Antimicrobial Therapy in Acne

15 May

INTRODUCTION

Antibiotic therapy in  acne  is a time-honored practice whose mechanism is only recently thoroughly understood. Initially,  it was assumed that the reduction in Pro- pionibacterium acnes was  the sole mechanism of antibiotic efficacy in acne, but  it is now  understood that  certain  antibiotic drugs are  also  potent anti-inflammatory agents via nonantibiotic mechanisms. In addition, the  induction of resistance has made antibiotic therapy problematic in many  patients.

BENZOYL PEROXIDE

Benzoyl  peroxide (BP) is a topical  disinfectant that  was  originally used  as a peeling agent  for  acne.  Its  mechanism of action  is  through lowering P.  acnes populations by  oxidative killing,  and  the  drug is extremely effective  as  a topical  agent.  When applied to the skin,  BP breaks  down into  benzoic  acid  and  hydrogen peroxide (1,2). It assumed that  the  peroxide accounts for  the  majority of bactericidal activity,  but no studies have been performed to assess the activity  of benzoic  acid in acne.

The major side effect of BP is irritation, which  usually is easily managed with moisturizers. However, BP has been reported as a contact  sensitizer in as many  as

4% of patients and can reach nearly  75% when  applied to leg ulcers (3), but in clini- cal acne practice actual  contact  allergy  is rarely  noted.  As a heavy  prescriber of the drug, I see, at most,  a case every  few years.

Various  concentrations of BP are available, but there  is no convincing data  to prove that high concentrations are more effective than lower ones. P. acnes reduction is as effective by 2.5% as 10% BP (4), and  one small study shows  therapeutic equiv- alence  between 2.5%, 5%, and  10% BP gels and  a lower  rate of irritation with  2.5% than the higher concentrations (5). BP washes are useful  in particular for trunk acne since  they  can  cover  a large  area  easily,  but  in  the  past  have  been  of fairly  low potency. Newer formulations have  been  designed to  have  greater substantivity and  are capable of P. acnes reductions near  that  of traditional gels and  creams.  As a  single  agent,  BP is  superior to  clindamycin (6). Combination products of BP plus  erythromycin or  clindamycin have  been  developed and  are  more  effective clinically  than  either  product alone  (6,7).

MACROLIDES

Topical and  oral erythromycin and  topical  clindamycin have been well-established acne treatments for  decades, but  have  become   much   less  effective  in  the  past

15 years  or so due  to the acquisition of resistance by P. acnes. Resistant bacteria are now induced quickly  by macrolide therapy because  most patients have a portion of

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their  normal skin  flora  that  is genetically resistant, and  that  subgroup expands under the  selective  pressure of therapy (8 – 11). Resistant bacteria make  for acne that resists therapy and erythromycin resistant strains are typically resistant to clin- damycin and  vice versa.

Resistance can be combated by the addition of BP to topical  macrolide regi- mens.  It  has  been  clearly  shown that  such  combination products are  not  only more  effective  than  monotherapy with  macrolides, but also do not permit the sur- vival  of resistant populations of P. acnes (6).

Other  macrolides for  example, azithromycin have  been  reported in  small studies to be of value  in acne (12), but no data  is available on the effect of resistance on the utility  of these  drugs.

TETRACYCLINES

The  tetracycline family  of antibiotics are  extremely useful  in  acne  because they have  multiple modes of  action,  functioning as  antibiotics that  reduce bacterial populations, and  as anti-inflammatory drugs that  attack  acne from a second front.

Tetracyclines, especially doxycycline and minocycline are highly  anti- inflammatory in many  cell systems (Table 1). Neutrophil and monocyte chemotaxis is inhibited through calcium  chelation, blunting the migration of cells to the follicle (13). Granuloma formation in vitro  (14) and  in vivo  (15) is inhibited; with  mino- cycline  and   doxycycline roughly  10-fold  more   active  than   tetracycline. In  this model, macrolides and cephalosporines were inactive. Protein kinase C is inhibited (15), perhaps interfering with  signal  transduction. Generation of reactive  oxygen species  and  the oxidative burst  in neutrophils is decreased (16). Nitric  oxide  pro- duction is modulated (17). Matrix metalloprotease and collagenase activity is inhib- ited  (18 – 20). In vivo, tetracyclines have  been  demonstrated to be highly  active  in treating purely inflammatory diseases including rheumatoid arthritis, bullous pem- phigoid, and  sarcoidosis (21). Nonantibiotic derivatives of doxycycline have  been recently developed  that   are  highly   anti-inflammatory  and   even  antineoplastic through inhibition of angiogenesis and  may be of use in acne and  other  inflamma- tory diseases (22 – 24).

Concentrations  of  tetracyclines  that   are   below   the   antibiotic threshold still  have  anti-inflammatory activity.  Low  doses  of doxycycline and  minocycine that  do  not  affect bacterial growth decrease the  production of neutrophil chemo- attractants by P. acnes (25,26). Subminimal inhibitory doses  also  retain  the  ability to inhibit  inflammation in vivo  and  improve diseases such  as acne,  rosacea,  and periodontitis (27 – 29).

Antibiotic  resistance  is  less   a  problem  with   the   tetracyclines  than   the macrolides, but resistance in P. acnes has been documented. In general, tetracycline resistant strains are cross-resistant to doxycycline but sensitive to minocycline (30).

Choice  of oral antibiotic by dermatologists for treating acne has shifted over the past few decades. Currently, the once frequently prescribed tetracycline is used relatively infrequently, with  the  majority of patients treated with  doxycycline or minocycline. Tetracycline has  multiple disadvantages, including greatest effect of diet  on absorption, lower  anti-inflammatory and  antibacterial activity,  and  lower effect  on  acne  lesions  (30 – 32). There  are  few  studies that  address the  relative potency of these  two  drugs in treating acne,  and  the  few that  do  are fairly  small and  do not involve  the more severe patients and  manage to show  only equivalence (33). However, there is good reason to believe that minocycline is the stronger drug. In my experience, there  have  been many  patients with  significant acne who  fail to respond to doxycycline yet have  an excellent  response when switched to minocy- cline.  The reason for this  may  lie in the  greater lipophilicity of minocycline and the greater activity  in a lipid  milieu.  This is reflected in a 10-fold greater reduction of P. acnes by minocycline when  compared with  doxycycline (32).

The side effect profile (Table 2) of doxycycline and minocycline also differs, most notably in the incidence of photosensitivity with  doxycycline and  the occurrence of hypersensitivity  reactions with  minocycline. Photosensitivity  is  very  common at higher doses  of doxycycline. The minocycline hypersensitivity reactions are uncom- mon and  include urticaria, serum sickness-like reactions, and what  has been termed a lupus-like reaction that  in reality  is probably not an activation of systemic lupus erythematosus but a generalized drug-induced reaction that resembles lupus (34).

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