial diarrhea.² Consequently, stool culture may not be requested in cases of healthcare-associated diarrhea, even after C. difficile has been excluded. However, as demonstrated by the case reported by Thakkar and Agrawal,³ staphylococcal enterocolitis has not disappeared; thus, it appears likely that some cases are being misdiagnosed or undiagnosed.

How commonly does staphylococcal enterocolitis occur? Cases as severe as the one presented by Thakkar and Agrawal certainly are not common in clinical practice, but less severe forms of the disease could be missed, particularly if cultures are not obtained as part of the evaluation. Two studies have recently been published addressing this issue. Boyce and Havill compared the relative diagnostic yields of C. difficile toxin and toxin-producing S. aureus over 1 year using a rigorous definition of nosocomial diarrhea and standardized assays; the rates for both were similar and approximately 10%.⁴ In contrast, Asha and colleagues found C. difficile toxin to be 60 times more common than S. aureus on stool examination⁵; these authors also found genotypic evidence of case clustering and nosocomial transmission. These findings suggest that the relative frequency of C. difficile– and S. aureus–related colitis can be influenced by local factors such as infection prevention measures or antibiotic choice. An intriguing hypothesis is that temporal variations in the relative incidence of staphylococcal enterocolitis and C. difficile–associated disease can be linked to changes in antibiotic usage patterns.⁶ For example, lincomycin and clindamycin effectively inhibit S. aureus but have limited activity against C. difficile; the use of these antibiotics during the 1970s and early 1980s may have contributed to the apparent dominance of C. difficile–associated diarrhea. The more recent increased use of metronidazole, which has activity against C. difficile, but not against S. aureus, might be expected to lead to a reemergence of staphylococcal enterocolitis. Of note, Thakkar and Agrawal''s patient was treated with a fluoroquinolone and metronidazole and then developed toxic megacolon, with gram-positive cocci seen histologically. The relative frequency of staphylococcal enterocolitis may also be underestimated if response to empiric oral vancomycin is used to support a presumptive diagnosis of C. difficile–related disease, as vancomycin effectively treats colitis due to either S. aureus or C. difficile toxin.

Staphylococci produce a wide spectrum of gastrointestinal disease, ranging from food poisoning to enterocolitis. A hemorrhagic or dysentery-like presentation without prominent small-bowel involvement may resemble inflammatory bowel disease or even C. difficile toxin–associated colitis, in contrast to the toxigenic form, which is a classic secretory diarrhea, often with high stool volumes that may be multiple liters per day in an adult. Staphylococcal enterocolitis has also been implicated as a cause of toxic shock syndrome in a child⁷ and an adult.⁸

Disease pathogenesis is largely toxin-mediated. S. aureus strains can produce a wide variety of toxins, including the toxic shock toxin (TSST-1), staphylococcal enterotoxins, and the enterotoxin-like proteins that can function as superantigens, with both local and systemic effects.⁹ Several enterotoxins have been detected in strains associated with enterocolitis.⁴ These toxins are responsible for the observed elevations in C-reactive protein concentrations and erythrocyte sedimentation rates in patients with enterocolitis. Most of the genes for enterotoxin production are carried by plasmids, bacteriophages, or heterologous genetic elements referred to as pathogenicity islands,¹⁰ and different strains of S. aureus produce different combinations of toxins, which explains some of the diversity in disease presentation. Organism density can influence enterotoxin production through a quorumsensing system.¹¹

In the absence of tissue invasion, enterotoxins are produced in the lumen, whereas inflammatory cells are largely confined to the lamina propria, indicating that the toxins can pass through an intact membrane.¹² Some epithelial cells have been shown to display toxin receptors (eg, for TSST-1), but for the most part, the toxic effects of staphylococcal enterotoxins appear to be mediated, through their effects on T lymphocytes, particularly CD4+ T cells. The extent of the response is a consequence of the ability of staphylococcal enterotoxins to act as superantigens and activate lymphocytes to provoke cytokine secretion in the absence of normal control mechanisms. Superantigens bind to the T-cell receptor and to MHC class II molecules in a way that is independent of antigen specificity.¹³ In contrast to normal T-cell antigen stimulation, which involves around 1:10,000 CD4 T lymphocytes, staphylococcal superantigens may stimulate as many as 50% of the cells, resulting in a cytokine storm that affects intestinal structure and function. Differences in specific superantigen binding may account for some of the variability in disease severity observed during infection.

The necessary involvement of CD4 lymphocytes has been shown in animal studies. Treatment of immune-competent mice with intraperitoneal enterotoxin produced an enteropathy marked by reduced villus height and increased crypt depth, and these changes were not seen in similarly treated T-cell–deficient mice. However, repopulation with mixed lymphocytes or with CD4+cells restored the enteropathic response.¹⁴ In a similar experiment, intestinal fluid secretion was also shown to depend upon the presence of CD4+ lymphocytes both in vivo and in vitro.¹⁵ In vitro data suggest that diarrhea is the result of cytopathic effects, a direct effect of toxin on epithelial cell function or an indirect effect mediated by the release of cytokines.

The host mounts an immune response to S. aureus and its toxins. In mice, mucosal immunization with an attenuated staphylococcal enterotoxin was protective against lethal shock.¹⁶ Intestinal epithelial cells and intraepithelial lymphocytes also moderate the effects of staphylococcal infection. However, protection may not be complete; immunity to a single set of toxins may not be adequate if there is a change in the colonizing strain of S. aureus, for example, related to antibiotic use, entry into a hospital environment, or exposure to a new strain in the community. These points support the importance of interventions to decrease nosocomial disease transmission such as enhanced hand and environmental hygiene, identification of and contact isolation of carriers (eg, methicillin-resistant S. aureus), use of antibiotic stewardship, and education of staff.^17,18

In terms of treatment, vancomycin is the drug typically used in the treatment of infections, though the use of oral vancomycin to treat staphylococcal enterocolitis has not been studied specifically. Improved management of staphylococcal enterocolitis will depend upon greater awareness and recognition of its existence.