Antibiotics for Upper Respiratory Tract Disease

Acute infectious upper respiratory tract disease in the cat is most commonly ascribed to viral infection, and when secondary bacterial invasion is suspected, empiric antibiotic therapy is often used initially. Flora of the upper respiratory tract (Staphylococcus, Streptococcus, Pasteurella, Escherichia coli, and anaerobes) can overwhelm local defenses and colonize the nasal cavity, leading to clinical signs of sneezing and mucopurulent nasal discharge. Other bacteria such as Chlamydia, Mycoplasma, Bordetella, and Streptococcus canis or Streptococcus equi var. zooepidemicus might act as primary pathogens. When purulent discharge is present or signs have been present for >10 days, antibiotics are commonly administered for 5–7 days to reduce bacterial numbers and decrease bacterial invasion of epithelium damaged by viral infection. Doxycycline at 5–10 mg/kg orally (PO) once a day is recommended because of its efficacy against both typical and atypical bacteria, its tissue penetration, and because it is well tolerated by most animals. The primary adverse effect from this drug is esophageal stricture formation. To ensure that it passes completely into the gastrointestinal tract, water or food should be administered immediately after the pill is given. Commercially available doxycycline suspensions that have a high enough concentration to allow administration of the appropriate dose are less likely to induce esophageal damage but are not available in every country. The stability of compounded or liquid formulations of doxycycline is variable, and a compounded suspension more than 7 days old should not be used due to lack of efficacy (Papich et al. 2013). Administration of sucralfate substantially reduces doxycycline absorption and at least 2 hours should pass between dosing of these two drugs (KuKanich and KuKanich 2014). To avoid these complications, amoxicillin is a reasonable alternative antibiotic, although it is important to remember that penicillin derivatives are ineffective against Chlamydia and Mycoplasma spp., a cell‐wall‐deficient bacteria. If a kitten or cat with acute upper respiratory signs fails to respond to empiric treatment within 7–10 days, a diagnostic work‐up is advised to rule out other nasal conditions (see Chapter 4). This would include collection of a sample for culture and susceptibility testing before use of an antibiotic with a different spectrum.

In chronic upper respiratory tract disease in the cat, mucosal tissue is often devitalized and there is accumulation of inflammatory products. Resolution of disease is difficult if not impossible to achieve; however aerobic bacterial infection is a common complication (Johnson et al. 2005) that can respond partially to treatment. Doxycycline and azithromycin are attractive drugs to use in such cases because they possess anti‐inflammatory effects as well as antimicrobial action. Both of these drugs have efficacy against most of the organisms that have been isolated in cats with chronic rhinosinusitis, including anaerobes, and thus could be used for empiric therapy when owners cannot perform extensive diagnostic testing. Culture and susceptibility testing might indicate that a fluoroquinolone would be a rational antibiotic choice in some cases. This class of drugs has excellent efficacy against most Gram‐negative bacteria and Mycoplasma. However, a high dose can 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) have efficacy against anaerobic organisms as well as others, which is beneficial in some cases. For cats with underlying osteomyelitis or suspected anaerobic infections, a drug such as clindamycin could be effective in controlling clinical signs because it penetrates bone tissue. Caution is warranted when administering clindamycin because this drug has also been associated with development of esophageal strictures.

The appropriate duration of antimicrobial treatment for feline chronic rhinosinusitis in the cat has not been evaluated. When treating the bacterial component of chronic feline rhinosinusitis, consideration should be given to using a relatively long course of antibiotics (2–4 weeks) to achieve maximal control of bacterial numbers. In some cases, chronic use of antibiotics is required, although the benefit of this therapy has to be weighed against the risk of antimicrobial resistance, as well as the challenges of owner compliance. Also, the waxing and waning course of disease can make it difficult to assess therapeutic response as well as to decide when to discontinue medication.

Bacterial involvement in canine inflammatory rhinitis appears to be less prominent than in the feline syndrome, although few studies have evaluated bacterial 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 a broad‐spectrum antibiotic (e.g. amoxicillin‐clavulanic acid) can help alleviate nasal discharge, although it will often recur. In these situations, recurrent nasal discharge could also indicate persistence of the fungal infection, warranting additional diagnostic testing.

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 lower respiratory infection requires antibiotics directed at Gram‐negative and Gram‐positive aerobes, anaerobes, and Mycoplasma organisms. A rational choice for initial therapy of a serious, newly diagnosed infection (before final culture results are available) would include a fluoroquinolone with a penicillin drug. Dosing depends on whether the antibiotic is concentration‐dependent or time‐dependent (Table 3.2). More frequent administration is required for those drugs that are time‐dependent. Parenteral administration is preferred for dogs with serious infection and systemic signs that require hospitalization. Enrofloxacin has good efficacy against most Gram‐negative organisms as well as many Gram‐positive organisms and Mycoplasma spp., and it has been demonstrated to accumulate in the epithelial lining fluid of the lung, making it a rational empiric choice. Ciprofloxacin, a generic human product similar to enrofloxacin, has variable absorption in the dog (Papich 2017) and is not preferred for use, even though it can be substantially cheaper than one of the veterinary formulations. An additional consideration is that fluoroquinolones have no efficacy against anaerobes, necessitating the addition of a second antibiotic such as a penicillin derivative while culture results are pending. The exception to this is pradofloxacin, as noted above. While this can be an appropriate choice for pneumonia in the cat, it is contraindicated in dogs because of bone marrow toxicity. Importantly, due to the emergence of bacterial resistance, beta‐lactam type antibiotics are not recommended for infection with bacteria in the Enterobacteriacae family (E. coli, Klebsiella, etc.) (Rheinwald et al. 2015).

Anaerobic susceptibility testing is rarely performed by clinical laboratories because organisms are difficult to grow on susceptibility plates; however, most are sensitive to penicillins, and a potentiated penicillin is best to use for anaerobic infections. Other drugs with good anaerobic activity include clindamycin, metronidazole, and chloramphenicol, and these drugs also have excellent pulmonary penetration. Bacteroides spp. can be resistant to clindamycin (Jang et al. 1997) and a potentiated penicillin, metronidazole, or chloramphenicol would be a better choice 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 is commonly associated with vomiting or anorexia and sometimes central nervous system depression or bone marrow suppression. Use of maropitant in the first several days of administration can lessen GI side effects, however, chloramphenicol is also a bacteriostatic drug and rarely indicated for in‐hospital treatment, unless a multi‐drug‐resistant organism is isolated. If prescribed for therapy at home, owners must be instructed to wear gloves to administer the drug given concerns about human health.

Azalides (azithromycin and clarithromycin) have efficacy against Gram‐positive and Gram‐negative organisms and Mycoplasma spp. as well as some anaerobes. These drugs have the advantage of producing high and prolonged tissue levels, typically resulting in enhanced bacterial killing. In the cat, there is 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), allowing it to be administered on an every other day basis. The clinical 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 both upper and lower respiratory infections.

In general, antibiotic treatment should be used for immediate control of infectious lung disease and the length of therapy in dogs with uncomplicated pneumonia is based on clinical response. Reduction in clinical signs of cough and tachypnea, improvement in parameters of oxygenation (when available), and resolution of an inflammatory leukogram would signify appropriate response to therapy. Future studies might identify specific biomarkers that could signal when adequate antimicrobial therapy has been achieved. Currently, treatment for 7–14 days is often considered sufficient for control of disease, and achieving radiographic resolution of infiltrates is no longer recommended for determining the length of antimicrobial therapy (Wayne et al. 2017; Vientos‐Plotts et al. 2021). However, chronic antibiotic therapy can be required to control clinical signs in dogs with bronchiectasis and animals with ciliary dyskinesia because mucus accumulation with trapping of bacteria in secretions can result in severe and recurrent or persistent pneumonia. In these cases of complicated pneumonia, long‐term antimicrobial therapy should be determined by results of bacterial culture and sensitivity, as well as considerations of the anticipated side effects of medications (Table 3.3). The antibiotic chosen should have proper efficacy, should penetrate the airways and lung parenchyma, and should be relatively free of side effects.

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

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 (see Chapter 4), and Histoplasma capsulatum, Blastomyces dermatitidis, or Coccidioides immitis organisms in the lower respiratory tract. Pneumocystis spp. are also responsible for fungal pneumonia, although treatment relies on the use of trimethoprim‐sulfa rather than standard antifungal medication discussed here. Nasal aspergillosis is also a special condition, which responds best to extensive debridement of fungal plaques and single or multiple infusions of topical antifungal therapy rather than oral therapy (see Chapter 4). When treating lower respiratory tract infection associated with fungal organisms, long‐term therapy (from 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 3.4).

The triazoles (itraconazole, fluconazole, voriconazole, posaconazole) are fungistatic agents that inhibit the P450 enzymes involved in the synthesis of ergosterol, a key component of the fungal cell membrane. Itraconazole (Sporanox^®, Itrafungol^®) can be used as sole therapy for pulmonary fungal infection, or it can be used following initial fungicidal therapy with amphotericin B for prolonged control of disease. Itraconazole is excreted by the liver, and side effects of therapy include hepatic toxicity, dermatotoxicity, and anorexia. Capsules and suspensions have different bioavailability, resulting in different dosing recommendations. Also, capsules should be given with food, while the solution is administered on an empty stomach. Compounded formulations of itraconazole are not advised because of variable absorption, which can negatively influence response to therapy. Fluconazole is renally excreted, thus a reduced dosage is recommended for animals with renal insufficiency. Fluconazole is available in generic form and can be preferred for animals that require long‐term therapy due to cost savings, although bioequivalence among different generic preparations should not be presumed. Monitoring steady state serum concentration (after ~3 days of treatment) for therapeutic efficacy can be important to ensure resolution of disease because of individual variations in bioavailability, as well as the general variability in the pharmacokinetic properties of fluconazole (KuKanich et al. 2020). In animals that achieved clinical remission from various fungal infections, the median (range) serum fluconazole concentrations were 19.4 (8.1–79.0) μg/ml (dogs) and 35.8 (6.0–95.2) μg/ml (cats) (KuKanich et al. 2020). Compounded and generic formulations of fluconazole can have variable pharmacokinetic properties and stability (LaPorte et al. 2017; KuKanich et al. 2020) and therefore should be avoided, as for itraconazole. Fluconazole has no efficacy against Aspergillus species.

Voriconazole (Vfend^®, Pfizer, New York) and posaconazole (Noxafil^®, Merck&Co., Inc, Whitehouse Station, NJ) are newer triazoles with improved antifungal activity. Use of these drugs has been limited by their expense, as well as reports of neurotoxicity in cats administered voriconazole. Posaconazole appears to be the favored medication for treatment of sino‐orbital aspergillosis in the cat, and a pharmacokinetic study suggested that 30 mg/kg PO followed by 15 mg/kg every other day would attain trough levels similar to those proven efficacious in humans (Mawby et al. 2016). The suspension has low bioavailability (16% in cats, 26% in dogs) and there is variable absorption of the delayed‐release tablets in dogs, with values up to 159% (Kendall and Papich 2015; Mawby et al. 2016); however, posaconazole has been associated with relatively few side effects when used clinically. Because the delayed‐release tablet can be administered every other day, it could be cost‐effective for use in cats as well as dogs.

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