Dr. Roane FQ EXAM 2

Question 1

What is considered the old quinolone?

Answer 1

Nalidixic acid

Question 2

What is Nalidixic acid used for?

Answer 2

Simple UTI infections

Question 3

What is the prototype of Fluoroquinolones?

Answer 3

Ciprofloxacain 2nd Gen (Cipro)

Question 4

How are Fluoroquinolones diffrent from Quinolones?

Answer 4

Flourid-atom added to the core structure
-> Improvement in safety and efficacy

Question 5

Spectrum activity of FQ

Answer 5

-Legionella, Salmonella, Shigella
-E. coli, Neisseria (gonorrhea) Proteus sp, Vibrio cholerae, Campylobacter jejuni

BUT IT CHANGES

Question 6

Spectrum activity of FQ by generation

Answer 6

1st GEN: Gram (-) rods
2nd GEN: more Gram (-) rods, Gram (+) cocci, Mycoplasma and Chlamydia

3rd: retain gram (-) and Mycoplasma, Chlamydia; more specific gram (+) cocci

4th: retain gram (-), improves gram (+) cocci and bacilli, gains anaerobic coverage

JUST NEED TO KNOW: Coverage increases with GEN

Question 7

How are Fluoroquinolones classified?

Answer 7

Older group: Ciprofloxacin, norfloxacin, and ofloxacin

Newer group (respiratory FQ): Gemifloxacin, levofloxacin, and moxifloxacin

Question 8

Despite activity against resistant bacteria, what is the downside of FQ?

Answer 8

-variety of serious adverse effects causing multiple FQs to be withdrawn

-Grepafloxacin, Sparfloxacin, Trovafloxin, Gatifloxacin,…

-Delafloxacin (Baxdela): indicated for acute skin infections (ABSSSI) -> Blackbox warning: Tendinitis and tendon rupture, Peripheral neuropathy, CNS effects

Question 9

What is the MOA for FQs?

Answer 9

-Binding and inhibiting DNA Gyrase (gram (-)) and topoisomerase IV (gram (+)) -> involved in unwinding DNA for replication

-Bacteriocidal

Question 10

Where does FQ bind to inhibit the bacteria?

Answer 10

-it binds to the subunit GyrA

-The DNA Gyrase consists of the Gyr A and Gyr B subunit

Question 11

How does the resistance of bacteria against FQ occur?

Answer 11

Ciprofloxacin binds to a specific acid -> after mutation it doesn’t bind anymore

Question 12

Which serious disease is resistant to Ciprofloxacin?

Answer 12

Meningococcal disease caused by Ciprofloxacin-resistant N. gonorrhea (10-14% fatal)

-colonizes mucosal surfaces of the nasal pharynx -> transmitted through direct contact with the nasal secretion of infected patients

Question 13

What is the MOA of Nitrofurantoin?

Answer 13

-When chemically reduced by bacteria, it forms highly reactive free radicals that cause DNA damage in microbes

Question 14

Side effects of Nitrofurantoin

Answer 14

-Colors the urine brown
-Hemolytic anemia in pts. with glucose-6-phosphate dehydrogenase deficiency

Question 15

Why might Nitrofurantoin cause harm to patients with G6PD deficiency?

Answer 15

-G6PD converts NADP+ to NADPH
-NADPH replenishes GSH (Glutathione)
GSSG (oxidized) to GSH (reduced)

-GSH is an Antioxidant which provides protection against free radicals, like those caused by Nitrofurantoin

Question 16

MOA of Methenamine (hexamine)

Answer 16

• At low pH in the urine Methenamine is converted to Formaldehyde -> antiseptic in the UTI (and analgesic) - no resistance against Formaldehyde

-Alternate use: topical for hyperhidrosis, antiperspirant, solid fuel for camping

Question 17

What is the consequence of DNA Replication ahead of the two replication folks?

Answer 17

-Supercoiling
-increased tension

Question 18

How is the tension relieved?

Answer 18

Topoisomerase I: cuts 1 strand -> passes the other strand through the cut -> reseals -> decrease in 1 twist on the supercoil

Topoisomerase 2: cuts 2 strands -> passes another double-strand to the cut -> reseal -> decrease in 2 twists on the supercoil

Question 19

Which bacterial enzymes is responsible for removing superhelical twist on the bacterial DNA?

Answer 19

DNA Gyrase (Topoisomerase II)

-also involved in the initiation of replication and transcription of many genes

Question 20

What does the bacterial DNA Gyrase consist of?

Answer 20

-2x Gyrase A subunits
-2x Gyrase B subunits

Question 21

What is the role of Topoisomerase IV?

Answer 21

Separating the new from the old semiconservative (1 old and 1 new strand) DNA helices

Question 22

MOA FQ Gyrase

Answer 22

-FQ binds to DNA Gyrase and Topoisomerase IV
-It stabilizes the Enzyme-DNA-complex -> breaks in the DNA -> cell death
-Interferes with DNA when binding to DNA Gyrase

Question 23

The Gyrase of which organisms are used as a target for FQ?

Answer 23

Gram-negative bacteria

Question 24

MOA FQ Topoisomerase IV

Answer 24

-In gram-positives (Staph, Strep) - Gyrase as the secondary target

-FQ disrupts the separation between the new and old DNA in the cell -> cell death

Question 25

What affects the potency and spectrum of activity of different FQs?

Answer 25

Affinity to DNA Gyrase and Topoisomerase IV or both

Question 26

How does bacteria require resistance?

Answer 26

-Mutations in chromosomal genes altering target enzymes DNA Gyrase and Topoisomerase IV Frequency: 10^-6

Question 27

What are the factors that affect the activity of FQs after mutation?

Answer 27

Number of mutations, location of the mutations, and which of the enzymes is affected

Question 28

Where do mutations occur in Gyrases and Topoisomerase IV?

Answer 28

Gyrase: gyrA or gyrB genes Topoisomerase IV: ParC or ParE gene -> reduced affinity of FQ for the enzymes

Question 29

Why are FQ antibiotics with similar affinity and potency against both target enzymes beneficial?

Answer 29

Because mutation on both enzymes are required for resistance

Question 30

What kind of improvements were accomplished due to the addition of the Fluor atom to the quinolone structure?

Answer 30

-Potency -Antimicrobial spectrum -Pharmacokinetics -Safety

Question 31

Spectrum of activity of Ciprofloxacin (oldest FQ)

Answer 31

Narrow mainly gram-negative

Question 32

The spectrum of activity of the "newer" FQ

Answer 32

-Gram-negative -Gram-positive: Pneumo cocci -atypical pathogens ->called respiratory FQ

Question 33

What are the respiratory FQs?

Answer 33

-Levofloxacin -Gemifloxacin -Moxifloxacin

Question 34

Common Clinical use of FQ

Answer 34

-Community-acquired pneumonia -UTI -> compromised due to resistance (especially E.coli (most common for UTI) Strep pneumonia Haemophilus influenzae Moraxella spp atypical species