Systematic review of the adverse effects of cutaneous leishmaniasis treatment in the New World

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Acta Tropica 118 (2011) 87ndash96

Contents lists available at ScienceDirect

Acta Tropica

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ystematic review of the adverse effects of cutaneouseishmaniasis treatment in the New World

uiz F Oliveiraalowast Armando O Schubacha Maria M Martinsb Socircnia L Passosaaquel V Oliveiraa Mauro C Marzochia Carlos A Andradea

Instituto de Pesquisa Cliacutenica Evandro Chagas (IPEC)Fiocruz BrazilInstituto de Comunicacatildeo e Informacatildeo Cientiacutefica e Tecnoloacutegica em Sauacutede (ICICT)Fiocruz Brazil

r t i c l e i n f o

rticle historyeceived 30 September 2010eceived in revised form 7 February 2011ccepted 12 February 2011vailable online 21 March 2011

eywordsystematic review Cutaneouseishmaniasistreatmentntiprotozoal agentsadverse effects

a b s t r a c t

Pentavalent antimonials are first-line drugs for the treatment of the cutaneous form of American tegu-mentary leishmaniasis Second-line drugs include amphotericin B and pentamidine Although these drugshave been used for decades there are no systematic reviews about their safety The objective of thisreview was to identify and classify the main adverse effects associated with these drugs and to estimatethe frequency of these effects whenever possible Intervention studies case series and case reports con-taining information regarding clinical laboratory or electrocardiographic adverse effects of drugs usedfor the treatment of cutaneous leishmaniasis were systematically retrieved from 10 databases searchedbetween August 13 2008 and March 31 2009 The 65 studies included in this review had treated a totalof 4359 patients from 12 countries infected with eight different Leishmania species Despite the smallnumber of drugs used in these studies a wide variability in the therapeutic regimens was observed Asa consequence the adverse effects of pentavalent antimonials and pentamidine needed to be classifiedjointly according to system irrespective of formulation daily dose duration of treatment and route ofadministration The frequencies of adverse effects were calculated based on the data of 32 articles involv-ing 1866 patients The most frequently reported clinical adverse effects of pentavalent antimonials andpentamidine were musculoskeletal pain gastrointestinal disturbances and mild to moderate headacheElectrocardiographic QTc interval prolongation and a mild to moderate increase in liver and pancreatic

enzymes were additional adverse effects of pentavalent antimonials Patients treated with liposomalamphotericin B had mild dyspnea and erythema The adverse effects associated with miltefosine werevomiting nausea kinetosis headache diarrhea and a mild to moderate increase in aminotransferasesand creatinine Although closer surveillance is needed for the treatment of cutaneous leishmaniasisantileishmanial drugs are basically safe and severe side effects requiring the discontinuation of treatmentare relatively uncommon

copy 2011 Elsevier BV All rights reserved

ontents

1 Introduction 882 Methods 88

21 Search strategies and selection criteria 8822 Data extraction 88

3 Results 8831 Pentavalent antimonials 89

32 Pentamidine 33 Amphotericin B 34 Miltefosine

lowast Corresponding authorE-mail addresses luizfilipeol07gmailcom (LF Oliveira) armandoipecfiocruzbr (A

onialambertipecfiocruzbr (SL Passos) raquelvasconcellosipecfiocruzbr (RV Olivearlosandrade07gmailcom (CA Andrade)

001-706X$ ndash see front matter copy 2011 Elsevier BV All rights reservedoi101016jactatropica201102007

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4 Discussion 90Conflicts of interest 94Acknowledgments 94Appendix A Supplementary data 94References 94

Introduction

Leishmaniases are parasitic diseases caused by different pro-ozoan species of the genus Leishmania including those ofhe subgenus Leishmania which display dermotropism or vis-erotropism in the Old World (Southern Europe the Middle Eastsia and Africa) and New World (Latin America) and of the sub-enus Viannia which are exclusively dermotropic (New World)he parasites are transmitted by the bite of different sandflypecies (Marzochi and Marzochi 1994) Leishmaniases caused byermotropic species are endemic in 82 countries with an inci-ence of approximately 15 million cases per year About 90f cutaneous leishmaniasis cases are concentrated in Brazil andix other developing countries (WHO 2007) American tegumen-ary leishmaniasis a term comprising cutaneous forms with aotential to evolve to secondary mucosal forms is mainly causedy Leishmania (Viannia) braziliensis and is endemic in variousegions of the Americas (Lainson 1983 Jones et al 1987 Brasil010)

Pentavalent antimonials are the first-line drugs for the treat-ent of the cutaneous form of leishmaniasis in the New World

he recommended dose range is 10ndash20 mgkgday for a minimumeriod of 20 days (Berman 1988 Herwaldt and Berman 1992erwaldt 1999 Brasil 2010) Other therapeutic regimens are alsosed but no consensus exists over which is the best one (Tuont al 2008 Gonzaacuteles et al 2009) In view of their higher toxic-ty amphotericin B and pentamidine are second-line drugs whichre recommended in cases of contraindication intolerance or resis-ance to antimonials (Berman 1988 Lima et al 2007) The efficacyf different drugs seems to vary according to the Leishmania speciesnvolved (Romero et al 2001a)

Adverse drug effects are unfavorable events associated in timeith the use of a medication and may have a causal relationship

Deeks et al 2006) The safety of a drug is related to morbiditynd mortality resulting from the incidence and severity of adverseffects (Kane-Gill et al 2006) Although the drugs recommendedor the treatment of cutaneous leishmaniasis have been used forecades and some adverse effects are known there are no system-tic reviews about their safety (Blum et al 2004 Blum and Hatz009 David and Craft 2009)

Systematic reviews give priority to efficacy over safety (Loket al 2007) We found only two systematic reviews on the treat-ent of cutaneous leishmaniasis in the New World but none of

hem considered safety-related issues (Tuon et al 2008 Gonzaacutelest al 2009)

The objective of the present systematic review was to identifynd classify the main clinical laboratory and electrocardiographicdverse effects associated with drugs recommended for the treat-ent of the cutaneous form of leishmaniasis in the New World and

o estimate the frequency of these adverse effects

Methods

21 Search strategies and selection criteria

The searches and review process were performed accordingto a pre-established protocol restricted to the cutaneous form ofleishmaniasis in the New World Intervention studies case seriesand case reports in which patients were treated with the rec-ommended drugs and clinical laboratory or electrocardiographicadverse effects were recorded were included In the case of exper-imental drug studies in which the control group received theapproved drugs only this group was evaluated Studies using milte-fosine were included since this drug is currently under evaluationfor the treatment of cutaneous leishmaniasis in the New WorldThere were no restrictions in terms of patient age or language ofthe published articles

The following scientifically reliable databases providing elec-tronic access to bibliographic references were chosen PubMedLiteratura Latino-Americana e do Caribe em Ciecircncias da Sauacutede(LILACS) Cochrane Scopus Web of Science Science DirectExcerpta Medica Database (Embase) Scielo Highwirepress andScirus Search strategies combining the following keywords wereelaborated for each database adverse effects adverse drug reac-tion and side effects preceded by the names of the drugsselected (antimony sodium stibogluconate meglumine antimoni-ate pentamidine isethionate pentamidine mesylate amphotericinB miltefosine) and treatment drug therapy leishmaniasis cuta-neous The Scirus database also covered grey literature Thecomplete search strategies are summarized in Appendix A Thesearches were started on August 13 2008 and were updated untilMarch 31 2009 The reference lists of all articles were reviewedmanually for the identification of new articles

A database of the electronic search results was created with theEndNote X1 program Duplicate citations were eliminated Poten-tially relevant titles and abstracts were independently selected bythe pairs of reviewers LFGOCAFA and LFGOAOS Divergences wereresolved by consensus or by a third reviewer if necessary

22 Data extraction

The quality of the studies initially selected was evaluated inde-pendently by the same pairs of reviewers Studies in which themonitoring of clinical laboratory or electrocardiographic adverseeffects was described in the methods section were considered tobe adequate Independent data extraction was performed by fillingout a standard form (Appendix B) During this step divergenceswere also resolved by consensus or by a third reviewer if nec-essary The severity of adverse effects was classified according tothe criteria adopted by the Acquired Immunodeficiency SyndromeClinical Trials Group (NIH 2004) The articles approved were clas-sified according to the type of study country of contraction ofthe infection and therapeutic regimen A list of adverse effectswas obtained and frequencies were calculated whenever possi-ble

The present systematic review was conducted according tohe PRISMA guideline (Preferred Reporting Items for Systematiceviews and Meta-Analyses) (Liberati et al 2009)

3 Results

The search of the 10 databases initially yielded 1358 abstracts86 of them were selected for complete reading of the articles In

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ddition 36 articles were obtained by cross-referencing resultingn 122 studies Of these the following 65 studies were approvednd included in the systematic review 31 clinical trials 28 caseeries and six case reports (Fig 1)

The 65 studies included had treated a total of 4359 patientsho contracted the infection in the following countries Brazilolombia Panama Bolivia Guatemala French Guiana Peruenezuela Ecuador Mexico and Argentina The Leishmania species

nvolved were L (Viannia) braziliensis L (V) guyanensis L (V)anamensis L (V) naiffi L (V) shawi L (Leishmania) mexicana LL) amazonensis and L (L) chagasi

1 Pentavalent antimonials

A total of 2900 patients received treatment with pentavalentntimonials Of these 937 participated in clinical trials 1594 inase series seven were case reports and 362 corresponded tohe control groups of experimental drug studies Doses below andbove the recommended range (10ndash20 mgkgday) were employedn the different therapeutic regimens (Oliveira-Neto et al 1997abopke et al 1991) Some authors adopted fixed doses irrespective

f body weight (Oster et al 1985 Henderson and Jolliffe 1985avin et al 1990 Hepburn et al1993a Oliveira-Neto and Mattos006 Chulay et al 1988) However 778 of the studies used theaximum dose recommended (20 mgkgday)

ica 118 (2011) 87ndash96 89

The most frequently reported clinical adverse effects weremusculoskeletal pain nausea vomiting diarrhea abdominal painheadache anorexia asthenia fatigue fever exanthema erythemaand urticaria (Table 2) Romero et al (2003) observed a high inci-dence of severe cutaneous reactions (719 = 037) among patientstreated with 20 mg meglumine antimoniatekgday when com-pared to historical control patients (154 = 002) The authorsdetected high concentrations of other heavy metals in the drug lotHerpes zoster was a complication cited by other authors (Kopkeet al 1991 Oliveira-Neto et al 1997b Wortmann et al 1998Seaton et al 1999 Passos et al 2001) Intramuscular adminis-tration was associated with mild to moderate pain at the site ofapplication In some cases local pain was intense and required theinterruption of treatment or change of the route of administra-tion (Krolewiecki et al 2007) The most frequently reported localreactions in the case of intravenous administration were throm-bophlebitis phlebitis and edema (Oster et al 1985 Chulay et al1988 Navin et al 1992 Hepburn et al 1993a Arana et al 1994)Pancreatitis has been reported in two studies (Saldanha et al 2000Wortmann et al 2002) In the first study the authors comparedmeglumine antimoniate with SSG BP88 administered at a doseof 20 mgkgday for 20 continuous days Three cases of pancre-atitis were observed in the control group (N = 47) and 11 in thestudy group (N = 64) However all cases were classified as mildie only elevated serum levels of pancreatic enzymes associatedwith abdominal pain Wortmann et al (2002) compared a dose of20 mg sodium stibogluconatekgday and interrupted treatment in7 patients (4 of 19 patients in the group submitted to 10 days oftreatment and 3 of 19 patients in the 20-day treatment group)who presented severe pancreatitis The criterion for the diagno-sis of pancreatitis was not specified in the study All 7 patientsdeveloped symptoms of pancreatitis within the first 10 days oftreatment Hepatitis was rarely cited and was related to treatmentwith 20 mgkgday for more than 10 days (Martinez et al 1997)

The most frequently cited laboratory adverse effects were a mildto moderate increase in liver and pancreatic enzymes (Table 3)However treatment interruption was necessary on some occasions(Gasser et al 1994 Zlotogorski et al 1998 Seaton et al 1999 Depset al 2000 Scope et al 2003 Soto et al 2004a) Other adverseeffects included elevated creatine phosphokinase and alkalinephosphatase levels impaired renal function eosinophilia leukope-nia and thrombocytopenia (Scope et al 2003 De Paula et al2003 Name et al 2005) All of these alterations were transient andreturned to normal after the end of treatment except for two occa-sions when thrombocytopenia resulted in treatment interruption(Hepburn et al 1994a Seaton et al 1999)

The most frequently cited electrocardiographic abnormalitieswere QTc interval prolongation and ventricular repolarization dis-turbances (Table 3) Arrhythmias have been reported in threestudies Convit et al (1987) observed severe arrhythmia in apatient without any comorbidity and treatment was discontinuedIn another study (Saldanha et al 1999) one patient had to interrupttreatment with SSG BP88 on day 10 because of severe arrhyth-mia In the third study Lawn et al (2006) reported the case ofan 81-year-old patient with hypertension and cardiomegaly whopresented ventricular arrhythmias without cardiovascular involve-ment These arrhythmias were attributed to the use of thiazidediuretic that caused a reduction in plasma potassium levels duringtreatment

Rare but severe adverse effects were cited in the case reportsand generally occurred after the 15th day of treatment throm-bocytopenia and eosinophilic panniculitis (Hepburn et al 1993a

Oliveira-Neto et al 2004) Three cases of death were also reportedthe first was due to renal and hepatic insufficiency and occurred3 days after the end of treatment with meglumine antimoniateat a dose of 20 mgkgday for 30 days (Kopke et al 1993) The

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atient presented an electrocardiographic alteration in the ST seg-ent and T wave suggestive of ischemia After assessment by a

ardiologist and a normal ergometric test and echocardiogram theatient was released for treatment The second case of death wasue to acute tubular necrosis and occurred on day 20 of treatmentith meglumine antimoniate at a dose of less than 10 mgkgday

Rodrigues et al 1999) The patient was morbid obese (148 kg73 m) and had a history of alcoholism The third case was due toardiorespiratory insufficiency and occurred on day 12 of treatmentith sodium stibogluconate BP88 (Shandong Xinhua Pharmaceu-

ical Co) The patient was a healthy 22-year-old man receiving aose of 10 mgkgday (Costa et al 2003) No laboratory or elec-rocardiographic tests were performed before or during treatmenthe patient was admitted on day 11 of treatment and blockade ofhe right branch was detected

Intralesional treatment was reported in three studies (144atients) (Barrios et al 1986 Gadelha et al 1990 Oliveira-Netot al 1997c) Mild to moderate adverse effects were reported inbout 98 of cases pain erythema or edema at the site of appli-ation Urticaria hemorrhage lipothymia and the formation of aocal abscess were rarely observed

2 Pentamidine

A total of 1291 patients were treated with pentamidineenerally a dose of 2ndash4 mgkgday based on salt moiety wasdministered on alternate days with two to four applicationsTalhari et al 1985 Dimier-David et al 1992 Soto et al 1994acher et al 2001 Robledo et al 2006 Roussel et al 2006) Someuthors preferred the administration of a single dose of 7 mgkgDelobel and Pradinaud 2003 Roussel et al 2006)

The most frequently reported clinical adverse effects wereusculoskeletal pain anorexia abdominal pain nausea vomiting

eadache asthenia and fatigue (Table 2) Mild to moderate pain athe site of application was reported at a frequency higher than 20lterations in the sense of taste such as metallic or bitter taste andypotension were also observed (Dimier-David et al 1992 Soto-ancipe et al 1993 Soto et al 1994 Nacher et al 2001 Lai et al

002 Andersen et al 2005) Delobel and Pradinaud (2003) using aingle dose of 7 mgkg in a series of 26 cases observed rhabdomy-lysis in 23 patients The laboratory adverse effects of pentamidinere shown in Table 3 Two reports of hypoglycemia one of themevere were found (Soto-Mancipe et al 1993 Soto et al 1994)

The frequencies of adverse effects were calculated for pentava-ent antimonials and pentamidine based on the information of 32rticles involving 1866 patients irrespective of formulation doseuration of treatment or route of administration (Table 4)

3 Amphotericin B

Liposomal amphotericin B was evaluated in only one case seriesSolomon et al 2007) In that study seven patients were treatedith a total dose of 18 mgkg and mild dyspnea and erythema were

bserved in two patients

4 Miltefosine

Oral treatment with miltefosine was used in two clinical trialsne of these studies evaluated the efficacy and safety of the drugdministered at a daily dose of 50 mg for 28 days for the treatmentf cutaneous leishmaniasis caused by L (L) mexicana and L (V)raziliensis The intervention included 49 patients from Colombia

nd 40 from Guatemala (Soto et al 2004b) The clinical adverseffects reported were vomiting (63) nausea (36) kinetosis (29)eadache (27) and diarrhea (11) One patient presented severeeadache and kinetosis and discontinued the medication on the

ica 118 (2011) 87ndash96

penultimate day of treatment A mild to moderate increase inaminotransferases and creatinine was observed in 10 and 31of patients respectively In another clinical trial conducted inColombia on 72 patients Soto et al (2001) compared four differentdoses of miltefosine The main adverse effects (kinetosis vomitingand elevated aminotransferases) were more frequent and intensein the groups receiving the higher dose (150 mgday) One patientreceiving high doses reported mild to moderate abdominal pain

4 Discussion

This systematic review provides information regarding thesafety of treatment of 4359 patients of different ages with cuta-neous leishmaniasis caused by eight different Leishmania speciesin 12 countries of the New World One case series should be high-lighted in which L (L) chagasi the causative agent of visceralleishmaniasis was identified as the cause of one case of cutaneousleishmaniasis (Chulay et al 1988)

Although randomized clinical trials are considered to be the goldstandard for the evaluation of the efficacy of interventions caseseries and case reports were also included since rare and severeadverse effects are frequently reported in these studies In additionclinical trials tend to exclude older adults patients with chronicdiseases and other individuals who present a higher risk for adverseeffects (Loke et al 2007)

Despite the broad and meticulous search of 10 databases usingcarefully selected keywords with coverage of the grey literatureand no language restriction only 65 articles containing data aboutadverse effects were approved

Therapeutic trials in humans should follow the guidelines ofgood clinical practice and adequately report adverse effects (FDA1994 1996) However inadequate monitoring of clinical labora-tory and electrocardiographic adverse effects as well as the lack ofclassification according to criteria of severity was a constant find-ing in the articles evaluated As a consequence instead of reportingadverse effects individually it was necessary to categorize theminto gastrointestinal disturbances cardiovascular alterations neu-rological alterations taste alterations and cutaneous reactionsamong others

As shown in Table 1 the frequencies of one or more adverseeffects were reported in 44 articles (indicated by letter a in Table 1)However divergences among frequencies were expressive Themost common adverse effects were arthralgias and myalgias whichwere reported consistently Other effects such as itching respi-ratory alterations and balance disturbances were reported lessregularly Some studies limited their safety results to vague state-ments such as ldquono adverse effect was observedrdquo or ldquothe drugswere well toleratedrdquo Thus the true frequency of the adverseeffects shown in Table 4 might be underestimated In the remain-ing articles adverse effects were cited without reporting theirrespective frequencies We chose to complete the information withTables 2 and 3 which show the number of articles reporting adverseeffects according to the drug used for the treatment of cutaneusleishmaniasis in the New World

Despite the small number of drugs used in the studies includedin this review (meglumine antimoniate sodium stibogluconatefrom different manufacturers pentamidine isethionate and mesy-late liposomal amphotericin B and miltefosine) we observeda wide variability in the therapeutic regimens employed Asa consequence the adverse effects of pentavalent antimonialsand pentamidine needed to be considered jointly irrespective of

formulation daily dose duration of treatment and route of admin-istration

Mild to moderate clinical laboratory and electrocardiographicadverse effects were frequent In some cases these effects were

LF Oliveira et al Acta Tropica 118 (2011) 87ndash96 91

Table 1Studies providing information about the adverse effects of cutaneous leishmaniasis treatment in the New World

First author year Country N Males () Age range (years) Drug Therapeutic regimen (mgkgdayfrequency of doses route)

Clinical trials

Andersen 2005a Peru40

812f 18ndash60MA 20 20times continuous IV

40 PIe 2 7times alternate days

Arana 1994a Guatemala22

1000f NSMA 20 20times continuous IV

22 MA 20 10timescontinuous IV

Ballou 1987a Panama19

1000f NSSSG 20 20times continuous IV

21 SSG 10 20times continuous IV

Correia 1996a Brazil16

677f NSMA 10 20times continuous IM


De Paula 2003a Brazil41

NS NSMA 20 20times continuous IV


Deps 2000 Brazil32

730f 0ndash60MA 15 20times continuous IM

31 SSG BP88

Kopke 1991 Brazil14

NS NSMA 14 20times intermittent IV

12 MA 28 10times intermittent IVOliveira-Neto1997ba Brazil

12610f 11ndash66

MA 5 30times continuous IV11 MA 20 30times continuous IV

Oster 1985 NS 36 NS NS SSGd 600 mgday 10times continuous IV

Palacios 2001 Colombia68


68 MA 2010times continuous IM

Saacuteenz 1987a Panama29


30 SSG

Saldanha 1999a Brazil58

710f 7ndash60MA 20 20times continuous IMIV

69 SSG BP88



64 SSG BP88

Soto 1994a Colombia38

1000f 18ndash60PIe 2 4times alternate days


Soto2001a Colombia

16

100f NS

MTd 50 mgday 20times19 MTd 50 mgday 7times + 100 mgday 13times17 MTd 100 mgday 7times + 150 mgday 13times20 MTd 150 mgday 28times

Soto2004aa BoliviaColombia

2030880f NS

MA 20 20times continuous IM88 SSG1731 SSG BP88

Soto 2004ba Colombia 49910f NS

MTd 50 mgday 28timesGuatemala 40 MTd 50 mgday 28times

Soto-Mancipe1993a Colombia

231000f 18ndash25

MA 20 20times continuous IM27 PIe 2 7times alternate days

Wortmann 2002a Panama19



Control groups of experimental drug studiesArevalo 2007 Peru 7 550 NS MA 20 20times continuous IVArmijos 2004a Ecuador 36 NS 5ndash60 MA 20 10times continuous IMConvit 1987a Venezuela 42 670 NS MA 17 20times intermittent IMHepburn 1994aa Belize 17 1000 NS SSG 20 20times continuous IVHepburn 1994b Belize 7 1000 NS SSG 20 20times continuous IVKrolewiecki 2007a Argentina 23 870 NS MA 10 28times continuous IMMartinez 1992 Colombia 33 1000 18ndash35 SSG 20 15times NSMartinez 1997a Colombia 49 900 18ndash57 SSG 20 15times continuousNavin 1990a Guatemala 22 1000 18ndash60 MAd 850 mgday 15times continuous IMNavin 1992a Guatemala 40 1000 NS SSG 20 20times continuous IVSaacuteenz 1990a Panama 19 1000 17ndash67 SSG 20 20times continuous IMVelez 1997 Colombia 67 620 NS MA 20 20times continuous IM

Case seriesBarrios 1986a Brazil 6 NS NS MAd 1 ampule 2times IL

Chulay 1988a PanamaColombia3 NS

2ndash41MAd 850 mgday 20times continuous IM

20b NS SSG 10 10times intermittent NSDelobel 2003a French Guiana 26c NS NS PIe 7 single doseDimier-David1992 Bolivia

15 680f

3ndash65PIe 4 4times 48-h interval

11 PIe 4 5times 48-h intervalGadelha 1990a Brazil 64 590 NS MA 1ndash10 mL 1timesweek then 1times10 or 15

daysGasser 1994a Peru 10 1000 21ndash37 SSG 20 20times continuous IVHenderson 1985 NS 22 1000 18ndash31 SSGd 600 mgday 10times continuous NS

Hepburn 1993ba Belize101 1000

NSSSGd 600ndash800 mgday 10times intermittent IV

72 1000 SSGd 1200 mgday 14times intermittent IVHepburn 1994ca Belize 12 1000 NS SSG 20 20times continuous IV

Lai 2002 French Guiana235

910f 1ndash75PMe 210 mgday 7 a 10times

80 PIe 300 mgweek + 1times or 2timesLawn 2006a NS 60 650 NS SSG 20 21times continuous NS

Nacher 2001a French Guiana198

NS NSPIe 4 2times 48-h interval

12 NS 4 3times 48-h interval


Table 1 (Continued)


Name 2005Brazil 183

660f NSMA 20 20times continuous NS

Brazil 34 SSGOliveira-Neto 1997aa Brazil 159 530 NS MA 5 30times continuous IMOliveira-Neto 1997ca Brazil 74 590 NS MA NS ILOliveira-Neto 2006a Brazil 40 580 2ndash78 MAd 405 mgday alternate days IMPassos 2001 Brazil 358 NS NS MA 15 10 days intermittent IMRibeiro 1999a Brazil 62 NS 19ndash74 MA 15 10times intermittent NSRobledo 2006a Colombia 63 NS NS PIe 4 4times alternate daysRomero 2001b Brazil 118 800 NS MA 20 20times continuous IVIMRomero 2003a Brazil 73 690 14ndash32 MA 20 20times continuous IV

Roussel 2006a French Guiana281 850 NS PIe 4 4times alternate days137 790 NS PIe 7 single dose

Scope 2003a Bolivia 12 920 NS SSG 600 mgday 2times + 20 mgkgday 19timesSeaton 1999a Belize 13 1000 19ndash35 SSG 20 20times continuous IVSolomon 2007a Bolivia 7 710 21ndash24 LAB 3 6times (total dose 18 mgkg)

Talhari 1985 Brazil6

950f 4ndash64PIe 4 3times 48-h interval

13 PIe 4 4ndash9times 48-h intervalWortmann 1998a Panama 90 1000 19ndash42 SSG 20 10times intermittent NSZlotogorski 1998a BoliviaPeru 8 800 22ndash29 SSG 20 18times continuous IV

Case reportsCosta 2003 Brazil ndash ndash ndash SSG 10 20times continuousHepburn et al 1993a Belize ndash ndash ndash SSG 20 20times continuous

Oliveira-Neto 2004 Brazilndash ndash ndash MA 5 30times continuousndash ndash ndash MAd 850 mgday 30times continuous

Koerber 1978 Mexico ndash ndash ndash SSGd 600 mgday 10times continuousKopke 1993 Brazil ndash ndash ndash MA 20 30times continuousRodrigues 1999 Brazil ndash ndash ndash MA 81 20times continuous

MA meglumine antimoniate PI pentamidine isethionate SSG sodium stibogluconate SSG BP88 sodium stibogluconate (Shandong Xinhua Pharmaceutical Co) MTmiltefosine PM pentamidine mesylate LAB liposomal amphotericin B NS not specified IL intralesional IV intravenous IM intramuscular

a Articles that reported the frequency of one or more adverse effectsb Number of patients evaluated in the study (N = 56)c Number of patients evaluated in the study (N = 45)

saCmf

(

TN

Na

d Fixed dosee Dosage given in salt moietyf Combined percentage of groups

evere resulting in temporary or definitive treatment discontinu-tion or even in death (Kopke et al 1993 Rodrigues et al 1999osta et al 2003) The profile of adverse effects of pentavalent anti-

onials pentamidine and miltefosine was established and their

requencies were estimated whenever possiblePentavalent antimonials were used for the treatment of 665

n = 2900) of the patients Of these 784 (n = 2273) received

able 2umber and percentage of articles reporting clinical adverse effects according to drug us

Clinical adverse effects MA N = 28 SSG N

n n

Myalgiaarthralgia 22 786 13Gastrointestinal disturbances 20 714 11Headache 14 500 10Anorexia 11 393 5Astheniafatigue 11 393 3Fever 9 321 3Cutaneous reactions 8 286 4Cardiovascular alterations 5 178 2Local pain 4 143 2Taste alterations 3 107 1Respiratory alterations 3 107 ndashBalance disturbances 3 107 ndashNeurological alterations 2 71 3Itching 2 71 2Pancreatitis 1 36 1Thrombophlebitis 1 36 4Behavioral alterations 1 36 ndashLocal reaction ndash ndash 3Rhabdomyolysis ndash ndash ndash

Number of articles evaluated (case series clinical trials and control groups of experimenntimoniate SSG sodium stibogluconate SSG BP88 sodium stibogluconate Chinese fab

a Only one case series used pentamidine mesylate Dosage given in salt moiety

standard doses of 10ndash20 mgkgday High frequencies of mild tomoderate adverse effects were observed Most cutaneous reactionswere mild and disappeared within days after treatment However

Romero et al (2003) observed a high incidence of severe cutaneousreactions (37) which were attributed to high concentrations oflead cadmium and arsenic in the drug vials Treatment was inter-rupted and some patients required antihistaminic medication to

ed for the treatment of cutaneus leishmaniasis in the New World

= 21 SSG BP88 N = 3 Pia N = 12

n n

620 2 667 7 583524 1 333 10 833476 2 667 6 500238 2 667 2 167143 1 333 5 417143 2 667 2 167190 2 667 1 83

95 2 667 3 25095 ndash 8 66748 1 333 3 250ndash ndash ndash 1 83ndash ndash ndash 3 250

143 ndash ndash 3 25095 ndash ndash ndash ndash48 1 333 ndash ndash

190 ndash ndash ndash ndashndash ndash ndash 1 83

143 ndash ndash 1 83ndash ndash ndash 1 83

tal interventions) n number of studies reporting adverse effects MA megluminerication (Shandong Xinhua Pharmaceutical Co) PI pentamidine isethionate


Table 3Number and percentage of articles reporting laboratory and electrocardiographic adverse effects according to drug used for the treatment of cutaneus leishmaniasis in theNew World

Laboratory and electrocardiographic adverse effects MA N = 28 SSG N = 21 SSG BP88 N = 3 Pia N = 12

n n n n

ASTALT 11 393 12 571 2 667 1 83Lipaseamylase 4 143 6 286 2 667 ndash ndashCreatine phosphokinase 2 71 2 95 ndash ndash 2 167Alkaline phosphatase 1 36 1 48 1 333 ndash ndashEosinophilia 2 71 2 95 ndash ndash ndash ndashThrombocytopenia ndash ndash 3 143 ndash ndash ndash ndashLeukopenia ndash ndash 2 95 ndash ndash ndash ndashHypoglycemia ndash ndash ndash ndash ndash ndash 2 167Renal alterations ndash ndash 2 48 ndash ndash ndash ndashQTc prolongation 5 178 3 143 2 667 ndash ndashVrd 4 143 6 286 2 667 ndash ndashIschemic alterations 1 36 ndash ndash 1 333 ndash ndashArrhythmias 4 143 ndash ndash 2 667 ndash ndash

N Number of articles evaluated (case series clinical trials and control groups of experimental interventions) n number of studies reporting adverse effects MA meglumineantimoniate SSG sodium stibogluconate SSG BP88 sodium stibogluconate Chinese fabrication (Shandong Xinhua Pharmaceutical Co) PI pentamidine isethionate Vrdventricular repolarization disturbance AST aspartate aminotransferase ALT alanine aminotransferase

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mprove itching Heavy metals have been described as a cause ofllergic reactions that seem to be the result of local sensitivityCavelier and Foussereau 1995) In the case of severe cutaneouseactions such as maculopapular exanthema and extensive itchinge recommend the definitive discontinuation of treatment and these of antihistaminic medication to reduce exanthema and itching

n the case of mild cutaneous reactions temporary interruption ofreatment should be sufficient and therapy should subsequently beeinitiated

Hepatic and pancreatic abnormalities were transient andeturned to normal after the end of treatment QTc interval prolon-ation is a condition that if not detected early may cause suddennd fatal arrhythmia and was the most frequent electrocardio-raphic adverse effect We believe that weekly ECG monitoringhould be sufficient to prevent this condition Treatment shoulde discontinued if the QTc interval prolongation exceeds 450 msLawn et al 2006) It should be noted that there was no case ofospitalization or death due to arrhythmias Hepburn et al (1994c)tudied specifically cardiac adverse effects in young healthy sol-iers treated with sodium stibogluconate and found no case ofrrhythmia Severe arrhythmia occurred in three patients includ-ng one 42-year-old woman and an 81-year-old man with cardiacomorbidities We therefore suggest ECG and serum potassiumonitoring to be performed at least once a week in patients older

han 40 years or those with cardiac conditionsPentamidine was used in 296 (n = 1291) of the patients Of

hese 63 (n = 813) received doses of 2ndash4 mgday Treatment withentamidine has also been associated with a high incidence ofdverse effects Although hypoglycemia and insulin-dependentiabetes are expected adverse effects hypoglycemia was observed

n only two of 93 cases one of them severe (Soto-Mancipe et al993 Soto et al 1994 Brasil 2010) No case of diabetes waseported Total pentamidine doses higher than 1 g are believedo cause diabetes mellitus (Brasil 2010) However the total dosedministered could not be established in the patients studiedhigh frequency of rhabdomyolysis was reported in one of the

tudies however the authors only used elevated creatine phos-hokinase 2 and 15 days after treatment as a diagnostic criterionDelobel and Pradinaud 2003) The absence of observation of

aboratory adverse effects such as elevated liver and pancre-tic enzymes as well as of electrocardiographic adverse effectsTable 4) might be due to the lack of these exams or inade-uate routine monitoring of adverse effects Electrocardiographic

evaluation was performed in only one study (Dimier-David et al1992)

In Brazil amphotericin B deoxycholate is the first-choice drugfor the treatment of pregnant women and the second choice whenno response to treatment with pentavalent antimonials is obtainedor when their use is not possible (Brasil 2010) Classically ampho-tericin B has been associated with a high frequency of moderate tosevere adverse effects (Bennett 2006) The few studies identifiedin this review on the use of this drug for the treatment of Americantegumentary leishmaniasis analyzed patients with the cutaneousand mucosal form together These studies were excluded from thepresent review which was restricted to the cutaneous form Theonly publication included described mild adverse effects in two ofseven patients treated with liposomal amphotericin B (Solomonet al 2007) It was therefore not possible to evaluate the safetyprofile of different amphotericin B formulations Although liposo-mal amphotericin B has not yet been approved for the treatmentof cutaneous leishmaniasis in some countries such as Brazil thedrug might be indicated in cases in which other therapeutic options(pentavalent antimonials amphotericin B deoxycholate and pen-tamidine) have failed or are contraindicated (Brasil 2010)

Miltefosine is a promising drug recently introduced for the treat-ment of visceral leishmaniasis in the Old World The use of thisdrug for the treatment of American tegumentary leishmaniasis isbeing investigated The main adverse effects of the drug are relatedto its oral administration affecting the gastrointestinal tract inaddition to the observation of elevated aminotransferase and cre-atine phosphokinase levels (Soto et al 2001 Soto et al 2004bBerman 2008) In contrast to the studies using pentavalent antimo-nials amphotericin and pentamidine trials employing miltefosinehave followed the guidelines of good clinical practice This fact haspermitted the short-term accumulation of evidence regarding thesafety of this drug

The drugs used for the treatment of cutaneous leishmaniasis areadministered parenterally and are associated with a high frequencyof adverse effects The heterogeneity of studies and multiple safetyoutcomes reported in an incomplete and non-standardized mannerdid not permit to obtain combined measures for a meta-analysis inthis review

This review highlights the need for the application of definedcriteria to the classification of severity when collecting data onadverse effects in observational studies as well as the need forclinical trials employing drugs already used for the treatment of


Table 4Frequency of clinical laboratory and electrocardiographic adverse effects among patients treated with pentavalent antimonials and pentamidine isethionate

Signs and symptoms Pentavalent antimonials Pentamidine10ndash20 mgkgday 2ndash4 mgkgdaya

N N

Myalgiaarthralgia 848 486 289 249Gastrointestinal disturbances 361 174 312 215Headache 632 236 224 152Anorexia 257 194 15 467Astheniafatigue 127 189 128 211Fever 430 167 103 87Cutaneous reactions 238 59 38 53Cardiovascular alterations 254 67 77 78Respiratory alterations 76 105 40 50Local pain 42 643 526 316Itching 23 87 ndash ndashTaste alterations 154 253 40 175Neurological alterations 103 29 281 46Balance disturbances 77 52 88 227Behavioral alterations ndash ndash 38 53uarr ASTALT 268 433 ndash ndashuarr Lipaseamylase 157 599 ndash ndashLeukopenia 52 77 ndash ndashThrombocytopenia 42 71 ndash ndashHypoglycemia ndash ndash 83 24QTc prolongation 162 160 ndash ndashVrd 124 250 ndash ndashArrhythmia 61 33 ndash ndash

N aspar

Amrtdioe

C

A

A

A

t

R

A

A

A

A

Number of patients evaluated Vrd ventricular repolarization disturbance ASTa Dosage given in salt moiety

merican tegumentary leishmaniasis Most adverse effects wereild However due to the occurrence of severe events although

are we recommend the monitoring of clinical laboratory and elec-rocardiographic adverse effects at a minimum interval of 10 daysuring treatment and on day 30 after the end of treatment Monitor-

ng should include a complete blood count and the measurementf urea creatinine glucose electrolytes and liver and pancreaticnzymes in addition to an electrocardiogram

onflicts of interest

The authors declare no conflicts of interest

cknowledgments

LFGO was funded by Fundacatildeo Oswaldo Cruz and Fundacatildeo demparo agrave Pesquisa do Estado do Rio de Janeiro (FAPERJ)

ppendix A Supplementary data

Supplementary data associated with this article can be found inhe online version at doi101016jactatropica201102007

eferences

ndersen EM Cruz-Saldarriaga M Llanos-Cuentas A Luz-Cjuno M EchevarriaJ Miranda-Verastegui C Colina O Berman JD 2005 Comparison of meglu-mine antimoniate and pentamidine for peruvian cutaneous leishmaniasis AmJ Trop Med Hyg 72 133ndash137

rana BA Navin TR Arana FE Berman JD Rosenkaimer F 1994 Efficacy ofa short course (10 days) of high-dose meglumine antimonate with or with-out interferon-gamma in treating cutaneous leishmaniasis in Guatemala ClinInfect Dis 18 381ndash384

revalo I Tulliano G Quispe A Spaeth G Matlashewski G Llanos-Cuentas APollack H 2007 Role of imiquimod and parenteral meglumine antimoniate in

the initial treatment of cutaneous leishmaniasis Clin Infect Dis 44 1549

rmijos RX Weigel MM Calvopina M Mancheno M Rodriguez R 2004 Com-parison of the effectiveness of two topical paromomycin treatments versusmeglumine antimoniate for New World cutaneous leishmaniasis Acta Trop 91153ndash160

tate aminotransferase ALT alanine aminotransferase

Ballou WR McClain JB Gordon DM Shanks GD Andujar J Berman JD Chu-lay JD 1987 Safety and efficacy of high-dose sodium stibogluconate therapyof American cutaneous leishmaniasis Lancet 2 13ndash16

Barrios LA Costa JM Netto EM Vexenat CO Cuba CC Marsden PD 1986Intralesional glucantime in Leishmania braziliensis braziliensis infections TransR Soc Trop Med Hyg 80 173ndash174

Bennett JE 2006 Antimicrobial antifungal agents In Goodman LS Gilman ABrunton LL Lazo JS Parker KL (Eds) Goodman and Gilmanrsquos the Pharmaco-logical Basis of Therapeutics 11th ed The McGraw-Hill Companies New Yorkpp 1225ndash1242 (Chapter 48)

Berman JD 1988 Chemotherapy for leishmaniasis biochemical mech-anisms clinical efficacy and future strategies Rev Infect Dis 10560ndash586

Berman JJ 2008 Treatment of leishmaniasis with miltefosine 2008 status ExpertOpin Drug Metab Toxicol 4 1209ndash1216

Blum JA Hatz CF 2009 Treatment of cutaneous leishmaniasis in travelers 2009J Travel Med 16 123ndash131

Blum J Desjeux P Schwartz E Beck B Hatz C 2004 Treatment of cutaneousleishmaniasis among travelers JAC 53 158ndash166

Brasil 2010 Manual de Vigilacircncia da Leishmaniose Tegumentar Americana 3rd edMinisteacuterio da Sauacutede Brasiacutelia (DF)

Cavelier C Foussereau J 1995 Contact allergy to metals and their salts 3 Othersmetals Derm Beruf Umwelt 43 202ndash209

Chulay JD Oster CN McGreevy PB Hendricks LD Kreutzer RD 1988American cutaneous leishmaniasis presentation and problems of patient man-agement Rev Soc Bras Med Trop 21 165ndash172

Convit J Castellanos PL Rondon A Pinardi ME Ulrich M Castes M Bloom BGarcia L 1987 Immunotherapy versus chemotherapy in localised cutaneousleishmaniasis Lancet 21 401ndash405

Correia D Macecircdo VO Carvalho EM Barral A Magalhatildees AV de Abreu MVOrge ML Marsden P 1996 Estudo comparativo entre antimoniato de meg-lumina isotianato de pentamidina e sulfato de aminosidina no tratamento delesotildees cutacircneas primaacuterias causadas por Leishmania (Viannia) braziliensis RevSoc Bras Med Trop 29 447ndash453

Costa JM Garcia AM Recircbelo JM Guimaratildees KM Guimaratildees RM Nunes PM2003 Oacutebito durante tratamento da leishmaniose tegumentar americana comstibogluconato de soacutedio bp 88reg (shandong xinhua) Rev Soc Bras Med Trop36 295ndash298

David CV Craft N 2009 Cutaneous and mucocutaneous leishmaniasis DermatolTher 22 491ndash502

De Paula CDR Sampaio JHD Cardoso DR Sampaio RNR 2003 Estudo com-parativo da eficaacutecia de isotionato de pentamidina administrada em trecircs dosesdurante uma semana e de N-metil-glucamina 20mgSbVkgdia durante 20 diaspara o tratamento da forma cutacircnea da leishmaniose tegumentar americana

Rev Soc Bras Med Trop 36 365ndash371

Deeks JJ Higgins JPT Altman DG 2006 Including Adverse effects In HigginsJPT Green S (Eds) Cochrane Handbook for Systematic Reviews of Interven-tions John Wiley amp Sons Ltd Chichester UK (426 [updated September 2006]Appendix 6b The Cochrane Library Issue 4 2006)

a Trop

D

D

D

F

F

G

G

G

H

H

H

H

H

H

HH

J

K

K

K

K

K

L

L

L

L

L

L

LF Oliveira et al Act

elobel P Pradinaud R 2003 Rhabdomyolysis associated with pentamidineisethionate therapy for American cutaneous leishmaniasis J AntimicrobChemother 51 1319ndash1320

eps PD Viana MC Falqueto A Dietze R 2000 Avaliacaumlo comparativa da eficaacute-cia e toxicidade do antimoniato de N-metil-glucamina e do estibogluconato deSoacutedio BP88copyno tratamento da leishmaniose cutacircnea localizada Rev Soc BrasMed Trop 33 535ndash543

imier-David L Valda L Inofuentes A Mallea F David C Dedet JP 1992 Traite-ment de la leacutesion cutaneacutee de la leishmaniose agrave Leishmania braziliensis eacutechecde lrsquoisethionate de pentamidine Med Mal Infect 22 1183ndash1186

DA 1994 International Conference on Harmonisation of Technical Requirementsfor Registration of Pharmaceuticals for Human use Clinical Safety Data Man-agement Definitions and Standards for Expedited Reporting E2A (ICH E2A)httpwwwichorgcachecompo276-254-1html (cited 1994 Oct 27)

DA 1996 International Conference on Harmonisation of Technical Requirementsfor Registration of Pharmaceuticals for Human use ICH Harmonised Tripar-tite Guideline Guideline for Good Clinical Practice (GCP) E6 (R1) Version 10httpwwwichorgLOBmediaMEDIA482pdf (cited June 1996)

adelha AR Oliveira WC Assuncatildeo IJ Dourado HV 1990 Tratamento daleishmaniose tegumentar americana com injecotildees intralesionais de N-metil-glucamina An Bras Dermatol 65 201ndash203

asser Jr RA Magill AJ Oster CN Franke ED Groumlgl M Berman JD 1994Pancreatitis induced by pentavalent antimonial agents during treatment ofleishmaniasis Clin Infect Dis 18 83ndash90

onzaacuteles U Pinart M Reginfo-Pardo M Macaya A Alvar J Tweed JA2009 Interventions for American cutaneous and mucocutaneous leishmaniasisCochrane Database Syst Rev 15 CD004834

enderson A Jolliffe D 1985 Cardiac effects of sodium stibogluconate Br J ClinPharmacol 19 73ndash77

epburn NC Tidman MJ Hunter JA 1993a Cutaneous leishmaniasis in Britishtroops from Belize Br J Dermatol 128 63ndash68

epburn NC 1993b Thrombocytopenia complicating sodium stibogluconate ther-apy for cutaneous leishmaniasis Trans R Soc Trop Med Hyg 87 691

epburn NC Tidman MJ Hunter JA 1994a Aminosidine (paromomycin) versussodium stibogluconate for the treatment of American cutaneous leishmaniasisTrans R Soc Trop Med Hyg 88 700ndash703

epburn NC Siddique I Howie AF Beckett GJ Hayes PC 1994b Hepatotox-icity of sodium stibogluconate therapy for American cutaneous leishmaniasisTrans R Soc Trop Med Hyg 88 453ndash455

epburn NC Nolan J Fenn L Herd RM Neilson JM Sutherland GR Fox KA1994c Cardiac effects of sodium stibogluconate myocardial electrophysiolog-ical and biochemical studies QJM 87 465ndash472

erwaldt BL 1999 Leishmaniasis Lancet 354 1191ndash1199erwaldt BL Berman JD 1992 Recommendation for treating leishmaniasis with

sodium stibogluconate (Pentostam) and review of pertinent clinical studies AmJ Trop Med Hyg 46 296ndash306

ones TC Johnson Jr WD Barretto AC Lago E Badaro R Cerf B Reed SGNetto EM Tada MS Franca TF et al 1987 Epidemiology of American cuta-neous leishmaniasis due to Leishmania braziliensis braziliensis J Infect Dis156 73ndash83

ane-Gill S Rea RS Verrico MM Weber RJ 2006 Adverse-drug- event ratesfor high-cost and high-use drugs in the intensive care unit Am J Health SystPharm 63 1876ndash1881

oerber WA Koehn MC Jacobs PH Russell BJ 1978 Treatment of cutaneousleishmaniasis with antimony sodium gluconate Arch Dermatol 114 1226

opke LFF Vale ECS Arauacutejo MG Magalhatildees PA Furtado T 1991Tratamento da leishmaniose tegumentar americana pelo antimoniato de N-metil-glucamina estudo duplo-cego com doses de 14 mgKgdia e 28 mgKgdiade antimoniato An Bras Dermatol 66 87ndash94

opke LFF Cafeacute MEM Neves LB Scherrer MAR Machado-Pinto J SouzaMSLA et al 1993 Morte apoacutes uso de antimonial pentavalente em leishman-iose tegumentar americana An Bras Dermatol 68 259ndash261

rolewiecki AJ Romero HD Cajal SP Abraham D Mimori T MatsumotoT Juarez M Taranto NJ 2007 A randomized clinical trial comparing oralazithromycin and meglumine antimoniate for the treatment of American cuta-neous leishmaniasis caused by Leishmania (Viannia) braziliensis Am J TropMed Hyg 77 640ndash646

ai A Fat EJ Vrede MA Soetosenojo RM Lai A Fat RF 2002 Pentamidinethe drug of choice for the treatment of cutaneous leishmaniasis in Surinam IntJ Dermatol 41 796ndash800

ainson R 1983 The American leishmaniases some observations on their ecologyand epidemiology Trans R Soc Trop Med Hyg 77 569ndash596

awn SD Armstrong M Chilton D Whitty CJ 2006 Electrocardiographic andbiochemical adverse effects of sodium stibogluconate during treatment of cuta-neous and mucosal leishmaniasis among returned travellers Trans R Soc TropMed Hyg 100 264ndash269

iberati A Altman DG Tetzlaff J Mulrow C Goslashtzsche PC Ioannidis JPClarke M Devereaux PJ Kleijnen J Moher D 2009 The PRISMA statementfor reporting systematic reviews and meta-analyses of studies that evaluatehealth care interventions explanation and elaboration Ann Intern Med 151W65ndashW94

ima EB Porto C Motta JOC Sampaio RNR 2007 Tratamento da leishmaniosetegumentar americana An Bras Dermatol 82 111ndash124

oke YK Price D Herxheimer A 2007 Systematic reviews of adverse effectsframework for a structural approach BMC Med Res Methodol 7 32httpwwwbiomedcentercom1471-2288732 (accessed April 23 2008)

ica 118 (2011) 87ndash96 95

Martinez S Marr JJ 1992 Allopurinol in the treatment of American cutaneousleishmaniasis N Engl J Med 12 (326(11)) 741ndash744

Martinez S Gonzalez M Vernaza ME 1997 Treatment of cutaneous leishmani-asis with allopurinol and stibogluconate Clin Infect Dis 24 (2) 165ndash169

Marzochi MAC Marzochi KBF 1994 Tegumentary and visceral leishmaniasis inBrazil emerging anthropozoonosis and possibilities for their control Cad SaudePublica 10 (Suppl 2) S359ndashS375

Nacher M Carme B Sainte Marie D Couppieacute P Clyti E Guibert P PradinaudR 2001 Influence of clinical presentation on the efficacy of a short course ofpentamidine in the treatment of cutaneous leishmaniasis in French Guiana AnnTrop Med Parasitol 95 331ndash336

Name RQ Sampaio JHD Borges KT Tauil PL Nogueira LSC Sampaio RNR2005 Estudo cliacutenico epidemiologico e terapecircutico de 402 pacientes com leish-maniose tegumentar americana atendidos no Hospital Universitaacuterio de BrasiacuteliaDF Brasil An Bras Dermatol 80 249ndash254

Navin TR Arana BA Arana FE Meacuterida AM Castillo AL Pozuelos JL1990 Placebo-controlled clinical trial of meglumine antimonate (glucantime)vs localized controlled heat in the treatment of cutaneous leishmaniasis inGuatemala Am J Trop Med Hyg 42 43ndash50

Navin TR Arana BA Arana FE Berman JD Chajoacuten JF 1992 Placebo-controlledclinical trial of sodium stibogluconate (Pentostam) versus ketoconazole fortreating cutaneous leishmaniasis in Guatemala J Infect Dis 165 528ndash534

NIH 2004 Division of AIDS table for grading the severity of adults and pedi-atric adverse events December 2004 httpwwwucdmcucdaviseduclinicaltrialsdocumentsDAIDS AE gradingTable FinalDec2004pdf (accessedMay 25 2009)

Oliveira-Neto MP Schubach AO Mattos M Goncalves-Costa SC Pirmez C1997a A low-dose antimony treatment in 159 patients with American cuta-neous leishmaniasis extensive follow-up studies (up to 10 years) Am J TropMed Hyg 57 651ndash655

Oliveira-Neto MP Schubach AO Mattos M Goncalves-Costa SC Pirmez C1997b Treatment of American cutaneous leishmaniasis a comparison betweenlow dosage (5 mgkgday) and high dosage (20 mgkgday) antimony regimensPathol Biol (Paris) 45 496ndash499

Oliveira-Neto MP Schubach A Mattos M da Costa SC Pirmez C 1997c Intrale-sional therapy of American cutaneous leishmaniasis with pentavalent antimonyin Rio de Janeiro Brazilmdashan area of Leishmania (V) braziliensis transmission IntJ Dermatol 36 463ndash468

Oliveira-Neto MP Mattos M Cuzzi-Maya T Pirmez C 2004 Paniculite eosi-nofiacutelica localizada em consequumlecircncia de injecotildees intramusculares de composto deantimocircnio pentavalente para o tratamento de leishmaniasis tegumentar amer-icana An Bras Dermatol 79 463ndash469

Oliveira-Neto Manoel Paes de Mattos Marise da Silva 2006 An alternative anti-monial schedule to be used in cutaneous leishmaniasis when high doses ofantimony are undesirable Rev Soc Bras Med Trop 39 323ndash326

Oster CN Chulay JD Hendricks LD Pamplin CL Ballou WR Berman JDTakafuji ET Tramont EC Canfield CJ 1985 American cutaneous leishmani-asis a comparison of three sodium stibogluconate treatment schedules Am JTrop Med Hyg 34 856ndash860

Palacios R Osorio LE Grajalew LF Ochoa MT 2001 Treatment failure in chil-dren in a randomized clinical trial with 10 and 20 days of meglumine antimonatefor cutaneous leishmaniasis due to Leishmania viannia species Am J Trop MedHyg 64 187ndash193

Passos VM Barreto SM Romanha AJ Krettli AU Volpini AC GontijoCM Falcatildeo AL Lima-Costa MF 2001 Leishmaniose tegumentar na regiatildeometropolitana de Belo Horizonte aspectos cliacutenicos laboratoriais terapecircuticose evolutivos (1989ndash1995) Rev Soc Bras Med Trop 34 5ndash12

Ribeiro AL Drummond JB Volpini AC Andrade AC Passos VM 1999 Elec-trocardiographic changes during low-dose short-term therapy of cutaneousleishmaniasis with the pentavalent antimonial meglumine Braz J Med BiolRes 32 297ndash301

Robledo SM Puerta JA Munoz DL Guardo M Velez ID 2006 Eficacia y toler-ancia de la pentamidina en el tratamiento de la leishmaniasis cutaacutenea producidapor Leishmania (V) panamensis en Colombia Biomedica 26 (Suppl 1) 188ndash193

Rodrigues ML Costa RS Souza CS Foss NT Roselino AM 1999 Nephro-toxicity attributed to meglumine antimoniate (Glucantime) in the treatmentof generalized cutaneous leishmaniasis Rev Inst Med Trop Sao Paulo 4133ndash37

Romero GAS Hueb M DrsquoOliveira Jr A Schubach A 2001a Simpoacutesio sobreTratamento das Leishmanioses Rev Soc Bras Med Trop 34 58ndash68

Romero GAS Guerra MVF Paes MG Macecircdo VO 2001b Comparison ofCutaneous Leishmaniasis due to Leishmania (Viannia) braziliensis and L (V)guyanensis in Brazil Therapeutics response to Meglumine Antimoniate Am JTrop Med Hyg 65 456ndash465

Romero GA Flores MRM Noronha EF Macecircdo VO 2003 High frequency ofskin reactions in patients with leishmaniasis treated with meglumine antimo-niate contaminated with heavy metals a comparative approach using historicalcontrols Mem Inst Oswaldo Cruz 98 145ndash149

Roussel M Nacher M Freacutemont G Rotureau B Clyti E Sainte-Marie D CarmeB Pradinaud R Couppieacute P 2006 Comparison between one and two injec-tions of pentamidine isethionate at 7 mgkg in each injection in the treatment

of cutaneous leishmaniasis in French Guiana Ann Trop Med Parasitol 100307ndash314

Saacuteenz RE Paz HM Johnson CM Narvaacuteez E Vaacutesquez AM 1987 Evaluacion dela efectividad y toxicidad del pentostam y del glucantime em el tratamiento dela leishmaniasis cutacircnea Rev Meacuted Panamaacute 12 148ndash157

9 a Trop

S

S

S

S

S

S

S

S

S


aacuteenz RE Paz H Berman JD 1990 Efficacy of ketoconazole against Leishmaniabraziliensis panamensis cutaneous leishmaniasis Am J Med 89 147ndash155

aldanha ACR Romero GAS Merchan-Hamann E Magalhatildees AV MacedoVO 1999 Estudo comparativo entre estibogluconato de soacutedio BP88reg e anti-moniato de meglumina no tratamento da leishmaniose cutacircnea eficaacutecia eseguranca Rev Soc Bras Med Trop 32 383ndash387

aldanha ACR Romero GAS Guerra C Merchan-Hamann E Macedo VO2000 Estudo comparativo entre estibogluconato de soacutedio BP 88reg e antimoniatode meglumina no tratamento da leishmaniose cutacircnea toxidade bioquiacutemica ecardiacuteaca Rev Soc Bras Med Trop 33 383ndash388

cope A Trau H Anders G Barzilai A Confino Y Schwartz E 2003 Experiencewith New World cutaneous leishmaniasis in travelers J Am Acad Dermatol49 672ndash678

eaton RA Morrison J Man I Watson J Nathwani D 1999 Out-patient par-enteral antimicrobial therapymdasha viable option for the management of cutaneousleishmaniasis QJM 92 659ndash667

olomon M Baum S Barzilai A Scope A Trau H Schwartz E 2007 Liposomalamphotericin B in comparison to sodium stibogluconate for cutaneous infectiondue to Leishmania braziliensis J Am Acad Dermatol 56 (4) 612ndash616

oto J Buffet P Grogl M Berman J 1994 Successful treatment of Colombiancutaneous leishmaniasis with four injections of pentamidine Am J Trop MedHyg 50 107ndash111

oto J Toledo J Gutierrez P Nicholls RS Padilla J Engel J Fischer C Voss ABerman J 2001 Treatment of American cutaneous leishmaniasis with miltefo-

sine an oral agent Clin Infect Dis 33 E57ndashE61

oto J Valda-Rodriquez L Toledo J Vera-Navarro L Luz M Monasterios-TorricoH Vega J Berman J 2004a Comparison of generic to branded pentavalentantimony for treatment of new world cutaneous leishmaniasis Am J Trop MedHyg 71 577ndash581

ica 118 (2011) 87ndash96

Soto J Arana BA Toledo J Rizzo N Vega JC Diaz A Luz M GutierrezP Arboleda M Berman JD Junge K Engel J Sindermann H 2004bMiltefosine for new world cutaneous leishmaniasis Clin Infect Dis 381266ndash1272

Soto-Mancipe J Grogl M Berman JD 1993 Evaluation of pentamidine forthe treatment of cutaneous leishmaniasis in Colombia Clin Infect Dis 16417ndash425

Talhari S Sardinha JCG Schettini APM Arias J Naiff RD 1985 Tratamento daleishmaniose tegumentar americana resultados preliminares com a pentamid-ina An Bras Dermatol 60 361ndash364

Tuon FF Amato VS Graf MS Siqueira AM Nicodemo AC Amato Neto V2008 Treatment of New World cutaneous leishmaniasismdasha systematic reviewwith a meta-analysis Int J Dermatol 47 109ndash124

Velez I Agudelo S Hendrickx E Puerta J Grogl M Modabber F BermanJ 1997 Inefficacy of allopurinol as monotherapy for Colombian cuta-neous leishmaniasis A randomized controlled trial Ann Intern Med 126232ndash236

WHO 2007 Report of the Consultative Meeting on Cutaneous LeishmaniasisGeneva

Wortmann GW Aronson NE Byrd JC Grever MR Oster CN 1998 Herpeszoster and lymphopenia associated with sodium stibogluconate therapy forcutaneous leishmaniasis Clin Infect Dis 27 509ndash512

Wortmann G Miller RS Oster C Jackson J Aronson N 2002 A randomizeddouble-blind study of the efficacy of a 10- or 20-day course of sodium sti-

bogluconate for treatment of cutaneous leishmaniasis in United States militarypersonnel Clin Infect Dis 35 261ndash267

Zlotogorski A Gilead L Jonas F Horev L Klaus SN 1998 South Americancutaneous leishmaniasis report of ten cases in Israeli travelers J Eur AcadDermatol Venereol 11 32ndash36

8

1

ttcAgTsddostpbr2

mTpHueiatoi

w(aefda2

emte

aamt

2

tR


4 Discussion 90Conflicts of interest 94Acknowledgments 94Appendix A Supplementary data 94References 94

Introduction

Leishmaniases are parasitic diseases caused by different pro-ozoan species of the genus Leishmania including those ofhe subgenus Leishmania which display dermotropism or vis-erotropism in the Old World (Southern Europe the Middle Eastsia and Africa) and New World (Latin America) and of the sub-enus Viannia which are exclusively dermotropic (New World)he parasites are transmitted by the bite of different sandflypecies (Marzochi and Marzochi 1994) Leishmaniases caused byermotropic species are endemic in 82 countries with an inci-ence of approximately 15 million cases per year About 90f cutaneous leishmaniasis cases are concentrated in Brazil andix other developing countries (WHO 2007) American tegumen-ary leishmaniasis a term comprising cutaneous forms with aotential to evolve to secondary mucosal forms is mainly causedy Leishmania (Viannia) braziliensis and is endemic in variousegions of the Americas (Lainson 1983 Jones et al 1987 Brasil010)

Pentavalent antimonials are the first-line drugs for the treat-ent of the cutaneous form of leishmaniasis in the New World

he recommended dose range is 10ndash20 mgkgday for a minimumeriod of 20 days (Berman 1988 Herwaldt and Berman 1992erwaldt 1999 Brasil 2010) Other therapeutic regimens are alsosed but no consensus exists over which is the best one (Tuont al 2008 Gonzaacuteles et al 2009) In view of their higher toxic-ty amphotericin B and pentamidine are second-line drugs whichre recommended in cases of contraindication intolerance or resis-ance to antimonials (Berman 1988 Lima et al 2007) The efficacyf different drugs seems to vary according to the Leishmania speciesnvolved (Romero et al 2001a)

Adverse drug effects are unfavorable events associated in timeith the use of a medication and may have a causal relationship

Deeks et al 2006) The safety of a drug is related to morbiditynd mortality resulting from the incidence and severity of adverseffects (Kane-Gill et al 2006) Although the drugs recommendedor the treatment of cutaneous leishmaniasis have been used forecades and some adverse effects are known there are no system-tic reviews about their safety (Blum et al 2004 Blum and Hatz009 David and Craft 2009)

Systematic reviews give priority to efficacy over safety (Loket al 2007) We found only two systematic reviews on the treat-ent of cutaneous leishmaniasis in the New World but none of

hem considered safety-related issues (Tuon et al 2008 Gonzaacutelest al 2009)

The objective of the present systematic review was to identifynd classify the main clinical laboratory and electrocardiographicdverse effects associated with drugs recommended for the treat-ent of the cutaneous form of leishmaniasis in the New World and

o estimate the frequency of these adverse effects

Methods

21 Search strategies and selection criteria

The searches and review process were performed accordingto a pre-established protocol restricted to the cutaneous form ofleishmaniasis in the New World Intervention studies case seriesand case reports in which patients were treated with the rec-ommended drugs and clinical laboratory or electrocardiographicadverse effects were recorded were included In the case of exper-imental drug studies in which the control group received theapproved drugs only this group was evaluated Studies using milte-fosine were included since this drug is currently under evaluationfor the treatment of cutaneous leishmaniasis in the New WorldThere were no restrictions in terms of patient age or language ofthe published articles

The following scientifically reliable databases providing elec-tronic access to bibliographic references were chosen PubMedLiteratura Latino-Americana e do Caribe em Ciecircncias da Sauacutede(LILACS) Cochrane Scopus Web of Science Science DirectExcerpta Medica Database (Embase) Scielo Highwirepress andScirus Search strategies combining the following keywords wereelaborated for each database adverse effects adverse drug reac-tion and side effects preceded by the names of the drugsselected (antimony sodium stibogluconate meglumine antimoni-ate pentamidine isethionate pentamidine mesylate amphotericinB miltefosine) and treatment drug therapy leishmaniasis cuta-neous The Scirus database also covered grey literature Thecomplete search strategies are summarized in Appendix A Thesearches were started on August 13 2008 and were updated untilMarch 31 2009 The reference lists of all articles were reviewedmanually for the identification of new articles

A database of the electronic search results was created with theEndNote X1 program Duplicate citations were eliminated Poten-tially relevant titles and abstracts were independently selected bythe pairs of reviewers LFGOCAFA and LFGOAOS Divergences wereresolved by consensus or by a third reviewer if necessary

22 Data extraction

The quality of the studies initially selected was evaluated inde-pendently by the same pairs of reviewers Studies in which themonitoring of clinical laboratory or electrocardiographic adverseeffects was described in the methods section were considered tobe adequate Independent data extraction was performed by fillingout a standard form (Appendix B) During this step divergenceswere also resolved by consensus or by a third reviewer if nec-essary The severity of adverse effects was classified according tothe criteria adopted by the Acquired Immunodeficiency SyndromeClinical Trials Group (NIH 2004) The articles approved were clas-sified according to the type of study country of contraction ofthe infection and therapeutic regimen A list of adverse effectswas obtained and frequencies were calculated whenever possi-ble

The present systematic review was conducted according tohe PRISMA guideline (Preferred Reporting Items for Systematiceviews and Meta-Analyses) (Liberati et al 2009)

3 Results

The search of the 10 databases initially yielded 1358 abstracts86 of them were selected for complete reading of the articles In


Fl

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3

actaiKoN2m








ica 118 (2011) 87ndash96 89






9 a Trop

pmcpdw(1cwtdtTt

peacl

3

Ga(Na(

mhtAhM2soas

lad

3

(wo

3

Oaobaehh







2 Pentamidine






3 Amphotericin B



4 Miltefosine



ica 118 (2011) 87ndash96


4 Discussion












Clinical trials
















Deps 2000 Brazil32


31 SSG BP88

Kopke 1991 Brazil14



12610f 11ndash66








30 SSG



69 SSG BP88



64 SSG BP88




Soto2001a Colombia

16

100f NS



2030880f NS





231000f 18ndash25










15 680f














Table 1 (Continued)


Name 2005Brazil 183













saCmf

(

TN

Na








n n







= 21 SSG BP88 N = 3 Pia N = 12

n n

620 2 667 7 583524 1 333 10 833476 2 667 6 500238 2 667 2 167143 1 333 5 417143 2 667 2 167190 2 667 1 83









n n n n



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N N


N aspar

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D

D

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ica 118 (2011) 87ndash96 95


























9 a Trop

S

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ica 118 (2011) 87ndash96












Fl

aias

wCVip(

3

actaiKoN2m








ica 118 (2011) 87ndash96 89






9 a Trop

pmcpdw(1cwtdtTt

peacl

3

Ga(Na(

mhtAhM2soas

lad

3

(wo

3

Oaobaehh







2 Pentamidine






3 Amphotericin B



4 Miltefosine



ica 118 (2011) 87ndash96


4 Discussion












Clinical trials
















Deps 2000 Brazil32


31 SSG BP88

Kopke 1991 Brazil14



12610f 11ndash66








30 SSG



69 SSG BP88



64 SSG BP88




Soto2001a Colombia

16

100f NS



2030880f NS





231000f 18ndash25










15 680f














Table 1 (Continued)


Name 2005Brazil 183













saCmf

(

TN

Na








n n







= 21 SSG BP88 N = 3 Pia N = 12

n n

620 2 667 7 583524 1 333 10 833476 2 667 6 500238 2 667 2 167143 1 333 5 417143 2 667 2 167190 2 667 1 83









n n n n



ia(rwuItr

rgagsb(hsdaicmt

tpadi1rtaAsp(la(q


















N N


N aspar

Amrtdioe

C

A

A

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t

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A

A

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A







cknowledgments




eferences
























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D

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F

F

G

G

G

H

H

H

H

H

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K

K

K

K

K

L

L

L

L

L

L






























ica 118 (2011) 87ndash96 95


























9 a Trop

S

S

S

S

S

S

S

S

S












ica 118 (2011) 87ndash96











9 a Trop

pmcpdw(1cwtdtTt

peacl

3

Ga(Na(

mhtAhM2soas

lad

3

(wo

3

Oaobaehh







2 Pentamidine






3 Amphotericin B



4 Miltefosine



ica 118 (2011) 87ndash96


4 Discussion












Clinical trials
















Deps 2000 Brazil32


31 SSG BP88

Kopke 1991 Brazil14



12610f 11ndash66








30 SSG



69 SSG BP88



64 SSG BP88




Soto2001a Colombia

16

100f NS



2030880f NS





231000f 18ndash25










15 680f














Table 1 (Continued)


Name 2005Brazil 183













saCmf

(

TN

Na








n n







= 21 SSG BP88 N = 3 Pia N = 12

n n

620 2 667 7 583524 1 333 10 833476 2 667 6 500238 2 667 2 167143 1 333 5 417143 2 667 2 167190 2 667 1 83









n n n n



ia(rwuItr

rgagsb(hsdaicmt

tpadi1rtaAsp(la(q


















N N


N aspar

Amrtdioe

C

A

A

A

t

R

A

A

A

A







cknowledgments




eferences
























a Trop

D

D

D

F

F

G

G

G

H

H

H

H

H

H

HH

J

K

K

K

K

K

L

L

L

L

L

L






























ica 118 (2011) 87ndash96 95


























9 a Trop

S

S

S

S

S

S

S

S

S












ica 118 (2011) 87ndash96














Clinical trials
















Deps 2000 Brazil32


31 SSG BP88

Kopke 1991 Brazil14



12610f 11ndash66








30 SSG



69 SSG BP88



64 SSG BP88




Soto2001a Colombia

16

100f NS



2030880f NS





231000f 18ndash25










15 680f














Table 1 (Continued)


Name 2005Brazil 183













saCmf

(

TN

Na








n n







= 21 SSG BP88 N = 3 Pia N = 12

n n

620 2 667 7 583524 1 333 10 833476 2 667 6 500238 2 667 2 167143 1 333 5 417143 2 667 2 167190 2 667 1 83









n n n n



ia(rwuItr

rgagsb(hsdaicmt

tpadi1rtaAsp(la(q


















N N


N aspar

Amrtdioe

C

A

A

A

t

R

A

A

A

A







cknowledgments




eferences
























a Trop

D

D

D

F

F

G

G

G

H

H

H

H

H

H

HH

J

K

K

K

K

K

L

L

L

L

L

L






























ica 118 (2011) 87ndash96 95


























9 a Trop

S

S

S

S

S

S

S

S

S












ica 118 (2011) 87ndash96












Table 1 (Continued)


Name 2005Brazil 183













saCmf

(

TN

Na








n n







= 21 SSG BP88 N = 3 Pia N = 12

n n

620 2 667 7 583524 1 333 10 833476 2 667 6 500238 2 667 2 167143 1 333 5 417143 2 667 2 167190 2 667 1 83









n n n n



ia(rwuItr

rgagsb(hsdaicmt

tpadi1rtaAsp(la(q


















N N


N aspar

Amrtdioe

C

A

A

A

t

R

A

A

A

A







cknowledgments




eferences
























a Trop

D

D

D

F

F

G

G

G

H

H

H

H

H

H

HH

J

K

K

K

K

K

L

L

L

L

L

L






























ica 118 (2011) 87ndash96 95


























9 a Trop

S

S

S

S

S

S

S

S

S












ica 118 (2011) 87ndash96














n n n n



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D

D

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H

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H

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K

K

K

K

L

L

L

L

L

L






























ica 118 (2011) 87ndash96 95


























9 a Trop

S

S

S

S

S

S

S

S

S












ica 118 (2011) 87ndash96














N N


N aspar

Amrtdioe

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A

A

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R

A

A

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cknowledgments




eferences
























a Trop

D

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ica 118 (2011) 87ndash96 95


























9 a Trop

S

S

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S

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ica 118 (2011) 87ndash96











a Trop

D

D

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ica 118 (2011) 87ndash96 95


























9 a Trop

S

S

S

S

S

S

S

S

S












ica 118 (2011) 87ndash96











9 a Trop

S

S

S

S

S

S

S

S

S












ica 118 (2011) 87ndash96











Systematic review of the adverse effects of cutaneous leishmaniasis treatment in the New World

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Transcript of Systematic review of the adverse effects of cutaneous leishmaniasis treatment in the New World