Streptograms
Streptograms are a group of antibiotics , the representatives of which are mixtures of two structurally different components. Both components inhibit the protein synthesis of bacteria and thus prevent their further growth. Their combination causes a superadditive, i.e. synergistic , antibiotic effect.
Streptograms gained importance primarily through the progressive development of resistance to older antibiotics such as penicillins or macrolides . They are currently not available on the pharmaceutical market.
structure
.png)
Streptograms are naturally formed in the secondary metabolism of a number of species of Streptomyces and Actinoplanes . They always consist of two components, one of which belongs to group A and the other to group B. The individual compounds of each group differ slightly in some substituents, functional groups or amino acid components.
Group A
The group A streptograms are polyunsaturated macrolactones . They contain peptide and polyketide structural elements . The cyclic structure is created by an intramolecular ester bond between the carboxy group of the C-terminal amino acid, usually proline (pristinamycin II) and a hydroxyl group. Structural variations arise, for example, when the proline is replaced by alanine (madumycin II) or cysteine (griseoviridin).
Group B
Group B streptogramins represent branched cyclic hexa- or hepta depsipeptide from the class of peptide - Antibiotics are generally have group B streptogramins following sequence:.
3- Hydroxypicolinic acid , L - threonine , D -amino butyric acid (or D - alanine ), L - proline , L - phenylalanine (or 4 N , N - (dimethylamino) - L -phenylalanine), X , L - phenylglycine . The radical X usually stands for L -4-oxo or 4-hydroxy pipecolic acid , but aspartic acid or proline can also be present at this point.
Examples
| combination | Streptogramin group A |
Streptogramin group B |
|---|---|---|
| Natural | ||
| Pristinamycin | Pristinamycin IIA (= streptogramin A) |
Pristinamycin IA (= streptogramin B) |
| Virginiamycin | Pristinamycin IIA | Virginiamycin S1 |
| Semi-synthetic | ||
| RP 59500 ( Synercid ) | Dalfopristin | Quinupristin |
| NXL103 (XRP 2868) | Floprist | Linopristine |
Chemical modifications create variants that can be used therapeutically because they are more soluble in water (dalfopristin, quinupristin) or orally effective (flopristin, linopristin).
Mechanism of action
The representatives of both subgroups bind to the P-site of the 50S subunit of the ribosome and thus inhibit the elongation of protein synthesis. Viewed individually, these two active ingredients are only bacteriostatically effective, which means that they can only inhibit the growth of bacteria, but not destroy them. Used together, often in a 70:30 mixture of a group A streptogramin with a group B streptogramin, shows a synergism that even kills bacteria directly ( bactericidal effect). This is possible due to a change in the conformation of the 50S subunit after group A streptogramins have bound, which enable group B streptogramins to show a 100-fold higher activity.
Group A streptograms alone block an early phase of elongation by blocking the donor and acceptor sites on the ribosome. It is only possible for them to bind to the ribosome if it is free from a bound acyl-tRNA . Group B streptograms, however, can occupy the ribosome in any phase of protein synthesis and thus lead to an inhibition of elongation and to the release of incomplete peptides .
Resistance mechanisms and spectrum of action
Although the field of application of this class of antibiotics should be limited to multi-resistant bacteria, various resistance mechanisms are already known. Interestingly, because of the similar mechanism of action, there is often cross-resistance between streptogramins, macrolides and lincosamides , which can be attributed to various 23S rRNA methylases , i.e. enzymes that can methylate RNA molecules. This changes the place of action of these antibiotics in such a way that an interaction between antibiotic and ribosome is no longer possible.
Another widespread mechanism of bacteria, similar to tumor cells, is to expel the unwanted substance before it can take effect. So they found ABC transporter , a family ATP -dependent pumps that are specific to streptogramins. Direct cross resistance is not to be expected from these pumps, as these transporters act depending on the chemical structure of the substances. However, plasmids have been found that contain several genes for antibiotic resistance, which also include streptograms. In addition, lyases were found that are able to split streptograms and thus deactivate them directly.
Today it can be assumed that most gram-positive bacteria such as staphylococci , streptococci and enterococci are sensitive to Synercid, including the multi-resistant strains. Enterococcus faecalis , which shows natural resistance due to an efflux pump , as well as enterobacteria and pseudomonads are excluded from this . The spectrum of activity also includes aerobic gram-negative bacteria such as Moraxella catarrhalis , Legionella , Neisseria , Haemophilus influenzae , but to a lesser extent, as well as anaerobic bacteria such as Bacteroides , Lactobacillus , Clostridium perfringens and Clostridium difficile .
The area of application is now limited to complicated skin infections , staphylococci sensitive to group A streptococci and methicillin, as well as infections with vancomycin- resistant strains of Enterococcus faecium and nosocomial pneumonia, i.e. pneumonia acquired in hospital .
Side effects
Restrictions in the use of streptogramin antibiotics result on the one hand from frequent interactions with other drugs , and on the other hand from undesirable effects such as muscle and joint pain, nausea or inflammation at the infusion site.
The streptograms used clinically today do not show good oral bioavailability , which is why they must be administered intravenously . This can lead to local irritation of the peripheral veins . Edema , inflammation of the surrounding tissue and the venous wall ( phlebitis ) and thrombosis were observed . It is therefore recommended to administer streptograms through a CVC in order to keep the local concentration lower due to the larger lumen . Up to 30% of patients experience dose-dependent muscle pain ( myalgia ) and joint pain ( arthralgia ), which can be easily treated with conventional analgesic therapy, be it with NSAIDs or opioid analgesics , and which disappear completely after treatment has ended. Less common adverse drug reactions are increased conjugated bilirubin , hyponatremia and anemia .
Streptograms inhibit the hepatic monooxygenase CYP3A4 , a system that is responsible for the breakdown of various drugs. The most prominent examples include amiodarone , ciclosporine , diazepam , lidocaine , warfarin and phenytoin . If such drugs are combined with streptogramins or if the liver is damaged, dose adjustments should be considered. Renal insufficiencies do not require a dose reduction.
Individual evidence
- ↑ R. Kosla et al .: streptogramin: A new class of antibiotics . Indian J Med Sci. 1999 Mar; 53 (3): 111-9. PMID 10798011
- ↑ Bergeron M, Montay G: The pharmacokinetics of quinupristin / dalfopristin in laboratory animals and in humans . In: J. Antimicrob. Chemother. . 39 Suppl A, May 1997, pp. 129-38. PMID 9511077 .
- ↑ a b Mukhtar TA, Wright GD: Streptogramins, oxazolidinones, and other inhibitors of bacterial protein synthesis . In: Chem Rev.. . 105, No. 2, February 2005, pp. 529-42. doi : 10.1021 / cr030110z . PMID 15700955 .
- ↑ Woodford N: Biological counterstrike: antibiotic resistance mechanisms of Gram-positive cocci . In: Clin. Microbiol. Infect. . 11 Suppl 3, May 2005, pp. 2-21. doi : 10.1111 / j.1469-0691.2005.01140.x . PMID 15811020 .
- ↑ Eliopoulos GM: Quinupristin-dalfopristin and linezolid: evidence and opinion . In: Clin. Infect. Dis. . 36, No. 4, February 2003, pp. 473-81. PMID 12567306 .
- ↑ a b Fraser TG, Hansen C, Long JK: Newer antibiotics for serious gram-positive infections . In: Cleve Clin J Med . 73, No. 9, September 2006, pp. 847-53. PMID 16970136 .
- ↑ Olsen KM, Rebuck JA, Rupp ME: Arthralgias and myalgias related to quinupristin-dalfopristin administration . In: Clin. Infect. Dis. . 32, No. 4, February 2001, pp. E83–6. PMID 11181142 .
- ↑ Lincosamides, Oxazolidinones, and Streptogramins . The Merck Manual. November 2005. Retrieved August 24, 2008.