infeksi strepto

240 THE NEW ENGLAND JOURNAL OF MEDICINE Jan. 25, 1996

REVIEW ARTICLES

CURRENT CONCEPTS

STREPTOCOCCAL INFECTIONS OF SKIN AND SOFT TISSUES

A

LAN

L. B

ISNO

, M.D.,

AND

D

ENNIS

L. S

TEVENS

, M.D., P

H

.D.

From the Medical Service, Miami Veterans Affairs Medical Center, and theDepartment of Medicine, University of Miami School of Medicine, both in Mi-ami (A.L.B.); and the Infectious Diseases Section, Boise Veterans Affairs Medi-cal Center, Boise, Idaho, and the University of Washington School of Medicine,Seattle (D.L.S.). Address reprint requests to Dr. Bisno at the Veterans AffairsMedical Center, 1201 N.W. 16th St., Miami, FL 33125.

1996, Massachusetts Medical Society.

S

TREPTOCOCCUS PYOGENES

(group A in theLancefield classification) is one of the most com-

mon human pathogens. Although this ubiquitous organ-ism is responsible for a wide array of illnesses, most at-tention has focused on its relation to acute pharyngitis,because of the frequency of that condition and its poten-tial for inciting acute rheumatic fever. The recent resur-gence of invasive group A streptococcal infections,

1,2

however, is a reminder that the pathogen can cause avariety of skin and soft-tissue infections, some of whichare severe and even life-threatening.

S

TREPTOCOCCAL

P

YODERMA

Pyoderma, or impetigo, is a localized, purulent infec-tion of the skin that is prevalent among economicallydisadvantaged children of below school age, especiallyin warm, humid climates. The often numerous lesionsbegin as vesicles that rapidly become pustules and thenrupture to form the characteristic thick, honey-coloredcrusts. Impetiginous lesions that extend more deeply intothe epidermis and produce shallow ulcers are known asecthyma. Pyodermal lesions usually occur on exposedareas such as the face and extremities. Systemic reac-tion to them is infrequent, but regional lymphadenopa-thy is common.

The strains of group A streptococcus that cause pyo-derma differ in serotype and certain other biologic char-acteristics from those classically associated with acutestreptococcal pharyngotonsillitis. Strains of some M pro-tein types associated with pyoderma (e.g., 49 and 55) arehighly nephritogenic and have given rise to communityoutbreaks of acute glomerulonephritis after streptococcalinfection. A persisting enigma, though, is the fact thatstreptococcal pyoderma does not incite acute rheumaticfever. Proposed explanations for this phenomenon in-clude both the dissimilarities in the immune responses to

cutaneous and pharyngeal infection

3-5

and an intrinsicabsence of rheumatogenic potential in the streptococcalstrains that cause pyoderma.

6

Until recently, it was thought that experienced clini-cians could confidently distinguish the lesions of strep-tococcal impetigo from those of bullous impetigo dueto

Staphylococcus aureus.

Recent reports, however, havefound

Staph. aureus,

either alone or in combination with

Strep. pyogenes,

to be the predominant etiologic agent innonbullous impetigo.

7

Because most such staphylococciproduce penicillinase, treatment of nonbullous impeti-go with penicillin alone now frequently fails.

8

Penicil-linase-resistant oral penicillins, however, are highly ef-fective. The efficacy of erythromycin, long a mainstayof treatment of streptococcal pyoderma, may be compro-mised in areas where erythromycin-resistant staphylo-cocci or streptococci are prevalent. Topical applicationof mupirocin, an antibiotic derived from

Pseudomonas flu-orescens

and exhibiting excellent activity in vitro againststreptococci and staphylococci, has resulted in high ratesof cure.

9

Treatment of streptococcal pyoderma has notbeen shown to prevent acute glomerulonephritis.

10

E

RYSIPELAS

AND

C

ELLULITIS

Extensive infection of the integument by

b

-hemolyt-ic streptococci may take the form of erysipelas or cellu-litis. Although the two conditions are readily distin-guished when they appear in typical form, there is arange of possible tissue involvement, and differentiationmay not always be clear-cut. Both conditions are man-ifested by local signs of inflammation (warmth, erythema,and pain) and, in most instances, by fever and leukocy-tosis as well. Both may be accompanied by lymphangitisand lymphadenitis.

Portals of entry for the pathogens may include localtrauma or abrasions and psoriatic, eczematous, or tineallesions. Facial erysipelas may follow a streptococcal in-fection of the upper respiratory tract. Patients with im-paired lymphatic drainage of the extremities are proneto recurrent episodes of cellulitis. These may occur, forexample, in the extremities of women with breast carci-noma who have undergone axillary-node dissection orwomen who have had radical pelvic surgery, and in thelimb in which saphenous venectomy has been performedin patients with coronary bypass grafts.

11

Acute strepto-coccal cellulitis, at times associated with bacteremia,may also occur in association with the parenteral injec-tion of illicit drugs.

12

The causative agents in such casesmay be streptococci of groups A, B, C, or G.

13-15

Penicil-lin is the antimicrobial agent of choice.

Erysipelas

Erysipelas involves the more superficial layers of theskin and cutaneous lymphatics, whereas cellulitis ex-tends more deeply into the subcutaneous tissues. This

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Vol. 334 No. 4 CURRENT CONCEPTS 241

anatomical distinction is the basis for the clinical differ-entiation of the two entities. In typical erysipelas, thearea of inflammation is raised above the surroundingskin, and there is a distinct demarcation between in-volved and normal skin (Fig. 1). In cellulitis, neither ofthese clear distinctions between infected and uninfectedskin is present. Although the older literature indicatesthe face as the typical site of erysipelas, up to 85 per-cent of cases now occur on the legs and feet.

17

Bloodcultures are positive for the pathogen in only about5 percent of cases. The great majority of cases are dueto group A streptococci, but erysipelas may also becaused by streptococci of groups G, C, and B

18

and,rarely, by staphylococci.

17

Acute Cellulitis

Although virtually all cases of classic erysipelas aredue to

b

-hemolytic streptococci, primarily group A, thedifferential diagnosis of cellulitis is more problematic.Some cases are due to

Staph. aureus,

and differentiationon clinical grounds alone may not always be possible.Unless purulent exudate is present to allow Gram’sstaining and culture, or unless blood cultures are posi-tive, an etiologic agent cannot often be established byroutine microbiologic techniques.

19

Serum levels of an-tistreptococcal antibodies, measured during the acutephase of illness, reflect past rather than current clinicalevents. When the etiologic agent is unknown, manage-ment should include antimicrobial agents that are effec-tive against both staphylococci and streptococci. Lesscommon causes of cellulitis include

Strep. pneumoniae,Haemophilus influenzae,

and — in appropriate epidemio-logic settings — vibrios, gram-negative bacilli such aspseudomonas and aeromonas, clostridia and other anaer-obes, legionella,

Erysipelothrix rhusiopathiae,

and

Helico-bacter cinaedi.

20

N

ECROTIZING

I

NFECTIONS

OF

THE

S

OFT

T

ISSUE

Many terms have been used to describe necrotizingsoft-tissue infections. A simplified classification is pro-vided in Table 1. More detailed descriptions of the man-ifestations and a differential diagnosis of infections dueto organisms other than group A streptococcus areavailable elsewhere.

21,22

Necrotizing fasciitis is a deep-seated infection of thesubcutaneous tissue that results in the progressive de-struction of fascia and fat. Although necrotizing fascii-tis due to group A streptococcus (Fig. 2), previouslycalled streptococcal gangrene, has been well known foryears, there has been a recent dramatic increase in therecognition and reporting of such infections.

24

More-over, these infections are commonly associated with theearly onset of shock and organ failure — characteristicsthat are used to define the streptococcal toxic shocksyndrome discussed below.

2,24

Predisposing factors for the development of necrotiz-ing fasciitis due to

Strep. pyogenes

include varicella (Fig.3), penetrating injuries, minor cuts, burns, splinters, sur-

gical procedures, childbirth, blunt trauma, and musclestrain.

2

Contact with an infected person may be associ-ated with secondary infection, though such cases are un-common. The patient’s use of nonsteroidal antiinflam-matory agents may delay diagnosis by attenuating thecardinal manifestations of inflammation.

2,24,25

Further-more, because such agents impair phagocytic functionand alter the host’s humoral immune responses, a minorinfection may develop into a fulminant one.

2,24,25

The first cutaneous clue to streptococcal necrotizingfasciitis is diffuse swelling of an arm or leg, followed bythe appearance of bullae filled with clear fluid, whichrapidly take on a maroon or violaceous color.

2,26

Unlessappropriate intervention is undertaken, there is likelyto be a rapid evolution to frank cutaneous gangrene,sometimes with myonecrosis, and an extension of theinflammatory process along fascial planes. There aremarked systemic symptoms, which may include shockand organ failure.

2

Although the diagnosis of necrotizing fasciitis is clearat this late stage, it is sometimes difficult to differentiatebetween cellulitis and necrotizing fasciitis at presenta-

Figure 1. Facial Erysipelas.The lesion is salmon red, raised, and clearly distinct from theuninvolved areas of the skin. Reprinted from Stevens

16

with thepermission of the publisher.




tion. The distinction is crucial, however, because cellulitisis amenable to antimicrobial therapy, whereas necrotiz-ing fasciitis requires the surgical débridement of necrotictissue in addition to the use of antimicrobial agents.

Computed tomographic or magnetic resonance imag-ing is useful in locating the site and depth of infection.

27

Frozen-section biopsy is also useful and provides timelyand specific information.

28

In situations in which thereis no cutaneous evidence of infection, yet severe pain andsymmetric swelling are present, measurements of muscle-compartment pressure may be useful, and if pressuresare elevated (i.e., more than 40 mm Hg), immediate fas-ciotomy is indicated; elevated compartment pressure,whether of infectious or noninfectious origin, contributesto extensive myonecrosis. When the issue of infectionremains in doubt and the patient is perilously ill, surgi-cal exploration is indicated. Surgery can establish a de-finitive diagnosis by providing material for culture,Gram’s staining, and histopathological examination. Di-rect observation of the nature and extent of the patho-logic process guides the decision regarding the necessityfor simple drainage, radical débridement, or guillotineamputation.

S

TREPTOCOCCAL

T

OXIC

S

HOCK

S

YNDROME

Clinical Features

The early onset of shock and organ failure and theisolation of group A streptococcus from a normally ster-ile site are the defining characteristics of the streptococ-cal toxic shock syndrome.

29

Necrotizing fasciitis, with orwithout myonecrosis, is present in about 50 percent ofpatients. A portal of entry from the skin or vaginal mu-cosa is observed in nearly 60 percent of patients; in theothers, the seeding of infection to deeper tissues from atransient bacteremia originating in the pharynx seemsthe most likely cause of the condition.

2,24,30

Symptomatic

sore throat may occasionally precedestreptococcal toxic shock syndrome.

2

The early symptoms of streptococ-cal toxic shock syndrome includemyalgia, malaise, chills, fever, nau-sea, vomiting, and diarrhea. In somepatients, particularly those with nec-rotizing fasciitis, pain at the site ofminor trauma may be the initialsymptom.

2

Phase 2 of the illness ischaracterized by tachycardia, fever,tachypnea, and — in patients whosubsequently have necrotizing fas-ciitis — increasing pain at the site ofinfection. The hallmark of phase 3 ispersistent fever, excruciating pain atthe infection site, and evidence ofshock and organ failure. Interesting-ly, evidence of renal impairment pre-cedes hypotension, which is presentin about 50 percent of patients at thetime of admission to the hospital anddevelops in all others within four to

eight hours after admission. Cutaneous evidence of nec-rotizing fasciitis, however, may be absent even in pa-tients who are hypotensive.

Results of laboratory studies that may indicate thestreptococcal toxic shock syndrome include a profoundleftward shift in the granulocytic series (i.e., 40 to 50percent immature granulocytes, including myelocytesand metamyelocytes), azotemia, hypocalcemia, hypoal-buminemia, thrombocytopenia, hematuria, and an ele-vated level of creatine kinase. Imaging studies, such asroutine x-ray films, may reveal only soft-tissue swelling.Gas in tissue suggests clostridial infection, type 1 nec-rotizing fasciitis (Table 1), or nonclostridial anaerobiccellulitis.

Virulence Factors of

Strep. pyogenes

and Their Rolein Pathogenesis

Clinical reports and epidemiologic studies have re-peatedly shown an association between streptococcaltoxic shock syndrome and group A streptococcal strainsof M protein types 1, 3, 12, and 28.

24,31-34

In every series,types 1 and 3 have been the most common. It should beemphasized that other strains, including strains whoseM protein is not typable, have been isolated from pa-tients with streptococcal toxic shock syndrome, with orwithout necrotizing fasciitis.

Streptococcal pyrogenic exotoxins, the substancesresponsible for the rash of scarlet fever, are suspectedof playing a critical part in the pathogenesis of strepto-coccal toxic shock syndrome. In experiments in animals,pyrogenic exotoxins have been shown to cause fever andlymphocytic blastogenesis and enhance endotoxin-induced shock.

35,36

These toxins,

35,37,38

as well as certainM protein fragments,

39

act as superantigens in vitro,having the unique ability to interact simultaneouslywith the major histocompatibility complex class II an-

Figure 2. Necrotizing Fasciitis Due to Group A Streptococcus.Extensive débridement was required to salvage the arm. Reprinted from Chelsom et

al.

23

with the permission of the publisher.




tigens on antigen-presenting cells and specific V

b

regionsof T-lymphocyte receptors in the absence of classic an-tigen processing. The consequence of such interaction isthe concomitant synthesis of the monokines tumor ne-crosis factor

a

, interleukin-1

b

, and interleukin-6, aswell as the lymphokines interleukin-2, interferon gam-ma, and tumor necrosis factor

b

.

35,37

This massive re-lease of cytokines is a plausible mechanism to explainthe dramatic shock and organ failure associated withstreptococcal toxic shock syndrome. In the UnitedStates, strains of streptococcus elaborating pyrogenicexotoxin A have been commonly found in associationwith streptococcal toxic shock syndrome regardless ofM protein type.

24,32,40

In Sweden, however, strains of Mprotein type 1 elaborating exotoxin B have predominat-ed.

31

Recently, two new pyrogenic exotoxins, SSA

41

andmitogenic factor, were isolated from strains of group Astreptococci.

35,42

A

NTIBIOTIC

T

HERAPY

Strep. pyogenes

continues to be exquisitely susceptibleto

b

-lactam antibiotics, and numerous studies have dem-onstrated the clinical efficacy of penicillin in treatingmost group A streptococcal infections, including pharyn-gitis, erysipelas, impetigo, and cellulitis. In more aggres-sive infections, such as necrotizing fasciitis, empyema,and myositis, penicillin treatment is still associated withhigh mortality and extensive morbidity.

2,24,33

Experimen-tal studies of infection substantiate a reduction in the ef-ficacy of penicillin when large numbers of organisms arepresent.

43,44

Eagle suggested that penicillin failed to haltthis type of infection because of the “physiologic state ofthe organism.”

43

This phenomenon has recently been at-tributed, both in vitro and in vivo, to inoculum effects.

45

Large inoculums reach the stationaryphase of growth quickly both in vitroand in vivo,

43

and penicillin is less ef-ficacious against slowly growing or-ganisms. Recently, it has been shownthat certain penicillin-binding pro-teins are not expressed by the strep-tococci during the stationary phase.

45

This loss of penicillin-binding pro-teins may be responsible for the inoc-ulum effects observed both in vivoand in vitro and may account for thefailure of penicillin to control severestreptococcal infection in both ani-mals and humans.

Conversely, the greater efficacyof clindamycin in experimental mod-els of fulminant streptococcal infec-tion

44,45

is probably related to itsmechanism of action — the inhibi-tion of protein synthesis — which isindependent of the size of the inocu-lum or the stage of bacterial growth.

45

In addition, clindamycin suppressesthe synthesis of bacterial toxins,

46,47

facilitates phagocytosis of

Strep. pyogenes

by inhibitingM protein synthesis,

47

has a long-lasting effect, and sup-presses the synthesis of penicillin-binding proteins that,in addition to being targets for penicillin, are also en-zymes involved in cell-wall synthesis and degradation.It has recently been shown that clindamycin suppres-ses lipopolysaccharide-induced monocyte synthesis oftumor necrosis factor

a

48

; the efficacy of the drug maythus also be related to its ability to modulate the im-mune response. Given these experimental results and thehigh mortality rate associated with streptococcal toxicshock syndrome, the administration of clindamycin inaddition to penicillin seems advisable in patients withthis disorder.

Patients with necrotizing fasciitis in whom the eti-ologic agents cannot be definitively identified should betreated with broad-spectrum antimicrobial regimenseffective against the potential pathogens listed in Table 1.Typical regimens would include expanded-spectrum pen-icillins and cephalosporins, clindamycin, and aminogly-cosides, in combinations suggested by the clinical man-ifestations and epidemiologic features of the case.

O

THER

T

HERAPIES

Prompt and aggressive exploration and débridementof suspected deep-seated infection with

Strep. pyogenes

are mandatory. Later, surgical intervention may be im-possible because of profound shock or because the in-fection has extended to vital areas that are impossibleto débride. The other supportive measures typicallyused in the management of shock and multiorgan fail-ure, including liberal fluid resuscitation, are indicated.

There are few objective reports of the efficacy of hy-perbaric-oxygen treatment in streptococcal necrotizing

Figure 3. Necrotizing Fasciitis Due to Group A Streptococcus in a Patient with Varicella.

The patient, a middle-aged man, acquired varicella from a household contact. Nec-rotizing fasciitis and streptococcal toxic shock syndrome subsequently developed.In addition to cutaneous inflammation and necrosis, varicella lesions are visible in

the photograph.




fasciitis, though one report suggested that in all typesof necrotizing fasciitis, hyperbaric oxygen reduced mor-tality and the need for additional débridement.

49

If hy-perbaric oxygen is to be employed, its use should not de-lay surgical intervention.

Therapy to neutralize circulating toxins is desirable,but the appropriate antibodies are not commerciallyavailable. Although two case reports describe the suc-cessful use of intravenous immune globulin in the treat-ment of streptococcal toxic shock syndrome,

50,51

the roleif any, of such therapy remains to be defined.

C

ONCLUSIONS

The clinical spectrum of streptococcal infections ofcutaneous and soft tissue ranges from localized impe-tigo to deeply invasive fasciitis with associated toxicshock. Physicians must recognize the early signs andsymptoms of invasive streptococcal infections becauseof the rapidity with which they progress and their poten-tial for a fatal outcome. The complex interplay betweenstrain virulence and host response underlies the evolutionof life-threatening streptococcal infections; understandingit better may lead to more efficacious forms of therapy.

R

EFERENCES

1. Bisno AL. Group A streptococcal infections and acute rheumatic fever.N Engl J Med 1991;325:783-93.

2. Stevens DL. Invasive group A streptococcus infections. Clin Infect Dis1992;14:2-11.

3. Kaplan EL, Wannamaker LW. Suppression of the antistreptolysin O re-sponse by cholesterol and by lipid extracts of rabbit skin. J Exp Med 1976;144:754-67.

4. Bisno AL, Nelson KE, Waytz P, Brunt J. Factors influencing serum antibodyresponses in streptococcal pyoderma. J Lab Clin Med 1973;81:410-20.

5. Kaplan EL, Anthony BF, Chapman SS, Ayoub EM, Wannamaker LW. Theinfluence of the site of infection on the immune response to group A strep-tococci. J Clin Invest 1970;49:1405-14.

6. Bisno AL, Pearce IA, Wall HP, Moody MD, Stollerman GH. Contrasting ep-idemiology of acute rheumatic fever and acute glomerulonephritis: natureof the antecedent streptococcal infection. N Engl J Med 1970;283:561-5.

7. Feingold DS. Staphylococcal and streptococcal pyodermas. Semin Derma-tol 1993;12:331-5.

8. Demidovich CW, Wittler RR, Ruff ME, Bass JW, Browning WC. Impetigo:current etiology and comparison of penicillin, erythromycin, and cephalexintherapies. Am J Dis Child 1990;144:1313-5.

9. Mertz PM, Marshall DA, Eaglstein WH, Piovanetti Y, Montalvo J. Topicalmupirocin treatment of impetigo is equal to oral erythromycin therapy. ArchDermatol 1989;125:1069-73.

10. Lasch EE, Frankel V, Vardy PA, Bergner-Rabinowitz S, Ofek I, RabinowitzK. Epidemic glomerulonephritis in Israel. J Infect Dis 1971;124:141-7.

11. Baddour LM, Bisno AL. Recurrent cellulitis after saphenous venectomy forcoronary bypass surgery. Ann Intern Med 1982;97:493-6.

12. Lentnek AL, Giger O, O’Rourke E. Group A beta-hemolytic streptococcalbacteremia and intravenous substance abuse: a growing clinical problem?Arch Intern Med 1990;150:89-93.

13. Baddour LM, Bisno AL. Non-group A beta-hemolytic streptococcal cellu-litis: association with venous and lymphatic compromise. Am J Med 1985;79:155-9.

14. Craven DE, Rixinger AI, Bisno AL, Goularte TA, McCabe WR. Bacteremiacaused by group G streptococci in parenteral drug abusers: epidemiologicaland clinical aspects. J Infect Dis 1986;153:988-92.

15. Bisno AL, Craven DE, McCabe WR. M proteins of group G streptococciisolated from bacteremic human infections. Infect Immun 1987;55:753-7.

16. Stevens DL. Streptococcal infections of skin and soft tissues. In: MandellGL, Stevens DL, eds. Atlas of infectious diseases. Vol. 2. Skin, soft tissue,bone, and joint infections. Philadelphia: Current Medicine, 1995:3.1-3.11.

17. Chartier C, Grosshans E. Erysipelas. Int J Dermatol 1990;29:459-67.18. Binnick AN, Klein RB, Baughman RD. Recurrent erysipelas caused by

group B streptococcus organisms. Arch Dermatol 1980;116:798-9.19. Hook EW III, Hooton TM, Horton CA, Coyle MB, Ramsey PG, Turck M.

Microbiologic evaluation of cutaneous cellulitis in adults. Arch Intern Med1986;146:295-7.

20. Kiehlbauch JA, Tauxe RV, Baker CN, Wachsmuth IK.

Helicobacter cinaedi

-associated bacteremia and cellulitis in immunocompromised patients. AnnIntern Med 1994;121:90-3.

21. Swartz MN. Cellulitis and subcutaneous tissue infections. In: Mandell GL,Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett’s principles andpractice of infectious diseases. 4th ed. New York: Churchill Livingstone,1995:909-29.

22.

Idem.

Myositis. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Doug-las and Bennett’s principles and practice of infectious diseases. 4th ed. NewYork: Churchill Livingstone, 1995:929-36.

23. Chelsom J, Halstensen A, Haga T, Hoiby EA. Necrotising fasciitis due togroup A streptococci in western Norway: incidence and clinical features.Lancet 1994;344:1111-5.

24. Stevens DL, Tanner MH, Winship J, et al. Severe group A streptococcal in-fections associated with a toxic shock–like syndrome and scarlet fever toxinA. N Engl J Med 1989;321:1-7.

25. Stevens DL. Invasive group A streptococcal infections: the past, present andfuture. Pediatr Infect Dis J 1994;13:561-6.

26. Meleney FL. Hemolytic streptococcus gangrene. Arch Surg 1924;9:317-64.27. Zittergruen M, Grose C. Magnetic resonance imaging for early diagnosis of

necrotizing fasciitis. Pediatr Emerg Care 1993;9:26-8.28. Stamenkovic I, Lew PD. Early recognition of potentially fatal necrotizing

fasciitis: the use of frozen-section biopsy. N Engl J Med 1984;310:1689-93.29. The Working Group on Severe Streptococcal Infections. Defining the group

A streptococcal toxic shock syndrome: rationale and consensus definition.JAMA 1993;269:390-1.

Table 1. Necrotizing Infections of the Soft Tissues.

T

YPE

U

SUAL

E

TIOLOGIC

A

GENTS

P

REDISPOSING

C

AUSES

C

LINICAL

M

ANIFESTATIONS

Meleney’s synergistic gangrene

Staph. aureus,

microaerophilic streptococci

Surgery Slowly expanding ulceration con-fined to superficial fascia

Clostridial cellulitis

Clostridium perfringens

Local trauma or surgery Gas in skin, fascia spared, little sys-temic toxicity

Nonclostridial anaerobic cellulitis

Mixed aerobes and anaerobes Diabetes mellitus Gas in tissues

Gas gangrene Clostridial species (

C. perfringens, C. histolyticum,

or

C.

septicum

)Trauma, crush injuries, epinephrine

injections, spontaneous cases re-lated to cancer, neutropenia, cancer chemotherapy

Myonecrosis, gas formation, evident systemic toxicity, shock

Necrotizing fasciitis type 1 Mixed anaerobes, gram-negative aerobic bacilli, enterococci

Surgery, diabetes mellitus, peripher-al vascular disease

Destruction of fat and fascia, skin may be spared; involvement of perineal area in Fournier’s gan-grene

Necrotizing fasciitis type 2 Group A streptococcus Penetrating injuries, surgical proce-dures, varicella, burns, minor cuts, trauma

Systemic toxicity, severe local pain, rapidly extending necrosis of sub-cutaneous tissues and skin, gan-grene, shock, multiorgan failure




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32. Schwartz B, Facklam RR, Breiman RF. Changing epidemiology of group Astreptococcal infection in the USA. Lancet 1990;336:1167-71.

33. Martin PR, Hoiby EA. Streptococcal serogroup A epidemic in Norway1987-1988. Scand J Infect Dis 1990;22:421-9.

34. Gaworzewska E, Colman G. Changes in the pattern of infection caused by

Streptococcus pyogenes.

Epidemiol Infect 1988;100:257-69.35. Norrby-Teglund A, Newton D, Kotb M, Holm SE, Norgren M. Superanti-

genic properties of the group A streptococcal exotoxin SpeF (MF). InfectImmun 1994;62:5227-33.

36. Kim YB, Watson DW. Streptococcal exotoxins: biological and pathologicalproperties. In: Wannamaker LW, Matsen JM, eds. Streptococci and strepto-coccal diseases: recognition, understanding, and management. New York:Academic Press, 1972:33-50.

37. Hackett SP, Stevens DL. Streptococcal toxic shock syndrome: synthesis oftumor necrosis factor and interleukin-1 by monocytes stimulated with py-rogenic exotoxin A and streptolysin O. J Infect Dis 1992;165:879-85.

38. Fast DJ, Schlievert PM, Nelson RD. Toxic shock syndrome-associatedstaphylococcal and streptococcal pyrogenic toxins are potent inducers oftumor necrosis factor production. Infect Immun 1989;57:291-4.

39. Kotb M, Ohnishi H, Majumdar G, et al. Temporal relationship of cytokinerelease by peripheral blood mononuclear cells stimulated by the streptococ-cal superantigen pep M5. Infect Immun 1993;61:1194-201.

40. Farley JD, Woo V, Shaw C, Smith JA. Invasive streptococcal disease in Brit-ish Columbia. Can Dis Wkly Rep 1990;16:257-9.

41. Mollick JA, Miller GG, Musser JM, Cook RG, Grossman D, Rich RR. Anovel superantigen isolated from pathogenic strains of Streptococcus pyo-genes with aminoterminal homology to staphylococcal enterotoxins B andC. J Clin Invest 1993;92:710-9.

42. Iwasaki M, Igarashi H, Hinuma Y, Yutsudo T. Cloning, characterization andoverexpression of a Streptococcus pyogenes gene encoding a new type ofmitogenic factor. FEBS Lett 1993;331:187-92.

43. Eagle H. Experimental approach to the problem of treatment failure with pen-icillin. I. Group A streptococcal infection in mice. Am J Med 1952;13:389-99.

44. Stevens DL, Gibbons AE, Bergstrom R, Winn V. The Eagle effect revisited:efficacy of clindamycin, erythromycin, and penicillin in the treatment ofstreptococcal myositis. J Infect Dis 1988;158:23-8.

45. Stevens DL, Yan S, Bryant AE. Penicillin-binding protein expression at dif-ferent growth stages determines penicillin efficacy in vitro and in vivo: anexplanation for the inoculum effect. J Infect Dis 1993;167:1401-5.

46. Stevens DL, Maier KA, Mitten JE. Effect of antibiotics on toxin productionand viability of Clostridium perfringens. Antimicrob Agents Chemother1987;31:213-8.

47. Gemmell CG, Peterson PK, Schmeling D, et al. Potentiation of opsonizationand phagocytosis of Streptococcus pyogenes following growth in the pres-ence of clindamycin. J Clin Invest 1981;67:1249-56.

48. Stevens DL, Bryant AE, Hackett SP. Antibiotic effects on bacterial viability,toxin production, and host response. Clin Infect Dis 1995;20:Suppl 2:S154-S157.

49. Riseman JA, Zamboni WA, Curtis A, Graham DR, Konrad HR, Ross DS.Hyperbaric oxygen therapy for necrotizing fasciitis reduces mortality andthe need for debridements. Surgery 1990;108:847-50.

50. Barry W, Hudgins L, Donta ST, Pesanti EL. Intravenous immunoglobulintherapy for toxic shock syndrome. JAMA 1992;267:3315-6.

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