gemifloxacin and Haemophilus-Infections

This review focuses on the activity of gemifloxacin, a new respiratory fluoroquinolone, against the two most important bacterial pathogens associated with lower respiratory tract infections, namely Streptococcus pneumoniae and Haemophilus influenzae.

Topics: Anti-Bacterial Agents; Drug Resistance, Multiple; Fluoroquinolones; Gemifloxacin; Haemophilus Infections; Haemophilus influenzae; Humans; Naphthyridines; Pneumococcal Infections; Streptococcus pneumoniae

Community-acquired lower respiratory tract infections (LRTIs) are more prevalent in the elderly than in children and younger adults and form a significant proportion of all consultations and hospital admissions in this older age group. Furthermore, in a world of increasing life expectancy the trend seems unlikely to be reversed. Antimicrobial treatment of community-acquired pneumonia (CAP) must cover Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis, and in many circumstances should also cover the intracellular (atypical) pathogens. In contrast, acute exacerbations of chronic bronchitis (AECB) are mainly associated with H. influenzae and S. pneumoniae and not with atypical bacteria: in severe cases, other Gram-negative bacteria may be involved. Frequently in LRTIs, the aetiology of the infection cannot be identified from the laboratory specimens and treatment has to be empirical. In such situations it is important to not only to use an antibiotic that covers all likely organisms, but also one that has good activity against these organisms given the local resistance patterns. Gemifloxacin is a new quinolone antibiotic that targets pneumococcal DNA gyrase and topoisomerase IV and is highly active against S. pneumoniae including penicillin-, macrolide- and many ciprofloxacin-resistant strains, as well as H. influenzae and the atypical pathogens. In clinical trials in CAP and AECB, gemifloxacin has been shown to be as effective a range of comparators and demonstrated an adverse event profile that was in line with the comparator agents. In one long-term study in AECB significantly more patients receiving gemifloxacin than clarithromycin remained free of recurrence after 26 weeks. The improved potency, broad spectrum of activity and proven clinical and bacteriological efficacy and safety profile should make it a useful agent in the 21st century battle against community-acquired LRTIs.

Topics: Anti-Bacterial Agents; Bronchitis; Chlamydophila Infections; Community-Acquired Infections; Fluoroquinolones; Gemifloxacin; Gram-Negative Bacterial Infections; Haemophilus Infections; Humans; Legionnaires' Disease; Moraxellaceae Infections; Naphthyridines; Pneumococcal Infections; Pneumonia, Bacterial; Pneumonia, Mycoplasma; Staphylococcal Infections

The ability to identify agents with the optimal combination of potency, pharmacokinetics and pharmacodynamics should help to maximize bacteriological cure and thus minimize the potential for selection and spread of resistance. Gemifloxacin demonstrated excellent correlation between efficacy and the AUC0-24h/MIC ratio whereas there was little correlation with time above MIC. Thus, gemifloxacin is similar to other quinolones in that it is the amount of drug present, not the frequency of administration, that determines antibacterial effect. In a neutropenic murine thigh model of infection, caused by Gram-negative bacilli, a AUC0-24h/MIC ratio of approximately 100 was necessary to protect >90% of the animals, which is similar to data reported previously for other quinolones. However, in order to achieve the same protection in an immunocompetent murine infection caused by Streptococcus pneumoniae, the AUC-24h/MIC ratio was approximately 25. The magnitude of this AUC0-24h/MIC ratio did not alter for strains exhibiting penicillin or macrolide resistance. Importantly, when gemifloxacin was examined against strains of S. pneumoniae with well-characterized ciprofloxacin resistance (including mutations in gyrase, parC and parE as well as efflux strains) there was little impact on the in vivo efficacy. Overall, the data showed a trend towards a decrease in the AUC0-24h/MIC ratio for these more resistant strains. The lower AUC0-24h/MIC ratio was especially noticeable for the efflux mutants suggesting that the quinolone efflux mechanism may be down-regulated in vivo and may be of minimal relevance to the clinical activity of gemifloxacin against S. pneumoniae. The efficacy of gemifloxacin, in comparison with other oral agents used to treat respiratory infections, has also been evaluated in a rat model using doses, and therefore AUC0-24h/MIC ratios, that approximate those in man. These data confirm the excellent activity of gemifloxacin against strains of Haemophilus influenzae and S. pneumoniae, including those demonstrating penicillin, macrolide and quinolone resistance.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Area Under Curve; Drug Resistance, Microbial; Fluoroquinolones; Gemifloxacin; Haemophilus Infections; Haemophilus influenzae; Humans; Mice; Microbial Sensitivity Tests; Naphthyridines; Pneumococcal Infections; Rats; Streptococcus pneumoniae

An open-label, non-comparative study assessed the clinical and bacteriological efficacy of gemifloxacin (320 mg, once-daily for 7 days) in lower respiratory tract infections (LRTI). Patients with acute exacerbation of chronic bronchitis (AECB, n=261) or community-acquired pneumonia (CAP, n=216) were enrolled into the study. Clinical success rates at follow-up (days 21-28) in the intent-to-treat (ITT) population were high, 83.1% in AECB patients (95% CI: 77.9, 87.4) and 82.9% in CAP patients (95% CI: 77.0, 87.5). High bacteriological success rates were achieved (bacteriological ITT population), 91.2% (52/57) in AECB patients (95% CI: 80.0, 96.7) and 77.9% (60/77) in CAP patients (95% CI: 66.8, 86.3). Gemifloxacin was well tolerated with a low incidence of adverse events. Gemifloxacin treatment resulted in high clinical and bacteriological success rates and is a well-tolerated therapy for the treatment of LRTIs.

Topics: Adult; Aged; Anti-Infective Agents; Bronchitis; Chronic Disease; Community-Acquired Infections; Drug Administration Schedule; Female; Fluoroquinolones; Gemifloxacin; Gram-Negative Bacterial Infections; Haemophilus Infections; Humans; Klebsiella Infections; Male; Middle Aged; Naphthyridines; Pneumococcal Infections; Pneumonia, Bacterial; Staphylococcal Infections; Treatment Failure

The activity of gemifloxacin against Haemophilus influenzae and Moraxella catarrhalis was compared to those of 11 other agents. All quinolones were very active (MICs,

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Bacterial Proteins; Colony Count, Microbial; Drug Resistance, Microbial; Fluoroquinolones; Gemifloxacin; Haemophilus Infections; Haemophilus influenzae; Humans; Microbial Sensitivity Tests; Moraxella catarrhalis; Naphthyridines; Polymerase Chain Reaction; Sequence Analysis, DNA

The in vivo efficacy of the novel quinolone gemifloxacin (SB-265805) was examined in a rat respiratory tract infection (RTI) model against four strains of Streptococcus pneumoniae and two strains of Haemophilus influenzae with varying susceptibilities to standard antimicrobial agents. Animals were infected intrabronchially to produce pneumonia and therapy with oral gemifloxacin, amoxycillin-clavulanate, ciprofloxacin, cefuroxime, azithromycin, trovafloxacin, grepafloxacin or levofloxacin was started 24 h after infection. The doses administered were chosen to approximate in the rat the serum or tissue concentrations measured in humans following therapeutic dosing. Therapy continued once- or twice-daily for 3 days, and approximately 17 h after the end of therapy the lungs were excised for bacterial enumeration. Following infection with strains of S. pneumoniae, gemifloxacin produced a 3-5 log reduction in bacterial numbers compared with untreated animals. Gemifloxacin was as effective as amoxycillin- clavulanate, and was as potent or more potent than all other comparators. Notably, the quinolone agents trovafloxacin, ciprofloxacin, grepafloxacin and levofloxacin were significantly less effective (P < 0.01) than gemifloxacin: these agents reduced bacterial numbers by < or =3 log compared with untreated animals. Gemifloxacin produced a marked response against H. influenzae infection, reducing bacterial numbers significantly (P < 0.01) compared with untreated controls. Gemifloxacin was significantly more potent than cefuroxime and azithromycin. None of the other comparator agents was more potent than gemifloxacin. The excellent efficacy seen in these experimental models of RTI with S. pneumoniae and H. influenzae confirms the in vitro activity of gemifloxacin against these organisms. This indicates that gemifloxacin may be of significant benefit in the treatment of RTI.

Topics: Animals; Anti-Infective Agents; Fluoroquinolones; Gemifloxacin; Haemophilus Infections; Haemophilus influenzae; Male; Naphthyridines; Pneumococcal Infections; Rats; Rats, Sprague-Dawley; Respiratory Tract Infections