Activity of moxifloxacin against clinical isolates of Streptococcus pneumoniae from England and Wales

A. P. Johnsona,*, M. Warnera, R. C. Georgeb and D. M. Livermorea

a Antibiotic Resistance Monitoring and Reference Laboratory and b Respiratory and Systemic Infection Laboratory, Central Public Health Laboratory, Colindale, London NW9 5HT, UK


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The activity of moxifloxacin was assessed against 1269 isolates of Streptococcus pneumoniae, comprising 462 isolates referred from UK hospitals, primarily for confirmation of resistance to first line agents, and 807 isolates from an enhanced surveillance of invasive infections. Resistance rates to penicillin, erythromycin, tetracycline and chloramphenicol were 88.7% (32.6% intermediate and 56.1% fully resistant), 50, 48 and 22.7%, respectively, for the former, and 8.0 (4.5% intermediate and 3.5% fully resistant), 14.7, 9.0 and 0.6% for the latter. Ninety-four per cent of the referred isolates and 99% of the surveillance isolates were susceptible to moxifloxacin at <=1 mg/L. Moxifloxacin may therefore be a useful drug for the treatment of patients with pneumococcal infections due to antibiotic-resistant strains or those with severe invasive disease.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Penicillin-resistant pneumococci were first isolated in the USA and Australia in the 1960s, and their prevalence has since increased worldwide.1,2 The antibiotic susceptibilities of pneumococci from cases of bacteraemia or meningitis reported to the PHLS from over 200 microbiology laboratories in England and Wales indicate that the prevalence of penicillin resistance rose from 0.3% in 1989 to 7.4% in 1997.3,4 Multi-centre point prevalence surveys in the UK confirmed this trend, with penicillin resistance rates of 1.5% in 1990, 3.9% in 1995 and 8.9% in 1999, albeit with local variation.5,6 Prevalence rates of penicillin resistance among pneumococci from other countries such as Spain, the USA and South Korea are as high as 30–70%.79 An additional concern is that resistance to unrelated drugs such as macrolides, tetracycline, chloramphenicol or cotrimoxazole is generally more prevalent in penicillin-resistant pneumococci than in penicillin-susceptible strains.8 Multi-resistance is commonly clonal, with multi-resistant lineages of serotypes 6B, 9V and 23F having spread between countries or continents.1012

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 1–2 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.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Bacteria

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 104–105 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, 0.1–1 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


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Pneumococci referred primarily for confirmation of resistance(s)

This population was highly biased towards resistant organisms (TableGo). 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 (TableGo), 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 2–4 mg/L, respectively, but there were suggestions of a small second peak at MIC 4–8 mg/L, for moxifloxacin and at >=8 mg/L for ciprofloxacin (FigureGo, a).


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Table. Activity of moxifloxacin and comparator agents against S. pneumoniae
 


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Figure. Distribution of MICs of ciprofloxacin ({blacksquare}) and moxifloxacin ({blacksquare}) for 462 referred pneumococci (a) and 807 invasive pneumococci from the surveillance programme (b).

 
Invasive pneumococci received as part of the national surveillance programme

Summary MIC data for moxifloxacin and comparators for invasive isolates from the surveillance programme are shown in the TableGo. 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 (TableGo), although only 0.6% were resistant to ciprofloxacin at 8 mg/L. The MIC distributions for moxifloxacin and ciprofloxacin were both unimodal (FigureGo, 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 2–8 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 2–8 mg/L of ciprofloxacin for inhibition.


    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Antibiotic resistance in pneumococci is now considered to be a global problem. Although the prevalence of resistance in the UK, particularly to penicillin, is currently lower than that seen in many other countries, it has none the less been increasing with time. This is reflected in the occurrence of resistance, including multi-resistance, in many of the referred isolates tested here. Critically, however, pneumococcal multi-resistance rarely encompasses quinolones.17 The present study showed that, in contrast to other antibiotics, the mode MICs, MIC50s and MIC90s of the quinolones were no higher for the referred pneumococci than for the unselected surveillance isolates, and that the referred group contained only a tiny excess of quinolone-resistant isolates.

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 2–4 mg/L (FigureGo, 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 2–4 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.


    Acknowledgments
 
We thank Terri Parsons and Dot James for laboratory assistance and data entry. We also thank Dr Chris Thomson for useful discussions and Bayer for financial support.


    Notes
 
* Corresponding author. Tel: +44-20-8200-4400 Ext. 4237; Fax: +44-20-8358-3292; E-mail: ajohnson{at}phls.nhs.uk Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Received 3 May 2000; returned 30 August 2000; revised 28 September 2000; accepted 29 November 2000