CHAPTER 59 Antimicrobial Therapy of the Respiratory System
The successful antimicrobial treatment of lower respiratory tract infections in horses can be challenging because of difficulties associated with effective antimicrobial delivery, the potential for toxic side effects, the required duration of therapy, and the overall expense of treatment. Antibacterial drugs remain the most clinically important antimicrobial agents, whereas the use of antivirals and antifungals is of increasing clinical interest. When designing a therapeutic regimen to address a pulmonary infection, careful consideration must be given to the pharmacokinetic characteristics of the antimicrobials used as well as to the unique physiology of the lower respiratory tract and the pharmacodynamics of antimicrobial drugs within the lungs. The characteristics of the pathogens being targeted and the degree of pulmonary and pleural involvement must also be taken into consideration to ensure that an appropriate therapeutic regimen is selected.
The clinical efficacy of antimicrobial therapy is directly related to the antimicrobial concentrations achieved at the site of infection and the period over which therapeutic concentrations are maintained. Effective delivery of antimicrobials to respiratory tract tissues is complicated by several factors. Foremost is the fact that most infectious disease within the respiratory tract begins in the airway, on the epithelial surface or in the epithelial lining fluid, rather than within the pulmonary parenchyma. Inherently the airway lumen is external to the body, and consequently the respiratory epithelium presents an effective barrier to movement of antimicrobials from the circulation to the site of infection. To overcome this barrier it is necessary to use antimicrobials that can be transported across the epithelium or to deliver the antimicrobial directly onto the mucosal surface.
INDICATIONS FOR ANTIMICROBIAL THERAPY
Clinical signs of a lower respiratory tract infection may include fever, cough, nasal discharge, tachypnea, dyspnea, depression, inappetence, and pleurodynia. Coughing is indicative of large airway inflammation and increased irritability. Changes in clinical status often represent important indicators of the progression of lower respiratory infections, and these may include persistence or worsening of fever, an alteration in the character of cough, and signs of systemic inflammation.
Clinical pathology data can be useful, with leukocytosis, neutrophilia, left shift, and hyperfibrinogenemia present in more severe lower respiratory infections. Imaging studies may aid in the staging and localization of lower respiratory infections, with ultrasonography being useful in assessing the superficial pulmonary tissues and the pleural cavity and radiology useful in the assessment of bronchial and interstitial abnormalities. Airway cytology is important because it provides a clearer indication of the character of pulmonary inflammation, especially regarding the predominant type of inflammatory cells and the presence and type of bacteria.
Tracheal aspirates are most commonly used because they are easily obtained in a sterile manner, allowing for culture of the sample. These can be obtained by either the percutaneous approach or the endoscopic approach using a guarded endoscopic aspiration catheter. Bronchoalveolar lavage (BAL) is less commonly used for the assessment of lower respiratory infections because of the potential for contamination when the sampling device is advanced through the upper respiratory tract, which renders culture results suspect. Despite this limitation BAL can provide an important indication of small airway inflammation and involvement; the presence of suspected focal pulmonary involvement is an indication for bronchoscopy and targeted BAL.
CONSIDERATIONS REGARDING PULMONARY ANTIMICROBIAL THERAPY
Characteristics of the Lung
When one attempts to apply knowledge of the pharmacokinetics and pharmacodynamics of antimicrobials to the conditions encountered in the lower respiratory tract, it becomes apparent that somewhat different rules apply. This is because most available information about antimicrobial therapy comes from studies using soft tissue models, where water-soluble antimicrobials, which easily cross the endothelium, are able to achieve high concentrations within the interstitium. By comparison, the blood-bronchus barrier, formed by the epithelial tight junctions in the bronchial epithelium, substantially impairs the ability of water-soluble drugs to move across the respiratory epithelium. Consequently, although these compounds can achieve adequate interstitial concentrations in the lung tissue, they cannot achieve high concentrations in the lumen of the respiratory tract unless the respiratory epithelial barrier has been compromised by injury or inflammation. For example, it is difficult even to detect the water-soluble antimicrobial gentamicin in the pulmonary epithelial lining fluid of healthy adult horses following administration of 6.6 mg/kg intravenously, despite high peak concentrations being achieved within the systemic circulation.
Characteristics of Antibacterial Drugs
The most basic criteria that must be considered in selecting an antimicrobial regimen are the route of administration, the ability of the drug to reach the site of infection, and the risk of adverse reactions. With regard to the route of administration, oral administration has the distinct advantages of being relatively simple and having a greater level of safety than the intramuscular (IM) or intravenous (IV) routes. However, these advantages may be outweighed by poor oral bioavailability, especially in adult horses. IM administration overcomes the concerns regarding bioavailability and is particularly desirable for drugs requiring moderate systemic concentrations over time, but it can be associated with patient discomfort and local muscle injury as well as the risk of adverse reactions, such as those associated with inadvertent injection of procaine penicillin G into the vasculature. IV administration achieves very high peak concentrations but may necessitate larger daily dosages or more frequent administration and carries the associated risk of thrombophlebitis.
The most important characteristic determining the ability of an antimicrobial compound to cross the blood-bronchus barrier is lipid solubility. Highly lipophilic drugs can readily cross the intact epithelium and achieve high concentrations in the lumen of the respiratory tract. Lipophilic drugs include macrolides, chloramphenicol, fluoroquinolones, tetracyclines, potentiated sulfonamides and rifampin. A related characteristic is the ability of the drug to accumulate intracellularly, particularly within the alveolar macrophage, which can actually result in intracellular concentrations that are higher than the peak concentration within the systemic circulation. This capacity is critical for effective treatment of intracellular infections, such as Rhodococcus equi pneumonia in foals. Intracellular accumulation also maintains therapeutic concentrations in the lower respiratory tract for longer than would be expected based on the systemic pharmacokinetics. Examples of drugs that achieve high intracellular concentrations are the macrolides, rifampin, chloramphenicol, and fluoroquinolones.