a Antibiotic Resistance Monitoring and Reference Laboratory and b Respiratory and Systemic Infection Laboratory, Central Public Health Laboratory, Colindale, London NW9 5HT, UK
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Abstract |
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Introduction |
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The therapy of infections caused by multi-resistant pneumococci is problematic, and there is a need for new agents, particularly those suitable for oral administration. Although ciprofloxacin has only marginal anti-pneumococcal activity, with MICs commonly in the range 12 mg/L, newer fluoroquinolones with increased anti-pneumococcal activity have been developed.13 We report here the activity of the new 8-methoxy fluoroquinolone moxifloxacin against pneumococci, including both isolates (frequently multi-resistant) referred from UK hospitals for sensitivity testing and isolates collected as part of a comprehensive surveillance of invasive pneumococcal infections in England and Wales.
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Materials and methods |
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One thousand two hundred and sixty-nine isolates of Streptococcus pneumoniae received by the Antibiotic Resistance Monitoring and Reference Laboratory (ARMRL) or the Respiratory and Systemic Infection Laboratory (RSIL) between December 1998 and April 1999 were tested. These comprised two groups: (i) 462 consecutive isolates submitted at the discretion of source laboratories, primarily for confirmation of resistance to first line agents; and (ii) 807 isolates received as part of an enhanced national surveillance programme, which seeks all pneumococci from blood, CSF and other normally sterile sites, irrespective of resistance. In this programme, hospitals reporting cases of pneumococcal bacteraemia or meningitis to the PHLS as part of the national surveillance scheme3,4 are contacted by RSIL and asked to refer the isolates for serotyping and susceptibility testing.
Susceptibility testing
MICs were determined on Diagnostic Sensitivity Test (DST) agar (Oxoid, Basingstoke, UK) containing 5% lysed horse blood (TCS Microbiology, Buckingham, UK), incubated for 18 h at 37°C in air. The inocula comprised 104105 cfu/spot, delivered with a multipoint inoculator. Isolates were classified as susceptible, intermediate or resistant to penicillin if their MICs were 0.06 mg/L, 0.11 mg/L or
2 mg/L, respectively.14 Isolates were categorized as susceptible or resistant to the other agents tested using published criteria.15,16
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Results |
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This population was highly biased towards resistant organisms (Table). The proportions intermediately or fully resistant to penicillin were 32.6 and 56.1%, respectively, while the proportions resistant to erythromycin, tetracycline and chloramphenicol were 50, 48 and 22.7%. Of the 462 isolates, 158 (34.2%) were resistant to any one of penicillin, erythromycin, tetracycline or chloramphenicol, 98 (21.2%) were resistant to any two, 94 (20.3%) to any three and 83 (18%) to all four. Twenty-nine isolates (6.3%) were susceptible to all four agents. Ninety-four per cent of the referred isolates were susceptible to moxifloxacin at
1 mg/L, whereas only 2% were susceptible to ciprofloxacin at
1 mg/L (Table
), although only 6.1% were resistant to ciprofloxacin at 8 mg/L. The MIC distributions for moxifloxacin and ciprofloxacin had major modes at 0.25 mg/L and 24 mg/L, respectively, but there were suggestions of a small second peak at MIC 48 mg/L, for moxifloxacin and at
8 mg/L for ciprofloxacin (Figure
, a).
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Summary MIC data for moxifloxacin and comparators for invasive isolates from the surveillance programme are shown in the Table. The proportions of the unselected invasive isolates that are susceptible, intermediately resistant and fully resistant to penicillin were 92, 4.5 and 3.5%, respectively, whereas the proportions resistant to erythromycin, tetracycline and chloramphenicol were 14.7, 9.0 and 0.6%, respectively. Of the 807 isolates, 173 (21.4%) were resistant to any one of penicillin, erythromycin, tetracycline or chloramphenicol, 29 (3.6%) were resistant to any two, seven (0.9%) to any three and two (0.3%) to all four. Five hundred and ninety-six isolates (73.6%) were susceptible to all four agents. Ninety-nine per cent were susceptible to moxifloxacin at
1 mg/L, whereas only 1% were susceptible to ciprofloxacin at
1 mg/L (Table
), although only 0.6% were resistant to ciprofloxacin at 8 mg/L. The MIC distributions for moxifloxacin and ciprofloxacin were both unimodal (Figure
, b), with mode MICs of 0.25 and 4 mg/L, respectively.
Correlation of susceptibility to ciprofloxacin and moxifloxacin
Throughout both groups of isolates the MICs of moxifloxacin were related to those of ciprofloxacin, with moxifloxacin showing four- to 16-fold greater activity than ciprofloxacin. Of 33 isolates with high-level resistance to ciprofloxacin (MIC > 8 mg/L) 29 were resistant to moxifloxacin (MICs 28 mg/L), whereas the moxifloxacin MICs for the remaining four were 0.5 or 1 mg/L. Five further isolates with reduced susceptibility to moxifloxacin (MICs of 2 or 4 mg/L) required MICs of 28 mg/L of ciprofloxacin for inhibition.
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Discussion |
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Despite the lack of frank cross-resistance with other agents, earlier quinolones such as ciprofloxacin, have been limited by their marginal activity against pneumococci. The mode ciprofloxacin MIC for pneumococci is 24 mg/L (Figure, a) and several authors have cautioned against the drug's use in pneumococcal disease.18 However, newer quinolones offer increased anti-pneumococcal activity and, among the compounds presently licensed in Europe and the USA, moxifloxacin has the lowest MIC for the species.19 Moxifloxacin at a concentration of 1 mg/L was active against >99% of the invasive isolates collected in the national surveillance programme, and against 94% of referred isolates, which had a bias towards resistance to first-line agents. Greater activity of moxifloxacin was also noted among isolates with reduced sensitivity to quinolones. Four of 33 isolates with ciprofloxacin MICs of >8 mg/L remained susceptible to moxifloxacin at
1 mg/L, and a further 15 showed only a slight reduction in susceptibility, with MICs of 24 mg/L.
The activity of moxifloxacin against pneumococci resistant to first-line agents, either alone or in combination, suggests that it is a valuable addition to the antibiotic arsenal. Nevertheless, two notes of caution need to be sounded. First, quinolone resistance is a class effect and, although moxifloxacin retained some activity against some pneumococci with high ciprofloxacin MICs there was a general correlation between the MICs of the two compounds. Secondly, although there is presently little association between pneumococcal resistance to quinolones and to other agents, Chen et al.20 noted that the prevalence of pneumococci with ciprofloxacin MICs > 4 mg/L in Canada had risen from 0% in 1988 to 1.7% in 1997. Isolates with raised quinolone MICs were obtained only from age groups likely to have received quinolones, which had been increasingly prescribed during the study period. These observations indicate a disturbing potential for emergence of resistance, but this should not be exaggerated as the increase in resistance was slow and concerned a period when none of the available quinolones achieved a high area under the curve:MIC ratio for pneumococci. Quinolones such as moxifloxacin, with intrinsically better anti-pneumococcal activity, may well prove even less selective.
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Acknowledgments |
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Notes |
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References |
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Received 3 May 2000; returned 30 August 2000; revised 28 September 2000; accepted 29 November 2000