British Journal of Ophthalmology, 1984, 68, 841-845

Exogenous ocular candidiasis associated withintravenous heroin abuseTANIA C. SORRELL,'2 CATHERINE DUNLOP,3 PETER J. COLLIGNON,' ANDJOHN A. HARDING3

From the 'Infectious Disease Medical Unit, Westmead Centre,2Department of Medicine, University ofSydney,and the 3Ophthalmology Unit, Westmead Centre, Australia

SUMMARY Seven young men developed disseminated candidiasis within 10 days of a single episodeof intravenous heroin abuse. Sequential development of eye and skin lesions was noted in all cases.The bone or costal cartilage was involved in five. Ocular manifestations of candidiasis includedepiscleritis, chorioretinitis, and endophthalmitis. A presumptive diagnosis of candida chorio-retinitis was established rapidly by culture of Candida albicans from involved skin and costalcartilage. Systemic therapy with amphotericin B plus 5-fluorocytosine resulted in cure of theepiscleritis, chorioretinitis, osteomyelitis, costochondritis, and skin infection. Pars plana vitrectomywith local instillation of amphotericin B was required to cure chorioretinitis associated with vitrealextension of infection.

The importance of eye lesions in the clinical diagnosisof disseminated candidiasis and in determination oftherapy has been appreciated only recently.' 2

In a review of ocular manifestations of candidasepticaemia characteristic white, fluffy, chorioretinallesions with or without haemorrhage or extensioninto the vitreous humour were described. Lesscommon lesions included Roth spots, papillitis, iritis,abscesses of the ciliary body, inflammation of theanterior chamber, and conjunctivitis. Deep organinvolvement was identified in 80% of patients withendophthalmitis.2The incidence and evolution of eye and other

metastatic lesions in candidiasis is poorly docu-mented, as patients usually present with disseminateddisease following an unidentified episode offungaemia. In September 1982 we identified a limitedoutbreak of disseminated candidiasis, presumed tobe due to intravenous inoculation of contaminatedheroin. The purpose of this paper is to describe thedevelopment of ocular lesions in these patients andto discuss aspects of early diagnosis and optimalmanagement.

Materials and methods

In September 1982 a 26-year-old male presented toWestmead Hospital with disseminated candidiasisCorrespondence to Dr T. C. Sorrell, Department of Medicine,Westmead Centre, Westmead NSW 2145, Australia.

following a single episode of intravenous abuse ofheroin. Eight friends had also injected themselveswith heroin from the same batch on the same night,and were contacted for follow-up. Two of the eighthad boiled the heroin prior to injection and remainedwell. Disseminated candidiasis was diagnosed in theother six patients. Six of the seven patients withcandidiasis were admitted to hospital. Clinical evi-dence of systemic infection was sought by dailygeneral physical examination. Ocular examinationsincluded visual acuity, slit-lamp examination,tonometry, direct, indirect and Goldmann three-mirror funduscopy. Episcleritis was diagnosed in thepresence of localised anterior subconjunctival andepiscleral injection, with overlying chemosis andminimal local discomfort. Chorioretinitis was identi-fied as white circumscribed retinal lesions with orwithout haemorrhage, or overlying vitreous haze.Endophthalmitis was diagnosed when retinal lesionsextended anteriorly into the vitreous humour.

Case reports

CASE 1The index case was a 26-year-old man who wasadmitted to hospital with fever, anorexia, and blurredvision. Ten days previously he and eight friends hadinjected themselves intravenously with heroin. Sixhours after injection the patient experiencedanorexia, then nausea and vomiting, generalised

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Tania C. Sorrell, Catherine Dunlop, Peter J. Collignon, andJohn A. Harding

aches, and abdominal pain. The pain abated after sixhours. The anorexia and nausea persisted. Threedays after the injection he noted blurring of vision,occasional 'spots' before the eyes, and 'redness' ofboth eyes, especially the right. Jaundice was alsonoted on day 3; this increased over two days, thensubsided. On the fifth day he first noticed 'pimples' inthe scalp and beard area; these subsequently becamemore numerous and appeared in axillary and pubichair-bearing areas. On the day of presentation (day10) the patient complained of pain over the righteighth costal cartilage. He had been well in the pastand had abused heroin twice in the 12 months beforeadmission.On physical examination his temperature was

37-4°C. Multiple pustules and subcutaneous noduleswere associated with hair follicles in the scalp andbeard area. A few pustules were present in the leftaxillary and pubic hair-bearing areas. Enlarged, non-tender, occipital lymph nodes were present bilaterally.Cardiovascular examination was normal. Asmall areaof tenderness and minimal swelling was found at theeighth costochondral junction on the right side.General examination was otherwise normal.The eyes showed bilateral conjunctival injection.

On ophthalmoscopy the right vitreous humourappeared hazy. The right macula was obscured bytwo rounded, white lesions which extended anteriorlyinto the vitreous humour. The optic disc appearedoedematous. In the left eye, two small areas ofchorioretinitis were noted near the fovea. Slit-lampexamination revealed cells in the vitreous humourand anterior chamber of each eye. Visual acuity was2/60 for the right eye and 6/6 for the left.

Investigations showed abnormal liver function withgamma glutamyl transpeptidase 255 U/l (normal 8-43), alkaline phosphatase 159 U/I (normal 30-115),bilirubin 15 ismol/l (normal 2-21). The creatinine was73 ,umol/l (normal 60-125), haemoglobin 13-0 g/dl,white cell count 16.3 x 101/l with 70% neutrophils,platelets 328x 109/l, ESR 61 mm/h. The titre ofantibody to Candida albicans (indirect haem-agglutination) was 10240 (negative if less than orequal to 160), cytomegalovirus titre 4, toxoplasmosishaemagglutination titre 256, toxoplasmosis comple-ment fixation titre less than 4, serum cryptococcalantigen negative, hepatitis B surface antibodypositive. Chest x-ray was normal. Microbiologicalsamples were obtained from pubic lesions, faciallesions, and neck and scalp biopsies. Candida albicanswas isolated on blood agar and Sabouraud's mediumwithin 48 hours in all cases. Forty-eight hour sub-cultures from Robertson's cooked meat medium alsoyielded Candida albicans. The urine contained a traceofprotein and 10-1000x 109leucocytes/l. Three bloodand urine cultures, including fungal cultures, were

Fig. 1 Right eye ofthe index case immediately prior toinitiation ofantifungal therapy. A largefluffy exudate(arrow) with surrounding smaller lesions is seen in themacular area. A small haemorrhage is located inferiorly tothe optic disc. The nasal margin ofthe optic disc is blurred.

negative. A "mtechnetium bone scan demonstratedan area of increased uptake at the medial end of theeighth right rib. Histology of a scalp biopsy showedacute folliculitis. Blastospores and pseudohyphaewere present in a few of the most inflamed hairfollicles. Pseudohyphae were also identified in hairshafts.The patient was treated with oral 5-fluorocytosine

(150 mg/kg/day) and intravenous amphotericin B(maintenance 0*5 mg/kg/day). The skin lesions,cartilage pain, and hepatitis resolved after 20 days oftherapy; the serum creatinine rose to 175 [tmol/l.The areas of chorioretinitis in the left eye remained

static for one week, then regressed. The lesions in theright eye progressed on therapy (Figs. 1, 2). A rightpars plana vitrectomy was performed seven days afterinstitution of systemic antifungal therapy andamphotericin B, 5[tg, was instilled slowly, anterior tothe retina. Material obtained at vitrectomy did notyield Candida albicans on culture of the concentrate,but Gram stain revealed budding yeasts. The post-operative course was complicated by intraocularhaemorrhage and uveitis. Vision in the eye wasrestricted to appreciation of hand movements only.A course of 1016 mg of amphotericin B with con-comitant 5-fluorocytosine was completed over 31days.On review four months later the patient remained

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Exogenous ocular candidiasis associated with intravenous heroin abuse

Fig. 2 Right eye ofthe index case on the seventh day ofantifungal therapy. Thefundus appears blurred due togeneralised vitreal haze. The macular exudates have enlarged(arrow) and are extending anteriorly into the vitreoushumour.

asymptomatic. General physical examination was

normal. Two small residual areas of pigmentationwere present in the left eye; visual acuity was normal.In the right eye central vision was reduced to apprecia-tion of hand movements and peripheral vision toappreciation of objects. The right retina could not bevisualised because of residual vitreous haemorrhage.Slit-lamp examination revealed clearance of cellsfrom the anterior chamber. The serum antibody titreto Candida albicans had fallen to 640.

CASES 2-7The six other patients had injected themselves withheroin on the night of 26 August 1982. Two differentsyringes and two samples of heroin, obtained fromthe same dealer, were used. Juice from the samelemon was used as an additive. None of thesematerials was available for culture. Symptomsexperienced by these patients were similar to those ofthe index case. Clinical findings are summarised inTable 1.

OCULAR FINDINGS IN DISSEMINATEDCANDIDIASISEpiscleritisOf the 14 eyes examined episcleritis was present inthree. Mild, local discomfort and redness of the eyeswere noted one to two days after injection of heroin.Examination approximately 15 days later revealed noevidence of anterior or posterior uveitis. An area ofunilateral episcleritis overlay the insertion of the leftmedial rectus muscle in one patient. Bilateral epi-scleritis in a second patient was confined to the areaover the insertion of the inferior rectus muscles.

Histological examination of conjunctival biopsiesone week after the start of antifungal therapy revealedmild, non-specific inflammation. Cultures and stain-ing of sections with periodic acid Schiff reagent andGomori methenamine silver reagent were negativefor fungi.

Chorioretinitis and endophthalmitisSix patients complained of blurred vision, 'floaters,'and redness ofthe eye(s) four to six days after injectionof heroin. Chorioretinitis was noted on examinationof five patients; bilateral involvement was seen inthree of these. On slit-lamp examination of a furtherpatient in whom there was no evidence of chorio-retinitis a few cells were noted in the vitreous humour.

Table 1 Features ofdisseminated candidiasis following heroin abuse

Patient Chorioretinitis Vitreal Episcieritis *Hepatitis tOsteo- Costo- Skin Indirectextension myelitis chondritis lesions haemagglutination

to C. albicans atpresentation

I Bilateral +(Unilateral) - + + + + 102402 Unilateral - + + - + + 25603 Unilateral - - + + - + 12804 Bilateral - - + + + + 51205 Bilateral t(Unilateral) - + - - + 12806 Nil - + + - + + 51207 Nil Cells in - + - - + 2560

vitreous(bilateral)

* Hepatitis defined by abnormal serum liver enzyme levels.tBone scan positive in each.tThis patient had received systemic prednisone 20 mg/d plus predsol eye drops, for 7 days prior to admission.

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Tania C. Sorrell, Catherine Dunlop, PeterJ. Collignon, andJohn A. Harding

Fig. 3 Multiplefluffy exudates with vitreal extension are Fig. 4 A single Roth spot (arrow) is seen clearly in theseen in the leftfundus. Small haemorrhages arepresent paramacular area ofthefundus ofthe left eye.peripherally. Generalised blurring ofthe optic disc is welldemonstrated.

The foci of chorioretinitis were located at theposterior pole of the eye, usually near the macula.Lesions adjacent to the optic disc (two eyes) wereassociated with blurring of the disc margin (Figs. 1and 3). In one case the lesion was adjacent to thecilioretinal artery. Coarse pigmentary changes werenoted in four eyes. A single Roth spot was present inthe inferior temporal quadrant of one eye (Fig. 4).The chorioretinal lesions varied in size from small'dots' to large, pale, fluffy lesions which extendedinto the vitreous humour.

LABORATORY DIAGNOSISCandida albicans was cultured from skin lesions in allpatients and from costal cartilage in one. Indirecthaemagglutinating antibody titres were elevated inall (Table 1). Two patients underwent vitrectomyseven and 21 days respectively after commencementof antifungal therapy; Candida albicans was notcultured from surgical samples of vitrectomy fluid.

MANAGEMENTTherapy with amphotericin B and 5-fluorocytosinewas instituted in six of the seven patients. Fourpatients received approximately 1 g of amphotericinB. Skin, musculoskeletal, and small eye lesions werecured by this therapy. A therapeutic pars planavitrectomy with local instillation amphotericin B (5,ug) was undertaken in two patients after progressionof chorioretinal lesions on systemic antifungal

therapy. This procedure, although curative of theinfection, was complicated by intravitreal haem-orrhage and persistence of poor visual acuity in bothcases. A further patient, (patient 2, Table 1), whoabsconded after receiving 300 mg of amphotericinB, returned five weeks later with increased painand swelling over his sixth left costal cartilageand again refused treatment. The small eye lesionsseen initially had resolved. He was then lost tofollow-up. The seventh patient presented with mildfolliculitis. Eye examination revealed only occasionalcells in the vitreous humour. These lesions resolvedspontaneously.

Discussion

Characteristic chorioretinal and other eye lesions arean important clinical indicator of disseminatedcandidiasis.2 Certain eye lesions may be peculiar toheroin abusers-for example, vitreous involvementwithout chorioretinitis as observed by us and Snip etal.3 and prominent inflammation of the anteriorchamber.4 Episcleritis, present in two of our cases,has not been described previously. As Candidaalbicans was not isolated from conjunctival biopsiesobtained from these patients after one week of afungal therapy, evidence for the aetiological role ofthis agent in the episcleritis remains circumstantial.

Macronodular or follicular skin lesions confined tohair-bearing areas, and associated with occipitallymphadenopathy, were distinctive clinical featuresofour cases and may be characteristic of disseminated

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candidiasis in heroin abusers.5 The diagnosis ofcandidiasis was made readily by histological exam-ination and culture of material from these skin lesionsand supported by high titres of serum haemagglutin-ating antibody to Candida albicans. In one patient C.albicans was also isolated from an area of costo-chondritis. Culture of samples obtained from twopatients at vitrectomy were negative for C. albicans,despite concentration of the specimens. Otherworkers have reported improvement in yield offungalorganisms after concentration of samples.4 Previousantifungal therapy may have affected yields from ourpatients. Serological tests have often been unhelpfulin the diagnosis of disseminated candidiasis, particu-larly in immunosuppressed patient. ' High titres werefound at presentation in our cases, all previouslynormal hosts; titres were substantially lower at the endof therapy, consistent with recent candidal infection.

Optimal regimens of antifungal therapy forendophthalmitis, chorioretinitis, and disseminatedcandidiasis have not been defined. Small lesions mayresolve spontaneously (our case 7). Courses of up to2 g of amphotericin B have been recommended fordeep-seated infection. ' Combinations of ampho-tericin B and 5-fluorocytosine have been recom-mended because of potential synergistic activityagainst Candida albicans and prevention of theemergence of resistance to 5-fluorocytosine by theuse of amphotericin B. ' Cure was achieved with 1 g ofamphotericin B plus 5-fluorocytosine (150 mg/kg/day)in four of our cases. However, progression of eyelesions occurred during systemic therapy in twopatients with marked endophthalmitis. In one caseadministration of systemic corticosteroids prior todiagnosis may have promoted intravitreal extensionof chorioretinitis. Therapeutic vitrectomy plus intra-vitreal instillation of amphotericin B were curative inboth patients. This has been the experience of otherworkers.46 The value of intravitreal instillation ofamphotericin B remains controversial owing to itspotential retinal toxicity6-8 and the difficulty ofassessing its efficacy. Cure of endophthalmitis hasbeen achieved by vitrectomy in association withsystemic antifungal therapy,-9 and intravitrealamphotericif B has been used without resultantretinal toxicity.'"' However, pooling of high con-centrations of antifungal drugs in unformed vitreousmay result in local toxicity.'2 Uveitis and retinal andpreretinal haemorrhages were noted after local in-stillation of amphotericin B in our two patients whounderwent this procedure; these complications mayhave been caused by local drug toxicity.

The need for surgery to cure vitreal candidiasisreflects in part the poor penetration of amphotericinB into the vitreous humour.'3 Candidal infectionconfined to the choroid and retina may be cured bysystemic therapy alone, as noted by ourselves andothers.214 15

Further studies are required to determine the roleof amphotericin B and less toxic drugs such as keto-conazole in the management of ocular candidiasis.Cases of failure of ketoconazole therapy in candidaendophthalmitis have been reported,16 suggesting thatamphotericin B will remain the mainstay oftreatment.

We wish to thank Mr J. Gardiner and Dr R. Munro for micro-biological assistance and Robyn Eggington for typing the manuscript.

References

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2 Edwards JE Jr, Foos RY, Montgomerie JZ, Guze LB. Ocularmanifestations of candida septicaemia: Review of seventy-sixcases of hematogenous candida endophthalmitis. Medicine 1974;53: 47-75.

3 Snip RC, Michels RG. Pars plana vitrectomy in the managementofendogenous candida endophthatmitis. Am*Ophthalmol 1976;82: 699-704.

4 Aguilar GL, Blumenkrantz MS, Egbert PR, McCulley JP.Candida endophthalmitis after intravenous drug abuse. ArchOphthalmol 1979; 97: 96-100.

5 Collignon PJ, Sorrell TC. Disseminated candidiasis. Evidence ofdistinctive syndrome in heroin abusers. Br Med J 1983; 287:861-2.

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11 Perraut LE Jr, Perraut LE, Bleiman B, Lyons J. Successfultreatment of Candida albicans endophthalmitis with intravitrealamphotericin B. Arch Ophthalmol 1981; 99 1565-7.

12 Tolentino Fl, Foster S, Lahav M, Liu LHS, Rabin AR. Toxicityof intravitreous miconazole. Arch Ophthalmol 1982; 100: 1504-9.

13 Weinstein L. Miscellaneous antibacterial agents: antifungal andantiviral agents. In: Goodman LS, Gilman A, eds. Thepharmaco-logical basis oftherapeutics. New York: Macmillan, 1970: 1237.

14 Home MJ, Ma MH, Taylor RF, Williams R, Zylstra W. Candidaendophthalmitis. MedJ Aust 1975; 1: 170-2.

15 Ho PC, O'Day DM. Candida endophthalmitis and infection ofcostal cartilages. BrJ Ophthalmol 1981; 65: 333-4.

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