Fluoroquinolones

Levofloxacin achieves near-complete oral bioavailability (approximately 99%), allowing oral dosing to deliver plasma concentrations essentially equivalent to intravenous administration at the same dose. Moxifloxacin approaches 89% oral bioavailability, while ciprofloxacin achieves approximately 70–85%. These values support routine oral-to-intravenous interchange for levofloxacin and moxifloxacin on a one-to-one dose basis. A patient with a functioning gastrointestinal tract who can tolerate oral medications should in most cases receive the oral formulation, as plasma exposures are nearly equivalent and intravenous access carries its own risks.

Tissue penetration is extensive across the class. Lung concentrations exceed plasma by two- to fivefold. Ciprofloxacin achieves prostate concentrations several times higher than plasma, supporting its use in prostatitis. Intracellular accumulation within phagocytes is clinically relevant for infections caused by obligate or facultative intracellular pathogens (Legionella, Mycobacterium, Chlamydophila, Brucella). Bone penetration supports oral fluoroquinolones for osteomyelitis step-down therapy. Cerebrospinal fluid penetration is moderate (10–40% of plasma), insufficient for bacterial meningitis.

Ciprofloxacin and levofloxacin are eliminated predominantly by renal excretion of unchanged drug and require dose adjustment in significant renal impairment. For levofloxacin, the approach is to reduce dosing frequency rather than reduce each individual dose, to maintain peak concentrations that drive concentration-dependent killing. Moxifloxacin is eliminated primarily by hepatic conjugation with biliary and fecal excretion; it does not require dose adjustment in renal impairment but should be used cautiously in severe hepatic impairment.

The most clinically important drug interaction is chelation by polyvalent cations. Aluminum- and magnesium-containing antacids, calcium supplements, iron preparations, zinc-containing multivitamins, and sucralfate form insoluble complexes with fluoroquinolones in the gastrointestinal lumen, reducing oral absorption by 50–90%. Ciprofloxacin is most severely affected. The interaction is managed by timing: oral fluoroquinolones should be administered at least two hours before or four to six hours after any polyvalent cation-containing product. Clinicians must counsel patients explicitly—patients commonly take antacids or calcium supplements without recognizing the impact on antibiotic absorption, and this interaction is among the most common causes of fluoroquinolone treatment failure in the outpatient setting.

All fluoroquinolones prolong the corrected QT interval (QTc) by a direct cardiac effect. The rank order for QTc prolongation is moxifloxacin greater than levofloxacin greater than ciprofloxacin. Co-administration with other QT-prolonging agents (antiarrhythmics, antipsychotics, certain antiemetics) creates additive risk for torsades de pointes. Moxifloxacin is contraindicated in patients with known QTc prolongation, uncorrected hypokalemia, or concomitant use of other QT-prolonging drugs.

Ciprofloxacin inhibits the cytochrome P450 1A2 (CYP1A2) enzyme, increasing plasma concentrations of theophylline, caffeine, clozapine, and tizanidine. Co-administration with theophylline can precipitate theophylline toxicity; the ciprofloxacin-tizanidine combination is contraindicated due to severe hypotension risk. Levofloxacin and moxifloxacin have minimal CYP1A2 inhibitory activity.

Ciprofloxacin is the preferred fluoroquinolone for Pseudomonas aeruginosa infections, complicated urinary tract infection, pyelonephritis, intra-abdominal infections (combined with metronidazole), osteomyelitis step-down therapy, and post-exposure prophylaxis for anthrax. Uncomplicated cystitis should be treated with nitrofurantoin, trimethoprim-sulfamethoxazole, or fosfomycin in preference to fluoroquinolones unless local resistance rates to those agents exceed 20%.

Levofloxacin and moxifloxacin are the respiratory fluoroquinolones: they cover the full range of community-acquired pneumonia pathogens including Streptococcus pneumoniae (including penicillin-resistant strains), Haemophilus influenzae, Moraxella catarrhalis, and atypical organisms (Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella pneumophila) in a single agent. Levofloxacin at 750 mg daily is preferred when Pseudomonas coverage is required; moxifloxacin is preferred when anaerobic coverage is needed, such as in aspiration pneumonia. Levofloxacin and moxifloxacin are also used in second-line and multidrug-resistant tuberculosis regimens.

The most important resistance mechanism is sequential mutations in the genes encoding DNA gyrase and topoisomerase IV. A single mutation in the primary target gene reduces susceptibility modestly, often raising the minimum inhibitory concentration into the intermediate range. A second mutation in the same target or a mutation in the secondary target confers high-level resistance. This stepwise pattern means agents with balanced dual-target activity (moxifloxacin) suppress resistance emergence more effectively, since simultaneous mutations in both targets are required for survival.

Efflux pump overexpression actively extrudes fluoroquinolones from the bacterial cell, reducing intracellular drug concentrations below the threshold required for target inhibition. In gram-negative organisms, multidrug efflux systems can be overexpressed, often conferring simultaneous resistance to multiple antibiotic classes. Porin loss acts synergistically by reducing drug entry.

Plasmid-mediated quinolone resistance genes have fundamentally altered the epidemiology of fluoroquinolone resistance by enabling horizontal gene transfer between species. Plasmid-mediated quinolone resistance genes encode proteins that reduce fluoroquinolone binding to target enzymes, typically conferring low-level resistance that facilitates selection of high-level chromosomal mutations. Fluoroquinolone resistance genes frequently co-reside on plasmids carrying extended-spectrum beta-lactamase genes, making fluoroquinolone resistance nearly universal in extended-spectrum beta-lactamase-producing organisms.