Discussion and Comparison between 3rd & 4th generation Cephalosporins

Prepared By:

Asif Mohammad Abu Sufian (Id. 2005-2-70-061)

Fahima Hassan (Id. 2008-1-70-059)

Md. Asifur Rahman (Id. 2008-1-70-064)

Abdullah Al Sofian (Id. 2008-1-70-069)

Ikhtiar Ahmed (Id. 2008-1-70-070)

Introduction

β-lactam antibiotics

Inhibit the synthesis of a structural component of the bacterial cell wall

More than 20 derivatives

Often used as an alternative in patients who are sensitive to penicillin

Cephalosporins

Structural features

Classification

1st Generation Cephalexin, Cefazolin

2nd Generation Cefoxitin, Cefuroxime, Cefotetan

3rd Generation Cefotaxime, Ceftriaxone, Ceftazidime

4th Generation Cefepime, Cefpirome

History First isolated from cultures

of Cephalosporium acremonium

In 1948 by Italian scientist Giuseppe Brotzu

The first agent cephalothin was launched by Eli Lilly and Company in 1964.

Mechanism of action

Bactericidal

disrupt the synthesis of the peptidoglycan layer of bacterial cell walls

The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by transpeptidases known as penicillin-binding proteins (PBPs)

Mechanism of action (Cont.)

PBPs bind to the D-Ala-D-Ala at the end of muropeptides (peptidoglycan precursors) to crosslink the peptidoglycan

Cephalosporins mimic this site and competitively inhibit PBP crosslinking of peptidoglycan.

Pharmacokinetics Cephalosporins are given parenterally and

orally.

Extent of binding to plasma protein varies from one to another.

e.g. Cefazolin is 80% protein bound (hence, long t1/2 ) Cephalexin is 10-15% protein bound

Relatively lipid insoluble. Hence, do not penetrate cells or the CNS, except for third generations

Pharmacokinetics (Cont.)

Mostly excreted unchanged by the kidney (glomerular & tubular secretion), except, ceftazidime & cefoperazone (glomerular)

Probenecid slows their elimination and prolongs their half-live (except ceftazidime & cefoperazone)

Half-life 30-90 min; ceftriaxone 4-7 hr

3rd Generation Cephalosporins

Cefixime Type of Drug: 

Semi Synthetic Cephalosporin Derivative

Description:o Highly stable in the

presence of beta-lactamase enzymes

o The antibacterial effect of cefixime results from inhibition of mucopeptide synthesis in the bacterial cell wall

Description (cont.):

o cefixime binds to specific penicillin-binding proteins (PBPs) located inside the bacterial cell wall, causing the inhibition of the bacterial cell wall synthesis

o Cell lysis is then mediated by bacterial cell wall autolytic enzymes such as autolysins

Preparations: Cefixime Capsules, Cefixime Oral Suspension.

Uses: Cefixime is used to treat infections caused by bacteria

such as pneumonia; bronchitis; gonorrhea. It is also used to treat ear, lung, throat, and urinary tract infections.

Side effects: Stomach upset/pain, diarrhea, nausea, gas, headache,

or dizziness may occur.

Cefdinir

Type of Drug: Semi Synthetic Cephalosporin Derivate

Description:o Cefdinir stops bacteria from

multiplying by preventing bacteria from forming the walls that surround them

o Bacteria cannot survive without a cell wall

Drug interaction:o Antacids that contain aluminum or magnesium:

Decreased cefdinir absorption if given within 2 hours of antacids.

o Iron salts: Reduced cefdinir absorption if given within 2 hours of iron.

o Probenecid: increased blood level and prolonged half life of cefdinir.

Preparations:  Cefdinir Capsules,  Cefdinir Oral Suspension.

Uses:o Bronchitiso Middle ear infection o Sinus infectiono Pneumoniao Skin infection o Throat infection

Side Effects:

o Diarrheao Yeast infection o Nausea o Headache o Unexplained rash o Vomiting o Stomach pain

4th Generation Cephalosporins

Cefepime

Type of Drug: Semi Synthetic Cephalosporin Derivative.

Description:o Developed in 1994.o Has an extended spectrum

of activity against Gram-positive and Gram-negative bacteria.

Description (Cont.) :o Cefepime has good activity against important

pathogens including Pseudomonas aeruginosa, Staphylococcus aureus, and multiple drug resistant Streptococcus pneumoniae.

o A particular strength is its activity against Enterobacteriaceae.

Uses:o Cefepime is usually used to treat moderate-

severe nosocomial pneumonia, infections caused by multi-resistant microorganisms (e.g. Pseudomonas aeruginosa) and empirical treatment of febrile neutropenia.

Side effects:

o Swelling, redness, pain, or soreness at the injection site may occur. This medication may also infrequently cause loss of appetite, nausea, vomiting, diarrhea, or headache. 

Cefpirome

Type of Drug: Semi Synthetic Cephalosporin Derivative.

Description:o bactericidal at low

concentrations against an extremely broad spectrum of gram-negative and gram-positive pathogens.

Description (Cont.) :o Cefpirome is very stable against hydrolysis by broad

spectrum plasmid-mediated and chromosomally-mediated β-lactamases and compared to third generation cephalosporins, has a lower affinity for these enzymes.

Uses:o Cefpirome can be used in the infection caused

by Gram-negative bacteria, including Pseudomonas aeruginosa, and Gram-positive bacteria.

Side effects:

o Cefpirome produces potentially life-threatening effects which include Anaphylaxis, which are responsible for the discontinuation of Cefpirome therapy.

o Nausea,Vomiting, Abdominal pain, Rashes,  

Urticaria, Pseudomembranous colitis and Increase in liver enzymes also may occur.

Comparison Between 3rd and 4th

Generation Cephalosporins

3rd Generation 4th Generation

Decreased activity against gram- positive bacteria.

 extended-spectrum agents with similar activity against Gram-positive organisms as first-generation cephalosporins.

Broad spectrum activity against gram- negative bacteria.

Fourth-generation cephalosporins are Zwitterions that can penetrate the outer membrane of gram- negative bacteria.

Comparatively less resistance to beta-lactamases than 4th generation cephalosporins.

greater resistance to beta-lactamases than the third-generation cephalosporins

3rd Generation 4th Generation

Can cross the blood-brain barrier. May can cross blood-brain barrier.

 useful against meningitis caused by pneumococci, meningococci, H. influenzae, and susceptible E. coli, Klebsiella, and penicillin-resistant N. gonorrhoeae.

Effective in meningitis and also used against Pseudomonas aeruginosa.

The third generation cephalosporins are:Cefdinir, Cefixime, Cefpodoxime,Ceftibuten, CeftriaxoneCefotaxime.

The fourth generation cephalosporins are:Cefepime, Cefluprenam, Cefozopran, Cefpirome, Cefquinome.

Recent Development of third and forth generation

cephalosporin:A short review on some

research papers

Cephalosporin chemical reactivity and its immunological implications

to analyze the chemical reactivity of cephalosporins by IgE antibodies and to establish the basis of the allergenicity.

Third and fourth generation cephalosporins appear to be more involved in specific IgE reactions .

Lack of knowledge of the exact chemical structure of cephalosporin antigenic determinants.

Data indicate that R2 is not present in the final conjugate.

recognition by IgE antibodies is mainly directed to the R1 acyl side chain and to the beta-lactam fragment that remains linked to the carrier protein in the cephalosporin conjugation process.

Conjugation

Ceftazimide’s stability

In addition to the syn-configuration of the imino side chain, compared to other third-generation cephalosporins, the more complex moiety (containing two methyl and a carboxylic acid group) confers extra stability to β-lactamase enzymes produced by many Gram-negative bacteria.

The extra stability to β-lactamases increases the activity of ceftazidime against otherwise resistant Gram-negative organisms including Pseudomonas aeruginosa.

The charged pyridinum moiety increases water-solubility.

Novel bifunctional prodrug of ceftizoxime Ceftizoxime is a parenteral third-generation cephalosporin Unlike other 3rd generation cephalosporins , in ceftizoxime the

whole C-3 side chain has been removed to prevent deactivation by hydrolytic enzymes . It rather resembles Cefotaxime in its properties , however not being subjected to metabolism .

AS-924, a novel bifunctional prodrug of ceftizoxime. L-alanine was introduced into the aminothiazole-oxime moiety at the

C-7 position of the various lipophilic esters of CZX. Among these prodrugs, pivaloyloxymethyl 7beta-[(Z)-2-(2-(S)-

alanylaminothiazol-4-yl)-2-methoxyiminoa cetamido]-3-cephem-4-carboxylate hydrochloride (ceftizoxime alapivoxil, AS-924) was well absorbed after oral administration in experimental animals and showed potent therapeutic effects in mice.

Intramedullary spinal cord abscess treated with antibiotic therapy

A 58-year-old man presented with an intramedullary spinal cord abscess (ISCA).

He was treated under a diagnosis of cryptogenic ISCA with high-dose ampicillin and third- or fourth-generation cephalosporins, which resulted in complete recovery after 2 months.

Antibiotic treatment is comparable to surgery plus antibiotic treatment

Reason behind the resistance AmpC beta-lactamases are cephalosporinases encoded on

the chromosomes of many of the Enterobacteriaceae. AmpC beta-lactamases and extended-spectrum beta-

lactamases (ESBLs) :Klebsiella pneumoniae (K. pneumoniae)

R plasmids can be easily transferred between the resistant and sensitive negative bacilli. (1)

TEM-1 for genus Proteus & CTX-M-2 for P. mirabilis P. vulgaris & P. penneri :hyperproduction of cromosomal

encoded betalactamase. (2) Attention should be paid in using in food producing animals. A third-generation cephalosporin, ceftiofur, and a fourth-

generation cephalosporin, cefquinome: for veterinary use

Adverse drug reactions to a cephalosporins in patients with a history of penicillin allergy

Patients with penicillin allergy are more likely to develop a cephalosporin reaction compared with patients who reported a delayed, a probable, or an unknown penicillin reaction.

None of those patients who received a fourth-generation cephalosporin reacted.

Cefoperazone adverse effect: N-methylthiotetrazole (side chain and hypoprothrombinemia.

In vitro activity of cefepime and cefpirome compared to other third-generation cephem antibiotics against

gram-negative nosocomial pathogens

Klebsiella Enterobacter species

Pseudomonas aeruginosa

Other Gram negative bacteria

3rd generation cephalosporin

Ceftazidime↓ Ceftazidime↑Cefoperazone↓Ceftriaxone↓

4th generation cephalosporin

Cefepime Cefepime Cefepime↑Cefpirome↓(Resistant also)

Cefepime: new fourth-gen cephalosporin Fourth-generation cephalosporins, such as cefepime, have a

quaternary nitrogen that is positively charged at the 3-position, providing the properties of a zwitterion: faster than other 3rd gen.

A 2-aminothiazolyl-acetamido group in the side chain at the 7-position with an alpha-oxyimino substitution may enhance stability against beta-lactamases by preventing the enzymes' approach to the main nucleus.

not active in vitro against Enterococcus faecalis, Clostridium difficile, and methicillin- and cefazolin-resistant Staph. aureus.

In healthy adults, the volume of distribution is 13-22 L and the elimination half-life is 2-2.3 hours..

The most common adverse effects of cefepime are headache (2.4%), nausea (1.8%), rash (1.8%), and diarrhea (1.7%).