DNA Synthesis Inhibitors

• These notes cover inhibitors of DNA, RNA, folate, and nucleic acid synthesis.

Fluoroquinolones

• Mechanism: Inhibit DNA gyrase and DNA topoisomerase IV, blocking DNA replication by forming an enzyme-DNA-drug complex.
• Action: Bactericidal against a wide range of Gram-positive and Gram-negative bacteria.
• Resistance: Bacteria have developed resistance to some older fluoroquinolones.
• Interactions: Oral absorption is inhibited by antacids and FeSO4; increases the anticoagulation effect of warfarin.

Metronidazole

• Mechanism: Reduces reactive drug derivatives, damaging DNA, which is bactericidal.
• Spectrum: Effective against anaerobes, Clostridium difficile, pelvic inflammatory disease, trichomoniasis, used in a four-drug regimen for H. pylori, bacterial vaginosis, and giardiasis.
• Side Effects: Peripheral neuropathy and metallic taste.
• Interaction: May cause a disulfiram-like reaction if alcohol is consumed during treatment (severe flushing, tachycardia, hypotension).

Rifamycins

• Includes: Rifampin, rifabutin, and rifapentine.
• Mechanism: Inhibits RNA polymerase by binding to the beta subunit of DNA-dependent RNA polymerase.
• Spectrum: Concurrent use impacts medications used in critical care and CYP450 interactions. Rapid resistance develops in Mycobacterium tuberculosis if used alone. Used for meningococcal prophylaxis and chemoprophylaxis in contacts of children with H. influenzae type B. Variable Gram-positive activity (Staphylococcus, Epidermidis coag -, MSSA, MRSA +/- depending on infection site).
• Side Effect: Red discoloration of bodily fluids.
• Interactions: Rifampin is a CYP1A2, CYP2C9, CYP2C19, and CYP3A4 inducer, leading to many drug interactions and decreased blood levels of many medications. Rifabutin has a much lower impact.

Trimethoprim/Sulfamethoxazole Combination

• Mechanism: Synergistically inhibits folic acid synthesis at different steps. Sulfonamides compete with PABA to inhibit dihydropteroate synthase, while trimethoprim inhibits dihydrofolate reductase.
• Spectrum: Effective against Gram-positives (MSSA and MRSA), Gram-negatives. First-line drug for treating and preventing Pneumocystis jiroveci pneumonia (PJP).
• Contraindications: Megaloblastic anemia, infants, pregnant/breastfeeding women, and glucose-6-phosphate dehydrogenase deficiency.
• Side Effects: Rash, hypersensitivity ("sulfa"), megaloblastic anemia due to decreased folate, porphyria, hyperkalemia, hemolysis if glucose-6-phosphate dehydrogenase (G6PD) is deficient, photosensitivity, kernicterus in infants if taken during the 3rd trimester, and nephrotoxicity (tubulointerstitial nephritis).
• Interactions: Increases anticoagulation with warfarin and hyperkalemia with ACE inhibitors and ARBs.

Trimethoprim

• Action: Bacteriostatic.
• Mechanism: Inhibits dihydrofolate reductase, preventing the conversion of dihydrofolate to tetrahydrofolate, which is essential for bacterial folic acid production.
• Spectrum: Effective against staphylococci (including methicillin-resistant strains), beta-hemolytic streptococci, and Streptococcus pyogenes. Indicated for tropical bacterial infections (e.g., impetigo) caused by Gram-positive bacteria (like Staphylococcus aureus or Streptococcus pyogenes).
• Side Effects: Superinfection with prolonged inappropriate use.

Sulfamides

• Includes: Sulfadiazine, sulfisoxazole, sulfamethoxazole.
• Action: Bacteriostatic.
• Mechanism: Compete with PABA for binding to dihydropteroate synthase, blocking folic acid synthesis, which bacteria need to make DNA and RNA.
• Side Effects: Rash, hypersensitivity ("sulfa"), megaloblastic anemia due to decreased folate, porphyria, hyperkalemia, hemolysis if glucose-6-phosphate dehydrogenase (G6PD) is deficient, photosensitivity, and kernicterus in infants if taken during the 3rd trimester.

Nitrofurantoin

• Action: Bacteriostatic.
• Mechanism: Reduces reactive drug derivatives that damage DNA and inhibits bacterial RNA, protein, and cell wall synthesis.
• Spectrum: UTIs only (enterococci, BLP E. coli, Klebsiella, H. influenzae, ESBL). Used for treatment of uncomplicated UTIs and UTI prophylaxis.
• Contraindications: Pregnancy at 38-42 weeks gestation, oliguria, anuria, patients less than 1 month old, G6PD deficiency, long-term use.
• Side Effects: Long-term use can lead to peripheral neuropathy, hemolytic anemia, megaloblastic anemia, aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia, pancreatitis, and hepatitis. Short-term includes nausea, vomiting, diarrhea, and brown-yellow urine.

Antipseudomonal Fluoroquinolones

• Includes: Ciprofloxacin, levofloxacin, delafloxacin.
• Spectrum: Gram-positives covered by levofloxacin and delafloxacin, BLP: E. coli, Klebsiella, H. pneumoniae; SPACE, ESBL, CRE +/-, atypical organisms, and delafloxacin covers Pseudomonas aeruginosa and MRSA. Delafloxacin is the only quinolone with MRSA activity. Ciprofloxacin, levofloxacin, and moxifloxacin can be used to treat the plague (Yersinia pestis).
• Side Effects: Photosensitivity, tendinitis/tendon rupture (especially in children under 18), hyperglycemia, peripheral neuropathy, prolonged QT interval, and mental status changes.
• Contraindications: Use with other drugs that prolong the QT interval and in children under 18 and breastfeeding women due to the risk of tendon rupture.
• Interactions: Oral absorption inhibited by antacids, FeSO4, and increased anticoagulation effect of warfarin.

Respiratory Fluoroquinolones

• Includes: Levofloxacin, moxifloxacin, and gemifloxacin.
• Spectrum: Gram-positives (Streptococcus pneumoniae, Streptococcus pyogenes, viridans, and MSSA), BLP: E. coli, Klebsiella, H. pneumoniae; SPACE, ESBL, NO CRE, NO Pseudomonas aeruginosa (except levofloxacin), atypical organisms. Moxifloxacin does not require renal adjustment but cannot be used for UTIs.
• Side Effects: Photosensitivity, tendinitis/tendon rupture (especially in children under 18), hyperglycemia, peripheral neuropathy, prolonged QT interval, and mental status changes.
• Contraindications: Use with other drugs that prolong the QT interval and in children under 18 and breastfeeding women due to the risk of tendon rupture.
• Interactions: Oral absorption inhibited by antacids, FeSO4, and increased anticoagulation effect of warfarin.

Ophthalmic/Otic Fluoroquinolones

• Includes: Besifloxacin, gatifloxacin, ofloxacin, moxifloxacin, and ciprofloxacin.
• Spectrum: Gram-positives (variable), Gram-negatives, ciprofloxacin is active against Pseudomonas aeruginosa, and atypical organisms. Ophthalmic drops can be used for otic infections, but otic drops cannot be used for ophthalmic infections.
• Side Effects: Superinfection with prolonged use and conjunctival and/or otic erythema.
• Contraindications: Use with other drugs that prolong the QT interval and in children under 18 and breastfeeding women due to the risk of tendon rupture.
• Interactions: Oral absorption inhibited by antacids, FeSO4, and increased anticoagulation effect of warfarin.

Dapsone

• Action: Bacteriostatic.
• Mechanism: Inhibits dihydropteroate synthase and competes with para-aminobenzoic acid (PABA), inhibiting bacterial folic acid production.
• Spectrum: Effective against Mycobacterium leprae (leprosy or Hansen disease), Pneumocystis jiroveci pneumoniae (PJP), combined with pyrimethamine and leucovorin for Toxoplasmosis gondii.
• Contraindications: Megaloblastic anemia and in infants and pregnant/breastfeeding women.
• Side Effects: Hemolysis if glucose-6-phosphate dehydrogenase (G6PD) is deficient, kernicterus in infants if taken during the 3rd trimester, and nephrotoxicity (tubulointerstitial nephritis).
• Interactions: Increased anticoagulation with warfarin and hyperkalemia with ACE inhibitors and ARBs.

Fidaxomicin

• Mechanism: Inhibits RNA polymerase, thereby inhibiting RNA synthesis.
• Spectrum: Clostridium difficile, pseudomembranous colitis caused by Clostridium difficile, and prevention of recurrent Clostridium difficile infection in high-risk patients.