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On the intensive care where I used to work, some have policies rotating the antibiotics widely in use in these very, very sick patients, who can't do without, every three months, because developing antibiotic resistance by these bacteria is a real risk, making hospital acquired infection such a feared complication of having been hospitalized. This indeed did work in preventing the emergence of antibiotic resistance strains of bacteria.Otherwise risk Antibiotic-resistant 'superbugs' pose global health crisisOn ampicillin, its value, since it is old and has been much prescribed, isn't so high anymore, in The Netherlands we at present don't prescribe it for an UTI anymore because of high bacterial resistance to it. In the waste water of a US hospital it was found that of the large bowel bacteria (here most people harbor their resistant bacterial strains) from the feces 73.9% were ampicillin resistant see Incidence and transferability of antibiotic resistance in the enteric bacteria isolated from hospital wastewater. So even being resistant to ampicillin doesn't make your bowel bacteria the feared "super-resistant bugs".If you have time, this is a copy of an extensive discussion on the matter of acne treatment, including antibiotics and its risk, copied from Medscape, only to be accessed by medical personnel, alied professionals and students of those professions, the most important sentence for you would beI do think that we have been fortunate that even though there has been emergence of resistant bacteria, it hasn't appeared that we have strains that are dangerous to the individuals. So we haven't had clinical consequence with the resistance.This is the discussion:Long-term Oral Antibiotics for Acne: Focus on Safety (Slides With Transcript)Lawrence Eichenfield, MD:Hello, my name is Dr. Lawrence Eichenfield. I am Professor ofPediatrics and Dermatology at the University of California San DiegoSchool of Medicine in San Diego. I am Chief of Pediatric and AdolescentDermatology at Rady Children's Hospital and Health Center in San Diego.We are pleased to be together here today to have a Medscape spotlightpanel and CME activity entitled "Long-term Oral Antibiotics for Acne:Focus on Safety." Today I am joined by my colleagues, Diane Thiboutot,Professor of Dermatology at Pennsylvania State University College ofMedicine in Hershey, Pennsylvania, and Dr. Guy Webster, Professor in theDepartment of Dermatology at Jefferson Medical College in Philadelphia,Pennsylvania. Welcome, colleagues.Today we are going to discuss some aspects of acne and long-term therapy with oral antibiotics, specifically looking at aspects of safety. We'll start off discussingthe pathophysiology of acne and how it relates to current treatments for acne, a little bit about antibiotic resistance, some discussion on adverse events associated with oral antibiotics for acne, and then we will discuss a practical example of how we take our information and use it for taking care of patients. First of all, Diane Thiboutot will discuss the pathophysiology of acne. Diane?Diane M. Thiboutot, MD:Well, Larry, as we are all familiar, the pathophysiology of acne really involves 4 factors. You have the follicular hyperkeratinization where the cells that line the follicle become cohesive, and they are not shed onto the surface of the skin like they normally would be. The second is you have the Propionibacterium acnes bacteria. We're learning a lot more about P acnes resistance and the role that P acnes plays in inflammation. The third is sebum production. So the oil gland enlarges and produces more sebum, which sort of exacerbates the acne process. The last factor is the inflammation, and again we're learning a lot more about the inflammatory factors involved in acne.Dr. Eichenfield:From a core standpoint, what are the basic prerequisites of acne -- why a 4-year-old doesn't have acne as compared to a teenager.Dr. Thiboutot:Oh, well, that's interesting.That's where hormones play a role. So we know that infants can have acne in the early neonatal period, and that's a leftover from the maternal hormones. In addition,the adrenal gland of a very young baby is also quite active at making hormones. So during the period after infancy up until just prior to puberty, it's a relative period of quiescence of the hormones. So as a child begins to enter adrenarche where the adrenal gland starts making androgen hormones and then puberty, this is where the effects of hormones are noted on the sebaceous glands. At that point in time, thesebaceous glands become more active; they become enlarged; and that's where the acne process can begin to develop. But interestingly, acne has been noted by Dr. Lucky and others to occur even at the time of adrenarche, even before puberty. So there is that prepubescent type of acne that can also be bothersome for quite a few children.Dr. Eichenfield:And their mothers in particular.Dr. Thiboutot:ExactlyDr. Eichenfield:One way of looking at the different factors in acne... One question that often gets raised is: Why is someone's acne so much worse than someone else's? Is it one particular element of the process?Dr. Thiboutot:Yeah, we haven't really sorted that out yet. We know that we have the 4 factors involved, and we really don't know which factor comes first. Is it the keratinization disorder? Is it the sebum production? Is it the P acnes or the inflammation? We're really not sure, but what we do know is there seems to be a strong genetic component to acne, and I'm sure you have observed in your practice -- and you have as well -- that many times where the parent has severe acne the child is getting acne that is more severe and is getting it at a younger age. It's important to recognize these families and these children because getting earlytreatment for their acne is really important.Guy F. Webster, MD, PhD:I kind of take the view that the variation in inflammation is probably due to variation in the immune response to P acnes. Perhaps that element that is passed from bad acne in the father to the son is an ability to hyper-respond to P acnes.Dr. Eichenfield:Why don't we move over to some of the current treatments of acne, just a general overview, and then specifically some of the oral antibiotics and how they relate to the pathogenesis of acne and how you niche them in relationship to your different patients?Dr. Thiboutot:I think people always wonder why is it when I come out of the dermatologist's office do I have so many prescriptions for my acne?I think the reason is because apart from some very strong medications like isotretinoin, we don't have medications that address all of the pathogenic features. So we are prescribing different things to treat the P acnes, to reverse that follicular hyperkeratinization, to reduce sebum production, to reduce inflammation. So the therapy is really designed at trying to target the pathogenic factors. So we can go about that in different ways.Topical retinoids can reverse that abnormal keratinization, so they are used in that process. They also have anti-inflammatory activities.Antibiotics, both topical and oral, are used to treat the P acnes bacteria. Many of the topical and oral antibiotics can also have intrinsic anti-inflammatory activity.There are other things that are again aimed at inflammation. There is a topical dapsone product that has become available. Azelaic acid has been used to treat acne.In terms of sebum production there are really only 2 ways to attack that. One is with oral contraceptives in women or antiandrogens, such as spironolactone [off-label use], and then isotretinoin is really the major agent against sebum production. So we really don't have much in the way of therapies for reducing sebum production.Dr. Eichenfield:Two questions about products that we consider in therapy: One is where do you mix in benzoyl peroxide? Do you categorize that as an antibiotic because you didn't mention that in the collection of agents?Dr. Thiboutot:Benzoyl peroxides I look at as being antimicrobial and antibacterial, not as an antibiotic per se.Dr. Eichenfield:Okay, and now specifically since we are going to be discussing the safety of oral antibiotics, can you discuss the standard oral antibiotics and both when you generally use them in therapy and also which ones are most commonly used?Dr. Thiboutot:Yeah, in terms of oral antibiotics, tetracycline has been used for a long time. So there is tetracycline and members of the tetracycline family, like doxycycline and minocycline, and those are all available in oral formulations. With the doxycycline, there is a lower-dose anti-inflammatory dose doxycycline, which hasn't been really used in acne, but it has been used in other conditions like rosacea. With minocycline, that is thought to be the most potent antibiotic in acne, and it is available in a variety of formulations, and we have beenmoving more recently toward a weight-based dosing approach for minocycline to help to improve issues of safety. So those are most of the oral antibiotics. We used to use a lot of erythromycin years ago, but I think that nowadays the P acnes bacteria has become resistant to the erythromycin. In topicals, we use clindamycin oftentimes combined with benzoyl peroxide. A topical erythromycin can be used, butagain, [there is] the concern about the resistance as well.Dr. Eichenfield:We don't have time to go through all the treatments in acne, but I guess there are some combination products with retinoids and antibiotics that have also been introduced in the market.Dr. Thiboutot:Right, yeah. There are retinoids along with... There's a combination of a topical retinoid, tretinoin, along with clindamycin. There are also combinations of benzoyl peroxide along with clindamycin and with erythromycin. So the combination products are beneficial in that it helps to increase patient compliance, I think.Dr. Eichenfield: And recently, an adapalene-benzoyl peroxide has been introduced. But you had mentioned bacterial resistance. That's a good segue to turn over to Dr. Webster, and Guy, I'd like you to discuss what the issues are with bacterial resistance in acne.Dr. Webster:Resistance in acne is something that we didn't think about 25 years ago. Early in my scientific career my assignment was [to] go find resistant P acnes. [I] couldn't do it. Jim Leyden said, "go out and get it, son," and I as an eager college student and I did everything to P acnes that one could do to make it resistant, and it just wouldn't.Then all of a sudden, topical erythromycin was introduced therapeutically, and within about a year and a half we could find resistant P acnes at will in anyone who was using topical erythromycin. We know now that it takes 6 or 8 weeks in 2009 to generate resistant P acnes in a patient when you begin treatment with topical erythromycin or topical clindamycin. Clindamycin has a little bit lower resistance than erythromycin, but both are very high and both grow. The consequence ofthat is...Dr. Eichenfield:Even if the bacteria aren't resistant to get started.Dr. Webster:Exactly.Dr. Eichenfield:From someone else you will select out.Dr. Webster:You either have clones of resistant bacteria on you before treatment that are in the background or you meet somebody in school and trade a few bacteria, and before you know it the resistance is there. It's been shown to be increased in families of people who are on topical macrolides. It has kind of ruined topical macrolides as monotherapy for acne.We now need to do other things, like, for example, add benzoyl peroxide, which as you said Diane, is a disinfectant more than an antibiotic. So far there are no bugs that have figured out a way to resist being oxidized. So simultaneous treatmentwith erythromycin or clindamycin and benzoyl peroxide will keep the resistance down and keeps those drugs still active. What is the consequence for treating acne besides that? Well, the emergence of resistance has made it more difficult to treat acne because you've got to use more drugs. It has taken potent drugs and rendered them less potent, and it's kind of a warning to us as to what we better not be doing with other drugs like minocycline and doxycycline, which so far have a much lower incidence of resistance in acne. In addition [they] have the useful second mechanism of action of not only being antibacterial, but also being anti-inflammatory. So even when there is some level of resistance, the anti-inflammatory activity that they haveworks on making the acne better.What regimen should you start to try to keep people from being resistant? Well, one of them is the benzoyl peroxide that I talked about. Another is to be certain, especially when you have someone on an oral antibiotic, that you begin treatment also with a topical retinoid. We've all done studies showing that you can get patients to be weaned from oral antibiotics after several months if they have been started on topical retinoids simultaneously. The benefits of this are obvious: Less antibiotic means less chance to generate resistance; less pumping of antibiotic into theenvironment; and, in general, it seems it's not only good medicine, butit's like good public health to do that, too.The other question that comes up with resistance is: Not only are we making P acnesresistant and acne harder to treat, but are we raising up resistant normal flora in patients who are on acne drugs? The answer we used to give was absolutely not; it's not an issue; we've never seen it. But now there are some studies. Jim Leyden a couple of years ago did a very nice study where acne patients were treated for 12 weeks with [oral] tetracycline[s] [and/or topical antibiotics], had their oropharyngeal] Staphylococcus and Streptococcus cultured, and he found that streptococcal colonization [was more prevalent in acne patients receiving antibiotics].Many of those strep were resistant to tetracycline [antibiotics]. So [this was] a clear demonstration in acne patients in a short time that you can raise up resistant bugs to a drug that you might well use to treat a streptococcal infection, say in a pen[icillin]-allergic kid. So it's a real thing,and I think it's incumbent on all of us to try to find a way to use the oral antibiotics properly. Maybe not less, but to use them properly.Dr. Eichenfield:I do think that we have been fortunate that even though there has been emergence of resistant bacteria, it hasn't appeared that we have strains that are dangerous to the individuals. So we haven't had clinical consequence with the resistance. One of the ironies is that the same cycline products that we rely on for acne treatment that are used fairly broadly in the United States for acne treatment actually have very good efficacy against Staph aureus and...Dr. Webster:Yes, and MRSA [methicillin-resistant Staphylococcus aureus] in particular.Dr. Eichenfield:MRSA in particular. They have become commonly used for that. So at least the use and change on resistance patterns for P acnes is one issue, but for other bacteria it hasn't influenced its utility to be used for other agents.Dr. Thiboutot:But getting back to Guy's point, it does point to the fact that it's important for everyone to use them judiciously and use them only really for as long as you need.Dr. Eichenfield:Yes, both for the right patient selection, but also I think there has definitely been a move among acne experts to be judicious; use the least quantity or time course of oral antibiotics that you need in a wholetherapeutic regimen.Dr. Webster:Yeah, and sometimes this judicious use means actually going to an oral antibiotic sooner because you will get it over with quicker rather than fiddling around with lesser treatments and stepping your way up to the right drug. Maybe treating with more than they need to get it done and thenback off to topicals quickly.Dr. Eichenfield:I do think we take an approach of what is our projection of what set of medicines we may need for that particular individual, and being more aggressive with sets of therapy may actually allow you to use lessmedicine over time.Dr. Thiboutot:Yes, I agree.Dr. Eichenfield:Which is clearly in the interest of patients to get better sooner anyway. Okay, great. Well, why don't I discuss a little bit about some of the concerns we have with oral antibiotics for acne. I sort of separate the adverse events into the shorter-term adverse events and then the potential forlong-term adverse events.So short-term adverse events are things that can happen immediately or within a few weeks of therapy. With basically all of the general cycline-used products -- tetracycline, doxycycline, minocycline -- there are a few things that we can seeamong all of them. For instance, there is a low rate of urticaria that can occur with individuals who have been sensitized to the individual drug or to the class of drugs and can develop that with use within sometimes a few weeks of therapy. There are some GI [gastrointestinal] effects that we can see with our different drugs. Tetracycline is a difficult drug to use, not only because of the GI effects, but also toget good absorption, you should really take it on an empty stomach 1 hour before or 2 hours after meals, which is very hard for an individual to work into their schedule.Dr. Webster:It's a programmed noncompliance.Dr. Eichenfield: Yes, which is why most acne experts generally will use doxycycline or minocycline, and they can be used with or without food. Many people feel that food can decrease some of the side effects, and in some of the newer formulations there are daily preparations of minocycline that show that with food or without food you get the same level of absorption and no impact on a low level of GI side effects. How about the pigmentary issues with the systemic antibiotics? I think we are aware that sometimes with minocycline, in particular, you can get this bluish-gray discoloration with the medication. Do you worry about this?Dr. Thiboutot:It's something that I advise patients. Like you mentioned, it may be blue-gray; it may be isolated to a certain area; it could occur in areas of acne scarring. I do mention to patients if they do notice an area oftheir skin that is darkening to please let me know. But in my experience, when that has happened it has generally been in patients that have been on the medication for quite a long time. I'm not familiar that it happens in the relative short term.Dr. Eichenfield:I've seen it short-term, but that's against most of the literature and cumulative expert experiences. It's generally with longer-duration use and probably quantity of use. In one of the studies, there was a 2-yearlong-term safety study of one of the everyday oral minocycline products and they didn't see any in that 2-year period, but that's a product that is weight-based dosed at 1 mg/kg, which is probably half the dosing of what the traditional minocycline products are.Dr. Webster:In my practice there have been 2 main groups of patients who get the problem of pigmentation. Both of them are small groups, as you said. One is someone who has smoldering inflammation, whether it's old acne nodules that are just not going away on the back -- they can get bluish -- and the other is people with stasis dermatitis often get gray ankles. I think the commonality is smoldering inflammation and maybe even calcification because we know minocycline loves to bind to cations; that may have something to do with it.Dr. Eichenfield:Now doxycycline generally has less of those pigmentary problems, but doxycycline clearly has a dose-dependent photosensitivity, which makes it more limiting, I think, in different areas of the country depending,or times of the year.Dr. Thiboutot:One of the things that I've always been curious about is I don't know about you, but the patients that I have seen with the photosensitivity, oftentimes it's on the forearm and on the wrists. Have you noticed that?Dr. Eichenfield:No, absolutely.Dr. Webster:It's exposure.Dr. Thiboutot:It's peculiar. I don't...Dr. Eichenfield:I think it's truly in some patients at higher doses; at least it's a photosensitizer. We see it a lot. You see a lot on the dorsal hands, and I have seen it in bikers who wear biking gloves, and you just see this incredibly bizarre shape where the hole is in the glove. We also, having been practicing in San Diego, photo-onycholysis is a phenomenon that we see probably 1-3 times a year.Dr. Thiboutot:How does that appear? I haven't seen it.Dr. Eichenfield:Onycholysis is a lifting off of the nail, so what you see is what lookslike an expansion of the little white base of the nail, and the nailjust looks partially lifted off.Dr. Webster:It always starts at the base, which is bizarre.Dr. Eichenfield:But that's a rarer form than just having people come in who look rather red and sunburned, but we have people who it can really change their tendency to do that -- but that is also dose-dependent. The data shows that if you are at 100 mg twice daily, for a 50-kg person you will have a much higher chance, probably in the 10% to 15% range [or higher], of having photosensitivity than if you were at a lower dose per weight.Dr. Webster:But a little patient education, ie, use the sunscreen; don't take it if you areabout to go to the beach; maybe take it at night in the summertime.Dr. Eichenfield:Yes, try to make them aware that if suddenly they find that they are more sensitive, then they need to change their patterns.Dr. Webster:If they are aware and they burn, you are a hero. If they are not aware, you are a villain.Dr. Eichenfield:That may be appropriate. I'd like to move over to some of the long-term safetyissues with oral antibiotics. We related that we try to limit the use when we can, but I guess some questions I have are how much do we really have to worry about this? I saw this as 3 topic areas.One is the bacterial resistance, which I think we discussed to a degree.The other is: Do you worry about more problems with extended use with the different antibiotics vs is there an impact on the immune system, an impact on other infections?Then another question is there are these rare problems, which caninclude hepatitis or arthritis or lupuslike syndromes, that can be seen.They have been reported more with minocycline. What are some of theissues related to those? So I guess the first question is, why don't wesay, with systemic antibiotic use, do we worry about it impacting theimmune system or the ability to handle other infections?Dr. Webster:The short answer is no. As far as we know, these drugs are at best anti-inflammatory, which is very different from being anti-immune, and the cumulative dosing doesn't seem to make any changes in the ability of the host to defend itself.Dr. Eichenfield:Well, there was an interesting article by David Margolis [and colleagues].It was a retrospective database survey of a United Kingdom database where they looked at people who were put on oral antibiotics and then also looked on their recorded upper respiratory infections. It wasn't a prospective study but that actuallysuggested an interesting observation that you know they had 1-2 more colds per year, those individuals who were on antibiotics for acne.Dr. Webster:I'd like to see it a little bit more rigorously done.Dr. Eichenfield:In practice we certainly don't see that, and to be truthful, most of myacne patients if I said you could get 1-2 more colds per year -- yet oral antibiotics were adequately controlling their acne and their regimen of care -- they would be happy to keep on the oral antibiotic.How about those: There is some data or occasional rare cases of moresystemic effects from long-term oral antibiotic use -- hepatitis,arthritis, lupuslike syndromes?Dr. Webster:Do you really want to call that from long-term use or from idiosyncratic reaction? It's not as though there is a dose-dependent buildup of risk of hepatitis or autoimmunity. It's a unique event unrelated really to duration.Dr. Eichenfield:Yeah, I think that's correct. I mean there is -- the data that we have until very recently, there was no prospective data -- any sort of long-term safety registry for the use of any of the oral antibiotics. When you look for anything other than minocycline there is nothing at all in the literature. Those drugs generally got approved at a time at which there was no need for long-term safety databases.We do know that there are reports in the literature of lupuslike syndromes or hepatitis, and it's hard to figure out in the literature "what is the background noise." For instance, you can have abnormal LFTs [liver function tests] from otherthings, such as drinking and other aspects of things that may not be related to the medication. We are aware that there is a long-term 2-year safety study that I mentioned on a once-a-day oral minocycline product that tried to get a database looking at things like hyperpigmentation, GI side effects, as well as the lupuslike syndrome.Dr. Thiboutot:Now how long was that study in duration? Two years?Dr. Eichenfield:It was a 2-year long-term study, and it's interesting because, for instance, if you look at ANAs [antinuclear antibodies] the punch line is ANAs probably aren't predictive of anything, but there are some patients who developed positive ANAs during the study, but there were also patientswho had positive ANAs at the start of the study and they went away.Dr. Webster:There were patients who developed positive ANAs, stayed in the study, and had the ANA go away.Dr. Eichenfield:Even though they continued the medication. So when it comes to ANA data, you have to remember that ANAs are a population phenomenon, and depending upon what ANA you are calling positive, you can have 20% or 30% --at 1:40 it's over 30% of the population -- who will have a positive ANA. At 1:[320] it is still about 3% to 3.5%, in patients who are considered not to have rheumatologic disease or any hypersensitivity syndrome. So the ANA itself isn't that important, but we have had; there are rare cases of people who probably have either [an] arthritis-like syndrome or lupuslike syndrome that may be associated with minocycline, though it's rather rare. So any other comments on other concerns that people may have with long-term antibiotics from an adverse events standpoint?Dr. Webster:There are plenty of concerns that people bring in. Most of them are worried about weakening the immune system and just generally being on medicine you don't need. We know weakening the immune system is without data so far, and good medical practice would have you be not on medicine you don't need. So again it's back to the old adage of give them enough to get them better and then get them off of it.Dr. Eichenfield:I always hate that I'm spending a lot of time on adverse events to not... I wantto make sure that we are also very positive. We standardly use oral antibiotics for moderate-to-severe acne as part of the regular standard of care practice in dermatology because they can be highly, highly useful in controlling the inflammatory component of the disease. You can take a severe patient and make them mild or even better with regimens of care.One question I wanted to ask is:Let's say we have a typical scenario where someone comes in and theyhave moderate acne on the face and trunk. You put them on an oralantibiotic and a topical retinoid, for instance, plus or minus benzoylperoxide. The benzoyl peroxide of course we know gives an advantage thatyou may be decreasing the emergence of bacterial resistance, but theyare on a good systemic antibiotic to get some kick on things. We'reusing the retinoid to stop the plugging, and it's 3 months or 4 monthslater and they come back in the office, and they are 85% controlled andthrilled with the state of their acne.Dr. Webster:Well, I would say that's a miracle to start with. Because any acne patient who comes back at 3 months and is 85% better, it means they were actually using the medicine for 3 months. We know that outside of treating the disease, compliance in acne is a huge deal, and you can't wait 3 months to bring them back, as burdensome as that can be. You've got to see them every month or every 6 weeks and really push them to use the drugs, because truly if you don't use the drugs it doesn't make it better andneeds continual usage, not just spot usage. So what would I tell them assuming that they are that miracle patient?Dr. Eichenfield:Assuming that they are compliant and doing great, yeah.Dr. Webster:I would make sure they were using the retinoid faithfully, and if they had been I would take away their oral antibiotic.Dr. Thiboutot:I would do the same. I would continue them with the retinoid and the benzoyl peroxide.Dr. Eichenfield:Yeah, and many times in practice I actually have the discussion with the patient where I've said, "Look, we don't want you on long-term antibiotics if we can help it. You're doing great." We have a decision to make here, and it's really a binary decision. Try to get them off the oral antibiotic at that time substituting topical or rolling it on a few more months. Depending upon how severe their disease was previously, I wouldn't mind another 2 or 3 months on balance in taking care of thatpatient.Dr. Thiboutot:I think you really have to go by what their disease is telling you. That's absolutely important.Dr. Eichenfield:Yeah, but the general idea is that if you don't need to continue the oralantibiotics, it's great to get them off. But many times when you convertthem over they may flare, and then you may be back putting them onlonger-term use of oral antibiotics, which is still...Dr. Webster:Then you will also know who wasn't using the retinoid.Dr. Eichenfield:That may be, yes. So in other words, we definitely like to use those topicalmedicines when we are converting patients over into a good maintenanceregimen that may not need oral antibiotics. On the other hand, I think we're pretty comfortable using them when we need to. Well, I think we had a great overview of acne therapy and understanding how the pathogenesis of acne really leads to the therapies that we use and a good discussion on the placement of oral antibiotics, specifically in acne care, and some of the issues concerning their safety. I appreciate my panel members being involved. Thank you, Dr. Thiboutot and Dr. Webster. I'd like to thank the audience for viewing this program today.ReferencesLucky AW, BiroFM, Huster GA, Leach AD, Morrison JA, Ratterman J. Acne vulgaris inpremenarchal girls. An early sign of puberty associated with risinglevels of dehydroepiandrosterone. Arch Dermatol. 1994;130:308-314. AbstractLucky AW, BiroFM, Huster GA, Morrison JA, Elder N. Acne vulgaris in early adolescentboys. Correlations with pubertal maturation and age. Arch Dermatol.1991;127:210-216. AbstractLevy RM, HuangEY, Roling D, Leyden JJ, Margolis DJ. Effect of antibiotics on theoropharyngeal flora in patients with acne. Arch Dermatol.2003;139:467-471. AbstractTorok HM, et al.Foundation for Research and Education in Dermatology Winter ClinicalDermatology Conference; March 14-18, 2008; Kapalua, Hawaii. Poster.Layton AM,Cunliffe WJ. Phototoxic eruptions due to doxycycline -- a dose-relatedphenomenon. Clin Exp Dermatol. 1993;18:425-427. 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