WARNING:

To reduce the development of drug-resistant bacteria and maintain the effectiveness of FACTIVE and other antibacterial drugs, FACTIVE should be used only to treat infections that are proven or strongly suspected to be caused by bacteria.

MICROBIOLOGY

Gemifloxacin has in vitro activity against a wide range of Gram-negative and Gram-positive microorganisms. Gemifloxacin is bactericidal with minimum bactericidal concentrations (MBCs) generally within one dilution of the minimum inhibitory concentrations (MICs). Gemifloxacin acts by inhibiting DNA synthesis through the inhibition of both DNA gyrase and topoisomerase IV (TOPO IV), which are essential for bacterial growth. Streptococcus pneumoniae showing mutations in both DNA gyrase and TOPO IV (double mutants) are resistant to most fluoroquinolones. Gemifloxacin has the ability to inhibit both enzyme systems at therapeutically relevant drug levels in S. pneumoniae (dual targeting), and has MIC values that are still in the susceptible range for some of these double mutants. However, the presence of double mutants was not evaluated in clinical trials; therefore, the clinical significance of these in vitro data are unknown.

The mechanism of action of quinolones, including gemifloxacin, is different from that of macrolides, beta-lactams, aminoglycosides, or tetracyclines; therefore, microorganisms resistant to these classes of drugs may be susceptible to gemifloxacin and other quinolones. There is no known cross- resistance between gemifloxacin and the above mentioned classes of antimicrobials.

The main mechanism of fluoroquinolone resistance is due to mutations in DNA gyrase and/or TOPO IV. Resistance to gemifloxacin develops slowly via multistep mutations and efflux in a manner similar to other fluoroquinolones. The frequency of spontaneous mutation is low (10-7 to <10-10). Although cross- resistance has been observed between gemifloxacin and other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to gemifloxacin.

Gemifloxacin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Aerobic Gram-positive microorganisms

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

*MDRSP: multi-drug resistant Streptococcus pneumoniae, includes isolates previously known as PRSP (penicillin-resistant Streptococcus pneumoniae), and are strains resistant to two or more of the following antibiotics: penicillin (MIC ≥2 μg/mL), 2nd generation cephalosporins (e.g., cefuroxime), macrolides, tetracyclines and trimethoprim/sulfamethoxazole.

Aerobic Gram-negative microorganisms

Haemophilus influenza

Haemophilus parainfluenzae

Klebsiella pneumonia (many strains are only moderately susceptible)

Moraxella catarrhalis

Other microorganisms

Chlamydia pneumoniae

Mycoplasma pneumoniae

The following data are available,but their clinical significance is unknown**.**

Gemifloxacin exhibits in vitro minimal inhibitory concentrations (MICs) of 0.25 μg/mL or less against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of gemifloxacin in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials:

Aerobic Gram-positive microorganisms

Staphylococcus aureus (methicillin-susceptible strains only)
Streptococcus pyogenes

Aerobic Gram-negative microorganisms

Acinetobacter lwoffii

Klebsiella oxytoca

Legionella pneumophila

Proteus vulgaris

Haemophilus influenza

Haemophilus parainfluenzae
Klebsiella pneumoniae(many strains are only moderately susceptible)
Moraxella catarrhalis

Susceptibility Tests

**Dilution techniques:**Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs 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 gemifloxacin powder. The MICs should be interpreted according to the following criteria:

For testing Klebsiella pneumoniae:

For testing Haemophilus influenzae and Haemophilus parainfluenzaea:

a This interpretive standard is applicable only to broth microdilution susceptibility testing with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium (HTM)1.

The current absence of data on resistant strains precludes defining any results other than “Susceptible”. Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for further testing.

For testing Streptococcus pneumoniaeb:

b These interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration 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 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 concentration usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard gemifloxacin powder should provide the following MIC values:

c This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth microdilution procedure using Haemophilus Test Medium (HTM)1.

d This quality control range is applicable to only S. pneumoniae ATCC 49619 tested by a broth microdilution procedure using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.

**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 μg gemifloxacin to test the susceptibility of microorganisms to gemifloxacin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5 μg gemifloxacin disk should be interpreted according to the following criteria:

For testing Klebsiella pneumoniae:

For testing Haemophilus influenzae and Haemophilus parainfluenzaee:

e This interpretive standard is applicable only to disk diffusion susceptibility testing with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium (HTM).2

The current absence of data on resistant strains precludes defining any results other than “Susceptible”. Strains yielding zone diameter results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for further testing.

For testing Streptococcus pneumoniaef:

f These zone diameter standards apply only to tests performed using Mueller- Hinton agar supplemented with 5% defibrinated sheep blood incubated in 5% CO2.

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for gemifloxacin.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 5 μg gemifloxacin disk should provide the following zone diameters in these laboratory quality control strains:

g This quality control range is applicable to only H. influenzae ATCC 49247 tested by a disk diffusion procedure using Haemophilus Test Medium (HTM)2.

h This quality control range is applicable to only S. pneumoniae ATCC 49619 tested by a disk diffusion procedure using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood and incubated in 5% CO2.