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Tequin

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Tequin

CLINICAL PHARMACOLOGY

Gatifloxacin is administered as a racemate, with the disposition and antibacterial activity of the R- and S-enantiomers virtually identical.

Absorption

Gatifloxacin is well absorbed from the gastrointestinal tract after oral administration and can be given without regard to food. The absolute bioavailability of gatifloxacin is 96%. Peak plasma concentrations of gatifloxacin usually occur 1-2 hours after oral dosing.

The oral and intravenous routes of administration for TEQUIN can be considered interchangeable, since the pharmacokinetics of gatifloxacin after 1-hour intravenous administration are similar to those observed for orally administered gatifloxacin when equal doses are administered (Figure 1) (see DOSAGE AND ADMINISTRATION).

Figure 1: Mean Plasma Concentration-Time Profiles of Gatifloxacin Following Intravenous (IV) and Oral (PO) Administration of a Single 400-mg Dose to Healthy Subjects.

Pharmacokinetics

The mean (SD) pharmacokinetic parameters of gatifloxacin following oral administration to healthy subjects with bacterial infections and subjects with renal insufficiency are listed in Table 1. The mean (SD) pharmacokinetic parameters of gatifloxacin following intravenous administration to healthy subjects are listed in Table 2.

Table 1: Gatifloxacin Pharmacokinetic Parameters- Oral Administration

Cmax (mg/mL)

Tmaxa (h)

AUCb (mg.h/mL)

T ½ (h)

Cl/F (mL/min)

C1R (mL/min)

UR (%)

200 mg - Healthy Volunteers

Single dose (n=12)

2.0 ±0.4

1.00 (0.50, 2.50)

14.2 ± 0.4

-

241 ±40

-

73.8 ± 10.9

400 mg - Healthy Volunteers

Single dose (n=202)c

3.8 ±1.0

1.00 (0.50, 6.00)

33.0 ± 6.2

7.8±1.3

210 ±44

151 ±46

72.4 ± 18.1

Multiple dose (n=18)

4.2 ±1.3

1.50 (0.50, 4.00)

34.4 ± 5.7

7.1±0.6

199 ±31

159 ±34

80.2 ±12.1

400 mg - Patients with Infection

Multiple dose (n=140)d

4.2 ±1.9

-

51.3±20.4

-

147 ±48

-

-

400 mg - Single Dose Subjects with Renal Insufficiency

Clcr50 - 89 mL/min (n=8)

4.4 ±1.1

1.13 (0.75-2.00)

48.0 ± 12.7

11.2±2.8

148 ±41

124 ± 38

83.7±7.8

Clcr 30 - 49 mL/min (n=8)

5.1 ±1.8

0.75 (0.50, 6.00)

74.9 ± 12.6

17.2±8.5

92 ±17

67 ±24

71.1 ±17.4

Clcr <30 mL/min (n=8)

4.5 ±1.2

1.50 (0.50, 6.00)

149.3±35.6

30.7±8.4

48 ±16

23 ±13

44.7 ±13.0

Hemodialysis (n=8)

4.7 ±1.0

1.50 (1.00,3.00)

180.3±34.4

35.7±7.0

38 ±8

-

-

CAPD(n=8)

4.7 ±1.3

1.75 (0.50, 3.00)

227.0±60.0

40.3±8.3

31±8

-

-

a Media n (Minimum, Maximum)

b Single dose: AUC (0-¥ ), Multiple dose: AUC (0-24)

c n=184 for CVF, n=134 for C!R, andn=132 forUR

d Based on the patient population pharmacokinetic modeling, n=103 for Cmax

Cmax: Maximum serum concentration; Tmax: Time to Cmax; AUC: Area under concentration versus time curve; T½: Serum half-life; Cl/F: Apparent total clearance; ClR : Renal clearance; UR: Urinary recovery

Table 2: Gatifloxacin Pharmacokinctic Parameters- Intravenous Administration

Cmax(mg/mL)

Tmaxa(h)

AUCb(mg· h/mL)

T ½(h)

Vdss

Cl(mL/min)

ClR(mL/min)

UR(%)

200 mg - Healthy Volunteers

Single dose (n=12)

2.2 ± 0.3

1.00(0.67, 1.50)

15.9 ±2.6

11.1±4.1

1.9±0.1

214 ±36

155 ±32

71.7±6.8

Multiple dose (n=8)c

2.4 ± 0.4

1.00(0.67, 1.00)

16.8 ±3.6

12.3±4.6

2.0±0.3

207 ± 44

155 ±55

72.4±16.4

400 mg - Healthy Volunteers

Single dose (n=30)

5.5 ±1.0

1.00(0.50, 1.00)

35.1 ±6.7

7.4 ±1.6

1.5±0.2

196 ±33

124 ±41

62.3±16.7

Multiple dose (n=5)

4.6 ± 0.6

1.00(1.00, 1.00)

35.4 ±4.6

13.9±3.9

1.6±0.5

190 ±24

161±43

83.5±13.8

* Median (Minimum, Maximum)

b Single dose: AUC (0-¥ ), Multiple dose: AUC (0-24)

c n=7 for ClR and UR

Cmax: Maximum serum concentration; Tmax: Time to Cmax : AUC: Area under concentration versus time curve; T½- Serum half-life; Vdss: Volume of distribution; Cl: Total clearance; C1R: Renal clearance; UR: Urinary recovery

Gatifloxacin pharmacokinetics are linear and time-independent at doses ranging from 200 to 800 mg administered over a period of up to 14 days. Steady-state concentrations are achieved by the third daily oral or intravenous dose of gatifloxacin. The mean steady-state peak and trough plasma concentrations attained following a dosing regimen of 400 mg once daily are approximately 4.2 µg/mL and 0.4 µg/mL, respectively, for oral administration and 4.6 µg/mL and 0.4 µg/mL, respectively, for intravenous administration.

Distribution

Serum protein binding of gatifloxacin is approximately 20% in volunteers and is concentration independent. Consistent with the low protein binding, concentrations of gatifloxacin in saliva were approximately equal to those in plasma (mean [range] saliva: plasma ratio was 0.88 [0.46-1.57]). The mean volume of distribution of gatifloxacin at steady-state (VdSS) ranged from 1.5 to 2.0 L/kg. Gatifloxacin is widely distributed throughout the body into many body tissues and fluids. Rapid distribution of gatifloxacin into tissues results in higher gatifloxacin concentrations in most target tissues than in serum (Table 3).

Table 3: Gatifloxacin Tissue-Fluid/Serum Ratio (Range)a

Fluid or Tissue

Tissue-Fluid/Serum Ratio (Range)a

Respiratory

Alveolar macrophages

26.5 (10.9-61.1)

Bronchial mucosa

1.65 (1.12-2.22)

Lung epithelial lining fluid

1.67 (0.81-4.46)

Lung parenchyma

4.09 (0.50-9.22)

Sinus mucosa

1.78 (1.17-2.49)

Sputum (Multiple dose)

1.28 (0.49-2.38)

Skin

Skin blister fluid

1.00 (0.50-1.47)

Reproductive

Ejaculate

1.07 (0.86-1.32)

Seminal fluid

1.01 (0.81-1.21)

Vagina

1.22 (0.57-1.63)

Cervix

1.45 (0.56-2.64)

a Mean of individual ratios collected over 24 hours following single (100, 150, 200, 300, or 400 mg) or multiple (150 or 200 mg BID) doses of gatifloxacin except for skin blister fluid, where mean AUC ratio is presented.

Metabolism

Gatifloxacin undergoes limited biotransformation in humans with less than 1% of the dose excreted in the urine as ethylenediamine and methylethylenediamine metabolites.

In vitro studies with cytochrome P450 isoenzymes (CYP) indicate that gatifloxacin does not inhibit CYP3A4, CYP2D6, CYP2C9, CYP2C19, or CYP1A2, suggesting that gatifloxacin is unlikely to alter the pharmacokinetics of drugs metabolized by these enzymes (eg, midazolam, cyclosporine, warfarin, theophylline).

In vivo studies in animals and humans indicate that gatifloxacin is not an enzyme inducer; therefore, gatifloxacin is unlikely to alter the metabolic elimination of itself or other coadministered drugs.

Excretion

Gatifloxacin is excreted as unchanged drug primarily by the kidney. More than 70% of an administered TEQUIN (gatifloxacin (removed from us market - may 2006)) dose was recovered as unchanged drug in the urine within 48 hours following oral and intravenous administration, and 5% was recovered in the feces. Less than 1% of the dose is recovered in the urine as two metabolites. Crystals of gatifloxacin have not been observed in the urine of normal, healthy human subjects following administration of intravenous or oral doses up to 800 mg.

The mean elimination half-life of gatifloxacin ranges from 7 to 14 hours and is independent of dose and route of administration. Renal clearance is independent of dose with mean value ranging from 124 to 161 mL/min. The magnitude of this value, coupled with the significant decrease in the elimination of gatifloxacin seen with concomitant probenecid administration, indicates that gatifloxacin undergoes both glomerular filtration and tubular secretion. Gatifloxacin may also undergo minimal biliary and/or intestinal elimination, since 5% of dose was recovered in the feces as unchanged drug. This finding is supported by the 5-fold higher concentration of gatifloxacin in the bile compared to the plasma (mean bile: plasma ratio [range] 5.34 [0.33-14.0]).

Special Populations

Patients with Bacterial Infections

The pharmacokinetics of gatifloxacin were similar between healthy volunteers and patients with infection, when underlying renal function was taken into account (see Table 1).

Geriatric

Following a single oral 400-mg dose of gatifloxacin in young (18-40 years) and elderly (³65 years) male and female subjects, there were only modest differences in the pharmacokinetics of gatifloxacin noted in female subjects; elderly females had a 21% increase in Cmax and a 32% increase in AUC(0-¥) compared to young females. These differences were mainly due to decreasing renal function with increasing age and are not thought to be clinically important. No dosage adjustment based on age alone is necessary for elderly subjects when administering TEQUIN (gatifloxacin (removed from us market - may 2006)) .

Pediatric

The pharmacokinetics of gatifloxacin in pediatric populations (<18 years of age) have not been established.

Gender

Following a single oral 400-mg dose of gatifloxacin in male and female subjects, there were only modest differences in the pharmacokinetics of gatifloxacin, mainly confined to elderly subjects. Elderly females had a 21% increase in Cmax and a 33% increase in AUC(0-¥) compared to elderly males. Both results were accounted for by gender-related differences in body weight and are not thought to be clinically important. Dosage adjustment of TEQUIN (gatifloxacin) is not necessary based on gender.

Chronic Hepatic Disease

Following a single oral 400-mg dose of gatifloxacin in healthy subjects and in subjects with moderate hepatic impairment (Child-Pugh B classification of cirrhosis), Cmax and AUC(0-¥) values for gatifloxacin were modestly higher (32% and 23% respectively). Due to the concentration-dependent antimicrobial activity associated with quinolones, the modestly higher Cmax values in the subjects with moderate hepatic impairment are not expected to negatively impact the outcome of TEQUIN (gatifloxacin (removed from us market - may 2006)) therapy in this population. Dosage adjustment of TEQUIN (gatifloxacin (removed from us market - may 2006)) is not necessary in patients with moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of TEQUIN (gatifloxacin) is unknown.

Renal Insufficiency

Following administration of a single oral 400-mg dose of gatifloxacin to subjects with varying degrees of renal impairment, apparent total clearance of gatifloxacin (Cl/F) was reduced and systemic exposure (AUC) was increased commensurate with the decrease in renal function (see Table 1). Total gatifloxacin clearance was reduced 57% in moderate renal insufficiency (Clcr 30-49 mL/min) and 77% in severe renal insufficiency (Clcr <30 mL/min). Systemic exposure to gatifloxacin was approximately 2 times higher in moderate renal insufficiency and approximately 4 times higher in severe renal insufficiency, compared to subjects with normal renal function. Mean Cmax values were modestly increased. A reduced dosage of TEQUIN (gatifloxacin (removed from us market - may 2006)) is recommended in patients with creatinine clearance <40 mL/min, including patients requiring hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) [see PRECAUTIONS: General and DOSAGE AND ADMINISTRATION: Impaired Renal Function].

Diabetes Mellitus

The pharmacokinetics of gatifloxacin in patients with type 2 diabetes (non-insulin-dependent diabetes mellitus), following TEQUIN (gatifloxacin (removed from us market - may 2006)) 400 mg orally for 10 days, were comparable to those in healthy subjects.

Glucose Homeostasis

Disturbances of blood glucose, including symptomatic hyper- and hypoglycemia, have been reported with TEQUIN (gatifloxacin (removed from us market - may 2006)) , usually in diabetic patients. Therefore, careful monitoring of blood glucose is recommended when TEQUIN (gatifloxacin (removed from us market - may 2006)) is administered to patients with diabetes (see WARNINGS, PRECAUTIONS: Information for Patients, and Drug Interactions, and ANIMAL PHARMACOLOGY).

In a postmarketing study conducted in non-infected patients (n=70) with type 2 diabetes mellitus controlled primarily with either the combination of glyburide and metformin or metformin alone, daily administration of gatifloxacin 400 mg orally for 14 days was associated with initial hypoglycemia followed by hyperglycemia. Upon initiation of gatifloxacin dosing (ie, first 2 days of treatment), there were increases in serum insulin concentrations and resulting decreases in serum glucose, as compared to baseline glucose values, despite ingestion of dietary restricted meals. In some patients, the reductions in glucose produced signs and symptoms of hypoglycemia (asthenia, sweating, dizziness) and necessitated administration of additional food. With continued gatifloxacin dosing (ie, from the third day of treatment and throughout the dosing period) fasting serum glucose concentrations were increased compared to baseline. The serum glucose concentrations returned to baseline in most of these uninfected patients by 28 days after the cessation of gatifloxacin treatment. Single doses of insulin were administered to three patients in this study to correct the hyperglycemia during continued gatifloxacin administration.

In two premarketing studies, no clinically significant changes in glucose tolerance (via measurement of oral glucose challenge) and glucose homeostasis (via measurement of fasting serum glucose, serum insulin and c-peptide) were observed following single or multiple intravenous infusion doses of 200 to 800 mg TEQUIN (gatifloxacin (removed from us market - may 2006)) in healthy volunteers (n=30), or 400-mg oral doses of TEQUIN (gatifloxacin (removed from us market - may 2006)) for 10 days in patients (n=16) with type 2 (non-insulin-dependent) diabetes mellitus controlled on diet and exercise. Compared to placebo, transient modest increases in serum insulin of approximately 20-40% and decreases in glucose concentrations of approximately 30% were noted with the first dose of intravenous or oral gatifloxacin.

In another premarketing study, following administration of single oral 400-mg doses of TEQUIN (gatifloxacin (removed from us market - may 2006)) for 10 days in patients (n=16) with type 2 diabetes mellitus controlled with glyburide, decreases in serum insulin concentrations of approximately 30-40%, as compared to placebo, were noted following oral glucose challenge; however, these decreases were not accompanied by statistically significant changes in serum glucose levels. In this study, modest increases in fasting glucose (average increases of 40 mg/dL) were also noted by day 4 of continued gatifloxacin administration, although these changes did not reach statistical significance.

Photosensitivity Potential

In a study of the skin response to ultraviolet and visible radiation conducted in 48 healthy, male Caucasian volunteers (12 per group), the minimum erythematous dose was measured for ciprofloxacin (500 mg BID), lomefloxacin (400 mg QD), gatifloxacin (400 mg QD), and placebo before and after drug administration for 7 days. In this study, gatifloxacin was comparable to placebo at all wavelengths tested and had a lower potential for producing delayed photosensitivity skin reactions than ciprofloxacin or lomefloxacin.

Electrocardiogram

In premarketing studies of volunteer subjects with pre- and post-dose ECGs obtained in 55 male volunteers receiving oral or IV TEQUIN (gatifloxacin (removed from us market - may 2006)) doses of 200 to 800 mg, the mean change in the post-dose QTc interval was <10 msec and there were no subjects with prolonged post-dose QTc intervals of >450 msec. In a postmarketing study of 34 healthy male and female volunteers receiving single oral doses of TEQUIN (gatifloxacin (removed from us market - may 2006)) 400, 800, and 1200 mg and placebo, an association between increases in post-dose QTc interval changes from baseline and increases in gatifloxacin plasma concentrations were observed. At the therapeutic dose of 400 mg, the mean change in the post-dose QTc interval from baseline was <10 msec. There were no subjects with prolonged post-dose QTc intervals of >450 msec for males and >470 msec for females.

In a postmarketing clinical trial of 262 patients with respiratory tract infections receiving repeated 400-mg oral doses of TEQUIN (gatifloxacin (removed from us market - may 2006)) who were studied with pre- and post-dose ECGs, the mean change in the post-dose QTc interval was <10 msec following the first 400-mg dose. In another postmarketing study of patients, with an acute coronary syndrome occurring within 4 weeks prior to TEQUIN (gatifloxacin (removed from us market - may 2006)) administration, pre- and post-dose ECGs were obtained in patients who were administered TEQUIN (gatifloxacin (removed from us market - may 2006)) 400 mg orally after single (n=372) and repeated (steady state; n=36) dosing. The mean changes in the post-dose QTc interval in these patients were <10 msec after both single and repeated dosing.

There is limited information available on the potential for a pharmacodynamic interaction in humans between gatifloxacin and drugs that prolong the QTc interval of an electrocardiogram such as Class IA and Class III antiarrhythmics, cisapride, erythromycin, antipsychotics, and tricyclic antidepressants (see WARNINGS and PRECAUTIONS: Information for Patients).

Spirometry

No clinically significant changes in spirometry were observed following single or multiple 200-mg, 400-mg, 600-mg, and 800-mg intravenous infusion doses of TEQUIN (gatifloxacin (removed from us market - may 2006)) in healthy volunteers.

Drug-Drug Interactions

Systemic exposure to TEQUIN (gatifloxacin (removed from us market - may 2006)) is increased following concomitant administration of TEQUIN (gatifloxacin (removed from us market - may 2006)) and probenecid, and is reduced by concomitant administration of TEQUIN (gatifloxacin (removed from us market - may 2006)) and ferrous sulfate or antacids containing aluminum or magnesium salts. TEQUIN (gatifloxacin (removed from us market - may 2006)) can be administered 4 hours before the administration of dietary supplements containing zinc, magnesium, or iron (such as multivitamins).

Probenecid

Concomitant administration of TEQUIN (gatifloxacin (removed from us market - may 2006)) (single oral 200-mg dose) with probenecid (500 mg BID x 1 day) resulted in a 42% increase in AUC and a 44% longer half-life of gatifloxacin.

Iron

When TEQUIN (gatifloxacin (removed from us market - may 2006)) (single oral 400-mg dose) was administered concomitantly with ferrous sulfate (single oral 325-mg dose), bioavailability of gatifloxacin was reduced (54% reduction in mean Cmax and 35% reduction in mean AUC). Administration of TEQUIN (gatifloxacin (removed from us market - may 2006)) (single oral 400-mg dose) 2 hours after or 2 hours before ferrous sulfate (single oral 325-mg dose) did not significantly alter the oral bioavailability of gatifloxacin (see DOSAGE AND ADMINISTRATION).

Antacids

When TEQUIN (gatifloxacin (removed from us market - may 2006)) (single oral 400-mg dose) was administered 2 hours before, concomitantly, or 2 hours after an aluminum/magnesium-containing antacid (1800 mg of aluminum oxide and 1200 mg of magnesium hydroxide single oral dose), there was a 15%, 69%, and 47% reduction in Cmax and a 17%, 64%, and 40% reduction in AUC of gatifloxacin, respectively. An aluminum/magnesium-containing antacid did not have a clinically significant effect on the pharmacokinetics of gatifloxacin when administered 4 hours after gatifloxacin administration (single oral 400-mg dose) [see DOSAGE AND ADMINISTRATION].

Milk, Calcium, and Calcium-containing Antacids

No significant pharmacokinetic interactions occur when milk or calcium carbonate is administered concomitantly with TEQUIN (gatifloxacin (removed from us market - may 2006)) . Concomitant administration of 200 mL of milk or 1000 mg of calcium carbonate with TEQUIN (200-mg gatifloxacin dose for the milk study and 400-mg gatifloxacin dose for the calcium carbonate study) had no significant effect on the pharmacokinetics of gatifloxacin. TEQUIN (gatifloxacin (removed from us market - may 2006)) can be administered 4 hours before the administration of dietary supplements containing zinc, magnesium, or iron (such as multivitamins).

Minor pharmacokinetic interactions occur following concomitant administration of gatifloxacin and digoxin; a priori dosage adjustments of either drug are not warranted.

Digoxin

Overall, only modest increases in Cmax and AUC of digoxin were noted (12% and 19% respectively) in 8 of 11 healthy volunteers who received concomitant administration of TEQUIN (gatifloxacin (removed from us market - may 2006)) (400-mg oral tablet, once daily for 7 days) and digoxin (0.25 mg orally, once daily for 7 days). In 3 of 11 subjects, however, a significant increase in digoxin concentrations was observed. In these 3 subjects, digoxin Cmax increased by 18%, 29%, and 58% while digoxin AUC increased by 66%, 104%, and 79%, and digoxin clearance decreased by 40%, 51%, and 45%. Although dose adjustments for digoxin are not warranted with initiation of gatifloxacin treatment, patients taking digoxin should be monitored for signs and/or symptoms of toxicity. In patients who display signs and/or symptoms of digoxin intoxication, serum digoxin concentrations should be determined, and digoxin dosage should be adjusted as appropriate. The pharmacokinetics of gatifloxacin was not altered by digoxin.

No significant pharmacokinetic interactions occur when cimetidine, midazolam, theophylline, warfarin, or glyburide is administered concomitantly with TEQUIN. These results and the data from in vitro studies suggest that gatifloxacin is unlikely to significantly alter the metabolic clearance of drugs metabolized by CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2D6 isoenzymes.

Cimetidine

Administration of TEQUIN (gatifloxacin (removed from us market - may 2006)) (single oral dose of 200 mg) 1 hour after cimetidine (single oral dose of 200 mg) had no significant effect on the pharmacokinetics of gatifloxacin. These results suggest that absorption of gatifloxacin is expected to be unaffected by H2-receptor antagonists like cimetidine.

Midazolam

TEQUIN (gatifloxacin (removed from us market - may 2006)) administration had no significant effect on the systemic clearance of intravenous midazolam. A single intravenous dose of midazolam (0.0145 mg/kg) had no effect on the steady-state pharmacokinetics of gatifloxacin (once daily oral doses of 400 mg for 5 days). These results are consistent with the lack of effect of TEQUIN (gatifloxacin (removed from us market - may 2006)) in in vitro studies with the human CYP3A4 isoenzyme.

Theophylline

Concomitant administration of TEQUIN (gatifloxacin (removed from us market - may 2006)) (once daily oral doses of 400 mg for 5 days) and theophylline (300 mg BID oral dose for 10 days) had no significant effect on the pharmacokinetics of either drug. These results are consistent with the lack of effect of TEQUIN (gatifloxacin (removed from us market - may 2006)) in in vitro studies with the human CYP1A2 isoenzyme.

Warfarin

Concomitant administration of TEQUIN (gatifloxacin (removed from us market - may 2006)) (once daily oral doses of 400 mg for 11 days) and warfarin (single oral dose of 25 mg) had no significant effect on the pharmacokinetics of either drug nor was the prothrombin time significantly altered. These results are consistent with the lack of effect of TEQUIN (gatifloxacin (removed from us market - may 2006)) in in vitro studies with the human CYP2C9, CYP1A2, CYP3A4, and CYP2C19 isoenzymes (see PRECAUTIONS: Drug Interactions).

Glyburide

Pharmacodynamic changes in glucose homeostasis were seen with concomitant administration of TEQUIN (gatifloxacin (removed from us market - may 2006)) (once daily oral doses of 400 mg for 10 days) and glyburide (steady-state once daily regimen) in patients with type 2 diabetes mellitus. This was not associated with significant effects on the pharmacokinetic disposition of either drug. These latter results are consistent with the lack of effect of TEQUIN in in vitro studies with the human CYP3A4 isoenzyme (see CLINICAL PHARMACOLOGY: Glucose Homeostasis and WARNNIGS).

Microbiology

Gatifloxacin is an 8-methoxyfluoroquinolone with in vitro activity against a wide range of gram-negative and gram-positive microorganisms. The antibacterial action of gatifloxacin results from inhibition of DNA gyrase and topoisomerase IV. DNA gyrase is an essential enzyme that is involved in the replication, transcription, and repair of bacterial DNA. Topoisomerase IV is an enzyme known to play a key role in the partitioning of the chromosomal DNA during bacterial cell division. It appears that the C-8-methoxy moiety contributes to enhanced activity and lower selection of resistant mutants of gram-positive bacteria compared to the non-methoxy C-8 moiety.

The mechanism of action of fluoroquinolones including gatifloxacin is different from that of penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines. Therefore, fluoroquinolones may be active against pathogens that are resistant to these antibiotics. There is no cross-resistance between gatifloxacin and the mentioned classes of antibiotics.

From in vitro synergy tests, gatifloxacin, as with other fluoroquinolones, is antagonistic with rifampin against enterococci.

Resistance to gatifloxacin in vitro develops slowly via multiple-step mutations. Resistance to gatifloxacin in vitro occurs at a general frequency of between 1 x 10-7 to 10-10. Although cross-resistance has been observed between gatifloxacin and some other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to gatifloxacin.

Gatifloxacin 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

Staphylococcus aureus (methicillin-susceptible strains only)

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

Streptococcus pyogenes

*Multidrug-resistant Streptococcus pneumoniae (MDRSP) 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 (eg, cefuroxime), macrolides, tetracyclines, and trimethoprim/ sulfamethoxazole.

Aerobic gram-negative microorganisms

Escherichia coli

Haemophilus influenzae

Haemophilus parainfluenzae

Klebsiella pneumoniae

Moraxella catarrhalis

Neisseria gonorrhoeae

Proteus mirabilis

Other microorganisms

Chlamydia pneumoniae

Legionella pneumophila

Mycoplasma pneumoniae

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

Gatifloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of £2 µg/mL against most (³90%) strains of the following microorganisms; however, the safety and effectiveness of gatifloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic gram-positive microorganisms

Staphylococcus epidermidis (methicillin-susceptible strains only)

Staphylococcus saprophyticus

Streptococcus (Group C/G/F)

Streptococcus agalactiae

Streptococcus viridans group

Aerobic gram-negative microorganisms

Acinetobacter lwoffii

Citrobacter freundii

Citrobacter koseri

Enterobacter aerogenes

Enterobacter cloacae

Klebsiella oxytoca

Morganella morganii

Proteus vulgaris

Anaerobic microorganisms

Peptostreptococcus species

NOTE: The activity of gatifloxacin against Treponema pallidum has not been evaluated; however, other quinolones are not active against Treponema pallidum (see WARNINGS).

NOTE: Extended-spectrum b-lactamase producing gram-negative microorganisms may have reduced susceptibility to quinolones.

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 method 1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of gatifloxacin powder. The MIC values should be interpreted according to the following criteria:

For testing Enterobacteriaceae and Staphylococcus species:

MIC (µg/mL)

Interpretation

£2.0

Susceptible (S)

4.0

Intermediate (I)

>8.0

Resistant (R)

For testing Haemophilus influenzae and Haemophilus parainfluenzaea:

MIC (µg/mL)

Interpretation

£1.0

Susceptible (S)

a This interpretive standard is applicable only to broth microdilution susceptibility tests 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:

MIC (µg/mL)

Interpretation

£1.0

Susceptible (S)

2.0

Intermediate (I)

>4.0

Resistant (R)

For testing Streptococcus species other than Streptococcus pneumoniaeb:

MIC (µg/mL)

Interpretation

£2.0

Susceptible (S)

4.0

Intermediate (I)

>8.0

Resistant (R)

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

For testing Neisseria gonorrhoeaec:

MIC (µg/mL)

Interpretation

£0.125

Susceptible (S)

0.25

Intermediate (I)

>0.5

Resistant (R)

c These interpretive standards are applicable to agar dilution tests with GC agar base and 1% defined growth supplement.

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 gatifloxacin powder should provide the following MIC values:

Microorganism

MIC Range (µg/mL)

Enterococcus faecalis ATCC 29212

0.12 - 1.0

Escherichia coli ATCC 25922

0.008 - 0.03

Haemophilus influenzae ATCC 49247d

0.004 - 0.03

Neisseria gonorrhoeae ATCC 49226e

0.002 - 0.016

Pseudomonas aeruginosa ATCC 27853

0.5 - 2.0

Staphylococcus aureus ATCC 29213

0.03 - 0.12

Streptococcus pneumoniae ATCC 49619f

0.12 - 0.5

d This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth microdilution procedure using HTM. 1

e This quality control range is applicable to only N. gonorrhoeae ATCC 49226 tested by an agar dilution procedure using GC agar base with 1% defined growth supplement. 1

f This quality control range is applicable to only S. pneumoniae ATCC 49619 tested by a microdilution procedure using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood. 1

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 gatifloxacin to test the susceptibility of microorganisms to gatifloxacin.

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

The following zone diameter interpretive criteria should be used for testing

Enterobacteriaceae and Staphylococcus species:

Zone Diameter (mm)

Interpretation

³18

Susceptible (S)

15 - 17

Intermediate (I)

£14

Resistant (R)

For testing Haemophilus influenzae and Hemophilus parainfluenzaeg:

Zone Diameter (mm)

Interpretation

³18

Susceptible (S)

g This zone diameter standard is applicable only to tests 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 MIC results suggestive of a "nonsusceptible" category should be submitted to a reference laboratory for further testing.

For testing Streptococcus pneumoniaeh:

Zone Diameter (mm)

Interpretation

³21

Susceptible (S)

18 - 20

Intermediate (I)

£17

Resistant (R)

For testing Streptococcus species other than Streptococcus pneumoniaeh:

Zone Diameter (mm)

Interpretation

³18

Susceptible (S)

15 - 17

Intermediate (I)

£14

Resistant (R)

h These zone diameter standards only apply to tests performed using Mueller-Hinton agar

supplemented with 5% sheep blood incubated in 5% CO2.2

For testing Neisseria gonorrhoeae i:

Zone Diameter (mm)

Interpretation

³38

Susceptible (S)

34 - 37

Intermediate (I)

£33

Resistant (R)

i These interpretive standards are applicable to disk diffusion tests with GC agar base and 1% defined growth supplement 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 gatifloxacin.2

As with standardized dilution techniques, 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 gatifloxacin disk should provide the following zone diameters in these laboratory quality control strains:

Microorganism

Zone Diameter Range (mm)

Escherichia coli ATCC 25922

30-37

Haemophilus influenzae ATCC 49247j

33-41

Neisseria gonorrhoeae ATCC 49226k

45-56

Pseudomonas aeruginosa ATCC 27853

20-28

Staphylococcus aureus ATCC 25923

27-33

Streptococcus pneumoniae ATCC 49619l

24-31

j This quality control range applies to tests conducted with Haemophilus influenzae ATCC 49247 using Haemophilus Test Medium (HTM)2.

k This quality control range is only applicable to tests conducted with N. gonorrhoeae ATCC 49226 performed by disk diffusion using GC agar base and 1% defined growth supplement2.

l This quality control range is applicable only to tests conducted with S. pneumoniae ATCC 49619 performed by disk diffusion using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood.

CLINICAL STUDIES

Community-Acquired Bacterial Pneumonia and Community-Acquired Pneumonia Due to Multi-Drug Resistant Streptococcus pneumoniae (MDRSP)*

Clinical efficacy of gatifloxacin in the treatment of community-acquired bacterial pneumonia (CAP) was evaluated in two non-comparative Phase II/III studies and three Phase III studies comparing oral TEQUIN (gatifloxacin (removed from us market - may 2006)) to oral clarithromycin, TEQUIN (gatifloxacin (removed from us market - may 2006)) IV/oral to levofloxacin IV/oral, and TEQUIN (gatifloxacin (removed from us market - may 2006)) IV/oral to ceftriaxone IV (+/- erythromycin IV) with step-down to oral clarithromycin. Success rates for clinically evaluable patients with a bacterial pathogen isolated at baseline (see INDICATIONS AND USAGE) ranged from 88% to 90% for TEQUIN (gatifloxacin (removed from us market - may 2006)) -treated patients. Success rates were not statistically different from comparator therapy.

Gatifloxacin was also effective for the treatment of community-acquired pneumonia caused by multi-drug resistant Streptococcus pneumoniae (MDRSP) isolates. Of 27 clinically and microbiologically evaluable patients with MDRSP isolates obtained primarily from post-marketing studies of patients with CAP, 100% achieved clinical and bacteriological success post-therapy. The clinical cure rates and bacteriological success rates are shown in the table below.

*Multidrug-resistant Streptococcus pneumoniae (MDRSP) 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 (eg, cefuroxime), macrolides, tetracyclines, and trimethoprim/ sulfamethoxazole.

Table 6: Clinical and Bacteriological Success Rates for Gatifloxacin- Treated MDRSP CAP Patients (Population: Valid for Efficacy)

Screening Susceptibility

Clinical Success n/Na

Bacteriological Success n/Nb

Penicillin-resistant

10/10 (100%)

10/10 (100%)

2nd generation cephalosporin-resistant*

13/13 (100%)

13/13 (100%)

Macrolide-resistant**

24/24 (100%)

24/24 (100%)

Trimethoprim/sulfamethoxazole-resistant

12/12 (100%)

12/12 (100%)

Tetracylcine-resistant

14/14 (100%)

14/14 (100%)

a n = number of patients successfully treated; N = number of clinically evaluable patients with MDRSP (froma total of 27 patients).

b n = number of patients successfully treated (presumed eradication or eradication); N = number of microbiologically evaluable patients with MDRSP (from a total of 27 patients).

* 2nd generation cephalosporin tested was cefuroxime.

** Clarithromycin and erythromycin were the macrolide antimicrobials tested.

Not all isolates were resistant to all antimicrobial classes tested. Success and eradication rates are summarized in the table below.

Table 7: Clinical Success and Bacteriological Eradication Rates for Gatifloxacin-Treated MDRSP CAP Patients (Population: Valid for Efficacy)

Streptococcus pneumoniae with MDRSP

Clinical Success Rate

Bacteriological Eradication Rate

Resistant to at least 2 antimicrobials

12/12 (100%)

12/12 (100%)

Resistant to at least 3 antimicrobials

12/12 (100%)

12/12 (100%)

Resistant to at least 4 antimicrobials

2/2 (100%)

2/2 (100%)

Resistant to at least 5 antimicrobials

1/1 (100%)

1/1 (100%)

Bacteremias with MDRSP

3/3 (100%)

3/3 (100%)

REFERENCES

1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grows Aerobically - Fifth Edition; Approved Standard, NCCLS Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January 2000.

2. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests - Seventh Edition; Approved Standard, NCCLS Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne, PA, January 2000.

Last reviewed on RxList: 1/13/2005
This monograph has been modified to include the generic and brand name in many instances.

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