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Oxazolidinones and Streptogramins
Published in Thomas T. Yoshikawa, Shobita Rajagopalan, Antibiotic Therapy for Geriatric Patients, 2005
Stephen Marer, Shobita Rajagopalan
Separately, quinupristin and dalfopristin are generally bacteriostatic. However, the combination, i.e., Synercid, is synergistic and sometimes bactericidal against gram-positive organisms (hence the name Synercid: “synergy” and “tidal”). In addition, quinupristin/dalfopristin sometimes exhibits in vitro synergy in combination with a variety of other antibiotics for certain bacteria (2). In the future, given these in vitro phenomena, quinupristin/dalfopristin might be used in combination with other antibiotics to manage difficult to treat infections. Quinupristin/dalfopristin does have a postantibiotic effect that may have clinical importance.
Quinupristin–Dalfopristin
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Quinupristin–dalfopristin is available as an intravenous formulation only. Each single-use vial provides a total of 500 mg of sterile pyrogen-free lyophilized formulation of active drug (quinupristin, 150 mg; dalfopristin, 350 mg). The formulation should be reconstituted by slowly adding 5 ml of water with or without 5% dextrose. The vial should be then gently swirled by manual rotation without shaking to ensure dissolution of contents while limiting foam formation, and the solution should be allowed to sit for a few minutes until all the foam has disappeared. The resulting solution should be clear. The reconstituted solution should be added to 250 ml of 5% dextrose solution (approximately 2 mg/ml). An infusion volume of 100 ml may be used for central line infusions only. The desired dose should be administered by intravenous infusion (preferably via a central venous catheter) over 60 minutes. If moderate to severe venous irritation occurs after peripheral administration of quinupristin–dalfopristin, increasing the infusion volume to 500 or 750 ml should be considered. Concomitant administration of hydrocortisone or diphenhydramine does not appear to alleviate venous pain or inflammation. The formulation should not be diluted with saline solutions or heparin because quinupristin–dalfopristin is not compatible with these agents. Quinupristin–dalfopristin should not be mixed with or physically added to other drugs except for the drugs listed in Table 77.3, in which compatibility by Y-site injection has been established. With intermittent infusion of quinupristin–dalfopristin and other drugs through a common intravenous line, the line should be flushed before and after administration with 5% dextrose in water solution. Because quinupristin–dalfopristin contains no antibacterial preservative, it should be reconstituted under strict aseptic conditions. Vials are for single use. The storage time of the diluted solution should be as short as possible to minimize the risk of microbial contamination. Stability of the diluted solution before the infusion is established as 4 hour at room temperature or 54 hours if stored under refrigeration at 2–8°C. The solution should not be frozen. A 500-mg vial of quinupristin–dalfopristin costs approximately $85; the total daily cost of therapy with this agent would be $340 to $510; although prices may vary between regions (Lefebvre et al., 1997b).
Enterococci: Resistance Update and Treatment Options
Published in Robert C. Owens, Lautenbach Ebbing, Antimicrobial Resistance, 2007
Quinupristin/Dalfopristin (Q/D) is a semisynthetic parenteral streptogramin combination compound, which is derived from its parent natural compound pristinamycin, a product of Streptomyces pristinaspiralis, an oral and topical anti-staphylococcal agent that has been in clinical use since the 1980s in Europe. The major properties of this compound are summarized in Table 4. This antimicrobial is a 30:70 mixture of quinupristin and dalfopristin, which are semisynthetic derivatives of streptogramin types B and A, respectively. It is a unique antimicrobial since it acts through sequential ribosomal binding and is internally synergistic to produce a bactericidal action. Dalfopristin initially binds to the 50S bacterial ribosome, which induces a permanent conformational change that accelerates quinupristin ribosomal binding (71). Protein synthesis is impaired via both the interruption of peptide chain elongation, and the inhibition of formed peptide extrusion. Such synergism results in bactericidal activity against some important Gram-positive species including S. pneumoniae, S. agalacticae, and some strains of S. aureus. However, only bacteriostatic activity is present for the majority of E. faecium strains by time-killing curve studies. 23S ribosomal modification MLSb phenotype resistant, primarily encoded for by the ermB gene (erythromycin methylase), modifies the ribosomal attachment site for quinupristin, which limits protein-inhibitory activity to only the dalfopristin moiety (72). Erythromycin resistance serves as an excellent surrogate marker for the presence of the MLSb phenotype among enterococci. Q/D is also unique as an antienterococcal agent based on its marked disparity in in vitro susceptibility between E. faecium (MIC90 = 1–2 mg/mL) and E. faecalis (MIC90 = 8–16 mg/mL). This disparity is most likely due to altered ribosomal binding or presence of an active efflux pump. Clinical interest in the utility of Q/D for serious VRE infection began in the mid-1990s with a large-scale, noncomparative, open-label, emergency use program for multiresistant Gram-positive infection, principally vancomycin-resistant E. faecium and MRSA infection refractory or intolerant to vancomycin (73,74). The patient populations in both series had a high prevalence of acute and chronic comorbidities including diabetes, oncologic conditions, chronic liver disease, dialysis, mechanical ventilation, and prior organ transplantation. Q/D was administered at 7.5 mg/kg intravenously every 8 hr to patients with documented VRE bacteremia or nonbacteremic VRE infection, with the duration of treatment determined by the primary treating physicians. The overall success rate, defined as both clinical success and bacteriologic eradication, was 65.8% in the initial study and 65.6% in the follow-up study. There have been several reports of clinical cure combining Q/D with doxycycline or high dose-ampicillin in endocarditis; however, no larger scale experience has been performed (75–77).
Structure-activity relationship studies for inhibitors for vancomycin-resistant Enterococcus and human carbonic anhydrases
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Weiwei An, Katrina J. Holly, Alessio Nocentini, Ryan D. Imhoff, Chad. S. Hewitt, Nader S. Abutaleb, Xufeng Cao, Mohamed N. Seleem, Claudiu T. Supuran, Daniel P. Flaherty
Lack of effective treatment is a primary reason making VRE difficult to treat. Linezolid and daptomycin have been approved by the FDA as therapeutics for treatment of systemic VRE, with daptomycin showing a slightly increased survival rate compared to linezolid8. However, linezolid presents toxicity concerns including myelosuppression, serotonin syndrome, neuropathy, and lactic acidosis which may limit the length of treatment9. The synergistic 30:70 quinupristin-dalfopristin combination was also approved by the FDA in 1998, but the combination’s high toxicity prevents the therapy from being frequently utilised, except as a last-resort measure9. Thus there is an urgent need for the development of new anti-VRE therapeutics.
Streptogramins for the treatment of infections caused by Gram-positive pathogens
Published in Expert Review of Anti-infective Therapy, 2021
Sophie Reissier, Vincent Cattoir
Quinupristin-dalfopristin was firstly investigated on an emergency-use basis in the treatment of infections attributable to MDR Gram-positive bacteria, such as MRSA and VREF [29]. Its efficacy in the treatment of MRSA infections was documented in case reports, a comparative pilot study and two phase III studies, with clinical success rates consistently higher than 60% Table 5 [29,109]. In a small single-blind randomized study, quinupristin-dalfopristin has been also found to achieve similar response rates to vancomycin for the treatment of catheter-related bloodstream infections (Table 5) [110]. The efficacy of quinupristin-dalfopristin in the treatment of VREF infections was determined in three large prospective phase III studies, with clinical and bacteriological success rates between 50% and 70% (Table 5) [111–113]. The overall response rates varied according to the site of infection (<45% for endocarditis, intra-abdominal and intravascular infections) [111]. It is important to note that the treatment with quinupristin-dalfopristin may also favor an E. faecalis superinfection, because of the antimicrobial spectrum of quinupristin-dalfopristin excluded E. faecalis [111]. Two large randomized open multicenter trials have compared quinupristin-dalfopristin with standard therapy in patients suffering from presumed Gram-positive complicated skin and soft-tissue infections (SSSIs) with similar clinical and bacteriological success rates in the two groups (Table 5) [29,114]. For the treatment of nosocomial pneumonia, the efficacy of quinupristin-dalfopristin plus aztreonam versus vancomycin plus aztreonam was tested in a randomized, non-blind, multicenter study, and the equivalence of the two antimicrobial regimens was demonstrated (Table 5) [115]. Quinupristin-dalfopristin was also used successfully to treat a variety of infections, such as cellulitis, catheter-related bacteremia, osteomyelitis, peritonitis, septic arthritis/bursitis, and wound infections [29]. Finally, a single study has reported a clinical benefit (favorable clinical and microbiological response rates at 69% and 78%, respectively) in pediatric patients with severe Gram-positive infections [116]. Since 1999, the association quinupristin-dalfopristin is approved by the USA FDA for complicated SSSIs caused by oxacillin-susceptible S. aureus and S. pyogenes. In 1999, quinupristin-dalfopristin was also approved for the treatment of severe infections due to VREF associated with bacteremia, but approval was removed by USA FDA in 2010. In 2015, European Society of Cardiology recommended to use quinupristin-dalfopristin to treat infective endocarditis due to aminoglycosides, beta-lactams, and vancomycin-resistant E. faecium [117]. The efficacy of the streptogramin combination in infections due to clindamycin-resistant staphylococci (mostly hospital-acquired MRSA) remains controversial. The recommended dosages of quinupristin-dalfopristin are 7.5 mg/kg every 12 h for complicated SSTIs and 7.5 mg/kg every 8 h for VRE infections (IV infusion over 1 h).