Treatment of Cutaneous Larva Migrans with Ivermectin

Parasitic diseases, a large task for a few drugs….. Eric Caumes. University Pierre et Marie Curie, Paris Dept infectious and tropical diseases; Hop Pitié-Salpêtrière.

ESCMID Online Lecture Library Potential links of Interests

• In the past 4 years, I (or my department) have received honoraria from pharmaceutical companies (Sanofi, BMS, Pfizer, Baxter, Janssen) for lectures on SSTI & STDs as well as for participation in vaccine advisory boards (HPV, TBE) and CME programs.

• I am the Editor in Chief© of by the author Journal of Travel Medicine (IF = 1.47) ESCMID Online Lecture Library Paris, métro, Avril 2004

ESCMID Online Lecture Library Treatment of severe malaria in endemic countries : artesunate better than quinine

• Quinine has been the only option for parenteral therapy until recently.

• Current evidence shows that IV artesunate is more effective than quinine in treating severe malaria in endemic countries in Southeast Asia (SEAQUAMAT) and in sub-Saharan Africa (AQUAMAT) © by author

ESCMID Online Lecture Library Clinical benefits of artesunate

• Fast acting drug against several parasite stages including gametocytes • Reduces cytoadherence • Apparently beneficial safety profile • Easy to use (IV shot, no drug interaction…) • Better survival rates in pts with severe malaria, particularly in those with high parasitaemia. • Shorten the stay in the intensive© by authorcare unit • Shorten hospitalization, decreases the risk of nosocomial infections ESCMID Online Lecture Library Sinclair D, et al. Cochrane Database Syst Rev 2011:CD005967. For severe malaria, artesunate is the answer

• «Choosing the best antimalarial drug for severe malaria has been an important and difficult question. In The Lancet, this question has been answered definitively: artesunate is superior to quinine when both are given intravenously (Dondorp A et al. AQUAMAT study. Lancet 2010; 8 Nov) • « …. it is now unethical© byto continueauthor studies of severe malaria with quinine as a treatment group…. » ESCMID Online LectureShanks Library D. Lancet 2010; 8 Nov Treatment of imported severe malaria with artesunate instead of quinine – more evidence needed? additional unanswered questions :

• Generalizability of the findings from endemic countries to endemic coutries • Drug resistance • Safety profiles • Legal aspects, as there© is byno Goodauthor Manufacturing Practice conform drug available yet.

ESCMID OnlineCramer J Lectureet al. Malaria Journal Library 2011, 10 :256 -260 Following limitations to be addressed • most pts are children VS great majority of pts with imported severe malaria are adults, • quinine monotherapy VS combination of quinine with doxycycline or clindamycin • study population (ethnic, nutritional, general health aspects, semi-immune) VS non immune pts (caucasians, migrants) • supportive care other than© byanti author-malarial treatment may differ significantly in endemic countries VS hospitals in Western countries

ESCMID CramerOnline J et al. Lecture Malaria Journal Library 2011, 10:256 -260

Intravenous Artesunate for Severe malaria in Europe • Retrospective analysis of 25 travelers with severe malaria seen at 7 centers in Europe.

• Treatment with IV artesunate rapidly reduced parasitemia levels. All patients survived. • In 6 pts (24%), a self-limiting episode of unexplained hemolysis occurred. 5 pts required a blood transfusion. Pts with post-treatment ©hemolysis by author had received higher doses of IV artesunate

ESCMID OnlineZoller TLecture et al. Emerg Inf Library Dis 2011; 17: 771-777 Late onset hemolysis after artesunate treatment (15 d- 32d)

Parasit Hb Tt (d) Clearance Hemolysis Hb

30% 11.3 7 D4 D15 5.7 20% 13.2 7 D7 D32 6.1 30% 13.4 4 D5 D19 5.3 4% 13.4 7 D2 D15 5.7 © by author 9% 15.5 4 D2 D15 5.7 10% 11.2 3 NA D16 5.8

ESCMID OnlineZoller T et Lectureal. Emerg Inf Dis Library 2011; 17: 771 -777 Comparative study on imported severe malaria not feasible

• High number of pts will be needed if the outcome was mortality • Other (combined) outcomes may not unequivocally answer relevant questions • Travellers are a very heterogeneous patient group requiring stratification • Many travel medicine experts© by would author not be willing to randomize patients into artesunate versus quinine given existing evidence

ESCMID OnlineCramer J Lectureet al. Malaria Journal Library 2011, 10 :256 -260 LCL (French Guyana)

ESCMID Online Lecture Library Key drugs to treat LC leishmaniasis • Antimonials IM (NW) or IL (OW) • Pentamidine isethionate (NW; Lg complex) • Fluconazole oral (OW; L.major) • Ketoconazole oral (NW; L.mexicana) • Miltefosine oral (NW; not L.b complex) • Paromomycin Topical© by author (OW) • Heat, 50°C 30 sec (OW; L.tropica) ESCMID Online Lecture Library Wortmann G. Clin Infect Dis 2005; 40:1156-1158

L. major (Afghanistan) & Miltefosine

• 172 military personal Netherlands (Mazar el Sharif) Tt IL antimonials + cryotherapy in 172 pts : – 141 cured (81 %) – 31 failed (19%) • 31 failure + 3 expatriates = 34 patients Tt miltefosine 150 mg/jr x 28 jrs – 4 failed (AM iL, AM iM)© by author – 30 cured (88 %) • Decrease of the ejaculate in 21 pts (61 %) ESCMID Online Lecture Library Van Thiel PPAM et al, Clin Inf Dis 2010:50;80-83 Liposomal amphotericin B & LCL

• N = 20 milit. US (10 OW/10 NW) (Lm, Lt / Lb, Lg, Lp) • Ambisome : 3 mg/kg/d (2 hrs) (5-10 doses/pt, D1-5,D14,D21) [cumulated dose = 21 mg/kg (10 -30)] • Age : 29 ans ; 95 % M ; nb lesion/pt = 1 (1-11) • AE : 13 pts (65 %) : renal impairment : 9 (45 %), « infusion related toxicity » : 5 (25 %) • 16/19 pts (84 %) : cured • 3/19 (16%) : failed (cured after© bya 2nd author course) • Cost = 6500 US $ / cure (median dose)

Wortmann G etESCMID al. Am J Trop MedOnline Hyg 2010;83:1028 Lecture-1033 Library Tt LCL : clinically and species oriented

• Lésions < 1 cm & L. major or L. mex (spontaneous healing < 6 months) abstention local Tt : IL AM + cryotherapy, FluromadR • Lesions cosmeticaly not acceptable OR L. tropica or L. braziliensis (mucosal involvement, no spontaneous healing) IM AM Ambisome (3mg/kg© onby D1 author to J5, D14, D21 = 20 mg/kg cumulated dose)

Wortmann GESCMID et al. Am J Trop Online Med HygLecture 2010;83:1028 Library-1033 Anthelminthic drugs

• Pyrantel • Benzimidazoles • Diethyl carbamazine Nematodes • Ivermectin (et moxidectin)

• Niclosamide • Praziquantel • (oxamniquine) © by authorTrematodes • Triclabendazole • Nitazoxanide Cestodes ESCMID Online Lecture Library

Pharmacokinetics of benzimidazoles

300 Cmax (ng/ml) albendazole 250 mebendazole 45 -300 200 flubendazole 17 - 116 150 0,5-5 100

Concentration ng/ml Concentration 50 0 © by author 0 12 24 36 48

heures GottschallESCMID DW, et al. The Online metabolism Lecture of benzimidazole Library anthelmintics. Parasitol Today 1999; 6: 115–124. Pharmacokinetics of albendazole (10 mg/kg)

1,5 repas gras jus pamplemousse 1 eau

0,5

Concentration µg/ml Concentration 0 0 4 8© by12 author 16 20 24

heures Nagy J et al. Effect of grapefruit juice or cimetidine coadministration on albendazoleESCMID bioavailability. Online Am LectureJ Trop Med HygLibrary 2002; 66: 260-3 10/08/2007

Cerebral alveolar echinococcosis

Stauga S J Travel Med 2012, © by author In press

ESCMID Online Lecture Library

ESCMID Online Lecture Library 10/05/2010 Cerebral alveolar Echinococcosis After 3 years of treatment

Stauga S J Travel Med © by author 2012, In press

ESCMID Online Lecture Library Albendazole : double blind multicenter clinical trial in intestinal nematodes

n= 392 patients

Ascaridiasis 96 % Ancylostoma duodenale 96 % Single dose Necator americanus 90 % Trichuriasis 76 % 400 mg

Larva currens © by author

StrongyloidiasisESCMID Online Lecture Library Single and Double (D 14) Doses Ivermectin versus 7-Day Albendazole for Strongyloidiasis. ALB x 7 d IVE X1 IVE X2 800 mg/d 200µg/kg 200µg/kg N = 30 31 29

FU duration 19 wks 39 wks 26 wks (2–76) © by(2 author–74) (2–74) Cure rate 63% 96% 93% (P = 0.006) SuputtamongkolESCMID Y, et al.Online PLoS Negl Lecture Trop Dis Library 2011; 5: e1044 Creeping dermatitis

HrCLMESCMID Online Lecture Library Treatment of HrCLM

Local • thiabendazole (when still available)

• albendazole 10% based ointment x 10 days Oral • (thiabendazole : 50 mg/kg/d x 2- 4 d) • albendazole : 400-800© by mg/d author x 3 d • ivermectin : 12 mg single dose (adults)

ESCMID Online Lecture Library Caumes E. Clin Inf Dis 2000; 30: 811-14 4 Loiasis

ESCMID Online LectureCreeping Library dermatits Treatment of loiasis: 3 drugs

DEC* Albendazole Ivermectin Macrofilaria +++ +/- +/- Microfilaria + ++ +++ Daily dose 8-10 mg/kg 400 mg 150 ùg/kg Duration 21 days 21 days 1 day Nb courses 1-3 1 1/ 1-3 months Danger >30.000/ml © bySafe author >50.000/ml (> 2.000/ml) (>8.000/ml) * : diethylcarbamazine ESCMID Online Lecture Library Boussinesq M. J Travel Med 2012; 19: in press Treatment of loiasis: 4 rules

• Tt in specialized units or by specialized MD • Evaluating microfilarial load /microfilaremia (10 AM- 4 PM) is mandatory before any Tt • DEC & IVE can both induce potentially fatal encephalopathis in persons having microfilaremia > 30-50.000/ml • Definitive cure of loiasis© isby difficult author when DEC (the only drug with a proven macrofilaricidal effect) is not available

ESCMIDBoussinesq Online M. JLecture Travel Med 2012; Library 19: in press

Management of loiasis mf/ml Treatment < 2.000 Start with DEC; increase the daily dose every day up to 400 mg/d 2.000-8.000 Start with ivermectin; wait for 10 days; then use DEC if mf/ml OK 8.000-30.000 Start with albendazole; then use DEC or IVE then DEC according to mf/ml >30.000 Start with albendazole© by author or plasmapheresis; then use DEC or IVE then DEC according to mf/ml

ESCMID Online Lecture Library Boussinesq M. J Travel Med 2012; 19: in press Creeping dermatitis

• Clinical forms : cutaneous (9), GI (2), neurological (2) • Median age : 38 years; female/male sex ratio :1.6. • Return from South East Asia or Central America. • Median interval between symptom onset/treatment : 3.5 months. • Tt with albendazole in 12 cases and ivermectin in one case • Eight patients relapsed after a median of 2 months (1–7 months). These 8 patients had a total ©of by13 relapses, author the last occurring a median of 16 months (2–26 months) after initial treatment.

Cure rate with albendazole Strady C et al. Am J Trop Med Hyg = 5/12 (42%)ESCMID Online Lecture2009; 80: 33 Library–35 Ivermectin and Albendazole in 8 relapsing cases of imported gnathostomiasis N° Initial 1st 2nd 3rd 4th 1 Cut (Ive) Cut (Ive) 2 Cut (Alb) OPH (Ive) Strady C et al. Am J Trop Med 3 Cut (Alb) Cut (Alb) Hyg 2009; 80: 33–35

4 Cut (Alb) Cut (Alb) 5 GI (Alb) GI (Alb) 6 Cut (Alb) Cut (Alb)© byCut author (Alb) 7 Cut (Alb) Cut (Alb) Cut (Alb) 8 N (Alb)ESCMID N (Alb) Online NLecture (Ive) LibraryN (Alb) N (Alb) Acute urticaria with eosinophilia (acute schistosomiasis)

ESCMID Online Lecture Library Acute schistosomiasis in 14* travellers in Mali (S.haematobium) Signs % Interval/exposure Duration (d) Fever 93 19 d (15-24) 9 (2-30)

Urticaria 57 33 d (21-55) 4 (1-8) Cough 86 30 d (18-65) 61 ( 7-210) Eosino 100 47 d (25-119) 113 (1-190) Seroconversion 100 46© d (27by- 100)author NA

Ova in urines 57 196 d (124-330) NA

* : 10 treated, ESCMID Online Lecture Library Grandière-Perez L et al. Am J Trop Med Hyg 2006; 74: 814-818 4 worsened

Subungueal splinter hemorrhages in a 21 y old tourist with acute schistosomiasis (S.haematobium in urines, 4 months later), 1 month after bathing in a cascade in the Dogon area (Mali),ESCMID and 2 days after Online PRZ treatment Lecture for acute schistosomiasisLibrary Acute neuroschistosomiasis

Magnetic resonance imaging (T2 flair) showing borderzone infarcts suggestive of cerebral vasculitisESCMID in a 21 y old tourist Online with acute Lecture schistosomiasis Library (S.haematobium), 1 month after bathing in a cascade in the Dogon area (Mali), 2 days after PRZ treatment Lack of efficacy of praziquantel in 18 travelers infected with S.haematobium

Early Tt As Late Tt As Acute schisto

N = 8 4 6 Tt/exposure 14 d (10-15) 33 (28-40) 26 (20-39) Acute schisto 8 0 NA Chronic schisto 8 3 6 © by author Cured * 8 4 6

* : after 1 to 2 PRZQ ESCMIDGrandière Online-Perez Lecture L et al. Am J Trop Library Med Hyg 2006; 74: 814-818 S. mansoni: chemotherapy of infections different ages.

PZQ

Sabah AA, etESCMID al. Exp Parasitol Online 1986; 61:294 Lecture–303. Library Clinical Management of Acute Schistosomiasis: Still Challenging!

Jaureguiberry S, Caumes E. P J Travel Med 2011; 18: 365-366 Acute phase OVERLAP Chronic phase

In a patient who is infected with many schistosomulae, different phases of the parasitic life cycle overlap. This is not a synchronous process, and ©dozen/hundred by author schistosomulae of different stages of maturity coexist at a given time. In AS, schistosome egg excretion by mature chistosomes may thus coincide during several weeks with circulating schistosomulae ESCMID Online Lecture Library Clinical Management of Acute Schistosomiasis: Still Challenging!

• Wait at least 3 months after exposure before initiating PZQ. At the best, when ova are detected in stools or urines AND when there is no more symptoms of AS • Necessary to repeat the administration of PZQ to ensure effective treatment to take into account the schistosomulae that may not yet have reached the adult stage • corticosteroids use should© be by restricted author to patients with severe forms (cerebral vasculitis, myocarditis, etc.) and paradoxical reactions (40-56% of treated AS)

JaureguiberryESCMID S, Caumes Online E. J Travel Lecture Med 2011; 18:Library 365-366

CT scan: heterogeneous © by authorT2-weighted MRI: numerous Splenomegaly with echinococcal small calcifications cysts of the spleen. ESCMID Online Lecture Library Meyssonnier V et al. J Travel Med 2011; 18: 294–295 Management of cystic echinococcosis : 4 methods • Surgery, • Percutaneous sterilization techniques,

• Anti-parasitic treatment (albendazole) • Watch & wait, without adequate comparative© by evaluation author of efficacy, effectiveness, rate of adverse events, relapse rates, and cost.

Brunetti E et al. WHOESCMID-IWGE Expert Online consensus. Lecture Acta Tropica 2010; Library 114: 1–16. Cystic echinococcosis : Treatment Response to Benzimidazoles • 711 treated patients, 1159 liver and peritoneal cysts. • Overall 1–2 y after initiation of Tt 50%–75% of active C1 cysts were classified as inactive vs 30%–55% of CE2 and CE3 cysts. • However, 25% of cysts reverted to active status within 1.5 to 2 y after having initially responded and multiple relapses were observed; after the second and third treatment 60% of cysts relapsed within 2 y. © by author The efficacy of benzimidazoles has been overstated

ESCMID Online Lecture Library Stojkovic M et al. : A Systematic Review. PLoS Negl Trop Dis 2009: 3: e524. Conclusions

• Antiparasitic drugs are available for nearly all the species of protozoans, helminths and arthropods of medical interest • However they are not marketed in every country and some are prescribed outside their current indications • Lack of interest is obvious© by for author pharmaceutical companies ESCMID Online Lecture Library Thanks for your kind invitation and © by authorEuropean

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