cephalosporins Flashcards
cephalosporin MOA
the basic MOA of cephalosporins is the same as penicillins - Reaction with transpeptidases (penicillin-binding proteins) results in inhibition of peptidoglycan cross-linking. Note: many cephalosporins contain leaving groups “X” that facilitate b-lactam ring opening.
if X is a better leaving group, the drug is more reactive
resistance
Like the penicillins, the cephalosporins are hydrolyzed by b-lactamases
Over 340 different b-lactamases are known. Some are mainly penicillinases and others are mainly cephalosporinases. They can also be specific for certain antibiotics (eg. for methicillin and isoxazoyl penicillins).
allerginicity
Allergic reactions to cephalosporins are generally less common* and less severe* than with penicillins. However, since cross allergenicity is common*, cephalosporins should be used with caution, if at all, in patients who are allergic to penicillins. Fever and rashes (both idiopathic and delayed) are the most common manifestations and are exhibited in 1-3% of the population. The incidence of anaphylactic reactions to cephalosporins is estimated at 0.02%.
classification
Cephalosporins are classified historically as being first generation, second generation, third generation, fourth generation, or fifth generation. The general trend in going from the first generation to the third generation cephalosporins is enhanced Gram-negative activity** and a loss of efficacy toward Gram-positive bacteria.
1st generation
They are primarily active against Gram (+) cocci (Staphylococcus aureus and Staphylococcus pyogenes), group B streptococci (Streptococcus agalactiae) and Streptococcus pneumoniae.
Note: Cephalosporins that have an acetate (COOH) in the 3-position are metabolically inactivated by hydrolysis of the acetate by host esterases. This produces a hydroxymethyl acid that lactonizes (makes a ring).
The penicillin-binding proteins have an absolute requirement for a free carboxylic acid to mimic the terminal carboxylic acid of the terminal D-Ala-D-Ala moiety in their normal peptidoglycan substrate.
The acetate group has been replaced by a thio-linked thiadiazole in cefazolin, which unlike an acetate is stable to hydrolysis. The thio-linked thiadiazole in the 3-position can still act as a leaving group, thus activating the b-lactam ring.
In contrast to parenteral cephalosporins, the orally active cephalosporins have substituents at C-3 that are not chemically reactive**. Cephalexin is an example of an orally active first generation cephalosporin. Notice that it also has an ampicillin-type side chain at C-7 that makes it more stable and helps to confer oral activity, and it also confers activity against some Gram (–) bacteria.
In general, the orally active cephalosporins have unreactive side chains at C-3. The first generation, orally active cephalosporins have a methyl group at C-3.
second generation cephalosporins
These retain the antiGram (+) activity of the first group and Haemophilus influenzae as well. In addition, the second generation cephalosporins have better activity against Gram (–) bacteria including some strains of Acinetobacter, Citrobacter, Enterobacter, Escherichia coli, Klebsiella, Neisseria, Proteus, Providencia and Serratia.
Cefuroxime:
1) The carbamate side chain is less reactive toward enzymatic hydrolysis because of the electron-donating NH2 on the carbamate. This neutralizes the partial positive charge on the carbonyl carbon and makes it less susceptible to nucleophilic attack. The carbamate is also not a good leaving group, which enhances oral bioavailability in this case.
2) The oxime ether (methoximino) moiety conveys resistance to hydrolysis by most b-lactamases. The syn methoximino group is more resistant than the anti isomer. The syn-methoximino group is more resistant than the anti isomer, and the syn isomer can be photochemically isomerized to the anti isomer in solution to form a 1:1 mixture of syn and anti isomers.
3) Cefuroxime* penetrates the blood-brain barrier into the cerebrospinal fluid and is therefore useful in treatment of Haemophilus influenzae meningitis.
4) An orally active prodrug form of cefuroxime is available. Cefuroxime axetil, the 1(acetyloxy)ethyl ester of cefuroxime, is more lipophilic and therefore more readily absorbed from the GI tract. After absorption, it is hydrolyzed back to cefuroxime.
Like the orally active first generation cephalosporins, the orally active second generation cephalosporins generally have unreactive side chains at C-3. (i.e. Cl-)
Cefaclor:
a) The unreactive chlorine atom is bioisosteric with a methyl group. The van der Waals radius of a methyl group is 2.00 A, while that of a chlorine atom is 1.80 A.
b) It has an ampicillin-type side chain at C-7 that makes it more stable and helps to confer oral activity and activity vs. Gram-negative microorganisms.
c) Cefaclor is the chlorine analog of cephalexin.
3rd gen cephalosporins
These are less active against staphylococci than the first generation agents, but they are much more active vs. Gram (–) bacteria than either the first or second generation agents. They are frequently useful against nosocomial (hospital-acquired) multidrug-resistant strains. Morganella, Bacteroides fragilis and Pseudomonas aeruginosa and some enterobacteria are often sensitive. Almost all of the third generation cephalosporins have an aminothiazole substituent and contain an oxime ether at the 7-position.
Ceftazidime:
1) The large oxime ether moiety at C-7 conveys enhanced stability vs. b-lactamases.
2) The charged pyridinium ring at C-3 is a very good leaving group and strongly activates the b lactam ring. Also, the charged pyridinium ring imparts enhanced aqueous solubility.
3) The side chain carboxyl confers activity vs. Gram-negative organisms.
As with the other classes of cephalosporins, the presence of an unreactive substituent at C-3 increases oral bioavailability
Cefixime:
1) Cefixime does not contain a leaving group at C-3. The vinyl group is chemically stable.
2) It also has an oxime ether on the C-7 side chain that stabilizes the b-lactam vs. b-lactamases and enhances oral bioavailability.
3) The carboxylic acid in the side chain confers activity vs. Gram-negative microorganisms than the third generation cephalosporins.
4th gen cephalosporins
They retain the antibacterial spectrum of the third generation cephalosporins and also add Pseudomonas aeruginosa and some enterobacteria that are resistant to third generation cephalosporins. They are also more active against Gram (+) organisms.
Cefepime:
1) The syn methoximino group at C-7 stabilizes cefepime against b-lactamase and it also broadens the antibacterial spectrum vs. Gram (–) bacteria. It also has enhanced activity vs. Staphylococcus.
2) The N-methylpyrrolidine moiety is a good leaving group and therefore increases the reactivity of the b-lactam.
Ceftolozane:
1) The chemistry and mechanism of action of ceftolozane are very similar to cefepime.
2) Ceftolozane (approved in US January 2015) is a fourth generation cephalosporin that is combined with the b-lactamase inhibitor tazobactam (the combination is Zerbaxa). It is effective against many bacteria that are resistant to other antibiotics. It is used intravenously for treatment of both gram-positive and gram-negative bacteria.
5th generation cephalosporins
1) Ceftaroline fosamil is a prodrug that is hydrolyzed metabolically after IV infusion to ceftaroline, the pharmacologically active species, by a plasma phosphatase.
2) Ceftaroline is a broad-spectrum, fifth-generation cephalosporin antibiotic that is active vs. MRSA and is used vs. MRSA and community acquired bacterial pneumonia. Unlike most b-lactams, it is able to inhibit the MRSA PBP2a.
Cephamycins
The cephamycins have a 7-a methoxyl group, and they are often classified as second generation cephalosporins.
Cefoxitin:
1) It is used IV against a broad spectrum of gram-positive and gram-negative bacteria.
2) Cefoxitin is generally stable to hydrolysis by b-lactamases. It is a b-lactamase inducer.
Cefotetan
1) Cefotetan is used parenterally and has a broad spectrum of activity.
2) It releases N-methylthiotetrazole, which can cause hypoprothrombinemia (bleeding), and can also cause a reaction to ethanol that is similar to disulfuram (hangover).
3) Like cefoxetin, cefotetan is generally stable to b-lactamases
carbapenems
1) Imipenem is the N-formiminoyl derivative of thienamycin, a naturally occurring antibiotic isolated from Streptomyces cattleya. Thienamycin is too reactive to be used as a drug, since the primary amino group attacks the b-lactam intermolecularly. The N-formiminoyl group of imipenem prevents this from happening.
2) The carbapenems are carbon analogs of the penicillins. The sulfur that is present in the thiazolidine ring of the penicillins is replaced by a methylene group. This increases reactivity* because a methylene is smaller than a sulfur, so the ring strain is greater in the carbapenems.
3) Besides reacting with penicillin-binding proteins, imipenem reacts with and inhibits b lactamases.
4) Imipenem is hydrolyzed by renal dehydropeptidase-1, but this can be overcome by co-administration of the dehydropeptidase-1 inhibitor cilastatin**.
5) The combination of imipenem with cilastatin has broad spectrum antibiotic activity. It is active against both Gram (+) and Gram (–) bacteria. Imipenem and other drugs in the carbapenem class are commonly referred to as “magic bullets”*, and therefore their use is typically restricted in order to avoid widespread bacterial resistance. Imipenem is a good blactamase inducer.
6) The combination of imipenem with cilastatin is used to treat serious infections of the gut, GU tract, bone, skin, and endocardium.
7) Imipenem-cilastatin sodium is administered parenterally.
meropenem
1) Meropenem is an ultra-broad spectrum* injectable carbapenem antibiotic.
2) It is highly resistant to b-lactamases, and it is a more potent b-lactamase inhibitor* than imipenem.
3) The 1-b-methyl group confers stability to dehydropeptidase-1**, so meropenem can be administered without cilastatin.
doripenem
1) Doripenem is an ultra-broad spectrum injectable carbapenem antibiotic.
2) Doripenem is stable to b-lactamases and is a b-lactamase inhibitor, but it can be hydrolyzed by carbapenemases.
3) It is more active than other carbapenems vs. Pseudomonas aeruginosa, but it is not active vs. MRSA**.
4) The 1-b-methoxyl group confers stability to dehydropeptidase-1, so it can be administered without cilastatin.
Ertapenem
Ertapenem differs from other carbapenems in having a somewhat less broad spectrum* of activity (it is not active vs. Pseudomonas aeruginosa, and in contrast to other carbapenems it lacks activity vs. Acinetobacter and Enterococci). Like other carbapenems, it is not active vs. MRSA. It is highly protein bound* and it therefore has an extended half-life* (4 hours) that allows it to be administered IV once every 24 hours. Like the other carbapenems, it inhibits b-lactamases*.
monobactams
1) Aztreonam disodium is totally synthetic but the design was inspired by monocyclic b-lactam natural products called monobactams.
2) The sulfamic acid group takes the place of the C-2 carboxyl group in the penicillins and cephalosporins.
3) The antibiotic spectrum focuses almost completely on Gram (–) bacteria.
4) The electronegativity of the sulfamic acid activates the b-lactam ring toward hydrolysis and to reaction with penicillin-binding proteins.
5) It is used mainly in the treatment of severe infections with Gram (–) bacteria, especially those by penicillin-resistant* organisms acquired in hospitals.
6) Cross allergenicity* with penicillins and cephalosporins has not been reported* except for ceftazidime, which has an identical oxime ether sidechain.
7) A main advantage is that it can be used in patients that have penicillin allergy, with the exception of ceftazidime, which has cross reactivity due to an identical side chain.
