New quinolones--a fresh answer to the pneumococcus.

Streptococcus pneumoniae is the most frequent bacterial cause of community-acquired pneumonia, acute sinusitis and meningitis and is involved in a significant proportion of cases of acute exacerbation of chronic bronchitis. In addition, there is evidence that the incidence of invasive pneumococcal disease has increased. There is now concern over the increasing resistance of S. pneumoniae to penicillin and macrolides and the appearance of strains with reduced susceptibility to third-generation cephalosporins. As a result, there is a need for new agents with good activity against S. pneumoniae, especially those which can be administered orally. As an antibiotic class, fluoroquinolones have been available for use for over two decades. However, in the last 10 years the pharmaceutical industry has poured considerable resources into producing new fluoroquinolones aimed at improving upon the shortcomings of their predecessors, particularly in terms of potency and spectrum of activity. Although there have been several recent and well-publicized casualties in this area, most notably temafloxacin, trovafloxacin and grepafloxacin, others, such as levofloxacin and sparfloxacin, remain available and will shortly be joined by new compounds, e.g. moxifloxacin and gatifloxacin. Ciprofloxacin remains the most frequently used of the older fluoroquinolone agents. The newer fluoroquinolones offer a possible solution to the emerging problems in pneumococcal disease but there has been a cautious response to their introduction based on previous negative experience with ciprofloxacin in the treatment of pneumococcal infection. Some authors have since challenged this perception of ciprofloxacin. In a recent article in the Journal of Antimicrobial Chemotherapy, Legg & Bint urge caution in respect of fluoroquinolones in pneumococcal infection but we feel there are arguments for regarding the newer agents as potentially useful in this clinical setting. When MICs are compared, there are many data showing that the new quinolones have greater in vitro activity than ciprofloxacin against S. pneumoniae. In many studies these differences were large; for example, trovafloxacin was found to be 16-fold more potent than ciprofloxacin in one study, although others have recorded smaller differences. This advantage of new fluoroquinolones is retained in strains of S. pneumoniae with a reduced susceptibility to ciprofloxacin (MIC 0.5 mg/L). However, simply examining MIC data may not be appropriate, as fluoroquinolones exhibit both concentration-dependent bacterial killing and a post-antibiotic effect. Evidence suggests that the relationship between the MIC and the effective concentration of the antibiotic at the site of infection is the variable best linked to clinical outcome. With the exception of cerebrospinal fluid, the newer quinolones are widely distributed throughout the body, with preferential concentration in the respiratory compartment. Pharmacokinetic data also support the superiority of newer fluoroquinolones over ciprofloxacin, with the former possessing greater oral bioavailability and a longer serum halflife that normally allows once-daily dosing. These dual improvements shown by the new fluoroquinolones in terms of their potency and pharmacodynamics against S. pneumoniae suggest possible greater clinical effectiveness. Animal studies have demonstrated the superiority of new fluoroquinolones over ciprofloxacin in experimental pneumococcal infection and have also shown their equivalence to standard anti-pneumococcal therapy against infections caused by penicillin-sensitive strains of S. pneumoniae. Although Lacy et al. found trovafloxacin to be less active than amoxycillin against penicillinsensitive pneumococci in a murine sepsis model, it was more active than ciprofloxacin. In addition, trovafloxacin was more active than both ciprofloxacin and amoxycillin against penicillin-resistant strains. The mode of action of the new fluoroquinolones is similar to that of their predecessors with resistance in