DRUG THERAPY TOPICS A Status Report on the Use of Subantimicrobial-Dose Doxycycline: A Review of the Biologic and Antimicrobial Effects of the Tetracyclines James Q. Del Rosso, DO cne vulgaris and rosacea are among the most revealed that the use of subantimicrobial doses of common inflammatory dermatoses involv- doxycycline initiates anti-inflammatory activity A ing the face, with acne vulgaris occurring in that correlates with clinical efficacy. Doxycycline more than 35 million people and rosacea occurring at subantimicrobial doses has induced clinical in 14 million people. Perioral dermatitis, another responses in disorders such as acne vulgaris and common facial dermatosis, typically affects women. rosacea, without antibiotic activity against P acnes Since tetracycline became available in 1953, fol- and other commensal organisms and without emer- lowed by doxycycline in 1967 and minocycline in gence of antibiotic resistance. 1972, dermatologists have frequently used oral tetracyclines for the treatment of acne vulgaris, rosacea, and perioral dermatitis. In the treatment What has been the conventional of acne vulgaris, the major mechanism focus has use of oral antibiotic agents for the been the reduction of Propionibacterium acnes treatment of acne vulgaris and rosacea? organism counts, which correlates with reduction The oral tetracycline agents (tetracycline, doxycy- in inflammatory lesions. For rosacea and perioral cline, and minocycline) and the oral macrolide dermatitis, disorders that are not definitively asso- erythromycin have been the predominant oral ciated with bacterial pathogenesis, direct anti- antibiotics used for acne vulgaris, rosacea, and peri- inflammatory effects, such as inhibition of oral dermatitis for several decades. Owing to their neutrophil chemotaxis, have been suggested as overall efficacy and favorable safety profiles (even mechanisms related to clinical efficacy. For acne when used for the chronic therapy often required vulgaris, rosacea, and perioral dermatitis, recom- for management of dermatologic disease), collec- mended regimens with oral tetracyclines have tively these agents have been used for more than primarily used dosing schedules capable of induc- 172 years.1 A recent article reviewed published ing both antibiotic (antimicrobial) and anti- comparative and placebo-controlled trials of inflammatory effects. tetracycline, doxycycline, and minocycline that Enhanced understanding of inflammatory path- included 321 patients with acne vulgaris and ways in epithelial and mesenchymal tissues has 130 patients with rosacea.2 A common approach to the use of oral antibiotics in acne vulgaris and Accepted for publication June 1, 2004. rosacea is to achieve control initially with the use of From the Department of Dermatology, University of Nevada a high daily dosage, tapering to a lower dose for School of Medicine, Las Vegas. maintenance treatment.3-5 The clinician may initi- Dr. Del Rosso is a consultant and an advisory board member for CollaGenex Pharmaceuticals, Inc, and Medicis Pharmaceutical. ate therapy with a lower daily dosage because some Reprints: James Q. Del Rosso, DO, FAOCD, 4488 S Pecos Rd, patients require it (eg, patients with less than aver- Las Vegas, NV 89121. age body weight) or because short-term studies 118 CUTIS® Drug Therapy Topics have demonstrated efficacy with lower doses.1,3 A What is the prevalence of common finding noted by clinicians is that oral antibiotic-resistant P acnes? antibiotics at lower doses have often maintained con- Although earlier isolated cases of erythromycin- trol of both acne vulgaris and rosacea; this observa- resistant strains of P acnes were observed in 1971 tion is believed to be related to the anti-inflammatory and tetracycline-resistant strains were observed in effects of some antibiotics (such as tetracyclines) 1975, the initial observations of P acnes antibiotic rather than to their antimicrobial effects.6,7 resistance in patients with acne were reported in 1979.4,12,13 Over time, data collected from acne patients in several countries revealed an increased How have emerging trends emergence of antibiotic-resistant isolates of related to bacterial resistance to P acnes. A review of several reports indicated a antibiotics influenced dermatologic practice? prevalence rate of 20% in 1978, rising to 62% in Overall concerns related to increased bacterial 1996.14 Overall, the prevalence rates of P acnes resis- resistance to antibiotics have had an impact on all tance to erythromycin and clindamycin have out- disciplines of medicine, including dermatology. paced trends observed for resistance to tetracyclines; Several antibiotic resistance issues have emerged this trend may reflect the widespread prescribing of in common pathogens of dermatologic infections topical erythromycin and clindamycin for acne and inflammatory disorders. Examples include over the past 3 decades and their common usage macrolide-resistant Streptococcus pyogenes and without concurrent therapy with benzoyl peroxide.4 Staphylococcus aureus; methicillin-resistant S aureus; In Europe, approximately 50% of acne patients mupirocin-resistant S aureus; vancomycin-resistant appear to be colonized by P acnes strains that are S aureus; quinolone-resistant S aureus, Pseudomonas resistant to erythromycin or clindamycin, with up aeruginosa, and mycobacteria; and P acnes resistant to 20% of patients demonstrating tetracycline- to tetracyclines, macrolides, and lincosamides resistant isolates.4,15 Nevertheless, studies com- (eg, clindamycin).4,8 pleted over the past decade in several countries As a result of these emerging concerns, the have confirmed the definite trend of increased US Food and Drug Administration issued a warn- prevalence of P acnes resistance to several anti- ing notification in February 2003 urging caution biotics used to treat acne, including the tetracy- in prescribing systemic antibiotic therapy.9 In cline agents, erythromycin and clindamycin.14-18 addition, the issue of P acnes resistance to both Cross-resistance between antibiotics in similar topical and oral antibiotics has been addressed in structural classes (eg, tetracycline and doxycy- the literature over the past several years.4,10 How cline, erythromycin and clindamycin) has been these warnings, recommendations, and educa- reported frequently.4,12,14,17,18 However, differences tional initiatives will affect antibiotic prescribing in antibiotic penetration into affected follicles and patterns by dermatologists for disease states such variable antibiotic cross-resistance related to as acne vulgaris, rosacea, perioral dermatitis, and differences in minimum inhibitory concentrations clinically suspected cutaneous infections remains (MICs) may alter the clinical outcome in individ- to be determined. ual patients.4,14,17,18 Although P acnes is the pre- In the United Kingdom, concerns regarding dominant Propionibacterium species present on overall antibiotic use have reduced prescribing skin, other species, such as Propionibacterium patterns. The use of systemic antibiotics for all granulosum, have been ignored in most evaluations. indications decreased by 23.1% between the periods These other species may be operative in the patho- of 1995 to 1996 and 1999 to 2000, dropping from genesis of acne.4 44.5 million to 34.2 million prescriptions.4,11 In 1995, general practitioners wrote 1.6 million pre- scriptions for tetracycline agents and 0.8 million What is the impact of antibiotic-resistant for topical antibiotics for the treatment of acne. By P acnes on treatment outcomes in 2000, the number of prescriptions written had patients with acne vulgaris? dropped significantly, to 1 million for tetracycline It is important to recognize that resistance of agents and 0.7 million for topical antibiotics. The P acnes to antibiotics is not an all or nothing phe- overall reduction in antibiotic prescriptions for nomenon. In patients with acne vulgaris, up to 20% acne in the second half of the 1990s was 33%, of nonlesional follicles are colonized with P acnes, including a 37.5% drop in prescriptions for tetracy- with fewer than 1% of follicles involved in lesional cline agents and a 12.5% drop in prescriptions for activity at any given point.4,19 In acne patients eval- topical antibiotics.4 uated for the presence of antibiotic-resistant VOLUME 74, AUGUST 2004 119 Drug Therapy Topics P acnes isolates, patients with positive test results Coagulase-negative staphylococci may behave as for these organisms are not exclusively colonized nosocomial pathogens and may provide a pool of with antibiotic-resistant strains. The relative antibiotic resistance genes shared with other distribution of antibiotic-resistant and antibiotic- staphylococci, such as S aureus.10 susceptible P acnes strains demonstrates interpatient A recent study compared patients using oral or variability related to factors such as previous anti- topical antibiotics for acne with a control group not biotic use and origin of colonization (eg, person-to- treated with antibiotic therapy.20 A 3-fold increase person spread).4 in oropharyngeal S pyogenes was demonstrated in Several factors are involved in the pathogenesis the group using antibiotics. The incidence of of acne vulgaris and clinical response to treatment. S pyogenes resistance to at least one tetracycline The pathogenic influence of P acnes is one of sev- antibiotic was 85% in the group receiving antibi- eral components involved in the development of otics versus 20% in the control group. acne. As a result,