|Year : 1999 | Volume
| Issue : 3 | Page : 111-119
Streptogramins : A new class of antibiotics
R Khosla1, DD Verma2, A Kapur1, RV Aruna3, N Khanna4
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
R-1/58, Raj Nagar, Ghaziabad-201 002
Source of Support: None, Conflict of Interest: None
|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
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|| |
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  A and the quite similar virginiamycin S  .
Numerous streptogramins have been obtained in various laboratories.  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. 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. 
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|| |
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|| |
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|| |
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|| |
Both group A and group B streptogramins bind to bacterial ribosomes and inhibit the translation of messenger RNA (mRNA) at the elongation step. 
Group A stretptogramins inactivate the donor and acceptor sites of peptidyltransferase, thus interfering with the function of this enzyme.  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.  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|| |
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. , In addition, when each component is essentially bacteriostatic, the synergistic behaviors of the combination renders the mixture bactericidal. ,, The synergism extends the antibacterial spectrum of the 2 components to organisms such as erythromycin-resistant Staphylococcus aureus (for instance is methicillin-resistant strains), Listeria monocytogenes, Bacteroides fragilis, Clostridium prerfingens, and Neisseria More Details gonorrhoeae.  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.  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. 
| ¤ Antimicrobial Activity|| |
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.  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. , 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.  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. 
| ¤ Mechanisms of Resistance|| |
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.  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. , 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.  MLS resistance by active efflux has been described in S.epidermidis, affecting 14-membered ring macrolides and group B streptogramins.
| ¤ Pharmacokinetic Features|| |
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 .  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. 
| ¤ Summary|| |
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.
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