Clinical implications of antibiotic resistance in Acne Vulgaris Therapy: risk of systemic infection from Staphylococcus and Streptococcus

INTRODUCTION

Antibiotic use has been associated with the emergence of resistant organisms, increased exposure to and colonization with pathogenic organisms, and increased risk of infectious illness. The growing prevalence of antibiotic resistance is rapidly eroding one of our 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. However, even what was thought to be the appropriate use of antibiotics for acne and rosacea has led to problems with resistance because of the chronic nature of these conditions.

Antibiotic-resistant Propionibacterium acnes is on the rise. Although the effects of antibiotic use on cutaneous microbial environments have been well studied, the effects on noncutaneous surfaces such as the nose and throat have recently come to the attention of the medical community. Recent studies are forcing dermatologists to ask the following questions:

  1. Are acne patients on long-term antibiotics more likely to harbor potential pathogens in their nose/throat?
  2. Are these organisms more likely to be resistant?
  3. Are these patients at an increased risk for systemic infection?

The impact of acne antibiotics on P. acnes and coagulase-negative Staphylococcus sp. has been extensively documented in the past (1 5). This post focuses on recent advances in our knowledge relating to the influence of acne antibiotic use on two serious potential pathogens: Staphylococcus aureus and Streptococcus pyogenes.

STAPHYLOCOCCUS AUREUS

S. aureus is a facultatively aerobic, coagulase-positive, and gram-positive coccus, which appears as grapelike clusters on microscopy. Although some strains of S. aureus can be human commensals in the perineum and axilla, other strains of S. aureus produce toxins, for example, the toxin associated with bul-lous impetigo, the leukocidin of methicillin-resistant S. aureus (MRSA), toxic shock toxin, etc., making it a frequent cause of infections in both the hospital and the community (6,7). 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 (7).

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 carriage 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) pro-ducing R-lactamase was in 1947, and within a decade, 90% of hospital-acquired S. aureus was resistant to penicillin (6,8). Then in the 1950s, methicillin, a R-lactamase-insensitive R-lactam, was used to effectively treat PRSA, but by 1961, S. aureus had evolved again forming resistance to methicillin. 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 world-wide (6,7).

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 departments across the United States. They examined 422 patients presenting to 11 university-affiliated emergency departments with acute skin and soft tissue infections. S. aureus was isolated from 76% 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%. 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 (9).

As a consequence of studies such as Moran’s, clindamycin, trimethoprim-sulfamethoxazole, and doxycycline have been recommended as first-line out-patient treatment for community-acquired MRSA (9). Ironically, these anti-biotics are commonly prescribed as long-term therapy for acne vulgaris.

Coagulase-negative Staphylococcus resistance develops within weeks of usage. 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 coag-ulase-negative staphylococci to coagulase-positive staphylococci as described by Naidoo (10). This potential for horizontal transfer of resistance genes further emphasizes the concern that dermatologists might induce resistance against our main arsenal for MRSA, putting not only patients but potentially the whole community at risk for infection (10).

There are several plausible mechanisms that might account for why anti-biotic treatment predisposes to MRSA infection and/or colonization. Antibiotics can partially suppress the normal, protective flora, leaving cell surface receptors open to colonization with pathogens such as MRSA. Additionally, antibiotics can directly select for preexisting 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 later in the post), allowing for increased transmission (11).

There is strong evidence to suggest that people colonized with MRSA in their anterior nares are at an increased risk for MRSA infection. 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% 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 noncarriage. Persistent carriers are likely to be carrying higher loads of bacteria increasing their risk of infection and ability to disseminate bacteria into the environment (12 14). 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 (15 17). Approximately 20% (12 30%) of individuals are considered persistent S. aureus carriers, roughly 30% (16 70%) are intermittent carriers, and 50% (16 69%) of individuals are noncarriers (14 16,18).

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 treated either with topical eryth-romycin or with 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 15% to 40% during the course of treatment. These changes persisted for up to four weeks after the cessation of treatment before returning to baseline (19). 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 Dermatology 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% of S. aureus cultures from antibiotic users were resistant to at least one tetracycline compared to 18% of cultures from nonantibiotic users (20). This finding did not reach statistical significance. Similar effects on nasal S. aureus had been seen in prior studies (21).

GROUP A STREPTOCOCCUS

Str. pyogenes, also known as group A streptococcus (GAS), is a gram-positive coccus and an exclusively human pathogen. As a highly adhesive extracellular organism, its virulence is dependent on the presence of specific surface com-ponents as well as the production of exotoxins (22). GAS causes many human diseases ranging from mild superficial skin infections to life-threatening sys-temic diseases. Pharyngitis and impetigo are the most common infections attributed to GAS today, but it can also occasionally lead to purulent and non-purulent skin infections including cellulitis. It accounts for 15% to 30% of childhood cases of acute pharyngitis and 10% of adult cases (23). Therapy for these infections is primarily aimed to prevent both suppurative (tonsil-lopharyngeal cellulitis or abscess, otitis media, sinusitis, and necrotizing fas-ciitis) and nonsuppurative sequelae (acute rheumatic fever, poststreptococcal glomerulonephritis, and streptococcal toxic shock syndrome).

The oropharynx is the most common location for asymptomatic coloni-zation 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 (24 28). Therefore, asymptomatic GAS carriers represent one of the main GAS reservoirs from which the bacteria can be spread to the general population (22).

Fortunately, GAS still remains, for the most part, susceptible to R-lactam antibiotics. However, clinical failures to penicillin therapy can occur. Penicillin and other R-lactam antibiotics are most effective against rapidly growing bac-teria. They have the greatest efficacy when organisms are in the earlier stages of infection or in mild infections. The efficacy of R-lactams may decrease later in infections when bacterial growth slows as higher concentrations of GAS accu-mulate. Consequently, clindamycin is considered more effective in the treatment of invasive GAS infections (29,30). 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, multisystem organ failure, and death, making early recognition and effective treatment critical.

We revisit the study of Levy et al., this time focusing on prevalence and resistance patterns of GAS in the oropharynx of acne patients (20). In this study, 105 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 threefold increase in the prevalence of GAS in the oropharynx of patients on antibiotic therapy. Eighty-five percent of the GAS in the treated patients were resistant to at least one tetracycline antibiotic. 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 person’s 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 (21,31). An alternative less likely (blood levels so low) mechanism is systemic absorption of topically applied antibiotic, leading to hematogenous spread of drug to noncutaneous sites such as the oro-pharynx.

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). Although 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 (25,32,33).

To address the clinical ramifications of increased GAS oropharyngeal carriage, Margolis and colleagues (including author WPB) designed a follow-up study to investigate the association between acne antibiotic use and URTI. We 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 patients, 71.7% were being treated with topical and/or oral antibiotics (tetracycline, erythromycin, or clindamycin), while 28.3% were not on any antibiotic therapy. All acne patients were followed for one year with the main outcome measure being the onset of a URTI or a urinary tract infection (UTI). 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 (34). As was seen in the precursor study of Levy et al., these effects persisted regardless of the mode of antibiotic administration (oral alone, topical alone, combination). Because of 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.

Our research team then turned to the household contacts of acne patients for two main reasons: first, to better understand the potential mechanism behind this URTI risk, and second, to fully recognize the public health impact resulting from administration of antibiotics. We set out to determine whether household contacts of acne patients with documented UTRIs are at an increased risk of developing a URTI when compared with household contacts of acne patients without documented URTIs. We identified 98,094 household contacts of acne patients and found that a household contact of an acne patient who had a URTI was about 43% more likely to develop a URTI than one without this exposure. However, when exposure to an acne patient with a URTI was controlled for, exposure to an acne patient using antibiotics did not independently increase a contact’s risk of URTI. Therefore, the development of URTIs in household contacts is likely due to the direct transmission of the URTI infectious agent and not exposure to another’s use of an antibiotic. Consequently, although acne patients on antibiotics are about two times more likely to develop URTIs, they appear to be less likely to transmit these URTIs to their household contacts. While reassuring from a public health perspective, this finding likely supports the hypothesis that antibiotics are immunomodulatory, thus predisposing acne patients to infections from pathogens that are not virulent enough to cause infection in a fully immune competent host. One might hypothesize that the anti‑inflammatory properties of antibiotics such as tetracycline’s ability to inhibit neutrophil chemotaxis may increase susceptibility to infections (35).

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. This chronic use of antibiotics has led to resistance among cutaneous microbes such as P. acnes, making the treatment of acne patients more challenging. Of equal importance from a public health perspective, recent evidence suggests that antibiotic use has an effect on colonization rates and resistance patterns of potential pathogens in the nose and throat of acne patients. Although one study has shown an associ-ation between acne antibiotic use and systemic infection, future studies are needed to corroborate these findings, and further elucidate the true clinical rel-evance of the antibiotic-induced shifts in microbial flora.

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Jean-Paul Marat

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