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Original Articles
special topic
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.
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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.
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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
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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
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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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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-
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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
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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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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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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.
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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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