Fluconazole resistant candida in AIDS

Journal of Infection (1991) 22, 201-212

L e t t e r s to t h e E d i t o r

Actinomycosis of the tongue

Accepted for publication 16 July 199o Sir, Following the recent interest in actinomycosis in your journal 1-3 we would like to report a case involving the tongue. We believe this is only the second case reported from the British Isles in recent years, 4 although previous studies have suggested an overall incidence of 3 %.5 A 64-year-old clerk typist presented with a 2 weeks' history of discomfort and swelling of her tongue. She had no recollection of trauma, her dental hygiene was good and she was otherwise well. On examination there was a 3 cm × I cm purple swelling on the dorsum of the tongue to the left of the midline. T h e r e was no regional lymphadenopathy. Her chest X-ray was clear. A swab from the surface of the lesion failed to grow any pathogens. An incisional biopsy was carried out under local anaesthesia and histological examination showed actinomycotic colonies in the deep tissues of the tongue. T h e r e was no evidence of neoplasia. T h e biopsy material was not cultured. Although the discomfort in the tongue improved soon after commencing amoxycillin there was a more gradual regression of the swelling and it took 6 months for the surface papillae to regenerate. Antibiotic therapy was continued throughout this period. Although rare, actinomycosis should be borne in mind in the differential diagnosis of lesions of the tongue.

Departments of * Microbiology and -~Otolaryngology, Wythenshawe Hospital, Manchester M23 9L T, U.K.

B. J. Isalska* S. Habashit T . N . Stanbridge*

References i. Burden P. Actinomycosis. J Infect 1989; I9: 95-992. Birley HDL, Teare EL, Utting JA. Actinomycotic osteomyelitis of the thoracic spine in a penicillin-sensitive patient. J Infect i989; 19: 193-194. 3. Jewes LA, Laing RJC. Acute actinomycotic osteomyelitis of the skull with subdural empyema. J Infect 199o; 2o: 266-267. 4. Brignall ID, Gilhooly M. Actinomycosis of the tongue. A diagnostic dilemma. Br J Oral Maxillofac Surg 1989; 27: 249-253. 5- Cope Z. Actinomycosis. London: 1938. Oxford University Press.

F l u c o n a z o l e r e s i s t a n t c a n d i d a in A I D S

Accepted for publication 21 September 199o Sir, In a recent editorial on fluconazole in this journal Professor H a y I advocates intermittent therapy with short courses of the drug in the management of oral candidiasis in i m m u n o c o m p r o m i s e d patients to prevent the fungus acquiring tolerance to the drug. We have investigated the use of fluconazole as prophylaxis against

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recurrent oropharyngeal candidiasis in patients with A I D S 2 and report here four patients who developed resistance to it. Case ,

A 38-year-old homosexual male positive for antibody against h u m a n i m m u n o deficiency virus ( H I V ) presented with Pneumocystis carinii p n e u m o n i a in S e p t e m b e r I988. H e also had extensive oropharyngeal and oesophageal candidiasis. S p u t u m culture yielded a mixed growth of Candida albicans and C. glabrata. H e was c o m m e n c e d on oral fluconazole 5o m g once daily for I4 days with excellent clinical response and then began on a I5O m g weekly dose as prophylaxis against recurrent candidiasis. However, a week later he again complained of retrosternal pain and dysphagia and a relapse of candida oesophagitis was confirmed at oesophagoscopy. T h e culture of s p u t u m and biopsies revealed a pure growth of C. glabrata which was resistant to fluconazole and ketoconazole (see T a b l e I).

T a b l e I Sensitivity of candida isolates from the four patients MIC (#g/ml)

Case Case Case Case

i (Candida glabrata) 2 (C. albicans) 3 (C. albicans) 4 (C. albicans)

Fluconazole

Ketoconazole

> I o o / > xoo* 3-i/6"3" > 50/> 50* I2'5

3"I/6'3" o.o24/o.i9" Sensitivet Sensitivet

M I C = Minimum inhibitory concentration. * The strains were tested in two separate determinations by a tube dilution technique, hence the two values for each strain. t Disc method.

Case

2

A 26-year-old homosexual male was found to be H I V antibody positive in D e c e m b e r I986 when he presented with oral thrush. Barium examination was consistent with extensive oesophageal candidiasis. H e was c o m m e n c e d on ketoconazole 200 m g once daily but after 2 weeks he still had extensive oropharyngeal thrush. H e was changed to fluconazole 50 m g once daily for 2 weeks which resulted in clinical cure and he continued on I5O m g each week as prophylaxis. H e remained well for 20 months but in October I988 he had a recurrence of his oral candidiasis and C. albicans was cultured f r o m his mouth. M I C s showed sensitivity to ketoconazole but resistance to fluconazole (see T a b l e I). Case 3

A 23-year-old heterosexual male presented with a 3 m o n t h s ' history of oral candidiasis and dysphagia in June I988. H I V antibody test was positive and his T 4 count was 50 × IO6/1. Initial treatment had been with miconazole gel and amphotericin lozenges but the response was only partial. Fluconazole 5o m g daily produced good clinical response within a week and prophylaxis at 150 m g weekly followed. However, patient compliance was poor and he had several relapses f r o m August I988 onwards. T h e s e responded well to further courses of 5o m g fluconazole daily but a subsequent relapse

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failed to respond even after increasing the dose of fluconazole to Ioo mg daily with added amphotericin lozenges. T h e isolate proved resistant to fluconazole but sensitive to ketoconazole (see Table I). T h e treatment was changed to ketoconazole zoo mg daily and amphotericin lozenges with resulting clinical improvement and clearance of C. albicans. Case 4

A 25-year-old heterosexual H I V antibody positive intravenous drug abuser presented in I988 with severe oropharyngeal candidiasis unresponsive to miconazole gel. Within 3 days of commencing fluconazole 50 mg daily he was asymptomatic. During the ensuing 2 years he remained free of symptoms whilst he took fluconazole I5o mg weekly. However, he was variably compliant, and this resulted in breakthrough candidiasis which initially responded to supervised fluconazole. Recently, however, severe oropharyngeal candidiasis recurred and endoscopy showed an extensive oesophageal carpet of shaggy detachable white/green material. Cultures for viruses were negative but others showed a growth of C. albicans which was sensitive to amphotericin B, iconazole, nystatin and ketoconazole on disc testing. It was resistant to flucytosine. T h e M I C showed high resistance to fluconazole ( M I C I2"5 #g/ml) (see Table I). H e did not respond clinically to a variety of antifungals including oral fluconazole IOO mg daily, itraconazole 200 mg daily, ketoconazole 400 mg daily and oral amphotericin B lozenges 5/day. H e was therefore treated with intravenous amphotericin B with good response. Fluconazole has been shown to be highly effective and is superior to ketoconazole in the treatment of oropharyngeal candidiasis in A I D S ? Our patients illustrate the potential for drug resistance to develop. Eradication of the C. albicans infection in our first patient allowed a resistant glabrata strain to emerge resulting in relapse of disease within 3 weeks of commencing maintenance therapy. This is similar to a recent report of a n o n - A I D S patient in whom resistance developed within 9 days of oral fluconazole. 4 Our second patient at first responded very well and remained disease-free on prophylaxis for 20 months until relapse Occurred due to drug resistance. In the third and fourth patients the intermittent nature of their therapy may have led to resistance but this is only speculative. In patients with A I D S , the continued state of immunosuppression and the need for prolonged suppressive therapy for most opportunistic infections create the optimum conditions for the development of drug resistant organisms. Such trends have already become evident for herpes simplex virus 5 and cytomegalovirus. 6 Resistance to the earlier azole compounds used in the treatment of candida infections in n o n - A I D S patients has been widely reported. 7-9 Fluconazole has proved to be very useful in the management of oropharyngeal and oesophageal candidiasis in A I D S and the incidence of drug resistant candida strains will need to be monitored closely. Whether intermittent therapy will delay the emergence of such resistant strains remains a matter for debate. (We thank Dr P. F. Troke (Pfizer) for performing the MIC studies.) Regional Department of Infectious Diseases and Tropical Medicine, Monsall Hospital, Manchester M I o 8WR, U.K.

R. Fox K. R. Neal C. L. S. Leen M. E. Ellis B. K. Mandal

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Letters to the Editor References

I. Hay RJ. Fluconazole. J Infect 199o; 21: 1-6. 2. Leen CLS, Dunbar EM, Ellis ME, Mandal BK. Once weekly Fluconazole to prevent recurrence of oropharyngeal candidiasis in patients with AIDS-related complex : a double blind placebo-controlled study. J Infect 199o; 21: 55-60. 3. De Wit S, Weerts D, Goosens H, Chunech N. Comparison offluconazole and ketoconazole for oropharyngeal candidiasis in AIDS. Lancet 1989; i: 746-747. 4. Warnock DW, Burke J, Cope NJ, Johnson EM, Van Frannhofer NA, Williams EW. Fluconazole resistance in Candida glabrata. Lancet 1988; ii: 131o. 5. Erlich KS, Mills J, Chatis P e t al. Acyclovir resistant Herpes simplex virus infections in patients with the acquired immunodeficiency syndrome. N Engl J Med 1989; 32o: 293-296 • 6. Erice A, Chen S, Buron KK, Stanat SC, Balfour H, Jordan MC. Progressive disease due to gancyclovir resistant cytomegalovirus in immunocompromised patients. N Engl J Med 1989; 32o : 289-292. 7. Holt RJ, Azmi A. Miconazole resistant candida. Lancet 1978; i: 5o-51. 8. Horsburgh CR, Kirkpatrick CH. Long-term therapy of chronic mucocutaneous candidiasis with ketoconazole : experience with twenty one patients. Am ff Med 1983; 74 (Suppl. IB) : 23-29. 9. Kerridge D, Nicholas RO. Drug resistance in the opportunistic pathogens Candida albicans and Candida glabrata, ff Antimicrob Chemother 1986; 18 (Suppl. B): 39-49-

Candida albicans r e s i s t a n c e i n A I D S Accepted for publication 14 November 199o Sir, Oral candidosis is the commonest opportunistic infection seen in patients who are i m m u n o c o m p r o m i s e d as a result of H I V infection. Initially, systemic antifungal therapy with ketoconazole was widely used, but recently this imidazole has been superceded in many centres by the triazoles, fluconazole and itraconazole. Reasons for this include the poor absorption of ketoconazole in the presence of achlorhydria, which is c o m m o n in advanced H I V disease, and the rare association of this drug with fatal hepatotoxicity. However, we now report the isolation of fluconazole-resistant, ketoconazole-sensitive Candida albicans occurring in an A I D S patient with oesophageal candidosis. T h e patient, a 43-year-old homosexual male, developed dysphagia whilst on 50 mg fluconazole daily. H e had been taking this medication continuously over the previous 12 months as prophylaxis against recurrent oral candidosis. A presumptive diagnosis of oesophageal candidosis was made and the fluconazole was increased to 200 mg daily, as it was assumed that serum levels could have been low owing to concurrent treatment with rifampicin. 1 T h e r e was no clinical improvement during the following 4 weeks and the patient therefore underwent endoscopy. This revealed confluent plaques of candida obscuring oesophageal mucosal detail. T h e dosage of fluconazole was further increased to 4oo mg daily with some subsequent clinical improvement. Repeat endoscopy IO days later revealed persistent oesophageal candidosis, with a less florid appearance than before. T h e patient died 2 weeks later of an unrelated cause. T h e serum level of fluconazole measured 2 h after ingestion of a daily dose of 200 mg was 21"3 mg/1 (therapeutic range 1"3-3"4 mg/1). Candida albicans was cultured from material obtained at each oesophagoscopy. T h e sensitivity of each of the isolates to fluconazole, ketoconazole and itraconazole was measured using an agar dilution