Antibiotics that Inhibit DNA Replication and Folic Acid Synthesis

Question 1

How do fluoroquinolone inhibit DNA synthesis

Answer 1

Inhibit replication of DNA by interfering with DNA gyrase AND topoisomerase 4

Question 2

Spectrum of fluoroquinolones

Answer 2

Relatively broad spectrum

Gram positive and negative

Question 3

Precursor of fluoroquinolones

Answer 3

Naladixic Acid.

Question 4

Is overuse of fluoroquinolones leading to resistance?

Answer 4

Yes.

Question 5

How do fluoroquinolones enter bacteria

Answer 5

By passive diffusion. Inhibit replication of DNA by interfering with DNA gyrase AND topoisomerase 4

Question 6

What do bacterial cells use DNA gyrase and topoisomerase 4 for?

Answer 6

Essential for maintaining DNA in a stable and biologically active form that can be replicated. Action of fluoroquinolones leaves DNA strand cleaved.

Question 7

Are fluoroquinolones bacteriostatic or cidal?

Answer 7

Bactericidal activity. More pronounced as the concentration increases.

Question 8

Ciprofloxacin.

• not effective against
• Most potent against
• Drug of choice for

Answer 8

• MRSA
• Most potent against pseudomonas
• Drug of choice for anthrax.

Question 9

Levofloxacin

• Isomer of
• spectrum ?

Answer 9

Isomer of oflaxacin

Borad- Gram positive and negative

Question 10

Moxifloxacin
Enhanced activity against gram __
Poor activity against __
Use for UTI?

Answer 10

Enhanced activity against gram positive
Poor activity against pseudomonas
Does not concentrate in urine, so is not good for UTIs. Rest of fluoroquinolones will work for UTIs.

Question 11

Absorption of fluoroquinolones

Answer 11

Oral absorption is variable. Antacids, iron, zinc, and calcium can interfere.

Question 12

Which fluoroquinolones have the longest half lives

Answer 12

Levofloxacin and moxifloaxacin. Allow once daily dosing.

Question 13

Elimination of fluoroquinolones ?

Exception (moxifloxacin)

Answer 13

Mostly excreted really.

Moxifloxacin excreted by liver

Question 14

Adverse reactions of fluoroquinolones

Answer 14

• GI: nausea, vomiting, diarrhea
• CNS toxicity: drugs bind to GABA receptors. Headaches, dizziness. New FDA warning that has serious mental health side effects.
• Phototoxicity (Not as much as tetracyclines)
• Connective tissue problems. Especially with cartilage.
• FDA warning: Low blood sugar/hypoglycemia.

Question 15

3 FDA warnings for fluoroquinolones

Answer 15

1. Serious mental health side effects due to CNS toxicity.
2. Low blood sugar/ hypoglycemia
3. Now recommending avoiding the use of systemic fluoroquinolones when another alternative exists.

Question 16

The FDA recommended avoiding using systemic fluoroquinolones. What does this mean for eye drops?

Answer 16

Pills- low on list of use.

Eye drops- totally fine. Topically formulations are fine for children even.

Question 17

Avoid fluoroquinolones in who

Answer 17

SYSTEMIC fluoroquinolones. Pregnancy, nursing mothers, and children under 18 as it can cause cartilage erosion. Also avoid in patients with arrhythmia.

Except in cases of cystic fibrosis.

Question 18

fluoroquinolone drug interactions

Answer 18

Ciprofloxacin and ofloxacin increase theophylline levels. (bronchodilator) by interactions with P450.

All other fluoroquinolones raise levels of warfarin, caffeine, and cyclosporin.

Question 19

How do humans and bacteria get folate

Answer 19

Humans get folic acid from diet.

Many bacteria are impermeable to folic acid and make it on their own.

Question 20

Role of folate in cells

Answer 20

DNA and RNA synthesis depends on folate-derived cofactors. Cells cannot grow and divide without folate.

Question 21

Structure of sulfa drugs (Sulfonamides)

Answer 21

Structural analogues of PABA (intermediate in the synthesis of folate)

Question 22

Are sulfa drugs given alone

Answer 22

Rarely.

Question 23

How do sulfa drugs work?

Answer 23

Structural analogs of PABA. Compete with enzyme dihydroptoroate synthetase, an enzyme necessary for folate production and and inhibit it.

Question 24

Sulfa drugs

• Spectrum
• Not active against ___
• _____ is resistant

Answer 24

Wide specturm
Not active against anaerobes
Pseudomonas is resistant
Any organism that can get folic acid from the environment would not be susceptible.

Question 25

Resistance to sulfa drugs

Answer 25

Organisms that can obtain folic acid from the environment are not sensitive. Acquired resistance by altered enzyme, decreased cellular permeability so the drug can't diffuse in, or enhanced production of PABA.

Question 26

Why do you not apply sulfa drugs topically?

Answer 26

Risk of sensitization/rash. | Sulfacetamide available in ocular formation. Similar to gentimyocin. Causes topical allergic rxn.

Question 27

Distribution of sulfa drugs

Answer 27

Bound to serum albumin Penetrate well into CSF Can pass placenta

Question 28

mEtabolism of sulfa drugs

Answer 28

Primarily in liver | Metabolites are without antimicrobial activity but can still be toxic.

Question 29

Excretion of sulfa drugs

Answer 29

Eliminated by kidney and breast milk

Question 30

Adverse effects of Sulfa drugs

Answer 30

1. Crystalluria. Precipitate at neutral or acidic pH. Can cause nephrotoxicity. 2. Hypersensitivities. Rashes, angio-edema, stevens johnson syndrome possible. 3. Hemopoietic disturbances 4. Kernicterus. Increased bilirubin in the CNS. Occurs in newborns. 5. drug potentiation. Increases circulating warfarin levels.

Question 31

Trimethoprim MOA

Answer 31

Inhibits dihydrofolate reductase. Prevents conversion of dihydrofolic acid to tetrahydrofolic acid. Higher affinity for bacterial enzyme than mammalian.

Question 32

Trimethoprim spectrum

Answer 32

Similar to sulfa (broad spectrum gram positive and negative) but more potent. Therefore, can decrease dose.

Question 33

Resistance of trimethoprim

Answer 33

Develops in gram negative bacteria due to presence of altered enzyme.

Question 34

Trimethoprim. Drug is a weak ___. Accumulates in what kind of environments?

Answer 34

Weak base. Accumulates in acidic environments.

Question 35

Trimethoprim adverse effects

Answer 35

Folic acid deficiency. Especially in pregnant patients or those with poor diets (anemia, leukopenia, granulocytopenia) Can co-administer with folinic acid

Question 36

Bactrim is a combo of

Answer 36

Trimethoprim and sulfamethoxazole

Question 37

Why is bactrim a combo of Trimethoprim and sulfamethoxazole

Answer 37

Has greater activity than either drug used alone Similar half lives Drugs work well together Broader spectrum than sulfa drugs

Question 38

When is Bactrim effective

Answer 38

- UTIs - Respiratory tract infections - Pneumocystis jiroveci. Causes pneumonia in immunocompromised patients. - Good against MRSA, especially skin and soft tissue infections.

Question 39

Resistance with Bactrim?

Answer 39

Less frequent. Requires simultaneous resistance to both drugs.

Question 40

Pharmacokinetics of Bactrim

Answer 40

Administered orally Good volume of distribution Excreted via kidney

Question 41

Adverse effects of Bactrim

Answer 41

Skin rash. Especially in elder. Nausea, vomiting. Anemias or thrombocytopenia Caution in patients taking warfarin