Step 1 · Microbiology

Fluoroquinolones, Folate Antagonists & Metronidazole

Name: Fluoroquinolones, Folate Antagonists & Metronidazole
Creator: Veli Bakalov, MD

DNA breakers, folate starvers, and a drug that only works without oxygen

Microbiology·Pharmacology·4 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

Study materialsNo account needed

Card deckActive-recall cards · quick checks · quiz

High-yield

Fluoroquinolones inhibit DNA gyrase (topoisomerase II) and topoisomerase IV; resistance comes from gyrA/parC mutations and efflux pumps.
Ciprofloxacin covers gram-negative rods including Pseudomonas and anthrax; levofloxacin and moxifloxacin add pneumococcus and atypicals; antacids, calcium, iron and dairy chelate them.
Fluoroquinolones cause tendon rupture (age over 60, corticosteroids, transplant), QT prolongation, cartilage damage (avoid in children and pregnancy), myasthenia flares, dysglycemia, seizures, aortic dissection and neuropathy.
Sulfonamides block dihydropteroate synthase and trimethoprim blocks bacterial DHFR; together TMP-SMX is bactericidal.
TMP-SMX treats UTI, Pneumocystis (and prevents it with Toxoplasma), Nocardia and CA-MRSA skin infections.
TMP-SMX toxicity: SJS/TEN, G6PD hemolysis, kernicterus, crystalluria and warfarin potentiation (CYP2C9); trimethoprim causes hyperkalemia via ENaC, a benign creatinine rise and megaloblastic anemia.
Dapsone treats leprosy and prevents Pneumocystis but causes methemoglobinemia and G6PD hemolysis.
Metronidazole is reduced to DNA-damaging radicals only in anaerobes and protozoa; it treats Giardia, Entamoeba, Trichomonas, BV, B. fragilis and H. pylori and causes a disulfiram-like reaction, metallic taste and neuropathy.
Nitrofurantoin acts only in urine: use for cystitis, never pyelonephritis or CrCl below 30; it can cause pulmonary fibrosis, hepatotoxicity and G6PD hemolysis.

Fluoroquinolones

Mechanism. Ciprofloxacin, levofloxacin and moxifloxacin inhibit DNA gyrase (topoisomerase II), the main target in gram-negatives, and topoisomerase IV, the main target in gram-positives. They trap the enzyme on cleaved DNA, producing double-strand breaks and rapid, concentration-dependent killing. Resistance develops stepwise through point mutations in gyrA and parC, efflux pumps and plasmid-borne qnr genes.

Fluoroquinolones compared

Feature	Ciprofloxacin	Levofloxacin	Moxifloxacin
Pseudomonas	Most active	Active at high dose	No
Pneumococcus and atypicals	Weak	Yes ("respiratory")	Yes ("respiratory")
Anaerobes	No	No	Some
Urine levels	High: UTI, pyelonephritis	High	Low: not for UTI
Renal dose adjustment	Yes	Yes	No

Uses. Ciprofloxacin is the classic oral antipseudomonal drug and treats complicated UTI, pyelonephritis and anthrax. Levofloxacin and moxifloxacin cover S. pneumoniae and the atypicals (Mycoplasma, Chlamydophila, Legionella), which makes them options for community-acquired pneumonia.

Absorption. Oral bioavailability is excellent (about 100% for levofloxacin), so oral dosing often replaces IV. Magnesium and aluminum antacids, calcium, iron, zinc and dairy chelate fluoroquinolones in the gut, so doses are separated by several hours.

Fluoroquinolone toxicity

Tendons and cartilage. Tendinopathy and tendon rupture, classically of the Achilles tendon, are most likely over age 60, with corticosteroids and after kidney, heart or lung transplantation. Because the drugs damage growing cartilage in juvenile animals, they are avoided in children and pregnancy unless no alternative exists (for example, anthrax).

Other serious effects. QT prolongation with torsades risk; CNS toxicity (seizures, delirium, insomnia, especially in older adults); dysglycemia, both hypo- and hyperglycemia in diabetics; exacerbation of myasthenia gravis; aortic aneurysm and dissection; and peripheral neuropathy that may be permanent.

Because of these risks, fluoroquinolones are reserved for infections where safer drugs will not work, and they are avoided in patients with myasthenia gravis or known aortic aneurysm.

Folate antagonists and dapsone

Sequential blockade. Bacteria must build folate from PABA, whereas humans absorb preformed folate and lack the first enzyme. Sulfonamides are PABA analogs that inhibit dihydropteroate synthase; trimethoprim inhibits bacterial dihydrofolate reductase far more strongly than the human enzyme. Each drug alone is bacteriostatic; blocking two steps in sequence makes trimethoprim-sulfamethoxazole (TMP-SMX) bactericidal.

PABA → dihydropteroatedihydropteroate synthase: blocked by sulfonamides and dapsone
Dihydrofolate → tetrahydrofolatedihydrofolate reductase: blocked by trimethoprim and pyrimethamine (methotrexate targets the human enzyme)
Tetrahydrofolate → purines, thymidineDNA synthesis stalls

Uses of TMP-SMX. Cystitis where local resistance allows; Pneumocystis pneumonia, both treatment and prophylaxis (CD4 count below 200/μL); Toxoplasma prophylaxis (CD4 below 100/μL with positive IgG), so one drug prevents both infections; Nocardia; and CA-MRSA skin abscesses. Sulfonamides treat Nocardia, whereas penicillin treats Actinomyces. Dapsone alone and inhaled pentamidine prevent only Pneumocystis, and azithromycin is MAC prophylaxis.

Dapsone. A sulfone that also inhibits dihydropteroate synthase. It treats leprosy (with rifampin, with or without clofazimine), provides Pneumocystis prophylaxis when TMP-SMX is not tolerated, and treats dermatitis herpetiformis. It causes dose-related methemoglobinemia (cyanosis, chocolate-brown blood, pulse oximetry near 85% despite oxygen), treated with methylene blue unless the patient is G6PD deficient, and hemolysis in G6PD deficiency, so G6PD is tested first.

TMP-SMX adverse effects and interactions

Which component causes it?

Effect	Culprit	Mechanism or note
Rash up to SJS/TEN	Sulfamethoxazole	Sulfonamide hypersensitivity
Hemolysis	Sulfamethoxazole	Oxidant stress in G6PD deficiency
Kernicterus	Sulfamethoxazole	Displaces bilirubin from albumin; avoid near term and in newborns
Crystalluria, interstitial nephritis	Sulfamethoxazole	Crystals form in acidic urine; keep patients hydrated
Hyperkalemia	Trimethoprim	Blocks collecting-duct ENaC like amiloride; worse with ACE inhibitors, ARBs, renal impairment
Benign creatinine rise	Trimethoprim	Blocks tubular creatinine secretion; true GFR unchanged
Megaloblastic anemia, leukopenia, thrombocytopenia	Trimethoprim	Folate antagonism; reversed by leucovorin (folinic acid)

Interactions. Sulfamethoxazole inhibits CYP2C9 and displaces warfarin from albumin, so the INR can rise sharply and cause bleeding. TMP-SMX also increases phenytoin levels and sulfonylurea effects (hypoglycemia) and adds to methotrexate's folate antagonism, risking pancytopenia. Metronidazole and fluconazole are other CYP2C9 inhibitors that raise the INR.

Metronidazole and nitrofurantoin

Metronidazole mechanism. A prodrug that enters all cells, but its nitro group is reduced only by the low-redox-potential electron carriers (ferredoxin) of anaerobic bacteria and protozoa. The resulting nitro radicals break DNA and kill the organism; aerobic bacteria and human cells do not activate it.

Metronidazole uses. Giardia; Entamoeba histolytica (followed by a luminal agent such as paromomycin or iodoquinol to clear cysts); Trichomonas vaginalis, treating partners as well; bacterial vaginosis; anaerobes below the diaphragm such as B. fragilis in intra-abdominal infection, combined with gram-negative coverage; H. pylori regimens; and C. difficile only as a second-line option.

Metronidazole adverse effects. A disulfiram-like reaction with alcohol (aldehyde dehydrogenase inhibition lets acetaldehyde build up, causing flushing, headache, nausea, vomiting and tachycardia), a metallic taste, and peripheral neuropathy with prolonged courses. CYP2C9 inhibition raises the INR in patients on warfarin.

Nitrofurantoin. Bacterial flavoproteins reduce it to reactive intermediates that damage DNA and ribosomes. It reaches therapeutic levels only in urine, so it treats and prevents uncomplicated cystitis but never pyelonephritis, and it is avoided when creatinine clearance is below 30 mL/min. Toxicities include acute hypersensitivity pneumonitis within days, chronic pulmonary fibrosis with long-term use in older adults, hepatotoxicity, peripheral neuropathy, hemolysis in G6PD deficiency and a harmless brown discoloration of urine. It is avoided near term (38–42 weeks) and in early infancy because of neonatal hemolysis.