Efficacy and Tolerability of Quinacrine Monotherapy and Albendazole Plus Chloroquine Combination Therapy in Nitroimidazole-Refractory Giardiasis: a Tropnet Study
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Klinik für Infektiologie & Spitalhygiene Efficacy and tolerability of quinacrine monotherapy and albendazole plus chloroquine combination therapy in nitroimidazole-refractory giardiasis: a TropNet study Andreas Neumayr, Mirjam Schunk, Caroline Theunissen, Marjan Van Esbroeck, Matthieu Mechain, Manuel Jesús Soriano Pérez, Kristine Mørch, Peter Sothmann, Esther Künzli, Camilla Rothe, Emmanuel Bottieau Journal Club 01.03.21 Andreas Neumayr Background on giardia treatment: • 1st-line treatment: 5-nitroimidazoles: metronidazole (1957), tinidazole, ornidazole, secnidazole • cure rate of 5NIs in 1st-line treatment: ~90% • in the last decade, an increase of 5NI-refractory giardia cases has been observed in travel medicine clinics across Europe: Hospital for Tropical Diseases, London: 2008: 15% --> 2013: 40% 70% of 5NI-refractory cases imported from India • 2nd-line treatment: effectiveness of a 2nd round with a 5NI: ~17% alternative drugs: albendazole, mebendazole, nitazoxanide, quinacrine, furazolidone, chloroquine, paromomycin 2012 TropNet member survey: 53 centres use 39 different treatment regimens, consisting of 7 different drugs in mono- or combination-therapy in various dosages and durations JC 01.03.21 Nabarro LE et al. Clin Microbiol Infect. 2015;21:791-6. • by 2013, there were only 13 reports of 2nd-line therapy for giardiasis (8 case series, 5 individual case reports): n=110 Cure rates Albendazole 6/32 18.7% Paromomycin 5/17 29.4% Nitazoxanide 2/5 40.0% Albendazole + 5-NI 42/53 79.2% Quinacrine 19/21 90.5% Quinacrine + 5-NI 14/14 100% Quinacrine + Paromomycin 2/2 100% • 2013: TropNet "GiardiaREF" study kick-off: Study on efficacy and tolerability of two 2nd-line regimens in nitroimidazole-refractory giardiasis: Quinacrine JC 01.03.21 Meltzer E et al. Treatment of Giardiasis after Nonresponse to Nitroimidazole. EID 2014;20:1742-4. Quinacrine (syn. Mepacrine) • introduced in the 1930s as antimalarial drug: "Atabrine" • the leading antimalarial drug used during World War II • feared for neuropsychiatric side effects (toxic psychosis) • before metronidazole became available, atabrine was the only drug available for the treatment of giardiasis • metronidazole replaced quinacrine after showing it was as effective and had fewer side effects • orphan drug status: not licensed (not reimbursed by health insurance), availability , price • today, quinacrine appears to be the best treatment option for 5-NI refractory giardiasis… but what about the side effects? JC 01.03.21 Kavousi S. Am J Trop Med Hyg. 1979;28:19-23. • by 2013, there were only 13 reports of 2nd-line therapy for giardiasis (8 case series, 5 individual case reports): n=110 Cure rates Albendazole 6/32 18.7% Paromomycin 5/17 29.4% Nitazoxanide 2/5 40.0% Albendazole + 5-NI 42/53 79.2% Quinacrine 19/21 90.5% Quinacrine + 5-NI 14/14 100% Quinacrine + Paromomycin 2/2 100% • 2013: TropNet "GiardiaREF" study kick-off: Study on efficacy and tolerability of two 2nd-line regimens in nitroimidazole-refractory giardiasis: Quinacrine & Chloroquine + Albendazole JC 01.03.21 Meltzer E et al. Treatment of Giardiasis after Nonresponse to Nitroimidazole. EID 2014;20:1742-4. GiardiaREF study • Study objectives: Efficacy and tolerability of quinacrine monotherapy and albendazole + chloroquine combination therapy in nitroimidazole-refractory giardiasis • Study regimens: Quinacrine 100mg TID x 5 days Chloroquine 155mg BID + Albendazole 400mg BID x 5 days • Study design: prospective, open-label, multi-centric (Antwerp, Basel, Bordeaux, Munich) • Inclusion criteria: Patients having failed first-line treatment with a single or repeated 5-NI-course, defined as having persisting or relapsing symptoms + a positive stool microscopy positive ≥2 weeks after completing therapy • Exclusion criteria: (i) having received a non-5NI first-line treatment regimen, (ii) concomitant bacterial, helminthic or protozoal gastrointestinal infection, (iii) contraindications for the selected drug regimen according to the manufacturers’ specifications. JC 01.03.21 Endpoints: • Clinical outcome: Clinical cure: absence of gastrointestinal symptoms in week 5 after completing treatment. Clinical improvement: persisting gastrointestinal symptoms but improvement at week 5 after finishing treatment. Clinical failure: persisting gastrointestinal symptoms without improvement at week 5 after finishing treatment or relapse of the initial/similar symptoms following transient resolution at week 5 after finishing treatment. • Parasitological outcome: Parasitological cure: ≥2 stool samples tested negative for G. duodenalis by microscopy at week 5 after finishing treatment. Parasitological failure: detection of G. duodenalis by microscopy in a stool sample at week 5 after finishing treatment. JC 01.03.21 Results: • 2014–2020: enrolment of 106 patients (50 female: median age 33a [21–68], 56 male: median age 34a [8–59]) • 75% of NI-refractory infections acquired in India JC 01.03.21 • Clinical outcome: JC 01.03.21 • Parasitological outcome: JC 01.03.21 • Adverse events / side effects: Mild-moderate AEs: Qinacrine: 45% Albendazol-Chloroquin: 30% Discontinuation of treatment due to adverse events in only 1 of 106 patients: One quinacrine-treated patient developed self-limiting severe neuropsychiatric symptoms requiring short hospitalization: - sleep disturbance [VAS 9] - nightmares [VAS 9] - hallucinations [VAS 8] - psychotic symptoms [VAS 9] JC 01.03.21 How toxic is quinacrine? • 1945: Toxic psychosis in 35 of 7604 (0.4%) WWII soldiers receiving quinacrine as antimalarial drug (cumulative dose 2.1g) • 1946: Toxicity depends on cumulative dose: 2.1g low risk – 4.5g high risk • 1947: Prospective study on quinacrine CNS-toxicity: exposure of 5 healthy subjects to a cumulative dose of >4g: "All the subjects experienced some degree of motor restlessness, sleeplessness and awakening dreams, which were of frightening and nightmarish quality." • Treatment of giardiasis: cumulative dose 1.5g Conclusion: • Quinacrine is a highly effective 2nd-line treatment in NI-refractory giardiasis • Patients must be informed on potential neuopsychiatric side-effects, but the occurence of side-effects leading to discontinuation of treatment is rare • Albendazole + chloroquine is considerably less effective, but may still be an option if quinacrine is unavailable Gaskill HS, Fitz-Hugh T. Toxic Psychoses following Atabrine. Bulletin of the US Army Med12 Department 1945;86:63-9. Lidz T, Kahn RL. Toxicity of quinacrine (Atabrine) for the central nervous system. Arch Neurol 1946;56:284-9. Engel GL et al. Effect of quinacrine (atabrine) on the central nervous system. Arch NeurPsych. 1947;58:337-50. Danke für die Aufmerksamkeit! JC 01.03.21.