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Antimicrobial Agents and Chemotherapy, November 1999, p. 2720-2725, Vol. 43, No. 11
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Effects of Genes Encoding Resistance to
Streptogramins A and B on the Activity of Quinupristin-Dalfopristin
against Enterococcus faecium
Bülent
Bozdogan1 and
Roland
Leclercq1,2,*
Service de Microbiologie, Hôpital
Côte de Nacre, Université de Caen, 14033 Caen,1 and Service de
Bactériologie-Virologie, Hôpital Henri
Mondor-Université Paris XII, 94000 Créteil,2 France
Received 14 May 1999/Returned for modification 20 July
1999/Accepted 31 August 1999
 |
ABSTRACT |
Quinupristin-dalfopristin is a streptogramin combination active
against multiply resistant Enterococcus faecium. Among 45 E. faecium isolated from patients in various French
hospitals, only two strains were intermediate (MIC = 2 µg/ml)
and one, E. faecium HM1032, was resistant (MIC = 16 µg/ml) to quinupristin-dalfopristin, according to British Society for
Antimicrobial Chemotherapy and National Committee for Clinical
Laboratory Standards approved breakpoints. The latter strain contained
the vgb and satA genes responsible for
hydrolysis or acetylation of quinupristin and dalfopristin,
respectively, and an ermB gene (also previously referred to
as ermAM) encoding a ribosomal methylase. The two intermediate strains had an LSA phenotype characterized by
resistance to lincomycin (L), increased MICs (
8 µg/ml) of
dalfopristin (streptogramin A [SA]), and susceptibility
to erythromycin and quinupristin. This phenotype was also detected in
eight other strains susceptible to quinupristin-dalfopristin. No genes
already known and conferring resistance to dalfopristin by acetylation
or active efflux were detected in these LSA strains.
Nineteen other strains resistant to erythromycin but susceptible to the
quinupristin-dalfopristin combination displayed elevated MICs of
quinupristin after induction (from 16 to >128 µg/ml) and contained
ermB genes. The effects of ermB,
vgb, and satA genes on the activity of the
streptogramin combination were tested by cloning these genes
individually or in various combinations in recipient strains
susceptible to quinupristin-dalfopristin, E. faecium HM1070
and Staphylococcus aureus RN4220. The presence of both the
satA and vgb genes (regardless of the presence
of an ermB gene) was necessary to confer full
quinupristin-dalfopristin resistance to the host. The same genetic
constructs were introduced into E. faecium BM4107 which
displays a LSA phenotype. Addition of the satA
or vgb gene to this LSA background conferred
resistance to quinupristin-dalfopristin.
| |
INTRODUCTION |
In recent years, enterococci have
become one of the most common causes of nosocomial infections, while
certain strains have acquired resistance to all available antimicrobial
agents, including aminoglycosides, penicillins, and glycopeptides.
Quinupristin-dalfopristin is an antimicrobial combination developed for
the treatment of infections due to vancomycin-resistant
Enterococcus faecium (20). This antimicrobial
belongs to the streptogramin class which includes naturally synthesized
antibiotics composed of two chemically distinct factors, streptogramins
A (SA) and streptogramins B (SB).
Quinupristin-dalfopristin is a semisynthetic injectable streptogramin
mixture of quinupristin (SB) and dalfopristin
(SA) in a 30:70 ratio (9). Binding of these
factors to the 50S ribosomal subunit causes inhibition of protein
synthesis (37). Alone, each factor has a moderate
bacteriostatic activity, but in combination, they often display a
bactericidal synergistic effect (9). This is related to the
synergistic binding of the factors to their ribosomal target site. Each
factor binds a different site on the peptidyltransferase domain of the ribosome, but the binding of SA causes a conformational
change which increases the affinity of SB for its target
(36). Since SA and SB are chemically
unrelated and have different binding sites, the mechanisms of
resistance to these two streptogramin types are different. In E. faecium, an acetyltransferase encoded by the satA gene
inactivates streptogramins A (31). After completion of this
work, a new satG gene encoding a putative acetyltransferase which appeared to be prevalent in E. faecium was reported
(39). Both genes are related to the acetyltransferase genes
vat (7), vatB (2), and
vatC (4) reported in staphylococci. Resistance to
streptogramins B is due either to hydrolysis of the antibiotic mediated
by the vgb gene (12, 23) initially reported in
Staphylococcus aureus (6) or to modification of
the ribosomal target by a 23S rRNA methylase encoded by the
ermB gene (24, 38). Other staphylococcal genes
such as vga and vgaB conferring resistance to
SA by a putative efflux mechanism (3, 5) or
msrA encoding a protein which participates in the active
efflux of macrolides and SB (34) have not been
reported in enterococci.
Because of the synergism displayed by the two streptogramin types, it
has been suggested that acquisition of isolated resistance to
dalfopristin or quinupristin could have no or only partial negative
impact on the antimicrobial activity of the combination (13,
25). In fact, it has been shown that inhibitory synergy between
the two factors is maintained in vitro against E. faecium strains resistant to quinupristin by synthesis of a ribosomal methylase
(19). However, the consequences of inactivation of dalfopristin or quinupristin or the outcome of combined mechanisms of
resistance on the activity of quinupristin-dalfopristin have not been
systematically analyzed.
We have studied the activity of quinupristin-dalfopristin against 45 clinical strains of E. faecium isolated from patients in
different French hospitals in relation to the mechanisms of resistance
to quinupristin and dalfopristin. Recombinant plasmids containing the
three streptogramin resistance genes well characterized in enterococci,
ermB, satA, and vgb alone or in all
possible combinations, were also constructed. The plasmids were
introduced into E. faecium and S. aureus to
evaluate the impact of the various resistance mechanisms on the
activity of quinupristin-dalfopristin.
| |
MATERIALS AND METHODS |
Bacterial strains.
Forty-five clinical isolates of E. faecium isolated from patients in 16 French hospitals in 1995 and
identified according to the scheme of Facklam and Collins
(17) were included in the study. E. faecium
strains resistant to lincomycin and dalfopristin were further
identified by amplification of the D-Ala-D-Ala
ligase gene (ddl) specific to this species to differentiate
them from Enterococcus faecalis, which is intrinsically
resistant to both antibiotics (12). E. faecium
HM1070 and S. aureus RN4220 (18), which are
susceptible to macrolides, lincosamides, SA, and
SB, and E. faecium BM4107 (26), which
was resistant to lincomycin and SA by an unknown mechanism,
were used as recipient strains in the transformation experiments.
S. aureus BM3002 (vat vgb vga) and
Streptococcus pneumoniae HM30 (ermB)
(32) were used as control strains for PCR and hybridization experiments.
Antibiotic susceptibility testing.
Antibiotic susceptibility
was tested by the disk diffusion technique, and MICs of antibiotics
were determined by the agar dilution method using Mueller-Hinton medium
(Sanofi-Diagnostics Pasteur, Marnes-la-Coquette, France) according to
the recommendations of the Comité de l'Antibiogramme de la
Societé Française de Microbiologie (14). The
enterococcal strains were grown overnight without antibiotics or
induced with quinupristin (1 µg/ml). MICs of erythromycin,
quinupristin, dalfopristin, and quinupristin-dalfopristin were
determined for induced and noninduced cells. Proposed British Society
for Antimicrobial Chemotherapy and National Committee for Clinical
Laboratory Standards breakpoints (susceptible, MIC 
1 µg/ml;
resistant, MIC 4 µg/ml) were used for
quinupristin-dalfopristin (10).
Inactivation of antibiotics.
In all clinical isolates of
E. faecium, inactivation of quinupristin, dalfopristin, and
erythromycin by bacterial cells was screened for by the microbiological
method of Gots, using Micrococcus luteus ATCC 9341 as an
indicator organism and brain heart infusion agar plates containing
dalfopristin (0.5 µg/ml), quinupristin (1 µg/ml), or erythromycin
(0.2 µg/ml) (21).
Characterization of streptogramin resistance genes.
The
resistance genes were amplified by PCR using oligonucleotide primers
described previously. Primers I and J, universal for streptogramin A
acetyltransferase genes (2), were used to amplify a 144-bp
DNA fragment within the vat and satA genes or a
147-bp fragment within the vatB gene. Primers A and B were used to specifically amplify a portion of the vga gene, and
primers C and D were used to amplify a 920-bp fragment of the
vgb gene (28). Primers I and II were used to
amplify 639 bp of ermB genes (35). DNA fragments
amplified with primers I and J and primers C and D were sequenced by an
automated ABI PRISM 377 system (Perkin-Elmer Corporation, Norwalk,
Conn.). The erm amplicons were denatured for 10 min in a
boiling water bath, immediately cooled on ice for 5 min, immobilized on
Hybond-N+ membranes (Amersham France, Les Ullis, France) by
UV light, and then hybridized with probe made of an internal fragment
of the ermB gene of S. pneumoniae HM30 amplified
by PCR and labeled with digoxigenin (Boehringer Mannheim France,
Meylan, France).
Construction of recombinant plasmids.
The satA,
vgb, and ermB genes preceded by their putative
promoters were amplified from E. faecium HM1032 DNA by PCR
with the oligonucleotides shown in Table
1. The gene sequences were determined and
were >95% identical to the published sequences of satA
(31), vgb (6), and ermB
(33) genes. The oligonucleotides were modified by insertion
of restriction enzyme recognition sites for cloning in pUC18. PCR was
done as follows: (i) an initial step of 5 min at 94°C, (ii) 35 cycles
of PCR, with 1 cycle consisting of 30 s at 94°C, 30 s at
50°C, and 1 min at 72°C, and (iii) a final step of 12 min at
72°C. The amplification products were digested with the appropriate
enzymes and cloned separately in Escherichia coli DH10B.
Plasmids containing combinations of resistance genes in the 5'-to-3'
orientation and in the following order, satA-ermB, satA-vgb, vgb-ermB, and satA-vgb-ermB
were constructed. In a second step, the inserts were subcloned in the
shuttle multicopy vector, pJIM2246 (chloramphenicol resistant)
(30), into E. coli DH10B and then introduced by
transformation into E. faecium HM1070, E. faecium
BM4107 (22), and S. aureus RN4220
(32). In these constructs, the cloned genes were under the
control of the promoter of the chloramphenicol acetyltransferase gene
of plasmid pJIM2246 and satA and ermB were under
the control of their own putative promoter. In strains containing
satA and/or vgb, inactivation of dalfopristin
and/or quinupristin was checked.
| |
RESULTS |
Characterization of the phenotypes and mechanisms of resistance to
quinupristin and dalfopristin.
The distribution of quinupristin
and dalfopristin MICs for E. faecium clinical isolates is
shown in Fig. 1. The MICs at which 50 and
90% of the isolates are inhibited were equal to 0.5 and 1 µg/ml,
respectively. Only one strain, E. faecium HM1032, was resistant to the streptogramin (MIC = 16 µg/ml), and two were intermediate (MIC = 2 µg/ml). On the basis of susceptibility to erythromycin, lincomycin, quinupristin, and dalfopristin, a susceptible phenotype and three resistance phenotypes,
macrolide-lincosamide-streptogramin B resistance (MLSB),
LSA, MLSB SA could be distinguished
(Table 2). Sixteen strains had the
susceptible phenotype characterized by susceptibility to erythromycin
(MIC 1 µg/ml), lincomycin (inhibition zone diameters of 21
mm), quinupristin-dalfopristin (MIC 1 µg/ml), and by an MIC
of quinupristin or dalfopristin of less than 8 µg/ml. The
MLSB phenotype category which corresponds to
cross-resistance to macrolides, lincosamides, and SB but
susceptibility to SA (38) included 12 strains
which contained an ermB gene as shown by PCR and
hybridization experiments. Quinupristin MICs (SB) ranged
from 1 to 64 µg/ml but increased by 4 to 16 times after growth in the
presence of subinhibitory concentrations of this antibiotic for nearly
all the strains, indicating that this phenotype was most often
inducible. Against strains with an MLSB phenotype, the MIC
of quinupristin-dalfopristin, in comparison with those against the
susceptible isolates was not altered, even after induction with
quinupristin (Table 2). The LSA phenotype (10 strains) was
characterized by susceptibility to erythromycin together with
resistance to lincomycin and elevated MICs of dalfopristin ( 8 µg/ml). No gene responsible for inactivation or efflux was found by
PCR, and no inactivation of dalfopristin was detected. The
LSA phenotype resulted in no or in a slight increase in the MIC of quinupristin-dalfopristin which led to the classification of two
strains as intermediate according to the National Committee for
Clinical Laboratory Standards breakpoints (Fig. 1). Finally, association of MLSB with SA resistance resulted
in the MLSB SA phenotype in seven strains. As
expected, these isolates contained ermB-like genes, but six
did not harbor any gene known to confer resistance to SA.
In the latter strains, the MLSB SA phenotype could result from the presence of MLSB and LSA
determinants. In the seventh strain, E. faecium HM1032
resistant to quinupristin-dalfopristin, coexistence of
ermB-, satA-, and vgb-related genes
was found. Sequence determination of the fragments amplified with
primers specific for the satA and vgb genes
revealed greater than 95% identity with the prototype genes (6,
31). E. faecium HM1032 was also resistant to
vancomycin and teicoplanin due to the presence of the vanA
gene cluster as shown by PCR (15). Thus, resistance to the
combined streptogramins was observed for a single strain among 45, combining a minimum of three mechanisms of resistance to SA
and SB.
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FIG. 1.
Distribution of MICs of quinupristin and dalfopristin
for E. faecium strains according to the phenotype of
resistance to macrolides, lincosamides, and streptogramins. MIC
distribution is shown for all the strains (white bars) and for
particular phenotypes, namely, quinupristin- and
dalfopristin-susceptible strains (lightly stippled bars),
quinupristin-resistant (MLSB phenotype) and
dalfopristin-susceptible strains (medium stippled bars), and
dalfopristin-resistant strains (MICs 8 µg/ml)
(quinupristin-resistant or -susceptible) (black bars).
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TABLE 2.
Ranges of MICs of quinupristin, dalfopristin, and
quinupristin-dalfopristin for E. faecium by phenotype
and genotype
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|
Impact of combinations of ermB, satA, and
vgb genes on the activity of
quinupristin-dalfopristin.
The ermB, satA,
and vgb genes from E. faecium HM1032 were
amplified by PCR and cloned alone or in all possible combinations in
the shuttle vector pJIM2246. The constructs were then introduced into
E. faecium BM4107, E. faecium HM1070, and
S. aureus RN4220. Plasmid-free E. faecium BM4107
was used, in addition to the other two plasmid-free recipients
susceptible to SA and SB, since this strain
displayed an LSA phenotype which appeared to be prevalent in clinical isolates of E. faecium. This strain was
resistant to lincomycin (MIC = 16 µg/ml) and dalfopristin
(MIC = 128 µg/ml) and susceptible to quinupristin (MIC = 2 µg/ml) and quinupristin-dalfopristin (MIC = 1 µg/ml) and did
not contain any known gene of resistance to SA or
SB. The MICs of streptogramins for the transformants and
the recipients containing plasmid pJIM2246 as controls are shown in
Table 3. The presence of an inducible
ermB gene led to an increase in the MIC of quinupristin
(SB) which was enhanced after induction with quinupristin
(1 µg/ml) from twofold in E. faecium HM1070(pJIM2246)
ermB to eightfold in S. aureus RN4220 and
E. faecium(pJIM2246) ermB. As expected, the
activity of dalfopristin (SA) was not affected, and there
was no change in the MIC of quinupristin-dalfopristin, even after
induction with quinupristin (SB) (data not shown). However,
the moderate level of resistance to quinupristin conferred by the
ermB gene in the E. faecium HM1070 background is
a limitation to the interpretation of the impact of the gene on the
activity of the combination against this strain. Hydrolysis of
quinupristin mediated by the vgb gene led to a fourfold
increase in the MIC of quinupristin-dalfopristin for E. faecium HM1070 and S. aureus RN4220; however, the
transformants remained susceptible to the antimicrobial combination.
Acetylation of dalfopristin due to the satA gene resulted in
an eightfold increase in the MIC of this antibiotic for E. faecium HM1070 and S. aureus RN4220 but in only a
one-dilution increase in MIC of quinupristin-dalfopristin. Thus, the
presence of only one of these mechanisms of resistance to
SA or SB was not sufficient to confer
resistance to the streptogramin combination. The presence of the
ermB and vgb genes did not result in a further
increase in the level of resistance to quinupristin. Combination of the
ermB gene with satA yielded a one- or
two-dilution increase in the MIC of quinupristin-dalfopristin and led
to classification of E. faecium HM1070(pJIM2246)
(ermB satA) as intermediate. Only coexistence of the
satA and vgb genes conferred
quinupristin-dalfopristin resistance.
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TABLE 3.
MICs of quinupristin, dalfopristin, and
quinupristin-dalfopristin for three recipient strains containing the
ermB, satA, and vgb genes cloned in
various combinations on plasmid pJIM2246
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The LS
A background of
E. faecium BM4107 host
played an important role. The presence of the
satA or
vgb gene alone multiplied
the MIC of
quinupristin-dalfopristin by a factor which was similar
to that for the
other recipient strains (Table
3). However, since
the MIC of
quinupristin-dalfopristin for
E. faecium BM4107 was
equal to
1 µg/ml, this increase was sufficient to confer resistance
to the
antimicrobial. When the resistance genes were combined,
MICs increased
up to 16 µg/ml.
| |
DISCUSSION |
This study showed that only one strain among 45 clinical isolates
of E. faecium collected in France in 1995 was fully
resistant to quinupristin-dalfopristin. This prevalence is similar to
that reported in a previous study in the United States (16).
However, in 29 of the 45 strains studied, a mechanism of resistance to quinupristin (SB) or dalfopristin (SA) was
found. As observed both for clinical isolates and for isogenic pairs of
strains, the presence of an ermB-like gene conferring
resistance to quinupristin had no or a very weak influence on the MIC
of quinupristin-dalfopristin. This could result from the inducible
expression of the ermB-like genes in the strains studied
which is common for this determinant in enterococci, pneumococci, and
streptococci (33). The presence of dalfopristin
(SA) could prevent synthesis of the inducible ribosomal
methylase. However, the synergy between the two streptogramin factors
was observed even after preinduction of the bacterial cultures with
quinupristin (SB) and has been reported in staphylococci when the erm gene is expressed constitutively
(38). In fact, conservation of synergism is most probably
due to the mode of action of streptogramins: the factor A binds to its
target and may induce a conformational change in the ribosome, leading
to an increase in its affinity for factor B (13). The
ribosomal alteration should be sufficiently pronounced to overcome the
loss of affinity for the B molecule that results from rRNA methylation. Quinupristin modification mediated by the vgb gene had a
moderate impact on the MIC of quinupristin-dalfopristin which remained within the susceptible clinical category. Superposition of this mechanism of resistance onto target modification did not amplify the
level of resistance to quinupristin. This result differs from that
reported in a strain of E. coli where the ermB
and ereB (esterification of erythromycin) genes contribute
to erythromycin resistance in a more than additive fashion
(8).
According to the hypothesized mechanism of synergism between
SA and SB mentioned above, factor A of
streptogramins would have a key role in the synergy between
SA and SB. Therefore, alteration of the
activity of dalfopristin (SA) was expected to have a
deleterious effect on synergy. In a recent study, resistance to
quinupristin-dalfopristin in clinical isolates of staphylococci was
always related to resistance to type A streptogramins encoded by
vat or vatB genes associated with erm
genes (27). Surprisingly, acetylation of dalfopristin yielded only a modest increase in the MIC of quinupristin-dalfopristin for enterococci (Table 3). The moderate level of resistance to dalfopristin conferred by the satA gene suggested that
SA could in part escape chemical modification caused by the
enzyme. Therefore, enough drug might bind the ribosomes to trigger
synergy between SA and SB since the synergy is
expressed over a wide range of quinupristin/dalfopristin ratios
(11). The other type of resistance to dalfopristin was
detected in the clinical strains with an LSA phenotype.
This phenotype has been reported in staphylococci (1) but
not in E. faecium. The mechanism of resistance remains to be
elucidated in both bacterial genera. This phenotype resembles LSA resistance in E. faecalis which is intrinsic
to this species. Therefore, surveillance of the prevalence of this
phenotype in E. faecium requires accurate identification at
the species level, including genotypic techniques if necessary
(15). LSA resistance, when combined with
inactivation of quinupristin (SB) or dalfopristin (SA) led to full expression of quinupristin-dalfopristin
resistance. This phenotype appears nearly as prevalent as
MLSB in E. faecium, but in contrast to this
latter mechanism, acquisition of LSA resistance could be an
important step towards resistance to quinupristin-dalfopristin. Although this study showed that a combination of a minimum of two
resistance mechanisms to SA and SB was
necessary to confer resistance to the streptogramin combination, the
role of other unknown mechanisms conferring resistance to
streptogramins in enterococci remains to be assessed. In a recent
study, among 51 E. faecium resistant to
quinupristin-dalfopristin isolated in farm animals and in humans, only
37 contained a satA gene and one contained a vgb
gene (23). Finally, it remains to be established if the
synergistic effect of quinupristin (SB) and dalfopristin (SA) which is able to overcome isolated resistance to
either factor in vitro holds true in vivo. Studies in the animal model
of endocarditis indicate decreased in vivo activity of
quinupristin-dalfopristin against MLSB-resistant strains of
E. faecium (19). However, findings of the
Synercid emergency use program showed 70% successful treatment of
infections due to vancomycin-resistant E. faecium despite
the expression of MLS resistance in the vast majority of the strains
(16, 29).
| |
ACKNOWLEDGMENTS |
This work was supported in part by a grant from
Rhône-Poulenc Rorer.
We thank Jean-François Desnottes, Michael Dowzicky, Sylvie
Dutka-Malen, Céline Féger, and Harriette Nadler for helpful discussions.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: CHU de Caen,
Service de Microbiologie, Avenue Côte de Nacre, 14033 Caen Cedex,
France. Phone: (33) 2 31 06 45 72. Fax: (33) 2 31 06 45 73. E-mail:
leclercq-r{at}chu-caen.fr.
| |
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Antimicrobial Agents and Chemotherapy, November 1999, p. 2720-2725, Vol. 43, No. 11
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
