Pathophysiology, diagnosis, treatment and prognosis of foals with Rhodococcus equi pneumonia (Proceedings)
The main routes of infection are via ingestion (gastrointestinal) and inhalation (respiratory).
The main routes of infection are via ingestion (gastrointestinal) and inhalation (respiratory). Ingestion is thought to be the most common route of exposure but inhalation is thought to be the major route of exposure that leads to respiratory disease. Experimental nebulization with R.equi leads to pyogranulomatous pneumonia similar to that seen in natural cases of R.equi pneumonia.
Antibodies against R.equi are transferred to the foal via colostrum, however these antibodies do not protect foals from infection. Maternally-derived antibodies wane at 1-2 months of age. It is thought that all foals may be exposed to R.equi at an early age and foals less than 1 week of age are more susceptible to infection.
R.equi is a facultative intracellular organism that shares many characteristics with members of the genera, Mycobacterium. Virulence of R.equi is related to the presence of a large plasmid. After inhalation, R.equi are phagocytized by alveolar macrophages. Within the macrophages, R.equi inhibits phagosome-lysosome fusion to allow its survival within the macrophage. The organisms persist and multiply within the macrophage. Damaged macrophages release many organisms which then cause disease in surrounding tissues. Alveolar macrophages full of intracellular R.equi are usually contained within pyogranulomas of the pulmonary parenchyma. Alimentary infection occurs from ingestion of large numbers of R.equi from the environment or secondary to ingestion of R.equi expectorated from pulmonary infections.
The immunity to R.equi is highly complex and requires orchestrated activity of a variety of immune regulators and effectors . Antibodies are passed from the dam to the foal via colostrum. Immunity to R.equi in horses likely depends on both humoral and cell-mediated immune responses. R.equi-specific antibodies enhance phagosome-lysosome fusion, thereby enhancing the ability of alveolar macrophages to kill R.equi. Antibodies to the VapA proteins do not provide complete protection from R.equi but have been shown to enhance the pulmonary clearance of R.equi following heavy intrabronchial challenge in foals (Hooper-McGrevy 2001). Clearance of R.equi in adult horses is associated with a significant increase in bronchoalveolar lavage fluid CD4+ and CD8+ lymphocytes, lymphoproliferative responses to R.equi antigens, development of R.equi-specific cytotoxic T lymphocytes, and IFN-γ induction (Hines 2001 and 2003; Lopez 1002; Patton 2004). It is speculated that foals are immunocompromised in some way or that infection with virulent R.equi alters the immune responses in foals. Deficiency of IFN-γ may be at the reason for foal's susceptibility to R.equi infections.
Pulmonary lesions consist of suppurative bronchopneumonia with miliary to multifocal pyogranulomas. The typical findings include multiple firm, nodules separated by congested and partly atelectic lung. Nodules vary in size and some foci coalesce to form large lesions. Lesions are bilateral in most foals, although exceptions do occur. Suppurative tracheobronchial lymphadenopathy often is present. Pyogranulomas are sometimes encapsulated. Bronchial lymph nodes are typically enlarged, swollen and edematous and caseonecrotic foci may be present.
Histologically, the lesions are predominately pyogranulomatous. Early lesions are characterized by cellular influx into alveolar spaces, with macrophages, multinucleate giant cells and neutrophils. Neutrophils and macrophages contain intracellular gram-positive coccobacilli. As the disease progresses, necrosis involves alveolar sepate and spread to affect larger areas of the lungs, producing the caseous necrotic foci seen macroscopically.
Concurrent multifocal ulcerative colitis and typhlitis, and mesenteric lymphadenopathy occurs in about 50% of cases. Occassionally, a large abdominal abscess will form most often in a mesenteric lymph node. Peritonitis and adhesions frequently are present. Abscesses and pyogranulomatous lesions can occur anywhere in the body.
R.equi pneumonia is an INSIDIOUS DISEASE and EARLY DETECTION MAY BE DIFFICULT. Age of the foal is important diagnostically: R.equi should be considered in any foal 1-6 months old that has respiratory disease. Clinical disease most often develops prior to 4 months of age. Infections may remain subclinical in some cases. When clinical disease does develop, it may be insidious or fulminant signs may develop. Clinical signs may include elevated respiratory rate, tachycardia, abdominal breathing at rest, cough, nasal discharge, fever (102 - 106°F), depression, lethargy, weight loss, failure to gain weight, and diarrhea. Respiratory distress may be apparent as tachypnea, tachycardia, flared nostrils, increased abdominal effort to respiration, and sometimes cyanosis. Cyanosis may be present in severely affected foals. In acute cases, body condition is generally normal, however in chronic cases or cases with abdominal abscessation, weight loss or failure to grow may be seen. Some foals will develop peracute onset of severe signs of respiratory distress without any previous clinical signs. Other foals are simply found dead without any apparent clinical signs.
Some foals have R.equi infections concurrent with the syndrome of bronchointerstitial pneumonia and respiratory distress, but R.equi is not believed to be the etiology of this syndrome. Occassionally, R.equi is isolated from foals with Pneumocystis carinii pneumonia.
Extrapulmonary manifestations of R.equi are common, and can include metastatic sites of infection, immune mediated disorders and adverse effects from medications. Bacteremia is probably more common that recognized. Extrapulmonary disorders include gastrointestinal involvement (lymphadenitis, diarrhea, enterocolitis/typhlitis, peritonitis), immune-mediated polysynovitis, peripheral abscessation, uveitis, osteomyelitis, vertebral osteomyelitis, septic synovitis, pericarditis, guttural pouch empyema, pyogranulomatous dermatitis, neurological disorders, septic sinusitis and pyelonephritis (Chaffin 1997). R.equi may also cause disease without concurrent lung involvement. Such manifestations have included solitary abdominal abscessation (Nay 1996), cellulitis and subcutaneous abscessation (Perdrizet and Scott 1987) and osteomyelitis (Giguere and Lavoie 1994; Olchowy 1994). An intracranial abscess has been described in a foal that demonstrated a head tilt, ataxia, and strabismus (Janicek 2006). Uveitis, hypopyon, ulcerative lymphangitis, cellulitis, abscesses of the submandibular lymph nodes, nephritis, renal abscesses, liver abscesses have all been described in association with R.equi infections. For unknown reasons, pleural effusion is uncommon in foals with R.equi, but does occasionally occur.
Foals with abdominal disease may show diarrhea or colic. Ascites may develop in some foals resulting in a "pot-bellied" appearance. In such foals, extensive mesenteric lymphadenitis is generally present, resulting in lymphatic obstruction.
Approximately 1/3 of affected foals will have synovial distension of multiple joints (ie, hocks, stifles, carpi, fetlocks). Typically, these foals are not lame. The synovial distension is most often an immune-mediated polysynovitis. It is hypothesized that immune complexes deposit in the synovial membrane leading to acute reactive arthritis. Evaluation of synovial fluid reveals a nonseptic mononuclear pleocytosis with no bacterial growth. Histologic examination of synovium reveals lymphoplasmacytic synovitis. The synovitis general resolves as the foal responds to treatment.
R.equi can also cause septic polysynovitis, but generally such foals are lame. Osteomyelitis also can occur. Vertebral osteomyelitis has been reported in a number of foals. Stiff gait, reluctance to move, pain on palpation, and neurologic signs may be seen in such foals. Paresis, ataxia, paralysis or cauda equine syndrome (Chaffin 1995) may be apparent. Specific signs will vary depending upon the site of the lesion. Radiographs, ultrasound, CT, MRI, and scintigraphy may be needed for diagnosis.
A foal is suspected of having R.equi pneumonia if it originates from an endemic farm, has signs of pneumonia, a severe inflammatory leukogram and a prominent alveolar and/or interstitial pattern on thoracic radiographs (Ainsworth 1999). It is important to minimize stress during the physical examination of foals with suspected R.equi pneumonia, so as to not exacerbate respiratory distress.
Sporadic cases of R.equi infections occur in adult horses. Most involve suppurative bronchopneumonia, but intestinal disease, lymphadenitis, wound infections, osteomyelitis, abortions and other forms of infection have been reported. Immunodeficiency is usually suspected in such cases.
Auscultation findings do not always correlate with radiographic or pathologic findings. Crackles, wheezes, attenuated lung sounds, and referred large airway sounds may be detected over regions with large pyogranulomas. In some severely affected foals, the abnormal lung sounds are easily detected, but beware that auscultation alone misses many affected foals, particularly if the examiner is not extremely astute at auscultation, the environment is noisy, or the foal is in the early phases of the disease process. Remember that this disease can hide like a snake in the grass, and some foals will have large pyogranulomatous lesions that are not detected by auscultation.
Radiography is frequently used to evaluate foals with suspected R.equi pneumonia. Thoracic radiographs of foals can be obtained in the field using portable equipment. Radiographs are an extremely useful method for detection of pulmonary pyogranulomas. Often, there are discrete nodular or cavitary lesions compatible with pulmonary abscessation. Occassionally, gas is seen within the nodular lesions. Nodular densities displacing the trachea dorsally are suggestive of tracheobronchial lymphadenopathy. Other radiographic findings include interstitial and alveolar patterns.
When typical radiographic findings are identified, a tentative diagnosis of R.equi pneumonia can be made prior to obtaining culture results. However, other pathogens, such as Streptococcus zooepidemicus, can also cause abscessation and should be considered, especially in older foals. In some cases, foals affected with R.equi can be missed with radiograpy, particularly if abscesses are located near the heart, cranial to the heart, or in the ventral border of the lung, ventral to the crus of the diaphragm.
Ultrasound is very useful to detect consolidation and abscessation of the peripheral lung. Because ultrasound does not penetrate air-filled lung, only the periphery of the lung is imaged. Thus deep pulmonary abscesses can be missed with ultrasound. Fortunately, most foals with R.equi pneumonia have involvement of the peripheral lung, thus making ultrasound a valuable diagnostic tool.
Sonographic features of consolidated lung include ill-defined, hypoechoic regions of the lung. Vessels and bronchi may be visualized. Small bronchi are characterized by small linear hyperechoic foci, while vessels are seen as hypoechoic linear tubular structures within the parenchyma of the consolidated lung. Pulmonary abscesses are visible as hypoechoic areas of lung that do not contain vessels or bronchi.
Ramirez (2004) showed that ultrasound is a valuable alternative imaging modality for detection of pulmonary pathology attributed to R.equi. Ultrasonographically, pulmonary abscessation was identified in 12 foals and pulmonary consolidation with no detectable abscessation was identified in three others. Sonographic examination allowed detection of only pleural irregularities in one foal, which was subsequently found to have pyogranulomatous pneumonia radiographically. Results indicate that ultrasonography may be an accurate alternative imaging modality for detection of pulmonary pathology attributed to R.equi pneumonia in foals.
Slovis (AAEP, 2005) has demonstrated the effectiveness of using ultrasound to screen foals for early detection of R.equi in foals at endemic farms. Cortez (2008) also showed that ultrasonography was very efficient in detection of early cases of pneumonia.
Abdominal ultrasonography is indicated in affected foals to search for abdominal abscesses. Abscesses are variable in size and location, and usually contain homogeneous to heterogeneous material. Large intraabdominal abscesses differ from the classic mesenteric suppurative lymphadenitis caused by R.equi in which multiple small lymph nodes are involved. Ultrasound-guided aspiration can help collect samples for culture and cytology. In my experience, large abdominal abscesses are associated with a poor prognosis; however Valdes (2005) described successful management of a foal with septic pleuritis and abdominal abscessation with long-term antimicrobial therapy.
In people, CT and MRI are more often used to image lesions associated with R.equi. Computerized tomography (CT) may be valuable for identifying and characterizing extrapulmonary manisfestations of R.equi. CT has been reported to image a mediastinal abscess Wion 2001). MRI has been described to image a brain abscess (Janicek). MRI and CT have also been used to image septic physitis in foals. Scintigraphic perfusion imaging can be used to demonstrate perfusion defects in foals with R.equi pulmonary abscesses.
The classic abnormalities seen on a complete blood count include leukocytosis with a mature neutrophilia, hyperfibrinogenemia, and occassionally, anemia of chronic disease.
Tracheobronchial aspiration (TBA) is a preferred method of obtaining samples for culture, cytology for definitive diagnosis of R.equi. TBAs can be performed percutaneously or through an endoscope using a double or triple guarded catheter. When possible, and particulary when foals are in respiratory distress, I prefer to use the transendoscopic approach, as it is often less invasive, allows better sample collection, and does not seem to stress the foals as much as the percutaneous procedure. For foals in severe respiratory distress, I use other methods (rads, ultrasound, etc) for diagnosis and do not attempt TBA.
Cytologic examination of TBA samples is highly recommended. Intracellular Gram-positive pleomorphic coccobacilli will be detected in over 50% of cases. Sweeney (1987) reported that 61% of 48 culture-positive foals showed cytologic evidence of Gram-positive organisms. Cytology may identify the organism more rapidly than culture, thus allowing implementation of appropriate antimicrobial therapy while awaiting culture results.
Microbiologic culture of TBA samples is important as is susceptility testing. Many cases will be reveal pure growth of R.equi, but polymicrobic infections are not uncommon. False-negative results of culture occassionally occur, possibly because of previous antimicrobial treatment or overgrowth by other bacterial species (Sweeney, 1987). Culture does not allow differentiation between virulent and avirulent strains of R.equi. False-positive cultures of TBA samples also can occur. On endemic farms, 1 in 3 healthy foals may have positive TBA cultures for R.equi (Ardans 1986).
Giguere (2003) reported that 86% of foals with positive R.equi cultures at necropsy had positive antemortem cultures of TBA fluid.
Cultures of TBA samples typically show colonies within 48 hours of culture. Colonies appear irregularly round, smooth, semitransparent, and mucoid. Typically, they have a salmon-pink color.
In foals with sonographically visible lung abscesses, microbiologic culture of TBA samples resulted growth of R.equi in 52% of samples (Heyers 2005).
The use of PCR amplification based on the VapA gene sequence has been shown to be a more sensitive means of identifying R.equi in TBA fluid samples than bacterial culture, especially if the foal sampled is being treated with antimicrobials at that time (Sellon 2001; Halbert 2005).
Harrington (2005) reported that quantitative PCR is a rapid and reliable method for detecting and quantitating virulent R.equi. Halbert (2005) developed a multiplex PCR for simultaneous detection of R.equi bacteria and differentiation of VapA+ and VapA- isolates.
PCR (VapA gene) testing of TBA samples showed a sensitivity and specificity of 100 per cent and 90.6 per cent, respectively for detection of virulent R.equi in affected foals (Sellon 2001).
Pusterla (2007) used a real-time, TaqMan PCR assay of nasopharyngeal swabs and feces of 31 foals with pneumonia. Of the 31 foals, 19 had been treated with antimicrobials prior to sampling. Final classification of an R.equi confirmed case was based on all available information, including history, clinical presentation, radiographic and laboratory (CBC, biochemical panel, TW fluid cytology) results, culture and PCR results, and postmortem results. The final classification was used as a reference standard for the calculation of diagnostic sensitivity and specificity for culture of TW fluid, and PCR of TW fluid. Twelve of the 31 foals (39 per cent) were diagnosed with R.equi pneumonia. When compared to the reference standard cases, the sensitivity and specificity of TW culture was 82 per cent and 100 per cent respectively. PCR detection of R.equi from TW fluid samples showed 100 per cent sensitivity and specificity when compared to the reference standard cases.
As with any diagnostic technique, PCR results should always be interpreted in light of the individual history, clinical signs and other diagnostics from the foal and should only be used in conjunction with standard culture.
PCR testing of fecal samples
Testing feces for the presence of virulent R.equi may be of some value, particularly if the patient's clinical condition precludes tracheobronchial aspiration. However, some foals will shed virulent R.equi in feces without clinical disease. Faecal shedding is thought to occur either
passively via swallowing of R.equi-containing pulmonary secretions or due to the colonisation of the gastrointestinal tract, as shown to occur in 50 per cent of cases of R.equi pneumonia (Zink and others 1986).
Pusterla (2007) showed that PCR on fecal samples had 75 sensitivity and 100% specificity for detection of R.equi in 12 foals with R.equi.
Nasal or nasopharyngeal swabs do not yield a suitable sample for diagnosis of R.equi. One study showed that culture of nasopharyngeal swabs collected from foals with pneumonia showed poor accuracy in detection of R.equi-infected patients (Hashikura 2000). Another study (Pusterla 2007) showed low accuracy of nasopharyngeal swabs for detection of R.equi using PCR. Sellon (2001) reported that only six of 33 foals with R.equi pneumonia had a positive test via PCR from nasopharyngeal swabs
Serologic detection of antibodies against R.equi is probably of minimal value in making a diagnosis of R.equi pneumonia in an individual foal. The presence of antibodies indicates either exposure or maternal transfer of antibodies, but not necessarily infection.
Recent studies have demonstrated that serology was not useful for differentiating affected foals from unaffected foals. Martens (2002) reported a nested, case-control study of serologic testing in 26 foals. An agar gel immunodiffusion assay, synergistic hemolysis inhibition assay, and 3 ELISA assays were performed. None of the serologic assays differentiated affected from unaffected foals, either at the time of onset of clinical signs or at any time period prior to onset of clinical signs.
Giguere (2003) reported that serologic surveillance using an agar gel immunodiffusion assay was of litte benefit for early detection of R.equi infected foals.
R.equi is sensitive to many antimicrobials in vitro, but in vitro susceptibility does not correlate with efficacy in vivo. Aminoglycosides are highly active against R.equi in vitro, but are not effective for treatment. Before the use of lipid soluble antimicrobials for treatment of R.equi, survival rates were <20%. Because R.equi is a facultative intracellular pathogen that causes pyogranulomatous lesions, antimicrobials must be lipid soluble and have good tissue and macrophage penetration, and must be active in a acidic environment.
In the late-1980s, clinicians began using highly lipid-soluble antibiotics, such as erythromycin and rifampin, and survival rates climbed to > 85%. From the late-1980s until the late 1990s, a combination of erythromycin (25 mg/kg PO QID) and rifampin (5 mg/kg PO BID) was most often recommended. The 2 drugs had synergistic action in vitro against R.equi, but whether that occurs in vivo is unknown. Macrolides and rifampin are highly lipid-soluble, can penetrate pyogranulomas and can then penetrate into the cells where the bacteria are present.
Erythromycin therapy has limitations for treatment of R.equi. Erythromycin has variable absorption in foals when given orally, and requires multiple daily dosing. Administration of erythromycin has a high incidence of adverse effects. The most common adverse effect of erythromycin in foals is diarrhea. An idiosyncratic reaction characterized by hyperthermia and tachypnea has been reported in foals treated with erythromycin during hot weather. In one study, 36% of 73 foals treated with erythromycin developed diarrhea, and 25% developed hyperthermia, and 15% developed respiratory distress (Stratton-Phelps 2000).
Severe enterocolitis also has been reported in mares whose foals are being treated with erythromycin, presumably from ingestion of the foal's manure, which contains enough active erythromycin to disturb the mare's normal colonic microflora (Baverud 1998). Clostridium difficile has been isolated from affected mares.
Newer antimicrobials for treatment of R.equi include azithromycin (an azalide) and clarithromycin (a semisynthetic macrolide). Compared to erythromycin, these drugs are more chemically stable, have a greater bioavailability after oral administration, and achieve higher concentrations in phagocytic cells and tissues. In humans, the incidence and severity of adverse effects for these drugs also are considerably less than those of erythromycin.
Davis (2002) reported the pharmacokinetic properties of azithromycin in plasma, polymorphonuclear leukocytes (PMN), and alveolar cells after a single administration in foals. Azithromycin absorption after intragastric administration was variable with a mean systemic availability of 39% (±20%). The plasma half-life was 18.3 hours. Azithromycin had a very large volume of distribution of 11.6 L/kg, which was attributed to high tissue and intracellular concentrations, exhibited by the high concentration of azithromycin in neutrophils and alveolar cells. At 4 and 12 h after oral drug administration, azithromycin concentrations in PMNs were 89 and 202 times the corresponding plasma concentrations, respectively. In addition, azithromycin concentrations in PMN persisted for 120 h after oral administration and the half-life in PMNs was over 49 hrs. It was recommended to use a dosage of 10 mg/kg of azithromycin orally once daily for foals with R.equi pneumonia.
Another study reported by Jacks (2001) demonstrated that azithromycin had a half-life of 20.3 hours and a high volume of distribution in foals. After intragastric administration, time to peak serum concentration was 1.8 hours and bioavailability was 56%. After repeated intragastric administration, peak serum concentration was 0.63 ± 0.10 μg/ml. Bronchoalveolar cell and pulmonary epithelial lining fluid (PELF) concentrations were 15- to 170-fold and 1- to 16-fold higher than concurrent serum concentrations, respectively. Based upon PK values, minimum inhibitory concentrations of R.equi isolates, and drug concentrations in pulmonary epithelial lining fluid and bronchoalveolar cells, a single daily oral dose of 10 mg/kg was recommended for treatment of R.equi infections in foals. Persistence of high azithromycin concentrations in PELF and bronchoalveolar cells 48 hours after discontinuation of administration suggested that after 5 daily doses, oral administration at 48-hour intervals may be adequate.
Clarithromycin has also gained popularity recently for treatment of R.equi infections, and has numerous advantages over erythromycin. Jacks (2002) studied the disposition of clarithromycin in 6 foals administered 10 mg/kg intragastrically. Time to peak concentration was 1.5 hours and peak serum concentration was 0.92 ± 0.17 µg/ml. An oral dosage of 7.5 mg/kg PO q 12 hours was recommended for treatment of R.equi infections in foals.
Suarez (2007) described the pulmonary disposition of erythromycin, azithromycin and clarithromycin in foals. A single dose of 10 mg/kg of each drug was administeted intragastrically to 6 healthy foals. Peak drug activity in pulmonary epithelial lining fluid (PELF) was highest for clarithromycin. Erythromycin was not detectable in PELF of 4 foals. Peak drug activity in bronchoalveolar cells (BAL) was not different between clarithromycin and azithromycin, but activity for both drugs was higher than that of erythromycin. Terminal half-life of azithromycin in serum, PELF and BAL cells was higher than that for either of the other drugs. These results suggested that that longer intervals (longer than 24 or 48 hrs) between dosages of azithromycin may be sufficient for treatment of R.equi pneumonia. Also, once daily administration of clarithromycin at 10 mg/kg may be sufficient.
Giguere (2004) reported the results of a study comparing the efficacy of azithromycin-rifampin, clarithromycin-rifampin, and erythromycin-rifampin for the treatment of pneumonia caused by R.equi in foals. Eighty-one foals with naturally acquired pneumonia caused by R.equi were studied. Foals treated with clarithromycin-rifampin had significantly higher odds of overall short-term and long-term treatment success than foals treated with erythromycin-rifampin. Foals treated with clarithromycin-rifampin had a significantly higher percentage of radiographic improvement and a tendency toward higher odds of overall short-term and long-term treatment success compared to foals treated with azithromycin-rifampin. Among foals with severe radiographic lesions, the success rates of foals treated with clarithromycin-rifampin were significantly higher than that of foals treated with azithromycin-rifampin. There was a tendency for treated with clarithromycin to have a higher incidence of diarrhea (28%) than did foals treated with azithromycin (5%). The authors concluded that clarithromycin-rifampin is superior to azithromycinrifampin or erythromycin-rifampin for the treatment of pneumonia caused by R.equi in foals in a referral population.
Resistance has been documented to the commonly recommended medications. Giguere (2008) reported on 19 isolates that were resistant to at least 1 macrolide or rifampin. 2 isolates were resistant to rifampin only. The other 17 isolates were resistant to all 3 macrolide drugs, thus there is significant cross-resistance with the macrolide-type medications. The overall prevalence of R.equi isolates resistant to macrolides or rifampin was 3.7%. The survival rate of foals from which resistant isolates were cultured was only 25% which was less than that of foals with non-resistant isolates.
It is occasionally necessary to consider alternative antimicrobials to the macrolide/rifampin combination, because of resistance, diarrhea or financial concerns. A trimethoprim-sulfonamide combination (15-30 mg/kg q 12 hrs) has been reported effective in a few foals; however this drug combination is likely not nearly as effective as a macrolide-rifampin combination. Enrofloxacin alone or in combination has been effective in some foals, however, caution should be exercised because of potential for synovial effusion and lameness associated with chondrotoxicity. Chloramphenicol (50 mg/kg PO q 6 hrs) has been used by some practitioners with success (Baker, personal communication).
Tulathromycin shows promise as a new form of treatment of R.equi infections, but requires more study before it can be recommended as a first line of therapy. Tulathromycin is a semi-synthetic macrolide antibiotic with a large volume of distribution (Nowakowski 2004), a long elimination half-life (Benchaoui 2004) and a high concentration in lung tissue after IM injection in cattle and swine (Galer 2004). Tulathromycin is presently approved in the USA for the treatment of respiratory diseases in these species. Advantages of tulathromycin are the relatively low price, the small injection volume and the very convenient frequency of administration (only a single weekly injection).
Venner (2006) treated 37 foals with mild sonographic evidence of lung abscesses with tulathromycin (2.5 mg/kg IM once weekly), and treated 33 similar foals with a combination of azithromycin (10 mg/kg PO once daily for the first seven days of therapy, and every other day thereafter) and rifampin (10 mg/kg PO twice daily). Most foals in both groups responded to treatment, showing improvement in clinical scores and abscess scores. Adverse effects of tulathromycin included self-limiting diarrhoea in 11 foals; elevated temperature in 6 foals, and swellings at the injection site in 12 foals. This study showed promising results for tulathromycin as a monotherapy against lung abscesses in foals. Tilmicosin is not likely to be an effective therapy for R.equi infections (Womble 2006) in foals.
Doxycycline has also gained popularity as a treatment for R.equi pneumonia. Womble (2007) described the kinetics of doxycycline in foals 4-8 weeks of life, and showed that 10 mg/kg PO q 12 hrs would maintain serum, BAL and PELF concentrations adequate to inhibit growth of R.equi. I have minimal experience using this drug to treat R.equi, and I currently reserve doxycycline for foals that have isolates resistant to macrolides or that develop adverse effects from macrolide therapy.
.Citropins 1.1 (an antimicrobial peptide obtained from Australian tree frogs) has inhibitory effects against R.equi in vitro, and there is synergy when combined with clarithromycin, doxycycline and rifampin (Giacometti 2005). In vivo studies have not been performed.
In humans, R.equi infections have been treated with vancomycin, imipenem, aminoglycosides, ciprofloxacin, rifampin and erythromycin.
In addition to antimicrobials, additional therapy is required for some foals. Supportive care is needed to insure adequate hydration, nutrition. Keeping foals in a cool environment relieves the effort of respiration, and minimizes the risk of macrolide-associated hyperthermia. Non-steroidal anti-inflammatory drugs such as flunixin meglumine (0.25 – 1.0 mg/kg IV q 12 hrs) are often used to reduce fever and inflammation in the lung.
In foals with severe respiratory distress, I often use bronchodilatory drugs such as clenbuterol orally or albuterol administered via a nebulizer and an Aeromask, although the results are sometimes disapppointing. One should be cautious using aminophylline in combination with erythromycyin or clarithromycin because of risk of methylxanthine toxicity.
In addition, supportive care with IV fluids and electrolytes is often necessary. Insufflation of humidified oxygen is provided for hypoxemic foals via a nasopharyngeal cannula at 10-15 L/minute. Arterial blood gases are utilized to determine the need for and rate of delivery of oxygen therapy. Percutaneous provision of intratracheal oxygen has been described as well.
Local therapy, in combination with antimicrobial therapy, is needed for extrapulmonary sites of infection, such as septic joints, septic physitis, guttural pouch empyema and subcutaneous abscesses.
Repeated assessments of fever, attitude, effort of respiration, fibrinogen, WBC, sonograms and thoracic radiographs are used to monitor response to treatment. Duration of therapy is dictated by the severity and magnitude of the pulmonary abscesses, and the patient's response to therapy. Duration of treatment may range from 2 weeks for some subclinically affected foals to 3-4 weeks for mildly affected foals to 3-4 months for more severely affected foals. Repeated hematologies, radiographs and ultrasounds are used to determine when to discontinue medications.
It is my clinical impression that early detection of this disease seems to result in enhanced response to treatment. Foals detected early require less duration of therapy than foals in advanced stages of pulmonary abscessation.
Survival rates of foals with R.equi pneumonia are largely based on retrospective reports from university veterinary teaching hospitals; such mortality rate data may differ from that obtained directly from affected farms. Studies conducted prior to the routine use of erythromycin and rifampin for treatment (Ellisdale 1980; Bain 1963), cite mortality rates = 80% for foals with R.equi infection. At veterinary teaching hospitals, mortality rates for affected foals of 51% (Falcon 1985) and 58% (Sweeney 1987) are reported. With treatment with erythromycin and rifampin, a mortality rate of 12% (Hilledge 1987) was observed. At a university hospital with predmoninately advanced referral population of affected foals, a mortality rate of 41% (Chaffin 1997) was reported. Ainsworth (1998) reported a mortality rate of 28% among Standardbred and Thoroughbred foals admitted to 6 university teaching hospitals. On a Thoroughbred breeding farm in New South Wales, a mortality rate of 42% (8/19 foals) was reported (Raidal 1996). In a study of 64 breeding farms in Texas (Chaffin 2003), the overall case fatality rate was 29.2% for 113 affected foals. On 32 affected farms, the median case fatality rate was 25% (range, 0 to 100%). Case fatality rate was > 50% for 22% of affected farms. The median percentage of all foal deaths associated with R.equi pneumonia was 50%. These data indicate that on endemic farms, R.equi represents a major cause of foal deaths.
In another study of 220 foals at 2 endemic farms in Texas, 32 foals developed R.equi and of those 4 (12.5%) died (Chaffin 2003).
In a retrospective study (Ainsworth 1998) including 6 veterinary medical teaching hospitals, the overall survival rate of foals with pneumonia caused by R.equi was 72% and the proportion of foals that survived was significantly higher in Standardbreds (80%) than in Thoroughbreds (61%). Clinical or hematologic variables associated with survival from pneumonia caused by R.equi have varied considerably among studies. In one study of 115 cases (Ainsworth 1998), foals with extreme tachycardia, respiratory distress, and severe radiographic changes were less likely to survive, whereas clinicopathologic abnormalities were not associated with survival.
In another study (Falcon 1985) involving 39 foals, respiratory rate, temperature, WBC counts, and fibrinogen concentrations were significantly higher in nonsurvivors. In another study (Giguere 2004) radiographic scores, heart rate, and fibrinogen concentrations were significantly higher in nonsurvivors, whereas PaO2 and platelet counts were significantly higher in survivors.
Foals with abdominal abscesses is generally poor, although occasional patients will respond to antimicrobial treatment. Surgical removal has been attempted in some foals, but abdominal adhesions usually result in an inability to surgically resect the lesion(s).
Athletic performance of foals recovering from R.equi pneumonia
Foals that respond favorable to treatment and recover completey appear to perform athletically later in life, without residual pulmonary deficits.
In a retrospective study, Ainsworth (1998) showed that 45 of 83 (54%) foals that survived R.equi pneumonia eventually raced at least once, which was less than the general racing population. Racing performance of foals that raced as adults was not significantly different from that of the general racing population of the USA. The authors concluded that R.equi infection in foals is associated with a decreased chance of racing as an adult; however, foals that eventually go on to race perform comparably to the general racing population.
In another study, Ainsworth (1993) studied the effect of prior R.equi-induced pneumonia on pulmonary health in 5 horses (< 24 months old) using endoscopy, radiography, hematologic and bronchoalveolar lavage analyses, and pulmonary function testing. R.equi-induced pneumonia had been diagnosed in the 5 horses when they were foals. Results were compared with those of 5 age-matched healthy horses that lacked clinical or historical evidence of foalhood pneumonia. Significant differences in variables between the 2 groups of horses were not evident. The authors concluded that horses previously infected with and successfully treated for R.equi-induced pneumonia do not have detectable evidence of residual lung damage.
Funkquist (2002) studied pulmonary function and gas exchange during exercise for 7 Standardbred horses (3 years of age) that had R.equi pneumonia as foals. The gas exchange in Standardbred trotters previously infected with R.equi and successfully treated was not compromised during intense treadmill exercise compared with reference values for healthy, fit Standardbreds.
Bernard (1991) showed that R.equi pneumonia were not negatively affected in regards to their 2- and 3-year-old race earnings. Christley (1994) studied 11 horses previously affected with R.equi pneumonia – 7 of them raced as adults and 4 won at least 1 race.