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Penicillins: Ampicillin (this and all others in this set are B-Lactam antibiotics except vancomycin which is a glycopeptide and aztreonam) A. Mechanism of action  B. Spectrum  C. Distribution D. Excretion F. Adverse Effects G.  Drug Interactions E. Use
A. Mechanism of action:  Inhibits at stage III of cell wall synthesis-crosslinking, affecting PBP(penicillin binding proteins) such as transpeptidase.  As in all cell wall drugs (including vancomycin), these drugs create weakpoints and the bacterial cell will then kill itself using autolysins such as Murein hydrolases

B. Spectrum: ALWAYS for listeria, also drug of 1st choice for group B strep, P. Mirabilis, S. Pneumoniae, B. Burgdorferi, Enterococcus sp, and can be used against (not necessarily 1st choice) spirochetes.

 C. Distribution:  Orally, food decreases bioavailability; administer empty stomach.  Widely distrib in body but poor penetration to CSF, joints, ocular fluids unless inflamm: inc entry and dec active drug efflux by organic acid transport system in the choroid plexus.  

D. Excretion:  Rapidly from the kidneys, mostly due to active secretion in proximal tubule; reduce dose if impaired renal function.

F. Adverse Effects:  Hypersensitivity reactions, most common side effect; manifests as virtually every sort of allergic manifestation- anaphylaxis less common with oral administration.  Occurs due to major and minor determinants.  Major is the metabolite penicillenic acid-reacts irreversibly with sulfhydryl groups or amino residues in tissue proteins to form hapten protein conjugates.  Minor determinants are other breakdown products that can elicit antibody responses different from the major type, people allergic to the minor determinants are more likely to experience and anaphylactic reaction.  Unfortunately, allergy testing is available only for the major determinant (skin testing).  Diarrhea (oral) and skin reaction (injection site) can occur.  Neurologic issues such as seizure, confusion, agitation, coma can occur particularly with high doses (such as may be seen in a pt with renal failure who isn't treated properly).  Finally, ampicillin rash: cause unknown, not allergic rxn, pruritic, maculopapular eruptions with late onset (median 7 days).
G.  Drug Interactions:  Penicillins + aminoglycosides or Penicillins + B-lactamase inhibitors are synergistic, Penicillins + bacteriostatic agents are antagonistic.
E. Use:
Cephalosporins (third generation)
A. Mechanism of action  B. Spectrum  C. Distribution D. Excretion F. Adverse Effects G.  Drug Interactions E. Use
Cefotaxime, Ceftriaxzone

A. Mechanism of action:  B-lactam antibiotics; enhanced activity against  gram-negative bacteria due to inc affinity for PBP's and can better penetrate the CNS. 
 
   B. Spectrum:  Ceftriaxone is best drug for gonorrhea, ceftriaxone of cefotaxime are drugs of 1st choice for meningitis caused by H. influenza, S. Pneumoniae (if meningitis), and gram neg bacteria.  Not necc 1st choice but also affective against B. Burgdorferi and T. Pallidum. REMEMBER, 3rd and 4th gen cephalosporins not effective against LAME (L. monocytogenes, atypicals (chlamydia and mycoplasma), MRSA, and enterococcus.)

  C. Distribution:  MUST BE ADMINISTERED IM AND IV.  Penetrate well into most fluid spaces, even CNS-good for meningitis.

  D. Excretion: Most cephalosporins are excreted unchanged by active transport in the kidney.  Impaired renal fnx will inc half lives; dec dose.  *EXCEPTION: Ceftriaxone also eliminated by biliary secretion so no dosage adjustment needed in renal impairment. 

  F. Adverse Effects: Hypersensitivity reactions same as for penicillins, cross reactive; don't give to patients with a severe reaction of the immediate type to penicillin.  Local reactions at site of administration, nephropathy and tubular necrosis in patients with underlying renal disease or who are taking potentially nephrotoxic drugs (ex: cephalosporin + aminoglycosides)

   G.  Drug Interactions:  Cephalosporins + aminoglycosides = synergistic, cephalosporins + bacteriostatic agents (eg TCN)= antagonistic


E.   Effective against many gram pos and neg bacteria as well as anaerobic.
Cephalosporins (4th generation)
Cefepime  
 Comparable to 3rd-generation cephalosporins but more resistant to some beta-lactamases
Carbapenems- meropenem 
A. Spectrum  B. metabolism  C. Adverse Effects D.  Indications

Administered IV. 
 A. Spectrum:  Very broad; active against most gram neg and pos aerobic and anaerobic cocci and bacilli, highly resistant to most b-lactamases; potent induce of chromosomal cephalosporinase which hydrolyzes 3rd gen cephalosporins- a patient given this will likely be resistant to 3rd gen cephalosporins.  MRSA's have varying susceptibility.

B. metabolism: significant renal excretion; adjust dose in renal failure.

C. Adverse Effects:  Nausea and vomiting, potential for cross reactivity with other beta lactams.
 
D.  Indications:  Meropenem penetrates CNS; useful for bact meningitis, useful for hospital acquired antibiotic resistant infections (reserved for this)
Monobactam- Aztreonam (IM, IV) A. Spectrum  B. metabolism  C. Adverse Effects D.  Indications
A. Spectrum:  Penetrates CNS in presence of inflammation.  Pseudomonas and coliforms.

B. metabolism:  Renal excretion by both glomerular filtration and tubular secretion; adjust dose in renal failure.
 
C. Adverse Effects:  Local reactions at site of injury, no allergic cross-reactivity with other B-lactams.
 
D.  Indications:  USE IN PATIENTS ALLERGIC TO B-LACTAMS with infections caused by pseudomonas or coliforms.
Vancomycin (a glycopeptide) A. Mechanism of action  B. Spectrum  C. Distribution D. Excretion F. Adverse Effects G.  Drug Interactions E. Use
A. Mechanism of action:  Inhibits stage II of bacterial cell wall synthesis at the level of preventing the finished modified disaccharide from being separated from the membrane bound phospholipid and bound to an acceptor molecule (part of existing cell wall).  This is acheived by vancomycin binding D-Al-D-Al at the free carboxyl end.  This creates steric hindrance on the substrate so that it can't be acted upon by peptidoglycan synthetase.

B. Spectrum: Gram positive bacteria (cocci and bacilli)-particularly Mrsa, synergistic with aminoglycosides.   Used in empiric treatment of meningitis until susceptibility is confirmed.  

C. Distribution/D. Excretion: Poorly absorbed from GI tract, usually given by IV infusion.  Widely distributes except for CNS unless meninges are enflamed.  Eliminated by kidneys; adjust dose in patients with renal failure.
 
F. Adverse Effects: "red-neck or red-man syndrome" caused by release of histamine from cutaneous mast cells; related to dose and rapidity of infusion.  Ototoxicity; hearing loss first seen in high frequency range.  Nephrotoxicity, increased risk in pt's with underlying renal disease or those taking potentially nephrotoxic drugs (ex: aminoglycosides)
 
G.  Drug Interactions: E. Use:
Special:  Vancomycin resistance in bacteria is inducible upon exposure if the bacteria has the vanA gene- allows the bacteria to make a d-al-d-lactate terminal instead of d-al-d-al to allow cell wall synthesis to continue.
Inhibitors of B-Lactamase
Clavulanate, sulbactam, and tazobactam. 
Work by binding bacterial beta-lactamase enzymes (these enzymes destroy beta lactam antibiotics) and both inhibit them and irreversibly inactivate them.  Help to potentiate beta lactam antibiotic therapy.
Treatment of Meningitis: A. Community-acquired B.  Nosocomial meningitis 
Empiric treatment is often started before organism identified based on pt history and gram stain.


A. Comm acquired:  Ceftriaxone or cefotaxime + vancomycin.  Vancomycin should be stopped if organism proves to be susceptible to a third-generation cephalosporin or penicillin.  Ampicillin (+/- gentamicin) for L. Monocytogenes.  For neonatal meningitis: ampicillin + ceftriaxone or cefotaxime (with or without gentamicin)

B.  Nosocomial meningitis:  Vancomycin + 4th generation cephalosporin (cefepime), for gram neg bacilli meropenem can be used.
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