Cefquinome
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Cefquinome is a fourth-generation
cephalosporin The cephalosporins (sg. ) are a class of β-lactam antibiotics originally derived from the fungus ''Acremonium'', which was previously known as ''Cephalosporium''. Together with cephamycins, they constitute a subgroup of β-lactam antibiotics ...
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 Porins are beta barrel proteins that cross a cellular membrane and act as a pore, through which molecules can diffuse. Unlike other membrane transport proteins, porins are large enough to allow passive diffusion, i.e., they act as channels tha ...
of bacterial cell walls. 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 2.5 hours. It is less than 5% protein bound and is excreted unchanged in the urine.Intervet, "Cephaguard Injection Data Sheet,"


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°C. 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 about 18 kg each, were injected with 10 mg of cefquinome at the '' vena jugularis'' in the base of the left ear. Blood samples were withdrawn from the contralateral jugular vein. Male and female calves weighing between 110 and 140 kg were dosed with 10 mg of cefquinome per kg through the ''vena jugularis''. 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. Pharmacokinetic 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 Cefotaxime is an antibiotic used to treat a number of bacterial infections in human, other animals and plant tissue culture. Specifically in humans it is used to treat joint infections, pelvic inflammatory disease, meningitis, pneumonia, urin ...
. Against Gram-negative species, cefquinome has very limited ''
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
'' 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 Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
'' efficacy in experimental infections. In mouse models of septicaemia, cefquinome possessed high therapeutic efficacy. All infections were cured.


Intervet

Intervet Merck & Co., Inc. is an American multinational pharmaceutical company headquartered in Rahway, New Jersey, and is named for Merck Group, founded in Germany in 1668, of whom it was once the American arm. The company does business as Merck Sharp ...
developed cefquinome (Cobactan) to treat bovine respiratory disease, the most common disease in cattle. 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 Dermatitis is inflammation of the skin, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened. The area of skin involved can v ...
, infectious bulbar necrosis, and interdigital necrobacillosis. In calves, it is effective against ''E. coli'' septicaemia. For pigs, it is used to treat bacterial infections of the lungs and respiratory tract caused by '' P. multocida'', ''
Haemophilus parasuis ''Haemophilus'' is a genus of Gram-negative, pleomorphic, coccobacilli bacteria belonging to the family Pasteurellaceae. While ''Haemophilus'' bacteria are typically small coccobacilli, they are categorized as pleomorphic bacteria because of ...
'', ''
Actinobacillus pleuropneumoniae ''Actinobacillus pleuropneumoniae'' (previously ''Haemophilus pleuropneumoniae''), is a Gram-negative, facultative anaerobic, respiratory pathogen found in pigs. It was first reported in 1957, and was formally declared to be the causative agent o ...
'', and ''
Streptococcus suis ''Streptococcus suis'' is a peanut-shaped, Gram-positive bacterium, and an important pathogen of pigs. Endemic in nearly all countries with an extensive pig industry, ''S. suis'' is also a zoonotic disease, capable of transmission to humans from ...
''. Mastitis-metritis-agalactia syndrome involved with ''E. coli'', ''
Staphylococcus ''Staphylococcus'' is a genus of Gram-positive bacteria in the family Staphylococcaceae from the order Bacillales. Under the microscope, they appear spherical (cocci), and form in grape-like clusters. ''Staphylococcus'' species are facultative ...
'', '' Streptococcus'', and other cefquinome-sensitive organisms are also 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 ''Staphylococcus hyicus'' is a Gram-positive, facultatively anaerobic bacterium in the genus ''Staphylococcus.'' It consists of clustered cocci and forms white circular colonies when grown on blood agar. ''S. hyicus'' is a known animal pathogen. ...
'' and arthritis caused by ''Streptococcus'' spp. and ''E. coli''.


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. * It 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 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 is also used for other illnesses, such as “shipping fever”, a
pneumonia Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severity ...
-like illness commonly found in cattle.Associated Press, "Farmers, doctors battle over new drug for dairy cows," April 5, 2007, State and Regional


Concerns


Resistance and food-borne transmission

Of concern, the use of the drug in animals may lead to increases in
antibiotic resistance Antimicrobial resistance (AMR) occurs when microbes evolve mechanisms that protect them from the effects of antimicrobials. All classes of microbes can evolve resistance. Fungi evolve antifungal resistance. Viruses evolve antiviral resistance. ...
. Humans can be exposed to bacteria through food-borne transmission, raising chances of becoming exposed to resistant bacterial species, such as ''
Salmonella ''Salmonella'' is a genus of rod-shaped (bacillus) Gram-negative bacteria of the family Enterobacteriaceae. The two species of ''Salmonella'' are ''Salmonella enterica'' and ''Salmonella bongori''. ''S. enterica'' is the type species and is fur ...
'' 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 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 fourth-generation cephalosporin, effectiveness may be compromised. Although fourth-generation cephalosporin 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 fourth-generation cephalosporins for both human and veterinary use. Data indicate no changes occur 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.


Synthesis

Broad-spectrum fourth generation injectable aminothiazolyl cephalosporin.
Cefotaxime Cefotaxime is an antibiotic used to treat a number of bacterial infections in human, other animals and plant tissue culture. Specifically in humans it is used to treat joint infections, pelvic inflammatory disease, meningitis, pneumonia, urin ...
(1) is a potent cephalosporin antibiotic in its own right. Further modification of this drug by inclusion of a
quaternary ammonium cation In chemistry, quaternary ammonium cations, also known as quats, are positively charged polyatomic ions of the structure , R being an alkyl group or an aryl group. Unlike the ammonium ion () and the primary, secondary, or tertiary ammonium cations ...
gives a compound suitable for parenteral administration by increasing water solubility. The acid in
cefotaxime Cefotaxime is an antibiotic used to treat a number of bacterial infections in human, other animals and plant tissue culture. Specifically in humans it is used to treat joint infections, pelvic inflammatory disease, meningitis, pneumonia, urin ...
is first protected as its silyl ester (2) by derivatization with ''N''-methyl-''N''-(trimethylsilyl)trifluoroacetamide ( MSTFA). Treatment of this intermediate with
trimethylsilyl iodide Trimethylsilyl iodide (iodotrimethylsilane or TMSI) is an organosilicon compound with the chemical formula (CH3)3SiI. It is a colorless, volatile liquid at room temperature. Preparation Trimethylsilyl iodide may be prepared by the oxidative cleav ...
gives the allylic iodide (3). Displacement of halogen with 5,6,7,8-tetrahydroquinoline ( 2,3-cyclohexenopyridine) gives the corresponding quaternary salt. Hydrolysis of the silyl ester followed by adjustments of the pH leads to the
betaine A betaine () in chemistry is any neutral chemical compound with a positively charged cationic functional group, such as a quaternary ammonium or phosphonium cation (generally: onium ions) that bears no hydrogen atom and with a negatively charged ...
cefquinome (4).


See also

* ''
Campylobacter ''Campylobacter'' (meaning "curved bacteria") is a genus of Gram-negative bacteria. ''Campylobacter'' typically appear comma- or s-shaped, and are motile. Some ''Campylobacter'' species can infect humans, sometimes causing campylobacteriosis, a d ...
'' *
Cefepime Cefepime is a fourth-generation cephalosporin antibiotic. Cefepime has an extended spectrum of activity against Gram-positive and Gram-negative bacteria, with greater activity against both types of organism than third-generation agents. A 2007 ...
*
Cephalosporin The cephalosporins (sg. ) are a class of β-lactam antibiotics originally derived from the fungus ''Acremonium'', which was previously known as ''Cephalosporium''. Together with cephamycins, they constitute a subgroup of β-lactam antibiotics ...
* Enterococcus * Zwitterion


References


Further reading

* * *


External links

* {{Cell wall disruptive antibiotics Cephalosporin antibiotics Quinolines Thiazoles Ketoximes