SYNOPSES

Streptococcal Toxic-Shock Syndrome:Spectrum of Disease,
Pathogenesis, and New Concepts in Treatment

Dennis L. Stevens, Ph.D., M.D.
Professor of Medicine, University of
Washington School of Medicine, Seattle,
Washington Chief, Infectious Disease Section,
Veterans Affairs Medical Center, Boise, Idaho,
USA

ABSTRACT

Since the 1980s there has been a marked increase in the
recognition and reporting of highly invasive group A
streptococcal infections with or without necrotizing
fasciitis associated with shock and organ failure. Such
dramatic cases have been defined as streptococcal
toxic-shock syndrome. Strains of group A streptococci
isolated from patients with invasive disease have been
predominantly M types 1 and 3 that produce pyrogenic
exotoxin A or B or both. In this paper, the clinical
and demographic features of streptococcal bacteremia,
myositis, and necrotizing fasciitis are presented and
compared to those of streptococcal toxic-shock
syndrome. Current concepts in the pathogenesis of
invasive streptococcal infection are also presented,
with emphasis on the interaction between group A
Streptococcus virulence factors and host defense
mechanisms. Finally, new concepts in the treatment of
streptococcal toxic-shock syndrome are discussed.

An emerging pathogen can be one that is totally new
(e.g., human immunodeficiency virus), one that was
known but has only recently been identified (e.g.,
Helicobacter pylori), or one that is old but has
learned new tricks. The last type is, as Dr. Stanley
Falkow contends, merely trying to "make a living" in a
changing environment. Regardless of environmental
pressures, many old pathogens have become major
clinical problems because of increased virulence or
antibiotic resistance (e.g., penicillin-resistant
pneumococcus, multidrug resistant Mycobacterium
tuberculosis, methicillin-resistant Staphylococcus
aureus, and vancomycin-resistant Enterococcus faecium).

Arguably, group A Streptococcus (GAS) is the
quintessence of an old organism that has become more
virulent. In this manuscript, the epidemiology,
clinical spectrum, and pathogenesis of GAS
infection are discussed in relation to the
streptococcal toxic-shock syndrome (TSS).

Current and Historical Perspectives on the Prevalence
and Severity of Streptococcal Infections 

The British tabloids have recently coined the term
"flesh-eating bacteria" to describe invasive
necrotizing infections caused by GAS and have suggested
that epidemics of streptococcal infection
are imminent. Such aggrandizement is unfounded, yet it
has served to heighten public awareness of this
sporadic, but serious, infectious disease. Strictly
speaking, an epidemic is defined as an increase in the
prevalence of disease over a baseline endemic rate. In
this context, we are, in fact, experiencing an epidemic
of severe invasive GAS infections; however, few
concrete prospective population-based data support this
notion. Estimates suggest that the incidence of these
infections is 10 to 20 cases/ 100,000 population. Thus,
the stimulus for such public interest has not been the
incidence of the syndrome, but more likely, the
dramatic nature of these infections.

Whether these types of group A streptococcal infections
will decline, stay the same, or increase is not known.
History is replete with descriptions of epidemics of
GAS infections and their nonsuppurative sequelae. In
the 1600s, epidemics of scarlet fever spread from Italy
and Spain to Northern Europe (1), and in 1736, an
outbreak occurred in the American colonies, killing
4,000 people (2). Major epidemics of rheumatic fever
occurred in World War II in the U.S. military (3). Soon
afterward post-streptococcal glomerulonephritis struck
several regions of the United States (4,5).

Many of these epidemics waxed and waned before the
advent of antibiotics, suggesting that either changes
in socioeconomic conditions or variations in the
expression of virulence factors by the pathogen were
responsible. This concept is best exemplified by the
extraordinary mortality rate of scarlet fever
documented in the latter part of the 1880s in New York,
Chicago, and Norway; 25% to 30% of children with
scarlet fever died during that period (5,6). By 1900,
the mortality rate had dropped to under 2% in all three
locations. Since socioeconomic conditions likely did
not change markedly during that time and antibiotics
were not yet available, the decrease in mortality rates
must have been caused by reduced expression of a
streptococcal virulence factor or by the slow
acquisition of herd immunity to that factor.

The epidemiology of GAS infection is complex. More than
80 different M types of S. pyogenes exist, and five
separate and distinct scarlatina toxins, streptococcal
pyrogenic exotoxins (SPEs) (5) have also been
described; some of these can be transmitted to
different M types by bacteriophage. Minor drifts
in the antigenic or virulence properties of GAS could
account for the 5- to 6-year cycles of scarlet fever
documented by Kohler (9). In the same way as antigenic
shifts in influenza virus cause pandemics, major
alterations in GAS virulence properties could cause
major changes in clinical disease. The recent increases
in severe GAS infections, following a 50- to 60-year
span of relatively benign clinical disease, support
this notion.

Acute Life-Threatening Group A Streptococcal Infections

Streptococcal TSS

Recently, severe invasive GAS infections associated
with shock and organ failure have been reported with
increasing frequency, predominantly from North America
and Europe (8-18). These infections have been termed
streptococcal toxic-shock syndrome (TSS; Table 1) (19).
Persons of all ages are affected; most do not have
predisposing underlying diseases (11,20-25). This is in
sharp contrast to previous reports of GAS bacteremia,
in which patients were either under 10 or over 60 years
of age, and most had underlying conditions such as
cancer, renal failure, leukemia, or severe burns or
were receiving corticosteroids or other
immunosuppressing drugs (20-22). The complications of
current GAS infections are severe; bacteremia
associated with aggressive soft tissue infection,
shock, adult respiratory distress syndrome and renal
failure are common; 30% to 70% of patients die in spite
of aggressive modern treatments (Table 2) (1,8,24-26).

Table 1. Case definition of streptococcal toxic-shock syndrome
(streptococcal TSS) and necrotizing fasciitis*
____________________________________________________________
I. Streptococcal TSS
   A. Isolation of group A Streptococcus
      1. From a sterile site
      2. From a nonsterile body site
   B.Clinical signs of severity
      1. Hypotension
      2.  Clinical and laboratory abnormalities (requires two or  
          more of the following):
         a)Renal impairment
         b)Coagulopathy
         c)Liver abnormalities
         d)Acute respiratory distress syndrome
         e)Extensive tissue necrosis, i.e., necrotizing fasciitis
         f)Erythematous rash

  Definite Case = A1 + B(1+2)
  Probable Case = A2 + B(1+2)

II. Necrotizing fasciitis
    A.Definite case
      1. Necrosis of soft tissues with involvement of the fascia
    PLUS
      2.Serious systemic disease, including one or more of the 
        following:
        a)Death
        b)Shock (systolic blood pressure <90 mm of Hg).
        c)Disseminated intravascular coagulopathy
        d)Failure of organ systems
          a.respiratory failure
          b.liver failure
          c.renal failure
     3.Isolation of group A Streptococcus from a normally sterile 
       body site
    B.Suspected case
     1.1+2 and serologic confirmation of group A streptococcal
      infection by a 4-fold rise against:
       a)streptolysin O
       b)DNase B
     2.1+2 and histologic confirmation:
      Gram-positive cocci in a necrotic soft tissue infection
_______________________________________________________
*Streptococcal toxic-shock syndrome (streptococcal TSS) is 
defined as any group A streptococcal infection associated with 
the early onset of shock and organ failure.  Definitions
describing criteria for shock, organ failure, definite cases,
and probable cases are included below.
Source: reference 61.

_______________________________________________________
Table 2. Complications of group A streptococcal soft-tissue
infection

Complication                                  Percentage
                                              of Patients
Shock                                             95
Acute respiratory distress syndrome               55
Renal impairment                                  80
Irreversible                                      10
Reversible                                        70
Bacteremia                                        60
Death                                             30
 
_______________________________________________________
Source: reference 1.

Acquisition of Group A Streptococcus

The portal of entry of streptococci cannot be proven in
at least half the cases (8) and can only be presumed in
many others.Patients with symptomatic pharyngitis
rarely develop streptococcal TSS, though such cases
have been reported,especially in the last year.
Procedures such as suctionlipectomy, hysterectomy,
vaginal delivery, bunionectomy and bone pinning have
provided a portal of entry in many cases (author's
unpublished observations). Most commonly, infection
begins at a site of minor local trauma, which
frequently does not result in a break in the skin (8).
Numerous cases have developed within 24 to 72 hours of
minor nonpenetrating trauma, resulting in hematoma,
deep bruise to the calf, or even muscle strain. Virus
infections, such as varicella and influenza, have
provided a portal in other cases. In some cases the use
of nonsteroidal antiinflammatory agents may have either
masked the early symptoms or predisposed the patient to
more severe streptococcal infection and shock (1). For
the most part, these infections have occurred
sporadically and have not been associated with clusters
of cases or minor epidemics, though outbreaks of severe
GASinfections have occurred in closed environments such
as nursing homes (27,28).

Clinical Symptoms

Pain the most common initial symptom of streptococcal
TSS is abrupt in onset and severe, and usually precedes
tenderness or physical findings. The pain usually
involves an extremity but may also mimic
peritonitis,pelvic inflammatory disease, pneumonia,
acute myocardial infarction, or pericarditis. Twenty
percent of patients have an influenza-like syndrome
characterized by fever, chills, myalgia, nausea,
vomiting, and diarrhea (8). Fever is the
most common early sign, although hypothermia may be
present in patients with shock. Confusion is present in
55% of patients, and in some, coma or combativeness is
manifest (8). Eighty percent of patients have clinical
signs of soft tissue infection, such as localized
swelling and erythema, which in 70% of patients
progressed to necrotizing fasciitis or myositis and
required surgical debridement, fasciotomy or amputation
(8). An ominous sign is the progression of soft tissue
swelling to the formation of vesicles, then bullae,
which appear violaceous or bluish. In such patients,
emergent surgical exploration should be performed
to establish the diagnosis and distinguish GAS
infection from other necrotizing soft tissue
infections. Among the 20% of patients without soft
tissue findings, clinical symptoms include
endophthalmitis, myositis, perihepatitis, peritonitis,
myocarditis, and overwhelming sepsis. A diffuse,
scarlatina-like erythema occurs in only 10% of
patients. Nearly 50% of patients may have normal blood
pressure (systolic pressure >110 mm Hg) on admission
but develop hypotension within the subsequent 4 hours
(8). 

Laboratory Evaluation of Patients 

On admission, renal involvement is indicated by the
presence of hemoglobinuria and by serum creatinine
values that are, on average, >2.5 times normal. Renal
impairment precedes hypotension in 40% to 50% of
patients (8). Hypoalbuminemia is associated with
hypocalcemia on admission and throughout the hospital
course. The serum creatinine kinase level is useful in
detecting deeper soft-tissue infections; when the level
is elevated or rising, there is a good correlation with
necrotizing fasciitis or myositis.  Though the
initial laboratory studies demonstrate only mild
leukocytosis, the mean percentage of immature
neutrophils (including band forms, metamyelocytes, and
myelocytes) is striking, reaching 40% to 50%. Blood 
cultures are positive in 60% of cases (8).

Clinical Course

Shock is apparent at the time of admission or within 4
to 8 hours in virtually all patients (Table 2). In only
10% of patients does systolic blood pressure become
normal 4 to 8 hours after administration of
antibiotics, albumin, and electrolyte solutions
containing salts or dopamine; in all other patients,
shock persists. Similarly, renal dysfunction progresses
or persists in all patients for 48 to 72 hours in spite
of treatment, and many patients may require dialysis
(8). In patients who survive, serum creatinine values
return to normal within 4 to 6 weeks. Renal dysfunction
precedes shock in many patients and is apparent early
in the course of shock in all others. Acute respiratory
distress syndrome occurs in 55% of patients and
generally develops after the onset of hypotension (8).
Supplemental oxygen, intubation, and mechanical
ventilation are necessary in 90% of the patients
in whom this syndrome develops. Mortality rates vary
from 30% to 70% (1,8,24-26). Morbidity is also high; 13
of 20 patients in one series underwent major surgical
procedures, which included fasciotomy, surgical
debridement, exploratory laparotomy, intraocular
aspiration, amputation, or hysterectomy (8). 

Clinical Isolates 

M types 1, 3, 12, and 28 have been the most common
isolates from patients with shock and multiorgan
failure (8,29). Recently, 80% of strains in Sweden from
all types of GAS infection have been M type 1 (S. Holm,
pers. comm.). Pyrogenic exotoxin A and/or B was found
in most cases of severe infection. In the United
States, pyrogenic exotoxin A is most frequently
associated with these infections (8,23,29-33), while in
Sweden and the United Kingdom, exotoxin B has been most
common (12,25). Recently, streptococcal superantigen
(SSA), a novel pyrogenic exotoxin, was isolated from
an M 3 strain, albeit in small concentrations (34). In
addition, mitogenic factor (MF) has been demonstrated
in many different M types of GAS (35,36). 

Necrotizing Fasciitis

Necrotizing fasciitis, a deep-seated infection of the
subcutaneous tissue that progressively destroys fascia
and fat but may spare the skin and muscle, can be
caused by GAS, Clostridium perfringens, or C. septicum. 
Necrotizing fasciitis caused by mixed organisms such as
aerobic gram-negative bacteria, anaerobes, and
microaerophilic streptococci may develop in diabetic
patients or patients with open wounds contaminated with
bowel contents. Though Meleney called infections caused
by hemolytic streptococci "streptococcal gangrene"
(37), the process has been renamed necrotizing
fasciitis. His patients' infections began at the site
of trivial or inapparent trauma. Within 24 hours of the
initial lesion which frequently was only mild erythema
swelling, heat, erythema, and tenderness rapidly 
developed. During the next 24 to 48 hours, the erythema
changed from red to purple and then to blue, and
blisters and bullae, which contained clear yellow
fluid, appeared. On days 4 and 5, the purple areas
became gangrenous. From day 7 to day 10, the line of
demarcation became sharply defined, and the dead skin
began to separate at the margins or breaks in the
center, revealing an extensive necrosis of the
subcutaneous tissue. In more severe cases, the process
advance d rapidly until several large areas of skin
became gangrenous, and the intoxication rendered the
patient dull,unresponsive, mentally cloudy, or even
delirious. Meleney was the first to advocate aggressive
"bear scratch" fasciotomy and debridement. With this
treatment, together with irrigation with Dakains
solution, the mortality rate dropped to 20% (37).  

These older reports of necrotizing fasciitis (6) differ 
from reports of current necrotizing fasciitis cases
associated with streptococcal TSS (8). First, recent
cases have mainly occurred in young healthy persons who
had no underlying disease but sustained minor trauma to
an extremity. Earlier series describe older patients
with multiple medical problems (6). Meleney's cases
(reported from China) were probably among young healthy 
persons who sustained minor trauma, though the major
difference between them and present cases is the low
mortality rate (20% vs 20% to 60% in streptococcal TSS)
(6,37) before antibiotics were available (37). Analysis
of Meleney's reports also suggests that most of his
patients did not have shock or organ failure, nor did
they require amputation. In contrast, present cases of
necrotizing fasciitis caused by GAS are invariably
associated with severe manifestations of systemic
illness and high morbidity despite the absence of
underlying disease and the use of antibiotics,
dialysis, ventilators, intravenous fluids, and improved
surgical techniques. In summary, the high mortality
rate among current cases of streptococcal necrotizing
fasciitis could be due to the emergence of more
virulent streptococci (8). 

Streptococcal Myositis

Streptococcal myositis is an extremely uncommon GAS
infection. Adams et al. (38) documented only 21
reported cases from 1900 to 1985, and Svane (39) found
only four cases in more 20,000 autopsies. Severe pain
may be the only early symptom, and swelling and
erythema may be the only early physical findings,
though muscle compartment syndromes may develop rapidly
(8-10,38-41). Distinguishing streptococcal myositis
from spontaneous gas gangrene caused by C. perfringens
or C. septicum (42) may be difficult, though crepitus
or demonstration of gas in the tissue favors
clostridial infection (40). Patients with streptococcal
TSS may have both necrotizing fasciitis and
myositis (8,38). In published series, the case-fatality
rate for necrotizing fasciitis is 20% to 50%, whereas
GAS myositis has a fatality rate of 80% to 100% (6).
Aggressive surgical debridement is extremely important
for establishing a diagnosis and removing devitalized
tissue. 

Bacteremia

Streptococcal bacteremia has occurred most commonly in
the very young and in the elderly (5). Among children,
predisposing factors (other than scarlet fever) include
burns,varicella, malignant neoplasm,immunosuppression,
and age less than 2 years (5). In patients with scarlet
fever, the pharynx is the most common source of GAS.
Frequently such patients have complications, such as
extension of infection into the sinuses, peritonsillar
tissue, or mastoids (septic scarlet fever
or scarlet fever anginose); yet documented bacteremia
occurs in only 0.3% of febrile patients (43). Among the
children with varicella studied by Bullowa and Wischik
(43), GAS bacteremia occurred in only approximately
0.5% of patients. In elderly patients the source of GAS
infection is invariably the skin and is associated with
cellulitis or erysipelas (5). GAS sepsis in the elderly
(mean age, 50 to 60 years) has also been associated
with diabetes, peripheral vascular disease, malignancy,
and corticosteroid use. Not surprising, mortality
rates of 35% to 80% have been described in this patient
population. In the past, GAS bacteremia was rare among
persons 14 to 40 years of age; puerperal sepsis
accounted for most bacteremia in this age group.
Recently, intravenous drug abuse has emerged as a
leading cause of GAS bacteremia in this age group (5).
Martin and Hoiby have comprehensively demonstrated that
the prevalence of GAS bacteremia in Norway in the late
1980s increased in all age groups, but the greatest
increase (600% to 800%) was in adolescents and young
adults (10). Thus, the demographics of invasive
streptococcal infection have changed dramatically in
the past 4 to 6 years.  

Current Hypotheses Regarding Mechanisms of Shock and
Tissue Destruction Caused by Virulent Group A
Streptococci

Pyrogenic exotoxins cause fever in humans and animals
and also help induce shock by lowering the threshold to
exogenous endotoxin (5). Streptococcal pyrogenic
exotoxins A and B induce human mononuclear cells to
synthesize not only tumor necrosis factor-
(TNF) (44) but also interleukin- (IL-1) (45)
and interleukin-6 (IL-6) (45), suggesting that TNF
could mediate the fever, shock, and tissue injury
observed in patients with streptococcal TSS (8).
Pyrogenic exotoxin C has been associated with mild
cases of scarlet fever in the United States
(author's observations) and in England (46). The roles
of two newly described pyrogenic exotoxins, SSA and MF
(see section on "Clinical Isolates"), in streptococcal
TSS have not been elucidated.

M protein contributes to invasiveness through its
ability to impede phagocytosis of streptococci by human
polymorphonuclear leukocytes (47). Conversely,
type-specific antibody against the M protein enhances
phagocytosis (47). After infection with a  particular M
type, specific antibody confers resistance to challenge
to viable GAS of that M type (47). While M types 1 and
3 strains have accounted for most strains isolated
from cases of streptococcal TSS, many other M types,
including some nontyp-able strains, have also been
isolated from such cases. M types 1 and 3 are also
commonly isolated from asymptomatic carriers, patients
with pharyngitis, and patients with mild scarlet fever
(7,29).

Could streptococcal TSS be related to the ability of
pyrogenic exotoxin or M proteins type 1 or 3 to act as
"super antigens"(48)? Data suggest that this exotoxin
and a number of staphylococcal toxins (toxic shock
syndrome toxin-1 [TSST-1] and staphylococcal
enterotoxins A, B, and C) can stimulate T-cell
responses through their ability to bind to both
the Class II major histocompatibility ability complex
of antigen-presenting cells and the Vb region of the
T-cell receptor (48). The net effect would be to induce
T-cell stimulation with production of cyto- kines
capable of mediating shock and tissue injury. Recently,
Hackett and Stevens demonstrated that pyrogenic
exotoxin A induced both TNF and TNF from mixed
cultures of monocytes and lymphocytes (49), supporting
the role of lymphokines (TNF) in shock associated with
strains producing that exotoxin. Kotb et al. (50) have
shown that a digest of M protein type 6 can also
stimulate T-cell responses by this mechanism; however,
the role of specific superantigens in this or
any other infectious disease has not been proven. Proof
would require demonstration of massive expansion of
T-cell subsets bearing a V repertoire specific for the
putative superantigen. However, quantitation of such
T-cell subsets in patients with acute streptococcal TSS
demonstrated deletion rather than expansion, suggesting
that perhaps the life span of the expanded
subset was shortened by a process of apoptosis (51). In
addition, the subsets deleted were not specific for
streptococcal pyrogenic exotoxins A, B, C, or mitogenic
factor, suggesting that an as yet undefined
superantigen may play a role (51).

Cytokine production by less exotic mechanisms likely
contributes as well to the genesis of shock and organ
failure. Peptidoglycan, lipoteichoic acid (52), and
killed organisms (53,54) are capable of inducing TNFa
production by mononuclear cells in vitro (6,54,55).
Exotoxins such as streptolysin O (SLO) are also potent
inducers of TNF and IL-1. Pyrogenic exotoxin B, a
proteinase precursor, has the ability to cleave
pre-IL-1 to release preformed IL-1 (56). Finally, SLO
and exotoxin A together have additive effects in the
induction of IL-1 by human mononuclear cells (49).
Whatever the mechanisms, induction of cytokines in vivo
is likely the cause of shock, and these two exotoxins,
cell wall components, and the like, are potent inducers
of TNF and IL-1. 

The mere presence of virulence factors, such as M
protein or pyrogenic exotoxins, may be less important
in streptococcal TSS than the dynamics of their
production in vivo. Recently, Cleary et al. proposed a
regulon in GAS that controls the expression of a group
of virulence genes coding for known virulence factors
such as M protein and C5 peptidase (57). When
DNA fingerprinting was used, differences were shown
between M1 strains isolated from patients with invasive
disease and strains from patients with noninvasive GAS
infections (58). Finally, genetic information coding
for exotoxins A or C may be introduced to strains of
GAS by certain bacteriophage; after lysogenic
conversion,synthesis of exotoxin A would occur during
growth of the streptococcus (31,59,60). Multilocus
enzyme electrophoresis demonstrates two patterns that
correspond to the M1 and M3 type organisms that produce
pyrogenic exotoxin A, a finding that supports
epidemiologic studies implicating these strains in
invasive GAS infections (33).

The interaction between these microbial virulence
factors and an immune or nonimmune host determines the
epidemiology, clinical syndrome, and outcome. Since
horizontal transmission of GAS in general is well
documented, the only explanation for the absence
of a high attack rate of invasive infection is
significant herd immunity against one or more of the
virulence factors responsible for streptococcal TSS.
This hypothetical model explains why epidemics have not
materialized and why a particular strain of GAS can
cause different clinical manifestations in the same
community (8,61) (Figure 1 cannot be viewed in ASCII
format.) 

Treatment

Antibiotic Therapy-Cures and Failures with Penicillin

S. pyogenes continues to be exquisitely susceptible to
-lactam antibiotics, and numerous studies have
demonstrated the clinical efficacy of penicillin
preparations for streptococcal pharyngitis. Similarly,
penicillins and cephalosporins have proven efficacy in
treating erysipelas, impetigo, and cellulitis,
all of which are most frequently caused by S. pyogenes.
In addition, Wannamaker et al. (6) demonstrated that
penicillin therapy prevents the development of
rheumatic fever following streptococcal pharyngitis if
therapy is begun within 8 to 10 days of the onset of
sore throat. Nonetheless, some clinical failures 
of penicillin treatment of streptococcal infection do
occur. Penicillin treatment of S. pyogenes has failed
to eradicate bacteria from the pharynx of 5% to 20% of
patients with documented streptococcal pharyngitis 
(62-64). In addition, more aggressive GAS infections
(such as, necrotizing fasciitis, empyema, burn wound
sepsis, subcutaneous gangrene, and myositis)
respond less well to penicillin and continue to be
associated with high mortality rates and extensive
morbidity (6,8,9,12,15,38,65). For example, in a recent
report, 25 cases of streptococcal myositis had an
overall mortality rate of 85% in spite of penicillin
therapy (38). Finally, several studies in experimental
infection suggest that penicillin fails when large
numbers of organisms are present (66,67).

The Efficacy of Penicillin, Compared to Clindamycin, In
Fulminant Experimental S. pyogenes Infection

In a mouse model of myositis caused by S. pyogenes,
penicillin was ineffective when treatment was delayed
up to 2 hours after initiation of infection (67).
Survival of erythromycin-treated mice was greater than
that of both penicillin-treated mice and untreated
controls, but only if treatment was begun within 2
hours. Mice receiving clindamycin, however, had
survival rates of 100%, 100%, 80%, and 70%, even if
treatment was delayed 0, 2, 6, and 16.5 hours,
respectively (67,68). 

Eagle suggested that penicillin failed in this type of
infection because of the "physiologic state of the
organism"(66). This phenomenon has recently been
attributed to both in vitro and in vivo inoculum
effects (69,70). 

Inoculum Size and the "Physiologic State of the
Organism": Differential Expression of
Penicillin-Binding Proteins 

Penicillin and other -lactam antibiotics are most
efficacious against rapidly growing bacteria. We
hypothesized that large inocula reach the stationary
phase of growth sooner than smaller inocula both in
vitro and invivo. That high concentrations of S.
pyogenes accumulate in deep-seated infection is
supported by data from Eagle et al. (66). We compared
the penicillin-binding protein patterns from membrane
proteins of group A streptococci isolated from
different stages of growth, i.e., mid-log phase and
stationary phase. Binding of radiolabeled penicillin by
all penicillin-binding proteins was decreased in
stationary cells; however, PBPs 1 and 4 were
undetectable at 36 hours (69). Thus, the loss of
certain penicillin-binding proteins during
stationary-phase growth in vitro may be responsible for
the inoculum effect observed in vivo and may account
for the failure of penicillin in treatment of both
experimental and human cases of severe streptococcal
infection. 

The Greater Efficacy of Clindamycin in Experimental S.
pyogenes Infections: Mechanisms of Action

The greater efficacy of clindamycin is likely
multifactorial: First, its efficacy is not affected by
inoculum size or stage of growth (69,71); secondly,
clindamycin is a potent suppressor of bacterial toxin
synthesis (72,73); third, it facilitates 
phagocytosis of S. pyogenes by inhibiting M-protein
synthesis (73); fourth, it suppresses synthesis of
penicillin-binding proteins, which, in addition to
being targets for penicillin, are also enzymes involved
in cell wall synthesis and degradation (71); fifth,
clindamycin has a longer postantibiotic effect than
-lactams such as penicillin; and lastly, clindamycin
causes suppression of LPS-induced monocyte synthesis of
TNF (74). Thus, clindamycin's efficacy may also be
related to its ability to modulate the immune response. 

Other Treatment Measures

Though antibiotic selection is critically important,
other measures, such as prompt and aggressive
exploration and debridement of suspected deep-seated S.
pyogenes infection, are mandatory. Frequently, the
patient has fever and excruciating pain. Later,
systemic toxicity develops, and definite evidence of
necrotizing fasciitis and myositis appears. Surgical
debridement may be too late at this point. Prompt
surgical exploration through a small incision with
visualization of muscle and fascia, and timely Gram
stain of surgically obtained material may provide
an early and definitive etiologic diagnosis. Surgical
colleagues should be involved early in such cases,
since later in the course surgical intervention may be
impossible because of toxicity or because infection has
extended to vital areas impossible to debride (i.e.,
the head and neck, thorax, or abdomen).

Anecdotal reports suggest that hyperbaric oxygen has
been used in a handful of patients, though no
controlled studies are under way, nor is it clear that
this treatment is useful. 

Because of intractable hypotension and diffuse
capillary leak, massive amounts of intravenous fluids
(10 to 20 liters/day) are often necessary. Pressors
such as dopamine are used frequently, though no
controlled trials have been performed in streptococcal
TSS. In patients with intractable hypotension,
vasoconstrictors such as epinephrine have been used,
but symmetrical gangrene of digits seems to result
frequently (author's unpublished observations), often
with loss of limb. In these cases it is
difficult to determine if symmetrical gangrene is due
to pressors, infection, or both. 

Neutralization of circulating toxins would be
desirable; however, appropriate antibodies are not
commercially available in the United States or Europe.
Two reports describe the successful use of intravenous
gamma globulin in treating streptococcal TSS in
two patients (75,76). 

In summary, if a wild "flesh-eating strain" has
recently emerged, a major epidemic with a high attack
rate would normally be expected. Clearly, epidemics of
streptococcal infections, including impetigo,
pharyngitis, scarlet fever, and rheumatic  fever have
occurred in the past. However, in the last decade,
subsequent to early reports of streptococcal TSS, we
have observed that the incidence has remained
relatively low. I hypothesize that large outbreaks have
not occurred because 1) most of the population probably
has immunity to one or more streptococcal virulence
factors (6,25); 2) predisposing conditions (e.g.,
varicella, and use of NSAIDs) are required in a
given patient; and 3) only a small percentage of the
population may have an inherent predisposition to
severe streptococcal infection because of 
constitutional factors such as HLA Class II
antigen type (77,78), B-cell (79), or specific Vb
regions on lymphocytes. This last hypothesis is further
supported by the observation that secondary cases of
streptococcal TSS, though reported (80), have been
rare.

Dr. Stevens is chief, Infectious Diseases Section,
Veterans Affairs Medical Center, Boise, Idaho, and
professor of medicine, University of Washington School
of Medicine, Seattle.  He is a member of CDC's Working
Group on Streptococcal Infections and a consultant to 
the National Institutes of Health and the World Health 
Organization on Streptococcal Infections. On July 1994, 
he testified before Congress on Severe Streptococcal 
Infections and is currently President of the American 
Lancefield Society.

Address for correspondence: Infectious Disease Section
Veterans Affairs Medical Center, 500 West Fort 
Street (Bldg 6), Boise, ID 83702, USA, fax: 208-389-7965

References

1. Stevens DL, Tanner MH, Winship J,
Swarts R, Reis KM, Schlievert PM, et al.
Reappearance of scarlet fever toxin A among
streptococci in the Rocky Mountain West:
severe group A streptococcal infections
associated with a toxic shock-like syndrome. N
Engl J Med 1989; 321:1-7.

2. The Working Group on Severe
Streptococcal Infections. Defining the group A
streptococcal toxic shock syndrome: rationale
and consensus definition. JAMA 1993;
269:390-1.

3. Sennert D. De febribus libri quator.
Editio novissima. Cui accessit fasciculus
medicamentorum contra pestem. Libri IV. De
peste, Pestilentibusque ac Malingis Febribus.
Venice: Francisum Baba, 1641.

4. Douglass W. The practical history of a
new epidemical eruptive miliary fever, with an
Angina Ulcusculosa, which prevailed in Boston,
New England in the years 1735 and 1736.
Boston: T. Fleet, 1736.

5. Dillon HC. Impetigo contagiosa:
suppurative and nonsuppurative complication.
Clinical, bacteriologic and epidemiologic
characteristics of impetigo. Am J Dis Child
1968; 115:530-41.

6. Wannamaker LW, Rammelkamp CH, Jr.,
Denny FW, Brink WR, Houser HB, Hahn EO, et al.
Prophylaxis of acute rheumatic fever by
treatment of the preceding streptococcal
infection with various amounts of depot
penicillin. Am J Med 1951; 10:673-95.

7. Weaver GH. Scarlet Fever. In: Abt IA,
ed., Pediatrics. Philadelphia: W.B. Saunders
Co., 1925:298-362.

8. Stevens DL. Invasive group A
streptococcus infections. Clin Infect Dis
1992; 14:2-13.

9. Kohler W, Gerlach D, Knoll H.
Streptococcal outbreaks and erythrogenic toxin
type A. Zbl Bakt Hyg 1987; 266:104-15.

10. Martin PR, Hoiby EA. Streptococcal
serogroup A epidemic in Norway 1987-1988.
Scand J Infect Dis 1990; 22:421-9.

11. Holm S. Fatal group A streptococcal
infections. Presented at the 89th Conference
of the American Society for Microbiology, New
Orleans, LA, 1989.

12. Wheeler MC, Roe MH, Kaplan EL,
Schlievert PM, Todd JK. Outbreak of group A
streptococcus septicemia in children:
clinical, epidemiologic, and microbiological
correlates. JAMA 1991; 266:533-7.

13. Gaworzewska ET, Coleman G.
Correspondence: group A streptococcal
infections and a toxic shock-like syndrome. N
Engl J Med 1989; 321:1546.

14. Schwartz B, Facklam R, Breiman R. The
changing epidemiology of group A streptococcal
infections in the U.S.: association with
changes in serotype. Presented at the 30th
Interscience Conference on Antimicrobial
Agents and Chemotherapy, Atlanta, GA, 1990;
Abstract 88.

15. Bartter T, Dascal A, Carroll K, Curley
FJ. "Toxic strep syndrome": manifestation of
group A streptococcal infection. Arch Intern
Med 1988; 148:1421-4.

16. Hribalova V. Streptococcus pyogenes and
the toxic shock syndrome. Ann Intern Med 1988;
108:772.

17. Greenberg RN, Willoughby BG, Kennedy
DJ, Otto TJ, McMillian R, Bloomster TG.
Hypocalcemia and "toxic" syndrome associated
with streptococcal fasciitis. South Med J
1983; 76:916-8.

18. Jackson MA, Olson LC, Burry VF.
Pediatric group A streptococcal (GAS) disease
with multi-organ dysfunction. Presented at the
30th Interscience Conference on Antimicrobial
Agents and Chemotherapy, Atlanta, GA, 1990;
Abstract 195.

19. Thomas JC, Carr SJ, Fujioka K, Waterman
SH. Community-acquired group A streptococcal
deaths in Los Angeles County. J Infect Dis
1989; 160:1086-7.

20. Francis J, Warren RE. Streptococcus
pyogenes bacteraemia in Cambridge: a review of
67 episodes. Q J Med 1988; 256:603-13.

21. Barnham M. Invasive streptococcal
infections in the era before the acquired
immune deficiency syndrome: a 10 years'
compilation of patients with streptococcal
bacteraemia in North Yorkshire. J Infect Dis
1989; 18:231-48.

22. Braunstein H. Characteristics of group
A streptococcal bacteremia in patients at the
San Bernardino County Medical Center. Rev
Infect Dis 1991; 13:8-11.

23. Schwartz B, Facklam RR, Brieman RF.
Changing epidemiology of group A streptococcal
infection in the USA. Lancet 1990;
336:1167-71.

24. Holm SE, Norrby A, Bergholm AM, Norgren
M. Aspects of pathogenesis of serious group A
streptococcal infections in Sweden, 1988-1989.
J Infect Dis 1992; 166:31-7.

25. Stegmayr B, Bjorck S, Holm S, Nisell J,
Rydvall A, Settergren B. Septic shock induced
by group A streptococcal infections: clinical
and therapeutic aspects. Scand J Infect Dis
1992; 24:589-97.

26. Demers B, Simor AE, Vellend H,
Schlievert PM, Byrne S, Jamieson F, et al.
Severe invasive group A streptococcal
infections in Ontario, Canada: 1987-1991. Clin
Infect Dis 1993; 16:792-800.

27. Auerbach SB, Schwartz B, Facklam RR,
Breiman R, Jarvis WR. Outbreak of invasive
group A  streptococcal (GAS) disease in a
nursing home. Presented at the 30th
Interscience Conference on Antimicrobial
Agents and Chemotherapy, Atlanta, GA, 1990; 
Abstract 171.

28. Hohenboken JJ, Anderson F, Kaplan EL.
Invasive group A streptococcal (GAS) serotype
M-1 outbreak in a long-term care facility
(LTCF) with mortality. Presented at the 34th
Interscience Conference on Antimicrobial
Agents and Chemotherapy, Orlando, FL, 1994;
Abstract J189.

29. Johnson DR, Stevens DL, Kaplan EL.
Epidemiologic analysis of group A
streptococcal serotypes associated with severe
systemic infections, rheumatic fever, or
uncomplicated pharyngitis. J Infect Dis 1992;
166:374-82.

30. Belani K, Schlievert P, Kaplan E,
Ferrieri P. Association of exotoxin-producing
group A streptococci and severe disease in
children. Pediatr Infect Dis J 1991; 10:351-4.

31. Hauser AR, Goshorn SC, Kaplan E,
Stevens DL, Schlievert PM. Molecular analysis
of the streptococcal pyrogenic exotoxins.
Presented at the Third International American
Society for Microbiology Conference on
Streptococcal Genetics. Minneapolis, MN, 1990.

32. Hauser AR, Stevens DL, Kaplan EL,
Schlievert PM. Molecular analysis of pyrogenic
exotoxins from Streptococcus pyogenes isolates
associated with toxic shock-like syndrome. J
Clin Microbiol 1991; 29:1562-7.

33. Musser JM, Hauser AR, Kim MH,
Schlievert PM, Nelson K, Selander RK.
Streptococcus pyogenes causing
toxic-shock-like syndrome and other invasive
diseases: clonal diversity and pyrogenic
exotoxin expression. Proc Natl Acad Sci USA
1991; 88:2668-72.

34. Mollick JA, Miller GG, Musser JM, Cook
RG, Grossman D, Rich RR. A novel superantigen
isolated from pathogenic strains of
Streptococcus pyogenes with aminoterminal
homology to staphylococcal enterotoxins B and
C. J Clin Invest 1993; 92:710-9.

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

36. Norrby-Teglund A, Newton D, Kotb M,
Holm SE, Norgren M. Superantigenic properties
of the group A streptococcal exotoxin SpeF
(MF). Infect Immun 1994; 62:5227-33.

37. Meleney FL. Hemolytic Streptococcus
gangrene. Arch Surg 1924; 9:317-64.

38. Adams EM, Gudmundsson S, Yocum DE,
Haselby RC, Craig WA, Sundstrom WR.
Streptococcal myositis. Arch Intern Med 1985;
145:1020-3.

39. Svane S. Peracute spontaneous
streptococcal myositis: a report on 2 fatal
cases with review of literature. Acta Chir
Scand 1971; 137:155-63.

40. Yoder EL, Mendez J, Khatib R.
Spontaneous gangrenous myositis induced by
Streptococcus pyogenes: case report and review
of the literature. Rev Infect Dis 1987;
9:382-5.

41. Nather A, Wong FY, Balasubramaniam P,
Pang M. Streptococcal necrotizing myositis   a
rare entity: a report of two cases. Clin
Orthop 1987; 215:206-11.

42. Stevens DL, Musher DM, Watson DA, Eddy
H, Hamill RJ, Gyorkey F, Rosen H, et al.
Spontaneous, nontraumatic gangrene due to
Clostridium septicum. Rev Infect Dis 1990;
12:286-96.

43. Bullowa JGM, Wischik S. Complications
of varicella. I: their occurrence among 2,534
patients. Am J Dis Child 1935;49: 923-6.

44. Fast DJ, Schlievert PM, Nelson RD.
Toxic shock syndrome-associated staphylococcal
and streptococcal pyrogenic toxins are potent
inducers of tumor necrosis factor production.
Infect Immun 1989; 57:291-4.

45. Hackett SP, Schlievert PM, Stevens DL.
Cytokine production by human mononuclear cells
in response to streptococcal exotoxins. Clin
Res 1991; 39:189A.

46. Hallas G. The production of pyrogenic
exotoxins by group A streptococci. J Hyg
(Camb) 1985; 95:47-7.

47. Lancefield RC. Current knowledge of
type specific M antigens of group A
streptococci. J Immunol 1962; 89:307-13.

48. Mollick JA, Rich RR. Characterization
of a superantigen from a pathogenic strain of
Streptococcus pyogenes. Clin Res 1991;
39:213A.

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

50. Kotb M, Tomai M, Majumdar G, Walker J,
Beachey EH. Cellular and biochemical responses
of human T lymphocytes stimulated with
streptococcal M protein. Presented at the 11th
Lancefield International Symposium on
Streptococcal Diseases, Siena, Italy, 1990;
Abstract L77.

51. Watanabe-Ohnishi R, Low DE, McGeer A,
Stevens DL, Schlievert PM, Newton D, et al.
Selective depletion of Vb-bearing T cells in patients
with severe invasive group A streptococcal
infections and streptococcal toxic shock
syndrome. J Infect Dis 1995; 171:74-84.

52. Stevens DL, Bryant AE, Hackett SP.
Gram-positive shock. Curr Opin Infect Dis
1992; 5:355-63.

53. Hackett S, Ferretti J, Stevens D.
Cytokine induction by viable group A
streptococci: suppression by streptolysin O.
Presented at the 93rd Conference of the
American Society for Microbiology, Las Vegas,
NV, 1994; Abstract B-249.

54. Muller-Alouf H, Alouf JE, Gerlach D,
Ozegowski JH, Fitting C, Cavaillon JM.
Comparative study of cytokine release by human
peripheral blood mononuclear cells stimulated
with Streptococcus pyogenes superantigenic
erythrogenic toxins, heat-killed streptococci
and lipopolysaccharide. Infect Immun 1994;
62:4915-21.

55. Hackett SP, Stevens DL. Superantigens
associated with staphylococcal and
streptococcal toxic shock syndromes are potent
inducers of tumor necrosis factor beta
synthesis. J Infect Dis 1993; 168:232-5.

56. Kappur V, Majesky MW, Li LL, Black RA,
Musser JM. Cleavage of Interleukin 1B (IL-1B)
precursor to produce active IL-1B by a
conserved extracellular cysteine protease from
Streptococcus pyogenes. Proc Natl Acad Sci USA
1993; 90:7676-80.

57. Cleary R, Chen C, Lapenta D, Bormann N,
Heath D, Haanes E. A virulence regulon in
Streptococcus pyogenes. Presented at the Third
International American Society for
Microbiology Conference on Streptococcal
Genetics, Minneapolis, MN, 1990; Abstract 19.

58. Cleary PP, Kaplan EL, Handley JP,
Wlazlo A, Kim MH, Hauser AR, et al. Clonal
basis for resurgence of serious Streptococcus
pyogenes disease in the 1980s. Lancet 1992;
339:518-21.

59. Nida SK, Ferretti JJ. Phage influence
on the synthesis of extracellular toxins in
group A streptococci. Infect Immun 1982;
36:745-50.

60. Johnson LP, Tomai MA, Schlievert PM.
Bacteriophage involvement in group A
streptococcal pyrogenic exotoxin A production.
J Bacteriol 1986; 166:623-7.

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

62. Kim KS, Kaplan EL. Association of
penicillin tolerance with failure to eradicate
group A streptococci from patients with
pharyngitis. J Pediatr 1985; 107:681-4.

63. Gatanaduy AS, Kaplan EL, Huwe BB, McKay
C, Wannamaker LW. Failure of penicillin to
eradicate group A streptococci during an
outbreak of pharyngitis. Lancet 1980;
2:498-502.

64. Brook I. Role of
beta-lactamase-producing bacteria in the
failure of penicillin to eradicate group A
streptococci. Pediatr Infect Dis 1985;
4:491-5.

65. Kohler W. Streptococcal toxic shock
syndrome. Zbl Bakt 1990; 272:257-64.

66. Eagle H. Experimental approach to the
problem of treatment failure with penicillin.
I. Group A streptococcal infection in mice. Am
J Med 1952; 13:389-9.

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

68. Stevens DL, Bryant AE, Yan S. Invasive
group A streptococcal infection: new concepts
in antibiotic treatment. Int J Antimicrob
Agents 1994; 4:297-301.

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

70. Yan S, Mendelman PM, Stevens DL. The in
vitro antibacterial activity of ceftriaxone
against Streptococcus pyogenes is unrelated to
penicillin-binding protein 4. FEMS Microbiol
Lett 1993; 110:313-18.

71. Yan S, Bohach GA, Stevens DL.
Persistent acylation of high-molecular weight
penicillin-binding proteins by penicillin
induces the post-antibiotic effect in
Streptococcus pyogenes. J Infect Dis 1994;
170:609-14.

72. Stevens DL, Maier KA, Mitten JE. Effect
of antibiotics on toxin production and
viability of Clostridium perfringens.
Antimicrob Agents Chemother 1987; 31:213-8.

73. Gemmell CG, Peterson PK, Schmeling D,
Kim Y, Mathews J, Wannamaker L, et al.
Potentiation of opsonization and phagocytosis
of Streptococcus pyogenes following growth in
the presence of clindamycin. J Clin Invest
1981; 67:1249-56.

74. Stevens DL, Bryant AE, Hackett SP.
Antibiotic effects on bacterial viability,
toxin production and host response. Clin
Infect Dis 1995;20(Suppl 2):S154-7.

75. Barry W, Hudgins L, Donta ST, Pesanti
EL. Intravenous immunoglobulin therapy for
Toxic shock syndrome. JAMA 1992;
267(24):3315-6.

76. Yong JM. Letter. Lancet 1994; 343:1427.

77. Greenberg LJ, Gray ED, Yunis E.
Association of HL-A5 and immune responsiveness
in vitro to streptococcal antigens. J Exp Med
1975; 141:934-43.

78. Weinstein L, Barza M. Gas gangrene. N
Engl J Med 1972; 289:1129.

79. Zabriskie JB, Lavenchy D, Williams RCJ,
et al. Rheumatic-fever associated B-cell
alloantigens as identified by monoclonal
antibodies. Arthritis Rheum 1985; 28:1047-51.

80. Schwartz B, Elliot JA, Butler JC, Simon
PA, Jameson BL, Welch GE, et al. Clusters of
invasive group A streptococcal infections in
family, hospital, and nursing home settings.
Clin Infect Dis 1992; 15:277-84.