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Comparative Efficacy of Combination Therapeutics for Management of Canine Babesiosis.

Introduction

Babesiosis is one of the common and fatal vector borne hemoprotozoan disease in canines worldwide depending on the ecological ranges of their vector arthropods (Gray et al., 2009). The disease is characterised clinically by pyrexia with or without coffee colour urine, dark colour stool, jaundice, stunted growth and ascites in young ones, debility in chronic cases, disseminated intravascular coagulopathy (DIC), multiple organs failure in complicated cases etc. Treatment failure with single drug in canine babesiosis is a common problem, hence combined therapies of different combinations are indicated. The present study was aimed to find out comparative efficacy of different combination therapies against canine babesiosis.

Materials and Methods

Fifty (50) babesia infested dogs were randomly divided into five equal groups irrespective of age, sex and breed and five grouped into B, C, D, E and F. Ten healthy dogs were used as healthy control (group A). The positivity of animals to babesiosis was confirmed through microscopic examination of Geimsa stained thin blood smears of suspected animals (Thompson and Hunt, 1966).

The treatment combinations in different groups were as follows:

In group B, Diminazene diaceturate (Nilbery (a)) at the total dose of 7 mg/kg b. wt. I.M. in two divided doses 48 hours interval were advocated.

In group C, Clindamycin phosphate @ 25 mg/kg b. wt. I.V. at 12 hour interval for fourteen days was administered.

In group D, Diminazene diaceturate (Nilbery (a))@ 7 mg/kg b. wt. I.M. in two divided doses of 48 hours interval along with Clindamycin phosphate @ 25 mg/kg b. wt. I.V. at 12 hour interval for 14 days.

In group E, Doxycycline (Doxt-S (b)) @10 mg/kg b. wt. orally daily for fourteen days

In group F, Diminazene diaceturate (Nilbery (a)) @ 7 mg/kg b. wt. I.M. in two divided doses at 48 hours interval along with Doxycycline (Doxt-S (b)) @10 mg/kg b. wt. orally daily for fourteen days.

Intravenous fluid therapy and other supportive therapy like intravenous iron, steroids (Prednisolone), probiotic preparations, Pantoprazole and Vitamin B-complex injections were added as required.

Post-therapeutic evaluation was made on basis of microscopic examination of blood smears for presence of Babesia parasites, mortality of animals during treatment periods and different haemato-biochemical parameters likes Hb, PCV, TEC, thrombocyte count, AST, ALT, serum bilirubin direct, serum bilirubin total, creatinine and BUN at seven days intervals till fourteenth day post treatment.

Results and Discussion

On fourteenth day of post treatment, three dogs of group B, six dogs of group C and one dog of group E out of ten dogs of each therapeutic group were found positive for Babesia parasites on microscopic examination but all dogs of groups D and F were found undetected (Table-1). Low response in group B, C and E might be due to use of single drug (Susan et al., 2001) and on the other hand combined therapy produced good response in group D and F as stated by Suzuki et al. (2007) and Selvaraj et al. (2010).

The pre-treatment Hb level in all treatment groups was significantly lower (P<0.01) (ranging from 4.92[+ or -]0.64 to 5.4[+ or -]0.53) than healthy control group (14.16[+ or -]0.50), the pre-treatment PCV values (ranges from 15.32[+ or -]1.99 to 16.42[+ or -]1.68%) in all treatment groups were found to be significantly lower (P<0.01) than healthy control group (41.89[+ or -]1.51%) likewise the pre-treatment low count (P<0.01) of total erythrocyte (TEC) (ranging from 2.50[+ or -]0.19 to 2.68[+ or -]0.21) in all treatment groups were found to increase progressively at different days of posttreatment excepting the animals of group B and C. The significant increase of these parameters near to normal ranges in groups D, E and F might be due to combined therapies and significantly low level of these parameters in groups B and C might be due to use of single drug therapies and these types of findings also recorded by workers like Susan et al. (2001) and Birkenheuer et al. (2004).

Low level of haematological parameters in Babesia affected animals might be due to intravascular hemolysis, direct lysis of erythrocyte by the parasite or spontaneous lysis due to decreased osmotic pressure inside the erythrocyte or immune mediated lysis which were also recorded by earlier workers (Abdullahi et al., 1990; Irwin and Hutchison, 1991; Makinde et al., 1994; Jacobson and Swan 1995; Radi et al., 2004; Reyers et al., 1998; Dantes-Torres and Figuered, 2006; Alam, 2011; Bhattacharjee, 2011).

The pre-treatment low count of total thrombocyte (ranging from 38.4 [+ or -] 5.48 to 49.50 [+ or -] 6.37) in all treatment groups compared to healthy control group (227.50 [+ or -] 20.00) gradually found to increased progressively at different days of treatment excepting in group B and C. In group E and F, the count reached the normal range though these were not at the level of healthy control group. The satisfactory posttreatment count of thrombocytes in groups E and F might be due to efficacy of drugs used in Babesia affected animals. Low count of thrombocyte in canine babesiosis was also reported by many workers (Camacho et al., 2001; Radi et al., 2004; Furlanello et al., 2005; Bourdoiseau, 2006; Baric Rafaj et al., 2007; Mathe et al., 2007; Irwin, 2009; Trotta et al., 2009) might be due to coagulopathic consumption in disseminated intravascular coagulation (DIC), splenic sequestration in splenomegaly and immune mediated platelet destruction.

The significantly increased (P<0.01) pre-treatment AST value (ranging from 28.41[+ or -] 6.91 to 36.19 [+ or -] 3.38 U/L) in all treatment groups compared to healthy control group (12.52[+ or -]0.91 U/L) were found to have decreased gradually in all treatment groups on fourteenth day of post-treatment. Higher value of AST in Babesia positive cases was also recorded by many workers like Furlanello et al. (2005), Baric Rafaj et al. (2007) and Alam et al. (2011). The higher value of AST in our study might be due to tissue damage in organs viz. liver, skeletal muscles and heart muscle caused by tissue hypoxia (Uilenberg et al., 1989; Jacobson et al., 1996 and Lobetti et al., 1996) resulted from severe anaemia and lack of tissue perfusion oxygen.

The significantly increased (P<0.01) pre-treatment ALT values (ranging from 136.19[+ or -]3.38 to 180.01[+ or -] 28.77) in all treatment groups compared to healthy control group (68.92[+ or -]10.09) were found to have decreased gradually in treatment groups on fourteenth day of post-treatment. Higher ALT values in Babesia positive cases was also recorded by many workers like Furlanello et al. (2005), Baric Rafaj et al. (2007) and Alam et al. (2011). The higher value observed might be due to damage of liver tissue from tissue hypoxia and toxic level of bilirubinaemia (Uilenberg et al., 1989; Jacobson et al., 1996 and Lobetti et al., 1996) resulted from severe anaemia leading to lack of tissue perfusion of oxygen and production of bile pigments.

The significantly increased (P<0.01) pre-treatment direct serum bilirubin values (ranging from 1.26[+ or -] 0.32 to 2.32[+ or -]0.41) in all treatment groups compared to healthy control group (0.16 [+ or -] 0.02) were found to be decreased gradually in treatment groups excepting in group B and C on fourteenth day of post-treatment. From the finding of present study, it could be ascertained that in group B and C haemolysis continued even after treatment for Babesiosis along with single drug indicating improper response to therapy (Susan et al., 2001) and resulted continuation of haemolysis and production of direct serum bilirubin values, while direct serum bilirubin values in group D, E and F decreased from respective therapies (Vial and Gorenflot, 2006).

Though the significantly increased (P<0.01) pretreatment total serum bilirubin value (ranging from 2.79 [+ or -] 0.36 to 3.16 [+ or -] 0.63) in all treatment groups compared to healthy control group (0.47 [+ or -] 0.05) were found to have decreased gradually in all treatment groups except group C on 14th day of post-treatment, still they could not come down to the level of healthy control. The higher value of total serum bilirubin in Babesia positive cases was also reported by many workers (Boozer and Macintire, 2003; Hossain et al., 2003; Furlanello et al., 2005; Baric Rafaj et al., 2007 and Senthil Kumar et al., 2009). The higher value of total serum bilirubin obtained in present study might be due to over production of bilirubin resulting from excessive haemolysis caused by Babesia parasites.

The increased pre-treatment serum creatinine values (ranging from 2.13 [+ or -] 0.29 to 3.03 [+ or -] 0.46) in all treatment groups compared to healthy control group (1.24[+ or -]0.09) were found to have decreased gradually in all treatment groups on fourteenth day of posttreatment. The higher level of serum creatinine in Babesia positive cases was also recorded by Reyers et al. (1998) and Jacobson (2006) where they found severe increase of serum creatinine in seriously ill dogs affected with B. canis rossi infection. In contrast to present reports, Lobetti and Jacobson (2001) did not observe any alteration in serum creatinine value in canine babesiosis. The higher level of serum creatinine in present study might be due to toxic effect of increased level of bilirubin in circulation, severe dehydration and muscle catabolism as stated by Benjamin (1985). The level decreased with the correction of these conditions. A few dogs under trials with higher creatinine level died in spite of use of proper anti-babesial drugs and cause might be due to acute renal failure (ARF) in complicated Babesia infection as stated by Jacobson (2006).

The significantly increased (P<0.01) pre-treatment BUN values (ranging from 46.08[+ or -]5.25 to 51.16[+ or -] 9.07) in all treatment groups compared to healthy control group (21.86[+ or -]2.19) were found to have decreased gradually in all treatment groups. The higher level of BUN in the study might be due to severe dehydration, hypotension, muscle catabolism and renal disease as stated by Benjamin (1985). The level was found to have decreased with correction of these conditions. In present study, it was recorded that dogs died in different treatment groups had high level of BUN till death. The cause might be due to acute renal failure (ARF) in complicated Babesia infection as stated by Jacobson (2006).

Highest mortality recorded in animals of group C (30%) followed by 20 percent in group B and E and lowest in group D and F (10 percent each). Highest mortality in group C might be due to low response of Clindamycin singly to Babesia parasites which was also stated by Susan et al. (2001). Likewise, animals of group D and F were cured timely and properly due to use of combined therapy and same opinion also stated by Vial and Gorenflot (2006).

Efficacy of different treatment regimens based on few important haematological parameters, posttreatment microscopic detection of Babesia parasites and rate of mortality during the trial period. After treatment it was observed that different important parameters of group D and F reached to the comparable level with that of parameters of healthy group. The mortality rate in group D and F treatment regimens (10 percent) was found less than the groups B, C and E (20 percent). The treatment cost of group D (Diminazine and Clindamicin combination) was more than that of group F due to higher cost of Clindamycin than Doxycycline and Diminazine. Considering all the aspects, the group-F (Diminazene diaceturate with Doxycycline) treatment regimen was found superior over the other treatment groups.

Summary

An investigation was under taken during the period from 1st March, 2016 to 28th February, 2017 to study the comparative efficacies of different treatment regimens in canine babesiosis. In Babesia affected dogs, the levels of Hb, PCV, TEC and thrombocyte count were lower and the levels of AST, ALT, Bilirubin total and direct, serum creatinine, BUN were recorded higher than healthy dogs. On fourteenth day of treatment, mean values of different hemato-biochemical parameters of groups D, E and F were almost able to reach to level of group A (healthy group). The mortality was less in treatment groups D and F than in treatment groups B, C and E, but treatment cost of group D was more than other groups.

Considering all the factors, drugs used in group F (Diminazine and Doxycycline combination) was found more suitable for treatment of canine Babesiosis in terms of efficacy and economy.

Conclusion

From the present study, it may be concluded that combination of Diminazine and Doxycycline can be used effectively, safely and economically for treatment of canine babesiosis.

References

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B.C. Baishya (1), A. Phukan, G. Mahato (2), S. Goswami (3) and P. Kakati (4)

Department of Veterinary Clinical Medicine, Ethics and Jurisprudence

College of Veterinary Science

Assam Agricultural University (AAU)

Khanapara

Guwahati - 781022 (Assam)

(1.) Assistant Professor and Corresponding author. E-mail: bhabenchbaishya@gmail.com

(2.) Department of Epidemiology and Preventive Medicine

(3.) Department of Veterinary Pathology

(4.) Ph.D. Scholar, Department of Veterinary Parasitology

(a) - Brand of Intas Animal Health, Ahmedabad

(b) - Brand of Dr. Reddy's Laboratories Ltd., Hyderabad
Table 1: Microscopic detection of babesia parasites in different groups
on pre and post treatment days

Groups   Post treatment days
         0    7th   14th

B        10    5     3
C        10    8     6
D        10    1     -
E        10    1     1
F        10    1     -

Table 2: Mortality rate (%) in treatment groups during treatment period

Treatment   Number of dogs   Mortality rate (%)
groups      treated   died

Group-B       10       2            20
Group-C       10       3            30
Group-D       10       1            10
Group-E       10       2            20
Group-F       10       1            10

Table 3: Comparative evaluation of groups on 14th day of
post-treatment to evolve the best therapeutic regimen

Parameters                       Gr-A                 Gr-B

Hb (gm/dl)                 14.16[+ or -]0.50    4.05[+ or -]0.90
PCV (%)                    41.89[+ or -]1.51   14.28[+ or -]1.64
Thrombocyte               227.5[+ or -]20.19   44.11[+ or -]5.82
counts (x[10.sup.6]/ml)
Mortality (%)             --                   20
Babesia/positive          --                    3
dogs
Economy                   --                   Economic

Parameters                      Gr-C                Gr-D

Hb (gm/dl)                 3.13[+ or -]0.34     8.99[+ or -]0.58
PCV (%)                   13.43[+ or -]0.94    27.49[+ or -]1.92
Thrombocyte               42.00[+ or -]5.13   102.7[+ or -]6.23
counts (x[10.sup.6]/ml)
Mortality (%)             30                   10
Babesia/positive           6                   --
dogs
Economy                   Expensive           More expensive

Parameters                        Gr-E                Gr-F

Hb (gm/dl)                  8.14[+ or -]0.6     9.16[+ or -]0.81
PCV (%)                    26.74[+ or -]1.73   27.85[+ or -]2
Thrombocyte               102.7[+ or -]6.23   179.1[+ or -]31.90
counts (x[10.sup.6]/ml)
Mortality (%)              20                  10
Babesia/positive            1                  --
dogs
Economy                   Economic            Economic
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Title Annotation:Clinical Article
Author:Baishya, B.C.; Phukan, A.; Mahato, G.; Goswami, S.; Kakati, P.
Publication:Intas Polivet
Geographic Code:9INDI
Date:Jul 1, 2018
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