β-Lactam antibiotics: An introduction, classification, mechanism, structure, with its effects.

Βeta lactam antibiotics

Structure-of-beta-lactam-antibiotics

Beta-lactam is a class of antibiotics that blocks the activity of beta-lactamase enzymes, also called beta-lactamase. It prevents the degradation of beta-lactamase antibiotics with its action. They tend to have little antibiotic activity on their own.

Beta-lactamases are an antibiotic agent that contains the beta-lactam ring of susceptible penicillin and cephalosporins for inactivating the antibiotic. Some antimicrobials e.g.- cefazolin and cloxacillin are naturally resistant to certain Beta-lactamases.

The beta-lactam activity like -amoxicillin, ampicillin, piperacillin, and ticarcillin, etc., are can be restored and widened by combining them with a beta-lactamase inhibitor. Clavulanic acid, sulbactam, and tazobactam are all are in the class of beta-lactamase inhibitors.

Mechanism of action of Beta-lactam-

Beta-lactam antibiotics are having a bactericidal mechanism of action with their composition. These are inhibiting the growth of rapidly multiplying bacteria by inhibiting their cell wall synthesis and this occurs through inhibition of the enzymes that responsible for cell wall biosynthesis located in the cell membrane, the most common enzyme being penicillin-binding proteins (PBPs).

Mechanism-of-action-of-beta-lactam-antibiotics
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This binding interrupts the terminal transpeptidation process and induces, loss of viability and lysis, also through autolytic processes.

Classification of Beta-lactam-

classification-of-beta-lactum-antibiotics
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The class of beta-lactam antibiotics is one of the most commonly prescribed drug classes with numerous clinical indications in wide use. From a biochemical point of view, these drugs have a common feature, which is the beta-lactam ring. This class includes as follow-

-Penicillin’s

-Cephalosporins

-Carbapenems

-Monobactams

-Beta-lactamase inhibitors.

The resistance of Beta-lactam-

Resistance to beta-lactams is a growing phenomenon. It concerns above all Streptococcus pneumoniae and individual gram-negative bacilli such as Pseudomonas aeruginosa. With emerging resistance for antibiotics, it makes sense to look into mechanisms of resistance as it can help to decide which drugs to prescribe in different scenarios and ways to overcome the same.

Although bacterial resistance to beta-lactams mostly expresses through the production of beta-lactamases, other mechanisms are involved.

Structure of Beta-lactam-

structure-of-penicillin

SAR of Beta-lactam-

SAR-of-beta-lactam
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Other Beta-lactam structures-

Other-beta-lactam-structures
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Penicillin

The pure penicillin was the first antibiotic used clinically in 1941. Penicillin is a miracle that the rare toxic drug of its kind was the first to be discovered. Penicillin was initially been obtained from the fungus Penicillium notatum, but the present source is a high yielding mutant of P. chrysogenum.

The penicillin nucleus consists of fused thiazolidine and beta-lactam rings to which side chains are attached through an amide linkage.

Classification of penicillin with indications-

Natural penicillin

 Penicillin G, Penicillin V is used to treat selected gram-positive and gram-negative infections-

-Penicillin susceptible Streptococcus pneumonia and meningitis

-Streptococcal pharyngitis

-Endocarditis

-Skin and soft tissue infections

-Neisseria meningitides infections

-Syphilis

Penicillinase resistant penicillin-

Oxacillin, Nafcillin, Dicloxacillin are active against gram-positive organisms. Despite the occurrence of widespread resistance among staphylococci, they remain antibiotics of choice in managing methicillin-susceptible staphylococci (MSSA)-

-Skin and soft tissue infections (MSSA)

-Serious infections due to MSSA

Aminopenicillin-

These antibiotics have activity against gram-positive and gram-negative bacteria (Like- many Enterobacteriaceae) anaerobic organisms. They are commonly used together with beta-lactamase inhibitors.

Amoxicillin, Ampicillin-

-Upper respiratory tract infections (sinusitis, pharyngitis, otitis media)

-faecalis infections

-Listeria infections

-Aminopenicillins and beta-lactamase inhibitors- amoxicillin and clavulanate, ampicillin-sulbactam

-Upper respiratory tract infections (sinusitis, otitis media)

-Intra-abdominal infections

Carboxypenicillin and ureidopenicillin-

Ticarcillin (in carboxypenicillin) and piperacillin (in ureidopenicillin) have activity against aminopenicillin-resistant gram-negative bacilli (Pseudomonas aeruginosa). Are commonly combined with beta-lactamase inhibitors.

For more about- penicillin.

Mechanism of action of penicillin-

Penicillin interferes with the last step of bacterial cell wall synthesis, which is the cross-linking of adjacent peptidoglycan strands by a process known as transpeptidation. Since penicillin’s structurally resembled the terminal portion of the peptidoglycan strand, they compete for and bind to enzymes called penicillin-binding proteins (PBPs). That catalyzes transpeptidase and facilitates cross-linking of the cell wall. The result is the formation of a weakened cell wall and ultimately cell death. For this reason, penicillin is regarded as bactericidal and works in a time-dependent fashion.

Antibacterial spectrum-

The spectrum of the various penicillin’s is determined, in part- by their ability to cross the bacterial peptidoglycan cell wall to reach the penicillin-binding proteins (PBPs) in the periplasmic space. Factors determining PBP susceptibility to these antibiotics include size, charge, and hydrophobicity of the particular β-lactam antibiotic.

Structure of penicillin-

structure-of-penicillin
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Adverse effects of penicillin-

-Hypersensitivity

-Diarrhea

-Nephritis

-Neurotoxicity

-Hematologic toxicities

Cephalosporins

The cephalosporins are β-lactam antibiotics closely related both structurally and functionally to penicillin. Most of the cephalosporins are produced semi synthetically by their chemical attachment of side chains to 7-aminocephalosporanic acid. Cephalosporins have the same mode of action as penicillin, and they are affected by the same resistance mechanisms. However, they tend to be more resistant than the penicillin to certain β-lactamases.

Classification of a cephalosporin with indications-

First-generation cephalosporins-

Cefazolin, cephalexin, cefadroxil

-Skin and soft tissue infections serious infections due to MSSA

-Perioperative surgical prophylaxis

Second-generation cephalosporins-

Cefuroxime, cefoxitin, cefotetan, cefaclor, cefprozil

-Upper respiratory tract infections (sinusitis, otitis media)

-Cefoxitin, cefotetan-gynecologic infections,

-perioperative surgical prophylaxis

Third-generation cephalosporins-

Cefotaxime, ceftriaxone, cefpodoxime, cefixime, cefdinir, cefditoren, ceftibuten

-Community-acquired pneumonia, meningitis

-Urinary tract infections

-Streptococcal endocarditis

-Gonorrhea

-Severe Lyme disease.

Anti-pseudomonal Cephalosporins-

Ceftazidime, ceftolozone/tazobactam, ceftazidime/avibactam, cefepime

-Nosocomial infections-pneumonia

-Meningitis

-Urinary tract infections

-Intra-abdominal infections (with metronidazole)

Anti-MRSA cephalosporins-

Ceftaroline

-Community-acquired pneumonia

-Skin and soft tissue infection

For more about- cephalosporins.

Mechanism of action of cephalosporins-

Cephalosporins are bactericidal in nature, these are having the same mechanism as the other antibiotics- such as penicillin, but these are susceptible to Beta-lactamases. These are disrupting the synthesis of the peptidoglycan layer forming the bacterial cell wall. The layer of peptidoglycan is important for the cell wall structural integrity.

The resistance of Cephalosporins-

Resistance to the cephalosporins is either due to the hydrolysis of the beta-lactam ring by β-lactamases or reduced affinity for PBPs.

Structure of cephalosporins-

structure-of-cephalosporin
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Adverse effects of cephalosporins-

-Diarrhea

-Hypersensitivity reaction

-Nephrotoxicity

-Bleeding

-Neutropenia and thrombocytopenia

-Alcohol abuse

Carbapenems

It is synthetic Beta-lactam antibiotics that differ in structure from the penicillin, and in that the sulfur atom of the thiazolidine ring has been externalized and replaced by a carbon atom.The currently available drugs are-

– Imipenem

-Meropenem

-Doripenem

-Ertapenem

Structure of Carbapenems drugs-

structure-of-meropenem
Meropenem
structure-of-dotipenem
Dotipenem
structure-of-ertapenem
Ertapenem
structure-of-imipenem
Imipenem

Antibacterial spectrum of carbapenems-

Imipenem resists hydrolysis by most beta-lactamases, but not the metallo-beta-lactamases.

Carbapenem drug plays a role in empiric therapy because it is active against beta-lactamase-producing gram-positive and gram-negative organisms, anaerobes, and P. aeruginosa. Meropenem and doripenem have an antibacterial activity similar to that of imipenem. Doripenem may retain activity against resistant isolates of Pseudomonas. Unlike other carbapenems, ertapenem lacks coverage against P. aeruginosa, Enterococcus species, and Acinetobacter species.

Pharmacokinetics of carbapenems-

Imipenem, meropenem, and doripenem are administered IV and penetrate well into body tissues and fluids, including the CSF when the meninges are inflamed. Meropenem is known to reach therapeutic levels in bacterial meningitis even without inflammation. These agents are excreted by glomerular filtration. Imipenem undergoes cleavage by a de hydro peptidase found in the brush border of the proximal renal tubule. Compounding imipenem with cilastatin protects the parent drug from renal de hydro peptidase and, thus, prolongs its activity in the body. The other carbapenems do not require coadministration of cilastatin. Ertapenem is administered IV once daily.

Note– Doses of these agents must be adjusted in patients with renal insufficiency.

Adverse effects of carbapenems-

-Imipenem and cilastatin can cause nausea, vomiting, and diarrhea.

-Eosinophilia and neutropenia are short commons than other beta-lactams.

-High levels of imipenem may provoke seizures; however, the other carbapenems are less likely to do so.

-Carbapenems and penicillin share a common bicyclic core.

-The structural similarity may confer cross-reactivity between classes.

-While those with true penicillin allergy should use carbapenems cautiously, the cross-reactivity rate seen in studies is very low (less than 1%).

Monobactams-

The monobactams are which that disrupt bacterial cell wall synthesis and are because the beta-lactam ring is not fused to another ring.

Aztreonam-

Aztreonam, which is the only commercially available monobactam, has antimicrobial activity directed primarily against gram-negative pathogens, including the Enterobacteriaceae and P. aeruginosa. It lacks activity against gram-positive organisms and anaerobes. Aztreonam is administered either IV or IM and can accumulate in patients with renal failure.

structure-of-aztreonam
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 In monobactam, aztreonam is relatively nontoxic, but it may cause-

-Phlebitis

-Skin rash

-Abnormal liver function tests

Aztreonam has a low immunogenic potential, and it shows little cross-reactivity with antibodies induced by other β-lactams. Thus, aztreonam may offer a safe alternative for treating patients who are allergic to other penicillins, cephalosporins, and carbapenems.

Adverse effects of Monobactams-

-Hepatotoxicity, especially in infants and young children.

Beta-Lactamase Inhibitors-

Beta-lactamases are in the family of enzyme those produced by many gram-positive and gram-negative bacteria that inactivate beta-lactam antibiotics by opening the beta-lactam ring. Different β-lactamases differ in their substrate affinities. Three inhibitors of this enzyme clavulanic acid, sulbactam, and tazobactam are available for clinical use.

Clavulanic acid

Clavulanic acid is Obtained from Streptomyces clavuligerus. It has a β-lactam ring but not its own antibacterial activity. It inhibits a wide variety (class II to class V) of β-lactamases (but not the class I cephalosporinase) produced by both gram-positive and gram-negative bacteria.

Clavulanic acid is a ‘progressive’ inhibitor- binding with β-lactamase is reversible initially but becomes covalent later that the inhibition increasing with time. Clavulanic acid is also called a ‘suicide’ inhibitor because it gets inactivated after binding to the enzyme. Clavulanic acid permeates the outer layers of the cell wall of gram-negative bacteria and inhibits the periplasmically located beta-lactamase.

Structure of Clavulanic acid-
structure-of-clavulanic-acid
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Pharmacokinetics of clavulanic acid-

 Clavulanic acid has rapid oral absorption and a bioavailability of 60% that can also be injected. Its elimination t½ of 1 hour and tissue distribution matches amoxicillin, with which it is combined that called co-amoxiclav. However, it is eliminated mainly by glomerular filtration and its excretion is not affected by probenecid. Moreover, it is largely hydrolyzed and decarboxylated before excretion, while amoxicillin is primarily excreted unchanged by tubular secretion.

Adverse effects of clavulanic acid-

These are the same as for amoxicillin alone, but gastrointestinal tolerance is poorer, especially in children.

Other adverse effects are Candida, stomatitis, vaginitis, and rashes.

In some cases of hepatic injury have been reported with the combination.

Sulbactam-

Sulbactam is a semisynthetic β-lactamase inhibitor, related chemically as well as inactivity to clavulanic acid. Sulbactam is also a progressive inhibitor because it is highly active against class II to V but poorly active against class I β-lactamase.

On a weight basis, it is 2–3 times less potent than clavulanic acid for most types of the enzyme, but the same level of inhibition can be obtained at the higher concentrations achieved clinically. Sulbactam does not induce chromosome beta-lactamases, while clavulanic acid can induce some of them.

Oral absorption of sulbactam is inconsistent. Therefore, it is preferably given parenterally. It has been combined with ampicillin for use against beta-lactamase-producing resistant strains.

Indications are-

-PPNG gonorrhea, sulbactam per se also inhibits N. gonorrhea.

-Mixed aerobic-anaerobic infections, intraabdominal, gynecological, surgical, and skin and soft tissue infections, especially those acquired in the hospital.

-Pain at the site of injection, thrombophlebitis of the injected vein, rash, and diarrhea are the main adverse effects.

Structure of Sulbactam-

structure-of-sulbactam
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Tazobactam-

Tazobactam is another β-lactamase inhibitor similar to sulbactam. The pharmacokinetics of tazobactam matches with piperacillin with which it has been combined for use in severe infections like peritonitis, pelvic, urinary, and respiratory infections caused by beta-lactamase-producing bacilli. However, the combination of it is not active against the piperacillin-resistant Pseudomonas, because tazobactam (like clavulanic acid and sulbactam) does not inhibit inducible chromosomal beta-lactamase produced by Enterobacteriaceae. Tazobactam is also no help against Pseudomonas that develop resistance by losing permeability to the piperacillin.

Structure of Tazobactam-

structure-of-tazobactam
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