DNA, RNA, Folate, and Nucleic Acid Synthesis Inhibitors

DNA, RNA, Folate, and Nucleic Acid Synthesis Inhibitors

• These target DNA, RNA, and folate, disrupting nucleic acid synthesis.

Fluoroquinolones

• Inhibits DNA gyrase and DNA topoisomerase IV, blocking the DNA replication apparatus by forming an enzyme-DNA-drug complex.
• Resistance has developed over time, reducing effectiveness against certain pathogens.
• It is effective against a broad range of bacteria, including Gram-positive and Gram-negative pathogens.
• Oral absorption is inhibited by antacids and FeSO4 while increasing the anticoagulation effect of warfarin.

Metronidazole

• Reduces reactive drug derivatives that damage DNA and is bactericidal.
• It is effective against anaerobes, Clostridium difficile, pelvic inflammatory disease, trichomoniasis, and bacterial vaginosis. It is also part of the four-drug regimen for H. pylori and is effective against giardiasis.
• Side effects include peripheral neuropathy and a metallic taste.
• Alcohol use during treatment can cause a disulfiram-like reaction (severe flushing, tachycardia, hypotension).

Rifamycins

• This class includes rifampin, rifabutin, and rifapentine.
• Inhibits RNA polymerase by binding to the beta subunit of DNA-dependent RNA polymerase and is bactericidal.
• Concurrent use impacts medications used in critical care due to CYP450 interactions, and rapid resistance develops with Mycobacterium tuberculosis if it is used alone.
• Used for meningococcal prophylaxis and chemoprophylaxis in contacts of children with H. influenzae type B and has variable Gram-positive activity.
• Causes red discoloration of bodily fluids.
• It is a CYP1A2, CYP2C9, CYP2C19, and CYP3A4 inducer with many drug interactions, decreasing blood levels of many medications (primarily with rifampin, less so with rifabutin).

Trimethoprim/Sulfamethoxazole Combination

• Inhibits folic acid synthesis at different steps in the pathway, working synergistically.
• Sulfonamides compete with PABA inhibiting dihydropteroate synthase and trimethoprim inhibits dihydrofolate reductase.
• It is effective against Gram-positive organisms like MSSA and MRSA and Gram-negative organisms; it is the first-line drug for treating and preventing Pneumocystis jiroveci pneumonia (PJP).
• Contraindicated in megaloblastic anemia, infants, pregnant/breastfeeding women, and glucose-6-phosphate dehydrogenase deficiency.
• Side effects include rash, hypersensitivity to "sulfa," megaloblastic anemia, porphyria, hyperkalemia, hemolysis (if G6PD deficient), photosensitivity, kernicterus in infants (if mom takes during the 3rd trimester), and nephrotoxicity (tubulointerstitial nephritis).
• Increases anticoagulation with warfarin and hyperkalemia with ACE inhibitors and ARBs.

Trimethoprim

• Inhibits dihydrofolate reductase, preventing the production of bacterial folic acid (bacteriostatic).
• It is effective against staphylococci (including methicillin-resistant strains), beta-hemolytic streptococci, and Streptococcus pyogenes and is indicated for tropical bacterial infections caused by Gram-positive bacteria.
• Prolonged inappropriate use can lead to superinfection; side effects in humans (like megaloblastic anemia) are rare.

Sulfamides

• This class includes sulfadiazine, sulfisoxazole, and sulfamethoxazole.
• Competes with PABA for binding to dihydropteroate synthase, blocking folic acid synthesis (bacteriostatic).
• Side effects include rash, hypersensitivity to "sulfa," megaloblastic anemia, porphyria, hyperkalemia, hemolysis (if G6PD deficient), photosensitivity, and kernicterus in infants (if mom takes during the 3rd trimester).

Nitrofurantoin

• Reduces reactive drug derivatives that damage DNA and inhibits bacterial RNA, protein, and cell wall synthesis to a lesser degree (bacteriostatic).
• It is only used for UTIs (enterococci, BLP E. coli, Klebsiella, H. influenzae, and ESBL), treating uncomplicated UTIs, and UTI prophylaxis.
• Contraindications include pregnancy at 38-42 weeks gestation, oliguria, anuria, patients less than 1 month old, G6PD deficiency, and long-term use.
• Long-term use can lead to peripheral neuropathy, hemolytic anemia, megaloblastic anemia, aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia, pancreatitis, and hepatitis while short-term use includes nausea, vomiting, diarrhea, and brown-yellow urine.

Antipseudomonal Fluoroquinolones

• This class includes ciprofloxacin, levofloxacin, and delafloxacin.
• It is effective against Gram-positive organisms (levofloxacin and delafloxacin), BLP E. coli, Klebsiella, H. pneumoniae, SPACE, ESBL, CRE (+/-), atypical organisms; delafloxacin covers Pseudomonas aeruginosa and MRSA with delafloxacin being the only quinolone with MRSA activity.
• Ciprofloxacin, levofloxacin, and moxifloxacin can be used to treat the plague (Yersinia pestis).
• Side effects include photosensitivity, tendinitis/tendon rupture (especially in children <18 years), hyperglycemia, peripheral neuropathy, prolonged QT interval, and mental status changes.
• Contraindications include use with other drugs that prolong the QT interval and in children under 18 years and breastfeeding women.
• Oral absorption is inhibited by antacids and FeSO4 while increasing the anticoagulation effect of warfarin.

Respiratory Fluoroquinolones

• This class includes levofloxacin, moxifloxacin, and gemifloxacin.
• It is effective against Gram-positive organisms such as Streptococcus pneumoniae, Streptococcus pyrogenes, viridans, and MSSA; BLP E. coli, Klebsiella, H. pneumoniae; SPACE, ESBL; atypical organisms, but lacks CRE and Pseudomonas aeruginosa coverage (except levofloxacin).
• Moxifloxacin does not require renal adjustment but cannot be used for UTIs.
• Side effects include photosensitivity, tendinitis/tendon rupture (especially in children <18 years), hyperglycemia, peripheral neuropathy, prolonged QT interval, and mental status changes.
• Contraindications include use with other drugs that prolong the QT interval and in children under 18 years and breastfeeding women.
• Oral absorption is inhibited by antacids and FeSO4 while increasing the anticoagulation effect of warfarin.

Ophthalmic/Otic Fluoroquinolones

• This class includes besifloxacin, gatifloxacin, ofloxacin, moxifloxacin, and ciprofloxacin.
• It has variable activity against Gram-positive and Gram-negative organisms; 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 include superinfection with prolonged use and conjunctival and/or otic erythema.
• Contraindications include use with other drugs that prolong the QT interval and in children under 18 years and breastfeeding women.
• Oral absorption is inhibited by antacids and FeSO4 while increasing the anticoagulation effect of warfarin.

Dapsone

• Inhibits dihydropteroate synthase, competing with PABA and leading to inhibited bacterial folic acid production and bacterial growth (bacteriostatic).
• It is effective against Mycobacterium leprae and Pneumocystis jiroveci pneumonia (PJP).
• Contraindications include megaloblastic anemia, infants, and pregnant/breastfeeding women.
• Side effects include hemolysis (if G6PD deficient), kernicterus in infants (if mom takes during the 3rd trimester), and nephrotoxicity (tubulointerstitial nephritis).
• Increases anticoagulation with warfarin and hyperkalemia with ACE inhibitors and ARBs.

Fidaxomicin

• Inhibits RNA polymerase, thereby inhibiting RNA synthesis.
• It is effective against Clostridium difficile, pseudomembranous colitis caused by Clostridium difficile, and is used for the prevention of recurrent Clostridium difficile infection in high-risk patients.