Review
A new respiratory fluoroquinolone, oral gemifloxacin: a safety profile in context

https://doi.org/10.1016/j.ijantimicag.2004.02.014Get rights and content

Abstract

Gemifloxacin is a broad-spectrum quinolone antibacterial with enhanced potency against Gram-positive bacteria, including multi-drug resistant Streptococcus pneumoniae, and retained potency against Gram-negative bacilli and bacterial strains resistant to other antibiotics. It has proven particularly effective in respiratory and urinary tract infection. This review presents safety data from 6775 patients included in clinical trials, receiving either the recommended 320 mg once daily oral dose of gemifloxacin, or standard dose of other quinolones, macrolides or β-lactams (n=5248). Studies in healthy volunteer and special populations are also reported. Adverse experiences (AEs) were observed in 44.7% of gemifloxacin-treated patients and 47.5% of those who received comparator drugs. Mild gastro-intestinal adverse drug reactions (ADRs) (diarrhoea 5.1%, nausea 3.9%) predominated. Rash, usually maculo-papular and in no case proceeding to more severe eruptions, was observed in 3.6% of those receiving gemifloxacin. A higher incidence of rash (>20%) was observed in young women and was the subject of further study. Adverse drug reactions suspected or probably related to treatment occurred in 17.4% of patients receiving gemifloxacin and in 20% of those receiving comparator antibiotics. Diarrhoea and nausea were experienced by 3.6 and 2.7%, respectively, of gemifloxacin-treated patients (4.6 and 3.2% of comparators), rash by 2.8% (0.6% of comparators) and headache by 1.2% (1.5% of comparators). Gemifloxacin-related vomiting (0.9%), dizziness (0.8%) and taste perversion (0.3%) were uncommon. Treatment discontinuation followed one or more adverse drug reactions in 2.2% of gemifloxacin-treated patients (0.9% due to rash) and 2.1% of comparator-treated patients. A total of 63 deaths (33 receiving gemifloxacin) occurred in the trial population: none were considered related to treatment. A slight prolongation in QT interval (2.56 ms (S.D. ±24.5)) was observed in gemifloxacin-treated patients: no cardiac arrhythmias were reported. There was a low incidence of liver function tests (LFTs) classified as of potential clinical concern: gemifloxacin (0.4–1.2%), comparators (0.2–1.3%). Serious adverse events (SAEs), occurring during but not necessarily related to therapy, occurred in 3.6% of gemifloxacin-treated patients (4.3% of comparators). SAEs related to treatment agents were rare (0.4% in each group) and included rash (0.1%) and elevated liver enzymes (<0.1%). Gemifloxacin was well tolerated by the elderly, those with renal or hepatic impairment and when co-administered with omeprazole, digoxin, theophylline, warfarin (with which there were no significant interactions) and Maalox®. In conclusion, gemifloxacin 320 mg once daily demonstrated a favourable safety and tolerability profile similar to that of comparator antibiotics, including other quinolones.

Introduction

Gemifloxacin is a novel fluorinated, naphthyridone antibacterial agent which retains the excellent activity against Gram-negative pathogens associated with most members of the fluoroquinolone class whilst possessing enhanced potency against Gram-positive bacterial pathogens, notably Streptococcus pneumoniae, exceeding that of other third generation agents [1], [2].

The overall safety profile of the quinolones compares favourably with other antibacterial classes [3] although severe low frequency adverse drug reactions (ADRs) have occurred with a small number of specific quinolones. These have included temafloxacin haemolytic-uraemic syndrome [4], hepatotoxicity caused by trovafloxacin [3], [5], [6] and nephritis and skin reactions caused by tosufloxacin [3]. These agents have exclusively in common the 1 [2], [4] difluorophenyl side chain and such reactions probably do have, at least in part, an immune basis [7]. Severe phototoxicity is known to relate to side chain poly-fluorination and especially to compounds, such as Bay 3118 and clinafloxacin, with 8-chloro substitutions [3], [8], [9]. None of these structural properties applies to gemifloxacin.

Minor class ADRs, affecting the entire group and differing in frequency among class members, include those affecting the CNS, gastro-intestinal tract and skin [3], [8], [10]. Recently, a further class effect, prolongation of the rate corrected QT (QTc) interval (averaging 3–6 ms) similar to that with macrolides, has been recognised [11]. This has, exceptionally, been associated with cardiac arrhythmias in predisposed patients [7], [11], [12], [13], [14].

This review assesses the safety profile of gemifloxacin 320 mg (equivalent to 400 mg mesylate salt) in the context of the known class effects of both the second-generation quinolone antibacterials (ciprofloxacin and levofloxacin) and the more potent third generation congeners, notably the 8-methoxy sub-class—moxifloxacin and gatifloxacin. The safety profile of oral gemifloxacin and comparators is based on clinical trials involving 6775 patients receiving 320 mg gemifloxacin. In addition, results are presented from safety studies in healthy volunteers and special populations. The lack of those serious adverse events (AEs), which have recently been associated with other quinolone agents [3], [7], [11] is highlighted.

Section snippets

Materials and methods

The indications studied in the clinical trials comprised: acute exacerbations of chronic bronchitis (AECB) [9 trials], community-acquired pneumonia (CAP) [4 trials], urinary tract infection (UTI) [4 trials], acute bacterial sinusitis (ABS) [4 trials], skin and skin structure infections [1 trial] and non-gonococcal urethritis [1 trial]. The dose of oral gemifloxacin received was 320 mg once daily for between 5 and 14 days. Comparators, which included oral ciprofloxacin, ofloxacin, levofloxacin,

Demography and exposure

The clinical studies included 12,023 patients, of whom 6775 received oral gemifloxacin 320 mg once daily and 5248 received a comparator. All patients received at least one dose of study medication and were well matched with respect to demographic characteristics (Table 1). The most frequent actual durations of exposure to gemifloxacin were 4–5 days (3009 patients: 44.4% of 6775 total), 6–7 days (1911: 28.2%) and 8–10 days (812: 12.0%): 1903 (36.3%) patients received various comparators for 6–7

Discussion

The evolution of the quinolones during the 1990s has led to increasingly broad-spectrum compounds with markedly enhanced potency against Gram-positive pathogens. However, this has not been without molecular casualties [24] and a number of agents have been withdrawn or abandoned. This has resulted from haemolytic-uraemic syndrome (temafloxacin [4]), severe hepatic reactions (trovafloxacin [3], [25]), nephritis, dermatological and haematological reactions (tosulfoxacin [11]), severe phototoxicity

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