1 GR Micro Ltd., 79 William Road, London NW1 3ER, UK; 2 Public Health Research Institute, Newark, NJ, USA
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Abstract |
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Keywords: fluoroquinolones, respiratory tract infections, fluoroquinolone resistance, community-acquired pneumonia, acute exacerbation of chronic bronchitis
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Introduction |
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Streptococcus pneumoniae |
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The need for new agents for the empiric treatment of antimicrobial-resistant S. pneumoniae is indisputable and this quest has been a major focus for pharmaceutical research. Novel fluoroquinolone agents, including the clinically-available agents gemifloxacin, gatifloxacin and moxifloxacin, are among the new antibacterial compounds that have been developed to meet this demand and as a consequence they are often referred to as respiratory fluoroquinolones.12 Gemifloxacin is currently the only antimicrobial approved by the FDA for use against multidrug-resistant S. pneumoniae (DRSP, i.e. resistant to two or more of the following antibiotics: penicillin, second generation cephalosporins, macrolides, tetracyclines and trimethoprim/sulfamethoxazole).6
Gemifloxacin has very low MIC50 and MIC90 values of 0.015 and 0.03 mg/L, respectively, against clinical isolates of S. pneumoniae.13 This compares extremely favourably with levofloxacin, where the MIC50 and MIC90 for the same pneumococcal population are both 1 mg/L.13 Identical, or similar, levofloxacin MIC50 and MIC90 values have been described in other surveillance studies.8,9,14 These have not used gemifloxacin as a comparator but have found MIC50 and MIC90 values for gatifloxacin of 0.25 and 0.5 mg/L9,14 or 0.12 and 0.25 mg/L for moxifloxacin.8,15 Importantly, the enhanced potency shown by gemifloxacin also extends to those pneumococci that have decreased susceptibility or resistance to levofloxacin.1618 On a weight-for-weight basis, therefore, gemifloxacin is the most potent fluoroquinolone currently available for treatment of lower respiratory tract infection caused by S. pneumoniae, including levofloxacin-resistant isolates. This extra potency is the result of a high affinity for both the fluoroquinolone target enzymes DNA gyrase and topoisomerase IV,1921 a characteristic acknowledged by the FDA.6
Although the MIC is a useful measure of relative antibacterial activity, it is not a precise indicator of clinical utility because pharmacokinetic (PK) characteristics are not accounted for. The combined effect of PK characteristics and intrinsic activity (i.e. MIC) dictate the pharmacodynamic (PD) properties of each antibacterial. It has been suggested that the AUC24/MIC ratio is the most important PK characteristic for concentration-dependent antibacterial agents such as the fluoroquinolones. PK values for some fluoroquinolones are shown in Table 1. A ratio of at least 30 is required to expect a positive clinical or microbiological outcome with ciprofloxacin, levofloxacin or gatifloxacin against infections caused by S. pneu-moniae.2224 In this regard, levofloxacin has been shown to have a superior AUC24/MIC ratio than that of ciprofloxacin24 and gatifloxacin has a higher AUC24/MIC ratio than levofloxacin.14 The most likely reason for a drop in fluoroquinolone AUC24/MIC ratio (unless a patient has an underlying physiological problem) is when an infection is caused by a fluoroquinolone-resistant S. pneumoniae. A study using in vitro simulations of peak serum concentrations and AUCs has shown that moxifloxacin, gatifloxacin or gemifloxacin completely eradicated each of four low-level ciprofloxacin-resistant isolates (ciprofloxacin MIC 4 mg/L) to below the limit of detection.25 AUC24/MIC ratios ranged from 48 for gatifloxacin to 133 for gemifloxacin. Levofloxacin, on the other hand, was unable to eradicate one of the four isolates as evidenced by re-growth after 48 h. The AUC24/MIC ratio for levofloxacin with this particular isolate was 18, which explains the observed effect. In contrast, moxifloxacin, gatifloxacin and levofloxacin only produced AUC24/MIC ratios of 7.5, 6.0 and 4.4, respectively, against three high-level ciprofloxacin-resistant isolates (ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin and gemifloxacin MICs of 16, 8, 4, 2 and 0.12/0.25 mg/L, respectively) and as a consequence re-growth occurred with all three isolates.25 Conversely, gemifloxacin was active against two of these isolates where an AUC24/MIC ratio of 32 was reached. These data indicate that of the currently available fluoroquinolones, only gemifloxacin would have the potential to eradicate a respiratory tract infection caused by a high-level fluoroquinolone-resistant S. pneumoniae. This is in agreement with data from an earlier in vitro bactericidal activity investigation.26 Furthermore, the efficacy of gemifloxacin against high-level fluoroquinolone-resistant pneumococci has also been confirmed in a rabbit meningitis model27 and a guinea pig pneumococcal pneumonia model.28 In this latter study, unlike gemifloxacin, neither levofloxacin nor ciprofloxacin was able to eradicate the fluoroquinolone-resistant strain.28
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Published data on the use of established fluoroquinolones such as ciprofloxacin or levofloxacin in the treatment of pneumococcal infections are mixed. It has been highlighted that bacterial persistence, clinical relapse and development of resistance in S. pneumoniae are associated with the use of ciprofloxacin.12,38 On the other hand, others have suggested that S. pneumoniae eradication rates and clinical responses with ciprofloxacin can be high and that treatment failures may be the result of inadequate or inappropriate therapy.39 Generally, however, the use of ciprofloxacin against S. pneumoniae is not recommended. In contrast, levofloxacin has been approved by the FDA for the treatment of penicillin-resistant pneumococci in community-acquired pneumonia. Clinical trial data and case reports also suggest a use for levofloxacin against macrolide-resistant S. pneumoniae.40,41 Despite this, at least 25 reports of treatment failure with levofloxacin and S. pneumoniae pneumonia concurrent with the development of high-level quinolone resistance have been reported.4248 These cases are associated with resistance to levofloxacin that either developed during therapy or was present before therapy was initiated as a consequence of previous quinolone use. As discussed above, gemifloxacin is better placed to eradicate fluoroquinolone-resistant and other resistant isolates than other clinically available fluoroquinolones.
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Haemophilus influenzae |
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At present, fluoroquinolone resistance in H. influenzae is very rare and unlike with S. pneumoniae there is little difference in MIC between ciprofloxacin and the newer respiratory fluoroquinolones.9,52,53 However, there have been sporadic incidences of fluoroquinolone resistance associated with the treatment of chronic lung disease from patients in the USA,56 UK,57 Spain,58,59 and the Netherlands.60 An increase in fluoroquinolone resistance in H. influenzae from 0% in 1999 to 36% in 2001 has been reported recently in one long-term care facility in the USA.61 Therefore, full fluoroquinolone susceptibility, especially in the elderly or those on chronic antibacterial therapy, cannot be guaranteed.
Although fluoroquinolones possess a similar level of activity against fluoroquinolone-susceptible H. influenzae there are significant differences in potency against fluoroquinolone-resistant H. influenzae. In the SENTRY study, only 17 isolates of H. influenzae with reduced susceptibility to fluoroquinolones were found over 5 years.62 Against this fluoroquinolone-resistant subset, gemifloxacin possessed an MIC50 of 0.12 mg/L whereas levofloxacin and moxifloxacin both had an MIC50 of 0.5 mg/L and ciprofloxacin an MIC50 of 1 mg/L.62 Only sitafloxacin was more active (MIC50 = 0.03 mg/L) than gemifloxacin, but sitafloxacin is not available for clinical use. Similarly, gemifloxacin was the most active fluoroquinolone tested against a collection of nine fluoroquinolone-resistant H. influenzae isolates from Europe.63 Five isolates were four times more susceptible to gemifloxacin than ciprofloxacin, two were eight times more susceptible, one isolate was 16 times more susceptible and another was twice as susceptible to gemifloxacin as it was to ciprofloxacin.63 Therefore in instances where isolates of H. influenzae have reduced susceptibility to fluoroquinolones, gemifloxacin is less affected than other available fluoroquinolones. This difference is because of the strong affinity of gemifloxacin for DNA gyrase from H. influenzae.64 Furthermore, the improved potency of gemifloxacin includes an enhanced level of bactericidal activity against both fluoroquinolone-susceptible and -resistant isolates compared with ciprofloxacin, ofloxacin or grepafloxacin. However, others have shown that levofloxacin, moxifloxacin and gatifloxacin are all more bactericidal against an H. influenzae isolate than gemifloxacin.65 This anomaly is probably a result of the methodology used in this latter study, which was based on multiples of MIC.65 As gemifloxacin possessed an MIC 7.5 to 40 times lower than the comparator fluoroquinolones against this isolate, the gemifloxacin concentrations evaluated for their bactericidal activity were proportionally lower than the concentrations used to test the comparators and therefore the investigation was not a direct comparison.
There have been few PD studies of fluoroquinolones against H. influenzae, presumably because fluoroquinolone resistance is so rare and fluoroquinolone MICs are relatively low against this pathogen. However, in one study using an in vitro dynamic model, gemifloxacin was at least 30% more efficient than ciprofloxacin against H. influenzae.66 In a rat model of respiratory tract infection using two strains of fluoroquinolone-susceptible H. influenzae, gemifloxacin was considerably more potent than cefuroxime or azithromycin, and all fluoroquinolones reduced H. influenzae count in the lungs to the limit of detection.67 Using the same model, however, gemifloxacin was superior to ciprofloxacin and equivalent to levofloxacin against a fluoroquinolone-resistant H. influenzae isolate.68 These data support the contention that gemifloxacin has excellent activity against H. influenzae, particularly against those isolates that are resistant to other fluoroquinolones.
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Conclusions |
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Declarations of interest
I. M. has recently consulted, or been involved in quinolone research programmes, for Aventis, Bayer, BMS, Daiichi Pharmaceutical Co. Ltd., GeneSoft and GlaxoSmithKline in addition to work with other companies on non-quinolone antibacterials. G. S. T. consults for Bayer, BMS, Chiron, GeneSoft, Replidyne and Roche.
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Footnotes |
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References |
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