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Beta-lactam antibiotics

β-lactam antibiotics are antibiotics that contain a beta-lactam ring in their chemical structure.

This includes penicillin derivatives (penams), cephalosporins and cephamycins (cephems), monobactams, carbapenems and carbacephems.

Most β-lactam antibiotics work by inhibiting cell wall biosynthesis in the bacterial organism and are the most widely used group of antibiotics.

Core structure of penicillins and cephalosporins are the 2 most common groups of β-lactam antibiotics .

Bacteria often develop resistance to β-lactam antibiotics by synthesizing a β-lactamase, an enzyme that attacks the β-lactam ring.

To overcome this resistance, β-lactam antibiotics can be given with β-lactamase inhibitors such as clavulanic acid.

β-lactam antibiotics are indicated for the prevention and treatment of bacterial infections caused by susceptible organisms.

At first, β-lactam antibiotics were mainly active only against gram positive bacteria, but the development of broad-spectrum β-lactam antibiotics active against various Gram-negative organisms has increased their usefulness.

In uninflamed brain meninges, the penetration of beta-lactam antibiotics is low.

Common adverse drug reactions for the β-lactam antibiotics: diarrhea, nausea, rash, urticaria, superinfections.

Infrequent adverse effects include: fever, vomiting, erythema, dermatitis, angioedema, pseudomembranous colitis.

Pain and inflammation at the injection site is also common for parenterally administered β-lactam antibiotics.

Allergy/hypersensitivity, mmunologically mediated adverse reactions, to any β-lactam antibiotic may occur in up to 10% of patients: small fraction of which are truly IgE-mediated allergic reactions.

Anaphylaxis will occur in approximately 0.01% of patients.

There is perhaps a 5–10% cross-sensitivity between penicillin-derivatives, cephalosporins, and carbapenems.

It is contraindicated to use β-lactam antibiotics in patients with a history of severe allergic reactions (urticaria, anaphylaxis, interstitial nephritis) to any β-lactam antibiotic.

Rarely, allergic reactions have been triggered by exposure from kissing and sexual contact with a partner who is taking these antibiotics.

A Jarisch–Herxheimer reaction may occur after initial treatment of a spirochetal infection such as syphilis with a β-lactam antibiotic.

Mechanism of action of β-lactam antibiotics is the inhibition of cell wall synthesis.

Penicillin and most other β-lactam antibiotics act by inhibiting penicillin-binding proteins, which normally catalyze cross-linking of bacterial cell walls.

The cell wall plays an important role in bacterial reproduction.

Bacteria attempting to grow and divide in the presence of β-lactam antibiotics fail, and instead shed their cell walls, forming osmotically fragile spheroplasts.

β-lactam antibiotics are bactericidal, and act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls.

The peptidoglycan layer is important for cell wall structural integrity, especially in Gram-positive organisms, being the outermost and primary component of the wall.

All β-lactam antibiotics have a β-lactam ring in their structure, and the effectiveness of these antibiotics relies on their ability to reach the penicillin binding protein intact and their ability to bind to it.

There are two main modes of bacterial resistance to β-lactams: enzymatic hydrolysis of the β-lactam ring and possession of altered penicillin-binding proteins.

If the bacterium produces the enzyme β-lactamase or the enzyme penicillinase, the enzyme will hydrolyse the β-lactam ring of the antibiotic, rendering the antibiotic ineffective.

The genes encoding these enzymes may be inherently present on the bacterial chromosome or may be acquired via plasmid transfer,  and β-lactamase gene expression may be induced by exposure to β-lactams.

The production of a β-lactamase by a bacterium does not necessarily rule out all treatment options with β-lactam antibiotics.

β-lactam antibiotics may be co-administered with a β-lactamase inhibitor: Augmentin (FGP) is made of amoxicillin (a β-lactam antibiotic) and clavulanic acid (a β-lactamase inhibitor).

The clavulanic acid is designed to overwhelm all β-lactamase enzymes, and effectively serve as an antagonist so that the amoxicillin is not affected by the β-lactamase enzymes.

Another β-lactam/β-lactamase inhibitor combination is piperacillin/tazobactam with a broad spectrum of antibacterial activity that includes Gram-positive and -negative aerobic and anaerobic bacteria.

The addition of tazobactam to piperacillin has enhanced its stability against a wide range of β-lactamase enzymes including some Extended-Spectrum β-lactamases.

In the context of medical pharmacology, penicillins, cephalosporins, and carbapenems, while all have the β-lactam ring that serves as the fundamental structure, also have an auxiliary ring that carries a carboxylate group that is positioned on the same side as the carbonyl group within the β-lactam ring, and, as such, this structural configuration is critical to their antimicrobial activity.

Bacterial resistance to these antibiotics primarily occurs through the production of β-lactamases, enzymes that hydrolyze the amide bond of the β-lactam ring, thereby eliminating the antimicrobial activity of these antibiotics.

Some bacteria have evolved penicillin binding proteins with novel structures. β-lactam antibiotics cannot bind as effectively to these altered PBPs, and, as a result, the β-lactams are less effective at disrupting cell wall synthesis.

Notable examples of this mode of resistance include methicillin-resistant Staphylococcus aureus (MRSA)[32] and penicillin-resistant Streptococcus pneumoniae.

 

Guidelines recommend that adults with sepsis or septic shock should receive prolonged fusion of beta – lactams, after an initial bolus vs conventional intermittent infusion.

Up to 40% of patients treated with beta-lactam antibiotics in the ICU may not achieve antibiotic concentrations above the minimum inhibitory concentration during 50 to hundred percent of conventional dosing intervals.

In sepsis, many physiological changes in pharmacokinetic and phrarmocodynamic functions occur including increasing cardiac output leading to increased drug clearance, and leaky capillaries necessitating increased volume resuscitation leading to increased volume of distribution: these changes will result in lower antimicrobial, plasma concentrations, especially in the early phase before kidney failure sets in.

β-lactams are classified according to their core ring structures.

β-lactams not fused to any other ring are named monobactams.

Beta-lactam antibiotics

β-lactam antibiotics are antibiotics that contain a beta-lactam ring in their chemical structure.

This includes penicillin derivatives (penams), cephalosporins and cephamycins (cephems), monobactams, carbapenems and carbacephems.

Most β-lactam antibiotics work by inhibiting cell wall biosynthesis in the bacterial organism and are the most widely used group of antibiotics.

Core structure of penicillins and cephalosporins are the 2 most common groups of β-lactam antibiotics .

Bacteria often develop resistance to β-lactam antibiotics by synthesizing a β-lactamase, an enzyme that attacks the β-lactam ring.

To overcome this resistance, β-lactam antibiotics can be given with β-lactamase inhibitors such as clavulanic acid.

β-lactam antibiotics are indicated for the prevention and treatment of bacterial infections caused by susceptible organisms.

At first, β-lactam antibiotics were mainly active only against gram positive bacteria, but the development of broad-spectrum β-lactam antibiotics active against various Gram-negative organisms has increased their usefulness.

In uninflamed brain meninges, the penetration of beta-lactam antibiotics is low.

Common adverse drug reactions for the β-lactam antibiotics: diarrhea, nausea, rash, urticaria, superinfections.

Infrequent adverse effects include: fever, vomiting, erythema, dermatitis, angioedema, pseudomembranous colitis.

Pain and inflammation at the injection site is also common for parenterally administered β-lactam antibiotics.

Allergy/hypersensitivity, mmunologically mediated adverse reactions, to any β-lactam antibiotic may occur in up to 10% of patients: small fraction of which are truly IgE-mediated allergic reactions.

Anaphylaxis will occur in approximately 0.01% of patients.

There is perhaps a 5–10% cross-sensitivity between penicillin-derivatives, cephalosporins, and carbapenems.

It is contraindicated to use β-lactam antibiotics in patients with a history of severe allergic reactions (urticaria, anaphylaxis, interstitial nephritis) to any β-lactam antibiotic.

Rarely, allergic reactions have been triggered by exposure from kissing and sexual contact with a partner who is taking these antibiotics.

A Jarisch–Herxheimer reaction may occur after initial treatment of a spirochetal infection such as syphilis with a β-lactam antibiotic.

Mechanism of action of β-lactam antibiotics is the inhibition of cell wall synthesis.

Penicillin and most other β-lactam antibiotics act by inhibiting penicillin-binding proteins, which normally catalyze cross-linking of bacterial cell walls.

The cell wall plays an important role in bacterial reproduction.

Bacteria attempting to grow and divide in the presence of β-lactam antibiotics fail, and instead shed their cell walls, forming osmotically fragile spheroplasts.

β-lactam antibiotics are bactericidal, and act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls.

The peptidoglycan layer is important for cell wall structural integrity, especially in Gram-positive organisms, being the outermost and primary component of the wall.

All β-lactam antibiotics have a β-lactam ring in their structure, and the effectiveness of these antibiotics relies on their ability to reach the penicillin binding protein intact and their ability to bind to it.

There are two main modes of bacterial resistance to β-lactams: enzymatic hydrolysis of the β-lactam ring and possession of altered penicillin-binding proteins.

If the bacterium produces the enzyme β-lactamase or the enzyme penicillinase, the enzyme will hydrolyse the β-lactam ring of the antibiotic, rendering the antibiotic ineffective.

 

(An example of such an enzyme is New Delhi metallo-beta-lactamase 1, discovered in 2009.) The genes encoding these enzymes may be inherently present on the bacterial chromosome or may be acquired via plasmid transfer (plasmid-mediated resistance), and β-lactamase gene expression may be induced by exposure to β-lactams.[citation needed]

Clavulanic acid

Amoxicillin The production of a β-lactamase by a bacterium does not necessarily rule out all treatment options with β-lactam antibiotics. In some instances, β-lactam antibiotics may be co-administered with a β-lactamase inhibitor. For example, Augmentin (FGP) is made of amoxicillin (a β-lactam antibiotic) and clavulanic acid (a β-lactamase inhibitor). The clavulanic acid is designed to overwhelm all β-lactamase enzymes, and effectively serve as an antagonist so that the amoxicillin is not affected by the β-lactamase enzymes. Another β-lactam/β-lactamase inhibitor combination is piperacillin/tazobactam with a broad spectrum of antibacterial activity that includes Gram-positive and -negative aerobic and anaerobic bacteria. The addition of tazobactam to piperacillin has enhanced its stability against a wide range of β-lactamase enzymes including some Extended-Spectrum β-lactamases.[20] Other β-lactamase inhibitors such as boronic acids are being studied in which they irreversibly bind to the active site of β-lactamases. This is a benefit over clavulanic acid and similar beta-lactam competitors, because they cannot be hydrolysed, and therefore rendered useless. Extensive research is currently being done to develop tailored boronic acids to target different isozymes of beta-lactamases.[21] However, in all cases where infection with β-lactamase-producing bacteria is suspected, the choice of a suitable β-lactam antibiotic should be carefully considered prior to treatment. In particular, choosing appropriate β-lactam antibiotic therapy is of utmost importance against organisms which harbor some level of β-lactamase expression. In this case, failure to use the most appropriate β-lactam antibiotic therapy at the onset of treatment could result in selection for bacteria with higher levels of β-lactamase expression, thereby making further efforts with other β-lactam antibiotics more difficult.[22] In the context of medical pharmacology, penicillins, cephalosporins, and carbapenems, while all have the β-lactam ring that serves as the fundamental structure, also have an auxiliary ring that carries a carboxylate group that is positioned on the same side as the carbonyl group within the β-lactam ring, and, as such, this structural configuration is critical to their antimicrobial activity.[23] Bacterial resistance to these antibiotics primarily occurs through the production of β-lactamases, enzymes that hydrolyze the amide bond of the β-lactam ring, thereby eliminating the antimicrobial activity of these antibiotics. This resistance mechanism underscores the importance of the structural integrity of the β-lactam ring for the antibiotic’s function.[24] The color change from colorless or light yellow to amber or even red in an aqueous solution of a β-lactam antibiotic can denote β-lactamase hydrolysis of amide bonds in the β-lactam ring.[25][26] This is often observed with a chromogenic β-lactamase substrate like ceftriaxone, merapenem, or nitrocefin,[27] that undergoes a distinctive color change from yellow to red as the amide bond in the β-lactam ring is hydrolyzed by β-lactamase.[27][28] This color change is a visual indicator of the presence and activity of β-lactamase enzymes, which are responsible for conferring resistance to β-lactam antibiotics in many bacterial species. The hydrolysis of the β-lactam ring by β-lactamase enzymes renders the antibiotic ineffective, thereby allowing the bacteria to survive in the presence of the antibiotic.[28] Some β-lactam antibiotics like ceftriaxone and meropenem are known to be relatively unstable in solution, especially when stored for extended periods, and degrade in an aqueous solution even without the presence of β-lactamase.[29] For ceftriaxone, the color of solutions can range from light yellow to amber, depending on the length of storage, concentration, and diluent used.[30][31] A study found that meropenem concentrations dropped to 90% of the initial concentration at 7.4 hours at 22°C and 5.7 hours at 33°C, indicating degradation over time.[29] Possession of altered penicillin-binding proteins edit As a response to the use of β-lactams to control bacterial infections, some bacteria have evolved penicillin binding proteins with novel structures. β-lactam antibiotics cannot bind as effectively to these altered PBPs, and, as a result, the β-lactams are less effective at disrupting cell wall synthesis. Notable examples of this mode of resistance include methicillin-resistant Staphylococcus aureus (MRSA)[32] and penicillin-resistant Streptococcus pneumoniae. Altered PBPs do not necessarily rule out all treatment options with β-lactam antibiotics.[medical citation needed]

Guidelines recommend that adults with sepsis or septic shock should receive prolonged fusion of beta – lactams, after an initial bolus vs conventional intermittent infusion.

Up to 40% of patients treated with beta-lactam antibiotics in the ICU may not achieve antibiotic concentrations above the minimum inhibitory concentration during 50 to hundred percent of conventional dosing intervals.

In sepsis, many physiological changes in pharmacokinetic and phrarmocodynamic functions occur including increasing cardiac output leading to increased drug clearance, and leaky capillaries necessitating increased volume resuscitation leading to increased volume of distribution: these changes will result in lower antimicrobial, plasma concentrations, especially in the early phase before kidney failure sets in.

β-lactams are classified according to their core ring structures.

β-lactams not fused to any other ring are named monobactams.

 

 

 

 

 

 

 

 

 

 

 

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