Penicillin

 

Beta-lactam antibiotics

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   Historical aspects: β-lactam antibiotics constitute one of the most important and frequently use d groups   of antimicrobial agents. Penicillins and Cephalosporins are common classes included in this   category. The history of Penicillins is traced back to 1928 when Sir Alexander Fleming (British   bacteriologist) found that staphylococcal colonies underwent lysis as a result of mouldy growth. He   proposed that bacterial growth was inhibited by an antibacterial substance released by the mould.   Fleming named that substance as Penicillin after that mould, Penicillium notatum.
 
Penicillins

Chemical structure: Penicillins are a large group of naturally occurring and semi-synthetic antibiotics. They have a common nucleus, 6-amino penicillanic acid (6-APA that is formed by a 5-membered thiazolidine ring connected to a 4-memebered β-lactam ring). β-lactam is the key structural feature of all β-lactam antibiotics. Cleavage of β-lactam ring destroys the anti-bacterial activity, some resistant bacteria produce β-lactamase (penicillinase) enzyme that degrades the β-lactam ring. The carboxylic group attached to thiazolidine ring is the site of salt formation (e.g., sodium or potassium salts). Salt formation stabilizes the Penicillins and improves their solubility and pharmacokinetic profile. Cleavage of amide bond side-chain by amidase yields the 6-APA nucleus which is used in preparing semi-synthetic penicillins.

 
 
Mode of action: Penicillins (and other β-lactams) interfere primarily with the synthesis of bacterial cell wall. These drugs produce their anti-bacterial effects by binding to a family of proteins called penicillin binding proteins (PBP_S) which have been grouped as high molecular weight PBP_S (PBP-1A, PBP-1B, PBP-2 and PBP-3) and low molecular weight PBP_S (PBP-4, PBP-5 and PBP-6). The high molecular weight PBP_S are essentially involved in the maintenance of normal cell morphology, cell elongation and cell division. Inhibition of one or more of these PBP_S by β-lactams produces the antibacterial effects. The blockade of cell wall synthesis is also thought to activate the enzymes known as autolysins that degrade the abnormally formed peptidoglycan. In general gram positive bacteria are more susceptible to Penicillins because of their cell wall structure (lack of capsule and outer membrane as found in gram negative bacteria). Certain bacteria can become resistant to Penicillins through the acquisition of penicillinases or exhibiting a dormant/quiescent state.
Salient features: The Penicillins are poorly soluble, weak organic acids that are sensitive to heat, light, strong alcohols, oxidizing agents and reducing agents. A prolonged exposure of Penicillins to water promotes hydrolysis; so many penicillins require reconstitution with diluent just before injection.

 Some Penicillins are rapidly hydrolyzed and inactivated by gastric acids and β-lactamases. Gastric acid hydrolyses the amide side chain and opens the β-lactam ring whereas β-lactamase degrades the β-lactam ring giving rise to penicilloic acid derivatives. β-lactam antibiotics are most active during the log (logarithmic) phase of bacterial growth because they act against rapidly growing and replicating cells. They are less effective against formed bacterial cell wall. 

The efficacy of β-lactam antibiotics (and also that of Tetracyclines, Amphenicols, Macrolides and Potentited sulphonamides) is time dependent, therefore, for maximal efficacy the plasma concentration must be maintained above the MIC for longer period of time (conversely the efficacy of Aminoglycosides and Fluoroquinolones is said to be concentration dependent, therefore their antimicrobial activity increases as the drug concentration exceeds the MIC, and it is not essential to maintain drug levels above the MIC between doses. Furthermore, some drugs like Vancomycin and Rifampicin, exert both time-dependent and concentration-dependent activity). The efficacy of β-lactams may decrease in chronic/latent infections probably due to slow microbial growth.

Pharmacokinetics: The therapeutic concentration of Penicillins is readily achieved in body tissues and fluids but they do not penetrate into some sites such as brain, bones, cartilages, cornea and CSF unless these sites are inflammed. Penicillins do not undergo significant biotransformation and are generally excreted unchanged in the urine. Penicilloic acid derivatives that are formed as metabolites tend to be allergenic. Penicillins are excreted rapidly in urine some excretion of penicillins also occurs in milk. Renal tubular excretion can be deliberately inhibited by Probenicid to prolong the effective levels of penicillins in the body.
 

Classification of Penicillins
Narrow spectrum Penicillins (effective only against gram positive bacteria)		Broad spectrum Penicillins (effective against gram positive and gram negative bacteria excluding Pseudomonas)	Extended spectrum Penicillins (effective against gram positive and gram negative bacteria including Pseudomonas)	Potentiated Penicillins (Penicillins combined with β-lactamase inhibitors)
Beta-lactamase sensitive	Beta-lactamase resistant	(Aminopenicillins)	(Anti-pseudomonal penicillins)	(Beta-lactamase protected penicillins)
1. Acid susceptible (Natural) Penicillins e.g., penicillin G (Benzyl penicillin)	Methicillin	Amoxycillin	Carbenicillin	Amoxycillin+Clavulinic acid* = Co-amoxy clav (Augmentin)
2. Acid resistant (semi-synthetic) penicillins e.g., penicillin V	Oxacillin	Ampicillin	Mezlocillin
	Cloxacillin		Azlocillin	Ampicillin+Sulbactam*
			Piperacillin	Piperacillin +Tazobactam*

* β-lactamase inhibitor

Bacterial resistance: β-lactamase/penicillinase producing bacteria, quiescent/dormant bacteria, bacteria with altered penicillin binding proteins and gram negative bacteria with absence or mutation of aqueous porin channels appear to be resistant to Penicillins. Some strains of staphylococcus aureus (known as Methicillin-resistant staphylococcus aureus, i.e., MRSA) have acquired resistance (due to possession of altered penicillin-binding proteins) to Methicillin, Erythromycin, Aminoglycosides and Tetracyclines, therefore they are thought to be susceptible only to Vancomycin and Fluoroquinolones.

Clinical uses: Penicillins are widely used in human as well as in veterinary medicine for a wide range of systemic infections caused by susceptible bacteria. They are administered through a variety of routes including oral (tablets, suspension), parentral and topical (cutaneous, intra-ocular, intra-aural and intra-mammary). Penicillin G is used (either alone or in combination with Streptomycin) in all domestic animals against non-penicillinase producing pathogens and prophylactically before certain procedures like surgical operations, endoscopy and catheterization which are likely to cause bacteremia. Cloxacillin is used to treat ocular infections (in the form of ophthalmic preparations) and staphylococcus-induced bovine mastitis. Co-amoxyclav is the most frequently used Penicillin preparation (in human medicine) for the treatment of systemic infections caused by susceptible pathogens.

Adverse effects: Penicillins are among the safest antimicrobial drugs. However hypersensitivity is an infrequent but serious adverse effect. The major antigenic determinant of penicillin hypersensitivity reaction is its metabolite penicilloic acid which reacts with proteins and serves as heptan to cause an immune reaction characterized by rashes, urticaria, angio-neurotic edema (edematous condition that involves the swelling of underlying blood vessels and nerves). Cross-allergic reactions between Penicillins are well recognized. As penicillins are generally administered as sodium or potassium salts, cation toxicity is possible if larger quantities of drug are used. Sodium excess may aggravate the CHF. The penicillins are irritating to neuronal tissues and can provoke seizures, particularly when administered in high doses or when given intrathecally. Epileptic patients are at higher risk. Oral administration of Penicillins to ruminants can lead to dysbiosis [disruption of rumenal/enteric microflora leading to digestive disturbances (i.e., indigestion, diarrhea and probably vitamin deficiency)] and superinfection (destruction of dominant micro-oganisms in enteric environment shifts the growth curve towards the opportunistic bacteria).

Drug interactions: Combination of Penicillins and aminoglycosides can have synergistic or additive effect whereas use of Penicillins with bacteriostatic drugs (such as Tetracylines, Amphenicols, Macrolides and Lincosamides) may produce antagonistic action. Probenecid competitively blocks the renal tubular excretion of most Penicillins thereby increasing their plasma half-lives. Acid-labile Penicillins (e.g., Penicillin G) should not be mixed with normal saline or other substances having acidic P_H (because the acidic environment inactivates such Penicillins).