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PubMed1985

Nucleotide sequence of ermA, a macrolide-lincosamide-streptogramin B determinant in Staphylococcus aureus.

The complete nucleotide sequence of ermA, the prototype macrolide-lincosamide-streptogramin B resistance gene from Staphylococcus aureus, has been determined. The sequence predicts a 243-amino-acid protein that is homologous to those specified by ermC, ermAM, and ermD, resistance determinants from Staphylococcus aureus, Streptococcus sanguis, and Bacillus licheniformis, respectively. The ermA transcript, identified by Northern analysis and S1 mapping, contains a 5' leader sequence of 211 bases which has the potential to encode two short peptides of 15 and 19 amino acids; the second, longer peptide has 13 amino acids in common with the putative regulatory leader peptide of ermC. The coding sequence for this peptide is deleted in several mutants in which macrolide-lincosamide-streptogramin B resistance is constitutively expressed. Potential secondary structures available to the leader sequence of the wild-type (inducible) transcript and to constitutive deletion, insertion, and point mutations provide additional support for the translational attenuation model for induction of macrolide-lincosamide-streptogramin B resistance.

Amino Acid Sequence↗
PubMed1995

Quinupristin/dalfopristin (RP 59500): a new streptogramin antibiotic.

OBJECTIVE: To review the current knowledge on RP 59500 (quinupristin/dalfopristin, Synercid), a new streptogramin antibiotic, with respect to its pharmacology, pharmacokinetics, pharmacodynamics, mechanism of resistance, and in vitro inhibitory and bactericidal activity. DATA SOURCES: A MEDLINE search using keywords RP 59500, pristinamycin, virginiamycin, and streptogramin was performed. Relevant abstracts presented at recent scientific conferences also were consulted. STUDY SELECTION: Because RP 59500 is a relatively new investigational agent, relevant in vitro and animal studies were selected. All available human studies were included as well. DATA EXTRACTION: Data from in vitro and in vivo studies were included, with particular emphasis on human studies. DATA SYNTHESIS: RP 59500 is a new injectable streptogramin antibiotic consisting of a mixture o 2 synergistic pristinamycin compounds. RP 59500 possesses in vitro inhibitory and bactericidal activity against most isolates of gram-positive organisms including vancomycin-resistant Enterococcus faecium, selected gram-negative bacteria, and most anaerobic organisms. Based on preliminary data, the drug appears to be metabolized rapidly and extensively while exhibiting a significant postantibiotic effect. Data from ongoing clinical trials suggests that RP 59500 is well-tolerated except for mild injection site irritations. However, before the role of RP 59500 within the vast armamentarium of antimicrobials can be elucidated, additional studies need to be conducted to document its clinical efficacy. CONCLUSIONS: Based on in vitro susceptibility testing, in vivo studies, and preliminary clinical data, RP 59500 may be an alternative to the glycopeptides, especially for inherently resistant organisms. Further studies are needed to confirm this agent's in vitro activity and to establish its clinical efficacy.

Anti-Bacterial Agents↗
PubMed1998

The streptogramin antibiotics: update on their mechanism of action.

Antibiotics of the streptogramin class are an association of two types of chemically different compounds, group A molecules and group B molecules, acting in synergy. The combination of these molecules generally inhibits bacterial growth at a lower concentration than does either the group A or group B molecule alone and is often bactericidal against strains of bacteria for which each type of molecule alone is only bacteriostatic. The semisynthetic streptogramin quinupristin/dalfopristin (RP 59500), the first water-soluble member of this class, is under development for the treatment of severe infections caused by methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, penicillin-resistant Streptococcus pneumoniae, glycopeptide-resistant Enterococcus faecium, and other organisms. The streptogramins block the translation of mRNA into protein. Both group A and group B molecules bind to the peptidyl-transferase domain of the bacterial ribosome. The group B molecule stimulates the dissociation of peptidyl-tRNA from the ribosome and may interfere with the passage of the completed polypeptide away from the peptidyl-transferase centre. The group A molecule inhibits the elongation of the polypeptide chain by preventing both the binding of aminoacyl-tRNA to the ribosomal A site and the formation of the peptide bond. When the two types of molecule are used in combination, the binding of the group A molecule alters the conformation of the ribosome such that the affinity of the ribosome for the B molecule is increased. This accounts, in part or entirely, for the observed synergy. This synergy is unaffected by ribosomal modifications conferring resistance to the macrolides, lincosamides, and group B molecules alone.

Journal Article↗
PubMedDate not supplied

Lack of effect of streptogramins on hepatic drug metabolism enzymes in the rat.

Male Sprague-Dawley rats were treated with streptogramin derivatives (RP 7293, RP 54476, RP 57669, and RP 59500) or with the macrolide troleandomycin. Liver cytosol and microsomes were prepared, and the in vitro transformation of several model substrates studied. Furthermore, total and complexed microsomal cytochrome P-450 levels were compared. Hepatic cytochrome P-450 metabolite complexes were detected 4 days after troleandomycin treatment (500 mg/kg/day po), whereas such effects were not observed with po RP 7293 (500 mg/kg/day, 4 days) or with iv RP 54476 (12 mg/kg/day, 7 days), RP 57669 (6 mg/kg/day, 7 days), or RP 59500 (6 and 18 mg/kg/day, 7 days). The administration of troleandomycin resulted in statistically significant increases in liver weight (+20%), microsomal protein (+70%), total cytochrome P-450 (+187%), and cytosolic glutathione S-transferase activity (+32%). The activities of aniline hydroxylase, aminopyrine N-demethylase, and the high and low phases of 7-ethoxyresorufin O-deethylase were markedly decreased by 36% to 56%. In contrast, none of these hepatic parameters was changed significantly after administration of each streptogramin. These results suggest that streptogramins have not, in contrast to many commonly used macrolide antibiotics, had potent or specific effects on hepatic drug metabolizing enzymes in rats.

7-Alkoxycoumarin O-Dealkylase↗
PubMedDate not supplied

Degradation of macrolide-lincosamide-streptogramin antibiotics by Lactobacillus strains from animals.

Ability to degrade macrolide, lincosamide and streptogramin antibiotics was noted in Lactobacillus strains isolated from the caeca of pigs, cattle and poultry. Some of the strains degraded all the three classes of antibiotics while some degraded either macrolides and lincosamides or macrolidese and streptogramins. There were also strains which degraded only macrolide or streptogramin type A antibiotics. Strains with any of these degradation abilities were always resistant to the antibiotics concerned, but strains with resistance to these antibiotics were often, but not always able to degrade them.

Animals↗
PubMed1982

Resistance to macrolide-lincosamide-streptogramin antibiotics in enterococci from the intestines of animals.

Macrolide-lincosamide-streptogramin group B (MLS) resistant strains were found among enterococci isolated from caeca of poultry, pigs and cattle. The percentage of MLS resistance among the poultry strains was 70 per cent. The Streptococcus faecium strains were more susceptible than the other enterococcal strains to virginiamycin, a member of the streptogramin class of antibiotics. This was due to higher susceptibility of the S faecium strains to the virginiamycin component M which belongs to the streptogramin group A antibiotics. Ability to inactivate clindamycin, an antibiotic of the lincosamide class of antibiotics, was noted in an unclassified group D streptococcus strain isolated from a pig.

Animals↗
PubMed2003

The mechanism of action of macrolides, lincosamides and streptogramin B reveals the nascent peptide exit path in the ribosome.

The macrolide-lincosamide-streptogramin B class (MLS) of antibiotics contains structurally different but functionally similar drugs, that all bind to the 50S ribosomal subunit. It has been suggested that these compounds block the path by which nascent peptides exit the ribosome. We have studied the mechanisms of action of four macrolides (erythromycin, josamycin, spiramycin and telithromycin), one lincosamide (clindamycin) and one streptogramin B (pristinamycin IA). All these MLS drugs cause dissociation of peptidyl-tRNA from the ribosome. Josamycin, spiramycin and clindamycin, that extend to the peptidyl transferase center, cause dissociation of peptidyl-tRNAs containing two, three or four amino acid residues. Erythromycin, which does not reach the peptidyl transferase center, induces dissociation of peptidyl-tRNAs containing six, seven or eight amino acid residues. Pristinamycin IA causes dissociation of peptidyl-tRNAs with six amino acid residues and telithromycin allows polymerisation of nine or ten amino acid residues before peptidyl-tRNA dissociates. Our data, in combination with previous structural information, suggest a common mode of action for all MLS antibiotics, which is modulated by the space available between the peptidyl transferase center and the drug.

Anti-Bacterial Agents↗
PubMed2003

What is the role of streptogramins in intensive care?

The combination of two injectable streptogramins, quinupristin/dalfopristin, provides a new pharmacological choice proven to be therapeutically efficacious against most Gram-positive, multi-resistant microorganisms. They have been shown to be efficacious above all in critically ill patients hospitalized in intensive care who have unique alterations in homeostasis that makes tissue penetration of various pharmacological antimicrobials difficult. In cases of infection localized in difficult-to-treat sites, the combination with other drugs, such as cefepime, a glycopeptide or linezolid, is able to potentiate the action of the streptogramin with positive results which allow resolution of the illness. In this article, we review data from the literature on the use of quinupristin/dalfopristin in the treatment of Gram-positive, multi-resistant infections in critically ill patients.

Anti-Bacterial Agents↗
PubMed2004

Pneumococcal resistance to macrolides, lincosamides, ketolides, and streptogramin B agents: molecular mechanisms and resistance phenotypes.

The macrolides, lincosamides, ketolides, and streptogramin B agents (the MLKS(B) antimicrobial agents) have related chemical structures and share similar molecular targets on the 50S ribosomal subunit of Streptococcus pneumoniae. Mutations in rRNA or ribosomal proteins generate a variety of resistance phenotypes. The M phenotype of S. pneumoniae, which predominates in North America, affords low-level resistance to macrolides only (excluding macrolides with 16-member rings) by means of an efflux pump encoded by the mefA gene. The MLS(B) phenotype, which predominates in Europe, affords high-level resistance to macrolides, lincosamides, and streptogramin B agents and arises, in most cases, from dimethylation of adenine 2058 in the 23S rRNA of the 50S ribosomal subunit. Other, less common, phenotypes arise from other 23S rRNA modifications (ML and K phenotypes) or from amino acid substitution (MS(B) phenotype) or insertion (MKS(B) phenotype) into the 50S subunit ribosomal protein L4. In all cases, the decrease in susceptibility to ketolides (for example, telithromycin) is less than the decrease in susceptibility for other MLKS(B) agents.

Amino Acid Substitution↗
PubMed2004

A high frequency of macrolide-lincosamide-streptogramin resistance determinants in Staphylococcus aureus isolated in South Korea.

Genes conferring resistance to one of the macrolide-lincosamide-streptogramin (MLS) antibiotics may confer cross-resistance to others, because they have similar effects on bacterial protein synthesis. In Korea, over 70% of Staphylococcus aureus isolates are methicillin-resistant and erythromycin-resistant methicillin-resistant S. aureus (MRSA) is also prevalent. We investigated the frequency of MLS resistance in erythromycin-resistant S. aureus isolates. A total of 682 isolates of S. aureus were collected in a nationwide antibiotic resistance survey. Susceptibility to erythromycin, clindamycin, and quinupristin/dalfopristin was tested by disk diffusion. In all, 37% of the methicillin-susceptible S. aureus (MSSA) and 97% of the MRSA isolates were resistant to at least one of the MLS antibiotics, whereas all were susceptible to quinupristin/dalfopristin. Out of 518 strains that were resistant to erythromycin, 60 clindamycin-susceptible (30 MSSA, 30 MRSA) and 44 clindamycin-resistant isolates (14 MSSA, 30 MRSA) were selected at random from these strains. Thirteen genes related to MLS resistance were detected in these isolates by PCR. Of the 104 MSSA and MRSA strains tested, 98 harbored one or more erm gene. The most common was erm(A), with erm(C) next. But, msr(A), lnu(A), and mef(A) were rare and no resistance to streptogramin A was encountered.

Anti-Bacterial Agents↗
PubMed2002

Prevalence of resistance to macrolide, lincosamide and streptogramin antibiotics in Gram-positive cocci isolated in a Korean hospital.

To investigate the prevalence of resistance to macrolide, lincosamide and streptogramin (MLS) antibiotics in Gram-positive cocci isolated in a Korean hospital, we tested the antibiotic susceptibility of 1097 clinical isolates of Staphylococcus aureus, coagulase-negative staphylococci (CNS) and enterococci to the macrolides erythromycin, clarithromycin, azithromycin and josamycin, the lincosamide clindamycin and the streptogramin pristinamycin. These three groups of organisms were mostly resistant to macrolides and lincosamide, but were commonly susceptible to pristinamycin. The resistance phenotypes of erythromycin-resistant isolates were determined by the double-disc test with erythromycin and clindamycin, which showed that most exhibited constitutive MLS resistance. In order to determine the prevalence of the resistance genotypes and the resistance mechanisms, the presence of the erm(A), erm(B), erm(C) and mef genes in the erythromycin-resistant isolates was identified by PCR analysis. The resistance was due mainly to the presence of erm(A) in S. aureus (82.5%), erm(B) in enterococci (55%) and erm(C) in CNS (47.2%).

Anti-Bacterial Agents↗
PubMed2003

Oral streptogramins in the management of patients with methicillin-resistant Staphylococcus aureus (MRSA) infections.

OBJECTIVES: Chronic methicillin-resistant Staphylococcus aureus (MRSA) infections in debilitated patients are difficult to treat. We studied the clinical efficacy and safety of an oral streptogramin, pristinamycin, for these patients. PATIENTS AND METHODS: Patients were admitted consecutively to receive pristinamycin, usually with doxycycline, for 7-21 days. Fifty-six patients (average age 75 years) from hospital and community were treated for skin, soft tissue, chest and other infections. RESULTS: The overall clinical response rate was 39 of 53 patients (74%; 95% CI: 60%, 85%) cured or substantially improved, from 53 of 56 (95%) patients clinically and 49 of 56 (87.5%) patients bacteriologically evaluable. Toxic effects comprised gastrointestinal disturbances in eight patients (14%) and one (2%) possible skin rash. CONCLUSION: This study suggests that oral streptogramins may be useful in the management of debilitated patients with MRSA infections.

Administration, Oral↗
PubMed2006

European Surveillance of Antimicrobial Consumption (ESAC): outpatient macrolide, lincosamide and streptogramin (MLS) use in Europe.

BACKGROUND: Data on outpatient macrolide, lincosamide and streptogramin (MLS) use in Europe were collected from 25 countries within the ESAC project, funded by DG SANCO of the European Commission, using the WHO ATC/DDD methodology. METHODS: For the period 1997-2003, data on outpatient use of systemic MLS aggregated at the level of the active substance were collected and expressed in DDD (WHO, version 2004) per 1000 inhabitants per day (DID). Macrolide use was analysed in detail, using a classification based on their mean plasma elimination half-life. RESULTS: Total outpatient MLS use in 2003 varied by a factor of 11 between the country with the highest (9.36 DID in Greece) and lowest (0.85 DID in Sweden) use. MLS use showed high seasonal variation. Short-, intermediate- and long-acting macrolides were used most in 6, 18 and 1 countries, respectively (mainly erythromycin, clarithromyin and azithromycin, respectively). Lincosamide use was observed in all countries (mainly clindamycin) and substantial streptogramin use only in France (pristinamycin). From 1997 to 2003, MLS use increased in 14 countries and was most pronounced in Greece (increase of >5 DID). Except for Sweden, a relative increase of intermediate- (mainly clarithromycin) and/or long-acting (mainly azithromycin) macrolide use was observed, at the expense of short-acting macrolide (mainly erythromycin) use. CONCLUSION: The observed differences between European countries in the levels of MLS use and the extreme seasonal variations in their use suggest that this class of antibiotics is prescribed inappropriately in many countries. The MLS classification developed here facilitates a more comprehensive description of macrolide use in Europe. These data (collected as part of ESAC) could promote investigations that lead to a deeper understanding of the link between macrolide use and resistance.

Anti-Bacterial Agents↗
PubMed2001

The lactococcal secondary multidrug transporter LmrP confers resistance to lincosamides, macrolides, streptogramins and tetracyclines.

The active efflux of toxic compounds by (multi)drug transporters is one of the mechanisms that bacteria have developed to resist cytotoxic drugs. The authors describe the role of the lactococcal secondary multidrug transporter LmrP in the resistance to a broad range of clinically important antibiotics. Cells expressing LmrP display an increased resistance to the lincosamide, streptogramin, tetracycline and 14- and 15-membered macrolide antibiotics. The streptogramin antibiotic quinupristin, present in the fourth-generation antibiotic RP 59500, can inhibit LmrP-mediated Hoechst 33342 transport, but is not transported by LmrP, indicating that quinupristin acts as a modulator of LmrP activity. LmrP-expressing Lactococcus lactis cells in which a proton-motive force is generated accumulate significantly less tetracycline than control cells without LmrP expression. In contrast, LmrP-expressing and control cells accumulate equal amounts of tetracycline in the absence of metabolic energy. These findings demonstrate that the increased antibiotic resistance in LmrP-expressing cells is a result of the active extrusion of antibiotics from the cell.

Anti-Bacterial Agents↗
PubMed2004

Distribution of macrolide, lincosamide, streptogramin, ketolide and oxazolidinone (MLSKO) resistance genes in Gram-negative bacteria.

A number of different mechanisms of macrolide resistance have been described in Gram-negative bacteria. These include 16 acquired genes (esterases, phosphorylases, rRNA methylases, and effluxes) and include those thought to be unique to Gram-negative bacteria (both esterases and two of the phosphorylases) and those shared with Gram-positive bacteria (one phosphorylase) and those primarily of Gram-positive origin (rRNA methylases and efflux genes). In addition, mutations, which modify the 23S rRNA, ribosomal proteins L4 and/or L22, and/or changes in expression of innate efflux systems which occur by missense, deletion and/or insertion events have been described in five Gram-negative groups, while an innate transferase conferring resistance to streptogramin A has been identified in a sixth genus. However, the amount of information on both acquisition and mutations leading to macrolide, lincosamides, streptogramins, ketolides and oxazolidinones (MLSKO) resistance is limited. As a consequence this review likely underestimates the true distribution of acquired genes and mutations in Gram-negative bacteria. As use of these drugs increases, it is likely that interaction between members of the MLSKO antibiotic family and Gram-negative bacteria will continue to change resistance to these antibiotics; by mutations of existing genes as well as by acquisition and perhaps mutations of acquired resistant genes in these organisms and more work needs to be done to get a clearer picture of what is in the Gram-negative population now, such that changes can be monitored.

Anti-Bacterial Agents↗
PubMed2002

[Streptococcus pneumoniae strains resistance to macrolide, lincosamide, streptogramin, oxazolidinone and ketolide].

Over the last two decades, antimicrobial resistance in Streptococcus pneumoniae has been detected at an increasing rate. There have been several reports of increasing rate of macrolide resistance among the penicillin-resistant S. pneumoniae strains. The rapid evolution of such resistance necessitated new antimicrobials, such as streptogramins, oxazolidinones and ketolides, against beta-lactam and macrolide resistant pneumococci. This study was undertaken to determine the prevalence of macrolide resistance in pneumococci isolated in a Turkish University hospital and also to determine the activity of these newly developed agents against pneumococci. For that purpose a total of 264 pneumococci, isolated from clinical specimens, were tested for susceptibility against penicillin, erythromycin, clarithromycin, clindamycin, quinupristin/dalfopristin, linezolid and telithromycin by agar dilution method. Penicillin resistance and intermediate penicillin resistance was found in 7.6% and 40% of isolates respectively, while resistance rates of the tested isolates against erythromycin, clarithromycin and clindamycin were as 15.9%, 13.6% and 13.6%, respectively. Resistance to macrolides and clindamycin was higher among the penicillin-resistant isolates. No resistance was detected against quinupristin/dalfopristin, linezolid and telithromycin, except for four strains which had minimal inhibitory concentration (MIC) values of intermediately susceptible category to quinupristin/dalfopristin. These data indicate the presence of an important percentage of macrolide resistant pneumococci in our hospital. It can also be concluded that streptogramins, oxazolidinones and ketolides may be used as good alternatives especially in case of infections due to macrolide resistant pneumococci.

Anti-Bacterial Agents↗
PubMed1987

Determination of binding parameters of macrolides, lincosamides, and streptogramins to Legionella pneumophila.

Parameters of [3H]erythromycin binding to Legionella pneumophila were determined in vitro using both an equilibrium and a kinetic method. Different L. pneumophila serogroups, 1-3, and a virulent strain serogroup, 1, were tested. All strains of bacteria exhibited the same binding pattern, with a dissociation constant of 0.15 microM. Other macrolides, streptogramin B-types, and lincosamides competitively displaced bound erythromycin suggesting that these compounds share common binding sites on the bacteria. Minimum inhibitory concentration (MIC) values for macrolides, streptogramin B-types, and lincosamides were determined with buffered charcoal yeast extract (BCYE) medium. A good correlation (r = 0.994) was found between the corresponding inhibition constants of these antibiotics and their MIC. It was also noted that for lincosamides the microbiological inactivity was associated with a very low bacterium affinity. Thus, it is concluded that binding parameters of these antibiotics reflect their efficacy against L. pneumophila in vitro and may serve as a useful adjunct in developing new compounds.

Anti-Bacterial Agents↗
PubMed1999

Comparative analysis of staphylococcal plasmids carrying three streptogramin-resistance genes: vat-vgb-vga.

Several staphylococcal plasmids (26-45 kb) carry all three streptogramin-resistance (Sg(R)) genes, vat, vgb, and vga. Seven such plasmids harbored by independent strains belonging to three taxa (Staphylococcus aureus, S. simulans, and S. cohnii subsp. urealyticum) were compared and the deleted derivative of one of them, pIP680 (11.3 kb), carrying the three streptogramin-resistance genes was sequenced. The seven native plasmids had in common a 12.1-kb part cocarrying the three Sg(R) genes. Sequence analysis of pIP680 revealed that the simultaneous presence of these three genes has probably resulted from cointegration of two plasmids: (i) a pAMbeta1-like plasmid harboring vat-vgb and whose replication gene has been inactivated by an IS257 insertion and (ii) a functional vga plasmid whose replication is similar to that of two staphylococcal plasmids, pSX267 and pSK41.

ATP-Binding Cassette Transporters↗