Cephalosporin Lecture 14

Question 1

Structure and chemistry of cephalosporins

Answer 1

1. 7 aminocephalospornic acid derivatives

2. requieres beta lactam ring for activity

Question 2

MoA cephalosporins

Answer 2

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

Question 3

MoA cephalosporins 2

Answer 3

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

Question 4

Pharmacokinetic properties: cephalosporin

Answer 4

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

Question 5

adverse effects: cephalosporin

Answer 5

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

Question 6

Drug interactions: cephalosporin

Answer 6

anticoagulants (warfarin): potentiation of anticoagulant efects

alcohol: disulfiram like reaction
probenecid: prolongs excretion in cephalosporins that have tubular secretion

Question 7

First generation: cephalosporin

Answer 7

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

Common pareneteral products: cefazolin (ancef)

Gram positive: Staph, strep

Gram negative: minimal

Anaerobes (bacteroides): No

Question 8

Second generation: cephalosporin

Answer 8

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

Question 9

Second (Cephamycins): cephalosporin

Answer 9

Parenteral: cefoxitin (mefoxin), Cefotetan (cefotan)

Gram +: Staph Strep

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

Anaerobes: Yes

Question 10

Third generation: cephalosporin

Answer 10

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

Parenteral: ceftriaxone (rocephin), cefotaxime (claforan)

Gram +: Strep

Gram -: SACE

Anaerobes: no

Question 11

Third (antipseudomnal): cephalosporin

Answer 11

parentral: ceftaazidime (fortaz), cefoperazone (cefobid)

Gram +: Poor staph and strep

Gram -: SPACE

Anaerobes: no

Question 12

Fourth generation: cephalosporin

Answer 12

Paraenteral: cefepime (maxipime)

G +: Staph and Strep

G -: SPACE

Anaerobes: No

Question 13

Fifth Generation: cephalosporin

Answer 13

parenteral: Cetaroline (teflaro)

G+: Staph strep, enterococcus

G-: SCE, +/- pseudomonas

Question 14

Community acquired pneumonia: cephalosporin

Answer 14

third generation: ceftrixone, cefotaxime

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

Question 15

Spectrum of activity: cephalosporin

Answer 15

as cephalosporin generations increase, gram negative coverage increases

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

Question 16

Nosocomial pneumonia: cephalosporin

Answer 16

Third generation: ceftazidime

fourth generation: cefepime

consider double coverage if SPACE bugs involved

Question 17

Meningitis: cephalosporin

Answer 17

Third generation cephalosporins;

much higher doses must be used

Question 18

skin/soft tissue: cephalosporin

Answer 18

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)

Question 19

Surgical prophycxlaxis: cephalosporin

Answer 19

cefazolin (long half life, covers staph)

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

Question 20

fever in neutropenic patient: cephalosporin

Answer 20

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

Question 21

STD: cephalosporin

Answer 21

neisseria resistant to penicillin: carbapenems/monobactams

Question 22

Crabapenems

Answer 22

DIME

doripenem, imipenem, meropenem, ertapenem

Question 23

pharmacokinetics carbapenems

Answer 23

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

Question 24

AE: carbapenem

Answer 24

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

Question 25

Spectrum of activity

Answer 25

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

Question 26

Doripenem

Answer 26

newest carbapenem which covers SPACE and anaerobes (2008)

not approved to treat pneumonia

Question 27

Ertapenem

Answer 27

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

Question 28

AE: Monobactam (aztreonam)

Answer 28

Cross creaticity with penicillin is rare

hematologic: anaemia, leukopenia, thrombocytopneia

Question 29

Spectrum of activity: monobactam

Answer 29

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)