I.                 Cephalosporins-

A.     Structure- 2 rings.

B.     Mechanism- inactivate transpeptidases just like PNC, but less susceptible to lactamases.

C.    Spectrum-

1.     lactamase producers:  Klebsiella, N. gonorrhoeae

2.     potent inducers of -lactamases in other species:  Enterobacter and Pseudomonas.

3.     Staph. aureus and streptococci.

4.     Activity against G(-) pathogens increases from 1^st to 4^th generations.

5.     Activity against G(+) pathogens decreases from 1^st to 4^th generations.

6.     None are active against Enterococcus or Listeria.

D.    Pharmacology- Elimination by renal filtration and secretion.  Short T1/2 (0.5-1.8 hrs.)          *except ceftriazone and cefoperazone which are excreted in bile and have long T 1/2.

E.     Adverse effects-

1.     allergic reactions:  5-10% of those allergic to PNC will be allergic to 1^st generation Cephalosporins, and ~3% to 3^rd generation.

2.     Local irritation on administration

3.     Renal toxicity

F.     1^st Generation- give good G(+) coverage, but only a few G(-) rods: Proteus, E. coli, and Klebsiella.

1.     cefazolin (Ancef, Kefzol) Administered IM or IV q 6-8 hrs.  Its niche is surgical prophylaxis or post-surgical infection by Staph. aureus.  Does not cross BBB.

2.     cephalexin (generic, Keflex)  Oral administration. Its niche is as a PNC substitute for allergic Pts.  Also for Staph. skin infections.

G.    2^nd Generation-

1.     cefamandole (Mandol) has a methyl thiotetrazole (MTT) side chain.  Its side effects are coagulopathy with prolonged administration due to interference with synthesis of Vit. K-dependent clotting factors, and Antabuse-like reaction with alcohol.  Its niche is prophylaxis for surgical infections.

2.     cefuroxime (Zinacef) IM or IV administration.  Its niches are pneumonias, and skin & soft tissue infections.

3.     cefuroxime axetil (Ceftin) A pro-drug of cefuroxime.  Oral administration for upper and lower respiratory infections.

4.     cefaclor (Ceclor) oral administration. Niches are otitis media, and bacterial URI.

5.     cefoxitin (Mefoxin) administered IM or IV.  Good activity against anaerobes, so used for prophylaxis for abdominal or G/U surgery, PID, endometritis, and septic pelvic thrombophlebitis.

6.     cefotetan (Cefotan) administered IM or IV. Has MTT side chain. Niche same as cefoxitin.

H.    3^rd Generation- penetrate the CNS… use for meningitis.

1.     cefotaxime (Claforan) Administered IM or IV q 6-8 hrs. Decent against Staph. aureus, but not against Pseudomonas.  Its niches are pneumonias, meningitis, and otitis media.

2.     cephtriaxone (Rocephin)  Administered IM or IV q 12-24 hrs.  Interchangeable with cefotaxime with same uses.  Excreted slowly via bile, so you don’t need to adjust for renal failure. However, it may cause sludging of bile in GB or diarrhea.  Niches are home IV therapy, bacterial meningitis, pneumonias, Lyme Dz and drug of choice for gonorrhea.

3.     ceftazidime (Tazidime, Fortraz) Administered IM or IV q 8 hrs.  Active against Pseudomonas, but weak against staphylococci.

4.     cefoperazone (Cefobid) Administered IM or IV q 12 hrs.  Has MTT side chain.  Spectrum similar to ceftazidime.  Excreted in bile.

I.       4^th Generation- Cefepime penetrates CNS and is excreted by kidneys.  Has good activity against Pseudomonas as well as G(-) and G (+) organisms and chromosomal  -lactamases produced by Enterobacter.

II.               Monobactams- Aztreonam effective against G(-) only

A.     Structure- “naked” -lactam ring not fused with any other ring.

B.     Pharmacology- Administered IM or IV.  Renal excretion.

C.    Spectrum- only G (-) rods.  Pseudomonas resistant to ceftazidime will also be resistant to this.

D.    Adverse effects- safe in Pts allergic to PNC, but can cause rash and increased liver enzymes.  There is a possibility of cross-reaction between this and ceftazidime.

III.              Carbapenems- Imipenem & Meropenem

A.     Structure- carbon atom at position one of the 5-membered ring (where PNCs have a sulfur.)

B.     Pharmacology- Administered IM or IV.  Penetrates body fluids well and crosses BBB.  Metabolized by a dihydropeptidase in the kidney tubules.  This enzyme has two effects on imipenem:

1.     lost antimicrobial activity.

2.     Metabolites are mildly nephrotoxic.

To avoid these problems, imipenem is usually administered with cilastatin, an inhibitor of  dehydropeptidase.

C.    Adverse effects- N & V, diarrhea, skin rash, and  seizures, all more likely if administration is too rapid.  This should be given slowly, over at least 45 minutes.  Adverse effects may also occur in Pts with renal failure.  Meropenem has fewer side effects.

D.    Spectrum- active against G(-), G(+), and anaerobic organisms.  The wide spectrum is due to the carbapenem structure, which is resistant to many -lactamases. No activity against MRSA, Stenotrophomonas, or some Enterococcus.

IV.             Glycopeptides- Vancomycin & Teicoplanin (not available in U.S.)

A.     Structure- A tricyclic glycopeptide derived from a soil organism, Amycolatopsis.  It is able to bind to the D-Ala-D-Ala terminus to inhibit cross-linking.

B.     Pharmacology- No oral absorption and painful on IM injection, so its administration is IV q 6-12 hrs.  Well distributed in body fluids , except the CNS, which only gets some if there is inflammation there.  Renal excretion.  Not removed by dialysis.

C.    Adverse effects-

1.     “red man”/”red neck” syndrome- flushing, HA, nausea, urticaria, HypoTN.  Usually seen on first dose given too rapidly due to drug-induced histamine release from mast cells. (Not IgE)  Manage with antihistamines and give vancomycin more slowly.  Less frequent with teicoplanin.

2.     nephrotoxicity- not common now with pure formulations, but can happen if other nephrotoxic drugs are being used concurrently.

3.     auditory toxicity- with prolonged administration of high doses.  Hearing > vestibular.

4.     true allergy- rash, fever.

5.     irritation or local urticaria at injection site

6.     phlebitis.

D.    Niches- G(+) organisms only.  Drug of choice for MRSA, MRSE (epidermidis), severe Staph. or Strep. infections in Pts allergic to PNCs or cephalosporins, G(+) infections in Pts on hemodialysis, home IV therapy, and oral TX for Clostridium difficile-associated colitis (drug stays in gut lumen).    Not effective in some enterococcus that have altered D-Ala structure to D-Ala-D-lactate.

Tags: actamase producers, Carbapenems, Enterobacter, Glycopeptides, gonorrhoeae, Imipenem, Klebsiella, Meropenem, methyl thiotetrazole side chain, nephrotoxic, Pseudomonas, Renal toxicity, Staph Aureus, streptococci

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