Beta-Lactam Antibiotics : Penicillins

The beta-lactam antibiotics include Penicillin, Cephalosporins, Monobactams and Carbapenems.

Penicillin consists of a thiazolidine ring and a beta-lactam ring fused together and side chains attached through an amide link. Penicillin G (Benzyl Penicillin), the original penicillin used clinically, have a benzyl side chain.
The side chain of natural penicillin is split off by an amidase to produce 6-aminopenicillanic acid and other side chains are attached to it, to form several semisynthetic penicillins with unique antibacterial properties and different pharmacokinetic profiles.

The bacterial cell wall is composed of mucopeptide (peptidoglycan or murein) scaffolds, formed by alternating chains of N-acetyl glucosamine and N-acetyl muramic acid molecules, that are cross-linked by peptide chains.
The beta-lactam antibiotics interferes with the cross linking of peptidoglycans, presumably by acetylating the transpeptidase enzyme.
In gram-positive bacteria, the cell wall is almost entirely made of peptidoglycan, while the cell wall of gram-negative bacteria consists of alternating layers of lipoprotein and peptidoglycan. Hence, the gram positive bacteria are more susceptible to penicillin.

Benzyl Penicillin (Penicillin G)

Narrow spectrum, activity limited primarily to gram-positive bacteria, few gram negative and anaerobes.
Acid labile, destroyed by gastric acid and less than one third of an oral dose is absorbed in effective form.
Readily hydrolyzed by penicillinase, ineffective against most strains of S. aureus.
Many bacteria are inherently insensitive to Penicillin G, as the target enzymes and penicillin binding proteins have low affinity to Penicillin G or are located deeper under lipoprotein barrier where Penicillin G is unable to penetrate.
Most common drug implicated in hypersensitivity reactions, hence rarely used.

Phenoxymethyl Penicillin (Penicillin V)

Penicillinase Resistant Penicillin (Methicillin, Cloxacillin, Dicloxacillin)

Have side chains that protects the beta-lactam ring from penicillinase.
The side chain makes them less effective against non-penicillinase producing bacteria.
Indicated where infection is caused by penicillinase producing Staphylococci, that are not methicillin resistant.
Methicillin is no longer used because :
- Methicillin resistant Staphylococcus aureus (MRSA) have emerged in many areas.
- Methicillin can cause hematuria, albuminuria and interstitial nephritis.

Amino-penicillin (Ampicillin, Bacampicillin, Amoxicillin)

Active against all organisms sensitive to Penicillin-G.
Also inhibits non-beta-lactamase producing strains of many gram-negative bacilli eg. Haemophilus influenzae, Escherichia coli, Proteus, Salmonella, Shigella, H. pylori.
Ampicillin : Oral absorption is incomplete, food interferes with absorption. Diarrhea is common as the unabsorbed drug irritates the lower intestines and causes marked alteration of the bacterial flora.
Bacampicillin : Ester prodrug of ampicillin, almost completely absorbed.
Amoxicillin : Better oral absorption, food does not interfere with absorption. Incidence of diarrhea is lower.

Carboxy-penicillin (Carbenicillin, Ticarcillin)

Active against Pseudomonas aeruginosa and indole positive Proteus.
Carbenicillin is not penicillinase resistant, inactive orally and excreted rapidly in urine.
Ticarcillin : More active and produces fewer side effects. Replaced Carbenicillin for treating pseudomonas and proteus infections.

Ureido-penicillin (Piperacillin, Mezlocillin)

Eight times more effective than carbenicillin against pseudomonas, has good activity against Klebsiella, many Enterobacteriaceae and some Bacteroides.
Piperacillin is frequently used to treat serious gram-negative infections in neutropenic/ immunocompromised or burn patients.

Beta-lactamase inhibitors (Clavulanic acid, Sulbactam, Tazobactam)

inhibits Class II to Class V beta-lactamases produced by both gram-positive and gram-negative bacteria.
Not effective against Class I cephalosporinase.
Causes progressive inhibition - Inhibition increases with time, initially binds reversibly with beta-lactamase, but later becomes covalent.
Also called 'Suicide Inhibitor' as it gets inactivated after binding to beta-lactamase.

Amoxicillin and Clavulanic acid

Active against beta-lactamase producing resistant S. aureus (not MRSA), H. influenzae, N. gonorrhoeae, E. coli, Proteus, Klebsiella, Salmonella and Shigella.

Ampicillin and Sulbactam

Oral absorption of Sulbactum is inconsistent, however, in combination with ampicillin, absorption is better.

Piperacillin and Tazobactam

Used in severe infections like peritonitis and pelvic, urinary or respiratory infections caused by beta-lactamase producing bacilli.

Bacterial Meningitis (eg. caused by Neisseria meningitis, Streptococcus pneumoniae) : Benzyl Penicillin (high doses intravenously).
Bone and joint infections (eg. with S. aureus) : Flucloxacillin.
Skin and soft tissue infections (eg. with Streptococcus pyogens, S. aureus) : Benzyl Penicillin, Flucloxacillin. Animal Bites : Co-amoxiclav.
Pharyngitis (from S. pyogens) : Phenoxymethylpenicillin.
Otitis media (S. pyogens, H. influenzae) : Amoxicillin.
Bronchitis (mixed infection) : Amoxicillin.
Pneumonia : Amoxicillin.
Urinary tract infection (eg. Escherichia coli) : Amoxicillin.
Gonorrhea : Amoxicillin (plus Probenecid).
Syphilis : Procaine benzylpenicillin.
Endocarditis (eg. S. viridans or Enterococcus faecalis) High dose IV Benzylpenicillin.
Serious infection with Pseudomonas aeruginosa : Ticarcillin, Piperacillin.

Penicillin G (IV) : 1-4 x 10⁶ units q4-6h (25,000-400,000 units/kg/d in 4-6 doses).
Penicillin V (PO) : 250-500 mg qid (25-75 mg/kg/d in 4 doses).
Amoxicillin (PO) : 250-500 mg tid (20-40 mg/kg/d in 3 doses).
Amoxicillin/Potassium Clavulanate (PO) : 500/125 mg tid or 875/125 mg bid (20-40 mg/kg/d in 3 doses).
Piperacillin/Tazobactam (IV) : 3.375-4.5 g q4-6h (300mg/kg/d in 4-6 doses).

Beta-lactamases are a family of enzymes that inactivates beta-lactam antibiotics by opening the beta-lactam ring. eg. Penicillinase.
Penicillin Bindings Proteins (PBPs) : Proteins that act as targets to which penicillin binds and acts. Transpeptidase enzyme is one of these PBPs. Other PBPs are necessary for cell division, cell shape and other essential processes.
The peptidoglycan cell wall is unique to bacteria. No such substance is synthesized by higher animals. Hence, penicillin is practically non-toxic to humans.
Jarisch-Herxheimer reaction : Seen when penicillin is injected in a syphilitic patient, due to sudden release of spirochetal lytic products. May produce shivering, fever, myalgia, exacerbation of lesions, even vascular collapse. It does not reccur and does not need interruption of therapy.

Essentials of Medical Pharmacology 8th Edition (K.D. Tripathi)-Jaypee Brothers Medical Publishers (P) Ltd.
James Ritter, Rod Flower, Graeme Henderson, Yoon Kong Loke, David MacEwan, Humphrey Rang - Rang & Dale’s Pharmacology-Elsevier (2019).
Laurence L. Brunton - Goodman & Gilman's Manual of Pharmacology and Therapeutics-McGraw-Hill Medical (2008).
Basic and Clinical Pharmacology, 15th Edition, Bertram G. Katzung, Todd W. Vanderah, McGraw Hill.

*This article is an excerpt from the above mentioned books and Medical Sutras does not make any ownership or affiliation claims.