Cephalosporins

Cephalosporin antibiotics derived from “cephalosporin C” obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists of dihydrothiazine ring fused to a β–lactam ring 7-aminocephalosporanic acid

7-aminocephalosporanic acid has been modified by addition of different side chains to create a whole family of cephalosporin antibiotics. these have been conventionally divided into 5 generations

Mechanism of action All cephalosporins are bactericidal. MOA same as penicillin- Inhibit cell wall synthesis in a manner similar to penicillins Bind to different proteins than those which bind penicillin. PBP-1 &PBP-3 This explains diffenece in spectrum, potency & lack of resistance.

BACTERICIDAL Inhibition of transpeptidation Imperfect cell wall Osmotic drive Activation of autolysin enzymes Lysis of bacteria BACTERICIDAL

CLASSIFICATION Based on antimicrobial spectrum Chronological sequence of development Divided into generations.

First-generation agents Cephalexin (O) Cefadroxil (O) Cefazolin (i.m, i.v) Cefalothin (withdrawn)

Modest activity against E. coli, K. pneumoniae & Proteus mirabilis Exhibit good activity against gram-positive bacteria but modest activity against gram negative organisms. Most gram-positive cocci Strepto, Pneumo, Methicillin sens. Staph. are susceptible to first-generation cephalosporins Modest activity against E. coli, K. pneumoniae & Proteus mirabilis Most oral cavity anaerobes are sensitive.  However, the Bacteroides fragilis group is resistant.

Second-generation agents Cefaclor (O) Ceforanide Cefuroxime acetil (O) Cefuroxime (i.m , i.v) Cefoprozil Cefamandole (Banned) Cefoxitin (Banned) Cefotetan (Banned)

Exhibit somewhat increased activity against gram negative organisms, but much less active than third generation agents. Less active against gram positive cocci & bacilli compared to first gen. drugs. Use declined Clinically replaced by 3rd & 4th generation drugs .

Third-generation agents Cefotaxime Ceftriaxone Cefdinir Cefibuten Cefpodoxime Ceftizoxime Ceftazidime Cefoperazone (withdrawn)

Highly augmented activity against gram-negative organisms Less active than first generation agents against gram positive cocci & anaerobes. All are highly resistant to β-lactamases from gram negative bacteria. Some inhibit psuedomonas as well; ceftazidime, cefoperazone(withdrawn)

Some members of this group have enhanced ability to cross the blood-brain barrier eg. Ceftriaxone and are effective in treating meningitis caused by pneumococci, meningococci, H. influenzae and susceptible gram negative rods.

Fourth-generation agents Cefpirome P/E (im/iv) Cefepime P/E (iv) Cefozopran P/E

Highly active against G –ve organisms Similar to third gen drugs for g +ve bacteria The fourth generation drugs comparable to third generation but more resistant to hydrolysis by β-lactamases. Effective against bacterial infections resistant to earlier drugs

Fifth-generation agents Ceftobiprole Ceftaroline Active against, g +ve cocci especially MRSA penicillin resistant S. pneumoniae and enterococci

Resistance Impermeability to the antibiotic. to reach its site of action Alteration in PBPs -antibiotics bind with low affinity Elaboration of β-lactamases; that can hydrolyze the β-lactam ring and inactivate the cephalosporin (most prevalent mech)

Adverse reactions Pain after im injection Thrombophlebitis of injected vein. Diarrhoea more common with oral Ceferadine P/E Cefoperazone (Banned)

Hypersensitivity reactions Identical to penicillins, incidence is lower. shared β-lactam structure Allergic to penicillins- allergic to cephalosporins. CROSS-REACTIVITY. Rashes, frequent, anaphylaxis, angioedema, asthma, urticaria have also occurred.

Serious bleeding Cephalosporins potentially nephrotoxic drugs Cephaloridine (withdrawn) RTN Cephalothin (withdrawn) Acute tubular necrosis Serious bleeding Cefoperazone(Banned), Moxalactam(Banned). Due to hypoprothrombinemia.

Intolerance to alcohol Disulfiram like reaction Cefamandole (Banned) Cefotetan (Banned) Moxalactam (Banned) Cefoperazone (Banned)

Therapeutic Uses Extensively used & therapeutically important antibiotics Effective therapeutic & prophylactic agents

First Gen agents Excellent for skin & soft tissue infections Surgical prophylaxis first generation drugs are the preferred for prophylaxis in procedures in which skin flora are likely pathogens.

Second Gen agents Displaced by third generation agents for Gram negative infections Oral-RTI (replaced by augmentin)

Third Gen agents With/without aminoglycosides DOC- severe G -ve infections caused by Kleibsiella Enterobacter Proteus Providencia Serratia & haemophillus species.

Ceftriaxone is the therapy of choice for all forms of Gonorrhea 250 mg i.m as single dose i.v ceftriaxone for enteric fever Cefotaxime & ceftriaxone Community aquired pneumonia

Cefotaxime/ceftriaxone are used for initial treatment of meningitis because of their antimicrobial activity, good penetration into CSF & record of clinical success They are DOC - Meningitis due to H. influenzae Sensitive S. pneumonae N. meningitidis G-ve enteric bacteria Ceftazidime + aminoglycosides Psuedomonas meningitis DOC

Fourth Generation Agents Same as third generation drugs Indicated for hospital acquired infections resistant to commonly used antibiotics

Other β -lactam antibiotics

Other β -lactam antibiotics Newer classes of β-lactam antibiotics are the Monobactams Carbapenems Carbacephems Important therapeutic agents with a β-lactam structure & are neither penicillins nor cephalosporins

Monobactams Aztreonam Isolated from chromobacterium violaceum Only monobactam currently in clinical use β - lactam ring, lacking the thiazolidine ring. - a monobactam

Antimicrobial activity differs from those of other β -lactam antibiotics & more closely resembles that of an aminoglycoside Primarily affects : Aerobic gram negative microorganisms gram positive bacteria & anaerobic organisms are resistant Preferred-all sorts of gram negative infections in patients with renal impairment where aminoglycosides are to be avoided.

Stable to most β-lactamases elaborated by gram negative bacteria. i.m / i.v Therapeutic conc. in CSF in the presence of inflammed meninges, Alternative to cephalosporins for therapy of meningitis caused by G-ve bacilli

Carbapenems β-lactam antibiotic Broader spectrum of activity : than most other β-lactams . gram-negative rods gram-positive bacteria and anaerobes.

Carbapenems Imipenem Meropenem Ertapenem

Imipenem Derived from compound produced by Streptomyces cattleya Mechanism same as penicillins Bactericidal Resistant to hydrolysis by β-lactamase Marketed in combination with cilastin Inhibits degradation – by renal dipeptidase Without cilastin renal dehydropeptidases inactivate the drug which results in low urinary tract concentrations.

Adverse effects Nausea ,vomiting Seizures Patients allergic to other β-lactam antibiotics may have hypersenstivity reactions when given imipenem

Meropenem Therapeutic equivalence with imipenem Coadministration with cilastin not required Meropenem is less seizure producing compared to imipenem.

Ertapenem Differs from imipenam & meropenem larger serum half life, OD. Co-administration with cilastin not required less seizure producing compared to imipenem.

All are resistant to β – lactamases All bactericidal MOA same All are parenteral i.v, im painful Imipenem 6 hrly Meropenam 8 hrly All are resistant to β – lactamases All bactericidal MOA same Patients allergic to other β-lactam antibiotics may have hypersenstivity reactions when given imipenem/carbapenems.

Therapeutic uses Urinary tract infections Lower respiratory tract infections Intra-abdominal & gynaecological infections Skin, bone, joint, & soft tissue infections Especially cephalosporin/ penicillin resistant nosocomial bacteria.

Carbacephems Loracarbef Synthetic β-lactam antibiotic Similar to cefaclor Antibacterial activity resembles II generation cephalosporins.

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