Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSOR

DEPT. OF PHARMACOLOGYSSIMS & RC.

CEPHALOSPORINS

Cephalosporins: β-lactam antibiotics

Cephalosporins were first isolated from cultures of Cephalosporium acremonium by Italian scientist Giuseppe Brotzu

They consists of dihydrothiazine ring fused to a β-lactam ring containing appropriate side chain at position -7

β-lactam antibiotics

Classification of Cephalosporins

First Generation Cephalexin, Cefadroxil Cephazolin

Second Generation Cefuroxime Cefaclor Cefoxitin (cephamycin)

Good activity Staphs and Streps

Increased activity Gram negatives, Slightly less activity

against Gram Positives

Classification of Cephalosporins

Third Generation Ceftriaxone, Cefotaxime Ceftazidime

Fourth Generation CefipimeFifth GenerationCepftobiproleCeftaroline

Very good Gram negative coverageReasonable against Gram PositivesCeftazidime has anti-pseudomonal

activity

Very broad spectrum activity including Pseudomonas

MECHANISM OF ACTION Cephalosporins are bactericidal and have the same

mode of action as beta-lactam antibiotics. Cephalosporins disrupt the synthesis of the peptidoglycan layer of bacterial cell wall.

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 pencillin binding proteins (PBPs).

β-lactam antibiotics mimic this site and competitively inhibit PBP cross linking of peptidoglycan.

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First Generation Cephalosporins Cephazolin, cefadroxil, Cefazolin

Good activity v Streps & Penicillin Resistant Staphs.

Surgical prophylaxis for cardiac and vascular surgery, insertion of orthopaedic prostheses, H&N surgery and most gynaecological surgery.

Treatment of Soft tissue infections, particularly in the outpatient setting. (not for bite wounds as poor activity against anaerobes, salmonella, pseudomonas, enterobacter and Pasteurella)

Cefadroxil

Second Generation

Cefaclor, Cefuroxime(BBB), Cefoxitin, Cefotetan, Against Gram Negative organisms Cephalosporins with extended spectrum of activity

against--Indole positive Proteus, Klebsiella, Moraxella catarrhalis, Neisseria species

-Increased activity G-veH. influenzae, M. catarrhalis. P/K-stable against beta lactamases except for cefaclor Excreted unchanged through kidney (probenacid

increases activity)

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Second Generation

Route- IM inj are painful, IV is betterUsed for Community Acquired Respiratory Tract

Infections, Surgical prophylaxis for Colorectal Surgery. Treatment of post-operative wound infections.

Cefoxitin, cefotetan- anaerobes peritoniitis Cefuroxime- CAP, prophylaxis in colorectal

surgeries, vaginal or abdominal hysterectomies and appendicitis , because of activity against B.fraglis.

•Cefaclor-Oral, good activity against URTIs & UTIs. Moderate activity in soft tissue infections.

Third Generation

Cefixime, Cefpodoxime, Cefdinir, Ceftriaxone, Cefoperazone, CefotaximeGood, broad spectrum Gram negative cover with reasonable Gram Positive coverLong half life, Good CSF penetration. Drug of choice suspected bacterial meningitisRelatively good Penicillin Resistant PneumococciSpecial indications- Treatment of N. gonorrhoea, Chancroid, Lyme disease, Typhoid fever, Severe Shigella & Salmonella infections, Gram negative Brain abscess, endocarditis by HACEK organisms.

Third Generation

Ceftazidime-Activity v Pseudomonas also, but should not be used as Monotherapy for Pseudomonas infections.They have a broad spectrum of activity and further increased activity against Gram-negative organisms. They may be particularly useful in treating hospital acquired infections Extended-spectrum beta-lactamases are reducing the clinical utility of this class of antibiotics. They are also able to penetrate the CNS, making them useful against meningitis caused by pneumococci, meningococci, H. influenzae, and susceptible E.coli.

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Fourth Generation

Cefozopran, Cefpirome, cefipime

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

They also have a greater resistance to beta-lactamases than the third-generation cephalosporins.

Many can cross the blood-brain barrier and are effective in meningitis.

They are also used against Pseudomonas aeruginosa.

Fourth Generation

Cefipime Broad spectrum including Pseudomonas Enhanced activity against certain Gram negative

bacilli, including Enterobacter, Citrobacter and Serratia.

Uses. Severe Community Acquired Pneumonia requiring Intensive Care.

Cepftobiprole, CeftarolineCeftobiprole has been described as "fifth generation" though acceptance for this terminology is not universal.Ceftobiprole has powerful anti-pseudomonal characteristics and appears to be less susceptible to development of resistance.Ceftaroline is an injectable cephalosporin active against MRSA & penicillin resistant streptococcus pneumoniae It is inactive against Non fermenters & Carbapenemases producers.

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Fifth Generation

Uses

With exception of Cefipime, should not be used for treatment of Enterobacter, Serratia, Citrobacter infections due to induction of chromosomal Amp C beta-lactamases in these bacteria.

Not effective against Enterococci.

Antipseudomonal activity

Cefoperazone, Ceftazidime Cefpirome, Cefepime,Cefozopran, Ceftobipirole, Ceftaroline, ceftobiprole

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Cephalosporins:Mechanisms of Resistance

i) Antibiotic Destruction by Beta-lactamases (Enterobacteraciae)

ii) Alteration in the PBP target resulting in reduced binding affinity (MRSA, )

iii) Reduced penetration of the antibiotic through the membrane

iv) Increased Efflux of the DrugHypersensitivityCoagulation abnormalitypseudolithiasis

Adverse effects

HypersensitivityCoagulation abnormalityPseudolithiasis

CARBAPENEMS

Carbapenems are: - β-lactams that contain a fused β-lactam ring and a 5-membered ring system that differs from the penicillins in being unsaturated (double bond between C-2 and C-3) and containing a carbon atom instead of the sulfur atom.

Imipenem is N-form-imidoyl-thienamycin, the most stable derivatives of thienamycin.

Carbapenams

Meropenem is a second generation carbapenem. Meropenem is not hydrolyzed by DHP-

I(DeHydroPeptidase-1) and is resistant to most β-lactamases, including a few carbapenemases that hydrolyze carbapenem.

The lower incidence of nephrotoxicity of meropenem (compared with imipenem) has been correlated with its greater stability to DHP-I.

Monobactams

Monobactams have a monocyclic β-lactam ring and are resistant to β-lactamases.

Aztreonam was isolated from Chromobacterium violaceum .

Aztreonam is the first clinically useful monobactam. The antimicrobial activity of Aztreonam differs from

those of other β-lactam antibiotics and more closely resembles that of an aminoglycosides in activity without the nephrotoxicity of aminoglycosides

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