Drug Mech Exam 1

An antibacterial agent, is a molecule (synthetic or natural) capable of selectively inhibiting growth or survival of one or more species of micro-organism at low concentrations.

Minimum Inhibatory Concentration of an antibiotic, concentration which completely prevents the growth or survival of a micro-organism

Lowest concentration of an antibiotic to produce an effect

MIC measures potency(concentration)

dec. MIC, inc. potency

Dose to acheive a plasma concentration of ~ 4 to 8 times the MIC value.

Clinical dose must be associated with minimum or no toxicity to patient.

Dose of antibiotic used to treat infection in patient must have a high selectivity to bacterial cells for toxicity.

antibiotic that inhibits bacterial growth at the clinical dose

Inhibits bacterial cell growth, cell division, but bacteria is still alive

antibiotic that kills the bacteria at the clinical dose

• Tetracyclines
• Sulfonamides

• Penicillins
• Aminoglycosides
• Polypeptides
• Quinolones

Not really, because there are other factors invovled that affect the "effect" of the antibiotic

ex: tetracycline and aminoglycosides have same outcomes, but different binding sites, concentrations, doses.

Not really becuase two drugs can be -cidals but have different mechanism of actions

At the clinical dose, will inhibit cell division (growth) of microorganism. Bacteria will survive, but will stop multiplying.

Immune system will then kill off the bacteria

At the clinical dose, will inhibit the survival of microbes. (kills)

The prerequisite of a bacterial strain for the antibiotic's ability to exhibit its static/cidal effect.

The antibiotic will work against the bacteria.

• 1. Concentration (Dose)
• 2. Mechanism of Action
• 3. Microbial Susceptibility/Resistance
• 4. Microbial Species

(Concentration (is most impt) and Mechanism of Action are the two most important)

YES, if the antibiotic is given in high enough doses to kill all bacterial cells

Yes, majority of antibiotics have a -static and -cidal doses.

Yes, for only a few antibiotics, since their mechanism of actions are devestating to the bacterial cells.

ex: inhibiting cell wall synthesis (penicillin, vancomycin, polypeptides, polymixin B)

Bacteria must be susceptible withOUT resistance

YES, because of antimicrobial resistance. However, only in drugs with 2 effects or "targets."

ex: Senersid, antibiotic with 2 drug components, inhibits by 2 mechanisms of actions. Resistance at one binding site but NOT the other, therefore more "static" effect and no longer "cidal."

-If the difference between the "static" and "cidal" dose is HUGE, this means the cidal does is toxic to patients, and the clinical dose should be the "static" dose.

-If the difference between the "static" and "cidal" dose is SMALL, this means the cidal dose is not very toxic to patients, and the clinical dose should be "cidal" dose.

• Use "statics" if:
• -treating mild infections in outpatients

-ONLY used in immunocompetent patients

-Patients should NOT skip doses or stop taking (regardless if static or cidal drug)

• Use "cidals" if:
• -Patients have severe/life threatening infections

• -Patients are immunoCOMPROMISED
• -
• -Patients should NOT skip doses or stop taking (regardless if static or cidal drug)

affects only a limited number of baterial species/strains. Either just gram pos or just gram negs.

Minimizes the emergence of microbial resistance

Should always be used when possible because they are cheaper and lead to lesser resistance.

affects a large number of bacterial strains/species. Includes gram pos and gram negs.

Use only when ABSOLUTELY NECCESSARY, to minimize resistance.

invovles use of two or more antibiotics to treat infection

1. Provide broad spectrum empiric (inital) therapy in very ill patients

2. Treat polymicrobial (mixed) infections

3. Obtain ENHANCED activity for therapy (synergism)

1. increased overall toxicity

2. increased cost

3. Antagonism (some combintions=antagonistic)

4. Emergence of microbial resistance through selection

Enhanced effect of two drugs when given together, vs. each drug by itself.

Marked by FOURFOLD or greater REDUCTION in MIC of each drug when used in combination vs. when used alone. (dec. MIC, INC. Potency)

FIC <0.5

Combined INHIBATORY or killing effects of two or more drug. Effects are significantly LESS than expected with used together vs. when used alone.

FIC >4

COMBINED inhibitory or killing effect is the same when used together or alone.

FIC between 0.5 and 4 (0.5 <x>4)

Fractional Inhibitory Concentration Index

FIC index = FICa + FICb

• FICa=MIC drug a in combination
• MIC drug a alone
• FICb=MIC drug b in combination
• MIC drug b alone

• Synergism: <0.5
• Antagonism: >4
• Indifference: between 0.5 and 4

1. Blockage of sequential Steps in a metabolic pathway (combination antibiotic with 1 antibiotic inhibiting a step in a pathway, and the 2nd antibiotic inhibiting the next right after in the SAME pathway)

2. Inhibition of Enzymatic Inactivation (ex: some antibiotics inhibit certain enzymes in a bacterial cell that can inactivate antibiotics. Clavulanic acid inactivates B-lactamase to allow Amoxicillin to work)

3. Enhancement of antimicrobial agent uptake by bacterial cells (Penicillin breaks down cell wall to allow aminoglycosides to work; amphitercin pokes holes in fungi to allow fluoroquinolones to inhibit DNA/RNA synthesis)

4. Binding of ONE antibiotic ENHANCES the binding of another antibiotic (Senersid: binding of first drug enhances binding of second drug)

1. Inhibition of CIDAL drugs by STATIC drugs (static drugs stop cell division, but many cidal drugs need the cell to divide in order for it to work.) BUT keep in mind the MECHANISM OF ACTION of static/cidal drugs. ex: tetracyclines (static) and aminoglycosides (cidal), but they are INDEFERENT.

2. Induction of enzymatic inactivation. ex: some antibiotics induce production of certain bacterial enzymes that may inactivate the second antibiotic. ex: Penicillin (B-lactam) and Imipenem (induces B-lactamases)

-resistance is an increasingly important public health concern and factor in ALL hospital-acquired (nosocomial) infections and community acquired infections.

-Microbial resistance is EVOLUIONARY.

-Rapid emergence and dissemination of MDR strains.

1. Microbes ADAPT quickly to new environments

2. Microbes have SMALL number of genes, and single random gene mutations can have large impact on properties

3. Microbes replicate fast, and evolve fast

4. A mutation that helps a microbe survive can quickly become predominate throughout population

5. Microbes can get genes, including resistant genes, by direct transfer from their own species and from other species

6. Widespread and Inappropriate use of antibiotic theraypy (antibiotic use for viral infections, improper dosage, lack of bacterial information on organism, use of antibiotic in animal feed, antibiotics as OTC products in other parts of the world)

7. Patient NONCOMPLIANCE

Some people order their drugs from out of the country, and microbes can be easily transfered with international travels.

1. Drug inactivation by enzymes- bacteria can make enzyme that inactivates the antibiotic

2. Target Modification (chromosomal mutation)- result of spontaneous mutation on chromosome, leading to ability of bacteria to change chemistry of the "binding site" for the antibiotic.

3. Alteration in Target Accessibility- reducing permeability or increasing efflux of drugs with pumps. bacteria deny drug access to target inside the cell.

4. Development of Altered Metabolic Pathways- bacteria finds way to bypass the area in the metabolic pathway that is targeted by the antibiotic (bypass step that drug inhibits)

A combination of two or more mechanisms can exist in a single bacterial strain.

1. Nongenetic origin (nonmultiplying organism)

2. Genetic origin (resistant genes)

occurs in non-multiplying organisms, when bacteria stops dividing, they become harder (more resistant) to kill by mostly all antibiotics

EX: TB can be dormant for years in lung tissues, once immune system decreases, TB can multiply again and now can be treated with antibiotics

1. Chromosonal Resistance - gene mutation resistance located on chromosomes

2. Extrachromosomal Resistance - gene resistance located on plasmid

-Caused by a spontaneous mutation, occurs on bacterial chromosome

-Resistance becomes predominant in microbial population through SELECTION

-Lead mainly to TARGET MODIFICATION as the resistance mechanism

-Transfered by R-Factor (plasmids that contain genes encode for resistance)

-Leads mainly to DRUG INACTIVATION BY ENZYMES as the resistance mechanism

1. Transformation - direct insertion of R-Factor into a bacterial cell (not very common)

2. Transduction - R Factor are transfered via a virus

3. COnjugation -mating between bacterial cells (between species or non species can occur)*the most important mechanism that contribut to resistance

4. Transposition - transfer of R Factor when the gene is located on "transposons" (jumping genes- change locations) R Factor will jump and be incorporated in choromosmes leading to Chromosomal resistance