Florfenicol resistance:

Pasteurella multocida is a gram-negative bacterium of great economic importance in the cattle farming sector, since it represents one of the main pathogens associated with the Bovine Respiratory Syndrome (BRS) (1), which is considered the leading cause of economic losses in the livestock industry (2, 3).

These bacteria are present in the respiratory tract of healthy animals, where they behave as opportunists in case of immunodeficiency. Clinical symptoms caused by P. multocida include enzootic and to a lesser degree fibrinous pneumonia (shipping fever) (4, 5, 6, 7). Both are considered multifactorial syndromes, in which infectious and non-infectious factors are involved (8, 9).

Early detection of the disease and treatment with effective against the 3 gram-negative bacteria associated with BRS (P. multocida among them) are essential to stop its progression. In particular, long-term antibiotics, such as florfenicol, have been specifically developed to treat SRB (10). Florfenicol is one of the antibiotics which has a lower resistance level worldwide, especially when compared with most popular antibiotics such as or . Occurrence of of Occurrence of antimicrobial resistance of Pasteurella multocida in different Pasteurella multocida in Iran11. European countries13.

Florfenicol Italy 2002 France Holland

Enrofloxacin 2003 England Denmark

TMP-sulfa 2004

Oxytetracycline 2002

Amoxicillin+

Clavulanic 2003 2004 2002 Lincimycin Fluoquinolones 2003 Penicillin

% 2004 0 2 4 6 8 10 12 14 2002

Florfenicol Occurrence of antimicrobial resistance of 2003 Pasteurella multocida in Korea12. 2004

Florfenicol 2002 Tetracycline 2003 2004 Enrofloxacin 2002

Ceftiofur TMP-sulfa 2003

Tylosin 2004

Ampicillin 2002

Nalidix acid 2003

TMP-sulfa 2004 % % 0 10 20 30 40 50 60 70 0 5 10 15 20 25 30 0 Florfenicol

Occurrence of antimicrobial resistance of Occurrence of antimicrobial resistance of Pasteurella multocida in USA & Canada14. Pasteurella multocida in USA15.

Ceftiofur 2000 Ceftiofur 2001 2005 Enrofloxacin 2002 2006 Penicillin 2007 Ampicillin 2008 2009 Florfenicol

Tulathromycin TMP-sulfa

Tilmicosin Florfenicol

Tetracycline

Danofloxacin

Erythromycin

Tetracycline Sulfachlorpyridazine % % 0 10 20 30 40 50 60 0 10 20 30 40 50 60 70 80

Occurrence of antimicrobial resistance of Occurrence of antimicrobial resistance of Pasteurella multocida in Turkey16. Pasteurella multocida in Germany17.

Cefquinome Florfenicol

Ceftiofur

Erythromycin Florfenicol

Gentamicin Ampicillin TMP-sulfa

Enrofloxacin Ampicillin

Spectinomycin TMP-sulfa Sulfamethoxazole % % 0 0,5 1 1,5 2 2,5 3 3,5 4 0 10 20 30 40 50 60 70 Occurrence of antimicrobial resistance of Occurrence of antimicrobial resistance of Pasteurella multocida in Australia18. Pasteurella multocida in Japan19.

Ceftiofur

Tilmicosin Ceftiofur

Tulathromycin Celquinome

Cotrimoxazole Enrofloxacin

Florfenicol Florfenicol

Ampicillin Ampicillin

Penicillin Kanamycin

Erythromycin

Tetracycline % % 0 5 10 15 20 25 30 0 5 10 15 20 25

Conclusiones Florfenicol: One of the most powerful antibiotics exclusively for veterinary use. Broad spectrum with bactericidal effect against the most common pathogens. Highly effective and valuable alternative to traditional antibiotics. One of the lowest levels of resistance wordwide.

Bibliography

1. Frank GH: Pasteurellosis in cattle. In Pasteurella and Pasteurellosis. Edited by: Adlam C, Rutter JM. London, UK. Academic Press 197-222, 1989. 2. Gagea MI, Bateman KG, Van Dreumel T, et al: Diseases and pathogens associated with mortality in Ontario beef feedlots. J Vet Diagn Invest 18:18–2, 2006. 3. Snowder GD, Van Vleck LD, Cundiff LV, et al: 2006. Bovine respiratory disease in feedlot cattle: environmental, genetic, and economic factors. J Anim Sci 84:1999–2008, 2006, doi:10.2527/jas.2006-046. 4. Lillie LE: The bovine respiratory disease complex. Can Vet J 15: 233–242, 1974. 5. Watts JL, Yancey Jr RJ, Salmon SA, et al: A 4-year survey of antimicrobial susceptibility trends for isolates from cattle with bovine respiratory disease in North America. J Clin Microbiol 32: 725–731, 1994. 6. Fulton RW, Purdy CW, Confer A, et al: Bovine viral diarrhea viral infections in feeder calves with respiratory disease: interactions with Pasteurella spp., parainfluenza-3 virus, and bovine respiratory syncytial virus. Can J Vet Res 64: 151–159, 2000. 7. Welsh RD, Dye LB, Payton ME, et al: Isolation and antimicrobial susceptibilities of bacterial pathogens from bovine pneumonia: 1994–2002. J Vet Diagn Ivest 16: 426–431, 2004. 8. Ames TR: Dairy calf pneu- monia. The disease and its impact. Vet Clin North Am Food Anim Pract 13: 379–391, 1997. 9. Mosier DA: Bacterial pneumonia. Vet Clin North Am Food Anim Pract 13: 483–493, 1997. 10. The Merck Veterinary Manual Online, March 2012. 11. Mohammadi GR, Ghazvini K, Abbas PH: Antimicrobial susceptibility testing of Mannheimia haemolytica and Pasteurella multocida isolated from calves with dairy calf pneumonia. Arch Razi Instit 61 (2):91-96, 2006. 12. Önat K, Kahya S, Çarli KT: Frequency and antibiotic susceptibility of Pasteurella multocida and Mannheimia haemolytica isolates from nasal cavities of cattle. Turk J Vet Anim Sci 34 (1): 91-94, 2010. 13. Hendriksen RS, Mevius DJ, Schroeter A, et al: Prevalence of antimicrobial resistance among bacterial pathogens isolated from cattle in different European countries: 2002-2004. Acta Vet Scand 50:28, 2008, doi: 10.1186/1751-0147-50-28. 14. Portis E, Lindeman C, Johansen L, et al: A tenyear (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. J Vet Diagn Invest 24:932–944, 2012, doi: 10.1177/1040638712457559. 15. Welsh RD, Dye LB, Payton ME, et al: Isolation and antimicrobial susceptibilities of bacterial pathogens from bovine pneumonia: 1994–2002. J Vet Diagn Invest 16:426–431, 2004. 16. Önat K, Kahya S, Çarli KT: Frequency and antibiotic susceptibility of Pasteurella multocida and Mannheimia haemolytica isolates from nasal cavities of cattle. Turk J Vet Anim Sci 34 (1): 91-94, 2010. 17. Schwarz S, Kehrenberg C, Salmon SA, et al: In vitro activities of spectinomycin and comparator agents against Pasteurella multocida and Mannheimia haemolytica from respiratory tract infections of cattle. J Antimicrob Chemother 53:379-382, 2004, doi: 10.1093/jac/dkh059. 18. Dayao DA, Gibson JS, Blackall PJ, et al: Antimicrobial resistance in bacteria associated with porcine respiratory disease in Australia. Vet Microbiol 171(1–2):232–235, 2014. 19. Katsuda K, Hoshinoo K, Ueno Y, et al: Virulence genes and antimicrobial susceptibility in Pasteurella multocida isolates from calves. Vet Microbiol 167(3-4):737-41, 2013, doi: 10.1016/j.vetmic.2013.09.029. The low rate of resistance development, the low prevalence of transferable resistance determinants among bovine respiratory pathogens, and the limited use of phenicols in human and veterinary medicine explain the continued high degree of florfenicol susceptibility among bovine respiratory isolates.

SELECTAN® Florfenicol

SELECTAN® Florfenicol, in injectable solution. COMPOSITION PER ML: Florfenicol 300 mg. INDICATIONS: Diseases caused by florfenicol susceptible bacteria: -Swine: Treatment of acute outbreaks of respiratory disease caused by Actinobacillus pleuropneumoniae and Pasteurella multocida. -Cattle: Treatment of respiratory infections due to Mannheimia haemolytica, Pasteurella multocida and Histophilus somni. ADMINISTRATION ROUTE: Intramuscular. DOSAGE: -Swine: 1 ml/20 kg b.w., equivalent to 15 mg of florfenicol/kg b.w, into neck muscles, administered twice at 48 hours intervals. The volume administered per injection site should not exceed 3 ml. -Cattle: 1 ml/15 kg b.w., equivalent to 20 mg of florfenicol/kg b.w., administered twice at 48 hours intervals.The volume administered per injection site should not exceed 10 ml. WITHDRAWAL PERIOD: Meat: -Swine: 18 days. -Cattle: 30 days. Special precautions for storage: Not require any special storage conditions. PACKAGING: 50, 100 and 250 ml plastic bottles. Marketing authorisation holder: Laboratorios Hipra, S.A., Amer (Girona), SPAIN.