Moxifloxacin, a New Antibiotic Designed...
Moxifloxacin (BAY 12-8039) is a new 8-methoxy-fluoroquinolone antibacterial agent. The minimum inhibitory concentration for 90% of organisms (MIC90) is less than 0.25 mg/L for commonly isolated community-acquired respiratory tract pathogens including penicillin-susceptible and -resistant Streptococcus pneumoniae, Haemophilus sp, and Moraxella catarrhalis, and less than 1.0 mg/L for atypical pathogens such as Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila. To date, emergence of resistance to moxifloxacin has been uncommon, including selection of resistance under experimental conditions (methicillin-sensitive Staphylococcus aureus, S. pneumoniae). A postantibiotic effect is observed for both gram-positive and gram-negative bacteria. Human pharmacokinetics in healthy volunteers after a single 400-mg oral dose were mean maximum concentration (Cmax) 3.2 mg/L, area under the curve (AUC) 37 mg
hour/L, and terminal elimination half-life 12.0 hours. At steady-state, C max and AUC were approximately 4.5 mg/L and 48 mg
hour/L, respectively. Because of a balanced system of excretion, no dosage adjustments are required in patients with renal or hepatic impairment. Moxifloxacin also has excellent penetration into upper and lower respiratory tissues. Laboratory pharmacodynamic models suggest that MIC and AUC values predict therapeutic response. Notably, the drug can be administered once/day and is not associated with drug interactions secondary to altered hepatic metabolism. In addition, since its metabolism does not involve the cytochrome P450 system, many common drug interactions are absent. The agent is being investigated in clinical trials and shows promise as a safe and effective once-daily treatment of respiratory infections. In addition, its chemical structure and pharmacokinetic and pharmacodynamic properties indicate that it has enhanced potential to minimize emergence of bacterial resistance, which should make it an excellent choice for treating respiratory tract infections now and in the future.
Fluoroquinolones with systemic activity have been available for clinical use in the United States since 1987. Each currently available drug in this class has distinct microbiologic, pharmacokinetic, pharmacodynamic, and safety profiles. The older systemic quinolones (e.g., ciprofloxacin, ofloxacin) are characterized by broad-spectrum antibacterial in vitro activity, although borderline susceptibility and emerging resistance to some organisms were reported, especially for respi-ratory tract pathogens. In general, for older fluoroquinolones, in vitro activity against gram-positive organisms is not as potent as activity against gram-negative bacteria. To address these limitations, research efforts focused on modifying the quinolone molecule. Several newer agents (e.g., moxifloxacin, gatifloxacin), which became available in the late 1990s, appear to be valuable alternatives for patients with gram-positive or gram-negative respiratory tract infections.
Community-acquired respiratory tract infections, such as sinusitis, acute exacerbations of chronic bronchitis, and pneumonia, are increasingly common and are in part responsible for escalating health care costs. These infections are often bacterial, caused by Streptococcus pneumoniae, Haemophilus influenzae,Haemophilus parainfluenzae, Moraxella catarrhalis, Klebsiella pneumoniae, and Staphylococcus aureus and atypical pathogens such as Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila. Rapid and increasing resistance to commonly administered macrolide, beta-lactam, and penicillin antimicrobials by some of these pathogens has been reported.
Resistance among these organisms in the United States rose dramatically over the past 2 decades, with beta-lactamase production evident in approximately 40% of H. influenzae and more than 95% of M. catarrhalis isolates. In addition, almost 20% of pneumococci are highly resistant to penicillin and simultaneously resistant to other beta-lactam and macrolide antibiotics; 43.8% of S. pneumoniae strains isolated from patients in the United States with respiratory tract infections during 1997 were resistant to penicillin (27.8% intermediate, 16% high-level resistance). Another survey during the 1996-1997 respiratory season reported a significant rise in resistance levels, as approximately 34% of 9190 isolates of S. pneumoniae were penicillin resistant. Many of these resistant strains showed intermediate or high-level resistance to beta-lactams and macrolides, including amoxicillin-clavulanate, cefuroxime, ceftriaxone, and clarithromycin. In contrast, fluoroquinolones are very active against all pneumococcal isolates, independent of penicillin susceptibility. However, some of the older fluoroquinolones have only borderline activity against some isolates of S. pneumoniae, Streptococcus sp, and S. aureus.
The cited resistance rates were for hospital-acquired pathogens. The exact prevalence of resistant organisms in the community remains to be determined. In addition, reporting of resistance is based mainly on hospital-acquired pathogens. Resistance reporting, which is based on breakpoints and not on a drug's ability to cure an infection in patients, may or may not reflect clinical management problems, and reporting of resistance in hospital-acquired pathogens may or may not apply to treatment of respiratory infections in the community (out of hospital setting).
Rapid and increasing development of resistance of community-acquired respiratory tract pathogens to conventional antimicrobials suggests that some geographic locations may require different treatment strategies. An ideal new antimicrobial for treating these infections should have activity against all predominant respiratory pathogens, including the growing number of resistant organisms; have rapid killing; have low potential for inducing resistance; have optimal pharmacokinetic and pharmacodynamic profiles; show excellent tissue penetration; have an acceptable safety profile; and produce high clinical response rates. Several newer fluoro-quinolones with enhanced gram-positive activity, including grepafloxacin, trovafloxacin, moxi-floxacin, and gatifloxacin, have received approval from the Food and Drug Administration or are under review for the treatment of selected respiratory tract infections.
Although moxifloxacin (BAY 12-8039) has activity against a broad range of pathogens and may be effective in treating infections outside the respiratory tract, it was designed to be a "respiratory" drug. Most patients treated with moxifloxacin have had underlying upper or lower respiratory tract infections.
Moxifloxacin (BAY 12-8039) is a new 8-methoxy-fluoroquinolone antibacterial agent. The minimum inhibitory concentration for 90% of organisms (MIC90) is less than 0.25 mg/L for commonly isolated community-acquired respiratory tract pathogens including penicillin-susceptible and -resistant Streptococcus pneumoniae, Haemophilus sp, and Moraxella catarrhalis, and less than 1.0 mg/L for atypical pathogens such as Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila. To date, emergence of resistance to moxifloxacin has been uncommon, including selection of resistance under experimental conditions (methicillin-sensitive Staphylococcus aureus, S. pneumoniae). A postantibiotic effect is observed for both gram-positive and gram-negative bacteria. Human pharmacokinetics in healthy volunteers after a single 400-mg oral dose were mean maximum concentration (Cmax) 3.2 mg/L, area under the curve (AUC) 37 mg
hour/L, and terminal elimination half-life 12.0 hours. At steady-state, C max and AUC were approximately 4.5 mg/L and 48 mg
hour/L, respectively. Because of a balanced system of excretion, no dosage adjustments are required in patients with renal or hepatic impairment. Moxifloxacin also has excellent penetration into upper and lower respiratory tissues. Laboratory pharmacodynamic models suggest that MIC and AUC values predict therapeutic response. Notably, the drug can be administered once/day and is not associated with drug interactions secondary to altered hepatic metabolism. In addition, since its metabolism does not involve the cytochrome P450 system, many common drug interactions are absent. The agent is being investigated in clinical trials and shows promise as a safe and effective once-daily treatment of respiratory infections. In addition, its chemical structure and pharmacokinetic and pharmacodynamic properties indicate that it has enhanced potential to minimize emergence of bacterial resistance, which should make it an excellent choice for treating respiratory tract infections now and in the future.
Fluoroquinolones with systemic activity have been available for clinical use in the United States since 1987. Each currently available drug in this class has distinct microbiologic, pharmacokinetic, pharmacodynamic, and safety profiles. The older systemic quinolones (e.g., ciprofloxacin, ofloxacin) are characterized by broad-spectrum antibacterial in vitro activity, although borderline susceptibility and emerging resistance to some organisms were reported, especially for respi-ratory tract pathogens. In general, for older fluoroquinolones, in vitro activity against gram-positive organisms is not as potent as activity against gram-negative bacteria. To address these limitations, research efforts focused on modifying the quinolone molecule. Several newer agents (e.g., moxifloxacin, gatifloxacin), which became available in the late 1990s, appear to be valuable alternatives for patients with gram-positive or gram-negative respiratory tract infections.
Community-acquired respiratory tract infections, such as sinusitis, acute exacerbations of chronic bronchitis, and pneumonia, are increasingly common and are in part responsible for escalating health care costs. These infections are often bacterial, caused by Streptococcus pneumoniae, Haemophilus influenzae,Haemophilus parainfluenzae, Moraxella catarrhalis, Klebsiella pneumoniae, and Staphylococcus aureus and atypical pathogens such as Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila. Rapid and increasing resistance to commonly administered macrolide, beta-lactam, and penicillin antimicrobials by some of these pathogens has been reported.
Resistance among these organisms in the United States rose dramatically over the past 2 decades, with beta-lactamase production evident in approximately 40% of H. influenzae and more than 95% of M. catarrhalis isolates. In addition, almost 20% of pneumococci are highly resistant to penicillin and simultaneously resistant to other beta-lactam and macrolide antibiotics; 43.8% of S. pneumoniae strains isolated from patients in the United States with respiratory tract infections during 1997 were resistant to penicillin (27.8% intermediate, 16% high-level resistance). Another survey during the 1996-1997 respiratory season reported a significant rise in resistance levels, as approximately 34% of 9190 isolates of S. pneumoniae were penicillin resistant. Many of these resistant strains showed intermediate or high-level resistance to beta-lactams and macrolides, including amoxicillin-clavulanate, cefuroxime, ceftriaxone, and clarithromycin. In contrast, fluoroquinolones are very active against all pneumococcal isolates, independent of penicillin susceptibility. However, some of the older fluoroquinolones have only borderline activity against some isolates of S. pneumoniae, Streptococcus sp, and S. aureus.
The cited resistance rates were for hospital-acquired pathogens. The exact prevalence of resistant organisms in the community remains to be determined. In addition, reporting of resistance is based mainly on hospital-acquired pathogens. Resistance reporting, which is based on breakpoints and not on a drug's ability to cure an infection in patients, may or may not reflect clinical management problems, and reporting of resistance in hospital-acquired pathogens may or may not apply to treatment of respiratory infections in the community (out of hospital setting).
Rapid and increasing development of resistance of community-acquired respiratory tract pathogens to conventional antimicrobials suggests that some geographic locations may require different treatment strategies. An ideal new antimicrobial for treating these infections should have activity against all predominant respiratory pathogens, including the growing number of resistant organisms; have rapid killing; have low potential for inducing resistance; have optimal pharmacokinetic and pharmacodynamic profiles; show excellent tissue penetration; have an acceptable safety profile; and produce high clinical response rates. Several newer fluoro-quinolones with enhanced gram-positive activity, including grepafloxacin, trovafloxacin, moxi-floxacin, and gatifloxacin, have received approval from the Food and Drug Administration or are under review for the treatment of selected respiratory tract infections.
Although moxifloxacin (BAY 12-8039) has activity against a broad range of pathogens and may be effective in treating infections outside the respiratory tract, it was designed to be a "respiratory" drug. Most patients treated with moxifloxacin have had underlying upper or lower respiratory tract infections.