Department of Clinical Microbiology, Lothian University Hospitals NHS Trust, Western General Hospital, Edinburgh EH4 2XU, UK
Streptococcus pneumoniae is the most frequent bacterial cause of community-acquired pneumonia,1 acute sinusitis2 and meningitis3 and is involved in a significant proportion of cases of acute exacerbation of chronic bronchitis.4 In addition, there is evidence that the incidence of invasive pneumococcal disease has increased.5 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.6 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.7 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.8 Some authors have since challenged this perception of ciprofloxacin.9 In a recent article in the Journal of Antimicrobial Chemotherapy, Legg & Bint10 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 ciprofloxacin11 in one study, although others have recorded smaller differences.12,13 This advantage of new fluoroquinolones is retained in strains of S. pneumoniae with a reduced susceptibility to ciprofloxacin (MIC 0.5 mg/L).14 However, simply examining MIC data may not be appropriate, as fluoroquinolones exhibit both concentration-dependent bacterial killing15 and a post-antibiotic effect.16 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.15 With the exception of cerebrospinal fluid, the newer quinolones are widely distributed throughout the body, with preferential concentration in the respiratory compartment.14 Pharmacokinetic data also support the superiority of newer fluoroquinolones over ciprofloxacin, with the former possessing greater oral bioavailability and a longer serum half-life that normally allows once-daily dosing.15 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 infection17,18 and have also shown their equivalence to standard anti-pneumococcal therapy against infections caused by penicillin-sensitive strains of S. pneumoniae.18,19 Although Lacy et al.20 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 S. pneumoniae developing in two stages involving low frequency mutations in the genes encoding DNA gyrase and DNA topoisomerse IV. It has been suggested that the newer agents are less likely to select for highly resistant double mutants than their earlier comparators.21 With trovafloxacin it was found that first-step mutants had MICs within clinically achievable levels22 and other new fluoroquinolones show the same propensity. Another factor that may be relevant to the likelihood of inducing resistance is the rate of bacterial killing. Odenholt et al.23 found that levofloxacin had a greater and faster kill rate against pneumococci than did ciprofloxacin, and this may reduce the opportunities for the selection of resistance.
Although the above arguments are important in pointing to the promise of new fluoroquinolones in the management of pneumococcal infection, the future of these agents will be determined by the results of human clinical trials and subsequent experience in practice. Many published clinical studies have evaluated the efficacy of new fluoroquinolones in a variety of infections involving S. pneumoniae. Several papers report the use of new fluoroquinolones in acute infective exacerbations of chronic bronchitis, in comparison with either an older quinolone,24 a ß-lactam2527 or a macrolide.28,29 All demonstrate clinical equivalence of the quinolone with standard therapy. The limitations of such studies include the relatively small number of cases in which S. pneumoniae was isolated (31%)28 and the problem of determining the contribution of the organism in respect of the exacerbation.
Similar comparisons have been made using new fluoroquinolones in community-acquired pneumonia, where one would expect a higher proportion of pneumococcal infection. Again the trials have demonstrated clinical equivalence.3034 Only a minority of patients in each series was proven to suffer from pneumococcal infection and in very few cases was S. pneumoniae isolated from the blood. One study made an effort to recruit patients more likely to have severe pneumococcal pneumonia by using strict clinical inclusion criteria and enrolling only those patients who needed hospitalization.35 In this study, 329 patients were recruited, 54% of whom had proven pneumococcal pneumonia. Sparfloxacin was compared with high-dose amoxycillin and clinical equivalence was found.35 A small number of studies have assessed the use of new fluoroquinolones in acute bacterial sinusitis, where again S. pneumoniae is a common pathogen, and in each the quinolone was found to be equivalent to standard therapy.36,37 In other studies, the efficacy of new fluoroquinolones in severe disease was examined. Levofloxacin was compared with imipenem as empirical therapy in suspected bacteraemia.38 A total of 503 patients were recruited; 287 were demonstrated to have a bacterial infection with 47% of these suffering from pneumonia and, overall, 16% of bacterial isolates were S. pneumoniae. The two antibiotics were found to have equivalent efficacy. No clinical studies examining the use of new fluoroquinolones in pneumococcal meningitis have been published, but animal studies show promise.39,40
Anxiety about the use of fluoroquinolones in pneumococcal disease first came to the fore with the publication of a small number of cases where such infections developed in the face of ciprofloxacin treatment.8 Clinical experience with the new fluoroquinolones is, to date, much less than the accumulated ciprofloxacin data; nevertheless, there have been no similar reports involving these agents.
A recent extensive review of fluoroquinolone adverse events showed that, whereas a large number are class-related, others reflect the structure of individual compounds; for example, agents with a halogen at position 8, e.g. sparfloxacin and clinafloxacin, are associated with high incidences of phototoxicity.42 One class-related effect is the phenomenon of QT interval prolongation.43 Although all quinolones investigated for QT interval prolongation show this effect, as do several other types of drug, there are significant differences amongst quinolones in the magnitude of the QT prolongation and the antibiotic concentration required to produce it. For example, the doses of grepafloxacin and ciprofloxacin that produce cardiac arrhythmias have been reported as 1030 and 300 mg/kg, respectively.44 The recent withdrawal of grepafloxacin was prompted by cardiac adverse events. Other fluoroquinolones have been withdrawn because of adverse events for which the explanation remains obscure, examples are trovafloxacin (hepatotoxicity) and temafloxacin (haemolysis, renal failure and hypoglycaemia45). The remaining new fluoroquinolones show adverse event profiles similar to those of the older agents and levofloxacin, for example, has been well tolerated in clinical trials with adverse events no more common than with the comparator.32,41
With their good oral bioavailability and their potential for once-daily dosing, the new fluoroquinolones offer the opportunity to contain treatment costs; a French study has demonstrated financial savings when sparfloxacin was used in community-acquired pnuemonia.17 Similar potential cost benefits have been calculated for the use of quinolones in the management of acute exacerbations of chronic bronchitis.46
In the UK, the quinolones are the antibiotic class showing the fastest rate of growth in use.47 It is well demonstrated that mounting antibiotic usage is linked to ever-increasing resistance,48 although it is not yet known whether this is a proportional effect that antibiotic classes will show to the same degree. Recently, a number of reports have linked increases in quinolone use with the growth of quinolone resistance in S. pneumoniae.49,50 Concern has been expressed that the new fluoroquinolones may feed further the present expansion in quinolone prescriptions, so forcing the development of resistance. The introduction of new fluoroquinolones must be closely monitored in order to assess their impact upon the rate of emergence of quinolone resistance. Although the following theory needs to be tested in practice, there is experimental evidence that new fluoroquinolones may be less likely to select for resistance in S. pneumoniae than older quinolones51 and, hence, there may be benefit in choosing new fluoroquinolones in order to reduce the emergence of such resistance.
Hence, as a class the new fluoroquinolones offer a new line of approach to the treatment of pneumococcal infections with clear differences from older agents such as ciprofloxacin. They have thus far performed well clinically and, although some agents have had to be withdrawn because of side effects, we should not discard the whole class as a result. Whereas more data are required before the place of new fluoroquinolones in the management of pneumococcal disease is established, the encouraging scientific and clinical evidence to date should lead this to be pursued actively.
Notes
* Corresponding author. Tel: +31;44-131-537-1934; Fax: +31;44-131-537-1024; E-mail: rgm{at}wghmicro.demon.co.uk
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