Cephalosporins:

• These are a class of frequently used β-lactam antibiotics which are structurally and pharmacologically related to penicillins.
• It is semi-synthetic antibiotics derived from ‘cephalosporin-C’ obtained from fungus cephalosporium.
• All cephalosporins contain basic structure of dihydrothiazine ring fused to form a β-lactam ring having a secondary amine to form 7-aminocephalosporanic acid, the cephalosporin nucleus.

Classification:

Cephalosporins are generally classified in terms of their chronological sequence of development and their antimicrobial properties into 5 groups:

Mechanism of action:

Cephalosporin penetrate peptidoglycan layer and binds with transpeptidase known as penicillin binding protein

This results in failure of cross linkage of peptidoglycan layer

Peptidoglycan layer synthesis stops

Cell wall disrupts and bacteria dies

Bacterial resistance:

Bacteria acquires resistance to cephalosporins by following mechanism:

1. Elaboration of β-lactamases (cephalosporinases) which destroy cephalosporin
2. Alteration in target proteins which reduce the affinity for cephalosporins

• Decreased permeability to cephalosporins so drugs donot reach their site of action.

Antibacterial spectrum:

1^st generation:

• Active against gram +ve cocci. These include streptococci & staphylococci.
• Not active against penicillin resistant strains.

2^nd generation:

• Active against gram -ve bacilli
• Those include E.coli, Klebsiella, Proteus, H.influenzae, M.catarrhalis, Bacteroides (only cefoxitin, cefmetazole, cefotetan are effective against Bacteroides)

3^rd generation:

• Active against gram +ve cocci, gram -ve cocci, gram -ve bacilli and anaerobes
• Gram +ve cocci: Staphylococci, Streptococci
• Gram -ve cocci: Gonococci
• Gram -ve bacilli: Enterobacteriaceae, Serratia, pseudomonas (only Ceftazidime and Cefoperazone are active)
• Anaerobes: Bacteroides

4^th generation:

• More resistant to β-lactamase
• Same as 3^rd generation

Pharmacokinetics:

• Most are given parenterally as they are acid susceptible. Only few are acid resistant.
• Orally administered cephalosporins are well absorbed with bioavailability of 75-90%.
• They are widely distributed throughout body tissues and fluids inducing lungs, kidneys, bone, placenta and soft tissues. 3^rd generation also cross BBB
• Most cephalosporins donot undergo significant biotransformation and are excreted unchanged. Some are metabolized in liver
• They are mainly excreted via kidneys through tubular secretion and glomerular filtration.

Side effects/Adverse effects:

• They are relatively non-toxic but sometimes may show allergic reactions
• GI disturbances like nausea, vomiting, diarrhoea, pain at IM injection site & lethargy.
• Prolonged treatment causes interstitial nephritis, hepatitis, thrombocytopenia & neutropenia.

Contraindications & Precautions:

• In patients who are hypersensitive to cephalosporins.
• Prolonged treatment should be avoided particularly in cats
• It should be used cautiously in pregnant animals
• In patients with renal insufficiency

*Concomitant use of aminoglycosides and loop diuretics potentiate the nephrotoxic effect of cephalosporins.

Clinical Uses:

1^st generation is most commonly used in domestic animals in skin, soft tissues, urinary and respiratory tract infections.

First-generation cephalosporins:

• These drugs were developed in 1960s.
• They are usually active against many gram-positive bacteria, but only moderately active against gram -ve organism.
• Some of these drugs are given orally, while others are administered parenterally.
• These are first alternative to penicillins for treating infections caused by gram +ve aerobes.
• Used in all species for the treatment of bone and soft-tissue infections.

# Cefalotin:

• Injectable first generation semi synthetic cephalosporins antibiotic
• Available commercially as Cefalotin-sodium
• Freely soluble in water and slightly soluble in alcohol
• Active against Streptococcus, staphylococcus, clostridium and Proteus species and some strains of E.coli, Klebsiella, Salmonella, Shigella, Pasteurella, Actinobacillus and Haemophilus.
• Except Bacteroides fragilis, most anaerobes are very susceptible to it.
• They are highly resistant to staphylococcal β-lactamase.

Pharmacokinetics:

• They are not absorbed orally, so must be administered parenterally.
• Partly metabolized in liver and kidneys
• Excreted mainly via kidneys as unchanged drug.
• Plasma half-lives is about 40-50 min in dogs and 15-50 minutes in horses.

Indications:

• For treatment of infections caused by gram +ve aerobes.
• Mainly indicated for treatment of infections caused by β-lactamase producing staphylococcus.

Dose:

Dogs & cats: 10-30 mg/kg, IM,IV or SC, 3 times daily

Cattle: 55 mg/kg, SC, 4 times daily

Horses: 10-20 mg/kg, IM or IV, 4 times daily

Birds: 100 mg/kg, IM, 4 times daily

Cefalexin:

• It is orally active semi-synthetic first generation cephalosporins
• Less active against β-lactamase producing staphylococci
• It is rapidly and almost completely absorbed after oral administration
• Little bound to plasma proteins, attains high concentration in blood and bile
• Excreted mainly unchanged in urine
• Elimination half-lives ranges from 1-2 hours in dogs and cats.
• It is one of the most commonly used cephalosporins.
• It is used for treating cefalexin-sensitive infections caused by gram +ve cocci.
• It may cause salivation, tachypnoea and excitability in dogs and emesis and fever in cats.

Dose:

Dogs & cats: 10-15 mg/kg, PO,2 times daily

Cattle: 7 mg/kg, IM, once daily

Horses: 15 mg/kg, PO, 4 times daily

Second generation cephalosporins:

• Also called as HEN cephalosporins (H= Haemophilus influenzae, E= Enterobacter aerogenes & N= Neisseria)
• Its antibacterial spectrum is broader than that of first-generation cephalosporins and includes both gram +ve and gram -ve organisms.
• They are ineffective against Pseudomonas, Enterococcus, Actinobacter species.
• Relatively resistant to β-lactamases and used clinically for treatment of organisms resistant or not-susceptible to 1^st generation cephalosporins.
• These are not widely used in veterinary medicine.

Cefuroxime:

• It is semi-synthetic 2^nd generation cephalosporin.
• It is active against gram -ve bacteria resistant to 1^st generation cephalosporins whereas weaker activity against gram +ve organism.
• It is active against Enterobacter spp, indole positive Proteus spp, Klebsiella spp, Actinobacillus spp., and strains of Haemophilus.
• Less effective orally but well tolerated after IM or IV injection
• Well distributed to body tissues & fluids and attains good concentration in CSF.
• It is used primarily in human beings for the treatment of meningitis caused by H.influenzae, Meningococci & Pneumococci.
• Side effects include diarrhoea, nausea, vomiting & abdominal pain.
• Also used as injectable and intramammary cephalosporins in animals.

Dose:

Dogs & cats: 10 mg/kg, IV 2-3 times daily

                       20-50 mg/kg, IM or SC, 2-3 times daily.

# 3^rd generation Cephalosporins:

• These cephalosporins were introduced in 1980s.
• These drugs provide extended spectrum coverage against gram -ve organism including Pseudomonas, Enterobacter and Proteus sps.
• These drug reach CNS and should be administered parenterally.

Cefotaxime:

• It is semi-synthetic antibiotic which is considered as prototype of 3^rd generation cephalosporins.
• It has wider spectrum of activity. It is active against gram -ve bacteria. It is also effective against most gram +ve cocci except Enterococcus.
• It is not well absorbed after oral administration, so must be given parenterally.
• After IM or SC, it is well absorbed and distributed into body fluids & tissues.
• Partially metabolized in vivo to desacetylcefatoxime. These act synergistically with parent compound for antibacterial action. Desacetylcefatoxime is further metabolized into inactive metabolites and excreted in urine.
• Plasma half-lives is about 45-60 minutes in dogs & cats.
• It is used for the infections of respiratory tract, skin, bones, joints, urogenital system, meningitis & septicaemia.
• In veterinary medicine, cefotaxime sodium is primarily used in treatment of gram -ve meningitis in small animals.

Dose:

Dogs & cats: 25-50 mg/kg, IM,IV or SC, 2-3 times daily

Horses (foals): 20-30 mg/kg, IV, 4 times daily

Ceftiofur:

• It is potent third generation cephalosporins available as sodium and HCl salts in veterinary medicine
• Spectrum of activity is similar to cefotaxime.
• Resistant to β-lactamase enzyme
• They are metabolized into active metabolites such as desfuroylceftiofur, which provide longer duration of action.
• They have relatively longer elimination half-life in cattle (9-12 hours) which permits single dosing per day.
• As it is potent than other 3^rd generation cephalosporins its dose should be followed carefully.
• Higher dose produces adverse effects like anemia and thrombocytopenia.
• It has world wide approvals for respiratory diseases in ruminants, swine and horses.
• In cattle, it is used in treatment of bovine respiratory disease associated with Pasteurella hemolytica and P. multicide and Haemophilus somnus.
• In horses, it is indicated for the treatment of respiratory disease associated with strep. Zooepidimicus.
• In dogs, it is used for urinary tract infections.
• It is also approved for treatment of intradigital necrobacillosis (foot rot) and metritis infection in cattle, early mortality infections in day old chicks and turkey poults.

Dose:

For respiratory tract and other susceptible infection

Dogs: 4mg/kg, SC, 1-2 times daily

Horses: 2.2-4.4 mg/kg, IM, once daily

Swine: 3 mg/kg, IM once daily for 3-5 days

Cattle: 1.1-2.2 mg/kg, IM or SC, once daily for 3 days

Poultry: 0.08-0.2 mg/chick, SC

For urinary tract infections:

Dogs & cats: 2.2 mg/kg, SC, 1-2 times daily

Fourth generation cephalosporins:

• It is also called as anti-pseudomonal cephalosporins
• It has antibacterial spectrum of 3^rd generation but highly resistant to β-lactamases.
• Many of these cephalosporins are zwitter ions which can penetrate the outer membrane of gram -ve bacteria.

# Cefepime:

• It was developed in 1994
• It has broad spectrum of activity which includes gram +ve cocci, enteric gram -ve bacilli and Pseudomonas aeruginosa.
• Not active against MRSA, enterococci, Bacteroides fragilis & L. monocytogenes.
• They are highly resistant to β-lactamases.
• It should be administered IV only.
• It is less used in animals.

Fifth generation cephalosporins:

• It is recently introduced sub-class of cephalosporins
• It has powerful anti-pseudomonal action and are less susceptible to development of resistance.
• This includes ceftobiprole and ceftaroline.

# Ceftobiprole:

• It is recently introduced 5^th generation cephalosporins.
• It possess activity against MRSA, penicillin resistant streptococcus pneumoniae, pseudomonas aeruginosa and enterococci.
• It is suggested that it inhibits 2A PBP of MRSA, 2x PBP of S. pneumoniae as well as classic PBP-2 of MRSA.
• It is resistant to staphylococcal β-lactamases.
• It is available for use in human medicine in some countries and administered by IV route only.