Q&A Other

Answers to Frequently Asked Questions
About PIRSUE® Sterile Solution

(pirlimycin hydrochloride)

Importance of Staph and Strep Mastitis

What is the incidence of staphylococcal and streptococcal mastitis, and what is their impact on the dairy industry?
These figures will vary from location to location (Schukken, et al., 1989). In the two Zoetis studies (TR 782-9690-90-001 and TR 782-9690-90-002), gram-positive organisms comprised 84-90 percent of bacteria isolated from positive cultures. Gram-positive bacteria sensitive to PIRSUE isolated in these trials would include Bacillus cereus, Corynebacterium bovis, C. pyogenes, S. aureus, Staphylococcus spp., S. agalactiae and non-agalactia Streptococcus. With the annual loss per cow for mastitis estimated at $181 (US dollars), staph and strep mastitis cause a large percentage of this loss.

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PIRSUE Spectrum of Control

What is the spectrum of PIRSUE Sterile Solution?
PIRSUE Sterile Solution has been proven effective against Staphylococcus species such as Staphylococcus aureus and Streptococcus species such as Streptococcus agalactiae, Streptococcus dysgalactiae and Streptococcus uberis.

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Clinical and Subclinical Mastitis

What is the difference between clinical and subclinical mastitis, and how was PIRSUE tested on these types of mastitis?
Clinical mastitis is characterized by the presence of abnormal milk. Most types of clinical mastitis are treated with intramammary infusion. Many of these cows with clinical mastitis show few systemic clinical signs.

In subclinical mastitis infections, the cow may be harboring an infection, but it is not evident in the milk appearance. These cows can be identified with somatic cell count and microbiology. The veterinarian can diagnose the type of subclinical infection and recommend the proper course of treatment. PIRSUE has been shown to be effective against subclinical quarters.

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Is PIRSUE an effective treatment for clinical mastitis?

PIRSUE was developed as a primary treatment for mastitis. The trials to establish efficacy were done on actual clinical mastitis. PIRSUE is the only product on the market whose dosage was determined by its efficacy against clinical mastitis. This dose was confirmed during two trials where, again, the criterion for efficacy was clinical mastitis, regardless of the pathogen causing the problem.

In all of these efficacy trials, PIRSUE has been shown to be very effective in the treatment of clinical mastitis from the standpoint of bacteriologic cure, proportion of quarters returning to normal milk and time to return to normal milk. PIRSUE has excellent efficacy on gram-positive organisms, which are responsible for a large majority of clinical mastitis treated by dairymen. PIRSUE has a short milk discard period (36 hours in the United States). An antibiotic sensitivity disc is available and was developed using veterinary mastitis pathogens. PIRSUE provides a complete package for the treatment of clinical mastitis.

What are appropriate additional therapies to be used with PIRSUE for cows with systemic clinical signs?

No clinical, residue or metabolism data have been generated to support the use of PIRSUE with any other systemic treatment. These recommendations would have to come from a licensed veterinarian with an appropriate veterinarian-client-patient relationship. The use of any other treatment will affect both the milk discard period and slaughter withdrawal time. If other therapies are administered with pirlimycin, proper precautions must be taken before the cow is sold for slaughter or her milk put back into the bulk tank.

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Tissue Penetration of PIRSUE

How well does PIRSUE penetrate the udder?
Because of the basic nature of PIRSUE (pKa 8.5), it will penetrate more basic environments, such as a mastitic quarter, at higher levels than the beta-lactams, aminoglycosides or cephalosporins. PIRSUE will tend to accumulate in tissue and cells at levels two to three times that of the extracellular fluid level. PIRSUE administered in the quarter can be found in tissues such as the liver and kidney of the treated cow, indicating the ability of PIRSUE to penetrate tissue. In the labeled residue studies, 50 percent of the PIRSUE that was infused into the quarter was found systemically outside the udder.

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What role do intracellular bacteria play in chronic mastitis, and will PIRSUE be effective in their treatment?
PIRSUE penetrates leukocytes very easily, but its intracellular killing ability is limited. The ability of an antibiotic to kill intracellular bacteria, especially those found in leukocytes, may be of little influence on the final treatment of infection. Yancey, et al., reported that none of the antibiotics currently approved for treatment of mastitis in the lactating cow in the USA is effective against intracellular bacteria such as S. aureus. When S. aureus is present in these leukocytes, they're metabolically very inactive and therefore very resistant to any antibiotic therapy. Once these bacteria are released from the leukocyte and begin to become metabolically active again, the ability of PIRSUE to penetrate tissue will be of assistance in the treatment of these bacteria. This ability to penetrate tissue will be helpful in getting pirlimycin to places where tissue damage has occurred, such as micro abscesses and scarring of the udder, so that the drug will be available when these sequestered bacteria are released from the leukocyte.

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Duration of Control

How long can we expect therapeutic levels of PIRSUE to be present in the udder after the second treatment?
Levels of pirlimycin are maintained above the MIC for S. aureus (0.25-0.50 mg/mL or ppm) for 36-48 hours after the last treatment. Please note that with the presence of a safe concentration of 0.4 ppm, which is safe for humans, this level is still in the range of the MIC for S. aureus.

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What are the levels of pirlimycin in the milk during therapy, and how do they compare with MICs of the mastitis pathogens? Do these pirlimycin levels dip below MIC between treatments?
At 24 hours after the last treatment, levels were in the range of 0.82-1.29 ppm of pirlimycin. The MICs for most S. aureus, which would be the toughest MICs, were in the range of 0.25-0.50 micrograms per mL or ppm. A review of the milk residue data would indicate that during the entire treatment period, the levels of pirlimycin do not fall below the MIC and will maintain this level until approximately 36 hours after the last treatment.

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Would the infusion of a larger dose of PIRSUE be more effective and remove the need for a second infusion 24 hours later?
No, the 50 mg dose was found to be the most effective in clinical field studies. The infusion of levels of 100 and 200 mg into the quarter actually showed less performance than 50 mg on a percentage basis, though they were not statistically different. The second dose 24 hours later provides a total of almost 60 hours of pirlimycin at levels above the MIC for S. aureus. From results of both the dose titration and clinical efficacy trials, two doses of 50 mg of pirlimycin at a 24-hour interval provide the optimal dosage and clinical efficacy when compared to other dosage levels of pirlimycin and other mastitis products.

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PIRSUE vs. Other Lactating Mastitis Products

Why should I buy and use PIRSUE instead of the product I am currently using?
  • It works! The high cure rate reduces pathogen reservoirs.
  • Short, 36-hour milk withholding means more milk and less risk of human error.
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Are there other practical advantages for the dairyman?
The power of PIRSUE allows for once-a-day (24-hour) dosing. Unlike competitive tubes that require an infusion every 12 hours, PIRSUE can be administered by your best crew today with confidence that the second treatment will be administered at the same time - and by the same crew - tomorrow. This consistency of treatment means less chance of human error, especially in herds that milk three times daily.

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What advantage does PIRSUE have over B. lactus for the treatment of streptococcal mastitis during lactation?
In addition to a shorter milk withholding period (and less wasted milk), the major advantage is the drug's ability to penetrate tissue. The beta-lactams are acidic compounds and do not penetrate tissues or cells very well. In a cow with mastitis, the pH of the milk rises, which will make the beta-lactams more polar and less able to penetrate. In S. aureus infections, the beta-lactams have also been shown to induce the formation of "L" forms, which are very resistant to antibiotic treatment.

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What is the shelf-life of PIRSUE, and will it be effective after this date?
The shelf-life of PIRSUE is 36 months. After 36 months, the product should not be used.

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Milk and Meat Withdrawal

What is the milk withholding time? Are there any concerns with residues left in the milk after that time? What is the residue situation in the untreated quarters?
PIRSUE has a 36-hour milk discard period in the USA. A safe concentration for pirlimycin in milk was established by the FDA at 0.40 ppm. This means that residues below this level are safe for human consumption.

From the residue and metabolism studies done by Zoetis, we have established that 50 percent of the pirlimycin infused into the quarter is absorbed systemically. In the body, the pirlimycin moves back to the udder and is found in the milk of all four quarters (see Anatomy of the Udder). This means that if an individual quarter is treated for mastitis, the milk must be withheld from all four quarters to prevent the possibility of violative residue.

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Can calves be "run" on cows treated with PIRSUE?
The milk from treated cows will contain levels of pirlimycin that will be absorbed from the calf's GI tract and will cause detectable residues in that calf. It is recommended that this milk not be fed to these calves.

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My milk goes for cheese production. Will PIRSUE have any effects on this manufacturing?
No. A study was conducted by Dr. Robert Bradley in the Food Science Department at the University of Wisconsin to answer this question. Milk with known pirlimycin residue concentrations was used by Dr. Bradley to evaluate the growth of the starter cultures used in cheese manufacturing. This study demonstrated that with proper use of label directions, PIRSUE should not adversely affect the starter cultures used in the manufacture of fermented milk product. The routine screening assays detect pirlimycin at levels well below those that affect the tested starter cultures. Routine use of these screening assays will prevent damage to the starter cultures.

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What is the new pre-slaughter withhold period for animals treated with PIRSUE?

  • Following infusion twice at a 24-hour interval, treated animals must not be slaughtered for 9 days.

  • Following any extended duration of therapy (infusion longer than twice at a 24-hour interval, up to 8 consecutive days), animals must not be slaughtered for 21 days.

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Drug Resistance

Do mastitis pathogens develop resistance to PIRSUE very quickly?
Zoetis has screened over 500 clinically isolated milk pathogens (staphylococcal and streptococcal organisms) and has found less than 1 percent are resistant to PIRSUE. This family of antibiotics has not been used before in the treatment of mastitis, so the assessment of how quickly resistance will develop is premature based on the lincosaminides alone. Heavy use of the macrolides (erythromycin) may induce some resistance, due to the similarities in the method of action of these two types of antibiotics.

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Sensitivity Testing

What are your recommendations for antibiotic sensitivity testing for pirlimycin?
A sensitivity disc is available for use by the veterinarian. Zoetis has undertaken a very detailed study to determine the zones of antibiotic sensitivity and the MIC of a large group of veterinary pathogens causing bovine mastitis isolated from clinical field mastitis studies. A zone size greater than or equal to 13 mm indicates that bacteria are susceptible to PIRSUE. A zone size less than or equal to 12 mm indicates that the bacteria may be resistant to PIRSUE. These results will help to determine the size of the zone of sensitivity to determine potential efficacy of PIRSUE against mastitis pathogens found in the field. Mastitis pathogens from all over the USA were used for this work. This study resulted in the creation of one of the few sensitivity discs where the work was done with veterinary pathogens.

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Trial and Literature Review

What comparative efficacy data are available and what are the results? What data have been generated outside the USA?
Comparative efficacy studies were conducted in the United States, Europe and Canada. The comparative efficacy research was done all over the USA in 32 herds with 287 cows in 287 quarters. PIRSUE demonstrated a better percentage of efficacy against clinical mastitis than both cloxacillin and cephapirin, but the differences were not statistically different from each other. PIRSUE Sterile Solution (pirlimycin hydrochloride) showed equal results in proportion of quarters returning to normal milk and time required to return to normal milk. A comparative study in Europe compared the efficacy of PIRSUE to cloxacillin. In this study, the time to normal milk was significantly shorter for the cows treated with PIRSUE. Clinical cure rates were also numerically greater for cows treated with PIRSUE.

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What data have been published on pirlimycin?

RD Birkenmeyer, SJ Kroll, C Lewis, KF Stern, GE Zurenko. Synthesis and Antimicrobial Activity of Clindamycin Analogues: Pirlimycin, 1.2 a Potent Antibacterial Agent. J. Med. Chem. Feb. 1984, 27(2), pp. 216-223.

GA Kopia, EM Driscoll, KF Yeung, BR Lucchesi. Antiarrhythmic and Cardiovascular Actions of the New Antibiotic Agent Pirlimycin Adenylate. Pharmacology. 1983, 27(5), pp. 225-266.

LE Marrett, DD Kratzer, CC Miller, JW Lauderdale. The Antibiotics - Pirlimycin and Streptovaricin C - as Growth Enhancers for Broilers. Poult. Sci. 1987, 66, Suppl. 1, p. 139.

LE Marrett, RA Evans. Pirlimycin Growth Enhancers for Meat-Producing Animals. PCT Int. Appl. 1 December 1988, p. 15.

RA Rzepkowski, RJ Yancey, Jr., ST Chester, RE Barnes, JM Nappier. Efficacy of Pirlimycin Hydrochloride in the Treatment of Experimentally Induced Chronic Staphylococcal Mastitis in Lactating Dairy Cows. J. Dairy Sci. 1990, 73, Suppl. 1, p. 189.

RJ Yancey, Jr., ML Kinney, CW Ford. Efficacy of Lincosaminide Antibiotics in the Treatment of Experimental Staphylococcal Mastitis in Lactating Mice. J. Antimicrob. Chemother. February 1985, 15(2), pp. 219-232.

RJ Yancey, Jr., AJ Lallinger, MJ Kennedy, DD Kratzer. Efficacy of Pirlimycin, a New Lincosamide Antibiotic, in Treatment of Experimentally-Induced Swine Dysentery. Proceedings International Pig Veterinary Society, 10th Congress, Rio de Janeiro, Brazil. 1988, p. 124.

RJ Yancey, Jr., RA Rzepkowski, ST Chester, CW Ford. Efficacy of Pirlimycin Hydrochloride in the Treatment of Experimentally-Induced Staphylococcal Mastitis in Lactating Dairy Cows. Journal of Dairy Science. 1989, 72, Suppl. 1, p. 22.

VI Ahonkhai, CE Cherubin, MA Shulman, M Jhagroo, U Bancroft. In Vitro Activity of U-57930E, A New Clindamycin Analog, Against Aerobic Gram-Positive Bacteria. Antimicrob. Agents Chemother. 1982, 21:902-905.

JI Cialdella, JJ Vavra, VP Marshall. Susceptibility of Bacteria to Serum Lysis or Phagocytosis Following Growth in Subinhibitory Levels of Lincosamide or Spectinomycin Related Antibiotics. J. Antibiot. (Tokyo). July 1986, 39(7), pp. 978-984.

VK Dhawan, MB Bansal, H Thadepalli. In Vitro Activity of Pipecolic Acid Amide of Clindamycin (U-57930E) on Anaerobic Bacteria Compared with Those of Clindamycin, Cefoxitin, and Chloramphenicol. Antimicrob. Agents Chemother. August 1982. 22(2), pp. 350-351.

ME Evans, LS Patterson, CW Stratton. In Vitro Comparison of Clindamycin and Pirlimycin (U-57930E) Activity Against Staphylococcus Aureus. Antimicrob. Agents Chemother. August 1982, 22(2), pp. 334-335.

JA Garcia-Rodriguez, JE Garcia-Sanchez, J Prieto, A Sanchez-de-S-Lorenzo. Activity of Pirlimycin (U-57930E) Against Strains of the Bacteroides Fragilis Group. Antimicrob. Agents Chemother. November 1982, 22(5), pp. 893-894.

VP Marshall, WF Liggett, JI Cialdella. Enzymic Inactivation of Lincosaminide and Macrolide Antibiotics: Divalent Metal Cation and Coenzyme Specificities. J. Antibiot. 42(5), pp. 826-830.

VP Marshall, TE Patt, AD Argoudelis. Enzymic Nucleotidylylation of Lincosaminide Antibiotics. J. Ind. Microbial. 1(1), pp. 17-21.

SM Qadri, MR Karim, DJ Flournoy. In Vitro Activity of U-57930E Against Anaerobic Bacteria and Its Comparison with Clindamycin, Ampicillin, Carbenicillin and Tatracycline. J. Antibiot (Tokyo). January 1983, 36(1), pp. 42-46.

MS Sanchez, CW Ford, RJ Yancey, Jr. Evaluation of Antibiotic Effectiveness Against Staphylococcus Aureus Surviving Within the Bovine Mammary Gland Macrophage. J. Antimicrob. Chemother. 1988, 21(6), pp. 773-786.

MS Sanchez, CW Ford, RJ Yancey, Jr. Evaluation of Antibacterial Agents in a High-Volume Bovine Polymorphonuclear Neutrophil Staphylococcus Aureus Intracellular Killing Assay. Antimicrob. Agents Chemother. 29(4), pp. 634-638.

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