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Systemic Antibiotic Therapy for Acne: A Review
R. Kunynetz, MD, FRCPC
A limited number of antimicrobial agents have proven to be effective in acne therapy, both topically and systemically. Antimicrobials not only affect colonization of the follicle by Propionibacterium acnes, (as seen by reduced Wood’s lamp fluorescence of porphyrins in P. acnes), but also affect the inflammatory mediators in the follicle and dermis by decreasing neutrophil chemotaxis, and by modifying both complement pathways. Through inhibition of lipase production via protein synthesis inhibition, antimicrobials also result in a reduction of skin surface sebum fatty acid composition.1
The tetracycline family of antibiotics is broad spectrum with activity against many gram-positive and gramnegative bacteria, as well as mycoplasma, Chlamydia, Rickettsiae, Spirochetes and some parasites. Activity is becoming more limited by the emergence of resistant strains of gram-negatives, group A Streptococcus, and P. acnes.2 They inhibit protein-synthesis by binding to the 30S ribosomal subunit.
Absorption on an empty stomach is mandatory except with minocycline or doxycycline, which do not vary in the presence or absence of food. Absorption is decreased by concurrent ingestion of dairy products, aluminum hydroxide gels, calcium, magnesium, iron or zinc salts, and bismuth subsalicylate.2
Anticonvulsants (barbiturates, phenytoin, and carbemazepine) reduce the half-life and serum concentration of doxycycline, but not tetracycline. The latter can increase lithium levels. Tetracyclines potentiate oral anticoagulants by decreasing vitamin K bacterial production or impairing prothrombin effects. Though earlier reports suggested a possible decreased oral contraceptive effect due to tetracycline, a recent study concluded that concomitant use of oral antibiotics and oral contraceptives is not associated with a substantially increased risk of pregnancy.2-4
Potential Adverse Effects
The most common adverse reactions are gastrointestinal in origin such as epigastric burning, nausea, vomiting and bloating. Taking the drug with food can reduce such reactions, though absorption may be decreased (except with minocycline or doxycycline). Esophagitis and esophageal ulcers have been reported when ingestion took place just before bedtime with little or no water, and may be associated with hiccups or even mediastinitis.1,5 Liver inflammation is rare, however minocycline has been reported to be associated with fulminant hepatic failure necessitating liver transplantation.5,6
Tetracycline-resistant P. acnes has been shown to be resistant to doxycycline, but not to minocycline at 100 mg/day.1
Erythromycin is a prototype of the macrolide family of antibiotics, which include the newer azithromycin (Zithromax®), clarithromycin (Biaxin®), dirithromycin (Dynabac®), and roxithromycin (Rulid®). Of the four, only azithromycin has been significantly studied in acne therapy.9,10 Their mechanism of action is the same for all: bacterial cell wall penetration with reversible binding to the 50S ribosomal unit with RNA-dependent protein synthesis inhibition.2
The activity of azithromycin against gram-positive organisms such as staphylococci and streptococci is onehalf to a quarter of that of erythromycin. Erythromycinresistant strains of staphylococcus and streptococcus show cross-resistance to the new agents. Anaerobic activity is similar to erythromycin, but gram-negative activity is greater. Azithromycin has activity against pathogens found in human and animal bites, atypical mycobacteria, and Borrelia burdorferi.2 Its minimum inhibitory concentration against P. acnes is similar to other macrolides.10
The newer macrolides’ main advantage is consistent oral bioavailability:
Erythromycin through drug-drug interaction inhibits the cytochrome P-450 enzyme system, thus decreasing the metabolic clearance of carbamazepine, theophylline, phenytoin, digoxin, warfarin, terfenadine and methylprednisolone. Clarithromycin, unlike azithromycin, can also inhibit this enzyme system.2
Azithromycin and clarithromycin are well tolerated and cause gastrointestinal upset in about 3% of patients, appreciably less than erythromycin at 20-35%.9 Erythromycin-induced hepatotoxicity is seen more with the estolate form due to cholestasis. Rarely have reports of pancreatitis, exacerbation of myasthenia gravis, and pruritic eruptions from erythromycin been cited. Ototoxicity seems to be associated with higher than normal doses than that used for acne, presenting with highfrequency sensorineural hearing loss and vertigo.1 Clarithromycin and azithromycin have similar adverse effects such as headache (1-2%), elevated liver enzymes (<1%), and changes in white blood cell count (1%).9
Clindamycin, a derivative of lincomycin, binds to the 50S portion of the ribosome and inhibits protein synthesis.
Clindamycin is active against most anaerobes, grampositive cocci and some protozoa. Enterococci are generally resistant. Most aerobic gram-negative organisms are resistant. Its anaerobic activity includes P. acne.2
Clindamycin is well absorbed from the gastrointestinal tract and distributed in good concentrations to most tissues except cerebral spinal fluid and bile.2 It is metabolized in the liver with dosage adjustments needed for hepatic insufficiency.
*set cost to patient ranging from generic to brand name sources in Canadian dollars. Does not include dispensing fee, which varies greatly.
Neuromuscular blockers such as tubocurarine may have enhanced effects.2
Clostridium difficile toxin-mediated colitis has been reported in incidences from 0.1-10%.2 This is similar to the rate seen with ampicillin or cephalosporins.2 Gastrointestinal effects include nausea, vomiting, anorexia, and elevated hepatic enzymes. The most frequent side effect is a generalized morbilliform rash, though others reported include urticaria, maculo-papular rash, pruritus, fever, hypotension, polyarthritis, anaphylaxis and erythema multiforme/Stevens- Johnson syndrome.2
This drug combination selectively attacks bacterial nucleic acid synthesis of tetrahydrofolic acid, which is essential for endogenous protein metabolism in bacteria.2
TMP-SMX is active against many gram-positive aerobic cocci (e.g., S. aureus, S. pyogenes, and S. viridans) but S. pneumonia is increasingly resistant to the drug.2 P. aeruginosa is invariably resistant, but other Pseudomonas species are often sensitive. Anaerobes are usually not susceptible to it.
Both trimethoprim and sulfamethoxazole are well absorbed in oral form and have half-lives of 11 and 9 hours, respectively. They are excreted renally and are found widely in body fluids and tissues.2
TMP-SMX inhibits warfarin metabolism, prolonging prothrombin time. Interference in folic acid metabolism of patients on methotrexate dictates caution in their concomitant use.
The more common side effects are minor gastrointestinal upset and hypersensitivity reactions. Stevens-Johnson syndrome and toxic epidermal necrolysis are the most serious, though less ominous pustular eruptions, Sweet’s syndrome, and maculopapular eruptions in patients with AIDS have been reported.2 Reported hematologic changes include aplastic anemia, neutropenia, agranulocytosis, and thrombocytopenia. Headache, fatigue and tremor reflect possible nervous system effects. Potential renal changes include crystalluria, nephrolithiasis and interstitial nephritis. Cholestatic hepatitis is rare.
Antibiotic Resistance In Acne Therapy
Bacterial resistance to antibiotic therapy has quickly evolved to encompass not only therapy of true infections, but also propionibacteria, pathogenic in acne. Propionibacteria have been found to be resistant to one or more antibiotics in the UK, France, Germany, Japan, New Zealand and the US.3 Prevalence studies from the Dermatology Out-patients’ Clinic at Leeds sampled 2,853 patients between 1991 and 1996, and showed a steady increase of antibiotic-resistant propionibacteria from 34.5% in 1991, to 60% in 1996. Erythromycin resistance was the most common and resistance to minocycline was uncommon. Triple-resistance to tetracycline, erythromycin and clindamycin was seen in 16%. Not only is this a concern for the patient, but as well, antibiotic acne therapy promotes resistant coagulase-negative staphylococcus and propionibacteria on the skin of close contacts to treated patients.3 A profile of acne patients likely to carry such propionibacteria is shown in Table 2:
The fact that carriage of erythromycin-resistant propionibacteria is associated with therapeutic failure of oral erythromycin therapy has been well established. In topical therapy, the addition of either zinc or benzoyl peroxide to erythromycin renders good therapeutic results in patients with erythromycin-resistant P. acnes and decreases the number of such organisms on the skin.3
A majority of follicles in non-responding patients have subtherapeutic antibiotic levels.12 This variation is determined by sebum excretion rates, the degree of hyperkeratinization and ductal volumes. Since other therapies such as benzoyl peroxide and azelaic acid do not promote resistance, yet are effective against resistant and sensitive propionibacteria, alteration of the follicular microenvironment is hypothesized to be responsible for the reduction in resistant P. acnes colonization.3 This would explain the decrease in resistant P. acnes in 20 patients treated with isotretinoin by Leyden.11
The induction of resistant strains is more likely with longer treatment durations and sequential or concomitant use of structurally unrelated antimicrobials, which select for multiple-drug resistant flora. The onset of the resistant strains occurs between 12 and 24 weeks of therapy.3 Emergence of such strains may be related to poor patient compliance allowing for skin and serum drug levels to drop below the MIC of the drug for the given isolates.
There are multiple reasons for antibiotic poor response:3
P. acnes resistance to erythromycin has been associated with three specific point mutations in 23S mRNA, which are associated with three phenotypic types of resistant propionibacteria differing in the degree of resistance and cross-resistance to other macrolides and clindamycin.3 The mutations appear to be stable and the resistant strains may persist on the skin for long periods despite discontinuation of the drug.
Given the high rate of P. acnes resistance induction, oral erythromycin should be reserved for acne during pregnancy or young children. Erythromycin should not be first line acne therapy.
An acne therapy consensus panel published their “checklist” for minimizing the selection and spread of resistant strains of P. acnes in acne therapy.3 These are:
Despite being the most longstanding systemtic therapy for acne, when compared to retinoids and hormonal therapy, antimicrobials will continue to be an effective treatment only if they are used selectively and responsibly. This would involve more in-depth controlled studies into dosage, duration and the role of concomitant therapies. Otherwise, we are in danger of losing this effective and economical treatment in the control of this potentially permanently scarring disease.
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Last modified: Thursday, 21-Jun-2012 16:51:18 MDT