Drotrecogin alfa (activated) for nonmenstrual toxic shock syndrome associated with methicillin resistant Staphylococcus aureus infection.

Abstract: Nonmenstrual toxic shock syndrome (TSS) due to Staphylococcus aureus can lead to significant morbidity and mortality. While drotrecogin alfa (DA) has been employed in patients with Methicillin-resistant Staphylococcus aureus (MRSA) severe sepsis and septic shock, its utility in TSS remains unclear. The authors report a case of severe sepsis in the setting of MRSA-associated TSS that responded to treatment with DA. This case illustrates a potential role for DA in the treatment of toxic shock syndromes and emphasizes the importance of aggressive diagnostic and therapeutic modalities in approaching these conditions.

Key Words: toxin, treatment, Methicillin resistant Staphylococcus aureus, sepsis

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Drotrecogin alfa (DA) has been approved for use in patients with severe sepsis, (1,2) but its utility in the setting of toxic shock syndrome remains unclear. We report the successful use of DA in the treatment of multiorgan failure syndrome related to a nonmenstrual toxic shock syndrome (TSS) associated with a surgical mesh infection.

Case Report

A 51-year-old morbidly obese, diabetic female underwent herniorrhaphy employing a mesh graft. She was discharged on the third postoperative day. At the postoperative clinic visit on day 8, the surgical site incision was noted to have erythema around the edges. The patient received two weeks of oral ciprofloxacin, but evaluation on postoperative day 15 revealed persistent, clear drainage from the wound site. A wound culture was reported as negative. She was continued on ciprofloxacin for two more weeks. On postoperative day 45, she was noted to have edema and induration around the incision edges. Ultrasound revealed a seroma and she underwent debridement and fine needle aspiration of this seroma. Repeat wound culture was negative. She was given levofloxacin for a two week course along with vacuum-assisted closure (VAC) therapy at home. Three weeks later, she was admitted with severe sepsis of unclear etiology. At the time of presentation, her wound and mesh showed no apparent signs of infection and she had no rash. Antibiotics were begun empirically with imipenem, vancomycin, clindamycin, diflucan and Flagyl. Within 12 hours, the patient became hypotensive with a fever of 103[degrees]F, a low urine output, and an elevated white cell count of 11,000 with significant ban-demia. She required mechanical ventilation and treatment with multiple pressors at maximum doses to maintain hemodynamic stability. Drotrecogin alfa was started at a dose of 24 [micro]g/kg/h and was continued for two days, at which point a worsening coagulopathy (INR to 3.9, PTT to 143, and a drop in platelet count to 60,000) necessitated cessation of the drug. The patient remained on low-dose pressors and ventilatory support, and on hospital day 10, hemofiltration was initiated due to gradually worsening renal function that was attributed to her previous hypotension and sepsis. On day 10, she developed erythroderma with blistering on her anterior chest, upper abdominal wall and thighs. Wound microbiology revealed MRSA sensitive only to trimethoprim-sulfa-methoxazole, tetracyclines, rifampin and vancomycin, consistent with a hospital-acquired strain. The patient had no history of prior MRSA infection or colonization. There were no other obvious sources of infection except for the abdominal wound, creating a strong suspicion for a mesh-related staphylococcal infection. Mesh removal, however, was not carried out at this time based on the benign appearance of the wound. Over the next several days, the patient remained ventilated on low-dose pressors and broad spectrum antibiotics. Ultrasound of the indurated area over her surgical site revealed a fluid collection in the abdominal wall. However, abdominal CT scan did not show any definitive abscess collection. On day 18, an attempt was made to taper antibiotics, but the fever returned, accompanied by a worsening leukocytosis up to 34,000 cells/mm. (3)

On day 20, the toxic shock syndrome toxin assay (TSST) was reported positive for toxin B, and the mesh was removed. There was no apparent infection of the mesh, but within 24 hours following removal, her blood pressure and tachycardia improved, and she was completely weaned off ventilation and pressors. During this period, she again developed a generalized rash over her body which spontaneously resolved 48 hours later. Culture of the mesh revealed only MRSA with the same susceptibility panel as previous isolates. Her multiorgan failure completely resolved.

Discussion

This patient met the Centers for Disease Control criteria for TSS. (3,4) Nonmenstrual TSS strains are associated with the production of TSST-1 in only 50% of cases, and with enterotoxin B and C production in the residual 50% of cases. (5) Forty percent, however, are associated with characteristically benign-appearing wounds following a variety of surgical procedures. (6) This patient developed nonmenstrual TSS caused by MRSA (7) that colonized a wound and produced enterotoxin B. (8) Surgical removal of the mesh and wound debridement was successful in curing the patient. Of interest is the occurrence of a rash just shortly after surgical removal of the mesh graft, without significant hemodynamic compromise. We believe this rash was related to the release of enterotoxin B during surgical manipulation. Failure to manifest TSS in its full form might have been aborted by the patient's ability to produce antibodies to enterotoxin B, which was confirmed by detecting antibodies in her serum at the time the mesh was removed. (8,9)

There are no data on the use of DA in patients documented to have TSS. Data obtained from Eli Lilly from the PROWESS trial suggests that seven patients were reported to have "possible toxic shock syndrome" (in the comments section of their individual case report forms.) However, the size of the sample was too small to assess the potential use of DA in treatment of TSS (personal communication, Eli Lilly).

DA was used for a total of 48 hours in this patient, whose death appeared imminent in the setting of multiorgan failure. We believe that DA interrupted the iterative cycle of sepsis that was induced by staphylococcal toxin(s). This response, although short of being complete, may have provided a bridge until antimicrobials could suppress her infection and further diagnostic and therapeutic measures could be initiated. Complete resolution of her syndrome, however, absolutely required mesh removal.

Conclusion

The role of drotrecogin alfa in the treatment of toxic shock syndrome remains unclear. This case, however, emphasizes a potential role for DA in treating TSS and underscores the importance of aggressive diagnostic and therapeutic interventions in patients with these syndromes. The specific role of DA in the treatment of TSS needs further evaluation.

References

1. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699-709.

2. McCoy C, Matthews SJ. Drotrecogin alfa (recombinant human activated protein C) for the treatment of severe sepsis. Clin Ther 2003;25:396-421.

3. Reingold AL, Hargrett NT, Shands KN, et al. Toxic shock syndrome surveillance in the United States, 1980 to 1981. Ann Intern Med 1982;96:875-880.

4. Calandra T, Cohen J. The international sepsis forum consensus conference on definitions of infection in the intensive care unit. Crit Care Med 2005;33:1538-1548.

5. Czachor J, Herchline T. Bacteremic nonmenstrual staphylococcal toxic shock syndrome associated with enterotoxins A and C. Clin Infect Dis 2001;32:E53-E56.

6. Kain KC, Schulzer M, Chow AW. Clinical spectrum of nonmenstrual toxic shock syndrome (TSS): comparison with menstrual TSS by multivariate discriminant analyses. Clin Infect Dis 1993:16:100-106.

7. Sista RR, Oda G, Barr J. Methicillin-resistant Staphylococcus aureus infections in ICU patients. Anesthesiol Clin North America 2004;22:405-435, vi.

8. Durand G, Bes M, Meugnier H, et al. Detection of new methicillin-resistant Staphylococcus aureus clones containing the toxic shock syndrome toxin 1 gene responsible for hospital- and community-acquired infections in France. J Clin Microbiol 2006;44:847-853.

9. Kanclerski K, Soderquist B, Kjellgren M, et al. Serum antibody response to Staphylococcus aureus enterotoxins and TSST-1 in patients with septicaemia. J Med Microbiol 1996;44:171-177.

Dafer W. Haddadin, MD, Imran Q. Samnani, MD, and Jonathan P. Moorman, MD, PhD

From Department of Internal Medicine, Division of Infectious Diseases, East Tennessee State University, Johnson City, TN, and Medical Service, James H. Quillen VAMC, Mountain Home, TN.

Reprint requests to Dafer Haddadin, MD, FACP, Department of Internal Medicine, James H. Quillen COM, East Tennessee State University, Box 70622, Johnson City, TN 37614. Email: [e-mail]

Accepted April 11, 2006.

RELATED ARTICLE: Key Points

* Drotrecogin alfa may have a role in treating toxic shock syndrome.

* The underlying infections leading to toxic shock may be clinically difficult to diagnose.

* Aggressive diagnostic and therapeutic measures are often needed in the setting of nonmenstrual toxic shock syndrome.