Acne Vulgaris Systemic Therapy – Oral antibiotics
Acne vulgaris is one of the most common disorders encountered in dermatology practice accounting for approximately 8.8% of total visits to office-based dermatologists in the United States in 2006 (1). Treatment of acne in teenage patients accounts for greater than 2 million visits annually (2). Although peripubertal onset is most common, prepubertal onset is not uncommon, and several acne patients present after the teenage years, with approximately 10% of visits noted in patients 35 to 44 years of age (2,3). The negative psychosocial impact of acne in many affected patients is well documented (4,5).
Despite the multifactorial pathogenesis of acne vulgaris, Propionibacterium acnes, a component of the normal bacterial flora of sebaceous gland-rich skin of the face and upper trunk, appears to play a major role in the development of inflammatory acne lesions, and very likely comedonal lesions (6 8). P. acnes has been identified as a trigger of innate immune response and exhibits other proinflammatory properties that are believed to be operative in the development and progression of acne vulgaris (9,10). Current basic science and clinical research including identification of the P. acnes genome, analysis of innate immune response in acne inflammation, evaluation of the role of inflammation in comedogenesis, and microbiologic studies correlating P. acnes with specific treatments and therapeutic benefit, all support the goal of P. acnes suppression with antimicrobial therapy as a component of acne management (6 12). In addition to P. acnes suppression, some antibiotics such as the tetracycline derivatives also exhibit anti-inflammatory properties that appear to contribute to their therapeutic benefit in acne vulgaris (11,13,14).
USAGE PATTERNS WITH ORAL ANTIBIOTICS IN ACNE MANAGEMENT
Prescribing data from 2001 to 2006 in the United States show that office-based dermatologists prescribe 8 to 9 million oral antibiotic prescriptions annually, with two-thirds of prescriptions inclusive of tetracycline derivatives, primarily minocycline and doxycycline, used for therapy of acne and rosacea (15,16). Prior to approval of the extended-release tablet formulation of minocycline by the US Food and Drug Administration (FDA) in 2006, oral antibiotics have been utilized for acne based on widespread anecdotal experience and a collection of small clinical studies (17 19). Conventionally, the predominant oral antibiotics used for treatment of acne vulgaris in most countries have been tetracycline, doxycycline, minocycline, and erythromycin, with some locations outside of the United States also incorporating trimethoprim, primarily due to low cost (2,11,19 22). At present, doxycycline and minocycline are used more frequently than tetracycline and erythromycin by dermatologists in the United States, likely due to the marked emergence of P. acnes strains that exhibit decreased sensitivity to the latter two agents (11). Over time there has been a trend toward an increase in P. acnes strains becoming less sensitive to doxycycline and minocycline, which has been correlated with the frequency of their usage (11,23 25).
Tetracycline derivatives represent the predominant oral antibiotic agents used to treat acne vulgaris. Oral tetracycline and oxytetracycline have been available since the mid-1950s, doxycycline since 1967, and minocycline since 1972 (13). Reviews of acne treatment studies that incorporated use of tetracy-cline, doxycycline, and immediate-release minocycline formulations found a total of 12 studies (N = 953) completed between 1969 and 2001 (19 21). The studies, which assessed extended-release minocycline tablets, were completed prior to FDA approval and included one phase II dose-finding study and two phase III pivotal trials. These studies evaluated the efficacy and safety of weight-based dosing with once-daily administration of the extended-release minocycline tablet formulation (N = 1038) (18). The recommended dose of extended-release minocycline based on the completed studies is 1 mg/kg once a day (17 19). Alternative oral antibiotics, such as trimethoprim-sulfamethoxazole and azi-thromycin, have also been reported to be of benefit for acne treatment (26 28).
RATIONALE FOR USE OF ORAL ANTIBIOTIC THERAPY IN ACNE TREATMENT
Reduction of P. acnes organisms, with an ensuing decrease in inflammatory lesion development and possibly comedogenesis, is the primary objective of oral antibiotic therapy in acne (2,16,29). The greatest decrease in P. acnes colony counts has been demonstrated with minocycline, followed in order of magnitude by doxycycline, tetracycline, trimethoprim-sulfamethoxazole, and erythromycin (29). The clinical efficacy of oral antibiotic therapy for acne vulgaris is well established and recognized as a conventional component of rational acne treat-ment (2,11,12,17,18,20 22,29,30).
INDICATIONS AND RECOMMENDED DOSING OF ORAL ANTIBIOTICS USED IN ACNE THERAPY
The main indication for oral antibiotic therapy in acne vulgaris is moderate-to-severe inflammatory involvement on the face and/or trunk (12). Table1 depicts the recommended dosing schedule with oral antibiotics currently used most commonly for acne therapy by dermatologists in the United States. Antibiotic monotherapy should be avoided due to promotion of antibiotic-resistant bacterial strains, with oral antibiotic therapy best utilized in combination with a topical regimen (11,12,29 31). In patients with moderate-to-severe acne vulgaris, combination therapy using a topical regimen inclusive of benzoyl peroxide and a topical retinoid concurrently with an oral antibiotic is rational and optimizes efficacy (11,30 33). It is most rational to include a benzoyl peroxide containing formulation as part of the combination therapy regimen with an oral antibiotic, as benzoyl peroxide reduces the emergence of P. acnes antibiotic-resistant strains to multiple antibiotics including erythromycin, tetracycline, doxycycline, and minocycline (11 35). It has also been suggested that a short course of benzoyl peroxide therapy prior to initiating antibiotic therapy assists in the eradication of antibiotic-resistant P. acnes strains, thus enhancing the overall efficacy of antibiotic treatment (12,35 37).
Table 1 Major Oral Antibiotics Used for Treatment of Acne Vulgaris by Dermatologists in the United States
Usual dosage range
|50 100 mg once or twice daily||
Vestibular reactions may be dose related and may be more common with immediate release formulations (especially generic formulations with rapid release properties)
11, 19 22, 26
1 mg/kg/day (45 135 mg once daily)
Efficacy comparable to 2 mg/kg/day and 3 mg/kg/ day; potential for vestibular reactions appear to be lower than with immediate release formulations
75 100 mg once or twice daily 150 mg once daily
|Photosensitivity reported to be dose related (higher potential at 100 mg/day)||
19 22, 26
If not enterically coated, doxycline, especially the hyclate salt, is best administered with food and a large glass of water to reduce the risk of gastro-intestinal (GI) side effects such as esophagitis (12,22). Both doxycycline and minocycline may be administered with food; however, concomitant administration with iron supplements may decrease GI absorption of both agents (12,22). Concurrent ingestion of metal ions such as calcium, magnesium, and aluminum, found in many vitamin-mineral supplements and antacids, may significantly decrease absorption of tetracycline from the GI tract (12,22).
Among the macrolide antibiotic derivatives, oral erythromycin is best administered with food to reduce GI side effects. Azithromycin differs from erythromycin as it does not as commonly cause GI upset, and is best taken on an empty stomach to maximize GI absorption (12,22,26). Oral antibiotics that are commonly associated with GI side effects and esophagitis are best ingested with a large glass of water when the patient is upright and not prior to anticipated reclining for at least a few hours.
ORAL ANTIBIOTIC THERAPY IN ACNE VULGARIS AND ANTIBIOTIC RESISTANCE
Antibiotic resistance patterns develop over time due to selection pressure and transfer of antibiotic resistance genes resulting in the emergence of bacterial organisms that are less sensitive to previously effective antibiotics (23,24,36,38). Approximately three decades ago, it was shown that long-term oral antibiotic therapy administered over a mean duration of 21 months increased the minimum inhibitory concentration (MIC) for P. acnes up to 5-fold for tetracycline and 100- fold for erythromycin as compared to acne-free control subjects and those not receiving antibiotics (39). Several other reports have addressed the concern regarding emergence of P. acnes strains less sensitive to multiple topical and oral antibiotic agents used to treat acne vulgaris (23 25,36,40 43). Additionally, reports from the United Kingdom demonstrate a progressively increasing trend in P. acnes resistance to erythromycin, clindamycin, and/or tetracycline, noted to be 20%, 38%, 49%, and 62%, in 1988, 1993, 1995, and 1996, respectively (43).
Focused initiatives to alter how antibiotics are prescribed for acne vulgaris due to concerns regarding antibiotic resistance emerged in the early 1990s in the United Kingdom, with emphasis continuing into the millennium (38 40). A similar trend may have also occurred in the United States based on prescribing trends of acne medications reported in the 1990 to 2002 National Ambulatory Medical Care Survey (44). A substantial decline in several antimicrobial drug classes, such as benzoyl peroxide, topical clindamycin, oral erythromycin, and oral tetracycline agents, was noted, coupled with an increase in non-antimicrobial therapies, such as topical retinoids and oral isotretinoin. From 1995 to 2000, antibiotic prescriptions in the United Kingdom declined by 33%, with the majority of the decrease comprising oral antibiotic agents (25,45).
PROPIONIBACTERIUM ACNES ANTIBIOTIC RESISTANCE AND EFFICACY OF ORAL ANTIBIOTIC USE IN ACNE
Some studies have noted a poor therapeutic response of acne to antibiotics in patients with confirmed substantial quantities of P. acnes that demonstrate high MIC levels to macrolides and tetracyclines (25,36,39,46). It is important to recognize, however, that a direct correlation between prevalence of P. acnes resistance and poor therapeutic response to antibiotic therapy has not always been consistent (11). Factors potentially associated with a reduced response to antibiotic therapy may include preexisting antibiotic resistance, the quantity of antibiotic-resistant P. acnes strains in the individual patient, resistance to multiple antibiotics, use of antibiotics without concomitant use of benzoyl peroxide, repeated courses of antibiotic therapy especially without concomitant use of benzoyl peroxide, unnecessary switching of oral antibiotic agents despite previous efficacy, individual drug characteristics such as GI absorption and lipophilicity, relative effects on serum and tissue levels due to interference of GI absorption by coadministered chelating metal ions, and existence of P. acnes in a protective extracellular biofilm in vivo (11,12,17,18,22,36,39,47).
Although the prevalence of antibiotic-resistant P. acnes has been shown to be increasing globally over time, oral antibiotics, which have been used extensively over several years, continue to demonstrate efficacy in acne vulgaris, including doxycycline and minocycline (11,18,48 51). Importantly, some of the most recent data evaluating the efficacy of a commonly used oral antibiotic in acne may be culled from phase II and phase III studies, which evaluated extended-release minocycline as monotherapy for moderate and severe acne vulgaris for FDA approval (N = 1038) (18,51). The study results demonstrated a significantly greater inflammatory lesion reduction in actively treated subjects as compared to the placebo group and suggested a once-daily dose of 1 mg/kg (p < 0.001) (51). Properties other than antibiotic activity, which leads to reduction in P. acnes, may also be operative in acne treatment as some antibiotics demonstrate biologic activities unrelated to their antibiotic effects (13,14). For example, tetracycline derivatives such as minocycline and doxycycline exhibit multiple direct anti-inflammatory properties that appear to contribute to their therapeutic benefit in acne vulgaris (11,13,14,19,52).
ALTERNATIVE ORAL ANTIBIOTICS IN ACNE THERAPY
Among the alternative oral antibiotics reported for treatment of acne vulgaris, trimethoprim-sulfamethoxazole and azithromycin have been mentioned most frequently in the literature (12,22 28,53). In some patients with acne who are refractory to conventionally used oral antibiotics, trimethoprim-sulfamethoxazole has been reported to be effective (26,27). However, the frequent need for use of trimethoprim-sulfamethoxazole for treatment of cutaneous and systemic infections caused by community-acquired Staphylococcus aureus (CA-MRSA) and the possible risk of major side effects associated with its use, both support the recommendation that trimethoprim-sulfamethoxazole is best reserved for selected cases of refractory acne vulgaris (27).
Oral azithromycin has been reported to be effective in the treatment of acne vulgaris in four open studies (N = 187) and two investigator-blinded clinical trials (N = 241) with a variety of treatment regimens utilized (26,28). Most regimens have incorporated intermittent dosing schedules due to a long terminal half-life (68 hours) and the propensity of azithromycin to achieve high tissue level without the need for persistently high serum concentrations (26). Azithromycin is a commonly prescribed antibiotic in the general medical community, which is used to treat a variety of systemic infections in both adult and pediatric populations. This agent is also of benefit for therapy of intracellular pathogens such as Chlamydia spp. and atypical Mycobacterium spp. Therefore, use of azithromycin for treatment of acne is best reserved for selected cases, primarily to avoid widespread use that is likely to promote the increased emergence of antibiotic-resistant organisms (26).
Other alternative oral antibiotics that have been sporadically and randomly reported to be effective for acne treatment are cephalosporins and fluoroquinolones (26). The heavy dependence on these agents within the general medical community for both ambulatory and hospital-based treatment of a variety of systemic infections discourages their use for treatment of acne; however, exceptions may include short-term use for selected refractory cases and gram-negative acne/folliculitis.
DURATION OF ORAL ANTIBIOTIC USE IN ACNE THERAPY
As the vast majority of clinical trials evaluating acne therapies typically assess treatment over a relatively short duration of two to four months, scientific data on the long-term management of acne is sparse. The literature does strongly support that an oral antibiotic be used in combination with a rational topical regimen, preferably composed of a benzoyl peroxide containing formulation and a topical retinoid (11,12,22,30). This may allow for better ability to discontinue the oral antibiotic at some point based on response to treatment, and hopefully allow the topical regimen alone to maintain control of acne.
When oral antibiotic therapy is incorporated with a topical regimen for acne, it has been suggested that it be administered over a minimum period of 6 to 8 weeks and a maximum of 12 weeks to 6 months (11,12,22,30). Hard-and-fast rules on treatment duration with an oral antibiotic are not justifiable as treatment response among patients may be highly variable. At initial follow-up six to eight weeks after the start of therapy, if a substantial lack of efficacy is observed despite adequate compliance, a change in oral antibiotic therapy is reasonable (22,47). If partial improvement is observed, it may be reasonable to continue with the current therapy for an additional six to eight weeks to evaluate if further progress is achieved. Changing a regimen too frequently often results in suboptimal outcomes as a given regimen is never afforded a true opportunity to initiate its therapeutic effect.
Once control of acne is felt to be stable, which is usually achieved over a duration of three to six months assuming compliance is adequate, discontinuation of the oral antibiotic therapy may be suggested, with continuation of the topical regimen for long-term maintenance (12,22). Stabilized control of acne does not necessarily imply complete clearance, but may be defined as the observation that new inflammatory lesions have stopped or markedly decreased (12). As there is no consensus opinion on whether oral antibiotic therapy should be discontinued abruptly or tapered, clinical judgment is warranted. The author prefers abrupt discontinuation of the oral antibiotic once new inflammatory lesions have stopped or markedly decreased and most flat foci of residual inflammation secondary to resolving lesions have substantially faded.
Despite the alleged use of a topical maintenance regimen, some patients return with an acne flare within a few weeks to months after discontinuation of the oral antibiotic. In such cases, it is suggested to reinitiate therapy with the same oral antibiotic that was previously effective. Additionally, it is very important to incorporate use of benzoyl peroxide to suppress the presence and emergence of less antibiotic-sensitive P. acnes organisms (11,12,22,34,35,45,47). It is very important to reemphasize patient adherence to the topical therapy regimen, which has been shown to be optimized by incorporating a topical retinoid both initially and for long-term maintenance therapy (12,54).
ADVERSE REACTIONS OF ORAL ANTIBIOTICS USED FOR ACNE TREATMENT
All oral antibiotics may be associated with “nuisance” side effects such as GI upset, with the latter most commonly observed with erythromycin and doxycycline (12,22). Doxycycline is associated with dose-related phototoxicity, with appropriate photoprotection recommended (12,19,22).
The available literature regarding major side effects associated with minocycline, other than acute vestibular adverse events, relate to the use of immediate-release minocycline formulations, available since 1972. As extended-release minocycline has only been available since July 2006, and only in the US, it remains to be seen if the unique pharmacokinetic profile of this formulation, and weight-based dosing (1 mg/kg once daily), will alter the potential risk of other minocycline-induced side effects, beyond the reduction in acute vestibular adverse events discussed earlier.
Minocycline has been associated with cutaneous and/or mucosal hyper-pigmentation, including brown, gray, or blue pigmentation of skin and/or mucosa and blue discoloration of acne scars (12,22). A suggested correlation between hyperpigmentation and cumulative exposure to minocycline has been reported, with the time course of onset and resolution variable (55). If hyperpigmentation is noted, it is recommended that minocycline be discontinued for acne treatment. As cumulative minocycline exposure appears to correlate with risk of hyper-pigmentation, extended-release minocycline, dosed at 1 mg/kg/day, may be less likely to induce this side effect, however, further pharmacosurveillance is needed.
Drug hypersensitivity syndrome (DHS) has been reported with both minocycline and trimethoprim-sulfamethoxazole, and much less likely, doxycycline (56). The clinical presentation of DHS is fever, a diffuse exanthem-like skin eruption, and systemic abnormalities, including hepatitis and interstitial pneumonitis. The onset of DHS is typically within two to six weeks after first exposure to the inciting drug, with the most important component in manage-ment being early recognition and discontinuation of the offending agent. Despite the relative lack of association between doxycycline and tetracycline with DHS, it is not absolutely certain that these agents are safe in patients who have a history of DHS due to minocycline (56).
A lupus-like syndrome has been reported in association with minocycline use, especially with prolonged administration (56). Although any patient may be potentially affected, young females treated chronically over one to two years represent the majority of cases (56). Characteristic clinical findings include fever, malaise, and polyarthralgias, with a cutaneous eruption rarely noted. Associated laboratory abnormalities may include a positive antinuclear antibody (ANA) test, elevation of hepatic enzymes, and positivity for perinuclear anti-neutrophilic cytoplasmic antibodies (p-anca) directed against elastase or myeloperoxidase (56). The lupus-like syndrome due to minocycline is typically reversible after drug discontinuation, serologic positivity may be persistent for several months after stopping minocycline, and rechallenge with minocycline is not recommended.
A variety of relatively uncommon but potentially severe adverse reactions may be caused by trimethoprim-sulfamethoxazole, including DHS, toxic epi-dermal necrolysis (TEN), Stevens Johnson syndrome (SJS), and hematologic reactions (26,27,57). The onset of TEN and SJS is usually within the first one to two months after starting therapy (27). Although relatively uncommon, hema-tologic reactions reported in association with trimethoprim-sulfamethoxazole have included agranulocytosis, thrombocytopenia, and pancytopenia (27,57). The potential for hematologic toxicity related to either short-term or long-term (>3 months) administration of trimethoprim-sulfamethoxazole may be increased in patients receiving higher than conventional doses, and in those with preexisting folic acid deficiency and/or megaloblastic hematopoiesis (57).
There are no specific recommendations to routinely perform baseline or periodic laboratory testing with oral antibiotics used to treat acne vulgaris. A complete blood cell (CBC) with platelet count performed at baseline and periodi-cally in patients treated with trimethoprim-sulfamethoxazole may be prudent (57). Routine baseline or periodic laboratory monitoring is not generally recommended in patients treated with minocycline (56). Although routine laboratory monitoring recommendations may not be suggested with an oral antibiotic used for acne treatment, the medical history of the individual patient may prompt the clinician to avoid use of a specific oral antibiotic or to incorporate baseline and/or periodic laboratory monitoring.
Some adverse events related to oral antibiotic use result from drug-drug interaction. Erythromycin may inhibit hepatic cytochrome 3A4 enzymes responsible for the metabolism of other drugs, such as carbamazepine, cyclosporine, and some cholesterol-lowering agents, such as lovastatin, simvastatin, and atorvastatin, potentially leading to toxicity due to accumulation of the inhibited drug (22). Trimethoprim-sulfamethoxazole should be avoided in patients on methotrexate due to an increased risk of hematologic reactions (27,57).
Use of an oral antibiotic for acne during pregnancy is not recommended (12,22,26). Importantly, the suggestion that oral erythromycin is safe during pregnancy is not based on data evaluating prolonged administration over several months during pregnancy (26).
Oral antibiotic therapy is indicated for treatment of moderate-to-severe acne vulgaris and is recommended for use in combination with a rational topical therapy regimen. Overall, the efficacy and safety of conventional oral antibiotic therapy used for acne have been very favorable based on available studies and extensive clinical experience over many years. In general, the usual duration of treatment is three to six months if clinically feasible, with long-term maintenance achieved with topical therapy if possible. The progressive increase in antibiotic-resistant P. acnes strains over time has prompted suggested methods to reduce the risk of antibiotic resistance. Oral antibiotics used to treat acne vulgaris differ in their pharmacologic properties and adverse reaction profiles. In addition, clinicians need to remain cognizant of potential adverse reactions associated with individual oral antibiotics, especially those with more serious implications.
1. Weinstock MA, Boyle MM. Statistics of interest to the dermatologist. In: Thiers BH, Lang PG, eds. Year Book of Dermatology. Philadelphia: Elsevier Mosby, 2009:63.
2. James WD. Acne. N Engl J Med 2005; 352(14):1463 1472.
3. Krakowski A, Eichenfield LF. Pediatric acne: clinical presentations, evaluation, and management. J Drugs Dermatol 2007; 6(6):589 593.
4. Tan JKL. Psychosocial impact of acne vulgaris: evaluating the evidence. Skin Therapy Lett 2004; 9(7):1 3.
5. Rapp DA, Brenes GA, Feldman SR, et al. Anger and acne: implications for quality of life, patient satisfaction and clinical care. Br J Dermatol 2004; 151(1):183 189.
6. Bruggemann H. Insights in the pathogenic potential of Propionibacterium acnes from its complete genome. Semin Cut Med Surg 2005; 24(2):63 72.
7. Harper JC. An update on the pathogenesis and management of acne vulgaris. J Am Acad Dermatol 2004; 51(1):S36 S38.
8. Rosen T. The Propionibacterium acnes genome: from the laboratory to the clinic. J Drugs Dermatol 2007; 6(6):582 586.
9. McInturff JE, Kim J. The role of toll like receptors in the pathophysiology of acne. Semin Cut Med Surg 2005; 24(2):73 78.
10. Holland DB, Jeremy AHT. The role of inflammation in the pathogenesis of acne and acne scarring. Semin Cut Med Surg 2005; 24(2):79 83.
11. Leyden JJ, Del Rosso JQ, Webster GF. Clinical considerations in the treatment of acne vulgaris and other inflammatory skin disorders. Cutis 2007; 79(6S):9 25.
12. Gollnick H, Cunliffe W, Berson D, et al. Management of acne: report from a global alliance to improve outcomes in acne. J Am Acad Dermatol 2003; 49(1):S1 S37.
13. Del Rosso JQ. A status report on the use of subantimicrobial dose doxycycline: a review of the biologic and antimicrobial effects of the tetracyclines. Cutis 2004; 74:118 122.
14. Webster GW, Del Rosso JQ. Anti inflammatory activity of tetracyclines. Dermatol Clin 2007; 25(2):133 135.
15. Del Rosso JQ. Report from the scientific panel on antibiotic use in dermatology: introduction. Cutis 2007; 79(6S):6 8.
16. Del Rosso JQ, Leyden JJ, Thiboutot D, et al. Antibiotic use in acne and rosacea: clinical considerations and resistance issues of significance to dermatologists. Cutis 2008; 82(suppl 2[ii]):5 12.
17. Leyden JJ. Extended release minocycline first systemic antibiotic approved for the treatment of acne: introduction. Cutis 2006; 78(4S):4 5.
18. Del Rosso JQ. Recently approved systemic therapies for acne vulgaris and rosacea. Cutis 2007; 80(2):113 120.
19. Bikowski JB. Subantimicrobial dose doxycycline for acne and rosacea. Skin Med 2003; July August:234 245.
20. Feldman S, Carrecia R, Barham KL, et al. Diagnosis and treatment of acne. Am Fam Physician 2004; 69(9):2123 2130.
21. Haider A, Shaw JC. Treatment of acne vulgaris. JAMA 2004; 292(6):726 735.
22. Tan AW, Tan HH. Acne vulgaris: a review of antibiotic therapy. Expert Opin Pharmacother 2005; 6(3):409 418.
23. Ross JI, Snelling AM, Eady EA, et al. Phenotypic and genotypic characterization of antibiotic resistant Propionibacterium acnes isolated from acne patients attending dermatologic clinics in Europe, the USA, Japan and Australia. Br J Dermatol 2001; 144:339 346.
24. Ross JI, Snelling AM, Carnegie E, et al. Antibiotic resistant acne: lessons from Europe. Br J Dermatol 2003; 148(3):467 478.
25. Eady AE, Cove JH, Layton AM. Is antibiotic resistance in cutaneous propionibac teria clinically relevant? Implications of resistance for acne patients and prescribers. Am J Clin Dermatol 2003; 4:813 831.
26. Amin K, Riddle CC, Aires DJ, et al. Common and alternative oral therapies for acne vulgaris: a review. J Drugs Dermatol 2007; 6(9):873 880.
27. Bhambri S, Del Rosso JQ, Desai A. Oral trimethoprim sulfamethoxazole in the treatment of acne vulgaris. Cutis 2007; 79(6):430 434.
28. Rafiei R, Yaghoobi R. Azithromycin versus tetracycline in the treatment of acne vulgaris. J Drugs Dermatol 2006; 17(14):217 221.
29. Leyden JJ. The evolving role of Propionibacterium acnes in acne. Semin Cutan Med Surg 2001; 20:139 143.
30. Leyden JJ. A review of the use of combination therapies for the treatment of acne vulgaris. J Am Acad Dermatol 2003; 49(3):S206 S210.
31. Tanghetti E. The impact and importance of resistance. Cutis 2007; 80(1S):5 9.
32. Del Rosso JQ. Study results of benzoyl peroxide 5%/clindamycin 1% topical gel, adapalene 0.1% gel, and use in combination for acne vulgaris. J Drugs Dermatol 2007; 6(6):616 622.
33. Lookingbill DP, Dhalker DK, Lindholm JS. Treatment of acne with a combination clindamycin/benzoyl peroxide gel compared with clindamycin gel, benzoyl peroxide gel and vehicle gel: combined results of two double blind investigations. J Am Acad Dermatol 1997; 37:590 595.
34. Leyden J, Kaidbey K. Levy S, et al. The combination formulation of clindamycin 1% plus benzoyl peroxide 5% versus 3 different formulations of topical clindamycin alone in the reduction of Propionibacterium acnes. Am J Clin Dermatol 2001; 2:263 266.
35. Leyden JJ, Wortzman M. Baldwin EK. Antibiotic resistant Propionibacterium acnes suppressed by benzoyl peroxide 6% cleanser. Cutis 2008; 82:417 421.
36. Leyden JJ. Antibiotic resistance in the topical treatment of acne vulgaris. Cutis 2004; 73(6S):6 9.
37. Eady EA, Farmery MR, Ross JL, et al. Effects of benzoyl peroxide and erythromycin alone and in combination against antibiotic sensitive and resistant skin bacteria from acne patients. Br J Dermatol 1994; 131(3):331 336.
38. Del Rosso JQ, Leyden JJ. Status report on antibiotic resistance: implications for the dermatologist. Dermatol Clin 2007; 25(2):127 132.
39. Leyden JJ, McGinley KJ, Cavalieri S, et al. Propionibacterium acnes resistance to antibiotics in acne patients. J Am Acad Dermatol 1983; 8(1):41 45.
40. Eady EA, Jones CE, Tipper JL, et al. Antibiotic resistant propionibacteria in acne: need for policies to modify antibiotic use. Br Med J 1993; 306(6877):555 556.
41. Eady EA, Gloor M. Leyden JJ. Propionibacterium acnes resistance: a worldwide problem. Dermatology 2003; 206(1):54 56.
42. Simpson N. Antibiotics in acne: time for a rethink. Br J Dermatol 2001; 144(2): 225 228.
43. Cooper AJ. Systematic review of Propionibacterium acnes resistance to systemic antibiotics. Med J Aust 1998; 169(5):259 261.
44. Thevarajah S, Balkrishnan R, Camacho F, et al. Trends in prescription of acne medication in the US: shift from antibiotic to non antibiotic treatment. J Dermatol Treat 2005; 16:224 228.
45. Tanghetti E. Antibiotic resistance and the role of combination acne therapy: intro duction. Cutis 2007; 80(1S):3.
46. Eady EA, Cove JH, Holland KT. Erythromycin resistant propionibacteria in anti biotic treated acne patients: association with therapeutic failure. Br J Dermatol 1989; 121:51 57.
47. Ozolins M, Eady EA, Avery AJ, et al. Comparison of five antimicrobial regimens for treatment of mild to moderate facial acne vulgaris in the community: randomised controlled trial. Lancet 2004; 364(9452):2188 2195.
48. Simonart T, Dramaix M. Treatment of acne with topical antibiotics: lessons from clinical studies. Br J Dermatol 2005; 153:395 403.
49. Schlessinger J, Menter A, Gold M, et al. Clinical safety and efficacy studies of a novel formulation combining 1.2% clindamycin phosphate and 0.025% tretinoin for the treatment of acne vulgaris. J Drugs Dermatol 2007; 6(6):607 615.
50. Shalita AR, Myers JA, Krochmal L, et al. The safety and efficacy of clindamycin phosphate foam 1% versus clindamycin topical gel 1% for the treatment of acne vulgaris. J Drugs Dermatol 2005; 4:48 56.
51. Fleischer AB, Dinehart S, Stowe D, et al. Safety and efficacy of a new extended release formulation of minocycline. Cutis 2006; 78(4S):21 31.
52. Skidmore R, Kovach R, Walker C, et al. Effects of subantimicrobial dose doxycy cline in the treatment of moderate acne. Arch Dermatol 2003; 139:459 464.
53. Cunliffe WJ, Aldana OL, Goulden V. Oral trimethoprim: a relatively safe and suc cessful third line treatment for acne vulgaris. Br J Dermatol 1999; 141(4):757 758.
54. Campbell JL. A comparative review of the efficacy and tolerability of retinoid containing combination regimens for the treatment of acne vulgaris. J Drugs Der matol 2007; 6(6):625 629.
55. Del Rosso JQ. Systemic therapy for rosacea: focus on oral antibiotic therapy and safety. Cutis 2000; 66(4S):7 13.
56. Knowles SR, Shear SR. Cutaneous drug reactions associated with systemic features. In: Wolverton SE, ed. Comprehensive Dermatologic Drug Therapy. 2nd ed. Phila delphia: Saunders Elsevier, 2007:977 981, 982 983.
57. Remlinger KA. Hematologic toxicity of drug therapy. In: Wolverton SE, ed. Comprehensive Dermatologic Drug Therapy. 2nd ed. Philadelphia: Saunders Elsevier, 2007:901 903.