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Fluoroquinolones. Garenoxacin

Overview

The fluoroquinolones have proved to be one of the most commercially and clinically successful antibacterial classes for the treatment of community-acquired pneumonia.

Their broad spectrum of efficacy (improving with more recent launches against respiratory pathogens), safety, and convenient once-daily dosing have earned them a favorable position in the minds of clinicians.

Their main advantages in community-acquired pneumonia have been their broad-spectrum activity, particularly their high H. influenzae activity, compared with other agents such as the macrolides.

Also, their availability in oral and parenteral form has provided an important clinical advantage. The concerns associated with this class of agents include their potential to induce abnormal cardiac conductions (i.e., prolongation of the QT interval on electrocardiograms) and liver toxicity, which was associated with one drug (Pfizer’s trovafloxacin) that was subsequently withdrawn.

Also, fluoroquinolones currently on the market are contraindicated for use in children owing to cartilage growth concerns. Emerging fluoroquinolones in development provide potential advances over currently marketed agents, mainly in terms of higher potency against respiratory pathogens, retained activity against resistant pathogens, and a favorable safety profile.

Mechanism Of Action

Fluoroquinolones act by inhibiting bacterial topoisomerase IV and DNA gyrase, which are enzymes required for DNA replication, transcription, repair, and recombination. The exact nature of the interaction of quinolones with their target enzymes is not completely understood.

However, this interaction blocks the progression of DNA replication, leading to strand breaks and rapid cell death. These agents are potent inhibitors of nucleic acid synthesis.

Garenoxacin

Garenoxacin (Schering-Plough/Toyama’ s T-3811, des-F(6)-quinolone garenoxacin) is a potent, oral, broad-spectrum quinolone that has been submitted to the FDA for approval.

Garenoxacin

Garenoxacin has a broad spectrum of activity, similar to that displayed by the other new fluoroquinolones.

Garenoxacin shows the highest antibacterial activity against S. pneumoniae when compared with ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin, and it is more potent than ciprofloxacin, levofloxacin, and moxifloxacin against anaerobes.

It is also highly potent against ciprofloxacin-resistant strains of S. pneumoniae and Staphylococcus aureus, and like gatifloxacin, it is associated with a lower risk of promoting resistance development.

Garenoxacin has favorable pharmacokinetics and is expected to be administered as an oral or injectable once-daily formulation.

A 28-day Phase II trial compared the safety and tolerability of garenoxacin, dosed orally at 400 mg once daily, with that of placebo in 45 healthy volunteers; the trial showed the drug to be both safe and well tolerated, with no serious adverse effects.

Similarly, Phase II clinical trial results for the IV formulation show garenoxacin to be safe and well tolerated, with no serious adverse effects. No clinically significant effects on liver function and QT interval have been reported. In an open-label, multicenter, noncomparative study involving 208 patients with community-acquired pneumonia, researchers observed clinical cure in 161 (91%) of 176 evaluable patients treated with garenoxacin dosed orally at 400 mg once daily for ten days. In 125 bacteriologic-evaluable patients, 178 (89%) of 199 isolated pathogens were eradicated after treatment with garenoxacin.

The same study found that 25% of patients experienced more than one adverse event, including diarrhea (5%), nausea (4%), headache (2%), vaginitis (2%), dizziness (2%), and dry mouth (1%).

Garenoxacin

At present, fluoroquinolones are not approved for children younger than 18 years because they have been shown to cause arthropathy and cartilage damage in immature animals. (Even so, ciprofloxacin has been used in children for compassionate reasons — for example, life-threatening infections in pediatric patients with cystic fibrosis.) However, toxicological studies of garenoxacin’s effect on immature and juvenile joint cartilage have shown that this drug does not induce cartilage defects or significant arthropathy in immature rats or dogs. If its low chondrotoxic potential proves to be clinically relevant, garenoxacin could be used more widely than other emerging fluoroquinolones; indeed, it could become the first fluoroquinolone to be approved for use in all age-groups.

Overall, garenoxacin provides a favorable activity and safety profile. However, the agent may be the fourth respiratory fluoroquinolone on the market (following gatifloxacin, moxifloxacin, and gemifloxacin). Schering-Plough has significant marketing prowess in the respiratory market, which gives it a significant advantage in promoting the product.

However, Schering-Plough recently entered into a strategic agreement with Bayer to market Bayer’s moxifloxacin in the United States. It is unclear at this time whether this agreement will affect the development and prioritization of garenoxacin. Overall, however, garenoxacin is likely to face stiff competition in the community-acquired pneumonia fluoroquinolone market.

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