JDD Antimicrobial Resistance Review 2010

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Volume 9 Issue 6
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Original Articles
special topic
Journal of Drugs in Dermatology
The Development of Antimicrobial Resistance

Due to the Antibiotic Treatment of
Acne Vulgaris: A Review
Mital Patel MD, Whitney P. Bowe MD, Carol Heughebaert MD, Alan R. Shalita MD
Department of Dermatology, State University of New York, Downstate Medical Center, Brooklyn, NY
Abstract
Objective: To review recent studies on the use of antibiotics in acne vulgaris which provide insight into the development of antimicrobial resistance.
Data sources: Sources for this article were identified by searching the English literature by Medline for the period 1960 to March 2009.
Study selection: The following relevant terms were used: acne, acne vulgaris, acne and antibiotic therapy, acne and antimicrobial
resistance, acne and resistance mechanisms, acne and systemic infections, acne and antibiotic resistance and coagulase-negative
Staphylococcus aureus (S. aureus), acne and antibiotic resistance and upper respiratory infection.
Data synthesis: Both correct and incorrect use of antibiotics for acne vulgaris can promote antimicrobial resistance. The development of this resistance is promoted by several factors, including antibiotic monotherapy, long-term administration of antibiotics, indiscriminate use outside their strict indications, dosing below the recommended levels, and the administration of antibiotics without
concurrent benzoyl peroxide and/or topical retinoids.
Conclusion: Long-term use of antibiotics in the treatment of acne vulgaris can lead to antimicrobial resistance with serious and intractable problems not limited to Propionibacterium acnes (P. acnes), the skin and acne vulgaris themselves, but also to other bacterial species, with systemic consequences. These findings suggest that antibiotics should be prescribed in combination with benzoyl
peroxide and/or topical retinoids and be limited to a maximum of several months.
Introduction
he growing prevalence of antibiotic resistance is rapidly eroding one of the most formidable forces against
bacterial pathogens. The pervasive and indiscriminate
use of antibiotics is considered one of the most important inciting agents in this globally developing crisis. The emergence
and spread of multi-drug resistant bacterial infections, not just
in hospitals but also in the community, has further heightened
concerns. Long-term use of antibiotics results in selection pressure whereby antibiotics eliminate susceptible bacteria and
permit antibiotic-resistant bacteria to proliferate.
The authors conducted an extensive review of the literature

to date on acne antibiotic use and antimicrobial resistance.
Those references felt to contribute significantly to the current
understanding of the subject were selected and incorporated
in this review. Specifically, the impact of long-term use of oral
and topical acne antibiotic therapy on both cutaneous and
non-cutaneous microbial environments including the skin, nares, oropharynx and gastrointestinal tract are addressed. Resistance mechanisms and patterns resulting from acne antibiotic therapy seen in coagulase-negative staphylococci (CNS),
Staphylococcus aureus (S. aureus), and Group A streptococcus
(GAS) are each discussed. Furthermore, the potential link between long-term antibiotic use for acne and increased risk for
systemic infections, or infections that might be more challenging to treat with standard antibiotic therapy, is examined.
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For over 40 years, antibiotics have been a mainstay of treatment for inflammatory acne vulgaris. Acne is one of the most
common dermatological diseases, affecting more than 85 percent of adolescents and often continuing into adulthood.1 Every year over 2 million individuals have severe enough acne
to require treatment, which leads to over 5 million oral antibiotic prescriptions written each year.2 The duration of antibiotic therapy for treatment of acne is often long-term (i.e., more
than six months), making acne vulgaris a useful model to explore the consequences of sustained antibiotic exposure. The
implications of such use, including the emergence of resistant
organisms, increased exposure to and colonization with pathogenic organisms, and increased risk of developing infectious
illnesses, merits careful consideration.
methods
The authors conducted an extensive review of the literature
concerning the existence of bacterial resistance due to antibiotic therapy of acne vulgaris using the following keywords:
acne, acne vulgaris, acne and antibiotic therapy, acne
and antimicrobial resistance, acne and resistance mechanisms, acne and Staphylococcus aureus, acne and systemic
infections and acne and upper respiratory infection. Sources
for this article were identified by searching the English literature by Medline for the period 1960 to June 2009.
2010-Journal of Drugs in Dermatology. All Rights Reserved.

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June 2010 Volume 9 Issue 6
Articles were also obtained by bibliography review. The search

was limited to articles published in English. Observational and
interventional human studies with participants with participants of any age, sex or health status were included. Articles
were excluded if they reported only on the diagnosis, treatment, or pathogenesis of acne. The primary and secondary
authors (MP and WPB) reviewed the titles and abstracts of all
potentially relevant articles to determine whether they met the
eligibility criteria.
Acne and the Role of Antibiotics:

A Historical Perspective
Propionibacterium acnes (P. acnes) is a facultative anaerobic
bacterial component of normal skin flora.3 P. acnes resides predominantly in the pilosebaceous follicles and has been implicated as one of the factors in the pathogenesis of inflammatory
lesions in acne vulgaris.4,5 Obstruction of sebaceous follicles
due to altered follicular epithelial differentiation along with increased sebum production provides an environment in which
the anerobic bacteria can flourish. P. acnes metabolizes sebaceous triglycerides into fatty acids, which may promote inflammation The combination of keratin, sebum and P. acnes results
in generation of pro-inflammatory mediators and recruitment
of T lymphocytes, neutrophils and foreign body giant cells. P.
acnes has the ability to activate complement in addition to proinflammatory cytokines.6,7
Although acne is not an infection, antibiotics are used to reduce the number of P. acnes present on the skin and pilosebaceous follicles. In addition to this antimicrobial activity, antibiotics also demonstrate anti-inflammatory activity, inhibiting P.
acnes-associated inflammatory mediators and decreasing neutrophilic chemotaxis. Although P. acnes has been shown to be
susceptible to several antibiotics in vitro, many of these antibiotics are unable to penetrate the lipid-filled microcomedones in
vivo. Consequently, lipophilic antibiotics such as erythromycin,
clindamycin, and tetracycline, doxycycline and minocycline are
the antibiotics of choice for inflammatory acne vulgaris.8
M. Patel, W. P. Bowe, C. Heughebaert, A. R. Shalita
In the mid-1970s, studies showed that topical formulations of

antibiotics were also an effective and safe form of acne therapy.11 The topical formulations quickly became a widely used
treatment, especially for patients with mild to moderate acne.
In 1979, shortly after the introduction of topical antibiotics,
Crawford et al. re-opened the investigation of antibiotic resistant P. acnes. He and his colleagues showed the first signs of P.
acnes resistance to erythromycin and clindamycin both in vitro
and in vivo. Twenty percent of their patients (n=22) using topical
clindamycin or erythromycin therapy were carrying resistant P.
acnes.12 In 1983, Leyden and his colleagues further added to the
findings of Crawford et al. by showing that not only did P. acnes
exist in patients receiving long-term oral tetracycline and/or
erythromycin, but that it was common among these patients.
This manuscript was also the earliest documentation of P. acnes
resistance to tetracycline.13
Although the emergence of resistance coincided with the introduction of topical agents, a causal link between the two has not
been proven. A 10-year study between 1992 and 2001, which
monitored the prevalence of skin colonization with antibiotic
resistant organisms, demonstrated that resistance to erythromycin and clindamycin was more common than resistance to
tetracycline suggesting the topical agents may be more likely to
induce resistance.14 Alternatively, it has also been hypothesized
that increased selective ecologic pressures from the extensive
use of simultaneous topical and systemic agents may have
played a role in the emergence of resistance.13,14
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Since the availability of oral tetracycline and erythromycin in

the early 1950s, followed by doxycycline in 1967 and minocycline in 1972, dermatologists have extensively utilized oral antibiotics for the treatment of acne vulgaris.9 Despite the widespread use of oral acne antibiotic therapies in the 1960s and
1970s, signs of P. acnes antibiotic resistance did not emerge
until the late 1970s, following the introduction of topical antibiotic use for acne. In fact, Alan Shalita and Richard Marples were
unable to induce tetracycline resistance to P. acnes in vitro (Personal communication with Dr. Alan Shalita), despite repeated
subculturing of the organism in the presence of tetracycline.
Additionally, in 1967 Leyden and his colleagues were unable
to isolate antibiotic-resistant P. acnes on the skin of more than
1,000 subjects on anti-acne antibiotics.10
Propionibacterium acnes Resistance Mechanisms
There are several mechanisms in which bacteria can acquire resistance to antibiotics. Resistance can develop via the acquisition of mobile genetic elements such as plasmids that can be
transferred between species and, rarely, across genera. Some
bacteria produce enzymes that inactivate the antibiotic, while
others express a pump that extrudes the drug from the bacterial
cell. Furthermore, point mutations in bacterial DNA may lead to
changes in the RNA targets of antibiotics, acting as a type of camouflage for the bacteria, allowing it to go unrecognized even in
the presence of therapeutic levels of antibiotic. In P. acnes, point
mutations in genes encoding the 23S ribosomal RNA and the
16S rRNA have lead to resistance to erythromycin/clindamycin
and tetracycline, respectively.15This type of resistance pattern appears to be less threatening, as it does not involve gene transfer
of resistance determinants from other organisms. Consequently,
these resistant P. acnes cannot transfer their resistance to other
organisms.16 However, resistant strains have been isolated in
which mutations could not be identified, implying that other unknown mechanisms of resistance have evolved.17
Over the years, antibiotic-resistant P. acnes has been on the

rise both in the United States (U.S.) and worldwide, raising
concerns about the efficacy of treatment and the associated

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consequences of long-term antibiotic usage.9,14 A systemic

literature review showed that the prevalence of antibioticresistant P. acnes has increased from 20 percent in 1978 to 62
percent in 1996.18 Several studies have suggested that patients
who harbor resistant P. acnes are more likely to fail treatment
due to higher bacterial counts and poorer treatment responses.13,19,20 However, the extent to which treatment is compromised has not been well studied and cannot be universally
applied.21 The responses of different lesions, even on a single
patient, will be influenced by numerous factors such as route
of antibiotic administration, dosage of medication given, presence and acquisition of resistance, density of resistance organism once present and combination with other treatment
regimens (BPO, retinoids).14,20
Topical Acne Antibiotics:

Systemic Microbial Effects
Despite the prevalence of P. acnes antibiotic resistance, it has

rarely been seen as a pathogen in healthy individual.22,23 Additionally, P. acnes is susceptible to many antibiotics including
beta-lactam drugs, which remain effective because they are
not used in the treatment of acne vulgaris. Therefore antibiotic
resistant P. acnes that develops in acne patients places the patient and their close contacts at minimal risk for a difficult to
treat, systemic P. acnes infection. However, many potentially
pathogenic bacteria are carried as human commensals, which
can also develop resistance to antibiotics during acne therapy.
Furthermore, antibiotic use can impact upon the normal, protective flora of the acne patient, predisposing to colonization
(and theoretically infection) with pathogens that are not usually
found in these sites. This concept is known as bacterial interference, and will be discussed in more detail below.
Several case reports of pseudomembranous colitis in patients

using topical clindamycin emphasize the need for studying
the systemic absorption of topical clindamycin.27 Barza et al.
showed that after topical administration of 1% clindamycin hydrochloride, an average of 45 percent of clindamycin was absorbed systemically, but even greater amounts were absorbed
in select individuals.28 Eller et al. added to these finding by
showing a statistically significant difference in the bioavailability of clindamycin dependent on the type of preparation used.
A comprehensive review of the data regarding systemic availability of clindamycin after topical application was conducted
by Hoogdalem et al., concluding that a minimal amount of clindamycin is found systemically after topical treatment with the
highest bioavailability reaching 8 percent.27
Topical antibiotic therapy was expected to avoid some of

the unnecessary complications of long-term oral antibiotics
(as discussed above) for patients who had less severe acne.
However, if topical antibiotics find their way into the systemic
circulation they, too, can lead to systemic side effects. More
importantly, the hematogenous spread of transdermally
absorbed topical antibiotics can, like oral antibiotics, pose
a risk for systemic bacterial resistance and possibly even
infection. One of the mainstay topical antibiotic therapies
in acne patients, clindamycin, is of particular interest due
to the known association of systemic clindamycin with
pseudomembranous colitis.
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Oral Acne Antibiotics: Systemic Microbial Effects
Oral antibiotics are generally reserved for patients with

moderate-to-severe acne due to the potential clinical side effects such as stomach upset, diarrhea, nausea, headache and
vaginal candidiasis. In addition, several studies have shown
that oral tetracycline even in low doses favors multi-drug resistance organisms in the gastrointestinal tract of patients on
long-term therapy.2426 In some patients, the resistance patterns
persist for several months even after treatment has been discontinued. Furthermore, a study done by Adams et al. showed
that the changes in bowel flora after tetracycline use is not limited just to the patient, but also leads to resistance in the gastrointestinal flora of their close contacts.24 Patients receiving
oral tetracycline for treatment of acne vulgaris may be an important reservoir and vector for the transmission of resistance
factors.25 These findings raise concerns about the increasing
overall pool of antibiotic resistant organisms present in the
community.24 Although there is no evidence to date that the
impact of systemic antibiotics on gastrointestinal flora directly
increases infection rates, there is a theoretical concern that if
infections do occur, they may become significantly harder to
treat due to multi-drug resistance.
Although the percentage of topical clindamycin that is systemically absorbed appears to be reassuringly minimal, it is
unknown what serum concentration is necessary to result in
systemic alterations of the microflora at distant sites. Several researchers have investigated the impact of topical clindamycin on non-cutaneous microbial environments. Siegle
and his colleagues studied the effects of topical clindamycin phosphate on intestinal microflora after eight weeks of
use.29 Marginal changes in the colonic flora were noted, with
no apparent clinical significance. Additionally, Rietschel and
Duncan showed no association between the use of topical
clindamycin phosphate and the incidence of diarrhea.30 But
despite these reassuring findings, topical clindamycin is still
contraindicated in patients with a history of regional enteritis, ulcerative colitis or antibiotic-associated colitis.31 Although
topical clindamycin alone may not be enough to precipitate a
de novo case of colitis, these contraindications indicate that
there does exist a concern that the systemic absorption of this
drug very well might impact upon the normal balance of GI
flora. Along this same principle, the amount of antibiotic absorbed from daily topical usage among acne patients could
potentially alter other non-cutaneous environments such as
the nose and throat.

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Coagulase-Negative Staphylococci:
Antibiotic Resistance
Coagulase-negative staphylococci (CNS) are aerobic Grampositive cocci, which constitute the predominant microflora
of human skin. Long-term antibiotic use as prescribed in acne
therapy has been shown to impact resistance patterns of CNS
on human skin and mucous membranes. CNS had long been
regarded as apathogenic commensals, but their role as pathogenic organisms has increased.32 In most healthy individuals
CNS are not pathogenic; however in people at risk, the infections can be devastating. When the immune system is impaired
or the skin is irritated or injured, non-pathogenic organisms,
including CNS, may change their behavior and become pathogenic. Neonates, immunocompromised patients and patients
with intravascular catheters and/or prosthetic devices are at increased risk for systemic infections with CNS.33 Although most
acne patients are healthy and at minimal risk, there is evidence
that antibiotic effects on resistance patterns are not just limited to the user but also may impact upon their close contacts.
Consequently, from the late 1960s to the early 1990s numerous studies were conducted to examine the effects of long-term
oral and topical antibiotics on the development and spread of
drug resistance in human skin microflora.
Initially, studies, such as the one conducted by Goltz et al. in
1966, could not show the presence of resistant cutaneous organisms in patients on oral tetracycline medication during or
after treatment.34 Soon thereafter, in 1971, Marples and his
colleagues demonstrated that orally administered antibiotics
did alter the resident microbial flora of the skin. A three-week
course of one of the following oral antibiotics: tetracycline, demeclocycline, doxycycline, minocycline, ampicillin, penicillin,
erythromycin, clindamycin was given to healthy male subjects
from the Philadelphia House of Correction. Following therapy,
the flora collected the foreheads of subjects treated with any of
the four tetracycline drugs, erythromycin or clindamycin had
significantly higher amounts of resistant coagulase-negative
cocci.35 Following Marples work, Mills et al. found that topical
2 percent erythromycin was beneficial in treating acne, but also
noted a significant increase in the prevalence of erythromycinresistant CNS among treated patients.11 These findings were further supported by Bernstein and Shalita, who produced similar
data after four weeks of 2 percent topical erythromycin.36
for a six-month duration. They found that 67 percent of patients

on tetracycline and 33 percent of on minocycline developed
multi-drug resistant (greater than or equal to 3) CNS on their
skin during their treatment course.38 The results of these studies are of potential significance because antibiotic-resistant
coagulase-negative staphylococci can be a major cause of
serious infections in specific patient populations. However, absolute conclusions should be made with reservation since these
studies were limited by a small sample size and absence of
control groups. These study designs also lacked post-treatment
follow-up of the patients to determine the long-term effects of
topical antibiotics on skin flora.
Subsequently, two later studies addressed many of the limitations and unanswered questions present in the earlier studies.
Both studies were randomized controlled clinical trials with significantly larger sample sizes. In addition, both studies determined the prevalence of antibiotic-resistant CNS prior to treatment, during treatment, and following treatment. This study
design allowed for more comprehensive conclusions along
with a better assessment of the long-term implications. In the
first study, Vowels et al. conducted a clinical trial with 225 patients who were randomized into two groups with group one
receiving topical 2% erythromycin twice a day for six weeks
and group two receiving topical vehicle only two times a day
for six weeks.39 During the six weeks of therapy, patients were
swabbed and cultured from the forehead, back and anterior nares at weeks 0, 4, 6 and then 12 weeks (six weeks after treatment was discontinued). Their study showed that both the
prevalence and density of erythromycin-resistant coagulasenegative staphylococci significantly increased in the treatment
group (group 1) as compared to the placebo group (group 2).
Particularly of interest, the resistance patterns changed not just
at the site of application, but also at distant sites such as the
back and the anterior nares. In this study, the increase in resistance was transient and by six weeks post-treatment, most
patients were back to their baseline resistance patterns.
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Over the next few years, studies continued to show an increasing prevalence of antibiotic-resistant CNS. By 1992, Harkaway
and colleagues found erythromycin induced resistant CNS in
all patients receiving topical treatment.37 Even more concerning
are the findings of Eady et al. which showed that not only was
resistance developing to the oral antibiotic that the patients
were being treated with, but it was also leading to the development of multi-drug resistant CNS. Eady studied 25 patients
half treated with oral tetracycline and half with oral minocycline
A few years later, Mills et al. conducted a similar study with 208
patients who were also randomized into two groups, but their
study treated patients for 12 weeks in attempt to better mimic clinical treatment and then followed up for 12 weeks posttreatment.40 In support of Vowels, Mills also found a statistically
significant increase in the erythromycin-resistant coagulasenegative staphylococci on the face, back and anterior nares.
However, unlike Vowels work, their findings showed that the
changes in resistance patterns persisted even after 12 weeks
post-treatment with minimal if any regression to the baseline.
These findings are of importance since the resistant CNS serves
a reservoir of antibiotic resistance genes on the skin of acne patients. The longer the resistant organisms colonize the skin the
greater opportunity they have to spread both to other bacteria
and to other hosts.

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It is important to note that if the antibiotic effects were reaching

distant cutaneous areas on the treated patients, the possibility
of transferring the resistance to contacts must be considered.
Miller et al. studied the bacterial flora on the skin of 41 close
contacts of acne patients who had received anti-acne antibiotics
for a minimum of two years and 41 controls that had no contact
with antibiotic-treated acne patients. Their study showed that
close contacts of acne patients using antibiotic therapy also
have increased prevalence and density of resistant organisms
on the skin. Therefore, the skin of antibiotic-treated acne patients also serves as a source of antibiotic-resistant organisms
that can be transferred to and colonize untreated contacts.41 The
spread from one person to another further adds to the resistant
gene reservoir. These findings also become increasingly important if the contact is at risk for infection with CNS, which could
place them at risk for a difficult to treat infection.
Antibiotic resistance emerges more quickly in rapidly replicating bacteria, such as staphylococci, than in bacteria which
replicates slower, such as P. acnes.23 Therefore, even patients
with antibiotic-sensitive P. acnes can be colonized with resistant
CNS. Staphylococci typically develop resistance to erythromycin, clindamycin and tetracyclines when they acquire mobile
genetic information, such as transposons and plasmids, from
other bacteria within the species and, rarely, even bacteria from
other genera. In this way bacteria can accumulate multiple resistant genes over time. The resistance plasmids and transposons
also have been shown to transfer from coagulase-negative to
coagulase-positive staphylococci both in vitro and in vivo. This
emphasizes that a pool of resistance genes on the skin can be
transferred from CNS to more pathogenic staphylococci such
as S. aureus.42 Therefore, the changes in resistance patterns on
skin flora secondary to long antibiotic use may have more concerning consequences than just benign antibiotic resistance.
riage and increased risk of staphylococcal skin disease was reported. With the introduction of penicillin in 1943, S. aureus infections and mortality were briefly abated, but resistant strains
developed quickly. The first reported case of penicillin-resistant
S. aureus (PRSA) producing beta-lactamase was in 1947 and
within a decade 90 percent of hospital acquired S. aureus was
resistant to penicillin.43,45 Then in the 1950s, methicillin, a betalactamase-insensitive beta-lactam was used to effectively treat
PRSA, but by 1961 S. aureus had evolved again forming resistance to methicillin. Methicillin-resistant S. aureus (MRSA) was
first identified in the hospital setting and the rate increased
slowly and steadily until the late 1990s when there was spike in
the incidence of MRSA, which correlated with evidence of community acquired MRSA (CA-MRSA). Patients with no hospital
associated risk factors were developing MRSA infections and
by 2001 increasing numbers of outbreaks of CA-MRSA were
occurring worldwide.43,44
Just in the last decade, there has been a dramatic rise in the
incidence of reported CA-MRSA infections. A seminal study
conducted by Moran and his colleagues in 2006 demonstrated
that MRSA has become the most common identifiable cause
of skin and soft tissue infections among patients presenting to
emergency rooms across the U.S. They examined 422 patients
presenting to 11 university-affiliated emergency departments
with acute skin and soft-tissue infections. S. aureus was isolated from 76 percent of the patients, making it the most common
cause of community-acquired skin and soft tissue infections.
Seventy-eight percent of the S. aureus isolates were methicillin resistant, establishing the overall prevalence of MRSA at 59
percent. It is essential that isolates that are resistant to erythromycin but susceptible to clindamycin on initial testing be further evaluated using D-zone disk diffusion testing. This assay is
capable of identifying S. aureus strains that are capable of clindamycin resistance under certain circumstances, and therefore
must not be treated with clindamycin monotherapy.46
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Staphylococcus aureus
S. aureus is a facultatively anerobic, coagulase-positive, Grampositive coccus, which appears as grape-like clusters on microscopy. Although some strains can be human commensals,
S. aureus is the most virulent Staphylococcus species, making
it a frequent cause of infections in both the hospital and the
community.43,44 S. aureus primarily leads to skin and soft tissue infections such as impetigo, furuncles, carbuncles, cellulitis
and abscesses, but it is also capable of causing life-threatening
diseases such as pneumonia, meningitis, osteomyelitis, endocarditis and toxic shock syndrome. S. aureus does not depend
on a human host for survival; it can survive for extended periods of time on dry environmental surfaces increasing its ability
to infect new hosts.44
Since the discovery of S. aureus in 1880 by Alexander Ogston it
has become a significant organism across the field of medicine.
As early as 1931, an association between S. aureus nasal car-
As a consequence of studies such as Morans, clindamycin,

trimethoprim-sulfamethoxazole and doxycycline have been
recommended as first-line outpatient treatment for community-acquired MRSA.46 Ironically, these antibiotics are commonly
prescribed as long-term therapy for acne vulgaris.
CNS resistance develops within weeks of anti-acne antibiotics.
Less is known about how quickly S. aureus is capable of acquiring resistance to these drugs. Even if the S. aureus genome
itself is not directly altered by antibiotic treatment, resistance
genes can be transferred from coagulase-negative staphylococci to coagulase-positive staphylococci as described by Naidoo.
This potential for horizontal transfer of resistance genes further
emphasizes the concern that dermatologists might induce resistance against the main arsenal for MRSA, putting not only patients but potential the whole community at risk for infection.42

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There are several plausible mechanisms that might account for

why antibiotic treatment predisposes to MRSA infection and/or
colonization. Antibiotics can eradicate the normal, protective
flora, leaving cell surface receptors open to colonization with
pathogens such as MRSA. Additionally, antibiotics can directly
select for pre-existing MRSA in carriers, allowing these strains to
proliferate and even disseminate. Furthermore, the use of antibiotics can change low-level intermittent carriers to persistent carriers (discussed below) allowing for increased transmission.47
There is strong evidence to suggest that people colonized with
MRSA in their anterior nares are at an increased risk for MRSA
infection. Nasal carriage of S. aureus leads to an increased risk
of post-surgical S. aureus wound infections, S. aureus skin infections, and S. aureus infection in hemodialysis and peritoneal
dialysis patients.48 Although there are multiple sites on the body
that can be colonized with S. aureus, the anterior nares remain
the most common reservoir. Cross-sectional surveys have estimated nasal carriage rates of 27 percent in the general population. It should be noted that longitudinal studies have shown
there are three main patterns of S. aureus nasal carriage: persistent carriage, intermittent carriage and non-carriage. In any
given cross-sectional analysis, a carrier could represent either
a persistent or an intermittent carrier. Similarly, non-carriers
could represent either intermittent or non-carriers. It is particularly important to make this distinction because persistent carriers are likely to be carrying higher loads of bacteria increasing
their risk of infection and ability to disseminate bacteria into
the environment.4951 Persistent carriers typically carry the same
strain of S. aureus at all times, while intermittent carriers are
more likely to shift between various strains of S. aureus.5254 Approximately 20 percent (1230%) of individuals are considered
persistent S. aureus carriers, roughly 30 percent (1670%) are
intermittent carriers and 50 percent (1669%) of individuals are
non-carriers.50,52,53,55
tology department of the University of Pennsylvania who had

either been taking antibiotic therapy (oral, topical or both) for
at least three months or had not taken antibiotic therapy within
the past six months were enrolled. The oropharynx of each patient was swabbed and cultured and the growing bacteria were
tested for antibiotic resistance by agar disk diffusion. Although
they found similar prevalence rates of S. aureus colonization
between the two populations, 44 percent of the S. aureus cultures from antibiotic users.56 This finding did not reach statistical significance.
Group A Streptococci: Colonization and Infection

Streptococcus pyogenes, also known as Group A streptococcus (GAS), is a gram-positive coccus, and an exclusively human pathogen. As a highly adhesive extra-cellular organism, its
virulence is dependent on the presence of specific surface components as well as the production of exotoxins.57 GAS causes
many human diseases ranging from mild superficial skin infections to life-threatening systemic diseases. Pharyngitis and
impetigo are the most common infections attributed to GAS
today, but it can also occasionally lead to purulent and nonpurulent skin infections including cellulitis. It accounts for 1530
percent of childhood cases of acute pharyngitis and 10 percent
of adult cases.58 Therapy for these infections is primarily aimed
to prevent both suppurative (tonsillopharyngeal cellulitis or abscess, otitis media, sinusitis and necrotizing fasciitis) and nonsuppurative sequelae (acute rheumatic fever, post-streptococcal
glomerulonephritis and streptococcal toxic shock syndrome).
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A central concept integral to host colonization with pathogens

such as S. aureus is known as bacterial interference. In a
healthy nose, the ecological niche is already occupied with normal, protective flora. However, patients on antibiotic therapy
have significant changes in their flora that could allow virulent
organisms to take hold of epithelial receptors and proliferate.
Mills et al. followed 208 acne patients either treated with topical
erythromycin or vehicle. He noted an increase in the incidence
of S. aureus nasal carriage, and the rates of erythromycin resistant S. aureus among previous carriers increased from 1540
percent during the course of treatment. These changes persisted for up to four weeks after the cessation of treatment before
returning to baseline.40 A few years later, Levy et al. set out to
study the effects of antibiotics on the carriage of S. aureus in
the oropharynx, another area that commonly serves as a reservoir for S. aureus. In this study, 105 acne patients at the derma-
The oropharynx is the most common location for asymptomatic colonization of GAS. The asymptomatic carrier state, as evidenced by positive throat cultures in the absence of symptoms,
is typically not treated. However, it can still be easily transmitted from carrier to close contacts via respiratory droplets.5964
Therefore, asymptomatic GAS carriers represent one of the
main GAS reservoirs from which the bacteria can be spread to
the general population.57
Fortunately, GAS still remains, for the most part, susceptible to

beta-lactam antibiotics. However, clinical failures to penicillin
therapy can occur. Penicillin and other beta-lactam antibiotics
are most effective against rapidly growing bacteria. They have
the greatest efficacy when organisms are in the earlier stages
of infection or in mild infections. The efficacy of beta lactams
may decrease later in infections when bacterial growth slows
as higher concentrations of GAS accumulate. Consequently,
clindamycin is considered more effective in the treatment of
invasive GAS infections. Unlike penicillin, efficacy of clindamycin is not affected by the size of the inoculums or the stage of
bacterial growth. Furthermore, clindamycin is capable of suppressing the production of GAS toxins. Severe GAS infections
may lead to shock, multi-system organ failure and death, making early recognition and effective treatment critical.

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The authors revisited the study by Levy et al., this time focusing
on prevalence and resistance patterns of GAS in the oropharynx
of acne patients. Normal oropharyngeal flora includes commensal organisms such as peptostreptococcus and viridans streptococci, but can also include potentially virulent organisms such
as staphylococci, streptococci and haemophilus. In this study,
one hundred and seven consecutive acne patients presenting to
the dermatology department at the University of Pennsylvania
were enrolled.The oropharynx of each patient was swabbed and
cultured. GAS recovered from the oropharynx were identified
and tested for antibiotic resistance by agar disk diffusion. The
study demonstrated a three-fold increase in the prevalence of
GAS in the oropharynx of patients on antibiotic therapy. Eightyfive percent of the GAS in the treated patients was resistant to
at least one tetracycline antibiotic. Interestingly, the prevalence
rate of GAS colonization in acne patients even among those
not using antibiotics was higher than reported carrier rates in
asymptomatic individuals without acne.
These findings suggest that patients with acne may have relatively higher baseline rates of bacteria in their oropharynx.20 Of note,
the association between antibiotic use and GAS carriage was seen
with multiple modes of antimicrobial administration (oral alone,
topical alone, combination of oral and topical). This finding may
lead one to pose the question: how does the topical administration of antibiotic alter a distant site such as the oropharynx? The
authors postulated two plausible mechanisms. The first possible
explanation involves the direct transfer of antibiotics and/or bacterial organisms to the oropharynx via a persons fingers or by
devices such as eating utensils. This theory is supported by the
findings of several studies, which demonstrated an increase in
erythromycin resistant coagulase-negative staphylococci at sites
(back and anterior nares) where antibiotic was not directly applied.39,41 An alternative mechanism is systemic absorption of topically applied antibiotic, leading to hematogenous spread of drug
to non-cutaneous sites such as the oropharynx.
in the General Practice Research Database (GPRD). Of these patients, 71.7 percent were being treated with topical and/or oral
antibiotics (tetracycline, erythromycin or clindamycin) while 28.3
percent were not on any antibiotic therapy. All acne patients, regardless of whether they received antibiotic therapy, were followed for one year with the main outcome measure being the
onset of a URTI or a UTI. Their results showed that the odds
of a URTI in a patient receiving long-term antibiotics for acne
was 2.15 times greater than those in acne patients not receiving
antibiotics.67 As was seen in Levy et al.s precursor study, these
effects persisted regardless of the mode of antibiotic administration (oral alone, topical alone, combination). Also, in order to
ensure that these findings were not simply artifacts of increased
health care seeking behavior in acne patients, this cohort was
compared with a cohort of patients with hypertension. Due to
its retrospective design, a correlation can be drawn, but does
not necessarily imply causation. Although the true clinical implications need to be further studied in a controlled clinical trial
setting this study raises important considerations for both physicians and patients when choosing a treatment plan for acne.
The association demonstrated by Margolis et al. also raises questions about the risk of infection to close contacts of acne patients
on antibiotic therapy.Their contacts may be at heightened risk for
infection for two possible reasons. Firstly, a URTI is a highly contagious illness, which can easily be spread from infected patient
to close contacts. Secondly, it has been shown that the effects
of antibiotics on the cutaneous and intestinal microflora of acne
patients impact the flora of their close contacts.24,40 Although, the
changes in resistance patterns of the cutaneous and intestinal
microflora of user and contact are concerning, it still remains unknown if this places them at increased risk of clinical infection.
Bowe et al. set out to determine whether household contacts of
acne patients with documented UTRIs are at an increased risk
of developing a URTI when compared to household contacts
of acne patients without documented URTIs. They conducted a
retrospective cohort study of 98,094 contacts of acne patients
found using the General Practice Research Database of the United Kingdom. They showed the odds of a contact developing a
URTI when comparing those residing with an acne patient with a
documented URTI to those residing with an acne patient without
a URTI was 1.43 supporting that URTIs have the ability to spread
from person to person. Interestingly, exposure to acne patients
using antibiotics was not found to be an independent risk factor
for developing a URTI.
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Given the association between acne antibiotic therapy and

increased GAS oropharyngeal carriage, the next logical step
was to examine whether antibiotic therapy also placed acne
patients at an increased risk for an upper respiratory tract infection (URTI). While the vast majority of URTIs are not of bacterial
origin (in fact, only 10% of URTIs can be attributed to a bacterial
cause), recent studies have shown that infections may be polymicrobial. Bacterial colonization with one organism (e.g., GAS)
may facilitate the infectious capability of another (e.g., a respiratory virus), by influencing their cell surface receptors.60,65,66
To address the clinical ramifications of increased GAS oropharyngeal carriage, Margolis and colleagues designed a follow-up
study to investigate the association between acne antibiotic use
and URTI.They conducted a retrospective cohort study of 118,496
individuals, identified as carrying a diagnosis of acne vulgaris
Based on these findings, the increased risk of development of URTIs in household contacts is most likely due to direct spread of the
infectious agent rather than to exposure of a long-term antibiotic
user. In fact, the incidence of URTIs among contacts exposed to
acne patients who developed URTIs while using antibiotics was
significantly lower than the incidence of URTIs among contacts of
acne patients who developed an URTI while not using antibiotics.

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662
Therefore, although acne patients on antibiotics are more likely

to develop URTIs they are less likely to spread them.68 These findings are reassuring from a public health perspective. However,
they support the theory that antibiotic therapy is immunomodulatory, hence predisposing them to infections from pathogens that
would not cause infection in fully immune competent hosts. The
anti-inflammatory properties of antibiotics such as tetracycline
antibiotics, which inhibit neutrophilic chemotaxis, may increase
the susceptibility to infections.68 Therefore, even the anti-inflammatory doses of antibiotics may have effects on infection rates
even without altering the microflora and its resistance patterns.
Furthermore, the concept of bacterial interference may play a
role in these findings. The antibiotic therapy may be killing off the
commensal organism leaving antibiotic users more susceptible to
colonization with virulent organisms. Unfortunately, we are still
left with many questions since the true cause cannot be determined by a retrospective design.
conclusion
Bacterial resistance to antimicrobial treatment has become a
significant problem throughout the developed world. Acne vulgaris, the most common dermatological disease, is commonly
treated with long-term antibiotics. However, there are strong
reasons for concern. Given widespread and sometimes indiscriminate use of antibiotics, the potential for selection pressure
and the possibility of the transfer of resistant genes to potentially
pathogenic bacteria exists, and new mechanisms of resistance
continue to evolve in P. acnes. Indeed, it has been suggested
that this antibiotics lead to resistance not only in the causative
pathogen of acne, but also in other potentially pathogenic bacteria, particularly certain strains of S. aureus, coagulase-negative
staphylococci and Group A streptococci.69 This can lead to both
therapeutic failure of acne vulgaris and bacterial resistance at
other anatomical sites and in the patients environment. This literature review was conducted in an attempt to clarify the effect
of the antibiotic therapy on resistance patterns and the overall
health problems to which this resistance can lead.
question of whether the long-term antibiotics treatment of acne

vulgaris puts acne patients, their contacts and the wider community at increased risk of developing resistant infections such
as those caused by MRSA. GAS is a well-known cause of URTIs,
and asymptomatic GAS carriers represent one of the main reservoirs from which the bacteria can be spread. It has been demonstrated that patients on anti-acne antibiotics have are more likely
to develop URTIs.68 Further antibiotic therapy alone might impact
the normal balance of gastrointestinal flora via systemic absorption. The importance of this finding has yet to be determined.
It is imperative that steps must be taken to minimize the risk
of P. acnes developing resistance.69 It is important to limit the
use of antibiotics to the shortest possible period and to discontinue their use when further improvement is unlikely. Antibiotics should not be used for maintenance therapy of acne, and
simultaneous use of both oral and topical antibiotics should
be avoided. This is especially important when the antimicrobial
compounds are chemically unrelated.
Acne monotherapy should be strongly discouraged. Instead,
antibiotics should be combined with retinoids, which are anticomedogenic, comedolytic and anti-inflammatory, and/or benzoyl peroxide, which is bactericidal and has some keratolytic effects. This is particularly important for cases in which long-term
therapy is employed. These guidelines will hopefully result in
a lower risk of resistance development, both for P. acnes and
those strains likely to develop resistance due to antibiotic treatment of acne vulgaris.
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Many potentially pathogenic bacteria are carried as human commensals that can also develop resistance to antibiotics during acne
therapy. Patients treated for acne vulgaris may become important
reservoirs and vectors for the transmission of resistance factors,
and this effect is not limited to oral treatment. It has been shown
that antibiotic treatment for acne vulgaris can affect several potentially pathogenic bacteria, including CNS, S. aureus and GAS.
Several studies have shown that antibiotic-resistant CNS can
be a major cause of serious infections in certain patient populations, and this resistance can be transferred from CNS to more
pathogenic staphylococci such as S. aureus.32,33,37,42 The same antibiotics (clindamycin, trimethoprin-sulfamethoxazole and doxycycline) are used for both acne vulgaris and as first-line outpatient treatment for community-acquired MRSA.46 This raises the
acknowledgements
Drs. Patel, Bowe, Heughebaert and Shalita had full access to all
of the data in the study and take responsibility for the integrity
of the data and the accuracy of the data analysis. Study concept
and design: Drs. Bowe and Shalita. Acquisition of data: Drs.
Patel, Bowe and Heughebaert. Analysis and interpretation of
data: Drs. Patel, Bowe, Heughebaert and Shalita. Drafting of the
manuscript: Drs. Patel, Bowe, Heughebaert and Shalita. Critical
revision of the manuscript for important intellectual content:
Drs. Patel, Bowe, Heughebaert and Shalita. Obtained funding:
Dr. Heughebaert. Supervision: Dr. Shalita.
disclosures
This study was funded by the Belgian American Educational
Foundation (Carol Heughebaert, Fellow) and by the Health Science Center Brooklyn at Brooklyn Foundation.
The sponsors had no role in the design and conduct of the
study; in the collection, analysis and interpretation of data; or
in the preparation, review or approval of the manuscript.
Dr. Shalita is a consultant for Allergan, Galderma, Medicis and
Stiefel (GSK).

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663
Drs. Patel, Bowe and Heughebaert have no relevant conflicts of

interest to disclose.
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Address for Correspondence

Carol Heughebaert, MD
450 Clarkson Avenue
Brooklyn, NY 11203
Phone:.......................................................................(718) 270-1229
Fax:........................................................................... (718) 270-2794
E-mail:............................................................. cheugh@hotmail.com

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Journal of Drugs in Dermatology

The Development of Antimicrobial Resistance

The authors conducted an extensive review of the literature

2010-Journal of Drugs in Dermatology. All Rights Reserved.

Articles were also obtained by bibliography review. The search

Acne and the Role of Antibiotics:

M. Patel, W. P. Bowe, C. Heughebaert, A. R. Shalita

In the mid-1970s, studies showed that topical formulations of

Since the availability of oral tetracycline and erythromycin in

Propionibacterium acnes Resistance Mechanisms

Over the years, antibiotic-resistant P. acnes has been on the

2010-Journal of Drugs in Dermatology. All Rights Reserved.

M. Patel, W. P. Bowe, C. Heughebaert, A. R. Shalita

consequences of long-term antibiotic usage.9,14 A systemic

Topical Acne Antibiotics:

Despite the prevalence of P. acnes antibiotic resistance, it has

Several case reports of pseudomembranous colitis in patients

Topical antibiotic therapy was expected to avoid some of

Oral Acne Antibiotics: Systemic Microbial Effects

Oral antibiotics are generally reserved for patients with

2010-Journal of Drugs in Dermatology. All Rights Reserved.

M. Patel, W. P. Bowe, C. Heughebaert, A. R. Shalita

for a six-month duration. They found that 67 percent of patients

2010-Journal of Drugs in Dermatology. All Rights Reserved.

It is important to note that if the antibiotic effects were reaching

M. Patel, W. P. Bowe, C. Heughebaert, A. R. Shalita

As a consequence of studies such as Morans, clindamycin,

2010-Journal of Drugs in Dermatology. All Rights Reserved.

There are several plausible mechanisms that might account for

M. Patel, W. P. Bowe, C. Heughebaert, A. R. Shalita

tology department of the University of Pennsylvania who had

Group A Streptococci: Colonization and Infection

A central concept integral to host colonization with pathogens

Fortunately, GAS still remains, for the most part, susceptible to

2010-Journal of Drugs in Dermatology. All Rights Reserved.

M. Patel, W. P. Bowe, C. Heughebaert, A. R. Shalita

Given the association between acne antibiotic therapy and

2010-Journal of Drugs in Dermatology. All Rights Reserved.

Therefore, although acne patients on antibiotics are more likely

M. Patel, W. P. Bowe, C. Heughebaert, A. R. Shalita

question of whether the long-term antibiotics treatment of acne

2010-Journal of Drugs in Dermatology. All Rights Reserved.

M. Patel, W. P. Bowe, C. Heughebaert, A. R. Shalita

Drs. Patel, Bowe and Heughebaert have no relevant conflicts of

blind comparison of a clindamycin phosphate/benzoyl peroxide gel

2010-Journal of Drugs in Dermatology. All Rights Reserved.

M. Patel, W. P. Bowe, C. Heughebaert, A. R. Shalita

sociated risks. Clin Microbiol Rev. 1997;10(3):505-520.

Address for Correspondence

2010-Journal of Drugs in Dermatology. All Rights Reserved.

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