38- Antimicrobials & Antimicrobial Resistance

if we dont induce antibiotic resistant bacteria, what happens?

bacteria is constantly mutating and we selectively encourage bacteria growth w mutations that increases survival in presence of an antibiotic

whats constitutive resistance

bacteria are resistant to antibiotic bc they lack uptake system or targets of the antibiotic

unrelated to prev antibiotic exposure

ex of constitutive resistance

Penicillin G cannot enter Enterobacteriaceae

Aminoglycosides need active transport system which are not present in anaerobes so obligate anaerobes are resistant to aminoglycosides

whats acquired resistance

bacteria become resistant to antibiotics by mutation resulting in alteration of uptake systems or targets of antibiotics

is dependent on prev exposure

ex of acquired resistance

Staphylococci resistance to penicillin G (enzymes that inactivate antibiotic)

what are the 3 basic mechanisms for how acquired resistance works

1. alter drug target

2. alter drug uptake

3. inactivate the drug

describe 1. alter drug target

modify target site w methylation of rRNA

reduce significance of target site w development of alternative pathways

describe 2. alter drug uptake

inhibit uptake (decrease pore size) and increase excretion (tetracycline)

describe 3. inactivate the drug

synthesis of inactivating enzymes

-beta lactamase for penicillin/cephalo

-acetyl transferase w makes chloramphenicol into a non binding form

some bacteria produce beta lactamase enzymes. what does this do?

destroys/ deactivates beta lactam antimicrobials

describe multi antibiotic resistance

mult diff resistance mechanisms = diff classes

constant drug use eliminates sens cells

describe cross resistance

resistance due to a common mechanism so that resistance to one antibiotic implies resistance to others = same class

describe cross resistance: aminoglycosides

its unidirectional. Newer aminoglycosides have greater stability to destruction by enzymes than older

EX: resistance to amikacin (newer) implies resistance to older aminoglycosides (gentamicin)

describe cross resistance: B lactams

an organism could be resistant to several B lactams via production of B lactamase

EX: penicillin, ampicillin, cefazolin

what are the 2 basic mechanisms by which bacteria ACQUIRE resistance

1. changes in DNA via mutation

2. acquisition of DNA

describe acquired resistance via mutations

changes in genotype / DNA- most freq arise as errors during replication

*most mutations are lethal

acquired resistance via mutations are almost always lethal. when theyre not, they may…

1. confer selective disadvantages and be lost over time

2. no advantage and maintained at low levels

3. selective advantage - inc in population until they become dominant type

REMEMBER, antibiotic resistance only confers selective advantage IF…..

antibiotics are present (selective pressure)

-1 mutant w selective adv in a pop of 10^7 bacteria will overgrow the wild type in days

describe acquired resistance via genetic transfer

transfer of DNA b/t strains of a given species, diff species, or diff genera

*generates genetic diversity

*critical mechanism for bacterial adaptation to changing environment and host conditions

transformation of DNA transfer is important in what and involves what 2 mechanisms?

imp in antibiotic resistance and is responsible for multi-antibiotic resistance

2 mechanisms: transduction and conjugation

describe transduction of acquired resistance

transfer of DNA after bacteriophage infection

-bacteriophage DNA is integrated into bacterial chromosome

EX- transfer of a B lactamase from a resistant to susceptible S auerus

acquired resistance: once inside….

it integrates

1. entry

2. circulation

3. integration

4. replication

describe conjugation of acquired resistance

interbacterial DNA transfer thru sex pillus

plasmids can encode:

1. pilli genes

2. exotoxins

3. MULT antibiotic resistant genes (R plasmids)

plasmids usually encode factors NOT essential for growth and replication

how does bacteria transfer resistance during bacterial division and conjugation?

bacterial division- vertically

conjugation- horizontally

how can plasmids be transferred?

within a bacterial species, b/t species, b/t genera

-rare in g pos orgs

-common in g neg orgs esp enterobactio

EX- transferable drug resistance in salmonella

describe antibiotic selection

basis for selecting antibiotic thats effective against bacteria

1. gram related spectra (penicillin for + and gentamicin for -)

2. historical data (tetra for ricket, penicillin for strep)

3. in vitro sens and antibiotic sens testing

define susceptible

an infection due to the isolate may be treated in body sites w the recommended dosage

define resistant

resistant isolates are not inhibited by the usual achievable concentration of a drug and not reliable in tx

define intermediate

an infection due to the isolate may be treated in body sites where high dosage of drug can be used

what are the clinical considerations for prescribing antimicrobial drugs

toxicity

drugs may be toxic to kidneys, liver, nerves

quinolones should be careful w pregnancy

allergies

what are the diff routes of admin for antimicrobials

1. topical for external

2. oral

3. IM

4. IV

   1. know how the agent will get to infected tissues

effect of admin of chemo agent on oral, IM, IV

oral- steady concentration in blood

IM- sharp inc at first then steady

IV- continuously high

strategies for limiting bacterial resistance

1. surveillance systems for data collection

2. use antimicrobial susceptibility test

3. strict drug withdrawal periods

4. maintain high concentration in pt

5. use antibiotics only when necessary

6. use antimicrobials in combo (peni plus tetra)