Activity of faropenem, a new furanem, against European respiratory pathogens collected during 2000–2001: a comparison with other ß-lactam agents

Mark E. Jones1,*, Renée S. Blosser-Middleton2, Ian A. Critchley2, James A. Karlowsky2, Clyde Thornsberry3 and Daniel F. Sahm2

Focus Technologies, Inc., 1 Koninginneweg 11, Hilversum 1217 KP, The Netherlands; 2 Herndon, VA; 3 Franklin, TN, USA

Sir,

Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis comprise the most common causative agents of respiratory tract infections (RTIs). Resistance to penicillin and other ß-lactam agents commonly used as empirical therapies to treat RTIs is an established concern. This has prompted the development of new oral agents that can be used to treat RTIs in both adult and paediatric patients. Faropenem, an investigational compound, the first in the furanem class of compounds intended for oral administration and sharing structural similarities with ß-lactams, has been shown to exhibit broad-spectrum bactericidal activity,1 including activity against S. pneumoniae that are resistant to other agents.2,3 We tested faropenem and comparator ß-lactam agents against clinical isolates of S. pneumoniae (n = 1870), H. influenzae (n = 1995) and M. catarrhalis (n = 649) collected during the 2000–2001 respiratory season.

Clinically relevant organisms were isolated from patient specimens (one per patient) at 48 hospitals in France (8), Germany (10), Greece (5), Italy (8), Spain (8) and the UK (9). In total, 291 (126 penicillin-susceptible, 87 penicillin-intermediate, 78 penicillin-resistant) S. pneumoniae, 275 (91 ß-lactamase-positive, 184 ß-lactamase-negative) H. influenzae and 100 (98 ß-lactamase-positive, two ß-lactamase-negative) M. catarrhalis were collected from France; 506 (460 penicillin-susceptible, 37 penicillin-intermediate, nine penicillin-resistant) S. pneumoniae, 516 (42 ß-lactamase-positive, 474 ß-lactamase-negative) H. influenzae and 181 (174 ß-lactamase-positive, seven ß-lactamase-negative) M. catarrhalis were collected from Germany; 55 (35 penicillin-susceptible, 10 penicillin-intermediate, 10 penicillin-resistant) S. pneumoniae, 65 (four ß-lactamase-positive, 61 ß-lactamase-negative) H. influenzae and 30 (all ß-lactamase-positive) M. catarrhalis were collected from Greece; 364 (319 penicillin-susceptible, 28 penicillin-intermediate, 17 penicillin-resistant) S. pneumoniae, 352 (28 ß-lactamase-positive, 324 ß-lactamase-negative) H. influenzae and 102 (97 ß-lactamase-positive, five ß-lactamase-negative) M. catarrhalis were collected from Italy; 268 (122 penicillin-susceptible, 71 penicillin-intermediate, 75 penicillin-resistant) S. pneumoniae, 340 (65 ß-lactamase-positive, 275 ß-lactamase-negative) H. influenzae and 101 (96 ß-lactamase-positive, five ß-lactamase-negative) M. catarrhalis were collected from Spain; 386 (360 penicillin-susceptible, 16 penicillin-intermediate, 10 penicillin-resistant) S. pneumoniae, 447 (62 ß-lactamase-positive, 385 ß-lactamase-negative) H. influenzae and 135 (127 ß-lactamase-positive, eight ß-lactamase-negative) M. catarrhalis were collected from the UK. Isolates were submitted to a central laboratory (Focus Technologies, Herndon, VA, USA), subcultured on to blood (S. pneumoniae and M. catarrhalis) or chocolate (H. influenzae) agar and re-identified using standard methods. ß-Lactamase production in H. influenzae and M. catarrhalis was determined using nitrocefin (BBL DrySlide Nitrocefin; Becton Dickinson, Sparks, MD, USA). All isolates were tested by broth microdilution, in accordance with the NCCLS,4 against penicillin (S. pneumoniae only), ampicillin (H. influenzae and M. catarrhalis only), co-amoxiclav, cefaclor, cefuroxime, cefdinir, ceftriaxone and faropenem using dried microdilution panels (TREK Diagnostics, Westlake, OH, USA). MICs were interpreted according to the NCCLS 2002 published breakpoints.5

Table 1 illustrates the activity in vitro of faropenem and comparator ß-lactam agents against S. pneumoniae, H. influenzae and M. catarrhalis by country. Penicillin resistance among S. pneumoniae ranged from 1.8% (9/506) among isolates collected in Germany to 28.0% (75/268) among isolates collected in Spain. There was a high level of cross-resistance between penicillin and other ß-lactam agents, as the MIC90 of each agent showed a significant increase between penicillin-susceptible and -resistant isolates. Faropenem MIC90s were higher in countries with >18% penicillin resistance (France, Greece, Spain: MIC90s, 0.5–1 mg/L), compared with countries with lower prevalences of penicillin resistance (Germany, Italy, UK: MIC90s, 0.015–0.03 mg/L). Faropenem showed the highest activity against penicillin-resistant S. pneumoniae of all the ß-lactams tested with MIC90s of 0.5–1 mg/L in all countries; at least two-fold lower than co-amoxiclav (MIC90s, 2–8 mg/L), and equal to or lower than ceftriaxone (MIC90s, 1–2 mg/L). Cefaclor, cefdinir and cefuroxime were not active against penicillin-resistant S. pneumoniae in any of the countries surveyed.


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Table 1.  Susceptibilities of S. pneumoniae, H. influenzae and M. catarrhalis to faropenem and other ß-lactams
 
ß-Lactamase production among H. influenzae ranged from 6.2% (4/65) among the isolates collected in Greece to 33.1% (91/275) among the isolates collected in France. Faropenem activity was unaffected by ß-lactamase production, since faropenem MIC distributions (data not shown) and MIC90s (0.5–1 mg/L) in each country were equivalent for both ß-lactamase-positive and -negative isolates.

ß-Lactamase production among M. catarrhalis was >94% in all countries. Faropenem MIC90s were 0.5 mg/L in all countries and were comparable to those of co-amoxiclav (0.25 mg/L), cefdinir (0.25 mg/L), cefaclor (1 mg/L), cefuroxime (2 mg/L) and ceftriaxone (0.5 mg/L). All ß-lactams showed equivalent MIC90s between countries, which were attributed to similar rates of ß-lactamase production in the countries surveyed.

Penicillin-resistant S. pneumoniae was 10.6% (199/1870 isolates) overall, comparable to the 1999 SENTRY Antimicrobial Program (10.4%).6 Despite this apparent levelling off in the prevalence of penicillin-resistant S. pneumoniae, the current levels of resistance compromise the efficacy of penicillin and some orally available cephalosporins. Despite a reduction in the activity of faropenem associated with resistance to penicillin, MIC90s of <=1 mg/L were reported for all countries, below the tentative susceptible breakpoint (<=2 mg/L). Using this breakpoint, 99.9% of S. pneumoniae, 99.8% of H. influenzae and 100% of M. catarrhalis were susceptible to faropenem. From this study, faropenem demonstrates encouraging activity against contemporary European isolates of these respiratory pathogens and warrants further study.

Acknowledgements

We thank all participating hospitals for referring isolates. This study was conducted as part of the LIBRA Surveillance program and was sponsored by Bayer AG, Wuppertal, Germany.

Footnotes

* Corresponding author. Tel: +31-35-625-7290; E-mail: mjones{at}focusanswers.com Back

References

1 . du Plessis, M., Capper, T. P. & Klugman, K. P. (2002). In vitro activity of faropenem against respiratory pathogens. Journal of Antimicrobial Chemotherapy 49, 573–84.[Free Full Text]

2 . Schmitz, F.-J., Boos, M., Mayer, S., Verhoef, J., Milatovic D. & Fluit, A. C. (2001). In vitro activity of faropenem and 21 other compounds against 385 different genetically characterized isolates of antibiotic-resistant Streptococcus pneumoniae. Journal of Antimicrobial Chemotherapy 48, 148–52.[Free Full Text]

3 . Marchese, A., Debbia, E. A., Bryskier, A. & Schito, G. C. (1999). Antimicrobial activity of faropenem, a new oral penem, against lower respiratory tract pathogens. Clinical Microbiology and Infection 5, 282–7.[Medline]

4 . National Committee for Clinical Laboratory Standards. (2000). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically: Approved Standard M7-A5. NCCLS, Villanova, PA, USA.

5 . National Committee for Clinical Laboratory Standards. (2002). Performance Standards for Antimicrobial Susceptibility Testing: Tenth Informational Supplement M100-S12. NCCLS, Villanova, PA, USA.

6 . Hoban, D. J., Doern, G. V., Fluit, A. C., Roussel-Delvallez, M. & Jones, R. N. (2001). Worldwide prevalence of antimicrobial resistance in Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis from the SENTRY Antimicrobial Surveillance program, 1997–1999. Clinical Infectious Diseases 15, Suppl. 2, S81–93.





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