Drug Therapy

Antibiotics for Upper Respiratory Tract Disease

Empiric antibiotic therapy is often used in animals with presumed respiratory infection prior to obtaining definitive information on the bacteria involved because susceptibility results take 2–5 days to become available or because of an inability to obtain an appropriate sample. Treatment of presumed infections of the upper or lower respiratory tract requires knowledge of the normal flora found in these locations as well as an understanding of the species most likely to be pathogenic. In kittens with acute (likely viral) upper respiratory disease, flora of the upper respiratory tract (Staphylococcus, Streptococcus, Pasteurella, Bordetella, and anaerobes) may overwhelm local defenses and colonize the nasal cavity, leading to clinical signs of sneezing and mucopurulent nasal discharge. Antibiotics are commonly administered for 1–2 weeks to kittens with acute upper respiratory infection to reduce bacterial numbers and decrease bacterial invasion of epithelium damaged by viral infection. Fortunately, many commonly encountered bacterial strains remain susceptible to amoxicillin–clavulanic acid or to fluoroquinolones (Dossin et al. 1998). Azithromycin also has clinical efficacy for acute feline upper respiratory tract infection. It is important to remember that penicillin derivatives are ineffective against Mycoplasma spp., a cell-wall-deficient bacteria. Because this organism can be found in acute feline upper respiratory disease, use of doxycycline or a fluoroquinolone would be appropriate.

In chronic upper respiratory tract disease in the cat, aerobic bacterial infection is a common complication (Johnson et al. 2005). The chronic disease is typically characterized by devitalization of tissue with accumulation of inflammatory products, and resolution of disease is difficult to achieve. Doxycycline and azithromycin are attractive drugs to use in such cases because they possess anti-inflammatory effects as well as antimicrobial action. A fluoroquinolone is a rational antibiotic choice for some cases because these drugs have excellent efficacy against most Gram-negative bacteria and Mycoplasma. However, a high dose may be required for successful treatment of Pseudomonas infections, and this is not advisable in cats because of potential retinal toxicity. Newer fluoroquinolones (pradofloxacin and premafloxacin) also have some efficacy against anaerobic organisms. For cats with underlying osteomyelitis or suspected anaerobic infections, a drug such as clindamycin could be more effective in controlling clinical signs since it penetrates bone tissue.

When treating the bacterial component of feline upper respiratory tract disease, consideration should be given to using a long course (4–6 weeks) of antibiotics to achieve maximal control of bacterial numbers. In some cases, chronic use of antibiotics is required.

Bacterial involvement in canine inflammatory rhinitis appears to be less prominent than in the feline syndrome, although few studies have evaluated isolation rates in dogs with nasal discharge (Windsor et al. 2004). Secondary bacterial infection can develop in dogs that have been treated for nasal aspergillosis infections because of destruction of turbinates and loss of normal nasal defense mechanisms. In those cases, 7–10 days of any broad-spectrum antibiotic (e.g., amoxicillin-clavulanic acid) can help alleviate nasal discharge, although it will often recur.

Antibiotics for Lower Respiratory Tract Disease

Lower respiratory tract infection can be life-threatening and antibiotics should be based on culture and susceptibility testing whenever possible. However, when culture results are pending or when airway sampling is not clinically feasible, initial antibiotic choices must consider the likely species involved and reported susceptibility patterns of commonly encountered bacteria (Table 3.1).

Appropriate therapy for bacterial respiratory infection often requires antibiotics directed at Gram-negative and -positive aerobes, anaerobes, and Mycoplasma organisms. Rational choices for initial therapy of newly diagnosed infections (before final culture results are available) would include enrofloxacin with a penicillin drug, metronidazole, or clindamycin. Ticarcillin, a carboxypenicillin formulated only for intravenous use, is a valuable drug to employ in early treatment of pneumonia. It has improved efficacy in treatment of Pseudomonas infection as well as anaerobic infections; however, it is ineffective against Mycoplasma spp. Ticarcillin-clavulanate bypasses beta-lactamase resistance mediated by plasmids. Anaerobic susceptibility testing is rarely performed because organisms are difficult to grow on susceptibility plates however most are sensitive to penicillins. Bacteroides spp. are relatively resistant to clindamycin therapy (Jang et al. 1997) and penicillin, metronidazole or chloramphenicol would be better choices when infection with this anaerobe is documented. Chloramphenicol has excellent efficacy against a number of organisms commonly implicated in respiratory infection; however, use of this drug may be associated with central nervous system depression, anorexia, vomiting, or bone marrow suppression. Lower respiratory tract infections require 2–6 weeks of antibiotic treatment, and long-term therapy should be determined by results of bacterial culture and sensitivity in complicated cases.

Azalides (azithromycin and clarithromycin) have efficacy against Gram-positive and Gram-negative organisms and Mycoplasma. These drugs have the advantage of producing high and prolonged tissue levels, typically resulting in enhanced bacterial killing. Recent studies in the cat showed variability in drug half-life, but relatively high bioavailability (58%) and sustained accumulation of drug in tissues after a single oral dose of 5.4 mg/kg (Hunter et al. 1995). The efficacy of azithromycin in feline respiratory diseases is not yet known; however, its pharmacokinetic properties and pulmonary penetration could prove valuable in the treatment of respiratory infections. In general, antibiotic treatment should be used for immediate control of infectious lung disease; however, in some situations, chronic antibiotic therapy or intermittent pulse therapy with antibiotics may be required to control clinical signs in dogs with bronchiectasis and animals with ciliary dyskinesia. In these disorders, mucus accumulation with trapping of bacteria in secretions can result in severe and recurrent pneumonia. The antibiotic chosen should have proper efficacy, should penetrate the airway, and should be relatively free of side effects.

Table 3.1. Gram-stain characteristics and antibiotic susceptibility for common bacteria

Table 3.2. Side effects of commonly used antibiotics

If a fluoroquinolone is needed in an animal that is being treated with theophylline, it is important to note that this class of drug inhibits the metabolism of theophylline, and use of the two drugs together results in toxic plasma levels (Intorre et al. 1995). At least 30% reduction in theophylline dose is recommended when a fluoroquinolone is used concurrently.

Side Effects of Antibiotics

Virtually any antibiotic can be associated with gastrointestinal complaints of vomiting, diarrhea, or anorexia. Other important side effects are listed in Table 3.2.

Antifungal Therapy

Fungal infection in the respiratory tract most commonly involves Cryptococcus neoformans or Aspergillus fumigatus in the nasal cavity of cats or dogs, respectively, and Histoplasma capsulatum, Blastomyces dermatitidis, or Coccidioides immitis organisms in the lower respiratory tract. Nasal aspergillosis is a special condition, which appears to respond best to extensive debridement of fungal plaques and topical antifungal therapy (see Chapter 4). When treating fungal respiratory tract infection, long-term therapy (6 weeks to over 12 months) must be anticipated. Depending on the severity of disease, the presence of concurrent illness and the initial response to therapy, fungistatic or fungicidal agents administered orally or parenterally should be chosen (Table 3.3).

The azoles (itraconazole, fluconazole, voriconazole, posaconazole) are fungistatic agents that inhibit P450 enzymes involved in synthesis of ergosterol, a key component of the fungal cell wall. Itraconazole (Sporanox^®, Janssen Pharmaceuticals, Inc.) can be used as sole therapy for nasal or pulmonary fungal infection or can be used following amphotericin B for sustained control of disease. Itraconazole is excreted by the liver, and side effects of therapy include hepatic toxicity, dermatotoxicity, and anorexia. Fluconazole is available in generic form. It is renally excreted thus a reduced dosage is recommended for animals with renal insufficiency. Voriconazole (Vfend^®, Pfizer) and posaconazole (Noxafil^®, Schering-Plough) are new triazoles with improved antifungal activity.

Table 3.3. Antifungal drug therapy

Terbinafine is an allylamine fungistatic agent that is thought to act through inhibition of squalene epoxidase during the synthesis of ergosterol for the fungal cell membrane. Side effects are apparently rare. Flucytosine is a pyrimidine analog that also inhibits fungal synthesis. It is used only in combination with other antifungal agents because it is a relatively weak antifungal and because of rapid development of resistance. It is indicated primarily for treatment of central nervous system cryptococcosis.

Amphotericin B is a fungicidal drug that creates breaks in the fungal cell membrane. Because it is highly nephrotoxic, aggressive diuresis with 0.9% saline (20–40 mg/kg over 1–3 hours) is recommended prior to administration. After saline diuresis, the infusion line is flushed with 5% dextrose to avoid precipitation of the amphotericin in saline. A central vein is recommended to avoid thrombophlebitis, and the drug should be protected from light during administration. A test dose of 0.5 mg/kg in 5% dextrose solution is administered intravenously over 5–6 hours on the first day of therapy. Body temperature is continually measured during the infusion because of the likelihood of a drug fever. On the day after administration, renal parameters are measured, and if values are within normal limits, a dose of 1.0 mg/kg can be administered on the following day. This regimen is continued until renal insufficiency necessitates discontinuation of therapy or until fungal disease is under control, which may require cumulative dosages of 5–14 mg/kg. If residual disease is suspected or the animal can no longer tolerate intravenous therapy, oral azole treatment is used for continual control of disease. Amphotericin B can also be administered subcutaneously in fractious animals, those that cannot be hospitalized, or those that cannot be treated with oral medications. Amphotericin B at a dose of 0.5–0.8 mg/kg is diluted in 400–500 mL of 0.45% NaCl/2.5% dextrose and administered subcutaneously two to three times weekly until disease has resolved.

To reduce the likelihood of renal insufficiency, administration of amphotericin B lipid complex is recommended. The drug is given as a 20–30-minute infusion of 0.5–1.0 mg/kg and pretreatment with saline diuresis is not a requirement. This drug is more expensive than standard amphotericin B and is formulated in a single-use vial.

Antiviral Therapy

Viruses (feline herpes virus-1: FHV-1; feline calicivirus: FCV) have been implicated as major etiologic agents in acute feline upper respiratory disease. Because clinical signs are generally self-limiting, specific diagnostic tests to identify infecting organisms are rarely performed and antiviral therapy is rarely used. In the chronic disease syndrome, presence of the upper respiratory viruses is poorly correlated with disease status. Clinical signs may be due to direct cytopathic effects mediated by the virus or due to the host’s immunologic response to infection. Lower respiratory tract disease due to viral infection is less common but may occur with some upper respiratory tract viruses or due to infection with the mutated coronavirus (feline infectious peritonitis virus: FIP). Many respiratory manifestations of feline infectious peritonitis virus are related to the host’s immunologic response and subsequent vasculitis, and definitive diagnosis of FIP remains difficult. Controversy surrounding viral pathogenesis of disease and diagnostic methods makes it difficult to determine whether antiviral therapy is warranted in suspect cases.

Efficacy of antiviral agents in clinical feline respiratory diseases has not been established, however, pharmacokinetics have been studied for some drugs. Acyclovir and valacyclovir, a prodrug of acyclovir, are not recommended because of poor efficacy against FHV-1 and unacceptable toxicity. The most promising drug for use against FHV-1-related ocular disease is famcyclovir, although this drug has not been evaluated specifically for chronic nasal disease in the cat. Supplementation with oral lysine (250–500 mg PO BID) might be helpful in kittens or cats with upper respiratory disease that is presumed to be viral in origin. Lysine competes with arginine in FHV-1 protein synthesis, and inhibition of synthetic activity decreases replication of the virus. Supplementation does not result in systemic arginine depletion and no side effects have been reported.

Viruses associated with canine infectious respiratory disease complex can cause severe pneumonia in dogs, however specific antiviral therapy has been investigated for use in canine viral pneumonias.

Glucocorticoids

Corticosteroids are indicated for long-term control of feline bronchial disease, chronic bronchitis, and canine eosinophilic lung disease. Corticosteroids reduce inflammation by inhibition of phospholipase A2, the enzyme responsible for the initial metabolism of arachidonic acid into inflammatory mediators. Corticosteroids also decrease migration of inflammatory cells into the airway, thus decreasing the concentration of granulocyte products and reactants (major basic protein, eosinophil cationic protein, reactive oxygen species), which perpetuate epithelial injury.

Short-acting oral steroids are preferred for treatment of inflammatory airway disease in the dog or the cat to allow an accurate titration of the dose that controls clinical signs while inducing minimal side effects. Prednisolone is the preferred steroid to use in the cat, while either prednisone or prednisolone can be used in the dog. Long-acting glucocorticoids such as dexamethasone, triamcinolone, and methylprednisolone acetate do not have a therapeutic advantage over prednisone, and use of a repositol steroid could result in waxing and waning of inflammation between injections that perpetuates disease. The duration and dose of corticosteroid therapy will depend upon the severity and chronicity of respiratory signs, the extent of the infiltrates on radiographs, and the degree of inflammation on cytology. An individualized approach to anti-inflammatory treatment is required for each case, with a gradual reduction in dose to the minimal level that controls clinical signs.

The length of therapy required to alleviate signs is unknown; however, long-term therapy (2–3 months for dogs with chronic bronchitis and 4–5 months for dogs with eosinophilic disease) can be anticipated in most cases. Discontinuation of medication may be possible, although many cats with inflammatory airway disease will require life-long medication continually or intermittently. If disease worsens during lowering of the dose, a return to the higher dose of glucocorticoid that controlled clinical signs is generally required. Alternately, treatment with inhaled steroids, bronchodilators, or antitussive agents can be added depending on the disease process (see later).

Bronchodilators

The two main classes of bronchodilators used in veterinary medicine are methylxanthine derivatives (theophylline) and beta-agonists. While these agents provide only mild relaxation of airway smooth muscle and bronchodilation, they can be clinically helpful in reducing signs in dogs or cats with bronchitis or in allowing a reduction in the dosage of glucocorticoid required to control signs.

Methylxanthines

Methylxanthine agents such as theophylline and aminophylline are used clinically as bronchodilators. Although known pharmacologically as a phosphodiesterase inhibitor, the dose of theophylline used clinically does not result in sufficient accumulation of cyclic adenosine monophosphate to cause smooth muscle relaxation. Current research suggests that the clinical effects of methylxanthines likely result from adenosine antagonism or from alterations in cellular sensitivity to calcium. Theophylline may provide other beneficial effects by increasing diaphragmatic muscle strength, improving pulmonary perfusion, reducing respiratory effort, and stimulating mucociliary clearance (in dogs, but not in cats). Studies evaluating pharmocokinetics of one brand of extended-release theophylline suggested a dose of 10 mg/kg PO every 12 hours in a dog and 15 or 19 mg/kg once daily in the evening for the cat to approximate the human therapeutic range of 10–20 mg/mL. (Bach et al. 2004, Guenther-Yenke et al. 2007). Most extended release theophylline products can be split in half once and will retain the extended release properties. It is unknown whether generic forms of sustained-release theophylline are bioequivalent to the form that has been studied; however, these products would be preferred over aminophylline, which is poorly bioavailable in dogs and cats.

Adverse effects of methylxanthines are likely related to adenosine antagonism and include gastrointestinal upset, tachycardia, and hyperexcitability. It is essential to individualize drug therapy because there is a wide variation in the dose that causes side effects. Theophylline metabolism is influenced by many factors, including fiber in the diet, smoke in the environment, congestive heart failure, and the use of other drugs. Because of concerns about metabolism and unknown bioavailability, a reduced dosage can be considered initially (5 mg/kg every 12 hours in a dog and 5–10 mg/kg once daily in the cat), and if the animal tolerates the drug, the dosage may be increased as needed.

Methylxanthines are relatively weak bronchodilators and while they may be beneficial for adjunctive therapy in control of clinical signs, they are not recommended for use in an acute or emergency situation.

Beta-agonists

Administration of a beta-2 agonist (terbutaline or albuterol) results in bronchodilation due to direct relaxation of airway smooth muscle, and intravenous terbutaline has been shown to reduce airway resistance acutely in cats with constricted airways (Dye et al. 1996). Preliminary pharmacokinetic studies have established the safety of the drug, and the recommended dose is 0.01 mg/kg parenterally or 0.625 mg/cat PO BID. Small dogs can receive 0.625–1.25 mg PO every 12 hours, medium-sized dogs are given 1.25–2.5 mg PO every 12 hours, and larger dogs receive 2.5–5 mg PO every 12 hours. Active bronchoconstriction does not play a role in canine chronic bronchitis as it does in a subset of cats with bronchitis; however, albuterol at 50 µg/kg PO every 8 hours was efficacious in reducing cough in almost half the dogs evaluated in a review of canine chronic bronchitis (Padrid et al. 1990). Interestingly, the bronchodilator also resulted in a reduction in the severity of the pulmonary infiltrate. Theoretically, chronic use of a beta-agonist can result in downregulation of beta-receptor density and decreased efficacy of the drug, although it is unclear if this is recognized clinically. As with methylxanthines, beta-agonists may result in excitability or tremors during initial therapy, but animals usually become accustomed to the drug. Beta-2 agonists can be administered orally and are widely available for inhaled therapy; however, prolonged use of specific forms of albuterol could potentially worsen airway inflammation (Reinero et al. 2009).

Mucolytics

Marked controversy exists concerning the utility of mucolytic agents in human medicine, and there is little information on the use or efficacy of these preparations in veterinary patients. Clinical experience suggests that some dogs and cats with excessive production of airway secretions associated with chronic infectious or inflammatory diseases may benefit from their use. Conditions that might respond to mucolytic agents include feline chronic rhinosinusitis, canine lymphoplasmacytic rhinitis, chronic bronchitis, bronchiectasis, and pneumonia-associated with production of viscous secretions (e.g., Mycoplasma).

Mucolytic/expectorant agents such as N-acetylcysteine, bromhexine, S-carboxymethylcysteine, ambroxol, guaifenesin, and iodinated glycerol can thin the viscosity of mucin-containing secretions. These drugs act by a variety of mechanisms including breakage of disulfide bonds in airway mucoproteins, stimulation of serous airway secretions, or breakdown of acid mucopolysaccharide fibers in sputum. N-acetylcysteine and S-carboxymethylcysteine can be administered orally or by inhalation, although nebulization with N-acetylcysteine may result in bronchoconstriction or epithelial injury and this route is not routinely recommended. The rest of these agents are designed for oral use. N-acetylcysteine is reported to provide a variety of antioxidant and endothelial effects that might prove beneficial in respiratory patients. N-acetylcysteine is typically available in 600 mg capsules, and an empiric dose of 30–60 mg/kg (not to exceed 600 mg) PO BID–TID can be clinically efficacious in improving evacuation of mucus.

Antitussive Agents

The cough reflex is of major importance in animals because it serves the essential function of clearing secretions from the airway. Suppression of this reflex before resolution of inflammation can be deleterious because mucus can become trapped in small airways, and prolonged contact between inflammatory mediators in the mucus and epithelial cells perpetuates airway injury. If infection is present, cough suppression can lead to serious pneumonia. When clinical signs suggest that inflammation is resolving yet the cough persists, cough suppression is desirable because chronic coughing can lead to repeated airway injury and syncopal events. Cough suppressants are used almost exclusively in dogs rather than cats, and are often required in dogs with airway collapse or irritant tracheitis.

Over-the-counter dextromethorphan-containing compounds are only occasionally efficacious in some animals with airway disease. When more potent suppression of a dry cough is required, narcotic agents should be prescribed. Hydrocodone bitartrate (0.22 mg/kg PO every 6–12 hours) or butorphanol tartrate (0.5 mg/kg PO every 6–12 hours) can be used in dogs. These agents must be given at an interval that suppresses coughing without inducing excessive sedation. The drugs are initially given at a high dose several times daily and tapered to the lowest dose that controls clinical signs. Long-term therapy may be required in some patients; however, overuse should be avoided since tolerance can develop.

Routes of Administration

Nebulization can also be used simply to hydrate airway secretions and facilitate removal from the lower airway. This can be very beneficial for animals that suffer from diseases resulting in excessive mucus production or pooling of secretions in the lower airways. Sterile 0.9% saline dispensed as single-use vials without addition of preservatives is used most commonly, although some nebulizers require sterile water. A small aquarium, animal carrier, or plastic container can be modified to allow introduction of the nebulized liquid and venting of exhaled carbon dioxide (Figure 3.1). One to four treatments per day can be administered as needed. Gentle exercise or coupage following nebulization will encourage evacuation of airway mucus when treating lower respiratory disease (Figure 3.2).

Figure 3.1 Nebulization is performed in a cat carrier covered in plastic by using an ultrasonic nebulizer that creates particles <5 µm in size.

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