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36 Cards in this Set

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What are some host factors that can change the choice of antibiotic based on PK + toxicity?
-pregnancy
-lactation
-prematurity
-renal function
-hepatic function
-age
-allergy
-obesity
-edema
-drug interactions
-reliability
What are some drugs that distribute > ECF? (they enter into cells)
-macrolides
-tetracyclines
-quinolones
-rifamycin
-chloramphenicol
MIC
MBC
PAE
AUC
MIC= minimum inhibitory concentration. The lowest concentration of the drug that inhibits the growth of bacteria in vitro.
MBC- lowest concentration that kills bacteria in vitro. (rarely determined in practice)
“Post-antibiotic effect” (PAE)= growth inhibition that persists after the antibiotic has been removed (almost always assayed in vitro).
AUC (area under the curve)- the integrated sum from a graph of drug concentration vs. time. A measure of the total amount of exposure to a drug.
Which antibiotics have the shortest and longest PAE?
shortest= Beta lactam Ab
longest= aminoglycosides
Bactericidal and bacteriostatic drugs are usually equally effective. What are some indications for Bactericidal?
endocarditis, meningitis, infections in neutropenic patients
what are some classes of antibiotics?
Cell wall synthesis inhibitors
Protein synthesis inhibitors
DNA synthesis inhibitors
RNA polymerase inhibitors
Anti-metabolites
Miscellaneous
What are some cell wall synthesis inhibitors?
Penicillins
Cephalosporins
Carbapenems
Monobactams
Glycopeptides
Describe the core structure of penicillins
Beta-lactam ring is what is in common for all beta-lactam antibiotics
4-membered ring with nitrogen
If you cleave the indicated bond (green arrow), the ring opens up and the drug becomes inactive
All penicillins are modifications at the two indicated sites:site of acylation, and site of salt formation
What do all penicillins have in common?
-Are essentially non-toxic (unless allergy)
-Have short half lives (30-45 minutes) because they are renally excreted by GFR + tubular secretion (renal clearance is more than twice the clearance of inulin)
-Are cross-allergenic
-Do not cross the intact blood-brain barrier well.
Penicillins % oral absorption
Gram Positive Bacteria-no beta-lactamase
Penicillin G & V (15%)
Ampicillin (40%)
Amoxicillin (70%)
MSSA (for methicillin-sensitive S. aureus)
Methicillin
Oxacillin (30%)
Dicloxacillin (50%)
Nafcillin
Gram Positive Bacteria-no beta-lactamase
Penicillin G & V (15%)
Ampicillin (40%)
Amoxicillin (70%)
MSSA (for methicillin-sensitive S. aureus)
Methicillin
Oxacillin (30%)
Dicloxacillin (50%)
Nafcillin
Gram Positive Bacteria-no beta-lactamase
Penicillin G & V (15%)
Ampicillin (40%)
Amoxicillin (70%)
MSSA (for methicillin-sensitive S. aureus)
Methicillin
Oxacillin (30%)
Dicloxacillin (50%)
Nafcillin
Gram Positive Bacteria-no beta-lactamase
Penicillin G & V (15%)
Ampicillin (40%)
Amoxicillin (70%)
MSSA (for methicillin-sensitive S. aureus)
Methicillin
Oxacillin (30%)
Dicloxacillin (50%)
Nafcillin
Gram Negative Bacteria
Ampicillin (40%)
Amoxicillin (70%)
Pseudomonas
Carbenicillin (indanyl)- (35%)
Ticarcillin
Mezlocillin
Piperacillin
Is Penicillin G (Natural penicillin) Still Useful? What BT is it good for?
Prevention and treatment of Group A streptococcal infections (all β-hemolytic Strep.)
Prevention and treatment of syphilis
Endocarditis- viridans streptococci
Meningococcal infections
Actinomycosis
Leptospirosis
Rare cases of β-lactamase (–) S. aureus
β-lactamase stable penicillins
e.g., oxacillin, nafcillin, dicloxacillin
Treatment of S. aureus infections (Not MRSA).
Can be used to treat Streptococcal infections but are not drugs of choice.
Not active against Listeria or Enterococci.
Not active against Gram negative bacteria
MRSA changed its target binding
Aminopenicillins- Amoxacillin and Ampicillin
Active against Gram negative bacteria E. coli, Salmonella, Proteus that do not make β-lactamases.
Active against Gram positive bacteria that do not make β-lactamases.
Can be given orally or i.v.
Absorption: amoxacillin>ampicillin.
Crosses blood-brain barrier better than penicillin; used to treat Listeria and Hemophilus (β-lactamase [-]) meningitis.
Carboxy and Ureido Anti-Pseudomonal Penicillins
Carbenacillin, piperacillin, ticarcillin, mezlocillin
Active against Pseudomonas aeruginosa
Active against most enteric GNR, except those with certain β-lactamases; ureido>carboxy
Not active against β-lactamase (+) S. aureus.
Ureido (piperacillin and mezlocillin) are also active against Enterococci
Only indanyl carbenicillin is orally absorbed but blood levels not high enough to treat systemic Pseudomonas infections; used only for UTI.
Adverse Reactions to penicillins
Rash and other forms of allergy including interstitial nephritis
Reversible neutropenia due to marrow arrest
Hepatitis (nafcillin, oxacillin)
Platelet dysfunction due to coating
Na+ overload (carbenicillin is a disodium salt and used )
Structures of β-lactamase Inhibitors
Clavulanic acid, sulbactam, tazobactam

They all have beta-lactam rings
No intrinsic antibiotic activity, but they bind to the beta-lactamases, acylate them, and inhibit the enzymes that break down the penicillins and cephalosporins!
β-lactamase Inhibitors
Expand the spectrum of penicillins to include many β-lactamase (+) bacteria.
Bind and inactivate β-lactamases by forming a stable intermediate.
Only minor differences in activity among the 3 inhibitors.
What are beta lactamase inhibitors active and not active against?
-Active against β-lactamase enzymes made by: S. aureus, H. influenza, H. ducreyi, M. catarrhalis, B. fragilis, oral anaerobes, E. coli, Klebsiella, and Salmonella, including most ESBL.
-No activity against Pseudomonas, Enterobacter, Serratia, or Citrobacter β-lactamases (AmpC)
Not effective for treating resistance caused by altered PBP, e.g., MRSA, resistant pneumococci, moderately resistant gonococci
What are some similarities and differences between penicillins and cephalosporins?
5-membered thiazolidine ring in penicillin
6-membered dihydrothizine ring in cephalosporin
The drugs are quite similar and have the same mechanism of action
Both inhibit enzymes that cross-link the cell wall
Cephalosporins
Good tissue distribution except CSF
Most are renally excretion by GFR and
secretion.
Variable protein binding- affects t½
Cephalothin, cephapirin and cefotaxime are desacetylated in liver (cefotaxime is still active).
A few are partially excreted in bile
Cefotetan-20%
Cefoperazone-70%
Ceftriaxone-40%
What's the difference between 1st, 2nd and 3rd generation cephalosporins?
Second generation
In general, more activity against some gram negative bacteria
Less activity against Staphylococci than the first generation cephalosporins
Third generation
Much lower MIC for gram negative bacteria
Usually have longer half-lives; easier to use;AmpC-producing organisms only problem;ceftazidime has the most activity against Pseudomonas
-4th generation
Cefepime was developed to be stable to AmpC beta-lactamases
Can treat Enterobacter, Serratia; also very active against Pseudomonas
Fourth generation”
Cefepime - Maxipime
More stable to Gram negative chromosomal β-lactamases, e.g., Serratia, Enterobacter, Pseudomonas. Not completely resistant to those enzymes.
Long half life (2 hours).
Good activity against GPC too.
Cephalosporin Toxicities
Very safe
Small percentage of + Coombs test without anemia
MTT side chains can cause prolonged PT and bleeding, and antabuse reactions (moxalactam, cefoperazone, cefotetan).
Cefazolin
Use as alternative to penicillins for Staph infection
Longer half-life; only have to give it 3x/day (instead of every 4 hours)
Very good activity against beta-hemolytic Strep
Skin infections are commonly combined Staph and beta-Strep, so this is helpful
Cefoxitin and cefotetan
good against Bacteroides; stable against the Bacteroides beta-lacamases
Can be used to treat mixed anaerobic infections, gynecologic infections, intra-abdominal infections
Third generation cephalosporins
drugs of choice for treating Enterobacteriaceae infections, as long as the organisms are sensitive
If they’re ESBL, you obviously can’t use them
Cross BBB so can be better than penicillins for treating meningitis
Exception: Listeria is not an enterococcus, not susceptible to cephalosporins
Pharmocodynamics of Penicillins & Cephalosporins
These drugs should be dosed to keep blood levels at ~4 x MIC. There is no concentration dependant effect.
For Gram negative bacteria very little PAE.
For Gram positive bacteria, a short PAE.
Oral Cephalosporins
Well absorbed with no influence of food; absorption of esters is improved.
Better absorbed than oral penicillins
Excreted like parenteral drugs.
Same toxicities. (minimal)
Widely used because they don’t upset the GI tract (nausea, diarrhea); can be taken 3x/day so patients like them
Not the drug of choice for any infection
Carbapenem Structures
There are 4 carbapenems
Also have a beta-lactam ring
Sulfa group is outside the rings now
Imipenem was invented first
Potent but very unstable; had to add the little side chain to it in order to make a successful product
Newest drugs (doripenem and ertapenem
Carbapenems
Extremely potent, very broad spectrum drugs.
Four parenteral drugs available
Renally excreted (completely); imipenem is renally metabolized (by renal tubular enzyme, so given with a drug that inhibits the enzyme → raises blood level, urine level).
Stable to most beta-lactamases except S. maltophilia and rare B. fragilis isolates.
For the last decade carbapenamases in Klebsiella causing nosocomial infections (update: actually, now seeing carbapenamases in E. coli and Salmonella as well; becoming a huge problem)
Imipenem
Imipenem does cross the BBB and can cause seizures
Entirely related to the concentration in the blood
Cannot be given to anyone at more than 4g/day
Since it’s renally excreted, have to modify dose for patients w/ renal failure
Aztreonam
Active only against facultative Gram negative bacteria.
Not orally absorbed
Inactivated by some Klebsiella & P. aeruginosa β-lactamases, and by inducible β-lactamases in Enterobacter etc.
Poor inducer of β-lactamases
Given i.m. or i.v. 0.5-2.0 gm.
t½-1.5-2 hours so can be given q8h.
Excreted like penicillins
Crosses meninges poorly; not recommended for meningitis.
Very safe; small % diarrhea, rash, transaminases
Not cross allergenic with penicillins
Vancomycin
Large molecular weight glycopeptide; 1,485
Not absorbed from GI tract.
Completely renally excreted in proportion to GFR so long t½ (6 hrs.)
Distributes in body water; irregular penetration into bone.
Dosed at 15mg/kg bid.
Modify dose for renal impairment.
Vancomycin Toxicity
Ototoxicity more likely if blood level >80μg/ml. Heralded by tinnitus.
Red man syndrome: diffuse, itchy, flushed skin, warm feeling immediately after a rapid infusion due to histamine release from mast cells; not an allergy.
Vancomycin Uses
Use it orally to treat C. difficile diarrhea
Anaerobe in colon; makes toxin that causes colitis
Big problem in hospitals
Very toxic in soft tissue, so can’t use it IM
IV only, but don’t ever want it to extravasate into the patient
One of the drugs we use for treating MRSA
Dalbavancin Activity
Gram + bacteria including:
All S. aureus
Enterococci, but not VRE
Streptococci including S. pneumoniae
Gram + anaerobes including C. difficile
No Gram negative bacteria
Not orally absorbed
Only 20-30% renally excreted
Very small volume of distribution (extra-cellular)
95% protein bound to albumin
Very long T½ (150-250 hrs.)
Given once a week- convenient but prolonged exposure to sub-therapeutic levels may → acquired resistance.
Only studied for skin and soft tissue infections