SELECT NEWS Florfenicol Monograph: Injectable Therapy for Cattle Did you know that? Florfenicol is one of the most powerful antibiotics currently available in veterinary medicine with one of the lowest levels of resistance in Europe.
Florfenicol injectable therapy for Cattle Index 1.- Florfenicol structure and therapeutic implications... 4 2.- Pharmacokinetics... 5 3.- Mechanism of action... 6 4.- Spectrum of action... 8 - In vitro sensitivity of main microorganisms in cattle... 9 - Key facts on resistances... 10 5.- Conclusions... 11 Bibliography... 11
1 Florfenicol structure and therapeutic implications Florfenicol (FFC) is a synthetic antibiotic that belongs to the family of amphenicols and specifically is a fluorinated derivative of thiamphenicol. Its pharmacological profile is similar to its two predecessors chloramphenicol (CL) and thiamphenicol (TH), but with major improvements thanks to differential structural characteristics: Figure 1. Molecular structure of chloramphenicol, thiamphenicol and florfenicol. Nitrogen group: involved in irreversible aplastic anaemia in humans. Methylsulfonyl aromatic group enabled safety to be increased. X O H NH C CHCI 2 O 2 N C C CH 2 OH OH H Chloramphenicol O H NH C CHCI 2 H 3 C - SO 2 C C CH 2 OH OH H Thiamphenicol O H NH C CHCI 2 H 3 C - SO 2 C C CH 2 F X Chloramphenicol acetyltransferase (CAT), with the capacity to acetylate the hydroxyl group, is the most common and widespread bacterial resistance determinant for the phenicols. Florfenicol OH H A widest range of action: FFC is active against organisms resistant to CL and TH (Enterobacteria, Haemophilus spp., Pasteurella spp.). FFC, is not affected by the inactivation of the multiple CAT enzymes because the site of acetylation is blocked by the fluorine atom 8. Florfenicol is currently one of the most popular antibiotics in veterinary medicine for treating a wide variety of infectious diseases, due to its: wide range of action, and high sensitivity to most common pathogens in cattle 4
Florfenicol injectable therapy for Cattle 2 Pharmacokinetics - Intramuscular absorption: Excellent bioavailability, around 100% 1, 3. There were no statistically significant differences between florfenicol administered subcutaneously and intramuscularly at the recommended dose 1. - Plasmatic protein binding 2 : Calves, 3 to 6 months of age: 12.7%, with serum concentration of 0.5 mcg /ml. 13.2%, with serum concentration of 3 mcg /ml. 18.3%, with serum concentration of 16 mcg /ml. Cattle - Considered independent of drug concentration: 17.5%, with serum concentration of 5 mcg / ml. 18.6%, with serum concentration of 50 mcg / ml. - Distribution: Florfenicol is rapidly distributed to all tissues (including target tissues like lungs), reaching active concentrations in the organs and tissues similar to concentrations observed in serum 3. - Excretion Florfenicol is eliminated overall by the kidneys and all its metabolites are also eliminated in the faeces 2. SELECTAN Pharmacokinetic particulars: Injectable: Intramuscular administration at the recommended dose of 20 mg/kg maintains efficacious blood levels for 48 hours. Maximum mean serum concentration (Cmax) of 2.55 µ/ml occurs at 4.7 hours (Tmax) after dosing. The mean serum concentration 24 hours after dosing was 1.4 µ/ml. The harmonic mean elimination half-life was 26.2 hours 4. 5
3 Mechanism of action Florfenicol s mechanism of action is the inhibition of protein synthesis by the bacterial peptidyl transferase by binding to the 50S subunit of ribosomes (Figure 2) 11. By preventing the replication of the organism, FFC was initially classified as a bacteriostatic drug. However, several studies in vitro against different bacteria have demonstrated bactericidal activity when FFC is at concentrations similar to the MIC (Graphs 1 and 2) 5. Figure 2. Mechanism of action of phenicols in the microorganism. Gram - Antibiotic Gram + Only interact with ribosomal RNA. 50S site A RNA 23S Proteins Bind to the peptidyl transferase region of the 23S ribosomal RNA of the 50S ribosomal subunit. Translation inhibition Bacteriostatic / Bactericidal 6
Florfenicol injectable therapy for Cattle Graph 1. Time-kill curve of Florfenicol versus Pasteurella multocida. Florfenicol concentration (µg/ml): MIC = 1 (µg/ml) 0 0.125 0.25 0.5 1 2 4 8 16 10 9 Log (UFC/mL) 8 7 6 5 4 3 2 0 4 8 12 16 20 24 Time (hours) The MIC (1 µg/ml) and all higher concentrations resulted in a drop in bacterial count of more than 3 logs by 8 hours and more than 5 logs by 24 hours. Half the MIC (0.5 µg/ml) resulted in a drop of 3 logs by 24 hours of exposure. (Based on this graph the MIC is probably closer to 0.5 µg/ml.) 5. Graph 2. Time-kill curve of Florfenicol versus Histophilus somni. Florfenicol concentration (µg/ml): MIC = 0.5 (µg/ml) 0 0.125 0.25 0.5 1 2 4 8 16 10 9 8 Log (CFU/mL) 7 6 5 4 3 2 0 4 8 12 16 20 24 Time (hours) The MIC and all higher concentrations resulted in a drop in bacterial count to below the limit of detection as early as after 8 hours of exposure 5. Notes (definitions): MIC (Minimum Inhibitory Concentration): The lowest concentration of antimicrobial substance that prevents visible growth of microorganisms after 18 and 24 hours of culturing. MBC (Minimum Bactericidal Concentration): The lowest concentration of antimicrobial substance capable of killing 99.9% of inoculated microorganisms after 18 and 24 hours of culturing. Florfenicol is a time-dependent bactericidal antibiotic with a marked concentration dependence against several major veterinary pathogens 5. 7
4 Spectrum of action Florfenicol is a broad-spectrum antibiotic with activity against a variety of Gram-positive and Gram-negative bacteria isolated from cattle (Table 1). In vitro testing has shown that florfenicol is active against the most commonly bacterial pathogens in cattle diseases (Table 2). Table 1. Broad antimicrobial spectrum. GRAM + GRAM - Other Streptococcus spp. Staphylococcus spp. Arcanobacterium pyogenes Pasteurella spp. Haemophilus spp. Moraxella Bovis Fusobacterium necrophorum Bacteroides melaninogenicus Mycoplasma spp. Table 2. Activity (MIC 90 µg/ml) of florfenicol against selected bacteria in cattle 2, 4, 5, 7, 8. Pathogen Pasteurella multocida Mycoplasma hyopneumoniae Mannheimia haemolytica Histophilus somni Arcanobacterium pyogenes Moraxella Bovis Bacteroides melaninogenicus Fusobacterium necrophorum MIC90 0.5 2 0.5 0.5 1.56 * 0.5 0.25 0.25 *: MIC 50 8
Florfenicol injectable therapy for Cattle - In vitro sensitivity of main microorganisms in cattle 1. Florfenicol has specific activity against the most common culpable bacterial agents involved in bovine respiratory disease, pododermatitis and keratoconjunctivitis. The low MIC levels observed for several years (by government agencies and European scientists) show that it has not been possible to document development of resistance in these bacteria since the introduction of florfenicol in veterinary medicine 9, 10. Florfenicol is one of the antibiotics which has a lower resistance level, especially when compared with most popular antibiotics such as tetracycline or penicillins (Graph 3, 4 and 5). Graph 3. In vitro sensitivity of M. haemolytica, P. multocida and H. somni to different antibiotics 1. % resistance 25 20 15 10 5 M. haemolytica P. multicida H. somni 0 Florfenicol Ampicillin Oxytetracycline Penicillin Ceftifour Tilmicosin Amoxicillin Graph 4. Occurrence of antimicrobial resistance of Pasteurella multocida in different European countries 2004 9. 25 England % resistance 20 15 10 France Italy The Netherlands 5 0 Ampicillin Ceftifour Florfenicol Tetracycline TMP/ Sulphonamides 9
Graph 5. Occurrence of antimicrobial resistance of M. haemolytica in different European countries 2004 9. 50 England % resistance 40 30 20 France Italy The Netherlands 10 0 Ampicillin Ceftifour Fluoroquinolones Florfenicol Tetracycline TMP/ Sulphonamides - Key Facts on Resistances 6 : The development of antimicrobial resistance is an increasing problem in human and veterinary medicine that can be caused by many factors including: Target site mutations Over-expression of antimicrobial efflux pumps Acquisition of transferable resistance determinants These resistance mechanisms determine resistance emergence during clinical use of an antimicrobial drug. Florfenicol low resistance rates are consistent with 6 : The ribosomal RNA is the binding site of florfenicol Several nucleotide mutations are needed to mutate most ribosomes present in a bacterium and thus block florfenicol binding. Florfenicol is relatively resistant to constitutive antimicrobial efflux pumps in target pathogens. 10
Florfenicol injectable therapy for Cattle 5 Conclusions Florfenicol: One of the most powerful antibiotics exclusively for veterinary use. Broad spectrum antibiotic with bactericidal effect against most common pathogens. Highly effective and valuable alternative to traditional antibiotics. One of the lowest levels of resistance in Europe. Bibliography 1. Varma K. J. et al., Pharmacology, safety, and clinical efficacy of florfenicol following subcutaneous administration to cattle. 2. The United State Pharmacopeial Convention, 2007. 3. Jiang J. et al. 2006. Vet Pharmacol. Therapy 29:153-156. 4. HIPRA SELECTAN SPC 5. De Haas V. et al., 2002, XXII Buiatrics Congress, Hannover. 6. Schuster D. et al., 2004. XXIII Buiatrics Congress, Quebec City. 7. Yoshimura H, Kojima A, Ishimaru M. J Vet Med B Infect Dis Vet Public Health. 2000 Mar;47(2):139-43. 8. Zamora M. A. et al. Vet: Méx., 41 (3) 2010 9. Hendriksen et al. 2008. Acta Vet. Scand. 50: 19-28 10.- Priebe S. and Schwarz S., 2003. Antimicrob. Agents Chemother. 47: 2703-2705. 11.- Guérin-Faublée V., VetAgro Sup- Campus Lyon; Journées Nationales des GTV, Lille, 2010. 11
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. Reg. Nº: 1802 ESP.