Antimicrobial Photosensitive Reactions

REVIEW ARTICLE Antimicrobial Photosensitive Reactions Snejina G. Vassileva, MD; Grisha Mateev, MD; Lawrence Charles Parish, MD hotosensitivity reactions are recognized as unwanted adverse effects of an array of commonly administered topical or systemic medications, including nonsteroidal anti- inflammatory agents, antifungals, and antimicrobials. When a drug induces photosensitivity, exogenous molecules in the skin absorb normally harmless doses of visible and PUV light, leading to an acute inflammatory response. In phototoxic reactions, the damage to tissues is direct; in photoallergic reactions, it is immunologically mediated. In vitro and in vivo assay sys- tems can assist in predicting or confirming drug photosensitivity. The incidence of photosensitivity reactions may be too low to be detected in clinical studies and may become recognized only in the postmarketing stage of drug development. Some drugs have been withdrawn because of photosensitivity effects that appeared after general release. Photosensitivity reactions have been studied for a number of topical antimicrobials and for the sulfonamides, griseofulvin, the tetracyclines, and the quinolones. Incidence and intensity of drug phototoxicity can vary widely among the different compounds of a given class of antimicrobials. When phototoxic effects are relatively low in incidence, mild, reversible, and clinically manageable, the benefits of an antimicrobial drug may well outweigh the potential for adverse photosensitivity effects. Arch Intern Med. 1998;158:1993-2000 Photosensitivity caused by drug reac- bined with exposure to sunlight to treat tions may be defined as unwanted phar- vitiligo.1 These herbal remedies were redis- macological effects produced when the covered in the 1940s and identified as con- skin is sensitized by topical or systemic taining the phototoxic furocoumarins medications, or both, and exposed to UV (psoralens). The photobiologic activity of rays, either artificially or naturally. Such psoralens has been used in modern photo- peculiar and often distressing photobio- chemotherapy to treat an increasing num- logic reactions are commonly considered ber of chronic inflammatory dermatoses. to be the undesirable adverse effects of Many antiviral compounds obtained from commonly administered drugs such as plants, eg, thiophenes, polyacetylenes, fu- phenothiazines, amiodarones (antiarrhyth- ryl compounds, and alkaloids, are also pho- mics), nonsteroidal anti-inflammatory tosensitizers, and their biological proper- agents, and antimicrobials. Often the ben- ties are dependent on or augmented by light efits of many of these pharmaceuticals far of specific wavelengths, commonly long- outweigh the problems they present in the wave UV-A.2 While researchers continue presence of UV light. toexaminethepotentialofsuchcompounds Photosensitivity reactions have been for antiviral therapy and have identified sev- recognizedforhundredsofyears.Inthe13th eral substances that are phototoxic to hu- century, the Arab scholar Ibn El-Bitar noted manimmunodeficiencyvirus(serotype1),3,4 that certain plant extracts could be com- the adverse photosensitivity effects of cur- rent pharmaceuticals are of more immedi- From the Department of Dermatology, Medical University-Sofia, Sofia, Bulgaria ate clinical relevance. (Drs Vassileva and Mateev); and the Jefferson Center for International Dermatology, Photosensitivity has frequently Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pa (Dr Parish). been associated with local antiseptics, ARCH INTERN MED/ VOL 158, OCT 12, 1998 1993 ©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 antifungals (eg, griseofulvin), and tions, diagnosis, and means of initiation of biological changes, con- the antimicrobials nalidixic acid, preventing potential photosensi- sisting in damage of several macro- fluoroquinolones, sulfonamides, tivity reactions. molecules, particularly nuclear DNA. tetracyclines, and antiprotozoans. A third change involves molecules Although such reactions rarely BIOPHYSICAL AND absorbing a sufficient amount of en- involve the morbidity and mortal- BIOCHEMICAL BACKGROUND ergy for the formation of free radi- ity seen with other adverse effects, cals. These are highly reactive and including toxic epidermal necroly- Photosensitization is a process in can lead to substantial chemical ac- sis, Stevens-Johnson syndrome, which reactions to normally innocu- tivity with surrounding tissue dam- anaphylaxis, or systemic toxicity, ous radiation are induced in a bio- age.13,14,16 Skin reacts to such UV they do constitute a common der- logical system by the introduction damage with an acute inflamma- matologic and pharmaceutical of a specific radiation-absorbing sub- tory response, commonly known as concern.5 Not infrequently, the stance, referred to as a photosensi- sunburn. incidence of photosensitivity reac- tizer.13 The latter causes another In cases of drug photosensitiv- tions to antimicrobials is too low component of the system, a sub- ity, similar acute inflammatory reac- to be detected even in very careful strate, to be changed by radiation. tions occur in the skin in the presence analyses of phase 2 and 3 clinical Photosensitivity reactions are of foreign molecules (exogenous studies. During the postmarketing induced by a delimited range of the chromophores), which absorb nor- period, when larger groups of out- electromagnetic spectrum that in- mally harmless doses of UV and vis- patients are exposed to direct sun- cludes visible light and UV radia- ible radiation and create an electroni- light, photosensitivity may be rec- tion. Ultraviolet (200-400 nm) and cally excited state. Absorbed photons ognized as a major deterrent to visible (400-800 nm) lights, to which from the electromagnetic spectrum use of the drug. This was the case the skin is continually exposed, are are converted into chemical energy with nalidixic acid, a nonfluori- produced by the sun and artificial used in chemical reactions. These can nated quinolone uroantiseptic; an sources, such as tanning beds and transform the original chemical into increased incidence of severe bul- fluorescent lamps. The UV spec- a photoproduct, transfer the energy lous photosensitivity reactions trum is divided into 3 parts with ar- to a protein molecule, or shed the was seen following its introduc- bitrary limits, ie, UV-A (wave- energy as either light or heat.13,16 tion in 1962.6 length 320-400 nm), also called Clinically, this process can result in The members of the tetracy- black light; UV-B or “sunburn” ra- erythema, edema, and sometimes cline group have been reported to diation (wavelength 290-320 nm)14; blistering, as well as an increase in induce photosensitivity in 25% to and UV-C (wavelength 200-290 melanin formation. 90% of patients receiving demeth- nm).13-15 Of these wavelengths, only For most chemical photosensi- ylchlortetracycline, 20% receiving UV-A and UV-B are involved in pho- tizers, the absorption and the action doxycycline, 7% receiving metha- tosensitivity reactions, since UV-C spectra are nearly equal, lying either cycline, and more rarely for those is blocked by the ozone layer of the in the visible or UV range, usually receiving minocycline.7-9 For the atmosphere. Ultraviolet radiation UV-A and UV-B.17 Visible light- fluoroquinolones, a rapidly grow- penetrates the skin to varying de- induced photosensitivity occurs with ing group of new generation grees before being transmitted or porphyrins, several dyes, and the fluo- potent antibacterial quinolone absorbed by molecules acting as roquinolones tosufloxacin, sparfloxa- derivatives, the reported incidence substrates or endogenous chro- cin, enoxacin, and clinafloxacin. Pso- of photosensitivity varies from 1% mophores. The latter include epi- ralens,nonsteroidalanti-inflammatory to 4% for ciprofloxacin10 to 10% dermal keratins, melanin, nucleic agents, phenothiazines, griseofulvin, and even 19% for fleroxacin.11 No acids, hemoglobin, porphyrins, lipo- sulfonamides, tetracyclines, nalidixic member of these widely used sys- proteins, carotene, and aromatic acid, and most fluoroquinolones re- temic anti-infective agents has amino acids, such as tyrosine, tryp- act primarily with UV-A. A limited been withdrawn for photosensitiv- tophan, and histidine.13 number of chemicals, for instance ity adverse reactions, except tema- Photon absorption leads to an fleroxacin, depend mainly on UV-B floxacin.12 energy transfer, promoting the elec- activation.18 In vitro photosensitivity The problem of establishing tron status of the chromophore mol- requiring both UV-A and UV-B have the therapeutic parameters of a ecule to an excited singlet state.13 been reported with the quinolones, photosensitizing antimicrobial Such an excited molecule is short- oxolinic acid, pipemidic acid, rosoxa- preparation may lead the clinician lived and can undergo several trans- cin,18 and the newly developed fluo- to completely reject its use, on the formations. It may return to its roquinolone sparfloxacin.19 one hand, or underestimate its ground state with the emission of potential drawbacks in a non–life- heat (and sometimes fluorescence) MECHANISMS OF threatening situation, on the or cross to a triplet state, in which PHOTOSENSITIVITY other. The indications for the the molecule is very active chemi- clinical use of most anti-infective cally and often reacts with other Although the precise pathogenesis agents should therefore rely on chemicals.

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