Giardia: Confirming Resistance and Alternatives to the Nitroimidazoles

Giardia: Confirming resistance and alternatives to the nitroimidazoles

Kristine Mørch, MD, PhD National centre for tropical infectious diseases Haukeland university hospital ESCMIDBergen, NorwayeLibrary by author ESCMID eLibrary Picture acknowledgement: https://commons.wikimedia.org/w/index.php?curid=37743756 by author ESCMID eLibrary Picture acknowledgements: Christian Medical College, Vellore, by India. Haukeland University authorHospital; Hanevik K, Helgeland L, Giardiasis – natural course

• Symptoms1 – Diarrhoea, stomach pain, nausea, vomiting, flatulence, foul smelling stools, anorexia, fever and weight loss

• Experimental study2 – Asymptomatic: 40 – 50% – Spontanous clearance of parasites (after 5 – 41 days): 85% – Chronic infection: 15%

• Reports high endemic countries – Higher prevalence among cases than controls3 – Malnutrition and reduced cognitive function in children4,5 – Impeded growth due to malabsorption also in asymptomatic children6 – Enhanced pathogenicity in coinfection with rotavirus7

• Postinfectious complications – Irritable bowel syndrome and chronic fatigue8 ESCMID– Lactose intolerance9 eLibrary

1Nygård: BMC 2006. 2Rendtorff: Am J Hyg 1954. 3Kotloff: Lancet 2013. 3Haque: CID 2009. 3Tellevik: PLOS 2015. 4Berkman: Lancet 2002. 5Ignatius: PLOS 2012 6Prado: Parasitology 2005. 7Bhavnani: by Am J Epidem 2012. author 8Hanevik: Clin In fect Dis 2014. 9Pettoello: J Pediatr Gastroenterol Nutr 1989. Protracted infection – increased risk of complications

• Complications 2 years after giardiasis in Bergen (N=1017) – Abdominal symptoms (38%) – Fatigue (41%)

• Significant risk factors • Treatment resistant infection • Received two or more treatment courses • Sick leave > 2 weeks • Delayed education > 1 semester •ESCMIDIBS 39% and chronic fatigue 31%eLibrary six years after Mørch: BMC Inf Dis 2009. Hanevik: Clin Infect Dis 2014.by author Failure first line treatment

• Retrospective study travellers Spain 2007-09 – Nitroimidazole-failure • Total 22% (21/99) • Asia 33% (12/36)

• Bergen outbreak 2004 – Metronidazole-failure ESCMID• 3% (42/1268) eLibrary

Gutierrez: Travel Med and Inf Dis 2013. Mørch et al. Journal by of Infection 2008. author Nitroimidazole treatment failure - London Increase from 15% to 40%

80

70

60

50

40 Susceptible cases Refractory cases 30

20

10

0 ESCMID2008 2011 2012 eLibrary2013

India: 50% resistance Nabarro: Clin Microbiol Infect 2015. by author Antigiardial Efficacy clinical Effective dosage adults Comments agents studies (%)

Metronidazole 36 - 100 200 – 500mg tid x 5-7d Efficacy low when shorter than 5 d

Tinidazole 74 - 100 1.5 – 2g sd x 1d Single dose treatment as effective as Ornidazole 90 - 100 1-2g sd x 1d longer course due to longer half-life Secnidazole 79 - 100 2g sd x 1d

Nitazoxanide 56 - 94 500mg bid x 3d

Furazolidone 20 - 92 100mg qid x 10d

Albendazole 62 - 96 400mg sd x 5d 5 RCTs: Less effective than tinidazole1 10 RCTs: Similar effectivenes to metronidazole2 Mebendazole 0 - 95 200mg tid x 3 -5d

Quinacrine 77 - 100 100mg tid x 5d Risk neuropsychiatric side effects

Paromomycin 40 - 92 500mg tid x 7d Only drug recommended in first trimester of pregnancy ChloroquineESCMID86 10mg/kg bideLibraryx 5d Bacitracin zinc 95 120 000 U bid 10d One RCT 1995

Mørch: Giardiasis. PhD thesis http://hdl.handle.net/1956/3996 2010. Granados: Cochrane review 2012. 1Escobedo: Acta Tropica 2016. 2Pasupuleti: PLOS Negl Trop Dis 2014. by author Future or new drugs for giardiasis

• Structural modifications – enhanced activity – Metronidazole1, nitazoxanide2, benzimidazols3

• Auranofin4 – An approved anti-rheumatic drug – Effective in vitro and in rodents

• Fumagillin5 ESCMID– Orphan drug used for microsporidiosis eLibrary – Effective in vitro and in mice Vemuganti: BMC 2005

1Miyamoto: PNAS 2013. 2Navarrete-Vazquez: Bioorg & Med Chem 2015. 3Perez-Villanueva: Bioorg & Med Chem 2013. 4Tejman-Yarden: Antimicrobioal Agents and Chemotherapy by2013. 5Kulakova: author Antimicrobial Agents and Chemotherapy 2014. Resistance mechanisms - active area of investigation

ESCMID eLibrary Hanevik et al: Whole genome sequencing of byclinical isolates authorof Giardia. Clin Microbiol Infect 2015 Metronidazole activation – target for resistance?

• Pyruvat:ferredoxin oxidoreductase (PFOR) – reduce ferredoxin which further lead to reduction of metronidazole

• Downregulated PFOR – in vitro1 – in clinically resistant cultured samples2

• Functioning PFOR in resistant strains also reported1

• Other factors; in vitro studies3 – Nitroreductase 1 downregulated ESCMID– Nitroreductase 2 upregulated eLibrary 1Leitsch: J Antimicrob Chemother . 2011 . 2 Begaydarova . JIDC.by 2015. 3Müller : J AntimicrobauthorChemoth 2013. Leitsch: Curr Trop Med Rep 2015. Giardia resistant infection Treatment strategies ESCMID eLibrary by author Treatment ladder Bergen outbreak (N=38) Albendazole 400mg x 2 + metronidazole 250mg x 2 for one week

If failure

Paromomycin 500mg x 3 for one week

If failure

ESCMIDQuinacrine 100mgeLibrary x 3 + metronidazole 750mg x 3 for three weeks Mørch: Journal of Infection 2008. by author Results

Metronidazole + albendazole n =38 Cure Failure n = 30 (79%) n = 8 (21%)

Paromomycin n = 6

Cure Failure n = 3 (50%) n = 3 Quinacrine + metronidazole ESCMIDn =eLibrary 3 Cure n = 3 (100%) Mørch: Journal of Infection 2008. by author Combination treatment

• Controlled study Italy (n = 20)1: – Albendazole + metronidazole (n=10): 90% cure – Albendazole (n=10): 20% cure

• Retrospective study Spain (n=10)2 – Nitroimidazole + albendazole, paromomycin or quinacrine 7-10 d: 100% cure

• Retrospective study London (n=73)3 – Quinacrine + albendazole (n=7) or tinidazole (n=2): 100% cure – Tinidazole + albendazole (n=20): 60% cure

• Synergistic effect in vitro4 ESCMID– Quinacrine + metronidazole4 eLibrary 1Cacapardo : Clin Ter 1995. 2Lopez -Velez: Am J Trop Med byHyg 2010. 3Nabarro: ClinauthorMicrobiol and Infect 2015. 4Smith: Gastroenterology 1982. Immunocompromised patients

• Case series (n=6), 4 immunosupressed1 – Quinacrine + metronidazole or tinidazole: 5/6 cured – Paromomycin + bacitracin 3 months: 1/5 cured

• IgA deficiency case report2 – metronidazole and quinacrine monotherapy: Failure – Quinacrine + metronidazole for 2 weeks: Cured

• AIDS case report3 – Metronidazole and albendazole: Failure – Nitazoxanide 5 or 10 d: Failure ESCMID– Nitazoxanide 1.5g bid for 30 days eLibrary: Cured 2Nash: Clin inf Dis 2001. 2Taylor: CMAJ 1987. 3Abboudby: CID 2001 author Quinacrine monotherapy

• Retrospective study Spain (n=19)1 – Paromomycin (n=3) or albendazole (n=2): None cured – Quinacrine 7 d (n=14): 100% cure

• Family after travel to India (n=4)2 – Tinidazole (n=4): One cured – Quinacrine 5 d (n=3): All cured

• Treatment ladder travelers to Israel (n=12)3 – Albendazole (n=12): 40% cured – Nitazoxanide (n=4): 25% cured – Paromomycin (n=1): Cured – Quinacrine (n=2): Both cured • ESCMIDRetrospective study London (n=73) eLibrary4 – Quinacrine 7 d (n=11): 100% cured

1Munoz Gutierrez: Travel Med and Inf Dis 2013. 2Requena-Mendez: Clin Microbiol and Infect 2013. 3Meltzer: EID 2014. 4Nabarro: Clin Microbiol and Infect 2015. by author Quinacrine side effects

• Yellow discoloration of skin or sclerae – Common – Bilirubin normal – Related to cummulative dose – Self limiting

• Bergen cohort (n=3) SLE patient: ESCMID– Yellow skin or urine: 2 eLibraryFive months quinacrine 100mg/d Vidal: Actas Dermosilifiliogr 2013. Mørch : Journal of Infecionby2008. author Quinacrine Neuropsychiatric side effects • Case reports1,2,3 – 112 year old boy with CVID • Treatment refractory giardiasis for two years • Quinacrine 300mg 10 d • Psychotic just after termination of treatment • Recovered after 2 months anti-psychotic therapy

• Bergen cohort, quinacrine 3 weeks (n = 3)4 – Confusion (2) – Nightmares (1) – Dizziness (1)

• Spain cohort, quinacrine 7d (n=14)5 ESCMID– No major adverse events eLibrary

1Genel: Human psychopharmacology. 2002. 2Lindenmayer: J Clin Psychiatry. 1981. 3Weisholtz: South Med J 1982. 4Mørch: J of Infection 2008. 5Gutierrez: Travel Med and Inf Dis 2013. by author Conclusion • If treatment failure, a second line drug from a different class, and preferably combination treatment, should be used

• Genetic markers for resistance and routine drug susceptibility tests are not available – studies are needed

• Metronidazole + albendazole has shown synergistic effect in clinical studies

• Quinacrine is the most effective drug in treatment resistant patients

• Quinacrine for more than 5 days should be weighed ESCMIDagainst the risk for potential eLibrarysevere side effects by author Thank you for your attention

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