Therapy Eur J Dermatol 2004; 14: 391-9

Brigitte DRÉNO1 Vincenzo BETTOLI2 European recommendations on the use of oral Falk OCHSENDORF3 for Alison LAYTON4 Håkan MOBACKEN5 Hugo DEGREEF6

1 Department of Dermatology, Non-rational prescribing of oral antibiotics in acne is common, and there Hotel Dieu, Place Alexis Ricordeau, is currently an unmet need for up-to-date guidelines that specifically 44093 Nantes Cedex 01, France 2 Clinica Dermatologica, Azienda address these issues. Presented here is a set of recommendations on the Ospedaliera Arispedale S. Anna, use of oral antibiotics in acne, developed by a group of European acne Università degli Studi di Ferrara, specialists, designed to be considered by dermatologists and general Corso Giovecca 189, 44100 Ferrara, Italy practitioners in their daily practice throughout Europe. Recommenda- 3 Klinikum der Johann Wolfgang Goethe-Universitat, Zentrum tions cover optimal choice of , drug doses, duration of treat- der Dermatologie und Venerologie (ZDV) ment, combination treatment, and maintenance therapy. Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany Key words: Acne vulgaris, oral antibiotics, treatment recommenda- 4 Harrogate District Hospital, tions. Lancaster Park Rd, Harrogate, North Yorks, HG2 7SX, UK 5 Department of Dermatology, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden Disclaimer 6 University Hospital St Rafaël, These recommendations have been prepared for dermatologists and Department of Dermatology, general practitioners on behalf of the ‘European expert group on oral Kaucijnenvoer, 33, B3000 Leuven, antibiotics in acne’ and reflect the best data available at the time the Belgium report was prepared. Caution should be exercised in interpreting the data: the results of future studies may require alteration of the conclusions or Reprints: B. Dréno. recommendations of this report. It may be necessary or even desirable to Fax: (+ 33) 240083117 [email protected] depart from the recommendations in the interests of specific patients or special circumstances. Just as adherence to these recommendations may not constitute a defence against a claim of negligence, so deviation from them should not necessarily be deemed negligent. Article accepted on 16/7/2004

here are many different drugs available for the to the fact that much of the clinical evidence derives from treatment of acne vulgaris, including oral and topi- trials that vary greatly in acne definition, end-points, doses T cal antibiotics, topical , topical used, duration of treatments etc., making direct compari- , oral , oral anti-androgens, and zinc sons difficult. Perhaps as a consequence of this lack of salts. Many guidelines on how these different agents can be guidance, there is considerable variation in the way in optimally used have been published over the years. These which antibiotics are used to treat acne across Europe, and include the ‘Ad hoc committee report’ on the use of syste- their inappropriate use is alarmingly common (patients are mic antibiotics for treatment of acne vulgaris (1975) [1]; often treated for excessively long periods of time, and/or the American Academy of Dermatology ‘Guidelines for there is much variation in antibiotic dosage given). The care of acne vulgaris’ (1990) [2]; ‘Treatment of acne vul- preferred choice of antibiotic varies from country to garis: guidelines for primary care physicians’ (1991) [3]; country, with first generation cyclines ( HCl, ‘Oral treatment of acne’ in France (1999) [4]; and most and ) very popular in the UK, recently the ‘Global alliance to improve outcomes in acne’ preferred in Belgium, and lymecycline particularly popular consensus recommendations (2003) [5]. Figure 1 shows the among dermatologists in France, Italy, and Nordic coun- acne treatment algorithm proposed by the ‘Global alliance’, tries. Some of these differences may be accounted for by in which oral antibiotics, used in combination with topical climate (for example, , known to have the po- retinoids, are recommended for the treatment of moderate tential to cause dose-dependent photosensitivity, is less to severe inflammatory acne. commonly prescribed in Southern Europe during the sum- Other than the 1975 ad hoc committee report [1], the other mer), and by various pharmacoeconomic considerations. guidelines listed above provide general recommendations Thus, despite the problems in forming truly evidence-based on acne management, but fall short of providing detailed guidelines on the use of oral antibiotics in acne, there is guidance on the use of oral antibiotics. This is probably due clearly an unmet need for recommendations on the use of

EJD, vol. 14, n° 6, November-December 2004 391 Mild Moderate Severe Comedonal Papular/pustular Papular/pustular Nodular1 Nodular/ conglobate 1st3 Topical Topical retinoid + Oral antibiotic + Oral antibiotic + Oral isotretinoin2 topical antimicrobial topical retinoid +/– topical retinoid + BP BP Alternative3 or Alternative topical Alternative oral Oral isotretinoin or High dose oral antimicrobial + antibiotic + alternative oral antibiotic + topical alternative topical alternative topical antibiotic + retinoid + BP retinoid or azelaic retinoid +/– BP alternative topical acid4 retinoid +/– BP/azelaic acid4 Alternatives See 1st choice See 1st choice Oral antiandrogen + Oral antiandrogen + High dose oral for females3 topical topical retinoid +/– antiandrogen + retinoid/azelaic oral antibiotic topical retinoid +/– acid4 +/– BP +/– alternative alternative topical antimicrobial antimicrobial

Maintenance: Topical retinoid +/– BP

1Papulopustular acne with some nodular lesions; 2Second course in case of relapse; 3Consider physical removal of comedones. 4There was no consensus on this alternative recommendation. However, in some countries, azelaic acid prescribing is appropriate practice.

BP: benzoyl peroxide.

Figure 1. Acne treatment algorithm suggested by Gollnick et al. (2003) [5]. Reprinted from the Journal of the American Academy of Dertatology, Vol. 49 (I suppl.); Gollnick et al. Management of acne: a report from a global alliance to improve outcomes in acne, pages S1-S38, © 2003, American Academy of Dermatology, Inc, with permission from Elsevier. oral antibiotics that can be used in the daily practice of discussion and review. Recommendations are based on physicians treating acne across Europe. This paper there- efficacy, practical applicability in daily practice, fore presents the available clinical data and expert opinion, safety/tolerability, antimicrobial resistance, and pharmaco- followed by a set of detailed and user-friendly recommen- economic considerations. dations on many aspects of the use of oral antibiotics in acne. I. Literature review Methodology The pathophysiology of acne and rationale for using antibiotics These recommendations were developed over a series of There are a number of pathophysiologic components to three meetings in 2002 and 2003. During the first two acne, including sebaceous gland hyperplasia with sebor- meetings, a core of six independent European acne specia- rhoea; altered follicular growth and differentiation; micro- lists reviewed current practices around Europe; conducted a bial colonization; and inflammation and other immune res- systematic literature review (using Medline) covering the ponses [5]. The precursor lesion in all acne is the years 1992 to 2003; and discussed personal experiences. In microcomedone, which features altered follicular growth a final workshop, the findings of this core group were and differentiation, and sebaceous gland hyperplasia with presented to the wider group of 23 acne specialists, mainly seborrhoea. Microcomedones can then enlarge to form from Europe, but also Brazil and Morocco (Appendix 1) for non-inflammatory closed or open comedones, and micro-

392 EJD, vol. 14, n° 6, November-December 2004 bial colonization can result in the formation of inflamma- stone of oral antibiotic therapy in acne, and are discussed in tory lesions (papules, pustules, or nodules). By using diffe- detail later in this paper. rent agents in combination, acne pathophysiology can be targeted from a number of different angles simultaneously, improving therapeutic outcome [5]. For example, topical The utility of oral macrolides (mainly ) in retinoids (some of which have proven anti-inflammatory acne is increasingly limited due to the increasing problem properties) target the microcomedone, and are therefore of microbial resistance to these agents [23, 25]. Eady et al. suitable for use in combination with other drugs that target (1989) [26] demonstrated a clear correlation between car- Propionibacterium acnes and inflammation, and may be riage of erythromycin-resistant P. acnes and poor clinical suitable for maintaining remission following successful efficacy. There is frequently cross-resistance between treatment [6]. erythromycin and . Macrolides are therefore Microorganisms that are commonly present on the skin reserved for cases where cyclines are not tolerated, or are of patients with inflammatory acne include the yeasts contraindicated (e.g. pregnancy and breastfeeding). Pityrosporum spp., coagulase-negative staphylococci, and Clindamycin P. acnes [7]. Eradication of Pityrosporum spp., using anti- Although effective, oral clindamycin is rarely used in acne mycotic therapy, does not have any effect on acne [8], and because of potentially serious adverse effects [27]. Distur- use of antibiotics induces resistance in coagulase-negative bance of gastrointestinal flora by this agent can cause staphylococci well in advance of observed responses to overgrowth of Clostridium diffıcile and result in pseudo- treatment [9]. Studies have shown that infection with the membranous colitis. Diarrhoea is seen in 5-20% of patients gram-positive, pleomorphic, anaerobic rod, P.acnes causes using this agent [28]. inflammation of sterile cysts [10], but that dead P. acnes or Co-trimoxazole and trimethoprim living Staphylococcus epidermidis do not cause inflamma- tion [11]. Therefore P. acnes, has been implicated in in- The use of co-trimoxazole (trimethoprim plus sulpha- flammatory acne lesions. methoxazole) or trimethoprim alone is limited, and these The concentration of P. acnes generally correlates with agents are not licensed for use in acne. This is because of patient’s sebum production [12], but not with the degree of the potential for development of serious allergic reactions inflammation or the severity of acne [7, 13, 14]. However, to the sulphamethoxazole component of co-trimoxazole, the humoral and cellular immune responses to P. acnes which may be seen in up to 3% of patients. Therefore, these correlate with acne severity. Colonization with P. acnes agents are limited to situations where there is proven resis- results in secretion of extracellular enzymes, cytokines tance to other agents or as a third-line treatment [22, 29]. such as IL-1a, and heat-shock proteins, all of which have Quinolones mitogenic effects on T-cells [15-19]. Thus P. acnes is Although one Japanese study has shown efficacy of levo- associated with inflammatory acne not in a concentration- floxacin in acne [30], oral quinolones are not used in acne dependent manner, but in an inflammation-dependent man- because of the small amount of compelling efficacy data, ner. Antibiotics that can both reduce the number of P. acnes the problems of adverse events (seen in 3-6% of patients), and reduce inflammation by different mechanisms are the- potential for antibiotic resistance (particularly the develop- refore of utility in moderate to severe acne associated with ment of quinolone resistance in commensal bacteria [31]), papules, pustules, and nodules, and in acne conglobata high price, and unsuitability of these agents for adolescents (Figure 1). A recent study has shown that inflammation (due to potential effects on articular cartilage) [32]. Side features in the very earliest stages of acne lesion develop- effects include agitation, headache, hallucination, gastro- ment [20]. Follicles without microcomedonal features had intestinal disturbance, arthralgia, tendinitis, and photosen- elevated CD3 T-cells, CD4 T-cells, and macrophages in the sitivity. perifollicular and papillary dermis, as well as changes and activation of vascular intercellular adhesion molecules Mechanisms of action of antibiotics in acne [20]. Antibacterial actions As already discussed, the density of P. acnes on the skin of Oral antibiotics used in acne acne patients does not correlate well with the degree of Cyclines, macrolides, clindamycin, trimethoprim, co- inflammation or the severity of acne. Similarly, the magni- trimoxazole, and quinolones all have efficacy in acne [21, tude of the reduction in P.acnes counts following antibiotic 22]. Notably, penicillins, cephalosporins, , therapy does not correlate well with clinical efficacy [33, and have very limited effects in inflam- 34]. However, the fact that the presence of P. acnes appears matory acne [1, 23, 24]. to be associated with and apparently required for the for- mation of inflammatory lesions; that successful antibiotic Cyclines treatment of acne is associated with a reduction in the P. Cyclines (tetracycline HCl, oxytetracycline, lymecycline, acnes population; and that acne associated with doxycycline, and minocycline) have very good efficacy in erythromycin- or tetracycline-resistant P. acnes does not acne and generally have a good safety profile. Side effects always respond as well to treatment with those agents [26, include gastrointestinal disturbance, and some drug- 35, 36], may suggest an important role for antibacterial specific effects discussed later in this paper. There is cross- activity in the efficacy of antibiotics in acne. The different resistance within the class, but no cross-resistance to other classes of agents exert their antibacterial effects in different antibiotic classes. Cyclines are contraindicated in children ways. Cyclines, macrolides and clindamycin inhibit bacte- under 8-12 years (varying according to national licenses) rial protein synthesis (by different mechanisms); trimetho- and in pregnancy due to their effect on growing bone tissue prim and sulphamethoxazole interfere with bacterial folate (causing inhibition of skeletal growth in the foetus and metabolism; whilst quinolones inhibit bacterial DNA gy- discoloration of growing teeth). Cyclines form the corner- rase.

EJD, vol. 14, n° 6, November-December 2004 393 Non-antibacterial actions acnes [25]. Furthermore, 25 out of 39 acne specialists tes- Non-antibacterial actions include bacterial lipase inhibition ted were colonized by resistant strains, compared with [37-39], and anti-inflammatory/immunomodulatory effects 0 out of 27 non-dermatologist physicians [25]. Resistant [40-43]. P. acnes secretes lipases, which convert diglyceri- strains can be reduced by using the topical antibacterial des and triglycerides into free fatty acids. Free fatty acids in agent benzoyl peroxide at the site of application. However turn cause follicular hyperkeratinisation and contribute to no single available agent will fully eradicate antibiotic- the clinical picture of inflammatory acne. It has been shown resistant P. acnes. that cyclines and macrolides inhibit bacterial lipases, inde- Other ways of preventing the emergence of resistant strains pendent of their antibacterial effects [37-39]. include: Macrolides and cyclines also interact with the immune 1. Do not use antibiotics where other acne treatments can response in a complex way, and many different effects have be expected to bring about the same degree of benefit. been observed [40-43]. These include direct, dose- 2. Use antibiotics according to clinical need. dependent inhibition of lymphocyte mitosis; inhibition of 3. Do not use antibiotics as a monotherapy [5]. phagocytosis; decrease in the secretion of the pro- 4. Stop antibiotic therapy when you and the patient agree inflammatory cytokines TNF-a, IL-1 and IL-6; increase in there is no further improvement or the improvement is only the secretion of the anti-inflammatory cytokine IL-10; inhi- slight (one UK-based study suggested that 6-8 weeks into bition of leukotaxis; decreased activation of complement treatment might be one appropriate time-point at which to protein C3 (only noted with cyclines); modulation of assess response to antibiotics [36]). a-MSH (demonstrated with minocycline); and inhibition of 5. Try to avoid continuing antibiotics beyond six months. reactive oxygen species generation [44-47]. 6. Use benzoyl peroxide either concomitantly or pulsed as One of the main questions today concerning the efficacy of an anti-resistance agent. antibiotics in acne is to determine whether the main activity 7. Do not switch antibiotics without adequate justification of antibiotics in acne is antibacterial or antiinflammatory. (i.e. re-use the same antibiotic for subsequent courses if The observed efficacy of antibiotics used at low (sub-MIC) patients relapse). doses suggests that the non-antibacterial effects play an Risk factors for developing or acquiring antibiotic-resistant important role [34]. P. acnes include prolonged duration of antibiotic therapy, multiple courses of antibiotics, close contact with acne Antibiotic resistance in P. acnes patients being treated with antibiotics, and poor compliance Antibiotic resistance in P.acnes was first described in 1979, with treatment [25]. when erythromycin resistance was found in a single isolate Topical benzoyl peroxide has been shown to be active in the USA [48]. Since then, the incidence of resistance has against fully sensitive and resistant strains of P. acnes. This risen, and a recent survey, conducted throughout Europe, agent therefore reduces the likelihood of antibiotic- showed that at least 50% of acne patients are colonized by resistant P. acnes emerging and reduces the number of erythromycin- and clindamycin-resistant strains of P. ac- resistant bacteria in situ [49]. Other ‘anti-resistance’ agents nes, and as many as 20% are colonized with cycline- include topical zinc acetate [50] and oral isotretinoin [51]. resistant strains [25]. Resistance emerges through either The development of antibiotic resistance can also be redu- selection of pre-existing resistant bacterial strains, or ced by ensuring that antibiotics are not used unnecessarily, through de novo acquisition of a resistant phenotype. Emer- treatment duration is not excessively long, and patients ging antibiotic resistance in acne has been shown to deve- comply well with treatment [25]. Combining therapy with lop in response to antibiotic prescribing [25]. The duration topical retinoids will also expediate improvement while of treatment required before resistance emerges varies targeting the microcomedone [5]. greatly between patients, but the longer the duration of In cases where antibiotic resistance is suspected, these treatment, the more likely antibiotic-resistant P. acnes will drugs are often simply discontinued. Ideally, however, such emerge, and courses of 6 months are highly likely to result cases should be managed by first swabbing and culturing to in resistance. verify the presence of resistant strains, and then using There is a recognized correlation between the presence of non-antibiotic therapies such as topical benzoyl peroxide, antibiotic-resistant P. acnes and clinical response to treat- topical or systemic retinoids, hormonal therapies, or syste- ment with erythromycin and (although this is mic zinc salts. Raising antibiotic doses can also be consi- less well established) [26, 35, 36]. Antibiotic resistance dered. should therefore be considered as a possible contributory The use of oral cyclines in acne factor to, or possible cause of, therapeutic failure. High dose antibiotics will reduce sensitive strains and allow overgrowth of resistant strains in situ. However, depending Cyclines can be classified as ‘first generation’ (tetracycline on the mechanism of resistance, low dose antibiotics may HCl and oxytetracycline) and ‘second generation’(lymecy- also encourage overgrowth of resistant strains. In addition, cline, doxycycline, and minocycline). The key difference low dose antibiotics may induce de novo antibiotic resis- between first and second generation cyclines is their phar- tance in other commensal bacteria present (e.g. staphylo- macokinetic profiles (Table I). First generation cyclines cocci), which often develop resistance much more quickly must be taken at least twice daily and their absorption is than resistance in P. acnes. For these reasons, the common impaired by food and milk, whereas second generation practice of using low dose antibiotics for prolonged periods cyclines can be taken once or twice daily with their absorp- of time should not be recommended. tion unaffected by food. These differences may adversely Antibiotic-resistant strains can be transmitted between in- affect compliance with first generation cyclines (particu- dividuals, and studies have shown that 41-85.7% of untrea- larly among adolescents), which may lead to therapeutic ted close contacts of acne patients under long-term antibio- failure and the development of resistance. There are few tic treatment harbor erythromycin-resistant strains of P. pharmacokinetic differences between individual second

394 EJD, vol. 14, n° 6, November-December 2004 Table I. Pharmacokinetics of cyclines compared

Tetracycline Oxytetracycline Lymecycline Minocycline Doxycycline HCl

Absorption 75% 75% 80% 90% 90% Interaction with food Yes Yes No No No Interaction with milk Yes Yes No No Yes (although 30% less than first generation cyclines) Interaction with antacids, iron Yes Yes Yes Yes Yes preparations, and mineral supplements

t1/2 7-8 hours 8-10 hours 10 hours 17-18 hours 16-22 hours

Tmax 3-4 hours 2 hours 3 hours 2-3 hours 2-3 hours Serum protein binding 55-70% 27-35% 50% 80% 90% Clearance Renal Renal Renal Renal Biliary generation cyclines, although it is noteworthy that only total number of lesions by a mean of 47.9% and 58.7%, doxycycline is cleared by the liver, allowing this agent to be respectively (P = 0.0033); inflammatory lesions were used in patients with renal impairment. reduced by a mean of 45.6% vs 60.3%, respectively Efficacy (P = 0.0001); and non-inflammatory lesions were reduced by a mean of 47.6% vs 56.6%, respectively (P = 0.01) [58]. While the efficacies of first and second generation cyclines have not been compared in large randomized clinical trials, Mobacken (1993) [54] and Campo et al. (2002) [55] exa- second generation cyclines have been compared in a num- mined the effects of treatment for up to 6 months. After ber of clinical trials (Table II) [52-57]. It can be seen that 1 month of treatment with lymecycline (600 mg daily), there is little to choose between these molecules in terms of Mobacken (1993) [54] found that facial papules and pustu- efficacy, with reductions noted in the number of inflamma- les had reduced in number by 47.5%, compared with 76.5% tory lesions of 51-77% following 3-6 months of treatment. and 76% following a further 5 months of treatment with Efficacy and speed of response to treatment can be signifi- lymecycline at 300 mg or 600 mg daily, respectively. Thus cantly improved by using topical retinoids concurrently (to it can be seen that additional efficacy can be gained by target microcomedones, comedones and inflammation). In extending treatment with oral antibiotics beyond 1 month. a study of 242 acne patients, a three month course of Campo et al. (2002) [55] compared the efficacy of treat- lymecycline (300 mg daily) was compared with lymecy- ment with lymecycline (300 mg daily for 2 weeks, fol- cline (300 mg daily) plus topical (0.1%) applied lowed by 150 mg daily) plus topical adapalene, with mino- daily [58]. Lymecycline and combined therapy reduced the cycline (100 mg daily) plus topical adapalene for up to

Table II. Effıcacies of second generation cyclines compared

Study Design Lymecycline Minocycline Doxycycline (mean % reduction (mean % reduction (mean % reduction in number of lesions) in number of lesions) in number of lesions)

3 months 6 months 3 months 6 months 3 months

Schollhammer and Multicentre, randomized, parallel. 72.7 68.4 62.4 Alirezai 1994 [52]1 N=77 Bossuyt et al. Multicentre, randomized, parallel, 58.7 64.5 2003 [53]2 investigator-blind. N = 134 Mobacken et al. Open-label, parallel dose-ranging 76 (76.5) 1994 [54]3 study. N = 221 Campo et al. Multicentre, randomized, parallel, 67 77 62 67 2002 [55]4 investigator-blind. N = 152 Cunliffe et al. Multicentre, randomized, double- 50.6 52.2 1998 [56]5 blind, double-dummy. N = 144 Dubertret et al. Multicentre, randomized, double- 62 (56.4) 2003 [57]6 blind study. N = 270

1 This study compared lymecycline (300 mg daily for 2 weeks, then 150 mg daily), minocycline (100 mg daily for 2 weeks, then 50 mg daily), and doxycycline (100 mg daily for 2 weeks, then 100 mg every other day). 2 This study compared lymecycline (300 mg daily) with modified-release minocycline (100 mg daily). 3 In this study, patients received 600 mg lymecycline daily for 1 month, followed by either 600 mg lymecycline daily or 300 mg lymecycline daily. The valuein brackets refers to the population randomized to the lower dose. 4 This study compared lymecycline (300 mg daily for 2 weeks then 150 mg daily) plus topical adapalene, with minocycline (100 mg daily) plus adapalene. 5 This study compared lymecycline (300 mg daily for 2 weeks, then 150 mg daily) with minocycline (100 mg daily for 2 weeks, then 100 mg every other day). 6 This study compared lymecycline (300 mg OD), lymecycline (150 mg BD), and placebo. The value in brackets refers to the population randomized to the BD dose.

EJD, vol. 14, n° 6, November-December 2004 395 Table III. Prices (W) of second generation cyclines per treatment course across Europe at the time of writing

Country Lymecycline Minocycline Doxycycline (300 mg daily for 12 weeks) (100 mg daily for 12 weeks) (100 mg daily for 12 weeks)

Belgium 64.84 108.71 71.22 France 41.80 73.31 33.60 Germany Not currently available 73.96 32.35 Italy 103.201 37.44 34.69 Sweden 64.662 Not currently available 82.423 UK 47.97 114.68 54.08

1 300 mg daily for 2 weeks, then 150 mg daily for 10 weeks. 2 600 mg daily for 4 weeks, then 300 mg daily for 8 weeks. 3 200 mg daily for 4 weeks, then 100 mg daily for 8 weeks.

6 months, measuring efficacy every 2 months. After toms] syndrome, arthritis, vasculitis, and hepatitis) [68]. It 3 months, the number of acne lesions had reduced by 67% has been postulated that minocycline may generate a spe- and 62% in the lymecycline and minocycline groups, res- cific reactive species that could be responsable for such pectively, compared with 77% and 67%, respectively, after reactions [68]. Other effects include skin hyperpigmenta- 6 months of treatment. These two studies show that patients tion (particularly in areas exposed to the sun); single organ may benefit from treatment with oral antibiotics dysfunction (early onset, dose-related); Sweet syndrome; for > 1 month, but that there is little advantage in using pseudotumour cerebri [69]; and vestibular disturbances these agents for > 3 months. In addition, the risk of deve- [70]. In a review of minocycline efficacy and safety in acne, loping antibiotic resistance is known to increase when Garner et al. (2002) [64] suggested that because of a lack of treatment is continued beyond 3 months. These issues proven efficacy advantages over other agents, and an uncer- should be taken into account when considering extending tain safety profile, there could be no justification in conti- treatment beyond 3 months. nuing to use minocycline as a first line therapy in acne, and in France, the national regulatory authority (AFSSAPS) Safety and tolerability now recommends that oral minocycline should be reserved Tetracycline HCl and oxytetracycline are generally well as a second choice oral antibiotic in acne. tolerated, but can produce gastrointestinal disturbances. Like all cyclines, first generation molecules can inhibit Pharmacoeconomic considerations skeletal growth in the developing foetus and cause discolo- One of the problems with attempting to include a cost ration of growing teeth (particularly with tetracycline HCl). component in developing pan-European recommendations Cyclines are therefore contraindicated during pregnancy on antibiotic use is the very large variation in drug prices and in young children (under 8-12 years, depending on across Europe (Table III. e.g. minocycline is almost three national licenses). times more expensive in the UK than in Italy). For this Lymecycline has a good safety profile and is generally well reason, it is difficult to extrapolate data from one country to tolerated, occasionally causing, like other cyclines, tran- another. However, pharmacoeconomic analyses can be use- sient mild gastrointestinal disturbances, and rarely allergic ful at a national level [71]. reactions. One recent study by Bossuyt et al. (2003) [53] compared Doxycycline is noted particularly for causing photosensiti- the cost-effectiveness of minocycline (as Minocin MR®) vity. This effect is dependent on doxycycline dose, UVA with lymecycline (as Tetralysal 300®) for the treatment of intensity, and skin type. Photosensitivity also greatly in- acne in the UK, France and Belgium. In this study, ‘treat- creases the potential for phototoxicity (burning effects and ment success’ was defined as the percentage of patients in photo-onycholysis). Bjellerup and Ljunggren (1994) [59] which acne was ‘cleared’, ‘much improved’, or ‘improved’. compared the phototoxicity of doxycycline (200 mg daily) Treatment success was similar for both agents (98.4 and and lymecycline (1200 mg daily) using UVA light. In this 91.5% for lymecycline and minocycline, respectively, over study, lymecycline induced a slight increase in erythema all countries). However, ‘cost effectiveness’ (calculated as compared with placebo at 75 J.cm–2. In contrast, doxycy- treatment cost divided by treatment success) was 65.89, cline caused a highly significant increase in erythema com- 42.48, and 49.30 Euros per treatment success for lymecy- pared with placebo at 50, 75, and 100 J.cm–2. Patients and cline in Belgium, France, and UK, respectively, compared doctors should therefore be conscious of the dangers of with 118.81, 80.12, and 125.33 Euros per treatment success UVA solaria when using doxycycline, and this drug should for minocycline in Belgium, France, and UK, respectively. be used with caution in hot climates during the summer. This study shows that lymecycline is a more cost-effective Non-comedogenic sun-screens that protect against both acne treatment than minocycline in Belgium, France and UVB and UVA should be considered when taking doxycy- the UK, but particularly in the UK. cline (depending on dose and climate). Minocycline causes a number of rare but severe side effects, Cyclines and oral contraceptives: an interaction? including autoimmune disorders (lupus-like syndrome, Acne patients are often concerned about the potential inter- autoimmune hepatitis, arthritis, thyroiditis, polyarteritis action between cyclines and oral contraceptives. Cyclines, nodosa) [60-68]; and hypersensitivity reactions (pneumo- and other broad-spectrum antibiotics, could theoretically nitis, eosinophilia, serum-sickness-like syndrome, DRESS alter the gut flora, reducing the bacterially-induced hydro- [Drug Reactions with Eosinophilia and Systemic Symp- lysis of steroid conjugates formed in the liver and gut wall,

396 EJD, vol. 14, n° 6, November-December 2004 resulting in a decreased quantity of free steroid for reab- backed up by high quality evidence. The recommendations sorption, and hence reduced plasma levels of active steroid. below should therefore be viewed as guidance based on There have been occasional anecdotal reports of oral expert opinion of the available data. contraceptive failure in patients taking cyclines, and two These recommendations are intended to provide improved uncontrolled retrospective studies have claimed failure ra- patient benefit, and are based on analyses of efficacy, resis- tes of 1.2 and 1.4 per 100 years of therapy in patients taking tance, safety, cost effectiveness, expert opinion, and the cyclines [72, 73]. One controlled retrospective study exa- needs and limitations of daily practice. mined the failure rate of oral contraceptives in 356 patients who had taken oral contraceptives and antibiotics concur- First choice of antibiotic rently, compared with control patients [74]. This study showed no statistically significant difference between the 1. Based on advantages in efficacy, safety, and antibiotic two groups. A recent large review concluded that available resistance, cyclines should be used in preference to other scientific and pharmacokinetic evidence does not support classes of antibiotics in the treatment of acne. the hypothesis that antibiotics (with the exception of rifam- 2. Based on pharmacokinetic advantages, second genera- picin) lower the contraceptive efficacy of oral contracepti- tion cyclines should be used in preference to first generation ves [75]. In addition, the American College of Obstetrics cyclines. and Gynaecologists states that “tetracycline, doxycycline, 3. Based on side effect profiles1; lymecycline and doxycy- ampicillin and metronidazole do not affect oral contracep- cline should be used in preference to minocycline. The tive steroid levels” [76]. The weight of this evidence sug- choice of agent will depend on the patient characteristics, gests that oral cyclines do not interfere with oral contracep- season, UV exposure and country. tives and that alternative forms of contraception are not necessary whilst using these agents. Cycline doses Prescribing cyclines for patients with hyperseborrhoea 1. Lymecycline should be used at a dose of 300-600 mg In a study of 255 acne patients treated for 6 months, Layton daily. 2. Minocycline and doxycycline should be used at a dose et al. (1992) [77] found a correlation between sebum excre- 2 tion rate and degree of improvement in acne during treat- of 100-200 mg daily . ment with erythromycin, minocycline and oxytetracycline, 3. Tetracycline HCl and oxytetracycline should be used at with higher sebum rates being associated with a a dose of 1 g daily. poorer clinical response to treatment (r = – 0.529). The authors suggest that this could be due to a reduced concen- Duration of treatment tration of drug within the follicles as a result of drug 1. According to the available literature, oral antibiotics dilution with sebum. Layton et al. (1992) [77] suggest that –2 –1 should be used for 3 months. In clinical practice, they may when sebum excretion rates are > 2.5 µg.cm .min , hi- be continued longer until clinical improvement is achieved. gher doses of cyclines may be required (e.g. 600 mg ly- 2. If oral antibiotics are used for prolonged periods3, they mecycline daily, or up to 200 mg minocycline or doxycy- should only be continued where further clinical benefit is cline daily). When using higher doses, patients and likely, and should always be used in combination with an physicians should be conscious of the increased risk of side agent that reduces the likelihood of propionibacterial resis- effects (particularly with minocycline). tance emerging (e.g. benzoyl peroxide). 3. Compliance should be checked in patients who do not Conclusions respond well to therapy. Oral antibiotics are a mainstay of treatment for moderate to severe inflammatory acne (including acne on the trunk) Combination therapy and, while a number of questions remain unanswered (e.g. regarding the optimal dose of antibiotic, the optimal dura- 1. Oral antibiotics should not be used alone (as this will tion of treatment and the length of maintenance therapy), target only two pathophysiologic factors of acne). there is clearly an unmet need for practical, user-friendly 2. Oral antibiotics should be combined from the start of treatment guidelines for these drugs based on our current treatment with a topical retinoid (this will target three knowledge. The recommendations set out below provide pathophysiologic factors of acne, as well as the microcome- guidance on some of the key questions regarding oral done [the precursor of all acne lesions]). antibiotic therapy in acne (choice of oral antibiotic, doses, 3. Benzoyl peroxide can be used in combination with topi- and duration of therapy), as well as combination therapy cal retinoids and oral antibiotics, and should always be and maintenance therapy. By providing clear guidance that considered for patients receiving oral antibiotics for more can be used in daily practice, these recommendations than 3 months. should improve the care of acne patients. 4. Oral antibiotics should not normally be combined with topical antibiotics (this may increase the risk of P. acnes resistance and provides no additive benefit). II. Recommendations for the use of oral antibiotics 1 Lymecycline: rare side effects; doxycycline: rare side effects, but dose- dependent phototoxicity; Minocycline: rare but severe side effects. Due to wide differences between published acne studies 2 200 mg should be reserved for special cases such as hyperseborrhoea, with respect to disease definitions, end-points, doses used, and patients and physicians should be aware of potential side effects at this duration of treatments etc., as well as the many unanswered dose. questions that require further investigation, it is not cur- 3 Studies have shown most improvement occurs within the first 4 months rently possible to derive definitive treatment guidelines of treatment.

EJD, vol. 14, n° 6, November-December 2004 397 Maintenance therapy 19. Eady EA, Cove JH. Is acne an infection of blocked piloseba- ceous follicles ? Implications for antimicrobial treatment. Am J Clin 1. Maintenance therapy should be considered in order to Dermatol 2000; 1: 201-9. limit relapse. Optimal duration and dosing remains unde- 20. Jeremy AH, Holland DB, Roberts SG, Thomson KF, Cunliffe WJ. termined. Inflammatory events are involved in acne lesion initiation. J Invest Dermatol 2003; 121: 20-7. 2. Topical retinoids are the treatment of choice for mainte- 21. Leyden JJ. Current issues in antimicrobial therapy for the treat- nance therapy. ment of acne. J Eur Acad Dermatol Venereol 2001; 15 Suppl 3: 3. Maintenance therapy should be continued for as long as 51-5. individually needed (this recommendation is not currently 22. Meynadier J, Alirezai M. Systemic antibiotics for acne. Derma- tology 1998; 196: 135-9. evidence-based). 23. Plewig G, Kligman AM. Acne and rosacea.3rd ed. New York: 4. Benzoyl peroxide can be added to topical retinoids if Springer-Verlag. 2000. necessary (to decrease the number of antibiotic-resistant P. 24. Technote report 2001. www.ahrg.gov/clinic/evrptfiles.htm#acne. acnes). j 25. Ross JI, Snelling AM, Carnegie E, Coates P, Cunliffe WJ, Bettoli V, et al. Antibiotic-resistant acne: lessons from Europe. Br J Dermatol 2003; 148: 467-78. Acknowledgements. These recommendations were deve- 26. Eady EA, Cove JH, Holland KT, Cunliffe WJ. Erythromycin loped at workshops supported financially by Galderma resistant propionibacteria in antibiotic treated acne patients: asso- International. The authors have no financial interest in ciation with therapeutic failure. Br J Dermatol 1989; 121: 51-7. 27. Ray AJ, Donskey CJ. Clostridium difficile infection and concur- any of the products related to this work. rent vancomycin-resistant Enterococcus: colonization in a health care worker: case report and review of the literature. Am J Infect Control 2003; 31: 54-56. 28. Carrasco DA, Vander Straten M, Tyring SK. A review of antibio- tics in dermatology. J Cut Med Surg 2002; 6: 128-50. 29. Cunliffe WJ, Aldana OL, Goulden V. Oral trimethoprim: a relatively safe and successful third-line treatment for acne vulgaris. Br J Dermatol 1999; 141: 757-8. 30. Kawada A, Aragane Y, Tezuka T. Levofloxacin is effective for References inflammatory acne and achieves high levels in the lesions: an open study. Dermatology 2002; 204: 301-2. 31. Drlica K, Malik M. Fluoroquinolones: action and resistance. Curr Top Med Chem 2003; 3: 249-82. 1. Ad Hoc Committee report: systemic antibiotics for treatment of 32. Stahlmann R. Clinical toxicological aspects of fluoroquinolones. acne vulgaris: efficacy and safety. Arch Dermatol 1975; 111: Toxicol Lett 2002; 127: 269-77. 1630-6. 33. Leyden JJ, McGinley KJ, Mills OH, Kligman AM. Propionibacte- 2. Drake LA. Guidelines for care of acne vulgaris. 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398 EJD, vol. 14, n° 6, November-December 2004 47. Sainte-Marie I, Tenaud I, Jumbou O, Dreno B. Minocycline 60. Bernier C, Dréno B. Minocycline. Ann Dermatol Venereol 2001; modulation of alpha-MSH production by keratinocytes in vitro. Acta 128: 627-37. Derm Venereol 1999; 79: 265-7. 61. Eichenfield AH. Minocycline and autoimmunity. Curr Opin Pe- 48. Crawford WW, Crawford IP, Stoughton RB, Cornell RC. Labo- diatr 1999; 11: 447-56. ratory induction and clinical occurence of combined clindamycin and erythromycin resistance in corynebacterium acnes. J Invest 62. Sturkenboom MC, Meier CR, Jick H, Stricker BH. Minocycline Dermatol 1979; 72: 187-190. and lupus-like syndrome in acne patients. Arch Intern Med 1999; 49. Eady EA, Bojar RA, Jones CE. The effects of acne treatment with 159: 493-7. combination of benzoyl peroxide and erythromycin on skin carriage 63. Schlienger RG, Bircher AJ, Meier CR. Minocycline-induced of erythromycin resistant propionibacteria. Br J Dermatol 1996; lupus. 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Appendix 1. Attendees at meetings of the European expert panel on the use of oral antibiotics in the management of acne Elena Aravijskaya, Russia; Nicole Auffret, France; Rui Bello, Portugal; Vincenzo Bettoli, Italy; Olivier Chosidow, France; Brigitte Dréno, France; Daniele Innocenzi, Italy; Francois Jordaan, South Africa; Martin Kaegi, Switzerland; Jean Marie Lachapelle, Belgium; Hakima Lakhdar, Morocco; Julien Lambert, Belgium; Andrzej Langner, Poland; Alison Layton, UK; Håkan Mobacken, Sweden; Falk Ochsendorf, Germany; Pier Paulo Pedrazetti, Switzerland; Marie Manuela Pronesti, Italy; Franco Rogioletti, Italy; Werner Sinclair, South Africa; Alexandre Jose de Souza Sittart, Brazil; Dente Valentina, Italy; Sarah Wakelin, UK.

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