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Expert Opinion on Pharmacotherapy Sep 2002Gram-positive pathogens are associated with both community- and hospital-acquired infections. These infections may be life-threatening in hospitalised patients,... (Review)
Review
Gram-positive pathogens are associated with both community- and hospital-acquired infections. These infections may be life-threatening in hospitalised patients, especially in those with significant underlying acute or chronic diseases. Prompt and appropriate antimicrobial therapy is essential for avoiding morbidity and mortality. The concept of appropriate therapy is being redefined by increasing antimicrobial resistance, especially amongst Gram-positive pathogens. This has been most dramatic with penicillin-resistant Streptococcus pneumoniae in the community, including cross-resistance to other classes of antimicrobial agents. In the US, the incidence of methicillin-resistant Staphylococcus aureus (MRSA) with community isolates is significant. For hospital-acquired Gram-positive pathogens, MRSA, vancomycin-resistant Enterococcus species and vancomycin-intermediate resistant and -resistant S. aureus are a great concern, particularly as the frequency of recovery of these pathogens from infected patients increases. The net result of these various resistance issues is a reduction in the number of appropriate antimicrobial agents for treating infected patients. Quinupristin/dalfopristin is a parental streptogramin with a spectrum of activity that includes Gram-positive pathogens, including those resistant to other classes of antimicrobial compounds. In this review, data summarising the frequency of recovered Gram-positive pathogens from various infectious diseases, the escalating prevalence of resistance amongst Gram-positive pathogens and the factors making quinupristin/dalfopristin a suitable agent for treating patients infected with Gram-positive organisms will be discussed.
Topics: Animals; Drug Evaluation; Drug Resistance, Multiple, Bacterial; Gram-Positive Bacteria; Humans; Virginiamycin
PubMed: 12186626
DOI: 10.1517/14656566.3.9.1341 -
Expert Opinion on Investigational Drugs Feb 2001Streptogramins represent a unique class of antibiotics remarkable for their antibacterial activity and their unique mechanism of action. These antibiotics are produced... (Review)
Review
Streptogramins represent a unique class of antibiotics remarkable for their antibacterial activity and their unique mechanism of action. These antibiotics are produced naturally as secondary metabolites by a number of Streptomyces species and have been classified into two main groups. They consist of at least two structurally unrelated compounds, group A or M (macrolactones) and group B or S (cyclic hexadepsipeptides). Both groups bind bacterial ribosomes and inhibit protein synthesis at the elongation step and they act synergistically in vitro against many microorganisms. Streptogramins A and B act synergistically in vivo; the mixture of the two compounds is more powerful than the individual components and their combined action is irreversible. The pharmacokinetic parameters of group A and B streptogramins in blood are similar. The major gap, limiting the therapeutic use of the natural compounds, was represented by the lack dissolution in water. The synthesis of water-soluble derivatives of pristinamycin I(A) and II(B) has allowed the development of injectable, first represented by quinupristin/dalfopristin (Synercid) and oral formulations, represented by RPR-106972, streptogramins with fixed compositions. Streptogramins have demonstrated activity against Gram-positive microorganisms in vitro and in vivo, including those with multi-drug resistance. Moreover, the absence of cross-resistance to macrolides in many of these microorganisms and the rarity of cross-resistance between the two groups of antibiotics associated with the rapid bacterial killing are the principal features of the streptogramins, offering the possibility for treating the rising number of infections that are caused by multi-resistant Gram-positive bacteria.
Topics: Anti-Bacterial Agents; Bacteria; Drug Resistance, Microbial; Humans; Virginiamycin
PubMed: 11178336
DOI: 10.1517/13543784.10.2.185 -
Bioprocess and Biosystems Engineering May 2018The production of virginiamycin (VGM) from Streptomyces virginiae was improved by genome shuffling and ribosome engineering companied with a high-throughput screening...
The production of virginiamycin (VGM) from Streptomyces virginiae was improved by genome shuffling and ribosome engineering companied with a high-throughput screening method integrating deep-well cultivation and the cylinder-plate detecting. First, a novel high-throughput method was developed to rapidly screen large numbers of VGM-producing mutants. Then, the starting population of genome shuffling was obtained through ultraviolet (UV) and microwave mutagenesis, and four mutants with higher productivity of VGM were selected for genome shuffling. Next, the parent protoplasts were inactivated by UV and heat when a fusant probability was about 98%. Streptomycin resistance was used as an evolutionary pressure to extend positive effects on VGM synthesis. Finally, after five rounds of genome shuffling, a genetically stable strain G5-103 was obtained and characterized to be able to yield 251 mg/L VGM, which was 3.1- and 11.6-fold higher than that of the mutant strain UV 1150 and the wild-type strain, respectively.
Topics: DNA Shuffling; Genome, Bacterial; Streptomyces; Virginiamycin
PubMed: 29457193
DOI: 10.1007/s00449-018-1906-3 -
International Journal of Medical... Jan 2014Streptogramins are potent drugs against numerous highly resistant pathogens and therefore are used as antibiotics of last-resort human therapy. They consist of a mixture... (Review)
Review
Streptogramins are potent drugs against numerous highly resistant pathogens and therefore are used as antibiotics of last-resort human therapy. They consist of a mixture of two different types of chemical substances - the group A streptogramins, which are polyunsaturated macrolactones, and the group B streptogramins, representing cyclic hexadepsipeptides. Streptogramins are unique in their mode of action: each component alone exhibits a moderate bacteriostatic activity by binding to the bacterial 50S ribosomal subunit and thereby blocking translation, whereas the synergic combination of both substances is up to hundred fold more effective than the single compounds, resulting in a bactericidal activity. The streptogramin biosynthetic genes are organized as large antibiotic superclusters. These clusters harbour numerous regulatory genes, which encode different types of regulators that together form a complex hierarchical signalling system, which governs the regulation of streptogramin biosynthesis. Resistance is also regulated by this cascade. However, whereas resistance against streptogramins is quite well understood in diverse pathogenic organisms, only little is known about how the natural producer strains protect themselves against these toxic compounds. Here, we give an overview about the recent advances in streptogramin investigations with a main focus on the best-studied representatives, pristinamycin and virginiamycin. We concentrate on the biosynthesis of these compounds, their regulation and resistance determinants as well as their application in medicine and food industry.
Topics: Anti-Bacterial Agents; Biosynthetic Pathways; Drug Resistance, Bacterial; Drug Synergism; Food Industry; Humans; Microbial Viability; Pristinamycin; Virginiamycin
PubMed: 24119565
DOI: 10.1016/j.ijmm.2013.08.008 -
Poultry Science Oct 1990Two replicate trials, each involving 400 Arbor Acre male broiler chicks, were conducted to determine the effect of virginiamycin as a growth promoter when added to...
Two replicate trials, each involving 400 Arbor Acre male broiler chicks, were conducted to determine the effect of virginiamycin as a growth promoter when added to either the feed or drinking water. A control group received no growth promoter while one treatment group was provided a diet containing 11 mg of virginiamycin/kg. Another treatment group was provided drinking water containing virginiamycin in amounts calculated to ensure equivalent or one-half equivalent intake of the antibiotic. Virginiamycin supplementation had no significant (P greater than .05) effect on mortality or feed conversion ratios, regardless of the mode of administration. Body weights at 21 days of age but not at 42 days of age were significantly (P less than .05) heavier for broilers receiving virginiamycin via the drinking water. The inclusion of virginiamycin in the feed failed to improve body weights at either 21 or 42 days of age.
Topics: Animal Feed; Animals; Body Weight; Chickens; Drinking; Drug Residues; Food Additives; Growth Substances; Male; Random Allocation; Virginiamycin
PubMed: 2124689
DOI: 10.3382/ps.0691713 -
Journal of Animal Science Sep 2007Evaluations of the nutritional effect of antibiotics have largely centered on effects related to the digestibility and utilization of protein and energy. The current...
Evaluations of the nutritional effect of antibiotics have largely centered on effects related to the digestibility and utilization of protein and energy. The current study evaluated the potential effect of virginiamycin (VIR) on P digestibility in swine. A total of 70 barrows (mean initial BW = 51 to 64 kg) were used in 4 nutrient-balance experiments. A basal, corn-soybean meal diet that was not supplemented with any inorganic source of P was used in each experiment. In Exp. 1, two diets were tested: basal vs. basal plus 11 mg/kg of VIR. In Exp. 2, four diets were used with a 2 x 2 factorial arrangement of 0 and 11 mg/kg of VIR and 0 and 750 phytase (PHY) units/kg of diet (PU/kg). Experiments 3 and 4 were the same as Exp. 2, except PHY was reduced to 300 PU/kg. For all experiments, VIR improved P digestibility (32.71 to 37.72%, P < 0.001) and Ca digestibility (54.99 to 58.30%, P = 0.002). The addition of PHY improved both P and Ca digestibility (P < 0.001); 750 PU/kg increased P digestibility 27.3% (from 34.6 to 61.9%, P < 0.001), whereas 300 PU increased it 13.8% (from 33.4 to 47.2%, P < 0.001). In an experiment conducted to evaluate the long-term effects of VIR on gut microbial profile, pigs (24 gilts and 8 barrows; mean BW = 29.1 +/- 0.50 kg) were fed a simple corn-soybean meal diet for 16 wk with a 2 x 2 factorial arrangement of VIR (0 and 11 mg/kg) addition and 0.15% dicalcium phosphate deletion. The long-term feeding of VIR in both the control diet and the diet with a marginally reduced P level resulted in a change in ileal microbial profile. A positive numerical increment in the number of phytate-utilizing bacteria was observed in both the normal and P-deleted diets (log unit increments of 12.4 and 17.2% over the respective controls, P = 0.13) when VIR was added. The addition of VIR also tended to affect lactobacilli populations (main effect, P = 0.11; interaction, P = 0.02); VIR decreased lactobacilli in the normal-P diet but did not affect this bacterial population in the P-deleted diet. In conclusion, the antibiotic VIR improves both Ca and P digestibility in pigs. The increase in digestibility is not as great as that provided by PHY, but because the potential mechanism of action (altered microbial populations) differs from that of PHY (direct addition of an enzyme), there can be a degree of additivity in P digestibility improvement when both products are used.
Topics: 6-Phytase; Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Anti-Bacterial Agents; Calcium, Dietary; Digestion; Dose-Response Relationship, Drug; Female; Ileum; Male; Phosphorus; Phosphorus, Dietary; Random Allocation; Swine; Virginiamycin
PubMed: 17468424
DOI: 10.2527/jas.2006-733 -
Biochimica Et Biophysica Acta Jul 1981When the S component of virginiamycin binds in vitro to the 50 S ribosomal subunit, a change of fluorescence intensity proportional to the amount of complex formed... (Comparative Study)
Comparative Study
When the S component of virginiamycin binds in vitro to the 50 S ribosomal subunit, a change of fluorescence intensity proportional to the amount of complex formed occurs. Erythromycin competes with virginiamycin S for attachment to ribosomes, and removes previously bound virginiamycin S from its target, as revealed by spectrofluorimetric analysis. The 50 S subunits which are incubated with the M component of virginiamycin (50 S*) have an increased affinity for virginiamycin S (the association constants of virginiamycin S with ribosomes are 2.5 x 10(6) M-1 in the absence of virginiamycin M, and 15 x 10(6) M-1 in its presence). Erythromycin does not compete with virginiamycin S for attachment to 50 S* subunits nor is it able to remove virginiamycin S previously bound to the 50 S* subunit. Thus, virginiamycin M produces a change in ribosomes, which results in a tighter complex virginiamycin S-50 S* subunit. Such change does not require the presence of virginiamycin M, however, as shown by the observation that ribosomes to which labeled virginiamycin M is transiently linked bind virginiamycin S in a form that cannot be removed by erythromycin.
Topics: Binding Sites; Binding, Competitive; Erythromycin; Escherichia coli; In Vitro Techniques; Ribosomes; Virginiamycin
PubMed: 6793070
DOI: 10.1016/0005-2787(81)90177-5 -
Clinical Pharmacokinetics 2004Quinupristin/dalfopristin is a streptogramin antibacterial with a wide spectrum of Gram-positive antibacterial activity. The drug has minimal oral absorption and is... (Review)
Review
Quinupristin/dalfopristin is a streptogramin antibacterial with a wide spectrum of Gram-positive antibacterial activity. The drug has minimal oral absorption and is administered intravenously as a fixed 30 : 70 ratio of quinupristin to dalfopristin. A linear relationship has been observed between the dose administered and maximum plasma concentrations. Single-dose administration of 7.5 mg/kg produced a maximal plasma concentration of 2.3-2.7 mg/L for quinupristin and 6.1-8.2 mg/L for dalfopristin. The area under the concentration-time curve (AUC) obtained with the same dose was 2.7-3.3 and 6.5-7.7 mg. h/L for quinupristin and dalfopristin, respectively. Repeated administration results in 13-21% increases in maximum plasma concentrations and 21-26% increases in AUC for both quinupristin and dalfopristin. Quinupristin and dalfopristin exhibit steady-state volumes of distribution of 0.46-0.54 and 0.24-0.30 L/kg, respectively. Quinupristin exhibits higher protein binding (55-78%) than dalfopristin (11-26%), though both entities distribute well into tissues. Concentrations exceeding those in blood have been reported for the kidney, liver, spleen, salivary glands and white blood cells of primates. Extravascular penetration, as measured in blister fluid, is 40-80%. Both quinupristin and dalfopristin are extensively metabolised via nonenzymatic reactions. Quinupristin is conjugated to form two active compounds, a cysteine moiety and a glutathione moiety. Dalfopristin is hydrolysed to the active metabolite pristinamycin IIA. The metabolites exert antibacterial activity similar to that of the parent compounds. Quinupristin/dalfopristin is excreted primarily in the faeces (75-77%), with lesser renal excretion (15-19%). The elimination half-lives of quinupristin and dalfopristin are similar, and are 0.7-1.3 hours after single doses. The metabolites have slightly longer half-lives, ranging from 1.2 to 1.8 hours. With repeated doses, plasma clearance of quinupristin and dalfopristin is reduced by approximately 20% compared with single doses, resulting in clearances of 0.7-0.8 L/h/kg. Saturable protein binding has been hypothesised as a causative mechanism. Quinupristin/dalfopristin is an inhibitor of cytochrome P450 3A4, resulting in multiple drug interactions. Ciclosporin AUC increased by 5-222% when coadministered with quinupristin/dalfopristin. Careful monitoring of patients receiving drugs that are substrates of cytochrome P450 3A4 is suggested.Quinupristin/dalfopristin is administered at 7.5 mg/kg every 8-12 hours, depending upon the severity of infection. The pharmacodynamic parameter linked with antibacterial activity for quinupristin/dalfopristin appears to be the ratio of AUC to the minimal inhibitory concentration. The additional activity of a prolonged post-antibiotic effect may also be important for efficacy.
Topics: Anti-Bacterial Agents; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Female; Humans; Male; Virginiamycin
PubMed: 15005638
DOI: 10.2165/00003088-200443040-00003 -
Poultry Science Oct 2008Subtherapeutic and prophylactic doses of virginiamycin are capable of altering the intestinal microbiota as well as increasing several growth parameters in chickens. In...
Subtherapeutic and prophylactic doses of virginiamycin are capable of altering the intestinal microbiota as well as increasing several growth parameters in chickens. In spite of the fact that the microbiota plays a role in shaping the host's immune system, little information is available on the effects of in-feed antibiotics on the chicken immune system. The objective of this study was to examine the effects of an antibiotic, virginiamycin, on the development of antibody responses. Chickens were fed diets containing no antibiotics, along with either subtherapeutic (11 ppm) or prophylactic (22 ppm) doses of virginiamycin. Chickens were then immunized with keyhole limpet hemocyanin (KLH) and sheep red blood cells systemically, and with BSA and KLH orally. Although antibodies were detected against BSA in the intestinal contents of birds that were orally immunized, there was no difference among different treatment groups. Systemic IgG, and to a lesser extent IgM, antibody responses to KLH were greater (P < 0.05) in birds fed a diet containing 11 or 22 ppm of virginiamycin compared with control birds fed no antibiotic. No treatment effect was found in the sheep red blood cell-immunized birds. Results of the present study implicate virginiamycin in enhancing antibody responses to some antigens in chickens. Further studies are required to determine to what extent these effects on antibody response are mediated through changes in the composition of the microbiota.
Topics: Administration, Oral; Animal Feed; Animals; Anti-Bacterial Agents; Antibody Formation; Chickens; Growth; Hemagglutination Tests; Housing, Animal; Immunity, Mucosal; Immunization; Virginiamycin
PubMed: 18809861
DOI: 10.3382/ps.2008-00159 -
Biochemistry Jun 1986Virginiamycin S, a type B synergimycin inhibiting protein synthesis in bacteria, competes with erythromycin for binding to the 50S ribosomal subunits; the mechanism of...
Virginiamycin S, a type B synergimycin inhibiting protein synthesis in bacteria, competes with erythromycin for binding to the 50S ribosomal subunits; the mechanism of action of the two antibiotics is unclear. Energy-transfer experiments between virginiamycin S (which is endowed with inherent fluorescence due to its hydroxypicolinyl moiety) and fluorescent coumarinyl derivatives of ribosomal proteins L7 and L10 have been carried out to locate the binding site of this antibiotic on the ribosome. Previous studies have indicated that two L7/L12 dimers can attach respectively to a strong binding site located on the central protuberance and to a weak binding site located on the stalk of the 50S subunits and that protein L10 is located at the base of the stalk. The distance between ribosome-bound virginiamycin S and a fluorophore located at the strong binding site of proteins L7/L12 (Lys-51 of L7) was found to be 56 (+/- 15) A. Virginiamycin S, on the other hand, was located at a distance exceeding 67 A from the weak binding site of L7/L12 dimers. A fluorophore positioned on the unique cysteine (Cys-70) of protein L10 and ribosome-bound virginiamycin S proved to be more than 60 A apart. From data available on the location of proteins L7/L12 and L10, a model is proposed, whereby the virginiamycin S binding site is placed at the base of the central protuberance of the 50S subunits, in proximity of the presumptive peptidyl transferase center. The binding sites of macrolides and lincosamides (related antibiotics of the MLS group) are expected to be very close to that of virginiamycin S.
Topics: Binding Sites; Energy Transfer; Escherichia coli; Kinetics; Protein Binding; Ribosomal Proteins; Ribosomes; Spectrometry, Fluorescence; Virginiamycin
PubMed: 3087416
DOI: 10.1021/bi00360a011