Antibiotic Treatment for Acne Vulgaris

Antibiotic Treatment for Acne Vulgaris
Guy F. Webster, MD, PhD, FAAD,* and Emmy M. Graber, MD†
Although topical therapies alone can be very effective for milder acne, there are often cases for
which oral antibiotics are needed to control disease. Through both antibacterial and antiinflammatory effects, oral antibiotics in combination with other drugs such as retinoids and benzoyl
peroxide can be highly effective in the treatment of more severe disease. Patients and their
parents often have many questions regarding the safety and efficacy of long-term antibiotic use.
It is important for the physician to have a thorough understanding of the antibiotics at their
disposal as well as their side effects. Through careful discussion, antibiotic compliance can be
optimized and side effects minimized ultimately resulting in treatment success.
Semin Cutan Med Surg 27:183-187 © 2008 Elsevier Inc. All rights reserved.
A
ntibiotic therapy is a time-honored practice in acne
treatment. Although acne is not an infection, the normal
resident, Propionibacterium acnes, is the stimulus for inflammation in acne, and a reduction in P. acnes populations is
usually accompanied by clinical improvement.1 Many patients’ acne is effectively treated with the use of long-term
antibiotic regimens, and the practice is generally considered
to be safe and effective.
P. acnes contributes to the development of acne in several
ways. In 1963, P. acnes was first proposed to have a pathogenic role in acne when the bacteria was injected into the
sterile cysts of steatocystoma subsequently inducing inflammation.2 More than 40 years later, in 2004, the complete
genome of P. acnes was sequenced, thereby yielding a better
understanding of the many mechanisms in which P. acnes can
propagate acne. This Gram-positive, anaerobic and microaerobic bacteria is part of normal skin flora from birth to
death. Greater numbers of P. acnes are associated with greater
sebum production but are not correlated with acne severity.
Included in the many ways in which P.acnes can cause acne
are: (1) the upregulation of heat shock proteins, (2) binding
to toll-like receptors, (3) production of enzymes such as
lipases and sialidoses, and (4) production of porphyrins.3
Physicians often turn to antibiotic therapy for several types
of acne patients. Candidates for oral antibiotic therapy include (1) patients with moderate-to-severe inflammatory
acne, (2) patients who have failed a substantial trial of topical
therapies, and (3) patients whose acne covers a large surface
area, thus making topical therapy impractical.
*Hockessin, DE.
†SkinCare Physicians, Chestnut Hill, MA.
Reprint requests and correspondence: Guy F. Webster, MD, PhD, FAAD,
720 Yorklyn Road, Suite 10, Hockessin, DE 19707-8730. E-mail:
gfweb@earthlink.net
1085-5629/08/$-see front matter © 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.sder.2008.07.001
The mechanism by which antibiotics work in acne varies
with the drug. Some medications may have either antiinflammatory or antibacterial properties, whereas other medications possess both properties. Benzoyl peroxide and the macrolides clindamycin and erythromycin, which have minimal
antiinflammatory activity, work mainly by reducing P. acnes
levels, whereas the tetracycline family of antibiotics has both
potent antiinflammatory and antibacterial properties.
Antibiotics
Macrolides
Erythromycin, clindamycin, and azithromycin are 3 members of the macrolide family that are used for treating acne.
All exert their antibacterial effect by irreversibly binding to
the bacterial 50S ribosomal subunit, thus inhibiting translocation during protein synthesis. Oral erythromycin is administered at 500 mg twice daily. It should be taken with food
because it commonly causes gastrointestinal distress. Although erythromycin is safe in pregnancy and in lactating
women, erythromycin estolate should be avoided in these
patients because it my cause cholestatic jaundice. As an inhibitor of the cytochrome P450 system, erythromycin may
cause reduced clearance of theophylline, warfarin, carbamazepine, and cyclosporine.4
Although topical clindamycin is often used in the treatment of acne, the use of oral clindamycin is much more
limited due to its side effect profile. A total of 20% to 30% of
patients taking oral clindamycin will experience diarrhea.
Oral clindamycin may also promote the overgrowth of Clostridium difficile in the gastrointestinal tract in turn causing
pseudomembranous colitis.4,5
Scant studies have documented the efficacy of oral azithromycin as an acne therapy. One study demonstrated that
183
184
azithromycin given 500 mg daily for 4 consecutive days per
month for 3 months was as effective as doxycycline 100 mg
daily.6
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 as
a result of the acquisition of resistance by P. acnes. When first
introduced, topical macrolides were adequate monotherapy
in many patients, but currently it is rare for a patient with
significant disease to be well controlled on a topical macrolide alone. Resistant bacteria are now induced quickly by
macrolide therapy because most patients have a portion of
their normal skin flora that is genetically resistant, and that
subgroup expands under the selective pressure of therapy.7-10
Resistance can be combated by the addition of benzoyl peroxide to topical macrolide regimens. It has been clearly
shown that such combination products are not only more
effective than monotherapy with macrolides but also do not
permit the survival of resistant populations of P. acnes.11 Although resistance has been reported with the more commonly used macrolides, erythromycin and clindamycin, no
data are available on the effect of resistance on the azithromycin’s efficacy.
Tetracyclines
The tetracycline family of antibiotics is extremely useful in
acne because they have multiple modes of action, functioning
as antibiotics that reduce bacterial populations and as antiinflammatory drugs that attack acne from a second front. In the
United States, the available tetracyclines include tetracycline,
doxycycline, and minocycline. These drugs exert their antibacterial properties by blocking the 30S ribosomal subunit
and in turn inhibiting translation during protein synthesis.
The tetracyclines also have many antiinflammatory effects.
Neutrophil and monocyte chemotaxis is inhibited through
calcium chelation, blunting the migration of cells to the follicle.12 Granuloma formation in vitro13 is inhibited, with minocycline and doxycycline roughly 10-fold more active than
tetracycline. In this model, macrolides and cephalosporins
were inactive. Protein kinase C is also inhibited in the same
order of potency,13 suggesting that interference with signal
transduction is involved in the antigranuloma effect. The
generation of reactive oxygen species and the oxidative burst
in neutrophils is decreased by the tetracyclines. Nitric oxide
production is modulated,14 and matrix metalloprotease and
collagenase activity is inhibited.15-17 The antiinflammatory
potency of tetracyclines has been demonstrated in treating
purely inflammatory diseases including rheumatoid arthritis,
bullous pemphigoid, and sarcoidosis.18 Nonantibiotic derivatives of doxycycline have been recently developed that are
highly antiinflammatory and even antineoplastic through inhibition of angiogenesis and may be of use in acne and other
inflammatory diseases. A general problem with the tetracyclines is the potential for photosensitivity which, unfortunately, is enhanced in the nonantibiotic derivatives.19-21
Concentrations of tetracyclines that are below the antibiotic threshold still have antiinflammatory activity. Low doses
G.F. Webster and E.M. Graber
of doxycycline and minocycline that do not affect bacterial
growth decrease the production of neutrophil chemoattractants by P. acnes.22,23 Subminimal inhibitory doses also retain
the ability to inhibit inflammation in vivo and improve diseases
such as acne, rosacea and periodontitis.24-26 Subantimicrobial
doses of doxycycline may have as much antiinflammatory
activity as greater doses of the drug. A recent weight-based
study failed to demonstrate changed activity of the drug in
extremely heavy versus. low weight patients27 a roughly
4-fold difference in dosage, from which we may infer that
subantimicrobial dosages are on the “flat part” of the dose
response curve and higher doses would not be more effective
in antiinflammatory activity.
Although the tetracyclines can function in many ways to be
beneficial, the physician should be well versed in the potential side effects of these drugs. Tetracycline, often dosed at
500 mg twice daily for acne, must be taken on an empty
stomach (1 hour before eating or 2 hours after eating). Ingestion with food and especially dairy products can block the
absorption of tetracycline in the gut. Tetracycline can frequently cause gastrointestinal upset and may very rarely
cause esophagitis and pancreatitis. Caution should be advised when going out in the sun as tetracycline may cause sun
sensitivity or even induce pseudoporphyria. Rarely, a painful
photo-onycholysis may also be caused by tetracycline.28
Doxycycline, a second-generation member of the tetracycline
family, is often dosed at 100 mg twice daily to give optimal
antibacterial effects. Unlike tetracycline, doxycycline may be
taken with food. However, doxycycline has more potential to
induce a phototoxic reaction than tetracycline and extreme
care should be used when prescribing doxycycline in the
summer months.29
Another second-generation tetracycline, minocycline, is
also commonly dosed at 100 mg twice daily for acne, although 1 mg/kg has been shown to be an effective dosage for
the average acne patient and one with fewer side effects. Like
doxycycline, minocycline can be taken with food. Unlike the
other tetracyclines, the minocycline chemical structure has a
large side chain that increases its side effect profile. Because of
the high lipophilicity of minocycline, it can cross the blood–
brain barrier and may induce vestibular disturbances, such as
dizziness, vertigo, and ataxia.25 A blue– gray discoloration of
the skin may be seen with long-term minocycline use. This
hyperpigmentation may be distributed in scars, on sun-exposed skin, or diffusely. Hyperpigmentation seems to be dose
and duration related. Although no studies exist to document
this observation, it is our practice to limit the duration and
dose of minocycline as much as is possible. Rarely, minocycline may induce a serum sickness-like reaction characterized by arthralgias, urticaria, fever, and lymphadenopathy.
When this occurs, it typically starts just days to weeks after
beginning minocycline. Other less common side effects of
minocycline include drug induced lupus-like disease, vasculitis and hepatic failure.30
All of the tetracyclines should be used with caution in
patients with renal disease because they may increase uremia.31 Tetracyclines have an affinity for rapidly mineralizing
tissues and are deposited in developing teeth, where they
Antibiotic treatment for acne vulgaris
may cause irreversible yellow– brown staining. In addition,
the tetracyclines have been reported to inhibit skeletal
growth in the fetus. Therefore, they should not be administered to pregnant women, especially after the fourth month of
gestation and are not recommend for use in children younger
than 9 years of age in the treatment of acne. There are rare
reports of the tetracyclines causing hepatotoxicity, hypersensitivity reactions, leukocytosis, thrombocytopenic purpura
and pseudotumor cerebri.
Antibiotic resistance is less a problem with the tetracyclines than the macrolides, but resistance in P. acnes has been
documented. Antibiotic resistance has become increasingly
common in the last 30 years. In 1976, a study of 1000 patients with acne failed to find any resistant P. acnes. Two years
later, Crawford and coworkers found 20% of European acne
patients to be resistant to topical erythromycin (with also
cross-resistance to clindamycin). In 1983, Leyden and coworkers demonstrated that American acne patients who
showed no clinical improvement to antibiotics had P. acnes in
greater numbers and resistance to tetracycline or erythromycin. In 1995, Cooper showed increasing P. acnes resistance:
72.5% of patients were resistant to the macrolides erythromycin and clindamycin, 35.6% were resistant to tetracycline
and doxycycline, 17.5% were resistant to trimethoprim/sulfamethoxazole, and 15.7% had mixed resistance.32 Resistance to minocycline is still exceedingly rare, and resistance
to benzoyl peroxide is nonexistent. In general, tetracycline
resistant strains are cross resistant to doxycycline but sensitive to minocycline.33
Currently, the once frequently prescribed tetracycline is
used relatively infrequently by dermatologists, with the majority of patients treated with doxycycline or minocycline.
Tetracycline has multiple disadvantages, including greatest
effect of diet on absorption, lower antiinflammatory and antibacterial activity, and lower effect on acne lesions.34-36
There are few studies that address the relative potency of
minocycline versus doxycycline 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,36 perhaps
because the patients tested were not severe enough to tease
out the real differences between the medications. There is
good reason to believe that minocycline is the stronger drug.
In our experience, there have been many patients with significant acne that fail to respond to doxycycline who have an
excellent response when switched to minocycline. The reason for this may lie in the greater lipophilicity of minocycline
and the greater activity in a lipid milieu, which is reflected in
a 10-fold greater reduction of P. acnes by minocycline when
compared with doxycycline.36
Other Antibiotics
Ciprofloxacin and trimethoprim-sulfamethoxazole are both
sometimes useful in acne. No large, detailed studies exist to
document efficacy, but there are sufficient anecdotes to believe that they are effective in acne.37,38 Ciprofloxacin imparts
it antibacterial effect by inhibiting topoisomerase enzymes,
which are responsible for bacterial DNA replication, transcrip-
185
tion, and repair. Trimethoprim–sulfamethoxazole works by
blocking dihydrofolatereductase/dihydropteroatesynthetase,
thus impeding bacterial DNA purine and pyrimidine synthesis. Potential side effects include anemia, thrombocytopenia,
and agranulocytosis. Because trimethoprim–sulfamethoxazole has a sulfa moiety, a hypersensitivity reaction may occur. Whether either of these important antiinfectives should
receive wide usage in acne is a matter of some debate, but few
would dispute that they should be reserved for patients who
cannot be treated with conventional regimens.39
Benzoyl Peroxide
Although not often classified as an antibiotic, benzoyl peroxide (BP) can aid in the elimination of P. acnes. 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.40 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. It is possible that the
antioxidant activity of benzoic acid would be of some benefit
in the disease, but studies are lacking. There are reports of
contact sensitization to benzoyl peroxide,41 but the issue
rarely arises in acne therapy.
Several strengths 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,42 and one small study found therapeutic
equivalence between 2.5%, 5%, and 10% BP gels and a lower
rate of irritation with 2.5% than the higher concentrations.43
As a single agent, BP is superior to topical clindamycin.44
Combination products of BP plus erythromycin or clindamycin have been developed and are more effective clinically than
either product alone.44,45 The concomitant use of benzoyl peroxide with antibiotics will lessen P. acnes resistance to antibiotics
and increase the bactericidal effect of the antibiotic.46
The Problem of
Antibiotic Overuse
Overuse of antibiotics has received increased attention from
public health experts and the lay press for some time. The
emergence of multiple drug-resistant Staphylococcus aureus
has illustrated the urgency in reducing frivolous antibiotic
usage. Moreover, chronic antibiotic use has been implicated
in increasing the risk of breast cancer47,48 and increasing the
incidence of upper respiratory infections,49 all in studies that
have yet to be conclusively confirmed.
Whether or not this link to nonbacterial diseases proves to
be real, there is sufficient reason to avoid long-term antibiotic
therapy whenever possible. Acne is not a trivial disease but
one that can produce physical and emotional scarring and
one worthy of aggressive treatment. Acne, unfortunately, is
also not a short-term disease, nor is it one that is quickly
controllable in many patients, and prolonged courses of an-
G.F. Webster and E.M. Graber
186
tibiotics are often needed. Steps can be taken by the practitioner to minimize the need for chronic antibiotic treatment
by optimizing regimens so as to minimize antibiotic exposure.
First, the use of combination therapy with topical retinoids
should be begun early in treatment. It has been clearly shown
by good studies that many patients treated with oral antibiotic and topical retinoid for 12 weeks may have long-term
control of their acne with topical retinoids alone after 12
weeks.50,51 In our experience, almost 70% of patients with
moderately severe papular acne will have no need for oral
antibiotic use after 12 weeks, if they have used topical retinoids aggressively for the first 12 weeks. The patients in whom
antibiotics may be safely discontinued are the ones that have
had a significant improvement in their inflammatory lesions
after three months.
A second way to minimize antibiotic usage is to have patients who are severe enough to warrant isotretinoin receive
the drug sooner rather than later. In fact, isotretinoin has
been shown to reduce the carriage of resistant P. acnes during
the course of acne treatment.52 A prolonged trial of antibiotics is not justifiable if the patient is a legitimate candidate for
isotretinoin and has active scarring disease. It is our practice
to offer isotretinoin to nodular acne patients at the first visit
and then again after 4 to 6 weeks of insufficient progress on
antibiotic/retinoid therapy.
Third, when long-term antibiotic therapy is required, benzoyl peroxide, whether as a combination product or a wash
should be part of the regimen because of its ability to discourage the acquisition of resistance.53 It is important to remember, however, that this beneficial effect only applies to areas
in contact with the benzoyl peroxide. The gut and other areas
will have no protection against the acquisition of resistant
organisms.
Safety of Antibiotics
Used in Acne Therapy
In general, the antibiotics used in acne are safe and well
tolerated. Other than gastrointestinal upset, phototoxicity,
and the rare hypersensitivity reaction, acne patients have few
adverse reactions to their treatment. There are 2 issues that
remain problematic regarding acne therapy with antibiotics:
interaction with contraceptive therapy and elevation of the
risk of breast cancer.
Do Antibiotics Decrease the
Activity of Oral Contraceptives?
There have been numerous case reports of apparent contraceptive failure when administered along with antibiotics and
it is a well-established fear, particularly in the dental literature, that there is a contraindication to coadministration. The
basis for this concern is that antibiotics might change the
bowel flora and alter the metabolism and absorption of contraceptives. This has been well documented in the case of
only one antibiotic, rifampin54 and, in this case, the contraindication is a valid one. However good pharmacokinetic
data disprove the interaction of other antibiotics with contraceptives.54 It is the author’s practice to discuss the potential
for interaction and the lack of supporting data with patients.
We remind them as well that contraceptives have an inherent
failure rate and that adding a second medication can cause
compliance issues that might enhance that inherent failure
rate.
Do Antibiotics Increase
the Risk of Breast Cancer?
In 2004, a report was published in the general medical literature that asserted that long-term antibiotic use roughly doubled the risk of breast cancer in women.47 The risk was similar for all antibiotics studied and did not differ based on the
diagnosis that was treated. The authors explained the finding
by invoking altered gut metabolism of supposedly protective
phytosterols that are contained in foods. The study had several failings, not the least of which was to identify whether the
antibiotic was the problem or was merely a marker for the
actual risk factor eg, a chronic infection or a chronic inflammatory disease. A subsequent report from this group showed
no antibiotic dose-response effect and no effect on tumor
type.48
A recent report from another group studied the records of
2.1 million women and found a slight association between
doxycycline and macrolide use and breast cancer.49 Record
review suggested a link between the diagnosis of acne or
rosacea and a risk of breast cancer. Another report looked at
the timing of breast cancer diagnosis and long term antibiotic
therapy in a large series of Canadian patients.50 They found a
small increase in the risk of breast cancer in those who had
received antibiotics in the preceding 1 to 15 years, but there
was no correlation between risk and recent antibiotic use;
perhaps implying that the antibiotic use is a surrogate marker
for the underlying causal problem.
At this juncture, there is no answer as to whether antibiotic
therapy itself causes increased risk of breast malignancy, but
it seems prudent to make serious efforts to avoid frivolous use
of oral antibiotics for these reasons as well as because of
concerns about resistance.
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