300
EQUINE VETERINARY JOURNAL Eqiiiite iw. J . (1992) 24 (4) 300-304
Treatment of respiratory infections in horses with ceftiofur sodium S. D. FOLZ, 6.J. HANSON+. K. GRIFFIN, L. L. DINVALD, T. W. SWERCZEK*, R. D. WALKERt and J. H. FOREMANS Departments of Clinical Research/Product Development, Biostatistics & Research Information Systems, The Upjohn Company, Kalamazoo, Michigan 4900 1, USA; *Department of Veterinary Science, University of Kentucky, Lexington, Kentucky 40546, USA; tAnimal Health Diagnostic Laboratory, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan 48824, USA; and #Veterinary Medicine Teaching Hospital, College of Veterinary Medicine, University of Illinois, Urbana, Illinois 6 1807 , USA Summary Ceftiohr sodium was evaluated as a therapy for respiratory infections in horses. This cephalosporin antimicrobial was administered intramuscularly every 24 h and at a dose of 2.2 mglkg (1.0 mgllb) of body weight. The efficacy of ceftiofur sodium was compared with that of a positive control drug, ampicillin sodium (recommended dose of 6.6 mg/kg [3 mg/lb], given every 12 h). Both treatments were continued for 48 h after clinical symptoms were no longer evident (maximum of 10 days). Fifty-five (55) horses with naturally acquired respiratory infections were included in the study; 28 were treated with ceftiofur and 27 with ampicillin. Clinical improvement was recorded for 92.9% of the patients treated with ceftiofur and 92.6% of the animals receiving ampicillin. Both therapies reduced body temperatures to an afebrile level after 2 days of treatment. Complete recoverylcure was noted for 78.6% of the ceftiofur patients and 59.3% of the horses treated with ampicillin. Supporting variables (depressionlmalaise, respirationldyspnoea, nasal discharge) were assessed and these also substantiated the effectiveness of the treatments. Both antibiotics were well tolerated. Neither pain nor swelling were noted at the ceftiofur injection site(s). None of the animals developed diarrhoea. Data from this study indicated that ceftiofur sodium is an effective and safe treatment for respiratory infections in horses.
spread of pathogens to other tissues and duration of illness. The sodium salt of ceftiofur (Fig I), a new broad-spectrum plactamase-resistant cephalosporin, has potent antimicrobial activity (Yancey er a/ 1987). This drug has been shown to be efficacious for treatment of respiratory infections in cattle (Martel 1988; Gustin, Landser, Lomba and Lekeux 1990). and approved for use in beef and lactating cattle, and pigs in many countries. The recommended dosage in cattle is 1.1-2.2 m@g bodyweight, given once daily. In horses, 2.2 m a g (single treatment) achieved serum and lung drug levels adequate for inhibiting bacteria associated with respiratory infections (P. S. Jaglan, R. D. Roof, T. S. Arnold, T. D. Cox, D. R. Reeves and T. F. Flook, unpublished data). The study reported herein was designed to evaluate and compare the efficacy of ceftiofur sodium (2.2 m a g bwt, once daily) with an FDA-approved positive control drug.
Materials and methods Clinical investigators
Ten equine veterinary investigators were involved in this multilocation study, and included university clinicianslresearchers and equine practitioners. Each investigator collaborated with a microbiologist/microbiology laboratory for bacterial culture and pathogen identification.
Introduction MOST bacterial respiratory infections of horses are attributed to organisms that are normal inhabitants of the airway passages. They become clinically important when the animal is stressed and pulmonary defence mechanisms and/or clearance of bacteria are impaired. Streptococcus zooepidemicus is the most common cause of bacterial respiratory infections in horses (Bayly, Liggitt, Huston and Laegreid 1986). but other aerobes also are pathogenic (Reif 1979 Swerczek 1984; Moms 1984; Beech 1991). Bacteroides spp. and Clostridia spp. are the usual bacterial anaerobes causing disease in the respiratory tract (Sweeney, Divers and Benson 1985; Spurlock 1986). Successful treatment of respiratory infections in horses requires adequate host immunity, activated local pulmonary defence mechanisms and appropriate antibiotic therapy. New broad-spectrum antimicrobials that are effective for treatment of the common bacterial pathogens decrease the risk of toxicity,
CH,'
s-ca II
0
O
I
Na
) .X
Fig I : Striictrrre of cefrinfiir sodium
H2O
EQUINE VETERINARY JOURNAL
301
Patients
Eficacy parameters
For inclusion in this study, each horse had to meet the following Criteria: (a) rectal temperature equal to or greater than 102.5"F (39.2"C), and (b) minimally have one of the following respiratory infection characteristics: nasal discharge index > I , respiratory/dyspnoea index >I, or malaise/depression index > I . The indices were defined as follows: nasal discharge index, 1 = normaUabsent, 2 = serous discharge, 3 = purulent discharge; respiration/dyspnoea index, I = normal, 2 = abnormal respiration (respiratory rate 224, c60 respirations/min) and/or coughing, 3 = severely abnormal respiration (respiratory rate 260 respirations/min); malaise/depression index, 1 = normal (no depression), 2 = slightly depressed, 3 = moderately depressed, 4 = severely depressed and inactive. Throughout the study, each animal was scored daily for the above criteria. The mean ages for the horses in Group C (ceftiofur treatment) and Group A (ampicillin treatment) were 24.4 (range 5-96) and 21.8 (range 5-108) months, respectively. Sucking foals were not included in this study. Mean pre-treatment weights were 348.8 (range 144.1-909.1) and 302.1 (range 186.4-545.5) kg for Group C and Group A horses, respectively. Twenty-one (21) of Group C were purebred and 7 were of mixed breeding; 22 of Group A were purebred and 5 were of mixed breeding. Group C contained 15 males and 13 females, and Group A 14 males and 13 females.
The primary variables used to ascertain efficacy were overall recovery (number of animals completely recovered) and body temperature reduction (Day 3). Other supporting variables that were monitored included nasal discharge. malaise/depression, respiration/dyspnoea and body temperature (daily) while on treatment. On the last day of treatment and again at 7 days after treatment, each animal was scored for overall recovery/cure. The following index was used to categorise recovery on each of these days: 1 = complete recovery: clinical status (based on body temperature, respiration status, malaise status, nasal discharge) indicated respiratory infection had been completely resolved (animal was afebrile and asymptomatic); no additional antibiotic therapy needed for respiratory infection; 2 = partial recovery: clinical status indicated there had been clinical improvement. but the respiratory infection had not been completely resolved, additional antibiotic therapy recommended; 3 = treatment failure: no improvement in clinical status and additional antibiotic therapy needed for respiratory infection. The animals were also scored for nasal discharge, respiratioddyspnoea and malaise/depression (indices previously described).
Treatment
Horses meeting the specified inclusion criteria were assigned to a block or pair based on enrollment order. Within each block, one of the two treatments was randomly assigned to each horse. Concomitant antibacterial or anti-inflammatory therapies were not administered. The two treatments were ceftiofur sodium (Naxcel@ Sterile Powder, Excenel@ Sterile Powder, The Upjohn Company, Kalamazoo, MI, USA; 50 mg/ml) (Group C) or ampicillin sodium (Amp-Equine@, Beecham Laboratories, Bristol, TN, USA; 300 mg/ml) (Group A). For both treatments, a maximum of 10 ml was administered in isotonic saline per im injection site. All treatments were continued for 48 h after the animal became afebrile and asymptomatic, but did not exceed 10 days. Microbiology
Microbiological diagnostic procedures were utilised to identify the bacterial component(s) associated with the respiratory infection. When an animal met the inclusion criteria for the study, a transtracheal wash (preferred) or nasopharyngeal swab was obtained before treatment was initiated. The culture material was placed in transport medium and sent to a local microbiology laboratory for culture on blood agar and MacConkey's agar. Bacteria were identified by standard microbiological techniques. Thereafter those micro-organisms identified as potential pathogens were forwarded to Michigan State University for confirmation of identification and MIC testing. Susceptibility testing was performed on all of the viable isolates. Before MIC determination, identification of the bacterial isolates was confirmed using Vitek AMS@, API: N F P , AP1:Rapid Strep@, AP1:Staph Ident@, API:20E@ or by their biochemical reactions on triple-sugar iron agar, urea, motility-indole-ornithine,nitrate, trehalose, esculin and oxidase and catalase reactions. The MIC of each isolate was determined by standard procedures (Jones, Barry and Gavan 1985). and according to procedures outlined by the National Committee for Clinical Laboratory Studies (Waitz 1988). All isolates were tested in duplicate using separate plates for each replicate. The MIC was the lowest concentration of antibiotic for which no visible growth was observed, or the pellet was 52 mm in diameter.
Side-effectsladverse reactions
The investigators examined each of the animals daily for sideeffects and possible adverse reactions. This examination also included monitoring for clinical reactions (pain, swelling, host discomfort) at the injection sites. Statistical analysis
Although the study was initially planned as a randomized complete block design, some of the investigators did no complete all blocks. There were 7 incomplete, single-horse blocks, in addition to the 24 complete, paired-horse blocks. The difference in the mean temperature reduction between the two treatments was analysed using analysis of variance. Since two investigators had single observations, the difference between the effects of the two treatments by these investigators was statistically confounded; these two observations did not provide any additional information regarding treatment effects and so they were not used in the analysis. Their deletion from the analysis also eliminated the need to make assumptions to obtain estimates of the treatment differences. The success of the treatment was assessed using a weighted analysis of variance to compare the recovery rates of horses in the two treatments. To stabilise the variances of the cure rates, the data were transformed using the Freeman-Tukey transformation (Freeman and Tukey, 1950; Kotz and Johnson 1983). The use of this analysis necessitated the elimination of observations from incomplete blocks; the analysis therefore included the 48 observations from the 24 complete blocks. The analysis was performed using the GLM procedure of SAS (SAS 1990). In addition to the analysis of the primary variables, daily between-treatment differences of body temperature, nasal discharge, malaise/depression and respiration/dyspnoea were also examined for the treatment period and at 7 days after treatment. Differences in body temperature were analysed using analysis of variance as described above. The responses of the other variables were tested for relationships with the treatments using the Cochran-Mantel-Haenszel procedure of SAS (Koch and Edwards 1988; SAS 1990).
Results Before treatment, the horses in Groups C (N = 28) and A (N = 27) appeared clinically similar; in both groups there was a comparable spectrum of respiratory bacterial pathogens (Table 1).
EQUINE VETERINARY JOURNAL
302 104
3.0
103
2.5
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-
2
3
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E
8
5
102
Q)
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DPT Day
Day Fig 2 : Mean body temperature for horses treated with ceftiofur (0)or ampicillin (*). Day I was pretreatment; 7DPT was 7 days after treatment
TABLE 1: lncldence of bacterlal pathogens lnltlally cultured from horses Included In the study Organism Acinetobacter calcoaceticu~woffi Actinobacillus equuli/suis Aeromonas hydrophila Bacillus spp. Citrobacter freundii Enterobacter agglomerans/cioacae Escherichia coli Klebsiella pneumoniae/oxytoca Moraxella phenylpyruvica Pasteurella spp. Pseudomonas fluorescens Serratia spp Staphylococcus aureudintermedius Staphylococcusspp. Streptococcus equi Streptococcus zooepidemicus Streptococcus spp.
7 DPT
Group frequency distribution Ceftiofur Ampicillin Total
%
5
2
7
6.2
5
1
6
5.3
0 2 1 2
1 2 0 4
1 4 1 6
0.9 3.5 0.9 5.3
1 2
0 1
1 3
0.9 2.6
1 3 0 2 5
0 3 2 0 1
1 6 2 2 6
0.9 5.3 1.8 1.8 5.3
4 0 24
6 1 19
10 1 43
8.8 0.9 38.1
0
5
13
11.5
Fig 3: Mean nasal discharge rating for horses treated with ceftiofur (0) or ampicillin (*). Day I was pretreatment; 7DPT was 7 days after treatment. Index: I = normal, no discharge. 2 = serous discharge, 3 = purulent discharge
Transtracheal washes from 42 patients (21 in each group) were cultured; cultures from the remaining horses were obtained from nasopharyngeal swabs. The most common bacterial pathogen was Streptococcus zooepidemicus. Multiple bacterial respiratory pathogens were cultured from 10 horses in Group A and 15 in Group C. Mean body temperatures, nasal discharge, respiration/dyspnoea and malaise/depression indices for the two treatment groups are summarised in Figures 2-5. Mean body temperatures in both groups were highest immediately before treatment (Day I , Fig 2); all horses had a fever (>39.2"C [ 102.5'FI). In both groups body temperatures were reduced to an afebrile level shortly after treatment was initiated. Mean temperatures for both groups were
EQUINE VETERINARY JOURNAL Eqiiiite iw. J . (1992) 24 (4) 300-304
Treatment of respiratory infections in horses with ceftiofur sodium S. D. FOLZ, 6.J. HANSON+. K. GRIFFIN, L. L. DINVALD, T. W. SWERCZEK*, R. D. WALKERt and J. H. FOREMANS Departments of Clinical Research/Product Development, Biostatistics & Research Information Systems, The Upjohn Company, Kalamazoo, Michigan 4900 1, USA; *Department of Veterinary Science, University of Kentucky, Lexington, Kentucky 40546, USA; tAnimal Health Diagnostic Laboratory, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan 48824, USA; and #Veterinary Medicine Teaching Hospital, College of Veterinary Medicine, University of Illinois, Urbana, Illinois 6 1807 , USA Summary Ceftiohr sodium was evaluated as a therapy for respiratory infections in horses. This cephalosporin antimicrobial was administered intramuscularly every 24 h and at a dose of 2.2 mglkg (1.0 mgllb) of body weight. The efficacy of ceftiofur sodium was compared with that of a positive control drug, ampicillin sodium (recommended dose of 6.6 mg/kg [3 mg/lb], given every 12 h). Both treatments were continued for 48 h after clinical symptoms were no longer evident (maximum of 10 days). Fifty-five (55) horses with naturally acquired respiratory infections were included in the study; 28 were treated with ceftiofur and 27 with ampicillin. Clinical improvement was recorded for 92.9% of the patients treated with ceftiofur and 92.6% of the animals receiving ampicillin. Both therapies reduced body temperatures to an afebrile level after 2 days of treatment. Complete recoverylcure was noted for 78.6% of the ceftiofur patients and 59.3% of the horses treated with ampicillin. Supporting variables (depressionlmalaise, respirationldyspnoea, nasal discharge) were assessed and these also substantiated the effectiveness of the treatments. Both antibiotics were well tolerated. Neither pain nor swelling were noted at the ceftiofur injection site(s). None of the animals developed diarrhoea. Data from this study indicated that ceftiofur sodium is an effective and safe treatment for respiratory infections in horses.
spread of pathogens to other tissues and duration of illness. The sodium salt of ceftiofur (Fig I), a new broad-spectrum plactamase-resistant cephalosporin, has potent antimicrobial activity (Yancey er a/ 1987). This drug has been shown to be efficacious for treatment of respiratory infections in cattle (Martel 1988; Gustin, Landser, Lomba and Lekeux 1990). and approved for use in beef and lactating cattle, and pigs in many countries. The recommended dosage in cattle is 1.1-2.2 m@g bodyweight, given once daily. In horses, 2.2 m a g (single treatment) achieved serum and lung drug levels adequate for inhibiting bacteria associated with respiratory infections (P. S. Jaglan, R. D. Roof, T. S. Arnold, T. D. Cox, D. R. Reeves and T. F. Flook, unpublished data). The study reported herein was designed to evaluate and compare the efficacy of ceftiofur sodium (2.2 m a g bwt, once daily) with an FDA-approved positive control drug.
Materials and methods Clinical investigators
Ten equine veterinary investigators were involved in this multilocation study, and included university clinicianslresearchers and equine practitioners. Each investigator collaborated with a microbiologist/microbiology laboratory for bacterial culture and pathogen identification.
Introduction MOST bacterial respiratory infections of horses are attributed to organisms that are normal inhabitants of the airway passages. They become clinically important when the animal is stressed and pulmonary defence mechanisms and/or clearance of bacteria are impaired. Streptococcus zooepidemicus is the most common cause of bacterial respiratory infections in horses (Bayly, Liggitt, Huston and Laegreid 1986). but other aerobes also are pathogenic (Reif 1979 Swerczek 1984; Moms 1984; Beech 1991). Bacteroides spp. and Clostridia spp. are the usual bacterial anaerobes causing disease in the respiratory tract (Sweeney, Divers and Benson 1985; Spurlock 1986). Successful treatment of respiratory infections in horses requires adequate host immunity, activated local pulmonary defence mechanisms and appropriate antibiotic therapy. New broad-spectrum antimicrobials that are effective for treatment of the common bacterial pathogens decrease the risk of toxicity,
CH,'
s-ca II
0
O
I
Na
) .X
Fig I : Striictrrre of cefrinfiir sodium
H2O
EQUINE VETERINARY JOURNAL
301
Patients
Eficacy parameters
For inclusion in this study, each horse had to meet the following Criteria: (a) rectal temperature equal to or greater than 102.5"F (39.2"C), and (b) minimally have one of the following respiratory infection characteristics: nasal discharge index > I , respiratory/dyspnoea index >I, or malaise/depression index > I . The indices were defined as follows: nasal discharge index, 1 = normaUabsent, 2 = serous discharge, 3 = purulent discharge; respiration/dyspnoea index, I = normal, 2 = abnormal respiration (respiratory rate 224, c60 respirations/min) and/or coughing, 3 = severely abnormal respiration (respiratory rate 260 respirations/min); malaise/depression index, 1 = normal (no depression), 2 = slightly depressed, 3 = moderately depressed, 4 = severely depressed and inactive. Throughout the study, each animal was scored daily for the above criteria. The mean ages for the horses in Group C (ceftiofur treatment) and Group A (ampicillin treatment) were 24.4 (range 5-96) and 21.8 (range 5-108) months, respectively. Sucking foals were not included in this study. Mean pre-treatment weights were 348.8 (range 144.1-909.1) and 302.1 (range 186.4-545.5) kg for Group C and Group A horses, respectively. Twenty-one (21) of Group C were purebred and 7 were of mixed breeding; 22 of Group A were purebred and 5 were of mixed breeding. Group C contained 15 males and 13 females, and Group A 14 males and 13 females.
The primary variables used to ascertain efficacy were overall recovery (number of animals completely recovered) and body temperature reduction (Day 3). Other supporting variables that were monitored included nasal discharge. malaise/depression, respiration/dyspnoea and body temperature (daily) while on treatment. On the last day of treatment and again at 7 days after treatment, each animal was scored for overall recovery/cure. The following index was used to categorise recovery on each of these days: 1 = complete recovery: clinical status (based on body temperature, respiration status, malaise status, nasal discharge) indicated respiratory infection had been completely resolved (animal was afebrile and asymptomatic); no additional antibiotic therapy needed for respiratory infection; 2 = partial recovery: clinical status indicated there had been clinical improvement. but the respiratory infection had not been completely resolved, additional antibiotic therapy recommended; 3 = treatment failure: no improvement in clinical status and additional antibiotic therapy needed for respiratory infection. The animals were also scored for nasal discharge, respiratioddyspnoea and malaise/depression (indices previously described).
Treatment
Horses meeting the specified inclusion criteria were assigned to a block or pair based on enrollment order. Within each block, one of the two treatments was randomly assigned to each horse. Concomitant antibacterial or anti-inflammatory therapies were not administered. The two treatments were ceftiofur sodium (Naxcel@ Sterile Powder, Excenel@ Sterile Powder, The Upjohn Company, Kalamazoo, MI, USA; 50 mg/ml) (Group C) or ampicillin sodium (Amp-Equine@, Beecham Laboratories, Bristol, TN, USA; 300 mg/ml) (Group A). For both treatments, a maximum of 10 ml was administered in isotonic saline per im injection site. All treatments were continued for 48 h after the animal became afebrile and asymptomatic, but did not exceed 10 days. Microbiology
Microbiological diagnostic procedures were utilised to identify the bacterial component(s) associated with the respiratory infection. When an animal met the inclusion criteria for the study, a transtracheal wash (preferred) or nasopharyngeal swab was obtained before treatment was initiated. The culture material was placed in transport medium and sent to a local microbiology laboratory for culture on blood agar and MacConkey's agar. Bacteria were identified by standard microbiological techniques. Thereafter those micro-organisms identified as potential pathogens were forwarded to Michigan State University for confirmation of identification and MIC testing. Susceptibility testing was performed on all of the viable isolates. Before MIC determination, identification of the bacterial isolates was confirmed using Vitek AMS@, API: N F P , AP1:Rapid Strep@, AP1:Staph Ident@, API:20E@ or by their biochemical reactions on triple-sugar iron agar, urea, motility-indole-ornithine,nitrate, trehalose, esculin and oxidase and catalase reactions. The MIC of each isolate was determined by standard procedures (Jones, Barry and Gavan 1985). and according to procedures outlined by the National Committee for Clinical Laboratory Studies (Waitz 1988). All isolates were tested in duplicate using separate plates for each replicate. The MIC was the lowest concentration of antibiotic for which no visible growth was observed, or the pellet was 52 mm in diameter.
Side-effectsladverse reactions
The investigators examined each of the animals daily for sideeffects and possible adverse reactions. This examination also included monitoring for clinical reactions (pain, swelling, host discomfort) at the injection sites. Statistical analysis
Although the study was initially planned as a randomized complete block design, some of the investigators did no complete all blocks. There were 7 incomplete, single-horse blocks, in addition to the 24 complete, paired-horse blocks. The difference in the mean temperature reduction between the two treatments was analysed using analysis of variance. Since two investigators had single observations, the difference between the effects of the two treatments by these investigators was statistically confounded; these two observations did not provide any additional information regarding treatment effects and so they were not used in the analysis. Their deletion from the analysis also eliminated the need to make assumptions to obtain estimates of the treatment differences. The success of the treatment was assessed using a weighted analysis of variance to compare the recovery rates of horses in the two treatments. To stabilise the variances of the cure rates, the data were transformed using the Freeman-Tukey transformation (Freeman and Tukey, 1950; Kotz and Johnson 1983). The use of this analysis necessitated the elimination of observations from incomplete blocks; the analysis therefore included the 48 observations from the 24 complete blocks. The analysis was performed using the GLM procedure of SAS (SAS 1990). In addition to the analysis of the primary variables, daily between-treatment differences of body temperature, nasal discharge, malaise/depression and respiration/dyspnoea were also examined for the treatment period and at 7 days after treatment. Differences in body temperature were analysed using analysis of variance as described above. The responses of the other variables were tested for relationships with the treatments using the Cochran-Mantel-Haenszel procedure of SAS (Koch and Edwards 1988; SAS 1990).
Results Before treatment, the horses in Groups C (N = 28) and A (N = 27) appeared clinically similar; in both groups there was a comparable spectrum of respiratory bacterial pathogens (Table 1).
EQUINE VETERINARY JOURNAL
302 104
3.0
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7 8 9 1 0
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7
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2 3 4 5 6 7 8 9 1 0
DPT Day
Day Fig 2 : Mean body temperature for horses treated with ceftiofur (0)or ampicillin (*). Day I was pretreatment; 7DPT was 7 days after treatment
TABLE 1: lncldence of bacterlal pathogens lnltlally cultured from horses Included In the study Organism Acinetobacter calcoaceticu~woffi Actinobacillus equuli/suis Aeromonas hydrophila Bacillus spp. Citrobacter freundii Enterobacter agglomerans/cioacae Escherichia coli Klebsiella pneumoniae/oxytoca Moraxella phenylpyruvica Pasteurella spp. Pseudomonas fluorescens Serratia spp Staphylococcus aureudintermedius Staphylococcusspp. Streptococcus equi Streptococcus zooepidemicus Streptococcus spp.
7 DPT
Group frequency distribution Ceftiofur Ampicillin Total
%
5
2
7
6.2
5
1
6
5.3
0 2 1 2
1 2 0 4
1 4 1 6
0.9 3.5 0.9 5.3
1 2
0 1
1 3
0.9 2.6
1 3 0 2 5
0 3 2 0 1
1 6 2 2 6
0.9 5.3 1.8 1.8 5.3
4 0 24
6 1 19
10 1 43
8.8 0.9 38.1
0
5
13
11.5
Fig 3: Mean nasal discharge rating for horses treated with ceftiofur (0) or ampicillin (*). Day I was pretreatment; 7DPT was 7 days after treatment. Index: I = normal, no discharge. 2 = serous discharge, 3 = purulent discharge
Transtracheal washes from 42 patients (21 in each group) were cultured; cultures from the remaining horses were obtained from nasopharyngeal swabs. The most common bacterial pathogen was Streptococcus zooepidemicus. Multiple bacterial respiratory pathogens were cultured from 10 horses in Group A and 15 in Group C. Mean body temperatures, nasal discharge, respiration/dyspnoea and malaise/depression indices for the two treatment groups are summarised in Figures 2-5. Mean body temperatures in both groups were highest immediately before treatment (Day I , Fig 2); all horses had a fever (>39.2"C [ 102.5'FI). In both groups body temperatures were reduced to an afebrile level shortly after treatment was initiated. Mean temperatures for both groups were
