Lecture 8: Inhibitors of DNA Synthesis and UTI

Fluoroquinolones Drugs

Ciprofloxacin

Ofloxacin

Levofloxacin

Moxifloxacin

Delafloxacin

Gatifloxacin

Gemifloxacin

Fluoroquinolones

Inhibition of DNA gyrase (A subunit) and Topo IV

DNA synthesis inhibitor

bactericidal

iron, magnesium, aluminum, calcium ↓ absorption

Fluoroquinolones Spectrum

aerobic G- rods, good G+

Ciprofloxacin- P. aeruginosa

Ofloxacin- prostatitis

Levofloxacin- CAP

Moxifloxacin and Gemifloxacin- anaerobes

Gatifloxacin- ocular application only

Fluoroquinolones Adverse effects

Increase QT interval (cipro least/ moxi highest)

Cartilage erosions in animals

Tendinopathy and tendon rupture

Photosensitivity

Peripheral neuropathy, GBS

Dizziness, toxic psychosis, hallucinations, seizure

Contraindicated in:

Pregnant or nursing women and in children (cartilage damage) <18 years

Myasthenia gravis

Metronidazole

Inhibits DNA synthesis

metronidazole metabolites taken up into bacterial DNA, and form unstable molecules

bacteriocidal

G+ and G- anaerobes

C. difficile, alternate to oral vancomycin

Adverse Reactions:

Disgeusia – metallic taste

Disulfiram-like reaction

Urinary Tract Infections Treatment

Nitrofurantoin

Methenamine

Cefiderocol

Nitrofurantoin and Methenamine

Renally excreted

Achieve high urinary concentrations- Bactericidal activity in the urine – concentration dependent

Require acidic environment to be activated

Nitrofurantoin

damages bacterial DNA

G+ and G- bacteria aerobes

Most Proteus organisms and Pseudomonas are resistant

Oral

Don’t use if creatinine clearance is less than 50 mL/min

colors the urine brown

Adverse effects: pulmonary fibrosis & peripheral neuropathy, hemolytic anemia (in G6PD deficiency)

Contraindications: Pregnancy (38-42 weeks gestation), less than one month of age, impaired renal function, hypersensitivity

Methanamine

Oral, prodrug

Methenamine decomposes to formaldehyde and ammonia in the acid medium of urinary tract

Bactericidal

Bacterial resistance to formaldehyde does not develop

Nearly all bacteria are sensitive

Contraindications: hepatic and renal insufficiency

Cefiderocol

Cephalosporin – ICWS, binds to PBP

Iron-binding enables transport via iron-transport channels

Advantage: ability to overcome common forms of bacterial resistance

Use: Complicated UTI

Gram-negative aerobic microorganisms

Toxicity:

Seizures, GI

Contraindicated in individuals with known hypersensitivity to beta-lactams