Mastitis

The following is a letter from Dr. Benjamin Darien of the University of Wisconsin to CSA BioTech.

It is with great pleasure that I wish to thank you for the opportunity to investigate the efficacy of your ceragenin compound, CSA-44, as a novel new animal drug for the treatment of bovine mastitis. Using in vitro, ex-vivo and most recently, in vivo methodologies, I have pushed the therapeutic spectrum of CSA-44 as a first line antimicrobial for bovine mastitis. For celerity purposes, I have summarized my findings below by bullet point.

1. MIC90 established for CSA-44 against the major gram positive and gram-negative bovine mastitis pathogens.

a. We Used the FDA required Clinical and Laboratory Standards Institute (CLSI) guidelines for Performance Standards for Antimicrobial Disk and Dilution Susceptibility Tests for Bacteria Isolated from Animals

b. CSA-44 has in vitro MIC90 efficacy, the CSA-44 concentration (ug/mL) at which 90% of the same bacteria are susceptible.

c. CSA-44 demonstrates in vitro efficacy with Coagulase-negative staphylococci, Streptococcus dysgalactiae, Escherichia coli and clinical and subclinical Staphylococcus aureus

d. If you pursue CSA-44 in bovine mastitis clinical trials, I am confident you will be successful in achieving these claims.

2. CSA-44 has efficacy in treating pathogenic E. coli strains that attach and invade bovine mammary epithelial cells.

a. I used immortalized and primary bovine mammary epithelial cells and standardized adhesion and invasion methodologies to investigate CSA-44 antimicrobial efficacy.

b. Preliminary studies support the pharmacologic properties of CSA, a lipophilic compound with both and bactericidal activity and the ability to penetrate tissue (mammary epithelial cells).

c. That CSA-44 is a weak base, the mastitic environment is ideal for the CSA compound. CSA-44 will stay within the mammary gland and penetrate the tissue to kill invading pathogens.

3. In vivo studies confirm CSA-44 efficacy in treating a broad base of gram-negative and gram-positive pathogens responsible for naturally occurring acute and chronic bovine mastitis.

a. To date, I have treated almost 15 cases of naturally occurring acute mastitis and several cases of recurrent subclinical mastitis.

b. Comparing the clinical cure rate with the susceptibility results suggest that CLSI established break-point is well within the pharmacodynamics CSA-44 as an intramammary infusion.

4. Unique to CSA and not shared by any mastitis drug on the market (or in production, that I’m aware of), are its intrinsic biological properties!

a. CSA-44 is an almost natural compound, which breaks down to cholic acid (an approved FDA Food Safety compound) and amines, which are broken down by the natural microbiota.

b. That CSA-44 breaks down in a natural, biological process in conjunction with strong data demonstrating that CSA does not induce drug resistance will greatly facilitate its evaluation by FDA.

c. It is conceivable that CSA-44 could achieve a zero-with drawl label claim!

I want to thank you for the opportunity to evaluate this compound independent of your influences. I wish you great success in pursuing an NADA for CSA-44 for intramammary infusion to treat infectious bovine mastitis.

Most sincerely,

Benjamin J. Darien, DVM, MS, Diplomat ACVIM

Mastitis

THE PROBLEM

The cost of treating clinical-bovine mastitis, worldwide, is estimated at over $5 billion a year. The current products are primarily antibiotics that are effective against some of the gram-positive pathogens causing mastitis, but less effective against gram-negative pathogens, and for some pathogens, there is no FDA approved cure.

In 2008 there were 9,248,000 million dairy cows in the US. There are 238 million dairy cattle worldwide. Bovine mastitis is the most common and most costly disease of dairy cattle. Bovine Mastitis leads to drastic milk losses, premature culling of genetically superior cows, drug cost, veterinary cost, increased labor, milk withholding after treatment, reduced genetic improvement, changes in the hygienic and compositional quality of milk and impairment of the technological properties of milk, and decreased reproductive performance. Additionally, mastitis can be harmful to suckling newborns.

Mastitis affects every dairy farm and approximately 38% of dairy cows in the United States. At any given time there are 2-4% of all cattle that are out of commission due to clinical mastitis. The National Mastitis Council estimates that this devastating disease complex costs the dairy industry more than 2 billion dollars per year or approximately $180 to $200 per cow. These losses are primarily due to lost milk production and discarded milk (reduced milk accounts for about 70% of the total loss ), increased veterinary costs, and increased cow mortality.

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