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R Leclercq

Publications and source records attributed to R Leclercq.

At least 37 records · Page 2Linked to original sources
PubMed2001

Unusual inducible cross resistance to macrolides, lincosamides, and streptogramins B by methylase production in clinical isolates of Staphylococcus aureus.

Clinical strains of Staphylococcus aureus UCN7 and UCN8 were inducibly resistant to erythromycin, clindamycin, lincomycin, and quinupristin. This unusual inducible MLS(B) resistance was due to the presence of an erm(A) or an erm(B) gene, which both encode a ribosomal methylase, in S. aureus UCN8 and UCN7, respectively. The inducible cross resistance expressed by S. aureus UCN8 was associated with an 83-bp deletion in the attenuator of the erm(A) gene that removed the second of the two leader peptides and several inverted repeats. The presence of an inducible erm(B) gene in S. aureus UCN7 conferred a cross-resistance MLS(B) phenotype, similar to that usually observed in streptococci. Therefore, in S. aureus, besides the classical inducible MLS(B) phenotype characterized by inducible resistance to 14- to 15-membered ring macrolides, an additional type of inducible cross resistance to macrolides, lincosamides, and streptogramins B due to variants of erm(A) or erm(B) genes exist.

Anti-Bacterial Agents↗
PubMed2001

In vitro selection of resistance to clindamycin related to alterations in the attenuator of the erm(TR) gene of Streptococcus pyogenes UCN1 inducibly resistant to erythromycin.

A clinical isolate of Streptococcus pyogenes UCN1 intermediate to erythromycin (MIC 1 mg/L) and susceptible to clindamycin (MIC 0.03 mg/L) harboured an inducible erm(TR) gene encoding a ribosomal methylase. We have selected in vitro, in the presence of concentrations of clindamycin ranging from 0.12 to 1 mg/L, one-step mutants that are highly resistant to this antibiotic (MIC 64 mg/L) at a frequency of 10(-7). By contrast, in an erythromycin-susceptible strain of S. pyogenes UCN5, mutants could be selected only by a low concentration of clindamycin (0.12 mg/L) at a frequency of 10(-9). Clindamycin resistance in four of six S. pyogenes UCN1 mutants was associated with deletions of 163 and 6 bp, as well as a tandem duplication of 101 bp in the regulatory sequence of the erm(TR) gene. The role of these structural alterations in clindamycin resistance was demonstrated by cloning the erm(TR) gene from the wild-type and mutant strains in Escherichia coli DB10, a mutant susceptible to macrolides. Clindamycin resistance was expressed only when the erm(TR) gene was preceded by an altered attenuator. Mutations could lead to the formation of mRNA secondary structures accounting for the accessibility of the ribosome-binding site and the initiation codon of the ErmTR methylase to the ribosomes, and subsequently for the translation of the erm(TR) transcripts. The easy selection in one step of mutants resistant to high levels of clindamycin by concentrations of this antibiotic ranging from four to 40 times the MIC leads us to recommend caution in the use of clindamycin therapy in group A Streptococcus infections.

Anti-Bacterial Agents↗
PubMed2001

Overcoming antimicrobial resistance: profile of a new ketolide antibacterial, telithromycin.

Antimicrobial resistance amongst common respiratory pathogens has increased worldwide at an alarming rate and now threatens the clinical usefulness of a number of antibacterial agents. A major concern is the selection of resistance in the community, which tends to parallel the (often inappropriate) overuse of such agents. Such problems highlight the need for new antibacterial agents that retain activity against bacterial strains resistant to existing agents, and have a low potential to select for resistance or induce cross-resistance. Telithromycin is the first of a new family of antibacterials--the ketolides--and has been designed specifically for the treatment of community-acquired respiratory tract infections (RTIs). Numerous in vitro studies confirm the potent activity of telithromycin against pathogens commonly implicated in community-acquired RTIs, irrespective of their beta-lactam, macrolide or fluoroquinolone susceptibility. Against pneumococci, for example, MICs were < or = 1 mg/L irrespective of penicillin susceptibility, with > or = 98% of macrolide-resistant strains inhibited at < or = 0.5 mg/L, regardless of the underlying mechanism of resistance (including erm, mef and ribosomal L4 mutations). Against Haemophilus influenzae and Moraxella catarrhalis, including beta-lactamase-positive strains, telithromycin is at least as potent as azithromycin. In addition, telithromycin has a very low potential for selection of resistant isolates or induction of cross-resistance. Importantly, and unlike existing macrolides, telithromycin does not induce MLS(B) resistance, a finding explained by the presence of the innovative 3-keto group in its chemical structure. Telithromycin therefore represents an important addition to the therapeutic armamentarium in an era of increasing antimicrobial resistance, with an expected low likelihood of the development of resistance in clinical use.

Animals↗
PubMed2001

Activities of the combination of quinupristin-dalfopristin with rifampin in vitro and in experimental endocarditis due to Staphylococcus aureus strains with various phenotypes of resistance to macrolide-lincosamide-streptogramin antibiotics.

We evaluated the activities of quinupristin-dalfopristin (Q-D), alone or in combination with rifampin, against three strains of Staphylococcus aureus susceptible to rifampin (MIC, 0.06 microg/ml) and to Q-D (MICs, 0.5 to 1 microg/ml) but displaying various phenotypes of resistance to macrolide-lincosamide-streptogramin antibiotics: S. aureus HM1054 was susceptible to quinupristin and dalfopristin (MICs of 8 and 4 microg/ml, respectively); for S. aureus RP13, the MIC of dalfopristin was high (MICs of quinupristin and dalfopristin for strain RP13, 8 and 32 microg/ml, respectively); and S. aureus HM1054R was obtained after conjugative transfer of macrolide-lincosamide-streptogramin B constitutive resistance to HM1054, and the MIC of quinupristin for this strain was high (MICs of quinupristin and dalfopristin, 64 and 4 microg/ml, respectively). In vitro time-kill curve studies showed an additive effect [corrected] between Q-D and rifampin, at a concentration of four times the MIC, against the three strains. Rabbits with aortic endocarditis were treated 4 days with Q-D, rifampin, or their combination. In vivo, the combination was highly bactericidal and synergistic against strains susceptible to quinupristin (HM1054 and RP13) and sterilized 94% of the animals. In contrast, the combination was neither synergistic nor bactericidal against the quinupristin-resistant strain (HM1054R) and did not prevent the emergence of mutants resistant to rifampin. We conclude that the in vivo synergistic and bactericidal activity of the combination of Q-D and rifampin against S. aureus is predicted by the absence of resistance to quinupristin but not by in vitro combination studies.

Animals↗
PubMed2001

Macrolide resistance gene mreA of Streptococcus agalactiae encodes a flavokinase.

The mreA gene from Streptococcus agalactiae COH31 gamma/delta, resistant to macrolides and clindamycin by active efflux, has recently been cloned in Escherichia coli, where it was reported to confer macrolide resistance (J. Clancy, F. Dib-Hajj, J. W. Petitpas, and W. Yuan, Antimicrob. Agents Chemother. 41:2719--2723, 1997). Cumulative data suggested that the mreA gene was located on the chromosome of S. agalactiae COH31 gamma/delta. Analysis of the deduced amino acid sequence of mreA revealed significant homology with several bifunctional flavokinases/(flavin adenine dinucleotide (FAD) synthetases, which convert riboflavin to flavin mononucleotide (FMN) and FMN to FAD, respectively. High-performance liquid chromatography experiments showed that the mreA gene product had a monofunctional flavokinase activity, similar to that of RibR from Bacillus subtilis. Sequences identical to those of the mreA gene and of a 121-bp upstream region containing a putative promoter were detected in strains of S. agalactiae UCN4, UCN5, and UCN6 susceptible to macrolides. mreA and its allele from S. agalactiae UCN4 were cloned on the shuttle vector pAT28. Both constructs were introduced into E. coli, where they conferred a similar two- to fourfold increase in the MICs of erythromycin, spiramycin, and clindamycin. The MICs of a variety of other molecules, including crystal violet, acriflavin, sodium dodecyl sulfate, and antibiotics, such as certain cephalosporins, chloramphenicol, doxycycline, nalidixic acid, novobiocin, and rifampin, were also increased. In contrast, resistance to these compounds was not detected when the constructs were introduced into E. faecalis JH2-2. In conclusion, the mreA gene was probably resident in S. agalactiae and may encode a metabolic function. We could not provide any evidence that it was responsible for macrolide resistance in S. agalactiae COH31 gamma/delta; broad-spectrum resistance conferred by the gene in E. coli could involve multidrug efflux pumps by a mechanism that remains to be elucidated.

Amino Acid Sequence↗
PubMed2001

Antibiotic susceptibility and mechanisms of erythromycin resistance in clinical isolates of Streptococcus agalactiae: French multicenter study.

Among 126 Streptococcus agalactiae isolates collected in 10 French laboratories in 1999, 27 (21.4%) had macrolide resistance related to the presence of erm(B) (11 strains), erm(A) subclass erm(TR) (10 strains), and mef(A) genes (2 strains) and the presence of combinations of erm(B) and erm(A) genes or mef(A) genes (3 strains).

Anti-Bacterial Agents↗
PubMed2001

Characterization of mutations in the rpoB gene associated with rifampin resistance in Rhodococcus equi isolated from foals.

Treatment with a combination of erythromycin and rifampin has considerably improved survival rates of foals and immunocompromised patients suffering from severe pneumonia caused by Rhodococcus equi. Frequently, because of monotherapy, emergence of rifampin-resistant strains has been responsible for treatment failure. Using consensus oligonucleotides, we have amplified and sequenced the rifampin resistance (Rif(r))-determining regions of 12 rifampin-resistant R. equi strains isolated from three foals and of mutants selected in vitro from R. equi ATCC 3701, a rifampin-susceptible strain. The deduced amino acid sequences compared to those of four rifampin-susceptible R. equi strains showed several types of mutations. In 3 of the 10 strains isolated from one foal, His526Asn (Escherichia coli numbering) and Asp516Val mutations were associated with low-level resistance (rifampin MIC, 2 to 8 microg/ml), whereas His526Asp conferred high-level resistance (rifampin MIC, 128 microg/ml) in the 7 remaining strains. In strains from the two other foals, His526Asp and Ser531Leu mutations were found to be associated with high-level and low-level resistance, respectively. The in vitro mutants, highly resistant to rifampin, harbored His526Tyr and His526Arg substitutions. As described in other bacterial genera, His526, Ser531, and Asp516 are critical residues for rifampin resistance in R. equi, and the resistance levels are dependent on both the location and the nature of the substitution.

Actinomycetales Infections↗
PubMed2001

Overcoming bacterial resistance by dual target inhibition: the case of streptogramins.

Streptogramins A and B are chemically unrelated antimicrobials which act synergistically. This synergy is responsible for enhanced activity of the combination compared to each of the components and allows to overcome certain mechanisms of resistance to streptogramins B.. Although not completely elucidated, the mechanism of synergy is unique and based on a stable ribosome conformational change provoked by the binding of streptogramins A which unmasks a high affinity binding site for streptogramins B. A variety of resistance mechanisms to the A or B components by drug inactivation, target site modification, and active efflux have been reported. Acquired resistance to streptogramins A partially alters the synergy between the streptogramins A and B confirming the role of this component in the synergy. Full resistance in clinical isolates is due to combinations of genes for resistance to both components often associated on a single plasmid. Recently, a mutation in the L22 ribosomal protein of Staphylococcus aureus was found to confer resistance to streptogramins B and to abolish the synergy between A and B, probably by perturbing the association of this protein with 23S rRNA.

Anti-Bacterial Agents↗
PubMed2001

Safeguarding future antimicrobial options: strategies to minimize resistance.

Current antimicrobial therapy for community-acquired respiratory tract infections (RTIs) is empirical and is influenced by local differences in etiology and bacterial susceptibility. As the rates of resistance and cross-resistance to currently available classes of antimicrobial agents increase, their effectiveness becomes compromised. These issues demand improved strategies for antimicrobial usage, and the development of new agents that do not select resistance are essential to safeguard future antimicrobial efficacy. Strategies to minimize antimicrobial resistance among common RTIs include reducing antimicrobial consumption and controlling the development and spread of resistance through appropriate prescribing and the use of short-duration, once-daily treatments to improve patient compliance. Importantly, the ketolides, which are a new family of antimicrobials, have been recently developed specifically for the treatment of community-acquired RTIs. The first member of this new family, telithromycin, has been shown to have potent activity against common and atypical respiratory pathogens, including beta-lactam- and macrolide-resistant strains, and has a low potential to select for or induce cross-resistance. These properties, combined with its good tolerability across patient groups, make telithromycin an attractive option for the first-line empiric treatment of RTIs with the potential to limit the future development of resistance.

Anti-Bacterial Agents↗
PubMed2000

Macrolide resistance phenotypes and genotypes in French clinical isolates of Streptococcus pneumoniae. Observatoire de Normandie du Pneumocoque.

The aim of this study was to analyze the mechanisms of macrolide resistance in French clinical isolates of Streptococcus pneumoniae. A total of 838 strains of pneumococci were isolated in 1997 in Normandy, a region of western France, by 19 microbiology laboratories. Fifty-three percent had displayed diminished susceptibility to penicillin G and 50% were resistant to erythromycin. From this collection, 92 penicillin-intermediate or -resistant and 18 penicillin-susceptible strains resistant to erythromycin were studied. The presence of erm genes coding for ribosomal methylases and of mefE-like genes responsible for macrolide efflux was screened by a multiplex polymerase chain reaction and confirmed by DNA/DNA hybridization. Of the 110 strains studied, 108 were cross-resistant to erythromycin, spiramycin and clindamycin, including 105 strains containing ermB-related genes and three strains that contained a combination of ermB- and mefE-related genes. Two strains apparently susceptible to clindamycin but resistant to spiramycin also contained ermB-related genes. No strain was resistant to erythromycin alone or contained only a mef-like gene. Therefore, resistance to erythromycin is mostly related to ribosomal methylation in this region of France.

Anti-Bacterial Agents↗
PubMed2000

Characterization of isolates associated with emerging resistance to quinupristin/dalfopristin (Synercid) during a worldwide clinical program.

Quinupristin/dalfopristin (Synercid) is an i.v. antibiotic active against serious Gram-positive infections. Its unique dual mode of action means that the potential for resistance development is expected to be low. To determine the incidence of in vitro emerging resistance in worldwide clinical studies, susceptibility to quinupristin/dalfopristin was measured for baseline pathogens and corresponding on- or post-study isolates from 880 evaluable patients. In comparative studies of community-acquired pneumonia, complicated skin and skin structure infections, and nosocomial pneumonia, the incidence of emerging resistance was low (1 of 453; 0.22%; 95% CI: 0. 01-1.4%). Resistance development occurred in only one pathogen (methicillin-resistant Staphylococcus aureus). In noncomparative studies, six instances (1.8% of 338 evaluable cases; 95% CI: 0.7 to 4.0%) of emerging resistance (all vancomycin-resistant Enterococcus faecium) were confirmed, accompanied by therapeutic failure in four cases. Molecular typing did not confirm the identity of one pair of strains. Overall, the incidence of emerging resistance to quinupristin/dalfopristin was low.

Anti-Bacterial Agents↗
PubMed2000

In vitro activity of fusidic acid against streptococci isolated from skin and soft tissue infections.

The in vitro activity of fusidic acid was evaluated against 242 strains of streptococci isolated from skin and soft tissue infections during a prospective multicentre study. Nearly 90% of strains were isolated from dermatology, emergency and medicine units. Groups A, B, C and G streptococci represented, respectively, 41.9, 20.6, 4.4 and 27.8% of the strains. The activity of fusidic acid was dependent on the media used. MICs were generally one dilution lower with heart infusion agar than with Mueller-Hinton agar supplemented with 5% horse blood (MIC(90) for the whole streptococcal population = 8 mg/L and 16 mg/L, respectively). The distribution of MICs was unimodal and only two strains displayed MICs of fusidic acid >/= 64 mg/L. In both media, fusidic acid was moderately active against streptococci. However, antibiotic concentrations obtained in the skin exceed the MIC(90) of fusidic acid for streptococci, possibly explaining its clinical efficacy in the treatment of common cutaneous infections.

Anti-Bacterial Agents↗
PubMed2000

Activity of linezolid against Gram-positive cocci possessing genes conferring resistance to protein synthesis inhibitors.

Linezolid belongs to a new class of antimicrobials, the oxazolidinones, that act by inhibiting protein synthesis. To detect cross-resistance with other inhibitors of protein synthesis (chloramphenicol, macrolides, lincosamides, streptogramins, aminoglycosides and tetracyclines), the in vitro activity of linezolid was determined against isolates harbouring known genes conferring resistance to these antimicrobials. Neither the presence of modifying enzymes (LinA, LinA', LinB, Vgb, Vat, SatA, ANT(4') (4")-I, AAC(6')-APH(2"), APHA-3 and Cat), nor the presence of an efflux mechanism (MsrA, MefE, MefA, MreA, Vga, TetK and TeL), nor the modification or protection of antimicrobial target (because of ribosomal methylases or TetM and TetO) affected linezolid activity as demonstrated by similar in vitro activity against resistant isolates and sensitive control isolates.

Acetamides↗
PubMed2000

Influence of resistance to streptogramin A type antibiotics on the activity of quinupristin-dalfopristin in vitro and in experimental endocarditis due to Staphylococcus aureus.

We evaluated the activity of quinupristin-dalfopristin (Q-D) against three clinical strains of Staphylococcus aureus susceptible to Q (MIC, 8 microg/ml) and Q-D (MICs, 0.5 to 1 microg/ml) but displaying various levels of susceptibility to D. D was active against S. aureus HM 1054 (MIC, 4 microg/ml) and had reduced activity against S. aureus RP 13 and S. aureus N 95 (MICs, 32 and 64 microg/ml, respectively). In vitro, Q-D at a concentration two times the MIC (2xMIC) produced reductions of 4.3, 3.9, and 5.8 log(10) CFU/ml after 24 h of incubation for HM 1054, RP 13, and N 95, respectively. Comparable killing was obtained at 8xMIC. Q-D-resistant mutants were selected in vitro at a frequency of 2 x 10(-8) to 2 x 10(-7) for the three strains on agar containing 2xMIC of Q-D; no resistant bacteria were detected at 4xMIC. Rabbits with aortic endocarditis were treated for 4 days with Q-D at 30 mg/kg of body weight intramuscularly (i.m.) three times a day (t.i.d.) or vancomycin at 50 mg/kg i.m. t.i.d. In vivo, Q-D and vancomycin were similarly active and bactericidal against the three tested strains compared to the results for control animals (P < 0.01). Among animals infected with RP 13 and treated with Q-D, one rabbit retained Q-D-resistant mutants that were resistant to Q and to high levels of D (MICs, 64, >256, and 8 microg/ml for Q, D, and Q-D, respectively). We conclude that the bactericidal activity of Q-D against strains with reduced susceptibility to D and susceptible to Q-D is retained and is comparable to that of vancomycin. Acquisition of resistance to both Q and D is necessary to select resistance to Q-D.

Animals↗
PubMed1999

[In vitro activity of pristinamycin on respiratory bacteria].

TWO-PHASE ACTION: Pristinamycin is composed of two active substances A and B. Pristinamycin A (SA) first binds to the ribosome subunit 50s. Pristinamycin B (SB) then locks onto SA causing irreversible inhibition of bacterial protein production. WELL-ADAPTED ACTIVITY SPECTRUM: A member of the streptogramin family of antibiotics, pristinamycin is active against the main bacteria causing respiratory tract infections (pneumococci, S. aureus, H. influenzae) as well as against mycoplasma and anaerobic pathogens. ANTI-PNEUMOCOCCI ACTIVITY: Minimal inhibitory concentrations measured over the last 5 years have confirmed that the antibacterial activity of pristinamycin against pneumococci remains unchanged even for strains which develop resistance to other antibiotics, particularly to penicillin or erythromycin. OTHER BACTERIA: The activity of pristinamycin against H. influenzae is a constant finding (unimodal distribution of MIC). The persistent of pristinamycin activity against S. aureus strains, excepting a few SA- resistant strains and SA + SB- resistant strains, is remarkable. MIC studies have also demonstrated the constant susceptibility of Moraxella catarrhalis, non-groupable streptococci, anaerobic bacteria, and Legionella pneumophila.

Anti-Bacterial Agents↗