Pharmacotherapeutic group: Antibacterials for systemic use, third generation cephalosporins. ATCvet code: QJ01DD90
Pharmacodynamic properties
Ceftiofur is a third generation of cephalosporin, which is active against many Gram-positive and Gram-negative bacteria, including β–lactamase producing strains.
Ceftiofur inhibits the bacterial cell wall synthesis, thereby exerting its bactericidal properties.
Beta-lactams act by interfering with synthesis of the bacterial cell wall. Cell wall synthesis is dependent on enzymes that are called penicillin-binding proteins (PBP's).
Bacteria develop resistance to cephalosporins by four basic mechanisms:
1by altering or acquiring penicillin binding proteins insensitive to an otherwise effective β-lactam;
2by altering the permeability of the cell to β-lactams;
3by producing β-lactamases that cleave the β-lactam ring of the molecule, or
4by active efflux.
Some β-lactamases, documented in Gram-negative enteric organisms, may confer elevated MICs to varying degrees to third and fourth generation cephalosporins, as well as penicillins, ampicillins, β-lactam inhibitor combinations, and first and second generation cephalosporins.
Ceftiofur is active against the following microorganisms which are involved in respiratory diseases in pigs: Pasteurella multocida, Actinobacillus pleuropneumoniae and Streptococcus suis. Bordetella bronchiseptica is intrinsically non-susceptible to ceftiofur.
It is also active in cattle against:
•bacteria involved in respiratory disease: Pasteurella multocida, Mannheimia spp., Histophilus somni;
•bacteria involved in acute interdigital necrobacillosis (foot rot): Fusobacterium necrophorum, Bacteroides melaninogenicus (Porphyromonas asaccharolytica); and
•bacteria associated with acute post-partum (puerperal) metritis: Escherichia coli, Arcanobacterium pyogenes and Fusobacterium necrophorum.
The following Minimum Inhibitory Concentrations (MIC) have been determined for ceftiofur in European isolates (France, United Kingdom, Netherlands, Denmark, Germany, Belgium, Italy, Czech Republic, Ireland, Poland and Spain) collected from diseased animals between 2000 to 2012 (refer to Table):
Bacteria species | Origin | Year | Nb of strains | MIC of ceftiofur (µg/mL) |
Range | MIC50 | MIC90 |
Pasteurella multocida | Cattle | 2009 to 2012 | 149 | ≤0.002 – 0.12 | 0.015 | 0.015 |
Pigs | 2009 to 2012 | 152 | ≤0.002 – 0.06 | 0.04 | 0.04 |
Mannheimia haemolytica | Cattle | 2009 to 2012 | 149 | ≤0.002 – 0.12 | 0.015 | 0.015 |
Histophilus somni | Cattle | 2009 to 2012 | 66 | ≤0.002-0.008 | ≤0.002 | 0.004 |
Escherichia coli | Cattle | 2005 – 2006 | 163 | 0.06 – 1 | 0.23 | 0.44 |
Arcanobacterium pyogenes | Cattle | 2007 – 2008 | 30 | 0.06 – 0.25 | 0.09 | 0.12 |
Fusobacterium necrophorum | Cattle | 2000 to 2006 | 27 | 0.015 – 16 | 0.1 | 0.2 |
Actinobacillus pleuropneumoniae | Pigs | 2009 to 2012 | 157 | 0.008-2 | 0.015 | 0.03 |
Streptococcus suis | Pigs | 2009 to 2012 | 151 | –0.06-16 | 0.12 | 0.5 |
|
The following ceftiofur breakpoints are used: ≤2 µg/mL (Susceptible), 4 µg/mL (Intermediate) and ≥ 8 µg/mL (Resistant).
No breakpoints have been determined to date for the pathogens associated with foot rot or acute post-partum metritis in cows.
Pharmacokinetic particulars
After administration, ceftiofur is quickly metabolised to desfuroylceftiofur, the principal active metabolite.
Desfuroylceftiofur has an equivalent anti-microbial activity to ceftiofur against the bacteria involved in respiratory disease in animals. The active metabolite is reversibly bound to plasma proteins. Due to transportation with these proteins, the metabolite concentrates at a site of infection, is active and remains active in the presence of necrotic tissue and debris.
In pigs given a single intramuscular dose of 3 mg/kg body weight (bw), maximum plasma concentrations of 13.2 µg/mL were reached after 2 hours; the terminal elimination half-life (t½) of desfuroylceftiofur was 16.4 hours. No accumulation of desfuroylceftiofur has been observed after a dose of 3 mg ceftiofur/kg bw/day administered daily over 3 days.
The elimination occurred mainly via the urine (more than 70%). Average recoveries in faeces accounted for approximately 12-15% of the drug.
Ceftiofur is completely bioavailable following intramuscular administration.
After a single 1 mg/kg dose given subcutaneously to cattle, maximum plasma levels of 2.82 µg/mL are reached within 4 hours after administration. In other studies, on healthy cows, a Cmax of 2.25 µg/mL was reached in the endometrium 5 hours after a single administration. Maximum concentrations reached in caruncles and lochiae of healthy cows were 1.11 µg/mL and 0.98 µg/mL, respectively.
The terminal elimination half-life (t½) of desfuroylceftiofur in cattle is 12.1 hours. No accumulation was observed after a daily treatment over 5 days. The elimination occurs mainly via the urine (more than 55%) and the faeces (30%). Ceftiofur is completely bioavailable following subcutaneous administration.