Mechanism of Resistance

Question 1

Penicillins

Answer 1

Beta-lactamases (Plasmid-mediated)
Decreased permeability of the drugs through variable outer membranes (chromosome mediated)
Mutant and new PBPs (chromosome mediated)

Question 2

Cephalosporins

Answer 2

Beta-lactamases (Plasmid-mediated)
Decreased permeability of the drugs through variable outer membranes (chromosome mediated)
Mutant and new PBPs (chromosome mediated)

Question 3

Carbapenems

Answer 3

Decreased permeability of the drugs through variable outer membranes (chromosome mediated)
Mutant and new PBPs (chromosome mediated)

Question 4

Monobactams

Answer 4

Decreased permeability of the drugs through variable outer membranes (chromosome mediated)
Mutant and new PBPs (chromosome mediated)

Question 5

Vancomycin

Answer 5

Increase wall thickness (chromosome mediated)

Amino acid substitution D-ala is replaced with D-lactate (chromosome or plasmid mediated transposon)

Question 6

Daptomycin

Answer 6

Unknown

Question 7

Telavancin

Answer 7

Unknown

Question 8

Fosfomycin

Answer 8

Mutations that inactivate the non-essential glycerophosphate transporter

Question 9

Polymyxins

Answer 9

Alteration in the cell membrane lipid polysaccharides leading to intrinsic resistance (Proteus and Serratia)

Question 10

Tetracyclines

Answer 10

Either efflux pump that expels the drug out of the cell, thus preventing intracellular accumulation (transposon in plasmid), or bacterial proteins that prevent the binding of drug to the ribosome (transposon in chromosome or plasmid). Resistance to one drug doesn’t confer universal to all tetracyclines.

Question 11

Glycylcyclines

Answer 11

Over-expression of efflux pumps.

Question 12

Aminoglycosides

Answer 12

• The oxidative transport is not present, so there is no entry to the cell (plasmid mediated) like in P. aeruginosa in case of gentamicin.
• Ribosomal binding site mutations (chromosome mediated)
• Modification and inactivation by enzymes like adenylases, acetylases, phosphorylases (plasmid mediated) which are drug specific, so cross resistance can’t be presumed. Amikacin is the least vulnerable to these enzymes.

Question 13

Macrolides and Ketolides

Answer 13

• Decreased outer membrane penetration (chromosome mediated)
• Efflux pumps (plasmid mediated)
• Methylation of the 23S bacterial rRNA leading to decrease affinity to the 50S ribosomal subunit in G+ve bacteria (plasmid mediated)
• Enzyme inactivation such as phosphotransferase or esterases in G-ve bacteria (plasmid mediated)

Question 14

Fidaxomicin

Answer 14

Unknown

Question 15

Chloramphenicol

Answer 15

Inactivation by acetyltransferase enzyme (plasmid mediated)

Question 16

Clindamycin

Answer 16

• Decreased outer membrane penetration (chromosome mediated)
• Efflux pumps (plasmid mediated)
• Methylation of the 23S bacterial rRNA leading to decrease affinity to the 50S ribosomal subunit in G+ve bacteria (plasmid mediated)
• Enzyme inactivation such as phosphotransferase or esterases in G-ve bacteria (plasmid mediated)

Question 17

Quinupristin/Dalfopristin

Answer 17

• Methylation of 23S bacterial rRNA (Quinupristin)
• Inactivation of Dalfopristin by acetyltransferase enzyme (plasmid mediated)
• Efflux pumps

Question 18

Linezolid

Answer 18

Reduced binding at the target site (S. aureus and Enterococcus spp.)

Question 19

Fluoroquinolones

Answer 19

• Decreased drug intracellular accumulation by decrease the number of porins (chromosome mediated) or by efflux pumps (plasmid mediated)
• Mutant topoisomerase IV and DNA gyrase (chromosome mediated)

Question 20

Sulfonamides

Answer 20

• Altered dihydropteroate synthase or dihydrofolate reductase (chromosome mediated)
• Decreased cellular permeability
• Enhanced production of the natural substrate PABA
• Also bacteria that can obtain folate from their environment are naturally resistant

Question 21

Trimethoprim and pyrimethamine

Answer 21

• Altered dihydrofolate reductase

- Efflux pumpms

Question 22

Methenamine

Answer 22

Unknown

Question 23

Nitrofurantoin

Answer 23

Inhibition of nitrofuran reductase that converts the drug to its highly reactive form (chromosome or plasmid mediated)

Question 24

Isoniazid

Answer 24

• Mutation or deletion of KatG leading to loss of catalse-peroxidase enzyme which is required to activate the drug
• Varying mutations of the acyl carrier proteins
• Over-expression of the target enzyme InhA.
• All are chromosome mediated and cross-resistance may occur with Ethionamide

Question 25

Rifamycins

Answer 25

Mutant RNA polymerase (chromosome mediated)

Question 26

Pyrazinamide

Answer 26

Lack of pyrazinamidase enzyme

Question 27

Ethambutol

Answer 27

Mutation of arabinosyl transferase gene (chromosome mediated)

Question 28

Para-aminosalicylic acid (4-Aminosalicylic acid)

Answer 28

Unknown

Question 29

Capreomycin and Viomycin

Answer 29

Unknown

Question 30

Cycloserine

Answer 30

Unknown

Question 31

Ethionamide

Answer 31

Unknown

Question 32

Dapsone

Answer 32

Unknown

Question 33

Clofazimine

Answer 33

Unknown

Question 34

Bedaquiline

Answer 34

Unknown

Question 35

Polyenes

Answer 35

Decreased ergosterol content of the fungal membrane

Question 36

Flucytosine

Answer 36

Decreased levels of any of the enzymes in the conversion of 5-fluorouracil and beyond or increased synthesis of cytosine can develop during therapy

Question 37

Azoles

Answer 37

- Mutations in the C-14 alpha-demethylase gene that lead to decreased azole binding - Efflux pumps

Question 38

Echinocandins

Answer 38

- Alteration of glucan synthase | - Efflux pumps

Question 39

Squalene epoxidase Inhibitors

Answer 39

Unknown

Question 40

Griseofulvin

Answer 40

Unknown

Question 41

Ciclopirox

Answer 41

Unknown

Question 42

Nitroimidazoles

Answer 42

Unknown

Question 43

Aminoquinolines

Answer 43

Unknown

Question 44

Dehydroemetine

Answer 44

Unknown

Question 45

Artemisinin

Answer 45

Unknown

Question 46

Pentamidine

Answer 46

Unknown

Question 47

Suramin

Answer 47

Unknown

Question 48

Melarsoprol

Answer 48

Unknown

Question 49

Eflornithine

Answer 49

Unknown

Question 50

Nifurtimox

Answer 50

Unknown

Question 51

Sodium stibogluconate

Answer 51

Unknown

Question 52

Miltefosine

Answer 52

Unknown

Question 53

Atovaquone-proguanil

Answer 53

Unknown

Question 54

Pyrantel Pamoate

Answer 54

Unknown

Question 55

Ivermectin

Answer 55

Unknown

Question 56

Diethylcarbamazine

Answer 56

Unknown

Question 57

Praziquantel

Answer 57

Unknown

Question 58

Niclosamide

Answer 58

Unknown

Question 59

Neuroaminidase Inhibitors

Answer 59

Mutations in neuraminidase enzyme

Question 60

Adamantane antivirals

Answer 60

Change in one amino acid of the M2 matrix protein

Question 61

Nucleotide analogs

Answer 61

Unknown or altered or deficient thymidine kinase and DNA polymerases in the case of Acyclovir

Question 62

Protease Inhibitors

Answer 62

Accumulation of stepwise mutations of the protease gene (initial mutations result in decreased ability of virus to replicate, but as the mutations accumulate virions with high levels of resistance emerge)

Question 63

Nucleoside or Nucleotide Reverse Transcriptase Inhibitors (NTRIs)

Answer 63

Mutation in the viral RT codon 184, which confers a high degree of resistance to Lamivudine and Emtricitabin, but restores sensitivity to Zidovudine and Tenofovir. Concomitant use of agents with the same analog target is contraindicted

Question 64

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Answer 64

Mutations in the HIV-1 RT enzyme

Question 65

Entry Inhibitors

Answer 65

Unknown

Question 66

Integrase Inhibitors

Answer 66

Single point mutations within integrase gene. Dolutegravir has limited cross-resistance with other integrase inhibitors

Question 67

Interferons

Answer 67

Unknown