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Main Issue June 2009

"Antibiotics" in Dermatology: Facts and Myths

From clearing up long-standing misconceptions to making sense of new therapeutic developments, here are hard facts about antibiotics and their role in patient care.

By Joseph Bikowski, MD

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The introduction of antibiotics significantly changed the practice of medicine last century, and these agents continue to play a critical role in management of various diseases. Despite their therapeutic importance and versatility, these agents remain somewhat misunderstood by both patients and physicians. As we have learned over the last two decades, the class name itself is a misnomer; so-called "antibiotics" can confer notable anti-inflammatory effects. In light of growing concerns about proper use, problems associated with resistance, and new directions in formulation and use for non-infectious indications, it is helpful for dermatologists to recognize some important facts—and fiction—relating to "antibiotics."

MYTH #1. THE DISCOVERY OF "ANTIBIOTICS" DATES BACK TO THE EARLY PART OF LAST CENTURY.
Having discovered penicillin in the late 1920s, Alexander Fleming is commonly credited with initiating the development of antibiotic therapy. But his discovery came more than 30 years after the documented isolation in 1888 of Pyocyanase (secreted by Bacillus pyocyaneus) by E. de Freudenreich, a German scientist. Twelve years later, French physician Ernest Duchesne reported that Penicillium molds are bacteriocidal. Around the time of these discoveries, the word "antibiotic" from the Greek for "against life" emerged as an adjective to describe agents being investigated.

Of course, Fleming's documentation of a penicillium mold culture that prevented growth of staphylococci is better known than either of his predecessors'. Still, development of medicinal penicillin didn't occur for another two decades.

MYTH #2. ANTIBIOTIC IS A SPECIFIC TERM USED TO DESCRIBE A PARTICULAR CLASS OF AGENTS.
About a decade after Fleming's discovery, "antibiotic" was adopted in use as a noun to describe agents under investigation for their ability to inhibit bacterial growth in culture. In 1942 Selman Waxman,1 a microbiologist at Rutgers University, formally defined antibiotics, stipulating that they are:

antimicrobial agents, produced by a variety of microorganisms found among the filamentous fungi or molds, yeasts, actinomycetes, and bacteria. They are chemically and biologically distinct from the common antiseptic and germicidal agents, although certain synthetic preparations may have properties similar to those of antibiotic agents. They are primarily bacteriostatic in nature, that is, they inhibit the growth of bacteria, whereas their bactericidal activities are of only secondary consideration and require a longer period of time than that needed for ordinary disinfectants. One of the characteristic properties of antibiotic agents is their selective antibacterial action.

We have since learned that this apparently comprehensive definition of antibiotics overlooks important characteristic of this class of drugs as addressed below. For more on the actions of antibiotics as put forth by Waxman, see Table 1.

MYTH #3. DERMATOLOGISTS "ADOPTED" ANTIBIOTICS INTO USE FROM OTHER SPECIALTIES.
When Florey and Chain developed a medicinal form of penicillin in the early 1940s, the b-lactam antibiotic agent was immediately put to use preventing and treating infections in injured World War II soldiers, firmly establishing its role as an "antibiotic." Interestingly, the agent was of limited use early on, due to the need for refrigeration and limited viability of the drug in a patient's bloodstream. With Romansky and Rittman's beeswax-and-peanut oil formulation (1944), penicillin maintained activity for up to two months without refrigeration, and a single dose produced adequate serum levels for up to seven hours. Furthermore, a single injection of their formulation cured gonorrhea—a condition that then fell firmly under the purview of dermatology.2 A point worth noting is that the common admonition against drinking alcohol while on antibiotic therapy dates back to problems with early formulations of penicillin. Given concerns about rapid renal clearance of what was then an expensive drug, physicians warned patients to avoid alcohol, a mild diuretic. In fact, the drug was so expensive that in some instances, cleared penicillin reportedly was collected from patients' urine for reuse.

Development of bactericidal agents took a new turn with the patent approval of tetracycline in 1950. Development in the macrolide class of antibiotics led to a patent for erythromycin in 1953. Because tetracycline is chelated by heavy metals, it should not be taken with food, so the push for development of other tetracyclines was intended to obviate this concern. Doxycycline was introduced in 1968, followed in 1972 by minocycline.

A 1955 French publication3 described the use of tetracycline for pustular acne, with a second similar publication arriving the following year.4 The first published clinical study of tetracycline for acne appeared in 1956.5 Using antibiotics to treat acne made sense. Propionebacterium acnes had been implicated in the development of acne vulgaris, and the disease's hallmark pustular lesions signified an infectious etiology. Of note, while acne vulgaris (its name comes from an inaccurate reading of the Greek "akme" or point) lent its name to the bacterium, the organism has also been implicated in other conditions, including chronic blepharitis, endophthalmitis, endocarditis, and sarcoidosis. Studies have confirmed that tetracyclines inhibit P. acnes growth.

Publications from the mid-to-late 1950s show that tetracycline was tried with mixed results (in what with hindsight appears to be a relatively scattershot approach) for various dermatoses. These included bacterially-mediated diseases, such as lymphogranuloma venereum and donovanosis6 and furunculosis,7 as well as diseases which we currently know have no significant bacterial etiology, such as psoriasis (combined with phototherapy),7 eczema,8 and rosacea.9,10 Perhaps to some extent the persistence of the technically inaccurate "acne rosacea" moniker derived from the fact that rosacea, like acne vulgaris, responded to antibiotic therapy, suggesting potential similarities in their pathogeneses to correlate with their sometimes similar clinical presentations.

MYTH #4. ANTI-INFLAMMATORY EFFECTS OF TETRACYCLINES ARE SECONDARY TO ANTIBIOTIC EFFECTS.
The evidence now shows that "antibiotic" most accurately describes an action rather than define a class of drugs. Although the anti-inflammatory effects of tetracyclines were not initially appreciated does not imply that they are "secondary" effects. Anti-inflammatory properties of tetracyclines have been under investigation for at least three decades.

Early investigation focused on chemically-modified tetracycline (CMT) analogues, of which there are at least 10. These provide no antimicrobial effect and have current or theoretical applications in periodontitis, arthritis, osteoporosis, and cancer.12-14 Various analogues, modified so that the dimethylamino group from carbon-4 position (the side-chain required for antimicrobial activity) is removed, inhibit matrix metalloproteinases (collagenases and gelatinases) and lead to decreased expression of cytokines, including TNF, IL-1, and IL-6.15-17

Doxycycline administered at a subantimicrobial dose—a dose below the minimal inhibitory concentration—is effective for the management of inflammatory diseases. Twice-daily dosing of doxycycline hyclate is widely and effectively used for the management of periodontitis,28,29 which is shown to involve an increase in matrix metalloproteinases. Long-term sub-antimicrobial dose doxycycline therapy (up to 18 months) produced no changes in antimicrobial susceptibility in patients during the treatment period or up to six months post-treatment.

Studies have shown that minocycline has roughly 12-times the anti-inflammatory effect of tetracycline, and doxycycline has 33 times the effect.15 Investigation of the anti-inflammatory benefits of tetracyclines for acne began more than 25 years ago. Webster, McGinley, and Leyden showed that sub-MIC doses of tetracycline, declomycin and erythromycin inhibited in vitro lipase production by P. acnes.18 Subsequent in vitro investigations showed that tetracycline, minocycline, and erythromycin at sub-MIC levels produced decreased neutrophil chemotactic activity in P. acnes culture supernatants.19 These effects were more pronounced in P. acnes strains that had demonstrated antibiotic susceptibility than in non-susceptible strains. Akamatsu et al.20 showed that one-tenth the minimal inhibitory concentrations of erythromycin significantly suppressed neutrophil chemotactic factor production in all strains of P. acnes, P. granulosum and coagulase-negative staphylococcus (CNS).

Doxycycline 40mg once-daily is a sub-MIC formulation that is effective for rosacea, providing a 46-61 percent decrease in inflammatory lesion counts in Phase III trials sponsored by the manufacturer. These and similar findings support "anti-inflammatory dose doxycycline" as an apt name for this therapy.

MYTH #5. THE EMERGENCE OF MRSA OVER THE LAST DECADE TURNED DERMATOLOGISTS' ATTENTION TO PROBLEMS OF ANTIBIOTIC RESISTANCE.
The dermatology community has been aware of the risks of antibiotic resistance since the 1980s, when the first documented reports of P. acnes resistance to antibiotics emerged.21,22 Subsequent studies documented the phenomenon of antibiotic resistant acne and resultant treatment failure.23 Studies have found P. acnes resistance rates as high as 60 percent in some patient populations.24 Concerns about resistance led to development of new guidelines in acne management that emphasize topical antimicrobials and retinoids as well as shortened courses of systemic antibiotics in efforts to diminish dependence on oral antibiotics and thus limit risk of developing resistance.25

Among acne patients, development of resistance is not limited to P. acnes. Researchers have identified resistant strains of Staphylococcus epidermidis13,26,27 among acne patients treated with oral erythromycin and shown that systemic antibiotic therapy is associated with Streptococcus pyogenes colonization and resistance in the oropharynx.28

MRSA (Methicillin-resistant Staphylococcus aureus) is, of course, an issue of concern that has increased public awareness of resistance risks. Concern about long-term antibiotic use and subsequent resistance risk is especially high in light of the increase in reports of community-acquired MRSA skin and soft-tissue infections.29,30 Price et al report that MRSA accounted for just 1.5 percent of all strains of S. aureus at select dermatology outpatient clinics in 1988. In 1998 at these same clinics, 11.9 percent of all S. aureus strains were Methicillin-resistant.

In my own practice, the rates of MRSA have remained stable over five years. In 2008, I obtained 721 bacterial cultures. Of these, 260 (32 percent) were positive for Staph aureus, and 46 (seven percent of total) were positive for MRSA. This indicates that 19 percent of staph-positive cultures were MRSA.

Early last year, researchers described the multidrug resistant MRSA USA300 clone emerging in San Francisco and Boston; risk of infection was highest among men who had sex with men.32 This finding underscores the dynamic nature of bacterial resistance and the threat it poses not just in dermatology but in all of medicine.

Recognizing the growing problem of resistance and its potential impact on patient care, FDA mandated in February 2004 a warning regarding antibiotics, stating that they should only be used to treat infections. Subsequent labeling changes for antibiotic formulations reflects this.

MYTH #6. MECHANISMS FOR TRANSFER OF BACTERIAL RESISTANCE REMAIN POORLY UNDERSTOOD.
Thanks to genome sequencing and extensive investigation, we now know a great deal about the transfer of resistance between bacteria. Plasmid transfer is recognized as one of the major reasons for the increase in multiple-antibiotic resistant organisms and has been implicated in transfer of resistance among both gram-negative and gram-positive bacteria.33 A plasmid is a "packet" of double-stranded—usually circular—DNA separate from the chromosomal DNA that can transfer genetic material horizontally through a process called conjugation. The genetic material can become integrated into the host DNA and will be present in replicated cells. Studies describe an "amplification effect" of plasmid transfer within heterogenous bacterial populations with appropriate donors, where millions of bacteria can acquire a plasmid within a matter of days.34 Resistance has also been identified in plasmid-free strains, in which transposons have been identified,35 implicating either DNA transfer or viral transfer in the horizontal gene transfer (HGT) of resistance. Mobile genetic elements (MGEs) are known to spread between bacterium and to integrate.36 As one recent publication explained, "a crucial component of the prokaryotic world is the mobilome, the enormous collection of viruses, plasmids and other selfish elements, which are in constant exchange with more stable chromosomes and serve as HGT vehicles."37

Science has also revealed mechanisms of resistance within the bacterium. One of the primary methods of resistance is the efflux pump,38 whereby the bacterium essentially flushes out toxic substances (the antibiotic, in this case). Enzymatic deactivation is another mechanism; the modified (resistant) bacterium "disarms" the antibiotic either by degrading or altering it with enzymes.

MYTH #7. SUB-ANTIMICROBIAL IS MARKETING JARGON FOR "LOW-DOSE."
Antimicrobial activity of drugs is assessed by determination of the minimal inhibitory concentration (MIC) and/or the minimal bactericidal concentration (MBC). This figure is determined based on in vitro studies involving overnight aerobic incubation in a protein-free liquid medium at pH 7.2. The MIC is defined as "the minimal concentration of antibiotic that prevents the clear suspension of 105 CFU [Colony-forming Units]/mL from becoming turbid after overnight incubation; turbidity usually connotes at least a 10-fold increase in bacterial density."39 Bacteriostatic or bacteriocidal pharmacologic agents are formulated, dosed, and administered so that peak concentrations exceed the MIC for sufficient duration (which varies based on the type of antibiotic) to confer effects on bacteria.

A sub-MIC formulation is one for which peak plasma levels do not exceed the MIC. Since an agent that does not produce peak plasma levels of above the MIC cannot confer bacteriostatic or bacteriocidal actions, it may be considered sub-antimicrobial dose (SDD). In contrast, an antibiotic formulation described as "low-dose" confers bacteriocidal or bacteriostatic effects. The "low-dose" designation simply indicates that, from the range of dosages that will safely produce plasma concentrations above the MIC, the formulation so described is dosed at the lower rather than higher range. "Sub-antimicrobial" does not mean "sub-therapeutic."31 Data and clinical experience both show that sub–antimicrobial dose antibiotics can confer anti-inflammatory effects in the management of acne and rosacea.

RETHINKING "ANTIBIOTICS"
It is essential that dermatologists understand the realities of "antibiotic" therapy, recognizing the historical factors that influenced their development and use. Physicians must comprehend the anti-inflammatory nature of antibiotics and recognize the distinction between anti-inflammatory dose formulations and low-dose formulations. Dermatologists were among the specialists that quickly adopted standard antibiotics into practice and can remain on the forefront of the adoption of novel, sub-MIC formulations.

Dr. Bikowski has served on Advisory Boards and Speakers Bureaus and received honoraria from CollaGenex and Galderma. He has received honoraria and owned stock in Medicis and received honoraria and served on the Speaker's Bureau for Warner-Chilcott.

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