Mechanism of Action
Levofloxacin is the L-isomer of the racemate, ofloxacin, a quinolone antimicrobial agent. The antibacterial activity of ofloxacin resides primarily in the L-isomer. The mechanism of action of levofloxacin and other fluoroquinolone antimicrobials involves inhibition of bacterial topoisomerase IV and DNA gyrase (both of which are type II topoisomerases), enzymes required for DNA replication, transcription, repair and recombination.
Mechanism of Resistance
Fluoroquinolone resistance can arise through mutations in defined regions of DNA gyrase or topoisomerase IV, termed the Quinolone-Resistance Determining Regions (QRDRs), or through altered efflux.
Fluoroquinolones, including levofloxacin, differ in chemical structure and mode of action from aminoglycosides, macrolides and ⛚-lactam antibiotics, including penicillins. Fluoroquinolones may, therefore, be active against bacteria resistant to these antimicrobials.
Resistance to levofloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10
-9 to 10
-10). Cross-resistance has been observed between levofloxacin and some other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to levofloxacin.
Activity in vitro and in vivo
Levofloxacin has in vitro activity against Gram-negative and Gram-positive bacteria.
Levofloxacin has been shown to be active against most strains of the following bacteria both in vitro and in clinical infections as described in Indications and Usage ( 1):
Staphylococcus aureus (methicillin-susceptible isolates)
Staphylococcus epidermidis (methicillin-susceptible isolates)
Streptococcus pneumoniae (including multi-drug resistant isolates [MDRSP] 1)
1 MDRSP (Multi-drug resistant Streptococcus pneumoniae) isolates are strains resistant to two or more of the following antibiotics: penicillin (MIC ≥2 mcg/mL), 2nd generation cephalosporins, e.g., cefuroxime; macrolides, tetracyclines and trimethoprim/sulfamethoxazole.
The following in vitro data are available, but their clinical significance is unknown: Levofloxacin exhibits in vitro minimum inhibitory concentrations (MIC values) of 2 mcg/mL or less against most (≥90%) isolates of the following microorganisms; however, the safety and effectiveness of levofloxacin in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.
β-hemolytic Streptococcus (Group C/F)
β — hemolytic Streptococcus (Group G)
Viridans group streptococci
Anaerobic Gram-Positive Bacteria
When available, the clinical microbiology laboratory should provide the results of
in vitro susceptibility test results for antimicrobial drug products used in the resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.
Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC values should be determined using a standardized procedure. Standardized procedures are based on a dilution method 1,2,4 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of levofloxacin powder. The MIC values should be interpreted according to the criteria outlined in Table 9.
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure 2,3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5 mcg levofloxacin to test the susceptibility of bacteria to levofloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5 mcg levofloxacin disk should be interpreted according to the criteria outlined in Table 9. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5 mcg levofloxacin disk should be interpreted according the criteria outlined in Table 9.
Table 9: Susceptibility Interpretive Criteria for Levofloxacin
|Minimum Inhibitory Concentrations (mcg/mL)||Disk Diffusion (zone diameter in mm)|
|Haemophilus influenzae||≤2||– †||–||≥17||–||—|
S = Susceptible, I = Intermediate, R = Resistant
† The current absence of data on resistant isolates precludes defining any categories other than “Susceptible.” Isolates yielding MIC/zone diameter results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for further testing. A report of Susceptible indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of Intermediate indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test. 1,2,3,4 Standard levofloxacin powder should provide the range of MIC values noted in Table 10. For the diffusion technique using the 5 mcg disk, the criteria in Table 10 should be achieved.
Table 10: Quality Control for Susceptibility Testing
|Microorganism||Microorganism QC Number||MIC (mcg/mL)||Disk Diffusion (zone diameter in mm)|
|Enterococcus faecalis||ATCC 29212||0.25 – 2||—|
|Escherichia coli||ATCC 25922||0.008 – 0.06||29 – 37|
|Escherichia coli||ATCC 35218||0.015 – 0.06||—|
|Haemophilus influenzae||ATCC 49247||0.008 – 0.03||32 – 40|
|Pseudomonas aeruginosa||ATCC 27853||0.5 – 4||19 – 26|
|Staphylococcus aureus||ATCC 29213||0.06 – 0.5||–|
|Staphylococcus aureus||ATCC 25923||–||25 – 30|
|Streptococcus pneumoniae||ATCC 49619||0.5 – 2||20 – 25|
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