STEPTRACKERPHARMACOLOGY + MICROBIOLOGY | ANTIMICROBIALS | HIGH-YIELD REVIEW

DNA, Folate & Antimycobacterial Drugs

Some antibiotics wreck bacterial DNA or block the folate it's built from; TB needs a multidrug regimen because mycobacteria are slow, hidden and quick to mutate.

FOCUS ON
Fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin): inhibit DNA gyrase (topo II) and topo IV; bactericidal; UTI, pyelonephritis, prostatitis, respiratory (levo, moxi), anthrax, Pseudomonas (cipro). Adverse: tendinopathy/rupture (elderly, steroids), QT, aortic aneurysm, CNS (seizures, delirium), dysglycemia, cartilage damage (children, pregnancy), C. difficile; chelation. Metronidazole: free radicals damage DNA (anaerobes, protozoa); C. difficile (mild), BV, trichomonas, giardia, amebiasis, H. pylori; disulfiram-like reaction, metallic taste, neuropathy. Sulfonamides (block dihydropteroate synthase) + trimethoprim (blocks bacterial DHFR) → TMP-SMX: UTI, PJP treatment/prophylaxis, toxoplasmosis prophylaxis, MRSA skin, Nocardia; adverse — SJS, hemolysis (G6PD), hyperkalemia (ENaC block), ↑ creatinine, kernicterus, marrow suppression, ↑ warfarin. Nitrofurantoin: cystitis; pulmonary fibrosis, neuropathy; avoid low GFR. TB (RIPE): rifampin, isoniazid, pyrazinamide, ethambutol.
DRUG
MECHANISM
USE
SIGNATURE TOXICITY
Ciprofloxacin · levofloxacin · moxifloxacin
DNA gyrase (gram −) and topoisomerase IV (gram +) inhibition
UTI, prostatitis, Pseudomonas (cipro), pneumonia (levo/moxi), anthrax
Tendon rupture, QT, aortic dissection, seizures, glucose swings, myasthenia flare
Metronidazole · tinidazole
Reduced in anaerobes → free radicals break DNA
Anaerobes below diaphragm, BV, trichomonas, giardia, amebiasis, C. difficile
Disulfiram reaction, metallic taste, neuropathy; ↑ warfarin
TMP-SMX
Sequential folate blockade (DHPS + DHFR)
UTI, PJP, toxoplasmosis prophylaxis, MRSA skin, Nocardia, Isospora
SJS, hyperkalemia, ↑ creatinine, hemolysis (G6PD), marrow suppression, kernicterus
Nitrofurantoin
Reactive intermediates damage DNA and ribosomes
Uncomplicated cystitis (incl. pregnancy before term)
Pulmonary fibrosis, neuropathy, hemolysis; avoid if CrCl < 30
Rifampin · rifabutin · rifapentine
Blocks bacterial DNA-dependent RNA polymerase
TB, latent TB (4 months), MRSA adjunct, meningococcal/Hib prophylaxis
Orange body fluids, hepatitis, potent CYP inducer; rapid resistance alone
Isoniazid
Prodrug activated by KatG → ↓ mycolic acid synthesis
TB, latent TB
Hepatitis, peripheral neuropathy (give B6), drug-induced lupus, sideroblastic anemia, seizures in overdose (give B6)
Pyrazinamide
Active at acidic pH (macrophages)
First 2 months of TB therapy
Hepatotoxicity, hyperuricemia (gout)
Ethambutol
Blocks arabinosyltransferase (cell wall)
TB until susceptibility known
Optic neuritis — red-green color loss, ↓ acuity
Bedaquiline · pretomanid · linezolid
ATP synthase · cell wall/NO · protein synthesis
MDR/XDR TB
QT (bedaquiline), neuropathy, marrow
MAC drugs
Clarithromycin/azithromycin + ethambutol ± rifabutin
MAC infection; azithromycin prophylaxis when CD4 < 50 (if not on ART)
Rifabutin uveitis
Leprosy drugs
Dapsone (folate), rifampin, clofazimine
Tuberculoid and lepromatous leprosy
Dapsone hemolysis, methemoglobinemia; clofazimine skin discoloration
Latent TB treatment
Isoniazid + rifapentine weekly (3 mo), rifampin (4 mo), or isoniazid (6–9 mo)
Positive TST/IGRA, normal CXR
Rule out active disease first

Mechanism — folate pathway blockade

PABA → dihydropteroateSulfonamides, dapsone block
→
Dihydrofolate
→
DHFR → tetrahydrofolateTrimethoprim, pyrimethamine (microbes); methotrexate (human)
→
Purines, thymidine

TB drug toxicities

DRUG
MAIN TOXICITY
CLUE
Rifampin
Hepatitis, interactions
Orange urine, tears
Isoniazid
Hepatitis, neuropathy
Give pyridoxine
Pyrazinamide
Hepatitis, gout
↑ Uric acid
Ethambutol
Optic neuritis
Red-green color loss

How it's tested

COMMON CONFUSIONTrimethoprim causes hyperkalemia and a creatinine rise by blocking ENaC and tubular creatinine secretion — not always true AKI.
THE TRAPRifampin with OCPs, warfarin, HIV protease inhibitors or transplant drugs drops their levels — switch to rifabutin in HIV regimens.
YOUR APPROACHInfection site and organism → DNA/folate/mycobacterial drug → special population (pregnancy, child, G6PD, renal) → interactions.

If you see… think…

Achilles tendon rupture after UTI antibiotic in an older patient on steroids → fluoroquinolone
Flushing and vomiting after wine on antibiotic → metronidazole disulfiram-like reaction
Hyperkalemia on PJP prophylaxis → trimethoprim
Pulmonary fibrosis on long-term UTI prophylaxis → nitrofurantoin
Orange tears and urine → rifampin
Numb feet on TB therapy → isoniazid (give B6)
Gout flare on TB therapy → pyrazinamide
Color vision loss on TB therapy → ethambutol
Seizures refractory to benzodiazepines after overdose of a TB drug → isoniazid → pyridoxine
Methemoglobinemia on leprosy/PJP drug → dapsone