Long-term antibiotic therapy for balanitis xerotica obliteransWalter B. Shelley, MD, Ph.D, E. Dorinda Shelley, MD, Molly A Grunenwald, MD,
Timothy J. Anders, MD, and Anita Ramnath, MD Toledo, Ohio
In an uncontrolled study of 3 patients with balanitis xerotica obliterans we have observed significant improvement after long-term systematic antibiotic therapy. Two of the patients noticed softening of the skin as well as disappearance of pruritis, tenderness, and inflammatory changes within 3 weeks of receiving oral and intramuscular penicillin. The third patient experienced the same degree of improvement after a regimen of dirithromycin, 500 mg/day. Stopping the antibiotic for 1 month resulted in relapse, with improvement again on resumption. (J Am Acad Dermatol 1999;40:69-72.)
[CIRP note: This file does not include two photographs.]
Previous unpublished experience in controlling some cases of lichen sclerosus et atrophicus (LSA) with long-term systemic antibiotics led us to attempt similar treatment of a special variant of this disorder on the penis, balanitis xerotica obliterans (BXO). Localized to the glans penis and foreskin as white scarlike areas, BXO can be more disabling than widespread lichen sclerosus.1 Not only painful at times, it may result in an inability to retract the foreskin and sometimes leads to meatal stenosis.2 Fissures, erosions, and ulcers result in secondary bacterial infection, and sexual intercourse becomes impossible because of pain induced by erections. These chronic changes occasionally result in malignancy.3
We report the successful use of penicillin and dirthromycin in the treatment of 3 patients with BXO.
A 44-year old man was first seen in September 1994 for treatment of biopsy-confirmed BXO, present 3 years (Fig 1, A). It had improved slightly after intermittent application of 1% testosterone in Aquaphor, but the glans penis had a 3 cm atrophic white band extending onto the prepuce. Serologic tests for Lyme disease were negative: He was treated with intramuscular penicillin G bezathine suspension 2.4 million U, oral, amoxicilin/clavulanate potassium 250 mg 3 times daily, floucinolone acetonide 0.25% ointment, and ketoconazole 2% cream. After 3 weeks the area was no longer pruritic or tender and there was softening and thinning of the involved skin with decreased lichenification. He was then given a second injection of penicillin G benzathine (2.4 million U) and he continued the amoxicillin/clavulanate potassium. Two months later, further improvement was noted and he reported having normal painless erections (Fig 1, B). He was lost to follow-up after referral back to his urologist for continuing antibiotic treatment as needed.
A 45-year-old man consulted in March 1996 for treatment of a 14-year eruption of the glans penis with scaling, erythema, and multiple fissures that invarably flared after sexual intercourse. Circumcision had not helped. Patch tests for contact sensitivity were negative. A diagnosis of BXO was made and treatment was begun with intramuscular penicillin G benzathine (2.4 million U), oral penicillin G benzathine (2.4 million U), oral penicillin V potassium 500 mg 4 times daily, and the interdiction of all local treatment. He described dramatic improvement within several weeks, which was sustained with injections of penicillin G benzathine (2.4 million U) at 2-month intervals, and continuation of oral penicillin V potassium. After 1 year, excellent control of his problem was achieved and he was discharged from our care.
A 41-year-old man was first seen in April 1996, with a 13-year history of BXO unresponsive to muliple topical agents and 9 surgical incisions. The glans penis was exquisitely tender and painful, with fissured, scarred tissue and a white atrophic band in the penile sulcus. A repeat biopsy speciment showed only lichenified dermatitis. Because he stated that he was allergic to penicillin he was given short-term trials of cefuroxime axetil 150 mg 3 times daily and azithromycin 250 mg, 2 capsules each morning, produced rapid improvement and greatly lessened the pain. Stopping the dirithromycin after 1 month resulted in relapse, so it was resumed andf continued for 6 months, with further improvement. He was subsequently lost to follow-up.
[Two Photographs]Fig. 1 Case 1. Typical appearance of white sclerotic band of balanitis xerotica obliterans. A, Before treatment, note telangiectasia. B, After 4 months of penicillin therapy, softening of band and involution of telangiectasia.
For decades the dermatologic management of BXO has centered on 2 agents, topical testosterone propionate (2% in a water miscible base or ointment) and steroids by the topical or intralesional routes.4,5 Localized steroids had to be used with caution because they can induce further atrophy with fissuring. More recently laser surgery has been successful.6 Urologic care has focused on circumcision and meatal dilation, and on occasion meatotomy and meatoplasty.7
Our approach using long-term systemic antibiotics stems from the view that BXO and LSA may be caused by spirochetal infection with Borrelia burgdorferi.8 Spirochetes have been found in several cases of LSA as well as morphea.9,10 These conditions frequently coexist and may represent a continuous spectrum of disease.11 Both are included as late cutaneous manifestations (stage III of Lyme disease.12,13
LSA may also exist with acrodermatitis chronica atrophicans (ACA),14 a known manifestation of Lyme disease. Furthermore, LSA and morphea appear in approximately 10% of ACA cases.15 ACA has been treated successfully with penicillin since 1949,16 even though Borrelia spirochetes were not reported in ACA lestions until 35 years later.17
Antimicrobial therapy has been noted to improve patients with LSA and morphea, as well as ACA,14,15,18 with posttreatment biopsy specimens showing reduction in inflammation.15 LSA and ACA both have heavy bandlike infiltrates of lympcytes, plasma cells, mast cells, and macrophages.15 Plasma cells are common in all other lesions of Lyme disease, just as they are in syphilis, the prototype spirochetal disease with numerous cutaneous manifestations.15
Aberer, Neuman, and Lubec14 reported a case in which genital LSA (BXO) appeared simultaneously with ACA, 1 year after a tick bite . Oral penicillin treatment (penicillin V 1 million U 3 times daily for 24 days) improved both conditions but did not prevent recurrence 9 years later. Additional therapy with oral antibiotics (penicillin V 1.5 million U 3 times daily for ten days, 2 courses, with subsequent oxytetracycline 500 mg. twice daily for 10 days) again improved the lesions, but they recurred again, along with new LSA lesions on the upper back.
In this same patient dark-field microscopy of urine sediment revealed motionless coiled structures resembling spirochetes, similar to those detected in 5 of 9 other patients with genital LSA.14 This led to speculation that Borrelia had been excreted through the kidney after hematological spread. These spirochetes are known to have an affinity for kidney and urinary bladder tissue.19 Conceivably, BXO could result from direct infection of skin by spirochetes from urine, with the moist warm environment under the prepuce being conducive to spirochete growth. In this regard, circumcision in infancy virtually guarantees that BXO will never occur.20
Because tests for B burgdorferi in LSA and morphea have generally been negative in the United States and several European countries,21-23 skepticism about their possible usefulness has prevailed and conceptually blocked the use of antibiotics for treating these conditions. Only in Austraia have antibiotics apparently been widely used for treatment of LSA and morphea.14,18 Possibly, antigenic diversity among different strains and species of B burgdorferi could be interfering with serologic and polymerase chain reaction identification.24-26 New strains of Borrelia genospecies are also still being discovered, as in Japan.27 Future testing of urine and blood for B burgdorferi may be helpful, as shown with monoclonal antibodies28 and PCR studies.29
The ideal antibiotic treatment to prevent spread of LSA has not yet been established.30 We have found that long-term antibiotic treatment is more effective than the usual 1 to 3 week course. It is known that B burgedorferi spirochetes are sequestered in tissue, especially in fibroblasts, macrophages, and endothelial cells, as shown in tissue culture.31-33 Complete eradication of these “privileged” spirochetes may be difficult31 because antibiotics do not easily penetrate the cells. Therefore, the higher levels achieved by intramuscular routes of antibiotic administration may prove more successful. However, oral antibiotics appear to be successful when continued long enough to cover the cell-turnover time of a majority of infected endothelial cells, macrophages, and fibroblasts.
It must also be borne in mind that the improvement we have observed might not be because of antimicrobial activity of the antibiotics but rather a result of their effects on connective tissue metabolism and immune reactions.34,35 But no matter what this mode of action may be, antibiotics deserve therapeutic consideration by physicians searching for help for those patients who fail to respond to topical measures.
- Laymon CW, Freeman C. Relationship of balanitis xerotica obliterans to lichen sclerosus et atrophicus. Arch Dermatol Syphilol 1944;49:57-9.
- Meffert JJ, David BM, Grinwood RD. Lichen sclerosus. J Am Acad Dermatol 1995;32:393-416.
- Prede HB, Miller OF III, Tyler WB. Penile squamous cell carcinoma arising from balanitis xerotica obliterans. J Am Acad Dermatol 1993;29:469-73.
- Shelley WB, Shelley Ed. Advanced dermatologic therapy. Philadelphia: WB Saunders; 1987. p. 94-5.
- Bale PM, Lochhead A, Martin HCO, Gollow I. Balanitis xerotica obliterans in children. Pediatr Pathol 1987;7:617-27.
- Arndt KA, Dover JS, Olbricht SM, editors. Lasers in cutaneous and aesthetic surgery. Philadelphia: Lippincott-Raven; 1997. p. 243.
- Hinman FH Jr. Atlas of urologic surgery. 2nd ed. Philadelphia: WB Saunders; 1998;19:820-5.
- Schempp C, Bocklage D, Lange R, et al. Further evidence for Borrelia burgdorferi infection in morphea and lichen sclerosus et atrophicus confirmed by DNA amplification. J Invest Dermatol 1993;100:717-20.
- Aberer E, Kollegger H, Kristoferitsch W, Stanek G. Neurobolleiosis in morphea and lichen sclerosis et atrophicus. J Am Acad Dermatol 1998;19:820-5.
- Weber K, Preac-Mursic V, Reimers CD. Spirochetes isolated from two patients with morphea. Infection 1998;16:25-6.
- Uitto J, Santa Cruz DJ, Bauer EA, Eisen AZ. Morphea and lichen sclerosus: clinical and histopathological studies in patients with combined features. J Am Acad Dermatol 1980;3:271-9.
- Duray PH, Sterre AC. Clinical pathologic correlations of Lyme disease by stage. Ann Ny Acad Sci 1978;539:65-79.
- Malone MS, Grant-Kels JM, Feder HM Jr, Luger SW. Diagnosis of Lyme disease based on dermatologic manifestations. Ann Intern Med 1991;114:490-8.
- Aberer E, Neumann R, Lubec G. Acrodermatitis chronica atrophicans in association with lichen sclerosus et atrophicus: tubulo-interstitial nephritis and urinary excretion of spirochete-like organisms. Acta Derm Venereol (Stockh) 1987;67:62-5.
- Duray PH, Asbrink E, Weber K. The cutaneous manifestations of human Lyme disease: a widening spectrum. Adv Dermatol 1989;4:255-76.
- Thyresson N. The penicillin treatment of acrodermatitis atrophicans chronica (Herxheimer). Acta Derm Venerol (Stockh) 1949;29:572-621.
- Hinmann FH Jr. Atlas of urologic surgery. 2nd ed. Philadelphia: Lippincott-Raven: 1997. p. 243.
- Aberer E, Hovmark A, Hederstedt B. The spircochetal etiology of acrodermatitis chronica atrophicans Herxheimer. Acta Derm Venerol (Stockh) 1984;64:506-12.
- Schwan TG, Burgdorfer W, Schrumph ME, Karstens RH. The urinary bladder, a consistent source of Borrelia burgdorferi in experimentally infected white-foot mice (Peromyscus leucopus) J Clin Microbiol 1988;26:893-5.
- Ledwig PA. Weigand DA. Late circumcision and lichen sclerosus et atrophicus of the penis. J Am Acad Dermatol 1989;20:211-4.
- Tuffanelli DL, Tuffanelli LR, Hoke A. False-positive Lyme disease antibody test in morphea. J Am Acad Dermatol 1993;28:112-3.
- Meis JF. Koopman R, Van Bergen b, et al. No evidence for a relations between Borrelia burgdorferi infection and old lesions of localized scleroderma (morphea). Arch Dermatol 1993;129:386-7.
- Raguin G, Boisnic S, Souteyrand P, et al. No evidence for a spirochaetal origin of localized scleroderma. Br J Dermatol 1992;127:218-20.
- Schmidli J, Meyer J. Lyme borreliosis. Dermatologica 1991; 182:141-4.
- Stanek G, Wewalka G, Groh V, et al. Differences between Lyme disease and European arthopod-borne Borrelia infections [letter]. Lancet 1985;1:401.
- Dressler F. Ackermann R, Steere AC. Antibody responses to the three genomic groups of Borrelia burgdorheri in European Lyme borreliosis. J Infect Dis 1994;169:313-8.
- Hashimoto Y, Kawagishi N, Sakai H, et al. Lyme disease in Japan: analysis of Borrelia species using r RNA gene restruction fragment length polymorphism. Dermatologica 1995;191:193-8.
- Hyde FW, Johnson RC, White TJ, Shelburne CE. Detection of antigens in urine of mice and humans infected with Borrelia burgdorferi, etiologic agent of Lyme disease. J Clin Microbiol 1989;27:56-61.
- Goodman JL, Jurkovich P, Kramber JM, Johnson RC. Molecular detection of persistent Borellia burgdorferi in the urine of patients with active Lyme disease. Infect Immun 1991;59:269-78.
- Sigal LH. Lyme disease: a review of aspects of its immunology and immununopatheogenesis. Ann Immunol 1997;15:63-92.
- Georgilis K, Peacocke M, Klepmner MS. Fibroblasts protect the Lyme disease spirochete, Borelia burgdorferi, from ceftriaxone in vitro. J Infect Dis 1992; 166:440-4.
- Ma Y, Sturrock A, Weiss JJ. Intracellular localization of Borelia burgdorheri within human endothelial cells. Infect Immun 1991;59:671-8.
- Montgomery RR, Nathanson MH, Malawista SE. The fate of Borrelia burgdorferi, the agent for Lyme disease, in mouse macrophages. J Immunol 1993;150:909-15.
- Hauser WE Jr, Remington JS. Effect of antimicrobial agents on the immune response. In: Ristuccia AM, Cunha BA. Antimicrobial therapy. New York: Raven Press, 1984. p. 55-79.
- Vazquez D. The macrolide antibiotics. In: Corcoran JW, Hahn FE, editors. Antibiotics; vol 3—Mechanism of action of antimicrobial and antitumor agents. Berlin: Springer-Verlag; 1975. p. 459-79.
From the Division of Dermatology, Department of Medicine, Medical College of Ohio.
Reprint requests: Walter B. Shelley, MD, Ph.D, Medical College of Ohio, Ruppert Health Center, 3120 Glendale Ave, Toledo, OH 43614-5809.
Copyright © 1999 by the American Academy of Dermatology, Inc.
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