The Alexander Project 1996–1997: latest susceptibility data from this international study of bacterial pathogens from community-acquired lower respiratory tract infections

David Felmingham*, Reuben N. Grünebergand and the Alexander Project Group

GR Micro Ltd, 7–9 William Road, London NW1 3ER, UK


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The Alexander Project was established in 1992 to examine antimicrobial susceptibilities of bacterial isolates from community-acquired infections of the lower respiratory tract. Testing of a range of compounds was undertaken in a central laboratory. From 1992 to 1995, isolates were collected from geographically separated areas in countries in the European Union and various states in the USA. In 1996, the study was extended to include centres in Mexico, Brazil, Saudi Arabia, South Africa, Hong Kong and other European countries not included previously. Data generated by the project during 1996–1997 confirm France and Spain as European centres with high rates of resistance to penicillin among isolates of Streptococcus pneumoniae. Both intermediate (MIC 0.12–1 mg/L) and resistant (MIC 2 mg/L) phenotypes are present. Combined resistance rates (intermediate and resistant) were >=50% in 1997. Combined resistance rates in excess of 20% were found in the Republic of Ireland, Portugal, the Slovak Republic and Hungary. Penicillin resistance continues to evolve in the USA, with combined resistance rates of 16.4% (1996) and 18.6% (1997). In the new, non-European centres, e.g. Mexico and, in particular, Hong Kong (where resistant strains accounted for 50% of all isolates of S. pneumoniae in 1996 and 55.5% in 1997), there are centres where rates of resistance are high. Macrolide resistance is increasing generally among both penicillin-resistant and penicillin-susceptible isolates of S. pneumoniae. There is variation between countries, and in four out of the 16 centres for which both 1996 and 1997 data are available, rates of macrolide resistance have fallen. Overall, the percentage of S. pneumoniae strains that is resistant to macrolides exceeds the percentage that is resistant to penicillin. In 1996, 16.5% of all S. pneumoniae isolates were resistant to macrolides compared with 10.4% resistant to penicillin, and in 1997 respective rates were 21.9% and 14.1%. ß-Lactamase production was the principal mechanism of resistance observed among isolates of Haemophilus influenzae. However, considerable variation in the percentage of isolates producing ß-lactamase (0–37.1%) was observed within this species. Within Europe, in the Republic of Ireland, France and Belgium, more than 15% of isolates were ß-lactamase producers. In Spain rates were as high as 31.7%. Outside Europe and the USA high rates were described in Mexico (25%), Saudi Arabia (27.9%, 16.7%) and Hong Kong (37.1%, 28.9%). Of H. influenzae from the USA, 30.4% were ß-lactamase producers in 1996 and 23.3% in 1997. ß-Lactamase production among isolates of Moraxella catarrhalis was observed in >90% of the isolates tested in 1996 and 1997.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The problem of increasing levels of antimicrobial resistance amongst isolates of bacterial species commonly isolated from community-acquired respiratory tract infections, namely, Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis,1–3 is of growing concern to microbiologists and infectious disease physicians. The infecting pathogen is often unknown during the acute phase of the infection and therapy is thus empirical. The choice of therapy should reflect the local resistance profile.4

Surveillance of susceptibilities of individual isolates locally, nationally and worldwide, is desirable to inform empirical therapeutic choice and to influence prescription habits so that the further development of resistance may be slowed.5,6 To be useful and comparable, such studies must be of high quality.

The Alexander Project was established in 1992 to monitor the susceptibility of the major lower respiratory tract bacterial pathogens to a variety of antimicrobials and to identify trends in the development of resistance over time.7 For the first 4 years of the study (1992–1995), 10 European and five USA centres were monitored. In 1996 and 1997, the study was expanded to include centres located in Central and South America, the Middle East, South Africa, Hong Kong and other European countries not included previously. The general characteristics of the project were not altered, with isolates tested centrally at the laboratory of GR Micro Ltd, London, UK, using the same standard procedures that had been in use since the project began in 1992.7 Detailed data from the examination of isolates collected during 1996 and 1997 are now presented and, where possible, related to trends seen in previous years.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Collaborating centres

During 1996–1997, the following centres and investigators took part in the study: UK, London (D. Felmingham); Republic of Ireland, Dublin (L. Fenelon, E. Smith); France, Toulouse (J. Lemozy); Belgium, Leuven (J. Verhaegen); The Netherlands (co-ordinator A. J. de Neeling); Spain, Barcelona (J. Liñares); Portugal (co-ordinator J. Melo Cristino); Italy, Genoa (G. C. Schito); Germany, Weingarten (H. Grimm); Austria, Vienna (U. Theuretzbacher); Czech Republic (co-ordinator P. Urbásková); the Slovak Republic (co-ordinator P. Urbásková); Hungary (M. Konkoly-Thege); Poland (K. Trzcinski); Switzerland (co-ordinator J. Bille); USA (New York—U.-X. Chin, Cleveland—J. Washington, San Francisco (1997 only)—M. York); Mexico, Mexico City (J. Sifuentes-Osornio); Brazil, São Paulo (C. Mendes); Saudi Arabia, Riyadh (A. M. Shibl); South Africa, Johannesburg (K. Klugman) and Hong Kong, Pokfulam (W. H. Seto).

Bacterial isolates

Inclusion criteria for bacterial isolates, and transportation, storage, re-identification and the microbroth dilution susceptibility testing methods have been described in detail previously.7,8 In brief, centres were requested to collect up to 400 isolates from patients with community-acquired lower respiratory tract infection. Centres were instructed to avoid sending duplicate isolates from the same patient. Originally, the project accepted isolates of S. pneumoniae, H. influenzae, Haemophilus parainfluenzae, M. catarrhalis, Staphylococcus aureus and Klebsiella pneumoniae. However, by 1995 the consensus view of the project group was that H. parainfluenzae and K. pneumoniae should no longer be included, in view of the low numbers submitted for testing and their lesser importance in community-acquired respiratory tract infections. Isolates of S. aureus were collected up to and including 1997, but were submitted by only a few centres. Analysis of the MIC data produced has not, therefore, been undertaken for this species and further isolates will not be collected.

Antimicrobial susceptibility testing

MICs were determined at the central laboratory in London, using a broth microdilution method (Mueller–Hinton) with an inoculum of c. 104 cfu in 50 µL of medium.7,8 Breakpoint concentrations used to interpret MIC data qualitatively were based upon those published by the National Committee for Clinical Laboratory Standards of the USA (NCCLS, 1998),9 and are indicated in the tables and text. During the period covered by the Alexander Project, re-appraisal of the breakpoints defining susceptibility to certain antimicrobials has been undertaken by the NCCLS, and these new breakpoints will be used in this analysis.10

The antimicrobials and concentrations tested in 1996 and 1997 were: penicillin (0.004–8 mg/L), ampicillin (0.004–8 mg/L), co-amoxiclav (0.004–8 mg/L amoxycillin and 0.002–4 mg/L clavulanic acid), cefaclor (0.03–4 mg/L), cefuroxime (0.015–32 mg/L), cefixime (0.03–64 mg/L), ceftriaxone (0.004–4 mg/L), erythromycin (0.015–32 mg/L), clarithromycin (0.015–32 mg/L), azithromycin (0.015–32 mg/L), doxycycline (0.015–32 mg/L), chloramphenicol (0.03–64 mg/L), ciprofloxacin (0.008–16 mg/L), ofloxacin (0.008–16 mg/L) and co-trimoxazole (trimethoprim/sulphamethoxazole, 0.03/0.57–32/608 mg/L).


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Antimicrobial resistance in S. pneumoniae strains

A total of 2160 isolates of S. pneumoniae were submitted in 1996 and 2036 in 1997. Numbers collected by individual centres, with the percentage of penicillin-susceptible, -intermediate (MIC 0.12–1 mg/L) and -resistant (MIC >= 2 mg/L) isolates are presented in Table IGo.


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Table I. Penicillin susceptibility of isolates of S. pneumoniae—Alexander Project 1996–1997
 
Of the European centres included from the beginning of the Alexander Project, France and Spain are established as areas with high rates of S. pneumoniae penicillin resistance, with combined numbers of intermediate and resistant strains now accounting for some 50% of isolates submitted from these countries. Penicillin resistance is now reported in isolates from centres in the UK (London) and Italy (Genoa), but numbers remain low at present. Between 1992 and 1997, no penicillin-resistant strains were detected in Weingarten (Germany), but intermediate strains rose from 4% in 1996 to 14.5% in 1997. It will be interesting to see whether this anticipates the emergence of resistant strains in the future.

Of the western European countries that joined the project during 1996–1997, Portugal appears to be an established centre of penicillin resistance, though the rate is not yet as high as that seen in its geographical neighbour, Spain. Results of testing of isolates submitted from the Republic of Ireland also indicate the establishment of significant levels of penicillin resistance. Rates of resistance were low in Belgium, The Netherlands and Switzerland, and particularly low in Austria (0.9% in 1996). However, with only 2 years' data from these regions, general trends are more difficult to interpret.

Amongst eastern European countries, relatively high rates of penicillin resistance are present in the Slovak Republic, in comparison with much lower rates in its neighbour the Czech Republic. Data for Hungary also indicate a high rate of penicillin resistance (1996: 24.4% intermediate, 11.8% resistant). However, this is lower than reported in a study by Marton in 1995.11 In Poland, almost 10% of isolates are now resistant, with intermediate resistance falling in relative importance from 7.7% in 1996 to 5% in 1997. This may indicate a shift to a predominance of more highly resistant strains of S. pneumoniae in this country, and should be observed carefully.

During the lifetime of the Alexander Project, strains collected from a small number of centres in the USA have contained an increasing proportion of both intermediate and resistant isolates, with a switch from a predominance of intermediate to resistant isolates in 1994. Results presented here confirm a continued increase from 1996 to 1997, of intermediate isolates from 12.7 to 15.3%, and of resistant isolates from 16.6 to 18.6%.

In centres in Central and South America, high rates of penicillin resistance were seen in Mexico, with a change to a predominance of resistant isolates during the 2 years of monitoring. In São Paulo, Brazil, although the frequency of detection of intermediate isolates was high at 17.9% in 1996 and 14.1% in 1997, resistant isolates were seen infrequently.

Both Saudi Arabia (Riyadh) and South Africa (Johannesburg) were characterized by considerably higher rates of intermediate compared with fully resistant isolates. Conversely, in Hong Kong, low rates of intermediate resistance (5.6% in 1997), but the highest rate of resistant isolates in the study (55.5% in 1997) were observed.

Susceptibility of S. pneumoniae to ß-lactams

The comparative in vitro activities of the various ß-lactam antimicrobials for S. pneumoniae tested in the study are shown in Table IIGo. No change in the overall activity of the compounds against penicillin-susceptible isolates was observed. However, a general two-fold increase in MIC90 for all compounds except penicillin was seen, indicating a small change in distribution of MIC for the aminopenicillins and cephalosporins. For both years, as in those preceding, the most active compounds were ceftriaxone and co-amoxiclav.


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Table II. Comparative in vitro activity and percentage susceptibilitya of various ß-lactam antimicrobials against combined (intermediate and resistant) isolates of S. pneumoniae—Alexander Project 1996–1997, using NCCLS (1998)9 interpretative breakpoints
 
The comparative susceptibilities of isolates of S. pneumoniae to ß-lactams, using published breakpoints (NCCLS, 1998),9 are also shown in Table IIGo. Again, the two most active compounds were ceftriaxone (85% in 1997) and co-amoxiclav (84.2% in 1997).

Susceptibility of S. pneumoniae to non-ß-lactams

Overall rates of macrolide resistance for isolates of S. pneumoniae collected in 1996 and 1997 at 16.5 and 21.9%, respectively, now exceed those of penicillin resistance (10.4 and 14.1%, respectively), and are close to the combined rates of penicillin-resistant and penicillin-intermediate isolates (24.3% in 1997) (Table IIIGo). Similarly high resistance rates (21.8% in 1997) were found for doxycycline (Table IVGo), with high rates amongst isolates from Hong Kong, Poland, Spain, France, Italy, Belgium, Hungary and Mexico and, in 1997, Saudi Arabia, South Africa and the USA.


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Table III. Macrolide resistancea (%) for all isolates of S. pneumoniae and classified by penicillin susceptibility phenotype; S, susceptible; I, intermediate; R, resistant—Alexander Project 1996–1997
 

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Table IV. Doxycycline resistance (%), chloramphenicol resistance (%) and co-trimoxazole resistance (%) for all isolates of S. pneumoniae and classified by penicillin susceptibility phenotype: S, susceptible; I, Intermediate; R, resistant—Alexander Project 1996–1997
 
Chloramphenicol resistance (Table IVGo) was less common than penicillin, macrolide, doxycycline and co-trimoxazole resistance, with relatively high rates found in isolates from Hong Kong, Spain, France, the Slovak Republic, Poland, Italy, Mexico, the USA and Saudi Arabia.

Resistance to co-trimoxazole was widespread amongst the isolates of S. pneumoniae tested (Table IVGo). Although closely associated with penicillin resistance, high rates of resistance amongst penicillin-susceptible isolates were found in Spain, Italy, Poland, Hungary, Brazil and Hong Kong.

During the period of the study, neither the MIC50, MIC90, mode MIC nor the proportion of isolates requiring >=16 mg/L of ciprofloxacin or ofloxacin for inhibition have changed significantly, the vast majority of MICs following a unimodal distribution (Table VGo). Of the 8081 S. pneumoniae isolates tested since the Alexander Project was initiated in 1992, 0.3% (27 isolates) required a MIC >= 16 mg/L of either ciprofloxacin or ofloxacin. In 1997, isolates with a MIC >= 16 mg/L came from France (n = 1), Spain (n = 1), Germany (n = 1), Poland (n = 1), USA (two isolates, both from New York) and Hong Kong (n = 5).


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Table V. Distribution of MICs of ciprofloxacin and ofloxacin for isolates of S. pneumoniae—Alexander Project 1992–1997
 
Overall, the most active agents in 1996–1997 in terms of potency and percentage susceptibility against S. pneumoniae were ceftriaxone and co-amoxiclav.

Relationship between the susceptibilities of S. pneumoniae to different antimicrobials

Resistance to non-ß-lactam compounds was associated with penicillin resistance, with the exception of the fluoroquinolones (Tables III and IVGoGo). This association was most evident for co-trimoxazole, with more than 90% of penicillin-resistant isolates resistant to this agent. Approximately 50% of all penicillin-resistant isolates were also resistant to the macrolides, doxycycline and chloramphenicol.

Of particular interest are differences in the distribution of macrolide resistance amongst penicillin-susceptible and penicillin-resistant isolates from various locations. Isolates from France (Toulouse), Spain (Barcelona), Belgium (Leuven), Italy (Genoa) and Hong Kong exhibited high rates of macrolide resistance (Table IIIGo). However, within these five centres it is clear that different selective pressures are operating. For example, in Barcelona the majority of macrolide-resistant isolates are also penicillin resistant, whereas in Toulouse, Belgium and Hong Kong, macrolide resistance is also emerging rapidly in penicillin-susceptible isolates. A different pattern is apparent in Genoa, Italy, where macrolide resistance in excess of 20% is seen in penicillin-susceptible isolates. This is in an area in which the combined level of intermediate and resistant isolates is low (7.3% in 1997). The development of macrolide resistance independently of penicillin resistance is also seen in isolates from some, but not all, of those centres with more modest levels of macrolide resistance, including the UK, the Republic of Ireland, Switzerland, Hungary, Poland, the Slovak Republic, the USA, Mexico and Saudi Arabia. In Germany, Austria, the Czech Republic, The Netherlands, Portugal, Brazil and South Africa, macrolide resistance occurs at a relatively low level (<10%).

Antimicrobial resistance in H. influenzae

A total of 2820 isolates of H. influenzae were collected in 1996 and 2721 in 1997. The principal mechanism of resistance observed was the production of ß-lactamase, with an overall rate of 13.4% in both 1996 and 1997 (Table VIGo). Large numbers of ß-lactamase-producing strains were found in Hong Kong, Spain, France, Belgium, the Republic of Ireland, the USA, Mexico and Saudi Arabia. ß-Lactamase-negative, ampicillin-resistant strains (MIC >= 4 mg/L) were identified only rarely, with overall rates of 0.1% in 1996 and 0.3% in 1997. In 1996, four strains were found in Barcelona, Spain. In 1997, strains were isolated in Dublin, Republic of Ireland (n = 3), Portugal (n = 1) and the Slovak Republic (n = 2).


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Table VI. Antimicrobial susceptibility of isolates of H. influenzae—Alexander Project 1996–1997
 
Antimicrobial susceptibility of H. influenzae

Of the ß-lactam antimicrobials tested, co-amoxiclav, cefixime and ceftriaxone were the most active against H. influenzae, followed by cefuroxime and cefaclor (Table VIIGo).


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Table VII. Comparative in vitro activity of various ß-lactam antimicrobials against isolates of H. influenzae—Alexander Project 1996–1997
 
Rates of chloramphenicol resistance were low (1.9% in 1997); higher rates were seen in Brazil, Hong Kong, Saudi Arabia, Spain, the Republic of Ireland, South Africa, Belgium and France (Table VIGo). Analysis of chloramphenicol-resistant strains from the 6 years of collection indicates clearly an association with ß-lactamase production (Table VIIIGo).


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Table VIII. Association between chloramphenicol resistance and ß-lactamase production amongst isolates of H. influenzae—Alexander Project 1992–1997
 
Rates of doxycycline resistance of 1–2% were seen in centres in The Netherlands, Hungary, Poland and Saudi Arabia. Relatively higher rates were seen in São Paulo, Brazil and Hong Kong. Resistance levels of less than 1% were found in all other centres (Table VIGo).

Co-trimoxazole resistance was high in Barcelona, Spain, São Paulo, Brazil and Riyadh, Saudi Arabia and less than 10% in all other centres except those in Italy, Austria, the Slovak Republic, Hungary, Poland, USA, Mexico, South Africa and Hong Kong (Table VIGo).

Fluoroquinolone resistance was detected in four isolates in 1996 (one each in London, Toulouse, Barcelona and New York) and in one isolate from Portugal in 1997, making a total of 13 fluoroquinolone-resistant strains out of 11,539 isolates of H. influenzae examined in the Alexander Project since 1992—an overall rate of 0.1%.

The susceptibility of H. influenzae isolates to the macrolides followed a unimodal distribution in the rank order, azithromycin (mode MIC 0.5–1 mg/L) > erythromycin (mode MIC 4 mg/L) > clarithromycin (mode MIC 4–8 mg/L) (Table IXGo). Only eight of 11,539 isolates required >=8 mg/L azithromycin for inhibition.


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Table IX. Comparative potency of macrolide antimicrobials against isolates of H. influenzae—Alexander Project 1992–1997
 
Antimicrobial susceptibility of M. catarrhalis

ß-Lactamase production was the only resistance mechanism of importance identified in the isolates of M. catarrhalis tested. Overall, 90.4% of the 655 isolates collected in 1996 and 91.6% of 685 in 1997, produced ß-lactamase (Table XGo).


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Table X. Antimicrobial susceptibilitya of combined isolates of M. catarrhalis—Alexander Project 1996–1997
 
Co-amoxiclav and cefixime were the most active of the ß-lactam compounds tested (MIC90 0.25 mg/L) followed by ceftriaxone (MIC90 1 mg/L) and cefaclor (MIC90 2 mg/L) (Table XGo). Using the NCCLS breakpoints for H. influenzae,9 more than 99% of a total of 2998 isolates of M. catarrhalis tested since the project was established in 1992 would be considered susceptible to these compounds.

The rank order of activity of the three macrolides tested was azithromycin (MIC90 0.03 mg/L) > clarithromycin (MIC90 0.12 mg/L) > erythromycin (MIC90 0.25 mg/L). No macrolide resistance was detected in isolates from 1996 and 1997; all were inhibited by <=1 mg/L erythromycin, <=0.5 mg/L clarithromycin and 0.12 mg/L azithromycin (Table XGo).

All isolates of M. catarrhalis tested were susceptible to the fluoroquinolones and chloramphenicol, at least 99.7% to doxycycline and 97% to co-trimoxazole.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The data presented here add to those previously reported.7,8,12,13 However, a number of specific points need to be discussed in respect of this data group.

S. pneumoniae resistance

New centres in western Europe and eastern Europe showed high rates of S. pneumoniae resistance, though further data are required in order to elucidate trends. In particular, data from Dublin, Republic of Ireland, indicate that the high rates of resistance observed in Belfast, UK (1992–1995), are also present in other areas of Ireland, compared with relatively low rates on the UK mainland. Others have seen a similar pattern.14

In the USA centres, the rate of combined (intermediate and resistant) penicillin resistance has increased from 5.6% in 1992 to 18.6% in 1997. Although the total number tested in each year has been small, this trend has also been observed in a larger study, where rates of up to 52.9% (overall 23.6%) have been reported.15

Expansion of the Alexander Project has highlighted Hong Kong (with a rate of penicillin resistance of at least 50%) and South-East Asia as areas in which antimicrobial resistance is a major concern.16

Fluoroquinolone-resistant pneumococci are still found only rarely, and rates have not increased during the study period (1992–1997). More fluoroquinolone compounds are to be included from 1998 onwards, in order to observe any effects of the introduction of new agents of this class for the treatment of respiratory tract infections.

H. influenzae resistance

Results from the Alexander Project continue to demonstrate considerable variability in the prevalence of ß- lactamase production amongst isolates of H. influenzae worldwide. The rising trend in the USA slowed in 1997. However, Jacobs et al.17 reported 41.6% of 1676 isolates of H. influenzae from the USA in 1997 to be ß-lactamase producers. The low levels observed in this study may reflect a change in reporting centre from Worcester, Massachusetts, which has high rates of resistance (30% in 1995) to San Francisco, California, where the levels reported are lower.

As with S. pneumoniae, Hong Kong had a particularly high rate of ß-lactam-resistant H. influenzae in comparison with other centres in the study. ß-Lactamase-negative, ampicillin-resistant strains were identified only rarely (0.3% in 1997). However, in the Republic of Ireland (1997 = 1.5%), Spain (1996 = 1.8%) and the Slovak Republic (1997 = 2.6%), levels of detection of these strains indicate the need for vigilance.

Throughout the duration of the Alexander Project, the susceptibility of H. influenzae to the three macrolides tested has not changed and the use of arbitrary breakpoints seems inappropriate. As indicated by others, considerably more pharmacodynamic and clinical trial data are necessary if useful breakpoints are to be established for those compounds.17 Only a small number of isolates (eight of 11,539) were detected for which the MIC of azithromycin was >=1 mg/L. Further work is necessary to determine the mechanism(s) of resistance of these isolates.

M. catarrhalis resistance

Although strains of M. catarrhalis resistant to other classes of antimicrobials have been reported,18,19 results from the Alexander Project demonstrate clearly that the great majority of clinical isolates remain susceptible to co-amoxiclav, macrolides, doxycycline, chloramphenicol, the fluoroquinolones and co-trimoxazole, confirming the unique importance of ß-lactamase production as an antimicrobial resistance mechanism in this species. A large multi-centre USA study also found ß-lactamase production to be the most important mechanism of resistance in this organism.20

Future developments

It is anticipated that the complete, up-to-date Alexander Project data set will be made available in an electronic format in the near future. The results from 1992–1996 are available on the Alexander Network website (http://www.Alexander-Network.com). Bacterial isolates examined during the period of the study are stored, deep-frozen, in the central laboratory, representing an important resource for retrospective analysis.

The Alexander Project continues into 1998 and beyond. Additional testing centres have been established to enable processing of a greatly increased number of isolates from a wider geographical spread of collecting sites, underlining the global dimension of the study. The data collected thus far demonstrate increasing resistance rates in many countries and highlight the need for increased vigilance in monitoring and tracking changes in antimicrobial susceptibility in order to promote successful clinical therapy, maintain the utility of current agents and suggest targets for new therapeutic strategies. The results can be used to promote rational prescribing, by guiding clinicians in the choice of the most appropriate antimicrobial for the treatment of community-acquired respiratory tract infections in their area.


    Acknowledgments
 
The Alexander Project Group gratefully acknowledges the contribution of the following members of the scientific staff of GR Micro Ltd: M. J. Robbins, C. Dencer, I. Mathias, Y. Tesfaslasie, S. Brooks, K. Alldis and M. Hichens. Data analysis was undertaken by Micron Research Ltd, Upwell, Cambridgeshire PE14 9AR, UK. The Alexander Project is funded by SmithKline Beecham plc.


    Notes
 
* Corresponding author. Tel: +44-171-388-7320; Fax: + 44-171-388-7324; E-mail: gr.micro{at}dial.pipex.com

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    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Mandell, L. A. (1995). Community-acquired pneumonia. Etiology, epidemiology and treatment. Chest 108, Suppl., S35–42.[Free Full Text]

2 . Ball, P. (1995). Epidemiology and treatment of chronic bronchitis and its exacerbations. Chest 108, Suppl., S43–52.[Free Full Text]

3 . Goldstein, F., Bryskier, A. B., Appelbaum, P. C., Bauernfeind, A., Jacobs, M., Schito, G. C. et al. (1998). The etiology of respiratory tract infections and the antibacterial activity of fluoroquinolones and other oral bacterial agents against respiratory pathogens. Clinical Microbiology and Infection 4, Suppl. 2, 2S8–18.

4 . Felmingham, D. (1995). Antibiotic resistance. Do we need new therapeutic approaches? Chest 108, Suppl., S70–78.[Free Full Text]

5 . Jones, R. N. (1996). The emergent needs for basic research, education and surveillance of antimicrobial resistance. Problems facing the report from the American Society for Microbiology Task Force on Antimicrobial Resistance. Diagnostic Microbiology and Infectious Disease 25, 153–61.[ISI][Medline]

6 . House of Lords Select Committee on Science and Technology. (1998). Resistance to Antibiotics and Other Antimicrobial Agents. 7th Report. The Stationery Office, London.

7 . Felmingham, D. & Grüneberg, R. N. (1996). A multicenter collaborative study of the antimicrobial susceptibility of community-acquired, lower respiratory tract pathogens 1992–1993: The Alexander Project. Journal of Antimicrobial Chemotherapy 38, Suppl. A, 1–57.[ISI][Medline]

8 . Grüneberg, R. N. & Felmingham, D. (1996). Results of the Alexander Project: a continuing, multicenter study of the antimicrobial susceptibility of community-acquired, lower respiratory tract bacterial pathogens. Diagnostic Microbiology and Infectious Disease 25, 169–81.[ISI][Medline]

9 . National Committee for Clinical Laboratory Standards. (1998). Performance Standards for Antimicrobial Susceptibility Testing: Eighth Informational Supplement M100-S8. NCCLS, Wayne, PA.

10 . National Committee for Clinical Laboratory Standards. (1995). Performance Standards for Antimicrobial Susceptibility Testing: Sixth Informational Supplement M100-S6. NCCLS, Wayne, PA.

11 . Marton, A. (1995). Epidemiology of resistant pneumococci in Hungary. Microbial Drug Resistance 1, 127–30.[ISI][Medline]

12 . Felmingham, D. & Washington, J. (1999). Trends in the antimicrobial susceptibility of bacterial respiratory tract pathogens— findings of the Alexander Project 1992–1996. Journal of Chemotherapy 11, Suppl. 1, 5–21.[ISI][Medline]

13 . Goldstein, F. W. & Acar, J. F. (1996). Antimicrobial resistance among lower respiratory tract isolates of Streptococcus pneumoniae: results of a 1992–1993 western Europe and USA collaborative surveillance study. The Alexander Project Collaborative Group. Journal of Antimicrobial Chemotherapy 38, Suppl. A, 71–84.[ISI][Medline]

14 . Goldsmith, C. E., Moore, J. E. & Murphy, P. G. (1997). Pneumococcal resistance in the UK. Journal of Antimicrobial Chemotherapy 40, Suppl. A, 11–8.[Abstract/Free Full Text]

15 . Doern, G. V., Brueggemann, A., Holley, H. P. & Rauch, A. M. (1996). Antimicrobial resistance of Streptococcus pneumoniae recovered from outpatients in the United States during the winter months of 1994 to 1995: results of a 30-center national surveillance study. Antimicrobial Agents and Chemotherapy 40, 1208–13.[Abstract]

16 . Baquero, F. (1995). Pneumococcal resistance to ß-lactam antibiotics: a global geographic overview. Microbial Drug Resistance 1, 115–20.[ISI][Medline]

17 . Jacobs, M. R., Bajaksouzian, S., Zilles, A., Lin, G., Pankuch, G. A. & Appelbaum, P. C. (1999). Susceptibilities of Streptococcus pneumoniae and Haemophilus influenzae to 10 oral antimicrobial agents based on pharmacodynamic parameters: 1997 US surveillance study. Antimicrobial Agents and Chemotherapy 43, 1901–8.[Abstract/Free Full Text]

18 . Catlin, B. W. (1990). Branhamella catarrhalis, an organism gaining respect as a pathogen. Clinical Microbiology Reviews 3, 293–320.[ISI][Medline]

19 . Jorgensen, J. H., Doern, G. V., Maher, L. A., Howell, A. W. & Redding, J. S. (1990). Antimicrobial resistance among respiratory isolates of Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae in the United States. Antimicrobial Agents and Chemotherapy 34, 2075–80.[ISI][Medline]

20 . Doern, G. V., Bruggemann, A. B., Pierce, G., Hogan, T., Holley, H. P. & Rauch, A. (1996). Prevalence of antimicrobial resistance among 723 outpatient clinical isolates of Moraxella catarrhalis in the United States in 1994 and 1995: results of a 30-center national surveillance study. Antimicrobial Agents and Chemotherapy 40, 2884–6.[Abstract]

Received 5 February 1999; returned 27 May 1999; revised 23 August 1999; accepted 11 October 1999