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Track 2: Antimicrobials I (Dr. McCormick)
TUCA COP 2015
Terms in this set (78)
Microbial-host interactions involve what? (3)
1. Establish infection of host tissues
2. Overcome host immune defenses
3. Virulence factors allow the above to occur
How do microbes establish infection in host tissues?
Adhere, invade, kill host cells
Survive, grow, disperse, colonize new sites
How to microbes overcome host immune defenses?
complement, antibody, natural antibacterials, phagocytes, lymphocytes
What virulence factors allow microbial-host interaction?
exotoxins, endotoxins, capsules, adhesins
"substance made by living organism bactericidal or - static to other organisms"
All major classes of antibiotics have been derived from natural products: first lessons in pharmacognasy
what is the most pathological bacteria of all food born illnesses?
Where does Lysteria infection start?
Infection starts in the gut
Uptake by endothelial cells
How does Lysteria infection work?
Very slow infection:
Pathogens are intracellular
Actively manipulates host cell actin
Move cell to cell via pseudopodia
Avoids the immune system; no serum contact
How can Lysteria infection result in death?
Can lead to CNS infection; sepsis
Define selective toxicity.
Target microbe without harming host
More realistic = target microbe while minimizing host toxicity
What to consider when developing antimicrobials. (7)
1. selective toxicity
2. Killing; or 'cidal or 'static activity
3. Spectrum of activity
4. Pharmacokinetics; drug access to the site of infection (ex: for lysteria, a key element is that the pathogen is INTRACELLULAR)
5. Formulation; oral vs IV
6. resistance development
How do bacteria gain resistance to antimicrobials?
resistance genes on plasmids or chromosome
transfer by bacterial conjugation, viral transduction & transformation
What are the 4 bact resistance mechanisms?
2. reduced permeability
3. alteration of target
4. reduce target importance
What is empiric therapy?
Pathogen not known exactly, but suspected
Therapy based on experience of similar clinical situations
Often based on local bacteria resistance
What are the disadvantages of empiric therapy?
Ineffective, potentially costly
Exposure to unnecessary drug toxicity
Obscuring diagnosis (take samples before therapy, if possible)
What is bacteriostatic?
stop bacterial growth, needs host mechanisms to eradicate infection
***Requires immunocompetent host
Minimal inhibitory concentration (MIC)= minimum serum concentration that causes antibacterial activity
Two types of thresholds:
1. Time dependent
2. Concentration dependent
What are time-dependent antibiotics?
Optimal antibacterial activity when drug concentrations are maintained ABOVE the minimum inhibitory concentration (MIC)
Minimal or no post-antibiotic effect (PAE).
What is the recommended dosing for time-dep antibiotics?
Recommended dosing at 2 to 4 times the MIC throughout the dosing interval
What should you know about higher concentrations of time-dep antibiotics?
Higher concentrations do not result in greater anti-bacterial activity
What are concentration-dependent antibiotics?
Antibacterial activity is optimal WITH INCREASING drug concentration.
What is the PAE of conc-dependent antibiotis?
Concentrations of >10 times the MIC are needed for optimal anti-bacterial effect
Sometimes characterized by single daily dosing
Bactericidal action continues AFTER the serum concentration is LESS than the MIC.
What determines the efficacy of conc-dep antibiotics when looking at a graph?
Peak concentration and area under the concentration curve (AUC) determine efficacy of these antibiotics.
Define PAE (3)
Time during which bacteria are unable to divide because they failed to:
1. Re-synthesize necessary enzymes, either for metabolic activity and/or DNA synthesis
2. Recover from reversible non-lethal structural damage
3. Fight against the persistence or concentration of drug at the drug binding site, periplasmic space, tissue or intracellular location
Which drugs are time-dep with minimal or no PAE?
(these are "cidal" not "static")
Which drugs are conc-dep with PAE?
What is the most important measure of antibacterial efficacy?
Why do you think the PAE matters?
Because it affects the schedule of dosing
What is the bact cell structure?
bacteria = prokaryotic cells (no nucleus)
Different DNA polymerase and translation protein
Either G+ or G- (G+ stain purple bc of PG wall)
How G- structure diff from G+? (5)
1. thinner peptidoglycan
2. strong outer membrane
3. contains phosphoplipid, protein, LPS
(LPS = lipopolysaccharide, endotoxin [sepsis])
4. anchored to peptidoglycan
5. permeability barrier, e.g. porin proteins
What drugs target the PG wall?
Other cell wall synthesis inhibitors
What drugs inhibit protein synthesis in bacteria?
What drugs inhibit DNA synthesis in bacteria?
folic acid & DNA gyrase
Name the antimycobacterials.
Ethambutol or pyrazinamide
B-lactam antibiotics are (3)
2. pennicillins plus b-lactamase inhibitors
How does PG cell wall form in bact?
N-acetylmuramic acid (NAM)
and N-acetlylglucosamine (NAG) are covalenty crosslinked to form peptidoglycan cell wall
What's significant about the cell wall synthesis inhibitor structures?
All have the B ring that is ESSENTIAL for function (the ring looks like a square)
Also can be cleaved by β-Lactamase enzyme = resistance
How do penicillins cause the bacteria to lyse?
B/c Penicillin mimics structure of Ala-Ala, it can bind to the PBP, transpeptidase, and blocks PBP activity and therefore inhibits transpeptidation that cross-links peptidoglycan
***Also stimulate autolysins that break down peptidoglycan
RESULT = cell wall loses rigidity
Which penicillin drugs had narrow spectrum of activity for G+?
Pen G and Pen V
Which penicillin drugs had broad spectrum of activity for G+ AND many G-?
Ampicillin and Amoxacillin (AMINO)
How can bacteria have penicillin resistance? (7)
1. Destruction of agent by beta-lactamases, G+ & G-
2. Reduced permeability, porin protein changes, G-
3. Alteration of penicillin binding proteins = drug receptors; alteration of ratios of PBPs to favor PBP's that have lower drug binding (higher MIC)
4. Lack of a peptidoglycan cell wall, e.g. Mycoplasma
5. Metabolically inactive bacteria, i.e. slow growth rate - chronic infections
6. Lack of activation of autolysins
7. Location of pathogen (intracellular, biofilm) vs drug distribution
In regards to genes, resistance to penicillins if often carried on?
Resistance is oten carried on episomal plasmid DNA
Plasmid exchanged by conjugation, fast population transmission
What is the half life of penicillin?
Most have very short t1/2, which means frequent dosing
How is penicillin administered (parenteral)?
IV route preferred over painful IM = rapid + complete absorption.
How is penicillin administered (oral)?
Absorption varies for different penicillins (e.g. acid stability), allow 1h without food. Some are acid labile and degrade (not suitable for oral use)
How is penicillin distributed in the body?
does enter living cells, but varies by drug polarity
protein binding varies (relationship to efficacy unclear)
How is penicillin eliminated from the body?
Excretion - most are rapidly by kidneys unchanged (10% GF, 90% tubular secretion)
Tubular secretion partially blocked by probenecid - helps elevate serum + CNS levels
reduced doses in kidney failure**
Why are Ampicillin and Amoxicillin better against G-?
more water soluble
better penetration through porins
Great for UTI and upper resp tract infections; orally available (acid stable)
Name an "Antipseudomoanal Penicillin" that also is against G-
= oral form only
Largely replaced by Ticarcillin, Piperacillin
= parenteral dosage forms
Which penicillin is no longer used due to nephrotoxicity?
Which penicillin drugs do not require dosage adjustment in renal failure?
Oxacillin, Cloxacillin and Dicloxacillin (oral and parenteral forms)
What are the adverse effects of penicillin?
1. Hypersensitivity (0.7 - 4% patients)
-Type 1 (IgE-mediated) = most common
-rash, fever, bronchospasm
-various levels of severity
-anaphylactic shock most severe form
2. GI upset common, e.g. ampicillin
Destruction commensal organisms in gut =
Potential for overgrowth of resistant gut flora
Name the B-lactamase inhibitors
clavulanate, sulbactam, tazobactam
What's significant about B-lactamase inhibitors? (3)
1. Irreversibly inhibit B -lactamase
2. have no antibacterial activity alone
3. used in combination with B -lactam antibiotics
ex: Amoxicillin + clavulanate = Augmentin (PO)
How do different cephalosporin generations differ in spectrum of activity?
The two R substitutions give different spectrums of activity
1st Gen are active against?
most active vs. Gram+ bacteria
Strep and Staph A (MSSA only)
(As you go up in class you lose Staph coverage, but gain Strep coverage)
P: Proteus mirabilis
E: E. Coli
K: Klebsiella pneumoniae
2nd Gen are active against?
As active as 1st generation against Staph A
P: Proteus mirabilis
E: E. Coli
K: Klebsiella pneumoniae
3rd Gen are active against?
Gram+ Less active against Staph than 1st and 2nd Gen's
Which generation of ceph can cross the BBB?
3rd gen; will treat meningitis and with aminoglycosides for pseudomonas
4th Gen are active against?
- Less active against Staph A than 1st and 2nd Gen's
- More active against Strep
SA vs ST for each ceph gen
1: G+ SA>St
2: G+ SA>St
What are some adverse effects of ceph?
- cross sensitivity to penicillins [5-15%], empirical
- GI upset common [broad spectrum]
- nephrotoxicity [rare]
Which generation can inhibit Vitamin K production and can prolong bleeding time?
some 2nd generation
What kind of cephalosporins can have a disulfram-like effect?
MTT side chains
What is the disulfram effect?
A drug that blocks the enzyme acetaldehyde dehydrogenase
Taken with alcohol, leads to an accumulation of acetaldehyde in the blood
Acetaldehyde causes hangover symptoms
Any drug that causes this effect is said to have a "disulfram-like" effect; therefore, Need to council patients given oral dosage of MTT cephalosporins about potential side effects with alcohol
The methyltetrazolethiol (MTT) side chain is common to these cephalosporins:
Cefamandole, Cefmetazole, Cefonicid, Cefmenoxime, Cefotetan, Cefoperazone and Ceforamide
How are the bacteria resistant to ceph?
Inactivation by beta-lacatmase (similar to penicillins)
Alterations in PBP reduce efficacy (reduced drug binding)
What is "bacterial cross-resistance"?
Resistance to Penicillins and Cephalosporins is shared
1st and 2nd gen ceph are susceptible to?
plasmid encoded beta-Lactamase
3rd and 4th gen ceph are susceptible to?
less susceptible to plasmid encoded beta-lactamase, but are susceptible to a chromosomal encoded beta-lactamase (type 1) that are specific for cephalosporins
How are 3rd and 4th gen ceph excreted?
excretion by kidney, thus reduce dose in renal failure
exception!!! cefoperazone + ceftriaxone excreted via biliary tract.
What are two MTT related drug side effects?
Inhibition of vitK/increased clotting time and disulfram-like effect (with alcohol)
What kind of antibiotic is vancomycin?
Vancomycin is produced by?
MOA of Vancomycin
stops formation of peptidoglycan chains that form bacterial cell wall
cell membrane function also damaged
Does Vancomycin have a B ring?
Nope...that means it is resistant to B lactamase
What's significant about vancomycin?
bactericidal vs G+
synergistic w/ aminoglycosides (effective against multidrug resistant bacteria)
IV admin, systemic infections [endocarditis]
Used in prevention of infections after surgery
Hospital acquired pneumonia
What is the AE of vancomycin?
"Red Man" syndrome: histamine mediated vasodilation
Can be reduced by slow IV infusion
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