ANNALS OF SURGERYVol. 217, No. 2, 109-114C 1993 J. B. Lippincott Company

Streptococcal Toxic Shock-LikeSyndromeThe Importance of Surgical InterventionThomas F. Wood, M.D., Mark A. Potter, M.D., and Olga Jonasson, M.D.

From the Department of Surgery, The Ohio State University, Columbus, Ohio

Pyrogenic exotoxins A, B, and C produced by group A beta-hemolytic streptococci(Streptococcus pyogenes) may cause a syndrome characterized by fever, rash, desquamation,hypotension, and multi-organ-system dysfunction. This syndrome, the streptococcal toxicshock-like syndrome (TSLS), has a rapid and fulminant course closely resembling thestaphylococcal toxic shock syndrome (TSS) caused by the staphylococcal toxic shock syndrometoxin-1 (TSST-1). The recent recognition of this syndrome is thought to stem from the appearanceof more virulent strains of streptococci that have a greater tendency to produce potent exotoxinsthan prior strains. During the past 6 years, the authors have treated six patients with TSLS; threeof these patients have presented recently. The sites of streptococcal infection associated withthe development of the syndrome are frequently in soft tissue and skin. Early diagnosis,treatment with penicillin, and radical operative debridement are required.

Group A streptococcus, or Streptococcus pyogenes, isa pathogen responsible for a wide variety of infectiousdiseases as well as the delayed nonsuppurative sequelaeof acute rheumatic fever, acute streptococcal glomerulo-nephritis, and erythema nodosum. Group A streptococciare exquisitely sensitive to penicillin.Group A streptococci produce a variety of extracellu-

lar substances that have different antigenic and biologicactivities. These include the cytotoxins and hemolysinsstreptolysin 0 and S, as well as streptokinase. Strepto-coccal pyrogenic exotoxins (SPE) types A, B, and C, areresponsible for the fever and rash of scarlet fever, andeach has potent toxin properties that alter host defenseby increasing susceptibility to endotoxin shock, decreas-ing antibody response, inhibiting macrophage function,and activating lymphocytes.1 2 These exotoxins arehighly destructive to skin, muscle, and other soft tissue,and may cause a syndrome of fever, shock, a rash that

later desquamates, and multi-organ-system dysfunc-tion.3-25 The streptococcal toxic shock-like syn-drome has a rapid course and frequently fatal out-come.3'7,8,"2,"5,"7

Recent recognition of this syndrome appears to be re-lated to changing virulency of streptococcal infections.After several decades in which the severity of scarletfever and incidence of rheumatic fever and soft tissueinfections have decreased,26 there appears to be a reap-pearance and resurgence of exotoxin A-producingstrains with increased pathogenicity and virulency.2'27-29Although streptococcal TSLS is most often associatedwith exotoxin A-producing infections of soft tis-sues,3"15'28'29 the syndrome has also been reported in asso-ciation with exotoxin types B and C, and with strainsproducing combinations of the exotoxins.3'9"5"7'24'25'30'3'The toxic shock syndrome caused by Staphylococcus

aureus, first described in 1978,32 affects multiple systemsand is characterized by rapid onset of fever, vomiting,diarrhea, refractory hypotension, erythematous desqua-mating rash, conjunctival injection, a strawberry tongue,and varying degrees of multi-organ-system failure.33'34 It

109

Address reprint requests to Olga Jonasson, M.D., 410 West 10th Ave-nue, Columbus, OH 43210.

Accepted for publication April 27, 1992.

110 Wood, Potter, and Jonasson~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~..:.......... .. .. .................Case Age Sex Site(s) Predisposition Bacteremia Operations Deaths

1 (1985) 35 F Throat, Hodgkin's disease, + Chest tubesempyemas recent chemotherapy

2 (1985) 67 M Periorbital area Recurrent oral cancer + Debridementwith multipleoperations

3 (1987) 13 F Vagina Obesity + Hymenotomy,bilateralfasciotomy

4 (1990) 28 M Buttock cellulitis Systemic lupus - Debridement +and erythematosus withmyonecrosis immunosuppression

5 (1991) 48 F Breast and axilla Obesity + Debridement6 (1991) 38 F Leg cellulitis Obesity + Debridement

was found to be mediated by a toxin, most often toxicshock syndrome toxin- I (TSST- 1), produced by Staphy-lococcus aureus.35'36 Staphylococcal TSS usually in-volves infection of the mucous membranes and soft tis-sue of the female genital tract and is most often asso-ciated with the use of vaginal tampons. Recently, anincreasing proportion of nonmenstrual cases of TSShave been reported, these frequently involving surgicalwound infections.37'38 The mortality rate ofstaphylococ-cal TSS is approximately 3%.3739A similar clinical syndrome due to infections with

group A streptococci was suggested in 1983.4 A mortal-ity rate approaching 30% has been reported,'5 deathusually due to refractory hypotension and respiratoryfailure.'4'15 In contrast to staphylococcal TSS, strepto-coccal TSLS is usually accompanied by bacteremia.'5Streptococcal TSLS results from skin or soft tissue infec-tions, often with yellow bullae containing the organisms,and rarely is associated with tampon use.5"'

Since 1985, we have treated six patients with strepto-coccal toxic shock syndrome. One ofthese patients, case3, has been previously reported.30 Three ofthe cases havebeen recognized recently. In each case, radical operativedebridement or drainage was essential in the early phasesofthe illness and appeared to reverse the progressive dete-rioration in organ system function as well as the hypo-tension and acidosis that were prominent features of thesyndrome. This recent apparent increase in frequency ofstreptococcal TSLS is consistent with reports indicatingan alarming rise in the rate of serious complications ofgroup A streptococcal infections.3 4"1541'43

CASE REPORTSCase 1A 35 year old woman (Table 1) undergoing chemother-

apy for Hodgkin's disease developed a sore throat with

fever, vomiting, and chills. She was lethargic and had atemperature of 38.6 C, pulse rate of 160 beats/minute,respiratory rate of 22 breaths/minute, and blood pressureof 90/60 mmHg. She had a swollen, erythematous, andwarm right sternoclavicular joint and bilateral pleural ef-fusions. A leukocytosis, thrombocytopenia, azotemia,and evidence of liver dysfunction were present. Thora-centesis showed bilateral empyemas, and thoracostomytubes were placed. Cultures ofblood, throat, pleural fluid,and sternoclavicular joint fluid grew S. pyogenes. Penicil-lin was begun. Fever continued and an erythematous rashappeared. Evidence of pericardial tamponade developedand a pericardial window was performed, relieving a puru-lent pericarditis containing S. pyogenes. She gradually im-proved and was discharged on the 24th hospital day. Sub-sequent visits disclosed that the rash had desquamated.

Case 2A 67-year-old man with oral squamous cell cancer pre-

viously treated with operative and radiation therapy hadfever, hemoptysis, diarrhea, dehydration, and alteredmental status for 2 weeks. He was disoriented and lethar-gic. Temperature was 40.3 C, pulse rate 142 beats/min-ute, respiratory rate 32 breaths/minute, and blood pres-sure 130/76 mmHg. There was bilateral periorbital ery-thema and swelling with a yellow discharge. He hadleukopenia, thrombocytopenia, mild azotemia, and evi-dence of mild liver dysfunction. Cefamandole was begun.Gram's stain ofthe periorbital drainage showed gram-po-sitive cocci in chains. Over the next 3 days his conditionworsened and he became hypotensive (80/40 mmHg). Op-erative debridement of the infected areas of the head andneck was performed, and an arthrocentesis of a swollenright knee showed purulent fluid with gram-positive cocciin chains. Cultures of blood, urine, and periorbital drain-age grew S. pyogenes. Tobramycin, pipericillin, and clin-damycin were begun and the patient improved. A fine

Streptococcal Toxic Shock-like Syndrome 111

desquamation occurred over the patient's entire body. Hewas discharged on the 30th hospital day.

Case 330A 13-year-old previously healthy girl developed a

cough. Two weeks later she complained of a sore throatand developed nausea, diarrhea, fever of 40 C, and swell-ing of both legs. She became lethargic and cyanotic, andwas taken to an emergency department. There she wasfound to be febrile with a pulse rate of 150 beats/minute,respiratory rate of48 breaths/minute, and a systolic bloodpressure of 60 mmHg. She was transferred to the Colum-bus Children's Hospital. Physical examination ofthe peri-neum demonstrated a yellow purulent discharge from theintact hymenal opening. An arterial blood gas analysisdemonstrated a profound metabolic and respiratory aci-dosis. She had a leukocytosis, azotemia, severe liver dys-function, and coagulopathy. She had brown urine withmyoglobinuria and hematuria, and the creatinine phos-phokinase was markedly elevated. Nafcillin and gentami-cin were begun. Bilateral compartment syndromes werediagnosed, and four compartment fasciotomies were per-formed of the lower extremities. A hymenotomy was per-formed and yellowish fluid was drained. Gram's stain ofthe fluid demonstrated gram-positive cocci in chains andblood cultures grew S. pyogenes. Penicillin was begun.She became oliguric and required peritoneal dialysis. Onthe sixth hospital day, diffuse exfoliation was noted. Dialy-sis was discontinued on day 24. She was discharged onday 35.

Isolates ofthe S. pyogenes from this patient were sent toDr. Patrick Schlievert at the University of Minnesota forexotoxin analysis. This isolate was found to be a mucoidalstrain that produced SPE type C.

Case 4A 28-year-old man with chronic renal failure secondary

to systemic lupus erythematosus requiring prednisoneand azathioprine, presented with 6 hours ofpain and pur-ple discoloration of the right buttock after a strenuous legworkout with weights. He was febrile, hypotensive, anddifficult to arouse. Ceftriaxone was begun and he wastransferred to OSU Hospitals. He was lethargic, tempera-ture was 38.6 C, pulse rate 140 beats/minute, respirationswere controlled on a ventilator, and systolic blood pres-sure was 60 mmHg. A large, tense purple area was presenton the right buttock with bullous fluid-filled lesions anderythema extending to the right lower quadrant of theabdomen and right thigh. Blood transfusion was refused,and the family refused permission for operation. Penicil-lin was begun. The patient was anemic, leukopenic, andazotemic. He had a mild coagulopathy and liver dysfunc-tion. Creatinine phosphokinase was markedly elevated.Six hours later, permission for operation was given. Ex-tensive debridement of the right thigh, buttock, and groinwas performed, with findings of massive necrosis of skinand myonecrosis of the thigh and buttock. Gram's staindemonstrated many gram-positive cocci in chains, later

identified as S. pyogenes. The patient developed dissemi-nated intravascular coagulation and profound anemiaand died 21/2 hours after operation.

Case 5A 48-year-old obese woman in good health presented

with a 1-day history of fever of 39.4 C, chills, diarrhea,and a progressive painful swelling and erythema ofthe leftbreast and axilla. She was febrile and hypotensive and wasadmitted to a hospital where her blood pressure was 85/65mmHg. There was an erythematous, warm, and ecchy-motic area encompassing the left breast. Erythromycinwas begun. Hypotension persisted, and the inflammatoryarea of the left breast progressed with the development ofyellow bullae containing clear serous fluid with gram-po-sitive cocci in chains, later confirmed to be S. pyogenes.Erythromycin was discontinued and penicillin begun.The patient's condition deteriorated and femoral arterythrombosis occurred when a femoral arterial line wasplaced, necessitating thrombectomy. She became oliguricand acidotic, and was transferred to the OSU Hospitals.She was conscious and febrile, with a heart rate of 140beats/minute, assisted ventilation, and a blood pressure of90/63 mmHg. The left breast was involved with a largeinflammatory mass extending into the axilla with tensecutaneous bullae and geographic areas of necrosis. Shehad leukopenia, azotemia, and a markedly elevated creati-nine phosphokinase as well as a lactic acidosis and mildliver dysfunction.

Ampicillin/sulbactam was begun, and she was taken tothe operating room where a wide debridement of thebreast and axillary contents was performed. The tissuewas extensively infiltrated with gram-positive cocci inchains. Blood cultures grew S. pyogenes. Oliguria andthrombocytopenia developed and hemodialysis was insti-tuted. Diffuse exfoliation occurred and conjunctival in-jection and a strawberry tongue developed. Over the next6 days, she improved and ventilator and pressor supportwere discontinued. Hemodialysis was discontinued onthe 22nd hospital day. She was discharged on the 35thhospital day and has subsequently had secondary closureof the wound with breast reconstruction.

Case 6A 38-year-old morbidly obese woman developed a sore

throat; 6 days later she became lethargic and febrile withher temperature rising to 41 C. On admission to a hospi-tal, she was found to be azotemic. A "rapid strep screen"of a throat swab was positive. Because she was allergic topenicillin, cefazolin and gentamicin were begun. Her con-dition deteriorated and she was transferred to OSU Hospi-tals. On arrival she was lethargic, stridorous, and febrile.Her pulse rate was 108 beats/minute, respirations 24breaths/minute, and hypertension was present. Her leftleg was diffusely swollen and warm with an erythematousrash with tense yellow bullae. She had a leukocytosis and acompensated respiratory acidosis. Mild liver dysfunctionand marked elevation of creatinine phosphokinase were

112 Wood, Potter, and Jonasson

Characteristic

Age14 mo-76 yr Mean, 39 yr

SexFM

Not reportedPredominant site(s) of infection

Skin soft tissuesPharyngitis, sinusitisAbdominal pelvicBlood only

EmpyemaBacteremiaPredisposing conditions

ObesityTraumaCancer or immunosuppressionAlcohol or drug abuseVaricellaTampon use

PostpartumProctitisSinusitisDiabetesNone (healthy)

No.

38 (68%)18 (32%)

3

34 (58%)12 (20%)12 (20%)

1

34 (58%)

7

7

54322

111

23 (39%)

stance was a site not identified (bacteremia only). Bacter-emia was present in 34 patients (58%). Twenty-three pa-

tients were previously healthy without predisposing fac-tors. Operative debridement or drainage was necessaryin 69% of patients. Fourteen of 59 patients (24%) died.The Center for Disease Control (CDC) has established

criteria for the diagnosis of staphylococcal toxic shocksyndrome.33'34 These include four major criteria ofhypo-tension, fever, rash, and desquamation as well as multi-organ-system dysfunction, of which three or more sys-tems must be affected: gastrointestinal, muscular, mu-

cous membrane, renal, hepatic, hematologic, andcentral nervous system. Applying these criteria to thereported cases of streptococcal TSLS in which data wereavailable (Table 3), we find that the major and associatedsystemic criteria are fulfilled in nearly all patients withshock, fever, rash, and multi-organ-system dysfunctionpredominating.

Bacteriologic or serologic confirmation of infectionwith Streptococcus pyogenes was obtained in all patients,and blood cultures were positive in 34 (58%) of the pa-tients. When isolates of the organisms were analyzed forSPE expression 3,9,15,17,24,25,30 exotoxin type A predomi-nated, although type B was found alone or in combina-tion with exotoxin A in many isolates. Exotoxin type Cwas infrequently detected, alone or in combination (Ta-ble 4).

documented. Shortly after admission, she became acutelyhypotensive and bradycardia developed. She was stabi-lized with pressor support and 4.5 kg infected and ne-

crotic tissue was removed from the massive right leg. Van-comycin and gentamicin were begun. Cultures of bloodand the fluid from the bullae grew S. pyogenes. Her condi-tion improved, and ventilator support was discontinuedon the sixth hospital day. A desquamating rash developedand renal dysfunction improved without dialysis. On the21 st hospital day, the wound was closed with a split-thick-ness skin graft and she was discharged in good conditionon the 42nd hospital day.

REVIEW OF THE LITERATURESince the existence of a toxic shock-like syndrome

(TSLS) due to group A streptococci was first postulatedin 1 983,4 more than 50 patients have been reported withthe syndrome,3-25 consisting of hypotension, fever, rash,desquamation, and multi-organ-system dysfunction.Characteristics of these patients, including the patientsreported here, are summarized in Tables 2 and 3. Agesranged from 14 months to 76 years; 68% were female.Skin or soft tissue was the site of infection in most cases,with mucosal sites in pharynx or sinuses in 12 cases andabdominal or pelvic sites in 12 cases; in only one in-

DISCUSSIONInvasive infections with S. pyogenes have become

more serious and more frequent in recent years.28,41-43

No. of Patients(%

Major criteriaShockFeverRashDesquamation

Associated systemicdysfunction criteriaRenalGastrointestinalCentral nervous systemMyalgia or CPKMucous membraneHepaticHematologic

Operation requiredDeath

52 (88%)50 (85%)48 (81%)24 (41%)

51 (86%)35 (59%)31 (52%)27 (46%)27 (46%)26 (44%)25 (42%) (5 DIC)41 (69%)14 (24%)

CPK, creatine phosphokinase; DIC, disseminated intravascular coagulation.

[eq no El ;Y-.I" 9 A -. I W-Al 9 I =1..:.. ... :.., 1: Ilr .;.m.: .:. ...,

Streptococcal Toxic Shock-like Syndrome 113

Exotoxin No. of Patients

A 5B 2C 1A+B 5B+C 1A+B+C 3

Also, rheumatic fever, which had nearly disappeared inthe United States during this century, has reappeared insmall epidemics in a number of rural and urban-subur-ban locales."48 The renewal of virulence in S. pyogeneshas been associated with the recognition of a new syn-

drome of fulminant septicemia, shock, and multi-organ-system failure. The mortality rate of TSLS is approxi-mately 25%. First proposed in 1983,4 more than 50cases have now been described.3-25 Streptococcal TSLSdiffers from Staphylococcal TSS in that a site of infec-tion, usually in the skin or soft tissues, is present, andbacteremias occur in most patients; the mortality rate ofstaphylococcal TSS is 3%,37,39 whereas the mortality rateof streptococcal TSLS is at least 25%, with death usuallydue to refractory hypotension and multi-organ-systemfailure.The ability ofthe streptococci to colonize surfaces and

to invade tissues is related to the M protein on the sur-

face of the organism, which acts to inhibit phagocytosis,and to surface adhesins that facilitate colonization bybinding to mucous membranes.'2 Certain M proteinserotypes, specifically Ml and M3 serotypes, and heavyencapsulation of the organisms (mucoid strains) havebeen associated with many of the severe infections re-

cently studied.2'28The scarlatiniform rash, fever, shock and multi-organ-

system failure of TSLS usually follow an invasive infec-tion of skin or soft tissue and subsequent bacteremia.Many of the patients afflicted are otherwise healthy. Thesymptoms are caused by exotoxins produced by the or-

ganisms. Pyrogenic exotoxin A, which has extensiveamino acid homology to the staphylococcal toxic shocksyndrome enterotoxin-B49 has been implicated in mostpatients who have experienced TSLS. Strains producingexotoxin A had become uncommon, but have reap-

peared in association with increased virulence. 15.27Strains producing exotoxins B and C also have been iso-lated from patients with fatal infections. In 17 patientswith TSLS in which exotoxin type has been identified

(Table 4) 39.15.17,24,25,30 13 were associated with exotoxinA, either alone (5 patients,), with exotoxin B (5 patients),or with exotoxins B and C (3 patients). These pyrogenicexotoxins exert profound physiologic effects. Addition-ally, cell wall components ofS. pyogenes may initiate thecomplement cascade through the alternate pathway, andactivate T lymphocytes with probable release of inflam-matory cytokines.2Comparisons of restriction-fragment profiles ofstrains

of S. pyogenes associated with invasive (serious) andnoninvasive, uncomplicated infections, have deter-mined that a unique invasive (I) profile is found in 90%of serious infections but in only 44% of uncomplicatedinfections.29 Of great interest, the strains displaying the Iprofile have been isolated from patients worldwide. Thebacterial isolates bearing the I profile (serious disease)have been further characterized by Southern hybridiza-tion techniques, probing for the toxin gene, speA. Allisolates with the I profile were positive for the speA toxingene whereas none ofthe noninvasive (NI) profile strainscarried this gene.29 Thus, it appears that a highly virulentform of S. pyogenes has appeared globally, capable ofcausing severe, often fatal invasive infections.The invasive nature of these serious infections, with

extensive tissue necrosis, leads to the presence of a largebacterial inoculum with overwhelming exotoxin produc-tion and resistance to treatment with antibiotics alone.Although penicillin is bactericidal for streptococci, it hasno effect on exotoxins and also may be ineffectiveagainst large bacterial inocula in soft tissues (the Eagleeffect).50 Although clindamycin may be more effectiveunder these circumstances,5' surgical debridement ordrainage is often essential to reduce the bacterial load.Early recognition of this new syndrome is facilitated bythe fact that Gram's stain and cultures ofthe infected siteare nearly always positive for S. pyogenes and blood cul-tures are positive in most cases. Prompt initiation ofpen-icillin and or clindamycin therapy, accompanied by ag-gressive debridement and drainage, will be required toreduce the bacterial and exotoxin load and are necessarymeasures to lower the mortality rate.

References

1. Bisno A. Streptococcal infections. In Wilson JD, Braunwald E,Isselbacher KJ, et al., eds. Harrison's Principles of Internal Medi-cine. New York: McGraw-Hill, 1991, pp 563-569.

2. Bisno AL. Group A streptococcal infections and acute rheumaticfever. N Engl J Med 1991; 325:783-793.

3. Cone LA, Woodard DR, Schlievert PM, Tomory GS. Clinical andbacteriologic observations of a toxic shock-like syndrome due tostreptococcus pyogenes. N Engl J Med 1987; 317:146-149.

4. Bartter T, Dascal A, Carroll K, Curley FJ. Toxic strep syndrome: amanifestation ofgroup A streptococcal infection. Arch Intern Med1988; 148:1421-1424.

A :A 901

W191g.-I A :A

N-... :.- ........... :.:.:..... ".

.:.......................

114 Wood, Potter, and Jonasson

5. Brook MG, Bannister BA. Scarlet fever can mimic toxic shocksyndrome. Postgrad Med J 1988; 64:965-967.

6. Hribalova V. Streptococcus pyogenes and the toxic shock syn-drome. Ann Intern Med 1988; 108:772.

7. Paraskevaides EC, Wilson MC. Fatal disseminated intravascularcoagulation secondary to streptococcal cervicitis. Eur J ObstetGynecol Reprod Biol 1988; 29:39-40.

8. Shaunak S, Wendon J, Monteil M, Gordon AM. Septic scarletfever due to streptococcus pyogenes cellulitis. Q J Med 1988;69:921-925.

9. Connolly TJ, Pavelka DJ, Lanspa EF, Connolly TL. Toxic shock-like syndrome associated with necrotizing streptococcus pyogenesinfection. Henry Ford Hosp Med J 1989; 37:69-72.

10. Drabick JJ, Lennox JL. Group A streptococcal infections and atoxic shock-like syndrome (letter). N Engl J Med 1989; 321:1545.

11. Fikrig E, Worthington MT, Lefkowitz LB. Septic shock and acuterespiratory distress syndrome after salpingitis caused by strepto-coccus pyogenes group A. South Med J 1989; 82:634-635.

12. Hess EV, Grant KD. Group A streptococcal infections and a toxicshock-like syndrome (letter). N Engl J Med 1989; 321:1545-1546.

13. Schattner A, Hay E, Lifschitz-Mercer B, Gorbacz S, Bentwich Z.Fulminant streptococcal myositis. Ann Emerg Med 1989; 18:320-322.

14. Shearin RS, Boehlke J, Karanth S. Toxic shock-like syndrome as-sociated with Bartholin's gland abscess: case report. Am J ObstetGynecol 1989; 160:1073-1074.

15. Stevens DL, Tanner MH, Winship J, et al. Severe group A strepto-coccal infections associated with a toxic shock-like syndrome andscarlet fever toxin A. N Engl J Med 1989; 321:1-7.

16. Begovac J, Marton E, Lisic M, et al. Group A beta-hemolytic strep-tococcal toxic shock-like syndrome. Pediatr Infect Dis J 1990;9:369-370.

17. Chomarat M, Chapuis C, Lepape A, Bernard F. Two cases of se-vere infection with beta-haemolytic group A streptococci asso-ciated with a toxic-shock-like syndrome. Eur J Clin Microbiol In-fect Dis 1990; 9:901-903.

18. Christen RD, Moser R, Schlup P, Neftel KA. Fulminant group Astreptococcal infections: report of two cases. Klin Wochenschr1990; 68:427-430.

19. Gallo UE, Fontanarosa PB. Toxic streptococcal syndrome. AnnEmerg Med 1990; 19:1332-1334.

20. Herold AH. Group A f3-hemolytic streptococcal toxic shock froma mild pharyngitis. J Fam Pract 1990; 31:549-551.

21. Lersch C, Gain T, v. Siemens M, et al. Toxic shock-like syndromedue to severe hemolytic group A streptococcal infection. Klin Wo-chenschr 1990; 68:523-525.

22. McGlashan JA. Do streptococci cause toxic shock? BMJ 1990;301:1391-1392.

23. Whitted RW, Yeomans ER, Hankins GDV. Group A 13-hemolyticstreptococcus as a cause of toxic shock syndrome: a case report. JReprod Med 1990; 35:558-560.

24. Bradley JS, Schlievert PM, Sample TG. Streptococcal toxic shock-like syndrome as a complication of varicella. Pediatr Infect Dis J1991; 10:77-79.

25. Margolis DJ, Horlick SE. Group A streptococcus-induced bulloustoxic shock-like syndrome. J Am Acad Dermatol 1991; 24:786-787.

26. Stollerman GH. Global changes in group A streptococcal diseasesand strategies for their prevention. Adv Intern Med 1982; 27:373-406.

27. Stollerman GH. Changing group A streptococci: the reappearanceof streptococcal toxic shock. Arch Intern Med 1988; 148:1268-1270.

28. Musser JM, Hauser AR, Kim MH, et al. Streptococcus pyogenescausing toxic-shock-like syndrome and other invasive diseases:clonal diversity and pyrogenic exotoxin expression. Proc NatlAcad Sci USA 1991; 88:2668-2672.

29. Cleary PP, Kaplan EL, Handley JP, et al. Clonal basis for resur-gence of serious streptococcus pyogenes disease in the 1980s. Lan-cet 1992; 339:518-521.

30. Knezevich S, Torch M. Streptococcal toxic shocklike syndromeleading to bilateral lower extremity compartment syndrome andrenal failure. Clin Orthop 1990; 254:247-250.

31. Gaworzewska ET, Hallas G. Group A streptococcal infections anda toxic shock-like syndrome (letter). N Engl J Med 1989; 321:1546.

32. Todd J, Fishaut M, Kapral F, Welch T. Toxic-shock syndromeassociated with phage-group-I staphylococci. Lancet 1978;2:1116-1118.

33. CDC. Follow up on toxic shock syndrome. MMWR 1980; 29:441.34. CDC. Modification: Toxic-shock-syndrome, United States: 1970-

1982. MMWR 1982; 31:201.35. Bergdoll MS, Crass BA, Reiser RF, et al. A new staphylococcus

enterotoxin-F associated with toxic shock syndrome S. aureus iso-lates. Lancet 1981; 1:1017-1021.

36. Schlievert PM, Shands KN, Dan BB, et al. Identification and char-acterization ofan exotoxin from staphylococcus aureus associatedwith toxic shock syndrome. J Infect Dis 1981; 143:509-516.

37. Broome CV. Epidemiology oftoxic-shock-syndrome in the UnitedStates. Rev Infect Dis 1989; 11 (S 1):S 14-S21.

38. CDC. Reduced incidence of menstrual toxic shock syndrome-United States, 1980-1990. MMWR 1990; 39:421-422.

39. Bergdoll MS, Chesney PJ. Epidemiology oftoxic shock syndrome.In Toxic Shock Syndrome. Boca Raton: CRC Press, Inc., 1991, pp10-24.

40. Willoughby R, Greenberg RN. The toxic shock syndrome andstreptococcal pyrogenic exotoxins. Ann Intern Med 1983; 98:559.

41. Ispahani P, Donald FE, Aveline AJD. Streptococcus pyogenes bac-teremia: an old enemy subdued, but not defeated. J Infect 1988;16:37-46.

42. Givner LB, Abramson JS, Wasilauskas B. Apparent increase in theincidence ofinvasive group A beta-hemolytic streptococcal diseasein children. J Pediatr 1991; 118:341-346.

43. Wheeler MC, Roe MH, Kaplan EL, et al. Outbreak of group Astreptococcus septicemia in children: clinical, epidemiologic, andmicrobiologic correlates. JAMA 1991; 226:533-537.

44. Congeni B, Rizzo C, Congeni J, Sreenivasan VV. Outbreak ofacute rheumatic fever in northeast Ohio. J Pediatr 1987; 11: 176-179.

45. Hosier DM, Craenen JM, Teske DW, Wheller JJ. Resurgence ofacute rheumatic fever. Am J Dis Child 1987; 141:730-733.

46. Veasy LG, Wiedmeir SE, Orsmond GS, et al. Resurgence of acuterheumatic fever in the intermountain area of the United States. NEngl J Med 1987; 316:421-427.

47. Wald ER, Dashefsky B, Feidt C, et al. Acute rheumatic fever inwestern Pennsylvania and the tri-state area. Pediatrics 1987;80:371-374.

48. Kavey RW, Kaplan EL. Resurgence ofacute rheumatic fever. Pedi-atrics 1989; 84:585-586.

49. Johnson LP, L'Italien JJ, Schlievert PM. Streptococcal pyrogenictype A (scarlet fever toxin) is related to staphylococcus aureus en-terotoxin B. Mol Gen Genet 1986; 203:354-356.

50. Eagle H. Experimental approach to the problem oftreatment fail-ure with penicillin: I. Group A streptococcal infection in mice. AmJ Med 1952; 13:389-399.

51. Stevens DL, Gibbons AE, Bergstrom R, Winn V. The Eagle effectrevisited: efficacy of clindamycin, erythromycin, and penicillin inthe treatment of streptococcal myositis. J Infect Dis 1988; 158:23-28.