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Cephalosporin compounds were first isolated from cultures of Cephalosporium acremonium from a sewer in Sardinia in 1948 by Italian scientist Giuseppe Brotzu . He noticed that these cultures produced substances that were effective against Salmonella typhi, the cause of typhoid fever, which had beta-lactamase. Researchers at the Sir William Dunn School of Pathology at the University of Oxford isolated cephalosporin C. The cephalosporin nucleus, 7-aminocephalosporanic acid (7-ACA), was derived from cephalosporin C and proved to be analogous to the penicillin nucleus 6-aminopenicillanic acid, but it was not sufficiently potent for clinical use. Modification of the 7-ACA side-chains resulted in the development of useful antibiotic agents, and the first agent cephalothin (cefalotin) was launched by Eli Lilly in 1964.
First introduced into clinical use in 1964 (cephalothin).


Bicyclic ring structure

    ptr beta-lactam ring (in common with penicillins)

    ptr 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:

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

ptr Efflux pumps - MexAB-OprM efflux pump in Pseudomonas aeruginosa

ptr Decreased permeability of cell wall - less common for cephalosporins

ptr Alteration of drug itself by hydrolysis by beta-lactamases

ptr Numbers and types of beta-lactamases increasing

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

ptr 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.



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

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

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

First generation

ptr Oral and intravenous formulations

ptr Activity against E. coli, Klebsiella, Proteus

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

Second generation

ptr Oral and intravenous - cefuroxime axetil

ptr Anti-anaerobic activity (cephamycins) - cefoxitin

Third generation

ptr Non-anti-pseudomonal - ceftriaxone, cefotaxime

ptr Anti-pseudomonal - ceftazidime

Fourth generation

ptr cefepime


Usage of Cephalosporins in Human Medicine:

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

ptr Individual drug usage from January 2000 to December 2005:2

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

ptr 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

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

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

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

ptr These organisms may be resistant to other drugs.

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



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

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

ptr 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.

Cephalosporin StructureBeta-Lactam Ring:

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

2-Carboxyl Group:

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


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

3- Substituent (R3):

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

7-Substituent (R7):

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


Cephalosporin Structure-Activity Relationships: The 3-Position
 The 3-Position
 The 7-Position