Gatifloxacin

Gatifloxacin is absorbed well from the gastrointestinal tract (oral bioavailability is almost 100%). Therefore, patients can be switched from intravenous to oral therapy without an adjustment in dosage. High concentrations of gatifloxacin are achieved in plasma and target tissues/fluids. Gatifloxacin has a long plasma elimination half-life, thus allowing once-daily administration. Few clinically significant interactions between gatifloxacin and other drugs have been reported.

In patients with CAP, clinical response rates in recipients of intravenous/oral gatifloxacin 400 mg/day ranged from 86.8 to 98.0% and rates of bacterial eradication ranged from 83.1 to 100% (up to 28 days post-treatment). Gatifloxacin showed efficacy similar to that of amoxicillin/clavulanic acid, ceftriaxone (with or without erythromycin) with or without stepdown to clarithromycin, levo-floxacin or clarithromycin. Gatifloxacin was as effective as clarithromycin or amoxicillin/clavulanic acid, and was significantly more effective (in terms of clinical response; p < 0.035) than 7 to 10 days’ treatment with cefuroxime axetil in the treatment of acute exacerbations of chronic bronchitis. In acute sinusitis, gatifloxacin showed clinical efficacy similar to that of clarithromycin, trovafloxacin or amoxicillin/clavulanic acid. Genitourinary infections were also successfully treated with gatifloxacin.

Gatifloxacin is generally well tolerated. Its tolerability profile was broadly similar to those of comparator agents in comparative trials. The most common adverse events are gastrointestinal symptoms (oral formulation) and injection site reactions.

Conclusions: Gatifloxacin has an extended spectrum of antibacterial activity and provides better coverage of Gram-positive organisms (e.g. S. pneumoniae) than some older fluoroquinolones. The drug has favourable pharmacokinetic properties, is administered once daily and is at least as well tolerated as other fluoroquinolones. Gatifloxacin is a useful addition to the fluoroquinolones currently available for use in the clinical setting and has an important role in the management of adult patients with various bacterial infections. As with other fluoroquinolones, careful control of gatifloxacin usage in the community is important in order to prevent the emergence of bacterial resistance and thus preserve the clinical value of this agent.

Gatifloxacin tended to be more active than ciprofloxacin against most Gram-positive organisms in in vitro investigations. Gatifloxacin showed good activity against a range of Gram-positive organisms according to SENTRY data (from various geographical areas including the US and Europe), with minimum concentrations inhibiting 90% of strains (MIC₉₀) values ≤2 mg/L for S. epidermidis and 0.5 mg/L for S. pneumoniae (penicillin-susceptible or -resistant strains), viridans group and β-haemolytic streptococci.

In a Canadian survey involving 4151 clinical isolates, gatifloxacin was active against most Gram-positive organisms tested (MIC₉₀ values 0.25 to 16 mg/L) except Enterococcus faecalis (>16 mg/L) and vancomycin-resistant enterococci (32 mg/L). Gatifloxacin was more active than either ciprofloxacin or levofloxacin against 1128 Gram-positive isolates from patients with cancer. Gatifloxacin was also active against Mycoplasma hominis (MIC₉₀0.25 mg/L), Ureaplasma urealyticum (MIC₉₀0.5 mg/L), Chlamydia pneumoniae (MIC₉₀0.25 mg/L) and Mycobacterium tuberculosis (MIC₉₀ values 0.03land 0.25 mg/L).

The drug was active against a range of Enterobacteriaceae, including Escherichia coli, according to data from the SENTRY surveillance study, with MIC₉₀ values of 0.06 to 4 mg/L.

Gatifloxacin, ciprofloxacin and trovafloxacin were all very active against Haemophilus influenzae and Moraxella catarrhalis in the SENTRY survey, with 100% of organisms susceptible at breakpoint and MIC₉₀ values ≤0.03 mg/L. In smaller in vitro studies, gatifloxacin was active against a range of other Gram-negative bacteria, including Campylobacter jejuni (MIC₉₀4 mg/L) and Legionella spp. (MIC₉₀ 0.016 to 0.03 mg/L).

Gatifloxacin MIC₉₀ values ranged from 0.25 to 4 mg/L against most anaerobes tested in four surveys (involving 92 to 351 clinical isolates), but other studies found higher MIC₉₀ values for some Bacteroides spp. (8 to 32 mg/L).

Resistance to fluoroquinolones is mediated either by changes in the target site (DNA gyrase or topoisomerase IV) or changes that reduce intracellular drug accumulation; highly fluoroquinolone-resistant bacteria require multiple mutations in several genes (including gyrA, parC and those encoding for efflux). As gatifloxacin targets both DNA gyrase and topoisomerase IV, multiple mutations are required for the development of resistance.

The postantibiotic effects (PAEs) of gatifloxacin against S. pneumoniae, E. faecalis, K. pneumoniae and S. aureus ranged from 0.5 to 4.1 hours in two in vitro studies. Pre-exposure concentrations of gatifloxacin of 4 and 10 times the MIC (suprainhibitory concentrations producing longer PAEs) were within clinically achievable gatifloxacin concentrations for strains of S. pneumoniae, E. faecalis, S. aureus, E. coli and Pseudomonas aeruginosa, suggesting that serum gatifloxacin concentrations exceed the MICs during the entire 24-hour dosage interval recommended for the drug.

In animal investigations, gatifloxacin was effective in treating a range of infections (e.g. otitis media, pneumonia, systemic infection, meningitis) and was at least as effective as ciprofloxacin, levofloxacin, norfloxacin, meropenem, metronidazole and cefotaxime.

The absolute bioavailability of oral gatifloxacin is 96% and the oral and intravenous formulations are considered to be bioequivalent. Mean maximum serum or plasma concentrations (C_max) range from 3.4 to 4.5 mg/L with the recommended dose of oral gatifloxacin (400mg) and are slightly higher (4.5 or 5.5 mg/L) with intravenous gatifloxacin 400mg. C_max is attained 0.8 to 2 hours after oral administration and is linearly correlated with gatifloxacin dose in the range 100 to 800mg for the oral and 200 to 800mg for the intravenous formulation.

Steady-state serum or plasma gatifloxacin concentrations are reached after 2 to 3 days of administration. The mean elimination half-life (t½β) is 6.8 to 9.3 hours with oral gatifloxacin 400mg and is similar with the intravenous formulation.

Like other fluoroquinolones, gatifloxacin has a high apparent volume of distribution (1.6 or 1.7 L/kg with oral and 1.5 L/kg with intravenous administration) and exhibits low serum protein binding (20%).

Gatifloxacin generally penetrates well to target tissues and body fluids. Mean penetration ratios (tissue or fluid to serum or plasma drug concentration ratios) are ≥1.5 at respiratory system sites (alveolar macrophages, bronchial mucosa and epithelial lining fluid, lung parenchyma and paranasal sinus mucosa) and range from 0.99 to 2.01 at reproductive system sites (endometrium, portio vaginalis, uterine cervix, prostatic fluid and seminal fluid). Urine gatifloxacin concentrations are high; the mean peak concentration of the drug in urine is 675 mg/L after a single dose of oral gatifloxacin 400mg.

Gatifloxacin undergoes minimal metabolism and is excreted primarily by the kidney. Depending on the urine sampling interval, 65 to 90.2% of a single dose of oral gatifloxacin 400mg is recovered unchanged in the urine; cumulative faecal recovery of unchanged drug is 5.6 or 5.7% of the total dose.

Although the pharmacokinetic properties of gatifloxacin vary modestly with gender, advanced age and hepatic function, these variations are not considered clinically significant. However, gatifloxacin elimination decreases as a function of creatinine clearance (CL_cr) and patients with moderate to severe renal impairment should receive a reduced dose of the drug. Haemodialysis removes 14% and continuous ambulatory peritoneal dialysis removes 11% of a single oral dose of gatifloxacin 400mg.

In contrast to some older fluoroquinolones, absorption of orally administered gatifloxacin is not markedly affected by food or milk intake, but is reduced by administration of aluminium, magnesium or iron salts within 2 hours of administration of the fluoroquinolone. Gatifloxacin coadministration increases mean serum digoxin concentrations by 12%, suggesting that individuals receiving both these drugs should be monitored for digoxin toxicity, although digoxin toxicity in a patient receiving gatifloxacin has not been reported to date. Concomitant administration of probenecid and gatifloxacin significantly increases systemic exposure to gatifloxacin. Gatifloxacin does not inhibit the cytochrome P450 (CYP) system and thus is not expected to interfere with CYP-dependent metabolism of drugs.

Gatifloxacin has been evaluated in the treatment of adults with a wide range of infectious diseases in numerous clinical trials conducted in many countries.

In randomised, double-blind, trials in hospitalised patients or outpatients with CAP, oral or intravenous gatifloxacin 400mg once daily produced clinical response rates of 86.8 to 98.0% and bacterial eradication rates of 83.1 to 100% (up to 28 days post-treatment). Response rates in recipients of gatifloxacin were broadly similar to those achieved in patients who received amoxicillin/clavulanic acid, ceftriaxone (with or without erythromycin) with or without stepdown to clarithromycin, levofloxacin or clarithromycin.

Gatifloxacin (200 or 400mg once daily for 5 days) showed clinical and bacteriological efficacy statistically equivalent to that of a 10-day course of amoxicillin/clavulanic acid (500/125mg three times daily) 1 to 3 days after the end of treatment and at early follow up (7 to 14 days post-treatment) in patients with AECB in a trial conducted in Europe.

The clinical efficacy of oral gatifloxacin (administered for 5 to 10 days) was similar to that of orally administered clarithromycin, trovafloxacin or amoxicillin/clavulanic acid (administered for 5 to 14 days) in trials conducted in patients with acute sinusitis. In a published trial, 93% of patients treated with gatifloxacin 400 mg/day and 90% of those receiving clarithromycin 500mg twice daily had a response defined as clinical success at the test-of-cure assessment (7 to 14 days after the end of treatment). Preliminary results showed that clinical response rates were 88 and 87% for gatifloxacin 400 mg/day and trovafloxacin 200 mg/day, respectively (7 to 14 days after the end of treatment); clinical response rates in recipients of gatifloxacin 400 mg/day or amoxicillin/clavulanic acid 500/125mg three times a day were 85.3 and 82.3%, respectively, at a similar timepoint.

Gatifloxacin, administered as a single 400mg oral dose to patients with uncomplicated UTIs, produced clinical response rates of 81 and 93% in two randomised double-blind trials. Clinical response rates in patients treated with gatifloxacin 200mg daily for three days were 85 and 95%. Response rates were similar to those obtained in patients treated for 3 days with ciprofloxacin 250 or 100mg twice daily. Rates of bacterial eradication were also similar across all of the treatment groups in the two studies.

In patients with complicated UTIs, gatifloxacin produced clinical and bacteriological response rates that were similar to those achieved with ciprofloxacin. Gatifloxacin 400 mg/day for up to 14 days achieved clinical response rates of 69, 93 and 94%, compared with 65 and 91% in recipients of ciprofloxacin. In the single trial that compared gatifloxacin with levofloxacin, clinical responses were documented in 94 and 87% of patients, respectively.

Preliminary data from a large randomised trial showed that single-dose treatment with gatifloxacin (400 or 600mg) was as effective as a single 400mg dose of ofloxacin in men and women with uncomplicated gonorrhoea.

The clinical and bacteriological efficacy of gatifloxacin 400mg once daily for 7 to 10 days was similar to that of levofloxacin 500mg once daily for 7 to 10 days in 407 treated patients with uncomplicated skin and soft tissue infections.

Information on the tolerability of gatifloxacin has been obtained from phase II and III trials that included more than 5000 adults with a wide range of infections. Gatifloxacin, administered orally or intravenously, is usually well tolerated; treatment with the drug was seldom discontinued because of adverse events in clinical trials.

More than 90% of adverse events reported as being related to treatment with oral gatifloxacin (400mg once daily) were mild to moderate in severity. The most frequently reported adverse events in 3021 recipients of oral gatifloxacin 400mg once daily were nausea (incidence 8%), vaginitis (6%), diarrhoea (4%) and headache (4%). The tolerability profile of gatifloxacin was broadly similar to that of comparator drugs (ciprofloxacin, levofloxacin, ofloxacin, ceftriaxone, cefuroxime axetil or clarithromycin). In clinical trials, the adverse events that most commonly led to the discontinuation of oral gatifloxacin treatment were gastrointestinal symptoms, notably nausea, vomiting, diarrhoea and abdominal pain.

Preliminary results of a phase IV postmarketing study showed that gatifloxacin was usually well tolerated by patients with community-acquired respiratory tract infections (acute bacterial sinusitis, AECB and CAP) receiving treatment in the community setting. As documented in patients receiving gatifloxacin in comparative or noncomparative trials, nausea (incidence 4%) was the most common adverse event in the 15 625 patients included in this analysis; dizziness, diarrhoea and headache were documented as being the other most common events (incidence 1.7, 1.4 and 0.9%, respectively).

The most frequently reported adverse events in recipients of intravenous gatifloxacin 400mg once daily were injection site reactions (incidence 21 %), and gastrointestinal symptoms [nausea (10%), constipation (6%), diarrhoea (6%) and vaginitis (5%)].

There are no published reports of phototoxicity in patients with various infections receiving treatment with gatifloxacin at recommended dosages.

Gatifloxacin is available as an oral and intravenous formulation in some countries; in Europe, only the oral formulation is available at present. Oral gatifloxacin may be administered without regard to meals. No adjustment in dosage is required when switching between intravenous and oral formulations of gatifloxacin.

The recommended dosage for treatment of uncomplicated UTIs, uncomplicated urethral gonorrhoea and uncomplicated cervical and/or rectal gonorrhoea is a single dose of gatifloxacin 400mg; uncomplicated UTIs may also be treated with gatifloxacin 200mg once daily for 3 days. For all other indications, 400mg once daily is recommended. The recommended duration of treatment is 5 days for AECB, 7 to 10 days for complicated UTIs and pyelonephritis, 10 days for acute sinusitis and 7 to 14 days for CAP.

In patients with moderate to severe renal dysfunction [CL_cr < 2.4 L/h (<40 ml/min)] and/or those receiving haemodialysis or CAPD, the dosage of gatifloxacin should be reduced according to the recommended dosage scheme. In patients receiving haemodialysis, gatifloxacin should be administered after completion of the dialysis session.

Gatifloxacin is not recommended for the treatment of children, adolescents aged <18 years, nursing mothers or during pregnancy as well as in patients with known QTc interval prolongation or hypokalaemia and those receiving drugs known to prolong the QTc interval (such as class IA or class III antiarrhythmic agents). Patients receiving gatifloxacin with concomitant digoxin or warfarin should be carefully monitored for signs of digoxin or warfarin toxicity. In patients with diabetes mellitus receiving oral hypoglycaemics [e.g. glibenclamide (glyburide)] or insulin, careful daily monitoring of blood glucose is recommended.