Aminosidine (paromomycin) in the treatment of leishmaniasis imported into the United Kingdom

TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE (1992) 86, 617-619

Aminosidine (paromomycin) the United Kingdom

in the treatment

of leishmaniasis

617

imported

into

J. A. G. Scott’, R. N. Davidson’, A. H. Moody’, H. R. Grant2, D. Felmingham2, G. M. S. Scott2, P. OUiaro3 and A. D. M. Rrycesonl* ‘Hospital for Tropical Diseases, 4 St Pancras Way, London, NW1 OPE, UK; 2University College Hospital, Gower Street, London, WCIE 6AU, UK; 31nstitute of Infectious Diseases, IRCCS, S. Matteo, University of Pavia, and Farmitalia-Carlo Erba, Milan, Italy Abstract

We report 11 patients with leishmaniasis from different endemic areas, treated in the UK with intravenous aminosidine alone or in combination with other drugs. Clinical and parasitological cures were achieved in all 7 patients from the Mediterranean zone who had visceral disease,with one relapse. Two of 4 patients with cutaneous or mucosal diseasewere cured; the other 2, from Iraq and Iran., did not respond. Toxic effects were high-tone deafnessin 2 patients, one of whom had pre-existing renal Impairment, and transient, mild elevation of serum creatinine in 3. Aminosidine is an effective, tolerable and relatively non-toxic alternative to existing antileishmanial drugs for the treatment of visceral leishmaniasis. Further studies will be needed to assessits place in cutaneous and mucosal disease. Introduction

Pentavalent antimonial compounds are widely used for the treatment of visceral, mucosal, and complicated cutaneous leishmaniasis (BRYCESON,1987). However, the cost, toxicity and long duration of treatment with antimonial drugs, together with the emergence of resistant strains, has led to a search for alternative drugs. The increasing numbgr of reports of visceral leishmaniasis in patients immunosuppressed bv human immunodefivirus infectio~~MONTALbAN et al., 1989; PETERS et al., 1990) has increased the urgency of this search. ciency

Aminosidine is an aminoglycoside antibiotic produced by Streptomyces chrestomyceticus (ARCAMONE et al., 1959). In chemical structure it is identical to paromomycin (SCHILLINGS & SCHAFFNER. 1961). oroduced bv another .ktreptomyces species. Like ‘other’*&ninoglycoiide antibiotics aminosidine is poorly absorbed from the gastrointestinal tract. Intramuscular administrgtion affords prompt and complete absorption with peak levels obtained after one hour of 20 and 40 mg/L with doses of 0.5 and 1.0 g respectivelv. Intravenous administration of the same doses given in saline or 5% dextrose, over a oeriod of 100 min, vield a similar mofile. Aminosidine binds to serum p&ins to a limited extent and is eliminated unchanged through the kidneys. Its pharmacokinetic behaviour fits a multi-compartment model with a dominant elimination half-iife of approximately 2.3 h followed bv a slower elimination half life of about 40 h (KAHLME~IR et al., 1979). Although not absorbed by the gastrointestinal tract when taken orally it is active against several protozoa (Entamoeba histolytica, Giardia duodenalis, Balantidium coli) and tapeworms (Taenia saginata, T. solium. Dibhvllobothrium latum‘l. Aminosidine has also ‘I” .-.-.: shown good actlvlty in studies in animals (NEAL, 1987) and in vitro (MATTOCK & PETERS, 1975) against all Leishmania species tested (L. tropica, L. major, L. mexicana, L. braziliensis, L. garnhami, L. guyanenszs, L. donovani). In a clinical trial of its use in visceral leishmaniasis,

aminosidine alone given to KenyaD patients was more effective than sodium stibogluconate alone, and better results were obtained with a combination of the 2 drugs (CHUNGE et al., 1990). [See also THAKUR et al., 1992.1 We have studied aminosidine in the treatment of a wider geographical spectrum of cases imported into the UK and report our experience of this drug. Patients and Methods

Eleven patients, who had acquired leishmaniasis in endemic areas, were admitted to the Hospital for Tropical Diseases, London, UK, between August 1989 and December 1990. They were classified according to presentation into visceral (VL), cutaneous (CL), or mucosal (ML) disease.VL was diagnosed by the demonstration of ‘Author

for correspondence.

amastigotesin splenic aspirates (S), bone marrow aspirate (one). or liver bioosv (one). CL and ML were diagnosed &henamastigotes’w&e se& in slit skin smears0; biopsies from the lesions. Specific identification of the leishmania1 isolates was by mean? of isoenzyme analysis and/or deoxyribonucleic acid prqbes. Patients were treated with aminosidine sulphate (Gabbromycii, FarmitaliaGarlo Efba), for the indications shown in the Table, after giving informed consent. Initially, it was given only to patients unresponsive to? or intolerant of, sodium stibogluconate or pentamidme. Later, when its efficacy and safety had been confirmed, aminosidine was offered as first-line treatment. The drug was administered in a single daily dose of 14-16 mg/kg bodv mass diluted in 250 ml isotonic saline and infused intrl;venously over 90 tin Serum aSsaysof aminosidine were performed on the third day and repeated if clinically indicated. Treatment was coheuued for 2 1 d, or for one week after demonstratlon of parasitological cure, whichever was the longer. One p&ent who relapsed (caseA) was treated for 6 weeks after parasitological cure during his secondcourse of treatment. Serum aminosidine concentrations were determined usinrr a bioassav on Isosensitest@axar (Oxoid1 with Staphyl&occus au&us NCTC 6371 as th; i&icatoi organism. Toxicity was assessedby daily examination, and twice weekly measurementsof tire@,creaenine, aspartatetransaminase (AsT), haemoglobip, leucocyte and platelet counts. Audiograms were performed on 5 patients before and after treatment. Efficacy was assessedin VL by quantitative parasite counts on splenic aspirates perfdrmed weekly or fortnightly, and graded on a logarithmic ipdex 0 to 6+ (CHULAY & BRYCESON, 1983). Patient A did not have splenomegaly, and parasites were monitored in bone marrow aspirates. Patient E was too obese to undergo splenic aspiration safely: the diagnosis was made by liver biopsy. The clinical efficacv of treatment was monitored bv dailv records of body temperature and weekly examination df the size of the snleen and liver. In natients with CL/ML the size of the lesion was.recorded, &d parasites were assessed semi-quantitatively on slit skin smears, weekly during treatment and monthly thereafter. Results

Of eleven patients treated with aminosidine, 7 had VL, 2 had CL and 2 had &IL (see Table). Of those with CL, patient I had a large ulcer measuring 6~ 5 cm and patient H had two facial nodules. Visceral leishmaniasis

An uncomplicated clinical cure was achieved in 4 of 7 patients (B, E, F, G) with VL who received aminosidine as t,bt sole treatment for between 22 and 54 d. Of the remammg 3, patient A relapsed 4 months after an apparent

618 Table.

Clinical

and parasitological

results of the treatment

of leishmaniasis

Indication for Speciesof Endemic treatment Age Patient (years) Sex Leishmania area with aminosidine Visceralleishmaniasis 30 Male Not known Malta Reactiontu sodium Al stibogluconate A2 Relapse B 63 Female Not known Italy/ Reactionto sodium Spain stibogluconate Malta Unresponsive tu C 13 Male L. infanturn pentamidine D E F

47

Male

tnfanrum

G 42 Male L. mfantum Cutaneousleishmaniasis 22 Male L. major H

Concurrentdisease

Days of Parasitological treatmentOutcOme

Renalallograft, mild renalimpairment Non-insulin-dependent diabetesmellitus Nil

24 63 18

Clinical 0”tcOme

Initial cure,but Apparentcute,but relapsedat 4 months relapsedat 4 months Cure” Cureb Cure‘ Cure

22

Reductionof parasiticindex from 5+ to 3+

HepatitisC

31

Chronicoralsteroids for eczema AIDS

22 54

Reductionof parasiticindex from4+ to l+ Not availabledue tu obesity CUP2

Spain First-linetreatment

Nil

28

Cure

Cure.Died of Pneumocystis carinti pneumonia later Clinicalcute

Topicaltreatment failed;refused admission Cyprus First-linetreatment

Nil

Failure

Failure

Unresponsiveto sodium stibogluconate 55 Female Not known Spain Rashwith sodium stibogluconate 28 Male L. infanrum Malta First-linetreatment L.

with aminosidine

Italy

Iran

Improved.Cure with addition of sodium stibogluconate Improved.Cure completed with amphotericin Cure

Hypertension I 61 Female L. infanrum Cure Mucosalleishmaniasis 61 Male Not known Minor& Previousmyocardial Nil Cure J Greece infarction 49 Female L. rropica Failure K Iraq First-linetreatment Nil Failure “Parasitologicalcure’ indicatescompletedisappearance of parasitesfrom tissueaspiratesby the end of treatment. “Clinical cure’ of visceralleishmaniasismeanscompletealleviationof symptomsandresolutionof abnotmslphysicalsignsandlaboratorytestresults;of cutaneousand mucosalleishmaniasis,it meanshealing of the lesion. ‘Sufficientsodiumstibogluconatehad alreadybeengiven tn eradicateparasitesfrom the spleenbeforethe side effectsbecameintolerable;the fever, however,persisted. cure with aminosidine but was then successfully treated with a second course lasting 63 d. He was a renal allograft recipient on chronic immunosuppression with prednisolone 20 mg daily. A partial parasitological response was seen in the other 2: in patient D the index of the splenic aspirates fell from 4+ to l+ over 4 weeks but aminosidine was withdrawn when the patient developed hepatitis (peak AsT 867 iu/L), later demonstrated to be due to post-transfusional hepatitis C virus infection. He subsequently achieved a complete clinical and parasitological cure with amphotericin B (DAVIDSON er al., 1991). In atient C, a 13 years old boy, the parasitological index 4ell from 5+ to 3+ in the first two weeks. Sodium stibogluconate was then added, in the hope of accelerating the response to allow the child to return overseas sooner. Cutaneous and mucosal leishmaniasis Patients I and J, with CL and ML respectively, were cured uneventfully. In contrast, cases H and K, from Iran and Iraq, showed no reduction in the size of the lesions nor in the density of amastigotes in slit skin smears after 21 d of treatment with aminosidine. They were successfully treated with sodium stibogluconate. All 11 patients have been monitored for over 12 months without further relapse. Aminosidine dose and levels In the bioassay described, a linear relationship was obtained between inhibition zone diameter and log10 concentration of aminosidine over the range 2-32 mg/L. The recommended dose of aminosidine (14-16 mgikg) was received by all but 2 of the patients. Patient A, with a renal allograft and chronic renal impairment (creatinine clearance 40 mlimin), was maintained on a dosage of 7.5 mg/kg on alternate days, with aminosidine assays every 2-4 d. Doses were adjusted to produce an immediate pre-dose trough within the range O-4 mg/L and a one-hour peak within the range 20-30 mg/L. Patient E

had 15.5 peak 40.0 vels

normal renal function but the initial dosage of mglkgid was reduced to 13.5 mg/kg/d, as the first level was 32.8 mg/L. Patient D had a peak level of mg/L in the first assay. However, 3 subsequent leafter the same dose were within the range 22.926.8 mg/L. Tolerability and toxicity All the patients tolerated aminosidine well and none complained of any symptoms attributable to the drug. Fever settled and appetite returned promptly in all cases of VL. Two patients developed asymptomatic, bilateral, high-tone deafness. Pure tone audiograms recorded after treatment showed an increase in hearing thresholds from 10 dB to 80 dB at frequencies above 2000 HZ compared with normal audiograms before treatment. Of these 2, patient E had a single excessive peak level of aminosidine (32.8 mg/L) and patient A had a single excessive trough level (7.0 mg/L). The only other toxic peak, 40.0 mg/L in patient D, was accompanied by transient tinnitus but no deficit on audiometery. A mild, reversible elevation of urea and creatinine levels occurred in 3 patients (A, D and F). Discussion Parenteral aminosidine has been reported to be effective against CL in clinical studies from both Venezuela (SCORZAet al., 1986) and Russia (see BRYCESON, 1987). Topical aminosidine has also been shown to be effective against L. major in CL from Israel (EL-ON et al., 1985). In our experience of CL/ML, aminosidine had no useful activity in one case each from Iraq and Iran with L. major and L. tropica respectively but was curative in 2 patients who had acquired the disease in the Mediterranean region. Results obtained in vitro and from studies on aminosidine ointment do not suggest, however, that these species are resistant to the drug (MATTOCK & PETERS, 1975; EL-ON et al., 1985). For VL, aminosidine has been used previously in 53

619

patients in Kenya (CHUNGE et al., 1990). Given alone, for a mean treatment duration of 19 d, aminosidine had a significantly higher cure rate (15 of 19 patients) at 6 months than did sodium stibogluconate alone (6 of ll), althou h the best results were obtained with a combination oB both drues (all of 23 cured). Aminosidine caused fewer adverse eife&s than sodi& stibogluconate, and combination treatment was no more toxic than that with sodium stibogluconate alone, although audiograms were

not performed in this investigation. Our patients appear to have responded more slowly

than the Kenyan patients, possibly because they had severe, complicated VL or had parasites which were resistant to other drugs. None the less, our results corro-

borated the Kenyan experience. Ammosidine was effective in all 7 patients with VL with only one relapse, case

A, in whom chronic immunosuppression may have been a contributory factor. This patient had experienced marked adverse effects with sodium stibogluconate

in-

cluding acute pancreatitis and severepalindromic arthropathy (DONOVANet al., 1990) but achieved a definitive

cure with a second course of aminosidine lasting 63 d. A second patient with immunodeficiency (case F, with the acquired immunodeficiency syndrome [AIDS]) also re-

auired a longer course of treatment than usual (54 d) but iltimately ackieved both clinical and parastiolo&cal cure. In 2 Datients with VL (cases C. D) treatment could not be cohpleted with aminbsidine alone because of intercurrent medical and social problems. The efficacy, tolerability, ease of administration and relative safety of aminosidine were so impressive in the patients who were

resistant to, or intolerant of, normal primary treatment, that we later offered it to 4 patients as first-line therapy. Large scale studies are now warranted in several areas of endemic leisbmaniasis to establish optimum regimes of

aminosidine, to define the risks of toxicity in uncomplicated cases &d to examine its possible potentiation ofso-

dium stibogluconate. Ototoxicity could pose problems in patients with poor renal quire prolonged treatment Nevertheless., aminosidine to sodium stlbogluconate

function, or in those who rebecause of immunodeficiency. may be a suitable a’lternative

as the drug of choice for leishmaniasis and is certainly the most valuable of the secondline drugs currently available. Acknowledeements

We are grateful to colleagueswho referred patients, and to Dr David Evans and Mr Keith Howard, of the London School of Hygiene and Tropical Medicine, for typing the Leishmania isolates. Aminisodine was provided on a ‘named patient’ basis by Mr Paul Launchbury of Farmitalia-Carlo Erba, UK. References

Arcamone? F., Bertazzoli, C., Chione, M. & Scotti, T. (1959). Aminosldina: un nuovo antibiotic0 oligosaccaridico. Giornale de la Microbiologia,

7, 251-272.

Bryceson, A. D. M. (1987). Therapy in man.

In: TheLeishma-

niases in Biology and Medicine, volume 2, Peters, W. 81 Kil-

li;Fig;drick, -..

R. (editors). London: Acadenuc Press, pp.

_“..

Chulay, J. D. & Bryceson, A. D. M. (1983). Quantitation of amastigotes of Leishmania donovani in smearsof splenic aspirates from patients with visceral leishmaniasis. AmericanJourno1 of Tropical Medicine and Hygiene, 32,47%79.

Chunge, C. N., Owate, J., Pamba, H. 0. & Donno, L. (1990). Treatment of visceral leishmaniasis in Kenya by aminosidine alone or combined with sodium stibogluconate. Transactions of the Royal Society of Tropical Medicine and Hygiene, 84,221-

225. Davidson, R. N., Croft, S. L., Scott, A., Moody, A. G., Maini, M. & Bryceson, A. D. M. (1991). Liposomal amphotericin B in drug-resistant visceral leishmaniasis. Lancer, 337, 10611062. Donovan, K. L., White, A. D., Cooke, D. A. & Fisher, D. J. (1990). Pancreatitis and palindromic arthropathy with effusions associated with sodium stibogluconate treatment in a renal transplant recipient.3ournal of Infection, 21, 107-l 10. El-On, J., Livshin, R., Evan Paz, Z. & Weinrauch, L. (1985). Topical treatment of cutaneous leishmaniasis. British Medical 30urna1,291,1280-1281.

Kahhnetir, G. (1979). Gentamicin and tobromycin: clinical pharmacokinetics and nephrotoxicity aspects and assay techniques. ScandinavianJournal of Infectious Disease, 18, l-40. Mattock, N. M. & Peters, W. (1975). The experimental chemotherapy of leishmaniasis II. The activity in tissue culture of some antiparasitic and antimicrobial compounds in clinical use. Annals of Tropical Medicine and Parasitology, 69, 359371.

Montalban, C., Martinez-Fernandez, R., Calleja, J. L., GarciaDias, J. de D., Rubio, R., Dronda, F., Moreno, S., Yebra, M., Barros, C., Cobo, J., Marinez, M. C., Ruiz, F. & Costa, J. R. (1989). Visceral leishmaniasis (kala azar) as an opportunistic infection in patients infected with the human immunodeficiency virus in Spain. Re-views of Infectious Disease, 11, 655-660.

Neal, R. A. (1987). Experimental chemotherapy. In: The Leishmaniases in Siology and Medicine, volume 2, Peters, W. & Killi;iF;Fdnck, R. (editors). London: Academic Press, pp.

,,_ -._.

Peters, B. S., Fish, D. A., Golden, D. A., Bryceson, A. D. M. & Pinching. A. I. (1990). Visceral leishmaniasis in HIV infection and A&: &&al fiatures and responseto therapy. QuarterlyJourna1 of Medicine, 77, 1101-l 111. Schillings? R. T. & Schaffner, C. P. (1961). Differentiation of catenuhn-neomycin antibiotics: identity of catenulin, paromomycin, hydroxymycin and aminosidin. Antimicrobial Agents and Chemotherapy, 4,274285.

Scorza, J. V., Hernandez Opin?, A. Y. & Araujo, P. I. (1986). Nuevo tratamiento para la leishmaniasis tegumentaria. Dermatologia Venezolana, 24,82-84.

Thakur, C. P., Olliaro, P., Gothoskar, S., Bhowmick, S., Choudhury, B. K., Prasad, S., Kumar, M. & Verma, B. B. (1992). Treatment of visceral leishmaniasis (kala-azar) with aminosidine (=paromomycin)-antimonial compounds, a pilot study in Bihar, India. Transactions of the Royal Society of Tropical Medicine and Hygiene, 86, 615-616. j$;Td

10 June

1992; accepted for publication

2 July