Fluoroquinolones: Mechanism, Spectrum & Resistance

• Antimicrobials include quinolones, folic acid antagonists, and urinary tract antiseptics.

Fluoroquinolones

• Bacterial species have two distinct type II topoisomerases.
• DNA gyrase breaks the double-strand DNA and introduces negative supercoils.
• Topoisomerase IV separates daughter chromosomes once replication is completed.
• Fluoroquinolones bind to these enzymes and interfere with DNA ligation, causing chromosomal breaks and cell lysis.
• The main target for gram-negative bacteria is DNA gyrase, while for gram-positive bacteria, it is topoisomerase IV.
• Spectrum*
• First generation: Nalidixic acid (Moderate G-ve)
• Second generation: Ciprofloxacin (Expanded G-ve, mild G+ve)
• Third generation: Levofloxacin (Expanded G-ve, Moderate G+ve)
• Fourth generation: Moxifloxacin, Gemifloxacin, Delafloxacin (Expanded G-ve, improved G+ve)
• Resistance Mechanisms*
• Altered target binding happens due to mutations in bacterial genes encoding DNA gyrase or topoisomerase.
• The mutations alter the target site structure and reduce the binding efficiency of fluoroquinolones.
• Decreased accumulation occur via reduced membrane permeability or efflux pumps.
• Fluoroquinolone degradation can happen via acetylation to become inactive.
• Pharmacokinetics*
• Fluoroquinolones are bioavailable orally.
• Absorption is reduced if co-ingested with sucralfate, aluminum, magnesium-containing antacids, zinc or iron supplements, and calcium preparations.
• Fluoroquinolones distribute well to tissues, body fluids, bone, urine, and CSF.
• Fluoroquinolones are mostly excreted renally, requiring dose adjustments in renal impairment.
• Adverse Reactions*
• Can induce tendinitis
• Can cause Diarrhea, Nausea, Headache and Dissiness
• Can prolong the QT interval
• Can cause arrhythmia, seizures peripheral neuropathy and phototoxicity

Folate Antagonists

• Humans use dietary folate to synthesize tetrahydrofolic acid.
• Many bacteria cannot absorb folate derivatives and must synthesize folate de novo.
• Sulfonamides* (Mafenide – Sulfadiazine – Sulfasalazine)
• Sulfonamides are synthetic analogs of PABA and compete with it to inhibit dihydropteroate synthetase.
• The inhibition of dihydropteroate synthetase reduced the genesis of bacterial dihydrofolic acid, leading to a bacteriostatic effect.
• Sulfonamides exhibit some activity against both Gram-positive and negative bacteria.
• Resistance Mechanisms*
• Altered target via modification of dihydropteroate synthase occurs.
• Decreased permeability
• Pharmacokinetics*
• Most sulfonamides are well absorbed orally, except for sulfasalazine.
• Intravenous sulfonamides are used only in emergencies due to the risk of sensitization.
• Mafenide and silver sulfadiazine can be applied topically to reduce burn-associated sepsis.
• Sulfonamides are albumin-bound and can penetrate into the CSF and placenta.
• Sulfonamides are metabolized in the liver via acetylation into toxic metabolites
• These toxic metabolites may cause crystalluria and kidney damage.
• Sulfonamides are mainly excreted renally and, to some extent, in breast milk.
• Adverse Effects*
• Adequate hydration and alkalinization promotes ionization and reduces crystalluria.
• Hypersensitivity reactions include rash, angioedema, and Stevens-Johnson syndrome.
• Hemapoietic effects include hemolytic anemia in patients with G6PD deficiency.
• Kernicterus is bilirubin-associated brain damage in newborns as sulfonamides displace bilirubin from albumin binding that goes past the BBB (not well developed in newborns).
• Contraindications*
• Avoided in newborns and infants under 2 months and in pregnant women at term.
• Sulfonamides should not be given with methenamine due to potential crystallization with formaldehyde.

Trimethoprim

• Mechanism of Action*
• A potent inhibitor of bacterial dihydrofolate reductase inhibits active folic acid formation.
• It has greater affinity to bacterial than human dihydrofolate reductase, which accounts for its toxicity
• Spectrum*
• Similar spectrum to sulfamethoxazole with 20-50 fold greater potency.
• May be used alone for urinary tract infections (UTIs).
• Resistance mechanisms*
• Altered dihydrofolate reductase
• Efflux pumps & reduced permeability
• Pharmacokinetics*
• Exhibit good oral bioavailability.
• Higher concentrations are achieved in acidic prostatic and vaginal fluids due to being a weak base.
• Penetrates into the CSF
• Mostly renally excreted unchanged.
• Adverse Effects*
• Causes Folic acid deficiency symptoms (megaloblastic anemia, leukopenia, granulocytopenia).
• Symptoms are worse in pregnant patients and those with nutrient-poor diets.
• Blood disorders can be reversed by folinic acid (leucovorin), which does not enter bacteria.
• Acts as a potassium can cause hyperkalemia

Cotrimoxazole (trimethoprim + sulfamethoxazole)

• Mechanism of Action*
• Combined antimicrobial activity results from inhibition of two steps of tetrahydrofolic acid synthesis.
• Sulfamethoxazole inhibits PABA incorporation.
• Trimethoprim inhibits dihydrofolate reduction to tetrahydrofolate.
• Resistance*
• Less resistance due to combination.
• Pharmacokinetics*
• Is administered orally, but I.V. in certain conditions.
• Both agents are distributed throughout the body.
• Trimethoprim concentrates in acidic prostatic fluids.
• This helps cotrimoxazole to treat of prostatitis.
• Cotrimoxazole can readily crosses the BBB.
• Both parent drugs and their metabolites are excreted in the urine

Urinary Tract Antiseptics

• Methenamine*
• Mechanism of Action*
• Methenamine salts are hydrolyzed to ammonia + formaldehyde in acidic urine (pH ≤ 5.5).
• Formaldehyde denatures proteins and nucleic acids, which leads to bacteria cell death.
• Formulated with weak acid (e.g., hippuric acid) to maintain urine acidity and promote formaldehyde production.
• Spectrum*
• Used for chronic suppressive therapy to reduce the frequency of UTIs.
• Main benefit is its lack of resistance.
• Pharmacokinetics*
• Active orally with up to 30% decomposing in gastric juices, unless enteric coated.
• Renally excreted.
• Use should be avoided in hepatic insufficiency due to ammonia formation.
• Adverse Effects*
• GIT distress occur
• Higher doses may cause albuminuria, hematuria, and rashes.
• Methenamine mandelate is contraindicated in patients with renal insufficiency due to mandelic acid precipitation.
• The methenamine hippurate formulation is preferable.
• Sulfonamides react with formaldehyde; do not use concomitantly with methenamine because of the increased risk of crystalluria and mutual antagonism.

Nitrofurantoin

• First introduced in the 1960s for cystitis.
• It was rarely used until recently, when it was resurrected due to increased bacterial resistance.
• Mechanism of Action*
• Inhibits DNA and RNA synthesis.
• Pharmacokinetics*
• Bioavailable orally with 40% renal excretion
• Adverse Effects*
• Can cause Nausea, vomiting and diarrhea.
• This can be reduced with use of microcrystalline preparation
• Can cause pulmonary fibrosis and neuropathy (rare - exposure>1 month)

Fluoroquinolones bind to bacterial enzymes, interfering with DNA ligation and causing cell lysis. Gram-negative bacteria target DNA gyrase, while gram-positive bacteria target topoisomerase IV. Resistance occurs through mutations in genes encoding these enzymes.