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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 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.

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.

Recent qualitative analyses warn of potential future human health risks from emergence of antibiotic resistance in food-borne pathogens due to the use of similar antimicrobial drugs in both food animals and human medicine. While historical data suggest that human health risks from some animal antimicrobials, such as virginiamycin (VM), have remained low (McDonald et al., 2001), there is a widespread concern that "resistance epidemics" or endemics could arise in the future. How reassuring is the past about the future? This article applies quantitative risk assessment methods to help find out, using human health risks from VM and the nearly identical human antimicrobial quinupristin-dalfopristin (QD) as a case study. A dynamic simulation model is used to predict the risks of emerging resistance to human antimicrobials in human populations from given input assumptions. Bayesian Monte Carlo uncertainty analysis allows past data to constrain and inform selection of input parameter values, and thus to predict the possible future resistance patterns that are consistent with historical data. The results show that health risks from VM use in food animals are highly sensitive to the human prescription rate of QD. For realistic prescription rates, quantitative risks are less than 1 x 10(-6) even for members of the most-threatened (ICU patient) population, while societal risks are <1 excess statistical death per year for the whole U.S. population. Such quantitative estimates complement more qualitative assessments that discuss the possibility of future "resistance epidemics" (or endemics) without quantifying their probabilities.

Objectives: To determine whether myalgias/arthralgias occurring in cancer patients who receive quinupristin/dalfopristin are associated with biliary tract dysfunction., Methods: We studied 56 patients with vancomycin-resistant enterococcal infections who were treated with quinupristin/dalfopristin 7.5 mg/kg every 8 h for a mean duration of 12 days (range 2-52 days). Liver function tests, including a test for alkaline phosphatase, were performed before, during and after the end of therapy. All patients were followed for 1 month after completion of therapy., Results: Thirty-eight (68%) of the 56 patients responded. Myalgias/arthralgias were the leading adverse events occurring in 20 (36%) of the patients. Patients with myalgias/arthralgias had significantly higher levels of alkaline phosphatase (mean 318.7 IU/L) during the mid-term therapy cycle compared with patients without any joint or muscular pain (mean 216.3 IU/L, P = 0.05). In addition, 3/18 (16.6%) patients with myalgias/arthralgias had more than five-fold the normal levels of alkaline phosphatase, which did not occur in any of the other patients who did not develop myalgias/arthralgias (P = 0.04). All myalgias/arthralgias resolved after the discontinuation of quinupristin/dalfopristin. By univariate analysis, other factors associated with myalgias/arthralgias were relapse of haematological malignancy (P = 0.01), receiving tacrolimus within 1 month prior to treatment (P = 0.04) and receiving methotrexate during antimicrobial therapy (P = 0.05)., Conclusions: Myalgias/arthralgias occur frequently in cancer patients receiving quinupristin/dalfopristin and may be associated with biliary tract dysfunction, as measured by alkaline phosphatase or other factors that could lead to intra-hepatic cholestasis, such as relapse of haematological malignancy or treatment with tacrolimus or methotrexate.

Objectives: Quinupristin-dalfopristin and linezolid have been shown to be efficacious in the treatment of vancomycin-resistant Enterococcus faecium (VREF) infections. However, the two antibiotics have not been compared in terms of safety and efficacy in a prospective randomized study. The objective of this study was to compare the safety and efficacy of the two drugs in the treatment of VREF infections in cancer patients., Patients and Methods: Forty cancer patients with VREF infection were randomized to receive linezolid 600 mg every 12 h or quinupristin-dalfopristin 7.5 mg/kg every 8 h. All patients were followed up for 30 days after discontinuation of study drugs., Results: Linezolid and quinupristin-dalfopristin had comparable clinical responses (58% and 43%, respectively, P = 0.6). Myalgias and/or arthralgias occurred at a frequency of 33% in patients who received quinupristin-dalfopristin, but were not observed in the linezolid group (P = 0.03). In contrast, drug-related thrombocytopenia occurred in 11% of patients who received linezolid, but was not observed in the quinupristin-dalfopristin group (P = 0.2)., Conclusion: In cancer patients, quinupristin-dalfopristin treatment is associated with a relatively high frequency of myalgias/arthralgias; however, profound thrombocytopenia might limit the choice of linezolid in a subpopulation of cancer patients.

The streptogramin antimicrobial combination Quinupristin-Dalfopristin (QD) has been used in the United States since late 1999 to treat patients with vancomycin-resistant Enterococcus faecium (VREF) infections. Another streptogramin, virginiamycin (VM), is used as a growth promoter and therapeutic agent in farm animals in the United States and other countries. Many chickens test positive for QD-resistant E. faecium, raising concern that VM use in chickens might compromise QD effectiveness against VREF infections by promoting development of QD-resistant strains that can be transferred to human patients. Despite the potential importance of this threat to human health, quantifying the risk via traditional farm-to-fork modeling has proved extremely difficult. Enough key data (mainly on microbial loads at each stage) are lacking so that such modeling amounts to little more than choosing a set of assumptions to determine the answer. Yet, regulators cannot keep waiting for more data. Patients prescribed QD are typically severely ill, immunocompromised people for whom other treatment options have not readily been available. Thus, there is a pressing need for sound risk assessment methods to inform risk management decisions for VM/QD using currently available data. This article takes a new approach to the QD-VM risk modeling challenge. Recognizing that the usual farm-to-fork ("forward chaining") approach commonly used in antimicrobial risk assessment for food animals is unlikely to produce reliable results soon enough to be useful, we instead draw on ideas from traditional fault tree analysis ("backward chaining") to reverse the farm-to-fork process and start with readily available human data on VREF case loads and QD resistance rates. Combining these data with recent genogroup frequency data for humans, chickens, and other sources (Willems et al., 2000, 2001) allows us to quantify potential human health risks from VM in chickens in both the United States and Australia, two countries where regulatory action for VM is being considered. We present a risk simulation model, thoroughly grounded in data, that incorporates recent nosocomial transmission and genetic typing data. The model is used to estimate human QD treatment failures over the next five years with and without continued VM use in chickens. The quantitative estimates and probability distributions were implemented in a Monte Carlo simulation model for a five-year horizon beginning in the first quarter of 2002. In Australia, a Q1-2002 ban of virginiamycin would likely reduce average attributable treatment failures by 0.35 x 10(-3) cases, expected mortalities by 5.8 x 10(-5) deaths, and life years lost by 1.3 x 10(-3) for the entire population over five years. In the United States, where the number of cases of VRE is much higher, a 1Q-2002 ban on VM is predicted to reduce average attributable treatment failures by 1.8 cases in the entire population over five years; expected mortalities by 0.29 cases; and life years lost by 6.3 over a five-year period. The model shows that the theoretical statistical human health benefits of a VM ban range from zero to less than one statistical life saved in both Australia and the United States over the next five years and are rapidly decreasing. Sensitivity analyses indicate that this conclusion is robust to key data gaps and uncertainties, e.g., about the extent of resistance transfer from chickens to people.

The present study was made to determine the value of drug skin tests in patients with cutaneous adverse drug reactions (CADRs) due to a synergistin (pristinamycin) and to determine the frequency of cross-reactions between synergistins. 29 patients were referred during the onset of the CADR due to pristinamycin: 18 with maculopapular rash, 9 erythrodermas, 1 angioedema and 1 Stevens-Johnson syndrome. They all had patch tests with pristinamycin and, in most cases, with other synergistins [virginiamycin and dalfopristin-quinupristin (DQ)], prick tests (10 cases) and intradermal tests (IDT) (5 cases). Skin tests with synergistins were positive in 27 cases, patch tests with pristinamycin in 20/29 cases (69%), prick tests with pristinamycin in 3/9 cases on immediate (1 case) or on delayed (2 cases) readings, and IDT with DQ in 4/5 cases. Cross-reactions between synergistins occurred in 9/22 with virginiamycin and in 7/8 cases with DQ. Skin tests with synergistins are useful in investigating CADR due to pristinamycin. Synergistins are composed of 2 chains (1 depsipeptide and 1 macrocyclic lactone) with many structural analogies between all synergistins. According to the chemical structures and our results, it seems advisable to avoid all synergistins in patients with CADR due to pristinamycin.

The present study investigates, at farm level, the effect of the time-span between sampling and the last time a particular antimicrobial growth promoter (AGP) was included in the feed on the probability of selecting an AGP-resistant Enterococcus faecium isolate from a broiler flock. The probability that a randomly selected E. faecium isolate was resistant to avilamycin, erythromycin or virginiamycin was 0.91, 0.92 and 0.84, respectively if the isolate originated from a broiler flock fed either avilamycin- or virginiamycin-supplemented feed. As the time-span between sampling and the last AGP consumption increased, the probability of isolating an E. faecium isolate resistant to a particular AGP decreased (probability <0.2 within 3-5 years after last exposure to AGPs). The decrease in probability over time showed little farm-to-farm variation. The number of times a particular AGP was given to previous flocks reared in the same house had no effect on the probability of isolating a resistant isolate.

Quinupristin/Dalfopristin is a new combination of streptogramin antibiotics designed specifically to treat clinically significant infections due to Vancomycin-resistant Enterococcus Faecium. Sweet's syndrome is characterized by painful skin plaques, which is associated with dermal neutrophilic infiltration, fever and peripheral blood leukocytosis. Drug-induced Sweet's syndrome has a temporal relationship between drug ingestion, clinical presentation and the temporally-related resolution of lesions following drug withdrawal or on treatment with systemic corticosteroids. A 63-year-old woman received Quinupristin/Dalfopristin for acute pyelonephritis developed fever, arthralgia, vomiting, and painful erythematous skin plaques. A skin biopsy showed neutrophilic dermatosis, and there was rapid resolution of the symptoms and cutaneous lesions after discontinuation of Quinupristin/Dalfopristin, consistent with drug-induced Sweet's syndrome. To date, there has been no reported case of Sweet's syndrome associated with the use of Quinupristin/Dalfopristin.

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.

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.

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.

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.

Synercid (quinupristin/dalfopristin), the first semi-synthetic injectable streptogramin, is a promising alternative to glycopeptides against many Gram-positive multiresistant bacteria. Vancomycin is still considered an effective agent for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections but therapeutic failures with glycopeptides have been observed, even for the treatment of infections caused by S. aureus strains sensitive to vancomycin. Synercid, in combination with a glycopeptide, may address this problem without causing significant side effects due to the different toxicity patterns of the 2 antimicrobials. This study reports our experience with the combination of Synercid and vancomycin in 5 patients with severe infection caused by MRSA or methicillin-resistant coagulase-negative Staphylococcus.

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.

Between February 1994 and November 1998, 56 oncology patients infected with vancomycin-resistant enterococci (VRE) were treated with quinopristin-dalfopristin (Q-D) plus minocycline (MIN). Infections included bacteremia, urinary tract infection, pneumonia, and wound infection. The response rate was 68%, and the most frequent adverse event was arthralgia or myalgia (36%). Q-D-MIN is effective for VRE infection in cancer patients but is associated with a substantial frequency of arthralgia or myalgia.

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.

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 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.

NOSOCOMIAL PNEUMONIA DUE TO GRAM-POSITIVE COCCI: In a randomized multicentric trial comparing Synercid with vancomycin, the cure rate (56.3% vs 58.3%) were equivalent in the 2 treatment arms. Treatment failures were also similar: 44% vs 42%. Mortality (25% vs 22%) was likewise comparable, as was tolerance. SKIN AND SOFT TISSUE INFECTIONS: For erysipela, infections requiring surgical dissection, post-trauma infections, postoperative wound infections, or diabetes-related infections, the rate of success obtained in 2 open randomized comparative multicentric trials was equivalent in the 2 treatment arms: 68.2% for Syncercid, 70.7% for the compared treatments. EMERGENCY PRESCRIPTION: For E. faecium, the success rate was 74% based on clinical assessment and 70.5% based on bacteriological assessment. For meti-S S. aureus infections, the clinical success rate was 74% for all patients and 80% for bacteriologically evaluable patients; the bacteriological success rate was 74% and 71% respectively. In case of infection due to C-MLSB meti-R S. aureus, the percentage of clinical success was 89% for bacteriologically evaluable patients.

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.

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.

This study evaluated the frequency of and potential risk factors for arthralgias and/or myalgias associated with quinupristin-dalfopristin administration. Of 32 patients who received quinupristin-dalfopristin treatment, at least 15 (47%) developed arthralgias and/or myalgias. Clinicians should be aware of these adverse events associated with quinupristin-dalfopristin, which may occur more frequently than has been previously reported.

We describe our experience of quinupristin/dalfopristin for glycopeptide-resistant Enterococcus faecium (GREF) infections in 19 paediatric liver transplant recipients. The median patient age was 2 years and all were receiving immunosuppressive regimens. Quinupristin/dalfopristin was well tolerated and complete resolution of infection was seen in 74% of patients. Side-effects included reversible elevation of serum alkaline phosphatase, skin rash, itching, diarrhoea and vomiting, but therapy was not withdrawn from any patient. Quinupristin/dalfopristin appears safe and efficacious in critically ill immunocompromised children with renal or hepatic impairment.

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.

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.

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].

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.

Nosocomial pneumonia is a frequent complication in hospitalized patients. Gram-positive pathogens, particularly Staphylococcus aureus, are responsible for the increasing frequency of nosocomial pneumonia. To evaluate the efficacy and safety of intravenous quinupristin/dalfopristin (Synercid) in the treatment of nosocomial pneumonia caused by gram-positive pathogens we conducted a prospective, randomized, open-label, international, multicenter, comparative clinical trial. Two hundred ninety-eight patients with nosocomial pneumonia were enrolled in 74 active centers in five countries: a subgroup of 171 (87 quinupristin/dalfopristin-treated and 84 vancomycin-treated patients) were evaluable for the major efficacy end points. One hundred fifty received 7.5 mg/kg of quinupristin/dalfopristin every 8 h; 148 patients received 1 g of vancomycin every 12 h. Aztreonam at a dose of 2 g every 8 h could be administered in both groups for coverage of gram-negative organisms, and tobramycin was added for coverage against Pseudomonas aeruginosa. The primary efficacy end point was the clinical response between the seventh and the thirteenth day after the end of treatment in clinically evaluable patients with documented causative pathogen(s) at baseline (bacteriologically evaluable population). Therapy was clinically successful (cure or improvement) in 49 (56.3%) of patients receiving quinupristin/dalfopristin and 49 (58.3%) patients receiving vancomycin (difference, -2.0% [95% CI, -16.8% to 12.8%]) in the bacteriologically evaluable population. Equivalent clinical success rates were also observed in the all-treated population (n = 298), and in the bacteriologically evaluable patients intubated in baseline (39/72 [54%] compared with 36/67 [54%]). The by-pathogen bacteriologic response was similar in both treatment groups, with equivalent clinical success rates for Streptococcus pneumoniae, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus. Adverse events (venous and nonvenous) were equally distributed between groups; 15.3% of quinupristin/dalfopristin patients and 9.5% of vancomycin patients discontinued therapy because of an adverse clinical event. In this study quinupristin/dalfopristin was shown to be equivalent to vancomycin in the treatment of nosocomial pneumonia caused by gram-positive pathogens. Quinupristin/dalfopristin merits further evaluation for the treatment of nosocomial pneumonia caused by methicillin-resistant S. aureus.

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.

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.

The safety and tolerability of quinupristin/dalfopristin were assessed in both comparative and non-comparative trials (2298 quinupristin/dalfopristin-treated patients). In comparative clinical trials, the most frequent systemic adverse events related to quinupristin/dalfopristin were nausea (4.6%), diarrhoea (2.7%), vomiting (2.7%) and skin rash (2.5%). The comparator group showed similar rates, except that nausea was significantly more common (7.2%; P = 0.01). In non-comparative trials, arthralgia and myalgia were reported most frequently but were reversible upon treatment discontinuation. The renal, inner ear, cardiovascular and central nervous systems were not implicated as significant target organs for toxicity. The most frequent local adverse events related to infusion of quinupristin/dalfopristin were inflammation, pain, oedema, infusion site reaction and thrombophlebitis. Results of laboratory tests while on therapy were comparable for quinupristin/dalfopristin and comparator groups, except that increases in conjugated bilirubin of >5 x the upper limit of normal were reported in 5.5% of quinupristin/dalfopristin recipients; increases in total bilirubin of >5 x the upper limit of normal occurred in 1.5%. Comparator recipients more frequently had increases in alanine aminotransferase and alkaline phosphatase. Quinupristin/dalfopristin inhibits the cytochrome P450 3A4-mediated metabolism of drugs including midazolam, nifedipine, terfenadine and cyclosporin. Therefore, plasma drug monitoring and/or dosage reduction of these agents is prudent. Concomitant administration of drugs that can prolong the electrocardiographic QTc interval should be avoided. Quinupristin/dalfopristin is visually and chemically compatible with commonly used drugs of various classes, but it is not compatible with sodium chloride solution and certain other drugs, including some antimicrobials. Therefore, when prescribing quinupristin/dalfopristin, clinicians should be aware of the potential for peripheral venous intolerance, arthralgias and myalgias, increases in conjugated bilirubin, interactions with drugs metabolized by the cytochrome P450 3A4 isoenzyme and certain physico-chemical incompatibilities. However, multiple studies have shown that the safety and tolerability of quinupristin/dalfopristin are generally favourable, and that it provides clear benefits to ill patients with severe gram-positive infections.

Quinupristin-dalfopristin may be useful for treatment of organisms causing peritoneal dialysis-related peritonitis, including methicillin-resistant coagulase-negative staphylococci, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant enterococci. The pharmacokinetic profiles of single intravenous doses of this combination streptogramin antibiotic of 7.5 mg/kg of body weight were characterized for eight noninfected patients receiving continuous ambulatory peritoneal dialysis. Comparison was made to pharmacokinetic profiles determined for eight healthy volunteers matched by age, sex, and race. Drug was measured in dialysate up to 6 h following the dose. Plasma and dialysate were assayed for parent compounds and metabolites. Mean pharmacokinetic parameters were compared between groups. No statistically significant differences were observed between groups for maximal concentrations in plasma, times to maximal concentration, areas under the curve, distribution volumes, rates of total body clearance, or half-lives in plasma for quinupristin and dalfopristin. No statistically significant differences were observed in maximal concentrations in plasma, times to maximal concentration, areas under the curve, or half-lives for cysteine, the glutathione conjugates of quinupristin, or the pristinamycin IIA metabolite of dalfopristin. The measurements in dialysate of the parent and most metabolites were below the expected MICs. Dialysis clearance was insignificant. Quinupristin-dalfopristin was well tolerated in both groups, causing only mild adverse events that resolved prior to discharge from the study. The disposition of quinupristin, dalfopristin, or their primary metabolites following a single dose was unaltered in patients receiving peritoneal dialysis. Intravenous dosing of this antibiotic combination is unlikely to be adequate for the treatment of peritonitis associated with peritoneal dialysis.

Objective: To describe a case of a drug interaction between cyclosporine and quinupristin/dalfopristin (QND)., Case Summary: A patient who had undergone a kidney transplant and was receiving chronic cyclosporine therapy was treated with the investigational streptogramin antibiotic QND. Baseline trough cyclosporine concentrations ranged from 80 to 105 ng/ml. Two and 3 days after initiation of QND therapy, trough cyclosporine concentrations increased to 261 and 291 ng/mL, respectively. Following discontinuation of QND, the cyclosporine blood concentration decreased and the dosage was subsequently increased to the previous regimen., Discussion: A patient's cyclosporine blood concentration tripled 3 days after initiating therapy with QND. A one-third reduction in the cyclosporine dosage was required. QND was the most likely cause for the change in cyclosporine blood concentrations, probably due to inhibition of cyclosporine metabolism. This represents the first published case of an interaction between cyclosporine and QND., Conclusions: Frequent monitoring of cyclosporine concentrations with attention to the need for dosage modification is recommended when initiating or discontinuing QND therapy.