Cepravin Dry Cow is a long-acting intramammary cerate containing cefalonium dihydrate, a semi-synthetic cefalosporin antibiotic. It is formulated to give persistent antibiotic levels in the dry udder.

The cefalosporins are a family of drugs which are similar in chemical structure to the penicillins. The major difference being that penicillins are based on a β-lactam ring fused with a dihydrothiazine ring and cephalosporins on a β-lactam ring fused with a thiazolidone ring. The two families of antibiotics are collectively known as β-lactams.

Both cefalosporins and penicillins kill susceptible bacteria and the mode of action of the individual antibiotics of both families is the same.

The cell wall of bacteria is essential for their normal growth and development. Peptidoglycan is a heteropolymeric component of the cell wall which gives it rigidity. Peptidoglycan consists of glycan chains which are linear strands of two alternating amino sugars (N-acetylglucosamine and N-acetylmuramic acid) that are linked by peptide chains. Cefalonium and other β-lactams act by inhibiting the enzyme transpeptidase, usually following interaction with penicillin binding protein (PBP), which is responsible for the final stage of peptidoglycan synthesis. This inhibition of cell wall synthesis produces unstable forms of the bacterium during reproduction and these unstable forms lyse.

Therefore, these antibiotics are bactericidal in their mode of action.

β-Lactam antibiotics cannot kill or even inhibit all bacteria as there are various methods by which bacteria become resistant. These mechanisms include non-susceptible PBPs, failure of the antibiotic to penetrate to the site of action and production of β-lactamase enzymes. These enzymes hydrolyse the β-lactam ring producing an inactive derivative. Cefalosporins in general are not susceptible to the actions of β-lactamase enzymes, especially when compared with penicllin, ampicillin or amoxicillin.

The penicillins and cefalosporins have a high therapeutic index in both animals and man. The reason for this probably relates to their highly specific mode of action in attacking the bacterial cell wall. As mammalian cells do not have an outer cell wall like that found in bacteria the β-lactams are without effect on mammalian cell division. The most common adverse effect of the cefalosporins is a hypersensitivity reaction which in most cases manifests as maculopapular skin rashes after several days of therapy. They may be accompanied by eosinophilia and fever. Anaphylactic reactions are rare with the cephalosporins. There are no data available specifically on the effects of cephalonium in man.

Cefalonium is a broad spectrum cefalosporin antibiotic which has bactericidal activity against the majority of organisms associated with bovine mastitis. The antibacterial activity is not impaired in the presence of milk.

Cefalonium is active against non-β-lactamase and β-lactamase producing organisms:

Actinomyces pyogenes Citrobacter spp.

Corynebacterium ulcerans Enterobacter spp.

Escherichia coli Klebsiella spp.

Proteus spp. Staphylococcus aureus

Penicillin resistant strains of Staphylococcus aureus

Streptococcus agalactiae Streptococcus dysgalactiae

Effective levels of cefalonium are maintained in most quarters for up 10 weeks after infusion of Cepravin Dry Cow. Cattle treated with Cepravin Dry Cow have a lower incidence of Streptococcus uberis infection during the dry period and the immediate post-calving period, with accompanying lower somatic cell counts.

The serum pharmacokinetics of cefalonium have not been investigated in definitive studies so the serum half-life is not known. Some work in dogs has shown that the drug is absorbed following oral administration.

Pharmacokinetics of cefalonium in the target species has only been investigated following intramammary administration. Studies were originally conducted using Cepravin Dry Cow containing non-radiolabelled cefalonium. The presence of cefalonium and/or its biologically active metabolites was detected in urine or serum using a microbiological assay.

These original studies have been supplemented by a new study using C-14 radiolabelled cefalonium incorporated into the Cepravin Dry Cow formulation. In this study the serum, urine, faeces, tissue and milk were examined for the presence of radiochemical content. The results showed that cefalonium was extensively but slowly absorbed from the udder and excreted primarily in the urine. Between 7 and 13% of the radioactivity was eliminated in urine on each of the first three days post dosing whilst daily excretion in faeces was < 1% over the same period.

Mean blood concentration of radioactivity remained fairly constant during approximately 10 days after dosing which is consistent with slow but prolonged absorption of cefalonium from the udder. Plasma levels of radioactivity were generally higher than those found in blood indicating limited uptake of cefalonium and its metabolites into blood cells.

The results of the earlier work support the conclusion of the radiolabelled work. In these 2 studies Cepravin Dry Cow was given as a single infusion to 4 and 2 cows respectively. In one of the studies 2 additional cows were given repeated infusions of the formulation for 3 days. Antibiotic activity was detected in urine at concentrations which indicated rapid and significant absorption from the udder. Absorption and elimination of cefalonium and its metabolites was however more rapid in the older studies.

There are no data on the pharmacokinetics of cefalonium in humans. However, cefalonium is structurally related to cefaloridine, differing only by the presence of a carbamoyl moiety at the para-position of the pyridine ring. Cefaloridine is used in man and administered by the parenteral route. The half-life is about 1-1.5 hours and only about 20% is bound to plasma proteins. It is reported to be poorly absorbed after oral administration. Given the similarity in structures, cefalonium probably has similar properties.

Many cefalosporins are eliminated unchanged in urine by humans and laboratory animals. It is therefore very likely that most of the radioactivity in urine at early time points will be present as unchanged cefalonium. Results from the new study in cows show however that this is not the situation with milk. For the early milkings post calving the concentration of cefalonium in milk accounts for only a small proportion of the total radioactive residue. This indicates that any metabolism/degradation takes place within the udder. However, in addition to analysis for cefalonium concentrations milk samples were also analysed for microbiological residues using a validated method. It was determined that the metabolites/degradation products had no antibiotic activity.