LEVOFLOXACIN (Page 9 of 16)

12.4 Microbiology

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.

Drug 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 β-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). Although 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 a wide range of Gram-negative and Gram-positive microorganisms.

Levofloxacin is often bactericidal at concentrations equal to or slightly greater than inhibitory concentrations.

Levofloxacin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in Indications and Usage (1) :

Aerobic Gram-Positive Microorganisms

Enterococcus faecalis (many strains are only moderately susceptible)

Staphylococcus aureus (methicillin-susceptible strains)

Staphylococcus epidermidis (methicillin-susceptible strains)

Staphylococcus saprophyticus

Streptococcus pneumoniae (including multi-drug resistant strains [MDRSP]*)

Streptococcus pyogenes

* 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.

Aerobic Gram-Negative Microorganisms

Enterobacter cloacae

Escherichia coli

Haemophilus influenzae

Haemophilus parainfluenzae

Klebsiella pneumoniae

Legionella pneumophila

Moraxella catarrhalis

Proteus mirabilis

Pseudomonas aeruginosa * *

Serratia marcescens

** As with other drugs in this class, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with levofloxacin.

Other Microorganisms

Chlamydophila pneumoniae

Mycoplasma pneumoniae

Levofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of plasma levels as a surrogate marker in a rhesus monkey model for anthrax (post-exposure) [see Indications and Usage (1.13) and Clinical Studies (14.9)].

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%) strains of the following microorganisms; however, the safety and effectiveness of levofloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.

Aerobic Gram-Positive Microorganisms

Staphylococcus haemolyticus

β-hemolytic Streptococcus (Group C/F)

β-hemolytic Streptococcus (Group G)

Streptococcus agalactiae

Streptococcus milleri

Viridans group streptococci

Aerobic Gram-Negative Microorganisms

Acinetobacter baumannii

Acinetobacter lwoffii

Bordetella pertussis

Citrobacter koseri

Citrobacter freundii

Enterobacter aerogenes

Enterobacter sakazakii

Klebsiella oxytoca

Morganella morganii

Pantoea agglomerans

Proteus vulgaris

Providencia rettgeri

Providencia stuartii

Pseudomonas fluorescens

Anaerobic Gram-Positive Microorganisms

Clostridium perfringens

Susceptibility Tests

Susceptibility testing for levofloxacin should be performed, as it is the optimal predictor of activity.

  • Dilution techniques:

Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MIC values). These MIC values 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 method1 (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 11.

  • Diffusion techniques:

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5 mcg levofloxacin to test the susceptibility of microorganisms 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 11. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for levofloxacin.

Table 11: Susceptibility Interpretive Criteria for Levofloxacin
*
These interpretive standards are applicable only to broth microdilution susceptibility testing with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium.1
The current absence of data on resistant strains precludes defining any categories other than “Susceptible.” Strains yielding MIC/zone diameter results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for further testing.
These interpretive standards are applicable only to disk diffusion susceptibility testing with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium.2
§
These interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.
These zone diameter standards for Streptococcus spp. including S. pneumoniae apply only to tests performed using Mueller-Hinton agar supplemented with 5% sheep blood and incubated in 5% CO2 .
Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion (zone diameter in mm)
Pathogen S I R S I R
Enterobacteriaceae ≤ 24≥ 8≥ 1714 to 16≤ 13
Enterococcus faecalis ≤ 24≥ 8≥ 1714 to 16≤ 13
Methicillin-susceptible Staphylococcus species≤ 24≥ 8≥ 1714 to 16≤ 13
Pseudomonas aeruginosa ≤ 24≥ 8≥ 1714 to 16≤ 13
Haemophilus influenzae ≤ 2*≥ 17
Haemophilus parainfluenzae ≤ 2*≥ 17
Streptococcus pneumoniae ≤ 2§4§≥ 8§≥ 1714 to 16≤ 13
Streptococcus pyogenes ≤ 24≥ 8≥ 1714 to 16≤ 13
S = Susceptible, I = Intermediate, R = Resistant

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.

  • Quality Control:

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. For dilution technique, standard levofloxacin powder should give the MIC values provided in Table 12. For diffusion technique, the 5 mcg levofloxacin disk should provide zone diameters provided in Table 12.

Table 12: Quality Control for Susceptibility Testing
Microorganism Microorganism QC Number MIC (mcg/mL) Disk Diffusion (zone diameter in mm)
Enterococcus faecalis ATCC 292120.25 to 2
Escherichia coli ATCC 259220.008 to 0.0629 to 37
Escherichia coli ATCC 352180.015 to 0.06
Haemophilus influenzae ATCC 492470.008 to 0.03 32 to 40
Pseudomonas aeruginosa ATCC 278530.5 to 419 to 26
Staphylococcus aureus ATCC 292130.06 to 0.5
Staphylococcus aureus ATCC 2592325 to 30
Streptococcus pneumoniae ATCC 496190.5 to 2 20 to 25

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