β-lactam antibiotics

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β-lactam antibiotics:

These antibiotics have β-lactam rings.
Two major groups of this antibiotics include penicillin and cephalosporins
Monobactams and carbapenems are later additives.

# Penicillins:

It was the first antibiotic to be used clinically in 1941.
These are large group of naturally occurring and semi-synthetic antibiotics.
Penicillin nucleus consists of fused thiazolidine and β-lactam rings to which side chains are attached through amide linkage.

Classification:

They are broadly classified into the following groups depending on their spectrum of antibacterial activity and β-lactamase sensitivity.

Mechanism of Action:

Factor Influencing Activity of β-lactam Antibiotics:

These antibiotics are most active during the logarithmic phase of bacterial growth because they act against rapidly growing and replicating cells.
Efficacy of β-lactam antibiotic is time-dependent. Therefore, the plasma tissue concentration must be maintained above MIC for long periods of time to achieve maximal efficacy.
Efficacy is more in isotonic environment (isotonic to host and hypotonic to organism) because it causes rapid movement of fluid into hypotonic bacterial cell that results in rapid osmotic lysis.
Efficacy of β-lactam antibiotics decrease in chronic infections or when density of bacterial populations is more. It is due to the slow growth of microorganism in chronic infection.
β-lactam antibiotics do not produce significant post-antibiotic effect.

Antimicrobial spectrum:

Due to difference in bacterial cell wall structure, spectrum of penicillin differs.
In gram +ve bacteria layer of peptidoglycan layer in cell wall is porous. So, natural and narrow spectrum penicillin easily pass through these membrane to site of action despite their large molecular structure.
In case of gram -ve bacteria, cell wall consist of an additional outer membrane of LPS which are tight and consist of small porins channel. So, heavy molecular structure containing drug like natural penicillin cannot pass through these structure. So, broad spectrum penicillin is needed for antibacterial action as they are small in structure and can easily pass through porins to site of action. Broad spectrum penicillin acts on both gram +ve and gram -ve bacteria.

Bacterial resistance:

Bacteria develop resistance to penicillin by following methods:

By producing β-lactamases enzymes which destroy the β-lactam ring. Ex: S. aureus, E. coli, H. influenzae
By altering penicillin binding proteins. Ex: S. pneumoniae

Due to decreased ability of drug to penetrate its site of action.

Pharmacokinetics:

They are weak acids, so undergo oral absorption. Some penicillin may be destroyed by gastric acid when given orally. Such penicillin are administered parenterally.
After absorption, they are widely distributed throughout tissues
They donot undergo significant biotransformation and are excreted unchanged.
Excreted rapidly in urine.

Side effects/Adverse effects:

Hypersensitivity
Broad-spectrum penicillin may cause G.I disturbances, mainly diarrhoea and superinfection due to decrease in flora of G.I tract.
They can provoke seizures, when injected intrathecally or in high doses
Cation toxicity is possible if larger quantity of drug are used as they are generally administered as sodium or potassium salts.

Contraindications:

In patients those are hypersensitive to drugs
In renal disease
In pregnant animals

Indications:

For treatment of systemic infections caused by susceptible bacteria
Used topically in eye, ear and skin to prevent or treat local infections
Intramammary administration is used to prevent or treat bovine mastitis.

Narrow-spectrum Penicillin:

Penicillin G:

It is natural penicillin obtained from fermentation of mould Penicillium chrysogenum
It is first penicillin to be used clinically.
Prototype penicillin and most potent penicillin on weight basis.

Antibacterial spectrum:

Narrow spectrum β-lactam antibiotics
Antibacterial activity is limited to gram +ve and few gram -ve bacteria.
Bacteria like Staphylococcus, Streptococcus, Actinomyces, Erysipelothrix and Bacillus species are susceptible.
Gram -ve bacteria sensitive to penicillin are Haemophilus, Pasteurella, Leptospira and some species of Actinobacillus.
Bacterial resistance to penicillin G is usually due to elaboration of β-lactamases.

Pharmacokinetics:

They are destroyed by gastric acid when administered orally. So, they are given parenterally.
Rapidly absorbed after IM or SC administration & give high peak plasma concentration within 20-30 min.
After absorption, they are widely distributed throughout body tissues and fluids except CSF, brain, milk & joints.
Excreted largely unchanged in urine.

Contraindications:

In pregnant animals.
In renal failure patients

Indications:

In infections caused by gram +ve and few gram -ve bacteria
Also used before surgical operations, endoscopies and catheterization.

Table: List of important organisms and diseases sensitive to penicillin G in animals

Dose:

Crystalline form

Dogs & cats: 20,000 units/kg, IM, SC or slow IV, 4-6 times daily

Cattle: Upto 300,000 units/quarter, in mastitis.

Sheep & goats: 20,000-40,000 units/kg, IV, 4 times daily

Penicillin V:

It is a variant of penicillin G obtained by adding 2-phenoxyethanol to penicillium culture
It has similar antibacterial activity to those of penicillin G
After oral administration it is better absorbed than penicillin G as they are not destroyed by gastric acid
In veterinary medicine, it is used primarily by oral route in treatment of GI infections and mild to moderate systemic infections.

Dose:

Dogs & cats: 5-10 mg/kg, PO, 3 times daily

Horses: 40-60 mg/kg, PO, 3 times daily

Isoxazolyl Penicillin (Anti-staphylococcal penicillin):

Cloxacillin:

It is semi-synthetic penicillinase-resistant narrow spectrum penicillin
Isoxazolyl side chain makes it penicillinases as well as acid resistant.
Generally called anti-staphylococcal penicillin as they are specifically used in treatment of infections caused by staphylococcus.

Antibacterial spectrum:

It is narrow spectrum penicillin but is active against penicillinases producing staphylococci.
Antibacterial spectrum is narrower than that of penicillin G.

Pharmacokinetics:

They are resistant to gastric acid inactivation but incompletely absorbed from G.I tract.
Bioavailability after oral administration varies from 30-60%
They are highly bound to plasma protein
Excreted unchanged in urine and some through bile
Plasma half-life is about 30 minutes in dog.

Side effects:

Upset stomach, nausea, vomiting, diarrhea, gas, and mouth sores

Indications:

In treatment of skin, bone and soft-tissue infections and septicaemia
Frequently used in treatment of bovine mastitis.

Dose:

For systemic infections:

Dogs& cats: 20-40 mg/kg, PO, on empty stomach, 3 times daily

For mastitis:

Lactating cow (cloxacillin sodium): 200mg/quarter

Dry cow (cloxacillin benzathine): 500 mg/quarter, after last milking or early in dry period.

Non-isoxazolyl Penicillin:

Methicillin:

It is water-soluble penicillinase resistant semi-synthetic penicillin
It was previously used to treat infection caused by susceptible gram +ve bacteria and β-lactamase producing organism.
Inactive orally as it is destroyed by gastric acid.
Primarily excreted in urine but also found in bile and other body secretions
Presently, it is used in laboratory to determine the antibiotic sensitivity of S.aureus to other β-lactamase resistant penicillins.

Broad-spectrum Penicillins:

Ampicillin:

It is semi-synthetic penicillin having amino group in side chain
It is widely used as broad-spectrum penicillin in veterinary medicine for variety of diseases
It is broad spectrum antibiotic active against gram-ve anaerobes which are not covered by penicillin G.
Bacteria susceptible to ampicillin are Streptococcus, Staphylococcus (non-penicillinase producing), Corneybacterium, Clostridium, coli, Proteus, Haemophilus, Salmonella, Klebsiella, Brucella and Pasteurella species.

Pharmacokinetics:

Stable in gastric acid and well absorbed after oral administration
After absorption, ampicillin is widely distributed to many tissues & fluids.
Metabolized in liver
Excreted unchanged mainly in urine.

Indications:

For treatment of infection caused by susceptible bacteria
Disease include enteritis, mastitis, metritis, septicaemia, pneumonia
Also used for treatment of secondary infections associated with dermatitis.

Dose:

Dogs & cats: 10-20 mg/kg, PO, on empty stomach, 2-3 times daily

5-10 mg/kg, IM or SC, 2-3 times daily

Cattle & sheep: 5-10 mg/kg, IM, 1-2 times daily

Extended spectrum Penicillins/ Anti-pseudomonal penicillins:

Carbenicillin:

Broad-spectrum penicillin that is active against Pseudomonas aeruginosa and other bacteria resistant to aminopenicillins
It is acid labile and hydrolyzed by penicillinase
Not well absorbed after oral administration due to inactivation by gastric acid
It is given in high doses because it requires high concentration in blood to achieve anti-pseudomonal action.
Rapidly excreted in urine
It is specifically indicated for treatment of serious Pseudomonas or Proteus infections like burns, urinary tract infections & septicaemia.
It has low therapeutic index as it may cause neurotoxicity
It is generally used in combination with gentamycin or tobramycin

Dose:

Dogs & cats: 50 mg/kg, IM, SC or IV, 3-4 times daily

Potentiated Penicillin/β-lactamase protected penicillin:

These are combinations of β-lactamase inhibitor and broad-spectrum β-lactamase sensitive penicillin.
These drugs include:
Amoxicillin-clavulanic acid
Ampicillin-sulbactam acid
Ticarcillin-clavulanic acid
Ampicillin-flucloxacillin
Piperacillin-tazobactam

Amoxicillin-clavulanic acid:

It is combination of amoxicillin trihydrate with β-lactamase inhibitor clavulanate potassium in the ratio 4:1
Clavulanic acid protects the β-lactam ring from β-lactamases and potentiate the action of penicillin
The combination is well absorbed after oral administration and distributed well to body tissues and fluids
It is indicated in veterinary medicine for a numbers of skin and soft tissue infections and infection related to urinary, biliary and respiratory tract.