Public Health and Clinical Microbiology Laboratory, Royal Victoria Infirmary, Queen Victoria Road, Newcastle-upon-Tyne NE1 4LP, UK
Quinolone antibiotics were first introduced into clinical practice in the early 1960s. The original quinolone, nalidixic acid, had limited use due to low intrinsic activity and the rapid development of bacterial resistance. Addition of fluorine to the quinolone molecule expanded the spectrum of activity of quinolones, as exemplified by ciprofloxacin, which was introduced in 1987. However, whilst ciprofloxacin has a broad spectrum of activity against Gram-negative bacteria, it has less activity against Gram-positive bacteria, particularly Streptococcus pneumoniae.
Further manipulation of the quinolone nucleus has led to the development of newer quinolones with enhanced activity in vitro against S. pneumoniae and this, together with their other spectrum of activity, is being used to justify their use as empirical monotherapy in the treatment of respiratory tract infections. Of these newer quinolones, grepafloxacin, sparfloxacin, levofloxacin, moxifloxacin and trovafloxacin are currently, or shortly to be, available in Europe.
A careful evaluation of the activity of these new antibiotics against S. pneumoniae needs to be made before they are accepted as suitable for empirical therapy of infections likely to be due to this important pathogen. Furthermore, the important issue of the likelihood of the appearance of S. pneumoniae, resistant to the latest quinolones, must be addressed.
Correlations between the in-vitro activity of ciprofloxacin against S. pneumoniae and its clinical efficacy are instructive. In a large study of both penicillin-sensitive and penicillin-resistant isolates, a mean MIC50 of 1.1 mg/L (range 0.52 mg/L) and a mean MIC90 of 2 mg/L (range 14 mg/L) were found in the two groups respectively.1 These MICs are close to the current BSAC breakpoints for ciprofloxacin-sensitive S. pneumoniae <2 mg/L). Furthermore, the bactericidal activity was comparable with that of penicillin at concentrations of at least 4 x MIC.
This poor in-vitro activity of ciprofloxacin is of concern, but does it equate with poor activity in vivo?
In a mouse protection model, in which S. pneumoniaewas inoculated ip, the peak concentration/MIC ratio of ciprofloxacin needed to reach a value of 10.6 for 100% protection.2 In clinical practice such concentrations are rarely achieved. For example, following a 750 mg oral dose of ciprofloxacin, peak serum concentrations are only 34 mg/L. Also, when compared with penicillin there was an 83-fold difference in 50% protective dose in favour of penicillin.2
In a further study, this time using a mouse pneumococcal pneumonia model, the poor in-vivo activity of ciprofloxacin was demonstrated. Neither of the two S. pneumoniae strains used in this study were eliminated from the mouse lungs by any of the doses tested, despite good penetration of the drug into lung tissue. The poor efficacy of ciprofloxacin reflected its low in-vitro activity against S. pneumoniae.3
A number of clinical trials of ciprofloxacin in the treatment of lower respiratory tract infections have displayed high clinical efficacy although a criticism is that patients infected with S. pneumoniae may have been under represented in these studies. Concerns regarding the clinical efficacy of ciprofloxacin have been expressed in a number of case reports, when the antibiotic was used unsuccessfully to treat pneumococcal infections, most commonly of the respiratory tract, and subsequently, life-threatening complications developed. 4 ,5 ,6 The complications that arose during ciprofloxacin therapy included pneumococcal bacteraemia,4,5 meningitis and arthritis.6 A number of case reports have also shown that following the use of ciprofloxacin to treat Gram-negative infections, superinfections with S. pneumoniae have occurred.7,8
Although the rates of resistance of S. pneumoniae to ciprofloxacin are currently low, selection of resistance on exposure in vitro has been reported. Resistance to quinolones results from mutational alterations in the target sites: topoisomerase IV and DNA gyrase, coded for by the parC and gyrA genes respectively. Moreover, it has recently been observed that a third mechanism of ciprofloxacin resistance, in the form of an active efflux mechanism, exists in S. pneumoniae.9 Resistance results from single step mutations which lead to a stepwise increase in MICs and those organisms with MICs already close to the quinolone resistance breakpoint, e.g. S. pneumoniaeand ciprofloxacin, are much more likely to become resistant.
Considering that S. pneumoniae is the most common cause of community-acquired pneumonia (CAP) and mortality rates for pneumococcal pneumonia are reported to be in the region of 57%, then the empirical use of ciprofloxacin alone in patients with pneumonia is highly questionable.
Are the newer fluoroquinolones more reliable in treating pneumococcal infections?
Levofloxacin has been widely marketed with one of its prime indications being the treatment of CAP. Like ciprofloxacin, the levofloxacin data sheet warns that it may not be the optimal therapy in the most severe cases of pneumococcal pneumonia. This is despite its reported "excellent in-vitro activity against several S. pneumoniae isolates resistant to ciprofloxacin".10
In contrast, a number of studies have reported either no difference, or a slight increase, in in-vitro activity against S. pneumoniae in favour of levofloxacin over ciprofloxacin. In a recent multicentre UK study of 63 S. pneumoniae isolates, the activities of ciprofloxacin and levofloxacin were not statistically significantly different (geometric mean MICs 0.978 and 0.95 mg/L, respectively).11
In a larger UK study involving 583 S. pneumoniae isolates, there was only a two-fold difference between the levofloxacin and ciprofloxacin MIC90 (2 mg/L and 4 mg/L, respectively) and an equivalent MIC50.12 More worryingly, this study also reported the discovery of a strain with ciprofloxacin resistance (MIC > 16 mg/L) and cross-resistance to levofloxacin (MIC > 16 mg/L).
Since levofloxacin has not been extensively used in clinical practice, the prevalence of resistant mutants in the wild has not yet been been evaluated, but as with ciprofloxacin, levofloxacin resistant mutants may be selected using incremental increased concentrations of levofloxacin (MIC > 4 mg/L).13 It must be noted that in this study ciprofloxacin selected mutants from the susceptible to the resistant range more frequently than did levofloxacin.13 This apparent decreased frequency of mutation with the newer quinolones may not be such an advantage in vivo if cross-resistance between the quinolones exists. Such cross-resistance has been demonstrated in a number of in-vitro studies. Ciprofloxacin-resistant mutants (MIC 1632 mg/L) were shown to have cross-resistance with other quinolones, including sparfloxacin, in a study of non gyrA mediated ciprofloxacin-resistant laboratory mutants of S. pneumoniae.14
In clinical trials, levofloxacin has demonstrated high efficacy in treating respiratory tract infections and specifically in hospitalized patients with pneumonia. Levofloxacin was found to be as clinically effective as ceftriaxone, but with regard to the eradication rate of Gram-positive pathogens, ceftriaxone was superior to levofloxacin (95% versus 76%).15
With sparfloxacin, in-vitro data for pneumococci show it to have an MIC50 of 0.25 mg/L and an MIC90 of 0.5 mg/L compared with 1 mg/L and 2 mg/L, respectively, for ciprofloxacin, with no difference between the penicillin-sensitive and penicillin-resistant isolates.16 Further studies investigating the activity of sparfloxacin against S. pneumoniae with timekill methodology, demonstrated sparfloxacin to be bactericidal for only five of the 10 strains tested.17 This raises a concern that sparfloxacin may not be adequately bactericidal against pneumococci in infections in immunocompromised or neutropenic patients.
Grepafloxacin has increased in-vitro activity against S. pneumoniae compared with ciprofloxacin. A grepafloxacin MIC90 of 0.25 mg/L compared favourably with 2 mg/L for ciprofloxacin.18 However, eight clinical isolates in this study were found to be ciprofloxacin-resistant and although four had grepafloxacin MICs 12 dilutions lower, the remaining four were also grepafloxacin-resistant. This again emphasises the concern that S. pneumoniae may display cross-resistance between the older and the more recently introduced quinolones.
Clinically, the efficacy of grepafloxacin has been compared with amoxycillin in patients with acute bacterial exacerbations of chronic bronchitis. Overall, the clinical response was equivalent between the two groups but at follow-up, microbiological success with pneumococci was greater for amoxycillin than for grepafloxacin.19
At the present time, we can conclude that the newer quinolones are superior to ciprofloxacin and probably equivalent to ß-lactams for the treatment of pneumococcal respiratory tract infections. There are, however, some significant concerns. Some clinical trials suggest that microbiological eradication of pneumococci is inferior with quinolones compared to ß-lactams. More worrisome is the potential for increasing resistance of S. pneumoniaeto even the latest quinolones. It seems likely that strains, under the selective pressure of quinolone use, will be able to acquire sequentially several mutational resistance mechanisms, and this may happen over the short to medium term, rather than the long term. It may well be prudent not to use the newer quinolones as empirical first-choice agents for lower respiratory tract infections, especially in regions where the prevalence of penicillin-resistant pneumococci is low.
Notes
References
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