Avelox® Mechanism of Action and In Vitro Activity

In Vitro Activity

Avelox® (moxifloxacin) has in vitro activity against a wide range of Gram-positive, Gram-negative, atypical and anaerobic pathogens.

Table 1. Avelox® in vitro activity by pathogen

Mechanism of Action

The bactericidal action of Avelox® results from the inhibition of both type II topoisomerases (DNA gyrase and topoisomerase IV) required for bacterial DNA replication, transcription and repair.

Pharmacodynamic investigations have demonstrated that Avelox® exhibits a concentration-dependent killing rate.

Bacterial Resistance

Pathogenic bacteria employ a variety of strategies to persist and replicate when exposed to antimicrobial agents. It has been shown that resistance mechanisms which inactivate penicillins, cephalosporins, aminoglycosides, macrolides and tetracyclines do not interfere with the antibacterial activity of moxifloxacin. There is no cross resistance between Avelox® and these agents.

The efflux pump system is a mechanism that allows immediate survival of bacteria in the presence of an antimicrobial agent by actively expelling that agent across the cell membrane, thereby reducing the intracellular concentrations to sub-lethal levels. Some fluoroquinolones, including Avelox®, are not as affected by bacterial efflux systems due to the presence of the bulky bicycloamine substituent at the C-7 position, which hinders active efflux.

Specific point mutations on the bacteria reduce the binding of antimicrobial agents to specific enzymatic sites by altering the target site. It appears that the C8-methoxy moiety on Avelox® contributes to enhanced activity and lower selection of resistant mutants of Gram-positive bacteria compared to the C8-H moiety found on other fluoroquinolones. In vitro studies have demonstrated that resistance to Avelox® develops slowly by multiple step mutations. A very low overall frequency of resistance was demonstrated (10^-7 – 10^-10). Serial exposure of organisms to sub-MIC concentrations of Avelox® showed only a small increase in MIC values.

Cross resistance among quinolones has been observed. However, some Gram-positive and anaerobic organisms resistant to other quinolones are susceptible in vitro to Avelox®.

In Vitro Susceptibility Data

The frequency of acquired resistance may vary geographically and with time for certain species. Local area information on resistance of organisms is desirable, particularly when treating severe infections. The information presented in Table 2 below is provided as a guide to the susceptibility of an organism to Avelox®.

Table 2. EUCAST clinical MIC breakpoints for Avelox®

Clinical and Laboratory Standards Institute™ (CLSI) breakpoints are presented in the below Table 3 for MIC testing (mg/l) or disc diffusion testing (zone diameter [mm]) using a 5-μg moxifloxacin disc.

Table 3. CLSI MIC and disc diffusion breakpoints for Staphylococcus spp. and fastidious organisms (M100-S17, 2007) and MIC breakpoints for anaerobes (M11-A7, 2007)

The in vitro activity of moxifloxacin against Gram-negative, Gram-positive and anaerobic pathogens are presented below:

Table 4. MIC₉₀ range values for Gram-negative, Gram-positive and anaerobic pathogens¹

Pharmacokinetic / Pharmacodynamic Surrogates

In patients requiring hospitalisation, AUC / MIC greater than 125 and C_max / MIC of 8-10 are predictive for clinical cure. In outpatients these surrogate parameters may be smaller, i.e. AUC / MIC greater than 30-40.

Table 5. PK / PD surrogates for IV and oral administration of 400mg Avelox® calculated from single dose data

References

1. Burkhardt O and Welte T. 10 years' experience with pneumococcaol quinolone moxifloxacin. Expert Rev. Anti Infect Ther 2009; 7(6): 645-668.

For further information on using Avelox® in the management of bacterial infections, please consult your local country specific prescribing information.