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 VOLUME 79, MAY 2007 373 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. References 1.Roth RR, James WD. Microbiology of the skin: resident flora, ecology, infection. J Am Acad Dermatol. 1989;20:367-390. Cutaneous Diphtheroid Infection 2.Cotton DJ, Gill VJ, Marshall DJ, et al. Clinical features and therapeutic interventions in 17 cases of Bacillus bacteremia in an immunosuppresed patient population. J Clin Microbiol. 1987;25:672-674. 3.Henrickson K, Shenep JL, Flynn PM, et al. Primary cutaneous Bacillus cereus infection in neutropenic children. Lancet. 1989;1(8638):601-603. 4.Jerdan MS, Shapiro RS, Smith NB, et al. Cutaneous manifestations of Corynebacterium group JK sepsis. J Am Acad Dermatol. 1987;16:444-447. 5.van der Lelie H, Leverstein-Van Hall M, Mertens M, et al. Corynebacterium CDC group JK (Corynebacterium jeikeium) sepsis in haematological patients: a report of three cases and a systematic literature review. Scand J Infect Dis. 1995;27:581-584. 6.Cone LA, Dreisbach L, Potts BE, et al. Fatal Bacillus cereus endocarditis masquerading as an anthrax-like infection in a patient with acute lymphoblastic leukemia: a case report. J Heart Valve Dis. 2005;14:37-39. 7.Holdiness MR. Management of cutaneous erythrasma. Drugs. 2002;62:1131-1141. 8.Garman ME, Orengo I. Unusual infectious complications of dermatologic procedures. Dermatol Clin. 2003;21:321-335. 9.American Academy of Pediatrics. Diphtheria. In: Pickering LK, Peter G, Baker CJ, et al, eds, for the Committee on Infectious Diseases, American Academy of Pediatrics. Red Book: Report of the Committee on Infectious Diseases. Elk Grove Village, Ill: American Academy of Pediatrics; 2000:230-234. 10.Hofler W. Cutaneous diphtheria. Int J Dermatol. 1991;30:845-847. 11.Koopman JS, Campbell J. The role of cutaneous diphtheria infections in a diphtheria epidemic. J Infect Dis. 1975;131:239-244. 12.Pandit N, Yeswanth M. Cutaneous diphtheria in a child. Int J Dermatol. 1999;38:298-305. 13.Lodha R, Dash NR, Kapil A, et al. Diphtheria in urban slums in north India. Lancet. 2000;355:204. 14.Masawe AE, Nsanzumuhire H, Mhalu F. Bacterial skin infections in preschools and school children in coastal Tanzania. Arch Dermatol. 1975;111:1312-1316. 15.Ouahes N, Phillips TJ. Leg ulcers. Curr Problems Dermatol. 1995;7:109-142. 16.American Academy of Pediatrics. Clostridial infections. In: Pickering LK, Peter G, Baker CJ, et al, eds, for the Committee on Infectious Diseases, American Academy of Pediatrics. Red Book: Report of the Committee on Infectious Diseases. Elk Grove Village, Ill: American Academy of Pediatrics; 2000: 212-214. 17.Dixon TC, Meselson M, Guillemin J, et al. Anthrax. N Engl J Med. 1999;341:815-826. 18.McGovern TW, Christopher GW, Eitzen EM. Cutaneous manifestations of biological warfare and related threat agents. Arch Dermatol. 1999;135:311-322. 19.American Academy of Pediatrics. Anthrax. In: Pickering LK, Peter G, Baker CJ, et al, eds, for the Committee on Infectious Diseases, American Academy of Pediatrics. Red Book: Report of the Committee on Infectious Diseases. Elk Grove Village, Ill: American Academy of Pediatrics; 2000:168-170. 20.Boulinguez S, Viraben R. Cutaneous Bacillus cereus infection in an immunocompetent patient. J Am Acad Dermatol. 2002;47:324-325. 21.Cain DB, McCann VL. An unusual case of cutaneous listeriosis. J Clin Microbiol. 1986;23:976-977. 22.Barnett JH, Estes SA, Wirman JA, et al. Erysipeloid. J Am Acad Dermatol. 1983;9:116-123. 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
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