AHS Heartworm Hotline , Clinical Medicine , Columns , Parasitology

Heartworm Hotline: Doxycycline in the Management of Heartworm Disease 

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Clarke Atkins, DVM, Diplomate ACVIM (Internal Medicine & Cardiology)

The Heartworm Hotline column is cosponsored by Today’s Veterinary Practice and The American Heartworm Society (heartwormsociety.org). Each article presents a question or questions on a particular area related to heartworm infection, prevention, diagnostics, and/or treatment.

You asked…

What role does doxycycline play in the management of heartworm disease?

The exact role of doxycycline in the management of heartworm disease (HWD) is not well established. However, virtually all experts in the field would agree that doxycycline has a role in therapy and most U.S. veterinarians incorporate it into their management of HWD (Figure 1).

c02_fig01

Several important questions regarding doxycycline remain unanswered, including:

  • What is the optimum concomitant therapy (ie, most data to date have been generated using concomitant administration of ivermectin)?
  • What is the exact dosage, time-point for initiation, and duration of therapy?
  • What are the risk and cost to benefit ratios?
  • In which specific disease stage(s) is doxycycline useful?

Doxycycline versus Wolbachia

The benefits of doxycycline result from its ability to remove or reduce the burden of Wolbachia, a rickettsial organism that exists in a symbiotic relationship with heartworms (and other filarids), occupying the reproductive tract and lateral chords of the host parasite (Figure 2). Wolbachia are necessary for the parasite (in this case, Dirofilaria immitis) to develop, thrive, reproduce, and maintain infectivity.

c02_fig02

Doxycycline has been used to (presumably) rid the parasite of Wolbachia organisms; therefore, D immitis organisms do not thrive, may deteriorate and die, and have reduced reproductive potential, which helps manage HWD in infected dogs and reduces potential for infection in other dogs.

Potential and realized benefits derived from anti-Wolbachia therapy include:

1. Reduced Ability of Parasite to Reproduce

It has been shown that the Wolbachia organism is suppressed (killed) by doxycycline and the resulting, negative effects on the heartworm reproductive system renders the parasite infertile or less fertile (temporarily?), with reduced microfilarial numbers.1,2,3

2. Reduced Infectivity 

In doxycycline-treated dogs, even if microfilariae are produced and ingested in a mosquito’s blood meal, the resultant L3 are incapable of producing infection, reducing the spread of HWD.1,2,3

3. Potentiate Adulticidal Therapy and/or Enhancement of Slow- or Soft-kill Efficacy

Most agree that Wolbachia is an obligatory symbiont for D immitis, which gives hope that Wolbachia eradication with antibiotics would result in the nematode’s demise. Unfortunately, prolonged doxycycline therapy does not kill heartworms because they are not sufficiently bound to their bacterial symbionts.4

Nevertheless, 2 studies3,5 have demonstrated that doxycycline shortens the time until worm death when administered chronically with ivermectin/pyrantel at preventive dosages, but with a decreased dosing interval:3,5

Study 1: Using surgically transplanted worms, it was shown that a combination of:

  • Weekly ivermectin (at the monthly preventive dosage of 6 mcg/kg PO) and
  • Daily doxycycline (10 mg/kg PO Q 24 H for 24 weeks of a 36-week study) reduced heartworm burden by 78% after 9 months of therapy as compared to control dogs.3

Study 2: Using echocardiography, this study evaluated the effect of:

  • Daily doxycycline (10 mg/kg PO Q 24 H for 30 days) and
  • Ivermectin/pyrantel (6–14 mcg/kg PO every 15 days for 180 days; then monthly) on microfilariemia, heartworm antigenemia, and parasite load. In naturally-infected dogs from an endemic region of Italy, all dogs became negative for circulating microfilariae by day 90 and 73% became antigen negative by day 300.5

The results of these studies suggest that the combination of doxycycline and ivermectin is (slowly) adulticidal in dogs with D immitis, which indicates that doxycycline enhances therapy for the soft- or slow-kill method.

4. Effective, Safe, & Rapid Reduction of Microfilarial Burdens

In the transplanted worm model mentioned in Study 1, it was shown that a combination of weekly ivermectin (6 mcg/kg) and daily doxycycline (10 mg/kg Q 24 H) eliminated microfilariae over 8 to 12 weeks.3

This elimination is relatively fast, but not so rapid that therapy results in the adverse, shock-like reactions seen with rapid destruction of large numbers of microfilariae. In addition, subacute removal of microfilariae lessens the chance of macrocyclic lactone resistance, especially when the practitioner is forced to use the slow-kill method due to owner finances or difficulty attaining adulticide (ie, melarsomine).

5. Reduced Lung Reaction to Worm Death (Spontaneous & Postadulticide)

Study 1 also showed that the combination of weekly ivermectin (6 mcg/kg PO) and daily doxycycline (10 mg/kg PO Q 24 H) significantly reduced lung lesions after melarsomine therapy.3,6

6. Developing Larva Eliminated

Recently, McCall, et al, demonstrated that, while doxycycline (even with ivermectin) does not have rapid adulticidal efficacy, doxycycline monotherapy does stop the progression of infective larvae to adulthood when administered for the first 30 days of infection at 10 mg/kg PO Q 24 H.7

• If the 30 days of administration begin on day 40 of infection, however, the effect is partially lost, with 2% of L3 reaching adulthood.

• If the larvae reach 65 days before doxycycline is initiated, only 52% reach adulthood.7

Therefore, in addition to reducing adverse effects from heartworm death, doxycycline begun on the day of diagnosis will help close the potential seasonal window of continuous infection, which means that, during certain times of year when exposure is continuous (warmest months), the host may have developing larvae of all stages.

Benefits of Anti-Wolbachia Therapy

  • Reduces ability of parasite to reproduce
  • Reduces infectivity
  • Potential adulticidal therapy and/or enhancement of slow- or soft-kill efficacy
  • Reduces microfilarial burdens more effectively, safely, and rapidly
  • Reduces reaction to worm death, both spontaneous (presumably) and postadulticide
  • Kills or impairs developing larvae

Doxycycline Dosing

Currently the best data we have argues that the dosage, if tolerated, is 10 mg/kg PO Q 12 H for 30 days, administered prior to adulticidal therapy (Figure 3). If this dose is not tolerated, it can be reduced to 5 mg/kg PO Q 12 H.7

Microsoft Word - Edition_2_Doxy_v3a.doc

Figure 3. My preferred approach to adulticidal therapy in virtually all (severely affected or not) dogs infected with heartworms includes 3 doses of melarsomine, unless otherwise dictated by owner finances. Macrolide prophylaxis is begun at the time of diagnosis, if not already in use. Note: If microfilaremic, care should be taken to prevent or observe and treat adverse reactions, based on microfilarial numbers and macrolide used. It is imperative to eliminate microfilariae from patients receiving macrolides to reduce the chance of resistance to macrocyclic lactones developing. To view a similar algorithm depicting the American Heartworm Society’s therapy recommendations, see the 2012 Guidelines of the American Heartworm Society, Table 3, at heartwormsociety.org.

Author Recommendation: I advocate a second month’s delay in adulticidal therapy to allow the parasite to deteriorate maximally and, thereby, further reduce the pulmonary reaction to worm death.

Benefits include:

  • Prevention of maturation of recently acquired infection (tissue phases)
  • Reduced pulmonary reaction to dying worms
  • More rapid and complete eradication of microfilariae (potentially reducing risk of heartworm resistance to macrocyclic lactones)
  • Enhancement of vermicidal efficacy of ivermectin, if using slow-kill method.

AHS Recommendation: The American Heartworm Society recommends that, if the slow-kill method is used (only out of necessity), doxycycline should be repeated in 60 days, so the dog receives ivermectin monthly and doxycycline 1 month on, 2 months off, 1 month on, 2 months off, etc, until the antigen test is negative.8 While there are no data that demonstrate the efficacy of this approach, there are data that indicate recrudescence of Wolbachia by 300 days postdoxycycline.5

In summary, it appears that doxycycline not only has a role in the management of heartworm infection, but that this role will continue to grow and be further refined.

Should We Worry About Resistance?

Concern has been raised about the potential development of bacterial resistance if doxycycline is administered in all cases of HWD. In my opinion, this concern is worth considering as doxycycline is widely used and valuable to our profession (and physicians) for treatment of a variety of infectious processes. On the other hand, concerns for resistance generally occur when drugs are used at suboptimal dosages and durations of therapy. Neither of these result from the current treatment recommendations for HWD.

Figure Credits

Figure 2. Courtesy Dr. Laura Kramer
Figure 3. Modified from Atkins CE, Miller MW. Is there a better way to administer heartworm adulticidal therapy? Vet Med 2003; 98:310-317.

References

  1. McCall JW, Genchi C, Kramer L, et al. Heartworm and Wolbachia: Therapeutic implications. Vet Parasitol 2008; 158:204-214.
  2. Rossi MI, Pavia J, Mendes-de-Almeida, et al. Effects of doxycycline on the endosymbiont Wolbachia in Dirofilaria immitis (Leidy, 1856)—naturally infected dogs. Vet Parasitol 2010; 174:119-123.
  3. Bazzocchi C, Mortarino M, Grandi G, et al. Combined ivermectin and doxycycline treatment has microfilaricidal and adulticidal activity against Dirofilaria immitis in experimentally infected dogs. Int J Parasitol 2008; 38:1401-1410.
  4. Kramer L, Grandi G, Leoni M, et al. Wolbachia and its influence on the pathology and immunology of Dirofilaria immitis infection. Vet Parasitol 2008; 158:191-195.
  5. Bowman DD, Atkins CE. Heartworm biology, treatment, and control, in small animal parasites: biology and control. Vet Clin N Am Small Anim Pract 2009; 39:1127-1158.
  6. Grandi G, Quintavalla C, Mavropoulou A, et al. A combination of doxycycline and ivermectin is adulticidal in dogs with naturally acquired
    heartworm disease (Dirofilaria immitis). Vet Parasitol 2010; 169:347-351.
  7. Kramer L, Grandi G, Passeri B, et al. Evaluation of lung pathology in dogs treated with doxycycline or a combination of doxycycline and ivermectin before administration of melarsomine dihydrochloride (Immiticide). Vet Parasitol 2008; 158:191-195.
  8. McCall JW, Kramer L, Genchi C, et al. Effects of doxycycline on early infections of Dirofilaria immitis in dogs. Vet Parasitol 2011; 176:361-367.
  9. Guidelines of the American Heartworm Society, 2012; heartwormsociety.org.

ClarkeAtkinsClarke Atkins, DVM, Diplomate ACVIM (Internal Medicine & Cardiology), is the Jane Lewis Seaks Distinguished Professor of Companion Animal Medicine at North Carolina State University. He is also a member of the Today’s Veterinary Practice Editorial Peer Review Board and American Heartworm Society’s Executive Board. Dr. Atkins received the 2004 Norden Award recipient for excellence in teaching. His research involves canine and feline heartworm disease and pharmacologic therapies for cardiac disease. Dr. Atkins received his DVM from University of California–Davis and completed his internship at Angell Memorial Animal Hospital in Boston, Massachusetts.

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