Cefquinome

Cefquinome

Systematic (IUPAC) name
1-[[(6R,7R)-7-[[(2Z)-(2-Amino-4-thiazolyl)- (methoxyimino)acetyl]amino]-2-carboxy-8-oxo- 5-thia-1-azabicyclo[4.2.0-oct-2-en-3-yl]methyl]- 5,6,7,8-tetrahydroquinolinium inner salt
Clinical data
Pregnancy cat.	?
Legal status	? (US)
Pharmacokinetic data
Bioavailability	87%
Protein binding	<5%
Half-life	2½ hours
Excretion	Renal, unchanged
Identifiers
CAS number	84957-30-2
ATCvet code	QJ01DE90 QJ51DA92
ChemSpider	16736863 Y
UNII	Z74S078CWP Y
KEGG	D07652 Y
Chemical data
Formula	C23H24N6O5S2
Mol. mass	528.60 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C23H24N6O5S2/c1-34-27-16(14-11-36-23(24)25-14)19(30)26-17-20(31)29-18(22(32)33)13(10-35-21(17)29)9-28-8-4-6-12-5-2-3-7-15(12)28/h4,6,8,11,17,21H,2-3,5,7,9-10H2,1H3,(H3-,24,25,26,30,32,33)/b27-16-/t17-,21-/m1/s1 Y Key:YWKJNRNSJKEFMK-PQFQYKRASA-N Y
Y(what is this?)  (verify)

Cefquinome is a fourth generation cephalosporin with pharmacological and antibacterial properties valuable in the treatment of coliform mastitis and other infections. It is only used in veterinary applications.

Properties

Cefquinome is resistant to beta-lactamase. Chemically, its zwitterionic structure can facilitate rapid penetration across biological membranes, including porins of bacterial cell wall. Plus, it has a higher affinity to target penicillin binding proteins. The reactive site is a beta-lactam nucleus, while the main peripheral functional groups are a quaternary quinolinium, an aminothiazolyl moiety and an unusual O-alkylated oxime.

Cefquinome acts by inhibition of the cell wall synthesis, but it has a relatively short half-life of about two and half hours. It is less than 5% protein bound and is excreted unchanged in the urine.^[1]

Studies

Many studies have been conducted, mostly for animal use. One such study was conducted by the Pharma Research in Germany.

Test groups

Groups of albino mice, weighing 191 g, were dosed with 10 and 40 mg of cefquinome per kg. Blood samples were obtained from a cut at the tip of the tail and kept at 4 degrees Celsius. Urine was collected in metabolism cages.

Three male beagle dogs, weighing about 22 kg each, were dosed with 5, 10, and 20 mg/kg at the cephalic vein. Blood samples were drawn from the same vein in the opposite leg. Meanwhile, urine was collected by catheterization.

Pigs, five or six male and female in each group weighing approximately 18 kg each, were injected with 10 mg of cefquinome at the venajuglaris in the base of the left ear. Blood samples were withdrawn from the contralateral jugular vein.

Male and female calves were weighing between 110 and 140 kg were dosed with 10 mg of cefquinome per kg through the vera jucular.

Standard solutions were prepared from pooled murine blood and urine taken from untreated dogs, pigs, and calves.

Calculations

Cefquinome concentrations were calculated by regression analysis, using the standard curves in which logarithms of the concentration were proportional to the areas of the inhibition zones. Curve fitting was carried out by nonlinear regression with the computer program PHAKOK. Pharmokinetic analysis of the concentration-time data after administration indicated that the best curve fits were usually achieved by using an open two-compartment model.

Conclusion

Data indicate that cefquinome has high antibacterial activity in vitro against nearly all strains tested. In general, cefquinome is within the same range as cefpirome and cefotaxime. Against gram-negative species, cefquinome has very limited in vitro activity. The in vitro activity of cefquinome does not depend on the composition or pH of the test medium. The broad antibacterial spectrum and the high in vitro activity are reflected by high in vivo efficacy in experimental infections. In mouse models of septicemia, cefquinome possessed high therapetic efficacy. All infections were cured.

Intervet

Intervet developed cefquinome (Cobactan) to treat bovine respiratory disease, the most common disease in cattle.^[2] An injection, containing 25 mg cefquinome per ml, is given to cattle and pigs.

Treatment

In cattle, the injection should help against respiratory disease caused by Mannheimia haemolytica and Pasteurella multocida. It also helps with acute E. coli mastitis, dermatitis, infectious ulbar necrosis, and interdigital necrobacillosis (which is foul in the foot). In calves, it is E. coli septicaemia.

For pigs, it would treat the bacterial infections of the lungs and respiratory tract caused by P. multocida, Haemophilus parasuis, Actinobacillus pleuropneumoniae, and Streptococcus suis. Mastitis-Metritis-Agalactia Syndrome (MMA) involved with E. coli, Staphylococcus, Streptococcus, and other cefquinome-sensitive organisms will also be treated. In piglets, the mortality rate in cases of meningitis caused by Streptococcus suis is reduced. It is used in the treatment of mild or moderate lesions caused by Staphylococcus hyicus and arthritis caused by Streptococcus spp. and E. coli.

Usage

Shake the vial well before using.

Swab the septum before removing each dose. Use a dry sterile needle and syringe. An appropriately graduated syringe must be used to allow accurate administration of the required dose volume. This is particularly important when injecting small volumes, for example when treating piglets. The cap may be safely punctured up to 25 times. The 50 ml vial should be used for treating small piglets. When treating groups of animals, use a draw-off needle.

Caution/warnings

These are some factors to be aware of before treating.

• This product should not be used in animals known to be hypersensitive to β-lactam antibiotics.
• Should not be administered to animals with a body weight less than 1.25 kg.
• Use of the product may result in localised tissue reaction. Tissue lesions are repaired by 15 days after the last administration of the product.
• Hypersensitivity reactions to cephalosporins occur rarely.
• The product does not contain an antimicrobial preservative.
• To prevent the claimed infections in piglets, attention should be paid to hygiene and ventilation, and overcrowding should be avoided. When the first piglets are affected, careful examination of all animals in the same pen is recommended to enable an early treatment of any other infected piglets.

Clinical usage

Human use

Cefquinome is not approved for human use.

Veterinary medicine

Conditions of use are limited to therapeutic, parenteral, and individual animal use. Individual parenteral therapy of bovine respiratory disease data on cefquinome-related residues demonstrate that only very small amounts are present in the intestinal tract of treated cattle with gastrointestinal activation.

However, treatment should be short, meaning a single injection daily for about a week. Treatment should only be given by prescription. Cefquinome should not be used in feed or water.

Since 1994, in Europe, it was allowed to treat cattle by prescription only. In 1999, swine were included. By 2005, horses were allowed as well.

In the United States, approval is pending for treatment of bovine respiratory disease. Even so, this is only available by prescription.

Cefquinome are also used for other illnesses, such as “shipping fever,” a pneumonia-like illness commonly found in cattle.^[3]

Concerns

Resistance and food-borne transmission

There are concerns that the use of the drug in animals will lead to increases in antibiotic resistance. Humans can be exposed to bacteria through food-borne transmission, raising chances of becoming exposed to resistant bacterial species, such as Salmonella or E. coli. The potential for the development of antibiotic resistance increases as usage increases, by selecting bacteria which have acquired beta-lactamases.

Salmonella

The use of CEQ may cause resistance in Salmonella present in the intestinal tract of the target animal. Resistant Salmonella may also contaminate the carcass at slaughter and transfer to humans when used as food. When humans are infected and treated with a 4GC, effectiveness may be compromised.

Although 4GC resistance is very rare, they are active against bacteria carrying the AmpC-type β-lactamase resistance mechanism. Since the late 1990s, the US and EU have surveyed and gathered data for 4GCs for both human and veterinary use. Data indicate that there are no changes in resistance patterns of relevant food-borne pathogens.

FDA guidelines

• Administered products will be used in individual animals for short duration and by prescription only.
• The extent of use is ranked low.
• Avoid human drug resistance to fourth-generation cephalosporins by authorizing extra-label prohibition.

Footnotes

1. ^ Intervet, "Cephaguard Injection Data Sheet," http://www.intervet.co.uk/Products_Public/Cephaguard_Injection/090_Product_Datasheet.asp
2. ^ Rick Weiss, "FDA Rules Override Warnings About Drug", The Washington Post, March 4, 2007, sec. A01
3. ^ Associated Press, "Farmers, doctors battle over new drug for dairy cows," April 5, 2007, State and Regional

See also

• Beta-lactamase
• Campylobacter
• Cefepime
• Cephalosporin
• Enterococcus
• Salmonella
• Zwitterion

References

• “Farmers, doctors battle over new drug for dairy cows.” Associated Press. 5 Apr 2007.
• Belongia, Edward. “Beware wider use of antibiotics in animals.” Star Tribune. 9 Apr 2007.
• “Efficacy of Cefquinome.” Journal of Dairy Science, Vol. 80, No. 2, 1997.
• "Cephaguard Injection Data Sheet." Intervet. <http://www.intervet.co.uk/Products_Public/Cephaguard_Injection/090_Product_Datasheet.asp> July 2006.
• Johnson, Carl K. "Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment." <http://www.fda.gov/cvm/VMAC/VMAV0906Johnson.htm> 20 Sept 2006.
• Weiss, Rick. "FDA rules override warnings about drug." The Washington Post. 4 Mar 2007.

External links

• Intervet Product Datasheet
• Intro to CEQ & Overview of Microbial Safety Assessment
• Cefquinome Formulations for Parenteral Injection