Therapeutics - Antibiotic Resistance

Front 1

Mechanisms of Resistance

Back 1

1. Enzymatic inactivation
2. Alteration of antimicrobial binding site
3. Active efflux
4. Alterations in membrane permeability
5. Alteration in enzymatic pathways so that targeted enzyme is no longer essential for organism survival
6. Overproduction of antimicrobial targets

Front 2

Beta-lactamase - General

Back 2

-Diverse periplasmic enzymes that evolved from PBP.
-Hydrolyze beta-lactam antibiotics by splitting the amide bond of the beta-lactam ring

Front 3

2 types of beta-lactamases

Back 3

1. Chromosomal (inherent to the microbe genome and is encoded by genes)
2. Plasmid mediated (acquired by organism from extrinsic sources on function pieces of DNA)

Front 4

Beta-lactamase: Chromosomally Mediated-AmpC - General

Back 4

-Not easily transferred to other bacteria
-Preferentially hydrolyze cephalosporins
-Hydrolyze many of the 3rd generation beta-lactams that are resistant to hydrolysis by most plasmid mediated enzymes
-Are resistant to inhibition by beta-lactamase inhibitors

Front 5

Which organisms make Beta-lactamase: Chromosomally Mediated-AmpC (Which typically carry AmpC gene?)

Back 5

Produced by a variety of Gram-negatives:
-Serratia marcescens
-Pseudomonas aeruginosa
-Acinetobacter baumannii
-Citrobacter freundii
-Enterobacter sp.
-also in Morganella and indole positive Proteus sp.
-E. coli (constant basal rate, produced constitutively)

Front 6

Beta-lactamase: Plasmid Mediated - General

Back 6

Develops because of widespread antibiotic use, which increases resistance locally, then spreads nationally, and ultimately worldwide
-New enzymes result from single mutations in existing enzymes
-Plasmid mediated enzymes are always produced constitutively

Front 7

Beta-lactamase: Plasmid Mediated - What do they hydrolyze

Back 7

-penicillins
-cephalosporins
-broad spectrum cephalosporins
-extended spectrum beta-lactams (ESBL's)
-carbapenems

Front 8

What are the 2 main ESBL producing organisms?

Back 8

1. E. coli
2. Klebsiella sp.

Front 9

What are the 2 diseases that ESBL producing bacteria are most often seen in?

Back 9

1. UTI
2. Pneumonia

Front 10

What are the risk factors for infection with ESBL producing pathogens (non-antibiotic)?

Back 10

-prolonged hospital stay
-prolonged ICU or NICU stay
-long-term care facility
-delayed appropriate therapy
-indwelling catheter
-ET or NG tube
-gastrostomy or tracheostomy

Front 11

Risk factors for infection with ESBL producing pathogens (antibiotic risks)?

Back 11

-exposure to 3rd generation cephalosporins (ceftazadime)
-exposure to aztreonam or an aminoglycoside
-exposure to Cipro
-total antibiotic use

Front 12

Treatment for ESBL producing organisms

Back 12

-carbapenems
-beta-lactamase inhibitors (sulbactam, clavulanate, tazobactam)
-aminoglycosides (dependent on MIC)
-cefepime (4th generation)

Front 13

Pseudomonas Mechanisms of Resistance

Back 13

-AmpC cephalosporinase
-beta-lactamase
-metallo-carbapenemases
-outer membrane protein changes
-aminoglycoside modifying enzymes
-quinolone resistance
-efflux pumps
(always smart to treat Gram-negatives with 2 antibiotics with 2 different MOA's)

Front 14

S. aureus Pysiology and Resistance Mechanisms

Back 14

-resistance is attributed to inheritance of a mecA gene found on the mobile staph cassette chromosome mec (SCCmec)
-mecA has been transferred to S aureus over 20 times, resulting in 5 major lineages
-transfer of the mecA gene into S aureus strains already well adapted to survival in hospital and community setting has given rise to 2 major categories of MRSA (health-care associated and community-acquired; there is a difference between the two types)

Front 15

What is the emerging problem with S. aureus?

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-VISA - vancomycin-interediate S. aureus has emerged in MRSA strains (also known as glycopeptide intermediate S. aureus)
-VRSA - vancomycin resistant S. aureus has been reported in 4 cases in the US

Front 16

Intrinsic Resistance - General

Back 16

-inherent properties (cellular membrane, i.e. gram-negatives resistant to vancomycin)
-spontaneous mutation in chromosomal DNA
-an evolutionary process occurring only under selective antibiotic pressure

Front 17

Acquired Resistance - General

Back 17

-occurs via horizontal transfer of resistance genes from other organisms (i.e. by conjugation, transduction, transformation) (examples - plasmids, gene cassettes)
-can be integrated into the bacterial chromosome

Front 18

Acquired Resistance - Examples

Back 18

-ESBL
-MBL
-MRSA
-VRE
-Quinolone resistance
-Aminoglycoside resistance

Front 19

Intrinsic Resistance - Examples

Back 19

-"depressed" beta-lactamase expression
-quinolone resistance
-efflux pumps
-outer-membrane alterations
-VISA

Front 20

Bad Bugs with No Drugs

Back 20

NO ESKAPE
-Enterococcus faecium (VRE)
-Staphylococcus aureus
-Klebsiella pneumoniae
-Acinetobacter baumanii
-Pseudomonas aeruginosa
-Enterobacter spp.

Front 21

What is meant by "Antimicrobial Stewardship"?

Back 21

using the right agent, at the correct dose, for the appropriate duration in order to cure or prevent infection

Front 22

Time Dependent Killers - Examples

Back 22

1. beta-lactams
2. erythromycin
3. clarithromycin
4. oxalidinones
5. vancomycin*
6. clindamycin

Front 23

Concentration Dependent Killers - Examples

Back 23

1. aminoglycosides
2. metronidazole

Front 24

Vancomycin Dosing Goals

Back 24

-blood infections: vancomycin trough 4-5 times the MIC
-invasive infections (CNS, lung, bone): vancomycin trough 8-10 times the MIC

Front 25

Aminoglycoside Dosing Goals

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-depend on site of infection and MIC
-traditional dosing: goal peak of 6-12 with trough less than 2
-extended interval dosing: goal peak usually 8-10 times MIC (dependent on site of infection) with a 4-6 hour non-detctable level

Front 26

D-Test

Back 26

test antibiotic response to erythromycin and clindamycin; basically is a test for the presence of MLS gene; only use clindamycin if there is a full circle of no growth; if there is a D, this shows presence of MLS gene, do not use clindamycin