Cutaneous Diphtheroid Infection and Review of Other Cutaneous Bacillus C

Continuing Medical Education
Cutaneous Diphtheroid Infection
and Review of Other Cutaneous
Gram-positive Bacillus Infections
Peggy Lin Lee, MD; Bianca Lemos, MD; Sarah H. O’Brien, MD; Joseph C. English III, MD;
Matthew J. Zirwas, MD
GOAL
To understand Gram-positive Bacillus infections to better manage patients with the condition
OBJECTIVES
Upon completion of this activity, dermatologists and general practitioners should be able to:
1. Describe the dermatologic manifestations of Gram-positive Bacillus infections.
2. Identify treatments for Bacillus infections.
3. Discuss the transmission of Bacillus infections.
CME Test on page 378.
This article has been peer reviewed and approved
by Michael Fisher, MD, Professor of Medicine,
Albert Einstein College of Medicine. Review date:
April 2007.
This activity has been planned and implemented in accordance with the Essential Areas
and Policies of the Accreditation Council for
Continuing Medical Education through the
joint sponsorship of Albert Einstein College of
Medicine and Quadrant HealthCom, Inc. Albert
Einstein College of Medicine is accredited by
the ACCME to provide continuing medical education for physicians.
Albert Einstein College of Medicine designates
this educational activity for a maximum of 1 AMA
PRA Category 1 CreditTM. Physicians should only
claim credit commensurate with the extent of their
participation in the activity.
This activity has been planned and produced in
accordance with ACCME Essentials.
Drs. Lee, Lemos, O’Brien, English, and Zirwas report no conflict of interest. The authors report no discussion
of off-label use. Dr. Fisher reports no conflict of interest.
Cutaneous diphtheria is a rare infection in the
United States. This article presents a case of
Accepted for publication November 1, 2006.
Drs. Lee and English are from the Department of
Dermatology, University of Pittsburgh Medical Center,
Pennsylvania. Dr. Lee is Assistant Professor and Dr. English is
Associate Professor of Dermatology and Director of the
Dermatology Residency Program. Dr. Lemos was an intern,
Department of Medicine, University of Washington, Seattle.
Dr. O’Brien is from the Division of Pediatric Hematology/Oncology,
Columbus Children’s Hospital, Ohio. Dr. Zirwas is Assistant
Professor, Division of Dermatology, Ohio State University
Medical Center, Columbus.
Reprints: Matthew J. Zirwas, MD, 5965 E Broad St, Suite 290,
Columbus, OH 43213 (e-mail: [email protected]).
genital ulcerations, which were likely secondary to cutaneous coryneform bacterial infection, and reviews the literature concerning the
diagnosis and management of this entity. In
addition, we briefly review other Gram-positive
Bacillus bacterial infections of the skin.
Cutis. 2007;79:371-377.
Case Report
A 13-year-old white male oncology patient presented for his scheduled chemotherapy. Results of
a physical examination revealed multiple painful
annular to oval ulcers, 0.5 to 1 cm, with overlying
black eschar, elevated borders, and surrounding
VOLUME 79, MAY 2007 371
Cutaneous Diphtheroid Infection
Figure 1. Painful ulcers with overlying black eschar,
elevated borders, and surrounding erythema.
Figure 2. Gram-positive rods, some in a Y-shaped
configuration (Gram, original magnification 3400).
erythema on the scrotum and penis (Figure 1).
These ulcers had been present for approximately
one week prior to presentation. Results of a Gram
stain of the lesions revealed innumerable Grampositive rods (Figure 2). The neutrophil count
was less than 500 cells/mL (reference range,
1800–7800 cells/mL). The patient did not wish to
undergo a skin biopsy. A wound culture was strongly
positive for diphtheroids, but further speciation
was not performed.
The ulcers improved quickly with empiric
systemic antibiotic therapy with ciprofloxacin
hydrochloride. Based on the clinical examination and Gram stain results, we strongly suspected
that these ulcers were secondary to coryneform organisms, most likely Corynebacterium
diphtheriae, though we could not exclude infection
with Bacillus cereus.
372 CUTIS®
Comment
Under normal circumstances, resident microbial colonization supplements the skin’s innate and acquired
defense mechanisms against possible pathogens. However, infection occurs when these protective barriers,
most importantly the stratum corneum, are breached,
particularly in cases involving immunocompromised
patients.1 Although Gram-positive cocci are now the
most commonly isolated organisms among patients
with cancer bacteremia, species of Corynebacterium
and Bacillus (Gram-positive rods) are less frequently
isolated and tend to manifest in patients with prolonged neutropenia (Corynebacterium) or those with
central venous lines (Bacillus).2 Catheter-associated
Bacillus can be particularly problematic because
removal of the central venous line is often required
to cure the infection.
Less commonly, the occurrence of these organisms has been reported as the cause of primary
cutaneous infections. A review of culture reports
from a 5-year period at St. Jude Children’s Research
Hospital revealed 10 cases of primary cutaneous
B cereus infections, all occurring in neutropenic
children (absolute neutrophil count ,500 cells/mL)
undergoing treatment for cancer or aplastic anemia.3
In these cases, a vesicle or pustule developed on a
digit or limb, followed by rapidly spreading cellulitis.
Except for fever, the children were not systemically
ill, and interestingly, all cases arose in the spring
or summer.3
In immunocompromised patients with cancer, cutaneous Gram-positive Bacillus infections
can lead to systemic life-threatening illnesses.
Corynebacterium jeikeium sepsis and fatal B cereus
endocarditis have been reported in patients with
leukemia presenting initially with ulcers or subcutaneous nodules.4-6 Our patient had no systemic signs
of infection, and his skin lesions resolved with oral
ciprofloxacin hydrochloride therapy.
Gram-positive bacilli cause many different cutaneous infections (Table). Many of the superficial
noninvasive infections are quite common and easily
diagnosed. Invasive serious infections with Grampositive rods, on the other hand, are rare and may
be difficult to diagnose.
C diphtheriae—Bacteria of the Corynebacterium
species are abundant in occluded intertriginous
areas1,7 and, along with Brevibacterium, make up a
substantial fraction of the resident skin flora.1 In an
immunocompetent host with a normal stratum corneum barrier, C diphtheriae is nonpathogenic.8 However, infections are more common when patients
are neutropenic. Humans are the only recognized
reservoir for C diphtheriae, and infection may occur
in patients who have been fully immunized, partially
Cutaneous Diphtheroid Infection
Differential Diagnosis of Gram-positive Bacillus Infections
Gram-positive Bacillus Infections
Dermatologic Manifestations
Corynebacterium species
C diphtheriae
Painful ulcer with overlaying black eschar
C minutissimum
Erythrasma
Coinfection with Kytococcus sedentarius
Pitted keratolysis
C tenuis
Trichomycosis axillaris
Group JK (C jeikeium)
Normal inhabitants in the axillary and perineal
areas in healthy individuals
Endocarditis, sepsis in immunocompromised
individuals, cellulitis
Brevibacterium
Interdigital tinea pedis
Propionibacterium
(P acnes, P granulosum, P avidum)
Normal residents of sebaceous glands and hair
follicles (scalp, forehead, and back); cause acne
Clostridium species, most commonly C perfringens
Gas gangrene
Bacillus species
B anthracis
Malignant pustule; gastrointestinal anthrax;
woolsorter disease
B cereus
Nonhealing ulcer with black eschar
Listeria monocytogenes
Painful erythematous papules, pustules, and/or
petechiae over the arms and hands but may be
more diffuse in immunocompromised individuals
Fever, malaise, and lymphadenopathy may be present
Erysipelothrix rhusiopathiae
Present on dead animal matter, especially swine but
also fish, crabs, shellfish, and turkeys
Sharply marginated bluish erythematous polygonal
patches are distinctive
immunized, or unimmunized against the diphtheria
toxin.9 Excretion of organisms from nasal, throat,
eye, and skin lesion discharge/exudates may continue
for up to 2 to 6 weeks after infection. Transmission of
the organism usually occurs via contact with a carrier or patient. Transmissibility usually lasts less than
4 days after proper antimicrobial therapy has begun,
but transmission has been reported to occur related
to a chronic carrier state, even long after antimicrobial therapy.9 Risk of transmission is thought to
be greater in cutaneous cases than in respiratory
diphtheria, attributable to greater environmental
contamination by the cutaneous type.10,11 Peak incidence of disease is in the autumn and winter.9
Respiratory infection in unimmunized persons
usually results in obstructive respiratory symptoms
(eg, membranous nasopharyngitis, obstructive laryngotracheitis) after a 2- to 7-day incubation period.9
Toxic sequelae such as peripheral neuropathies and
myocarditis are reported complications due to the
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Cutaneous Diphtheroid Infection
Figure 3. Pitted keratolysis.
dissemination of diphtheria toxin.9,12 These systemic
complications are less frequent in cutaneous versus
respiratory diphtheria.10
Cutaneous diphtheria is rare (reported annual
incidence, 0.120.2 cases per million in developed
countries),10,12 and most cases are associated with
tropical areas, poor hygiene, crowded conditions,
immunosuppression, and/or poor socioeconomic
classes.9,13,14 Most cases in developed countries
involve travel to endemic areas,8,10,12 social factors
of poverty and overcrowding,8,10 or lack of booster
immunizations.8 C diphtheriae can complicate any
break in skin integrity, including surgical wounds,8,9
laser resurfacing wounds,8 insect bites,10,14 scars,8
scabies,10 paronychia,10 and impetigo.10,12
Primary cutaneous diphtheria most commonly
affects the hands, lower legs, and feet.10 Cutaneous
diphtheria usually begins as a painful vesicle filled
with straw-colored fluid or a pustule that breaks
down, leaving a well-demarcated, oval, shallow,
punched out–appearing ulcer.8,10,12,15 Ulcers range
from several millimeters to a few centimeters and
may be single or multiple. Wound edges are slightly
inverted, elevated, or undermined.10 Ulcers possess
an adhering membrane that progresses from gray to
black.12,15 The ulcer eventually becomes anesthetic,
and when the black eschar is removed, a serous,
serosanguineous, or hemorrhagic base is revealed.8,10
Surrounding skin usually is edematous and pink to
violaceous.10 Spontaneous healing has been reported
to take 6 to 12 weeks but may take as long as one
year, leaving depressed scars.8,10
Diagnostic tests for C diphtheriae include culture of material from under the membrane or the
membrane itself, nose, throat, or any other mucosal
or cutaneous lesion. Because special growth media
is required, laboratory personnel should be made
aware of the suspicion of C diphtheriae.9 Although
374 CUTIS®
reporting of cutaneous diphtheria is not required
(unlike respiratory disease), if the organism is isolated, it should be sent via the state health department to the US Centers for Disease Control and
Prevention.8,9 The strain should be tested for toxigenicity.9 Gram stain or methylene blue stain can
reveal irregular Gram-positive clubbed bacilli, lying
in a L,V, or Y conformation.10
Treatment of confirmed cases of respiratory
C diphtheriae is with antitoxin and antibiotics.9 Because of the possible systemic sequelae of
C diphtheriae, some experts recommend that cutaneous diphtheria be treated with antitoxin as well
as antibiotics, especially if there are extensive and
multiple lesions with pseudomembrane formation,
but this treatment is controversial. Systemic antibiotic therapy with penicillin or erythromycin for
10 days, in addition to thorough cleansing of the
ulcers with soap and water, is the recommended
therapy for cutaneous diphtheria.8,9 Alternate systemic antibiotics include clindamycin, rifampin,
fluoroquinolones, azithromycin, and clarithromycin.
For respiratory cases, antimicrobial therapy is not
recommended as sole therapy in lieu of antitoxin.
Treatment success is documented as 2 negative cultures at conclusion of treatment.9
Cutaneous Infections Involving Other Coryneform
Organisms—Corynebacterium minutissimum is the
organism implicated in the pathogenesis of erythrasma.7 Lesions are well-demarcated red to brown
patches with slight scale occurring in intertriginous
areas, such as the axilla, inframammary areas, toe
webs, intergluteal folds, and crural folds.7 Because
C minutissimum has the ability to produce porphyrin,1
results of a Wood lamp examination may reveal
coral red fluorescence of the patches.7 Risk factors
for development of infection are hyperhidrosis,
advanced age, diabetes mellitus, obesity, warm climate, and compromised immune status. Treatment is
with topical or systemic antibacterials (usually topical clindamycin or erythromycin). Topical tolnaftate
or miconazole nitrate also have been reported to be
effective. Differential diagnosis includes intertrigo,
seborrheic dermatitis, inverse psoriasis, lichen simplex chronicus, and candidiasis.7
Pitted keratolysis presents with asymptomatic,
shallow, sharply defined erosions of the stratum
corneum measuring up to several millimeters in
diameter (Figure 3). It is caused by proteolytic
enzymes produced by coryneform bacterium that
digest keratin.7 Soles of the feet are the most
commonly affected sites, but palms also may be
affected. Hyperhidrosis and malodor are frequent
associations. Coinfection with Kytococcus sedentarius
(formerly Micrococcus sedentarius) is seen. Treatment
Cutaneous Diphtheroid Infection
Figure 4. Clinical findings of trichomycosis axillaris.
is with topical antibiotics (erythromycin or clindamycin).7 Differential diagnosis of the palmar and/or
plantar pitting lesions includes punctate palmoplantar keratoderma, arsenical keratosis, basal cell nevus
syndrome, Darier disease, Cowden syndrome, warts,
psoriasis, pachyonychia congenita.
Trichomycosis axillaris is a superficial infection
of the pubic and/or axillary hair caused by
Corynebacterium tenuis and other coryneform species.7 Affected hairs demonstrate asymptomatic
yellow, red, or black nodules or sheathes that are
soft and removable (Figures 4 and 5). Treatment
includes oral or topical antibiotics and/or shaving of
the affected hairs.7
Group JK Corynebacterium (C jeikeium) are normal inhabitants in the axillary and perineal areas in
healthy individuals and can be seen in higher percentages in immunocompromised patients.7 Immunocompromised individuals with a break in skin
integrity, such as from an in-dwelling catheter or a
prosthetic or valvular device, are at greater risk to
develop endocarditis or sepsis. Cutaneous infections
(cellulitis), palpable purpura, skin necrosis, and a
papular eruption also may be observed. Treatment is
with vancomycin.7
Brevibacterium, often the cause of foot odor, are
frequently recovered in cultures from toe interspaces, particularly in cases of tinea pedis (Figure 6).
Brevibacterium are reported as the most rapidly growing coryneform bacteria.7
Propionibacterium species are normal residents
of sebaceous glands and hair follicles of the scalp,
forehead, and back. These organisms are the
most numerous anaerobes of the normal flora and
include Propionibacterium acnes, Propionibacterium
granulosum, and Propionibacterium avidum. P acnes
is implicated as one factor in the pathogenesis
of acne.7
Noncoryneform Gram-positive Bacillus Cutaneous
Infections—Clostridial myonecrosis also is known
as gas gangrene and presents as an acutely painful
wound that is edematous, exudative, and progressive.16 Crepitus may be present, and subcutaneous
gas may be seen on x-ray. Necrotic muscle is
retrieved at surgery and is caused by large Grampositive anaerobic bacilli of the Clostridium species,
most commonly Clostridium perfringens. Clostridial
myonecrosis can result in death within a few hours
if untreated. Treatment includes early and extensive surgical debridement, high-dose intravenous
antibiotics, and management of shock and fluidelectrolyte imbalance.16
Anthrax is caused by Bacillus anthracis, a large,
Gram-positive, aerobic, endospore-forming rod
that can cause 3 types of infection, depending on
the method of entry.4,17,18 Endospores enter the
body through abrasions (cutaneous anthrax, malignant pustule), ingestion (gastrointestinal anthrax),
or inhalation (pulmonary anthrax, woolsorter
disease).17,18 Endospores germinate into vegetative
bacteria with virulence factors, including exotoxin
and a capsule.17 In pulmonary and gastrointestinal
variants of anthrax, elevated levels of exotoxin are
responsible for severe septicemia, toxicity, and possible death. Luckily, 95% of cases of anthrax worldwide are of the cutaneous type, which have a lower
relative risk of morbidity and mortality.18 Infection
usually is from exposure to infected animals or their
products, and endemic areas include Turkey, Iran,
Afghanistan, and western Africa. Lesions begin as
small painless red macules or papules that evolve
into painless pustules that rupture.17-19 Classically,
a 1- to 5-cm brown to black eschar forms with
encircling edema.18 Early diagnosis and prompt institution of antibiotic therapy (usually high-dose penicillin, doxycycline, streptomycin, or ciprofloxacin
hydrochloride, though clindamycin, erythromycin,
first-generation cephalosporins, chloramphenicol,
aminoglycosides, and vancomycin can be used)
is the treatment.17-19 In untreated cases, fatality is
VOLUME 79, MAY 2007 375
Cutaneous Diphtheroid Infection
Figure 5. A plucked hair from an individual with
trichomycosis axillaris (original magnification 340).
Figure 6. Interdigital tinea pedis.
approximately 20%.18,19 Fortunately, with treatment,
fatality from cutaneous anthrax is rare.18
B cereus is most commonly associated with food
poisoning, but cases of cutaneous B cereus infection
have been reported, usually in immunocompromised
individuals. Boulinguez and Viraben20 reported a
case in an immunocompetent patient and reviewed
this disease. The lesion begins as an erythematous
papule that progresses into a vesicle with serous
or serosanguineous fluid. The vesicle ruptures to
form a dark and adherent crust and becomes surrounded by an erythematous halo that eventuates
into a nonhealing ulcer. Diagnosis is with culture,
and treatment has been reportedly successful with
ciprofloxacin hydrochloride or vancomycin.20
Cutaneous listeria is a rare disease caused by
Listeria monocytogenes, a Gram-positive rod that was
discussed by Cain and McCann.21 The eruption is
thought to be due to inoculation of the skin with
organisms from infected animals or their products.
Lesions typically are painful erythematous papules,
pustules, and/or petechiae over the arms and hands
but may be more diffuse in immunocompromised
individuals. Associated systemic symptoms of fever,
376 CUTIS®
malaise, and lymphadenopathy may be present.
In infants, the disease may be granulomatous. Immunocompromised individuals, as well as alcoholic,
elderly, and pregnant patients, also are susceptible. Serologic tests are needed to help identify the
organism because culture and Gram stain may be
inconclusive. L monocytogenes is responsive to most
antibiotics, including ampicillin, erythromycin,
penicillin, and tetracycline.21
Barnett22 reviewed Erysipelothrix rhusiopathiae, a
nonmotile smooth or curved Gram-positive rod that
often forms long-branching filaments. The organism is present on dead animal matter, especially on
swine but also on fish, crabs, shellfish, and turkeys.
Cutaneous symptoms often begin as painful swelling
and erythema at the site of inoculation. Sharply marginated bluish erythematous polygonal patches are
distinctive. The patch develops an elevated zone that
extends peripherally, while the central portion fades.
Vesicles often are present. New violaceous patches
occur in close proximity to existing lesions, and the
entire hand may become involved. There usually is
no desquamation. A generalized eruption has been
reported, and systemic symptoms of fever and arthritic
symptoms can occur. Rarely, endocarditis and/or
septicemia have been reported. Mild disease usually is
self-limited, but recurrence can affect individuals who
are not treated with antibiotics. Systemic antibiotics
may be used in localized or systemic disease (penicillin or erythromycin with rifampin).22
Conclusion
We present a case of cutaneous ulcers occurring in
an immunocompromised patient. We believe that
the clinical findings and Gram stain results strongly
suggest C diphtheriae as the etiologic agent, though we
were not able to confirm this with absolute certainty
because cultures were not speciated.
Superficial infections with Gram-positive rods,
such as trichomycosis axillaris, pitted keratolysis, erythrasma, toe web infections, and acne, are common
and generally easily recognized by dermatologists.
Invasive cutaneous infections with Gram-positive
rods, such as cutaneous diphtheria, gas gangrene,
cutaneous anthrax, cutaneous B cereus, cutaneous
listeriosis, and erysipeloid, on the other hand, generally are rare and may not be initially suspected.
Dermatologists must be aware of these less common
entities because delayed diagnosis could have significant consequences.
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Cutaneous Diphtheroid Infection
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DISCLAIMER
The opinions expressed herein are those of the authors and do not necessarily represent the views of the sponsor or its publisher. Please review complete prescribing
information of specific drugs or combination of drugs, including indications, contraindications, warnings, and adverse effects before administering pharmacologic
therapy to patients.
CONFLICT OF INTEREST STATEMENT
The Conflict of Interest Disclosure Policy of Albert Einstein College of Medicine requires that authors participating in any CME activity disclose to the audience any
relationship(s) with a pharmaceutical or equipment company. Any author whose disclosed relationships prove to create a conflict of interest, with regard to their
contribution to the activity, will not be permitted to present.
The Albert Einstein College of Medicine also requires that faculty participating in any CME activity disclose to the audience when discussing any unlabeled or
investigational use of any commercial product, or device, not yet approved for use in the United States.
VOLUME 79, MAY 2007 377