Dirofilaria Preventie si Tratament 4


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Dirofilaria Preventie si Tratament 4

  1. 1. Dirofilaria infections in animals and humans New insights in the prevention and treatment of canine and feline dirofilarial infections  Claudio Genchi, Med Vet, PhD, EVPC Dipl Dept of Veterinary Science and Public Health, Università degli Studi di Milano Bucharest, June 14th, 2012
  2. 2. Searching for an effective chemotherapy and prevention Until the first half of 900’s, no effective treatment: • Essential turpentine oil • Intravenous injections of 0.40% formalin • Antimony salts: till 11 injections G. Zanotti: Of the degree of receptiveness, diagnosis and, antimony therapy of canine filariosis. Profilassi 16: 79-87, 1943 The use of antimony salts was promptly given up for the severe side effects
  3. 3. In 1947 Otto and Maren suggested the use of thiacetarsamide (TCA) against heartworm infection. They were the first who experimented the efficacy of arsenical salts in HW infected dogs as a model for treatment of Wuchereria brancoftii human infection. At that time, Wuchereria infection was quite frequent in American soldiers fighting in the Pacific area. Otto GF, Maren TH. Possible use of an arsenical compound in threatment of heartworm in dogs. Vet Med 1947, 42: 128 Searching for an effective chemotherapy and prevention
  4. 4. TCA [Caparsolate]: histolesivity, difficultly to manage (2.2 mg/kg bw iv, 12 hours apart for 2 consecutive days), toxicity and discontinuity in efficacy limited an effective control of canine heartworm disease, mostly for severe infections. When melarsomine dihydrocloride was put on the market (1997), the production of tiacetarsamide was stopped. Searching for an effective chemotherapy and prevention
  5. 5. TCA vs Melarsomine [Immiticide®] TCA:  high affinity for red cells [Dirofilaria worms are not aematophagous]; the efficacy varies with the age and the sex of worms.  high content of arsenic  histolesivity, hepato- and nephrotoxicity Melarsomine dihydrocloride :  higher affinity for blood plasma  less content of arsenic, les hepato- and nephrotoxicity  Max blood concentration within about 150 min, 2-3 higher than TCA
  6. 6. The idea that it would be possible to prevent HW larval development to adult parasite preventing canine HW disease was developed at the beginning of 1960’s. Kume et al. (1962) confirmed the concept of HW prevention through daily administration of diethylcarbamazine (DEC). In the 90’s, macrocyclic lactones prevention was extended to both feline HW infection and to subcutaneous filarial infections (Dirofilaria repens). Searching for an effective chemotherapy and prevention
  7. 7. … before the discovery of macrocyclic lactones and of its efficacy against Dirofilaria larval stages: 2 options 1. Diethylcarbamazine (DEC) citrate: 1.25 mg DEC base/4.5 kg bw/day. To be effective, the treatment must begin shortly before the start of the transmission season and continue daily for 2 months after the end of the transmission season. The omission of only 2 or 3 consecutive doses can compromise efficacy and cause a lapse of protection. Side effects: vomiting, diarrhea, male infertility, severe anaphylactic reaction in microfilaremic dogs.
  8. 8. In 1980, John W. McCall presented the first results on the preventive efficacy of the ivermectin and concluded … in terms of efficacy, safety and infrequency of dosing, ivermectin looks promising as a chemoprofilactic agent against canine heartworm.
  9. 9. 25 years after Kume’s paper (1962), the introduction on the market of ivermectin (1987), milbemycin oxime (1990) and, more recently, of selamectin and moxidectin, made prevention possible through monthly administration of a preventive drug. From 2002, an injectable moxidectin formulation is on the veterinary market in some European countries. The drug is able to protect dogs against HW infection throughout the entire transmission season following a single injection. Searching for effective chemotherapy and prevention
  10. 10. Nowadays, several macrocyclic lactones products such as ivermectin, milbemycin oxime, selamectin and moxidectin are available in Europe for the prevention and control of canine and feline Dirofilaria infections. IVM and MBO formulations are; SLM formulation is for topical treatment (spot-on); moxidectin formulations are oral, topical (spot on) and injectable. All are safe [including ivermectin-sensitive dogs], a full efficacy is requested by regulatory authorities worldwide and they have retroactive activity [ML safe net or reach- back effect].
  11. 11. Do not forget: we say prevention but it is a larvicidal treatment: MLs monthly or injectable Treatment is effective against L3 and L4 larvae Treatment should begin within 1 month from the beginning of transmission by infected mosquitoes and the last dose should be given 1 month after transmission ceases
  12. 12. Dose of preventative drugs for canine HW prophylaxis Macrocyclic lactone Min-max dose Ivermectin Milbemycin oxime Moxidectin (tablets)¹ Moxidectin/imidacloprid spot on Moxidectin injectable³ Selamectin (spot-on)² 6 - 12 µg/kg bw 0.5 - 0.99 mg/kg bw 3 - 6 µg/kg bw 2.5 – 6.25 mg/kg bw 0.17 mg/kg bw 6 - 12 mg/kg bw ¹, ² the efficacy lasts 60 days; ³ full risk season efficacy
  13. 13. Dose of preventive drugs for the feline HW prophylaxis Macrocyclic lactone Minimum dose Ivermectin Milbemycin oxime Moxidectin/imidacloprid spot on Selamectin (pour-on)¹ 24 - 71.7 µg/kg bw 2 - 4 mg/kg bw 1 - 2 mg/kg bw 6 - 12 mg/kg bw 1 the efficacy lasts 60 days
  14. 14. Efficacy Preventative Dog Cat IVM MBO MOXI tablets MOXI pour on MOXI inject SLM D. immitis D. immitis, Toxocara, Toxascaris, Ancylostoma, Trichuris D. immitis D. immitis, D. repens, Toxocara, Toxascaris, Ancylostoma, Trichuris, Sarcoptes, Otodectes, Demodex (control) D. immitis, D. repens D. immitis, D. repens, Toxocara, Toxascaris, Ancylostoma, Cyenocephalides, Sarcoptes, Otodectes D. immitis, Toxocara, Toxascaris, Ancylostoma D. immitis, Toxocara, Toxascaris, Ancylostoma, D. immitis, D. repens, Toxocara, Toxascaris, Ancylostoma, Otodectes D. immitis, D. repens, Toxocara, Toxascaris, Ancylostoma, Cyenocephalides, Otodectes
  15. 15. Parasites age (mths) No. of treatments Efficacy % Vitality/motility of recovered worms IVM 6µg/kg/mth MBO 0.5 mg /kg/mth SLM 6 mg/top/mth 3 4 - 5 7 8 3 - 4 3 adulti 13 12-31 29 16 12-14 12 18 98 95-99 95 56 41-97 98.5 39 abnormal abnormal abnormal abnormal normal abnormal abnormal from Guerrero, McCall e Genchi, 2002 Reach-back efficacy of macrocyclic lactones
  16. 16. HW adulticide treatment: melarsomine dihydrocloride • Two intramuscular injections of 2.5 mg / kg 24 hours apart (standard regimen, not advised) ► Strongly advised two step treatment by giving one injection and then administering the standard pair of injections at least 60 days later One administration of melarsomine at the dose of 2.5 mg/kg kills about 90% of male worms and 10% of female worms resulting therefore in 50 % reduction of the worm burden (which is safer in terms of embolism and shock). A 10% death rate can be expected in dogs with High risk of thromboembolic complications when 2 doses are given initially.
  17. 17. Given strictly intramuscularly, deep in the lumbar (back) muscle. Do not administer at any other site. No more than 2 ml in the same site. Alternate sides. Use thin needles (21-22 gauge). Change the needle for the injection (to avoid subcutaneous tissues contamination)
  18. 18. Pulmonary thromboembolism is an inevitable consequence of a successful adulticide therapy. If several worms die widespread pulmonary thrombosis frequently develops. Mild thromboembolism may be clinically unapparent, but in severe cases life threatening respiratory distress can occur. Watch for: Coughing, Dyspnoea Fever Hemoptysis, Lipothymias The most critical time is 7-10 days following a melarsomine treatment but pulmonary thromboembolism can occur anytime in the following month
  19. 19. ANCILLARY THERAPY • REST • Calcium heparine • Prednisolone • Aspirine
  20. 20. REST• After treatment, the patient must be strictly confined for one month following the final treatment. • No walks, no running around. • The dog must live the indoors (or in cage in selected cases). The reason for this is that it is the most important thing to minimize embolism-related problems.
  21. 21. Calcium heparin  50-100 UI s.c. 3 times daily starting 1-2 weeks prior to and continuing for 4-6 weeks after adulticidal treatment NO
  22. 22. Prednisolone  0.5 mg/kg every other day from 5 th to 10 th day post adulticide treatment
  23. 23. Even though not recommended, IVM administered orally at the prophylactic dose of 6 µg/kg monthly throughout the year for a period of at least 2-2.5 years has been shown to kill adult parasites. To note that throughout this period the infection would persist and pathology continues to worsen. Furthermore the long-term use of a macrocyclic lactone in heartworm positive dogs is the potential for selection of resistant sub- populations of heartworms. This regimen should be restricted to selected cases, excluding active dogs, working dogs and heavily infected dogs. X-ray examination should be performed every 4-5 months throughout the treatment period to monitor the pulmonary patterns. What about the use of MLs as an adulticide drug?
  24. 24. Recently, it has been shown that a combination of ivermectin at 6 µg/kg given every 15 days for 180 days and doxycycline at 10 mg/kg once daily for 30 days is well tolerated, has good adulticide efficacy and reduces the risk of thromboembolism. Exercise should be rigidly restricted for the duration of the treatment process. An antigen test should be performed every 6 months and the combination treatment continued until two consecutive negative heartworm antigen tests have been obtained. Anecdotal reports on other macrocyclic lactones with adulticidal properties suggest similar results but no confirmatory studies have been published. IVM plus Doxy
  25. 25. Surgical heartworm removal via jugular vein in the dog Why, when and wherefore…
  26. 26. Surgical intervention is advised when several worms have been displaced into the right cardiac chambers producing sudden onset of caval syndrome. It can be accomplished under general anesthesia with flexible alligator forceps introduced via the jugular vein aided by fluoroscopic guidance which gives access not only to the right cardiac chambers but also to the major pulmonary arteries.
  27. 27. Whenever …  Caval Syndrome (compulsory!)  Dogs harboring large worm burden at ECHO examination (advised)
  28. 28. Flexible Alligator Forceps® Fujinon
  29. 29. SURGICAL TOOLS  flexible Alligator Forceps  fluoroscopy  basic suturing tools  2 haemostatic clips
  30. 30. Anaestetic protocol  Ketamin hydrocloride 5 mg/kg i.v.  Diazepam 0,25 mg/kg i.v.  Oxigen (mask)
  31. 31. technique main pulmonary artery
  32. 32. Surgical technique
  33. 33. Surgical technique
  34. 34. Surgical technique
  35. 35. Surgical technique
  36. 36. EFFICACY negativization of Ag test four months after surgery  Caval Syndrome 78%  Chronic Cases 65 % Average of removed heartworms 90%
  37. 37. In cats, adultice therapy with melarsomine is not advised. If a cat does not display overt clinical signs despite radiographic evidence of pulmonary vascular/interstitial lung disease consistent with HARD, it may be advised to allow time for self-cure. Subclinical cases can be monitored periodically (6- to 12-month intervals) by antibody and antigen re-testing and thoracic xR. In those cats destined to recover, regression of xR signs and especially seroconversion of a positive antigen test to negative status provide evidence that the period of risk probably has passed. Adulticide treatment of feline HW infection
  38. 38. Prednisone in diminishing doses is often an effective medical support for infected cats with radiographic evidence of lung disease, whether or not they are symptomatic. Also, this should be initiated whenever antibody-and/or antigen-positive cats display clinical signs. An empirical oral regimen is 2 mg/kg body weight/day, declining gradually to 0.5 mg/kg every other day by 2 weeks and then discontinued after an additional 2 weeks. At that time, the effects of treatment should be reassessed based on the clinical response and/or thoracic radiography. This treatment may be repeated in cats with recurrent clinical signs Adulticide treatment of feline HW infection
  39. 39. Compound Formulation Dose Safety Efficacy Melarsomine dihydrochloridre Injectable deep in the muscles 2.5 mg 24 hrs apart Toxicity, possible side effects if the compounds is injected in connective tissues NO efficacy D. repens adulticide treatment, is it possible?
  40. 40. Adult worms can be removed using a 19 Gauge needle, connected to a vacuum syringe
  41. 41. Compound Formulation Dose Safety Ivermectin Selamectin Moxydectin plus Doxycycline tablets/ chawable topical topical Per os 6 mcg/kg 12-24 mths 60 mg/kg 12-24 mths 1 mg/kg 6-12 mths 10 mg/kg daily 6-8 weeks/intervals 2-3 weeks Good Possible idiosyncratic intolerance in single subjects Because D. repens severe clinical signs can be as a consequence of Mfs sensitization
  42. 42. Compound Formulation Dose Reference Selamectin Ivermectin Moxidectin Topical Tablet per os Chewable Injectable SR 6 mg/kg bw 6 mcg/kg bw 0.17 mcg/kg bw Genchi et al., 2002 Fok et al., 2009 Marconcini et al., 1986 Pollono et al., 1998 Rossi et al., 2004 Dirofilaria repens prevention in dogs MLs [larvicidal treatment]: field data from owned dogs observed comparing the treatment season with previous data of prevalence
  43. 43. Formulation Dose Efficacy Reference IVM MOX Tablet per os Injectable SR Topical 6 mcg/kg bw 12 mcg/kg bw 0.17 mcg/kg bw 2.5 mg/kg bw 87% 93% 100% 100% Cancrini et al,1989 Genchi et al, 2010 Genchi et al, 2012 Dirofilaria repens prevention in dogs MLs [larvicidal treatment]: experimental data
  44. 44. MOXI is more lipophilic than IVM and it is stored in the fat, which may act as a drug reservoir. Compared to IVM, MOXI has a higher distribution volume and a longer half- life elimination. This may facilitate its distribution from the blood stream to different tissues and longer residence time for the drug in the body. D. repens larval stages and the adult worms are permanent residents in subcutaneous tissues, which are rich of connective and fat tissues and the high lipophilic nature of MOXI are probably the reason of the full efficacy. D. repens prevention: MOXI vs IVM
  45. 45. Canine and feline HW patent infection can be safely and effectively prevent by the use of macrocyclic lactones, bot throughout a monthly administration in the risk season or throughout moxidectin sustained release formulation injection. From WAAVP, FDA and EMEA guidelines of veterinary medicinal the efficacy of such a treatments must be 100% Background
  46. 46. What is new about HW? Canine HW infection: 2005 Most failures have been reported in HW-endemic states ... it is unclear whether these are representative of the rare occurrences of failure that have been in existence for a long time, but not reported regularly, or whether there is a true increase ineffectiveness … Results suggest that more comprehensive reporting will provide FDA/CVM more accurate surveillance information regarding efficacy. It will permit to better interpret both incidence and severity of ineffectiveness and possible emerging resistance and to convey this in any necessary updated labelling. It also indicates that practitioners should return to a more conservative testing schedule.
  47. 47. 2011 A controlled lab study was conducted to evaluate the efficacy of 4 commercial products. On Day −30, dogs were infected with 100 D. immitis L3. On Day 0, each dog group was treated with ivermectin/pyrantel (IVM 6.6 mcg/kg) or milbemycin oxime (500 mcg/Kg) orally, or selamectin (60 mg/kg) solution or moxidectin/imidacloprid topically (MOX 100mcg/kg). Group 5 dogs remained nontreated. At necropsy (Day 120), all 8 dogs in the no treated group were infected with adult D. immitis (34–70 worms/dog). One or more adult D. immitis and/or worm fragments were recovered from dogs in each treatment group (efficacy 95.6, 95.4 and 95.5% efficacy). No worms were recovered from any of the 8 dogs in Group 4 resulting in 100% efficacy.
  48. 48. Results: Thirteen of 14 control dogs had adult HW detected at necropsy with a geometric mean worm count of 22.3. One HW was found in 1 dog in each of the MBO and IVM treatment groups. Conclusions and Clinical Importance: Two currently approved macrocyclic lactone HW preventives used at their labelled dose rates were < 100% effective against a recent HW field isolate, supporting the hypothesis that the effectiveness of a single dose of these preventives can vary. This is important in guiding clients on expectations of product effectiveness. Experimental studies with a prouved lab resistant strain
  49. 49. The combination product of spinosad (anti-flea) and MBO provides effective control of canine heartworms. A single treatment at 30 days post infection showed high but incomplete effectiveness against a HWs isolate that had been shown to be partially refractory to treatment with marketed monthly heartworm preventives. Three consecutive monthly treatments provided complete control, providing support to the recommendation that heartworm prophylaxis should be maintained year round for optimal effectiveness. Experimental studies with a prouved lab resistant strain
  50. 50. Resistant field strain
  51. 51. Knott mf always positive IVM 50-200 µg MB 0.75-2 mg x 8 gg
  52. 52. D. immitis has exhibited a lower than expected heterozygosis and worm populations were found to be relatively homogeneous. For instance, the Japanese field samples were found to share several common combined genotypes with US field samples. The situation differs when laboratory isolates are compared with field isolates from the same country or with field strains from other countries (i.e. from US lab and US field and US lab and Japanese field). To note that the genetic polymorphism of D. immitis populations is a consequence of many factors both of the mammalian host and the invertebrate intermediate hosts (mosquito); however, all previous data were obtained from dogs in areas that have been intensively exposed to macrocyclic lactone preventatives for over 20 years (US, Japan and Italy). Nevertheless, the different field isolates studied by did show identical gene sequences. Towards resistance in Europe?
  53. 53. HW: last recommendations Before the seasonal HW preventive treatment: - Knott microfilariae, Ag test kit Before and after adulticide HW treatment: - Knott microfilariae, Ag test kit to assess the efficacy The presence of resistant microfilariae must be carefully checked to avoid the infection of mosquitoes and the spreading of resistance
  54. 54.  Although Dirofilaria does not appear entirely dependent on its bacterial symbiont Wolbachia, which can be killed by a prolonged antibiotic treatment, the clearing of bacteria from circulating microfilarie seems to prevent infective larvae which develop in mosquitoes from continuing their development in dogs.  The combination of heartworm preventatives with products designed to prevent mosquito blood-feeding activity (repellents) during the heartworm transmission season could be useful in protecting dogs from infection and from ectoparasite infestations that often occur in the same season. HW: last recommendations
  55. 55. Dirofilaria repens: last recommendations Before seasonal D. repens preventive treatment: - Knott microfilariae [No Ag test kit for filarial subcutaneous infections] Microfilaraemic dogs must be treated against mfs with macrocyclic lactones at the same dose to prevent patent D. immitis infection for 3-12 moths [Knott examination until negative results] to control the spreading of the infection and preserve human health. D. repens human infection is an emergent zoonosis in Europe and human cases are increasing.
  56. 56. Mf clerance from blood stream Ivermectin 6 mcg/kg Milbemicine ossime 0.5 mg/kg Selamectin 6 mg/kg Moxidectin 2.5 mg/kg Low efficacy (4-6 mth adm), mild reaction as a consequence of the death of some mfs Very effective, hypersensibility reactions in dogs with high microfilaraemia Low effecacy, no side effect after treatment in microfilaraemic dogs Efficacy after 4-6 moth administrations, no side effects Microfilaria treatment [mf clearance] Before the prophylactic treatment with MBO products, dogs must be Knott examined for circulating Mfs Interceptor, Sentinel, [MBO + lufenuron], Trifexis [MBO + spinosad]
  57. 57. Starting and ending HW temperature suitability in some European localities 2008 6-7 mth treatment May-Oct/Nov