Macrolide Antibiotic (Systemic Drug)
- Oral and parenteral macrolide antibiotics; potentially useful for treating a variety of bacterial infections in veterinary patients; not effective for treating Chlamydophila felis or Mycoplasma haemofelis infection in cats.
- Long tissue half-lives in dogs and cats.
- Contraindications include hypersensitivity to macrolides.
- Caution is advised with hepatic disease.
- Azithromycin is considered to be relatively safe during pregnancy in humans.
- Azithromycin is a common and cost-effective in the treatment of community-acquired pneumonia.
- Widely available in single dose packet form.
- Ineffective against viral infections (such as the common cold, flu).
- Adverse effects include potential GI effects (eg, anorexia, vomiting, diarrhea), but fewer as compared with erythromycin. 1
Azithromycin has a broad spectrum and favorable pharmacokinetic profile, and is used to treat a variety of bacterial, rickettsial, and parasitic infections in veterinary patients. It is often used to treat respiratory infections, skin infections and ear infections.
Azithromycin has some anti-inflammatory and immunomodulatory effects 2,3; however, the clinical relevance of these effects in veterinary species is unknown. Azithromycin has GI promotility properties in humans and has been used anecdotally as a prokinetic in dogs and cats. 4
Among prescription drugs, azithromycin is anecdotally used in cats with recurrent and refractory rhinosinusitis; however, it is best reserved for select cases (ie, when chlamydiosis is not likely and other antimicrobial agents [eg, doxycycline, amoxicillin] are not viable options) and has not been recommended for routine use in these patients. 5
Azithromycin has potential in the treatment of Rhodococcus equi infections in foals. Although azithromycin’s pharmacokinetics support oral dosing in adult horses, concerns for potential antimicrobial-associated enterocolitis indicate necessary caution when using this drug in adult horses. 6 The World Health Organization (WHO) has designated azithromycin as a Critically Important, Highest Priority antimicrobial for human medicine. 7
Azithromycin is primarily used to treat certain bacterial infections in dogs, cats and horses.
Azithromycin inhibits protein synthesis by penetrating bacterial cell walls and binding the 50S ribosomal subunits in susceptible bacteria. Azithromycin is a bacteriostatic antibiotic. Azithromycin can accumulate and persist in macrophages, neutrophils, and pulmonary epithelial lining fluid.
Azithromycin has a relatively broad spectrum with in vitro activity (does not necessarily indicate clinical efficacy) against gram-positive (eg, Streptococcus pneumoniae, Staphylococcus aureus ), gram-negative (eg, Haemophilus influenzae, Bartonella spp, Bordetella spp), and other organisms (eg, Mycoplasma pneumoniae, Borrelia burgdorferi ).
Azithromycin’s antiprotozoal effect against Babesia spp and Toxoplasma spp is through inhibition of apicoplast (ie, DNA-containing organelles) protein translation, which results in protozoal progeny death. 8
Azithromycin has been used to treat cryptosporidiosis in various species, but there is limited understanding of its potential efficacy for this use. In immunocompromised humans, 9 azithromycin has been shown to improve clinical symptoms related to infection but does not have an effect on Cryptosporidium shedding. It is unclear if azithromycin may have a similar result when used in animals. A positive effect on clinical signs and oocyst shedding has been identified in calves. 10 Azithromycin combined with toltrazuril was more effective than either agent alone in promoting rapid clinical recovery in calves with cryptosporidiosis. 11
Azithromycin combined with atovaquone appears to be effective in the treatment of dogs with Babesia gibsoni infections. 8,12-14 A combination of azithromycin and atovaquone was an effective treatment in dogs with piroplasmosis caused by B microti-like piroplasm 15 and theileriosis. 16
Azithromycin used alone or in combination with minocycline demonstrated efficacy against Pythium insidiosum in an experimental rabbit model.17
Azithromycin is ineffective in the treatment of Mycoplasma haemofelis or in the elimination of Chlamydophila felis in cats.
As compared with erythromycin, azithromycin has better absorption characteristics, longer tissue half-lives, and higher concentrations in tissues and WBCs. Concentrations of azithromycin are high in bronchial secretions, and azithromycin has excellent ocular penetration. 1
In dogs, azithromycin has 97% oral bioavailability. Peak serum concentration occurred ≈2 hours after oral administration. Tissue concentrations do not mirror serum concentrations after multiple doses. Serum half-life was ≈50 hours, and tissue half-lives in dogs may be up to 90 hours. Skin concentrations are 3.5 to 12 times higher than serum concentrations. 18 More than 50% of an oral dose is excreted unchanged in bile.19
In cats, azithromycin has 58% oral bioavailability and peak concentration was reached after 0.85 hours. Tissue half-lives are less than in dogs and range from 13 hours in adipose tissue to 72 hours in cardiac muscle. Cats excrete ≈66% of a dose unchanged in bile. 19
In foals, azithromycin is variably absorbed after oral administration, with a mean systemic bioavailability ranging from 40% to 60%. The effect of food on absorption is unclear. Azithromycin has a very high volume of distribution (11.6-18.6 L/kg). Elimination half-life is approximately 20 to 26 hours. The drug concentrates in bronchoalveolar cells and pulmonary epithelial fluid. Elimination half-life in polymorphonuclear leukocytes is approximately 2 days. 20-22 In adult horses, intragastric administration (tablets suspended in 500 mL of water) resulted in an average oral bioavailability of 45%, with peak levels occurring ≈1 hour after administration. Plasma elimination half-life after IV dosing was ≈18 hours. Plasma concentrations after a single intragastric dose remained above MIC90 for 6 to 12 hours for β-hemolytic streptococci, Pasteurella spp , and Staphylococcus spp. For these bacteria, intracellular concentrations of azithromycin in alveolar macrophages were above MIC90 for at least 48 hours and in neutrophils for at least 120 hours after a dose. 7
In goats, azithromycin has an elimination half-life of 32.5 hours (IV) and 45 hours (IM), an apparent volume of distribution (steady-state) of 34.5 L/kg, and a clearance of 0.85 L/kg/hour. 23
In sheep, azithromycin has an average elimination half-life of 48 hours (IV) and 61 hours (IM), an apparent volume of distribution (steady-state) of 34.5 L/kg, and a clearance of 0.52 L/kg/hr. 24
In rabbits, azithromycin has an elimination half-life of 24.1 hours (IV) and 25.1 hours (IM). IM injection has a high bioavailability but causes some degree of muscle damage at the injection site. 25
Contraindications / Precautions:
Azithromycin is contraindicated in animals hypersensitive to any macrolide antibiotic. Caution should be used when using azithromycin in patients with impaired hepatic function because it is primarily eliminated via liver metabolism.
Prolonged QT intervals can occur with use of azithromycin, which increases the risk for cardiac arrhythmias, including torsades de pointes. Caution should be used when combining azithromycin with other medications (eg, azole antifungals, cisapride, dolasetron, moxifloxacin, erythromycin, ondansetron) that may prolong QT intervals.
Exacerbations of symptoms related to myasthenia gravis or a new onset of syndromes have been reported in human patients. The clinical significance in veterinary patients is unknown.
Prescription order errors for azithromycin and azathioprine have occurred. Use of tall man letters (eg, aZITHROmycin, azaTHIOprine) may reduce the risk for errors. 1
Azithromycin can cause vomiting, reduced appetite, and diarrhea in small animals. As compared with erythromycin, azithromycin has significantly fewer GI adverse effects. Local reactions have occurred in patients receiving IV azithromycin.
In a preliminary study in horses, azithromycin (10 mg/kg PO once daily for 5 days) was observed to have no life-threatening adverse effects. Anhidrosis has been noted in foals but appears to be less significant than with erythromycin. 26 Some self-limiting GI side effects (eg, decreased appetite, change in fecal consistency) were observed, which raises concerns for potential serious antimicrobial-associated enterocolitis. 6
The following drug interactions with azithromycin have either been reported or are theoretical in humans or animals and may be of significance in veterinary patients.
- AMIODARONE: Increased risk of QT prolongation when combined with azithromycin
- ANTACIDS, ORAL (eg, magnesium- and aluminum-containing): May reduce the rate of absorption of azithromycin; administration is suggested to be separated by 2 hours
- AZOLE ANTIFUNGALS (eg, ketoconazole, voriconazole): Azithromycin may prolong QT intervals. This effect may be increased when combined with other agents that also prolong QT intervals and/or alter azithromycin metabolism.
- CISAPRIDE: No data exist on azithromycin, but other macrolides (eg, clarithromycin) are contraindicated with cisapride due to risk of QT prolongation; caution is advised.
- CYCLOSPORINE: Azithromycin may increase cyclosporine blood levels; careful monitoring is necessary.
- DIGOXIN: Increased risk for digoxin toxicity when used concurrently
- ESTRIOL: Azithromycin may decrease estriol’s therapeutic effect.
- LEFLUNOMIDE: Azithromycin may increase risk of hepatotoxicity.
- METHOTREXATE: Azithromycin may increase methotrexate levels and risk of hepatotoxicity.
- ONDANSETRON: Increased risk of QT prolongation when combined with azithromycin
- P-GLYCOPROTEIN SUBSTRATES (eg, colchicine, doxorubicin, vincristine): Azithromycin inhibits p-glycoprotein transport mechanisms and may increase serum concentrations of certain substrates mediated by this transport system.
- PHENYTOIN: Azithromycin may increase phenytoin blood levels; careful monitoring is necessary.
- PROCAINAMIDE: Increased risk of QT prolongation when combined with azithromycin
- QUINIDINE: Increased risk of QT prolongation when combined with azithromycin
- QUINOLONES: Increased risk of QT prolongation when combined with azithromycin
- QT PROLONGATION (eg,azole antifungals [ketoconazole, voriconazole], dolasetron, moxifloxacin, erythromycin, ondansetron): Azithromycin may prolong QT intervals. This effect may be increased when combined with other agents that also prolong QT intervals.
- SOTALOL: Increased risk of QT prolongation when combined with azithromycin
- TACROLIMUS: Azithromycin may increase tacrolimus blood levels; careful monitoring is necessary.
- THEOPHYLLINE: Azithromycin may reduce theophylline metabolism and increase risk of toxicity.
- WARFARIN: Increased risk for bleeding; careful monitoring is necessary. 1
- Signs of an allergic reaction to azithromycin may include hives, difficult breathing, swelling in the face or throat, a severe skin reaction, fever, sore throat, skin tenderness or skin rash. Call your doctor or veterinarian in the event that these symptoms appear.
- Azithromycin persisted in breast milk up to 48 hours after a dose with a median breast milk concentration of 1713 mcg/L at a median of 30.7 hours after the dose.
- According to the Food and Drug Administration (FDA), azithromycin may trigger an irregular heart rhythm in some patients.
- In rare cases, azithromycin can cause liver problems, particularly if there is preexisting liver disease.
Dogs: Susceptible infections (extra-label) - There is significant variability in anecdotal dosing recommendations. Most recommendations are 5 – 10 mg/kg PO once daily for 3 to 7 days. Because of the drug’s pharmacokinetics, after a few days of once-a-day dosing, some recommend every-other-day dosing or giving higher dosages (eg, 10 – 15 mg/kg) twice per week; these dosing regimens may be effective for longer-term treatment of some infections. 10 mg/kg PO every 24 hours for 3 days, weekly, has been recommended for skin infections, 18 although clinical data are lacking and azithromycin is not a recommended drug in recent superficial bacterial folliculitis guidelines. 27
Babesia gibsoni or B microti (extra-label): Azithromycin 10 mg/kg PO every 24 hours with atovaquone 13.3 mg/kg PO every 8 hours with a fatty meal for 10 days. Reserve immunosuppressive therapy for cases not rapidly responding (3-5 days) to antiprotozoal therapy. 11,13,14,27
Theileriosis (extra-label): Azithromycin 10 mg/kg PO every 24 hours with atovaquone 13.3 mg/kg PO every 8 hours with a fatty meal for 10 days. 16
Cryptosporidiosis (extra-label): 5 – 10 mg/kg PO twice daily for 5 to 7 days. 29
GI promotility (extra-label): 2 mg/kg IV, PO every 8 hours.4
Reducing gingival hyperplasia caused by cyclosporine (extra-label): 10 mg/kg PO once daily for 4 to 6 weeks. 29,30
Cats: Susceptible infections (extra-label) - There is significant variability in dosing recommendations. Most recommend 5 – 10 mg/kg PO every 24 hours for 3 to 7 days. Some infections require longer treatment durations (see below). Based on the drug’s pharmacokinetics, after a few days of once daily dosing, some recommend every 48 hours dosing or giving higher dosages (eg 10 – 15 mg/kg) twice weekly; these dosing regimens may be effective for longer-term treatment.
Sample indications and treatment recommendations follow:
a) Upper respiratory infections (extra-label): 5 – 10 mg/kg PO every 24 hours for 5 days, then every 72 hours (ie, every 3rd day) long-term. After an initial positive response to azithromycin, therapy should be continued for 6 to 8 weeks without changing the antibiotic. 32
b) Bartonellosis (extra-label): 10 mg/kg PO every 24 hours for 21 days. Response to therapy is rapid; most cats with anterior uveitis will show significant improvement in less than one week. Recurrence after 21 days of treatment with good flea control is low. Treatment failure in Bartonella positive cats indicates a polymicrobial disease syndrome. 33
c) Cryptosporidiosis (particularly in cats that are intolerant or nonresponsive to tylosin) (extra-label): 10 mg/kg PO every 24 hours; optimal duration of therapy is unknown but is usually several weeks. 34
d) Toxoplasmosis (extra-label): 10 mg/kg PO every 24 hours for a minimum of 4 weeks. 35
e) Cytauxzoonosis (extra-label): Azithromycin 10 mg/kg PO every 24 hours combined with atovaquone 15 mg/kg PO every 8 hours for 10 days. 36,37
f) GI promotility (extra-label): 2 mg/kg IV, PO every 8 hours. 4
Horses: Rhodococcus equi in foals (extra-label) - 10 mg/kg PO every 24 hours. Based on the drug’s pharmacokinetics, (persistence in bronchoalveolar cells and pulmonary epithelial lining fluid) after 5 days of once daily treatment, consideration should be given for every 48 hours dosing in foals responding to treatment. Some protocols combine azithromycin therapy with rifampin 5 mg/kg PO every 12 hours.
Cattle: Cryptosporidiosis in calves (extra-label) - Azithromycin 20 mg/kg PO once daily for 6 days combined with toltrazuril 20 mg/kg PO every other day for 3 treatments. 10 Alternatively, azithromycin 1500 mg per calf (NOT mg/kg) PO once daily for 7 days. 10
Rabbits: Staphylococcal osteomyelitis (extra-label) - Azithromycin 50 mg/kg PO every 24 hours with rifampin 40 mg/kg PO every 12 hours. 38
Jaw abscesses (extra-label): 15 – 30 mg/kg PO every 24 hours. Systemic antibiotic treatment is continued for 2 to 4 weeks postoperatively. Owners need to be advised to discontinue treatment if anorexia or diarrhea occurs. 39
Guinea Pigs: Pneumonia (extra-label) - 15 – 30 mg/kg PO every 24 hours. Owners need to be advised to discontinue treatment if soft stools develop. 40
Birds: Chlamydiosis (study done in experimentally infected cockatiels) (extra-label) - 40 mg/kg PO every 48 hours for 21 days (as effective as a 21- or 45-day treatment with doxycycline). Dosed via metallic feeding tube into crop using commercially available human oral suspension. 40
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