Bicyclic ring structure

    beta-lactam ring (in common with penicillins)

    6 membered sulfur containing dihidrothiaizine ring

Changes in side chain R group's gives changes in spectrum of activity, pharmacokinetics, etc.

Mechanism of action:

Cephalosporins disrupt the synthesis of the peptidoglycan layer of bacterial cell walls. The peptidoglycan layer is important for cell wall structural integrity. The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by transpeptidases known as penicillin binding proteins (PBPs). PBPs bind to the D-Ala-D-Ala at the end of muropeptides (peptidoglycan precursors) to crosslink the peptidoglycan. Beta-lactam antibiotics mimic this site and competitively inhibit PBP crosslinking of peptidoglycan

Mechanisms of resistance:

Changes in drug target of penicillin binding proteins - methicillin-resistant Staphyloccocus aureus

Efflux pumps - MexAB-OprM efflux pump in Pseudomonas aeruginosa

Decreased permeability of cell wall - less common for cephalosporins

Alteration of drug itself by hydrolysis by beta-lactamases

Numbers and types of beta-lactamases increasing

Can be chromosomally or extra-chromosomally (more easily transmitted to other organisms) mediated

Resistance to one cephalosporin can result in resistance others depending on mechanism

Resistance to cephalosporins can confer resistance to other beta- lactam drugs like penicillins as well.

Classification:

Divided into "generations" for convenience but many drugs in same "generation" not chemically related and different spectrum of activity

Currently four generations of cephalosporins but which generation a particular drug belongs often a matter of debate

Generalization that with increasing "generation" activity in vitro against Gram positive organisms decreases while activity against Gram negatives increases (but an oversimplification)

Oral and intravenous formulations

Activity against E. coli, Klebsiella, Proteus

In general, FDA approved for skin and soft tissue infections, urinary tract infections, respiratory tract infections

Oral and intravenous - cefuroxime axetil

Anti-anaerobic activity (cephamycins) - cefoxitin

Non-anti-pseudomonal - ceftriaxone, cefotaxime

Anti-pseudomonal - ceftazidime

cefepime

Usage of Cephalosporins in Human Medicine:

Inpatient setting most common diagnosis associated with billing for a cephalosporin is pneumonia1

Individual drug usage from January 2000 to December 2005:2

Cefazolin (1st generation) with approximately 37 million projected discharges

Ceftriaxone (3rd generation) with approximately 16 million projected discharges

Cefepime (4th generation) in approximately 2 million projected discharges2 with pneumonia as most common usage for drug (approx. 157,000)3

3rd and 4th generation cephalosporins used in hospital setting in seriously ill patients for serious and life-threatening diseases

Many of these diseases due to organisms that reside in the gastrointestinal tract

Drugs of last resort for serious infections due to food-borne pathogens Salmonella and Shigella

These organisms may be resistant to other drugs.

Quinolones may be effective but avoid in children due to potential for toxicities.

Conclusion:

Cephalosporins one of most widely used drug classes in the US and worldwide

Mechanisms of resistance to cephalosporins may confer resistance to other beta-lactam agents

Ranking of 4th generation cephalosporins as highly important and 3rd generation agents as critically important in Guidance 152; both critically important in WHO criteria

Ranking of antimicrobials according to importance in human medicine one factor to consider in overall risk-management strategy for use of drugs in animals according to Guidance 152

Cephalosporin Structure-Activity Relationship:

General relationships between structure and properties involve reactivity, formulation, spectrum of activity, PBP affinity, beta-lactamase resistance, oral activity, stabaility, metabolism, plasma protein binding, adverse reactions, etc.

Beta-Lactam Ring:

Required for PBP reactivity and antibacterial activity
Reactivity reduced compared to the penicillins (2 reasons)
Compare mechanism of action, resistance, pharmacodynamics, etc to penicillins

2-Carboxyl Group:

Acidic: Salt formation, product formulation
Prodrug formation
Elimination profile: Renal

X-Substituent:

Cephalosporins and cephamycins
Determines, in part, resistance to beta-lactamase inactivation

3- Substituent (R3):

Chemical/acid stability/instability
Metabolic stability/instability
Minimal impact on antibacterial activity
Protein binding and half-life: Heterocycles
Adverse Reaction and Drug Interaction
Some role in cephalosporin classification (generation)

7-Substituent (R7):

Incorporated by semisynthesis: Variable structures
Impact on spectrum of activity (beta-lactamases, PBP affinity, etc.)
Significant role in activity and classification by generation