Question 20

It has been proposed that another advantage of using the high-dose, short-course levofloxacin regimen is its potential to reduce the emergence of antibacterial resistance. Could you discuss whether this is a likely benefit of using this strategy?

This is definitely a very strong potential advantage in using the high-dose strategy. When evaluating the potential for developing resistance it is important to remember that different mechanisms of resistance are associated with different classes of antibacterials. For example, fluoroquinolones have maintained high sensitivity and low resistance rates because two mutations in DNA gyrase and topoisomerase are required before high-level resistance can develop. In contrast, resistance to penicillin and β-lactams is mediated through abnormal penicillin-binding proteins and production of β-lactamases. In regard to macrolides and tetracyclines, efflux resistance mechanisms and binding to ribosomal RNA are important mechanisms underlying resistance. Therefore, because two major mutations are required within the same molecule for levofloxacin resistance, the likelihood of this happening is reduced. This has allowed levofloxacin to maintain high sensitivity with very few isolates possessing high-level levofloxacin resistance.

The levofloxacin 750 mg regimen is exactly the type of regimen that helps to minimize resistance and it is important to stress that the higher dose can assure a quicker bacterial kill, and overcome the mutant prevention concentration (MPC) thereby reducing the likelihood of resistance developing (72). High-dose, short-course levofloxacin possesses an important advantage with pharmacokinetic features exploited to achieve quick kill while at the same time maintaining tolerability. This is supported by recent results published by Stein et al. (73) in a study that evaluated the urinary bactericidal activity (UBA) of levofloxacin against fluoroquinolone-resistant strains of E. coli. Blood and urine samples were taken from 10 healthy adults after receiving single doses of levofloxacin (250, 500, 750 and 1,000 mg). While each dose of levofloxacin demonstrated early bactericidal urinary activity the high-doses of 750 and 1,000 mg resulted in prolonged bactericidal activity in 9 of 10 subjects against E. coli isolates with MICs up to 32 μg/ml. Thus, high-dose levofloxacin can produce early and prolonged UBA against fluoroquinolone-resistant strains of E. coli.