British Journal of Dermatology 1997: 157:808-811,

Acute generalized exanthematous pustulosis following oralnystatin therapy: a report of three cases

A.KiJCHLER, H.HAMM, B.WEIDENTHALER-BARTH. E.KAMPGEN AND E - B , B R 6 C K E R

Departnwnt of Dermatology. University Hospital. University of Wiirzburg. D~^7(IHI) Wuriburg. Germany

Accepted for publication h \uni; 1997

S u m m a r y We report three cases of acute generalized exanthematous pustulosis (AGEP) following oraladministration of nystatin. All cases showed similar clinical features and histopathological Iindings,and a delayed-type hypersensilivily to nystatin could be demonstrated in patch and prick testing.Drug eruptions to nystatin are extremely rare. and. to our knowledge, AGEP has not been reportedpreviously.

Cutaneous reactions to systemically administered drugsare common. Pustular eruptions, however, are rare andhave mainly been attributed to various antibiotics.'Nystatin is a polyene antifungal drug that rarelycauses topical allergic reactions.'^" As it is hardlyabsorbed from the intestine after oral ingestion, sys-temic reactions are exceptional. There have only beensingle reports of a lixed drug eruption,^•'' a Stevens-Johnson syndrome,"^ a generalized urticarial eruption,**and the exacerbation of pre-existing acrodermatitiscontinua suppurativa of Hallopeau'* after oral therapy.We report three cases of a generalized pustular eruptionfollowing oral nystatin administration. In all cases,subsequent testing revealed delayed-type hypersen-sitivity to nystatin and to the specific preparation that

had been given before. To our knowledge, pustulareruptions due to nystatin have not been reportedpreviously.

Case reports

All three patients had been treated with diflerent oralpreparations of nystatin (Nystaderm*, Adidair* andBiofanal*) by their general practitioners. Within 1-2days after ingestion, all the patients developed a gener-alized, pruritic, erythematous or urticariai rash whichevolved into a pustular eruption during the next 1-2days (Eig, 1). Detailed clinical data are given in Table 1.Multiple swabs from pustular lesions were negative forbacterial or fungal growth except for one swab from the

Figure 1. Patienl 1: (a) detail of thecruptiiin: lb) pustules on the upper chest.

808 1997 British Association of Dermatologists

ACEP AND NYSTATIN H()9

» * .

Vki

i*

Figure 2. Patient I: photomicrograph ot a punch hiopsy trom theupper hack. Acanthosis with para keratosis, a subcorneal pustule lilledwilh neutrcphils, and papillary dermal oedema with a perivascularinfiltrate of neutrophils and a few eosinophils are evident (haematox-ylin and eosin: xfi40|.

nasal mucosa in patient 2 which showed Staplnilococcusaureus (negative for exfoliative toxin).

Histopathological examination of pustular lesionsrevealed similar changes in all patients. There wasslight acanthosis and spt)ngiosis with focal parakeratosisand a subcorneal pustule. The upper dermis showedoedema and perivascular inliltrates of neutrophils andeosinophils as well as a few extravasated erythrocytes.Dermal hlood vessels were dilated, hut there were nosigns of vasculitis (Fig. 2). Direct immunoiUiorescencewas negative.

All medication was stopped or changed to chemicallydifferent substances. Two of the patients were addition-ally giveti oral corticosteroids. The rashes cleared within7-14 days. As patient 2 was initially thought to sufferfrom toxic shock syndrome she underwent uninten-tional oral challenge with a different nystatin prepara-tion (MoronaP tablets) after proof of intestinal yeast

colonization. Eight hours after nystatin intake, thepatient again developed a pruritic erythema of the faceand neck which subsided under topical corticosteroidtherapy.

Two to four months later, patch tests were performedwith nystatin ^0% in petrolatum), the specific nystatin-containing preparation (ground tablet) atid with all thedrugs the patients had been taking at the time inquestion. Prick tests were performed with a suspensionof the ground tablet in 0 9% saline solution. Bolh patchand prick tests showed a delayed-type hypersensitivityto nystatin and to the specific preparation taken before(Table 1), In patient 3. oral challenge tests were per-formed with all the drugs she had been taking at thetime of the rash, except for nystatin. All drugs weretolerated without any skin reaction.

In our department, patch tests with lO'Xi nystatinin petrolatum have been performed in more than200 patients without any positive result. Furthermore.patch tests with the three nystatin preparationssuspected in our three patients were negative in 13consecutive controls.

Discussion

Acute generalized exanthetnatous pustulosis (AGEP) israre compared with other adverse drug reactions. How-ever, there has been increasing awareness of this con-dition in the recent dermatological literature. Since1969.'" acute generalized pusttilar eruptions due todrugs have been reported under various designations.among others 'toxic pustuloderma'.^''"^ and 'acutegeneralized exanthematous pustulosis*.'^ In theirextensive work. Roujeau et al.^ pointed out that AGEPis a distinct entity most likely to be caused by drugs andonly rarely by other causes. Hitherto, no pathogeneticconcept of this condition has been established.

Earlier cases of AGEP may have been misdiagnosed asgeneralized pustular psoriasis.'"* However, AGEP canclearly be differentiated from generalized pustular psor-iasis by the clinical course and by histopathologicalcriteria. ' ^'^ Further differetitial diagnoses includesubcorneal pustulosis of Sneddon and Wilkinson, con-ditiotis due to bacterial iniections. especially toxic shocksyndrome atid staphylococcal scalded skin syndrome,and pustulosis acuta generalisata.'' AGEP is usuallycaused by a wide range of drugs, the most important ofwhich are antibiotics (80"/.)- especially p-lactam anti-biotics. Occasional cases of AGEP have heen attributedto infection with enteroviruses.' hypersensitivity tomercury, or food poisoning. "

1997 British Association ot Dermatologists, Briti.^h journal of Dermatologi;, 137. SOS-811

810 A.KUCHLER et al.

Age/sexNystatin preparationInterval between nystatin

intake and exanthemaDuration of rashMaximum temperature

Blood cell countleucocytesneutrophilseosinophils

Erythrocyte sedimentationrale |mm/h|

Previous drug reactionTreattnent

Prick test vi'ith nystatinpreparation

Patch lest with nystatinpreparation

Patch test with nystatin]1)"A. in petrolatum

Patient 1

5f> years, femaleNystadertn ' tablets2 days

14 days37-2 °C

(T9X]() '

H 3%

3%12

nooral prednJKotone.

oral clemastlne

negative (2(1 min)

positive 12 daysl

positive [2 and

3 daysl

not done

Patient 2

2 3 years, female

Adiclair® tablets

1 day

6 days

39-2 "C

3 1 - 3 x 1 0 '

39%b%29

notopical corticosteroid

creatn

negative 120 min |

positive 12 daysl

positive 12 and

5 daysl

positive 12 and

3 days)

Patient 3

59 years, female

Biofanal* tablets

1 day

9 days

i7-bX-

11-8x10*56%7%15

yes (getitamicinloral methyl-prednisolone. i.v.antihistaminesnegative (20 min)positive (2 days)positive (2 and 5days)not done

Table 1. Clinical data of patients with acutegeneralized exanthematous pustulosis

The three cases presented here showed clinical andlaboratory features typical for AGEP: rapid onset ofpruritic erythematous lesions withiti 1-2 days afteringestion of the suspected drug, evolution into a gen-eralized pustular eruption, fever and leucocytosis withelevated neutrophil and eosinophil counts (patients 2and 3). and rapid clearing.''^ Patient 1 had no feverand a normal white blood cell count but markedneutrophilia. An infectious cause was ruled out bymultiple cultures from pustules. Histopathology wastypical for AGEP and different from changes seen inpsoriasis. All patients had no skin lesions for 8-18months of follow-up. In all of them, the personal andfamily history was negative for psoriasis.

Delayed-type bypersensitivity to nystatin could hedemonstrated in all cases both in patch and pricktests. The prick tests did not reveal any urticarialreaction after 20 min, but only a papular reactionafter 48-72 h. The specilic preparations (Adiclair®.Biofanal* and Nystaderm") were each patch tested in13 healthy volunteers and did not show any positive orirritant reaction, Intradermal tests were tiot performed,as in our experience they ofteti show false positiveresults to antibiotics. In addition, patient 2 was unin-tentionally challenged with a single oral dose of nystatinwhen she was still thought tt) suffer from toxic shocksyndrome. She developed identical skin lesions which

rapidly ceased after nystatin was withdrawn again. Inpatient 3, all drugs taken at the time of the rash exceptfor nystatiti were administered for challenge tests anddid not provoke any skin lesions.

There are only a few case reports on drug-inducedAGEP in which later allergic testing or even oral chal-lenge was perfonned.'^"''* Some authors detected adelayed-type reaction to the suspected drugs in patchtests. ' Moreau and Dompmartin" saw a pustularreaction in the test area when performing patch testswith the drugs in question in two patients. Trlieb andBurg^' demonstrated doxycycline as the causativeagent hy the lymphocyte transformatioti test and byunintentional challenge, but the patch test was negativefor doxycycline. In two other cases""" patch tests werenegative for the suspected drugs, and it was only by oralchallenge tests that the drugs' causative nature could beproved. Feind-Koopmans et al.^'^ found a negative patchtest but a positive intradermal reaction to the suspecteddrug. We suggest that at least an attempt should bemade to identify the causative agent of AGEP by patchand prick testing, even though there have been positiveresults only in a tninority of cases so far. Oral challengeshould be avoided because of possible severe adversereactions.

Nystatin is a polyene antibiotic produced by Strepto-niijces noursei. It is widely used in dermatology for

1997 British Association of Dennatologists, British journal of Dennaiologii. 1 i7. 808-811

AGEP AND NYSTATIN 811

topical treatment of cutaneous or mucosa! yeastinfections. Contact sensitization is very rare after topicalor oral application.'^""* Systemic adverse reactions areeven more exceptional as nystatin is hardly absorbedfrom the intestine.^"'* Pareek^ measured plasma con-centrations of nystatin after oral administration of500.()()() units (167 mg) in a patient who had developeda fixed drug eruption after nystatin ingestion. Plasmaconcentrations were less than 1 |xg/mL (i.e. less than3 units/mL) after 2 and 8 h. Nevertheless, within 8 h hispatient re-experienced the fixed drug eruption he hadshown before. Consequently, extremely low plasmaconcentrations of nystatin may be sufficient to cause asystemic reaction.

To sum up. we present three cases of ACiEP due to oralnystatin therapy with typical clinical features andcourses. In all cases, a delayed-type hypersensitivity tonystatin could be found. One patient underwent unin-tentional oral challenge and had identical lindings.Although systemic drug reactions due to nystatin areextremely rare, it has to be added to the list of potentialcauses for AGEP.

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1997 British Association of Dermatologists. British Journal oJ Dermatology, 137, 808-811