Antimicrobial agents and general considerations

Question 1

bacteriostatic

Answer 1

inhibitory concentrations much lower than bactericidal concentrations

Question 2

bactericidal

Answer 2

inhibitory concentrations similar to bactericidal concentrations
must be used when local or systemic host factors are impaired (i.e. chemo)

Question 3

MIC

Answer 3

minimum inhibitory concentration

Question 4

MBC

Answer 4

minimum bactericidal concentration

Question 5

How are MIC and MBC determined? Methods of testing

Answer 5

culture and sensitivity
-disk (innoculum on agar plate) diffusion method; Disk - Inhibition Diameter: set as sensitive, intermediate, resistant
-broth dilution method (VITEK or MICROSCAN); Broth or agar with increasing antimicrobial
concentration –> Inoculated with organism –> Check for growth after 18-24 hours; if clear, bacterial inhibition –> Aliquots of clear tube can be placed in antimicrobial free solution or on agar; conc with no growth is bactericidal

Question 6

Concentration-dependent killing

Answer 6

-rate and extent of killing increases with increasing drug concentration (aminoglycosides, quinolones)

Question 7

time-dependent killing

Answer 7

bactericidal activity continues as long as concentration above the MIC/MBC (beta lactams)

Question 8

Postantibiotic effect (PAE)

Answer 8

persistent suppression of bacterial growth after limited exposure to an antimicrobial agent

• compares the time it takes a bacterial culture to reach logarithmic growth after drug removal vs an untreated culture
• Reasons: recovery after reversible non-lethal damage to cell structures takes time, persistence of drug at binding site or within periplasm, need to synthesize new enzymes before new growth can occur
• may be longer in vivo due to postantibioitic leukocyte enhancement (PALE)

Question 9

empiric antimicrobial therapy

Answer 9

• initial therapy before causative pathogen is known
• covers likely pathogens until infecting organism is identified
• obtain specimen for laboratory - gram stain and culture
• treat based on likely infecting pathogen; goal is to choose drug that is selectively active for most likely infecting microorganism and least likely to cause toxicity

Question 10

definitive treatment

Answer 10

• once infecting microorganism identified
• based on in vitro testing for microbial identified
• use narrowest spectrum available

Question 11

PALE

Answer 11

postantibiotic leukocyte enhancement –> causes the PAE to be longer in vivo

Question 12

Spectrum of action: narrow, broad, extended

Answer 12

i. Narrow - only effective against one class of bacteria
ii. Broad - if they are effective against a range of bacteria
iii. Extended - if a narrow spectrum is modified chemically the new compound is effective against more bacteria than the parent compound

Question 13

Superinfection

Answer 13

Appearance of a new infection during chemotherapy of the primary one. Can happen if you remove normal body flora (they normally produce antibacterial substances (bacteriocins) and they compete for essential nutrients). The more “broad” the effect of the antimicrobial, the greater the possibility that a single microorganism will become predominant, invade the host and produce infection
-ex C. diff

Question 14

Pregnancy safety categorites

Answer 14

A - studies in pregnant women, no risk

B - animal studies no risk, but human not adequate or animal toxicity but human studies no risk

i. Beta lactams: penicillins, BCN + BLI, cephalosporins, astreonam, ertapenem, doripenem, meropenem
ii. Fosfomycin, clindamycin
iii. Macrolides: erythromycin, azithromycin
iv. Metronidazole
v. Nitrofurantoin

C - animal studies show toxicity, human studies inadequate but benefit of use may exceed risk

i. Beta lactams: impenem/cilastin
ii. Ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin
iii. Linezolid, tedizolid
iv. Macrolides: clarithromycin
v. Sulfonamides/trimethoprim
vi. Vancomycin

D - evidence of human risk, but benefits may outweigh

i. Aminoglycosides: Amikagcin, gentamicin, isepamicin, neitilmicin, streptomycin, tobramycin
ii. Tetracyclines

X - fetal abnormalities in human, risk > benefit

Question 15

synergy

Answer 15

total antibiotic activity greater than expected sum of the two (4-fold reduction MIC)
i. Ex) block sequential metabolic steps (TMP/SMX “Bactrim”); inhibitiron of enzymatic inactivation (Beta lactamase); enhanced antimicrobial uptake (aminoglycoside-PCN)

Question 16

Antagonism

Answer 16

antibiotic activity is less than activity of either drug alone
i. Ex) Bactericidal activity inhibited by static drug (Tetracyclin-PCN í PCN blocks cell wall growth but organism needs to be growing for this to work); Induction of enzyme inactivation (induce B lactamase production)

Question 17

indifference

Answer 17

combined antibiotic activity the same as that of the more active drug (broad spectrum abx coverage í neutropenic need broad spectrum)

Question 18

When to use combination therapy

Answer 18

i. Treatment of mixed infections
ii. Broaden empiric coverage
iii. Enhancement of antibacterial activity for specific infections (pseudomonas (?), Strep viridans endocarditis - synergy)
iv. Prevention of emergence of resistant microorganism (Tb)

Question 19

Antimicrobial prophylaxis - examples of when its commonly used

Answer 19

a. To protect healthy persons from acquisition of specific microorganisms
b. Situations: surgical prophylaxis most common, prevention of bacterial endocarditis (pts with strucutural heart problems undergoing dental, surgical, or other invasive procedures), recurrent infections, influenza, recurrent genital herpes simplex

Question 20

Mechanism of resistance: beta-lactams

Answer 20

A) Inactivation by beta-lactamase

1. Most common
2. Hundreds identified (may be specific to type of abtibiotic: penicillinases, cephalosporinases, metallo-beta-lactamase, carbapenemases)
3. Some bacteria produce only one form (staph, H. flu)
4. Some bacteria produce beta-lactamases that hydrolyze both penicillins and cephalosporins (pseudomonas, enterobacter)

B) Alteration in target PCN Binding Proteins (PBPs)- MRSA, strep pneumoniae, enterococci 


1. Reduced affinity - can overcome with very high concentrations
2. Resistance in one organism may result from replacement of its PBP with PBP from resistant organism

C) Permeability barrier preventing penetration of abx- Gram - organisms

1. Can down-regulate porins or not make 

2. Not so critical by itself; important with B lactamase 


D) Efflux pump- Gram - organisms 


Question 21

Mechanism of resistance: vancomycin

Answer 21

i. Modification of the D-ala-D-ala site; terminal D replaced by D-lactate

Question 22

mechanism of resistance: quinolones

Answer 22

i. Mutation of bacterial DNA gyrase (primarily Gram -) or topoisomerase IV (primarily Gram +) Decreased quinolone penetration into bacterial cells (active efflux pump)
ii. Can be inhibited experimentally by reserpine

Question 23

mechanism of resistance: tetracyclines

Answer 23

i. Decreased intracellular concentration due to decrease influx or increased efflux by active transport; plasmid mediated; often multi-drug resistance
ii. Production of proteins that interfere with ribosomal binding
iii. Enzymatic inactivation

Question 24

How has strep pneumonia and MRSA developed resistance to beta-lactams?

Answer 24

Alteration in their target PCN binding proteins
-Alteration in target Penicillin Binding Proteins (PBP’s)
-Reduced affinity – can overcome with very high
concentrations
-Resistance in one organism may result from replacement of its PBP with PBP from resistant organism

Question 25

what is meant by MLS type B resistance

Answer 25

a. Macrolide-lincomycin-streptogramin resistance (Gram +)
b. Production of methylase enzyme that modifies the ribosomal target í decreased drug binding
c. Cross resistance with clindamycin, lincomycin, and streptogramin

Question 26

Desired trough levels for vancomycin

Answer 26

Desired levels: trough 15-20 mcg/ml

Question 27

Desired trough levels for aminoglycosides

Answer 27

Gent, tobra, netilmicin: Peak 5-8 mcg/ml, trough ≤ 2mcg/ ml; Amikacin: peak 20-30 mcg/ml; trough 10 mcg/ml