Antibacterial Pharmacology III: DNA Disruptors: Sulfonamides, Fluoroquinolones, Nitroimidazoles

DNA Disruptors

- sulfonamides

- fluoroquinolones

- nitroimidazoles

Sulfonamide agents

- sulfamethoxasole/trimethoprim (SMX/TMP) (Bactrim, Septra)

- sulfadiazine, sulfisoxazole, sulfacetamide

sulfamethoxazole/trimethoprim (SMX/TMP)

- bactrim, septra

- PO, tablet, IV

- SS: 400 mg/80 mg

- DS: 800 mg/160 mg

- ratio of SMX to TMP will always be 5:1

What will Bactrim dosage be based on?

always based on the trimethoprim component

Normal bacterial mechanism: Folic acid

folic acid needed for DNA components (adenine, guanine, thymidine)

SMX/TMP MOA

- SMX inhibits dihydropteroate synthase --> blocks formation of folic acid

- TMP inhibits dihydrofolate reductase --> blocks formation of tetrahydrofolate

- ultimate result is blocking DNA production

- bacetricidal, time-dependent

SMX/TMP Spectrum of coverage for gram (+)

staph spp. including CA-MRSA

SMX/TMP Spectrum can also cover which OTHER pathogens?

- Pneumocystis jiroveci (PJP)

- Toxoplasma gondii

SMX/TMP Clinical Use

- Skin and soft tissue infections (SSTI), especially those caused by community-acquired MRSA

- PJP and toxoplasmosis prophylaxis/treatment in immunocompromised pts (HIV)

- Step-down therapy for severe gram-positive infections

SMX/TMP Metabolism

- weak inhibitor of CYP2C9

- SMX/TMP may increase the anticoagulant effects of Warfarin

SMX/TMP dose adjustment

renal adjustment REQUIRED

SMX/TMP ADRs

- hyperkalemia

- hemolytic anemia in G6PD deficiency

- increased anticoagulant effects of warfarin

SMX/TMP Contraindications

- sulfa allergy

- G6PD deficiency

Which of the following statements regarding sulfamethoxazole/trimethoprim (Bactrim) is correct?

A. SMX works by blocking the formation of tetrahydrofolate (later in the pathway), while TMP blocks the formation of folic acid

B. Instead of SMX/TMP, an alternative agent should be considered in a patient with a serum potassium of 4.9 mg/dL

C. It is safe for a patient with G6PD deficiency to take SMX/TMP

D. The ratio of SMX/TMP is 1:5

B. Instead of SMX/TMP, an alternative agent should be considered in a patient with a serum potassium of 4.9 mg/dL

Fluoroquinolone Medications

- ciprofloxacin IV, PO, ophthalmic, otic

- levofloxacin IV, PO

- moxifloxacin IV, PO, ophthalmic

- delafloxacin IV, PO

Normal bacterial mechanism that fluoroquinolones impact:

- topoisomerase cuts DNA to allow it to untangle

- once untangled, topoisomerase re-ligates strands together

- topoisomerase II: gram-negative bacteria

- topoisomerase IV: gram-positive bacteria

Fluoroquinolone MOA

- fluoroquinolones block topoisomerase

- block topoisomerase II in gram (-) bacteria

- block topoisomerase IV in gram (+) bacteria

- bactericidal, concentration-dependent

Fluoroquinolone spectrum of coverage for gram (+): Respiratory fluoroquinolones

- levofloxacin

- moxifloxacin

- reliable Strep. Pneumoniae coverage

Fluoroquinolone spectrum of coverage for gram (-): What are the ONLY oral agents used for P. aeruginosa coverage?

- levofloxacin

- ciprofloxacin

- ONLY PO agents for P. aeruginosa (rest are IV)

What else do fluoroquinolones cover?

- cover ATYPICAL pathogens

- moxifloxacin has coverage for anaerobic pathogens

Fluoroquinolone Clinical Use

- empiric coverage of complicated UTIs, but increasing resistance

- respiratory infections (CA-pneumonia) for levofloxacin and moxifloxacin

- step-down therapy for severe gram (-) infections

Levofloxacin IV to PO conversion

1:1, same dose and frequency

Absorption of fluoroquinolones is reduced by...

positive cations (Ca, Fe, Mg, Al)

Fluoroquinolone renal

- renal adjustments REQUIRED except moxifloxacin

- moxifloxacin does NOT require renal dose adjustment

Fluoroquinolone ADRs

- tendon inflammation and rupture

- QT prolongation

The physician comes to you, explaining that they are preparing to discharge a pt. They ask for your assistance in converting the pt's IV therapy to oral therapy. The pt was being managed with intravenous levofloxacin, 750 mg once daily for 5 days for community-acquired pneumonia. Today is day 2 o ftherapy. Which of the following doses is appropriate for the patient's outpatient oral levofloxacin management? What other fluoroquinolone could have been used for this lung infection?

A. 500mg po once daily

B. 250mg po once daily

C. 750mg po once daily

D. 750mg po twice daily

- C. 750mg po once daily

- moxifloxacin

Nitroimidazole medications

- metronidazole IV, PO

- tinidazole

Nitroimidazole MOA

- metronidazole is a prodrug

- in an anaerobic environment, the nitro group is reduced into a reactive metabolite that damages DNA so it cant be converted to RNA

- bactericidal, AUC:MIC dependent

Nitroimidazole Spectrum of coverage

- primarily covers anaerobic pathogens

- lacks coverage of gram-positive, gram-negative aerobic pathogens, and atypical pathogens

- RARELY used as monotherapy

Metronidazole IV to PO conversion

1:1

Metronidazole metabolism

- weak inhibitor of CYP3A4

- increases anticoagulant effects of warfarin

Metronidazole renal

NO renal adjustment required

Nitroimidazole ADRs

- metallic taste

- disulfiram-like reaction w/ alcohol

- increased anticoagulant effects of warfarin

T/F: You are working in the inpatient pharmacy and receive an order for IV Metronidazole 500mg TID. After reviewing the patient's labs, you note a serum creatinine of 2.5 mg/dL. Because of renal impairment, this pt may be at risk of toxicity, so an alternative agent should be chosen for anaerobic coverage

FALSE

Which DNA disruptors provide MSSA coverage?

- fluoroquinolones

- sulfonamides

Which DNA disruptor provides MRSA coverage?

sulfonamides- SMX/TMP

Which DNA disruptors provide coverage for P. aeruginosa?

- levofloxacin

- ciprofloxacin

Which DNA disruptors provide coverage for anaerobics?

- moxifloxacin

- metronidazole

Which DNA disruptors provide coverage for atypicals?

fluoroquinolones

Which DNA disruptor is used in PJP & toxoplasmosis prophylaxis/treatment in immunocompromised pts?

SMX/TMP

Which DNA disruptor class can cause QT prolongation?

fluoroquinolones

Which classes of DNA disruptors can increase warfarin's anticoag effect?

- sulfonamides- CYP2C9

- nitroimidazoles- CYP3A4

DNA dirsputors NOT renally adjusted

- moxifloxacin

- metronidazole

T/F: All DNA disruptor classes' MOA are bactericidal

TRUE

What are each of the DNA disruptor classes' MOA's dependent on?

- SMX/TMP - time-dependent

- fluoroquinolons - concentration-dependent

- nitroimidazoles - AUC:MIC-dependent