Gatifloxacin

Gatifloxacin (Tequin®) is an 8-methoxy fluoroquinolone approved in the US for use in the treatment of community-acquired pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB), acute sinusitis, uncomplicated and complicated urinary tract infections (UTIs), pyelonephritis, gonorrhoea and uncomplicated skin and skin structure infections.

Gatifloxacin has a broad spectrum of antibacterial activity in vitro and good clinical and bacteriological efficacy in patients with indicated infections following once-daily administration by the intravenous or oral routes. It is generally well tolerated; the most common adverse events are associated with the gastrointestinal tract and CNS. Recent approvals for the use of gatifloxacin in the treatment of CAP due to multidrug-resistant Streptococcus pneumoniae (MDRSP) and in uncomplicated skin and skin structure infections extend the role of this drug in the treatment of bacterial infections in the US.

Gatifloxacin, an 8-methoxy fluoroquinolone with a 3-methylpiperazinyl substitution at C-7, inhibits bacterial DNA gyrase and topoisomerase IV. It has a broad spectrum of activity against Gram-positive and Gram-negative aerobic bacteria and atypical bacteria, but has limited activity against most anaerobes.

Gatifloxacin is active against S. pneumoniae, including penicillin-resistant strains, and oxacillin-susceptible Staphylococcus aureus, with minimum concentrations required to inhibit 90% of strains (MIC90) of ≤0.5 mg/L. The percentage of Gram-positive isolates susceptible to gatifloxacin is similar to those of gemifloxacin, moxifloxacin and levofloxacin, and higher than that of ciproflox-acin. Gatifloxacin activity against enterococci is very limited.

Haemophilus influenzae and Moraxella catarrhalis are susceptible to gatifloxacin (both MIC90 ≤0.03 mg/L), and gatifloxacin is active against Neisseria gonorrhoeae, including ciprofloxacin-resistant and β-lactamase-positive strains (MIC₉₀ 0.016–0.06 mg/L). Gatifloxacin has good activity against Enterobacter spp. (MIC₉₀ 0.5–1 mg/L), Klebsiella spp. (MIC₉₀ 0.25–2 mg/L) and most isolates of Escherichia coli (MIC₉₀ 0.06 to >4 mg/L). Activity against Proteus mirabilis is variable (MIC₉₀ 2–16 mg/L). Like most other fluoroquinolones, gatifloxacin has poor activity against Pseudomonas aeruginosa (in North America, 61–67% of isolates were susceptible to gatifloxacin). The atypical respiratory organisms Chlamydophilia (Chlamydia) pneumoniae, Mycoplasma pneumoniae and Legionella spp. are also susceptible to gatifloxacin (MIC₉₀ 0.03–0.5 mg/L).

Surveillance programmes in the US have found that bacterial resistance to gatifloxacin among respiratory pathogens, including S. pneumoniae, is low (≤1%); in vitro studies suggest that gatifloxacin has a lower potential to select for mutants than older fluoroquinolones. The activity of gatifloxacin is concentration-dependent, and as with other fluoroquinolones, area under the concentration-time curve (AUC): MIC ratios of ≈30 or greater and >100–125 are considered predictors of clinical and bacteriological efficacy against S. pneumoniae and Gram-negative bacteria, respectively. In patients receiving oral gatifloxacin 400mg once daily, the probability of achieving an AUC: MIC ratio ≥30 for S. pneumoniae is 97.6%. Gatifloxacin shows a post-antibiotic effect against a range of bacteria.

The pharmacokinetic profile of gatifloxacin is similar after oral or intravenous administration and steady state is achieved after 3 days. Gatifloxacin concentrations achieved in most target tissues and fluids generally exceed the MIC₉₀ values for common pathogens at these sites. It is primarily excreted as unchanged drug through the kidneys, and dosage adjustments are recommended for patients with creatinine clearance <2.4 L/h (<40 mL/min). Coadministration of iron, zinc, magnesium or aluminium (but not calcium) salts significantly reduces the absorption of orally-administered gatifloxacin. Gatifloxacin increases plasma digoxin concentrations in some patients, and those receiving both drugs should be monitored for signs of digoxin toxicity. Gatifloxacin does not inhibit cytochrome P450 (CYP) enzymes and is unlikely to affect CYP-dependent metabolism of drugs.

A number of randomised, comparative trials have shown that once-daily gatifloxacin at US-approved dosages was as effective as comparator agents in the treatment of adults with a range of bacterial infections affecting the respiratory tract, genitourinary tract and skin or skin structures. In most studies, the primary endpoint was the clinical cure rate at the test-of-cure visit; for genitourinary tract infections, it was the bacteriological response.

In patients with CAP, intravenous and/or oral gatifloxacin 400mg once daily for 7–14 days achieved a clinical cure rate similar to that seen with comparators, including levofloxacin, clarithromycin and ceftriaxone/clarithromycin (95–97% vs 91–94%). Bacteriological eradication rates were 97–98% in gatifloxacin recipients and 92–93% in patients receiving comparator drugs. Gatifloxacin achieved 100% clinical and bacteriological success rates in 27 patients with CAP caused by MDRSP, based on data largely from post-marketing studies.

Oral gatifloxacin 400mg once daily for 5 days was as effective as standard 7- to 10-day regimens of gatifloxacin, clarithromycin or amoxicillin/clavulanic acid in patients with AECB. Clinical cure and bacteriological eradication rates were 79–89% and 87–98% with short-course gatifloxacin compared with 82–89% and 79–98% with the comparator regimens.

In patients with acute uncomplicated maxillary sinusitis of presumed bacterial origin, oral gatifloxacin 400mg once daily for 10 days achieved clinical cure rates similar to those with clarithromycin (14 days) or amoxicillin/clavulanic acid (10 days) [80–93% vs 72–90%]. Bacteriological efficacy was not assessed.

Treatment with either a single oral dose of gatifloxacin 400mg or gatifloxacin 200mg once daily for 3 days achieved similar bacteriological response rates to those seen with ciprofloxacin 250mg twice daily for 3 days in patients with acute uncomplicated UTIs. Clinical response rates were also equivalent to those with ciprofloxacin for the gatifloxacin 200mg regimen and (in one of two trials) single-dose gatifloxacin 400mg. Bacteriological and clinical response rates were also similar between gatifloxacin (400mg once daily) and ciprofloxacin (500mg twice daily), in patients with complicated UTIs or pyelonephritis treated for 7–10 days. Overall, for patients with UTIs including pyelonephritis, per-patient bacteriological response rates were 81–95% for gatifloxacin compared with 82–89% for ciprofloxacin. Clinical response rates were 81–100% versus 85–95%.

A single oral dose of gatifloxacin 400mg was as effective as a single dose of ofloxacin 400mg in patients with uncomplicated gonococcal infection. The per-patient bacteriological eradication rate was ≥99% in both groups. Symptoms resolved in 96% of men in both groups and 72% vs 78% of female gatifloxacin or ofloxacin recipients.

In patients with uncomplicated skin or skin structure infections, gatifloxacin 400mg once daily for 7–10 days achieved similar rates of clinical cure (91% vs 84%) and bacteriological eradication (92% vs 92%) to those seen with levoflox-acin 500mg once daily.

Gatifloxacin is generally well tolerated, with most adverse events being mild in severity. In pooled data from worldwide trials, the most common events related to gatifloxacin were generally associated with the gastrointestinal system (e.g. nausea, diarrhoea) or CNS (e.g. headache, dizziness). In a large, noncomparative post-marketing study, the incidence of gatifloxacin-related adverse events in patients aged ≥80 years was 18% compared with 13% in patients aged ≤79 years.

Disturbances of glucose homeostasis can occur in patients treated with gatifloxacin, particularly in those with diabetes mellitus; severe, sometimes life-threatening, hyper- and hypoglycaemic events have been reported. For example, five serious drug-related adverse events related to glucose homeostasis were reported in the post-marketing study (among >15 000 patients). Occasional cases of torsades de pointes have been reported with gatifloxacin. Gatifloxacin is not associated with phototoxicity, and tendon ruptures and hepatitis occur rarely. 1 The use of trade names is for product identification purposes only and does not imply endorsement.