Dermatol Clin 25 (2007) 663–676
Bacterial and Viral Skin Diseases
Eleonora Ruocco, MD, PhDa, Giovanna Donnarumma, MDb,
Adone Baroni, MD, PhDa, Maria Antonietta Tufano, MDb,*
a
Department of Dermatology, Second University of Naples, Via Pansini 5, 80131 Naples, Italy
b
Department of Experimental Medicine, Microbiology and Clinical Microbiology Section,
Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy
Unimpaired skin protects the underlying tissue
and is an excellent frontline defense against the
invasion of pathogenous microorganisms thanks
also to the presence of the skin microbiota.
Throughout the life of an individual the skin is
colonized by a number of microorganisms that
can vary from a few hundred per cm2 on the dry
surfaces of the forearm and back, where the prev-
alent bacterium is Staphylococcus epidermidis, to
10,000 per cm2 on the damp areas, such as the
armpits and groin, where propionibacteria pre-
dominate, but where corynebacteria and negative
coagulase staphylococci can also be observed.
What is surprising is that the skin microbiota is
made up of microorganisms belonging to a very
limited number of species and that the microbial
load of the healthy skin is kept consistent, consid-
ering the large variety and number of potential
colonizers to which the skin is prey. It is not
surprising, however, that the skin, the barrier
between the body and the environment, is the
site of frequent infections [1]. The integrity of
this barrier is influenced by the degree of scaling
but also by several factors whose alterations upset
the environmental balance of the resident flora
and predispose the subject to infection [2]. More-
over, the skin displays microbicidal activity even
when its physical integrity is impaired [3]. It
contains the bioactive molecules, among which
antimicrobial peptides such as defensins and
cathelicidins are of critical importance to the
host defense against microbial invasion [4].
* Corresponding author.
E-mail address: mariaan.tufano@unina2.it
(M.A. Tufano).
0733-8635/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.det.2007.06.008
At least two different populations of microorgan-
isms can be found in the skin microbiota: a perma-
nent or resident flora, which is always present, and
a temporary or transient flora, which settles on the
human skin only for a certain period of time.
The permanent flora is a stable population of
microorganisms that is more or less regularly
present on the skin in considerable numbers and
does not usually comprise pathogenous microor-
ganisms. The permanent flora is consistently
present and if removed reforms within 24 to 72
hours. It is made up of aerobic or microaerophil
microorganisms. The main bacterium resident on
free skin (ie, nonfollicular) is S epidermidis; in the
area of the follicular ostium, with a reduced
oxygen supply, are mainly present Propionibacte-
rium acnes, Propionibacterium granulosum, and
Propionibacterium avidum. Species of Peptococcus,
which are anaerobic staphylococci, are present in
20% of humans, especially on the forehead and
in the elbow crease. Gram-positive liophil bacteria
belonging to the genus Corynebacterium settle in
sebum-rich areas, whereas bacteria belonging to
the genus Brevibacterium are present in particu-
larly humid areas. Gram-negative bacteria are
not normal components of the skin flora.
The microorganisms that make up the transient
flora settle only temporarily on the skin from the
external environment or from the adjacent mucosal
areas. Unlike in the resident flora, the bacterial
species present are numerous, since most microor-
ganisms can at least temporarily survive on the skin.
They cannot, however, multiply and, therefore,
colonize the skin. In some subjects, Staphylococcus
aureus is present in the nose and peri-anal area and
can spread to other areas of the skin. Gram-negative
derm.theclinics.com
664 RUOCCO
bacteria can also be isolated, particularly those be-
longing to the Enterobacteriaceae and Pseudomona-
ceae families. The former are part of the normal
intestinal flora, the latter are found in the environ-
ment, most readily in damp places [5].
It is therefore evident that possible coloniza-
tion and invasion by pathogenous microorgan-
isms is counteracted both by the host defenses and
by the resident flora, which contrast colonization
by other microorganisms competing for nutrients
or producing peptides with antimicrobial activity
[2]. Most skin infections are therefore self-limiting
in healthy subjects. Infections arising in a healthy
skin are defined as primary infections. They are
usually caused by a single microbial species; the
entry point of the germ is often unknown,
although a slight trauma is probably implicated.
Instead, infections defined as secondary develop
on preexisting skin lesions, which, therefore, facil-
itate the entry of the microorganisms. Atopic
dermatitis, psoriatic lesions and other eczematous
disorders are the most common examples, but
also prone to this complication are surgical or
injury wounds, burns, insect bites or stings, ulcers,
and areas of maceration [6,7]. Secondary infec-
tions, usually polymicrobial, are generally caused
by microorganisms that in themselves have little
pathogenic power. When the humoral and cell
immune defenses are low, secondary infections
arise more readily and develop more rapidly [8].
Once the skin barrier has been penetrated, the
microorganisms belonging to the resident flora,
mainly coagulase negative anaerobic staphylococci,
can cause infections, especially skin abscesses.
However, also responsible for skin infections are
microorganisms that, acquired from the environ-
ment, are temporarily part of the skin flora, for
example S aureus and Streptococcus pyogenes.
In general, a skin infection can follow three
different events (Fig. 1):
 a lesion of the skin that favors infection from
the outside;
 skin manifestations of systemic infections,
which can spread through the blood from
the site of infection to the skin or by direct in-
vasion/penetration;
 skin damage caused by toxins.
Bacterial infections
Bacterial infections can be classified on the
basis of the site involved, although some skin
et al
infections with a bacterial etiology can involve
more than one part of the body.
Thus, infections with a bacterial etiology
associated with an inflammatory process limited
to the hair follicle are classified as folliculitis.
They are characterized clinically by the presence
of abscesses and the formation of typical papules
or pustules. Impetigo, erysipelas, and cellulitis
are widespread infections. Impetigo is an in-
fection limited to the epidermis and characterized
by a bullous rash that evolves in crusts and
pustules. Erysipelas is an acute erythematous
infection that spreads rapidly and is usually
associated with systemic symptoms. If the lesion
is located in the subcutaneous fat and mainly
involves the derma, it is called cellulitis. Both
infections are associated with an intense inflam-
matory process. Infections characterized by rap-
idly progressive cellulitis that causes extensive
damage to the tissue below the derma, in
particular to the muscular tissue, and impairs
the blood flow are known as necrotizing in-
fections, subsequent to which necrotizing fasciitis
and gas gangrene (infections not considered of
dermatological competence) arise.
The microorganisms most commonly involved
in skin infections of a bacterial etiology are listed
in Table 1.
Gram-positive cocci are responsible for most
skin infections and often the same microorganism
can cause different infections according to the
different layers of skin that it is able to colonize.
Staphylococci are generally aerobic, gram-
positive cocci catalase-positive, which appear in
irregular, so-called grapelike clusters under the
microscope, although single and paired cells are
the most common in a fluid culture. The dominant
species of staphylococcus on the skin is S epider-
midis on the face and chest, with a lesser but still
substantial role for Staphylococcus hominis. In
recent years there has been a much greater appre-
ciation of the role of the normal skin flora in
infection. Because of the normal colonization of
skin by coagulase-negative staphylococci it is
difficult to be sure that small, localized lesions
such as folliculitis are really caused by these or-
ganisms [9]. There are a number of miscellaneous
infections attributed to coagulase-negative
staphylococci. S epidermidis and S hominis,
coagulase-negative staphylococci, are now well-es-
tablished pathogens in certain areas of the skin,
while S aureus, a species of coagulase-positive
staphylococci, remains a potent pathogen able to
exhibit new antibiotic resistance patterns and to
 INFECTIOUS SKIN DISEASES
microorganism
blood vessel
Systemic infection
Dermis cells invasion
leukocytes
MACULA PAPULE
Fig. 1. Mucocutaneous lesion pathogenesis.
continue to infect both the immunocompetent-
and incompetent-host [10].
S aureus permanently colonizes the moist
squamous epithelium of the anterior nostrils of
20% of the population, and is transiently associ-
ated with another 60% [11]. Occasionally, the
organism can cause superficial skin infections.
Primary staphylococcal infections of the skin are
chiefly boils, foruncles and other localized pustu-
lar lesions, and impetigo plus its more severe man-
ifestation, scalded skin syndrome [12]. S aureus
expresses a wide range of secreted and cell-sur-
face–associated virulence factors, including
surface proteins that promote adhesion to dam-
aged tissue and to the surface of the host cells
[13], which bind proteins in the blood to help
evade immune responses and promote iron uptake
[14]. Most strains express a polysaccharide cap-
sule [15]. Moreover, S aureus has been regarded
as a noninvasive pathogen but it is now evident
that the bacterium can invade many types of
665
toxin or immuno-complex microorganism
Toxin-mediated infection Epithelial cells invasion
PAPILLOMA
BLISTER ULCER
host cells by a mechanism involving the formation
of a fibronectin bridge between the bacterial fibro-
nectin-binding proteins and host a5b1 integrin
molecules, which triggers internalization [16,17].
The ability of S aureus to cause infection seems
to depend on the ability of the organism to
produce a cocktail of enzymes or toxins that
contribute to the appearance of disease. The
microorganism can secrete a range of extracellular
enzymes such as proteases, a hyaluronidase, a li-
pase, and a nuclease that facilitate tissue destruc-
tion and the spread of membrane-damaging
toxins, which cause cytolytic effects on the host
cells and tissue damage, and superantigens, which
contribute to the symptoms of septic shock [18].
Toxic shock syndrome (TSS) is characterized
by fever, headache, and confusion, with an
erythematous rash resembling scarlet fever and
desquamation in the later stages. The symptoms
are also usually accompanied by diarrhea, vomit-
ing, and hypotensive shock. TSS is caused by
666 RUOCCO et al

Table 1 bullous impetigo has been reported as part of

Main bacteria that involve the skin
Microorganisms Diseases
Staphylococcus aureus Toxic shock syndrome
Pyoderma
Impetigo
Furuncle
Streptococcus pyogenes Scarlet fever
Streptococcal toxic
shock syndrome
Pyoderma
Erysipelas
Necrotizing fasciitis
Corynebacterium Erythrasma
minutissimum
Corynebacterium diphteriae Cutaneous diphtheria
Pseudomonas aeruginosa Septicemia
Ulcer
Propionibacterium acnes Acne
Folliculitis
Proteus Folliculitis
Mycobacterium ulcerans Buruli ulcer
exotoxins, the most common of which is toxic
shock syndrome toxin 1 (TSST-1), produced
mainly by strains of phage-group I S aureus.
This toxin acts as a superantigen, stimulating the
production of T cells and the release of cytokines
[19].
Scalded skin syndrome or Ritter disease is also
caused by a strain of toxigenous S aureus [20]. The
toxin implicated in this syndrome is known as
exfoliating toxin or scalded skin toxin. Initially
the skin lesions may be mild, but the toxin causes
the destruction of the desmosomes and the
detachment of the superficial layer of the epider-
mis. It is generally regarded as a sporadic disease
with most cases in children aged 0.5 to 2 years.
Few adult patients are reported, chiefly in the
immunosuppressed, although cases in immuno-
competent adults are known [21].
Impetigo is characterized by golden, stuck-on
crusts or blisters (bullae); the blisters are most
probably caused by small amounts of epidermo-
lytic toxin or by the toxin in an otherwise resistant
host [22]. About three quarters of the cases are in
patients younger than 20, with about 35% in
those younger than 10. In Europe it is chiefly
a staphylococcal disease, though one third of
lesions have both S aureus and S pyogenes. Amer-
ican experience would suggest a predominantly
streptococcal background, although there are
signs that this may be changing. In AIDS patients
an extensive atypical intertriginous form of
AIDS-related pruritis [23].
Besides infections such as boils or impetigo, S
aureus also colonizes and aggravates lesions such
as those of atopic dermatitis. Some studies indi-
cate that when the density of S aureus exceeds
a certain level, such as 106/cm2, an exudative or
impetiginized form of lesion occurs. The reason
for the overgrowth of S aureus in atopic dermatitis
and not in diseases such as psoriasis is not known
[24,25]. Protein A elicits a much less vigorous
response in atopics than in normal skin or psori-
atics, but this may be the result rather than a cause
of colonization. Attention has recently focused on
the skin lipids and there is some evidence that
fatty acids, which may control staphylococcal
colonization, are deficient in atopics [4,26].
The therapy of choice for staphylococcal
infections is usually a penicillase-resistant penicil-
lin. The administration of erythromycin is
frequent, although an increase in the frequency
of erythromycin-resistant strains has been
reported. Meticillin-resistant S aureus (MRSA) is
a problem particularly for hospitals; vancomycin
is the only drug available but strains resistant
to it are also emerging (vancomycin intensive
S aureus [VISA]) [27,28].
Skin infection with streptococci covers a range
from simple colonization to primary and second-
ary infections; the skin provides an important
portal of entry for systemic infection by these
organisms. Streptococci are gram-positive, spher-
ical, aerobic, and facultatively anaerobic bacteria,
arranged in chains or pairs. They are nonsporing,
catalase negative, oxidase negative, and mainly
nonmotile. Hemolysis on blood-agar culture
provides a useful division of streptococci into
those that are hemolytic (beta hemolytic, showing
a zone of complete hemolysis, and alpha hemo-
lytic or viridans streptococci, showing a zone of
incomplete hemolysis) and nonhemolytic (those
with no effect on red blood cells). Hemolytic
streptococci are further divided according to the
carriage of polysaccharide or teichoic acid or
Lancefield group antigens. Direct streptococcal
infection of the skin may take on a number of
forms [29,30]. S pyogenes (group A hemolytic
streptococcus) remains the major streptococcal
pathogen in these infections but non–group A
streptococci also play a part and have become
more commonly recognized with the widespread
use of modern, rapid laboratory test kits. S pyo-
genes is the etiological agent of streptococcal
impetigo and erysipelas, skin pathologies also
 INFECTIOUS SKIN DISEASES
caused by S aureus. Infection generally arises from
contact with infected skin lesions in other individ-
uals. Once S pyogenes has colonized the skin, it
invades the epithelium through small wounds,
with consequent development of the lesion. A
complex interaction of bacterial and host defense
factors underlies the initiation, development, and
clinical manifestations of streptococcal infection
[31]. The M-protein molecule is known to be a ma-
jor virulence factor of streptococci. It is present as
a double-stranded coiled-coil structure projecting
from the cell surface. The functional properties
of M-protein include binding of fibrinogen, fibro-
nectin, and b2-microglobulin; adherence to host
cells; interference with complement deposition;
and the conferring of resistance to phagocytosis
[32]. The quantity of M protein expressed on the
cell surface appears to be an important factor in
the pathogenesis: freshly isolated strains of group
A, C, and G streptococci, particularly those from
invasive infections, are often rich in this substance
[33], and serotypes of S pyogenes such as M1,
which express large quantities, are commonly
associated with an invasive disease [34]. Enhance-
ment of M-protein expression may be a factor
underlying the increased virulence observed
when streptococci are rapidly passed from host
to host. The binding of fibrinogen and fibronectin
by streptococcal surface structures may play an
important part in the attachment of microorgan-
isms to wounds and clots in the first stages of
colonization and infection [35]. Other projecting
cell-surface molecules with similarities to M
protein, such as F-protein, in their cell-wall
attachment structure show further functions
including the inactivation of complement C5a,
a major signal substance for the chemotactic
attraction of leukocytes, and binding to the Fc
portion of immunoglobulin (Ig) G and IgA
antibodies. Teichoic acids also contribute to the
virulence of S pyogenes by helping the microor-
ganism bind to the epithelial cells [36].
A streptococcal skin infection develops 24 to
48 hours from the penetration of the skin and
stimulates a marked inflammatory response. S
pyogenes elaborates a series of toxic products
and enzymes, like hyaluronidase, that helps the
microorganism to spread in the tissues. Lym-
phatic system involvement is common, which
causes lymphadenitis and lymphangitis. Skin
infection by S pyogenes may be complicated by
nonsuppurative sequelae such as nephritis and
scarlet fever; conversely, streptococcal infection
at other sites in the body may lead to skin
667
manifestations, such as in rheumatic fever and
acute guttate psoriasis. These conditions will be
discussed later in this article. Streptococcal
infections of the mouth; alimentary, respiratory,
and genitourinary tracts; or deeper structures
will not be discussed here except insofar as they
are relevant to the skin [37]. Many streptococcal
infections are toxin-mediated. Lysogenic strains
of S pyogenes produce one or more types of
pyrogenous exotoxins (previously called erythro-
genic), like SPE-A, SPE-B, and SPE-C, which
act on the blood vessels of the skin and cause a dif-
fuse rash arising in association with streptococcal
pharyngitis accompanied by scarlet fever. The
exotoxin that causes scarlet fever is generally
SPE-A [38]. Clinical manifestations similar to
staphylococcal toxic shock syndrome are often
supported by streptococcal toxins, particularly
the pyrogenous exotoxin A, generally produced
by M1, M3, or M5 phagotypes of the S pyogenes
strains. Streptococcal toxic shock syndrome
(STSS) varies somewhat from staphylococcal or
classic forms. In most cases the primary site of
infection is the skin, often in surgical wounds. In
other cases STSS follows chickenpox or can infect
immunodepressed patients. These clinical pictures
often contrast with those seen in patients with
staphylococcal toxic shock syndrome, in whom
the primary infection is often subclinical [39].
Necrotizing fasciitis is an acute or subacute
infection that spreads above the fascial planes
causing thrombosis of the vessels and necrosis of
the dermis and subcutaneous fat. It is usually
caused by hemolytic or anaerobic streptococci or
S aureus [40]. The disease may follow a trivial or
unapparent injury to the skin and presents
initially with cellulitis, which quickly develops
a dusky discoloration, hemorrhagic bullae, and
underlying areas of necrosis. There is risk of
septicemia and rapid death. Necrotizing fasciitis
is most commonly seen in elderly patients, often
in association with serious preexisting medical
disorders [41].
The rationale of antimicrobial therapy for
streptococcal infections of the skin is to hasten
the resolution of the lesion, to reduce the risks of
suppurative and nonsuppurative complications,
and reduce the chances of transmission of
infection to others. Streptococci are still remark-
ably sensitive to penicillin. Many alternative drugs
are available including erythromycin, tetracycline,
and cephalosporin [42].
Other gram-positive bacteria belonging to the
skin microbiota are coryneform bacteria. They are
668 RUOCCO
considered responsible for skin odor and can be
associated with pathologies of the skin. This
heterogeneous group of microorganisms includes
both aerobic and anaerobic pleomorphic bacteria
that do not form spores. Because of their similar-
ity to the diphtheria bacillus, these microorgan-
isms were formerly referred to as ‘‘diphtheroids.’’
In cutaneous infections, coryneform bacteria are
clearly involved both as a primary pathogen and
a secondary superinfection of other cutaneous
infections such as syphilis and streptococcal
pyoderma. There are several cutaneous lesions
from which coryneforms can be recovered and in
which they are seen as playing important patho-
physiological roles. These include trichomycosis
axillaris, erythrasma, interdigital toe-web-space
infections, acne, and pitted keratolysis [43].
About 20% of the population is colonized by
Corynebacterium minutissimum, which causes
erythrasma only in some cases [44]. Erythrasma
is a superficial cutaneous infection ranging from
low-grade scaling to thickly macerated areas of
the skin. The preferred sites are the skin folds;
predisposing factors are obesity, diabetes, and
hyperhydrosis. Most infections show a typical
reddish fluorescence with Wood’s light. The fluo-
rescence a result of a production of porphyrins,
which fluoresce under long-wave ultraviolet light
[45].
Corynebacterium diphtheriae is not an inhabi-
tant of normal skin, although it may be recov-
ered from intact skin under epidemic
conditions. This microorganism is more com-
monly found on mucous membranes [46]. The
skin may be the primary portal of entry; the mi-
croorganisms can be auto- or hetero-inoculated
in an otherwise insignificant wound; there is
a high frequency of asymptomatic carriers.
Strains of C diphtheriae have been divided into
gravis, intermedius, and mitis types on the basis
of physiological, morphological, and molecular
characteristics. Its pathogenic properties depend
on the ability to produce toxins; only the strains
infected by the pro-phage b have the toxþ gene
and produce the exotoxin. C diphtheriae infec-
tions are more common in tropical and subtrop-
ical areas but epidemics have been described in
temperate climates like North America. Erosive,
ulcerative lesions with thick crusts are the most
common clinical findings [47]. The key therapy
is the administration of the antitoxin, which
should be administered early on. Antibiotic ther-
apy can be performed with penicillin G or eryth-
romycin [48].
et al
Anaerobic coryneforms recovered from human
skin belong above all to the genus Propionibacte-
rium, and P acnes is the most numerous species.
This bacterium plays an important role in acne
but is not considered the cause. P acnes prolifer-
ates and generates inflammation-provoking
substances, resulting in the disruption of the
follicular epithelium and progressive inflamma-
tion as the contents of the follicle are injected
into the dermis. In addition to its role in acne, P
acnes is also a frequent opportunistic pathogen.
Some authors [49,50] report the isolation of P
acnes from an infected wound and in osteomyelitis
and endocarditis. There are several reports of
meningitis and botryomycosis due to P acnes.
The antibiotics used to treat acne include
tetracycline and erythromycin [51].
Gram-negative bacterial skin infections are
much less frequent than gram-positive infections,
but have considerable clinical importance.
Pseudomonas aeruginosa is the cause of some
superficial infections with particular characteris-
tics. The microorganism readily colonizes damp
environmental pockets and, as such, some areas
of the body. In recent years there has been an
increase in the cases of folliculitis from P aerugi-
nosa in people attending saunas, Jacuzzis, and
swimming pools. The skin rash is itchy papules
or pustules characteristically distributed in the
areas rich in apocrine and eccrine sweat glands.
There may be associated symptoms of the infec-
tion in other areas, eg, mastodynia and earache.
These disorders tend to have a spontaneous recov-
ery but the use of quinolones may be useful. The
genus Pseudomonas is frequently isolated from
surgical wounds, varicose ulcers, bedsores, and
burns, particularly during and after antibiotic
therapy. The presence alone of Pseudomonas in
these sites is a sign of infection, but the real danger
is that the germ may multiply in depth and cause
bacteremia [52].
Other gram-negative microorganisms can
cause folliculitis during antibiotic treatment for
acne, usually with tetracycline. When in young
people receiving therapy for acne there is an
increase in the pustular lesions, a gram-negative
superinfection of the follicules should be sus-
pected, in particular by Proteus or Pseudomonas.
It is often sufficient to suspend tetracycline, but
it is often necessary to switch to another antimi-
crobial according to the sensitivity studies. After
surgery or traumas associated with contamination
of the wound, serious skin infections by mixed
aerobic or anaerobic flora can occur [53]. These
 INFECTIOUS SKIN DISEASES
are generally cellulitis with diffuse necrosis of the
skin and subcutaneous layers, at times extending
to the muscles. These infections are extremely
difficult to classify because of overlapping of the
sites involved, of the germs responsible, and of
the clinical manifestations. Many of these infec-
tions are severe, rapidly progressive, and associ-
ated with high mortality. The flora is composed
of clostridia, other anaerobes, enterobacteria,
streptococci, and staphylococci. The therapy for
these syndromes is surgery with intense antibiotic
support. Because the infections are caused by
mixed aerobic anaerobic flora, broad-spectrum
therapy is indicated, such as aminoglycosides
plus clindamycin. Metronidazole, clindamycin,
piperacillin, and cefoxitin are useful against
anaerobes, and imipenem, ceftazidime, ciprofloxa-
cin, and combinations containing beta lactamase
inhibitors and the association of piperacillin and
tazobactam are effective against aerobes and
facultative bacteria [54].
Warty skin lesions may fallow the inoculation
of opportunist mycobacteria into superficial
abrasions. These atypical mycobacterial infections
of skin are caused by a group of nontuberculous
mycobacterial microorganisms [55]. Mycobacte-
rium marinum is the most common and causes
cutaneous infection in immunocompetent individ-
uals. This microorganism is found in fresh or salt
water, or fish, thus fishermen and those who keep
fish are at higher risk [56]. Other pathogens
include Mycobacterium avium-intracellular,
Mycobacterium ulcerans, Mycobacterium chelo-
nae, and Mycobacterium fortuitum. The infection
is mainly via inoculation or trauma. M chelonae
and M fortuitum are associated with injection
and occur more often in immunocompromised
individuals. Immunosuppression is associated
with disseminated disease [57]. M ulcerans disease
(Buruli ulcer) is an important health problem in
several West African countries. It is prevalent in
scattered foci around the world, predominantly
in riverine areas with a humid, hot climate. M ul-
cerans infection leads to necrosis of subdermal
tissue and secondary skin ulceration [58]. The
choice of therapy will depend on the site and
nature of the infection, the species of causative
organism and the presence of any underlying
predisposing condition. Moreover, the in vitro
susceptibility to antimicrobial drugs varies consid-
erably both between and within the species of
mycobacteria. In general, however, drug sensitiv-
ity tests have not proved helpful; the combina-
tions of drugs to which the bacilli are resistant
669
in vitro often prove effective in vivo. Therapy is
therefore usually empirical and often based on
anecdotal evidence or retrospective surveys [59].
Viral infections
Viruses cannot be considered a component of
the normal flora of the skin but the skin is
a frequent site of manifestations of viral infection.
The lesions may be limited or widespread as part
of a systemic infection. Many common systemic
virus infections are clinically apparent, mainly as
a generalized maculopapular skin rash. For these
virus infections, after an initial replication phase
in or close to the site of infection, generally the
oropharynx, there is systemic viremia with seeding
of the skin. It is probable that the rash is immune-
mediated. In other cases, the skin lesion caused by
the virus is a vesicular lesion. In these cases the
skin lesions are the sites of viral replication and
are infectious [60]. The microorganisms most
commonly involved in skin infections of a viral
etiology are listed in Table 2.
During the past decade, increasing attention
has been paid to papillomaviruses and the condi-
tions they cause. This interest is largely because of
advances that have been made in the detection
and characterization of nucleic acids, as papillo-
mavirus cannot be isolated in any routine cul-
tures, and because of its association with cervical
carcinoma. Human papillomaviruses (HPV) con-
tain double-stranded DNA and are classified into
types on the basis of their nucleotide sequences.
There are now at least 90 human HPV types,
sequentially numbered from 1, with some further
divided into subtypes alphabetically if distinctive
endonuclease restriction patterns are seen [61].
The types of HPV are associated with the particu-
lar consequences of infection. Infection is primar-
ily of the squamous epithelium, and although
there are many manifestations, the common
wart (verruca vulgaris) and plantar warts are the
usual presentations. The principal sites are on
the hands and feet, and they are a major cause
of dermatological consultation. Plantar warts are
most commonly caused by HPV-1, -2, -4, -31,
and -32. The virus enters through skin abrasions
and infects the cells of the basal layers of the
skin. There is no diffusion to the deep tissues.
Viral replication is slow and is closely dependent
on the differentiation of the host cells. Viral
DNA is present in the basal cells, but the viral an-
tigens and the infecting virus are produced only
when the cells start to become squamous and
670 RUOCCO et al

Table 2
Main viruses that involve the skin
Virus family Virus genus Virus and disease
Herpetoviridae Herpesvirus Herpes simplex Stomatitis, genital herpes, etc.
Varicella-zoster Chickenpox, Zoster
Herpesvirus type 6 Roseola infantum
Poxviridae Molluscipoxvirus Molluscum contagiosum
Papovaviridae Papillomavirus Papillomavirus Warts
Picornaviridae Enterovirus Coxsackievirus A, B Hand, foot, and mouth disease
Echovirus
Paramyxoviridae Morbillivirus Measles
Togaviridae Rubivirus Rubella
Parvoviridae Parvovirus Parvovirus B19 Erythema infectiosum,
aplastic crisis

keratinized once they reach the surface. The incu-
bation period is usually about 4 to 6 months, with
transmission by direct contact or by fomite. The
natural history is of regression, with about two
thirds resolving within 2 years. Other benign
skin lesions include flat warts (HPV-3 and -12)
and butchers warts (HPV-7) [62]. Epidermodysla-
sia verruciformis is a rare condition. It is an
HPV-specific disorder of cell-mediated immunity
resulting in disseminated warty lesions that persist
for life. An autosomal recessive mode of inheri-
tance is probable. Up to 23 types of HPV infect
these patients, such as HPV-5, -8, -9, and -12,
and most do not cause lesions in healthy subjects
[63]. Genital warts have attracted great attention
because of their association with genital cancer.
The common type of genital wart is the condy-
loma acuminatum, which is due to infection with
HPV-6 or -11. The incubation period is about 1
to 6 months and may occur not only on the exter-
nal genitalia, but also on the mucosal surfaces of
the vagina and urethra. They rarely become
malignant and usually spontaneously resolve.
Infection may often be asymptomatic, so the pos-
sibilities of transmission are enhanced since the
infected person does not seek treatment. The
malignant potential of papillomaviruses has been
recognized for many years, but it is only in the
past 15 years that involvement in carcinoma of
the cervix has been demonstrated The detection
of HPV DNA by hybridization techniques has
implicated HPV, particularly HPV-16 and -18, in
a range of cervical lesions from carcinoma in
situ to invasive cervical carcinoma. In malignant
cells, the HPV genoma has been integrated into
the cell genome, rather than remaining extrachro-
mosomal. These HPV types also occur commonly
in sexually active women with no cervical lesions,
so the role of the detection of HPV-16 and -18 in
the management of women with a clinically and
cytologically normal cervix remains to be defined
[64].
Papillomaviruses have also been implicated in
human malignancies of the skin, such as squa-
mous cell carcinoma in patients with epidermo-
dysplasia verruciformis, and a similar carcinoma
may occur in immunocompromised renal trans-
plant recipients, who have a high risk of
developing warts [65].
Herpes simplex virus (HSV) is probably the
most common virus infecting the human skin.
HSV is divided into types 1 and 2 according to
a number of features including DNA fragment
size after endonuclease restriction analysis. As
with all herpes viruses, they are large, enveloped
virions with an icosahedral nucleocapsid consist-
ing of 162 capsomeres, arranged around a linear,
double-stranded DNA core. The DNAs of HSV-
1 and HSV-2 are largely colinear, and consider-
able homology exists between the HSV-1 and
HSV-2 genomes. These homologous sequences
are distributed over the entire genomic map, and
most of the polypeptides specified by one viral
type are antigenically related to polypeptides of
the other viral type. This results in considerable
cross-reactivity between the HSV-1 and HSV-2
glycoproteins, although unique antigenic deter-
minants exist for each virus. Viral surface glyco-
proteins mediate HSV attachment to and
penetration into the cells and provoke host
immune responses. Eleven glycoproteins of HSV
have been identified (gB, gC, gD, gE, gG, gH, gI,
gJ, gK, gL, and gM), with a 12th predicted (gN).
gD is the most potent inducer of neutralizing
 INFECTIOUS SKIN DISEASES
antibodies and appears to be related to viral
entry into a cell; gB is also required for in-
fectivity. Antigenic specificity is provided by gG,
with the resulting antibody response, thus allow-
ing the distinction between HSV-1 (gG-1) and
HSV-2 (gG-2) [66,67].
HSV-1 is generally associated with oro-labial
disease, with most infections occurring during
childhood, and HSV-2 with genital disease with
infection following sexual debut [68]. However, it
is possible for HSV-2 to cause oro-labial herpes
and HSV-1 to cause genital herpes [68].
Primary infection with HSV-1 usually occurs
in childhood and is often asymptomatic, al-
though it can present as stomatitis, occasionally
severe. After primary oral infection, the virus
becomes latent in the neurons of the trigeminal
ganglia, with reactivation likely later in life. The
natural history is of a few hours of nonspecific
tingling, followed by the development of vesicles,
scabbing, and resolution over a few days. Two
biologic properties of HSV that directly influence
human disease are latency and neurovirulence.
During HSV infection, virions are transported by
retrograde flow along axons that connect the
point of entry into the body to the nuclei of
sensory neurons. Viral multiplication occurs in
a small number of sensory neurons, and the viral
genome then remains in a latent state lifelong.
With periodic reactivation brought on by events
such as physical or emotional stress, fever, UV
light, and tissue damage, the virus is transported
back down the axon to replicate again at or near
the original point of entry into the body. Such
reactivation can result in clinically apparent
disease (lesions) or a clinically inapparent
(asymptomatic or subclinical) infection. The
mechanisms by which HSV establishes latency
are currently under investigation. Neurovirulence
refers to the affinity with which HSV is drawn to
and propagated in neuronal tissue. This can
result in profound disease with severe neurolog-
ical sequelae, as is the case with neonatal HSV
central nervous system (CNS) disease and with
herpes simplex encephalitis in older children and
adults [69].
Although there is debate about the usefulness
of antivirals, such as acyclovir, continuous oral
therapy is often recommended for herpetic
infections to suppress a recurrence [60].
Molluscum contagiosum is a disease caused by
a poxvirus of the Molluscipox virus genus that
produces a benign self-limited papular rash of
multiple umbilicated cutaneous tumors. This
671
common viral disease is confined to the skin and
mucous membranes. It has an incubation period
from 1 week to 6 months. The lesions vary in
number from one to many hundreds, and develop
from papules to flesh-colored or pearly nodules,
which often have an umbilicated center. Systemic
symptoms are rare. In adults they usually occur
on the trunk, genital area, and thighs, and
infection may be sexually transmitted. In children,
in whom infection is more common, the lesions
are predominantly on the trunk and proximal
extremities. The disease usually lasts 6 to 9
months, although individual lesions persist for
only about 2 months. The virus has not been
cultured and, if necessary, a specific diagnosis can
be attained by electron microscopy [70].
Measles, rubella, parvovirus B19, and some
enteroviruses produce generalized maculo-papu-
lar rashes and it may not be easy to distinguish
between them clinically, particularly in infections
of the latter three. Transmission is by the
respiratory route for measles, rubella, and
parvovirus B19, but is fecal-oral for the
enteroviruses.
Measles virus, a member of the Morbillivirus
genus, is an enveloped virus with a nonsegmented
negative-strand RNA genome. It has two enve-
lope glycoproteins, the hemoagglutinin (H) and
the fusion (F) protein, which are responsible for
receptor binding and membrane fusion, respec-
tively. The measles virus causes a common child-
hood disease with high fever and typical skin
rash. Measles has an incubation period of about
10 to 11 days, the rash being preceded by a 2- to
3-day prodrome of fever, coryza, and conjunctivi-
tis, with the appearance of the characteristic ele-
vated white Koplik’s spots on the mucosa of the
mouth. The rash usually starts around the head
and spreads to the trunk and extremities, with
resolution after a few days [71]. Complications
are not uncommon, arising in about 3% to 4%
of cases, and include bacterial pneumonia and
otitis media. Postinfectious encephalitis occurs at
a rate of about 1 in 2000 to 5000 cases and carries
significant mortality. Subacute sclerosing panen-
cephalitis (SSPE) occurs after an interval of
some years in about one in a million cases. It
reflects a persistent infection with measles virus.
Patients present with intellectual impairment and
progress to motor dysfunction, coma, and death.
In the immunocompromised child, measles may
occur without a rash but lead to encephalitis or
giant-cell pneumonia, which have high fatality
rates [72].
672 RUOCCO
The use of live attenuated vaccines given in the
second year of life has led to a great decline in
incidence of measles in countries with a high
uptake. Despite the introduction of measles
vaccine in the late 1960s, biannual epidemics
were still occurring up to the late 1980s. The
introduction of mumps, measles, and rubella
(MMR) vaccine in 1988, together with more
active vaccination campaigns, have led to an
increased uptake of vaccine. This follows the
example set by the United States, where measles
is now an uncommon disease, although it still
presents occasional problems of institutional out-
breaks in adolescents who are not immunized or
have vaccine failure [73].
Rubella virus is a positive-sense, single-
stranded RNA virus belonging to the Togaviridae
family of the genus Rubivirus [74]. Infection with
rubella virus usually results in a mild disease
that only rarely produces significant sequelae.
Rubella has a somewhat longer incubation period
of 16 to 17 days and, particularly in children, is
a mild disease, often asymptomatic. It is transmit-
ted through aerosol and is less contagious than
measles, but more than parotitis. The virus
initially multiplies in the local lymphoid tissues,
then spreads to the spleen and distant lymph
nodes. Continuous multiplication in these tissues
brings on, a week after infection, a viremic phase
and an onset of the virus in the respiratory tract
and in the skin and, in some cases in the placenta,
joints, and kidneys. The pink macular rash usually
starts on the face, spreads centrifugally, and lasts
only 2 to 3 days. The major complication of
rubella is intrauterine infection and fetal damage
if infection occurs during the first 4 months of
pregnancy. Persistent infection with rubella virus
can lead to immunopathological problems pre-
senting after birth, such as pneumonia. No effec-
tive antiviral treatment exists. Live attenuated
rubella vaccines have been available since the
1970s to prevent congenital rubella. It is given
by parenteral route, generally associated with
the vaccine for measles and parotitis [75].
The human parvovirus B19 belongs to the
genus Erythrovirus and is the only member of
the family Parvoviridae to cause a wide range of
human diseases in both children and adults [76].
The virus is nonenveloped, and its genome con-
sists of a linear, single-stranded DNA molecule
of approximately 5600 nucleotides with terminal
palindromic inverted sequences of 383 nucleotides
at both ends. Infection with parvovirus B19
cannot be differentiated clinically from rubella in
et al
the adult. In the child, but not in the adult, the
rash, erythema infectiosum (or Fifth disease), is
usually accompanied by a malar erythema leading
to the alternative name of slapped cheek
syndrome. In patients with hemolytic anemia,
such as sickle cell disease and hereditary spherocy-
tosis, the transient inhibitory effect of parvovirus
B19 on the bone marrow may lead to aplastic
crisis. Infection during pregnancy does not lead
to fetal damage, although hydrops fetalis, intra-
uterine death, and stillbirth may occur after infec-
tion in the second trimester [77]. No vaccine is
available.
Human herpes type 6 (HHV-6) is the sixth
member of the herpes virus family that includes
herpes simplex virus 1 and 2, varicella-zoster
virus, cytomegalovirus (CMV), and Epstein-Barr
virus. It is a member of the beta-herpes virus
subfamily, of the Roseolavirus genus. HHV-6 is
an enveloped DNA virus of 160 to 200 nm in
diameter and approximately 167 kbp in length.
The sequence difference between variant A and B
is about 4%, and the two can be differentiated by
restriction fragment length polymorphism, mono-
clonal antibodies, polymerase chain reaction
(PCR) and in vitro growth characteristics [78].
The isolation and characterization of HHV-6
was first reported in 1986 using cultures of periph-
eral blood leukocytes (PBL) from patients with
acquired immune deficiency syndrome (AIDS)
and lymphoproliferative disease. HHV-6 preferen-
tially infects CD4þ T lymphocytes, but can also
infect other cell lines of epithelial, fibroblastic,
and neuronal origin with different efficiency. The
clinical syndrome of exanthem sabitum (or rose-
ola infantum, sixth disease) was first described in
1913; however, its etiological link to HHV-6 was
first identified in 1988. Approximately 50% to
60% of children are infected by HHV-6 by 12
months of age and almost all children are infected
by the age of 2 to 3 years. This illness is character-
ized by a high fever that resolves with the appear-
ance of a pinkish macular rash. Studies have
implicated HHV-6 as an etiological agent of
meningitis and encephalitis in the immunocom-
promised [79].
Antiviral agents that have been found to be
effective in vitro against HHV-6 include ganciclo-
vir, foscarnet, and cidofovir. In otherwise healthy
children HHV-6 infection is usually self-limited
and no antiviral treatment is needed [80].
Varicella-zoster virus (VZV) is a highly cell-
associated member of the Herpesviridae family
and one of the eight herpes viruses to infect
 INFECTIOUS SKIN DISEASES
humans. It is a double-stranded DNA virus and is
most closely related to herpes simplex virus types
1 and 2. These viruses rapidly proliferate and
invade and destroy the infected cells. The virus is
ubiquitous in most populations worldwide and
the primary infection causes varicella, more com-
monly known as chickenpox. VZV is neurotropic
and establishes latency in sensory neurons.
Reactivation from latency, usually during periods
of impaired cellular immunity, causes herpes
zoster (shingles). Varicella is a common childhood
infection with an incubation period of 14 to 16
days. A shortened incubation period can be
encountered especially in immunocompromised
patients. The skin lesions progress rapidly
through the stages of macules to papules to
vesicles that rapidly burst and form a crust. The
lesions appear in series; therefore, all stages in
their genesis can be seen at any one time. Patients
with varicella are generally considered to be
infectious 2 days before the appearance of the
rash and 7 days after the onset, when the vesicles
have crusted. In children with normal cellular
immunity, varicella is usually a benign and self-
limiting illness. In adults, however, varicella
presents a higher risk of complications such as
viral pneumonia, encephalitis, and skin sepsis.
Varicella in the first 5 months of pregnancy may
occasionally cause fetal damage [81].
Herpes zoster mainly affects a single derma-
tome of the skin. It may occur at any age but the
majority of patients are older than 50. The latent
virus reactivates in a sensory ganglion and tracks
down the sensory nerve to the appropriate
segment. The lower cervical, thoracic, and lum-
bar posterior root ganglia are most commonly
involved. The rash is commonly preceded by
paresthesia, burning pains, and tenderness of the
skin. The trigeminal ganglion is another common
site of reactivation and the ophthalmic branch of
this nerve is 20 times more likely to be involved
than the other 2 branches. Facial palsy associ-
ated with vesicles in the external auditory meatus
is known as the Ramsay-Hunt syndrome and is
thought to be a form of zoster involving the
VIIth nerve. The skin lesions are usually accom-
panied by local pain, which often precedes the
lesions, but pain may occur without visible
lesions (zoster sine herpete). The most severe
complication in healthy individuals is persistent
pain at the site of the lesions that may last for
several months [82]. Some benefit may be had
from early use of acyclovir, but whether this in-
fluences postherpetic neuralgia has been debated.
673
Zoster in pregnancy presents no hazard to the fe-
tus or neonate [83].
Last, it is known that immunocompromised
patients present many additional problems
regarding viral skin infections, but it is not known
whether this is a consequence of therapy or of
underlying problems, such as lymphoma or HIV
infection. These infections, such as HSV and VZV
with a latent state are more likely to reactivate
and disseminate rather than remain as a localized
lesion. Varicella and measles may be life threat-
ening. Rubella does not seem to present any
particular risk, and parvovirus B19 and enterovi-
ruses only rarely present problems. The dissemi-
nation of warts can occur in molluscum
contagiosum.
In conclusion, the past decade has seen exciting
developments in identifying the etiological agents
for syndromes manifesting in the skin, but there
are still others for which a viral origin seems
likely.
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