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Structure and chemistry of cephalosporins

1. 7 aminocephalospornic acid derivatives
2. requieres beta lactam ring for activity

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MoA cephalosporins

A bacterial cell walls form by cross linking of different peptidoglycan strands as the third and final stage of their wall synthesis. The amino group at one end of a pentaglycine chain reacts with the peptide bond between two D alanine residues. A peptide bond is formed between glycine and one of the D ala residues, while the other D ala s released. The cross linking reaction is catalyzed by glycopeptide transpeptidase or a portion of the penicillin binding proteins

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MoA cephalosporins 2

The cephalosporins like penicillin, mimic D ala D ala and therefore are incorporated into the active site of the transpeptidase. Once bound, it forms an irreversible covalent bond with a serine of the enzyme and the cross bridging is halted. Hence, it exhbits cidal activity since the microorganisms can not survive without a formed cell wall

Efficacy of a particular cephalosporin related to its affinity for PBP

susceptible to some beta lactamase (hydrolysis)

beta lactam ring is unstable in an acid medium

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Pharmacokinetic properties: cephalosporin

orally administered cephalosporins are rapidly and throughly absorbed. Oral cephalosporins are available as prodrug esters and nonesterified compounds: cefuroxime axetil and cefpodoxime proxetil (prodrug esters hydrolyzed in the intestines to the active drug. food enhances absorption)

most cephalosporins are renally excreted and require dosage adjustments in patients with renal insufficiency; hepatic elimination (80%) for cefoperazone and ceftriaxone

third generation cephalosporins penetrate well into the CSF especially with inflamed meninges

Following an IV infusion the fifth generation, ceftraoline fosamil (prodrug), is rapidly converted by plasma phosphateases into active ceftaroline

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adverse effects: cephalosporin

1. hypersensitivity reaction: 5-15% cross reactivty with penicillins; generally considered safe in non-IgE mediated (anaphylaxis) penicillin allergic patients

2. Hematologic: bleed is associated with those cephalosporins that have a methylthiotetrazole side chain (cefamandole, cefoperazone, cefotetan) due to hypoprothrombinemia (disturbance in vitamin K dependent clotting facotrs by blocking the vitamin K epoxide reductase)

3. Gastrointestinal: diarrhe due to primary biliary excretion: cefoperazone, ceftriaxone and cefpodoxime; Psedomembranous colitis (overgrowth of toxin producing C difficile) is rare.

4. Renal: Interstitial nephritis (rare)

5. Alcohol, disulfiram like in tolerence: cefamandole, cefoperazon (NMTT side chain).

6. Ummunologic: serum sickness like illness in children: cefaclor

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Drug interactions: cephalosporin

anticoagulants (warfarin): potentiation of anticoagulant efects

alcohol: disulfiram like reaction

probenecid: prolongs excretion in cephalosporins that have tubular secretion

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First generation: cephalosporin

Oral products: cephalexin (keflex), cefadroxil (duracef)

Common pareneteral products: cefazolin (ancef)

Gram positive: Staph, strep

Gram negative: minimal

Anaerobes (bacteroides): No

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Second generation: cephalosporin

Oral: cefuroxime axetil (ceftin), cefprozil (cefzil), cefaclor (ceclor)

parenteral products: cefuroxime (zinacef)

Gram Positive: Staph, strep

Gram negative: (H. Flu, M. Cat, E coli) PEK

Anaerobes: no

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Second (Cephamycins): cephalosporin

Parenteral: cefoxitin (mefoxin), Cefotetan (cefotan)

Gram +: Staph Strep

Gram -: H. Flu, M. Cat, E Coli, PEK

Anaerobes: Yes

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Third generation: cephalosporin

Oral: Cefdinir (monicef), cefixime (suprax), cefopodoxime (vantin)

Parenteral: ceftriaxone (rocephin), cefotaxime (claforan)

Gram +: Strep

Gram -: SACE

Anaerobes: no

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Third (antipseudomnal): cephalosporin

parentral: ceftaazidime (fortaz), cefoperazone (cefobid)

Gram +: Poor staph and strep

Gram -: SPACE

Anaerobes: no

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Fourth generation: cephalosporin

Paraenteral: cefepime (maxipime)

G +: Staph and Strep

G -: SPACE

Anaerobes: No

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Fifth Generation: cephalosporin

parenteral: Cetaroline (teflaro)

G+: Staph strep, enterococcus

G-: SCE, +/- pseudomonas

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Community acquired pneumonia: cephalosporin

third generation: ceftrixone, cefotaxime

these do not covery atypical pneumonia (adding macrolide, doxy/tetra or FQN to do so)

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Spectrum of activity: cephalosporin

as cephalosporin generations increase, gram negative coverage increases

generally do not cover: enterococcus or atypicals (legionella, mycoplasma, chlamydia)

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Nosocomial pneumonia: cephalosporin

Third generation: ceftazidime

fourth generation: cefepime

consider double coverage if SPACE bugs involved

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Meningitis: cephalosporin

Third generation cephalosporins;

much higher doses must be used

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skin/soft tissue: cephalosporin

first generation cephalosporins (staph/strep)

cephamycin, 3/4 generation ceph in combo with other agents for severe infections like diabetic foot (g+, anaerobes, g-)

Fifth generation (covers MRSA if MIC <1.0)

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Surgical prophycxlaxis: cephalosporin

cefazolin (long half life, covers staph)

cephaymycins (abdominal/GI surgeries) (bacteriodies in stomach)

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fever in neutropenic patient: cephalosporin

ceftazidime +/- vancomycin (febrile neutropenic guidelines)

cefepime +/- vancomyice (febrile neutropenic guidelines)

cefepime covers staph and strep that ceftaz doesn't

vancomycin would cover staph and MRSA/ strep and enterococcus

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STD: cephalosporin

neisseria resistant to penicillin: carbapenems/monobactams

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Crabapenems

DIME

doripenem, imipenem, meropenem, ertapenem

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pharmacokinetics carbapenems

binds to PBP resulting in cidal effect

ertapenem has longest half life: allows once daily administration

extensive renal metabolism of imipenem by the brush border enzyme dehydropeptidase-1 is inhibited by cilastatin

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AE: carbapenem

imipenem: seizures in patients with epilepsy or if not adjusted appropriately for renal function. (meropenem does not cause and can be used for meningitis)

cross reactivty with penicillin: 5-15%

hematologic: anaemia, leukopenia, thrombocytopneia

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Spectrum of activity

excellent activity against a wide range of microorganisms (g+, G-, and anaerobic bacteria). Binds to PBP (PBP-1 and PBP2) of susceptible bacteria to induce a cidal effect.

useful in treating serious nosocomial infections caused by multiple organisms or ESBL producing bacteria

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Doripenem

newest carbapenem which covers SPACE and anaerobes (2008)

not approved to treat pneumonia

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Ertapenem

similar coverage to Unasyn (fence), once daily, excepte no enterococcus coverage, convenient for home health patients who have to administer their meds to themselves

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AE: Monobactam (aztreonam)

Cross creaticity with penicillin is rare

hematologic: anaemia, leukopenia, thrombocytopneia

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Spectrum of activity: monobactam

gram negative SPACE

Useful in treating serious nosocomial infections caused by mutliple organisms

CAP with risk factors for pseudomonas (bronchiectasis

HAP with severe PCN allergy (late onset or risk factors for MDR pathogens)