CLINICAL AND LABORATORY INVESTIGATIONS

Pediatric Dermatology Vol. 11 No. 4 293—303

Impetigo: An Overview
Gary L. Darmstadt, M.D., and Alfred T. Lane, M.D.
Department of Dermatolog y, Stanford Universit y School of Medicine, Stanford, California

Abstract: This article reviews in detail the pathogenesis, clinical char-

acteristics and management of impetigo in children. Impetigo is the
most common bacterial skin infection of children. Most cases of
nonbullous impetigo and all cases of bullous impetigo are caused by
Staphylococcus aoreos. The remainder of cases of nonbullous
impetigo are due to group A beta hemolytic streptococci (GABHS).
GABHS colonize the skin directly by binding to sites on fibronectin
that are exposed by trauma. In contrast,
S. aureos colonizes the nasal epithelium first; from this reservoir,
coloni- zation of the skin occurs. Patients with recurrent impetigo
should be eval- uated for carriage of S. aoreos. Superficial, localized
impetigo may be treated successfully in more than 90% of cases with
topical application of mupirocin ointment. Impetigo that is widespread
or involves deeper tis- sues should be treated with a beta-lactamase-
resistant oral antibiotic. The choice of antibiotics is affected by the local
prevalence of resistance to erythromycin among strains of S. atzreos,
antibiotic cost and availability, and issues of compliance.

Skin complaints or findings are noted in 20% to
30% of children who attend general pediatric clinics
(Table 1) (1,2). Bacterial skin infection is the single
most common diagnosis among those with skin
problems, accounting for 17% of all clinic visits.
The most common bacterial skin infection of chil-
dren is impetigo, which makes up approximately
10% of all skin problems (1,2).
PATHOGENESIS
In order to understand the pathogenesis of im-
petigo, it is essential to appreciate the factors which
alter the normal flora of the skin and which promote
colonization and infection of the skin with patho-
genic bacteria. This subject has recently been re-
viewed extensively by Roth and James (3).
Resident and Transient Cutaneous Flora
Normal skin microflora falls into two broad catego-
ries: 1) resident flora which are attached to the skin
Address correspondence to Gary L. Darmstadt, M.D., De-
partment of Dermatology, Stanford University School of Medi-
cine, 900 Blake Wilbur Drive, Palo Alto, CA 94304.
and are present in relatively stable numbers, and
2) transient flora, which are introduced from the
envi- ronment onto exposed skin and lie free on
the skin surface, without attachment in the
absence of a dis- turbance in the integrity of the
skin (3). The most important of the transient
bacteria are the group A beta-hemolytic
streptococci {Streptococcus p yo- genes; GABHS)
and StaphylocoCCuS aureus.
Coagulase-negative staphylococci are the most
numerous of the resident flora, whereas coagulase-
positive S. aureus encounters a high degree of nat-
ural resistance to colonization of the skin. Most
body sites are free from colonization with S. aureus
(4). However, persistent nasal carriage is detected
in 20Po to 40% of normal adults (5,6), and up to 20%
of people may be colonized on the perineum (7). In
contrast, patients with atopic dermatitis will yield
S. aureus from upwards of 90% of skin lesions and
70% of cultures from nonlesional skin (8,9).
Coryneform organisms are lipophilic, pleomor-
293
294 Pediatric Dermatology Vol. 11 No. 4 December 1994

TABLE 1. Skin Disorders of Patients Who Present to a

General Pediatric Clinic dermidis is the most common vaginal organism,
and consequently, is the predominant organism in
Percentage of Disorders the neonate; it favors colonization of the upper part
of
Diagnosis the body (12). Within hours, coryneform bacteria
Tunnessen* Haydent also take up residence on neonatal skin. After the
Skin Infections
first few weeks of life, the neonatal skin microflora
Bacterial 17.5 17.4 resembles that of the adult. In the interim, however,
Impetigo 10.0 8.9
Scarlet fever NR 4.3 gram-negative rods and S. aureus, which has a pro-
Cellulitis 6.0 2.6 pensity to colonize the umbilicus and nasopharynx,
Folliculitis 1.5 0.9 may gain a foothold and cause disease. Antibiotic
Viral 6.5 8.5
Fungal 10.0 9.8 treatment, whether systemic or topical, may de-
Atopic dermatitis 14.5 9.4 crease the density of coryneforms, with a corre-
Diaper dermatitis 11.0 15.7 sponding increase in density of coagulase-negative
Contact dermatitis 8.5 4.7
Seborrheic dermatitis 0.5 5.5 micrococci and gram-negative rods (13). Topical
corticosteroids have little effect on the microflora,
* Pediatr Dermatol l984;1:219- except in patients with atopic dermatitis in whom
222. I Am J Dis Child
1985;139:36—38. the density of S. aureus may decrease following
NR = not reported. their application (14), perhaps through healing of
phic gram-positive rods which are normal residents the skin.
of moist, intertriginous areas of skin (3). Brevibac-
terium preferentially grow in toe webs, especially in
Mechanism of Skin Colonization
association with tinea pedis, and are implicated in
foot odor (10). Propionibacteria are anareobes The process of colonization of the skin involves ir-
which grow in hair follicles and sebaceous glands. reversible adherence to a specific receptor on the
Propionibacterium ocnes, the predominant species, host cell via an adhesin, an antigen on a filamentous
is present in all adults and is the most numerous or- projection from the bacterial cell wall. A major
ganism at sites of high sebum production such as component of the adhesins for staphylococci and
the scalp, forehead, and back. While micrococci streptococci are teichoic acids. Correspondingly,
and coagulase-negative staphylococci usually live the epithelial cell receptor for teichoic acid is com-
on the surface of the stratum corneum and upper posed of fibronectin (15). The difference in normal
parts of hair follicles, the corynebacteria and propi- microflora at different anatomic sites reflects site-
onibacteria are more often found deep in follicular specific differences in receptors (3). Similarly, the
canals. Candida species, most commonly C. albi- pathogenic potential of transient microflora is also
cans, colonize the oral mucous membranes in up to affected by cell surface receptors. For example,
40% of individuals; normal skin is seldom colo- GABHS which are isolated from the skin adhere
nized, except in individuals who have psoriasis or more strongly to skin epithelium than to buccal mu-
atopic dermatitis, or are immunosuppressed. cosa; the opposite is true for streptococci isolated
from the oral cavity (16). This may help explain
why the types of GABHS that cause phayngitis
Factors That Modify the Resident Flora
differ from those that cause impetigo. The inability
Factors that modify the resident flora and may fa- of streptococci and staphylococci to colonize unbro-
cilitate colonization by transient, pathogenic ken epithelium may be due to the absence of avail-
GABHS and S. aureus include increased tempera- able fibronectin on the skin surface. Breaks in the
ture, humidity, presence of cutaneous disease, age skin, however, may reveal fibronectin receptors, al-
of the patient, and history of antibiotic treatment. A lowing GABHS or S. aureus organisms to colonize
decrease in temperature favors the nonpathogenic, the skin (17) and potentially lead to the develop-
coagulase-negative staphylococci over pathogenic ment of impetigo.
coagulase-positive S. aureus and decreases the vir- Knowledge of bacterial adhesins could lead to
ulence of infection with the latter organisms (11). novel approaches to prevention or treatment of bac-
Nasal carriage of S. aureus in neonates or in pa- terial skin infections. Topical application of a puri-
tients with atopic dermatitis has been associated fied bacterial adhesin such as teichoic acid, or of
with an increased number of days of hospitalization cell surface receptors such as flbronectin, might
(5). Colonization of the skin begins at birth. S. epi- competitively block pathogenic staphylococci and

streptococci from adhering to the skin (18,19).
Competitive binding to cell surface receptors by
resident flora or transient flora of low virulence may
also prevent pathogenic bacteria from colonizing
the skin. A nonvirulent strain of S. aureus has been
useful in neonates during nursery epidemics to pre-
vent colonization of the nasal mucosa with a patho-
genic strain of S. aureus (20), and in adults to pre-
vent spread of recurrent staphylococcal abscesses
within families (21).
Defenses Against Colonization by
Pathogenic Bacteria
Once a pathogenic bacteria has adhered to the skin,
it must overcome several avenues of host defense
before infection can develop. Intact stratum cor-
neum provides the first and foremost mechanism of
defense. Cells of the stratum corneum overlap, and
are tightly adherent, providing a mechanical bar-
rier. In addition, the stratum corneum turns over an
average of every 14 days, favoring the readherence
of resident flora over the relatively weakly adherent
pathogenic microflora. To overcome this barrier,
staphylococci have been observed to advance be-
tween corneocytes, through intercellular spaces
(22). Likewise, S. aureus has a predilection for en-
tering the skin at appendageal structures (3).
Breakdown products of the stratum corneum, in-
cluding free fatty acids, polar lipids, and gly-
cosphingolipids, have antistaphylococcal and an-
tistreptococcal activity (22). Many of the resident
flora, particularly the lipophilic corynebacteria,
have lipases, and thus contribute to defense against
GABHS and S. aureus by liberating fatty acids from
the triglycerides of sebum (23). The acid mantle
thus created favors growth of propionibacteria,
which in turn produce propionic acid; this com-
pound has relatively more antimicrobial activity
against organisms than against resident flora.
Humoral immunity may aid in defense against in-
fection through secretion of IgA in sweat. The cel-
lular immune system, including antigen presenta-
tion by epidermal Langerhans cells, plays an
important role in defending from infection, as evi-
denced by patients with defects in cellular immunity
such as mucocutaneous candidiasis and chronic
granulomatous disease who have increased suscep-
tibility to cutaneous infection.
A mechanism whereby a given organism can
gain an advantage over others is through the
production of antibiotics which harm other
organisms but not the producer of the substance.
Gram-negative bac-
Darmstadt and Lane: Impetigo 295
teria tend to produce substances with a wide-
spectrum of activity, whereas the substances se-
creted by gram-positive organisms tend to affect
only the same or closely related species of bacteria.
These narrow-spectrum substances are called bac-
teriocins (24). Bacteriocin producers, including S.
aureus, tend to increase in number and become the
predominant species when the skin is damaged (25).
As expected, based on the above review of fac- tors
which modify the balance of skin flora, condi-
tions that favor development of impetigo include
warm ambient temperature, humidity, preexisting
dermatitis such as atopic dermatitis or tinea capitis,
crowded living conditions, and poor hygiene.
CLINICAL CHARACTERISTICS
Nonbullous Impetigo
There are two classic forms of impetigo: nonbullous
and bullous. Nonbullous impetigo accounts for
more than 70% of cases of impetigo (26-31). Le-
sions of nonbullous impetigo typically begin on skin
of the face or extremities which has been trauma-
tized; intact skin is resistent to impetiginization or
even colonization (32), perhaps due to unavailabil-
ity of fibronectin receptors for teichoic acid moities
on GABHS and S. aureus organisms. The most
common lesions which precede nonbullous im-
petigo include chickenpox, insect bites, abrasions,
lacerations, and burns. A tiny vesicle or pustule
forms initially and rapidly develops a honey-
colored, crusted plaque which is generally less than
2 cm in diameter. Lesions are associated with little
to no pain or surrounding erythema, and constitu-
tional symptoms are generally absent. Pruritis oc-
curs occasionally, regional adenopathy is found in
up to 90% of cases (29,33), and leukocytosis is
present in approximately 50% of patients (34).
Without treatment, lesions may progress slowly for
several weeks and occasionally may form a chronic
ulcer, but in most cases will resolve spontaneously
without scarring within approximately two weeks
(35). The differential diagnosis of nonbullous im-
petigo includes viral (herpes simplex, varicella
zoster), fungal (tinea corporis, kerion), and para-
sitic infections (scabies, pediculosis capitis), all of
which may become impetiginized secondarily (36).
From the 1940s to the mid 1960s, nonbullous im-
petigo in the United States was primarily of staphy-
lococcal origin (27,36). During the later 1960s and
the 1970s, GABHS became the predominant patho-
genic organism. Prospective studies of impetigo in
an endemic area, the Red Lake Indian reservation
296 Pediatric Dermatology Vol. 11 No. 4 December 1994
of Minnesota, during 1969 demonstrated that early
lesions of nonbullous impetigo more commonly
grew pure cultures of GABHS (36%) than S. aureus
(9%); GABHS more commonly outlasted staphylo-
cocci in mixed lesions which were cultured sequen-
tially; and while the same strain of GABHS per-
sisted in 85% of sequentially cultured lesions
during an average time of 12.6 days to spontaneous
heal- ing, the strain of staphylococcus changed in
57% of lesions (35). Unlike today, the clinical
response of nonbullous impetigo to penicillin was
found to be the same, regardless of whether culture
of the lesion grew pure GABHS as opposed to
either mixed GABHS and penicillin-resistant
staphylococci (37), or pure penicillin-resistant
staphylococci (38). A possible explanation for this
finding was that S. au- reus produced a bacteriocin,
which interfered with growth of GABHS in culture
(39).
Studies during the 1960s also clarified the differ-
ing natural history of GABHS and staphylococci in
lesions of nonbullous impetigo. In 21 of 31 (70%)
cases of impetigo in Red Lake Native American
children, the skin became colonized with GABHS
an average of 10 days before development of inn
petigo; in approximately 74% of episodes, the same
serotype was recovered from normal skin and the
subsequent lesion of impetigo (40). After gaining a
foothold in the skin, GABHS then colonized the na-
sopharynx; in 74% of episodes of impetigo, the
same strain of GABHS was recovered from the
nose and throat an average of 15 and 20 days, re-
spectively, after the appearance of lesions of im-
petigo. Among family contacts, streptococcal skin
infection developed without going through interme-
diate respiratory colonization or infection. Routine
cultures of normal skin of the wrist, ankle, and back
were three times more likely to be positive for
GABHS (31Wo of 4021 cultures) than cultures
from the nose (11% positive) or throat (10%
positive) (40). These data suggest that the upper
respiratory tract does not serve as the reservoir for
infection of the skin with GABHS, but vice versa
(40,41).
In contrast to streptococci, staphylococci gener-
ally spread from the nose to normal skin, and
thence are able to infect the skin (29,35). Among 31
patients with bullous impetigo, 19 (61%) had con-
current impetigo and a positive staphylococeal cul-
ture from the nose or throat; 79% of cultures grew
the same strain from both sites (29). At the Red
Lake Indian Reservation, a single strain of Staphy-
lococcus, phage type 75, accounted for the majority
of staphylococcal isolates from the respiratory tract
(56Po), normal skin (68%), and skin lesions (58%)
of 37 children (35).
During the early 1980s S. aureus again became
the predominant organism of nonbullous impetigo
in the United States (42). Staphylococci can now be
cultured from approximately 80% or more of
lesions of impetigo of most populations, and is the
sole pathogen in approximately 50% to 60% of
cases (3, 27,30,31,43,44). Furthermore, several
recent stud- ies have demonstrated that treatment
regimens which utilize antistaphylococcal agents
now pro- duce cure rates superior to those regimens
which employ beta-lactamase sensitive antibiotics.
Lesions of nonbullous impetigo which grow
staphylococci in culture cannot be distinguished
clinically from those which grow pure cultures of
GABHS (26,29,30,42). Whereas S. aureus can be
cultured from lesions of impetigo on children of all
ages, GABHS is most common in children of pre-
school age and is unusual before 2 years of age ex-
cept in highly endemic areas (36,45).
The staphylococcal types which cause nonbul-
lous impetigo are variable and are from phage group
2, which is associated with scalded skin and toxic
shock syndromes, in the minority of cases (29).
Several serotypes of GABHS, termed “impetigo
strains,” are found most frequently in lesions of
nonbullous impetigo (41) and are different from
those that cause pharyngitis. The risk of developing
impetigo following colonization with GABHS var-
ies with the specific serotype (40).
Bullous Impetigo
Bullous impetigo is always caused by coagulase-
positive S. aureus; approximately 80% are from
phage group 2, 60% are type 71, and most of the
remainder are types 3A, 3B, 3C, and 55 (29,46).
Flaccid, transparent bullae develop most commonly
on skin of the face, buttocks, trunk, perineum, and
extremities (27,29). Rupture of bullae occurs easily,
leaving a narrow rim of scale at the edge of a shal-
low, moist erosion (29). Surrounding erythema and
regional adenopathy are generally absent.
Unlike nonbullous impetigo, lesions of bullous
impetigo are a manifestation of localized staphylo-
coccal scalded skin syndrome (SSSS) and therefore
develop on intact skin. When 6. aureus of phage
group 2 were injected into newborn mice, a gener-
alized exfoliative erythroderma developed, regard-
less of whether the S. aureus organisms had been
isolated from lesions of patients with bullous iron-
petigo or SSSS (47).

HISTOPATIIOLOGY
On histopathologic examination, lesions of bullous
impetigo show vesicle formation in the subcorneal
or granular region, occasional acantholytic cells
within the blister, spongiosis, edema of the papil-
lary dermis, and a mixed infiltrate of lymphocytes
and neutrophils around blood vessels of the super-
ficial plexus. Neutrophils are generally visible
within the blister cavity. Unless staphylococci can
be cultured from the bullae or, less commonly, can
be seen on gram stain, it may be impossible to dif-
ferentiate bullous impetigo from pemphigus folia-
ceus histopathologically. Pemphigus foliaceus tends
to have more acantholysis and fewer neutrophils
within the subcorneal blister and may have dyskera-
totic changes in cells of the granular layer (48).
Clin- ically, pemphigus folliaceus differs from
impetigo in its presentation with multiple small
flaccid blisters which easily rupture, leaving
erythematous, crusted erosions. Subcorneal pustular
dermatosis may also be indistinguishable,
histopathologically, from im- petigo, but its clinical
presentation is that of crops of grouped pustules in
a serpiginous outline, gener- ally on the abdomen or
in the axillary and inguinal folds, sparing the face.
Nonbullous impetigo has histopathologic findings
similar to the bullous vari- ant, except that blister
formation is slight.
The differential diagnosis of bullous impetigo
also includes allergic contact dermatitis, bullous
pemphigoid, burns, dermatitis herpetiformis, and
erythema multiforme. Although these conditions
are histopathologically distinct from impetigo, each
may become impetiginized secondarily.
COMPLICATIONS
Potential complications of either nonbullous or bul-
lous impetigo include osteomyelitis, septic arthritis,
pneumonia, and septicemia (29). Positive blood cul-
tures are rare, but are more common with skin than
respiratory infection with GABHS (46). Cellulitis
has been reported in approximately 10% of patients
with nonbullous impetigo, but rarely follows the
bullous form (29). Lymphangitis, suppurative lym-
phadenitis, guttate psoriasis, and scarlet fever may
follow streptococcal disease occasionally. There is
no correlation between number of lesions and clini-
cal involvement of the lymphatics or development
of cellulitis in association with streptococcal im-
petigo (29).
Infection with nephritogenic strains of GABHS
may result in acute poststreptococcal glomerolone-
Darmstadt and Lane: Impetigo 297
phritis (APSGN). The clinical character of impetigo
lesions is not different between those that lead to
APSGN and those that do not (29,33). Fewer than
5% of patients with APSGN are less than 2 years of
age; it most commonly affects those 3 to 7 years
old. The latent period from onset of impetigo to de-
velopment of APSGN averages 18 to 21 days,
which is longer than the 10-day latency period
following pharyngitis (41,49).
APSGN occurs sporadically, due primarily to M
type 12 infection of the pharynx, and epidemically
following either pharyngeal or skin infection.
Impetigo-associated epidemics are caused by M
groups 2, 49, 53, 55, 56, 57, and 60 (41,49), whereas
M groups 1 and 12 are most often associated with
APSGN following pharyngitis. M types 1 and 12 are
rarely isolated from lesions of impetigo.
The most common site of GABHS infection
which results in APSGN varies according to geo-
graphic location. While 76% of symptomatic
APSGN in children in Chicago was associated with
upper respiratory tract infection (50), 40% to 80% of
episodes of APSGN in children in the southeast fol-
lowed impetigo (41,51,52). In general, since the
1960s APSGN in the United States has appeared
more frequently following pharyngitis than impetigo
(53).
The true incidence of APSGN is difficult to de-
termine, as many mild or subclinical cases go unde-
tected. A prospective study of 248 children with
streptococcal infection demonstrated that 22% de-
veloped asymptomatic urinary abnormalities, a low
serum C3 concentration, or both (54). The risk of
nephritis after impetigo varies widely with the strain
of GABHS. During an epidemic of acute nephritis
due to M group 49 GABHS, 24% of children with
streptococcal impetigo developed acute nephritis or
unexplained hematuria; the risk was highest in chil-
dren less than 6'/2 years of age (43%) (55). Multiple
subclinical and clinical cases of nephritis often oc-
cur within a family (41). Strains of GABHS which
are associated with endemic impetigo in the United
States have little or no nephritogenic potential (55).
There have been no cases of glomerulonephritis
among the more than 500 patients from trials which
compared the efficacy of erythromycin and mupiro-
cin treatments (28,30,31,43,44,56,57).
IMMUNE RESPONSE TO
STREPTOCOCCAL IMPETIGO
Anti-DNAase B is the test of choice for detecting
preceding streptococcal impetigo. Of patients with
298 Pediatric Dermatology Vol. 11 No. 4 December 1994
uncomplicated impetigo and impetigo-associated
APSGN, 67% and 92%, respectively, had elevated
antideoxyribonuclease B (anti-DNAase B) titers
(33). After an episode of nonbullous impetigo
caused by GABHS, the antistreptolysin O response
is slight or absent, perhaps due to binding of strep-
tolysin O by lipids, including cholesterol, in the
skin (58). In one study, 43% and 51% of patients
with uncomplicated impetigo and impetigo-
associated APSGN, respectively, developed an
elevated ASO titer. The anti-DNAase B response is
greater after impetigo than after pharyngitis,
whereas the ASO titer is more highly elevated
following pharyngitis (49). The antihyaluronidase
test is also thought to be superior to the ASO test in
documenting a pre- ceding streptococcal skin
infection (59). The strep- tozyme test measures
more than five antibodies to streptococcal antigens,
including ASO, anti- DNAase B, and
antihyaluronidase. When only one of the antibodies
is minimally elevated, however, false negative
results may be obtained (60). In addi- tion, the
combination of individual ASO and anti- DNAase
B tests is more effective than the strep- tozyme test
in detecting preceding GABHS infection (61).
Treatment, whether systemic or top- ical, in cases of
APSGN following impetigo, does not prevent the
development of APSGN in the in- dex case (36,62),
but may prevent spread of im- petigo to others and
thus reduce the incidence of APSGN in the
community. Acute rheumatic fever does not occur
as a result of impetigo.
TREATMENT
Several studies have demonstrated that topical
(neomycin, bacitracin, polysporin, gentamicin, or
mixtures of these) or systemic antibiotic treatment
is superior to placebo or cleansing with 3% hexa-
chlorophene soap (63). Furthermore, cleansing with
3% hexachlorophene soap adds little to no benefit
over systemic antibiotics alone (36). Until the intro-
duction of mupirocin (Bactroban), topical antibiot-
ics were inferior to systemic antibiotics (64,65).
Factors to consider when selecting the optimal
antibiotic for treatment of impetigo include ease of
use, low potential for adverse reactions, delivery of
a high concentration of drug to the site of infection,
low risk for development of bacterial resistance or
cross resistance to other agents, chemical structure
and mechanism of action which is unrelated to other
antibiotics, activity against common bacterial skin
pathogens (i.e., GABHS, S. aureus, including
methicillin resistant and beta-lactamase producing
strains), utility as a single agent, lack of alteration
of resident skin and gut flora, and competitive
price.
Topical Antibiotics
Mupirocin is produced during fermentation by
Pseudomonas fluorescens. It was first introduced in
the United Kingdom in 1985. Its chemical structure
is unique among antibiotics, and it is highly unlikely
to cause photoreactions because the wavelength of
ultraviolet light which it is capable of absorbing to
the greatest degree (222 nm) never reaches the
earth’s surface, but rather is filtered out by the
ozone layer (66). Mupirocin is bactericidal at the
concentration achieved following topical applica-
tion and is not absorbed systemically. Even when
administered systemically, however, mupirocin is
converted rapidly to an inactive metabolite (67).
Therefore, side effects from mupirocin, especially
contact hypersensitivity, appear to be due to the
polyethylene glycol vehicle rather than the active
ingredient (67). Mupirocin’s mode of action is the
reversible inhibition of bacterial isoleucyl-tRNA
synthetase; it has a relatively low afflnity for mam-
malian isoleucyl-tRNA synthetase. Micrococcus
spp. , coryneforms, and propionibacteria are less
sensitive than GABHS or S. aureus to mupirocin
(68); thus, the natural skin flora is left relatively un-
disturbed. Rare instances of bacterial resistance to
mupirocin have been reported (68,69). Coagulase-
negative staphylococci, S. aureus, and GABHS are
thought to share a common antibiotic resistance
gene pool, which theoretically could be transferred
from the resident flora, particularly S. epidermidis,
to pathogens during infections (68,69). Most pa-
tients who have demonstrated resistance to mupiro-
cin have been treated irregularly and/or prophylac-
tically for prolonged periods of time (more than two
weeks).
Several studies have demonstrated that mupiro-
cin applied three times daily for 7 to 10 days is
equal to or greater in effectiveness than oral
erythromycin ethylsuccinate 30 to 50 mg/kg/day for
7 to 10 days for treatment of impetigo in children
(30,31,43,44, 56,57). Treatment success rate with
mupirocin was greater than 90%, regardless of
whether the length of treatment was 7, 8, or 10
days. There were fewer side effects of treatment
(30,31,43,56), in some cases lesions cleared more
rapidly, and the rate of erradication of pyogenic
bacteria was equivalent
(28) or greater (30,57) in those treated with topical
mupirocin compared with systemic erythromycin.
A cost-effectiveness analysis evaluated the total

cost, including physician fees, transportation ex-
penses, and cost of the medication for a 10-day
course of treatment with mupirocin compared with
erythromycin ethylsuccinate. Although the cost of
treatment was significantly greater for mupirocin
($62.30) than for erythromycin ($56.85), this extra
cost was offset by increased side effects (43% vs
22%) and number of schooldays (3.0 vs 1.2) and
workdays (0.5 vs 0.2) missed in the group treated
with erythromycin (28).
Studies which have compared the effectiveness
of mupirocin with erythromycin have generally re-
stricted their patient population to those with super-
ficial, localized primary pyoderma. Low-grade fe-
ver (31,56) and regional adenopathy (31), however,
are not absolute contraindications to treatment with
mupirocin. Lesions around the mouth should prob-
ably not be treated with mupirocin, as the medica-
tion may be licked off (30).
A patient with recurrent impetigo should be eval-
uated for S. aureus carriage. Colonization of the
nares, via teichoic acid adhesins (70), correlates
with carriage at other sites such as the perineum
(71) and the axillae, but screening for nasal carriage
alone may miss approximately one-fourth of carri-
ers (72). The flrst clinical trial of mupirocin for
elim- ination of nasal carriage of 5. aureus
demonstrated that application of mupirocin four
times daily for five days to the anterior nares
eliminated nasal car- riage within two days in all 32
patients (73). Coagulase-negative staphylococci and
coryneforms became the dominant nasal flora, and
may have contributed to prevention of reaquisition
of S. au- reus by the mechanism of bacterial
interference (74); there was no overgrowth of gram-
negative or- ganisms (73). Twenty-two weeks after
therapy, however, half of the patients were
recolonized with
S. aureus; 29% reacquired the same phage type
(73). Several studies have reproduced these results,
showing elimination of nasal carriage of methicillin-
sensitive and methicillin-resistant S. aureus
(MRSA) from greater than 90% of patients within
two to four days (75,76). In time, however, mea-
sured in weeks to months, the nares become recol-
onized. Mupirocin is better tolerated intranasally
when formulated as a calcium ointment than as Bac-
troban, which utilizes polyethylene glycol as the ve-
hicle (75,77). Calcium mupirocin ointment, how-
ever, is not currently available in the United States.
Although rates of staphylococcal infection have
been reduced in patients with atopic dermatitis (78)
and those on hemodialysis (79) following elimina-
tion of nasal carriage, it is recommended that use of
Darmstadt and Lane: Impetigo 299
mupirocin for elimination of nasal carriage be re-
served for outbreaks, primarily when MRSA is in-
volved (76,80), to minimize the emergence of resis-
tant strains of S. aureus. Consideration should also
be given to using mupirocin intranasally for those
with recurrent impetigo, particularly if the phage
types which are cultured from the nares and lesions
of impetigo are identical repeatedly.
Systemic Oral Antibiotics
Penicillins
The majority of strains of S. aureus isolated from
lesions of impetigo in various areas of the United
States are resistant to penicillin or amoxicillin (26,
27,31,57), resulting in treatment failure rates of one-
fourth or more (26,27,42). Given that lesions of
non- bullous impetigo due to GABHS or S. aureus
cannot be distinguished clinically (26,29,30,42),
treatment with penicillin or amoxicillin is no longer
appropriate (81). Adding clavulanic acid, a beta-
lactamase inhibitor, to amoxicillin significantly im-
proved the efflcacy of amoxicillin from a 20Po fail-
ure rate to no failures (82). In two studies,
amoxicillin (20 [83] or 25 [84] mg/kg/day given
TID for 10 days) plus clavulanic acid (Augmentin)
was compared with cefaclor (20 mg/kg/day given
TID for 10 days) for treatment of impetigo in
children. Augmentin produced an equivalent rate of
clinical cure (89% [83] or 86% [84) for Augmentin
versus 81Po [83] or 90% [84] for cefaclor) but a
superior rate of bacteriologic cure (86% (83) or
100% [84) for
Augmentin versus 33% [83) or 90% [84] for ce-
faclor). Treatment with cloxacillin resulted in a
100% cure rate among 33 children with impetigo
(85).
CephalospDrins
The first generation cephalosporin, cephalexin (40
to 50 mg/kg/day for 10 days) produced more rapid
(21 to 23 patients cured within three to five days)
clearing of lesions of impetigo than did erythromy-
cin estolate (30 to 40 mg/kg/day for 10 days; 16 of
25 patients cured within three to five days), but the
cure rate at the end of 10 days of treatment was
equivalent (100% for cephalexin versus 94% for
erythromycin) (26).
Cefprozil (Cefzil) is a second generation cephalo-
sporin which has greater in vitro activity than
cefaclor or cephalexin against GABHS and
methicillin-susceptible S. aureus (86). Cefprozil (20
mg/kg once daily), cefaclor (20 mg/kg divided three
times daily), or erythromycin ethylsuccinate (30
mg/kg/d divided four times daily), each given for 5
300 Pediatric Dermatology Vol. 11 No. 4 December 1994

TABLE 2. Cost of Antibiotics for Treatment of Impetigo

Dosing
Antibiotic*t Dose (mg/kg/day) Interval Costs
Augmentin 82“ 4 20 TID $29.50
Cephalexin26# 87 # 88 40 TID $19.75
Cefaclor" ' 4 20 TID $31.05
Cefadroxil" 30 BID $24.95
Cefprozil'“ 8 20 QD or BID $35.35
Cefpodoxime" 10 BID $58.95
Clarithromycin’0 15 BID $24.30
Clindamycin" 15 TID or QID $28.45
Dicloxacillin 8’ 30 QID $25.95
Erythromycin ethy1succinate§ 40 TID or QID $15.40
Erythromycin estolate°6 ’ 2 30 TID or QID $10.25
1
Mupirocin' 0'3 43 44#56#5 15 g tube TID $18.25

* All antibiotics listed have been shown in clinical trials to be highly efficacious (> 85Wo
clinical cure) for treatment of impetigo in children.
I Superscripts indicate reference number for use of given antibiotic for treatment of im-
petigo.
I Cost based on treatment of a 20-kg child for seven days. Price for prescription filled at
Stanford University Medical Center Outpatient Pharmacy.
§ References 30,3l,43,44,56,57,88,9l,92.

to 10 days, produced an equivalent, greater than

90% clinical response and bacteriologic eradication
rate of S. aureus and GABHS in patients with a va-
riety of skin infections, approximately one-fourth of
which were impetigo (87,88). The incidence of ad-
verse reactions was equivalent for the three medi-
cations (88). The primary advantage of cefprozil
was the ease of once daily administration.
Cefpodoxime proxetil is an oral third-generation
cephalosporin which has shown 92% clinical effi-
cacy in the treatment of impetigo in 66 children (89).
This agent has not been compared with other agents
for treatment of impetigo.
Miscellaneous
Clindamycin (15 mg/kg/day given TID or QID for
10 days) and erythromycin ethylsuccinate (40
mg/kd/ day given QID for 10 days) produced
equivalent rates of clinical (99% for both agents)
and bacterio- logic (99% for both agents) cure of
lesions of im- petigo in children which were
predominantly strep- tococcal in etiology (91).
Clindamycin has not been evaluated for treatment
of impetigo during the era of staphylococcal-
predominant impetigo but would be expected to
provide excellent staphylococcal coverage.

Macrolides Summary of Treatment

Clarithromycin is a new macrolide antibiotic which
offers the advantage of fewer gastrointestinal side
effects and less frequent dosing than erythromycin.
Clarithromycin has superior activity in vitro com-
pared with erythromycin against erythromycin-
sensitive S. aureus and GABHS, but no better ac-
tivity against erythromycin-resistant GABHS and
S. aureus or methicillin-resistant S. aureus (81). A
recent study of 231 children with skin infection,
three-fourths of whom had impetigo, showed that
clarithromycin (7.5 mg/kg twice daily for 10 days)
and cefadroxil, a first generation cephalosporin (15
mg/kg twice daily for 10 days) produced equivalent
rates of clinical (86% and 94%, respectively) and
bacteriologic (96Po and 99%, respectively) cure
(90). Fifteen percent of 5. aureus isolates, however,
were resistant to clarithromycin, compared with
5% resistance to cefadroxil.
In areas with a high prevalence of erythromycin-
resistant strains of S. aureus, a child with superfi-
cial, localized impetigo not involving the mouth
could be treated successfully with mupirocin ap-
plied topically three times daily for seven days. For
impetigo that is more widespread or involves
deeper tissues as in cellulitis, furunculosis, or sup-
purative lymphadenitis, a beta-lactamase-resistant
oral antibiotic should be prescribed. In areas with a
low prevalence of S. aureus resistance to erythro-
mycin, erythromycin ethylsuccinate (40 mg/kg/day
divided three to four times daily for seven days) or
erythromycin estolate (30 mg/kg/day divided three
to four times daily) are preferred oral therapies
(92). If there is widespread erythromycin resistance
in the community, alternative oral antibiotics which
have been shown to be more than 85% effective in
children for treatment of impetigo include cloxacil-
 Darmstadt and Lane: Impetigo 301

lin; amoxicillin plus clavulanic acid; clindamycin; 16. Alkan M, Ofek I, Beachey E. Adherence of pharyn-
or a cephalosporin such as cephalexin, cefaclor, ce- geal and skin strains of group A streptococci to hu-
fadroxil, cefprozil, or cefpodoxime. The choice man skin and oral epithelial cells. Infect Immun
1977;
18:555—557.
among these various agents may be guided i7. Cole GW, Silverberg NL. The adherence of Staphy-
primari- ly by issues of cost (Table 2), local lococcus aureus to human corneocytes. Arch
availability, and compliance. Clarithromycin may Derma- tol 1986;122: 166—169.
be advantageous
primarily in instances of intolerance to erythromy- 15. Kuusela P, Vartio T, Vuento M, et a1. Binding sites
cin, but would not be expected to provide cure for streptococci and staphylococci in fibronectin. In-
fect Immun 1984;45:433—436.
rates superior to erythromycin in areas with high
rates of
S. aureus resistance to erythromycin.
There is little evidence to suggest that a 10-day
course of therapy is superior to 7-day course. If a
satisfactory clinical response is not achieved
within seven days, a culture should be taken by
swabbing beneath the lifted edge of a crusted
lesion. If a re- sistant organism is detected, an
appropriate antibi- otic should be given for an
additional seven days.

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