A pharmacological perspective on the use of Benzylpenicillin-G in the production of veterinary medicine in Latin America

Main Article Content

Lilia Gutiérrez
Héctor Sumano
Luis Ocampo
Agustín Nieto
Itzcoatl Aquino

Abstract

Benzylpenicillin-G (BP-G) is one of human and veterinary medicine’s most widely used antibacterial drugs. It represents a large market for the Phar­maceutical Industry, and various combinations with frail pharmacological support have been made available to veterinarians. The crystalline sodium and potassium salts of BP-G and the benzathine salt of BP-G have been incorporated into many existing preparations, arguing that higher and more prolonged concentrations are obtained. However, there are not evidence published. Notwithstanding the above, these preparations are presented as sustained-release ones and capable of achieving therapeutic concentrations. There are no pharmacokinetic bases for such combinations of BP-G deriva­tives. It is unlikely that such combinations provide better serum profiles than those offered by an adequate dose of only procaine BP-G. The incorporation of the BP-G benzathine is prohibited in many countries. In Latin America, such combinations limit the amount of procaine BP-G that should be in­jected, ideally ≥ 20 000 IU/kg of body weight every 12-24 h. Within the framework of the rational use of antimicrobial drugs in veterinary medicine advanced by the World Health Organization (WHO) and based on pharma­cological considerations, it is proposed that combinations of BP-G derivatives be restricted, allowing only BP-G procaine preparations. Also, formulations of BP-G incorporating other active principles should offer solid pharmacological support. To date, combined preparations of BP-G have shown no formal pharmacological support. Based on the information presented in this review, it is feasible to conclude that the only BP-G derivative that should be available for veterinary medicine is procaine BP-G.

Keywords:
Bencylpenicillin-G pharmacokinetics/pharmacodynamics antibacterial resistance commercial preparations

Article Details

Author Biographies

Lilia Gutiérrez, Universidad Nacional Autónoma de México, Facultad de Medicina Veterinaria y Zootecnia / Departamento de Fisiología y Farmacología, Ciudad de México, México.

Physiology and Pharmacology department

Héctor Sumano, Universidad Nacional Autónoma de México, Facultad de Medicina Veterinaria y Zootecnia / Departamento de Fisiología y Farmacología, Ciudad de México, México

Physiology and Pharmacology department

Luis Ocampo, Universidad Nacional Autónoma de México, Facultad de Medicina Veterinaria y Zootecnia / Departamento de Fisiología y Farmacología, Ciudad de México, México

Physiology and Pharmacology department

Agustín Nieto, Universidad Nacional Autónoma de México, Facultad de Medicina Veterinaria y Zootecnia / Departamento de Fisiología y Farmacología, Ciudad de México, México

Physiology and Pharmacology department

References

Papich MG. Pharmacokinetic–pharmacodynamic (PK–PD) modeling and the rational selection of dosage regimes for the prudent use of antimicrobial drugs. Veterinary Microbiology [Internet]. 2014(Jul);171(3–4):480–6. doi: 10.1016/j. vetmic.2013.12.021.

Ocampo L, Páez D, Sumano H, Auro A. Actividad antibacteriana in vitro y biodisponibilidad en vacas de varios preparados de benzilpenicilina G, sola o combinada con sulfato de dihidroestreptomicina. Veterinaria México. 2000;31(3):201–7.

Halleran JL, Papich MG, Li M, Lin Z, Davis JL, Maunsell FP, et al. Update on withdrawal intervals following extralabel use of procaine penicillin G in cattle and swine. Journal of the American Veterinary Medical Association [Internet]. 2022(Jan);260(1):50–5. doi: 10.2460/javma.21.05.0268.

Sumano H, Ocampo L, Gutiérrez L. Farmacología veterinaria. 4th ed. México: Aranda; 2016.

Plumb DC. Plumb’s Veterinary Drug Handbook. 9th ed. USA: Wiley-Blackwell; 2018. 1973 p.

Uboh CE, Soma LR, Luo Y, McNamara E, Fennell MA, May L, et al. Pharmacokinetics of penicillin G procaine versus penicillin G potassium and procaine hydrochloride in horses. American Journal of Veterinary Research [Internet]. 2000(Jul);61(7):811–5. doi: 10.2460/ajvr.2000.61.811.

Schwartz KJ. Swine Disease Manual. 3rd ed. Iowa: American Association of Swine Veterinarians; 2004. 192 p.

Weinstein MP, Klugman KP, Jones RN. Rationale for revised penicillin susceptibility breakpoints versus Streptococcus pneumoniae: coping with antimicrobial susceptibility in an era of resistance. Clinical Infectious Diseases [Internet]. 2009(Jun);48(11):1596–600. doi: 10.1086/598975.

Soares T, Paes AC, Megid J, Eduardo P, Ribolla M. Antimicrobial susceptibility of Streptococcus suis isolated from clinically healthy swine in Brazil Résumé. The Canadian Journal of Veterinary Research. 2014;78:145–9.

Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing: 18th informational supplement. CLSI. Wayne, PA: Clinical and Laboratory Standards Institute; 2008.

McDougall S, Clausen LM, Hussein HM, Compton CWR. Therapy of subclinical mastitis during lactation. Antibiotics [Internet]. 2022(Feb);11(2):209. doi: 10.3390/antibiotics11020209.

Chander Y, Gupta SC, Goyal SM, Kumar K, Murray H. Sub-therapeutic use of antibiotics and prevalence of antibiotic resistant Bacteria on Swine Farms. Research Journal of Microbiology. 2007;2(9):654–63.

Roesch M, Perreten V, Doherr MG, Schaeren W, Schällibaum M, Blum JW. Comparison of antibiotic resistance of udder pathogens in dairy cows kept on organic and on conventional farms. Journal of Dairy Science [Internet]. 2006(Mar);89(3):989–97. doi: 10.3168/jds.S0022-0302(06)72164-6.

Garmo RT, Waage S, Sviland S, Henriksen BIF, Østerås O, Reksen O. Reproductive performance, udder health, and antibiotic resistance in mastitis bacteria isolated from Norwegian Red cows in conventional and organic farming. Acta Veterinaria Scandinavica [Internet]. 2010(Dec);52(1):11. doi: 10.1186/1751-0147-52-11.

Alves-Barroco C, Caço J, Roma-Rodrigues C, Fernandes AR, Bexiga R, Oliveira M, et al. New insights on Streptococcus dysgalactiae subsp. dysgalactiae isolates. Frontiers in Microbiology [Internet]. 2021;12:1–16. doi: 10.3389/fmicb.2021.686413.

Crespi E, Pereyra AM, Puigdevall T, Rumi M V., Testorelli MF, Caggiano N, et al. Antimicrobial resistance studies in staphylococci and streptococci isolated from cows with mastitis in Argentina. Journal of Veterinary Science [Internet]. 2021;22(6):1–10. doi: 10.4142/jvs.2021.22.e82.

Denamiel G, Llorente P, Carabella M, Rebuelto M, Gentilini E. Anti-microbial Susceptibility of Streptococcus spp. Isolated from Bovine Mastitis in Argentina. Journal of Veterinary Medicine Series B [Internet]. 2005;52(3):125–8. doi: 10.1111/j.1439-0450.2005.00830.x.

Portis E, Lindeman C, Johansen L, Stoltman G. A ten-year (2000–2009) study of antimicrobial susceptibility of bacteria that cause bovine respiratory disease complex— Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni —in the United States and Canada. Journal of Veterinary Diagnostic Investigation [Internet]. 2012(Sep);24(5):932–44. doi: 10.1177/1040638712457559.

Guérin-Faublée V, Tardy F, Bouveron C, Carret G. Antimicrobial susceptibility of Streptococcus species isolated from clinical mastitis in dairy cows. International Journal of Antimicrobial Agents [Internet]. 2002;19(3):219–26. doi: 10.1016/S0924-8579(01)00485-X.

Yáñez JA, Remsberg CM, Sayre CL, Forrest ML, Davies NM. Flip-flop pharmacokinetics –delivering a reversal of disposition: challenges and opportunities during drug development. Therapeutic Delivery [Internet]. 2011;2(5):643–72. doi: 10.4155/tde.11.19.

Callens BF, Haesebrouck F, Maes D, Butaye P, Dewulf J, Boyen F. Clinical resistance and decreased susceptibility in Streptococcus suis isolates from clinically healthy fattening pigs. Microbial Drug Resistance [Internet]. 2013;19(2):146–51. doi: 10.1089/mdr.2012.0131.

Sumano LH, Ocampo CL, López PG. Serum and synovial concentrations of penicillin G in horses after two different dose schemes. Equine Practice. 1994;16(2):18–21.

Kimura K, Suzuki S, Wachino J-ichi, Kurokawa H, Yamane K, Shibata N, et al. First molecular characterization of group B streptococci with reduced penicillin susceptibility. Antimicrobial Agents and Chemotherapy [Internet]. 2008(Aug);52(8):2890–7. doi: 10.1128/AAC.00185-08.

Gruet P, Maincent P, Berthelot X, Kaltsatos V. Bovine mastitis and intramammary drug delivery: review and perspectives. Advanced Drug Delivery Reviews [Internet]. 2001(Sep);50(3):245–59. doi: 10.1016/S0169-409X(01)00160-0.

Gomes F, Rodrigues M, Martins N, Ferreira I, Henriques M. Phenolic plant extracts versus penicillin G: in vitro susceptibility of Staphylococcus aureus isolated from bovine mastitis. Pharmaceuticals [Internet]. 2019(Aug 31);12(3):128. doi: 10.3390/ph12030128.

Kietzmann M, Niedorf F, Gosselline J. Tissue distribution of cloxacillin after intramammary administration in the isolated perfused bovine udder. BMC Veterinary Research [Internet]. 2000(Oct);23(5):303–10. http://www.biomedcentral. com/1746-6148/6/46.

Thornsberry C, Burton PJ, Yee YC, Watts JL, Yancey RJ. The activity of a combination of penicillin and novobiocin against Bovine Mastitis pathogens: development of a disk diffusion test. Journal of Dairy Science [Internet]. 1997(Feb);80(2):413–21. doi: 10.3168/jds.S0022-0302(97)75952-6.

Greenway DLA, England RR. The intrinsic resistance of Escherichia coli to various antimicrobial agents requires ppGpp and σs. Letters in Applied Microbiology [Internet]. noviembre de 1999;29(5):323–6. doi: 10.1046/j.1472-765X.1999.00642.x.

Lees P. PK-PD integration and PK-PD modelling: alternatives to dose titration studies for selecting optimal dosage schedules of antimicrobial drugs. The Royal Veterinary College. 2011.

Bengtsson B, Jacobsson S, Luthman J, Franklin A. Pharmacokinetics of penicillin‐G in ewes and cows in late pregnancy and in early lactation. Journal of Veterinary Pharmacology and Therapeutics [Internet]. 1997(Aug);20(4):258–61.

doi: 10.1046/j.1365-2885.1997.00066.x.

DeDonder KD, Gehring R, Baynes RE, Tell LA, Vickroy TW, Apley MD, et al. Effects of new sampling protocols on procaine penicillin G withdrawal intervals for cattle. Journal of the American Veterinary Medical Association [Internet]. 2013(Nov);243(10):1408–12. doi: 10.2460/javma.243.10.1408.

FDA. The judicious use of medically important antimicrobial drugs in food-producing animals. Guidance for Industry [Internet]. 2012(Jul); 201:1–19.

EMA. Opinion following an Article 20 referral for veterinary medicinal products containing benzathine benzylpenicillin intended for administration to food producing species [Internet]. Vol. EMA/308369. 2014.

Ranheim B, Ween H, Egeli AK, Hormazabal V, Yndestad M, Søli NE. Benzathine penicillin G and procaine penicillin G in piglets: comparison of intramuscular and subcutaneous injection. Veterinary Research Communications. 2002;26(6):459–65. doi: 10.1023/A:1020590408947.

Sjölund M, Ekstrand C, Wallgren P, Bondesson U, Pringle M, Bengtsson B. Exposure to benzylpenicillin after different dosage regimens in growing pigs. Acta Veterinaria Scandinavica [Internet]. 2020(Dec 17);62(1):55. doi: 10.1186/ s13028-020-00552-0.

Dubreuil P, Daigneault J, Couture Y, Guay P, Landry D. Penicillin concentrations in serum, milk, and urine following intramuscular and subcutaneous administration of increasing doses of procaine penicillin G in lactating dairy cows. Canadian Journal of Veterinary Research. 2001;65(3):173–80.

Abbeloos E, Pyörälä S, Rajala-Schultz P, Myllys V. Determination of the intramammary dose of benzylpenicillin required to maintain an adequate concentration in the milk to inhibit gram-positive bacteria in the clinically normal udder for 24 hr. Journal of Veterinary Pharmacology and Therapeutics [Internet]. 2018(Oct);41(5):691–8. doi: 10.1111/jvp.12671.

Kalmus P, Simojoki H, Orro T, Taponen S, Mustonen K, Holopainen J, et al. Efficacy of 5-day parenteral versus intramammary benzylpenicillin for treatment of clinical mastitis caused by gram-positive bacteria susceptible to penicillin in vitro. Journal of Dairy Science [Internet]. 2014(Apr);97(4):2155–64. doi: 10.3168/jds.2013-7338.

Fischbach H, Welch H, King EQ, Levine J, Price CW, Randall WA. Procaine penicillin and sulfonamide antagonism. Journal of the American Pharmaceutical Association (Scientific ed) [Internet]. 1949(Oct);38(10):544–6. doi: 10.1002/ jps.3030381005.

Keefer CS. The uses of Penicillin and Streptomycin. Lawrence, Kansas: University of Kansas Press; 1949. 72 p.

Taponen S, Dredge K, Henriksson B, Pyyhtiä AM, Suojala L, Junni R, et al. Efficacy of intramammary treatment with procaine penicillin G vs. procaine penicillin G plus neomycin in bovine clinical mastitis caused by penicillin-susceptible, gram-positive bacteria - a double blind field study. Journal of Veterinary Pharmacology and Therapeutics [Internet]. 2003 Jun;26(3):193–8. doi: 10.1046/j.1365-2885.2003.00473.x.

Franklin A, Olof H, Rantzien MH, Aström G. Effect of procaine benzylpenicillin alone or in combination with dihydrostreptomycin on udder pathogens in vitro and in experimentally infected bovine udders. American Journal of Veterinary Research [Internet]. 1984(Jul);45(7):1398–402.

Sumano H, Brumbaugh GW. Farmacología clínica de los aminoglucósidos y los aminociclitoles en medicina veterinaria. Veterinaria México. 1995;26(1):15.

van Duijkeren E, Schwarz C, Bouchard D, Catry B, Pomba C, Baptiste KE, et al. The use of aminoglycosides in animals within the EU: development of resistance in animals and possible impact on human and animal health: a review. Journal of Antimicrobial Chemotherapy [Internet]. 2019(Sep);74(9):2480–96. doi: 10.1093/jac/dkz161.

Whittern T, Hanlon D. Dihydrostreptomycin or streptomycin in combination with penicillin G in dairy cattle therapeutics: A review and re-analysis of published data Part 2: Resistance and residues. New Zealand Veterinary Journal [Internet]. 1997(Dec 22);45(6):223–9. doi: 10.1080/00480169.1997.36034.

Whittem T, Hanlon D. Dihydrostreptomycin or streptomycin in combination with penicillin G in dairy cattle therapeutics: A review and re-analysis of published

data Part 1: Clinical pharmacology. New Zealand Veterinary Journal [Internet]. 1997(Jan 10);45(5):178–84. doi: 10.1080/00480169.1997.36022.

Aldeek F, Canzani D, Standland M, Crosswhite MR, Hammack W, Gerard G, et al. Identification of penicillin G metabolites under various environmental conditions using UHPLC-MS/MS. Journal of Agricultural and Food Chemistry [Internet]. 2016(Aug 10);64(31):6100–7. doi: 10.1021/acs.jafc.5b06150.

Veterinary Medicine Expert Committee on Drug Information, United States Pharmacopeia. USP veterinary pharmaceutical information monographs--anti-inflammatories. Journal of Veterinary Pharmacolgy Therapeutics. 2004;27(Suppl 1):1–110. doi: 10.1111/j.1365-2885.2004.562-572.x

Moreno-Opo R, Carapeto R, Casimiro R, Rubio C, Muñoz B, Moreno I, et al. The veterinary use of diclofenac and vulture conservation in Spain: updated evidence and socio-ecological implications. Science of the total environment [Internet]. 2021(Nov);796:148851. doi: 10.1016/j.scitotenv.2021.148851.

Yasmeen R, Asif L, Djeffal S. Impact of diclofenac a non-steroidal anti-inflammatory veterinary pharmaceutical drug on vultures. Pakistan Journal of Zoology [Internet]. 2021;54(1):423–31. doi: 10.17582/journal.pjz/20191121081106.

Leemann W, De Weck AL, Schneider CH. Hypersensitivity to carboxymethyl-cellulose as a cause of anaphylactic reactions to drugs in cattle. Nature [Internet]. 1969(Aug);223(5206):621–3. doi: 10.1038/223621a0.

Li M, Gehring R, Riviere JE, Lin Z. Probabilistic physiologically based pharmacokinetic model for penicillin G in milk from dairy cows following intramammary or intramuscular administrations. Toxicological Sciences [Internet]. 2018(Jul);164(1):85–100. doi: 10.1093/toxsci/kfy067.

Payne MA, Craigmill A, Riviere JE, Webb AI. Extralabel use of penicillin in food animals. Journal of the American Veterinary Medical Association [Internet]. 2006(Nov);229(9):1401–3. doi: 10.2460/javma.229.9.1401.

Lupton SJ, Shelver WL, Newman DJ, Larsen S, Smith DJ. Depletion of penicillin G residues in heavy sows after intramuscular injection. Part I: Tissue residue depletion. Journal of Agricultural and Food Chemistry [Internet]. 2014(Jul);62(30):7577–85. doi: 10.1021/jf501492v.