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Antimicrobial Agents and Chemotherapy, January 2006, p. 237-242, Vol. 50, No. 1
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.1.237-242.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Activity of a New Oral Streptogramin, XRP2868, against Gram-Positive Cocci Harboring Various Mechanisms of Resistance to Streptogramins

Michel Dupuis and Roland Leclercq^*

Service de Microbiologie and EA 2128 Relations Hôte et Microorganismes des Épithéliums, Hôpital Côte de Nacre, Université de Caen, 14033 Caen cedex, France

Received 1 September 2005/ Returned for modification 21 September 2005/ Accepted 16 October 2005

Top Abstract Introduction Materials and Methods Results Discussion References

 
The antibacterial activity of XRP2868, a new oral streptogramin composed of a combination of RPR132552 (streptogramin A) and RPR202868 (streptogramin B), was evaluated against a collection of clinical gram-positive isolates with characterized phenotypes and genotypes of streptogramin resistance. The effects of genes for resistance to streptogramin A or B on the activity of XRP2868 and its components were also tested by cloning these genes individually or in various combinations in gram-positive recipient strains susceptible to quinupristin-dalfopristin. The species tested included Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae, and other species of streptococci. XRP2868 was generally fourfold more potent than quinupristin-dalfopristin against S. aureus, E. faecium, and streptococci and had activity against E. faecalis (MICs = 0.25 to 1 µg/ml). XRP2868 appeared to be affected by the same mechanisms of resistance as those to quinupristin-dalfopristin. Nevertheless, the strong activity of factor A of the oral streptogramin enabled the combination to be very potent against streptogramin-susceptible staphylococci, streptococci, and E. faecium (MICs = 0.03 to 0.25 µg/ml) and to retain low MICs against the strains harboring a mechanism of resistance to factor A or factor B of the streptogramin. However, the combination of mechanisms of resistance to factors A and B caused an increase in the MICs of XRP2868, which reached 1 to 4 µg/ml. As with the other streptogramins, there was a reduction in the bactericidal effect of XRPR2868 when the staphylococcal strains acquired a constitutively expressed erm gene.

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Multidrug resistance in gram-positive cocci has increased at an alarming rate in clinical settings worldwide, and overcoming bacterial resistance has become more important than ever. Several new drugs have been proposed as alternatives for the treatment of severe infections caused by multiply resistant gram-positive organisms, i.e., linezolid, daptomycin, tigecycline, and quinupristin-dalfopristin. Quinupristin-dalfopristin, an injectable streptogramin, was among the first to be developed internationally (3). Streptogramins have the advantage of bactericidal activity against pneumococci and staphylococci, provided that they are susceptible to clindamycin (11). However, quinupristin-dalfopristin can be administered only parenterally; and except for pristinamycin, which is available in France, oral streptogramins are not available (5). In addition, the administration of quinupristin-dalfopristin requires the presence of a deep-vein catheter because of venous toxicity (21). Therefore, the value of the international development of a new oral streptogramin that can be used as a replacement or as the treatment of first choice has become obvious.

XPR2868 is a new investigational oral streptogramin that is composed of a mixture of 70% RPR132552 (streptogramin group A) and 30% RPR202868 (streptogramin group B) (18). The new compound was shown to inhibit staphylococci, Streptococcus pneumoniae, nonpneumococcal streptococci, Haemophilus influenzae, and anaerobes at concentrations of 1 µg/ml or less (10, 12, 18). XRP2868 was approximately fourfold more potent than quinupristin-dalfopristin against Staphylococcus aureus and Enterococcus faecium (10).

Streptogramins cause inhibition of protein synthesis by binding of the streptogramin A (S_A) and streptogramin B (S_B) components to the 50S ribosomal subunit. Each streptogramin factor binds to a different site on the peptidyltransferase domain of the ribosome, but the binding of S_A increases the affinity of S_B for its target (5). Since S_A and S_B are chemically unrelated and have different binding sites, the mechanisms of resistance to these two streptogramin types are different (13). In E. faecium and staphylococci, acetyltransferases encoded by genes belonging to the vat family inactivate S_A. Other staphylococcal genes, such as vga(A) and vga(B), mediate resistance to S_A by a putative efflux mechanism. Resistance to S_B is due either to lyases encoded by the vgb genes, initially reported in S. aureus and then in enterococci, or to modification of the ribosomal target by a 23S rRNA methylase encoded by the erm genes widely distributed in numerous species of gram-positive organisms (14). In addition, in staphylococci, the msr(A) gene encodes a protein which probably participates in the active efflux of macrolides and S_B (20). Generally, because of the synergism displayed by the two streptogramin types, acquisition of isolated resistance to S_A or S_B has only a partial negative impact on the antimicrobial activity of the combination (4).

The aim of this study was to investigate the behavior of XRP2868 and those of the two factors that compose it against strains exhibiting characterized mechanisms of resistance to factor A or factor B of the streptogramins and to compare their behaviors to that of quinupristin-dalfopristin.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Bacterial strains. We used one collection of laboratory strains and one collection of clinical isolates. The set of laboratory strains was composed of isogenic pairs of S. aureus, E. faecium, Enterococcus faecalis, S. pneumoniae, and oral streptococci. Thirty-seven constructs containing resistance genes for S_A or S_B were tested and were compared with their susceptible counterparts. Some streptogramin-resistant strains were described previously, and others were constructed for this study. They were obtained either by cloning determinants of resistance on multicopy vectors pAT392 and pJIM2246 (2, 4) or by in vitro mutation of susceptible S. aureus, S. pneumoniae, and Streptococcus gordonii strains or transformation of S. pneumoniae CP1000 or S. gordonii strain Challis (4, 6, 15, 23). In some constructs, resistance genes were combined.

One hundred forty-seven clinical isolates obtained between 2000 and 2005 from various clinical samples and selected as presenting various phenotypes of resistance to macrolides and/or streptogramins were also tested. This collection included 23 S. aureus isolates, 16 coagulase-negative staphylococci, 18 E. faecium isolates, 11 E. faecalis isolates, 32 S. pneumoniae isolates, 23 oral streptococci, and 24 group A and group B streptococci.

S. aureus ATCC 29213, E. faecalis ATCC 29212, and S. pneumoniae ATCC 49619 and ATCC 6303 were used as controls for determination of the MICs of the antibiotics.

Susceptibility to streptogramins. The MICs of XRP2868, each of its two components (RPR132552 [factor A] and RPR202868 [factor B]), quinupristin-dalfopristin, quinupristin, and dalfopristin were determined by the agar dilution method with Mueller-Hinton (MH) medium (bioMérieux, La-Balme-les-Grottes, France) not supplemented or supplemented with 5% sheep blood for streptococci, according to the recommendations of the Comité de l'Antibiogramme de la Societé Française de Microbiologie (8). All antibiotics were supplied by Aventis-Pharma (Romainville, France). Inocula of approximately 10⁴ CFU per spot were applied with a replicator, and the plates were examined for growth after overnight incubation at 37°C.

Killing experiments. Time-kill curves were used to test the bactericidal activity of XRP2868 against S. aureus strains according to a proposed CLSI (formerly NCCLS) guideline (17). Three clinical isolates were tested. One was susceptible to macrolides and streptogramins, and two contained an erm(A) or an erm(C) gene and were constitutively resistant to macrolides-lincosamides-streptogramin B (MLS_B phenotype). Strains of S. aureus RN4220 containing the vector plasmid pAT392 (2) and derivatives with the erm(A) or erm(C) gene cloned on pAT392 were also tested. Briefly, overnight Trypticase soy broth cultures were diluted in MH broth. After 3 h of incubation at 37°C under aeration, cells were added to fresh prewarmed MH broth in 40-ml glass tubes to yield an inoculum of ca. 5 x 10⁶ CFU/ml. Immediately after inoculation, XRP2868 was added at a final concentration of 2 and 10 times the MIC of the compound against the strains.

Cultures were further incubated at 37°C with aeration. Just before and at 3, 6, and 18 h after the addition of antibiotics, 0.1-ml samples were removed from the flasks; serially diluted; and subcultured onto MH agar plates by using a spiral plater (Spiral System Inc., Intersciences, Cincinnati, OH), which prevents carryover effects. They were then incubated for 48 h at 37°C before the numbers of CFU were counted. Bactericidal activity was defined as a reduction of 3 log₁₀ of the initial inoculum. An antibiotic-free control was included on each occasion.

Characterization of resistance genes by PCR. Clinical isolates resistant to antimicrobials were tested for the presence of resistance genes by PCR. Specific oligonucleotide primers described previously were used to amplify the major erm genes [erm(A), erm(A) subset ermTR, erm(B), and erm(C)] encoding ribosomal methylases; the mef(A), msr(A), vga(A), and vga(B) genes encoding efflux proteins; the vat(A), vat(B), vat(D), and vat(E) genes encoding streptogramin A acetyltransferases; and the vgb(A) and vgb(B) genes encoding a streptogramin B lyase (1, 4, 19).

Top Abstract Introduction Materials and Methods Results Discussion References

 
Activity of XRP2868 against clinical isolates. XRP2868 was generally four times more potent than quinupristin-dalfopristin against the S_A- and S_B-susceptible isolates, with MICs ranging from 0.008 to 0.06 µg/ml for staphylococci, E. faecium, and streptococci (Tables 1 to 3). The oral streptogramin displayed activity against E. faecalis, with MICs equal to or less than 1 µg/ml, although this species is considered intrinsically resistant to streptogramins.

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TABLE 1. Activities of streptogramins against clinical isolates of staphylococci

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TABLE 3. Activities of streptogramins against clinical isolates of streptococci

In S. aureus and coagulase-negative staphylococci expressing the MLS_B phenotype, the presence of erm(A) or erm(C) genes raised the MIC of RPR202868 (S_B) when the genes were constitutively expressed (Table 1). However, the synergism was maintained between the A and the B factors, and the MICs of XRP2868 were similar to or 1 dilution greater than those for the susceptible isolates. Similarly, the presence of the erm(B) or the ermTR genes in enterococci and streptococci weakly affected the activity of the streptogramin combination (Tables 2 and 3). Streptococci resistant to erythromycin by macrolide efflux encoded by the mef(A) class of genes remained fully susceptible to RPR202868, RPR132552, and XRP2868 (Table 3).

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TABLE 2. Activities of streptogramins against clinical isolates of enterococci

Significant increases in the MICs of XRP2868 (0.5 to 8 µg/ml) were found in S. aureus (Table 1) and E. faecium (Table 2) when resistance to factor A was expressed by the isolates, either alone in the case of the LS_A phenotype (resistance to lincomycin and streptogramin A) or combined with resistance to factor B of the streptogramins. In the latter case, S_A and S_B resistance was associated with the presence of the vat (S_A acetyltransferase), vgb (S_B lyase), and erm genes in various combinations. Interestingly, XRP2868 remained active against the group B streptococci with the LS_A phenotype, which were recently reported from New Zealand (16).

Again, XRP2868 was generally four times more active than quinupristin-dalfopristin against the clinical isolates with S_A or S_B resistance, regardless of the nature of the resistance determinants.

Activity of XRP2868 against laboratory strains. The MIC results for the laboratory strains of staphylococci, enterococci, and streptococci are listed in Tables 4, 5, and 6, respectively.

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TABLE 4. Activities of streptogramins against laboratory strains of S. aureus

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TABLE 5. Activities of streptogramins against laboratory strains of enterococci

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TABLE 6. Activities of streptogramins against laboratory strains of streptococci

Against the susceptible control strains of S. aureus, enterococci, and streptococci, the MICs of XRP2868 were similar to those for the susceptible clinical isolates. The activity of the S_B component of XRP2868 (RPR202868) was less than (for S. aureus) or superior to (for enterococci) that of quinupristin. By contrast, the potency of the S_A component of XRP2868 (RPR132552) was always greater than that of dalfopristin.

The presence of the erm(A) or the erm(C) gene in S. aureus RN4220 (Table 4) and the presence of erm(B) from plasmid pAMß1 in E. faecalis JH2-2 (Table 5), which confer the MLS_B phenotype with constitutive resistance to S_B, led to an increase in the MIC of S_B (quinupristin and RPR202868). By contrast, the presence of an inducible erm(B) gene in S. aureus RN4220, enterococci, and streptococci did not affect or only moderately affected the activity of S_B. Indeed, as we have previously shown for quinupristin, inducible S_B resistance could be fully expressed only after previous induction with S_B (4). In all cases, as for the clinical isolates, there was a weak effect or no impact on the MICs of XRP2868 and quinupristin-dalfopristin since synergism was maintained between the A and the B factors.

Similarly, when other genes for resistance to either streptogramin factor were introduced individually into recipient strains, there was no impact or only a weak impact on the MIC of XRP2868, regardless of the mechanism of resistance (efflux or inactivation). By contrast, a significant increase in MICs of XRP2868 (in general, 8 or 16 times) was found when genes for resistance to S_A and S_B were combined. However, in S. aureus, the efflux of S_A [vga(A) gene] did not significantly contribute to streptogramin resistance. Also, superposition of inactivation of S_B (vgb gene) onto S_B target modification [erm(A) gene] did not amplify the level of resistance to quinupristin. By contrast, the coexistence of the vat(D) and vgb genes in the combinations of resistance genes was the most efficient at conferring resistance to streptogramins. The greatest impact on the MICs of XRP2868 was obtained when the gene combinations were introduced into E. faecium BM4107, showing that the LS_A background of this host, due to an unknown mechanism, played an important role in resistance to streptogramin combinations.

Mutation of ribosomal targets of streptogramins may also confer resistance to these antimicrobials. Susceptible strain S. aureus RN4220 was transformed with DNA encoding the L22 mutation, which resulted in transformants that were erythromycin, quinupristin, and quinupristin-dalfopristin resistant (15). In this study, the MICs of XRP2868 and RPR202868 (factor B) were multiplied fourfold for the transformant. Similarly, mutation of protein L22 yielded a 32-fold increase in the MIC of XRP2868 in S. pneumoniae. Mutation of the L4 protein also markedly altered the potency of XRP2868 in S. gordonii.

As for the clinical isolates, irrespective of the acquired mechanism of resistance, XRP2868 remained two to four times more potent than quinupristin-dalfopristin.

Bactericidal activity of XRP2868 against S. aureus with constitutively expressed erm genes. The bactericidal activity was demonstrated at 18 h for the laboratory strain of S. aureus RN4220/pAT392, which is susceptible to macrolides-lincosamides-streptogramins (MLS), at concentrations of 2 and 10 times the MIC of XRP2868 (0.06 µg/ml) (Fig. 1A). The MICs of XRP2868 were equal to 0.12 and 0.06 µg/ml for the derivatives containing the erm(A) and erm(C) genes, respectively. However, XRP2868 was no longer bactericidal against both constructs at concentrations equal to 2 or 10 times the MIC (Fig. 1B).

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FIG. 1. Time-kill curves for (A) Staphylococcus aureus RN4220/pAT392, (B) S. aureus RN4220/pAT392erm(A) (open symbols), and S. aureus RN4220/pAT392erm(C) (closed symbols) grown in Mueller-Hinton broth in the absence of XRP2868 (controls; squares) or in the presence of XRP2868 at concentrations of 2 (triangles) and 10 (circles) times the MIC.

Similarly, bactericidal activity was also achieved at 10 times the MIC of XRP2868 against the clinical isolate susceptible to MLS but not against the two clinical isolates containing the constitutively expressed erm(A) or erm(C) gene (2.5 and 2 log₁₀ reductions in bacterial counts at 18 h, respectively) (data not shown).

Top Abstract Introduction Materials and Methods Results Discussion References

 
The study confirmed previous data from Eliopoulos et al., who showed that the new oral streptogramin XRP2868 was approximately fourfold more potent than quinupristin-dalfopristin against S. aureus, E. faecium, and streptococci (10). The strong activity of RPR132552, the S_A component of XRP2868, seemed to be the driver for the greater potency of the oral streptogramin compared to that of quinupristin-dalfopristin.

Interestingly, the oral streptogramin displayed activity against E. faecalis. This species is considered intrinsically resistant to lincosamides (lincomycin and clindamycin), S_A, and streptogramin combinations. In E. faecalis OG1RF, resistance has been related to the expression of a chromosomal lsa gene, which appears to be species specific and which could possibly participate in the synthesis of an efflux pump (22). Resistance to factor A of streptogramins seems to explain the weak activities of streptogramins against E. faecalis, since clinical isolates in which the lsa gene was inactive were susceptible to quinupristin-dalfopristin (9). Both RPR132552 (S_A) and RPR202868 (S_B) had only weak activities against the E. faecalis strain, strain JH2-2, that we tested in our study. However, these activities were superior to those of dalfopristin and quinupristin, respectively, which can explain the relatively low MIC of XRP2868. The clinical potential of this enhanced potency of the oral streptogramin against E. faecalis remains to be demonstrated.

The use of clinical isolates and of constructs with known streptogramin resistance genes allowed the more accurate assessment of the impact of streptogramin resistance genes on the activity of XRP2868 and of its two components.

As expected, the mechanisms of resistance to factor A or factor B of streptogramins affected the activities of the corresponding factors composing XRP2868 (Tables 1 to 3). Isolated or combined resistance to S_A or S_B multiplied the MIC of XRP2868 by a factor that resulted in an MIC similar to that for quinupristin-dalfopristin. However, due to the greater potency of XRP2868, the MICs of the new oral streptogramin remained lower than those of quinupristin-dalfopristin. The significant impact of the streptogramins on the MICs was observed when the mechanisms of resistance to both S_A and S_B were combined. The most efficient minimal combination was that of acetylation of S_A with inactivation by a lyase of S_B. The fact that clinical isolates with elevated MICs of XRP2868 or quinupristin-dalfopristin contained resistance gene combinations confirmed these conclusions. There were a few exceptions, such as isolated mutations of ribosomal proteins L22 and L4 in S. aureus and streptococci, which were sufficient to alter the potency of XRP2868. In particular, mutations of protein L22 have been reported in mutants of S. aureus selected during treatment with quinupristin-dalfopristin and in an in vivo model of aortic endocarditis in rabbits (15, 23). These mutations confer resistance to erythromycin and S_B and suppress in part the synergism between S_A and S_B (15) It remains to be established if the MIC of XRP2868 reached by the mutants is sufficient to be responsible for clinical failure.

From a clinical point of view, streptococcal or staphylococcal isolates resistant to streptogramin combinations are rare. The most frequent resistance is that to S_B due to ribosomal methylation, which has a weak impact on the MICs of the streptogramin combinations. However, this work confirmed that, as for the other streptogramins, the bactericidal activity of XRP2868 against staphylococcal strains expressing a constitutive MLS_B phenotype was altered.

In conclusion, the new oral streptogramin XRP2868 and its S_A and S_B components are affected by the same mechanisms of resistance as the other streptogramins, quinupristin-dalfopristin, pristinamycins IA and IIB, and virginiamycins S and M. However, the strong activity of compound A combined with the synergistic effect of the two factors, which is often maintained despite the acquisition of resistance, shows that it provides superior potency against a broad range of gram-positive organisms. The oral streptogramin XRP2868 might be useful as a substitute for parenteral antimicrobials and might also be attractive for the treatment of community-acquired infections due to pneumococci, streptococci, and community-associated strains of oxacillin-resistant S. aureus.

 
This study was supported by a grant from Aventis Pharma.

We thank Michel Auzou and Caroline Caill for excellent technical assistance.

 
* Corresponding author: Mailing address: CHU de Caen, Service de Microbiologie, Avenue Côte de Nacre, 14033 Caen Cedex, France. Phone: (33) 02 31 06 45 72. Fax: (33) 02 31 06 45 73. E-mail: leclercq-r{at}chu-caen.fr.

Top Abstract Introduction Materials and Methods Results Discussion References

 

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Antimicrobial Agents and Chemotherapy, January 2006, p. 237-242, Vol. 50, No. 1
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.1.237-242.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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