Overview and Introduction
Streptogramins are a class of antibiotics produced by species of the genus Streptomyces, notably Streptomyces pristinaespiralis and Streptomyces virginiae. They belong to the broader group of protein synthesis inhibitors and are classified under the macrolide-lincosamide-streptogramin (MLS) family due to their shared mechanism of action.
Streptogramins are particularly significant in the treatment of multidrug-resistant Gram-positive infections, including those caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE). Their clinical utility has expanded with the development of semisynthetic combinations, notably the quinupristin/dalfopristin mixture.
Classification of Streptogramins
Streptogramins are divided into two structurally and functionally distinct subgroups:
| Subgroup | Characteristics |
|---|---|
| Group A | Polyunsaturated cyclic peptides (e.g., dalfopristin) |
| Group B | Macrolactones (e.g., quinupristin) |
Mechanism of Action
The combination works by inhibiting bacterial protein synthesis through distinct but complementary mechanisms:
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Dalfopristin (Group A) binds to the 50S ribosomal subunit, inducing a conformational change that enhances the binding of quinupristin.
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Quinupristin (Group B) then binds to a nearby site on the 50S subunit and blocks the elongation of polypeptide chains by interfering with peptide bond formation and chain translocation.
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The combined effect is bactericidal against most susceptible organisms, although bacteriostatic activity may be observed individually.
Formulation
Quinupristin/Dalfopristin (Synercid)
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Ratio: 30:70 (quinupristin : dalfopristin)
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Available as intravenous injection
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Administered via central venous catheter due to risk of phlebitis and pain at peripheral infusion sites
Spectrum of Activity
Streptogramins are primarily active against:
Gram-positive Bacteria
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Enterococcus faecium (including VRE) – Bactericidal
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Staphylococcus aureus (including MRSA)
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Streptococcus pyogenes
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Streptococcus pneumoniae (penicillin-resistant strains)
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Corynebacterium spp.
Gram-negative Bacteria
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Limited activity; not effective against Enterobacteriaceae or Pseudomonas
Atypical Bacteria
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Mycoplasma spp., Chlamydia spp. – Some inhibitory activity
Indications
Currently, streptogramins are used for:
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Vancomycin-resistant Enterococcus faecium (VRE) bloodstream infections
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Complicated skin and soft tissue infections caused by MRSA or MSSA
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Off-label: Reserved in some settings for multidrug-resistant Gram-positive infections
Pharmacokinetics of Quinupristin/Dalfopristin
| Parameter | Description |
|---|---|
| Absorption | IV only (no oral bioavailability) |
| Distribution | Widely distributed; low CSF penetration |
| Protein binding | 75–80% |
| Metabolism | Hepatic (CYP3A4 metabolism) |
| Elimination | Biliary excretion (major), renal (minor) |
| Half-life | Quinupristin ~0.8 hr; Dalfopristin ~0.7 hr |
Adverse Effects
| System Affected | Adverse Reactions |
|---|---|
| Injection site | Pain, inflammation, thrombophlebitis (very common) |
| Musculoskeletal | Arthralgia, myalgia (up to 47% in some trials) |
| Hepatic | Elevated transaminases |
| Gastrointestinal | Nausea, diarrhea |
| Hematologic | Anemia, eosinophilia (rare) |
| Hypersensitivity | Rash, pruritus, urticaria |
Drug Interactions
Due to metabolism via the cytochrome P450 3A4 enzyme (CYP3A4), streptogramins can inhibit the metabolism of co-administered drugs:
| Interacting Drug | Effect |
|---|---|
| Cyclosporine, Tacrolimus | ↑ Serum levels → risk of nephrotoxicity |
| Midazolam, Diazepam | ↑ Sedative effect |
| Statins | ↑ Risk of myopathy |
| Warfarin | ↑ INR → increased bleeding risk |
| Calcium channel blockers | ↑ Plasma levels → hypotension, bradycardia |
Contraindications and Cautions
| Population/Condition | Considerations |
|---|---|
| Hypersensitivity | Contraindicated in patients with known streptogramin allergy |
| Severe hepatic impairment | Use with caution; adjust dose or monitor closely |
| Central line requirement | Peripheral administration is discouraged |
| Pregnancy category B | Use only if clearly needed |
| Breastfeeding | Unknown; consider risk/benefit |
Resistance Mechanisms
Resistance to streptogramins can occur via:
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Target site modification – Methylation of 23S rRNA (erm genes)
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Enzymatic inactivation – Lactonases or acetyltransferases
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Efflux pumps – e.g., msr genes for macrolide resistance
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Cross-resistance – With macrolides and lincosamides (MLS phenotype)
Notably, Enterococcus faecalis is intrinsically resistant to quinupristin/dalfopristin due to efflux and rRNA modification.
Comparative Advantages
| Feature | Streptogramins (Q/D) |
|---|---|
| Bactericidal activity | Synergistic combination |
| Multidrug-resistant coverage | Effective against MRSA, VRE faecium |
| β-lactam alternative | Useful in penicillin allergy |
| Post-antibiotic effect | Prolonged suppression after exposure |
Limitations
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Restricted to IV route
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Severe venous irritation
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Not active against Gram-negative pathogens
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Expensive and reserved for resistant infections
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Widespread use limited by side effects and resistance risk
Clinical Guidelines and Use
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IDSA Guidelines: Streptogramins like quinupristin/dalfopristin are considered second-line options for vancomycin-resistant E. faecium.
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EUCAST and CLSI breakpoints: Provide MIC interpretations for susceptible isolates
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Antimicrobial stewardship programs typically restrict use to specialist approval
Drug Development and Derivatives
Research continues into next-generation streptogramins to overcome resistance and improve tolerability:
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Novel analogs targeting efflux-resistant strains
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Semi-synthetic derivatives with better bioavailability
Examples of Approved Streptogramin Drugs
| Drug Name | Components | Brand Name | Route |
|---|---|---|---|
| Quinupristin/Dalfopristin | 30:70 synergistic combination | Synercid | IV |
| Virginiamycin | Mixture of M1 and S1 components | Veterinary use | Oral/feed |
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