Pharmacodynamic properties
This product is a combination consisting of cefalexin and kanamycin at ratio 1.5 : 1.
Cefalexin represents a first generation cephalosporin and belongs to the class of ß-lactam antibiotics. It provides a mainly time-dependent antibacterial activity against gram-positive pathogens by inhibiting the synthesis of the bacterial peptidoglycan cell wall.
Kanamycin belongs to the class of aminoglycosides and provides bactericidal activity against Gram-negative pathogens and against Staphylococcus aureus. Kanamycin provides mainly a concentration-dependent antibacterial activity through inhibition of bacterial protein synthesis and reduction of translation fidelity at ribosomal level.
The combination of cefalexin and kanamycin showed a bactericidal mode of action against Staphylococcus aureus, Streptococcus dysgalactiae, Streptococcus uberis and Escherichia coli. The effect of cefalexin and kanamycin in combination is mainly time-dependent.
Minimum inhibitory concentration, checkerboard analysis, kill kinetic and post antibiotic effect data demonstrate an advantage of the combination by broadening the activity spectrum and by showing synergistic antibacterial activity: the effect of cefalexin is enhanced by kanamycin and vice versa.
Further, the combination produces a larger suppression of bacterial growth (post antibiotic effect) against all target mastitis pathogens compared with the individual compounds.
Staphylococcus aureus has the potential to evade the immune system and establish deep-seated infection in the mammary gland. Thus, as is the case for other intramammary products, bacteriological cure rates in the field are expected to be low. In vitro studies have demonstrated that isolates (2002-2004 and 2009-2011) of S. aureus are susceptible to the combination of active substances.
In vitro studies demonstrate that isolates of S. agalactiae (collected in 2004) and coagulase-negative staphylococci (collected in 2004 and 2009-2011) are susceptible to the combination of active substances.
Three mechanisms of resistance to cephalosporin are known: reduced permeability of the cell wall, enzymatic inactivation and absence of specific penicillin binding sites.
Exogenous ß-lactamase production is the main method for Staphylococcus aureus and other Gram-positives bacteria to inactivate cephalosporins. Genes for ß-lactamases are found in both, chromosomes and plasmids, and may be moved by transposons. Gram-negative bacteria express low levels of species specific ß-lactamases within the periplasmic space, which contributes to resistance by hydrolysis of susceptible cephalosporins.
Resistance to kanamycin can be either chromosomal or plasmid-mediated. The clinical resistance to aminoglycosides is mainly caused by plasmid-specified enzymes, which are found in the periplasmic space of the bacteria. The enzyme binds to the aminoglycoside and prevents it binding to the ribosome and thus aminoglycoside can no longer inhibit protein synthesis.
The occurrence of co-resistance, induced by specific enzyme systems that are encoded for resistance, is particularly family specific for the ß-lactams and aminoglycosides. There are incidences of multiple resistances and this is mainly due to the way in which a resistance gene is transferred either by transposons or integrons to plasmids, which then encode for resistance to both the ß-lactams and aminoglycosides.
Pharmacokinetic particulars
After intramammary infusion on two consecutive days at 24 hour intervals the absorption and distribution of both active ingredients in the blood stream were fast but limited.
Kanamycin plasma concentrations reached a Cmax of 0.504 and 1.024 µg/ml after the first and second dose respectively at Tmax of six and four hours respectively. Plasma cefalexin levels reached 0.85 to 0.89 µg/ml two hours after administration.
The available metabolism data indicate that both parent substances, cefalexin and kanamycin, are the major compounds with antimicrobial activity.
Following intramammary administration of the product, cefalexin and kanamycin were mainly excreted via milk during milking. The highest concentrations of kanamycin A in milk were detected 12 hours after the first dose, with concentrations ranging between 6360 to 34500 µg/kg. Kanamycin A concentrations peaked again after the second dose administration with residues detected in the range of 3790 to 22800 µg/kg. The highest concentrations of cefalexin in milk were detected at 36 hours, with concentrations ranging between 510 µg/kg and 4601µg/kg.