Bromhexine Hydrochloride 8.6mg/g
For the treatment of respiratory infections in horses due to organisms susceptible to the combination of sulfadimidine and trimethoprim.
Bromo Tmps Oral Powder provides broad spectrum antibacterial and mucolytic activity in a palatable oral powder. It is indicated for the treatment of respiratory infections caused by organisms susceptible to a combination of sulfadimidine and trimethoprim, as seen in pneumonia in foals, strangles, and in complicated equine viral respiratory disease. Bromhexine is an effective mucolytic reducing clinical signs and complications of respiratory disease. Using Bromo Tmps Oral Powder avoids the adverse side effects such as sweating, excitation and tachycardia, often seen with the use of beta-adrenergic bronchodilators. Both sulfadimidine and trimethoprim are rapidly absorbed after oral administration, and reach therapeutic plasma levels within approximately 30 minutes after administration. Bacteria susceptible to this drug combination include, but are not limited to, Actinobacillus equuli, Escherichia coli, Powderurella caballi, Proteus vulgaris, Staphylococcus aureus, S. intermedius, Streptococcus equi subspecies equi and zooepidemicus. Bromhexine acts on respiratory goblet cells to reduce viscosity and tenacity of respiratory mucus increase the permeability of the alveolar/ capillary barrier, and increase gamma globulins IgA and IgG. Bromhexine is also rapidly absorbed after oral administration with peak plasma levels reached within one hour.
Sulfadimidine is a pyrimidine sulfonamide antimicrobial agent. Sulfonamides, being structural analogues of para-aminobenzoic acid (PABA), competitively inhibit the incorporation of PABA into dihydropteric acid, the precursor of folic acid. Subsequent reduction in the level of folic acid reduces the production of nucleic acids in sensitive bacteria. Mammalian cells require preformed folic acid and thus are unaffected by sulfonamides.
The antibacterial actions of sulfonamides are reduced in the presence of blood, pus and tissue breakdown products, which contain purines and thymidine, as the bacterial requirement for folic acid is decreased in such media. Sulfadimidine is readily absorbed following oral administration and therapeutic plasma levels are rapidly attained. Sulfadimidine is widely distributed to all body tissues and fluids. Concentrations are above plasma levels in kidney; similar to plasma levels in pleural, peritoneal, synovial and ocular fluids; slightly lower in CSF, muscle and milk. Sulfadimidine undergoes extensive metabolism via acetylation, hydroxylation, oxidation and conjugation. The parent compound and its metabolites are excreted predominantly in the urine by glomerular filtration. Sulfadimidine undergoes passive tubular resorption thus prolonging the time course of drug action. Plasma half-life in the horse has been variously estimated at between 6.4 and 9.8 hours.
Trimethoprim is a diaminopyrimidine antimicrobial agent. It acts by preventing the reduction of dihydrofolate to tetrahydrofolate which is required by bacteria for biosynthesis of purines, pyrimidines and some amino acids. Trimethoprim is readily absorbed from the gastrointestinal tract and, like sulfadimidine, rapidly reaches therapeutic levels in plasma. It is widely distributed in body tissues/fluids including bone, prostate, CSF, pleural, peritoneal, synovial and ocular fluids. Studies in humans and several animal species have demonstrated that trimethoprim reaches higher concentrations in all tissues, except brain, than those achieved in plasma. The drug is extensively metabolised in the horse and is excreted in the urine by glomerular filtration and active tubular secretion. Plasma half-life in the horse has been variously estimated at between 4.1 and 4.6 hours.
Sulfadimidine and trimethoprim have similar antibacterial spectra, trimethoprim being approximately 20 times more potent than sulfadimidine. The combination blocks two sequential obligate enzymatic reactions in the microbial folate synthetic pathway. A synergistic action is demonstrated by the enhanced antimicrobial activity (potentiation) of the combination compared with the antimicrobial activity of either agent singly. The minimum inhibitory concentrations (MICs) of the combination for susceptible bacteria are substantially lower than those of either of the individual agents. The combination of sulfonamide/trimethoprim is bactericidal while either drug alone is bacteriostatic. Folate-synthesising bacteria which are resistant or moderately resistant to either drug alone are frequently susceptible to the combination.
The correlation of antibacterial sensitivity in vitro cf. in vivo is among the highest of all antimicrobial agents. The spectrum of bacteria sensitive to the combination includes: Staphylococci, Streptococci, Fusobacterium, Enterobacter, Corynebacterium (excluding Corynebacterium [Rhodococcus] equi), Salmonella, Shigella, Klebsiella, Powderurella, Haemophilus, Proteus spp. and most E. coli; some Brucella and Nocardia spp. Most Pseudomonas spp. are insensitive. Resistance to the combination by gram-negative bacteria is associated with the presence of R Factors. Resistance by Staphylococcus aureus and Haemophilus spp .is chromosomal, and is rarely encountered except in patients previously exposed to the combination.
Bromhexine Hydrochloride is a synthetic derivative of the alkaloid, vasicine. Bromhexine acts selectively on mucopolysaccharide-producing goblet cells in the respiratory tract to a far greater extent than in other organs. Its action is threefold:
(i) Bromhexine causes de-polymerization of mucopolysaccharide, reducing viscosity and tenacity of respiratory mucus. This facilitates expectoration and suppresses tussive irritation. Increased production of highly viscous bronchial and alveolar secretion is not only a clinical sign of, but also an exacerbating factor in, respiratory disease. Disordered ciliary function and difficult expectoration set up a vicious cycle in which mucus tenacity may lead to chronic bronchitis. Bromhexine is a specific agent to prevent this complication. It has minimal secretolytic effect where mucus viscosity is initially low.
(ii) Bromhexine increases the permeability of the alveolar/capillary barrier. This increases the concentration of antibacterial agents in respiratory secretions, obtaining a greater luminal dose effect at the site of the disease.
(iii) There are specific protein changes in bronchial secretion following bromhexine administration. After 2 to 3 days there is a significant increase in gamma globulin and a decline in albumin and alpha globulin. The gamma globulins which increase are IgA and IgG. IgM is unchanged.
Bromhexine is rapidly absorbed following oral administration, peak plasma levels being reached within approx. 1 hour. It is lipophilic and rapidly redistributed from plasma into respiratory, liver and adipose tissue. Bromhexine undergoes extensive hepatic metabolism and is excreted via the urine and bile.
MICs of the 5:1 combination of sulfadimidine and trimethoprim for the major bacterial respiratory pathogens (primary and secondary) considered of clinical significance in the horse under Australian conditions have been established. Microrganisms used in MIC determination were isolated from clinical cases of respiratory disease, and are therefore of particular relevance to equine practice in Australia. A microrganism is considered susceptible if the mean drug concentration is twice the MIC for that microrganism. The following bacteria have been demonstrated sensitive to the combination at the recommended dose rate:
Proteus vulgaris Staphylococcus aureus
Streptococcus equi subspecies equi
Streptococcus equi ss zooepidemicus
The degree of potentiation attained by combining the two antimicrobial agents has been demonstrated in a study that revealed in all susceptible pathogens substantially lower MICs for the combination than for either agent alone. Antimicrobial activity of the combination was found to be up to 1024 times that of sulfadimidine alone, and up to 128 times that of trimethoprim alone.
Pharmacokinetic trials in horses have established that both sulfadimidine and trimethoprim are readily and rapidly absorbed after oral administration and reach therapeutic plasma levels within approximately 30 minutes of administration. Trial results demonstrate that the formulation is efficiently absorbed even when administered with food.
MICs of the sulfadimidine-trimethoprim combination vary widely for the range of respiratory pathogens which are of significance in equine respiratory disease. In order to ensure efficacy against the major equine respiratory pathogens, the dose rate of Bromo Tmps Oral Powder has been calculated to produce drug levels which would be therapeutic against those pathogens for which the MIC is greatest.
Once daily dosing of Bromo Tmps Oral Powder at recommended dose rates will produce average steady state levels of sulfadimidine/trimethoprim which are effective against many of the major bacterial respiratory pathogens of clinical significance in horses in Australia.
Twice daily dosing of Bromo Tmps Oral Powder is recommended in preference to once daily dosing as the minimum (trough) concentrations of sulfadimidine and trimethoprim are potentially subtherapeutic in some individuals for some sensitive pathogens under a once daily dose regimen.
DIRECTIONS FOR USE
For oral administration only. Administer on damp food with honey or molasses. Add one level scoop (12g) per 200kg bodyweight twice daily in feed. Twice daily dosing is recommended to maintain therapeutic levels of active drugs in all situations.
The degree of potentiation between sulfadimidine and trimethoprim allows for significantly reduced dosages of both drugs. Antimicrobial activity of the combination has been found to be up to 1024 times that of sulfadimidine alone, and up to 128 times that of trimethoprim alone. The spectrum of bacteria sensitive to this antibiotic combination includes; Staphylococci, Streptococci, Fusobacterium, Eneterobacter, Corynebacterium (excluding Rhodococcus equi), Salmonella, Shigella, Klebsiella, Powderurella, Haemophilus, Proteus spp and most E.coli, some Brucella and Nocardia spp. Most Pseudomonas spp are insensitive. Bacterial culture and sensitivity testing should be carried out in cases of nonresponsive or chronic infection.
MEAT WITHHOLDING PERIOD
DO NOT USE less than 28 days before slaughter for human consumption.
RACING/EVENT WITHHOLDING PERIOD
If used in performance animals, the regulations of the relevant authorities regarding medication should be observed.
Sulfadimidine may possibly affect development and/or reproduction. Trimethoprim may possibly affect bone. Handle with care.
If poisoning occurs, contact a doctor or Poisons Information Centre. Phone Australia 131126 or in New Zealand 0800 764 766. Additional information is listed in the Material Safety Data Sheet available from RANDLAB AUSTRALIA in Australia phone (02) 9534 8207 or in New Zealand (09) 298 3072.
Dispose of empty container by wrapping with paper and putting in garbage.
Store below 30°C (Room temperature). Protect from light. Keep lid tightly closed.
APVMA Approval No. 62490/500G/0308 (Australia)
ACVM 10112 (New Zealand)