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The Development of Antimicrobial ResistanceDue to the Antibiotic Treatment of

Acne Vulgaris: A ReviewMitl ptel Md, Whitney p. Bowe Md, crol Heughebert Md, aln R. Shlit Md

dertment of dermtology, Stte University of New York, downstte Meil center, Brooklyn, NY

JUNE2010 655 Volume9 Issue6

COPYRIGHT 2010 ORIGINAL ARTICLES JOURNALOFDRUGSINDERMATOLOGY

SPECIAL TOPIC

Objective:To review recent studies on the use of antibiotics in acne vulgaris which provide insight into the development of antimi-

crobial 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

Staphylococcusaureus(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 develop-

ment of this resistance is promoted by several factors, including antibiotic monotherapy, long-term administration of antibiotics, in-

discriminate 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 in-

tractable problems not limited to Propionibacterium acnes(P. acnes), the skin and acne vulgaris themselves, but also to other bacte-

rial 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.

ABSTRACT

INTRODUCTION

The growing prevalence of antibiotic resistance is rap-idly eroding one of the most formidable forces against

bacterial pathogens. The pervasive and indiscriminate

use of antibiotics is considered one of the most important in-

citing 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 pres-

sure whereby antibiotics eliminate susceptible bacteria and

permit antibiotic-resistant bacteria to proliferate.

For over 40 years, antibiotics have been a mainstay of treat-

ment for inflammatory acne vulgaris. Acne is one of the most

common dermatological diseases, affecting more than 85 per-

cent of adolescents and often continuing into adulthood.1Ev-

ery year over 2 million individuals have severe enough acne

to require treatment, which leads to over 5 million oral anti-

biotic prescriptions written each year.2The duration of antibi-

otic therapy for treatment of acne is often long-term (i.e., more

than six months), making acne vulgaris a useful model to ex-

plore the consequences of sustained antibiotic exposure. The

implications of such use, including the emergence of resistant

organisms, increased exposure to and colonization with patho-

genic organisms, and increased risk of developing infectious

illnesses, merits careful consideration.

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, na-

res, oropharynx and gastrointestinal tract are addressed. Re-

sistance mechanisms and patterns resulting from acne antibi-

otic therapy seen in coagulase-negative staphylococci (CNS),

Staphylococcus aureus (S. aureus), and Group A streptococcus

(GAS) are each discussed. Furthermore, the potential link be-

tween long-term antibiotic use for acne and increased risk for

systemic infections, or infections that might be more challeng-

ing to treat with standard antibiotic therapy, is examined.

METHODS

The authors conducted an extensive review of the literature

concerning the existence of bacterial resistance due to anti-

biotic therapy of acne vulgaris using the following keywords:

acne, acne vulgaris, acne and antibiotic therapy, acne

and antimicrobial resistance, acne and resistance mecha-

nisms, acne and Staphylococcus aureus, acne and systemic

infections and acne and upper respiratory infection. Sources

for this article were identified by searching the English litera-

ture by Medline for the period 1960 to June 2009.

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JOURNALOFDRUGSINDERMATOLOGY

June2010 Volume9 Issue6

M. ptel, W. p. Bowe, c. Heughebert, a. R. Shlit

Articles were also obtained by bibliography review. The search

was limited to articles published in English. Observational and

interventional human studies with participants with partici-

pants of any age, sex or health status were included. Articles

were excluded if they reported only on the diagnosis, treat-

ment, 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 PerspectivePropionibacterium acnes (P. acnes) is a facultative anaerobic

bacterial component of normal skin flora.3P. acnes resides pre-

dominantly in the pilosebaceous follicles and has been impli-

cated as one of the factors in the pathogenesis of inflammatory

lesions in acne vulgaris.4,5Obstruction of sebaceous folliclesdue to altered follicular epithelial differentiation along with in-

creased sebum production provides an environment in which

the anerobic bacteria can flourish. P. acnesmetabolizes seba-

ceous triglycerides into fatty acids, which may promote inflam-

mation The combination of keratin, sebum and P. acnesresults

in generation of pro-inflammatory mediators and recruitment

of T lymphocytes, neutrophils and foreign body giant cells. P.

acneshas the ability to activate complement in addition to pro-

inflammatory cytokines.6,7

Although acne is not an infection, antibiotics are used to re-

duce the number of P. acnespresent on the skin and piloseba-ceous follicles. In addition to this antimicrobial activity, antibi-

otics also demonstrate anti-inflammatory activity, inhibiting P.

acnes-associated inflammatory mediators and decreasing neu-

trophilic chemotaxis. Although P. acneshas been shown to be

susceptible to several antibiotics in vitro, many of these antibi-

otics 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

Since the availability of oral tetracycline and erythromycin in

the early 1950s, followed by doxycycline in 1967 and minocy-

cline in 1972, dermatologists have extensively utilized oral an-

tibiotics for the treatment of acne vulgaris.9Despite the wide-

spread use of oral acne antibiotic therapies in the 1960s and

1970s, signs of P. acnesantibiotic resistance did not emerge

until the late 1970s, following the introduction of topical antibi-

otic use for acne. In fact, Alan Shalita and Richard Marples were

unable to induce tetracycline resistance to P. acnes in vitro (Per-

sonal 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

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

antibiotics were also an effective and safe form of acne ther-

apy.11The 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 resis-

tant 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.12In 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 intro-

duction 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 erythro-

mycin and clindamycin was more common than resistance to

tetracycline suggesting the topical agents may be more likely to

induce resistance.14Alternatively, 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

Propionibacterium acnes Resistance MechanismsThere are several mechanisms in which bacteria can acquire re-

sistance to antibiotics. Resistance can develop via the acquisi-

tion 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 cam-

ouflage 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 ap-

pears to be less threatening, as it does not involve gene transfer

of resistance determinants from other organisms. Consequently,

these resistant P. acnescannot transfer their resistance to other

organisms.16 However, resistant strains have been isolated in

which mutations could not be identified, implying that other un-

known mechanisms of resistance have evolved.17

Over the years, antibiotic-resistant P. acneshas 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 antibiotic-

resistant P. acnes has increased from 20 percent in 1978 to 62

percent in 1996.18Several studies have suggested that patients

who harbor resistant P. acnes are more likely to fail treatment

due to higher bacterial counts and poorer treatment respons-

es.13,19,20 However, the extent to which treatment is compro-

mised has not been well studied and cannot be universally

applied.21The 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, pres-

ence and acquisition of resistance, density of resistance or-

ganism once present and combination with other treatment

regimens (BPO, retinoids).14,20

Despite the prevalence of P. acnesantibiotic resistance, it has

rarely been seen as a pathogen in healthy individual. 22,23Ad-ditionally, P. acnesis 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. acnesthat develops in acne patients places the pa-

tient 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, pro-

tective 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 interfer-ence, and will be discussed in more detail below.

Oral Acne Antibiotics: Systemic Microbial EffectsOral antibiotics are generally reserved for patients with

moderate-to-severe acne due to the potential clinical side ef-

fects 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 re-

sistance organisms in the gastrointestinal tract of patients on

long-term therapy.2426In some patients, the resistance patterns

persist for several months even after treatment has been dis-

continued. Furthermore, a study done by Adams et al. showed

that the changes in bowel flora after tetracycline use is not lim-

ited just to the patient, but also leads to resistance in the gas-

trointestinal flora of their close contacts.24 Patients receiving

oral tetracycline for treatment of acne vulgaris may be an im-

portant reservoir and vector for the transmission of resistance

factors.25These findings raise concerns about the increasing

overall pool of antibiotic resistant organisms present in the

community.24Although 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.

Topical Acne Antibiotics:Systemic Microbial EffectsTopical 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.

Several case reports of pseudomembranous colitis in patients

using topical clindamycin emphasize the need for studyingthe systemic absorption of topical clindamycin.27 Barza et al.

showed that after topical administration of 1% clindamycin hy-

drochloride, an average of 45 percent of clindamycin was ab-

sorbed 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 bioavailabil-

ity of clindamycin dependent on the type of preparation used.

A comprehensive review of the data regarding systemic avail-

ability of clindamycin after topical application was conducted

by Hoogdalem et al., concluding that a minimal amount of clin-

damycin is found systemically after topical treatment with the

highest bioavailability reaching 8 percent.

27

Although the percentage of topical clindamycin that is sys-

temically 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. Sev-

eral researchers have investigated the impact of topical clin-

damycin on non-cutaneous microbial environments. Siegle

and his colleagues studied the effects of topical clindamy-

cin phosphate on intestinal microflora after eight weeks of

use.29Marginal 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 enteri-

tis, ulcerative colitis or antibiotic-associated colitis.31Although

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 ab-

sorbed 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 ResistanceCoagulase-negative staphylococci (CNS) are aerobic Gram-

positive 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 patho-

genic organisms has increased.32 In most healthy individuals

CNS are not pathogenic; however in people at risk, the infec-

tions 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 patho-

genic. Neonates, immunocompromised patients and patients

with intravascular catheters and/or prosthetic devices are at in-

creased risk for systemic infections with CNS.33Although most

acne patients are healthy and at minimal risk, there is evidencethat antibiotic effects on resistance patterns are not just lim-

ited to the user but also may impact upon their close contacts.

Consequently, from the late 1960s to the early 1990s numer-

ous 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 or-

ganisms in patients on oral tetracycline medication during or

after treatment.34 Soon thereafter, in 1971, Marples and his

colleagues demonstrated that orally administered antibioticsdid alter the resident microbial flora of the skin. A three-week

course of one of the following oral antibiotics: tetracycline, de-

meclocycline, 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.35Following 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 erythromycin-

resistant CNS among treated patients.11These findings were fur-

ther supported by Bernstein and Shalita, who produced similar

data after four weeks of 2 percent topical erythromycin.36

Over the next few years, studies continued to show an increas-

ing prevalence of antibiotic-resistant CNS. By 1992, Harkaway

and colleagues found erythromycin induced resistant CNS in

all patients receiving topical treatment.37Even 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 devel-

opment of multi-drug resistant CNS. Eady studied 25 patients

half treated with oral tetracycline and half with oral minocycline

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.38The results of these stud-

ies are of potential significance because antibiotic-resistant

coagulase-negative staphylococci can be a major cause of

serious infections in specific patient populations. However, ab-

solute 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 limita-

tions and unanswered questions present in the earlier studies.

Both studies were randomized controlled clinical trials with sig-

nificantly larger sample sizes. In addition, both studies deter-mined the prevalence of antibiotic-resistant CNS prior to treat-

ment, 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 pa-

tients 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.39During the six weeks of therapy, patients were

swabbed and cultured from the forehead, back and anterior na-

res at weeks 0, 4, 6 and then 12 weeks (six weeks after treat-

ment was discontinued). Their study showed that both theprevalence and density of erythromycin-resistant coagulase-

negative 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 re-

sistance was transient and by six weeks post-treatment, most

patients were back to their baseline resistance patterns.

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 mim-

ic clinical treatment and then followed up for 12 weeks post-

treatment.40In support of Vowels, Mills also found a statistically

significant increase in the erythromycin-resistant coagulase-

negative 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 pa-

tients. 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 pa-

tients also serves as a source of antibiotic-resistant organisms

that can be transferred to and colonize untreated contacts.41The

spread from one person to another further adds to the resistant

gene reservoir. These findings also become increasingly impor-

tant 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 repli-

cating bacteria, such as staphylococci, than in bacteria which

replicates slower, such as P. acnes.23Therefore, even patients

with antibiotic-sensitive P. acnescan be colonized with resistant

CNS. Staphylococci typically develop resistance to erythromy-

cin, 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 resis-

tant 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. Thisemphasizes that a pool of resistance genes on the skin can be

transferred from CNS to more pathogenic staphylococci such

as S. aureus.42Therefore, the changes in resistance patterns on

skin flora secondary to long antibiotic use may have more con-

cerning consequences than just benign antibiotic resistance.

Staphylococcus aureus

S. aureusis a facultatively anerobic, coagulase-positive, Gram-

positive coccus, which appears as grape-like clusters on mi-

croscopy. Although some strains can be human commensals,

S. aureusis the most virulent Staphylococcus species, making

it a frequent cause of infections in both the hospital and the

community.43,44 S. aureusprimarily leads to skin and soft tis-

sue infections such as impetigo, furuncles, carbuncles, cellulitis

and abscesses, but it is also capable of causing life-threatening

diseases such as pneumonia, meningitis, osteomyelitis, endo-

carditis and toxic shock syndrome. S. aureusdoes not depend

on a human host for survival; it can survive for extended peri-

ods of time on dry environmental surfaces increasing its ability

to infect new hosts.44

Since the discovery of S. aureusin 1880 by Alexander Ogston it

has become a significant organism across the field of medicine.

As early as 1931, an association between S. aureusnasal car-

riage and increased risk of staphylococcal skin disease was re-

ported. With the introduction of penicillin in 1943, S. aureusin-

fections 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 acquiredS. aureuswas

resistant to penicillin.43,45Then in the 1950s, methicillin, a beta-

lactamase-insensitive beta-lactam was used to effectively treat

PRSA, but by 1961 S. aureushad evolved again forming resis-

tance 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 com-

munity 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. aureuswas isolat-

ed 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 methicil-lin resistant, establishing the overall prevalence of MRSA at 59

percent. It is essential that isolates that are resistant to erythro-

mycin but susceptible to clindamycin on initial testing be fur-

ther evaluated using D-zone disk diffusion testing. This assay is

capable of identifying S. aureus strains that are capable of clin-

damycin resistance under certain circumstances, and therefore

must not be treated with clindamycin monotherapy.46

As a consequence of studies such as Morans, clindamycin,

trimethoprim-sulfamethoxazole and doxycycline have been

recommended as first-line outpatient treatment for communi-

ty-acquired MRSA.46Ironically, 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. aureusis capable of acquir-

ing 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 staphylococ-

ci to coagulase-positive staphylococci as described by Naidoo.

This potential for horizontal transfer of resistance genes further

emphasizes the concern that dermatologists might induce resis-

tance against the main arsenal for MRSA, putting not only pa-

tients 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 antibi-

otics can change low-level intermittent carriers to persistent car-

riers (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 in-

fections, and S. aureus infection in hemodialysis and peritoneal

dialysis patients.48Although there are multiple sites on the body

that can be colonized with S. aureus, the anterior nares remainthe most common reservoir. Cross-sectional surveys have esti-

mated nasal carriage rates of 27 percent in the general popula-

tion. It should be noted that longitudinal studies have shown

there are three main patterns of S. aureusnasal carriage: per-

sistent 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 particu-

larly important to make this distinction because persistent car-

riers 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 samestrain of S. aureus at all times, while intermittent carriers are

more likely to shift between various strains of S. aureus.5254Ap-

proximately 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

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 nor-

mal, 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. aureusnasal carriage, and the rates of erythromycin resis-

tantS. aureusamong previous carriers increased from 1540

percent during the course of treatment. These changes persist-

ed for up to four weeks after the cessation of treatment before

returning to baseline.40A 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 reser-

voir for S. aureus. In this study, 105 acne patients at the derma-

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 pa-

tient 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. aureuscolonization

between the two populations, 44 percent of the S. aureuscul-

tures from antibiotic users.56This finding did not reach statisti-

cal significance.

Group A Streptococci: Colonization and InfectionStreptococcus pyogenes, also known as Group A streptococ-

cus (GAS), is a gram-positive coccus, and an exclusively hu-

man pathogen. As a highly adhesive extra-cellular organism, its

virulence is dependent on the presence of specific surface com-

ponents as well as the production of exotoxins.57GAS causesmany human diseases ranging from mild superficial skin in-

fections 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 nonpu-

rulent skin infections including cellulitis. It accounts for 1530

percent of childhood cases of acute pharyngitis and 10 percent

of adult cases.58Therapy for these infections is primarily aimed

to prevent both suppurative (tonsillopharyngeal cellulitis or ab-

scess, otitis media, sinusitis and necrotizing fasciitis) and non-

suppurative sequelae (acute rheumatic fever, post-streptococcal

glomerulonephritis and streptococcal toxic shock syndrome).

The oropharynx is the most common location for asymptom-

atic colonization of GAS. The asymptomatic carrier state, as evi-

denced by positive throat cultures in the absence of symptoms,

is typically not treated. However, it can still be easily transmit-

ted 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 clindamy-

cin is not affected by the size of the inoculums or the stage of

bacterial growth. Furthermore, clindamycin is capable of sup-

pressing the production of GAS toxins. Severe GAS infections

may lead to shock, multi-system organ failure and death, mak-

ing 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 commen-

sal organisms such as peptostreptococcus and viridans strepto-

cocci, 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. Eighty-

five 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 inasymptomatic individuals without acne.

These findings suggest that patients with acne may have relative-

ly higher baseline rates of bacteria in their oropharynx.20Of 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 administra-

tion 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 bac-

terial organisms to the oropharynx via a persons fingers or bydevices 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 ap-

plied.39,41An alternative mechanism is systemic absorption of topi-

cally applied antibiotic, leading to hematogenous spread of drug

to non-cutaneous sites such as the oropharynx.

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 infec-

tion (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 poly-

microbial. Bacterial colonization with one organism (e.g., GAS)

may facilitate the infectious capability of another (e.g., a respi-

ratory virus), by influencing their cell surface receptors.60,65,66

To address the clinical ramifications of increased GAS oropha-

ryngeal 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

in the General Practice Research Database (GPRD). Of these pa-

tients, 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, re-

gardless of whether they received antibiotic therapy, were fol-

lowed 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.67As was seen in Levy et al.s precursor study, these

effects persisted regardless of the mode of antibiotic adminis-

tration (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 im-plications need to be further studied in a controlled clinical trial

setting this study raises important considerations for both physi-

cians and patients when choosing a treatment plan for acne.

The association demonstrated by Margolis et al. also raises ques-

tions 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 con-

tagious 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, thechanges in resistance patterns of the cutaneous and intestinal

microflora of user and contact are concerning, it still remains un-

known 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 Unit-

ed 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.

Based on these findings, the increased risk of development of UR-

TIs 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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Therefore, although acne patients on antibiotics are more likely

to develop URTIs they are less likely to spread them.68These find-

ings are reassuring from a public health perspective. However,

they support the theory that antibiotic therapy is immunomodula-

tory, 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.68Therefore, even the anti-inflam-

matory 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 deter-

mined by a retrospective design.

CONCLUSION

Bacterial resistance to antimicrobial treatment has become a

significant problem throughout the developed world. Acne vul-

garis, the most common dermatological disease, is commonly

treated with long-term antibiotics. However, there are strong

reasons for concern. Given widespread and sometimes indis-

criminate 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 causativepathogen of acne, but also in other potentially pathogenic bacte-

ria, particularly certain strains of S. aureus, coagulase-negative

staphylococci and Group A streptococci.69This can lead to both

therapeutic failure of acne vulgaris and bacterial resistance at

other anatomical sites and in the patients environment. This lit-

erature 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.

Many potentially pathogenic bacteria are carried as human com-

mensals 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 poten-

tially pathogenic bacteria, including CNS, S. aureusand GAS.

Several studies have shown that antibiotic-resistant CNS can

be a major cause of serious infections in certain patient popula-

tions, and this resistance can be transferred from CNS to more

pathogenic staphylococci such as S. aureus.32,33,37,42The same an-

tibiotics (clindamycin, trimethoprin-sulfamethoxazole and doxy-

cycline) are used for both acne vulgaris and as first-line outpa-

tient treatment for community-acquired MRSA.46This raises the

question of whether the long-term antibiotics treatment of acne

vulgaris puts acne patients, their contacts and the wider com-

munity 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 reser-

voirs from which the bacteria can be spread. It has been demon-

strated that patients on anti-acne antibiotics have are more likely

to develop URTIs.68Further antibiotic therapy alone might impact

the normal balance of gastrointestinal flora via systemic absorp-

tion. The importance of this finding has yet to be determined.

It is imperative that steps must be taken to minimize the risk

of P. acnesdeveloping resistance.69It is important to limit the

use of antibiotics to the shortest possible period and to discon-

tinue their use when further improvement is unlikely. Antibiot-

ics should not be used for maintenance therapy of acne, and

simultaneous use of both oral and topical antibiotics shouldbe 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 anti-

comedogenic, comedolytic and anti-inflammatory, and/or ben-

zoyl peroxide, which is bactericidal and has some keratolytic ef-

fects. 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 treat-

ment of acne vulgaris.

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 Sci-

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

interest to disclose.

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Carol Heughebaert, MD450 Clarkson Avenue

Brooklyn, NY 11203

Phone: ......................................................................(718) 270-1229

Fax: .......................................................................... (718) 270-2794

E-mail: ............................................................cheugh@hotmail.com

ADDRESS FOR CORRESPONDENCE

jdd.antimicrobial.resistance.review.2010

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