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Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, October 1999, p. 2542-2546, Vol. 43, No. 10
University Hospital St. Radboud, Department
of Medical Microbiology, 6500 HB Nijmegen, The Netherlands
Received 2 February 1999/Returned for modification 12 April
1999/Accepted 29 July 1999
In vitro susceptibilities of 4,208 enterococci (83%
Enterococcus faecalis isolates, 13.6% Enterococcus
faecium isolates, and 3.4% isolates of other species) from
patients in 27 European countries towards 16 antibiotics were
determined. High-level resistance to gentamicin varied by country
(range, 1 to 49%; mean, 22.6% ± 12.3%) and per species (19.7%
E. faecalis isolates, 13.6% E. faecium
isolates, 3.4% by other species). Vancomycin resistance was detected
in 0.06% E. faecalis, 3.8% E. faecium, and
19.1% isolates of other species. All enterococci were susceptible to LY 333328 and everninomicin, and 25% of E. faecalis
isolates and 85% of other enterococci were susceptible to
quinupristin-dalfopristin. The MIC of moxifloxacin and trovafloxacin
for ciprofloxacin-susceptible E. faecalis at which 90% of
the isolates were inhibited was 0.25 to 0.5 µg/ml.
Development of new glycopeptides,
streptogramins, everninomicin, and fluoroquinolones with enhanced
activity against gram-positive bacteria is of special interest because
of their potential use in the treatment of infections caused by
resistant enterococci (13, 15, 17). We determined the in
vitro susceptibilities of 4,208 strains to 16 antibiotics.
Isolates.
The strains were isolated from clinical material in
49 European hospitals in 27 countries, collected from 1 January
until 1 April 1997 on behalf of a study on the prevalence of
vancomycin-resistant enterococci (VRE) in Europe (14). The
number of isolates per hospital was limited to 100 consecutive,
unique isolates; an average of 155.9 isolates per country were
included. Most hospitals were teaching hospitals. The isolates came
from blood and cerebrospinal fluid (n = 191)
respiratory tract (212), abdomen (554), wounds (604), urine
(2,270), and other clinical materials (377). Strains were identified by
biochemical tests using Facklam and Collins' recommendations
(7) and by testing for
methyl- Susceptibility testing.
MICs were determined by broth
microdilution (2) with Mueller-Hinton broth. The
antimicrobial agents tested were gentamicin, vancomycin,
teicoplanin, LY 333328, everninomicin, quinupristin-dalfopristin, erythromycin, ciprofloxacin, sparfloxacin, trovafloxacin,
moxifloxacin, chloramphenicol, amoxicillin, cefpirome, imipenem,
and meropenem. Drugs were reconstituted according to the
manufacturers' directions. The final inoculum size was 3 × 105 to 5 × 105 CFU/ml. Plates were
incubated at 35°C for 20 h. High-level resistance (HLR) to
gentamicin was defined as an MIC of Distribution.
Strain distribution was 3,493 (83%)
Enterococcus faecalis, 574 (13.6%) E. faecium,
and 141 (3.4%) other Enterococcus species, including
Enterococcus gallinarum (50 strains), Enterococcus
durans (30 strains), Enterococcus casseliflavus (21 strains), Enterococcus avium (19 strains), E. faecalis biochemical variant (10 strains), Enterococcus
hirae (5 strains), Enterococcus pseudavium (3 strains), Enterococcus mundtii (2 strains), and
Enterococcus raffinosum (1 strain). This distribution
resembled that in other parts of the world (6, 9, 16). VRE
were found in 0.06% of E. faecalis (vanA)
strains, 3.8% of E. faecium (vanA and
vanB) strains, and 52% of E. gallinarum
(vanC) strains. Susceptibility data are listed in the tables
and are discussed by antimicrobial agent or group.
HLR to gentamicin.
HLR to gentamicin was demonstrated in all
countries, with a prevalence ranging from 1 to 48% (mean, 22.6% ± 12.3%). This overall prevalence is lower than that in other parts
of the world (6, 9, 16). Countries with high percentages of
resistance were scattered over Europe; there were no geographic
relationships. There was no indication of clonal spread of a single
resistant organism. HLR to gentamicin was combined with vancomycin
resistance in one E. faecalis, five E. faecium,
and two E. gallinarum isolates (Table
1). HLR to gentamicin was often
combined with fluoroquinolone resistance in E. faecalis and E. faecium (Table
2).
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Antimicrobial Susceptibility Patterns of
Enterococci Causing Infections in Europe
ABSTRACT
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-D-glucopyranoside (4). The
identification of VRE was confirmed by the API 20 STREP system
(BioMerieux, Marcy l'Etoile, France). PCR analyses (5)
showed that 18 isolates contained the vanA gene, 5 contained the vanB gene, and 28 contained the vanC gene.
512 µg/ml, vancomycin resistance (VRE) was defined as an MIC of 8 µg/ml. VRE were also tested with the E-test (AB Biodisk, Solna, Sweden) according to the
directions of the manufacturer. Interpretive criteria were published by
the National Committee for Clinical Laboratory Standards (NCCLS)
(11) except where noted in the tables. Enterococcus faecalis ATCC 29212 and Staphylococcus aureus ATCC 2921 were used as reference strains. Statistical analysis was performed by
the chi-square test.
TABLE 1.
HLR to gentamicin and vancomycin among 4,208 clinical
isolates of enterococci by species
TABLE 2.
MIC50s, MIC90s, MIC ranges, and
percentages of susceptibility for beta-lactams, carbapenems,
quinolones, and chloramphenicol for 4,208 enterococci of which 846 were HLR
Amoxicillin. Amoxicillin resistance was strongly correlated with HLR to gentamicin in E. faecium: 85% of E. faecium isolates with HLR to gentamicin were amoxicillin resistant in comparison to 40% of E. faecium strains with no HLR to gentamicin (P < 0.0001); accordingly, 91% of E. gallinarum isolates with HLR to gentamicin were amoxicillin resistant in comparison to 33% of E. gallinarum isolates with no HLR to gentamicin (P < 0.005).
Carbapenems. The MICs of imipenem ranged from 0.03 to 256 µg/ml. The MICs of imipenem were consistently twice or four times lower than those of meropenem (Table 2). E. faecium strains were more often resistant than E. faecalis strains (P < 0.0005). HLR was linked with resistance against meropenem for E. faecalis (P < 0.0005) and against imipenem and meropenem for E. faecium and the other species (P < 0.0005).
Cefpirome. Only E. faecalis isolates with no HLR to gentamicin were susceptible to cefpirome, with the MICs for a majority of the isolates equal to 8 µg/ml. Resistance of E. faecium was almost complete.
Chloramphenicol. The MICs for the majority of E. faecalis, E. faecium, E. durans, E. avium, E. casseliflavus, and E. gallinarum isolates were at the breakpoint of 8 µg/ml; strains with HLR to gentamicin were more likely to be resistant to chloramphenicol. Chloramphenicol resistance was not linked to vancomycin resistance. This may suggest a possible role of chloramphenicol in VRE infections (10).
Fluoroquinolones. The MICs of sparfloxacin, trovafloxacin, and moxifloxacin for the majority of E. faecalis strains were 0.12 to 0.25 µg/ml, which is two to four times lower than those of ciprofloxacin. Over 90% of E. faecalis isolates were susceptible at the breakpoint. The activities of sparfloxacin, trovafloxacin, and moxifloxacin towards E. faecium were much lower, with susceptibilities of 78, 83, and 84%, respectively. The susceptibility of the other species resembled that of E. faecalis. The MICs of sparfloxacin, trovafloxacin, and moxifloxacin for ciprofloxacin-resistant strains were higher than those for ciprofloxacin-susceptible isolates, thus reflecting fluoroquinolone cross-resistance (13, 16). Decreased fluoroquinolone susceptibility was not linked to vancomycin resistance. Fluoroquinolone resistance was linked with HLR to gentamicin: 79% of E. faecalis isolates with HLR to gentamicin were resistant to ciprofloxacin in comparison with 6% of strains with no HLR to gentamicin (P < 0.0005); accordingly, 52% of E. faecium isolates with HLR to gentamicin were resistant to ciprofloxacin in comparison to 33% of E. faecium strains with no HLR to gentamicin (P < 0.005). The high linkage between fluoroquinolone resistance and gentamicin resistance is unexplained; there were no geographic trends because these strains were found in every country. It is also unlikely that clonal spread of a single organism resulted in wide-spread resistance in 27 countries.
Glycopeptides.
Resistance to vancomycin was high (MIC, 256
µg/ml) in 18 strains with the vanA gene (two E. faecalis and 16 E. faecium strains) and one with
vanB (E. faecium); resistance was moderate (MIC, 8 to 32 µg/ml) in four E. faecium strains (containing
vanB) and 27 strains with vanC (26 E. gallinarum and 1 E. casseliflavus strain). The vanA-containing
strains were resistant to teicoplanin (MIC, 16 to 25 µg/ml).
Vancomycin resistance was seldom linked with gentamicin resistance, in
contrast with findings in other parts of the world (1, 6,
18). Except towards the vanA-containing strains,
teicoplanin was the most active glycopeptide, being eight times or more
as active as vancomycin and LY 333328. There was no cross-resistance
between vancomycin and LY 333328 (Table 3).
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Everninomicin. The activity of everninomicin was comparable to that of LY 333328, with the MICs ranging from 0.03 to 2 µg/ml.
Quinupristin-dalfopristin. The MICs of quinupristin-dalfopristin ranged from 0.03 to 64 µg/ml. Overall, E. faecalis strains were less susceptible than strains of E. faecium and other species (12, 13), yet development of increased resistance by E. faecium during therapy is a matter of concern (3).
LY 333328, everninomicin, and quinupristin-dalfopristin were the only compounds tested which inhibited enterococci independently of their susceptibilities to gentamicin and vancomycin. The MICs at which 90% of the isolates were inhibited that we found for LY 333328, everninomicin, and quinupristin-dalfopristin were in the range reported by others (8, 15, 16, 17). These drugs compared favorably with teicoplanin in activity against vanA strains. Multiresistance is not uncommon, but our percentages were much higher than those given by others (16). Multiresistance and cross-resistance result in limitations in clinical use, especially by loss of synergistic combinations which are often needed for enterococcal infections. New agents like LY 333328, everninomicin, and quinupristin-dalfopristin, which do not (or do not yet) display cross-resistance are therefore of great value.| |
ACKNOWLEDGMENTS |
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We thank Hannie Roelofs-Willemse, Wilma Kraak, Yvonne Peters, Melanie Wattenberg, and Emma Keuleyan for technical assistance.
This study was supported by grants from Bayer AG, Leverkusen, Germany; Eli Lilly BV, Nieuwegein, The Netherlands; Pfizer BV, Capelle a/d IJssel, The Netherlands, Rhone-Poulenc Rorer BV, Amstelveen, The Netherlands; and Schering-Plough Research Institute, Kenilworth, N.J.
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FOOTNOTES |
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* Corresponding author. Mailing address: University Hospital St. Radboud, Department of Medical Microbiology, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Phone: 30-24-3614356. Fax: 30-24-354 0216. E-mail: j.hoogkamp{at}mmb.azn.nl.
Members of the European VRE Study Group are as follows: Austria, C. Jebelean, H. Mittermayer, and M. Rotter; Belgium, M. J. Struelens; Bulgaria, E. E. Keuleyan; Croatia, A. Boras;
Czechoslovakia, J. Schindler; Denmark, A. Bremmelgaard, J. Renneberg,
N. Frimodt-Moeller, and A. Lester; Finland, O. O. Liimatainen and J. Vuopio-Varkila; France, A. Andremont, C. Muller-Serleys, J. Etienne, and J. Raymond; Germany, L. Bader,
J. Heesemann, R. Luetticken, R. R. Reinert, G. Peters, R. Gross, and P. M. Shah; Greece, G. Syrogiannopoulos and O. Vavatsi-Manou; Hungary, A. Marton and E. Nagy; Israel, C. Block and P. Yagupsky; Italy, G. A. Botta, G. Marchiaro, and S. Stefani; Latvia, D. Gardovska and L. Drukalska; Lithuania, V. Usonis; The Netherlands, H. P. Endtz, J. G. M. Koeleman, and J. F. G. M. Meis; Norway, A. Sundsfjord; Poland, M. Basta,
P. B. Heczko, and E. Torbicka; Portugal, J. Melo-Cristino; Russia, I. A. Popova; Slovak Republic, V. Krcmercy, Jr.; Slovenia, M. Gubina; Spain, F. Asensi-Botet,
C. Riestra, J. R. Cervilla, A. Trilla, and J. Villa;
Sweden, L. G. Burman, M. H. Laurel, and M. Rylander; Switzerland, R. Frei; Turkey, G. Kanra; United
Kingdom, P. R. Chadwick, E. H. Price, and H. Holzel.
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