b lactams

Penicillins.Cephalosporins.Carbapenems.Monobactams.

Types of B lactams:

Penicillins

Mechanism of Action

All beta-lactam antibiotics, including penicillins and cephalosporins, are inhibitors of bacterial cell wall synthesis.

The antibiotic must first bind to the penicillin-binding protein (PBP) located within the cytoplasmic membrane of the cell wall. Once bound, the antibiotic can cause various effects that eventually lead to cell death, but primarily they inhibit the cross-linking of the peptide chains and there by, prevent the development of normal peptidoglycan structure.

Chemical Structure

all contain the four-membered beta-lactam ring.The antibacterial activity of these molecules resides

in the ring itself, and cleavage of the ring by

bacterial beta-lactamases inactivates the compound.

All penicillins are derived from the 6-aminopenicillanic acid nucleus, which consists of:

five-membered thiazolidine (penam) ring.

four-membered beta-lactam ring. a side chain.

Manipulations in the side chain result in the formation of other penicillins, which differ in their spectrum of activity, beta-lactamase resistance, and pharmacokinetic properties

Mechanisms of Resistance

Either by:1.destruction of the antibiotic by beta-

lactamases2.decreased penetration of the antibiotic to

reach the PBP3.and decreased affinity of the PBP to the

antibiotic

Some bacteria, such as Staphylococcus species, Haemophilus influenzae, gonococci, and most gram-negative enteric rods produce beta-lactamases (penicillinases). These enzymes can break the beta-lactam ring of the antibiotic, rendering it ineffective .

To overcome this resistance, some antibiotics are combined with beta-lactamase inhibitors, such as

Clavulanic acid to prevent the destruction of the beta-lactam ring.

Other penicillins, such as nafcillin, are resistant to beta-lactamase destruction due to the positioning of their side chain.

Bacteria differ in their number and types of PBPs.Antibiotics differ in their affinity to bind to the PBP. Also, mutations in the PBPs can cause an organism once sensitive to become resistant

Classification

The penicillins have been divided into categories based on their spectrum of activity

The natural penicillins (penicillin G) were the first agents in the penicillin family to be used clinically to treat infections. Shortly after the introduction of penicillin, the emergence of penicillinase-producing staphylococci caused the natural penicillins to be ineffective for these organisms.

This led to the development of the penicillinase-resistant penicillins, also known as the antistaphylococcal penicillins. Methicillin was the first of this group. The addition of a side chain protected the beta-lactam ring by sterically inhibiting the action of the penicillinase.

Examples:CloxacillinDicloxacillinMethicillin Not availableNafcillinOxacillin

The need for penicillins with extended activity against gram-negative microorganisms prompted further manipulations of the side chains. This led to the development of three new classes of penicillins:

the aminopenicillins: Amoxicillin and Ampicillin

Carboxypenicillins: Carbenicillin and Ticarcillin

ureidopenicillins :Mezlocillin and Piperacillin

Antimicrobial Activity and Therapeutic UsesThe natural penicillins have excellent gram-

positive activity and until recently were considered the drug of choice for many infections caused by pneumococci, streptococci, meningococci, and non-β-lactamase-producing staphylococci and gonococci. Emerging resistance to these drugs is changing the way these infections are treated

The penicillinase-resistant penicillins, also known as the antistaphylococcal penicillins, have excellent activity against both Streptococcus and Staphylococcus species (including those strains of penicillinase-producing Staphylococcus aureus) but no activity against gram negative bacteria. They are considered the drugs of choice for the treatment of staphylococcal infections, commonly seen in cellulitis or other skin infections, for example

Aminopenicillins were the first group of penicillin antibiotics to have activity against both gram-positive and gram-negative bacteria.

ampicillin has more activity against enterococci, but somewhat less activity against S. pyogenes,Streptococcus pneumoniae, Neisseria species, and Clostridium species. It also has some activity against gram negative bacteria such as Escherichia coli, Proteus mirabilis, Salmonella,Shigella,Listeria, and non-β-lactamase-producing strains of H. influenzae.The emergence of resistant organisms,however, is limiting its use clinically.

Carboxypenicillins have the same antibacterial spectrum of activity as ampicillin,but with greater gram-negative activity. Carbenicillin and ticarcillin are the two drugs in this class.

They also have activity against indole positive Proteus,Enterobacter,Providencia,Morganella and Pseudomonas aeruginosa. Unlike the aminopenicillin, ampicillin, carbenicillin and ticarcillin are not very active against enterococci

The ureidopenicillins and piperazine penicillins have the broadest spectrum of activity among the penicillins, covering many gram-positive and gram-negative bacteria. The addition of the ureido group to the penicillin structure produces the antibiotics azlocillin and mezlocillin,

whereas the addition of the ureido group and a piperazine side chain produces piperacillin. Their coverage is very similar to that of the carboxypenicillins but with enhanced activity against P. aeruginosa

CEPHALOSPORINS

Mechanism of Action

Cephalosporins, like other beta-lactam antibiotics, inhibit peptidoglycan cross-linkage and therefore bacterial cell wall synthesis. Like the penicillins, all cephalosporins are bactericidal

Chemical StructureThe 7-aminocephalosporanic acid nucleus of the

cephalosporin is very similar to the 6-aminopenicillanic acid nucleus of the penicillin.

In addition to the beta lactam ring,a six-membered dihydrothiazine (cephem) ring,two side chains. The six-membered cephem ring confers a

relative resistance to certain beta-lactamases compared to the penam ring. Unlike the penicillins, manipulation of the cephalosporin’s structure is allowed in two places versus one, resulting in the formation of other antibiotics with different spectrums of activity and pharmacokinetic properties

Mechanisms of Resistance

Like penicillins, bacterial resistance to cephalosporins can be mediated through three major mechanisms:

1.alterations in PBPs.2. formation of beta lactamases

(cephalosporinases) that inactivate the drug. 3. decreased ability of the antibiotics to

penetrate the cell wall and reach its PBP.

Classification

Cephalosporins have traditionally been divided into four major groups or “generations” based on their spectrum of activity:

First GenerationCefadroxilCefazolinCephalexinCephalothin Not availableCephapirinCephradine

Antimicrobial Activity and Therapeutic Uses

First-generation cephalosporins are active against the gram-positive cocci, staphylococci, and streptococci, but not enterococcus species. Among the gram-negative bacteria, E. coli, Klebsiella pneumoniae, and P. mirabilis are usually susceptible.

Even though the first-generation cephalosporins have a broad spectrum of activity and have few side effects, they are rarely the drugs of choice to treat any infection. However, when penicillins are to be avoided, they are commonly prescribed to treat skin infections, streptococcal pharyngitis.

Second Generationo Cefacloro Cefamandole Not availableo Cefmetazole Not availableo Cefonicido Cefotetano Cefoxitino Cefprozilo Cefuroxime

In general, the second-generation cephalosporins are less active against staphylococci and streptococci compared to the first-generation agents but are more active against selected gram negative bacilli. Enterobacter, Klebsiella and indole-positive Proteus spp. are usually sensitive, although P. aeruginosa is not.

Cefoxitin, cefotetan, cefmetazole, and cefamandole all have moderate activity to Bacteroides fragilis and can be useful in mixed infections such as peritonitis or diverticulitis. These agents are also commonly prescribed for surgical prophylaxis, especially intraabdominal procedures .

Cefuroxime is active against H. influenzae, Moraxella catarrhalis, and S. pneumoniae and therefore useful in the treatment of bronchitis and community-acquired pneumonia.

First- and second-generation oral cephalosporins, such as cefadroxil, cefaclor, and cefprozil, are commonly prescribed in upper respiratory tract infections, such as otitis media, pharyngitis/tonsillitis, and sinusitis.

Third GenerationCefdinir.Cefixime.Cefoperazone.Cefotaxime.Cefpodoxime.Ceftazidime.Ceftibuten.Ceftizoxime.Ceftriaxone.

Most third-generation cephalosporins have less staphylococcal and streptococcal activity than the first- or second-generation agents, but possess even better activity against gram-negative bacteria, including P. aeruginosa and Enterobacter spp.

Only cefoperazone and ceftazidime have activity against P. aeruginosa, and the latter is commonly prescribed in combination to treat such infections.

Ceftazidime is also used in immunocompromised patients to treat fever of unknown etiology.

The third- and fourth-generation cephalosporins are the only cephalosporins that penetrate the central nervous system and therefore may be used to treat meningitis, depending on the organism.

The newest generation of cephalosporins represents an attempt to maintain good activity against gram-positive as well as gram-negative organisms, including P. aeruginosa, and is designated as fourth-generation cephalosporins .To date only one antimicrobial agent, cefepime, is considered a fourth-generation cephalosporin.

CARBAPENEMS

Include:Imipenem, meropenem, and ertapenem

Like all beta-lactam antibiotics, carbapenems inhibit bacterial cell wall synthesis. Their chemical structure is similar to the penicillins, but with a few modifications.

The carbapenems have the broadest antimicrobial spectrum of activity of any beta-lactam antibiotics available to date. They have excellent activity against both aerobic and anaerobic gram-positive and gram-negative bacteria.

Among the gram-positive organisms, the carbapenems are active against most strains of methicillin-sensitive S.aureus (MSSA) and coagulase-negative staphylococci, Streptococcus spp., and E. faecalis.

The two older carbapenems exhibit excellent activity to the majority of gram-negative bacteria, including troublesome nosocomial pathogens such as P. aeruginosa.

Ertapenem, on the other hand, has excellent activity against most gram-negative pathogens except P. aeruginosa. In cases of documented or suspected infections due to Pseudomonas spp., ertapenem should not be used.

The carbapenems are also active against most strains of clinically significant anaerobes. Due to their broad spectrum of activity, many clinicians think carbapenems should be reserved for the treatment of mixed bacterial infections and the treatment of resistant aerobic gram-negative bacteria that are not susceptible to other beta-lactam antibiotics

The most frequent side effects associated with carbapenem administration are phlebitis, nausea, vomiting, diarrhea, and rash .

Seizures occurred in 1% to 3% of treated patients but occurred more commonly in patients with renal insufficiency or underlying central nervous system disease .

MONOBACTAMS

Aztreonam is a monocyclic beta-lactam antibiotic known as a monobactam.

Its unique chemical structure is composed solely of the four-membered beta-lactam ring and a side chain. It lacks the five- or six-membered side ring shared by the penicillins and cephalosporins, respectively. Like other beta-lactam antibiotics.

aztreonam exerts its bactericidal action by binding to PBPs, disrupting the formation of the peptidoglycan chain and ultimately inhibiting bacterial cell wall synthesis

Aztreonam binds primarily to the PBP-3 located on Enterobacteriaceae, Pseudomonas spp., and other gram-negative aerobic organisms, but not to the PBPs found on gram-positive bacteria.

As a result, aztreonam has a narrow spectrum of activity, limited to gram-negative bacteria.

Because it is limited to the treatment of gram-negative infections, it is commonly used in combination with another antimicrobial for empiric therapy.

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