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Another threat to the availability of isotretinoin: ocular side effects have aviation authorities considering restricting use from (even potential) pilots

  • Author(s): Burkhart, Craig G
  • et al.
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Another threat to the availability of isotretinoin: Ocular side effects have aviation authorities considering restricting use from (even potential) pilots
Craig G Burkhart MD MPH
Dermatology Online Journal 14 (7): 2

University of Toledo College of Medicine, Sylvania, Ohio. cgbakb@aol.com

Abstract

Current concerns about persistent visual abnormalities after the use of isotretinoin may lead the Federal Aviation Administration to further restrict its use in pilots or future pilots.


One side effect that has barely registered above the radar screen with isotretinoin is potentially persistent ocular abnormalities, namely corneal opacities, raised intracranial pressure, and retinal abnormalities, specifically night blindness. Thus far, the Federal Aviation Administration of the United States of America has only limited employees from flying at night while on isotretinoin, but more restrictions on pilots are being considered. Indeed, there is some concern whether the use of isotretinoin may totally rule out a career in flying [1, 2].

There are numerous issues here. First, the fact is that some persistent visual defects with isotretinoin can be demonstrated by electroretinograms and these alterations persist for at least 8 years in some individuals [3]. Thus, not all the ocular side effects are temporary and spontaneously resolve. Inasmuch as vision is for all practical purposes via cones, the importance of an isotretinoin-induced functional defect with rods may be insignificant.

Secondly, guidelines by aviation authorities are often bordering on ridiculous. For example, finasteride use requires aircrew be grounded for 7 days for observation. Topical minoxidil can not be prescribed for pilots for fear of a few cases of possible fainting and dizziness with the drug. Nevertheless, in terms of isotretinoin, some countries already have higher restrictions on pilots who might use the drug. For example, in England not only can't a pilot fly for a month after using isotretinoin, he or she must have a form ophthalmologic examination before returning to the cockpit [4].

Could questionable ocular deficiencies also lead to restrictions in isotretinoin usage with other professions in which good night vision is required? With lawyers, anything is possible. Who could have foreseen the iPledge Program and all the guidelines related to mood alterations with this drug?

To steer away from further restrictions on isotretinoin, it may be prudent to reconsider present dosing of the drug. In short, lower dosing may reveal much less tendency toward any persistent ocular side effects. Although Gary Peck's initial studies took a dose of isotretinoin which was one-tenth of the amount that caused teratogenicity in rabbits, there has never been a dose of isotretinoin, to date, that hasn't delivered excellent clinical results over 4 to 5 months of therapy [5]. Indeed, 10 mg of isotretinoin has been a sufficient amount for 20 weeks in my clinical practice to give equivalent results to higher dosing in terms of completeness of clinical response and longevity of the remission.

To assess dosing issues, one must appreciate how the drug works in acne. Obviously, isotretinoin causes temporary sebaceous gland shrinkage, but the effects of this anatomical alteration require an appreciation of the acne biofilm [6]. There is growing evidence that alteration of the physical, biological, and chemical environment of the pilosebaceous unit is the primary function of all acne therapy [7].

Expanding on this concept, most bacteria exist not as free-floating microorganisms, but as biofilms. This designation means that populations of bacteria adhere to environmental surfaces (such as the pilosebaceous lining) and encase themselves in an extracellular polysaccharide which they secrete. The extracellular matrix usually comprises two-thirds of the biofilm mass and acts as a protective exoskeleton and physical barrier, limiting the effective antimicrobial concentrations within the biofilm microenvironment. In acne, the Propionibacterium acnes biofilm allows the organism to survive in hostile environments [6, 7, 8]. The complete P. acnes genome supports the existence of the P. acnes biofilm [9]. In short, the P. acnes genome contains clusters of genes involved in polysaccharide capsule biosynthesis of a glycocalyx polymer, which account for adherence to a surface in biofilm formation secreted by the organisms [10]. For example, there are several sequences granting the genomic machinery necessary to make biofilm, such as UDP-N-acetylglucosamine 2 epimerase and glycosyl transferases [5]. Indeed, these substances assisting adherence of the bacteria that likely contribute to corneocyte adhesion and the production of comedones as well [11].

Propionibacterium acnes is the overwhelmingly predominant microorganism in the pilosebaceous unit. It is serologically and biochemically identical to Corynbacteriaum parvum, a potent stimulator of the reticuloendothelial system. It is an indigenous bacterium that has been suggested to be pathogenic in several cutaneous disease states including granulomas in sarcoidosis [12]. Moreover, incriminating studies such observing API 20A systems, 16sRNA sequencing, DNA-DNA hybridization, XTT reduction method, and scanning electron microscopy have suggested that the P. acnes biofilm is an inciting factor for orthopedic infections [13] and in fatal bacterial granulomas after trauma [14, 15].

Standard laboratory in vitro bacterial sensitivity studies with P. acnes from fatal bacterial granulomas did not identify antiobiotics that were clinically effective in vivo possibly due to the increased antibacterial resistance from biofilm formation. However, the P. acnes biofilm can be formed in vitro, in which it takes 96 hours for maturation of the biofilm in culture. Of significance from such studies are that certain antibiotics, such as lincomycin, in sub-minimal inhibitory concentrations, enhances and accelerates the biofilm forming ability of the P. acnes. Thus, long-term therapy with certain antibiotics can improve biofilm formation and clinically aggravate the condition. Of note, the minimum inhibitory concentration of P. acnes was not affected by long term therapy with minocycline, one of the common antibiotics used in the treatment of acne.

Isotretinion probably acts in several ways; one of these is by significantly shrinking the sebaceous glands. By doing so, the P. acnes biofilm is greatly altered. As the glands begin to shrink in the first 2 months of isotretinion therapy, these bacteria are still capable of secreting substances that may be quite inflammatory, potentially leading to a labile clinical course. As the full 4- or 5-month treatment course is completed, the P. acnes biofilm is considerably altered, bacterial counts are greatly diminished, and clinical resolution is usually achieved. To reestablish an acne biofilm that enhances production of a corneocyte plug, the bacteria have to reattach to the follicular lining in many cases, this just doesn't occur following a treatment course with isotretinoin, especially in patients over 20 years of age. The dosing of isotretinoin may not be the major factor in determining bacterial reattachment to the follicular lining and reestablishment of the pathological biofilm conditions. Indeed, topical measures post-isotretinoin treatment may be more important than presently appreciated.

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