Photosensitivity from nalidixic acid*

British Journal of Dermatology (1974) 91, 523.

Photosensitivity from nalidixic acid' C.A.RAMSAYt AND E.OBRESHKOVAJ Department of Photobiology, Institute of Dermatology, London E9 6BX. Accepted for publication 25 March 1974

SUMMARY

Seven patients with a bullous photodermatitis from nalidixic acid are described. Bullae develop characteristically on the dorsal aspects of the feet and on the lower legs, but also elsewhere, in patients taking the drug who are exposed to a high level of ambient sunlight. At times, the cUnical picture may be confused with porphyria cutanea tarda. Abnormal reactions to sunlight may continue for several months after the acute stage, whether or not the drug is stopped, but some patients may continue to take the drug if direct sunlight on the skin is avoided. Investigations showed that long wave ultraviolet radiation appears to be responsible for the reaction and it proved possible to induce photosensitivity in three volunteers who took the drug for i week.

Photosensitivity induced by drugs is uncommon in the U.K., but nalidixic acid, according to the Register of Adverse Reactions (1971), is one of the drugs that causes it most often. It is also a drug which seems to produce a photodermatitis with several characteristic features. Since 1968, we have seen seven patients with such a photodermatitis and this paper reports the clinical and photobiological features. CLINICAL DETAILS

Nalidixic acid was taken for recurrent urinary tract infection by all seven patients, all female, aged 25-55 years. Three patients were taking other drugs at the time of the skin reaction: Case 5 an oral contraceptive (Sequens, Eli Lilly & Co. Ltd); Case 6 oral prednisolone, 5 mg daily and intermittent antispasmodics (Franol, Winthrop Labs) for asthma; and Case 7 frusemide, butobarbitone and a mixture of neomycin and a poorly absorbed sulphonamide against diarrhoea which she had obtained in Spain. The type of reaction and site of lesions These were both characteristic. Each patient developed blisters on the dorsa of the feet and, except for Case 2, on the dorsa of the hands. Three patients (Cases i, 2 and 5) also had blisters on the lower * Presented in an abridged version at the Royal Society of Medicine, 15 February 1973 (Proceedings of the Roval Society of Medicine, 66, 747)-

t In receipt of a grant from the Medical Research Council. J Present address: Department of Dermatology, University of Sofia, Bulgaria.

523

524

C.A.Ramsay and E.Obreshkova TABLE r. Clinical details of patients Age Case no. (years)

Duration of Whether drug Sex photosensitivity stopped

I

25

2

44

F F

3

55

F

4

37

F

5 6

29

F

29

F

7

40

F

6 weeks 3 weeks 15 months (a) 3 months (b) 3 months 2^ months (a) 1-2 weeks (b) 6 weeks 3 months

Yes No Yes No Yes Yes Yes

legs. On one patient (Case 4) patchy erythema preceded the blisters. Although the peripheral exposed parts of the limbs were so characteristically affected other areas of skin did not escape. Erythema of the face occurred in two patients (Cases 3 and 4) and a few small blisters on the forehead in another two (Cases 6 and 7). Covered parts of the body were not affected. After the acute bullous reaction had settled, four patients (Cases i, 2^ 4 and 7) had skin fragihty and two of them (Cases i and 2) blisters following minor trauma. Latent period before development of rash and solar exposure required A high level of ambient sunlight seemed to be more important than the length of time the drug had been taken. Thus one patient (Case 5) had been taking nalidixic acid for 5 weeks, went on holiday in Spain and a week later blisters appeared on the hands, feet and lower legs. Another patient (Case 2) developed blisters on the second day of her summer holiday in Malta after taking the drug for 7 months without previous trouble. By contrast another patient (Case 4) had her first bullous reaction whilst in the sun on holiday at the English coast, after a week of the drug. The bullae settled slowly over 2-3 months on returning to London, and the drug was continued during the next year with no further ill effects. One year after the first reaction, whilst still on the drug, a recurrence developed a week after solar exposure at an English seaside resort. Yet another patient (Case 6) developed her first reaction 6 weeks after stopping the drug when on summer holiday in England. She started the drug again i month after the first blisters had healed and developed a recurrence within 6 days, again whilst on holiday in the sun. Duration of photosensitivity New blisters, evidently sun induced, continued to appear for up to 3 months in all patients, whether or not the drug was stopped and at times were apparently provoked by mild trauma to the skin. For example, in one patient (Case 3) the blisters of the acute episode ceased to appear after a few days and they slowly healed 7 days after the drug was withdrawn. But she seemingly continued to have minor abnormal reactions to sunlight for more than i year after finishing the drug. These have taken the form of erythema and swelling of the dorsal aspects of the hands and feet after being exposed for 45 min to sunlight passing through window glass. These symptoms are now slowly regressing.

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525

INVESTIGATIONS AND RESULTS

Biopsie'i In two patients biopsies of blisters were obtained. One (Case 5) from the toe, 6 weeks after the drug was stopped, showed a blister in the superficial epidermis. Biopsies of bhsters on the feet in the other patient (Case 7), 2 and 3 months after the blisters had first appeared and whilst new lesions were still developing, both showed a sub-epidermal bulla with little or no inflammatory reaction. Qualitative tests of porphyrin metabolism These tests (Rimington, 1958; Rimington & Cripps, 1965) were negative in blood, urine and stools in all patients except for one (Case 6) whose stool was not examined. The absorption spectrum A solution of nalidixic acid in o-i N sodium hydroxide (pH 8-4) was examined in a Beckman SP.800 recording spectrophotometer. Peak absorption was at 260 nm. At wavelengths above 290 nm there was broad absorption between approximately 320 and 340 nm (Fig. i). 2 h

8 10

20

40 60 60 IOO

225

250

275

300

325

350

Wnvelenqth (nm)

FIGURE I. Absorption spectrum of nalidixic acid (10

in 0 1 N sodium hydroxide, pH 84).

Photopatch tests Photopatch tests were carried out on three patients (Cases 2, 4 and 5) by applying varying concentrations of the drug to skin under closed patches in duplicate. After 48 h the patches were removed, and one set of test sites was exposed for 30 min to a bank of 4 x 20 W 'black light' fluorescent tubes, approximately 30 cm from the skin. All test sites were read again at 96 h. Both irradiated and nonirradiated patch tests were negative. Irradiation monochromator tests These were made on the skin with a prism instrument and 2 kW xenon arc at various wavebands between 300 and 600 nm (Magnus et al., 1959)- It was possible to test only three patients whilst they were taking the drug (Cases 2, 4 and 6). One of these (Case 2) gave completely normal results, another (Case 4) developed delayed erythema at 340 nm on one of two test sites with a dose of 7 J/cm". The tests in the third patient (Case 6) were normal on the first occasion 5 weeks after stopping

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C.A.Raymay and E.Obreshkova

the drug but, when repeated after 30 g of the drug had been taken over the course of a week, they showed immediate erythema at 320 and 340 nm with doses of i-o and 1-5 J/cm respectively. In all other patients the irradiation tests were carried out several weeks to several months after stopping the drug. In two (Cases 3 and 7) clinical photosensitivity was still present when the tests were performed. Case 3 showed delayed papular type responses at 3075 and 320 nm but was other, wise normal; Case 7 showed delayed erythema at one of two sites irradiated at 360 nm. The remaining two patients (Cases i and 5) had normal results but tests were performed when the skin was normal and after the drug had been stopped. Tests on volunteers In addition to the narrow waveband tests with the monochromator described above, a broad band long wave UVR source was also used. A 5 cm^, i mm thick dichroic mirror (Balzer) in the xenon arc beam was used to separate the UVR, which it reflects at 45°, from the visible and infra red radiation, which it transmits. The reflected UVR was then passed through nickel oxide and WG 345 filters and focused on to the skin with a crown glass lens (diameter 6 4 cm, focal length 1175 cm). The skin was thus irradiated with a band of UVR extending from about 320 to 400 nm. A total dose of 45 J/cm^ produced no reaction, apart from occasional, transient pigment darkening, in twenty normal subjects One volunteer who showed no reaction to the long wave UVR source took nahdixic acid (4 g daily) for I week. At the end of this time irradiation with the long wave UVR source f45 J/cm~) produced immediate and delayed erythema- Repeated at intervals after the drug had been stopped positive results occurred up to 6 months, after which the test became negative. Two other volunteers took nalidixic acid in a dose of 4 g daily and were tested with monochromatic radiation at 300,320. 340 and 360 nm before and after taking the drug for i week. Transient immediate erythema at 320 and 360 nm was seen after the drug in both subjects and one also showed this reaction at 340 nm, but tests were otherwise normal. Unfortunately the long wave UVR source described above was not available for these volunteers until 2 weeks after the drug had been taken. At this time, however, a dose of longwave UVR of 45 I/cm" produced delayed erythema appearing at 6-8 h after irradiation and persisting for approximately 2 days Similar results were obtained in both volunteers at intervals for the next 6 months after which the tests became negative. Animal studies Hairless mice were used. A solution of nalidixic acid in o-i N NaOH was diluted to i mg/ml with 09^ o NaCl, the pH adjusted to 7-73 with o-1 N HCl and the solution sterilized by millipore filtration. In one group of thirteen mice 200 //g of drug were injected intradermally and 20 mins later the site was irradiated with the long wave UVR source or with monochromatic UVR at 330, 360, 380 and 400 nm (the doses given were 10-40 J/cm^). The reaction was assessed after the intraperitoneal injection of 0-2 ml of a solution of Coomassie Blue (40 mg/ml) immediately and at intervals for 48 h after irradiation. Another group of six mice was injected intraperitoneally with 300 /ig of the drug daily for 7 days and then the flank skin irradiated with the longwave UVR source (45 J/cm^). The reaction was again assessed by means of intraperitoneal Coomassie Blue. The results of the irradiation tests with the drug by both routes were consistently negative. DISCUSSION

The bullous type of photodermatitis which occurs in patients taking nalidixic acid usually presents a

Photosensitivity frotn nalidixic add

527

very characteristic clinical picture. The patient is almost invariably female and develops the reaction after exposure to excessive amounts of sunlight. A period varying from a few days up to a year may elapse between starting the drug and the development of the rash, the length of the apparent delay period being determined seemingly by the opportunity for exposure to sunlight. In all of otu: patients the reaction developed whilst on holiday in the summer, either in this country or abroad. Although the eruption may occur on any exposed site, there is a predilection for the lower legs and feet. One important differential diagnosis to be considered in some patients is porphyria cutanea tarda (PCT)j especially when lesions lie on the dorsal aspects of the hands. The history of fragihty of the skin and blisters after minor trauma may also cause confusion with PCT. However, we have never seen milia, although common in PCT, in nahdixic acid photosensitivity. There is no reason to think that nalidixic acid is porphyrinogenic as porphyrin excretion was normal in all of our patients. This confirms the findings of Birkett, Garretts & Stevenson (1969) who investigated five patients for porphyrin excretion and found it normal. Another characteristic feature of the nalidixic acid reaction is the persistence of the photosensitivity often for 2-3 months after the drug has been stopped; new blisters continue to appear though perhaps some are induced by trauma. In one of our patients mild photosensitivity had persisted for more than I year after an acute episode but eventually resolved. The pattern of the morphology, distribution and natural history in our patients is very similar to that reported by Zehckson (1964); Guilaine (1965); Susskind & Lyell (1965); Burry & Crosby (1966); Baes (1968) and Birkett, Garretts & Stevenson, (1969). In those instances where skin biopsy was performed a sub-epidermal blister was found (Baes, 1968; Birkett et al., 1969). This was seen in one of our patients, but in another the blister was intra-epidermal, probably due to regeneration of the blister base. The mechanism of the photosensitivity remains unsolved. The drug is rapidly absorbed and almost entirely excreted by the kidneys. Tissue levels, estimated after long term administration in animals, gave little evidence of accumulation, though unfortunately skin was not examined (McChesney ct al.y 1964). Alexander & Forman (1971) reported their experience with the lymphocyte transformation test in patients with reactions to nahdixic acid, the test being negative in those with the bullous type of response. The negative photopatch tests in the three of our patients examined are similar to the negative results reported by Baes (1968) in twelve normal volunteers. He used 290-320 nm from a water cooled mercury arc and long wave UVR from the same source with a Schott WG 5 filter. In the same way, Birkett et al. (1969) were unable to induce photosensitivity in seven normal persons with oral nalidixic acid using a medium pressure mercury vapour lamp for irradiation. The minimal erythema dose was determined before and 2 weeks after taking the drug. However, these authors did not use filtered radiation and it is possible that only small amounts of longwave UVR were administered. If the absorption spectrum of the drug (Fig. i) is in any way related to the action spectrum, then longwave UVR would be expected to be important. Although our animal studies were unsuccessful, we were able to induce abnormal photosensitivity with the drug in human volunteers. The transient immediate erythema, which occiu:red with monochromatic radiation between 320 and 360 nm, must be interpreted with caution. That this did not develop before the drug was taken may lead one to suspect that the reaction was significant, but normal skin may not uncommonly develop transient immediate erythema at these wavelengths. However, the results with the broad band UVR source were more definite. One volunteer continued to give persistent delayed erythematous reactions with this source for 6 months after taking the drug, although the reaction was negative before the drug was started. Similarly, two other volunteers gave positive reactions for the same length of time after the drug. These two volunteers were not tested with this source before the drug was taken.

C.A.Rajnsay and F Obreshkova but the fact that the test eventually became negative suggests that the drug was responsible. The results obtained with monochromatic radiation in our patients must be interpreted with care, because when abnormal reactions developed (immediate or delayed erythema) they were not always reproducible. The indefinite results obtained with monochromatic UVR, compared with the more clear cut results with the broad band longwave UVR source, are probably due to the much larger total dose that can be given with the latter. The evidence supporting this buUous reaction as a photodermatosis due to nahdixic acid on clinical grounds is circumstantial but strong. Our experience suggests that patients may continue to take the drug providing they avoid direct sunlight on the skin. It would probably also be wise to give similar advice to all patients taking the drug until further evidence is forthcoming as to the mechanism underlying the reaction. ACKNOWLEDGMENTS

We wish to thank Dr G.C.Weils for the histological reports and our colleagues for referring the patients. Winthrop Laboratories kindly supplied Negram tablets for the volunteers and the nahdixic acid for the animal studies. The Honorary Editors of The Proceedings of the Royal Society of Medians kindly gave permission for details in the abridged version of this paper to be pubhshed. REFERENCES & FORMAN, L . (1971) Which of the drugs cau-cd the rash? Or the value of the lymphocyte transformation test in eruptions caused by nalidixic acid. British Jowiial of Dermatology, 84, 429. BAES, H . (1968) Photosensitivity caused by nalidixic acid. Dermatologica, 136, 61. BiRKETT, D.A., GARRETTS, M . & STEVENSON^ C . J . (1969) Phototoxic buUous eruptions due to nalidixic acid. British Journal of Dermatology, 81, 342. BuRRY, J.N. & CROSBY, R . W . L . (1966) A case of photoxicity to nalidixic acid. Medical Journal of Australia, 2, 698. GuiLAiNE, M.J. (1965) firuptions ^rythemato-buUeuses, de type photo-toxique, avec un nouveau bact^ricide urinaire: l'acid nalidixique. Bulletin de la Sociiti Fran^aise de Dermatologie et de Syphiligraphie, 72, 729. MAGNUS, I.A., PORTER, A.D., MCCREE, K.J., MORELAND, J . D . & WRIGHT, W.D. (1959) A monochromator. An apparatus for the investigation of the responses of the skin to ultra-violet, visible and near infra-red radiation. British Journal of Dermatology, 71, 261. MCCHESNEY, E.W., FROELICH, E.J., LESHER, G.Y., CRAIN., A . V . R . & Rosi, D. (1964) Absorption, excretion and metabolism of a new antibacterial agent, nalidixic acid. Toxicology and Applied Pharmacology, 6, 292. REGISTER OF ADVERSE REACTIONS (1973) Published by Committee on Safety of Medicine, Department of Health and Social Security. RIMINGTON, C . (1958) Investigation of porphyria. Broadsheet No. 20. The Association of Clinical Pathologists. RIMINGTON, C . & CRIPPS, D . J . (1965) Biochemical and fluorescence microscopy screening tests for erythropoietic protoporphyria. Lancet, i, 624. SusSKiND, W. & LYELL, A . (1965) Suspected reactions to nalidixic acid, British Medical Journal, i, 316. ZELICKSON, A.S. (1964) Phototoxic reaction with nalidixic 2LC\d. Journal of the American Medical Association, 190, 556.

ALEXANDER, S.