Anti-infective Pharmacogenomics

Question 1

What are the intrinsic factors that influence variable drug response

Answer 1

Pharmacogenomics
Age (peds/geriatrics)
Gender
Body weight
Concurrent illnesses (renal/ hepatic)

Question 2

What are the extrinsic factors that influence variable drug response

Answer 2

Concurrent medications (DDI)
alcohol consumption
Adherence
Lifestyle factors (diet, exercise, smoking)

Question 3

Genetic variability can influence various enzyme that categorized into gene involved in

Answer 3

Pharmacokinetics
Pharmacodynamics
Off target proteins

Question 4

Pharmacokinetics

Answer 4

Proteins related to pharmacokinetics participate in ADME

Question 5

Pharmacodynamics

Answer 5

Proteins are directly associated with the drug target such as receptors

Question 6

Off target proteins

Answer 6

Proteins that are not directly linked to the drugs ADME or primary target yet can influence the drugs response.

Question 7

Goals of pharmacogenomicics in ID

Answer 7

Improve drug efficacy (optimal dosing)
Minimize risk of adverse effects (avoid drug toxicity)
Predict treatment failure due to anti-infective resistance

Question 8

PGX does NOT replace therapeutic use T/F

Answer 8

True

Question 9

What are the two types of genomics in the ID world

Answer 9

Host genomic
Microbial/viral genomics

Question 10

Host genomics

Answer 10

Genetic predisposition to drug toxicity

Genetic predisposition to significantly change drugs metabolism

Question 11

Microbial/viral genomics

Answer 11

Rapidly replicated increases probability of mutation and development of drug resistance

Question 12

What class of antibotic is included in the CPiC medication guidelines

Answer 12

Aminoglycosides
-Amikacin
-Gentamicin
-Plazomicin
-Tobramycin

some gram of positive, mostly gram negative

Question 13

What is the MOA of aminoglycoside

Answer 13

Disrupt protein synthesis by irreversibly binding to 16s of ribosome complex

Question 14

What is the adverse effect associated with aminoglycoside? What is the vareient associated if any?

Answer 14

Nephrotoxicity

Ototoxicity
-MTXRNR1 = higher risk

Question 15

Where does the MT-RNR1 gene reside and also known as ?

Answer 15

Human mitochondrial genome

Mitochondrially encoded 12s ribosomal RNA

Question 16

Genetic alterations in MTRNR1 gene is associated with

Answer 16

Predisposition to aminoglycoside induced hearing loss

Question 17

Genetic alteration in MTRN1 causes 12s rRNA subunit protein to more closely resemble the bacterial 16s rRNA subunit —>

Answer 17

Increase aminoglycoside off target binding

Question 18

MTRNR1 increased risk hearing loss CIPC recommendation

Answer 18

Very high risk

Avoid aminoglycoside antibiotics unless the high risk of permanent hearing loss is outweighed by the severity of the infection and lack of saf or effective alternative

Question 19

MTRNR1 normal risk hearing loss CIPC recommendation

Answer 19

Normal risk

Use aminoglycoside antibiotics at standard doses for the shortes feasible course with therapeutic dose monitoring

Evaluate regularly for hearing loss

Question 20

MTRNR1 uncertain risk hearing loss CIPC recommendation

Answer 20

Weak or no evidence for MT RNR1

Use aminoglycoside antibiotics at standard doses for the shortes feasible course with therapeutic dose monitoring

Evaluate regularly for hearing loss

Question 21

What should you do if there is no effective alternative to an aminoglycoside antibiotic available

Answer 21

Evaluate for hearing loss frequency during therapy

Question 22

What antifungal medication has a CPIC recommendation?

Answer 22

Voriconazole

Question 23

Indication of voriconazole and MOA

Answer 23

Invasive aspergillosis

It impairs fungal growth and proliferation by weakening the fungal cell membrane

Inhibits CYP450 14 a-demethylase , disrupting estrogterol synthesis in fungi

Question 24

What is the gene of interest for voriconazole for the CIPIC guidelines

Answer 24

CYP2C19

Question 25

Voriconazole adverse effects

Answer 25

Hepatotoxicity Neurotoxicity Visual hallucinations Encephalopathy Neuropathy Photopsia Rash Photosensitivity Periostitis

Question 26

What therapeutic concentration rand of voriconazole should be measured after steady state is achieved?

Answer 26

Cmin/ trough Invasive aspergillosis:1-5 ug/ml

Question 27

Individual that metabolizes voriconazole efficiently are at risk for

Answer 27

Treatment failure bc of low trough levels (<0.5) —> sub therapeutic Extentsiom of hospital stay

Question 28

Individual that are NOT able to metabolizes voriconazole efficiently are at risk for

Answer 28

Adverse drug reactions , trough concentration >5-5.5 mg/L —> Supratherapeutic Hepatotoxicity Neurotoxicity Visual hallucinations

Question 29

CYP2C19 ultra rapid metabolized

Answer 29

An individual carrying two increased function alleles

Question 30

CYP2C19 rapid metabilzer

Answer 30

An individual carrying one normal function allele and one increases function allele

Question 31

CYP2C19 normal metabilizer

Answer 31

Individual carrying two normal function alleles

Question 32

CYP2C19 intermediate metabilizer

Answer 32

An individual carrying one normal function allele and one no function allele or one no function allele and one increased function allele

Question 33

CYP2C19 poor metabilizer

Answer 33

Carrying two no function allele

Question 34

Voriconazole dosing recommendations for Ultra rapid and rapid metabolizers

Answer 34

Consider an alternative antifungal agent not affected by CYP2C19 variations Isavuconazole Posaconazole Liposomal amphotericin B Potential SUBtheraputic levels

Question 35

Voriconazole dosing recommendations for poor metabolizers

Answer 35

Consider an alternative antifungal agent not affected by CYP2C19 variations Isavuconazole Posaconazole Liposomal amphotericin B Avoid ADR Potential SUPRAtherapeutic levels

Question 36

What three antiviral medications has CIPIC recommendations

Answer 36

Atazanavir (protease inhibitors)* Abacavir (NRTIs)* Efavirenz

Question 37

What are we concerned with abacavir and what gene/allele is associated with it?

Answer 37

Hypersensitivity reaction HLAB*57:01

Question 38

What is the sensitivity observed with abacavir associated with

Answer 38

Individual gene factors that increase hypersensitivity reactions HLA-B*7:01

Question 39

What is abacavir’s hypersensitivity associated with

Answer 39

Off target effect

Question 40

CPIC recommendation for abacavir who is a carrier of HLA-B*57:01

Answer 40

Significantly increased risk of hypersensitivity Abacavir not recommended

Question 41

CPIC recommendation for abacavir who is a NONcarrier of HLA-B*57:01

Answer 41

Low or reduced risk of hypersensitivity Use abacavir per standard dosing guidelines

Question 42

What is the concern for atazanavir and what is the gene of interest?

Answer 42

Hyperbillirubinemia UGT1A1 (phase ll )

Question 43

What factors increase risk for hyperbilirubinemia

Answer 43

Decrease UGTA1A1 production or function DDI: inhibition of UGT1A1 (ABACTAVIR).

Question 44

What is atazanavir effect?

Answer 44

Off target effect UGT1A1 DOES NOT contribute to metabolism nor PD

Question 45

Recommendation for UGT1A1 for normal/extensive and intermediate metabolizers

Answer 45

No need to avoid atazanavir

Question 46

Recommendation for UGT1A1 for poor metabolizers

Answer 46

Consider alternative agent particularly where jauis of concern to patient