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PubMed1992

Antimicrobial activity of ten macrolide, lincosamine and streptogramin drugs tested against Legionella species.

RP59500, a semisynthetic pristinamycin combination, and 14 other antimicrobial agents were tested against 108 Legionella strains. Of the ten macrolide, lincosamine and streptogramin agents tested, the new streptogramin RP59500 ranked seventh in order of activity against Legionella pneumophila on the basis of MIC90 results as follows: clarithromycin = 14-OH clarithromycin (MIC90 0.12 mg/l) > roxithromycin > erythromycin = tylosin = virginiamycin > RP59500 (MIC90 1 mg/l) = azithromycin > dirithromycin > clindamycin (MIC90 8 mg/l). Of all 14 drugs tested in this study, rifampicin was the most potent with an MIC90 of 0.008 mg/l. In this retrospective study of Legionella strains (1981-1990 isolates), we observed no trend toward resistance to the agents investigated.

Amino Sugars↗
PubMedDate not supplied

Occurrence of macrolide-lincosamide-streptogramin resistances among staphylococcal clinical isolates at a university medical center. Is false susceptibility to new macrolides and clindamycin a contemporary clinical and in vitro testing problem?

A total of 2189 staphylococcal strains at the University of Iowa Hospitals and Clinics (Iowa City, IA) were initially screened to determine the incidence of constitutive (29.8%) and potential inducible macrolide-lincosamide-streptogramin (MLS) resistance (11.3%). Staphylococcus haemolyticus and S. epidermidis (62.5% and 55.3%) showed the highest incidence of constitutive resistance. Staphylococcus hominis had the highest incidence of inducible resistance (40.6%), while S. aureus had the lowest rate for both resistance types. The overall ratio of constitutive-inducible MLS resistance was 4:1. Among strains initially speciated using the Vitek System GPI card, there was only a 69% species identification reproducibility, and 78% accuracy versus a reference identification method. A random sample of 105 Staphylococcus spp. isolates with discordant macrolide (erythromycin resistant) and lincosamide (clindamycin susceptible) susceptibility patterns were tested against 16 antimicrobial agents by using a reference broth microdilution method. All erythromycin-resistant Staphylococcus spp. were also resistant to other 14-member macrolides and azithromycin, while all organisms remained susceptible to clindamycin, rifampin, vancomycin, and the streptogramin compounds (RP59500 and virginiamycin). Resistance to teicoplanin was identified among some oxacillin-resistant S. haemolyticus strains. Of 105 isolates, 65 (62%) showed inducible MLS resistance, 28 (27%) were noninducible, and 12 (11%) were either fully susceptible or resistant to the MLS drugs (Vitek System interpretation errors). MLS disk induction tests revealed two inducible resistance phenotypes: ML and MLS. Staphylococcus aureus showed the highest inducible resistance rate at 95% with an MLS-predominant pattern. In contrast, endemic S. haemolyticus isolates did not demonstrate inducible resistance that is, efflux-mediated erythromycin resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Bacterial Agents↗
PubMed2000

Serious streptococcal infections produced by isolates resistant to streptogramins (quinupristin/dalfopristin): case reports from the SENTRY antimicrobial surveillance program.

The emergence and sustained prevalence of Gram-positive organisms resistant to antimicrobials has been of interest for over a decade. Quinupristin/dalfopristin (formerly RP 59500 or Synercid) is a new injectable streptogramin combination that has been reported to have activity against Gram-positive organisms, even those with documented MLS(B) resistance. However, the two case reports presented here illustrate three well-documented Streptococcus spp. strains (S. mitis, S. pneumoniae) to be resistant to quinupristin/dalfopristin (MICs at 3, 8, and 12 microg/ml) following referral as routine isolates in the SENTRY Antimicrobial Surveillance Program. The S. pneumoniae pleural fluid isolate was cross-resistant to erythromycin. Both bacteremic S. mitis strains were resistant to macrolides (erythromycin, azithromycin, clarithromycin), lincosamides (clindamycin), and fluoroquinolones. Patient histories indicated no prior use of MLS class antimicrobials for the S. mitis case, but the patient having the S. pneumoniae isolate did receive prior treatment of erythromycin and clindamycin. All isolates had modestly increased penicillin MICs of 0.12 microg/ml. The mode of resistance to quinupristin/dalfopristin was not evident (sat A-negative by PCR); and these cases illustrate the existence of streptogramin-resistant isolates before the introduction of this antimicrobial class into human clinical practice.

Adult↗
PubMed1998

Failure of pristinamycin treatment in a case of pneumonia caused by a streptogramins B-type resistant pneumococcus.

We report a failure of pristinamycin treatment in a case of pneumonia caused by streptogramins B-type resistant pneumococcus. We suggest that (i) streptogramins therapy should be avoided, if a previous treatment failure has been observed with a macrolide and/or if the antibiogram shows the MLS(B) co-resistance phenotype, and (ii) beta-lactams should remain the first-line antibiotics used for treatment of pneumococcal respiratory infections.

Aged↗
PubMed1998

Pharmacodynamics of macrolides, azalides, and streptogramins: effect on extracellular pathogens.

The efficacy of macrolides against extracellular pathogens depends on extracellular levels of free drug and the organisms' patterns of susceptibility to the macrolides. The effect of macrolides against most bacteria is considered time-dependent. The size of inoculum affects erythromycin's activity against streptococci and, moreover, against staphylococci. The optimal effect is observed at a pH of 8. A significant postantibiotic effect (PAE), lasting approximately 9 hours, has been shown with erythromycin and roxithromycin against gram-positive cocci. Azalides share the same properties. For the streptogramin synercid, a dose-dependent bactericidal activity within a range of low concentrations has been demonstrated. The serum area under the curve appeared to be the best predictor of in vivo effect on the mouse thigh model. Synercid also exhibited a prolonged PAE (approximately 10 hours) against the main pathogens of its spectrum. A better knowledge of the pharmacodynamic properties of macrolides and streptogramins is essential for definition of proper dosing regimens.

Anti-Bacterial Agents↗
PubMed1996

Quinupristin-dalfopristin (RP 59500): an injectable streptogramin combination.

The pharmacology, pharmacokinetics, activity, and potential clinical role of quinupristin-dalfopristin (RP 59500) are described. Quinupristin-dalfopristin is the first injectable formulation of the streptogramin antibiotics. Streptogramin drug products are each composed of two chemically distinct compounds, which when administered together act synergistically by inhibiting bacterial protein synthesis. Quinupristin-dalfopristin has shown activity in vitro against many strains of streptococci and staphylococci, including methicillin- and erythromycin-resistant strains of staphylococci. The combination is more active against Enterococcus faecium than Enterococcus faecalis. It has also shown activity in vitro against certain gram-negative organisms and anaerobes. The mean maximum blood concentration at the end of a one-hour infusion ranged from 0.95 mg/L for a 1.4-mg/kg dose to 24.2 mg/L for a 29.4-mg/kg dose; there was a linear correlation between dose and mean area under the concentration-time curve. Mean half-life ranged from 1.27 to 1.53 hours. The drug is under investigation in the United States in Phase III trials. Of 60 evaluable patients with documented bacteremia involving E. faecium resistant to vancomycin, 40 (67%) had a favorable clinical response. Of 11 patients with bacteremia caused by methicillin-resistant Staphylococcus aureus, 78% had a favorable response. The efficacy of quinupristin-dalfopristin in treating resistant infections has also been suggested by smaller studies and case reports. The drug may be useful in the prophylaxis of endocarditis. Adverse reactions are generally mild and transient. Quinupristin-dalfopristin may be useful in treating serious gram-positive infections, but more clinical study is needed.

Animals↗
PubMed1986

Macrolide, lincosamide and streptogramin resistance in Campylobacter jejuni/coli.

Strains of erythromycin-resistant Campylobacter jejuni/coli isolated in the United Kingdom, Canada and Europe, were also resistant to tylosin, spiramycin and clindamycin and, like sensitive strains, were insensitive to virginiamycin and pristinamycin component B. These were designated as macrolide-lincosamide-streptogramin generalized resistant organisms and macrolide-lincosamide generalized resistant on the basis of patterns of resistance to pristinamycin components A and B. Two erythromycin-sensitive strains whose resistance to spiramycin and tylosin had been produced in the laboratory showed cross resistance to erythromycin, but were still sensitive to clindamycin. These were characterized as macrolide-streptogramin A inducible resistant organisms. The isolates tested were identified and all were found to be C. coli, except for two strains, one erythromycin-resistant and one erythromycin-sensitive, which hydrolyzed hippurate and were thus identified as C. jejuni.

Anti-Bacterial Agents↗
PubMed1987

Origin and evolution of genes specifying resistance to macrolide, lincosamide and streptogramin antibiotics: data and hypotheses.

Resistance to macrolide, lincosamide and streptogramin antibiotics is due to alteration of the target site or detoxification of the antibiotic. Postranscriptional methylation of 23S ribosomal rRNA confers resistance to macrolide (M), lincosamide (L) and streptogramin (S) B-type antibiotics, the so-called MLSB phenotype. Several classes of rRNA methylases conferring resistance to MLSB antibiotics have been characterized in Gram-positive cocci, in Bacillus spp, and in strains of actinomycetes producing erythromycin. The enzymes catalyze N6-dimethylation of an adenine residue situated in a highly conserved region of prokaryotic 23S rRNA. In this review, we compare the amino acid sequences of the rRNA methylases and analyze the codon usage in the corresponding erm (erythromycin resistance methylase) genes. The homology detected at the protein level is consistent with the notion that an ancestor of the erm genes was implicated in erythromycin resistance in a producing strain. However, the rRNA methylases of producers and non-producers present substantial sequence diversity. In Gram-positive bacteria the preferential codon usage in the erm genes reflects the guanosine plus cytosine content of the chromosome of the host. These observations suggest that the presence of erm genes in these micro-organisms is ancient. By contrast, it would appear that enterobacteria have acquired only recently an rRNA methylase gene of the ermB class from a Gram-positive coccus since the genes isolated in Escherichia coli and in Gram-positive cocci are highly homologous (homology greater than 98%) and present a codon usage typical of the latter micro-organisms. As opposed to the MLSB phenotype which results from a single biochemical mechanism, inactivation of structurally related antibiotics of the MLS group involves synthesis of various other enzymes. In enterobacteria, resistance to erythromycin and oleandomycin is due to production of erythromycin esterases which hydrolyze the lactone ring of the 14-membered macrolides. We recently reported the nucleotide sequence of ereA and ereB (erythromycin resistance esterase) genes which encode erythromycin esterases type I and II, respectively. The amino acid sequences of the two isozymes do not exhibit statistically significant homology. Analysis of codon usage in both genes suggests that esterase type I is indigenous to E. coli, whereas the type II enzyme was acquired by E. coli from a phylogenetically remote micro-organism. Inactivation of lincosamides, first reported in staphylococci and lactobacilli of animal origin, was also recently detected in Gram-positive cocci isolated from humans.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1989

New macrolides active against Streptococcus pyogenes with inducible or constitutive type of macrolide-lincosamide-streptogramin B resistance.

Macrolide-resistant bacteria can be classified as inducibly resistant or constitutively resistant. Inducibly resistant bacteria are resistant to 14-membered macrolides, such as erythromycin and clarithromycin (A-56268), but are susceptible to the 16-membered macrolides, such as tylosin and spiramycin, as well as to clindamycin. Constitutively resistant bacteria are resistant to macrolide-lincosamide-streptogramin B antibiotics. In this study, the MICs of several erythromycin and clarithromycin analogs against macrolide-susceptible and macrolide-resistant Streptococcus pyogenes strains were determined. Four 11,12-carbamate analogs of clarithromycin had lower MICs than erythromycin did against S. pyogenes with the inducible or constitutive type of macrolide-lincosamide-streptogramin B resistance. Five 11,12-carbonate analogs of erythromycin with modifications at the 4" position of cladinose had lower MICs than did erythromycin against S. pyogenes with the constitutive type of resistance, and one of these compounds, which had a naphthyl-glycyl substitution at the 4" position, had a lower MIC than erythromycin against both the inducibly resistant and constitutively resistant strains. Two analogs of erythromycin with a modification on the 4" position of cladinose had lower MICs than erythromycin did against the constitutively resistant organisms but not against the inducibly resistant organisms. Thus, 14-membered macrolides can be modified so as to confer a low MIC when tested in vitro.

Aminoglycosides↗
PubMed1995

In vitro activities of a streptogramin (RP59500), three macrolides, and an azalide against four respiratory tract pathogens.

Broth microdilution tests were carried out with 2,671 respiratory tract isolates from 19 medical centers throughout the continental United States. The tests compared a streptogramin (RP59500) to erythromycin, dirithromycin, clarithromycin, and azithromycin against Streptococcus pneumoniae, S. pyogenes, Haemophilus influenzae, and Moraxella catarrhalis. Against macrolide-susceptible strains, the potency of RP59500 was similar to that of the macrolides: the azalide, azithromycin, was two to four times more potent against H. influenzae. The azalide and three macrolides showed nearly complete cross-resistance. At 2.0 micrograms/ml or less, the streptogramin, RP59500, was active against both macrolide-resistant and -susceptible strains of S. pneumoniae (MIC for 50% of the strains tested, 0.25 microgram/ml; MIC for 90% of the strains tested, 0.5 microgram/ml).

Erythromycin↗
PubMed1997

Streptogramin B biosynthesis in Streptomyces pristinaespiralis and Streptomyces virginiae: molecular characterization of the last structural peptide synthetase gene.

Streptomyces pristinaespiralis and S. virginiae both produce closely related hexadepsipeptide antibiotics of the streptogramin B family. Pristinamycins I and virginiamycins S differ only in the fifth incorporated precursor, di(mono)methylated amine and phenylalanine, respectively. By using degenerate oligonucleotide probes derived from internal sequences of the purified S. pristinaespiralis SnbD and SnbE proteins, the genes from two streptogramin B producers, S. pristinaespiralis and S. virginiae, encoding the peptide synthetase involved in the activation and incorporation of the last four precursors (proline, 4-dimethylparaaminophenylalanine [for pristinamycin I(A)] or phenylalanine [for virginiamycin S], pipecolic acid, and phenylglycine) were cloned. Analysis of the sequence revealed that SnbD and SnbE are encoded by a unique snbDE gene. SnbDE (4,849 amino acids [aa]) contains four amino acid activation domains, four condensation domains, an N-methylation domain, and a C-terminal thioesterase domain. Comparison of the sequences of 55 amino acid-activating modules from different origins confirmed that these sequences contain enough information for the performance of legitimate predictions of their substrate specificity. Partial sequencing (1,993 aa) of the SnbDE protein of S. virginiae allowed comparison of the proline and aromatic acid activation domains of the two species and the identification of coupled frameshift mutations.

Amino Acid Sequence↗
PubMed1998

Antipneumococcal activities of a ketolide (HMR 3647), a streptogramin (quinupristin-dalfopristin), a macrolide (erythromycin), and a lincosamide (clindamycin).

Four different compounds belonging to the macrolide-lincosamide-streptogramin B (MLSb) class of antimicrobial agents were tested against 611 Streptococcus pneumoniae strains. The ketolide (HMR 3647, previously RU66647) and the streptogramin (quinupristin-dalfopristin) were both active against pneumococci with high-level MLSb resistance (clindamycin-resistant strains) as well as those with low-level macrolide resistance (clindamycin-susceptible strains).

Anti-Bacterial Agents↗
PubMed1998

Prevalence and characterization of the mechanisms of macrolide, lincosamide, and streptogramin resistance in isolates of Streptococcus pneumoniae.

Of a total of 147 erythromycin-resistant Streptococcus pneumoniae isolates, 64 (43.5%) were resistant to erythromycin, clindamycin, and streptogramin B (MLSB phenotype), 57 of which possessed the ermB gene. Eighty-two (55.8%) were resistant to erythromycin alone (M phenotype), 81 of which possessed the mefE gene. One was erythromycin and streptogramin B resistant but susceptible to clindamycin (MS phenotype) and possessed neither the erm gene nor the mefE gene.

Anti-Bacterial Agents↗
PubMed2000

Characterization of a variant of vga(A) conferring resistance to streptogramin A and related compounds.

A variant of the vga(A) gene (1,575 bp), encoding an ATP-binding cassette protein conferring resistance to streptogramin A and related antibiotics, was cloned from the chromosome of a Staphylococcus aureus clinical isolate and sequenced. The sequence of the variant was similar to that of the vga(A) gene (83.2% identity). However, the G+C content of the variant (35.6%) was higher than that of vga(A) (29%) and there was no cross hybridization between vga(A) and the variant at high stringency (> or =60 degrees C), the highest temperature at which a signal was detected being 55 degrees C. Unlike previous reports for vga(A) and vga(B), the variant of vga(A) may be present in multiple copies in the genome. These copies are chromosomal in some isolates and both chromosomal and plasmid-borne in others. Nucleotide sequences hybridizing at 65 degrees C with the vga(A) variant were found in all the staphylococcal strains harboring plasmids carrying both vga(B) and vat(B), which also encode resistance to streptogramin A.

Alleles↗
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↗
PubMed1983

A complex attenuator regulates inducible resistance to macrolides, lincosamides, and streptogramin type B antibiotics in Streptococcus sanguis.

Macrolide-lincosamide-streptogramin B resistance specified by Streptococcus sanguis plasmid pAM77 involves an adenine methylase, whose synthesis, demonstrable both phenotypically and by analysis of methionine-labeled proteins made in Bacillus subtilis minicells, is inducible by erythromycin, lincomycin, and streptogramin type B antibiotics. Localization of the methylase structural gene, including its control region in DNA fragments obtained with restriction endonucleases, has been deduced from DNA blot experiments with characterized target and probe DNAs from other streptococci, combined with DNA sequence analysis and comparison of the putative streptococcal methylase sequence with that of a cognate methylase in staphylococcal plasmid pE194. The streptococcal methylase migrates electrophoretically in polyacrylamide gels with the mobility of a 29,000-dalton protein. The sequence organization of the putative streptococcal methylase mRNA leader sequence partially resembles its staphylococcal counterpart and can support a similar mechanism of secondary structure rearrangement leading to methylase synthesis. The deduced 5' leader sequence preceding the pAM77 methylase structural gene sequence comprises approximately 155 nucleotides within which one can identify a putative control peptide 36 amino acid residues in length (in contrast to 19 in the pE194 peptide) and at least 14 possible classes of overlapping inverted complementary repeat sequences (in contrast to 3 in the pE194 control region), one of which can sequester the sequence AGGAG 7 nucleotides upstream from the putative (methionine) start codon of the streptococcal methylase. Comparison of the pAM77 and pE194 methylase amino acid sequences and their respective nucleotide sequences shows 51% conservation of amino acid residues (124 of 244) and 59% conservation of nucleotide residues (433 of 738), which suggests a common origin for the two methylase structural gene sequences. Differences in mRNA base composition associated with conserved amino acid residues occur mostly in the third nucleotide ("wobble") position of codons and may reflect adaptation of methylase genes to optimal expression in host cells with differing codon use patterns.

Amino Acid Sequence↗
PubMed1993

An increase of 63 kDa-protein present in the cell membranes of Staphylococcus aureus that bears a plasmid mediating inducible resistance to partial macrolide and streptogramin B antibiotics.

A plasmid, pEP2104 (23.9 kilobase pairs), from Staphylococcus aureus carries a gene that specifies inducible resistance to 14-membered (erythromycin, EM, and oleandomycin, OL) and 16-membered macrolide (mycinamicin I and II), but not to all of the latter, and to streptogramin type B antibiotics (partial macrolide- and streptogramin-B-antibiotic resistance: PMS-resistance) (L. Jánosi, E. Bán, Acta Microbiol. Acad. Sci. Hung., 29, 187 (1982) and Y. Nakajima et al., J. Pharmacobio-Dyn., 15, 319 (1992)). The induced cells of strain 8325(pEP2104) did not inactivate EM, OL, josamycin, rokitamycin or mikamycin B (MKM-B), and the cell-free extract of the strain did not inactivate EM or MKM-B, either. Ribosomes from the cells whose PMS-resistance was induced by EM were sensitive not only to EM or spiramycin, but also to MKM-B. A 63000-dalton protein increased to a great extent only in the cell membrane fractions of induced 8325(pEP2104), and may be involved in PMS-resistance.

Anti-Bacterial Agents↗
PubMed1992

Inducible resistance to a 16-membered macrolide, mycinamicin, in Staphylococcus aureus resistant to 14-membered macrolides and streptogramin B antibiotics.

Staphylococcus aureus 8325(pEP2104), a transductant derived from S. aureus PM2104 isolated clinically in Hungary (L. Janosi, and E. Ban, Acta Microbiol. Acad. Sci. Hung., 29: 187-200, 1982), exhibited an inducible resistance to the 14-membered macrolides [erythromycin (EM) and oleandomycin (OL)] and streptogramin B (MKM-B) antibiotics, but not to the 16-membered macrolides and lincosamides. This resistance was referred to as PMS-resistance phenotype (L. Jánosi, Y. Nakajima, and H. Hashimoto, Microbiol. Immunol., 34: 723-735, 1990). In addition to EM, OL, and MKM-B, however, the strain was recently and first observed to have inducible resistance to mycinamicin, a 16-membered ring macrolide. Thereby, we propose that the reference stated just above as PMS-resistance has to be extended to such 16-membered macrolides as mycinamicin. An optimum concentration of erythromycin or oleandomycin for induction of PMS-resistance was 1.35 mu g/ml in the strain 8325(pEP2104). The concentration was about 30 times as great as that (0.05 mu g/ml) required for induction of well-known co-resistance to macrolide-lincosamide-streptogramin B antibiotics in S. aureus ISP447.

Anti-Bacterial Agents↗