Cell wall inhibitor Cephalosporins Dr. Naza M. Ali Lec 5 13-12-2016 D

Cephalosporins The cephalosporins are beta-lactam antibiotics that are closely related both structurally & functionally to penicillins. Are produced semisynthetically by the chemical attachment of side chains to 7-aminocephalosporanic acid.

Mechanism of action and resistance Bind to PBPs on bacterial cell membrane to inhibit bacterial cell wall synthesis. Structural differences from penicillins render cephalosporin less susceptible to penicillinase produced by staphlococci, but many bacteria are resistance through the production of other beta-lactamase that can inactivate cephalosporins. Resistance also from decreased in membrane permeability to cephalosporins and from changes in PBPs. Methicillin-resistant staphylococci are also resistant to cephalosporin.

1.First-generation drug Antibacterial spectrum 1.First-generation drug Cefazolin ( parenteral) , Cephalexin and Cefadroxil (oral) active against +gm cocci (staphylococci, streptococci) Proteus, E.coli , K pneumoniae (PEck) Used in surgical prophylaxis in selected condition.

2.Second generation: have greater activity against three additional gram-negative H. influenzae, Enterobacter aerogenes, Neisseria whereas activity against gram-positive is weaker HENPEcK Cefoxitin, Cefotetan active against Bacteroides Fragilis / IV Cefuroxime in community acquire pneumonia / oral Cefaclor in otitis, lower RTI , sinusitis / oral Cefamandole active against H. influenza

3.Third generation: have enhanced activity against gram-negative bacilli and some are able to cross BBB Ceftriaxone or Cefotaxime drug of choice in meningitis and for empiric therapy Ceftriaxone , Cefixime drug of choice in gonorrhea Ceftazidime, Cefoperazone activity against P.aeruginosa Cefpodoxime, Cefdinir are orally

4.Fourth generation: Cefepime parenterally has a wide antibacterial spectrum. Combine gram positive activity of 1st generation with wider gram negative spectrum of 3rd generation. ( Enterobacter, E. coli, K. pneumoniae, Proteus mirabilis, P. aeruginosa).

5. Fifth generation: Ceftobiprole Ceftaroline A new cephalosporin with activity against Methicillin-Resistant Staphylococcus (MRSA)

1st Spectrum Name of drugs treatment Gm+ cocci, PEck Cefazolin / Inj Generation Spectrum Name of drugs treatment 1st Gm+ cocci, PEck Cefazolin / Inj Cephalexin /oral Cefdroxil / oral surgical prophylaxis, penetration to bone pharyngitis 2nd HENPEcK Bacteroides fragilis Cefoxitin /inj Cefotetan / inj Cefuroxime oral Cefaclor /oral community acquire Pneumonia Otitis, lower RTI, sinusitis 3rd gram-negative bacilli some are able to cross BBB Ceftriaxone /inj Cefotaxime /inj Ceftriaxone/ inj Cefixime /oral Meningitis Gonorrhea P. aeruginosa Ceftazidime/ inj Cefoperazone/inj Cefpodoxime/oral Cefdinir/ oral

4 th Spectrum Name of drug Disease wide antibacterial . Generation Spectrum Name of drug Disease 4 th wide antibacterial . Combine gram positive 1st with wider gram negative 3rd Enterobacter, E. coli, K. pneumoniae, Proteus mirabilis, P. aerugin, Cefepime parenteral 5th MRSA Enterobacter, Gm-ve rods Ceftobiprole, Ceftaroline:

Pharmacokinetics Administration: IV , IM or oral Distribution: cross the placenta Fate: tubular secretion and GF (Ceftriaxone is excreted through the bile into the feces)

Adverse effects: Allergic manifestations Patients who have had an anaphylactic response, Stevens-Johnson syndrome to penicillins should not receive cephalosporins. Should be avoided or used with caution in individuals who are allergic to penicillins ( 8-10% show cross- sensitivity). Cephalosporin that contain methylthiotetrazole group: Cefamandole, cefotetan, cefoperazone cause hypoprothrombinemia and bleeding disorders.

Other Beta-Lactam Antibiotics Dr. Naza M Ali Lec 6 13-12-2016

Other beta-Lactam Antibiotics A. Carbapenems B. Monobactam C. Beta-Lactamase inhibitors

A. Carbapenems Chemically different from penicillins but retaining the beta-lactam ring structure. Imipenem, meropenem, ertapenem , doripenem Have wide activity against gram positive cocci, gram negative rods, anaerobes. Plays a role in empiric therapy because it is active against penicillinase-producing gram-positive and gram- negative organism, anaerobes, P. aeruginosa Used in combination with aminoglycoside for pseudomonal infection

They are used parenterally & are useful for infections caused by organism resistant to other antibiotics. They are drugs of choice for infections caused by Enterobacter. Imipenem is compounded with cilastatin to protect it from metabolism by renal dehydropeptidase. Imipenem & meropenem are administered IV and penetrate well into body tissues & fluids, including CSF when meninges are inflamed.

B. Monobactam Drugs with monocyclic beta-lactam ring. Aztreonam is resistant to action of beta -lactamases. has antimicrobial activity against gram-negative rods (Enterobacteriaceae) including pseudomonas It lacks activity against gram-positive organisms and anaerobes. It is administered (IV or IM), is excreted in urine, it can accumulate in patients with renal failure. Aztreonam is relatively nontoxic, can use as alternative for treating patients who are allergic to penicillins or cephalosporins.

C. Beta-Lactamase Inhibitors Hydrolysis of the beta-lactam ring by enzymatic cleavage or by acid, destroys the antimicrobial activity. Clavulanic acid, Sulbactum, Tazobactam contain a beta-lactam ring but, by themselves, do not have significant antibacterial activity. They bind to and inactivate beta-lactamases protecting the antibiotics that are substrates for these enzymes. clavulanic acid and amoxicillin combination.

contain bete lactam ring Gm+ cocci gm- rods (enterobacteriaceae) Carbapenem: Imipenem, Meropenem Ertapenem differ in str contain bete lactam ring Gm+ cocci gm- rods (enterobacteriaceae) anaerobes pseudomonas +aminoglycosid Parenterally Monobactam: Aztreonam Monocyclic beta lactam ring narrow spec. -ve rode P. aeruginosa No activity for +ve No toxic,safe IM,IV Beta-lactam inhibitors: Clavulanic acid, Sulbactam, tazobactam Contain beta lactum ring, do not have significant antibacterial activity Oral, parenteral