Introduction: There are many veterinary products containing β-lactam antibiotics which are used for mastitis treatment in cows. The aim of the study was to determine whether mastitis could have any effect on amoxicillin (AMX) or penicillin G procaine (PEN) withdrawal period from milk, in the context of current maximum residue limits established by the European Commission.
Material and Methods: The study was conducted on 17 dairy Black and White cows with clinical mastitis during the lactation period. The first group (n = 8) received 200 mg of amoxicillin (AMX), whereas the second group (n = 9) received 200,000 IU/mg of penicillin G procaine (PEN) by intramammary administration. For the measurement of AMX and PEN concentrations in milk, the liquid chromatography tandem mass spectrometry method was applied. Pharmacokinetic calculations were performed using Phoenix WinNonlin 6.4 software.
Results: The determined AMX and PEN half-life values in the mammary gland suggest that the drug withdrawal is at a level of 99.9% within 81 h (≈3.5 days) and 116 h (≈5 days) after administration of AMX and PEN, respectively. The present research indicates that, at 60 h after administration, the average PEN concentration in the milk from cows with clinical signs of mastitis may still reach 4.96 g/kg and that of AMX can even be 6.92 g/kg.
Conclusion: The results obtained confirm that, in mastitis cases, a 72-h withdrawal period is sufficient for elimination of AMX to a lower level than the established maximum residue limit (MRL) values. However, in the case of PEN, at 69 h after administration, the drug concentration may be close to that of the determined MRL.
If the inline PDF is not rendering correctly, you can download the PDF file here.
1. Bengtsson B. Jacobsson S.O. Luthman J. Franklin A.: Pharmacokinetics of penicillin-G in ewes and cows in late pregnancy and in early lactation. J Vet Pharmacol Ther 1997 20 258–261.
2. Błądek T Posyniak A Gajda A Gbylik M Żmudzki J.: Multi-class procedure for analysis of antibacterial compounds in animal tissues by liquid chromatography tandem mass spectrometry. Bull Vet Inst Pulawy 2011 55 741–748.
3. Bruno F. Curini R. di Corcia A. Nazzari M. Samperi R.: Solid-phase extraction followed by liquid chromatography-mass spectrometry for trace determination of beta-lactam antibiotics in bovine milk. J Agric Food Chem 2001 49 3463–3470.
4. Burmańczuk A. Roliński Z. Kowalski C. Zań R.: Pharmacokinetic - pharmacodynamic model and ampicillin residue depletion after intramammary administration in cows. J Vet Res 2016 60 169–176.
5. Christensen J.M. Smith B.B. Murdena S.B. Hollingshead N.: The disposition of five therapeutically important antimicrobial agents in llamas. J Vet Pharmacol Ther 1996 19 431–438.
6. Concordet D. Toutain P.L.: The withdrawal time estimation of veterinary drugs revisited. J Vet Pharmacol Ther 1997 20 380–386.
7. Craigmill A.L. Pass M.A. Wetzlich S.: Comparative pharmacokinetics of AMX administered intravenously to sheep and goats. J Vet Pharmacol Ther 1992 15 72–77.
8. Delis G.A. Koutsoviti-Papadopoulou M. Siarkou V.I. Kounenis G. Batzias G.C.: Pharmacodynamics of amoxicillin against Mannheimia haemolytica and Pasteurella multocida and pharmacokinetic/pharmacodynamic (PK/PD) correlation in sheep. Res Vet Sci 2010 89 418–425.
9. Elsheikh H.A. Taha A. Khalafalla A. Osman I. Wasfi I.: Pharmacokinetics of amoxicillin trihydrate in Desert sheep and Nubian goats. Vet Res Commun 1999 23 507–514.
10. EMA European Medicines Agency. Synulox Lactating Cow Article 34 referral-Annexes I II and III 2011 pp. 1–25.
11. EMA European Medicines Agency/Committee for Medicinal Products for Veterinary Use (CVMP). Penicillins Summary Report 2008 pp. 1–2.
12. EMA European Medicines Agency/Committee for Medicinal products for Veterinary Use (CVMP) 2013/EWP/141272/2011 pp. 4–5.
13. EMA European Medicines Agency/Committee for Medicinal Products for Veterinary Use (CVMP). Guideline on withdrawal periods for milk 2000 pp. 1–26.
14. Escudero E. Cárceles C.M. Vicente S.: Pharmacokinetics of amoxicillin/clavulanic acid combination and of both drugs alone after intravenous administration to goats. Br Vet J 1998 152 551–559.
15. Escudero E. Espuny A. Vicente M.S. Cárceles C.M.: Comparative pharmacokinetics of an ampicillin/sulbactam combination administered intramuscularly in lactating sheep and goats. Can J Vet Res Jan 1999 63 25–30.
16. EU Commission. Decision 2002/657/EC Implementing Council Directive 96/23/EC concerning the performance of analytical methods and the interpretation of results 2002 L221 8–36.
17. EU Commission. Agriculture and Rural Development Markets and prices Medium-term prospects for EU agricultural markets and income 2015 2015–2025.
18. FDA Food and Drug Administration. Chapter I – food and drug administration department of health and human services. subchapter e – animal drugs feeds and related products. part 526 – Intramammary dosage form new animal drugs. Sect. 526.1696a – Penicillin G procaine. Title 21 Volume 6 Revised as of April 1 2015.
19. FDA Food and Drug Administration. Chapter I – food and drug administration department of health and human services. subchapter e – animal drugs feeds and related products. part 526 – intramammary dosage form new animal drugs. Sect. 526.1696a – Amoxicillin trihydrate. Title 21 Volume 6 Revised as of April 1 2015.
20. Fernandez C. Modamio P. Mestorino N. Errecalde J.O. Marino E.L.: Pharmacokinetics of sodium and trihydrate amoxycillin in sheep after intravenous and intramuscular administration. J Vet Pharmacol Ther 2007 30 263–266.
21. Fernandez-Varon E. Escudero-Pastor E. Carceles-Rodriguez C.: Pharmacokinetics of an ampicillin-sulbactam combination after intravenous and intramuscular administration to neonatal calves. Vet J 2005 169 437–443.
22. Frimodt-Moller N.: How predictive is PK/PD for antibacterial agents? Int J Antimicrob Ag 2002 19 333–339.
23. Gibaldi M. Perrier D.: Pharmacokinetics. edited by Marcel Dekker New York 1982.
24. Guterbock W.W. Eenennaam A.L. Anderson R.J. Gardner I.A. Cullor J.S. Homberg C.A.: Efficacy of intramammary antibiotic therapy for treatment of clinical mastitis caused by environmental pathogens. J Dairy Sci 1993 76 3437–3441.
25. Jacoby G.A. Munoz-Price L.S.: The new beta-lactamases. NEJM 2005 352 380–391.
26. Jayachandran C. Singh M.K. Banerjee N.C.: Pharmacokinetics and distribution of ampicillin in plasma milk and uterine fluid of female buffaloes. Vet Res Commun 1990 14 47–51.
27. Khaskheli M. Malik R.S. Arain M.A. Soomro A.H. Arain H.H.: Detection of beta-lactam antibiotic residues in market milk. Pak J Nutr 2008 7 682–585.
28. Kreil V. Lüders C. Hallu R. Rebuelto M. Betancourt L.: Pharmacokinetics of ampicillin in Alpacas (Lama pacos). Arch Med Vet 2001 2 241–246.
29. Kreil V.E. Ambros L. Montoya L. Hallu R. Rebuelto M. Bramuglia G.: Pharmacokinetics of sodium and trihydrate amoxicillin after intravenous and intramuscular administration in llamas (Lama glama). Small Ruminant Res 2012 102 208–212.
30. Movassagh M.H. Karami A.R.: Beta-lactam antibiotics residues in pasteurised milk by Beta Star test in the north west region of Iran. ARPN J Agri Biol Sci 2011 6 7–10.
31. Nisha A.R.: Antibiotic residues - a global health hazard. Vet World 2008 1 375–377.
32. Sawada Y. Hanano M. Sugiyama Y. Iga T.: Prediction of the disposition of beta-lactam antibiotics in humans from pharmacokinetic parameters in animals. J Pharmacokinet Biopharm 1984 12 241–261.
33. Zheng N. Wang J. Han R. Xu X. Zhen Y. Qu X. Sun P. Li S. Yu Z.: Occurrence of several main antibiotic residues in raw milk in 10 provinces of China. Food Addit Contamin Part B 2013 2 84–89.