Antibacterial
Streptogramins B (Quinupristin) and Streptogramins A (Dalfopristin) combined at a 30:70 ratio make up Quinupristin/Dalfopristin (Q/D)[1]. Quinupristin/Dalfopristin is a semisynthetic injectable streptogramin that combines two synergistic antibiotic components, Quinupristin (a type B streptogramin) and Dalfopristin (a type A streptogramin), in a 30:70 weight-to-weight ratio. Both components are derived from pristinamycin[2].

Streptogramins B (Quinupristin) and Streptogramins A (Dalfopristin) combined at a 30:70 ratio make up Quinupristin/Dalfopristin (Q/D)[1]. Quinupristin/Dalfopristin is a semisynthetic injectable streptogramin that combines two synergistic antibiotic components, Quinupristin (a type B streptogramin) and Dalfopristin (a type A streptogramin), in a 30:70 weight-to-weight ratio. Both components are derived from pristinamycin[2].

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The study reports on the in vitro activity of the combination drug quinupristin/dalfopristin (Q/D) against clinical isolates of Enterococcus faecium. Dalfopristin is a streptogramin A component of this combination. The Minimum Inhibitory Concentrations (MICs) for Q/D against resistant isolates ranged from 4 mg/L to 64 mg/L as determined by the broth microdilution method. These MIC values reflect the activity of the combined drug, not dalfopristin alone. [1]
Streptogramin A antibiotics like dalfopristin are bacteriostatic when used alone but act synergistically with streptogramin B antibiotics (like quinupristin) to become rapidly bactericidal against most Gram-positive organisms. [1]

In a rat model of experimental aortic valve endocarditis caused by MRSA, treatment with the combination drug quinupristin/dalfopristin (Q/D) significantly reduced bacterial counts in aortic valve vegetations compared to the infected, untreated control group. The mean bacterial titer (log₁₀ CFU/g) in the Q/D-treated group was 5.9 ± 1.1, which was significantly lower than the control (9.7 ± 0.4). There was no significant difference in efficacy between the Q/D group and the vancomycin or teicoplanin treatment groups. [2]
A referenced study (not conducted in this paper but cited) indicated that in experimental endocarditis, quinupristin (streptogramin B) was homogeneously distributed within infected vegetations, but dalfopristin (streptogramin A) accumulated primarily at the periphery of the vegetations. This differential distribution may affect the overall bactericidal effectiveness of the combination. [2]

In the rat model of experimental aortic valve endocarditis, the combination drug quinupristin/dalfopristin (Q/D) was administered intravenously. The dosing regimen was as follows: a dose of 30 mg/kg (presumably of the combined drug) was given twice daily. Additionally, due to the short half-life of dalfopristin in rats, an extra 10 mg/kg of dalfopristin was infused daily over a period of 6 to 12 hours. Treatment was initiated 48 hours after bacterial challenge and continued for 3 days. [2]

Absorption, Distribution and Excretion
Quinuprine and dalfopristin are distributed in the milk of rats… The pharmacokinetics of quinuprine/dalfopristin following intravenous infusion of radiolabeled and unlabeled drugs have been studied in rats, monkeys, and humans. In rats and monkeys, quinuprine and dalfopristin are rapidly eliminated from the blood and widely distributed in tissues. However, they enter the central nervous system or cross the placenta with minimal penetration and appear not to remain significantly in the body after discontinuation of administration. The blood elimination half-life of quinuprine is approximately 0.6 hours in rats and approximately 0.5 hours in monkeys; the blood elimination half-life of dalfopristin is approximately 0.6 hours in rats and approximately 0.2 hours in monkeys. Both compounds are primarily excreted into feces via bile; quinuprine is primarily excreted unchanged, while dalfopristin requires extensive prior metabolism. The metabolites of dalfopristin include the microbially active prostatin PIIA, while the metabolites of quinupristin include microbially active glutathione and cysteine-conjugated derivatives. Quinupristin and dalfopristin appear to be metabolized similarly in humans. Following intravenous administration, both compounds are rapidly cleared from the bloodstream, with an elimination half-life of approximately 1 hour for quinupristin and approximately 0.4–0.5 hours for dalfopristin. The pharmacokinetic characteristics of quinupristin are dose-independent, as is the case when dalfopristin is used in combination with RP 12536. Extravascular diffusion of quinupristin/dalfopristin has been evaluated in human non-inflammatory interstitial fluid. Fecal excretion is the primary route of elimination for both parent drugs and their metabolites (75% to 77% of the dose). Urinary excretion accounts for approximately 15% of the quinupristin dose and 19% of the dalfopristin dose. Preclinical data in rats showed that approximately 80% of the dose was excreted via bile, suggesting that bile excretion is likely the primary fecal excretion route in humans. Metabolites/Metabolites are converted to active unconjugated metabolites via hydrolysis. Quinuprine and dalfopristin can be converted into several major active metabolites: two conjugated metabolites of quinuprine (bound to glutathione and cysteine, respectively) and one unconjugated metabolite of dalfopristin (formed by hydrolysis). These metabolites have synergistic effects with complementary parent drugs. This conversion occurs in vitro via a non-enzymatic reaction, independent of cytochrome P-450 (CYP) and glutathione transferase. Biological Half-Life The elimination half-life is approximately 0.70 hours. The elimination half-lives of quinuprine and dalfopristin are approximately 0.85 hours and 0.70 hours, respectively.
The pharmacokinetics of quinupristin/dalfopristin following intravenous infusion of radiolabeled and unlabeled drugs have been studied in rats, monkeys, and humans. …The blood elimination half-life of quinupristin in rats is approximately 0.6 hours and in monkeys approximately 0.5 hours; the blood elimination half-life of dalfopristin in rats is approximately 0.6 hours and in monkeys approximately 0.2 hours. Both compounds are rapidly cleared from the bloodstream after intravenous administration, with an elimination half-life of approximately 1 hour for quinupristin and approximately 0.4–0.5 hours for dalfopristin.

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This study indicates that due to the short half-life of dalfopristin in rats, an additional daily infusion is required in animal experimental protocols. [2]

Protein Binding
Moderate Interactions In healthy volunteers, concomitant administration of Synercid and nifedipine (repeated oral) and midazolam (intravenous bolus) resulted in elevated plasma concentrations of these drugs. The Cmax of nifedipine and midazolam increased by 18% and 14% (median), respectively, and the AUC increased by 44% and 33%, respectively. In vitro drug interaction studies showed that Synercid significantly inhibited the metabolism of cyclosporine A, midazolam, nifedipine, and terfenadine by cytochrome P450 3A4. Furthermore, in 24 subjects treated with Synercid 7.5 mg/kg q8h for 2 consecutive days, followed by 300 mg cyclosporine on day 3, the results showed a 63% increase in AUC, a 30% increase in Cmax, a 77% prolongation of half-life, and a 34% decrease in clearance of cyclosporine. When cyclosporine must be used in combination with Synercid, therapeutic concentration monitoring of cyclosporine should be performed.
Drug interaction between Synercid and digoxin cannot be ruled out, but it is unlikely to occur through CYP3A4 enzyme inhibition. Synercid has shown in vitro activity against Eubacterium lentum (MIC 0.25 μg/mL tested on both strains). Digoxin is partially metabolized by intestinal bacteria; therefore, the inhibition of digoxin's intestinal metabolism (by Eubacterium lentum) by Synercid may lead to drug interaction.
This article reports a case of a 21-year-old female patient who received oral cyclosporine 150 mg/day after kidney transplantation. Two days after starting intravenous quinupristine/dalfopristin (20 mg/kg/day), her cyclosporine plasma concentration increased. The baseline trough concentration of cyclosporine was 80–105 ng/ml. Two and three days after starting quinupristine/dalfopristin treatment, the trough concentration of cyclosporine increased to 261 ng/ml and 291 ng/ml, respectively. After the cyclosporine dose was reduced to 100 mg/day, the blood concentration returned to baseline levels. Upon discontinuation of quinupristin/dalfopristin, the cyclosporine blood concentration decreased, and the dose was increased back to the previous treatment regimen.

[1]. Characteristic of Enterococcus faecium clinical isolates with quinupristin/Dalfopristin resistance in China. BMC Microbiol. 2016 Oct 21;16(1):246.

[2]. Comparison of antimicrobial agents as therapy for experimental endocarditis: caused by methicillin-resistant Staphylococcus aureus. Tex Heart Inst J. 2010;37(4):400-4.

Therapeutic Uses

Antimicrobial Drugs
Quinuprine and dalfopristin are indicated for intravenous administration in adults for the treatment of serious or life-threatening infections caused by vancomycin-sensitive vancomycin-resistant Enterococcus faecalis (VREF) strains, including infections associated with VREF bacteremia. Quinuprine and dalfopristin are marketed in the United States under the FDA’s accelerated approval program for this indication. This program allows for drug approval based on the analysis of surrogate response endpoints (e.g., clearance of bacteremia) rather than clinical endpoints (e.g., infection cure or survival). Controlled clinical trials are currently underway to validate the effectiveness of these surrogate endpoints. /US Product Label Includes/
Quinuprine and dalfopristin are indicated for intravenous administration for the treatment of complicated skin and soft tissue infections caused by Staphylococcus aureus (methicillin-sensitive strains) or Streptococcus pyogenes (Group A β-hemolytic streptococci). /US Product Label Includes/
Semi-synthetic streptomycin antibiotics: Quinuprine/dalfopristin has potent bactericidal activity against Staphylococcus aureus. Researchers investigated whether quinuprine/dalfopristin, like other subinhibitory concentrations of bactericidal antibiotics, enhances the release of exotoxins from Gram-positive cocci. This study used two-dimensional SDS-PAGE combined with MALDI-TOF/MS analysis and Western blotting to explore the effects of quinuprine/dalfopristin on the release of Staphylococcus aureus exotoxins. The results showed that subinhibitory concentrations of quinuprine/dalfopristin reduced the release of tumor necrosis factor secreted by macrophages induced by Staphylococcus aureus. Furthermore, quinuprine/dalfopristin (rather than linezolid) attenuated the cytotoxic effect of Staphylococcus aureus on infected host cells. The addition of quinuprine/dalfopristin to Staphylococcus aureus cultures at different growth stages reduced the release of specific virulence factors (such as autolysins, protein A, α- and β-hemolysins, and lipases) in a dose-dependent manner. Conversely, other presumed non-toxic exotoxins were unaffected. The results of this study indicate that sub-inhibitory concentrations of quinuprine/dalfopristin can inhibit the release of Staphylococcus aureus virulence factors, which may be particularly beneficial for the treatment of Staphylococcus aureus infections, as both bactericidal and antitoxin activities may be advantageous in treating such infections.
Drug Warnings

Intravenous adverse reactions (e.g., thrombophlebitis, pain) may occur; therefore, the infusion line should be flushed with 5% glucose solution after peripheral infusion of quinuprine and dalfopristin. Do not flush with sodium chloride solution or heparin solution due to possible incompatibilities. For moderate to severe adverse reactions, recommended measures include increasing the infusion volume, changing the infusion site, or establishing central venous access.
Clinical studies have shown that concomitant use of hydrocortisone or diphenhydramine does not alleviate intravenous adverse reactions.
Diarrhea is a common side effect of antibiotics and usually resolves upon discontinuation of the antibiotic.
Sometimes, patients may experience watery or bloody stools (with or without stomach cramps and fever) even two months or longer after starting antibiotic treatment, even after taking the last dose of antibiotics. If this occurs, the patient should contact their doctor as soon as possible. Since quinuprine and dalfopristin have been reported to cause Clostridium difficile-associated diarrhea and colitis, ranging in severity from mild to life-threatening, the possibility of Clostridium difficile infection should be considered in patients who experience diarrhea during or after treatment. To determine whether myalgia/arthralgia in cancer patients treated with quinuprine/dalfopristin is related to biliary dysfunction, we studied 56 patients with vancomycin-resistant enterococcal infection treated with quinuprine/dalfopristin at a dose of 7.5 mg/kg every 8 hours for a mean duration of 12 days (range 2–52 days). Liver function tests, including alkaline phosphatase testing, were performed before, during, and after treatment. All patients were followed up for one month after the end of treatment. Of the 56 patients, 38 (68%) responded. Myalgia/arthralgia was the major adverse event, occurring in 20 (36%) patients. During the intermediate treatment cycle, alkaline phosphatase levels were significantly higher in patients with myalgia/arthralgia than in those without joint or muscle pain (mean values of 318.7 IU/L and 216.3 IU/L, respectively, P = 0.05). Furthermore, 3 out of 18 patients with myalgia/arthralgia (16.6%) had alkaline phosphatase levels exceeding five times the normal value, while this was not observed in other patients without myalgia/arthralgia (P = 0.04). All cases of myalgia/arthralgia resolved upon discontinuation of quinupristin/dalfopristin. Univariate analysis revealed other factors associated with myalgia/arthralgia including recurrence of hematologic malignancies (P = 0.01), tacrolimus use within one month prior to treatment (P = 0.04), and methotrexate use during antimicrobial therapy (P = 0.05). Cancer patients receiving quinupristin/dalfopristin often experience myalgia/arthralgia, which may be related to biliary dysfunction and can be assessed by alkaline phosphatase or other factors that may lead to intrahepatic cholestasis (such as recurrence of hematologic malignancies or treatment with tacrolimus or methotrexate). For more complete data on drug warnings for dalfopristin (13 in total), please visit the HSDB record page. Pharmacodynamics: Dalfopristin is a streptomycin antibiotic derived from prilistatmycin IIA. Dalfopristin is a streptomycin class A antibiotic. Clinically, it is used in combination with quinupristin (a streptomycin class B antibiotic) in a fixed 30:70 ratio, known as quinupristin/dalfopristin (Q/D). [1]
Quinupertine/dalfopristin (Q/D) combination is an effective vancomycin alternative for treating multidrug-resistant Enterococcus faecalis infections, including vancomycin-resistant strains (VREF). [1]
Resistance to Q/D (and its component dalfopristin) in Enterococcus faecalis can be mediated by enzymatic modification. Specifically, modification of dalfopristin by acetyltransferases encoded by genes such as vatD and vatE can disable it, thereby eliminating its synergistic effect with quinupertine and leading to resistance. The vatE gene was detected in a Q/D-resistant isolate in this study. [1]
This study focuses primarily on the epidemiology and resistance mechanisms of quinolone/dalfopristin drugs in clinically isolated Enterococcus faecalis from China and does not provide detailed pharmacological or toxicological analysis of the single component dalfopristin. [1]

C34H50N4O9S

690.85

690.33

C, 59.11; H, 7.30; N, 8.11; O, 20.84; S, 4.64

112362-50-2

6323289

Slightly yellow to yellow powder
White solid

1.27g/cm3

940.5ºC at 760 mmHg

approximately 150 °C

522.6ºC

0mmHg at 25°C

1.575

3.616

2

11

7

48

1340

5

S(C([H])([H])C([H])([H])[N+]([H])(C([H])([H])C([H])([H])[H])C([H])([H])C([H])([H])[H])([C@]1([H])C([H])([H])C([H])([H])N2C(C3=C([H])OC(C([H])([H])C(C([H])([H])[C@@]([H])(C([H])=C(C([H])([H])[H])C([H])=C([H])C([H])([H])N([H])C(C([H])=C([H])[C@@]([H])(C([H])([H])[H])[C@@]([H])(C([H])(C([H])([H])[H])C([H])([H])[H])OC(C21[H])=O)=O)O[H])=O)=N3)=O)(=O)=O.S(C([H])([H])[H])(=O)(=O)[O-] |c:48,65,t:55|

SUYRLXYYZQTJHF-VMBLUXKRSA-N

InChI=1S/C34H50N4O9S/c1-7-37(8-2)16-17-48(44,45)28-13-15-38-31(28)34(43)47-32(22(3)4)24(6)11-12-29(41)35-14-9-10-23(5)18-25(39)19-26(40)20-30-36-27(21-46-30)33(38)42/h9-12,18,21-22,24-25,28,31-32,39H,7-8,13-17,19-20H2,1-6H3,(H,35,41)/b10-9+,12-11+,23-18+/t24-,25-,28-,31-,32-/m1/s1

(12Z,32S,33R,6R,7R,8E,13E,15E,17S)-33-((2-(diethylamino)ethyl)sulfonyl)-17-hydroxy-6-isopropyl-7,15-dimethyl-5-oxa-11-aza-1(4,2)-oxazola-3(1,2)-pyrrolidinacycloicosaphane-8,13,15-triene-2,4,10,19-tetraone

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : 100~125 mg/mL ( 144.74~180.94 mM )
Ethanol : ~100 mg/mL

Solubility in Formulation 1: ≥ 2.08 mg/mL (3.01 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (3.01 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (3.01 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.08 mg/mL (3.01 mM)

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 (Please use freshly prepared in vivo formulations for optimal results.)