different systemic agent within one year was 1.28 (95% CI 1.16-1.42) for those prescribed spironolactone when compared with doxycycline hyclate, 0.99 (95% CI 0.90-1.09) for those prescribed spironolactone when compared with minocycline, and 1.10 (95% CI 0.99-1.23) for those prescribed spironolactone when compared with low-dose extended-release minocycline. Switching from spironolactone to isotretinoin occurred after a median of 167 days (IQR 102-265 days). Switching from oral tetracycline-class antibiotics to isotretinoin occurred after a median of 200 days (IQR 121-282 days) (Table 3). Figure 1 summarizes the systemic agents being prescribed to patients at time points 90, 180, 270, and 360 days after starting either spironolactone or an oral tetracycline-class antibiotic. A sensitivity analysis to assess the potential impact of differing acne severity between the spironolactone and oral tetracycline-class antibiotic groups on the primary outcome is available in Table 4. In this analysis, the adjusted odds ratio did not change substantially from the original estimate across a range of values for the prevalence of severe acne between the two groups. In many plausible scenarios, the odds ratio for switching becomes smaller and favors spironolactone. In other scenarios, the odds ratio does become more significant, but under most plausible scenarios, the odds ratio does not become larger than 1.16 (95% CI 1.08-1.26). DISCUSSION
In this large, retrospective study, the frequency of switching to another systemic agent within the first year of treatment
was similar among women with acne who were started on spironolactone compared with those started on oral tetracycline-class antibiotics. In addition, the frequency of switching to isotretinoin was more common among women who were started on oral tetracycline-class antibiotics than those started on spironolactone. Since switching may reflect treatment failure, whether due to lack of efficacy, side-effects, cost, or other factors, these results suggest that spironolactone may have similar clinical effectiveness to oral tetracycline-class antibiotics, particularly for adult women.Compared to oral antibiotics, spironolactone represents an enticing therapeutic alternative for women with moderate to severe acne, with a favorable side-effect profile.43 While spironolactone is pregnancy category C and contraception is recommended for patients on spironolactone due to concerns about potential feminization of the fetus, oral tetracycline-class antibiotics are also contraindicated in pregnancy and are category D.44,45 Although there have been concerns about a potential association between spironolactone and breast cancer based on animal studies, large population-based studies have not confirmed such a risk;43,46,47 in contrast, there is evidence that pronged antibiotic use may be associated with increased risk of breast and colon cancer.7,14 In addition, recent work has suggested that potassium monitoring is not required in young, healthy women.48 Given that oral antibiotics are included in the first-line therapeutic regimens for moderate to severe acne, spironolactone may represent a favorable alternative therapy, especially for adult women.3In addition, smaller studies have suggested that spironolactone is effective for women with all types of acne, not only for women with acne on the lower face or acne characterized by flares associated with the menstrual cycle.22,23,25 It is likely that spironolactone is underutilized in the treatment of acne in women and increased utilization of spironolactone may decrease reliance on oral antibiotics and associated complications from antibiotic use. Since oral antibiotics are currently used much more often than spironolactone, the opportunity to increase the use of spironolactone for the treatment of acne in women is substantial.5In subgroup analyses, spironolactone compared favorably to oral tetracycline-class antibiotics among adults, while it performed inferiorly to oral tetracycline-class antibiotics among adolescents. There are several potential explanations for this finding, including that spironolactone is less effective for adolescents than adults, that adolescents who are prescribed spironolactone have more severe acne than adults, or that therapeutic expectations differ among adolescents than adults. This latter explanation is important to consider, as adolescents may expect more rapid improvement in their acne or have more significant concerns about acne scarring than adults. It is also possible that hormonal factors may be less influential in adolescent acne and hence spironolactone may be less effective in this population.Of note, a recent meta-analysis comparing oral contraceptive pills to oral antibiotics in the treatment of acne found that while
was similar among women with acne who were started on spironolactone compared with those started on oral tetracycline-class antibiotics. In addition, the frequency of switching to isotretinoin was more common among women who were started on oral tetracycline-class antibiotics than those started on spironolactone. Since switching may reflect treatment failure, whether due to lack of efficacy, side-effects, cost, or other factors, these results suggest that spironolactone may have similar clinical effectiveness to oral tetracycline-class antibiotics, particularly for adult women.Compared to oral antibiotics, spironolactone represents an enticing therapeutic alternative for women with moderate to severe acne, with a favorable side-effect profile.43 While spironolactone is pregnancy category C and contraception is recommended for patients on spironolactone due to concerns about potential feminization of the fetus, oral tetracycline-class antibiotics are also contraindicated in pregnancy and are category D.44,45 Although there have been concerns about a potential association between spironolactone and breast cancer based on animal studies, large population-based studies have not confirmed such a risk;43,46,47 in contrast, there is evidence that pronged antibiotic use may be associated with increased risk of breast and colon cancer.7,14 In addition, recent work has suggested that potassium monitoring is not required in young, healthy women.48 Given that oral antibiotics are included in the first-line therapeutic regimens for moderate to severe acne, spironolactone may represent a favorable alternative therapy, especially for adult women.3In addition, smaller studies have suggested that spironolactone is effective for women with all types of acne, not only for women with acne on the lower face or acne characterized by flares associated with the menstrual cycle.22,23,25 It is likely that spironolactone is underutilized in the treatment of acne in women and increased utilization of spironolactone may decrease reliance on oral antibiotics and associated complications from antibiotic use. Since oral antibiotics are currently used much more often than spironolactone, the opportunity to increase the use of spironolactone for the treatment of acne in women is substantial.5In subgroup analyses, spironolactone compared favorably to oral tetracycline-class antibiotics among adults, while it performed inferiorly to oral tetracycline-class antibiotics among adolescents. There are several potential explanations for this finding, including that spironolactone is less effective for adolescents than adults, that adolescents who are prescribed spironolactone have more severe acne than adults, or that therapeutic expectations differ among adolescents than adults. This latter explanation is important to consider, as adolescents may expect more rapid improvement in their acne or have more significant concerns about acne scarring than adults. It is also possible that hormonal factors may be less influential in adolescent acne and hence spironolactone may be less effective in this population.Of note, a recent meta-analysis comparing oral contraceptive pills to oral antibiotics in the treatment of acne found that while 
