Optimizing therapy for vancomycin-resistant enterococcal bacteremia in children.

PURPOSE OF REVIEW: Uncertainties exist regarding the optimal treatment for vancomycin-resistant enterococcal (VRE) bloodstream infections, particularly in settings in which ampicillin cannot be used. RECENT FINDINGS: Quinupristin-dalfopristin, linezolid, and daptomycin, all approved between 1999 and 2003, represent the mainstays of therapy for VRE bacteremia, although only linezolid has been specifically approved by the United States Food and Drug Administration for this indication. The main objective of this review is to compare the relative efficacies, dosing strategies, and side-effect profiles of quinupristin-dalfopristin, linezolid, and daptomycin for VRE bacteremia in the pediatric population. A brief description of recently approved broad-spectrum Gram-positive agents that may have a role in the management of VRE bacteremia in upcoming years is also provided. SUMMARY: Linezolid, despite its bacteriostatic activity against VRE, may be the most versatile of the available drugs. It has activity against both Enterococcus faecalis and E. faecium, can be administered orally, and resistance appears to be less of a concern with linezolid compared with the other agents. Additionally, the results of two recent meta-analyses demonstrate more favorable outcomes with linezolid compared with daptomycin for the treatment of VRE bacteremia. The clinical pharmacokinetics of linezolid have been well described in children. The most notable concern with linezolid, however, is toxicities associated with prolonged use. Until more prospective data are available, we favor linezolid as first-line therapy for the treatment of VRE bacteremia in children.

Quinupristin-dalfopristin versus linezolid for the treatment of vancomycin-resistant Enterococcus faecium bacteraemia: efficacy and development of resistance.

Quinupristin-dalfopristin and linezolid are widely used for the treatment of vancomycin-resistant Enterococcus faecium (VREF) infections. Increasing resistance of VREF to quinupristin-dalfopristin and linezolid is a cause for concern. To determine the efficacy of and the rate of development of resistance to quinupristin-dalfopristin and linezolid, we analyzed all episodes of clinically significant VREF bacteraemia at a tertiary-care hospital from January 2003 to June 2007. The main outcomes were rates of 30-day mortality, microbiological response, and development of resistance. Fifty-two patients were treated with quinupristin-dalfopristin and 61 were treated with linezolid. Baseline demographic and clinical characteristics were similar between the 2 groups. There were no significant between-group differences in 30-day mortality (48% in the quinupristin-dalfopristin group vs 41% in the linezolid group; p = 0.45) or microbiological response (60% vs 66%; p = 0.51). However, prolonged bacteraemia (18% of 45 evaluable cases vs 4% of 55 evaluable cases; p = 0.04) and development of resistance in blood isolates (11% vs 0%; p = 0.02) were more frequently observed in the quinupristin-dalfopristin group than in the linezolid group. There was no significant difference between the efficacy of quinupristin-dalfopristin and linezolid. However, prolonged bacteraemia and the development of resistance were more common in quinupristin-dalfopristin-treated patients.

The in vitro effects of quinupristin/dalfopristin, erythromycin and levofloxacin at low concentrations on the expression of different cell adhesion molecules on the surface of endothelial cells (Eahy926).

OBJECTIVES: Infusion phlebitis is a common clinical problem associated with some antimicrobial agents. The pathomechanism of infusion phlebitis has not yet been elucidated, however, it has been proposed that chemical irritation of the endothelium leads to subsequent sterile inflammation with recruitment and migration of leukocytes. In the present study, cultured endothelial cells were exposed to antibiotics at clinically relevant concentrations to detect changes in various cell surface markers. METHODS: Cells from the endothelial hybrid cell line Eahy926 were exposed to quinupristin/dalfopristin, erythromycin and levofloxacin at increasing concentrations (3, 10, 30 and 100 mg/l) for 24 h. After washing, the cells were marked with monoclonal antibodies against different cell surface antigens (intercellular cell adhesion molecule-1 [ICAM-1], platelet-endothelial cell adhesion molecule-1 [PECAM-1], vascular cell adhesion molecule-1 [VCAM-1], E-selectin, L-selectin, CD34, alpha(2), alpha(5), beta(1) and beta(4) integrin chains and analysed by flow cytometry. For comparison, cells were either untreated or incubated with tumor necrosis factor alpha (TNF-alpha) at a concentration of 10 ng/ml and analysed for ICAM-1, VCAM-1 and E-selectin expression. RESULTS: There was an increase in ICAM-1 expression on endothelial cells with increasing concentrations of quinupristin/dalfopristin. VCAM-1, E-selectin, L-selectin and CD34 showed an excursive upregulation at the concentration of 100 mg/l only, while no consistent changes were observed for PECAM-1 and the integrins. Markedly less prominent changes in the expression of these adhesion molecules were seen with erythromycin while no relevant changes at all occurred with levofloxacin. The absolute change in ICAM-1 activation with quinupristin/dalfopristin at 100 mg/l (34.4%) was less pronounced than that observed after stimulation with TNF-alpha (>80%). CONCLUSIONS: The results of this study indicate that antibiotics with a high potential for local cytotoxicity may cause an inflammatory response by endothelial cells even at rather low concentrations. The increase in expression of cell surface markers involved in cell-cell interaction could be an important mechanism in the development of infusion phlebitis.

Treatment of vancomycin-resistant Enterococcus faecium infections with quinupristin/dalfopristin.

Clinicians caring for patients with vancomycin-resistant Enterococcus faecium (VREF) infections face severe constraints in the selection of treatment. Quinupristin/dalfopristin (Synercid) is active in vitro against VREF, with a MIC(90) of 1.0 microg/mL. We investigated the clinical efficacy and safety of this agent in a multicenter, prospective, noncomparative, emergency-use study of 396 patients. Patients were included if they had signs and symptoms of active infection, including bacteremia of unknown origin, intra-abdominal infection, and skin and skin-structure infection, with no alternative antibiotic therapy available. The mean duration of treatment was 20 days (range, 4-40 days). The clinical response rate was 68.8% in the evaluable subset, and the overall response rate was 65.6%. The most common adverse events related to quinupristin/dalfopristin were arthralgias and myalgias. Related laboratory abnormalities were rare. In this severely ill patient population, quinupristin/dalfopristin was efficacious and demonstrated an acceptable safety profile in the treatment of VREF infection.

Pharmacokinetics of quinupristin/ dalfopristin in patients with severe chronic renal insufficiency.

OBJECTIVE: To compare the pharmacokinetic profile of a single intravenous injection of quinupristin/dalfopristin, a new injectable streptogramin, in healthy young individuals and patients with severe chronic renal insufficiency. A secondary objective was to assess the relative tolerability of this dose in these patients compared with healthy individuals. PATIENTS AND PARTICIPANTS: 13 patients with severe chronic renal insufficiency (creatinine clearance 6 to 28 ml/min/1.73m2) were individually matched for gender, bodyweight and age to a healthy volunteer. METHODS: Participants received a single dose of quinupristin/dalfopristin 7.5 mg/kg bodyweight as a continuous 1-hour intravenous infusion, followed by serial blood sampling. RESULTS: The disposition profile of unchanged quinupristin was similar in the 2 groups. However, the elimination of quinupristin derivatives in patients with renal impairment tended to be decreased: mean peak plasma drug concentration (Cmax) and area under the concentration-time curve from zero to infinity (AUCinfinity) of quinupristin plus its active derivatives were about 1.4 times higher in the patients with renal impairment compared with healthy volunteers. The mean Cmax and AUCinfinity of both unchanged dalfopristin and dalfopristin plus its active derivatives were about 1.3 times higher in renally impaired patients than in healthy volunteers. Adverse events were generally mild and transient. No severe or serious adverse events were reported and no participants prematurely discontinued the study. Venous tolerability tended to be better in healthy volunteers than in the patients with renal impairment. CONCLUSION: These results suggest that no formal reduction in the dosage of quinupristin/dalfopristin is necessary in patients with severe chronic renal impairment.

Quinupristin/dalfopristin: a review of its use in the management of serious gram-positive infections.

UNLABELLED: Quinupristin/dalfopristin is the first parenteral streptogramin antibacterial agent, and is a 30:70 (w/w) ratio of 2 semisynthetic pristinamycin derivatives. The combination has inhibitory activity against a broad range of gram-positive bacteria including methicillin-resistant staphylococci, vancomycin-resistant Enterococcus faecium (VREF), drug-resistant Streptococcus pneumoniae, other streptococci, Clostridium perfringens and Peptostreptococcus spp. The combination also has good activity against selected gram-negative respiratory tract pathogens including Moraxella catarrhalis, Legioniella pneumophila and Mycoplasma pneumoniae. Quinupristin/dalfopristin has poor activity against E. faecalis. The combination is bactericidal against staphylococci and streptococci, although constitutive erythromycin resistance can affect its activity. As for many other agents, quinupristin/dalfopristin is generally bacteriostatic against E. faecium. In patients with methicillin-resistant S. aureus (MRSA) or VREF infections participating in prospective emergency-use trials, quinupristin/dalfopristin 7.5 mg/kg every 8 or 12 hours achieved clinical or bacteriological success in > or =64% of patients. Emergence of resistance to quinupristin/dalfopristin was uncommon (4% of patients) in those with VREF infections. Quinupristin/dalfopristin 7.5 mg/kg 8- or 12-hourly also achieved similar clinical success rates to comparator agents in patients with presumed gram-positive complicated skin and skin structure infections or nosocomial pneumonia (administered in combination with aztreoman) in 3 large multicentre randomised trials. Systemic adverse events associated with quinupristin/dalfopristin include gastrointestinal events (nausea, vomiting and diarrhoea), rash and pruritus. Myalgias and arthralgias also occur at an overall incidence of 1.3%, although higher rates (2.5 to 31%) have been reported in patients with multiple comorbidities. Venous events are common if the drug is administered via a peripheral line; however, several management options (e.g. use of central venous access, increased infusion volume) may help to minimise their occurrence. Hyperbilirubinaemia has been documented in 3.1% of quinupristin/dalfopristin recipients versus 1.3% of recipients of comparator agents. Quinupristin/dalfopristin inhibits cytochrome P450 3A4 and therefore has the potential to increase the plasma concentrations of substrates of this enzyme. CONCLUSIONS: Quinupristin/dalfopristin, the first parenteral streptogramin, offers a unique spectrum of activity against multidrug-resistant gram-positive bacteria. In serious gram-positive infections for which there are other treatment options available, the spectrum of activity and efficacy of quinupristin/ dalfopristin should be weighed against its tolerability and drug interaction profile. However, in VREF or unresponsive MRSA infections, where few proven treatment options exist, quinupristin/dalfopristin should be considered as a treatment of choice for these seriously ill patients.

Synercid Aventis.

Rhône-Poulenc Rorer (RPR) developed Synercid (RP-59500), an injectable synergistic combination of quinupristin and dalfopristin as a treatment for a variety of infections caused by Gram-positive anaerobic bacteria. The treatment was approved in the UK in July 1999, for use in patients with nosocomial pneumonia, skin and soft tissue infections and clinically significant infections due to Enterococcus faecium when there is no other active antibacterial agent [337556,335257]. It was launched in the UK and the US in September 1999 [342899]. In December 1999, Synercid successfully completed the Mutual Recognition Procedure in the EU under Aventis Pharma for use in patients with these infections [351525]. In September 2000, Merrill Lynch predicted first-year sales in 1999 of Euro 15 million, rising to Euro 171 million in 2004 [384874]. In January 1999, BT Alex Brown predicted sales of US $88 million in 1999 rising to US $450 million in 2002 [318220]. In April 1999, ABN Amro predicted annual sales of DM 30 million in 1999, rising to DM 150 million in 2002 [328676].

Experience with quinupristin/dalfopristin in treating infections with vancomycin-resistant Enterococcus faecium in children.

BACKGROUND: The emergence and spread of vancomycin-resistant Enterococcus faecium (VREF) has presented serious therapeutic difficulties because of the lack of reliably active antibiotics. Quinupristin/dalfopristin is a new injectable streptogramin antibiotic that is active against most strains of VREF. Experience with this agent in adults with VREF infections is well-documented; however, there are few reports of its use in children. We report on eight children with VREF infections who received quinupristin/dalfopristin under a compassionate use protocol. METHODS: Quinupristin/dalfopristin was administered according to the manufacturer's recommendations. Clinical and laboratory data were recorded for each patient. RESULTS: The infections treated comprised six cases of bacteremia and two of peritonitis. All patients had serious underlying conditions. Seven patients recovered fully. One patient died, having experienced a relapse of his infection after quinupristin/dalfopristin was discontinued. None of the patients experienced side effects or other adverse events. CONCLUSION: Quinupristin/dalfopristin was well-tolerated and generally effective in children with infections caused by VREF. There is increasing evidence that it may be more effective than other currently available antibiotics in some such patients.

Clinical experience with quinupristin-dalfopristin as rescue treatment of critically ill patients infected with methicillin-resistant staphylococci.

OBJECTIVES: To describe the efficacy and safety of quinupristin-dalfopristin (Q-D) as rescue therapy in critically ill patients with severe infections caused by methicillin-resistant staphylococci unresponsive to vancomycin treatment. DESIGN: Observational study in the context of the compassionate use programme for Q-D. METHODS: Twelve mechanically ventilated patients suffering from severe staphylococcal infections, pretreated unsuccessfully with vancomycin despite in vitro sensitivity, were included. Patients received, intravenously, Q-D 7.5 mg/kg body weight 3 times daily. The duration of Q-D therapy averaged 11.8 days (range: 1-26 days). The outcome variables were clinical efficacy and bacteriological eradication. RESULTS: Methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) were isolated in three patients each, and both bacteria were isolated from six patients. Eradication of pathogen(s) was achieved in 7 of 12 patients (66%). Five patients (42%) died due to severe co-morbidity. Adverse events related to Q-D were not observed and neither renal nor liver function was adversely affected. CONCLUSIONS: Quinupristin-dalfopristin appears to be an efficient and safe antimicrobial drug for the rescue treatment of staphylococcal infections in critically ill patients. It may be considered as a treatment option in cases of vancomycin treatment failure.

Multiple-dose pharmacokinetics and safety of two regimens of quinupristin/dalfopristin (Synercid) in healthy volunteers.

Quinupristin/dalfopristin (Q/D) is a novel streptogramin antibiotic for the treatment of severe gram-positive infections. The purpose of this open, nonrandomized, parallel-group, phase I trial was to evaluate Q/D pharmacokinetics after single and repeated doses under the two different dosing regimens corresponding to the effective doses and to evaluate tolerability. Two groups of 10 healthy volunteers received multiple 1-hour intravenous infusions of 7.5 mg/kg Q/D either every 8 or 12 hours for 4 or 5 days, respectively. Plasma concentrations of Q, D, and metabolites were determined using high-performance liquid chromatography and selective microbiological assays. The two regimens q8h and q12h lead to the same disposition profile after single and repeated administration. Single-dose data confirmed the high plasma clearances of Q and D (about 0.90 l/h/kg) obtained previously. Unchanged drugs were the main components in plasma, with each of the three metabolites representing about 20% (in terms of the AUC ratio) of the parent drugs. Comparable steady-state concentrations were reached from day 2 of both regimens. A similar moderate increase in Cmax and AUC (about 20%) of parent drugs was observed between the first and last day of treatment. This phenomenon, which was also observed for the metabolites, was not expected considering the short terminal disposition half-lives of the parent drugs and trough plasma concentrations of all components mostly below the limits of quantitation at steady state, whatever the dosing regimen. The clearances of parent drugs at steady state were about 20% lower as compared with that observed following the first drug administration (statistically significant difference). No trend suggesting a treatment effect on any laboratory parameter, vital signs, or electrocardiographic parameters was identified. However, 80% of subjects reported venous adverse events probably related to treatment.

Quinupristin/dalfopristin: a therapeutic review.

BACKGROUND: The proliferation of multidrug-resistant gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium (VREF), has created a pressing need for effective alternative antibiotics. Quinupristin/dalfopristin is a new combination streptogramin product with a selective spectrum of antibacterial activity, mainly against gram-positive aerobic bacteria. It has been assessed primarily in emergency-use protocols, in hospitalized patients with skin and skin-structure infections, and in patients with VREF bacteremia. OBJECTIVES: The objectives of this review were to summarize important results of in vitro microbiologic studies; to provide information on relevant pharmacokinetic parameters, drug interactions, and Y-site compatibility; and to assess efficacy and safety data from clinical studies of quinupristin/dalfopristin. METHODS: Articles included in this review were identified by a MEDLINE search of the literature published between 1966 and September 2000 using the terms Synercid, quinupristin, and dalfopristin. Additional articles were retrieved from the reference lists of articles identified in the MEDLINE search. RESULTS: In vitro analysis of the spectrum of activity of quinupristin/dalfopristin has confirmed its relatively selective coverage of gram-positive aerobic bacteria. Both quinupristin and dalfopristin undergo hepatic metabolism and are extensively excreted in the feces. Combination quinupristin/dalfopristin inhibits the cytochrome P450 3A4 pathway, and caution is warranted with concomitant use of other medications eliminated via this pathway. In trials in patients with VREF infections, treatment success with quinupristin/dalfopristin varied depending on the site of infection, ranging from 51.9% in bacteremia of unknown origin to 88.9% in urinary tract infections. The results of comparative clinical trials suggest that quinupristin/dalfopristin has similar efficacy to that of commonly used antibiotics, including cefazolin, oxacillin, and vancomycin, in patients with skin and skin-structure infections or nosocomial pneumonia. The most frequently reported adverse effects with administration of quinupristin/dalfopristin were infusion-site inflammation, pain, and edema; other infusion-site reactions; and thrombophlebitis. Arthralgia, myalgia, nausea, diarrhea, vomiting, and rash occurred in 2.5% to 4.6% of patients and were the most frequently reported systemic adverse events. CONCLUSIONS: Outcomes data from clinical trials indicate that quinupristin/dalfopristin has the potential to play an important role in the treatment of bacteremia, complicated skin and skin-structure infections, and nosocomial pneumonia caused by VREF. Issues of bacterial resistance to quinupristin/dalfopristin and other appropriate uses of this combination agent remain to be elucidated.

Hyperbilirubinemia during quinupristin-dalfopristin therapy in liver transplant recipients: correlation with available liver biopsy results.

STUDY OBJECTIVE: To review the liver histopathology in transplant recipients who developed hyperbilirubinemia during therapy with quinupristin-dalfopristin, a new streptogramin antibiotic, and to ascertain whether objective histologic evidence of adverse drug effect could be correlated to serum bilirubin levels. DESIGN: Retrospective analysis. SETTING: University of Pittsburgh Medical Center. PATIENTS: From a database of 34 liver recipients who received quinupristin-dalfopristin for vancomycin-resistant Enterococcus faecium infection who were prospectively enrolled in a multicenter, open-label, emergency-use protocol, the data for a subset of 25 patients who underwent one or more liver biopsies during therapy were reviewed for this study. INTERVENTIONS: Quinupristin-dalfopristin was administered intravenously at 7.5 mg/kg every 8 hours. Available serum bilirubin levels from before, during, and 1 week after therapy were tabulated. Liver biopsy results obtained within 1 week before and during therapy were retrospectively reviewed. Histopathologic results were characterized and correlated to bilirubin level. MEASUREMENTS AND MAIN RESULTS: Cholestatic changes were already present in 15 of 17 patients who underwent biopsy before therapy. During therapy, the most common findings from 40 biopsies (25 patients) were cholestasis (33 biopsies), acute rejection (10), and periportal inflammation (8). There was no evidence of drug-specific histopathologic injury. CONCLUSION: Hyperbilirubinemia in these patients was likely multifactorial and most frequently due to sepsis and prior graft injury.

Risk factors for arthralgias or myalgias associated with quinupristin-dalfopristin therapy.

STUDY OBJECTIVE: To evaluate risk factors for the development of arthralgias or myalgias associated with quinupristin-dalfopristin. DESIGN: Retrospective chart review and case-control analysis. SETTING: An 850-bed tertiary care medical center. PATIENTS: All adult and pediatric patients who had received quinupristin-dalfopristin through either a compassionate-use protocol (February 1996-October 1999) or in the year after quinupristin-dalfopristin was added to the hospital formulary (November 1999-October 2000) were included in this study. Case patients were those who developed arthralgias or myalgias while receiving quinupristin-dalfopristin therapy; control patients were those who received quinupristin-dalfopristin but did not develop arthralgias or myalgias. INTERVENTION: Medical records, pharmacy dispensing information, and microbiology data were reviewed by a physician and a pharmacist, both of whom specialized in infectious diseases. Presence or absence of arthralgias or myalgias was the primary outcome assessed. MEASUREMENTS AND MAIN RESULTS: Quinupristin-dalfopristin was administered to 68 patients during the period defined by the study. Arthralgias and myalgias could not be assessed in 18 of the 68 patients because they were sedated and paralyzed, or they were young children who could not communicate the presence of pain. Univariate analysis demonstrated that significant risk factors for arthralgias or myalgias associated with quinupristin-dalfopristin were female sex, chronic liver disease, receipt of liver transplant, elevated bilirubin level at baseline, major surgery, and receipt of either mycophenolate or cyclosporine. Multivariate analysis demonstrated a strong association with chronic liver disease, receipt of liver transplant, elevated bilirubin level at baseline, and receipt of either cyclosporine or mycophenolate. Of 50 evaluable patients receiving quinupristin-dalfopristin, 25 had pain that may have been associated with this antimicrobial agent. CONCLUSION: The mechanism for development of arthralgias or myalgias associated with quinupristin-dalfopristin remains unknown, but these adverse events are more likely to occur in patients with chronic liver disease and those who have received a liver transplant or are receiving cyclosporine or mycophenolate.

Quinupristin-dalfopristin: an overview.

Synercid (RP 59500), the first injectable streptogramin antibiotic, is composed of two semisynthetic pristinamycin derivatives, quinupristin and dalfopristin. Individually, each component has bacteriostatic activity against staphylococci and streptococci, but together, the agents exhibit synergy, leading to bactericidal activity. The combination drug, however, is bacteriostatic against Enterococcus faecium and has poor activity against Enterococcus faecalis. Despite a short half-life, an extended postantibiotic effect allows the agent to be dosed every 8-12 hours. Both drugs are largely hepatically metabolized and excreted in bile. Although not metabolized by cytochrome P450 3A4, quinupristin-dalfopristin can inhibit agents that are metabolized through this pathway. Dosage adjustments may be necessary in patients with hepatic dysfunction. Alterations in renal function have minimal effects on the agent's pharmacokinetics. Adverse events include arthralgia, myalgias, and infusion-related pain. Based on available data, quinupristin-dalfopristin appears to have a role in treating severely ill patients with infections due to multiresistant gram-positive pathogens.

Quinupristin-dalfopristin (RP 59500): an injectable streptogramin combination.

The pharmacology, pharmacokinetics, activity, and potential clinical role of quinupristin-dalfopristin (RP 59500) are described. Quinupristin-dalfopristin is the first injectable formulation of the streptogramin antibiotics. Streptogramin drug products are each composed of two chemically distinct compounds, which when administered together act synergistically by inhibiting bacterial protein synthesis. Quinupristin-dalfopristin has shown activity in vitro against many strains of streptococci and staphylococci, including methicillin- and erythromycin-resistant strains of staphylococci. The combination is more active against Enterococcus faecium than Enterococcus faecalis. It has also shown activity in vitro against certain gram-negative organisms and anaerobes. The mean maximum blood concentration at the end of a one-hour infusion ranged from 0.95 mg/L for a 1.4-mg/kg dose to 24.2 mg/L for a 29.4-mg/kg dose; there was a linear correlation between dose and mean area under the concentration-time curve. Mean half-life ranged from 1.27 to 1.53 hours. The drug is under investigation in the United States in Phase III trials. Of 60 evaluable patients with documented bacteremia involving E. faecium resistant to vancomycin, 40 (67%) had a favorable clinical response. Of 11 patients with bacteremia caused by methicillin-resistant Staphylococcus aureus, 78% had a favorable response. The efficacy of quinupristin-dalfopristin in treating resistant infections has also been suggested by smaller studies and case reports. The drug may be useful in the prophylaxis of endocarditis. Adverse reactions are generally mild and transient. Quinupristin-dalfopristin may be useful in treating serious gram-positive infections, but more clinical study is needed.

Linezolid and quinupristin/dalfopristin: novel antibiotics for gram-positive infections of the skin.

With the continuing development of clinical drug resistance among bacteria, the need for new, effective agents to treat multi-drug-resistant Gram-positive infections remains important. With treatment options limited, it has become critical to identify antibiotics with novel mechanisms of activity. Several new drugs have emerged as possible therapeutic alternatives. This review focuses on agents newly introduced and FDA-approved for the treatment of skin and skin structure infections: linezolid and quinupristin/dalfopristin.

Two new treatment options for infections due to drug-resistant gram-positive cocci.

Gram-positive cocci, including enterococci and Staphylococcus aureus, have become the leading cause of hospital-acquired infections, and their resistance to antibiotics is increasing. Two important new drugs-quinupristin/dalfopristin (Synercid) and linezolid (Zyvox)-were designed specifically to treat infections due to drug-resistant gram-positive cocci. But their use must be tempered by their cost, toxicity, and concerns about further development of resistant strains.

[Epidemiological context: microbiological value of Synercid]. / Contexte épidémiologique: intérêt microbiologique de Synercid.

MECHANISM OF ACTION: Synercid', an antibiotic designed around the concept of molecular synergism, is composed of 70% dafopristin or spectrogramin A and 30% quinupristin or spectrogramin B. First, dafopristin binds to the ribosomal 50S unit changing the conformation of the ribosome. This increases the affinity of quinupristin that in turn binds to the bacterial ribosome. This double binding interrupts protein synthesis and blocks bacterial growth. ACTIVITY: In vitro, Synercid is particularly active against Gram positive cocci, irrespective of the strain's resistance phenotype. It is notably active against meti-sensitive and meti-resistant S. aureus, S. pneumoniae, S. pyogenes and Enterococcus faecium. MECHANISMS OF RESISTANCE TO MACROLIDES/LINCOSAMIDES/STREPTOGRAMINS: The most frequently encountered mechanism is a modification of the ribosomal target. Two other mechanisms can also be operating: enzyme inactivation or efflux phenomenon. Another mechanism of resistance, LSA phenotype, remains poorly understood. Only a very small proportion of the patients are concerned by resistance (9 patients in a study enrolling 880 patients).

[Experimental models: interactions Synercid and beta-lactam antibiotics]. / Apport des modèles expérimentaux: associations Synercid et beta-lactamines.

UNLABELLED: SYNERCID ALONE IN A RAT MODEL OF EXPERIMENTAL ENDOCARDITIS: Trials conducted using 2 injections daily showed that animals infected with meti-R resistant Staphylococcus aureus strains sensitive to erythromycin were cured in 3 days. The same is not true for infections caused by C-MLSB-R staphylococci. The daily dose cannot be increased due to the venous toxicity of Synercid, leading to the idea of testing Synercid in combination with other antibiotics. IN VITRO STUDIES: Several antibiotics have been tested in combination with Synercid. Several beta-lactams have been shown to exhibit an additive or synergetic effect on a collection of meti-R and meti-S S. aureus strains. IN VIVO STUDIES: In animals infected with C-MLSB-R meti-R S. aureus, the combination Synercid + cefepime increases the activity of cefipime and prevents selection of beta-lactam highly resistant strains. The results obtained with the Synercid + cefpirome combination are even more eloquent. Finally, Synercid, alone or in combination with these 2 cephalosporins, does not select resistant strains.

[Experimental models: interaction of Synercid with other anti-Gram positive agents]. / Apports des modèles expérimentaux: associations Synercid et autres agents anti-Gram positif.

EXPERIMENTAL DATA: In case of resistance to quinupristin, the bacteriostatic synergism is preserved but the in vivo bactericidal effect of Synercid declines. On the other hand, no selection of resistant mutants has been observed. In case of isolated resistance to dafopristin, there is no reduction in the bactericidal effect of Synercid; there is however a possible risk of selecting resistant mutants. To become resistant to Synercid, S. aureus strains have to become resistant to both quinupristin and dafopristin, a highly unlikely situation. POTENTIAL COMBINATIONS: Among the combinations of Synercid with other antibiotics, the combination with vancomycin would have particular interest for clinical applications, increasing bactericidal activity. This would be the case for severe S. aureus infections with a large inoculum and even more so for meti-R resistant strains with a C-MLSB phenotype. Combination with rifampicin would be another possibility, but only for strains not resistant to quinupristin.