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 ¤  Chemical Structures
 ¤  Naturia mixture
 ¤  Chemically defin...
 ¤  Semisynthetic de...
 ¤  Mechenlsm of Action
 ¤  Synergism of Gro...
 ¤  Antimicrobial Ac...
 ¤  Mechanisms of Re...
 ¤  Pharmacokinetic ...
 ¤  Summary
 ¤  References
 ¤  Article Figures

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ORIGINAL CONTRIBUTION
Year : 1999  |  Volume : 53  |  Issue : 3  |  Page : 111-119
 

Streptogramins : A new class of antibiotics


1 Ranbaxy Research Laboratories, 20, Sector 18, Gurgaon 122 001, India
2 Department of Pharmacology, S.B. College of Science and Technology, Holambi Khurd, New Delhi-110082, India
3 Department of Biochemistry, Universal College of Medical Sciences, Bhairawa, Nepal, Nepal
4 Department of Pharmacology. University College of Medical Sciences & G.T.B. Hospital, Shahdara, Delhi110095, India

Correspondence Address:
R Khosla
R-1/58, Raj Nagar, Ghaziabad-201 002
India
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PMID: 10798011

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How to cite this article:
Khosla R, Verma D D, Kapur A, Aruna R V, Khanna N. Streptogramins : A new class of antibiotics. Indian J Med Sci 1999;53:111-9

How to cite this URL:
Khosla R, Verma D D, Kapur A, Aruna R V, Khanna N. Streptogramins : A new class of antibiotics. Indian J Med Sci [serial online] 1999 [cited 2014 Oct 31];53:111-9. Available from: http://www.indianjmedsci.org/text.asp?1999/53/3/111/12209


Streptogramins are a group of natural cyclic peptides produced by a number of Streptomyces spp. They are a unique class of antibac­terials as each member of the class is a combination of at least 3 structurally unrelated molecules (group A and group B). Group A streptogramins are polyunsaturated macrolactones and group B strep­togramins are cyclic hexadepsi­peptides.

Group A and B molecules act synergistically against most sus­ceptible bacterial isolates. Render­ing the combination bactericidal and active against a wide variety of Gram-positive bacteria and selected Gram-Negative bacteria, and reducing the possibility of selection of resistant variants of each of the components.


 ¤ Chemical Structures Top


The group A streptogramins contain lactam and lactone linka­ges, and incorporate an oxazale ring, as illustrated in [Figure 1]. The main compounds in this group are pristinamycin IIA and pristina­mycin 11B [Table 1].

The group B streptogramins are cyclic hexadepsipeptides with a molecular weight of about 800 [Figure 1] the 2 principal com­pounds in this group being pris­tinamycin [1] A and the quite similar virginiamycin S [1] .

Numerous streptogramins have been obtained in various labora­tories. [2] These antibacterials never­theless form a homogeneous group of drugs and only a few prepara­tions have been developed com­mercially. The naturally occurring antibacterial pristinamycin, isolat­ed from Streptomyces pristinaes­piralis, includes 2 major compo­nents: 30 to 40% pristinamycin IA and 60 to 70% pristinamycin IIA.[3] Virginiamycin, which is produced by S. virginiae, is also a natural antibacterial and quite similar to pristinmycin. Both pristinamycin and virginiamycin are insoluble in water, however, and the unavailabi­lity of a parenteral form meant that, until recently, streptogramins could not be used for the treatment of the most severe infections.

Quinupristin - dalfopristin (Q­D) is a new water-soluble, semi­synthetic, injectable antibiotic that is derived from natural strepto­gramins and that is combined in a 30/70 ratio. [4]

Quinupristin/dalfopristin is made from a 30:70 mixture of 2 purified water-soluble components, RP 57669 (quinupristin) and RP 54476 (dalfopristin). These components are derived from natural pristina­mycin IA and IIB, respectively.

[Table 1] Streptogramins: Classification


 ¤ Naturia mixture Top


Pristinamycin : produced by Strep­tomyces pristinaespiralis and made up of several molecules in irregu­lar proportions.

Virginiamycin : produced by S.virginiae and slightly different from pristinamycin. Synonym: staphylo­mycin.


 ¤ Chemically defined natural molecules Top


Group A streptogramins Pristinamycin IIA see [Figure 1] Syno­nyms: streptogramin A mikamycin A. PA114A, vemamycin A, osteo­grycin A, virginiamycin M1, staphy­lomycin M, Pristinamycin IIB. Synonyms: oseo­grycin G, virginiamycin M2

Group B streptogramins Pristinamycin IA. Synonyms: strep­togramin B, mikamycin B, PA114B. Ba, osteogrycin B, synergistin B Pristinamycin IC. Synonyms: vema­mycin B, osteogrycin B1.


 ¤ Semisynthetic derivatives Top


Quinupristin or RP 57669, derived from natural pristinamycin IA Dalfopritin or RP 54476, derived from natural pristinamycin IIB Synercid R or RP 59500, a 30:70 mixture of RP 57669 and RP 54476


 ¤ Mechenlsm of Action Top


Both group A and group B strep­togramins bind to bacterial ribo­somes and inhibit the translation of messenger RNA (mRNA) at the elongation step. [5]

Group A stretptogramins inacti­vate the donor and acceptor sites of peptidyltransferase, thus inter­fering with the function of this en­zyme. [5] They block 2 of the peptide chain elongation steps aminoacyl­transfer RNA (tRNA) at the A site of the ribosomes and peptide bond formation with peptidyl tRNA at the P site. This action is partly due to the presence of the antibacterial on the ribosome, and partly to the con­formational alterations consecutive to this binding.

Group B streptogramins inter­fere with the correct positioning of peptidyl tRNA at the P site. [5] They inhibit peptide bond formation, re­sulting in a release of incomplete peptide chains. The latter proces­ses are template dependent, i.e. they selectively affect mRNA cod­ing for basic amino acids and prodline.


 ¤ Synergism of Group A and Group B Streptogramins Top


The in vitro antibacterial activity of the combination of group A and Group B streptogramins is at least 10-fold greater than the sum of the activity of the individual compo­nents. [6],[7] In addition, when each component is essentially bacterio­static, the synergistic behaviors of the combination renders the mix­ture bactericidal. [7],[8],[9] The synergism extends the antibacterial spectrum of the 2 components to organisms such as erythromycin-resistant Staphylococcus aureus Scientific Name Search  (for in­stance is methicillin-resistant strains), Listeria monocytogenes, Bacteroides fragilis, Clostridium prerfingens, and  Neisseria More Details gonor­rhoeae. [5] Several animal models have been used to study the in­vivio efficacy and pharmacodyna­mics of quinupristin/dalfopristin against infections caused by Staphylococcus aureus and Strep­tococcus spp. [11] Studies of its effi­cacy in animal models of septicae­mia, thigh infection, pneumonia and aortic endocarditis have shown it to be as active as vanco­mycin against S. aureus, including some methicillin-resistant strains (MRSA), and as active as high doses of amoxycillin against peni­cillin-resistant and multi-resistant strains of Streptococcus pneumo­niae. Thus, quinupristin/dalfor­pristin appears to have potential as an alternative to vancomycin in the management of severe staphylococ­cal and streptococcal infections including those caused by MRSA and multi-resistant pneumococci. Synergism between group A and group B streptogramins has been demonstrated in a mousemodel. [7]


 ¤ Antimicrobial Activity Top


Antimicrobial activity of quinu­pristin-dalfopristin (RP 59500, Synercid) was tested against over 28,000 recent clinical isolates from 200 medical centers in the United States and Canada. [10] Standardized tests [disk diffusion, broth micro­dilution, Etest (AB BIODISK, Solna, Sweden] were utilized and validated by concurrent quality control tests. Remarkable agree­ment was obtained between test method results for characterizing the collection by the important emerging resistances: 1) oxacillin resistance among Staphylococcus aureus (41.0 to 43.7%); 2) vanco­mycin resistance among Entero­coccus faecium (50.0 to 52.0%) and 3) the penicillin nonsuscepti­ble rate for pneumococci (31.1% overall, with 10.6% at MICs of >or =2 micrograms/mL). The quinu­pristin-dalfopristin MIC90 for van­comycin-resistant E. faecium was 1 microgram/mL, and only 0.2% of isolates were resistant. Other Enterococcus species were gene­rally not susceptible to the strepto­gramin combination but were ususally inhibited by ampicillin (86 to 95%; MIC 50, 1.0 microgram/ mL). Among all tested enterococci, the rate of vancomycin resistance was 16.2%. The quinupristin-­dalfopristin MIC90 (0.75 micro­gram/mL) for 4,626 tested Strep­tococcus pneumoniae strains was not influenced by the penicillin or macrolide susceptibility patterns. When five regions in the , USA and Canada were analyzed for signifi­cant streptogramin and other anti­microbial spectrum differences, only the Farwest region had lower number of streptogramin-suscept­ble E. faecium. Canadian strains were generally more susceptible to all drugs except chloramphenicol and doxycyline when tested against E. faecalis (73% and 89% suscep­tible, respectively). The U.S. Southeast region had S. pneumo­niae strains less susceptible to macrolides (73%,) but had more susceptibility among E. faecium isolates tested against vancomycin and ampicillin. The Northeast re­gion of the USA, had the greatest rate of vancomycin resistance among enterococci. Strains retest­ed by the monitor because of quinupristin-dalfopristin resistance (MICs, >or=4 micrograms/mL) were generally not confirmed (2.2%, validation), and only 0.2% of E. faecium isolates were identified as truly resistant. The most common errors were: 1 ) species misidentification 28.0%); 2 incorrect susceptibility results (65.6%); and 3) mixed cultures (4.3%) tested by participants. Overall, quinupristin-dalfopristin was consistently active (>or=90%, susceptible) against major Gram­positive pathogens in North America, regardless of resistance patterns to the drug classes and geographic location of the isola­tion.

Streptogramins share in vitro in­hibitory potency against a wide range of aerobic and anaerobic Gram-positive organisms and against a limited number of Gram­ negative bacteria. [14],[15] Quinupristin/ dalfopristin exerts rapid bacteri­cidal activity against hte majority of susceptible strains, and is as active at pH 6 as at pH 8. There is no appreciable inoculum effect. [6] 2.4 hours at the minimum inhibi­tory concentration (MIC), and more than 5 hours at 4 timse the MIC] has been observed against s. aureus. [16]


 ¤ Mechanisms of Resistance Top


Macrolides, lincosamides, and streptogramins (MLS) have tradi­tionally been functionally grouped because they share similar modes of action. However, different me­chanisms of resistance to the MLS group have been documented, in­cluding intrinsic and acquired resis­tance. [9] Intrinsic resistance is illus­trated by many Gram-negative bacilli, e.g. Entrerobacteriaceae, which have an outer membrane thought to limit the entry of hydro­phobic and relatively large (mole­cular mass >500) MILS molecules. Intrinsic resistance of this type af­fects all MLS antibacterials.

At least 3 mechanisms of acquir­ed resistance have been recogniz­ed: modification of the drug tar­get; drug inactivation; and active efflux. [17],[18] Modification of the drug target typically consists of altera­tions (methylation) of the 23S ribosomal RNA, resulting in resis­tance to all macrolides, lincosa­mides, and group B streptogra­mins (i.e. the so-called MLSB phenotype of resistance) but not group A streptogramins [Table 4].

Drug inactivation and active confer resistance to structurally re­lated antibacterials of the MILS group. [12] MLS resistance by active efflux has been described in S.epi­dermidis, affecting 14-membered ring macrolides and group B strep­togramins.


 ¤ Pharmacokinetic Features Top


One problem that has limited the pharmaco-dynamic and pharmaco­kinetic evaluation of streptogra­mins in severe infections has been the technical difficulties associated with the blood assay of these com­plex compounds. However, more recent developments have improv­ed our knowledge of the pharma­cokinetics of streptogramins.

A specific and sensitive HPLC method was developed to measure simultaneously quinupristin (RP 57669) and dalfopristin (RP 54476) and their main metabolites in hu­man plasma . [20] The metabolites measured by this method were RP 69012 (glutathione-conjudated) and their main metabolites in hu­man plasma. The metabolites mea­sured by this method were RP 69012 (glutathione-conjugated) and RPR 100391 (cysteine-conju­gated) from quinupristin and RP 12536 (natural pristinamycin IIA), from dalfopristin. Solid-phase ex­traction with disposable cartidges was combined with reversed-phase HPLC and fluorimetric detection for RP 57669, RP 69012 and RPR 100399 and UV detection for RP 54476 and RP 12536. The method provided good recovery and low limits of quantiation (0.025 mg 1 (-1) for RP 57669, RP 54476 and RP 12536, and of 0.010 mg 1 (-1) for RP 69012 and RPR 100391 ). The validated range of concentrations of the method was : 0.025-5000 mg 1 (-1) for RP 57669, RP 54476 and RP 12536 and 0.010.0.750 mg 1 (-1) for RP 69012 and RPR 100391.

In rats and monkeys quinupristin and dalfopristin undergo rapid eli­mination from the blood and wide tissue distribution.-. They do not penetrate the central nervous sys­tem or cross the placenta to any significant degree and they do not appear to be subject to significant body retention following cessation of administration. The blood elimi­nation half-life of quinupristin was approximately 0.6 h in rats and 0.5 h in monkeys, and that of dal­fopristin was approximately 0.6 h and 0.2 h, respectively. Both com­pounds are primarily eliminated through the bile into the faces; quinupristin is mainly excreted un­changed whereas dalfopristin is extensively metabolized before­hand. The metabolites include the microbiologically active pristina­mycin PIIA for dalfopristin and the microbiologically active glutathi­one- and cysteine-conjugated deri­vatives for quinupristin. Following intravenous administration in hu­mans both compounds are rapidly cleared from the blood with elimi­nation half-lives of approximately 1 h for quinupristin and 0.4-0.5 h for dalfopristin. The pharmacokine­tic profile of quinupristin is dose­-indipendent and so is that of dal­fopristin and RP 12536 when con­sidered together.

After an oral dose of pristinamy­cin 2g, peak plasma concentrations of the main components, pristina­mycin IA and IIB, were approxi­mately 0.8 mg/L and 0.6 mg/L, respectively, at about 3 hours. The plasma elimination half-life values of the 2 components were approxi­mately 4 and 3 hours, res­pectively. [19]


 ¤ Summary Top


Streptogramin antibiotics repre­sent a unique class of antibacte­rials in the each member of the class consists of at least 2 struc­turally unrelated molecules: group a streptogramins (macrolactones) and group B streptogramins (cyclic hexadepsipeptides). Both group A and group B streptogra­mins inhibit protein synthesis at the ribosomal level, and they act syner­gistically against many isoaltes their combination generating bac­tericidal activities and reducing the possibility of emergencs of resis­tant strains. The mechanisms of acquired resistance to group B streptogramins remain unaffected by target modifications and active efflux. The pharmacokinetic para­meters of group A and group B streptogramins in blood are quite similar. In addition, both the A and B group penetrate and accumulate in macrophages and in the bacte­rial gegetations of experimental endocarditis.

Until recently, the complex and irregular composition of naturally occurring pristinamycin and virgi­niamycin, as well as the unavailabi­lity of soluble forms, have limited the clinical development of strep­togramins. The synthesis of water soluble derivatives of pristinamycin IA and IIB has now allowed the development of injectable strepto­gramins with fixed compositions. This unique class of antibacterials will have a significant clinical im­pact in a world of increasing multi­drug resistance affecting the Gram­positive cocci, especially staphylococci and pneumococci. The absence of cross-resistance to macrolides in many of these iso­lates and the rapid antibacterial killing against these species bright future for this class of antibiotics.[21]

 
 ¤ References Top

1.Aumercier M, Le Gof is F. Mecha­nism of action of the macrolide and streptogramin antibiotics. In : Bry­skier AJ, Butzler JP, Neu HC et al., editors. Macrolides chemistry, pharmacology and clinical use. Paris : Arnette Blackwell, 1993: 115-23.  Back to cited text no. 1    
2.Cocito C. Antibiotics of the virgi­niamycin family, inhibitors which contain synergistic components. Microbiol Rev 1979;43:145-98.  Back to cited text no. 2    
3.Pars PM, Barriere JC, Smith C. et al. The chemistry of pristina­mycin. In,: Recent progress in the chemical synthesis of antibiotics. .Berlin : Heidelberg. 1990: 183-248.  Back to cited text no. 3    
4.Aeschlimann JR, Rybak MJ. Phar­macodynamic analysis of the acti­vity of quinupristin-daflopristin against vancomycin-resistant en­trococcus faecium with differing MBCs via time-kill-curve and postantibiotic effect methods. Anti­microb Agent Chemother 1998 Sep; 42(9):2188-2192.  Back to cited text no. 4    
5.Di Giambattista M, Chinali G, Cocito C. The molecular basis of the inhibitory activities of type A and type B synergimycins and re­lated antibiotics on ribosomes. J Antimicrob Chemother 1989:24:485­-507.  Back to cited text no. 5    
6.Neu. HC, , Chin NX, Gu JW. The in vitro activity of new streptogra­mins RP 59500, RP 57669 and RP 54476, alone and in combination. J Antimicrob Chemother 1992:30 Suppl. A:83-94.  Back to cited text no. 6    
7.Bouanchaud DH. In vitro and in vivo synergic activity and frac­tional inhibitory concentration (FIC) of the components of a semi­synthetic streptogramin RP 59500. J Antimicrob Chemother 1992:30 Suppl. A: 95-100.  Back to cited text no. 7    
8.Videau D. Etude de l'activite bac­tericide de la pristinamycine. Pa­thol Biol 1982;30:529-34.  Back to cited text no. 8    
9.Pankuch GA, Jacobs MR, Apple­baum PC, Study of comparative antipneumococcal activities of penicillin G, RP 59500, erythro­mycin, sparfloxacin, ciprofloxacin, and vancomycin by using time-kill methodology. Antimicrob Agent Chemother 1994;38:2065-72.  Back to cited text no. 9    
10.Jones RN, Ballow CH, Biedenbach DJ, et al. Antimicrobial activity of quinupristindaflopristin (RP 59500, Synercid) tested against over 28,000 recent clinical isolates from 200 medical centers in the United States and Canada. Diagn Micro­biol Infect Dis 1998 437-451.  Back to cited text no. 10    
11.Hoban DJ, Weshnoweski B, Palat­nick L, et al. In vitro activity of streptogramin RP 59500 against staphylococci, including bacterici­dal kinetic studies. J Antimicrob Chemother 1992:30 Suppl. A:59-66.  Back to cited text no. 11    
12.Verbist L, Verhaegan J. Compara­tive activity of RP 59500. J Anti­microb Chernother 1902:30 Suppl. A: 39-44.  Back to cited text no. 12    
13.Pechere JC. In vitro activity- of RP 59500, a semisynthetic streptogramin, against staphylococci and streptococci. J Antimicrob Chemo­ther 1992:30 Suppl. A: 15-18.  Back to cited text no. 13    
14.Inoue M, Okamoto R, Okubo T. et al. Comparative in vitro activity of RP 59500 against clinical bac­terial isolates. J Antimicrob Chemother 1992:30 Suppl. A:45-52.  Back to cited text no. 14    
15.Goto S, Miyazaki S, Kaneko Y. The in vitro activity of RP 59500 against gram-positive isolates. J Antimicrob Chemother 1992: 30 Suppl. A: 25-8.  Back to cited text no. 15    
16.Nougayrede A, Berthaud N, Bou­hanchaud DH. Post-antibiotic ef­fects of RP 59500 with Staphylo­coccus aureus. J Antimicrob Che­mother 1992:30 Suppl. A: 101-6.  Back to cited text no. 16    
17.Leclercq R, Courvalin P, Mecha­nisms of resistance to macrolides and functionally related antibiotics. In: Bryskier AJ, Butzler JP, Neu HC et al., editors. Macrolides chemistry, pharmacology and clini­cal use. Paris : Arneeta Blackwell. 1993:125-42.  Back to cited text no. 17    
18.Leclercq R, Nantas L, Soussy C, et al. Activity of RP 59500, a new parenteral semisynthetic strepto­gramin, against staphylococci with various mechanisms of resistance to macrolide-lincosamide-strepto­gramin antibiotics. J Antimicrob Chemother 1992: 30 Suppl. A: 67-75.  Back to cited text no. 18    
19.Koechlin C, Kempf JF, Jehl F, et al. Single oral dose pharmacokine­tics of the two main components of pristinamycin in humans. J Antimicrob Chemother 1990:25: 651-6.  Back to cited text no. 19    
20.Le Liboux A, Pasquier O. Montay G. Simultaneous high-performance liquid chromatographic determina­tion of quinupristin, daflopristin and their main metabolites in human plasma. J Chromatogr B Biomed Sci Appl 1998 Apr 24; 708(1-2):161-168.  Back to cited text no. 20    
21.Bergeron M, Montay G. The phar­macokinetics of quinupristin/ dalfopristin in laboratory animals and in humans. J Antimicrob Chemother 1997 May; 39 Suppl A: 129-138.  Back to cited text no. 21    


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