Beyond the antimicrobial: what's the evidence for adding another drug for infectious diseases? (Proceedings)

In this session we will take an evidence-based medicine approach to ancillary therapy of bovine respiratory disease, bovine toxic mastitis, bovine neonatal enteric disease, and retained placenta/metritis. The literature reviewed here is not presented as being all-inclusive, but rather as a summary of many commonly cited articles on these subjects. The citations are primarily peer reviewed, but some are from freedom of information (FOI) summaries and a few are proceedings papers or abstracts. The depth of the information is beyond the scope of this proceedings paper, so references and discussion are provided here only for the respiratory disease portion. References and discussions will be available for toxic mastitis, enteric disease, retained placenta/metritis from the author.

Bovine respiratory disease

No published data could be found to support the use of Vitamin B or C, vaccines (at the time of therapy), antihistamines, anthelmintics, probiotics, or oral electrolytes in the ancillary therapy of bovine respiratory disease. For the purposes of this presentation, we will examine the published data concerning the use of steroidal and non-steroidal anti-inflammatory drugs as ancillary therapy for respiratory disease.

Glucocorticosteroids?

Decades after publication of the study described here, there is still only one published clinical trial addressing the use of steroids for ancillary therapy of BRD as you would encounter it clinically in the United States. One of two treatments was administered to animals identified as displaying clinical signs of BRD. Common drugs for the two treatment groups included IV oxytetracycline (5 mg/lb) and IM pyrelamine (250 mg total dose) on a daily basis for 3 days. Treatment group 1 also received 20 mg dexamethasone every day while treatment group 2 received a 10 ml placebo injection. The same treatments for each group were continued through day 9, as needed, for non-responders. Response was significantly different at P ≤ 0.05 and relapse rate was significantly different at P ≤ 0.01.

These findings aren't that surprising since dexamethasone, at 0.04 mg/kg daily (0.9 ml/100 lbs of a 2 mg/ml solution) for 3 days, is used as a research model to suppress neutrophil function in cattle. This model was utilized in small Holstein calves in conjunction with induced Haemophilus somnus pneumonia to demonstrate that this dexamethasone regimen increased lung lesions. An IBR latency model in rabbits demonstrated that a single high-dose injection of dexamethasone (2.8 mg/kg) could bring about reactivation of latent BHV-1. Other studies have failed to show significant differences in treatment response using prednisone acetate, methyl prednisolone, or methyl-prednisolone-succinate in natural and induced respiratory disease.

Non-Steroidal Anti-inflammatory Drugs (NSAIDS)

The NSAID currently labeled specifically for BRD in the United States is Flunixin meglumine (Banamine® Injectable Solution, Schering-Plough Animal Health). The label includes indications for the control of pyrexia associated with bovine respiratory disease, acute bovine mastitis, and endotoxemia. The inflammation indication on the label is for the control of inflammation in endotoxemia. Flunixin meglumine is considered an effective analgesic, anti-inflammatory, and antipyretic. The mechanism of action is cyclooxygenase inhibition.

The outlines below summarize published studies and the Freedom of Information (FOI) summaries of flunixin meglumine effects on respiratory disease outcome.

Flunixin BRD study 1

12 week old dairy calves, induced Pasteurella haemolytica pneumonia 4 treatment groups - no treatment, oxytetracycline (10 mg/kg IM SID for 3 days), flunixin meglumine (2.2 mg/kg IV SID for 3 days), and both oxytetracycline and flunixin meglumine. Results: Flunixin combined with oxytetracycline reduced lung lesions and dropped rectal temperature more quickly than OTC or flunixin alone.

Flunixin BRD study 2

12-week-old calves, PI3 virus administered into the upper airways. 2 treatment groups: Flunixin meglumine (2.2 mg/kg IV SID for 3 days) and controls. Results: Flunixin reduced the number of calves coughing, the number of calves with fever (> 39.7° C), and the number of calves with tachypnea as compared to untreated controls. There was a marked decrease in pulmonary consolidation in the treated group.

Fluinxin BRD study 3

Calves receiving 3 methylindole (3MI) intratracheally 2 treatment groups: flunixin meglumine (2.2 mg/kg) on the mornings of days 1, 2, and 3 when they started displaying respiratory rates twice that of baseline, and negative controls. Results: Respiratory rates of the treated calves did not significantly differ from that of environmental controls which did not receive the 3MI, while the untreated calves which received 3MI had significantly elevated respiratory rates. Flunixin calves had much less pronounced alveolar epithelial hyperplasia as compared to controls.

Flunixin BRD study 4

Housed beef calves, undifferentiated respiratory disease (a rectal temperature > 39.5° C, respiratory rate > 30/minute, and an increased respiratory effort). Further treatment based on a rectal temperature of 39.5° C on day 4. 2 treatment groups: Tilmicosin phosphate (10 mg/kg SC, once) vs. therapy with tilmicosin phosphate (10 mg/kg SC, once) combined with flunixin meglumine (2.2 mg/kg IV, once). Results: 17/51 tilmicosin calves (27.9 %) required further therapy while 9/58 tilmicosin/flunixin calves (15.5 %) were treated again. This difference was not significant. No mortalities occurred.

Flunixin BRD study 5

Freedom of Information Summary study. 363 calves (heifers, steers, and bulls) 6-12 months old (mean weight 420 lbs.) at 3 locations. Naturally occurring respiratory disease. 2 treatment groups: OTC injectable solution administered for 3 consecutive days at 10 mg/kg (4.5 mg/lb.) IM, as compared to OTC injectable solution (as above) plus flunixin meglumine at 2.2 mg/kg SID for 1-3 days (administered again on days 2 and 3 if temp. not below 104.0° F). Duration of study: 10 days, treatment failure was defined as developing severe recurrent respiratory disease (score of 3 or more on scale of 0=normal, 1=slightly ill, 2=moderately ill, 3=very ill, and 4-moribund) from the end of the 3 days of treatment to the end of the study. Results: No significant difference in mortality, flunixin led to a significant improvement in character of respiration and lower rectal temperature. 47/179 (26%) failures in OTC group, 40/181 (22%) in OTC/f group. Not statistically significant, little or no difference in lung pathology between groups, OTC group numerically superior to OTC/f group in weight gain (16.5 lbs. Vs. 10.6 lbs. respectively) but this was not significantly significant.

Flunixin BRD study 6

Freedom of Information Summary #2. 81 male Holstein calves (3-4 months, mean 82.3 kg) with naturally occurring BRD (acute clinical signs of pneumonia with elevated rectal temp ≥104.0 ° F and respiratory rate ≥ 40/minute). 2 treatments: OTC injectable solution administered for 3 consecutive days at 10 mg/kg (4.5 mg/lb.) IM, as compared to OTC injectable solution (as above) plus flunixin meglumine at 2.2 mg/kg SID for 1-3 days (administered again on days 2 and 3 if temp. not below 104.0° F). Results: No deaths during the study, there were more clinically normal animals in OTC/f group on days 2 and 3. Statistically significant and a statistically significant advantage in rectal temperature to OTC/f group on days 1, 2, and 3. For treatment failures, 40% treatment failures in OTC/f group, 47% treatment failures in OTC group. 44% of the OTC treatment group occurred on day 3, while 24% of the OTC/f treatment failures occurred on day 3. Weight gain – 4.6 kg for OTC/f, 4.0 KG for OTC. Not statistically significant.

What about other NSAIDs for ancillary therapy of BRD?

If there is published evidence that phenylbutazone or aspirin change therapeutic outcome in BRD therapy I have not been able to find it. The pharmacokinetics, published anti-inflammatory effects in cattle, and dosing strategies of these compounds in cattle have been previously summarized. Practitioners should be aware that the residue potential of phenylbutazone in cattle is coming under increased scrutiny.

A report evaluating Meloxicam has provided, to our knowledge, the first evidence of a demonstrated economic benefit to using a NSAID in the treatment of respiratory disease in feedlot cattle. In animals treated for BRD, mean average daily gain and mean carcass weight were superior in the meloxicam treated cattle.

A clinical trial was undertaken to investigate the efficacy of a single dose of carprofen (CPF) in the treatment of bovine respiratory disease in cattle. Tilmicosin was used as a basal treatment in all animals. Six hours after dosing, body temperature and respiratory rates in animals treated with CPF-tilmicosin had decreased and were significantly lower than in the animals treated with tilmicosin alone (P < 0.05). Over the period of clinical observation, CPF-tilmicosin treatment produced a clinical resolution of the pneumonia similar to treatment with tilmicosin alone.

A study comparing treatment of naturally occurring respiratory disease treated with ceftiofur alone or in combination with carprofen, flunixin meglumine or ketoprofen has been published. During the first 24 hours of the study, the pyrexia of the three groups treated with a NSAID was reduced significantly more than the pyrexia of the group treated with ceftiofur alone, and two and four hours after treatment the reduction in pyrexia was significantly greater in the groups treated with flunixin and ketoprofen than in the group treated with carprofen. There were no statistically significant differences between the four groups with respect to depression, illness scores, dyspnoea or coughing. There was less lung consolidation in the three groups treated with a NSAID than in the animals treated with ceftiofur alone, but the difference was significant only in the group treated with flunixin.

A study evaluating diclofenac and flunixin as adjuncts to BRD therapy in Holsteins also included a control group. During the first 48 h, improvement of adverse signs of respiratory disease, such as pyrexia and elevated respiratory rate, and of a high clinical index score was significant in the two adjunct groups compared with the calves receiving antibiotic alone. The reduction in pyrexia was greatest in the diclofenac group. There were no statically significant differences between treatment groups with regard to eventual perceived recovery from respiratory disease in 14 days.

References

Christie BM, Pierson RE, Braddy PM, et al. Efficacy of corticosteroids as supportive therapy for bronchial pneumonia in yearling feedlot cattle. Bov Pract 12:115-117, 1977.

Roth JA, Kaeberle ML. In vivo effect of ascorbic acid on neutrophil function in healthy and dexamethasone-treated cattle. Am J Vet Res 46:2434-2436, 1985.

Chiang YW, Roth JA, Andrews JJ. Influence of recombinant bovine interferon gamma and dexamethasone on pneumonia attributable to Haemophilus somnus in calves. Am J Vet Res 51: 759-762, 1990

Rock D, Lokensgard TL, Kutish G. Characterization of dexamethasone-induced reactivation of latent bovine herpesvirus1. Journal of Virology 66:2484-2490, 1992.

Espinasse J, Bost F, Madelenat A, et al. Efficacite d'une nouvelle cephalosporine (ceftiofur) associee ou non a un antiinflammatoire steroidien (succinate de methyl prednisolone) dans un modele experimental de Pasteurellose respiratoire du veau a Pasteurella haemolytica bio-serogroupe A1. In Proceedings, XVII World Buiatrics Congress, XXV American Association of Bovine Practitioners Conference, St. Paul, MN, 1992:159-164.

Espinasse J, Allaire R, Raynaud JP. Combined corticosteroid and antibiotic therapy in bovine respiratory disease (BRD) of young cattle: Clinical Results. The Bovine Practitioner 21:59-61, 1986.

Selman IE, Allan EM, Dalgleish RG, et al. Evaluation of the efficacy of flunixin meglumine using four different experimentally induced bovine respiratory disorders. Proceedings, Int Symp Nonsteroidal Anti-inflammatory agents. 1986:23-32.

Selman IE, Allan EM, Gibbs HA, et al. Effect of anti-prostaglandin therapy in experimental parainfluenza type 3 pneumonia in weaned, conventional calves. Vet Rec 115:101-105, 1984.

Selman IE, Allan EM, Gibbs HA, et al. The effect of antiprostaglandin therapy in an acute respiratory distress syndrome induced in experimental cattle by the oral administration of 3, methylindole. The Bovine Practitioner 22:124-126, 1985.

Scott PR. Field study of undifferentiated respiratory disease in housed beef calves. Vet Rec 134:325-327, 1994.

Apley MD. Ancillary Therapy of Bovine Respiratory Disease, in The Veterinary Clinics of North America, Food Animal Practice, Update on Bovine Respiratory Disease, W. B. Saunders, Philadelphia. 13(3):1997.

Friton G, Cajal, C, et al. Pharmaco-economic benefit of Meloxicam (Metacam) in the treatment of respiratory disease in feedlot cattle. Proceedings of 23rd World Buiatrics Conference, Vol 34, 2004. And also Friton Gm, Cajal C, et al. Long-term effects of meloxicam in the treatment of respiratory disease in fattening cattle Vet Rec 156(25), 809-11,2005.

Elitok B, Elitok OM. Clinical efficacy of carprofen as an adjunct to the antibacterial treatment of bovine respiratory disease J Vet Pharmacol Ther. 2004 Oct;27(5):317-20.

Lockwood PW, Johnson JC, et al. Clinical efficacy of flunixin, carprofen and ketoprofen as adjuncts to the antibacterial treatment of bovine respiratory disease. Vet Rec 142:392-392, 2003.

Guzel M, karakurum MC, Durgut R, et al. Clinical efficacy of diclofenac sodium and flunixin meglumine as adjuncts to antibacterial treatment of respiratory disease of calves. Aust Vet J 88:236-239, 2010