Use of recombinant human activated protein C in nonmenstrual staphylococcal toxic shock syndrome

shock syndrome (TSS) is a serious, potentially life-threatening condition resulting from an overwhelming immunological response to an exotoxin released by Staphylococcus aureus and group A streptococci. High index of suspicion, early diagnosis and aggressive therapeutic measures must be instituted in view of high mortality of the TSS. In recent years, new agents have been tested to reduce morbidity and mortality in patients with severe sepsis, in addition to standard supportive measures. Among them, recombinant human activated protein C (rhAPC) has been reported to signi ﬁ cantly reduce mortality and morbidity in patients with severe sepsis and two or more acute organ failures. We describe our experience with this drug in the early reversal of septic shock from TSS.


Introduction
Toxic shock syndrome (TSS) is known for its rapid, dramatic and fulminant onset and can lead to signifi cant morbidity and mortality. Quick recognition of the syndrome is important for enabling appropriate and prompt treatment. The authors report a case of severe sepsis in the setting of TSS that responded to treatment with recombinant human activated protein C (rhAPC).

Case Report
A 27-year-old male, with no signifi cant past history, had painful furuncle in the right axillary region. This was associated with moderate to high-grade fever. He underwent aspiration of the abscess on fourth day of his illness at a private clinic. After the aspiration, he had a sudden and transient (for 1 min) loss of consciousness, which was attributed to a vasovagal attack. This was followed by repeated episodes of vomiting. He was then brought to Indraprastha Apollo hospital, New Delhi, for management.
On admission, he was found to be febrile (temperature 38.4°C), having a diffuse macular erythematous rash, and slight confusion without any focal neurological signs (GCS-14/15). His heart rate was 122/min and BP was 78/30 mm of Hg. He seemed clinically dehydrated and was given fl uid challenge of 1 l NS, due to which his BP increased to 98/46 mm of Hg. On local examination, there was a 1-cm diameter, circular, non-tense blister at the right axilla.
A clinical diagnosis of TSS was made and empirical antibiotic therapy, with specific cover against Staphylococcus aureus, was prescribed using vancomycin 1 g i.v. 12 hourly, ceftrioxone 2 g i.v. 12 hourly, and clindamycin 600 mg i.v. 8 hourly after taking two sets of peripheral blood cultures, urine culture and fl uid from the blister. He was already on amoxycillin and clavulanic acid, which were started outside the hospital. His condition continued to deteriorate and he had increasing vasopressor requirement and worsening of leukocyte counts. His computed tomography (CT) scan of head was normal, CT of neck showed enlarged bilateral cervical lymph nodes which were not clinically palpable, CT of chest showed minimal bilateral pleural effusion, and CT of abdomen showed mild ascites. Rickettsial serology was performed which turned out to be negative.
On Day 2 of his admission, we decided to use a 96hour infusion of rhAPC at a rate of 24 μg/kg/hour, in view of worsening multiorgan failure. Fluid from the blister came positive for Sta. aureus, which is sensitive to vancomycin and resistant to cloxacillin. Other cultures including blood and urine were negative. His antibiotics were de-escalated and ceftriaxone was stopped. During the next 96 hours, there was improvement in his organ failure with vasopressors weaned off, and APACHE II and SOFA scores decreased to 8 and 4, respectively [Tables 1 and 2]. He was extubated on Day 6 of admission and transferred out of ICU on Day 7.

Discussion
TSS can be classifi ed on microbiological basis into Staphylococcus aureus TSS, Streptococcus pyogenes (group A streptococcus) TSS. Staphylococcal TSS was first described by Dr. James K. Todd in 1978. [2] Currently, there are two well-recognized forms of staphylococcal TSS: menstrual and nonmenstrual TSS. Over 90% of menstrual TSS and 60% non-menstrual TSS is associated with a Sta. aureus toxic shock syndrome toxin-1 (TSST-1). [3] The mechanism of shock and tissue destruction in TSS is infection by certain strains of Sta. aureus and group A streptococci, followed by the production of one or more toxins. These toxins are then absorbed systemically and produce the systemic manifestations of TSS with mediators such as interleukin 1 (IL-1) and tumor necrosis factor (TNF).  reported. [8][9][10][11] This is the fi rst case report from the Indian subcontinent.

The Centre for Disease Control and Prevention has
In our report, the vasoactive agents were rapidly weaned following use of rhAPC and the patient had a remarkable recovery with APACHE II score of 8 on its completion. Apart from its evident effect on the coagulation system and the ability of rhAPC to correct the deranged coagulation system in severe sepsis, a series of pleiotropic modulating effects of APC on infl ammatory cytokines and cells as well as protective effects on disrupted endothelium have been reported. [12] Since the TSST-1 is a potent inducer of infl ammatory markers like IL-1 and TNF which interplay a pivotal role in the pathophysiology of TSS, rhAPC may have had an inhibitory effect on IL-1 levels in patient with TSS. [13] We did not measure IL-1 levels in this patient, and hence, could not observe the effect of rhAPC on IL-1. This response, although short of being complete, may have provided a bridge until antimicrobials could suppress his infection and further diagnostic and therapeutic measures could be initiated.
In conclusion, TSS is a diagnosis of exclusion. Aggressive diagnostic, therapeutic modalities and high clinical suspicion are required in approaching these conditions. The role of Drotrecogin alfa in TSS is still under investigation but could be an option in patients with high risk of death due to septic shock. described some diagnostic criteria for Sta. aureus TSS [ Table 3]. [4,5] They suggested that confi rmation of TSS requires all the major criteria listed, plus any three or more of the minor criteria. Our patient fulfi lled most of the criteria for TSS case defi nition proposed by the US Centre for Disease Control and Prevention. [4] The management of TSS should be aggressive and includes resuscitation and management bundles of severe sepsis and septic shock. [6] After taking adequate cultures from the wound site and blood, early appropriate antibiotics should be administered. Antibacterial agent selection is complex and subject to change as resistance patterns emerge. Initial empirical antibiotic regimen should include both staphylococcal TSS and streptococcal TSS as differentiating two of them on clinical grounds alone is diffi cult. Intravenous penicillin G should be administered in addition to a beta-lactamase resistant antibiotic until a bacteriologic diagnosis is confirmed by culture. Alternatively, a fi rst-generation cephalosporin with vancomycin can be used. For patients with group A streptococcal infection, the administration of clindamycin (600-900 mg i.v. q 8 hourly) is recommended because of its multiple effects like inhibiting M protein synthesis, synthesis of penicillin binding proteins, postantibiotic effect and suppression of lipopolysaccharide-induced monocyte synthesis of TNF. [7] Besides using appropriate antibiotics, early source control with debridement of infected/necrotic wounds should also be instituted.
After resuscitation as per Surviving Sepsis Campaign 2008, we could not stabilize the patient with multisystem organ failure, so the decision for rhAPC was then taken in view of septic shock, worsening organ dysfunction and high risk of death (APACHE II > 25). [1] Use of rhAPC as an adjuvant therapy in shock due to TSS has been Gastrointestinal (vomiting or diarrhea) Erythematous rash; skin desquamation, 1-2 weeks after onset of illness Central nervous system (disorientated or alterations in consciousness without focal neurological signs when fever and hypotension are absent) Hypotension (systolic<90mmHg) Mucus membrane hyperemia Muscular (severe myalgia or raised creatine kinase levels at least twice upper limit of normal) Hepatic (thrombocytopenia, liver function tests twice upper limit of normal) Renal impairment (urea or creatinine twice upper limit of normal)