- Email: [email protected]
The Efficacy and Safety of Amoxicillin, Trimethoprim-Sulfamethoxazole, and Spironolactone for Treatment-Resistant Acne Vulgaris
Advances in Dermatology 23 (2007) 155–163
ADVANCES IN DERMATOLOGY The Efficacy and Safety of Amoxicillin, Trimethoprim-Sulfamethoxazole, and Spironolactone for Treatment-Resistant Acne Vulgaris Cheryl Bansal Turowski, MDa, William D. James, MDb,* a
Department of Dermatology, Drexel University College of Medicine, Philadelphia, PA, USA Department of Dermatology, University of Pennsylvania School of Medicine, 3600 Spruce Street, 2 Maloney Building, Philadelphia, PA 19104, USA
b
EDITORIAL COMMENT Most acne therapy trials compare an active intervention with placebo or another therapy. In general, if treatments fail, there is a relative lack of guidance as to which drugs reasonably may be expected to have a successful outcome as second- or thirdline options. Although isotretinoin is a superb medication for treatment-resistant acne, many patients cannot tolerate it or do not desire to use it. This article helps define the response to therapy of three oral medications for patients who failed initial treatment. This was accomplished via a retrospective chart analysis to determine the efficacy of amoxicillin, trimethoprim-sulfamethoxazole (TMP-SMX), and spironolactone, alone or at times in combination, for treatment-resistant acne. Amoxicillin is not a medication commonly used for acne. It is not reported as an effective drug for this condition in formal studies, but I have seen excellent responses in patients who have gram-negative folliculitis and, thus, have extended its use to help other patients who have had treatment-resistant acne. TMP-SMX and spironolactone are reported effective; the authors support the use of these medications in patients failing prior therapies. Amoxicillin, TMP-SMX, and spironolactone alone or in combination offer effective alternate therapies for treatment-resistant acne. William D. James, MD
A
cne vulgaris is a common disease, which, in most cases, can be controlled with topical or systemic medications. Systemic therapy for moderate to severe acne includes oral antibiotics, oral birth control pills, spironolactone, and isotretinoin. Tetracyclines and their derivatives, erythromycin, and clindamycin are used with success; some patients, however, fail to clear when using these medications in combination with topical agents. *Corresponding author. E-mail address: [email protected] (W.D. James).
0882-0880/07/$ – see front matter doi:10.1016/j.yadr.2007.07.003
ª 2007 Elsevier Inc. All rights reserved.
156
TUROWSKI & JAMES
Hormonal therapy, such as spironolactone or oral birth control pills, are most useful in women who have failed antibiotics, have an underlying endocrinologic disorder, or have flared after successful use of isotretinoin. Isotretinoin is a superbly effective therapy for patients who have acne whose disease has failed to respond to aggressive topical and oral medications. Up-to-date, evidence-based studies to guide physicians on the relative efficacy of oral interventions, which might be used to place medications on a hierarchy of treatment scale, generally are lacking [1], with the exception of isotretinoin. This drug clearly is the most useful of all therapies in producing remissions of disease even in patients who prove resistant to all prior oral and topical agents. Frequently, patients cannot or will not take isotretinoin because they are unable (because of administrative requirements, distance, cost, and pregnancy) or unwilling (because of widespread publicity about uncommon but serious potential side effects). The purpose of this study is to determine the usefulness of amoxicillin, TMP-SMX, and spironolactone in the treatment of resistant acne in such patients. MATERIALS AND METHODS A retrospective chart analysis was conducted of 713 patients who had acne seen by one of the authors (WDJ) from 2001 to 2006. The patients seen were referred primarily after having failed therapy with many agents over an extended period of time. A total of 81 patients fulfilled the inclusion requirements of the study, namely, past or current treatment with amoxicillin, TMP-SMX, or spironolactone, alone or in combination. Prior ineffective or nontolerated treatment included many topical products, usually in combinations of two or three, and tetracyclines (including minocycline and doxycycline) (40 patients), isotretinoin (10 patients), and oral birth control pills (14 patients). Many of the patients who failed oral therapy refused isotretinoin and, thus, were started on amoxicillin, TMP-SMX, or spironolactone. A 1 to 10 scale was developed to quantify the severity of acne. Scores of 1 and 2 correlated with severe acne (comedones, papules, pustules, and cysts); 3 and 4, moderately severe acne (no cysts); 5 and 6, moderate acne (fewer lesions and less generalized in extent); 7 and 8, mild acne (primarily comedonal with few inflammatory lesions, generally involving only the face); and 9 and 10, very mild to clear (two or fewer lesions was given a score of 9, and completely clear scored as 10). Improvement was calculated by subtracting the average pretreatment score from average post-treatment score. An improvement of 1 to 4 was considered ‘‘improved,’’ 5 to 7 ‘‘marked improvemen,’’ and 8 to 9 ‘‘complete response.’’ Patients were seen 6 to 8 weeks after initiation of treatment (71 of 81 patients), in the majority of cases for many months more. Those patients who did not return to clinic (9 of 81) were called by telephone for subjective assessment of improvement. One patient could not be reached. Amoxicillin was given in dosages ranging from 250 mg (2 to 3 times daily) (11 patients) to 500 mg (2 times a day) (2 patients). TMP-SMX was given as Bactrim DS once per day (2 patients) or twice per day (20 patients), with a total
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dosage of trimethoprim ranging from 160 to 320 mg per day and a total dosage of sulfamethoxazole ranging from 800 to 1600 mg per day. Spironolactone was given in dosages of 50 to 200 mg per day (50 to 100 mg [38 patients] and 200 mg [one patient]). Tapering of the dose to discontinuance was attempted when complete response was achieved, with reliance on topical medications for control the desired outcome. Sixteen patients were taking combination estrogen/progesterone hormonal therapy in the form of oral birth control pills (14 patients) and subcutaneous delivery vehicles (2 patients). Four patients were started on oral birth control pills concurrently with spironolactone. Simultaneous adjustments in topical therapy also usually were undertaken. Generally, prior ineffective or irritating treatments were abandoned and new combinations of two topicals were selected. Often, this meant third-line agents were used. In the view of patients and the treating physician, such changes likely contributed to a minority of the improvement, considering these patients already had failed multiple topical and oral agents. RESULTS Amoxicillin Five men and eight women took amoxicillin alone (Table 1). Ages ranged from 16 to 32. Average follow-up at final assessment was 162 days. Ten patients had a pretreatment score of 1 to 4, and three patients had pretreatment scores of 5. One patient worsened on amoxicillin. Twelve patients had post-treatment scores of 8 to 10. Overall, two patients were ‘‘improved,’’ six ‘‘markedly improved,’’ and four had a ‘‘complete response.’’ There were no adverse events related to amoxicillin use. Trimethoprim-sulfamethoxazole Sixteen men and six women took TMP-SMX alone. Ages ranged from 16 to 60. Average follow-up at final assessment was 282 days. Twenty patients had a pretreatment score of 1 to 4, and two patients had pretreatment scores of 5. One patient developed a cutaneous hypersensitivity reaction after 2 weeks and the drug was discontinued. One week after the drug was discontinued, the eruption disappeared. Five had post-treatment scores of 5 to 7, and 16 had posttreatment scores of 8 to 10. Overall, three patients were ‘‘improved,’’ thirteen ‘‘markedly improved,’’ and five had a ‘‘complete response.’’ Spironolactone Thirty-nine patients took spironolactone alone. All were women. Ages ranged from 18 to 59. Average follow-up at final assessment was 585 days. One patient could not be reached for follow-up by telephone. All 39 patients had a pretreatment score of 1 to 4. Three patients had post-treatment scores of 1 to 4, eleven had post-treatment scores of 5 to 7, and 24 had post-treatment scores of 8 to 10 (total of 38 patients). Overall, five patients were ‘‘improved,’’ twenty-two ‘‘markedly improved,’’ and six had a ‘‘complete response.’’ Two patients did not improve on spironolactone and discontinued the drug. There were three
158
Table 1 Results
Drug Amoxicillin TMP-SMX Spironolactone Amoxicillin þ spironolactone Spironolactone þ TMP-SMX
Number of patients ‘‘markedly improved’’
Number of patients who had ‘‘complete response’’
Number of patients worsened
Number of adverse effects
Total patients
Median prescore
Median postscore
Number of patients ‘‘improved’’
13 22 39 2
4 2.5 2 1.5
9 9 8 10
2 3 5 0
6 13 22 0
4 5 6 2
1 0 2 0
0 1 3 0
0
1
2
0
0
3
3
9.5
TUROWSKI & JAMES
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adverse events related to spironolactone use: breast tenderness, palpitations, and orthostatic hypotension. All of these resolved within 2 weeks of cessation of spironolactone use. Combination therapies Three women took TMP-SMX along with spironolactone, whereas two took trimethoprim and spironolactone. Ages ranged from 18 to 26. Four patients had a pretreatment score of 1 to 4, and one had pretreatment score of 5 to 7. All five had post-treatment scores of 8 to 10. Overall, two patients were ‘‘markedly improved,’’ and three had a ‘‘complete response.’’ There was one adverse reaction to spironolactone (orthostatic hypotension), which disappeared within 1 week of cessation of spironolactone. Two women took spironolactone and amoxicillin. Their ages were 32 and 47. Both patients had pretreatment scores of 1 to 4 and post-treatment scores of 8 to 10. Overall, both patients had a ‘‘complete response’’ at the end of the study. DISCUSSION Amoxicillin Amoxicillin has been used anecdotally in the treatment of refractory acne vulgaris, but there are no studies of efficacy for amoxicillin for this indication. Concurrent topical therapy included retinoids (six patients), topical clindamycin with benzoyl peroxide (four patients), azelaic acid (one patient), and benzoyl peroxide preparations (two patients). Seven of the nine patients previously had used tetracycline or a tetracycline derivative (minocycline or doxycycline) without improvement. Two patients had no history of prior antibiotic use for acne treatment. Both patients who used amoxicillin after failing on TMP-SMX achieved excellent results. No patients had used isotretinoin prior. There were no side effects related to amoxicillin use. Trimethoprim-sulfamethoxazole There are a few studies on the usefulness of TMP-SMX in the treatment of acne, but many dermatologists do not use it frequently because of possible serious adverse effects associated with chronic TMP-SMX use. In 1971, Cotterill and colleagues [2] first reported the effectiveness of TMP-SMX in comparison with oxytetracycline and found TMP-SMX as effective as oxytetracycline in the treatment of acne vulgaris. Subsequently, in a double-blind study of 42 patients, 22 were given TMP-SMX (80 mg TMP plus 400 mg SMX) and 21 were given placebo, and after 5 weeks, patients given TMP-SMX saw a 62% decrease in their lesions compared with 9% decrease in patients who were given placebo [3]. In a double-blind crossover study, 33 patients given TMPSMX saw a significant improvement in comedones and pustules when these two clinical entities were taken together [4]. In all three of these studies, side effects were rare and not statistically significant when compared with side effects from placebo.
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In addition to the combination TMP-SMX used in the treatment of acne, trimethoprim alone is shown in two studies as effective in the treatment of acne vulgaris [5,6]. A drug eruption may occur, usually within 3 weeks of initiation of therapy [6]. The most important side effects seen with TMP-SMX treatment include hypersensitivity, toxic epidermal necrolysis, Stevens-Johnson syndrome (SJS), hematologic abnormalities [7], and renal abnormalities. Hypersensitivity skin reactions may occur in 3% to 5% of patients taking TMP-SMX. [8–11] One of the authors’ patients taking TMP-SMX developed such an eruption that resolved quickly on cessation of the drug. Most drug eruptions occur within 3 to 8 weeks of starting treatment and resolve rapidly on cessation of drug intake [6]. Estimates of a severe skin reaction (erythema multiforme/SJS, toxic epidermal necrolysis) are 1 in 100,000 [12]. In a population-based follow-up study of 232,390 people who were prescribed TMP-SMX, four developed erythema multiforme/SJS [13]. A similar study found three cases of TMP-SMX–associated severe skin disorders, a risk of 2.8 per 100,000 (95% CI, 0.9–8.2) [14]. A wide range of hematologic abnormalities is ascribed to treatment with TMP-SMX. These include thrombocytopenia, agranulocytosis, anemia (macrocytic, megaloblastic, hemolytic, and aplastic), eosinophilia, and sulfhemoglobinemia [15]. Most untoward effects in otherwise healthy patients occur within 2 weeks of onset of therapy [16]; however, chronic use of TMP-SMX can predispose patients (especially the immunosuppressed) to hematologic abnormalities. Predisposing factors include known folic acid or vitamin B12 deficiency (pregnancy, the elderly, patients who have malabsorption or malnutrition, alcoholics, patients receiving phenytoin, or those who have chronic hemolysis [such as sickle-cell disease]) [11,15,17]. In addition, TMP-SMX is shown to have teratogenic effects [18]. TMP-SMX should not be given to patients who have glucose-6-phosphate dehydrogenase deficiency [10], but few clinicians routinely screen patients for this enzyme deficiency. Severe cytopenias may develop with concurrent methotrexate use; thus, this combination should be avoided. Thrombocytopenia is reported with TMP-SMX therapy [19,20]. In a study of 1121 patients who did not have AIDS, one developed thrombocytopenia [21]. A 40-year-old man developed thrombocytopenia, neutropenia, generalized rash, and oral candidiasis after 5 days of TMP-SMX therapy; he died shortly thereafter [22]. Another study reported a 54-year-old woman who developed thrombocytopenia 1 day after finishing a 10-day course of TMP-SMX for sinusitis. She was treated with platelet transfusions and prednisone and recovered [23]. The estimated excess risk for thrombocytopenia associated with TMP-SMX therapy is 38 patient cases per 1 million users per week [23]. Chronic use of TMP-SMX can lead to leukopenia, agranulocytosis, and anemia (including macrocytic, megaloblastic, and aplastic). The estimated risk for agranulocytosis attributable to the use of TMP-SMX is 1.6 per million patients [24]. A 6-year population-based cohort study found six cases of TMP-SMX– associated blood disorders, a risk of 5.6 per 100,000 (95% CI, 2.6–12.2) [14].
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Asymptomatic hyperkalemia recently has been recognized to occur in HIVinfected patients on high-dose TMP-SMX, the elderly, and anyone who has renal insufficiency treated with TMP-SMX [25–28]; the mechanism is believed to involve the effect of trimethoprim on distal tubule potassium secretion [29]. Mild increases in serum creatinine levels can be seen with trimethoprim use as a result of inhibition of tubule secretion of creatinine, but the effect is not important clinically [30]. In a study of 1121 patients treated with TMP-SMX, four (0.4%) exhibited an increase in serum creatinine without adverse event [21]. TMP-SMX may be mildly nephrotoxic in patients who have underlying renal insufficiency; acute tubular necrosis is described [21]. Severe crystalluria may occur in patients who have severe renal insufficiency [10,15]. Incidences of true renal toxicity are more likely in patients who have underlying renal insufficiency. Because most acne patients are young, healthy people who do not have cardiac or renal dysfunction, these considerations generally are less concerning. Another issue of importance is the possibility that Staphylococcus aureus develops resistance to TMP-SMX during chronic administration for acne. Currently, this antibiotic has great usefulness in the treatment of communityacquired methicillin-resistant Staphyloccocus aureus abscesses. It is recommended that once control is achieved, lowering the dose and discontinuance (with maintenance treatment provided by topical medications) be attempted. Spironolactone The authors’ results show seven patients were ‘‘improved,’’ twenty-two ‘‘almost clear,’’ and five ‘‘clear.’’ Concurrent topical therapy included topical retinoids (22 patients), azelaic acid (4 patients), combination estrogen and progesterone preparations (15 patients), and benzoyl peroxide preparations (11 patients). Twenty-six patients previously had used tetracycline or a tetracycline derivative (minocycline or doxycycline) without improvement. Both patients who used spironolactone in conjunction with amoxicillin achieved excellent results. Four patients had used isotretinoin prior. One patient did not improve on spironolactone and discontinued the drug. There were three adverse events likely related to spironolactone use: breast tenderness, palpitations, and orthostatic hypotension. All of these resolved within 2 weeks of cessation of spironolactone use. There are few studies on the implications of acne and hirsuitism for breast cancer risk; however, women who have acne, hirsuitism, and polycystic ovaries have higher levels of androgens than women who do not have these disorders. The authors have noticed anecdotally that adult women who have acne on the spectrum of hyperandrogenemia, polycystic ovary syndrome, and metabolic syndrome seem to have a low incidence of familial breast cancer. These women are more likely to respond to hormonal therapies for control of acne vulgaris, such as spironolactone. In the authors’ clinic, of these 40 women who had adult acne considered for treatment with spironolactone, only one had an immediate family member who had breast cancer. Three had
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grandmothers who had breast cancer, one had a maternal aunt who had breast cancer. There are many theories describing the pathogenesis of adult acne in women. This disease is not difficult to diagnose, but it may prove at times difficult to treat. Many women who have elevated serum androgens or enhanced pilosebaceous unit sensitivity to androgens experience significant improvement of acne with spironolactone alone or in conjunction with amoxicillin. Side effects of spironolactone are uncommon, as the usual dose required (50 to 100 mg) is low. When present, they were mild and respond to discontinuance of the medicine. Four patients, after failing these interventions, went on to take isotretinoin. SUMMARY In situations where acne has proved resistant to other systemic agents or they are not indicated and isotretinoin is not desired by patients, the authors find amoxicillin, TMP-SMX, and spironolactone, alone or in combination, useful alternatives. In women who have acne, spironolactone can be used, and in patients who have sulfa allergy, amoxicillin can be used. It is important to continue alternate topical therapy along with these interventions to augment the improvement and to assist in the eventual discontinuance of oral medication. All of the authors’ patients were using topical therapy concomitantly and, although this may have contributed to improvement, the authors believe the addition of amoxicillin, TMP-SMX, or spironolactone contributes to the majority of improvement. Tetrospective chart analysis provides supportive data for amoxicillin, TMP-SMX, and spironolactone in the treatment of refractory acne vulgaris. References [1] James WD. Acne. N Engl J Med 2005;352(14):1463–72. [2] Cotterill JA, Cunliffe WJ, Forster RA, et al. A comparison of trimethoprim-sulphamethoxazole with oxytetracycline in acne vulgaris. Br J Dermatol 1971;84(4):366–9. [3] Hersle K. Trimethoprim-sulphamethoxazole in acne vulgaris: a double-blind study. Dermatologica 1972;145:187–91. [4] Macdonald RH, Macconnell LE, Dunsmore IR. Trimethoprim-sulphamethoxazole versus placebo in acne vulgaris. Br J Clin Pract 1972;26(2):97–8. [5] Gibson JR, Darley CR, Harvey SG, et al. Oral trimethoprim versus oxytetracycline in the treatment of inflammatory acne vulgaris. Br J Dermatol 1982;107(2):221–4. [6] Cunliffe WJ, Aldana OL, Goulden V. Oral trimethoprim: a relatively safe and successful third-line treatment for acne vulgaris [Letter]. Br J Dermatol 1999;141:757–8. [7] Tan HH. Antibacterial therapy for acne: a guide to selection and use of systemic agents. Am J Clin Dermatol 2003;4(5):307–14. [8] Smilack J. Trimethoprim-sulfamethoxazole. Mayo Clin Proc 1999;74:730–4. [9] Libecco JA, Powell KR. Trimethoprim-sulfamethoxazole: clinical update. Pediatrics in Review 2004;25:375–80. [10] Cockerill FR, Edson RS. Trimethoprim-sulfamethoxazole. Mayo Clin Proc 1991;66: 1260–9. [11] Foltzer MA, Reese RE. Trimethoprim-sulfamethoxazole and other sulfonamides. Med Clin North Am 1987;71(6):1177–92.
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[12] Lawson DN, Paice BJ. Adverse reactions to trimethoprim-sulfamethoxazole. Rev Infect Dis 1982;4:429–33. [13] Jick H, Derby LE. A large population-based follow-up study of trimethoprim-sulfamethoxazole, trimethoprim, and cephalexin for uncommon serious drug toxicity. Pharmacotherapy 1995;15(4):428–32. [14] Myers MW, Jick H. Hospitalization for serious blood and skin disorders following co-trimoxazole. Br J Clin Pharmacol 1997;43(6):649–51. [15] Wormser GP, Keusch GT. Trimethoprim-sulfamethoxazole in the United States. Ann Intern Med 1979;91:420–9. [16] Gleckman R, Alvarez S, Joubert DW. Drug therapy reviews: trimethoprim-sulfamethoxazole. Am J Hosp Pharm 1979;36(7):893–906. [17] Bjornson BH, McIntyre AP, Harvey JM, et al. Studies of the effects of trimethoprim and sulfamethoxazole on human granulopoeisis. Am J Hematol 1986;23:1–7. [18] Czeizel AE, Rockenbauer M, Sorensen HT, et al. The teratogenic risk of trimethoprim-sulfonamides: a population based case-control study. Reprod Toxicol 2001;15(6):637–46. [19] Malnick SD, Atali M, Israeli E, et al. Trimethoprim-sulfamethoxazole-induced rash, fever, abnormal liver function tests, leukopenia, and thrombocytopenia. Ann Pharmacother 1993;27:1139–40. [20] Ahmad S. Severe thrombocytopenia-hemorrhage due to trimethoprim-sulfamethoxazole: a case report. Rev Infect Dis 1982;4:429–33. [21] Jick H. Adverse reactions to trimethoprim-sulfamethoxazole in hospitalized patients. Rev Infect Dis 1982;4(2):426–8. [22] Kocak Z, Hatipoglu CA, Ertem G, et al. Trimethoprim-sulfamethoxazole induced rash and fatal hematologic disorders. J Infect 2006;52(2):e49–52. [23] Yamreudeewong W, Fosnocht BJ, Weixelman JM. Severe thrombocytopenia possibly associated with TMP-SMX therapy. Ann Pharmacother 2002;36:78–82. [24] [Author unknown]. Anti-infective drug use in relation to the risk of agranulocytosis and aplastic anemia. Arch Intern Med 1989;149:1036–40. [25] Greenberg S, Reiser IW, Chou SY, et al. Trimethoprim-sulfamethoxazole induces reversible hyperkalemia. Ann Intern Med 1993;199:291–5. [26] Alappan R, Perazella MA, Buller GK. Hyperkalemia in hospitalized patients treated with trimethoprim-sulfamethoxazole. Ann Intern Med 1996;124:316–20. [27] Perazella MA, Mahnensmith RL. Trimethoprim-sulfamethoxazole: hyperkalemia is an important complication regardless of dose. Clin Nephrol 1996;46:187–92. [28] Ellison DH. Hyperkalemia and trimethoprim-sulfamethoxazole. Am J Kidney Dis 1997;29: 959–62. [29] Velazquez H, Perazella MA, Wright FS, et al. Renal mechanism of trimethoprim-induced hyperkalemia. Ann Intern Med 1993;119:296–301. [30] Naderer O, Nafziger AN, Bertino JS Jr. Effects of moderate-dose versus high-dose trimethoprim on serum creatinine and creatinine clearance and adverse reactions. Antimicrob Agents Chemother 1997;41:2466–70.
ADVANCES IN DERMATOLOGY The Efficacy and Safety of Amoxicillin, Trimethoprim-Sulfamethoxazole, and Spironolactone for Treatment-Resistant Acne Vulgaris Cheryl Bansal Turowski, MDa, William D. James, MDb,* a
Department of Dermatology, Drexel University College of Medicine, Philadelphia, PA, USA Department of Dermatology, University of Pennsylvania School of Medicine, 3600 Spruce Street, 2 Maloney Building, Philadelphia, PA 19104, USA
b
EDITORIAL COMMENT Most acne therapy trials compare an active intervention with placebo or another therapy. In general, if treatments fail, there is a relative lack of guidance as to which drugs reasonably may be expected to have a successful outcome as second- or thirdline options. Although isotretinoin is a superb medication for treatment-resistant acne, many patients cannot tolerate it or do not desire to use it. This article helps define the response to therapy of three oral medications for patients who failed initial treatment. This was accomplished via a retrospective chart analysis to determine the efficacy of amoxicillin, trimethoprim-sulfamethoxazole (TMP-SMX), and spironolactone, alone or at times in combination, for treatment-resistant acne. Amoxicillin is not a medication commonly used for acne. It is not reported as an effective drug for this condition in formal studies, but I have seen excellent responses in patients who have gram-negative folliculitis and, thus, have extended its use to help other patients who have had treatment-resistant acne. TMP-SMX and spironolactone are reported effective; the authors support the use of these medications in patients failing prior therapies. Amoxicillin, TMP-SMX, and spironolactone alone or in combination offer effective alternate therapies for treatment-resistant acne. William D. James, MD
A
cne vulgaris is a common disease, which, in most cases, can be controlled with topical or systemic medications. Systemic therapy for moderate to severe acne includes oral antibiotics, oral birth control pills, spironolactone, and isotretinoin. Tetracyclines and their derivatives, erythromycin, and clindamycin are used with success; some patients, however, fail to clear when using these medications in combination with topical agents. *Corresponding author. E-mail address: [email protected] (W.D. James).
0882-0880/07/$ – see front matter doi:10.1016/j.yadr.2007.07.003
ª 2007 Elsevier Inc. All rights reserved.
156
TUROWSKI & JAMES
Hormonal therapy, such as spironolactone or oral birth control pills, are most useful in women who have failed antibiotics, have an underlying endocrinologic disorder, or have flared after successful use of isotretinoin. Isotretinoin is a superbly effective therapy for patients who have acne whose disease has failed to respond to aggressive topical and oral medications. Up-to-date, evidence-based studies to guide physicians on the relative efficacy of oral interventions, which might be used to place medications on a hierarchy of treatment scale, generally are lacking [1], with the exception of isotretinoin. This drug clearly is the most useful of all therapies in producing remissions of disease even in patients who prove resistant to all prior oral and topical agents. Frequently, patients cannot or will not take isotretinoin because they are unable (because of administrative requirements, distance, cost, and pregnancy) or unwilling (because of widespread publicity about uncommon but serious potential side effects). The purpose of this study is to determine the usefulness of amoxicillin, TMP-SMX, and spironolactone in the treatment of resistant acne in such patients. MATERIALS AND METHODS A retrospective chart analysis was conducted of 713 patients who had acne seen by one of the authors (WDJ) from 2001 to 2006. The patients seen were referred primarily after having failed therapy with many agents over an extended period of time. A total of 81 patients fulfilled the inclusion requirements of the study, namely, past or current treatment with amoxicillin, TMP-SMX, or spironolactone, alone or in combination. Prior ineffective or nontolerated treatment included many topical products, usually in combinations of two or three, and tetracyclines (including minocycline and doxycycline) (40 patients), isotretinoin (10 patients), and oral birth control pills (14 patients). Many of the patients who failed oral therapy refused isotretinoin and, thus, were started on amoxicillin, TMP-SMX, or spironolactone. A 1 to 10 scale was developed to quantify the severity of acne. Scores of 1 and 2 correlated with severe acne (comedones, papules, pustules, and cysts); 3 and 4, moderately severe acne (no cysts); 5 and 6, moderate acne (fewer lesions and less generalized in extent); 7 and 8, mild acne (primarily comedonal with few inflammatory lesions, generally involving only the face); and 9 and 10, very mild to clear (two or fewer lesions was given a score of 9, and completely clear scored as 10). Improvement was calculated by subtracting the average pretreatment score from average post-treatment score. An improvement of 1 to 4 was considered ‘‘improved,’’ 5 to 7 ‘‘marked improvemen,’’ and 8 to 9 ‘‘complete response.’’ Patients were seen 6 to 8 weeks after initiation of treatment (71 of 81 patients), in the majority of cases for many months more. Those patients who did not return to clinic (9 of 81) were called by telephone for subjective assessment of improvement. One patient could not be reached. Amoxicillin was given in dosages ranging from 250 mg (2 to 3 times daily) (11 patients) to 500 mg (2 times a day) (2 patients). TMP-SMX was given as Bactrim DS once per day (2 patients) or twice per day (20 patients), with a total
ACNE VULGARIS
157
dosage of trimethoprim ranging from 160 to 320 mg per day and a total dosage of sulfamethoxazole ranging from 800 to 1600 mg per day. Spironolactone was given in dosages of 50 to 200 mg per day (50 to 100 mg [38 patients] and 200 mg [one patient]). Tapering of the dose to discontinuance was attempted when complete response was achieved, with reliance on topical medications for control the desired outcome. Sixteen patients were taking combination estrogen/progesterone hormonal therapy in the form of oral birth control pills (14 patients) and subcutaneous delivery vehicles (2 patients). Four patients were started on oral birth control pills concurrently with spironolactone. Simultaneous adjustments in topical therapy also usually were undertaken. Generally, prior ineffective or irritating treatments were abandoned and new combinations of two topicals were selected. Often, this meant third-line agents were used. In the view of patients and the treating physician, such changes likely contributed to a minority of the improvement, considering these patients already had failed multiple topical and oral agents. RESULTS Amoxicillin Five men and eight women took amoxicillin alone (Table 1). Ages ranged from 16 to 32. Average follow-up at final assessment was 162 days. Ten patients had a pretreatment score of 1 to 4, and three patients had pretreatment scores of 5. One patient worsened on amoxicillin. Twelve patients had post-treatment scores of 8 to 10. Overall, two patients were ‘‘improved,’’ six ‘‘markedly improved,’’ and four had a ‘‘complete response.’’ There were no adverse events related to amoxicillin use. Trimethoprim-sulfamethoxazole Sixteen men and six women took TMP-SMX alone. Ages ranged from 16 to 60. Average follow-up at final assessment was 282 days. Twenty patients had a pretreatment score of 1 to 4, and two patients had pretreatment scores of 5. One patient developed a cutaneous hypersensitivity reaction after 2 weeks and the drug was discontinued. One week after the drug was discontinued, the eruption disappeared. Five had post-treatment scores of 5 to 7, and 16 had posttreatment scores of 8 to 10. Overall, three patients were ‘‘improved,’’ thirteen ‘‘markedly improved,’’ and five had a ‘‘complete response.’’ Spironolactone Thirty-nine patients took spironolactone alone. All were women. Ages ranged from 18 to 59. Average follow-up at final assessment was 585 days. One patient could not be reached for follow-up by telephone. All 39 patients had a pretreatment score of 1 to 4. Three patients had post-treatment scores of 1 to 4, eleven had post-treatment scores of 5 to 7, and 24 had post-treatment scores of 8 to 10 (total of 38 patients). Overall, five patients were ‘‘improved,’’ twenty-two ‘‘markedly improved,’’ and six had a ‘‘complete response.’’ Two patients did not improve on spironolactone and discontinued the drug. There were three
158
Table 1 Results
Drug Amoxicillin TMP-SMX Spironolactone Amoxicillin þ spironolactone Spironolactone þ TMP-SMX
Number of patients ‘‘markedly improved’’
Number of patients who had ‘‘complete response’’
Number of patients worsened
Number of adverse effects
Total patients
Median prescore
Median postscore
Number of patients ‘‘improved’’
13 22 39 2
4 2.5 2 1.5
9 9 8 10
2 3 5 0
6 13 22 0
4 5 6 2
1 0 2 0
0 1 3 0
0
1
2
0
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adverse events related to spironolactone use: breast tenderness, palpitations, and orthostatic hypotension. All of these resolved within 2 weeks of cessation of spironolactone use. Combination therapies Three women took TMP-SMX along with spironolactone, whereas two took trimethoprim and spironolactone. Ages ranged from 18 to 26. Four patients had a pretreatment score of 1 to 4, and one had pretreatment score of 5 to 7. All five had post-treatment scores of 8 to 10. Overall, two patients were ‘‘markedly improved,’’ and three had a ‘‘complete response.’’ There was one adverse reaction to spironolactone (orthostatic hypotension), which disappeared within 1 week of cessation of spironolactone. Two women took spironolactone and amoxicillin. Their ages were 32 and 47. Both patients had pretreatment scores of 1 to 4 and post-treatment scores of 8 to 10. Overall, both patients had a ‘‘complete response’’ at the end of the study. DISCUSSION Amoxicillin Amoxicillin has been used anecdotally in the treatment of refractory acne vulgaris, but there are no studies of efficacy for amoxicillin for this indication. Concurrent topical therapy included retinoids (six patients), topical clindamycin with benzoyl peroxide (four patients), azelaic acid (one patient), and benzoyl peroxide preparations (two patients). Seven of the nine patients previously had used tetracycline or a tetracycline derivative (minocycline or doxycycline) without improvement. Two patients had no history of prior antibiotic use for acne treatment. Both patients who used amoxicillin after failing on TMP-SMX achieved excellent results. No patients had used isotretinoin prior. There were no side effects related to amoxicillin use. Trimethoprim-sulfamethoxazole There are a few studies on the usefulness of TMP-SMX in the treatment of acne, but many dermatologists do not use it frequently because of possible serious adverse effects associated with chronic TMP-SMX use. In 1971, Cotterill and colleagues [2] first reported the effectiveness of TMP-SMX in comparison with oxytetracycline and found TMP-SMX as effective as oxytetracycline in the treatment of acne vulgaris. Subsequently, in a double-blind study of 42 patients, 22 were given TMP-SMX (80 mg TMP plus 400 mg SMX) and 21 were given placebo, and after 5 weeks, patients given TMP-SMX saw a 62% decrease in their lesions compared with 9% decrease in patients who were given placebo [3]. In a double-blind crossover study, 33 patients given TMPSMX saw a significant improvement in comedones and pustules when these two clinical entities were taken together [4]. In all three of these studies, side effects were rare and not statistically significant when compared with side effects from placebo.
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In addition to the combination TMP-SMX used in the treatment of acne, trimethoprim alone is shown in two studies as effective in the treatment of acne vulgaris [5,6]. A drug eruption may occur, usually within 3 weeks of initiation of therapy [6]. The most important side effects seen with TMP-SMX treatment include hypersensitivity, toxic epidermal necrolysis, Stevens-Johnson syndrome (SJS), hematologic abnormalities [7], and renal abnormalities. Hypersensitivity skin reactions may occur in 3% to 5% of patients taking TMP-SMX. [8–11] One of the authors’ patients taking TMP-SMX developed such an eruption that resolved quickly on cessation of the drug. Most drug eruptions occur within 3 to 8 weeks of starting treatment and resolve rapidly on cessation of drug intake [6]. Estimates of a severe skin reaction (erythema multiforme/SJS, toxic epidermal necrolysis) are 1 in 100,000 [12]. In a population-based follow-up study of 232,390 people who were prescribed TMP-SMX, four developed erythema multiforme/SJS [13]. A similar study found three cases of TMP-SMX–associated severe skin disorders, a risk of 2.8 per 100,000 (95% CI, 0.9–8.2) [14]. A wide range of hematologic abnormalities is ascribed to treatment with TMP-SMX. These include thrombocytopenia, agranulocytosis, anemia (macrocytic, megaloblastic, hemolytic, and aplastic), eosinophilia, and sulfhemoglobinemia [15]. Most untoward effects in otherwise healthy patients occur within 2 weeks of onset of therapy [16]; however, chronic use of TMP-SMX can predispose patients (especially the immunosuppressed) to hematologic abnormalities. Predisposing factors include known folic acid or vitamin B12 deficiency (pregnancy, the elderly, patients who have malabsorption or malnutrition, alcoholics, patients receiving phenytoin, or those who have chronic hemolysis [such as sickle-cell disease]) [11,15,17]. In addition, TMP-SMX is shown to have teratogenic effects [18]. TMP-SMX should not be given to patients who have glucose-6-phosphate dehydrogenase deficiency [10], but few clinicians routinely screen patients for this enzyme deficiency. Severe cytopenias may develop with concurrent methotrexate use; thus, this combination should be avoided. Thrombocytopenia is reported with TMP-SMX therapy [19,20]. In a study of 1121 patients who did not have AIDS, one developed thrombocytopenia [21]. A 40-year-old man developed thrombocytopenia, neutropenia, generalized rash, and oral candidiasis after 5 days of TMP-SMX therapy; he died shortly thereafter [22]. Another study reported a 54-year-old woman who developed thrombocytopenia 1 day after finishing a 10-day course of TMP-SMX for sinusitis. She was treated with platelet transfusions and prednisone and recovered [23]. The estimated excess risk for thrombocytopenia associated with TMP-SMX therapy is 38 patient cases per 1 million users per week [23]. Chronic use of TMP-SMX can lead to leukopenia, agranulocytosis, and anemia (including macrocytic, megaloblastic, and aplastic). The estimated risk for agranulocytosis attributable to the use of TMP-SMX is 1.6 per million patients [24]. A 6-year population-based cohort study found six cases of TMP-SMX– associated blood disorders, a risk of 5.6 per 100,000 (95% CI, 2.6–12.2) [14].
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Asymptomatic hyperkalemia recently has been recognized to occur in HIVinfected patients on high-dose TMP-SMX, the elderly, and anyone who has renal insufficiency treated with TMP-SMX [25–28]; the mechanism is believed to involve the effect of trimethoprim on distal tubule potassium secretion [29]. Mild increases in serum creatinine levels can be seen with trimethoprim use as a result of inhibition of tubule secretion of creatinine, but the effect is not important clinically [30]. In a study of 1121 patients treated with TMP-SMX, four (0.4%) exhibited an increase in serum creatinine without adverse event [21]. TMP-SMX may be mildly nephrotoxic in patients who have underlying renal insufficiency; acute tubular necrosis is described [21]. Severe crystalluria may occur in patients who have severe renal insufficiency [10,15]. Incidences of true renal toxicity are more likely in patients who have underlying renal insufficiency. Because most acne patients are young, healthy people who do not have cardiac or renal dysfunction, these considerations generally are less concerning. Another issue of importance is the possibility that Staphylococcus aureus develops resistance to TMP-SMX during chronic administration for acne. Currently, this antibiotic has great usefulness in the treatment of communityacquired methicillin-resistant Staphyloccocus aureus abscesses. It is recommended that once control is achieved, lowering the dose and discontinuance (with maintenance treatment provided by topical medications) be attempted. Spironolactone The authors’ results show seven patients were ‘‘improved,’’ twenty-two ‘‘almost clear,’’ and five ‘‘clear.’’ Concurrent topical therapy included topical retinoids (22 patients), azelaic acid (4 patients), combination estrogen and progesterone preparations (15 patients), and benzoyl peroxide preparations (11 patients). Twenty-six patients previously had used tetracycline or a tetracycline derivative (minocycline or doxycycline) without improvement. Both patients who used spironolactone in conjunction with amoxicillin achieved excellent results. Four patients had used isotretinoin prior. One patient did not improve on spironolactone and discontinued the drug. There were three adverse events likely related to spironolactone use: breast tenderness, palpitations, and orthostatic hypotension. All of these resolved within 2 weeks of cessation of spironolactone use. There are few studies on the implications of acne and hirsuitism for breast cancer risk; however, women who have acne, hirsuitism, and polycystic ovaries have higher levels of androgens than women who do not have these disorders. The authors have noticed anecdotally that adult women who have acne on the spectrum of hyperandrogenemia, polycystic ovary syndrome, and metabolic syndrome seem to have a low incidence of familial breast cancer. These women are more likely to respond to hormonal therapies for control of acne vulgaris, such as spironolactone. In the authors’ clinic, of these 40 women who had adult acne considered for treatment with spironolactone, only one had an immediate family member who had breast cancer. Three had
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grandmothers who had breast cancer, one had a maternal aunt who had breast cancer. There are many theories describing the pathogenesis of adult acne in women. This disease is not difficult to diagnose, but it may prove at times difficult to treat. Many women who have elevated serum androgens or enhanced pilosebaceous unit sensitivity to androgens experience significant improvement of acne with spironolactone alone or in conjunction with amoxicillin. Side effects of spironolactone are uncommon, as the usual dose required (50 to 100 mg) is low. When present, they were mild and respond to discontinuance of the medicine. Four patients, after failing these interventions, went on to take isotretinoin. SUMMARY In situations where acne has proved resistant to other systemic agents or they are not indicated and isotretinoin is not desired by patients, the authors find amoxicillin, TMP-SMX, and spironolactone, alone or in combination, useful alternatives. In women who have acne, spironolactone can be used, and in patients who have sulfa allergy, amoxicillin can be used. It is important to continue alternate topical therapy along with these interventions to augment the improvement and to assist in the eventual discontinuance of oral medication. All of the authors’ patients were using topical therapy concomitantly and, although this may have contributed to improvement, the authors believe the addition of amoxicillin, TMP-SMX, or spironolactone contributes to the majority of improvement. Tetrospective chart analysis provides supportive data for amoxicillin, TMP-SMX, and spironolactone in the treatment of refractory acne vulgaris. References [1] James WD. Acne. N Engl J Med 2005;352(14):1463–72. [2] Cotterill JA, Cunliffe WJ, Forster RA, et al. A comparison of trimethoprim-sulphamethoxazole with oxytetracycline in acne vulgaris. Br J Dermatol 1971;84(4):366–9. [3] Hersle K. Trimethoprim-sulphamethoxazole in acne vulgaris: a double-blind study. Dermatologica 1972;145:187–91. [4] Macdonald RH, Macconnell LE, Dunsmore IR. Trimethoprim-sulphamethoxazole versus placebo in acne vulgaris. Br J Clin Pract 1972;26(2):97–8. [5] Gibson JR, Darley CR, Harvey SG, et al. Oral trimethoprim versus oxytetracycline in the treatment of inflammatory acne vulgaris. Br J Dermatol 1982;107(2):221–4. [6] Cunliffe WJ, Aldana OL, Goulden V. Oral trimethoprim: a relatively safe and successful third-line treatment for acne vulgaris [Letter]. Br J Dermatol 1999;141:757–8. [7] Tan HH. Antibacterial therapy for acne: a guide to selection and use of systemic agents. Am J Clin Dermatol 2003;4(5):307–14. [8] Smilack J. Trimethoprim-sulfamethoxazole. Mayo Clin Proc 1999;74:730–4. [9] Libecco JA, Powell KR. Trimethoprim-sulfamethoxazole: clinical update. Pediatrics in Review 2004;25:375–80. [10] Cockerill FR, Edson RS. Trimethoprim-sulfamethoxazole. Mayo Clin Proc 1991;66: 1260–9. [11] Foltzer MA, Reese RE. Trimethoprim-sulfamethoxazole and other sulfonamides. Med Clin North Am 1987;71(6):1177–92.
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[12] Lawson DN, Paice BJ. Adverse reactions to trimethoprim-sulfamethoxazole. Rev Infect Dis 1982;4:429–33. [13] Jick H, Derby LE. A large population-based follow-up study of trimethoprim-sulfamethoxazole, trimethoprim, and cephalexin for uncommon serious drug toxicity. Pharmacotherapy 1995;15(4):428–32. [14] Myers MW, Jick H. Hospitalization for serious blood and skin disorders following co-trimoxazole. Br J Clin Pharmacol 1997;43(6):649–51. [15] Wormser GP, Keusch GT. Trimethoprim-sulfamethoxazole in the United States. Ann Intern Med 1979;91:420–9. [16] Gleckman R, Alvarez S, Joubert DW. Drug therapy reviews: trimethoprim-sulfamethoxazole. Am J Hosp Pharm 1979;36(7):893–906. [17] Bjornson BH, McIntyre AP, Harvey JM, et al. Studies of the effects of trimethoprim and sulfamethoxazole on human granulopoeisis. Am J Hematol 1986;23:1–7. [18] Czeizel AE, Rockenbauer M, Sorensen HT, et al. The teratogenic risk of trimethoprim-sulfonamides: a population based case-control study. Reprod Toxicol 2001;15(6):637–46. [19] Malnick SD, Atali M, Israeli E, et al. Trimethoprim-sulfamethoxazole-induced rash, fever, abnormal liver function tests, leukopenia, and thrombocytopenia. Ann Pharmacother 1993;27:1139–40. [20] Ahmad S. Severe thrombocytopenia-hemorrhage due to trimethoprim-sulfamethoxazole: a case report. Rev Infect Dis 1982;4:429–33. [21] Jick H. Adverse reactions to trimethoprim-sulfamethoxazole in hospitalized patients. Rev Infect Dis 1982;4(2):426–8. [22] Kocak Z, Hatipoglu CA, Ertem G, et al. Trimethoprim-sulfamethoxazole induced rash and fatal hematologic disorders. J Infect 2006;52(2):e49–52. [23] Yamreudeewong W, Fosnocht BJ, Weixelman JM. Severe thrombocytopenia possibly associated with TMP-SMX therapy. Ann Pharmacother 2002;36:78–82. [24] [Author unknown]. Anti-infective drug use in relation to the risk of agranulocytosis and aplastic anemia. Arch Intern Med 1989;149:1036–40. [25] Greenberg S, Reiser IW, Chou SY, et al. Trimethoprim-sulfamethoxazole induces reversible hyperkalemia. Ann Intern Med 1993;199:291–5. [26] Alappan R, Perazella MA, Buller GK. Hyperkalemia in hospitalized patients treated with trimethoprim-sulfamethoxazole. Ann Intern Med 1996;124:316–20. [27] Perazella MA, Mahnensmith RL. Trimethoprim-sulfamethoxazole: hyperkalemia is an important complication regardless of dose. Clin Nephrol 1996;46:187–92. [28] Ellison DH. Hyperkalemia and trimethoprim-sulfamethoxazole. Am J Kidney Dis 1997;29: 959–62. [29] Velazquez H, Perazella MA, Wright FS, et al. Renal mechanism of trimethoprim-induced hyperkalemia. Ann Intern Med 1993;119:296–301. [30] Naderer O, Nafziger AN, Bertino JS Jr. Effects of moderate-dose versus high-dose trimethoprim on serum creatinine and creatinine clearance and adverse reactions. Antimicrob Agents Chemother 1997;41:2466–70.