Third-generation beta-lactam antibiotics are effective against a wider range of microorganisms than are older antibiotics. Cefotaxime, moxalactam, cefoperazone, ceftizoxime, ceftazidime, cefsulodin, and ceftriaxone were used to treat 102 patients

2. Introduction
Structure-Activity Relationship
Clinical Pharmacokinetics
Mechanism of Action
Uses
Adverse Effects & Contraindications
3th Generation Cephalosporin-Resistant
1st VS 3th generation cephalosporin
Use of 3th Generation Cephalosporins for Treatment of
Neonatal Infections
3th generation cephalosporins versus conventional
antibiotics for treating acute bacterial meningitis

3. Introduction
belong to the beta-lactam group of bactericidal
antibiotics.
 Based on the timeline of drug discovery and their antimicrobial
properties, these antibiotic agents are grouped into different
generations.
 In general, as we move from first to third, the microbicidal
activity of cephalosporins decreases against gram-positive
organisms but increase against gram-negative bacilli.
 Furthermore, the resistance against beta-lactamases increases
from first to fifth generations.

4.  In terms of antibacterial activity, the third-generation
cephalosporins are broad-spectrum antimicrobial agents with
activity against both gram-negative and gram-positive organisms.
 Nevertheless, they are more active against gram-negative
bacteria and organisms that are resistant to the first and second
regeneration cephalosporins.
 Furthermore, these agents seem to be less active against several
gram-positive bacteria, such as Streptococcus and
Staphylococcus species.
 Third-generation cephalosporins show more stability to beta-
lactamases than first or second generations, especially those
produced by Klebsiella, Haemophilus influenzae, and Escherichia
coli.

7. Structure-Activity Relationship
The third-generation cephalosporins are semisynthetic analogs with different
chemical substitutions on a 7-aminocephalosporanic nucleus. As a result of these
chemical modifications, improvements in the antibacterial spectrum as well as
pharmacokinetic properties have occurred. In general, the new cephalosporins
have longer half-lives, higher and prolonged serum concentrations, and increased
cerebrospinal fluid penetration.
Many analogs of Cephalosporin have been made and the structure-activity
relationship (SAR) conclusions are as follows:
 The 3-lactam ring is essential
 A free carboxyl group is needed at position 4
 The bicyclic system is essential
 The stereochemistry of the side-groups and the rings is important
These results tally closely with those obtained for the penicillins and there are only
a limited number of places where modifications can be made, Those places are:
 the 7-acylamino side-chain
 the 3-acetoxymethyl side-chain
 substitution at carbon 7

10. Clinical Pharmacokinetics
 Third-generation cephalosporins administration can be oral, intramuscular, or
intravenous.
 Except for ceftibuten and cefdinir, all the oral compounds are esters and are
hydrolyzed by esterases in the gastrointestinal tract for absorption.
 Have high oral bioavailability with established therapeutic plasma
concentrations and low potential for toxicity.
 Some drugs are poorly absorbed in the gastrointestinal tract and are
administered only intramuscularly or intravenously like ceftriaxone,
ceftazidime, and cefotaxime.
 Ceftriaxone has high protein binding capacity and has the longest-half life,
administered as a once-daily dose.
 Have excellent penetration into most body fluids and the extracellular fluid of
most tissues, especially in the presence of inflammation.
 Have poor penetration into the intracellular compartment and vitreous humor.
 Most cephalosporins are excreted primarily in the urine, so their doses require
adjustment in renal insufficiency.
 Cefoperazone and ceftriaxone, which have significant biliary excretion, but do
not require doses adjustment in renal or hepatic insufficiency.

11. Mechanism of Action
 Peptidoglycans are cross-linked in the final step of bacterial cell wall synthesis
to make peptidoglycan polymers with the help of membrane-anchored
enzymes (i.e., transpeptidases, carboxypeptidases, and endopeptidases),
collectively called penicillin-binding proteins (PBPs).
 The beta-lactam ring structure of third-generation cephalosporins mimics the
“D-Ala-D-Ala” moiety of the natural substrate of PBPs. Structural binding of
cephalosporin antibiotics to the active site of PBPs in bacterial cell walls leads
to:
 inhibition of their enzymatic activity
 defective peptidoglycan synthesis
 an inability to construct a functional cell wall
 subsequent death of the bacterial cells by osmotic lysis

12. Uses
 Third-generation cephalosporins may be used to treat the
following types of infections when caused by susceptible strains
of bacteria:
 Bacteremia/septicemia
 Bone and joint infections
 Central nervous system infections
 Gynecological infections
 Intra-abdominal infections
 Lower respiratory tract infections
 Skin and skin structure infections
 Urinary tract infections.
 Cephalosporins are not usually used as a first-choice antibiotic.
They tend to be reserved for use when other antibiotics (often
penicillins) cannot be used.

13. Adverse Effects
1. Pain and phlebitis at injection sites.
2. Immediate and delayed hypersensitivity reactions.
3. Various hematological disorders, nephrotoxicity,
hepatotoxicity, gastrointestinal disturbances, and fever.
4. Suppression of endogenous gut flora leading to a
reduction in vitamin K synthesis and occasionally
causing clinically significant bleeding and
pseudomembranous colitis.
5. Inhibition of acetaldehyde dehydrogenase, causing
acute ethanol intolerance, this appears to be restricted
to compounds that contain methyltetrazolethiol group
like cefoperazone.

14. Contraindications
1. In patients with a known allergy to the cephalosporin group of
antibiotics.
2. Cephalosporins share molecular similarity with penicillins and
could lead to allergic reactions in 10% of patients with known
allergy to penicillins.
3. In patients who have a history of severe anaphylactic reactions
with these agents.
4. Ceftriaxone has the affinity for binding to albumin by replacing
bilirubin and is contraindicated in jaundiced neonates at risk
for bilirubin encephalopathy.
5. Patients should avoid alcohol consumption while on third-
generation agents to avert disulfiram-like reactions.
6. Because third-generation cephalosporins are pregnancy
category B medications under the prior FDA rating system,
they are not contraindicated in pregnancy.

15. 3th Generation Cephalosporin-Resistant
 The prevalence of extended spectrum beta-lactamase producing
pathogen colonization at hospital admission was almost 10%, with
previous colonization, antibiotic use, travel, long-term care facility
residence, and acid-suppressive therapy as risk factors.
 Third-generation cephalosporin-resistant Enterobacteriaceae (3GCREB)
have recently emerged in many countries. The gut is the reservoir for
infections with these organisms.
 German researchers have published results from a multicenter study
performed at six German tertiary care hospitals.
 The study involved 4376 patients admitted to general wards with
various diagnoses who received stool or rectal swab screening for
3GCREB within the first 3 days of their hospital stay.
 Of the 4376 patients, 416 were 3GCREB positive, an admission
prevalence of 9.5%.
 Escherichia coli was the most common 3GCREB species, accounting for
79.1%, followed by Klebsiella pneumoniae (8.5%), Enterobacter spp.
(5.7%), and Citrobacter spp. (4.8%).

16. 1st VS 3th generation cephalosporins
 Are very effective against Gram-positive bacteria, but they’re
only somewhat effective against Gram-negative bacteria.
 First-generation cephalosporins might be used to treat:
• skin and soft tissue infections
• UTIS
• strep throat
• ear infections
• pneumonia
 Some first-generation cephalosporins are used as
prophylactic antibiotics for surgery involving the chest,
abdomen, or pelvis.
 Examples of first-generation cephalosporins include:
cephalexin (Keflex), cefadroxil (Duricef), cephradine (Velosef).

17.  Are more effective against Gram-negative bacteria compared to both the first
and second generations. They’re also more active against bacteria that may be
resistant to previous generations of cephalosporins. The third generation also
tends to be less active than previous generations against Gram-positive
bacteria, including Streptococcus and Staphylococcus species.
 One third-generation cephalosporin, ceftazidime (Fortaz), is often used to
treat, pseudomonas infections including hot tub folliculitis.
 Third-generation cephalosporins may also be used to treat:
• skin and soft tissue infections
• pneumonia
• UTIs
• gonorrhea
• meningitis
• Lyme disease
• sepsis
 A few examples of third-generation cephalosporins include:
cefixime (Suprax), ceftibuten (Cedax). cefpodoxime (Vantin)

18. Use of 3th Generation Cephalosporins for
Treatment of Neonatal Infections
 The advent of the third-generation cephalosporins (cefotaxime, ceftizoxime,
cefoperazone, ceftriaxone…) has piqued the interest of physicians who care
for newborn infants.
 These compounds are extraordinarily active against enteric gram-negative
bacilli and the following important pathogens: Haemophilus influenzae,
Streptococcus agalactiae (group B streptococci), Neisseria meningitidis, and
Streptococcus pneumoniae.
 With the exception of cefuroxime, a recently approved second-generation
drug, the older cephalosporins have not been used extensively by
pediatricians, nor have they been recommended for initial empiric therapy of
any infectious condition. The principal reasons for their limited use were
relatively poor penetration into cerebrospinal fluid, lack of uniform activity
against all strains of H influenzae, and inadequate activity against many
strains of gram-negative enteric bacilli.
 The third-generation cephalosporins are different. They are not only active
against the major bacterial pathogens of infants and children, but they also
achieve excellent cerebrospinal fluid.

19. 3th generation cephalosporins versus conventional
antibiotics for treating acute bacterial meningitis
 Acute bacterial meningitis is a life-threatening illness.
 Bacteria that cause meningitis are often thought to be resistant to
conventional (older) antibiotics, and so doctors often prescribe newer
antibiotics (called third-generation cephalosporins).
 Commencing treatment early is vitally important and the choice of antibiotic
is often made without any knowledge of possible drug resistance.
 This review examined 19 studies with 1496 participants to see whether there
is a difference in effectiveness between conventional and newer antibiotics.
This review found no differences. Adverse effects in both approaches were
similar, except for diarrhea, which was more common in the cephalosporin
group.
 Only three studies dealt with adults; the remaining studies recruited
participants aged 15 years and younger.
 Therefore, we believe that the results probably pertain more to children.
 Conventional and newer antibiotics seem reasonable options for initial,
immediate treatment. The choice may depend on availability, affordability,
and local policies.