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Oral Trimethoprim/Sulfamethoxazole in the Treatment of Acne Vulgaris

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Oral Trimethoprim/Sulfamethoxazole in the Treatment of Acne Vulgaris DRUG THERAPY TOPICS Oral Trimethoprim/Sulfamethoxazole in the Treatment of Acne Vulgaris Sanjay Bhambri, DO; James Q. Del Rosso, DO; Avani Desai, MD Oral trimethoprim/sulfamethoxazole (TMP-SMX) is vulgaris.2 TMP-SMX may be advantageous because approved by the US Food and Drug Administration of the synergistic effects of its 2 antibacterial agents, for the treatment of urinary tract infections, the bactericidal activity, the drug’s potential ability shigellosis, acute otitis media in pediatric to decrease the emergence of resistance because of its patients, and Pneumocystis carinii pneumonia. individual components, and the lack of widespread or TMP-SMX has been used off label in dermatology chronic use in the United States in the patient popu- to treat various skin conditions, including acne lation most commonly treated for acne vulgaris.2-10 vulgaris and other skin and soft tissue infections, especially those infections caused by methicillin- resistant Staphylococcus aureus. What efficacy data is available on the use of Cutis. 2007;79:430-434. TMP-SMX for the treatment of acne vulgaris? The use of TMP-SMX (trimethoprim 80 mg/ sulfamethoxazole 400 mg) as monotherapy in the cne vulgaris is a common disorder of the treatment of acne vulgaris was first reported in 1971 pilosebaceous unit. Tetracycline has been by Cotterill et al2 who compared the drug’s effective- A used in the treatment of acne vulgaris since ness with that of oxytetracycline. The study included the mid to late 1950s, with doxycycline and minocy- 42 subjects aged 12 to 32 years who were randomly cline becoming available in 1967 and 1972, respec- selected to receive 250 mg of oxytetracycline or tively.1 Tetracycline antibiotics have been shown to TMP-SMX for 3 months. TMP-SMX was shown to be effective in most patients, though some patients be equally effective as oxytetracycline in the treat- may show less than adequate response, which may be ment of acne vulgaris.2 because of factors such as the presence of less sensitive Hersle4 conducted a double-blind, randomized, Propionibacterium acnes strains, poor compliance, and crossover trial that involved 43 subjects started adverse effects. Oral trimethoprim/sulfamethoxazole on one tablet daily of TMP-SMX or placebo in (TMP-SMX) was found to be effective in patients a 5-week period. The results of the trial revealed who were refractory to tetracycline use for acne a greater reduction in acne lesions in subjects treated with TMP-SMX than in subjects treated 4 Accepted for publication April 19, 2007. with placebo. Hersle also noted that 2 subjects Drs. Bhambri and Del Rosso are from Valley Hospital Medical previously treated unsuccessfully with tetracyclines Center, Las Vegas, Nevada. Dr. Del Rosso also is from the exhibited remarkable improvement when treated University of Nevada School of Medicine, Las Vegas, and Touro with TMP-SMX. Macdonald et al7 also showed University Nevada College of Osteopathic Medicine, Henderson. TMP-SMX to be effective in acne vulgaris, espe- Dr. Desai is from SUNY Downstate Medical Center, Brooklyn. Drs. Bhambri and Desai report no conflict of interest. Dr. Del Rosso cially in reducing the number of pustules and is a consultant, researcher, and speaker for CollaGenex open comedones. Pharmaceuticals, Inc; Coria Laboratories, Ltd; Doak Jen8 conducted a double-blind randomized study Dermatologics, a subsidiary of Bradley Pharmaceuticals, Inc; involving 30 subjects who received 4 weeks of either Galderma Laboratories, LP; Intendis, Inc; Medicis TMP-SMX twice daily or oxytetracycline 250 mg Pharmaceutical Corporation; OrthoNeutrogena; QLT Inc; Ranbaxy Laboratories Limited; SkinMedica; Stiefel Laboratories, twice daily, followed by 8 weeks of the opposite Inc; and Warner Chilcott. agent administered once daily. Similar to results Reprints not available from the authors. reported earlier by Cotterill et al,2 Jen8 found that 430 CUTIS® Drug Therapy Topics TMP-SMX was as effective as oxytetracycline in the reliable indicator of free fatty acid content.2 Neither treatment of acne vulgaris. trimethoprim nor sulfamethoxazole alone have any Oral trimethoprim has been recommended as a effect on the titratable acidity. It is possible that third-line oral antibiotic in the management of acne TMP-SMX acts by inhibiting the lipolytic activity vulgaris based on an open-label randomized study of the surface bacteria.2,6 reported by Bottomley and Cunliffe.11 Fifty-six sub- Tetracyclines and TMP-SMX may possibly act jects with acne vulgaris who failed previous treatment on different sites in the pathway of sebum produc- with at least 2 courses of oral antibiotic therapy with tion because some patients treated unsuccessfully other agents received trimethoprim 300 mg twice with tetracycline antibiotics improve when treated daily used concurrently with topical clindamycin with TMP-SMX.2 An alternative consideration may lotion 1% twice daily for at least 4 months. At the be differences in sensitivity of P acnes strains to end of the initial 4-month treatment period, marked individual tetracyclines or TMP-SMX among differ- improvements in severity grading of both facial and ent patients, especially in those patients previously truncal acne were observed. Twenty-one subjects con- treated with chronic administration of tetracycline. tinued the treatment regimen for 8 additional months without loss of efficacy.11 Importantly, more current acne treatment recommendations suggest that pro- What potential adverse reactions have been longed antibiotic therapy should be used in combina- reported with the use of TMP-SMX? tion with other agents, such as topical retinoids and Overall, TMP-SMX is well-tolerated by most patients benzoyl peroxide, the latter used to both augment in both adult and pediatric populations. Few adverse efficacy and reduce the potential for emergence of less effects were reported in studies that evaluated sensitive strains of P acnes.12,13 TMP-SMX in the treatment of acne vulgaris. Ten days after starting TMP-SMX, Cotterill et al2 noted one subject who developed a transient skin What is the mechanism of action of TMP-SMX? eruption that cleared spontaneously while the sub- Trimethoprim is a competitive inhibitor of dihydro- ject was still on the TMP-SMX therapy. In the study folate reductase and blocks the conversion of dihy- conducted by Macdonald et al,7 2 subjects who were drofolic acid into tetrahydrofolic acid. Sulfonamides, on the TMP-SMX therapy were noted to experi- such as sulfamethoxazole, inhibit the conversion of ence headaches/dizziness and a red macular eruption, paraaminobenzoic acid to dihydrofolic acid.3 Sul- respectively. No adverse effects were noted in the fonamides are bacteriostatic, but the combination of studies by Hersle4 and Jen,8 but it is important to TMP-SMX is shown to be bacteriocidal.14,15 note that the study sizes were small (43 subjects and Surface lipids, which play a vital role in the 30 subjects, respectively). development of acne vulgaris, are derived from A variety of side effects have been reported in exogenous sources, sebaceous glands, epidermal patients treated with TMP-SMX for conditions other cells, and keratin. In sebaceous-rich areas, such as than acne vulgaris. The most commonly reported the forehead, skin surface lipids are prominently side effects are upper gastrointestinal disturbances made up of sebum, which plays an important role in (eg, nausea) and maculopapular skin eruptions; the pathogenesis of acne vulgaris. Sebum is fraction- lower gastrointestinal symptoms such as diarrhea ated into free fatty acids, which are then synthesized are less common.16-18 Rare anaphylactic reactions to into triglycerides and wax esters. Strauss and Pochi9 TMP-SMX have been reported and are attributed showed that when free fatty acids (fractionated from to the sulfamethoxazole component because sulfon- sebum) are injected into the skin, they produce amides are recognized causes of hypersensitivity.16-18 an inflammatory response similar to that seen in Johnson et al19 reported 2 cases of anaphylactoid acne vulgaris. reactions in which patients presented with fever, In a study of 17 subjects, Cotterill et al10 looked hypotension, and bilateral pulmonary infiltrates at the effect of TMP-SMX on the sebum excretion within hours after receiving TMP-SMX. Sporadic rate. TMP-SMX produced a marked decrease in cases of anaphylaxis caused by trimethoprim alone sebum free fatty acids after 1 and 2 months of ther- have been reported.20 apy while inversely increasing sebum triglycerides. Cutaneous reactions have been reported with However, TMP-SMX did not have any effect on the TMP-SMX therapy.17-23 Symptoms usually begin sebum excretion rate or on the levels of squalene, within one week of starting the medication and wax esters, or cholesterol.10 resolve after the discontinuation of the drug. TMP-SMX reduces the free fatty acid content The most common cutaneous eruptions seen of the sebum4 and the titratable acidity of sebum, a with TMP-SMX therapy are maculopapular or VOLUME 79, JUNE 2007 431 Drug Therapy Topics morbilliform in nature, secondary to a type IV hyper- agranulocytosis, neutropenia, hypoprothrombine- sensitivity reaction involving T lymphocytes. Cuta- mia, aplastic anemia, nonhemolytic anemia, and neous reaction rates to TMP-SMX are estimated to pure red cell aplasia.16,18,22,36-44 The incidence of be approximately 4% to 5% in healthy patients any hematologic adverse reaction associated with and approximately 15% in patients infected with the use of TMP-SMX has
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