Doxycycline

(doxycycline hyclate/hydrochloride [used in the injectable form, tablets and capsules], doxycycline monohydrate [used in oral powder for reconstitution], doxycycline calcium [used in oral syrup form])

Brands

Vibramycin, Vibra Tabs, Vibravenos Tetracycline (long acting injectable form of Doxycycline).

Availability

Tablets/Capsules (hyclate/hydrochloride and monohydrate): 50 mg, 100 mg
Suspension (monohydrate): 5 mg/mL in 60mL bottles
Powder for injection in 100 mg vials, 200 mg vials.

Pharmacology

Doxycycline is a bacteriostatic, semi-synthetic tetracycline derived from oxytetracycline. It is seen as a hydrochloride in injectable, or oral form, and monohydrate as an oral powder that is reconstituted.

Tetracyclines, as a class, generally act as broad-spectrum bacteriostatic agents inhibiting protein synthesis by reversibly binding to the 30S subunit of bacterial ribosome; thereby blocking access of aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex preventing the growth of susceptible bacterial organisms. They are also believed to reversibly bind to 50S ribosomes, plus altering the permeability of cytoplasmic membrane in susceptible organisms.¹

Doxycycline, and to a lesser degree the other tetracyclines, have been shown to exhibit anti-inflammatory properties, down regulating proinflammatory cytokines and chemokines possibly by direct inhibition of nitrate release. This anti-inflammatory action, not mediated by way of glucocorticoid or antihistaminic pathways, can help to decrease inflammation thus opening airways in chronic respiratory disease of rats.²^,³^,⁴^,⁶

Of the tetracyclines, doxycycline and minocycline are the most lipid soluble thus allowing them to penetrate body tissues and fluids, passing easily through the lipid bilayer of bacteria and limiting bacterial proliferation.^2,³ Both doxycycline and minocycline are virtually completely absorbed in the GI tract, when taken orally, and are not noticeably impaired when taken with food or dairy. As with minocycline, blood levels of doxycycline are sustained longer providing a longer half-life than other tetracyclines. The longer half-life, and better central nervous system penetration of both doxycycline and minocycline, compared with other tetracyclines, tend to make them a preferred drug choice, of the tetracyclines, in small animals.
*Note: animal studies indicate that the tetracyclines cross the placenta and penetrate fetal tissue, as well as being excreted in breast milk. It is recommended that it not be given in pregnancy or during lactation.

Doxycycline, as well as minocycline, are uniquely eliminated through the GI tract and excreted primarily in the feces in an inactive form, and therefore do not adversely affect intestinal flora making it less likely to cause diarrhea. They are also excreted through the kidneys to a lesser extent than other tetracyclines, making them a drug of choice where there is a history of renal insufficiency.

The fact that both doxycycline and minocycline have almost complete absorption, a long half-life, and slow excretion permits once daily dosing where appropriate.

Indications

Useful in treating infections caused by Mycoplasma pulmonis, spirochetes, chlamydia and rickettsia; doxycycline is the antibiotic of choice in the treatment of both acute and chronic upper and lower respiratory infection, in rats, involving susceptible organisms.

In acute and chronic respiratory disease Doxycycline may be given orally, or by injection, simultaneously with the antibiotic enrofloxacin (Baytril), or azithromycin (Zithromax), or amoxicillin. Doxycycline may also be used simultaneously with oral bronchodilators (e.g., theophylline or aminophylline), or with nebulized treatments of gentamicin and/or albuterol in normal or 7% saline.

Doxycycline may be used in some infections where Gram-positive strains of staphylococcus and streptococci are susceptible. It may also be used in some soft tissue infections, and urinary tract infections, resulting from Gram-negative bacteria, and in the treatment of gastric and duodenal disease caused by Helicobacter pylori.

Drug Interactions or Contraindications

The class of tetracyclines can have impaired absorption when given with antacids that contain aluminum, calcium, zinc, or magnesium, or with iron containing preparations (e.g., multivitamins). Although doxycycline, compared to other tetracyclines, has the least affinity for calcium ions, it is still being recommended to give 2 hours before or after those cation-containing products.
Bacteriostatic tetracycline drugs may interfere with the bactericidal effect of the penicillins, cephalosporins, and the aminoglycosides. However, there continues to be discussion regarding whether this interaction is clinically significant.¹
Doxycycline can increase levels/toxicity of oral digoxin.
Doxycycline has been shown to retard fetal skeletal development. It is not recommended to give in rats under 4 months of age, or to pregnant animals unless the benefit outweighs the risk.

Adverse Reactions

Blood: neutropenia, eosinophilia

CNS: increased intracranial pressure, seizures

GI: diarrhea

Skin: phlebitis, itching, abscess from injectable

Other: hepatotoxicity

Dosage Recommendations

2.5 mg/lb, PO, BID. *Note: 100 mg capsule in 4mL water/fresh daily = .10mL/lb given for 14 to 30 days (as recommended on RMCA Drug Chart) ⁴

or

5 mg/kg, PO, q12hr, ¹^, ³⁴^, ⁴²

Doxycycline 5 mg/kg, PO, + , Enrofloxacin 10 mg/kg, PO, q12hr in rats with mycoplasma / chronic respiratory infection. ²⁷^, ³⁴^, ⁴¹^, ⁴⁴

5 mg/kg to 10 mg/kg, PO, q12hr ¹^,²^,^{(see also “Consultants” below)}^, ³⁸. In CRD (chronic respiratory disease) administration can be given over the course of several weeks (i.e., do not stop after 4, 6 or 8 weeks), and may be maintained thereafter on long term low dosing.². *Note: see “Doxycycline in Treatment Regimen”, in this monograph, below.

Long acting injectable Vibravenos:
70 mg/kg to 100 mg/kg, SQ or IM; once every 7 days. ²⁶^, ²⁷^, ²⁹^, ³⁴^, ⁴¹^, ⁴⁴^, ²

Long acting injectable Vibravenos:
70 mg/kg, SQ or IM; once every 7 days (as derived from ⁶; and as recommended by Animal Medical Center Manhattan).

Doxycycline in Treatment Regimen

The following dosage guideline for use of doxycycline in rats with early or mild URI suspected to have Mycoplasma as the pathogen, is recommended by Dr. Michael Hutchinson, DVM; Animal General, Cranberry Township, PA. ¹⁸, and is based on his experience treating rats and current literature:

Doxycycline 5 mg/kg, PO (oral), q12hr for 10-30 days.
If not responding in reasonable time frame, give along with enrofloxacin.

For moderate to serious and advanced lung infection:

Doxycycline at 10 mg/kg³⁸, q12hr, along with enrofloxacin at 15 mg/kg ³⁴^, ³⁵, q12hrs, and add nebulized treatments with gentocin and albuterol. In addition, include dexamethasone in the treatment regimen.
For treatment regimen recommended by Dr. Hutchinson, see articles Mycoplasma or Pneumonia in the Health section of the Rat Guide. Also see individual monographs for more information on the above drugs in the Medication section of the Rat Guide.

*Note: In rats with respiratory illness, where the suspected pathogen is believed to be mycoplasma, the use of doxycycline in combination with enrofloxacin has been found to be effective at controlling clinical signs of illness. ¹⁸

Considerations

Doxycycline may be given with food or dairy. Reports indicate that doxycycline appears to be only 20% hindered by the intake of food or dairy and is not deemed clinically significant. ⁶
Although the manufacturer states that it does not affect the GI flora it is recommended that a probiotic containing lactobacillus be given, such as Bene-Bac, if the drug is used in conjunction with other antibiotics that adversely affect normal GI flora.
In treating suspected polymicrobial infections, where a broader coverage may be needed, synergistic or combination drugs may be used. The following drugs may be seen used simultaneously with doxycycline: fluoroquinolones (e.g., enrofloxacin or ciprofloxicin) ¹, or azithromycin, or amoxicillin, or aminoglycosides (e.g., amikacin or gentamicin); or clindamycin.
Please note that it is imperative to discuss the changing or adding of any medications during your rat’s treatment with your veterinarian to prevent future resistance of microbes to the drugs prescribed.
Reconstituted monohydrate oral suspension in water can be stored at room temperature for 14 days. Stability can not be guaranteed beyond the 14th day.
If mixing tablets or capsules in water, stability ranges from 12 to 48 hours. It is advisable to mix fresh daily. While some 2002 literature indicates that it may remain stable for up to 14 days if refrigerated, other studies show that the stability of doxycycline concentration compounded from commercial tablets or capsules in water can not be assured after 7 days.¹⁰
Powder if stored in tightly closed container is stable for up to one year.
Reconstituted Doxycycline Hyclate/Hydrochloride, and long acting Vibravenos should be refrigerated and kept for 72 hours following reconstitution.
While it is important to note that use of decomposed tetracyclines may cause potentially fatal nephrotoxicity (Fanconi’s or Fanconi’s-like syndrome) due to formation of anhydro-4-epitetracycline, a product of degradation; the absence of a hydroxyl group in C-6 prevents formation of the nephrotoxic compound in doxycycline. However, it remains strongly recommended to discard any outdated (expired) or decomposed medications properly.

Consultants

Michael Hutchinson, DVM. Animal General, Cranberry Township, PA.
Thomas M. Donnelly, DVM, DACLAM |Warren Institute | 712 Kitchawan Rd, Ossining NY 10562-1118 USA

Reference

Plumb, D. (2008). Doxycycline. Plumb’s Veterinary Drug Handbook (6th ed., p. 331). Stockholm, Wis.: PharmaVet.
Donnelly TM. Symposium Konijnen & Knaagdieren (Rabbit & Rodents Symposium). Held November 27-29, 2008, Burgers Zoo, Arnhem, Netherlands. Proveto, Utrecht, Netherlands (2008). What are treatment options for Mycoplasma pulmonis in rats?
Dalvi, P., Singh, A., Trivedi, H., Ghanchi, F., Parmar, D., & Mistry, S. (2011). Effect of doxycycline in patients of moderate to severe chronic obstructive pulmonary disease with stable symptoms. Ann Thorac Med, 6(4), 221-6. Retrieved April 13, 2012, from http://www.thoracicmedicine.org/text.asp?2011/6/4/221/84777
Krakauer, T., & Buckley, M. (2003). Doxycycline is anti-inflammatory and inhibits staphylococcal exotoxin-induced cytokines and chemokines. Antimicrob Agents Chemother, 47(11), 3630-3.
Leite, L., Carvalho, A., Brito, G., Viana, G., Ferreira, P., Pessoa, I., et al. (2011). Anti-inflammatory properties of doxycycline and minocycline in experimental models: an in vivo and in vitro comparative study. Inflammopharmacology, 19(2), 99-110.
Hoyt, J., Ballering, J., Numanami, H., Hayden, J., & Robbins, R. (2006). Doxycycline modulates nitric oxide production in murine lung epithelial cells. J Immunol, 176(1), 567-72. Retrieved April 13, 2012, from https://www.jimmunol.org/content/176/1/567.full.html#ref-list-1 .
Quesenberry, K., & Carpenter, J. (2012). Ferrets, Rabbits, and Rodents, Clinical Medicine and Surgery (Third Edition ed.). St. Louis: Saunders.
Doxycycline. (n.d.). Retrieved December 12, 2008, from www.ashp.org/s_ashp/docs/files/practice_and_policy/doxycycline.pdf.
Vibramycin (doxycycline calcium, doxycycline hyclate, doxycycline monohydrate) U.S. Physician Prescribing Information. (n.d.). Retrieved December 12, 2008, from http://media.pfizer.com/files/products/uspi_vibramycin_vibra-tabs.pdf.
Redelsperger, I. M., Taldone, T., Riedel, E. R., Lepherd, M. L., Lipman, N. S., & Wolf, F. R. (2016). Stability of doxycycline in feed and water and minimal effective doses in tetracycline-inducible systems. Journal of the American Association for Laboratory Animal Science : JAALAS, 55(4), 467–474. PMID: 27423155; PMCID: PMC4943619.
Papich, M. G., Davidson, G. S., & Fortier, L. A. (2013). Doxycycline concentration over time after storage in a compounded veterinary preparation, Journal of the American Veterinary Medical Association, 242(12), 1674-1678. https://doi.org/10.2460/javma.242.12.1674

revised 2012, 2020, 2021