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Gentamicin: Systemic exposure to a contact allergen
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Gentamicin: Systemic exposure to a contact allergen Ruby Ghadially, MB., C h . B . , and Colin A. R a m s a y , M.D., D.Ch., F.R.C.P.(Lond), F.R.C.P.(C) Toronto, Ontario, Canada A case is presented of an allergic dermatitis provoked by intravenous gentamicin in a patient previously sensitized by topical medications. Patch tests confirmed hypersensitivity to gentamicin and neomycin. The nature of reactions to contact allergens given systemically and the nature of cross-reactions between aminoglycoside antibiotics are reviewed. (J AM ACAD DERMATOL 1988; 19:428-30.) The possibility of sensitization to ointments and creams that are used therapeutically by patients with stasis ulcers is well documented. Generalization of this primary eczematous eruption is also not uncommon. Eczematous eruptions are uncommon, however, as manifestations of systemic drug allergy and may provide a valuable clue in endogenous exposure to a contact allergen. We present the case of an otherwise healthy 84year-old woman previously sensitized to topical gentamicin, who subsequently developed an eczematous eruption after her first dose of intravenous gentamicin. The nature of this reaction was confirmed by positive patch test results.
CASE REPORT An 84-year-old white woman was admitted to the hospital in May 1986 after a 4-month history of worsening stasis ulceration. For 3 years she had had recurrent ulcerations because of stasis. The most recent ulcerations had been present for 4 months. Multiple bacteriologic specimens had shown Pseudomonas aeruginosa, and therefore her treatment had been acetic acid soaks followed by gentamicin cream applied twice daily. However, the area of induration and erythema around the lesions continued to increase, and she was finally admitted to the hospital. She had had a stripping
From the Division of Dermatology, University of Toronto. No reprints available.
428
procedure for varicose veins 12 years earlier and had occasionally taken acetylsalicylic acid. Her history was otherwise unremarkable. On her admission, examination revealed two full-thickness ulcerations, one 3 • 3 cm and the other 2 x 2 cm, located over the right tibia anteriorly. A well-demarcated, tender, erythematous, indurated area extended from just below the knee to just above the ankle, enclosing the full circumference of the leg. Superficially, the area was crusted and weeping. A few eczematous plaques were present on the dorsal aspects of the arms. The initial plan was to treat her Pseudomonas infection systemically and, because of the suspicion of an irritant or an allergic reaction, to discontinue previous topical treatment and use Burow's solution compresses with Bactigras dressings (chlorhexidine acetate-impregnated gauze) twice daily. Several hours after the first intravenous dose of gentamicin, the patient developed an itchy eczematous eruption on both arms, which extended to the sides of her neck. The gentamicin was discontinued, and she was treated topically with betamethasone valerate (Betnovate cream 0.1%) to areas surrounding the ulcers, and with povidone-iodine (Betadine) and Bactigras to the ulcers. This produced prompt resolution of her rash and improvement of the erythema and induration surrounding the ulcers, although the bacteriologic cultures still showed a significant growth of Pseudomonas. After clearance of the eruption, patch tests with the A1-Test unit were performed on the upper part of the back. The patient was tested with a standard series of allergens and gentamicin sulphate 20% in petrolatum.~ After 2 days she showed a strong ( + + ) reaction to neomycin
Volume 19 Number 2, Part 2 August 1988
Gentamicirc Systemic exposure to a contact allergen
sulphate 20% and benzocaine 5%. By the fourth day she also had a strong ( + +) reaction to gentamicin sulphate 20%.
429
GENTAMICIN CfH3 H C-NHCH 3
NH2
* H2
DISCUSSION The patient in this report demonstrates two interesting sequelae of contact allergy: first, a generalized spread of the primary eruption, and second, a reaction to contact allergen administered intravenously. Approximately 30% of patients with stasis dermatitis have secondary eruptions when they are first seen by a dermatologist) Many are referred because of this secondary eruption, which is a valuable pointer to the diagnosis of contact allergy when it is superimposed on a stasis dermatitis. Dissemination of an allergic contact dermatitis in association with stasis ulceration tends initially to be unilateral, occurring around the sensitized area, whereas later it may become bilateral and usually spreads to involve the face, arms, and trunk. Characteristically the eruption is eczematous. However, other manifestations such as erythema multiforme, purpura, and vasculitis have all been observed in secondary spread of allergic contact dermatitis. 3 Systemic exposure to contact allergens results in an eczematous contact-type eruption known as "systemic" or "endogenic" allergic contact dermatitis.4 This reaction may cause a flare at the site of a previous dermatitis, the reactivation of an earlier positive patch test, or a generalized eruption. Also described are flares of previous dyshidrosis, symmetric maculopapular eruptions, and urticarial eruptions. 4 Accompanying these systemic reactions may be symptoms such as headache, fever, malaise, nausea, vomiting, and diarrhea. 5 In our patient it was the eczematous nature of her "drug rash" that alerted us to the possibility that it represented systemic exposure to a contact allergen. The mechanism of systemic contact dermatitis is not fully elucidated. The rapid onset of symptoms within a few hours of exposure to the antigen, as in our patient, suggests that a process other than a type 4 reaction, as seen in contact dermatitis, is responsible. Several studies have shown precipitating antibodies in serum in response to the administration of certain antigens. This reaction has
NH2 ~
0
O
C OH
NEOMYCIN CH2NH 2
/,o NH2
.NH2
_\
,
/ OH
Fig. 1. *Deoxystreptamine ring. (Neomycin 4,6-di-Osubstituted, gentamicin and kanamycin 4,5-di-Osubstituted.) been demonstrated both in sensitized human beings given oral nickeP and in sensitized guinea pigs injected with chromate. 7 It has therefore been suggested that circulating immune complexes are responsible for this type of reaction. However, further studies with nickel-sensitive patients showed a significant rise in the lymphocyte transformation test after ingestion of nickel, s Thus it appears that both types 3 and 4 reactions may be taking place. Patch tests with suspected allergens are valuhble in finding the cause of an allergic contact dermatitis, and the systemic administration of such contact allergens must be avoided to prevent severe reactions with systemic symptoms and even type 1 anaphylaxis. Practically all patients with systemic contact dermatitis will have positive patch test reactions.
430
Ghadially and Ramsay
The patient in this report had positive patch test reactions to neomycin, gentamicin, and benzocaine. In a study of eight patients with stasis dermatitis, three had positive patch test reactions to gentamicin 20% but not to neomycin 20%.~ Thus it is evident that topical gentamicin can cause sensitization. However, most reports are of crosssensitivity to neomycin. In one study of 100 patients sensitized to neomycin, 40 also had positive patch test reactions to gentamicin, although it was well known that none had previously been exposed. 9 In patients sensitized originally to gentamicin the situation is more complex. Because numerous over-the-counter preparations contain neomycin, it is impossible to be sure which drug was the primary sensitizer and which was the secondary allergen in a given patient. Gentamicin and neomycin are aminoglycoside antibiotics. Gentamicin sulfate is produced by Micromonospora purpurea and neomycin by Streptomyces fradiae. All clinically used aminoglycosides except streptomycin contain a deoxystreptamine. Attached to this hexose nucleus are two or more amino sugars joined by glycoside linkage (Fig. 1). Neomycin is more closely related to paromomycin and butirosin than to kanamycin and gentamicin. Those in the first group all contain neosamine, a diamino sugar, and have a similarly substituted deoxystreptamine, which is reflected in the very close cross-sensitivity between neomycin and butirosin (90%) compared to only 55% between neomycin and gentamicin in one study.l~ It appears most likely that cross-sensitivity to neomycin in the case of gentamicin and kanamycin is due to the deoxystreptamine ring (Fig. 1). In conclusion, a secondary eruption of eczematous nature in a patient with stasis ulceration may
Journal of the American Academyof Dermatology
be a fairly common clue to the existence of contact dermatitis superimposed on stasis dermatitis. In addition, it should be remembered that eczematous eruptions are uncommon as a manifestation of systemic drug allergy and should alert the physician to the possibility of systemic exposure to a contact allergen. Once the identity of the offending agent has been established, it is usually possible to predict cross-sensitivities to various agents with similar chemical structures. REFERENCES 1. CroninE. Contact dermatitis. Edinburgh:Churchill Livingstone, 1980. 2. HjorthN, Fregert S. In: Rook A, Wilkinson DS, Ebling FJS, eds. Textbook of dermatology. 3rd ed. Oxford: Blackwell, 1982. 3. Meneghini CL, Angetini G. Secondary polymorphic eruptions in allergic contact dermatitis. Dermatologia 1981;163:63-70. 4. FisherAA. Contactdermatitis. 3rd ed. Philadelphia:Lea & Febiger, 1986. 5. Menn6T, Hjorth N. Reactions from systemic exposure to contact allergens. Semin Dermatol 1982;1March:1. 6. Veien NK, Christiansen AH, Svejgaard E, Kaaber K. Antibodies against nickel-albumin in rabbits and man. Contact Dermatitis 1979;5:378-82. 7. PoltikL, Turk JL. Studies on the effect of systemic administration of sensitizers in guinea pigs with contact sensitivity to inorganic metal compounds. II. The flareup of previous test sites of contact sensitivity and the development of a generalized rash. Clin Exp Immunol 1968;3:253-62. 8. Veien NK, Svejgaard E, Menne T. In vitro lymphocyte transfoimation to nickel: a study of nickel-sensitivepatients before and after epicutaneous and oral challenge with nickel. Acta Derm Venereol (Stockh) 1979;59: 447-51. 9. Pirila V, Hirvonen ML, Rouhunkoski S. The pattern of cross-sensitivity to neomycin. Dermatologica 1968; 136:321-4. 10. Schorr WF, Wenzel FJ, Hededus SI. Cross sensitivity and aminoglycosideantibiotics. Arch Dermatol 1973; 107:533-9.
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Gentamicin: Systemic exposure to a contact allergen Ruby Ghadially, MB., C h . B . , and Colin A. R a m s a y , M.D., D.Ch., F.R.C.P.(Lond), F.R.C.P.(C) Toronto, Ontario, Canada A case is presented of an allergic dermatitis provoked by intravenous gentamicin in a patient previously sensitized by topical medications. Patch tests confirmed hypersensitivity to gentamicin and neomycin. The nature of reactions to contact allergens given systemically and the nature of cross-reactions between aminoglycoside antibiotics are reviewed. (J AM ACAD DERMATOL 1988; 19:428-30.) The possibility of sensitization to ointments and creams that are used therapeutically by patients with stasis ulcers is well documented. Generalization of this primary eczematous eruption is also not uncommon. Eczematous eruptions are uncommon, however, as manifestations of systemic drug allergy and may provide a valuable clue in endogenous exposure to a contact allergen. We present the case of an otherwise healthy 84year-old woman previously sensitized to topical gentamicin, who subsequently developed an eczematous eruption after her first dose of intravenous gentamicin. The nature of this reaction was confirmed by positive patch test results.
CASE REPORT An 84-year-old white woman was admitted to the hospital in May 1986 after a 4-month history of worsening stasis ulceration. For 3 years she had had recurrent ulcerations because of stasis. The most recent ulcerations had been present for 4 months. Multiple bacteriologic specimens had shown Pseudomonas aeruginosa, and therefore her treatment had been acetic acid soaks followed by gentamicin cream applied twice daily. However, the area of induration and erythema around the lesions continued to increase, and she was finally admitted to the hospital. She had had a stripping
From the Division of Dermatology, University of Toronto. No reprints available.
428
procedure for varicose veins 12 years earlier and had occasionally taken acetylsalicylic acid. Her history was otherwise unremarkable. On her admission, examination revealed two full-thickness ulcerations, one 3 • 3 cm and the other 2 x 2 cm, located over the right tibia anteriorly. A well-demarcated, tender, erythematous, indurated area extended from just below the knee to just above the ankle, enclosing the full circumference of the leg. Superficially, the area was crusted and weeping. A few eczematous plaques were present on the dorsal aspects of the arms. The initial plan was to treat her Pseudomonas infection systemically and, because of the suspicion of an irritant or an allergic reaction, to discontinue previous topical treatment and use Burow's solution compresses with Bactigras dressings (chlorhexidine acetate-impregnated gauze) twice daily. Several hours after the first intravenous dose of gentamicin, the patient developed an itchy eczematous eruption on both arms, which extended to the sides of her neck. The gentamicin was discontinued, and she was treated topically with betamethasone valerate (Betnovate cream 0.1%) to areas surrounding the ulcers, and with povidone-iodine (Betadine) and Bactigras to the ulcers. This produced prompt resolution of her rash and improvement of the erythema and induration surrounding the ulcers, although the bacteriologic cultures still showed a significant growth of Pseudomonas. After clearance of the eruption, patch tests with the A1-Test unit were performed on the upper part of the back. The patient was tested with a standard series of allergens and gentamicin sulphate 20% in petrolatum.~ After 2 days she showed a strong ( + + ) reaction to neomycin
Volume 19 Number 2, Part 2 August 1988
Gentamicirc Systemic exposure to a contact allergen
sulphate 20% and benzocaine 5%. By the fourth day she also had a strong ( + +) reaction to gentamicin sulphate 20%.
429
GENTAMICIN CfH3 H C-NHCH 3
NH2
* H2
DISCUSSION The patient in this report demonstrates two interesting sequelae of contact allergy: first, a generalized spread of the primary eruption, and second, a reaction to contact allergen administered intravenously. Approximately 30% of patients with stasis dermatitis have secondary eruptions when they are first seen by a dermatologist) Many are referred because of this secondary eruption, which is a valuable pointer to the diagnosis of contact allergy when it is superimposed on a stasis dermatitis. Dissemination of an allergic contact dermatitis in association with stasis ulceration tends initially to be unilateral, occurring around the sensitized area, whereas later it may become bilateral and usually spreads to involve the face, arms, and trunk. Characteristically the eruption is eczematous. However, other manifestations such as erythema multiforme, purpura, and vasculitis have all been observed in secondary spread of allergic contact dermatitis. 3 Systemic exposure to contact allergens results in an eczematous contact-type eruption known as "systemic" or "endogenic" allergic contact dermatitis.4 This reaction may cause a flare at the site of a previous dermatitis, the reactivation of an earlier positive patch test, or a generalized eruption. Also described are flares of previous dyshidrosis, symmetric maculopapular eruptions, and urticarial eruptions. 4 Accompanying these systemic reactions may be symptoms such as headache, fever, malaise, nausea, vomiting, and diarrhea. 5 In our patient it was the eczematous nature of her "drug rash" that alerted us to the possibility that it represented systemic exposure to a contact allergen. The mechanism of systemic contact dermatitis is not fully elucidated. The rapid onset of symptoms within a few hours of exposure to the antigen, as in our patient, suggests that a process other than a type 4 reaction, as seen in contact dermatitis, is responsible. Several studies have shown precipitating antibodies in serum in response to the administration of certain antigens. This reaction has
NH2 ~
0
O
C OH
NEOMYCIN CH2NH 2
/,o NH2
.NH2
_\
,
/ OH
Fig. 1. *Deoxystreptamine ring. (Neomycin 4,6-di-Osubstituted, gentamicin and kanamycin 4,5-di-Osubstituted.) been demonstrated both in sensitized human beings given oral nickeP and in sensitized guinea pigs injected with chromate. 7 It has therefore been suggested that circulating immune complexes are responsible for this type of reaction. However, further studies with nickel-sensitive patients showed a significant rise in the lymphocyte transformation test after ingestion of nickel, s Thus it appears that both types 3 and 4 reactions may be taking place. Patch tests with suspected allergens are valuhble in finding the cause of an allergic contact dermatitis, and the systemic administration of such contact allergens must be avoided to prevent severe reactions with systemic symptoms and even type 1 anaphylaxis. Practically all patients with systemic contact dermatitis will have positive patch test reactions.
430
Ghadially and Ramsay
The patient in this report had positive patch test reactions to neomycin, gentamicin, and benzocaine. In a study of eight patients with stasis dermatitis, three had positive patch test reactions to gentamicin 20% but not to neomycin 20%.~ Thus it is evident that topical gentamicin can cause sensitization. However, most reports are of crosssensitivity to neomycin. In one study of 100 patients sensitized to neomycin, 40 also had positive patch test reactions to gentamicin, although it was well known that none had previously been exposed. 9 In patients sensitized originally to gentamicin the situation is more complex. Because numerous over-the-counter preparations contain neomycin, it is impossible to be sure which drug was the primary sensitizer and which was the secondary allergen in a given patient. Gentamicin and neomycin are aminoglycoside antibiotics. Gentamicin sulfate is produced by Micromonospora purpurea and neomycin by Streptomyces fradiae. All clinically used aminoglycosides except streptomycin contain a deoxystreptamine. Attached to this hexose nucleus are two or more amino sugars joined by glycoside linkage (Fig. 1). Neomycin is more closely related to paromomycin and butirosin than to kanamycin and gentamicin. Those in the first group all contain neosamine, a diamino sugar, and have a similarly substituted deoxystreptamine, which is reflected in the very close cross-sensitivity between neomycin and butirosin (90%) compared to only 55% between neomycin and gentamicin in one study.l~ It appears most likely that cross-sensitivity to neomycin in the case of gentamicin and kanamycin is due to the deoxystreptamine ring (Fig. 1). In conclusion, a secondary eruption of eczematous nature in a patient with stasis ulceration may
Journal of the American Academyof Dermatology
be a fairly common clue to the existence of contact dermatitis superimposed on stasis dermatitis. In addition, it should be remembered that eczematous eruptions are uncommon as a manifestation of systemic drug allergy and should alert the physician to the possibility of systemic exposure to a contact allergen. Once the identity of the offending agent has been established, it is usually possible to predict cross-sensitivities to various agents with similar chemical structures. REFERENCES 1. CroninE. Contact dermatitis. Edinburgh:Churchill Livingstone, 1980. 2. HjorthN, Fregert S. In: Rook A, Wilkinson DS, Ebling FJS, eds. Textbook of dermatology. 3rd ed. Oxford: Blackwell, 1982. 3. Meneghini CL, Angetini G. Secondary polymorphic eruptions in allergic contact dermatitis. Dermatologia 1981;163:63-70. 4. FisherAA. Contactdermatitis. 3rd ed. Philadelphia:Lea & Febiger, 1986. 5. Menn6T, Hjorth N. Reactions from systemic exposure to contact allergens. Semin Dermatol 1982;1March:1. 6. Veien NK, Christiansen AH, Svejgaard E, Kaaber K. Antibodies against nickel-albumin in rabbits and man. Contact Dermatitis 1979;5:378-82. 7. PoltikL, Turk JL. Studies on the effect of systemic administration of sensitizers in guinea pigs with contact sensitivity to inorganic metal compounds. II. The flareup of previous test sites of contact sensitivity and the development of a generalized rash. Clin Exp Immunol 1968;3:253-62. 8. Veien NK, Svejgaard E, Menne T. In vitro lymphocyte transfoimation to nickel: a study of nickel-sensitivepatients before and after epicutaneous and oral challenge with nickel. Acta Derm Venereol (Stockh) 1979;59: 447-51. 9. Pirila V, Hirvonen ML, Rouhunkoski S. The pattern of cross-sensitivity to neomycin. Dermatologica 1968; 136:321-4. 10. Schorr WF, Wenzel FJ, Hededus SI. Cross sensitivity and aminoglycosideantibiotics. Arch Dermatol 1973; 107:533-9.