Quinolones & Folic Acid Antagonists

Sulfonamides

• Common organisms include Enterobacteriaceae, Haemophilus influenzae, Streptococcus spp., Staphylococcus spp., and Nocardia
• Sulfonamides are effective against these organisms
• Bacteria that obtain folate from their environment are naturally resistant to sulfa drugs
• Acquired bacterial resistance to sulfa drugs can arise from plasmid transfers or random mutations
• Resistance may be due to:
  • Altered dihydropteroate synthetase
  • Decreased cellular permeability to sulfa drugs
  • Enhanced production of the natural substrate, PABA
• Organisms resistant to one member of this drug family are resistant to all

Sulfonamides Pharmacokinetics

• Most sulfa drugs are well absorbed following oral administration
• Sulfasalazine is not absorbed when administered orally or as a suppository and is reserved for the treatment of chronic inflammatory bowel diseases
• Intestinal flora split sulfasalazine into sulfapyridine and 5-aminosalicylate, with the latter exerting the anti-inflammatory effect
• Absorption of sulfapyridine can lead to toxicity in patients who are slow acetylators
• Intravenous sulfonamides are generally reserved for patients who are unable to take oral preparations or have severe infections

Urinary Tract Antiseptics/Antimicrobials

Methenamine

• Mechanism of action: Methenamine salts are hydrolyzed to ammonia and formaldehyde in acidic urine (pH ≤ 5.5)
• Antibacterial spectrum: Methenamine is active against E. coli, Enterococcus spp., and Staphylococcus spp.
• Pharmacokinetics: Methenamine is orally absorbed, with up to 30% decomposing in gastric juices, unless protected by enteric coating

Nitrofurantoin

• Introduced into clinical practice for the management of cystitis in the early 1950s
• Works by inhibiting DNA and RNA synthesis
• Susceptible organisms include E. coli, Klebsiella spp., Enterococcus spp., and Staphylococcus spp.
• Common adverse effects leading to discontinuation are nausea, vomiting, headache, and dizziness
• Carries boxed warnings for tendinitis, tendon rupture, peripheral neuropathy, and CNS effects (hallucinations, anxiety, insomnia, confusion, and seizures)

Fluoroquinolones

• Discovery led to the development of numerous compounds utilized in clinical practice
• Modifications of the quinolone nucleus expanded the spectrum of activity, improved pharmacokinetics, and stabilized compounds against common mechanisms of resistance
• Unfortunately, overuse resulted in rising rates of resistance in gram-negative and gram-positive organisms, increased frequency of Clostridium difficile infections, and identification of numerous untoward adverse effects
• Consequently, these agents have been relegated to second-line options for various indications

Fluoroquinolone Pharmacokinetics

• Binding to plasma proteins ranges from 20% to 84%
• Distributes well into all tissues and body fluids
• Concentrations are high in bone, urine (except moxifloxacin), kidney, prostatic tissue (but not prostatic fluid), and lungs as compared to serum
• Penetration into cerebrospinal fluid is good, and these agents may be considered in certain central nervous system (CNS) infections
• Accumulation in macrophages and polymorphonuclear leukocytes results in activity against intracellular organisms such as Listeria, Chlamydia, and Mycobacterium
• Most fluoroquinolones are excreted renally; dosage adjustments are needed in renal dysfunction
• Moxifloxacin is metabolized primarily by the liver, and while there is some renal excretion, no dose adjustment is required for renal impairment

Fluoroquinolone Adverse Reactions

• Common adverse effects leading to discontinuation are nausea, vomiting, headache, and dizziness
• Carry boxed warnings for tendinitis, tendon rupture, peripheral neuropathy, and CNS effects (hallucinations, anxiety, insomnia, confusion, and seizures)
• Patients taking fluoroquinolones are at risk for phototoxicity resulting in exaggerated sunburn reactions
• Patients should use sunscreen and avoid excessive exposure to ultraviolet (UV) light