Quinupristin Mesilate

(BANM, rINNM)
Quinupristin Mesilate Chemical formula
Synonyms: Mesilato de quinupristina; Quinupristin Mesylate; Quinupristine, Mésilate de; Quinupristini Mesilas; RP-57669 (quinupristin). N{(6R,9S,10R,13S,15aS,18R,22S,24aS)-22-[p-(Dimethylamino)benzyl]-6-ethyldocosahydro-10,23dimethyl-5,8,12,15,17,21,24-heptaoxo-13-phenyl-18-{[(3S)-3-quinuclidinylthio]methyl}-12H-pyrido[2,1f]pyrrolo[2,1l][1,4,7,10,13,16]-oxapentaazacyclononadecin-9-yl}-3-hydroxy-picolinamide methanesulphonate; 4-[4azabicyclo[2.2.2]oct-3-ylthio]methyl}-4-oxoboxylic acid)-virginiamycin S 1 methanesulphonate.
Cyrillic synonym: Хинупристина Мезилат.

💊 Chemical information

Chemical formula: C53H67N9O10S,CH4O3S = 1118.3.
CAS — 120138-50-3 (quinupristin).

💊 Adverse Effects and Treatment

The adverse effects most frequently reported in patients receiving quinupristin/dalfopristin include nausea and vomiting, diarrhoea, skin rash, pruritus, headache, and pain. Myalgia and arthralgia have occurred and may be severe; symptoms may be improved by decreasing the dose frequency. Eosinophilia, anaemia, leucopenia, and neutropenia are also common. Individual cases of severe thrombocytopenia and pancytopenia have been reported. Pseudomembranous colitis has also been reported. Hyperbilirubinaemia and raised liver enzyme values may occur. Pain and inflammation at the injection site is common, and thrombophlebitis has occurred. Quinupristin/dalfopristin is not removed by peritoneal dialysis, and removal by haemodialysis is considered unlikely.

Effects on the musculoskeletal system.

References.
1. Olsen KM, et al. Arthralgias and myalgias related to quinupristin-dalfopristin administration. Abstract: Clin Infect Dis 2001; 32: 674. Full version: http://www.journals.uchicago.edu/ doi/pdf/10.1086/318702 (accessed 12/08/08
2. Carver PL, et al. Risk factors for arthralgias or myalgias associated with quinupristin-dalfopristin therapy. Pharmacotherapy 2003; 23: 159–64
3. Raad I, et al. Relationship between myalgias/arthralgias occurring in patients receiving quinupristin/dalfopristin and biliary dysfunction. J Antimicrob Chemother 2004; 53: 1105–8
4. Gupte G, et al. Quinupristin-dalfopristin use in children is associated with arthralgias and myalgias. Pediatr Infect Dis J 2006; 25: 281.

💊 Precautions

Quinupristin/dalfopristin should be used with caution in patients with hepatic impairment and avoided in severe impairment, as elevated plasma concentrations of quinupristin and dalfopristin and their metabolites have been found in patients with hepatic dysfunction, and elevated concentrations of quinupristin metabolites have occurred in patients with hyperbilirubinaemia. The combination is contra-indicated in patients who have plasma-bilirubin concentrations greater than 3 times the normal upper limit. Prolongation of the QT interval has been seen in animals given quinupristin/dalfopristin; therefore caution is advised in patients at risk of cardiac arrhythmias.

💊 Interactions

Quinupristin/dalfopristin inhibits the cytochrome P450 isoenzyme CYP3A4 and it may therefore inhibit the metabolism of a number of drugs. In particular, there is a theoretical possibility of serious ventricular arrhythmias when given with drugs that prolong the QT interval, such as astemizole, cisapride, and terfenadine. Quinupristin/dalfopristin has been shown to increase plasma concentrations of ciclosporin, midazolam, nifedipine, and tacrolimus. The use of ergot alkaloids with quinupristin/dalfopristin should be avoided.

💊 Antimicrobial Action

Quinupristin/dalfopristin is a semisynthetic streptogramin antibacterial. Quinupristin and dalfopristin each have bacteriostatic activity and in combination usually act synergistically to produce bactericidal activity. The streptogramins act on the ribosome to block protein synthesis. Quinupristin/dalfopristin is active against a range of Gram-positive bacteria including meticillin- and multi-
drug-resistant strains of Staphylococcus aureus and S. epidermidis, vancomycin-resistant Enterococcus faecium (but not E. faecalis), and penicillin- and macrolide-resistant Streptococcus pneumoniae. It is also active against the anaerobe Clostridium perfringens, and Gram-negative bacteria Legionella pneumophila, Moraxella catarrhalis (Branhamella catarrhalis), Mycoplasma pneumoniae, and Neisseria meningitidis.
1. Schouten MA, Hoogkamp-Korstanje JAA. Comparative in-vitro activities of quinupristin-dalfopristin against Gram-positive bloodstream isolates. J Antimicrob Chemother 1997; 40: 213–19
2. Pankuch GA, et al. Postantibiotic effect and postantibiotic subMIC effect of quinupristin-dalfopristin against Gram-positive and negative organisms. Antimicrob Agents Chemother 1998; 42: 3028–31
3. Johnson AP, et al. Susceptibility to quinupristin/dalfopristin and other antibiotics of vancomycin-resistant enterococci from the UK, 1997 to mid-1999. J Antimicrob Chemother 2000; 46: 125–8
4. Ling TK, et al. In vitro activity and post-antibiotic effect of quinupristin/dalfopristin (Synercid). Chemotherapy 2001; 47: 243–9
5. Eliopoulos GM, Wennersten CB. Antimicrobial activity of quinupristin-dalfopristin combined with other antibiotics against vancomycin-resistant enterococci. Antimicrob Agents Chemother 2002; 46: 1319–24
6. Hancock RE. Mechanisms of action of newer antibiotics for Gram-positive pathogens. Lancet Infect Dis 2005; 5: 209–18.

Resistance.

Although uncommon, isolated reports of E. faecium resistant to quinupristin/dalfopristin have emerged,1-7 and have included a link to the use of the streptogramin virginiamycin as an animal food additive.3,4
1. Eliopoulos GM, et al. Characterization of vancomycin-resistant Enterococcus faecium isolates from the United States and their susceptibility in vitro to dalfopristin-quinupristin. Antimicrob Agents Chemother 1998; 42: 1088–92
2. Bozdogan B, et al. Plasmid-mediated coresistance to streptogramins and vancomycin in Enterococcus faecium HM1032. Antimicrob Agents Chemother 1999; 43: 2097–8
3. Werner G, et al. Association between quinupristin/dalfopristin resistance in glycopeptide-resistant Enterococcus faecium and the use of additives in animal feed. Eur J Clin Microbiol Infect Dis 1998; 17: 401–2
4. Hershberger E, et al. Quinupristin-dalfopristin resistance in gram-positive bacteria: mechanism of resistance and epidemiology. Clin Infect Dis 2004; 38: 92–8
5. Oh WS, et al. High rate of resistance to quinupristin-dalfopristin in Enterococcus faecium clinical isolates from Korea. Antimicrob Agents Chemother 2005; 49: 5176–8
6. Donabedian SM, et al. Quinupristin-dalfopristin resistance in Enterococcus faecium isolates from humans, farm animals, and grocery store meat in the United States. J Clin Microbiol 2006; 44: 3361–5
7. Karanika M, et al. Reduced susceptibility to quinupristin/dalfopristin in Enterococcus faecium in Greece without prior exposure to the agent. Int J Antimicrob Agents 2008; 31: 55–7.

💊 Pharmacokinetics

After parenteral doses, quinupristin and dalfopristin are rapidly metabolised. At steady state, the half-life of quinupristin and its metabolites is about 3 hours and that of dalfopristin and its metabolites about 1 hour. Elimination half-lives of unchanged quinupristin and dalfopristin are 0.9 and 0.75 hours, respectively. Protein binding ranges from 55 to 78% for quinupristin and 11 to 26% for dalfopristin. The main route of excretion is biliary, with 75 to 77% of a dose detectable in the faeces. Urinary excretion accounts for 15% of the quinupristin and 19% of the dalfopristin dose. Negligible amounts are removed by peritoneal dialysis and probably also by haemodialysis.
Distribution into milk has been found in studies in rats.
1. Bearden DT. Clinical pharmacokinetics of quinupristin/dalfopristin. Clin Pharmacokinet 2004; 43: 239–52.

💊 Uses and Administration

Quinupristin/dalfopristin is a streptogramin antibacterial related to pristinamycin. Quinupristin and dalfopristin are semisynthetic derivatives of pristinamycin I and pristinamycin IIA respectively, and are used in the ratio 3:7. Quinupristin/dalfopristin is active against a range of Gram-positive and some Gram-negative organisms, but it is reserved for the treatment of serious infections with multidrug-resistant Gram-positive bacteria, specifically MRSA and vancomycin-resistant Enterococcus faecium. Quinupristin/dalfopristin is given as the mesilate salts by intravenous infusion, in glucose 5% over 60 minutes, in a dose of 7.5 mg/kg (equivalent to quinupristin 2.25 mg/kg and dalfopristin 5.25 mg/kg) every 8 or 12 hours for at least 7 days. To minimise venous irritation, the vein should be flushed with glucose 5% after each infusion; alternatively, the infusion may be given through a central venous catheter. The injection should not be diluted with saline solutions since it is incompatible with sodium chloride. Doses may need to be reduced in patients with hepatic impairment (see below).
1. Bayston R, et al., eds. Quinupristin/dalfopristin—update on the first injectable streptogramin. J Antimicrob Chemother 1997; 39 (suppl A): 1–151
2. Wood MJ (ed). Quinupristin/dalfopristin–a novel approach for the treatment of serious Gram-positive infections. J Antimicrob Chemother 1999; 44 (suppl A): 1–46
3. Lamb HM, et al. Quinupristin/dalfopristin: a review of its use in the management of serious Gram-positive infections. Drugs 1999; 58: 1061–97
4. Drew RH, et al. Treatment of methicillin-resistant Staphylococcus aureus infections with quinupristin-dalfopristin in patients intolerant of or failing prior therapy: for the Synercid Emergency-Use Study Group. J Antimicrob Chemother 2000; 46: 775–84
5. Allington DR, Rivey MP. Quinupristin/dalfopristin: a therapeutic review. Clin Ther 2001; 23: 24–44
6. Linden PK, et al. Treatment of vancomycin-resistant Enterococcus faecium infections with quinupristin/dalfopristin. Clin Infect Dis 2001; 33: 1816–23
7. Goff DA, Sierawski SJ. Clinical experience of quinupristin-dalfopristin for the treatment of antimicrobial-resistant gram-positive infections. Pharmacotherapy 2002; 748–58
8. Eliopoulos GM. Quinupristin-dalfopristin and linezolid: evidence and opinion. Clin Infect Dis 2003; 36: 473–81
9. Brown J, Freeman BB. Combining quinupristin/dalfopristin with other agents for resistant infections. Ann Pharmacother 2004; 38: 677–85
10. Manfredi R. A re-emerging class of antimicrobial agents: streptogramins (quinupristin/dalfopristin) in the management of multiresistant gram-positive nosocomial cocci in hospital setting. Mini Rev Med Chem 2005; 5: 1075–81.

Administration in hepatic impairment.

Licensed product information states that in clinical studies of quinupristin/dalfopristin the incidence of adverse effects in patients with chronic liver impairment or cirrhosis was similar to that in patients with normal liver function. However, pharmacokinetic studies have shown that systemic exposure to quinupristin/dalfopristin and their metabolites may be increased in those with hepatic impairment. In some countries it has therefore been recommended that quinupristin/dalfopristin should be avoided in patients with severe hepatic impairment, and that for those with moderate impairment a dose reduction to 5 mg/kg (equivalent to quinupristin 1.5 mg/kg and dalfopristin 3.5 mg/kg) should be considered if 7.5 mg/kg is not tolerated.

💊 Preparations

Proprietary Preparations

Multi-ingredient: Arg.: Synercid†; Austral.: Synercid; Austria: Synercid; Braz.: Synercid; Canad.: Synercid; Cz.: Synercid; Fin.: Synercid†; Fr.: Synercid; Ger.: Synercid†; Gr.: Synercid; Hung.: Synercid; Irl.: Synercid; Israel: Synercid; Ital.: Synercid; Mex.: Synercid†; Neth.: Synercid; NZ: Synercid; Pol.: Synercid; Port.: Synercid; S.Afr.: Synercid†; Spain: Synercid; Swed.: Synercid†; Switz.: Synercid†; UK: Synercid; USA: Synercid.
Published May 08, 2019.