virginiamycin and Gram-Positive-Bacterial-Infections

Streptogramins (pristinamycin and quinupristin-dalfopristin) can be interesting options for the treatment of infections due to Gram-positive cocci, especially multidrug-resistant isolates.. This review provides an updated overview of structural and activity characteristics, mechanisms of action and resistance, pharmacokinetic/pharmacodynamic, and clinical use of streptogramins.. The streptogramin antibiotics act by inhibition of the bacterial protein synthesis. They are composed of two chemically distinct compounds, namely type A and type B streptogramins, which exert a rapid bactericidal activity against a wide range of Gram-positive bacteria (including methicillin-resistant staphylococci and vancomycin-resistant enterococci). Several mechanisms of resistance have been identified in staphylococci and enterococci but the prevalence of streptogramin resistance among clinical isolates remains very low. Even if only a few randomized clinical trials have been conducted, the efficacy of pristinamycin has been largely demonstrated with an extensive use for 50 years in France and some African countries. Despite its effectiveness in the treatment of severe Gram-positive bacterial infections demonstrated in several studies and the low rate of reported resistance, the clinical use of quinupristin-dalfopristin has remained limited, mainly due to its poor tolerance. Altogether, streptogramins (especially pristinamycin) can be considered as potential alternatives for the treatment of Gram-positive infections.

Topics: Animals; Anti-Bacterial Agents; Drug Resistance, Bacterial; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Pristinamycin; Randomized Controlled Trials as Topic; Streptogramins; Virginiamycin

Enterococcus species are the second most common cause of nosocomial infections in the United States and are particularly concerning in critically ill patients with preexisting comorbid conditions. Rising resistance to antimicrobials that were historically used as front-line agents for treatment of enterococcal infections, such as ampicillin, vancomycin, and aminoglycosides, further complicates the treatment of these infections. Of particular concern are Enterococcus faecium strains that are associated with the highest rate of vancomycin resistance. The introduction of antimicrobial agents with specific activity against vancomycin-resistant Enterococcus (VRE) faecium including daptomycin, linezolid, quinupristin-dalfopristin, and tigecycline did not completely resolve this clinical dilemma. In this review, the mechanisms of action and resistance to currently available anti-VRE antimicrobial agents including newer agents such as oritavancin and dalbavancin will be presented. In addition, novel combination therapies including β-lactams and fosfomycin, and the promising results from in vitro, animal studies, and clinical experience in the treatment of VRE faecium will be discussed.

Topics: Animals; Anti-Bacterial Agents; Cross Infection; Drug Therapy, Combination; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Teicoplanin; Vancomycin; Vancomycin Resistance; Virginiamycin

To review the literature on the pharmacotherapy of bloodstream infections (BSI) caused by vancomycin-resistant enterococci (VRE).. A MEDLINE literature search was performed for the period 1946 to May 2014 using the search terms Enterococcus, enterococci, vancomycin-resistant, VRE, bacteremia, and bloodstream infection. References were also identified from selected review articles.. English-language case series, cohort studies, and meta-analyses assessing the options in the pharmacotherapy of VRE BSIs in adult patients were evaluated.. Studies were identified that utilized linezolid, quinupristin/dalfopristin (Q/D), and daptomycin. In all, 8 comparative retrospective cohort studies, 2 meta-analyses of daptomycin and linezolid, and 3 retrospective comparisons of linezolid and Q/D were included for review. Mortality associated with VRE BSIs was high across studies, and the ability to determine differences in outcomes between agents was confounded by the complex nature of the patients included. Two meta-analyses comparing daptomycin with linezolid for VRE BSIs found modest advantages for linezolid, but these conclusions may be hampered by heterogeneity within the included studies.. VRE BSIs remain a difficult-to-treat clinical situation. Differences in toxicity between the agents used to treat it are clear, but therapeutic differences are more difficult to discern. Meta-analyses suggest that a moderate advantage for linezolid over daptomycin may exist, but problems with the nature of studies that they included make definitive conclusions difficult.

Topics: Acetamides; Anti-Bacterial Agents; Bacteremia; Daptomycin; Gram-Positive Bacterial Infections; Humans; Linezolid; Oxazolidinones; Vancomycin; Vancomycin-Resistant Enterococci; Virginiamycin

Uncertainties exist regarding the optimal treatment for vancomycin-resistant enterococcal (VRE) bloodstream infections, particularly in settings in which ampicillin cannot be used.. 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.. 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.

Topics: Acetamides; Adolescent; Child; Child, Preschool; Daptomycin; Drug Resistance, Multiple, Bacterial; Enterococcus faecalis; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Linezolid; Oxazolidinones; Risk Factors; Treatment Outcome; Vancomycin; Vancomycin-Resistant Enterococci; Virginiamycin

An overview of the mechanism of action, dosing, clinical indications, and toxicities of the glycopeptide vancomycin is provided. The emerging gram-positive bacterial resistance to antimicrobials and its mechanisms are reviewed. Strategies to control this emergence of resistance are expected to be proposed. Newer antimicrobial agents that have activity against vancomycin-resistant organisms are now available and play a critical role in the treatment of life-threatening infections.

Topics: Aminoglycosides; Anti-Bacterial Agents; Daptomycin; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Peptides, Cyclic; Teicoplanin; Vancomycin; Virginiamycin

Since the 1970s, resistance to antimicrobial agents has become an escalating problem. In the last 25 years, treatment of infections caused by Gram-positive bacteria has been more problematical than ever, with infections being caused by multidrug-resistant organisms, particularly methicillin-resistant staphylococci, penicillin- and erythromycin-resistant pneumococci, and vancomycin-resistant enterococci. There is a continuing effort in the pharmaceutical industry to develop new antimicrobial agents for the treatment of resistant infections. Linezolid, quinupristin-dalfopristin, daptomycin, tigecyline, new glycopeptides and ceftobiprole are the main agents recently introduced or under clinical development. This review summarises their major properties, the results of recent studies with these agents, and future treatment possibilities.

Topics: Acetamides; Anti-Infective Agents; Cephalosporins; Daptomycin; Glycopeptides; Gram-Positive Bacterial Infections; Linezolid; Minocycline; Oxazolidinones; Tigecycline; Virginiamycin

Though the increased resistance to antibiotics observed worldwide is not a major concern in France, treatment of methicillin-resistant S. aureus has important limitations. New antibiotics have recently been marketed or will soon be (quinupristin-dalfopristin, linelozide, tigecyclin, daptomycin, ceftobiprole, dalbavancin). Their role, which has been documented in several forms of acute infections, remains to be established in infective endocarditis. At present, only treatment of methicillin-resistant S. aureus right-sided endocarditis justifies the use of daptomycin, preferably in association with rifampicin, when the use of vancomycin is not possible or contraindicated.

Topics: Acetamides; Anti-Bacterial Agents; Daptomycin; Drug Resistance, Bacterial; Endocarditis; Gram-Positive Bacterial Infections; Humans; Linezolid; Minocycline; Oxazolidinones; Tigecycline; Virginiamycin

Multi-antibiotic resistant Gram-positive cocci represent emerging pathogens especially in the setting of the immunocompromised, hospitalized patients, in particular when surgery, invasive procedures, or prosthetic implants are of concern, patients are admitted in intensive care units, or underlying chronic disorders and immunodeficiency are of concern, and broad-spectrum antibiotics and/or immunosuppressive drugs are widely administered. The spectrum of available antimicrobial compounds for an effective management of these relevant infections is significantly impaired in selection and clinical efficacy by the emerging and spread of methicillin-resistant and more recently glycopeptide-resistant Gram-positive microbial strains linezolid, together with the recently licensed quinupristin-dalfopristin, daptomycin and tigecycline, followed by a number of glycopeptides, fluoroquinolones, and other experimental compounds represent an effective response to these concerns, due to their innovative mechanisms of action, their maintained or enhanced activity against multiresistant pathogens, their effective pharmacokinetic/pharmacodynamic properties, their frequent possibility of synergistic activity with other compounds effective against Gram-positive pathogens, and a diffuse potential for a safe and easy administration, also when compromised patients are of concern. The main problems related to the epidemiological and clinical features of multiresistant Gram-positive infection, the potential clinical indications of all recently available compounds compared with the standard of treatment of resistant Gram-positive infections, and updated data on efficacy and tolerability of linezolid have to be clarified.

Topics: Acetamides; Administration, Oral; Anti-Infective Agents; Daptomycin; Drug Resistance, Multiple, Bacterial; Enterococcus; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Injections, Intravenous; Linezolid; Microbial Sensitivity Tests; Minocycline; Oxazolidinones; Practice Guidelines as Topic; Staphylococcus aureus; Streptococcus pneumoniae; Teicoplanin; Tigecycline; Time Factors; Vancomycin; Virginiamycin

Four newer antibiotics are available to treat gram-positive bacterial infections that are resistant to traditional antibiotics and to vancomycin. They should preferably be used with the help of an infectious-disease consultant: specific therapy should be chosen on the basis of the bacteria involved, the site of infection, whether the patient has kidney or liver disease, other medications the patient is taking, and side effects that develop.

Topics: Acute Disease; Adolescent; Anti-Bacterial Agents; Daptomycin; Drug Resistance, Bacterial; Female; Gram-Positive Bacterial Infections; Humans; Middle Aged; Vancomycin; Virginiamycin

An overview of the mechanism of action, dosing, clinical indications, and toxicities of the glycopeptide vancomycin is provided. Emerging gram-positive bacterial resistance to antimicrobials and its mechanisms are reviewed. Strategies to control emergence of resistance are proposed. Newer antimicrobial agents with activity against vancomycin-resistant organisms are now available and play a critical role in the treatment of life-threatening infections.

Topics: Anti-Bacterial Agents; Daptomycin; Gram-Positive Bacterial Infections; Humans; Vancomycin; Virginiamycin

Quinupristin-dalfopristin and linezolid demonstrate in vitro activity against a wide range of gram-positive bacteria, including many isolates resistant to earlier antimicrobials. Quinupristin-dalfopristin is inactive against Enterococcus faecalis but has been effective for treatment of infections due to vancomycin-resistant Enterococcus faecium associated with bacteremia. In comparative trials, linezolid proved to be equivalent to comparator agents, resulting in its approval for several clinical indications. The almost-complete bioavailability of linezolid permits oral administration. Each agent can cause adverse effects that may limit use in individual patients. Resistance to these drugs has been encountered infrequently among vancomycin-resistant E. faecium. Resistance to quinupristin-dalfopristin is rare among staphylococci in the United States, and resistance to linezolid is very rare. Whether there is any benefit to use of these agents in combination regimens, and whether there are circumstances in which they might be alternatives to cell-wall active antibiotics for treatment of bone or endovascular infections, are questions that deserve further study.

Topics: Acetamides; Animals; Anti-Bacterial Agents; Bacteremia; Drug Therapy, Combination; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Linezolid; Microbial Sensitivity Tests; Oxazolidinones; Vancomycin Resistance; Virginiamycin

Vancomycin-resistant enterococci (VRE) are an important cause of hospital-acquired infections and an emerging infectious disease. VRE infections were resistant to standard antibiotics until quinupristin/dalfopristin (QD), a streptogramin antibiotic, was approved in 1999 for the treatment of vancomycin-resistant Enterococcus faecium infections in people. After that decision, the practice of using virginiamycin in agriculture for animal growth promotion came under intense scrutiny. Virginiamycin, another streptogramin, threatens the efficacy of QD in medicine because streptogramin resistance in enterococci associated with food animals may be transferred to E faecium in hospitalised patients. Policy makers face an unavoidable conundrum when assessing risks for pre-emergent pathogens; good policies that prevent or delay adverse outcomes may leave little evidence that they had an effect. To provide a sound basis for policy, we have reviewed the epidemiology of E faecium and streptogramin resistance and present qualitative results from mathematical models. These models are based on simple assumptions consistent with evidence, and they establish reasonable expectations about the population-genetic and population-dynamic processes underlying the emergence of streptogramin-resistant E faecium (SREF). Using the model, we have identified critical aspects of SREF emergence. We conclude that the emergence of SREF is likely to be the result of an interaction between QD use in medicine and the long-term use of virginiamycin for animal growth promotion. Virginiamycin use has created a credible threat to the efficacy of QD by increasing the mobility and frequency of high-level resistance genes. The potential effects are greatest for intermediate rates of human-to-human transmission (R0 approximately equal 1).

Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Ecosystem; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Risk Assessment; Streptogramins; Virginiamycin

Topics: Acetamides; Anti-Bacterial Agents; Bacterial Proteins; Depression, Chemical; Drug Resistance, Multiple, Bacterial; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Linezolid; Oxazolidinones; Virginiamycin

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.

Topics: Acetamides; Anti-Bacterial Agents; Biological Availability; Drug Therapy, Combination; Gram-Positive Bacterial Infections; Half-Life; Humans; Linezolid; Microbial Sensitivity Tests; Oxazolidinones; Randomized Controlled Trials as Topic; Skin Diseases, Bacterial; Virginiamycin

Gram-positive pathogens, primarily Staphylococcus aureus, coagulase-negative staphylococci, viridans group streptococci, and enterococci, are now the predominant causes of infection in neutropenic haematology/oncology patients, but are often resistant to multiple antibiotics. Glycopeptides have been the only alternative antibiotic treatments for multidrug-resistant Gram-positive infections to date. However, glycopeptides are not always effective or well tolerated, and can produce nephrotoxic or ototoxic effects. Quinupristin/dalfopristin is a recently introduced streptogramin antibiotic that is active in vitro against most of the major Gram-positive pathogens causing infection in neutropenic patients. Recent studies of the in vitro susceptibility of clinical isolates of Gram-positive pathogens to quinupristin/dalfopristin are summarized. Pre-clinical and clinical studies of the efficacy and safety of quinupristin/dalfopristin in the treatment of Gram-positive infections are reviewed. Quinupristin/dalfopristin is active in vitro against the vast majority of recent isolates of relevant Gram-positive pathogens, including methicillin-resistant staphylococci, viridans group streptococci, and vancomycin-resistant Enterococcus faecium, but excluding Enterococcus faecalis. Pre-clinical and clinical data indicate the efficacy of quinupristin/dalfopristin in infections caused by these organisms, including bacteraemia and catheter-related infections. Quinupristin/dalfopristin is not associated with nephrotoxicity or ototoxicity. Quinupristin/dalfopristin is a potential alternative to glycopeptides in haematology or oncology patients with multidrug-resistant Gram-positive infections, especially those who are unresponsive to, or intolerant of, glycopeptides.

Topics: Anti-Bacterial Agents; Cross Infection; Drug Resistance, Bacterial; Drug Therapy, Combination; Female; Follow-Up Studies; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Hematologic Neoplasms; Humans; Male; Microbial Sensitivity Tests; Neutropenia; Randomized Controlled Trials as Topic; Risk Assessment; Sensitivity and Specificity; Treatment Outcome; Virginiamycin

The epidemiology of gram-positive pathogens in the intensive care unit are reviewed, recent trends in antimicrobial resistance among these organisms are discussed, and the significance of these data with respect to treatment are considered.. Results of surveillance studies published in 2001 and 2002 have demonstrated that gram-positive organisms such as Staphylococcus aureus, coagulase-negative staphylococci, and enterococci are among the most common bacteria infecting patients in intensive care units. Furthermore, these organisms are becoming increasingly resistant to available antimicrobial agents, and 2002 has ushered in worrisome developments such as the appearance of vancomycin-resistant S. aureus. Community-acquired methicillin-resistant S. aureus and the rise in incidence of vancomycin-resistant enterococci are other problems of great concern. Novel antibiotics such as quinupristin/dalfopristin and linezolid have activity against these agents, but resistance may develop to these agents as well. Studies have shown that infections caused by antibiotic-resistant organisms may be associated with increased morbidity, mortality, and costs. Exposure to antibiotics is a major risk factor for producing antibiotic resistance in patients, and methods to limit the spread of these organisms include restriction of antibiotic use, infection control, surveillance programs, and isolation procedures.. An awareness of the prevalence and patterns of resistance among gram-positive nosocomial pathogens is vital for the appropriate treatment of hospitalized patients. In addition, efforts must be made to minimize the selection and spread of these organisms.

Topics: Acetamides; Anti-Bacterial Agents; Anti-Infective Agents; Community-Acquired Infections; Drug Resistance, Microbial; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Intensive Care Units; Linezolid; Methicillin Resistance; Oxazolidinones; Staphylococcus aureus; Treatment Outcome; United States; Vancomycin; Virginiamycin

The combination of two injectable streptogramins, quinupristin/dalfopristin, provides a new pharmacological choice proven to be therapeutically efficacious against most Gram-positive, multi-resistant microorganisms. They have been shown to be efficacious above all in critically ill patients hospitalized in intensive care who have unique alterations in homeostasis that makes tissue penetration of various pharmacological antimicrobials difficult. In cases of infection localized in difficult-to-treat sites, the combination with other drugs, such as cefepime, a glycopeptide or linezolid, is able to potentiate the action of the streptogramin with positive results which allow resolution of the illness. In this article, we review data from the literature on the use of quinupristin/dalfopristin in the treatment of Gram-positive, multi-resistant infections in critically ill patients.

Topics: Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Gram-Positive Bacterial Infections; Humans; Intensive Care Units; Streptogramins; Virginiamycin

The new semi-synthetic streptogramin antibiotic combination quinupristin/dalfopristin (Synercid) is a promising alternative for a treatment of infections with multiple resistant gram-positive pathogens, e.g. glycopeptide- and multi-resistant Enterococcus faecium. Streptogramins consist of two unrelated compounds, a streptogramin A and B, which act synergistically when given in combination. Mechanisms conferring resistance against both components are essential for resistance against the combination in E. faecium. In this species resistance to streptogramin A compounds is mediated via related acetyltransferases VatD and VatE. Resistance against streptogramins B is either encoded by the widespread ermB gene cluster conferring resistance to macrolide-lincosamide-streptogramin B antibiotics or via expression of the vgbA gene, which encodes a staphylococcal-type lactonase. E. faecalis is intrinsically resistant to streptogramins. Due to a wide use of streptogramins (virginiamycins S/M) in commercial animal farming a reservoir of streptogramin-resistant E. faecium isolates had already been selected. Determinants for streptogramin resistance are localized on plasmids that can be transferred into an E. faecium recipient both in vitro in filter-matings and in vivo in the digestive tracts of rats. Hybridization and sequencing experiments revealed a linkage of resistance determinants for streptogramins A and B on definite plasmid fragments.

Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Drug Synergism; Drug Therapy, Combination; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Streptogramins; Virginiamycin

Serious infection with vancomycin-resistant enterococci (VRE) usually occurs in patients with significantly compromised host defences and serious co-morbidities, and this magnifies the importance of effective antimicrobial treatment. Assessments of antibacterial efficacy against VRE have been hampered by the lack of a comparator treatment arm(s), complex treatment requirements including surgery, and advanced illness-severity associated with a high crude mortality. Treatment options include available agents which don't have a specific VRE approval (chloramphenicol, doxycycline, high-dose ampicillin or ampicillin/sulbactam), and nitrofurantoin (for lower urinary tract infection). The role of antimicrobial combinations that have shown in vitro or animal-model in vivo efficacy has yet to be established. Two novel antimicrobial agents (quinupristin/ dalfopristin and linezolid) have emerged as approved therapeutic options for vancomycin-resistant Enterococcus faecium on the basis of in vitro susceptibility and clinical efficacy from multicentre, pharmaceutical company-sponsored clinical trials. Quinupristin/dalfopristin is a streptogramin, which impairs bacterial protein synthesis at both early peptide chain elongation and late peptide chain extrusion steps. It has bacteriostatic activity against vancomycin-resistant E. faecium [minimum concentration to inhibit growth of 90% of isolates (MIC(90)) = 2 microg/ml] but is not active against Enterococcus faecalis (MIC(90 )= 16 microg/ml). In a noncomparative, nonblind, emergency-use programme in patients who were infected with Gram-positive isolates resistant or refractory to conventional therapy or who were intolerant of conventional therapy, quinupristin/dalfopristin was administered at 7.5 mg/kg every 8 hours. The clinical response rate in the bacteriologically evaluable subset was 70.5%, and a 65.8% overall response (favourable clinical and bacteriological outcome) was observed. Resistance to quinupristin/dalfopristin on therapy was observed in 6/338 (1.8%) of VRE strains. Myalgia/arthralgia was the most frequent treatment-limiting adverse effect. In vitro studies which combine quinupristin/dalfopristin with ampicillin or doxycyline have shown enhanced killing effects against VRE; however, the clinical use of combined therapy remains unestablished. Linezolid, an oxazolidinone compound that acts by inhibiting the bacterial pre-translational initiation complex formation, has bacteriostatic activity against both va

Topics: Acetamides; Animals; Anti-Bacterial Agents; Clinical Trials as Topic; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Enterococcus; Gram-Positive Bacterial Infections; Humans; In Vitro Techniques; Linezolid; Oxazolidinones; Risk Factors; Vancomycin Resistance; Virginiamycin

Quinupristin + dalfopristin* (Synercid -- Aventis Pharma Ltd) is a new combination antibacterial product licensed for treating patients with a variety of Gram-positive infections. Here we assess its place in clinical practice.

Topics: Anti-Bacterial Agents; Drug Costs; Drug Resistance, Bacterial; Gram-Positive Bacterial Infections; Humans; Superinfection; Virginiamycin

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.

Topics: Acetamides; Anti-Bacterial Agents; Cross Infection; Drug Interactions; Drug Resistance, Microbial; Drug Therapy, Combination; Enterococcus; Gram-Positive Bacterial Infections; Gram-Positive Cocci; Humans; Linezolid; Methicillin; Oxazolidinones; Virginiamycin

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.. 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.. 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.. 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.. 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.

Topics: Anti-Bacterial Agents; Bacteremia; Cross Infection; Drug Interactions; Drug Therapy, Combination; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests; Pneumonia, Bacterial; Skin Diseases, Bacterial; Vancomycin Resistance; Virginiamycin

Infections due to multidrug-resistant Gram-positive bacteria are a growing worldwide problem, particularly among seriously ill patients. A number of studies have demonstrated that patients infected with either methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant enterococci (VRE) are at higher risk for mortality and medical resource expenditures.. A non-systematic evidence-based review of linezolid, the first commercially available oxazolidinone, and quinupristin/dalfopristin, the first injectable streptogramin, for management of these multidrug-resistant infections was conducted.. As infections due to VRE increase and vancomycin-insensitive MRSA emerge, vancomycin is becoming less effective for managing Gram-positive infections. Preclinical comparative studies demonstrated that linezolid and quinupristin/dalfopristin are highly effective in eradicating both susceptible and resistant staphylococci, streptococci, and enterococci. Clinical experience, including phase III and compassionate-use data, with these newer agents in the treatment of MRSA and VRE infections are discussed.. The clinical experiences thus far with linezolid and quinupristin/dalfopristin for MRSA and VRE infections have demonstrated efficacy, making these agents important additions to the limited number of therapeutic alternatives for Gram-positive infections.

Topics: Acetamides; Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Enterococcus; Gram-Positive Bacterial Infections; Humans; Linezolid; Methicillin Resistance; Oxazolidinones; Staphylococcal Infections; Staphylococcus aureus; Vancomycin Resistance; Virginiamycin

Topics: Acetamides; Adult; Aged; Anti-Bacterial Agents; Anti-Infective Agents; Area Under Curve; Child; Cross Infection; Drug Combinations; Gram-Positive Bacterial Infections; Humans; Infant; Infant, Newborn; Linezolid; Microbial Sensitivity Tests; Oxazolidinones; Tissue Distribution; Virginiamycin

Gram-positive infections impose a major burden on patients and the healthcare systems globally. The need to treat these infections correctly in an empirical fashion is of paramount importance. Further complicating this changing aetiology is the emergence of resistant strains which are no longer predictably susceptible to standard first-line antimicrobials such as oxacillin or vancomycin. Thus new agents such as linezolid have been developed to assist with initial empirical prescribing in infections where Gram-positive pathogens may be present. The characteristics of linezolid, including spectrum of activity, pharmacodynamic profile, tolerablility and overall efficacy should strengthen confidence when considering initial antimicrobial therapy in patients in risk areas. Future agents also being developed to fight multi-resistant Gram-positive infections include oritavancin, daptomycin and the glycylcyclines; however, these are still in the development phase.

Topics: Acetamides; Anti-Infective Agents; Drug Resistance, Bacterial; Drugs, Investigational; Gram-Positive Bacterial Infections; Humans; Linezolid; Oxazolidinones; Vancomycin Resistance; Virginiamycin

Changing patterns of pathogens and antibiotic susceptibility present clinicians with difficult choices for antimicrobial prescribing. In particular, multiresistant staphylococci, enterococci and pneumococci present problems in many settings. The number of predictably active antimicrobials is decreasing in many centres, with significant consequences for both patients and society as a whole. New antimicrobial options have been few in recent years and several promising quinolones have been compromised by formulation and/or toxicity issues. Nevertheless, the recent introduction of linezolid and quinupristin/dalfopristin provides clinicians with valuable new options against Gram-positive cocci. These options should further increase with the likely introduction of daptomycin, oritavancin and tigilcycline. A range of surveillance programmes helps monitor the ever-changing patterns of resistance and thus guides clinicians in their empirical prescribing. Empirical use of powerful newer agents may be justifiable in seriously ill patients in those settings, units and countries where there is a substantial background rate of resistance.

Topics: Acetamides; Anti-Bacterial Agents; Chemistry, Pharmaceutical; Cross Infection; Drug Resistance, Bacterial; Drugs, Investigational; Europe; Gram-Positive Bacterial Infections; Humans; Infection Control; Linezolid; Oxazolidinones; Practice Patterns, Physicians'; United States; Virginiamycin

Vancomycin is a safe, effective antibiotic for a variety of serious gram-positive infections. Because of emerging resistance in enterococci and staphylococci and the emerging threat of spread of vancomycin-resistant genes to other gram-positive organisms, judicious use of vancomycin should be promoted. Quinupristin/dalfopristin, a streptogramin antibiotic, and linezolid, an oxazolidinone, show promise against some strains of gram-positive bacteria that are resistant to vancomycin.

Topics: Acetamides; Anti-Bacterial Agents; Drug Resistance, Microbial; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Linezolid; Oxazoles; Oxazolidinones; Teicoplanin; Vancomycin; Virginiamycin

Topics: Acetamides; Anti-Infective Agents; Clinical Trials as Topic; Drug Approval; Drug Therapy, Combination; Gram-Positive Bacterial Infections; Humans; Linezolid; Oxazolidinones; Virginiamycin

Infections caused by multiple-resistant Gram-positive organisms continue to occur at an alarming rate worldwide. Two new and unique antimicrobial agents targeted specifically against such organisms, quinupristin/dalfopristin and linezolid, have been approved for use in the USA in the past year and will play an important role in the treatment of life-threatening infections. In addition, several new fluoroquinolones have been approved recently or will be available in the near future to aid in the treatment of infections caused by resistant strains of Streptococcus pneumoniae.

Topics: Acetamides; Anti-Bacterial Agents; Clinical Trials as Topic; Drug Approval; Fluoroquinolones; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Linezolid; Lipoglycopeptides; Oxazolidinones; Virginiamycin

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.

Topics: Animals; Anti-Bacterial Agents; Bacteremia; Clinical Trials as Topic; Drug Resistance, Microbial; Drug Synergism; Drug Therapy, Combination; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests; Virginiamycin

The Gram-positive cocci have clearly re-emerged as important pathogens world-wide in the past two decades. Staphylococci, including the coagulase-negative staphylococci and Staphylococcus aureus, and the enterococci account for approximately one-third of all blood stream infections and as much as 50% of nosocomial blood stream infections. Although Streptococcus pneumoniae is often considered a community-acquired pathogen, it is also an important cause of nosocomial infection. The hallmark of these Gram-positive pathogens is increasing resistance to available antimicrobial agents. Of particular note is resistance to glycopeptides (vancomycin and teicoplanin), aminoglycosides (high-level), and penicillins among the enterococci (especially E. faecium), resistance to penicillinase-resistant penicillins (oxacillin and methicillin) and fluoroquinolones (ciprofloxacin and ofloxacin) among staphylococci, and resistance to penicillin, other beta-lactams and macrolides among the pneumococci. The recent detection of decreased susceptibility to vancomycin among S. aureus is also quite ominous. In many instances the ability of the clinical laboratory to accurately characterize these resistant isolates is suboptimal, further compounding the problem. Increased understanding of resistance mechanisms and correlations of resistance genes with the phenotypic expression of resistance has allowed for modifications and improvements of reference susceptibility tests and interpretive breakpoints. New compounds for effective therapy of infection with multi-resistant Gram-positive species are clearly needed. To this end, the streptogramin combination, quinupristin/dalfopristin, has demonstrated significant activity against oxacillin-resistant staphylococci, penicillin-resistant streptococci, and vancomycin-resistant E. faecium. Other candidate drugs including Gram-positive active fluoroquinolones (clinafloxacin, grepafloxacin, moxifloxacin, gatifloxacin, and trovafloxacin) and novel compounds such as the everninomicin derivatives (SCH27899), ketolides, and oxazolidinones (linezolid) have been shown to be active against these organisms and are under rapid clinical development.

Topics: Anti-Bacterial Agents; Community-Acquired Infections; Drug Resistance, Microbial; Enterococcus; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Staphylococcus; Streptococcus pneumoniae; Virginiamycin

Gram-positive bacteria (e.g. Staphylococcus aureus and Streptococcus pyogenes) are the main cause of skin and skin structure infections (SSSI). Treatment presents a clinical challenge to the physician, particularly with the increase in multidrug-resistant strains and widespread cross-resistance to antibiotic treatment. Initial treatment of SSSI involves the use of fluoroquinolones or penicillinase-resistant penicillins. If infection is caused by methicillin-resistant staphylococci, therapy with glycopeptides is warranted. However, in the last few years several cases of infection caused by strains of S. aureus with reduced susceptibility to glycopeptides have been reported. Quinupristin/dalfopristin is a new streptogramin that has shown efficacy in the management of multidrug-resistant gram-positive infections. Two major studies suggest that in the treatment of complicated SSSI, the clinical efficacy of quinupristin/dalfopristin is equivalent to that of vancomycin and/or oxacillin and vancomycin and/or cefazolin.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Fluoroquinolones; Gram-Positive Bacterial Infections; Humans; Skin Diseases, Bacterial; Virginiamycin

Vancomycin-resistant Enterococcus faecium (VREF) is an opportunistic pathogen, which causes infections among severely ill, hospitalized patients, in whom it is likely to increase the risk of progressive local or systemic disease and to worsen the prognosis. Because these organisms are often highly resistant to penicillin, ampicillin and many other antimicrobials including the glycopeptides, there are few proven therapeutic alternatives for the treatment of infection caused by VREF. Quinupristin/dalfopristin is highly active against VREF in vitro. A prolonged post-antibiotic effect, good polymorphonuclear leucocyte/macrophage penetration and slow release, and active metabolites allow this agent to be used with an 8 or 12 h dosing interval. The combined results from a Phase III non-comparative study and an emergency-use study of quinupristin/dalfopristin for the treatment of VREF infection produced a clinical response rate (cure or improvement) in 142 (73.6%) of 193 clinically evaluable patients. The baseline pathogen was eradicated or presumed eradicated from 110 of 156 (70.5%) bacteriologically evaluable patients. Fifty-two per cent of the severely ill patients in these two studies died, but no death was attributed to quinupristin/dalfopristin therapy. The most common adverse event was arthralgia (9.1%). Quinupristin/dalfopristin has demonstrated efficacy for the treatment of serious VREF infections, including those that have failed conventional therapy.

Topics: Anti-Bacterial Agents; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Vancomycin Resistance; Virginiamycin

Topics: Animals; Anti-Bacterial Agents; Drug Resistance, Microbial; Enterococcus faecium; Gram-Positive Bacterial Infections; Growth Substances; Humans; Risk Factors; Virginiamycin

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.. 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.

Topics: Anti-Bacterial Agents; Drug Resistance, Microbial; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Virginiamycin

Over recent years gram-positive bacterial pathogens have become dominant in many forms of nosocomial infections. The principal pathogens in severe infections are Staphylococcus aureus and enterococci. The utility of the traditional antibiotics used for nosocomial sepsis, particularly beta-lactam agents, has been severely compromised by the spread of resistance and there was, often, no therapeutic alternative to the glycopeptide antibiotics, vancomycin and teicoplanin, for empirical (and often also the specific) therapy of infections caused by methicillin-resistant S. aureus (MRSA) and Enterococcus spp. This reliance on glycopeptides, however, is now also threatened by acquired resistance. Vancomycin-resistant enterococci (VRE), particularly E. faecium, have become a therapeutic problem in many European cities and are now endemic in some hospital wards. The recent reports from several continents of MRSA with reduced glycopeptide-susceptibility (GISA) is of grave concern. New agents are needed to meet these threats and several classes of compounds are under development. One class is the streptogramins and the combination of quinupristin/dalfopristin (Synercid) is nearing licensing. Clinical trials and a compassionate use programme have already shown it to have considerable promise for the treatment of the most problematic forms of gram-positive nosocomial sepsis, including MRSA and vancomycin-resistant E. faecium infections that had failed therapy with other antibiotics.

Topics: Anti-Bacterial Agents; Cross Infection; Drug Resistance, Microbial; Gram-Positive Bacterial Infections; Humans; Sepsis; Staphylococcal Infections; Virginiamycin

Considerable research over the past decade has thrown up two novel antibiotic preparations which are effective in 'difficult' Gram positive infections. Their imminent arrival is welcomed at a time when the emergence of resistance to last line drugs is rapidly spreading. Their careful use is, however, crucial if long-term value is to be preserved.

Topics: Acetamides; Anti-Bacterial Agents; Anti-Infective Agents; Drug Prescriptions; Drug Resistance, Microbial; Drug Therapy, Combination; Gram-Positive Bacterial Infections; Humans; Linezolid; Oxazoles; Oxazolidinones; Safety; Virginiamycin

Topics: Animals; Anti-Bacterial Agents; Drug Resistance, Microbial; Enterococcus faecium; France; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests; United States; Virginiamycin

In recent years there has been a dramatic worldwide increase in the prevalence of multiple drug-resistant strains of common Gram-positive bacteria. This highlights the need for a new class of antibiotic with activity against these organisms. Quinupristin/dalfopristin, the first injectable streptogramin antibiotic, has a unique spectrum of activity, encompassing most Gram-positive cocci (including multi-drug-resistant strains), respiratory pathogens and anaerobes, Gram-positive, and a prolonged post-antibiotic effect. Quinupristin/ dalfopristin is active in vitro against multi-drug-resistant isolates of Staphylococcus aureus, coagulase-negative staphylococci, penicillin-resistant pneumococci and vancomycin-resistant Enterococcus faecium. Clinical case reports have shown that the combination is active against intra-abdominal, aortic graft, bacteraemia and hydrocephalus shunt infections caused by multi-drug-resistant enterococci, particularly E. faecium. In almost all of these clinical situations the enterococcal infection had displayed resistance to all other antimicrobial therapies. Preliminary clinical data have demonstrated the activity of quinupristin/ dalfopristin against S. aureus bacteraemia, and quinupristin/dalfopristin may also prove useful in the treatment of pneumococcal infections. Thus, possible future applications of the combination include the treatment of multi-drug-resistant strains of staphylococci, streptococci and enterococci. Quinupristin/dalfopristin may prove useful in the treatment of staphylococcal infections in children, invasive systemic pneumococcal infections, and nosocomial and community-acquired Gram-positive infections in patients unable to tolerate beta-lactam antimicrobial agents or glycopeptide antibiotics.

Topics: Anti-Bacterial Agents; Coagulase; Drug Resistance, Multiple; Enterococcus; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Methicillin Resistance; Staphylococcus; Streptococcus; Virginiamycin

Dramatic changes in the epidemiology and susceptibility patterns of Gram-positive cocci during the last decade have mandated new approaches to the management of many bacterial infections. For example, there has been a sharp increase in the incidence of infections caused by Staphylococcus aureus, particularly those resistant to methicillin (MRSA), and methicillin-resistant coagulase-negative staphylococci, particularly those associated with foreign bodies and indwelling medical devices. Additionally, the worldwide spread of Streptococcus pneumoniae strains resistant to penicillin and macrolides, and the emergence of enterococci (particularly Enterococcus faecium) resistant to vancomycin, teicoplanin and other antibiotics, present further therapeutic problems. New antibacterial agents are urgently required to meet the challenges posed by these epidemiological trends. The semisynthetic streptogramins, a unique class of antibacterials currently under development, offer promise in the treatment of such multiresistant infections. Possible future applications include treatment of infections caused by the following organisms: MRSA, enterococci resistant to vancomycin, macrolides or lincosamides; and beta-lactam-resistant streptococci. They may also prove useful as therapy for children with staphylococcal infection and patients with multiresistant infections who are unable to tolerate vancomycin, including patients with skin and soft tissue infections caused by Gram-positive pathogens, patients with osteomyelitis, foreign body associated infections, endocarditis and sepsis due to Gram-positive bacteria. Clinical trials are required to evaluate the efficacy and tolerability of streptogramins in these settings.

Topics: Anti-Bacterial Agents; Bacteremia; Forecasting; Gram-Positive Bacterial Infections; Humans; Incidence; Methicillin Resistance; Microbial Sensitivity Tests; Virginiamycin

The incidence of vancomycin resistance among enterococci, and Enterococcus faecium in particular, has increased sharply in the last few years. This shift toward infection with resistant Gram-positive organisms is thought to be the consequence of certain features specific to the intensive care setting: a high concentration of severely compromised patients; continued use of indwelling devices and invasive procedures; and widespread, empiric use of antimicrobial agents directed against Gram-negative bacilli. Measures that can be taken to prevent the development of bacterial resistance in the ICU include strict adherence to infection control policies and asepsis, and rational use of antibiotics. Current antimicrobial regimens for serious enterococcal infections consist of a combination of ampicillin, penicillin G, or vancomycin plus streptomycin or gentamicin. High levels of resistances among some enterococcal isolates, however, may render these strategies ineffective. A new agent, quinupristin/dalfopristin (RP 59500), has demonstrated encouraging in vitro activity against vancomycin-resistant E. faecium. Initial clinical reports, though limited, are similarly promising. Although phase III clinical trials with RP 59500 are not completed, the agent is available through an emergency-use program for patients with severe Gram-positive infections who cannot tolerate or do not respond to all other clinically appropriate antibiotics.

Topics: Drug Resistance, Microbial; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Intensive Care Units; Vancomycin; Virginiamycin

Quinupristin-dalfopristin (RP 59500) is an injectable streptogramin antibiotic. It possesses a wide spectrum of activity against Gram-positive bacteria including methicillin-resistant staphylococci, glycopeptide-resistant. Enterococcus faecium and penicillin-resistant pneumococci. Quinupristin-dalfopristin has activity against some anaerobes and selected Gram-negative pathogens. Quinupristin-dalfopristin, by way synergism of between its 2 components, is unaffected by most forms of bacterial resistance. Rare forms of macrolide-lincosamide-streptogramin group B resistance may affect its activity; however, at present the incidence of strains with this type of resistance remains low. Quinupristin-dalfopristin is bactericidal against streptococci and staphylococci but has weak or no bactericidal activity against enterococci. In a compassionate use programme, 67% of 95 evaluable patients with vancomycin-resistant Gram-positive infections or intolerant of vancomycin showed improvement with eradication of infection.

Topics: Animals; Anti-Bacterial Agents; Clinical Trials as Topic; Drug Resistance, Microbial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Virginiamycin

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.. 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.. 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).. 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.

Topics: Acetamides; Adult; Aged; Enterococcus faecium; Female; Gram-Positive Bacterial Infections; Humans; Linezolid; Male; Microbial Sensitivity Tests; Middle Aged; Oxazolidinones; Pilot Projects; Prospective Studies; Vancomycin Resistance; Virginiamycin

To determine whether myalgias/arthralgias occurring in cancer patients who receive quinupristin/dalfopristin are associated with biliary tract dysfunction.. 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.. 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).. 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.

Topics: Aged; Alkaline Phosphatase; Anti-Bacterial Agents; Antimetabolites, Antineoplastic; Antineoplastic Agents; Arthralgia; Biliary Tract Diseases; Enterococcus; Female; Gram-Positive Bacterial Infections; Humans; Immunosuppressive Agents; Liver Function Tests; Male; Methotrexate; Middle Aged; Muscular Diseases; Neoplasms; Pain; Recurrence; Risk Factors; Tacrolimus; Virginiamycin

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.

Topics: Adolescent; Adult; Area Under Curve; Biological Assay; Chromatography, High Pressure Liquid; Drug Therapy, Combination; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Half-Life; Humans; Infusions, Intravenous; Male; Metabolic Clearance Rate; Skin Diseases, Bacterial; Time Factors; Virginiamycin

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.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Antineoplastic Agents; Child; Drug Therapy, Combination; Enterococcus; Enterococcus faecalis; Enterococcus faecium; Female; Gram-Positive Bacterial Infections; Humans; Immunity; Male; Middle Aged; Minocycline; Neoplasms; Pain; Vancomycin Resistance; Virginiamycin

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.

Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Superinfection; Treatment Outcome; Vancomycin Resistance; Virginiamycin

The efficacy and safety of quinupristin/dalfopristin for treatment of infections due to vancomycin-resistant Enterococcus faecium were evaluated in 24 hospitalized patients with documented infections (19 bacteremias, 5 localized infections) caused by vancomycin-resistant E. faecium that was susceptible to quinupristin/dalfopristin in vitro. Patients received iv quinupristin/dalfopristin at a dosage of either 7.5 mg/kg every 8 h or 5 mg/kg every 8 h. A favorable clinical response (cure or improvement) occurred in 19 (83%) of 23 evaluable patients; bacteriologic eradication occurred in 17 (74%) of 23 evaluable patients. A favorable clinical response was observed in 12 (80%) of 15 patients who were treated with 7.5 mg/kg of quinupristin/dalfopristin every 8 h and in 7 (88%) of 8 patients treated with 5 mg/kg of quinupristin/dalfopristin every 8 h. Two of four treatment failures were associated with a decrease in the in vitro susceptibility of vancomycin-resistant E. faecium to quinupristin/dalfopristin. Superinfections developed in 6 patients (26%), but only one was caused by Enterococcus faecalis that was resistant to quinupristin/dalfopristin. Myalgias and arthralgias were the only adverse events related to quinupristin/dalfopristin. These conditions occurred in 8 (33%) of 24 patients and were dose-related (8 cases in 16 patients treated with 7.5 mg/kg of quinupristin/dalfopristin every 8 h, no cases in 8 patients treated with 5 mg/kg every 8 h). Mortality associated with vancomycin-resistant E. faecium infection was 17% (4 of 23 patients), whereas mortality from other causes was 52% (12 of 23 patients). These results suggest that quinupristin/dalfopristin is effective as treatment for vancomycin-resistant E. faecium infections in critically ill patients with serious underlying conditions. Except for myalgias and arthralgias at higher dosages, the drug is well-tolerated.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Child; Child, Preschool; Drug Therapy, Combination; Enterococcus faecium; Female; Gram-Positive Bacterial Infections; Hospitalization; Humans; Infant; Male; Microbial Sensitivity Tests; Middle Aged; Treatment Outcome; Vancomycin Resistance; Virginiamycin

A progressive increase in the incidence of vancomycin resistance in strains of Enterococcus faecium (VREF) has severely constrained treatment options for patients with infection caused by this emerging pathogen. Quinupristin/dalfopristin (Synercid), the first injectable streptogramin antibiotic, is active in vitro against VREF, with an MIC90 of 1.0 mg/L. We studied the clinical efficacy and safety of quinupristin/dalfopristin in the treatment of VREF infection. Two prospective studies were conducted simultaneously. The first enrolled only patients with VREF infection; the second included patients with infection caused by other gram-positive bacterial pathogens in addition to VREF. Patients were enrolled if they had signs and symptoms of active infection and no appropriate alternative antibiotic therapy. The recommended treatment regimen of quinupristin/dalfopristin was 7.5 mg/kg i.v. every 8 h for a duration judged appropriate by the investigator. A total of 396 patients with VREF infection were enrolled. The most frequent indications for treatment included intra-abdominal infection, bacteraemia of unknown origin, urinary tract infection, catheter-related bacteraemia, and skin and skin structure infection. This patient population had a high prevalence of severe underlying illness, including a history of diabetes mellitus, transplantation, mechanical ventilation, dialysis, chronic liver disease with cirrhosis and oncological disorders. The mean (+/- S.D.) duration of treatment was 14.5 +/- 10.7 days (range: 1-108). The majority of patients (82.1%) were treated every 8 h, as assessed on day 2 of treatment, while 15.9% were treated every 12 h. The clinical success rate was 73.6% [142/193 clinically evaluable patients; 95% confidence interval (CI): 67.4%, 79.8%], the bacteriological success rate 70.5% (110/156 bacteriologically evaluable patients; 95% CI: 63.4%, 77.7%) and the overall success (both clinical and bacteriological success) rate 65.8% (102/156 bacteriologically evaluable patients; 95% CI: 57.9%, 72.9%). VREF bacteraemia at entry, mechanical ventilation and laparotomy were associated with a worse outcome. Quinupristin/dalfopristin was generally well tolerated. The most common systemic adverse events related to treatment were arthralgias (9.1%) and myalgias (6.6%). Related laboratory abnormalities were infrequent. In these severely ill patients with VREF infection and no other clinically appropriate therapeutic alternatives, quinupristin/dalfopristi

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Child; Child, Preschool; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Infant; Microbial Sensitivity Tests; Middle Aged; Prospective Studies; Treatment Outcome; Vancomycin Resistance; Virginiamycin

Quinupristin/dalfopristin (Synercid), the first injectable streptogramin antibiotic available for the treatment of complicated gram-positive skin and skin structure infections, was compared with standard comparators (cefazolin, oxacillin or vancomycin) in one USA and one international trial. These two randomized, open-label trials of virtually identical design enrolled a total of 893 patients (450 quinupristin/dalfopristin, 443 comparator). The majority of patients had erysipelas, traumatic wound infection or clean surgical wound infection. Staphylococcus aureus was the most frequently isolated pathogen in both treatment groups and polymicrobial infection was more common in the quinupristin/dalfopristin group than in the comparator group. The clinical success rate (cure plus improvement) in the clinically evaluable population was equivalent between the two treatment groups (68.2% quinupristin/dalfopristin, 70.7% comparator; 95% CI, -10.1, 5.1) despite a shorter mean duration of treatment for quinupristin/dalfopristin patients. In the bacteriologically evaluable population, by-patient and by-pathogen bacteriological eradication rates were somewhat lower for quinupristin/dalfopristin (65.8% and 66.6%, respectively) than for the comparator regimens (72.7% and 77.7%, respectively). The lower bacteriological response rates in the quinupristin/dalfopristin group were, in part, due to a higher rate of polymicrobial infections and a higher incidence of patients classified as clinical failure, a category which included premature discontinuation of treatment because of local venous adverse events. The bacteriological eradication rate for quinupristin/dalfopristin was higher in monomicrobial infections than in polymicrobial infections (72.6% versus 63.3%, respectively), whereas the corresponding rate for the comparator regimens was lower for monomicrobial infections than polymicrobial infections (70.8% versus 83.1%). This finding was not unexpected, since the spectrum of quinupristin/dalfopristin is focused on gram-positive pathogens and additional antibiotics to treat gram-negative bacteria were not required per protocol. The systemic tolerability of both treatment regimens was qualitatively similar. A higher rate of drug-related venous adverse events was reported for quinupristin/dalfopristin (66.2%) than for the comparator regimen (28.4%). Premature discontinuation of study drug was primarily due to adverse clinical events for quinupristin/dalfopristin (19.1%), w

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Cefazolin; Cephalosporins; Female; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Hospitalization; Humans; Male; Middle Aged; Oxacillin; Penicillins; Skin Diseases, Bacterial; Vancomycin; Virginiamycin

Serious infection with vancomycin-resistant Enterococcus faecium (VREF) strains has no proven effective antimicrobial therapy. We compared the clinical and bacteriological outcomes of 20 patients with VREF bacteraemia treated with quinupristin/dalfopristin (RP 59500), an investigational streptogramin, with a historical cohort of 42 patients with VREF bacteraemia treated with other agents. Quinupristin/dalfopristin demonstrated in-vitro bacteriostatic activity against all 20 initial VREF blood isolates (MIC range 0.03-0.50 mg/L) by macrobroth dilution. The clinical characteristics of both groups were comparable for major outcome-dependent variables. There were five cases of recurrent VREF bacteraemia in the quinupristin/dalfopristin-treated cohort and 21 in the controls (P = 0.11); persistence of VREF at the primary site was found in six and 18 of the evaluable patients with follow-up cultures in these two cohorts (P = 0.06). In-hospital mortality was high in both groups: 65% in the quinupristin/dalfopristin group and 52% in the control group; however, VREF-associated mortality was significantly lower in the quinupristin/dalfopristin group (five and 17 respectively; P = 0.05). Follow-up susceptibility testing of five VREF isolates in the quinupristin/ dalfopristin group did not demonstrate resistance to quinupristin/dalfopristin. Quinupristin/ dalfopristin may be a useful agent for the therapy of serious VREF infection. Further clinical investigations are warranted to confirm or refute its clinical efficacy.

Topics: Adult; Anti-Bacterial Agents; Bacteremia; Cohort Studies; Drug Resistance, Microbial; Enterococcus faecium; Female; Follow-Up Studies; Gram-Positive Bacterial Infections; Humans; Male; Middle Aged; Treatment Outcome; Vancomycin; Virginiamycin

Multicenter surveillance of antimicrobial susceptibility was performed for 235 vancomycin-resistant Enterococcus faecium (VREfm) isolates from 18 Taiwanese hospitals. The minimum inhibitory concentrations (MICs) of eravacycline, omadacycline, lipoglycopeptides, and other comparator antibiotics were determined using the broth microdilution method. Nearly all isolates of VREfm were not susceptible to teicoplanin, dalbavancin, and telavancin, with susceptibility rates of 0.5%, 1.7% and 0.5%, respectively. Tigecycline and eravacycline were active against 93.2% and 89.7% of the VREfm isolates, respectively. Moreover, the susceptibility rates of quinupristin/dalfopristin, tedizolid, and linezolid were 59.1%, 84.2%, and 77.4%, respectively. Additionally, 94% of the VREfm isolates were classified as susceptible to daptomycin, and the MICs of omadacycline required to inhibit VREfm growth by 50% and 90% were 0.12 and 0.5 mg/L, respectively. Susceptibility rates of VREfm isolates to synthetic tetracyclines and daptomycin were slightly lower and to oxazolidinone-class antibiotics were much lower in Taiwan than those in other parts of the world. Continuous monitoring of VREfm resistance to novel antibiotics, including synthetic tetracyclines, oxazolidinone-class antibiotics, and daptomycin, is needed in Taiwan.

Topics: Aminoglycosides; Anti-Bacterial Agents; Bacteremia; Daptomycin; Drug Resistance, Bacterial; Enterococcus faecium; Epidemiological Monitoring; Gram-Positive Bacterial Infections; Humans; Linezolid; Lipoglycopeptides; Microbial Sensitivity Tests; Oxazolidinones; Taiwan; Tetracyclines; Tetrazoles; Tigecycline; Vancomycin; Vancomycin-Resistant Enterococci; Virginiamycin

To find a therapeutic alternative for the treatment of skin and soft tissue infections, we evaluated the effects of combinations of retapamulin with macrolide, lincosamide, and streptogramin (MLS) antibiotics against Staphylococcus aureus, Streptococcus pyogenes, Enterococcus faecium, and Enterococcus faecalis. Using both the disk diffusion test and checkerboard assay, we initially examined the effects of combinations of retapamulin with MLS antibiotics against standard strains of these species. Combinations of retapamulin with erythromycin, quinupristin/dalfopristin and quinupristin showed synergistic activity against E. faecalis only. Synergy of retapamulin with clindamycin and dalfopristin was not observed. Then, a checkerboard assay was performed to evaluate the effects of the combinations against 15 clinical strains of E. faecalis. Retapamulin and quinupristin, the most synergistic combination, showed activity against all erythromycin-susceptible, -intermediate, and -resistant strains tested. Among the eight strains with high-level erythromycin resistance, five strains were synergistically inhibited in the presence of only 1 μg of retapamulin per ml. Time-kill assay revealed that combinations of retapamulin with erythromycin and quinupristin were bacteriostatic. These results suggest that combinations of retapamulin with erythromycin and quinupristin have in vitro synergistic activity against E. faecalis, including strains with high-level erythromycin resistance.

Topics: Anti-Bacterial Agents; Bridged Bicyclo Compounds, Heterocyclic; Diterpenes; Drug Synergism; Enterococcus faecalis; Enterococcus faecium; Erythromycin; Gram-Positive Bacterial Infections; Humans; Macrolides; Microbial Sensitivity Tests; Staphylococcus aureus; Streptococcus pyogenes; Virginiamycin

High-throughput sequencing (HTS) has successfully identified novel resistance genes in enterococci and determined clonal relatedness in outbreak analysis. We report the use of HTS to investigate two concurrent outbreaks of glycopeptide-resistant Enterococcus faecium (GRE) with an uncharacterised resistance mechanism to quinupristin-dalfopristin (QD). Seven QD-resistant and five QD-susceptible GRE isolates from a two-centre outbreak were studied. HTS was performed to identify genes or predicted proteins that were associated with the QD-resistant phenotype. MLST and SNP typing on HTS data was used to determine clonal relatedness. Comparative genomic analysis confirmed this GRE outbreak involved two distinct clones (ST80 and ST192). HTS confirmed the absence of known QD resistance genes, suggesting a novel mechanism was conferring resistance. Genomic analysis identified two significant genetic determinants with explanatory power for the high level of QD resistance in the ST80 QD-resistant clone: an additional 56aa leader sequence at the N-terminus of the lsaE gene and a transposon containing seven genes encoding proteins with possible drug or drug-target modification activities. However, HTS was unable to conclusively determine the QD resistance mechanism and did not reveal any genetic basis for QD resistance in the ST192 clone. This study highlights the usefulness of HTS in deciphering the degree of relatedness in two concurrent GRE outbreaks. Although HTS was able to reveal some genetic candidates for uncharacterised QD resistance, this study demonstrates the limitations of HTS as a tool for identifying putative determinants of resistance to QD.

Topics: Anti-Bacterial Agents; Disease Outbreaks; Drug Resistance, Bacterial; Enterococcus faecium; Genes, Bacterial; Glycopeptides; Gram-Positive Bacterial Infections; High-Throughput Nucleotide Sequencing; Humans; Microbial Sensitivity Tests; Multilocus Sequence Typing; Phylogeny; Polymorphism, Single Nucleotide; Virginiamycin

Quinupristin/dalfopristin (Q/D) is a valuable alternative antibiotic to vancomycin for the treatment of multi-drug resistant Enterococcus faecium infections. However, resistance to Q/D in E. faecium clinical isolates and nosocomial dissemination of Q/D-resistant E. faecium have been reported in several countries and should be of concern.. From January 2012 to December 2015, 911 E. faecium clinical isolates were isolated from various specimens of inpatients at the first Affiliated Hospital of Wenzhou Medical University located in Wenzhou, east China. Of 911 E. faecium clinical isolates, 9 (1.0 %, 9/911) were resistant to Q/D, with the Q/D MIC values of 64 mg/L(1), 32 mg/L(1), 16 mg/L(3), 8 mg/L(1) and 4 mg/L(3) determined by broth microdilution. All Q/D-resistant isolates were susceptible to vancomycin, tigecycline and teicoplanin but resistant to penicillin, ampicillin and erythromycin. vatE was only found in one Q/D-resistant E. faecium isolate while vatD was not detected in any of the isolates tested. 8 of 9 Q/D-resistant E. faecium isolates were found be positive for both ermB and msrC. The combinations of Q/D resistance determinants were ermB-msrC (7 isolates) and ermB-msrC-vatE (one isolate). ST78, ST761, ST94, ST21 and ST323 accounted for 4, 2, 1, 1 and 1 isolate, respectively, among which ST78 was the prevalent ST.. Q/D-resistant E. faecium clinical isolates were first described in China. Carriage of vatE, ermB and msrC was responsible for Q/D resistance.

Topics: Anti-Bacterial Agents; Bacterial Proteins; China; Cross Infection; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Enterococcus faecium; Genes, Bacterial; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests; Multilocus Sequence Typing; Prevalence; RNA, Ribosomal, 16S; Vancomycin; Virginiamycin

Cross-resistance to macrolide, lincosamide, and streptogramin B (MLSB) antibiotics is mainly mediated by the erm (erythromycin ribosome methylation) genes that encode 23S rRNA methylases in enterococi, and various mechanisms are involved in the streptogramin B resistance. Prevalence of MLSB resistance and its genetic mechanisms were analyzed for a total of 159 strains of Enterococcus faecium isolated from clinical specimens in a university hospital in Japan from 1997 to 2006. Resistance to erythromycin (EM) and clindamycin was detected in 88.1% and 89.9% of all the strains examined, respectively, and expression of resistance was totally constitutive. Although none of the strain was resistant to quinupristin/dalfopristin (Q/D), 28 strains (17.6%) showed intermediate resistance to Q/D (MIC: 2 μg/ml). The erm(B) gene was detected in 139 strains (87.4%), and msrC was found in all the strains examined, whereas no other known MLSB resistance genes were identified. The erm(B) regulator region (RR) containing a coding region of the leader peptide was classified into 13 genetic variations (L1-L3, M, S1-S7, D, and R genotypes) in 56 strains. However, no relatedness was identified between the erm(B) RR genotype and EM resistance, or reduced susceptibility to Q/D, although most of Q/D-intermediate strains were assigned to the L1, L2, and S1 genotypes. Q/D-intermediate strains were classified into five multiple-locus variable-number tandem-repeat analysis (MLVA) types, including four types of clonal complex (CC)-C1, five sequence types (STs), including four STs of CC-17, and several resistance gene/virulence factor profiles. The present study revealed the occurrence of Q/D-intermediate E. faecium, which are composed of heterogeneous strains in Japan, and more genetic diversity in the erm(B) RRs than those reported previously.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Bacterial Typing Techniques; Base Sequence; Drug Resistance, Bacterial; Enterococcus faecium; Genetic Variation; Gram-Positive Bacterial Infections; Humans; Japan; Macrolides; Methyltransferases; Microbial Sensitivity Tests; Molecular Sequence Data; Polymerase Chain Reaction; Sequence Analysis, DNA; Virginiamycin

Vancomycin-resistant Enterococcus faecium (VR E. faecium) is a rare cause of meningitis and is associated with substantial mortality. Limited therapeutic options are available for the treatment of VR E. faecium meningitis. The optimum therapy has not been established.. We retrospectively identified adult cases of meningitis due to VR E. faecium that occurred at the Massachusetts General Hospital from 1999 to 2011 and performed a literature search for published adult cases using Medline and Embase.. At our institution, 4 cases of meningitis due to VR E. faecium were identified. Three out of our 4 cases were successfully treated with linezolid in combination with rifampicin, or with daptomycin in combination with quinupristin-dalfopristin (QD), and 1 out of 4 with linezolid monotherapy. The literature search yielded 18 cases published to date. Published cases showed bacterial cure with linezolid, chloramphenicol or QD (intravenous (IV) and intrathecal (IT)) monotherapy, or linezolid in combination with ampicillin, gentamicin, rifampicin or chloramphenicol, or daptomycin in combination with gentamicin or QD.. Bacterial cure of meningitis due to VR E. faecium can be achieved with various antimicrobial drugs used as monotherapy or in combination. IT in addition to IV therapy should be considered dependent on the pharmacological properties of the drugs. We also reported the successful treatment of a case with a vancomycin-resistant, linezolid-intermediate isolate with QD and daptomycin. The paucity of cases with this clinical syndrome does not allow the identification of an optimal treatment regimen.

Topics: Acetamides; Adult; Anti-Bacterial Agents; Daptomycin; Enterococcus faecium; Female; Gram-Positive Bacterial Infections; Humans; Linezolid; Male; Meningitis, Bacterial; Microbial Sensitivity Tests; Middle Aged; Oxazolidinones; Retrospective Studies; Vancomycin Resistance; Virginiamycin

This study updates the activity of telavancin against Gram-positive pathogens collected from USA hospitals (2007-2009). Telavancin (MIC(50/90), 0.12/0.25 μg/mL) was active against coagulase-negative staphylococci and methicillin-resistant Staphylococcus aureus (100% susceptible), for which only daptomycin (MIC(50/90), 0.25/0.5 μg/mL; 99% susceptible) and quinupristin/dalfopristin (MIC(50/90), ≤ 0.25-0.5/0.5 μg/mL; 99% susceptible) exhibited similar activity. Telavancin (MIC(50/90), 0.25/0.5 μg/mL) inhibited 96.5% of Enterococcus faecalis at the Food and Drug Administration breakpoint (MIC, ≤ 1 μg/mL), where ampicillin (99.9% susceptible), daptomycin (99.9% susceptible), and linezolid (100% susceptible) also demonstrated high-level coverage. Telavancin inhibited, respectively, 100.0% and 91.7% of VanB-phenotype E. faecalis and E. faecium at ≤ 1 μg/mL, whereas it was less active against VanA strains. Telavancin was uniformly active against Streptococcus pneumoniae and resistant subsets, and demonstrated good potency (MIC(90), 0.06-0.12 μg/mL) against other streptococci, regardless of resistance to other drugs. This assessment reveals potent activity of telavancin against Gram-positive isolates collected from USA hospitals with no evidence of emergence of resistance.

Topics: Aminoglycosides; Anti-Bacterial Agents; Cross Infection; Daptomycin; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Hospitals; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; United States; Virginiamycin

Fifty-four quinupristin/dalfopristin-resistant Enterococcus faecium (QDREF) isolated from chickens and pigs during 2002-2003 in Korea were screened by PCR for the presence of streptogramin resistance genes vatD, vatE, and vgbA, and macrolide resistance gene ermB. None of the QDREF isolates carried vgbA and vatD genes, while vatE and ermB were detected in 9.2% and 74% of the isolates, respectively. Twenty-six percent (14/54) of the QDREF isolates contained none of the resistance determinants tested. Pulsed-field gel electrophoresis (PFGE) patterns revealed high heterogeneity: 47 different patterns for 54 QDREF evaluated. Identical PFGE types were observed in two pairs of chicken isolates and a pair of pig isolates, respectively, but chicken isolates did not share PFGE pattern with pig isolates, suggesting clonal spread of QDREF strain between the same species of animals but not between different species of animals. This is the first report, to our knowledge, of vatE-positive E. faecium isolates and also the first evidence of clonal spread of QDREF strain between animals in Korea.

Topics: Animals; Anti-Bacterial Agents; Chickens; Drug Resistance, Multiple, Bacterial; Enterococcus faecium; Gram-Positive Bacterial Infections; Korea; Poultry Diseases; Streptogramins; Swine; Swine Diseases; Virginiamycin

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.

Topics: Acetamides; Adult; Aged; Anti-Bacterial Agents; Bacteremia; Chi-Square Distribution; Enterococcus faecium; Female; Gram-Positive Bacterial Infections; Humans; Linezolid; Logistic Models; Male; Middle Aged; Oxazolidinones; Prognosis; Risk Factors; Treatment Outcome; Vancomycin Resistance; Virginiamycin

The last decade saw an alarming increase in antibiotic resistance in infections, with more than 13 million deaths per year from infections. Counter strategies include hygiene, antibiotic restriction and new antibiotics such as quinupristin, linezolid, tigecycline, daptomycin and dalbavancin. Presently, pharmacogenomics with basic research is revealing new antimicrobial peptides and is applying old drugs in new ways to break resistance. New approaches with host-directed drug targeting emerge to circumvent resistance. A future systems perspective from large-scale molecular techniques and bioinformatic modeling allows pharmacogenomics to reveal new intervention angles. This includes the fight against resistance and its transmission, improved vaccines, disarmament of microbes and antibiotic options from novel molecular targets (lipids, RNA and carbohydrates). Such a system perspective is also essential for improved diagnostics and individualized medicine. However, an increase in public awareness and closer cooperation of industry and basic research are essential to turn research into powerful new drugs that will enable us to treat new arising infections in the future.

Topics: Acetamides; Animals; Anti-Bacterial Agents; Bacterial Infections; Computational Biology; Daptomycin; Drug Delivery Systems; Drug Resistance, Microbial; Drug Resistance, Multiple, Bacterial; Forecasting; Gram-Positive Bacterial Infections; Gram-Positive Cocci; Humans; Linezolid; Minocycline; Oxazolidinones; Pharmacogenetics; Systems Biology; Tigecycline; Virginiamycin

Topics: Animals; Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Poultry Diseases; Swine Diseases; Virginiamycin

Earlier reports have shown a high mortality of invasive infection due to vancomycin-resistant Enterococcus faecium (VREF). Most of these studies have been conducted in US hospitals prior to the advent of newer VREF-active antimicrobials, and the reported poor outcomes have been explained by the limited choices for effective antimicrobial therapy.. A total of 25 cases of invasive VREF infection were seen during an outbreak in a tertiary care hospital. Patient characteristics and outcomes were evaluated by a structured retrospective chart review and descriptive analysis.. Severe underlying diseases such as leukemia not in remission (86%) were highly prevalent among patients with invasive VREF infection. Fifty-two percent of underlying diseases and/or comorbidities were considered according to the McCabe classification as rapidly fatal. Most patients had received high-dose cytotoxic chemotherapy, and many were neutropenic at the onset of VREF infection. Concomitant infection due to other organisms was found in 48% of the patients. All patients had received extensive antibiotic treatment prior to the onset of VREF infection. Resistance to linezolid was observed in four cases. Overall survival at day 30 was 48%. Four deaths were considered to be directly related to VREF infection.. Invasive VREF infection during this outbreak was confined to patients with severe underlying comorbidity. The mortality of VREF infection remained high, despite treatment with newer VREF-active antibiotics such as linezolid and quinupristin-dalfopristin.

Topics: Acetamides; Adult; Aged; Anti-Bacterial Agents; Comorbidity; Disease Outbreaks; Enterococcus faecium; Female; Gram-Positive Bacterial Infections; Hospitals; Humans; Linezolid; Male; Middle Aged; Oxazolidinones; Retrospective Studies; Treatment Outcome; United States; Vancomycin Resistance; Virginiamycin

During 2005-2006, a total of 865 Enterococcus faecium isolated from patients from eight Greek hospitals were tested for susceptibility to quinupristin/dalfopristin (Q/D). Among them, 250 genetically unrelated strains (28.9%) were found to be intermediate-resistant to Q/D (minimum inhibitory concentration (MIC) 1.5-4 mg/L); all were resistant to dalfopristin (MIC=16-64 mg/L), whilst 69% were resistant to quinupristin, carrying the ermB gene. No strain was found to carry any of the known genes, such as vatE and vatD, involved in Q/D resistance, indicating that a non-transferable undetermined mechanism is responsible for the expression of low-level Q/D resistance. The high percentage of Q/D-intermediate-resistant E. faecium in Greece was not associated with prior consumption of the agent or with the veterinary use of virginiamycin.

Topics: Acetyltransferases; Bacterial Proteins; Drug Resistance, Bacterial; Enterococcus faecium; Gram-Positive Bacterial Infections; Greece; Humans; Microbial Sensitivity Tests; Virginiamycin

The impact of antibiotic resistance on the clinical outcome of patients with vancomycin-resistant Enterococcus (VRE) bacteremia remains unclear. There are limited data comparing patient outcomes during the early era of vancomycin resistance with the period of more-potent antibiotic availability.. A retrospective review was conducted of 113 patients with VRE bacteremia at a single institution from August 1993 to September 2005. Patients were assigned to a group on the basis of initial antibiotic choice for treatment of VRE (linezolid, quinupristin-dalfopristin, or combinations of other agents, before newer options were available). Outcome measurements were examined for the initial episode of VRE bacteremia, and multiple logistic regression analysis was performed to compare group outcomes.. Overall mortality was 37.2% (42 of 113 patients). VRE bacteremia caused or significantly contributed to death in 29 (69%) of 42 patients. Seventy-one patients were initially treated with linezolid, 20 with quinupristin-dalfopristin, and 22 with combinations of other agents. Univariate analysis indicated significantly more deaths in the quinupristin-dalfopristin group (odds ratio, 5.45; 95% confidence interval, 1.89-15.9) and in the other-agents group (odds ratio, 2.94; 95% confidence interval, 1.09-7.94) than in the linezolid group. However, after adjustment for severity of illness, treatment group was not a significant independent factor.. Despite the development of antimicrobial agents with greater potency against VRE, a significant change in clinical outcome was not observed. This suggests that vancomycin resistance does not significantly influence mortality and points to the continued need for prospective, randomized clinical trials.

Topics: Acetamides; Adult; Anti-Bacterial Agents; Bacteremia; Enterococcus; Female; Gram-Positive Bacterial Infections; Humans; Linezolid; Male; Oxazolidinones; Retrospective Studies; Treatment Outcome; Vancomycin Resistance; Virginiamycin

Topics: Acetamides; Anti-Bacterial Agents; Cross Infection; Daptomycin; Drug Resistance, Bacterial; Enterococcus faecium; Glycopeptides; Gram-Positive Bacterial Infections; Humans; In Vitro Techniques; Linezolid; Microbial Sensitivity Tests; Minocycline; Oxazolidinones; Tigecycline; Virginiamycin

Putative virulence factors of Enterococcus faecalis have been proposed by several workers and, by analogy, these have been linked to strains of endodontic origin. However, their distribution within the cell population is unknown. In the present study, isolates were taken from the dental root canals of two defined human populations, Lithuanian and Finnish, and examined for a range of virulence properties. In addition, surface-associated molecules and intracellular proteins were compared using matrix-assisted laser desorption-ionization/mass spectrometry (MALDI-TOF-MS) and ProteinChip capture/MS (SELDI-TOF-MS), respectively.. Twenty-three Lithuanian and 35 Finnish dental root canal isolates were included. The esp, gelE, ace and efaA genes were detected by polymerase chain reaction, and cytolysin and gelatinase phenotypes were determined by hydrolysis of horse blood agar and gelatine agar, respectively. Protein extracts and surface-associated molecules of whole cells were analysed by SELDI-TOF-MS and MALDI-TOF-MS, respectively.. Presence of esp (n = 15), cytolysin (n = 9), ace (n = 55) and efaA (n = 58) was not statistically different in the two samples, whereas gelE and gelatinase production was detected more frequently in the Finnish material (chi-squared, P < 0.01). Analysis of protein profiles by SELDI-TOF-MS showed clustering of cytolysin-producing strains, whereas MALDI-TOF-MS generated profiles that clustered according to the samples' origin and, furthermore, to atypical quinupristin-dalfopristin susceptibility.. A high prevalence of virulence factors was demonstrated in both population types. SELDI-TOF-MS and MALDI-TOF-MS proved useful in distinguishing between different E. faecalis phenotypes and they may be useful technologies for elucidating the eco-distribution of E. faecalis in humans.

Topics: Anti-Bacterial Agents; Antigens, Bacterial; Bacterial Proteins; Carrier Proteins; Dental Pulp Cavity; Enterococcus faecalis; Finland; Gelatinases; Gram-Positive Bacterial Infections; Humans; Lithuania; Membrane Glycoproteins; Membrane Proteins; Molecular Epidemiology; Perforin; Periapical Periodontitis; Pore Forming Cytotoxic Proteins; Protein Array Analysis; Proteome; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Virginiamycin; Virulence Factors

VanA glycopeptide resistance has persisted on broiler farms in the UK despite the absence of the antimicrobial selective pressure, avoparcin. This study aimed to investigate the contribution of horizontal gene transfer of Tn1546 versus clonal spread in the dissemination of the resistance.. One hundred and one vancomycin-resistant Enterococcus faecium isolated from 19 unrelated farms have been investigated. Tn1546 characterization by long PCR and ClaI-digestions of amplicons showed a very low diversity of Tn types (n=4) in comparison to the high genotypic diversity demonstrated by PFGE (n=62). Conjugation experiments were carried out to assess the transfer of vancomycin resistance. Co-transfer of vanA together with erm(B) positioned on the same conjugative plasmid containing a replicon similar to pRE25 was demonstrated and also the presence of different plasmid replicons, associated with antimicrobial resistance on several unrelated farms.. Horizontal transfer of vancomycin resistance may play a more important role in the persistence of antimicrobial resistance than clonal spread. The presence of different plasmid replicons, associated with antimicrobial resistance on several unrelated farms, illustrates the ability of these enterococci to acquire and disseminate mobile genetic elements within integrated livestock systems.

Topics: Animals; Blotting, Southern; Chickens; DNA Primers; DNA Transposable Elements; Enterococcus faecium; Gene Transfer, Horizontal; Gram-Positive Bacterial Infections; Lincosamides; Macrolides; Plasmids; Poultry Diseases; Replicon; Reverse Transcriptase Polymerase Chain Reaction; Streptogramin B; United Kingdom; Vancomycin Resistance; Virginiamycin

The antibacterial activities of clindamycin, synercid, telithromycin, linezolid and mupirocin were evaluated against erythromycin-resistant Gram-positive coccal clinical isolates collected in Korean hospitals. In Staphylococcus aureus, synercid, linezolid and mupirocin were the most active agents. Against coagulase-negative staphylococci (CNS), synercid, linezolid and mupirocin were also active. Telithromycin and synercid resistance was common against enterococci, only linezolid and mupirocin were active. The reason of low activity of telithromycin against staphylococci and enterococci is because most of the isolates were constitutively resistant to erythromycin. Synercid, telithromycin, linezolid and mupirocin were active against streptococci.

Topics: Acetamides; Anti-Bacterial Agents; Clindamycin; Drug Resistance, Bacterial; Erythromycin; Gram-Positive Bacterial Infections; Gram-Positive Cocci; Humans; Ketolides; Korea; Linezolid; Microbial Sensitivity Tests; Mupirocin; Oxazolidinones; Virginiamycin

We compared the results of Quinupristin/Dalfopristin (Q/D) susceptibility tests by the Positive Combo Panel (Type 11) of the MicroScan Walk Away 96 analyzer (Dade Behring, Inc.) with those obtained by the reference agar dilution method. From September 2003 to August 2004, a total of 410 E. faecium isolates were obtained from clinical samples. Of these, 65 (15.9%) strains were non-susceptible, and 345 (84.1%) strains were susceptible to Q/D. We collected consecutively 65 Q/D non-susceptible E. faecium isolates (42 resistant, 23 intermediate), and randomly selected 32 Q/D susceptible E. faecium isolates using the MicroScan system. The minimal inhibitory concentrations (MICs) of Q/D, vancomycin, and teicoplanin were determined by the agar dilution method according to CLSI guidelines. The agreement rates between the two methods were 100% for Q/D-susceptible strains, 85.7% for Q/D-resistant strains, and 26.1% for Q/D-intermediate strains of E. faecium. The major error rate (S-->R) was 11.9%, and the minor error rate (S-->I) was 13.0%. No very major errors were found. We conclude that for MicroScan 'non-susceptible' test results for Q/D, it is necessary to confirm the result using a reference method. The Q/D-resistance rate was higher in glycopeptide-susceptible (78.0% for vancomycin, 82.0% for teicoplanin) than glycopeptide-resistant E. faecium (22.0% for vancomycin, 16.0% for teicoplanin). Further studies are needed to determine whether Q/D use in hospitals or virginiamycin use in animals, or other factors, are responsible for the high rates of glycopeptide-susceptible and Q/D-resistant E. faecium strains in Korea.

Topics: Anti-Bacterial Agents; Colony Count, Microbial; Drug Resistance, Microbial; Enterococcus faecium; Gram-Positive Bacterial Infections; Microbial Sensitivity Tests; Reproducibility of Results; Teicoplanin; Vancomycin; Virginiamycin

It is a hot clinical issue whether newly approved antimicrobial agents such as daptomycin, linezolid, quinupristin/dalfopristin (synercid) and tigecycline are active enough to be used for infections caused by vancomycin resistant bacteria. We performed susceptibility tests for mupirocin, which is in widespread clinical use in Korea, and four new antimicrobials, daptomycin, linezolid, quinupristin/dalfopristin and tigecycline, against vancomycin-resistant Enterococcus faecalis and Enterococcus faecium isolated from Korean patients in 1998 and 2005 to evaluate and compare the in vitro activity of these antimicrobials. Among these agents, quinupristin/dalfopristin, which is rarely used in hospitals in Korea, showed relatively high resistance to several vancomycin-resistant enterococci (VRE) isolated in 2005. Likewise, daptomycin, linezolid and tigecycline have not yet been in clinical use in Korea. However, our results showed that most of the 2005 VRE isolates were already resistant to linezolid and daptomycin (highest minimum inhibitory concentration (MIC) value >100 microg/ml). Compared with the other four antimicrobial agents tested in this study, tigecycline generally showed the greatest activity against VRE. However, four strains of 2005 isolates exhibited resistance against tigecycline (MIC >12.5 microg/ml). Almost all VRE were resistant to mupirocin, whereas all E. faecium isolated in 1998 were inhibited at concentrations between 0.8 to approximately 1.6 microg/ml. In conclusion, resistances to these new antimicrobial agents were exhibited in most of VRE strains even though these new antibiotics have been rarely used in Korean hospitals.

Topics: Acetamides; Anti-Bacterial Agents; Daptomycin; Drug Resistance, Bacterial; Enterococcus faecalis; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Korea; Linezolid; Microbial Sensitivity Tests; Minocycline; Mupirocin; Oxazolidinones; Tigecycline; Vancomycin Resistance; Virginiamycin

In this study, we investigated the change in the resistance of Enterococcus faecium strains isolated from Dutch broilers against erythromycin and virginiamycin in 1998, 1999 and 2001 by logistic regression analysis and survival analysis. The E. faecium strains were isolated from caecal samples that had been randomly collected from six slaughterhouses. Moreover, between the sample collection in 1998 and the sample collection in 1999, virginiamycin and the macrolide antibiotics (of which erythromycin is a member) have been banned in The Netherlands from use in broiler feeds as growth promoter. In the logistic regression analysis we used the internationally accepted cut-off values to determine whether bacteria were resistant or not. In the survival analysis, inhibition of bacterial growth was the event and time to event was replaced by concentration of antibiotic to event. As a consequence, changes in the growth of bacteria can be tested over an entire range of concentrations and no cut-off value for resistance has to be determined. We performed the survival analysis by use of a Cox logistic model with an odds ratio (OR) for the increase of the odds of the basic hazard rate as outcome. Both the logistic regression and the survival analyses showed that resistance to erythromycin and virginiamycin decreased during the study period. In the logistic regression model the ORs associated with the fraction of bacteria inhibited by the antibiotics in 2001 as compared to 1998 were 3.76 (2.57-5.49) for erythromycin and 11.65 (7.68-17.66) for virginiamycin. The corresponding ORs from the survival analysis were lower; 2.88 (2.21-3.76) and 2.11 (1.80-2.49), respectively. The reason for the differences between the ORs of the survival analysis and the logistic regression analysis is probably because most changes in resistance included the cut-off value and logistic regression specifically examines those changes.

Topics: Abattoirs; Animals; Anti-Bacterial Agents; Cecum; Chickens; Colony Count, Microbial; Drug Resistance, Bacterial; Enterococcus faecium; Erythromycin; Gram-Positive Bacterial Infections; Logistic Models; Microbial Sensitivity Tests; Netherlands; Odds Ratio; Poultry Diseases; Proportional Hazards Models; Reference Values; Survival Analysis; Virginiamycin

Topics: Adolescent; Anti-Bacterial Agents; Arthralgia; Child; Child, Preschool; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Infant; Muscular Diseases; Organ Transplantation; Treatment Outcome; Vancomycin Resistance; Virginiamycin

Enterococcus faecalis strains with multiple antibiotic resistances can cause infections that are difficult to treat. The microbial flora in treatment-resistant apical periodontitis is dominated by E. faecalis, and is a potential source of infections at other sites.. Sensitivities to a range of antibiotics were determined for 59 endodontic E. faecalis isolates from Finland and Lithuania. The DNA sequence of the gene responsible for the species' intrinsic quinupristin-dalfopristin resistance, lsa, was determined from two isolates with diminished resistance. Four pairs of isolates from the same root canal were typed by pulsed-field gel electrophoresis.. A high prevalence of resistance to rifampicin was found, whereas all isolates were susceptible or showed intermediate susceptibility to penicillin and ampicillin and four isolates were unusually susceptible to cefotaxime. No vancomycin or high-level gentamicin resistance was detected. Nine of 59 isolates were susceptible to quinupristin-dalfopristin. A fully quinupristin-dalfopristin-susceptible isolate also susceptible to clindamycin produced a truncated Lsa polypeptide, and an isolate with borderline quinupristin-dalfopristin-susceptibility had mutations proximal to the predicted ribosomal binding site. Pulsed-field gel electrophoresis showed that the same root canal could harbor two different strains of E. faecalis during the course of the same infection.. Despite the differing antibiotic usage in Finland and Lithuania, E. faecalis from endodontic infections in these countries showed similar susceptibility patterns with levels of resistance considered typical for the species, and decreased resistance to clindamycin and quinupristin-dalfopristin as well as lesions in the lsa gene which were similar to those described in other clinical isolates.

Topics: Anti-Bacterial Agents; ATP-Binding Cassette Transporters; Base Sequence; Dental Pulp Cavity; DNA Mutational Analysis; Drug Resistance, Multiple, Bacterial; Electrophoresis, Gel, Pulsed-Field; Enterococcus faecalis; Finland; Genes, Bacterial; Gram-Positive Bacterial Infections; Humans; Latvia; Microbial Sensitivity Tests; Molecular Epidemiology; Molecular Sequence Data; Periapical Periodontitis; Virginiamycin

In this study, quinupristin/dalfopristin (Q/D)-resistant Enterococcus faecium isolates (33 from poultry farms and 1 from a human outpatient) with Q/D minimal inhibitory concentrations ranging from 4 microg/mL to 32 microg/mL were analysed. Polymerase chain reaction detected the presence of vat(E) in all isolates. Using pulsed-field gel electrophoresis (PFGE), 14 distinct PFGE patterns were identified. The human E. faecium isolate was distinguishable from the 33 farm isolates by PFGE. Southern hybridisation localised the vat(E) gene to an 11 kb plasmid and resulted in five plasmid hybridisation types. The vat(E)-carrying plasmid from the human isolate showed a nearly identical hybridisation pattern to a plasmid from a farm isolate. This study showed that the vat(E) gene, conferring resistance to Q/D, was carried on different plasmids in a heterogeneous group of E. faecium, some of which may be acquired by E. faecium capable of infecting humans.

Topics: Acetyltransferases; Animals; Anti-Bacterial Agents; Bacterial Proteins; Blotting, Southern; Chickens; Electrophoresis, Gel, Pulsed-Field; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests; Plasmids; Polymerase Chain Reaction; Poultry Diseases; Turkeys; Virginiamycin

Three hundred sixty-one quinupristin-dalfopristin (Q-D)-resistant Enterococcus faecium (QDREF) isolates were isolated from humans, turkeys, chickens, swine, dairy and beef cattle from farms, chicken carcasses, and ground pork from grocery stores in the United States from 1995 to 2003. These isolates were evaluated by pulsed-field gel electrophoresis (PFGE) to determine possible commonality between QDREF isolates from human and animal sources. PCR was performed to detect the streptogramin resistance genes vatD, vatE, and vgbA and the macrolide resistance gene ermB to determine the genetic mechanism of resistance in these isolates. QDREF from humans did not have PFGE patterns similar to those from animal sources. vatE was found in 35%, 26%, and 2% of QDREF isolates from turkeys, chickens, and humans, respectively, and was not found in QDREF isolates from other sources. ermB was commonly found in QDREF isolates from all sources. Known streptogramin resistance genes were absent in the majority of isolates, suggesting the presence of other, as-yet-undetermined, mechanisms of Q-D resistance.

Topics: Animals; Animals, Domestic; Anti-Bacterial Agents; Bacterial Proteins; Cattle; Chickens; Drug Resistance, Bacterial; Electrophoresis, Gel, Pulsed-Field; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Meat; Turkeys; United States; Virginiamycin

The escalation of antibiotic resistance among Gram-positive pathogens presents increasing treatment challenges and requires the development of innovative therapeutic agents. Here, we present the antimicrobial properties of structurally unusual bisanthraquinone metabolites produced by a marine streptomycete and four semi-synthetic derivatives. Biological activities were measured against clinically derived isolates of vancomycin-resistant Enterococcus faecium (VRE), and methicillin-susceptible, methicillin-resistant, and tetracycline-resistant Staphylococcus aureus (MSSA, MRSA, and TRSA, respectively). The most potent antibiotic displayed MIC(50) values of 0.11, 0.23, and 0.90microM against a panel (n=25 each) of clinical MSSA, MRSA, and VRE, respectively, and was determined to be bactericidal by time-kill analysis.

Topics: Anthraquinones; Anti-Bacterial Agents; Cells, Cultured; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Methicillin Resistance; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus; Tetracycline Resistance; Vancomycin Resistance; Virginiamycin

The incidence of multidrug-resistant Enterococcus faecium is increasing despite advances in antibacterial therapy. Thus, new antibiotics are required to treat hospital- or community-acquired infections caused by these multidrug-resistant organisms. The aim of this study was to compare the therapeutic efficacy of quinupristin-dalfopristin (QD) alone, or in combination with gentamicin (G), teicoplanin (T), imipenem (I) or levofloxacin (L) against a strain of multidrug-resistant E. faecium in an experimental model of aortic valve endocarditis in rabbits. The study group consisted of 28 control animals. Eighty-two animals were treated with one of the following antibiotic regimens: G1: 18 animals QD (30 mg/kg/8 h); G2: 18 animals QD+G (6 mg/kg/12 h); G3: 16 animals QD+T (20 mg/kg/12 h); G4: 14 animals QD+I (60 mg/kg/8 h); and G5: 16 animals QD+L (20 mg/kg/12 h). The response to therapy was determined by the comparison of the number of CFU/g of E. faecium in each vegetation. In vitro, time-kill studies looking for synergy for the combinations that showed better efficacy in vivo were done. The sensitivity of the strain was intermediate to QD, resistant to T and I, and sensitive to L. There was no high-level resistance to G. QD alone revealed a significant decrease (p <0.001) in the CFU/g in the control group (9.49 vs. 7.31). There were no differences in the average of CFU/g between the QD alone (G1), QD+G (G2) and QD+T (G3) groups. These three groups revealed a significant difference in decrease of CFU/g respect of the group control (p <0.001). There were no differences in the average of CFU/g between QD+I (G4) and QD+T (G5). These two groups revealed the greatest decrease in average CFU/g (G4: 4.38 and G5: 4.04) with differences respect of the group control (p <0.0001) and respect of the groups G1, G2 and G3 (p <0.001). We did not detect any alteration of MIC from QD in the course of the treatment for either of the final isolations. Only the time kill corresponding to concentrations of I 32 mg/l (0.25 x MIC) and QD 1 mg/l (0.25 x MIC presents a descending slope in the curve at 4 and 8 h, suggesting an early synergy phenomenon, which was lost after 8 h. In light of these results, the combination QD with I and L may be considered suitable alternatives for the treatment of multiresistant E. faecium.

Topics: Aged; Animals; Anti-Bacterial Agents; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Endocarditis, Bacterial; Enterococcus faecium; Female; Gentamicins; Gram-Positive Bacterial Infections; Humans; Imipenem; Levofloxacin; Microbial Sensitivity Tests; Ofloxacin; Rabbits; Teicoplanin; Virginiamycin

To evaluate the antibiotic susceptibilities of Propionibacterium acnes isolates from central nervous system (CNS) infections to agents used in current treatment regimens.. MICs of 16 reference antibiotics were determined by an agar dilution method for 24 consecutive strains of P. acnes isolated from individual patients with intracranial empyema or brain abscess. Bactericidal activities of antibiotics against P. acnes PAN14 were studied at 0.25-2 x MIC using a time-kill method.. All of the isolates were resistant to fosfomycin, intermediate or resistant to metronidazole and susceptible to all the other antibiotics tested, except for nine strains, which were intermediate to ofloxacin. Among antibiotics tested alone in time-kill experiments, vancomycin was the most effective drug and exhibited bactericidal activity after 24 h at 1x and 2 x MIC, whereas cefotaxime and ciprofloxacin were bactericidal after 48 h at 2 x MIC. No significant bactericidal activity could be demonstrated with the other antibiotics tested alone. The addition of cefotaxime to vancomycin resulted in bactericidal activity at lower concentrations (0.5 x MIC), whereas synergy was observed between quinupristin/dalfopristin and cefotaxime at 2 x MIC. In contrast, antagonism was observed between cefotaxime and linezolid, and ciprofloxacin and clindamycin.. Our data suggest that P. acnes isolates causing CNS infections remain highly susceptible to most antibiotics used for the treatment of such infections. Moreover, we showed that cefotaxime, vancomycin and ciprofloxacin possess good bactericidal activities against P. acnes, and that these activities may be enhanced when vancomycin is combined with cefotaxime or when cefotaxime is combined with quinupristin/dalfopristin.

Topics: Acetamides; Cefotaxime; Central Nervous System Infections; Drug Therapy, Combination; Gram-Positive Bacterial Infections; Humans; Linezolid; Microbial Sensitivity Tests; Oxazolidinones; Propionibacterium acnes; Vancomycin; Virginiamycin

Risk management of food-animal antibiotics has reached a crucial juncture for public health officials worldwide. While withdrawals of animal antibiotics previously used to control animal bacterial illnesses are being encouraged in many countries, the human health impacts of such withdrawals are only starting to be understood. Increases in animal and human bacterial illness rates and antibiotic resistance levels in humans in Europe despite bans on animal antibiotics there have raised questions about how animal antibiotic use affects human health. This paper presents a quantitative human health risk and benefits assessment for virginiamycin (VM), a streptogramin antibiotic recommended for withdrawal from use in food animals in several countries. It applies a new quantitative Rapid Risk Rating Technique (RRRT) that estimates and multiplies data-driven exposure, dose-response, and consequence factors, as suggested by WHO (2003) to estimate human health impacts from withdrawing virginiamycin. Increased human health risks from more pathogens reaching consumers if VM use is terminated (6660 estimated excess campylobacteriosis cases per year in the base case) are predicted to far outweigh benefits from reduced streptogramin-resistant vancomycin-resistant Enterococcus faecium (VREF) infections in human patients (0.27 estimated excess cases per year in the base case). While lack of information about impacts of VM withdrawal on average human illnesses-per-serving of food animal meat precludes a deterministic conclusion, it appears very probable that such a withdrawal would cause many times more human illnesses than it would prevent. This qualitative conclusion appears to be robust to several scientific and modeling uncertainties.

Topics: Animal Husbandry; Animals; Animals, Domestic; Anti-Bacterial Agents; Drug Resistance; Drug Resistance, Microbial; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Public Health; Risk Assessment; Virginiamycin

Our objective was to evaluate and compare the in vitro activity of daptomycin, linezolid, and quinupristin/dalfopristin against clinical bloodstream isolates of Gram-positive pathogens from a large cancer center in the Northeastern United States. Minimum inhibitory concentrations (MICs) were determined for daptomycin, quinupristin/dalfopristin, and linezolid against 258 isolates; bactericidal activity was evaluated using time-kill experiments against 14 representative pathogens. Vancomycin-resistant enterococci represented the largest proportion of bacteria tested (32% of the isolates), followed by methicillin-resistant coagulase-negative staphylococci (23%), and vancomycin sensitive enterococci (14%). Against staphylococci, the MIC90 was 1 microg/mL for both daptomycin and quinupristin/dalfopristin and 4 microg/mL for linezolid. Against enterococci, the MIC90 for both daptomycin and linezolid was 4 microg/mL and was 16 microg/mL for quinupristin/dalfopristin. The quinupristin/dalfopristin MIC90 for Enterococcus faecium was 2 microg/mL. Two enterococci were linezolid resistant and remained susceptible to daptomycin. In vitro time-kill studies found daptomycin to be rapidly bactericidal against the majority of organisms tested, killing 99.9% of bacteria within 6 h. Quinupristin/dalfopristin was bactericidal against staphylococci and bacteriostatic against most enterococci. Linezolid was bacteriostatic against all organisms evaluated. Daptomycin, quinupristin/dalfopristin, and linezolid each demonstrated in vitro activity against this collection of organisms. Future clinical studies to evaluate a potential role for these agents in the management of infections in cancer patients, including the treatment of febrile neutropenia, appear warranted.

Topics: Acetamides; Anti-Bacterial Agents; Daptomycin; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Immunocompromised Host; Linezolid; Microbial Sensitivity Tests; Neoplasms; Oxazolidinones; Virginiamycin

Linezolid is an oxazolidinone antibiotic used in the treatment of infections caused by vancomycin-resistant enterococci. Resistance to linezolid has been associated with a G2576U mutation in domain V of the 23S rRNA.. We present clinical details and susceptibility data from multiple Enterococcus faecium strains isolated from a liver transplant patient over 13 months. MICs of linezolid, vancomycin and quinupristin/dalfopristin were determined using Etest. Molecular typing was performed by pulsed-field gel electrophoresis. Domain V of the 23S rRNA gene in the vancomycin-resistant Enterococcus faecium was amplified. Linezolid concentrations were analysed by HPLC.. We report the emergence of resistance to linezolid in a vancomycin-resistant Enterococcus faecium during linezolid treatment. After discontinuation of the linezolid therapy, the isolate reverted to susceptibility. However, after re-administration of linezolid the vancomycin-resistant Enterococcus faecium became resistant to linezolid again. The isolates that were resistant to linezolid had a G2576T mutation in their 23S rDNA.. We describe a clinical case that shows the shift of a vancomycin-resistant Enterococcus faecium from linezolid resistance to susceptibility and then back to resistance again related to linezolid therapy.

Topics: Acetamides; Adult; Anti-Bacterial Agents; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Linezolid; Liver Transplantation; Male; Microbial Sensitivity Tests; Mutation; Oxazolidinones; Time Factors; Vancomycin Resistance; Virginiamycin

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.

Topics: Animal Feed; Animal Husbandry; Animals; Anti-Bacterial Agents; Chickens; Denmark; Drug Administration Schedule; Drug Resistance, Bacterial; Enterococcus faecium; Erythromycin; Gram-Positive Bacterial Infections; Linear Models; Logistic Models; Markov Chains; Microbial Sensitivity Tests; Monte Carlo Method; Oligosaccharides; Poultry Diseases; Time Factors; Vancomycin; Virginiamycin

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 200

Topics: Animal Husbandry; Animals; Australia; Chickens; Drug Resistance, Bacterial; Enterococcus faecium; Food Contamination; Food Microbiology; Gram-Positive Bacterial Infections; Humans; Meat; Models, Biological; Risk Assessment; Risk Management; United States; Virginiamycin

Infections may complicate cardiovascular surgery or may require surgery as an adjunct to successful treatment. Staphylococci, which are among the major pathogenic bacteria causing such infections, can be resistant to many of the older antibiotics.. The properties of several newer antimicrobial agents, recently approved or still investigational, were reviewed, with an emphasis on in vitro activities against staphylococci.. The 2 approved agents, linezolid and quinupristin-dalfopristin, and several investigational agents being developed demonstrate in vitro antimicrobial activity against staphylococci. Three of these agents, daptomycin, which was approved by the US Food and Drug Administration in September 2003, and oritavancin and dalbavancin, which are in advanced stages of clinical development, are discussed.. Although clinical studies are required, the in vitro anti-staphylococcal activities of several agents suggest that these antimicrobial agents might be useful options for some infections in patients who are intolerant of older antibiotics or who are infected with organisms that are resistant to older agents.

Topics: Acetamides; Anti-Bacterial Agents; Daptomycin; Drug Resistance, Bacterial; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Linezolid; Lipoglycopeptides; Methicillin Resistance; Oxazolidinones; Staphylococcal Infections; Staphylococcus aureus; Teicoplanin; Virginiamycin

A total of 839 clinical isolates of Gram-positive cocci from Norway including Staphylococcus aureus (n = 214), coagulase negative Staphylococcus spp. (n = 100), Streptococcus pyogenes (n = 99), Streptococcus agalactiae (n = 80), Streptococcus pneumoniae (n = 127), Streptococcus spp. viridans group (n = 70), Enterococcus faecalis (n = 75), and Enterococcus faecium (n = 74), were tested by E-test for susceptibility to a range of antimicrobials including the novel antibiotics quinupristin-dalfopristin and linezolid. Subgroups of oxacillin resistant S. aureus and coagulase negative Staphylococcus spp., penicillin non-susceptible S. pneumoniae and vancomycin resistant Enterococcus spp. were specifically included as they are the intended targets for these new drugs. All isolates were susceptible to linezolid (MIC5o and MIC9o 0.25-2.0 mg/l, MIC range 0.12-2 mg/l). Staphylococcal and streptococcal isolates were also susceptible to quinupristin-dalfopristin except for some intermediately susceptible viridans group isolates (MIC54, and MIC90 0.25-2 mg/l, MIC range 0.125-2 mg/l). Enterococcus faecium (MIC90 = 4.0 mg/l) and Enterococcus faecalis (MIC50 = 8.0 mg/l, MIC90 > or = 32 mg/l) were less susceptible to this substance. There was no linkage between reduced susceptibility to linezolid or quinupristin-dalfopristin and resistance to other classes of antimicrobials. The study demonstrated a high prevalence of in vitro susceptibility to linezolid and quinupristin-dalfopristin, which is necessary for their use in the treatment of infections with resistant Gram-positive pathogens. The results were used to evaluate the appropriateness of breakpoints and to define a baseline for monitoring possible future emergence of resistance to quinupristin-dalfopristin and linezolid in Norway.

Topics: Acetamides; Anti-Infective Agents; Drug Resistance, Bacterial; Gram-Positive Bacterial Infections; Gram-Positive Cocci; Humans; Linezolid; Microbial Sensitivity Tests; Norway; Oxazolidinones; Virginiamycin

The use of antibiotics for animal growth promotion has been controversial because of the potential transfer of antibiotic resistance from animals to humans. Such transfer could have severe public health implications in that treatment failures could result. We have followed a risk assessment approach to evaluate policy options for the streptogramin-class of antibiotics: virginiamycin, an animal growth promoter, and quinupristin/dalfopristin, a antibiotic used in humans. Under the assumption that resistance transfer is possible, models project a wide range of outcomes depending mainly on the basic reproductive number (R(0)) that determines the potential for person-to-person transmission. Counter-intuitively, the benefits of a ban on virginiamycin were highest for intermediate values of R(0), and lower for extremely high or low values of R(0).

Topics: Animal Husbandry; Animals; Animals, Domestic; Anti-Bacterial Agents; Bacterial Infections; Drug Resistance, Bacterial; Enterococcus faecium; Gram-Positive Bacterial Infections; Growth Substances; Health Policy; Humans; Models, Biological; Public Health; Risk Assessment; Streptogramins; Virginiamycin

The susceptibility of 135 vancomycin-resistant Enterococcus faecium bacteremic isolates to linezolid and quinupristin-dalfopristin was determined. All were susceptible to linezolid, while 88% were susceptible to quinupristin-dalfopristin prior to the clinical use of the drugs at our hospital. More than 6 months after their clinical use, a decrease in susceptibility was noted for only linezolid at 83%. This was related in part to a single G2576U gene mutation in domain V of the 23S rRNA gene.

Topics: Acetamides; Anti-Bacterial Agents; Drug Utilization; Electrophoresis, Gel, Pulsed-Field; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Linezolid; Oxazolidinones; Point Mutation; RNA, Bacterial; RNA, Ribosomal, 23S; Vancomycin Resistance; Virginiamycin

Enterococci are uncommon causes of CNS infection. We describe a case of ventriculitis and Ommaya reservoir infection due to vancomycin-resistant Enterococcus faecium successfully treated with the combination of i.v. quinupristin/dalfopristin and i.v. linezolid. The patient deteriorated after receiving three dosages of intraventricular quinupristin/dalfopristin. He recovered after discontinuation of intraventricular quinupristin/dalfopristin.

Topics: Aged; Brain Neoplasms; Central Nervous System Infections; Drug Resistance, Bacterial; Drug Therapy, Combination; Enterococcus faecium; Follow-Up Studies; Gram-Positive Bacterial Infections; Humans; Injections, Intralesional; Lymphoma; Male; Opportunistic Infections; Risk Assessment; Treatment Outcome; Vancomycin; Virginiamycin

Synercid, a new semisynthetic streptogramin-derived antibiotic containing dalfopristin and quinupristin, is used in treatment of life-threatening infections caused by glycopeptide-resistant Enterococcus faecium and other bacterial pathogens. However, dissemination of genes encoding virginiamycin acetyltransferases, enzymes that confer resistance to streptogramins, threatens to limit the medical utility of the quinupristin-dalfopristin combination. Here we present structures of virginiamycin acetyltransferase D (VatD) determined at 1.8 A resolution in the absence of ligands, at 2.8 A resolution bound to dalfopristin, and at 3.0 A resolution in the presence of acetyl-coenzyme A. Dalfopristin is bound by VatD in a similar conformation to that described previously for the streptogramin virginiamycin M1. However, specific interactions with the substrate are altered as a consequence of a conformational change in the pyrollidine ring that is propagated to adjacent constituents of the dalfopristin macrocycle. Inactivation of dalfopristin involves acetyl transfer from acetyl-coenzyme A to the sole (O-18) hydroxy group of the antibiotic that lies close to the side chain of the strictly conserved residue, His-82. Replacement of residue 82 by alanine is accompanied by a fall in specific activity of >105-fold, indicating that the imidazole moiety of His-82 is a major determinant of catalytic rate enhancement by VatD. The structure of the VatD-dalfopristin complex can be used to predict positions where further structural modification of the drug might preclude enzyme binding and thereby circumvent Synercid resistance.

Topics: Acetyltransferases; Alanine; Anti-Bacterial Agents; Binding Sites; Catalysis; Crystallography, X-Ray; Drug Resistance; Enterococcus faecium; Gram-Positive Bacterial Infections; Histidine; Ligands; Models, Chemical; Models, Molecular; Mutagenesis, Site-Directed; Protein Binding; Protein Conformation; Virginiamycin

To demonstrate nosocomial transmission of Enterococcus faecium resistant to quinupristin/dalfopristin and vancomycin/teicoplanin among paediatric patients in a German hospital ward.. Multiply-resistant E. faecium were isolated from three female patients aged 9 months, 2 and 15 years during a 10 day time span. Antibiotic susceptibilities were determined by microbroth dilution. Clonal relatedness among the isolates was investigated via SmaI-macrorestriction analysis by PFGE, multilocus sequence typing (MLST), and plasmid profiling. Presence of virulence and resistance determinants was tested by polymerase chain reaction (PCR). Selected resistance genes were localized by Southern hybridizations.. A single E. faecium isolate per patient was investigated. All exhibited resistances to quinupristin/dalfopristin, vancomycin/teicoplanin, streptomycin (high-level), penicillin/ampicillin, erythromycin, oxytetracycline, chloramphenicol, rifampicin and fusidic acid. The isolates were susceptible to linezolid only and intermediately resistant to fluoroquinolones including moxifloxacin. PFGE revealed identical patterns for all three isolates. PCRs for virulence determinants hyaluronidase and enterococcal surface protein, esp, were negative, whereas PCR for the enterocin A gene was positive. MLST identified clonal type [8-5-1-1-1-1-1] belonging to a clonal subgroup C1 of hospital- and outbreak-related E. faecium. Southern hybridizations located several resistance genes (erm(B), vat(D), vanA) on a large plasmid, which was transferable in mating experiments with an E. faecium recipient.. These data show routes of dissemination of resistance to multiple antibiotics including streptogramins and glycopeptides in E. faecium via vertical and/or horizontal gene transfer. The isolates spread in the absence of a direct selective pressure, as none of the patients had received earlier streptogramin or glycopeptide therapy.

Topics: Anti-Bacterial Agents; Child; Cross Infection; Drug Resistance; Enterococcus faecium; Female; Genes, Bacterial; Gram-Positive Bacterial Infections; Humans; Intensive Care Units, Pediatric; Microbial Sensitivity Tests; Phylogeny; Plasmids; Reverse Transcriptase Polymerase Chain Reaction; Vancomycin Resistance; Virginiamycin

A 56-year-old man with diabetes mellitus and cadaveric renal transplantation had vancomycin-resistant Enterococcus faecium tricuspid valve endocarditis. Relapse followed 6 weeks of treatment with intravenous gentamicin and high-dose ampicillin. On the basis of previous data suggesting the potential for synergistic activity of quinupristin/dalfopristin plus high-dose ampicillin, therapy with this combination was administered for 63 days. Cure was achieved and later confirmed at 2-year follow-up.

Topics: Ampicillin; Anti-Bacterial Agents; Bacteremia; Diabetes Mellitus, Type 1; Drug Resistance, Bacterial; Drug Therapy, Combination; Endocarditis, Bacterial; Enterococcus faecium; Gentamicins; Gram-Positive Bacterial Infections; Humans; Immunocompromised Host; Kidney Transplantation; Male; Microbial Sensitivity Tests; Middle Aged; Penicillins; Recurrence; Treatment Outcome; Vancomycin Resistance; Virginiamycin

Repeat episodes of musculoskeletal infarction coupled with immunosuppression predispose sickle cell patients to infectious complications throughout their lives. Osteomyelitis is a familiar complication of sickle cell disease, and it may result in significant morbidity, especially when occurring in multiple sites. Staphylococcus and Salmonella remain the most common causes of osteomyelitis in sickle cell patients. Vancomycin-resistant enterococcus (VRE) infections have been reported mainly in connection with bacteremias and infections outside of the musculoskeletal system. To our knowledge, only a few cases of VRE long bone osteomyelitis have been reported in the literature. A few antimicrobial agents are available to treat VRE infections. The occurrence of VRE osteomyelitis is a major clinical concern, especially in an immunocompromised host, such as a sickle cell patient. We present a case of multiple long bone vancomycin-resistant Enterococcus faecium (mixed organisms) osteomyelitis in a sickle cell patient, and we report on a new method of using quinupristin-dalfopristin as part of the management plan to treat a complicated VRE infection successfully. We discuss the mechanism of action of anti-VRE drugs and the future direction to combat VRE in orthopedic infections.

Topics: Anemia, Sickle Cell; Anti-Bacterial Agents; Drug Combinations; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Immunocompromised Host; Osteomyelitis; Vancomycin Resistance; Virginiamycin

Topics: Acetamides; Aged; Anti-Bacterial Agents; Drug Resistance, Bacterial; Drug Therapy, Combination; Enterococcus faecium; Female; Gram-Positive Bacterial Infections; Humans; Linezolid; Oxazolidinones; Spain; Treatment Failure; Vancomycin Resistance; Virginiamycin

Life-threatening infections with multiresistant gram-positive bacteria are increasing. Treatment with quinupristin/dalfopristin (Q-D) has turned out to be effective against such resistant pathogens.. We report on treatment of six patients on dialysis (four with additional liver injury) and of one renal graft recipient with normal renal function who had severe infections caused by multiresistant Staphylococus epidermidis (1/7), methicillin-resistant Staphylococcus aureus (4/7) and vancomycin-resistant Enterococcus faecium (2/7).. Six out of seven patients were cured by therapy with Q-D in adjusted doses lasting for 10 to 34 days. Pharmacokinetics of Q-D and its metabolites were determined and remained within the therapeutic range, despite a modest increase of all compounds at the presumed steady state. The concentrations of the metabolites of Q-D were clearly lower than the parent drugs, including those of quinupristin-conjugated derivatives, which has not been reported previously.. These preliminary results suggest that: a) neither quinupristin nor dalfopristin or its metabolites accumulated despite the long duration of treatment; b) no adjustment of the standard dosage regimen (three times 7.5 mg/kg/day) is necessary in end-stage renal disease.

Topics: Aged; Aged, 80 and over; Bacteremia; Critical Illness; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Enterococcus faecium; Female; Follow-Up Studies; Gram-Positive Bacterial Infections; Humans; Kidney Failure, Chronic; Male; Methicillin Resistance; Middle Aged; Prospective Studies; Risk Assessment; Sampling Studies; Staphylococcal Infections; Treatment Outcome; Vancomycin Resistance; Virginiamycin

Antibiotic-resistant Gram-positive pathogens are an increasingly common cause of serious pediatric infections. Although quinupristin/dalfopristin demonstrates favorable activity against resistant Gram-positive pathogens (including many vancomycin-resistant and methicillin-resistant staphylococci), published experience in the pediatric patient population is limited.. We retrospectively analyzed data from the global quinupristin/dalfopristin Emergency-Use Program, which enrolled patients with serious Gram-positive infections who had no further therapy options because of resistance to, failure on or intolerance to standard antibiotic treatments. Our subset included safety and efficacy data from pediatric patients (age <18 years). There were no restrictions on underlying diseases, severity of illness or prior/concomitant antimicrobial use.. Between May 1995 and October 1999, 127 pediatric patients with 131 infections were enrolled. Microbiologic confirmation of etiology was available in 124 patients. All patients had 1 or more concomitant conditions, including malignancy and solid organ or bone marrow transplantation. The most frequent causative pathogens were vancomycin-resistant (80%), spp. (7%), methicillin-resistant (6%) and (4%). All but 21 patients received intravenous quinupristin/dalfopristin 7.5 mg/kg every 8 h. The favorable clinical response rate of quinupristin/dalfopristin was 86 of 124 (69%); the favorable microbiologic response rate was 97 of 124 (78%). Eleven patients (8%) had nonvenous adverse events classified as possibly or probably related to quinupristin/dalfopristin.. Quinupristin/dalfopristin demonstrated favorable response rates and was reasonably well-tolerated in pediatric patients with serious Gram-positive infections unable to receive alternative therapy. In our opinion quinupristin/dalfopristin is a therapeutic option for the management of such infections.

Topics: Adolescent; Bacteremia; Child; Child, Preschool; Confidence Intervals; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Evaluation Studies as Topic; Female; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Infant; Infusions, Intravenous; Male; Microbial Sensitivity Tests; Probability; Prognosis; Retrospective Studies; Severity of Illness Index; Treatment Outcome; Virginiamycin

Vancomycin-resistant Enterococcus faecium and faecalis (VRE) remains a major complication among critically ill patients. A 26-year-old patient with 65% total body surface area burns (TBSA) was infected with several E. faecium strains during his admission that were resistant to vancomycin. Because chloramphenicol was the standard treatment at this time, this drug was initiated until, the organism was identified as E. faecium and reported as susceptible to quinupristin-dalfopristin. Given these data, it was then decided to discontinue the chloramphenicol therapy. Quinupristin-dalfopristin therapy resulted in initial reduction of fever and white blood cell counts that continued over the next 5 days. However, on day 7 of quinupristin-dalfopristin therapy, a return of fever and elevation of the white blood cell count was noted and a repeated E. faecium blood culture demonstrated sudden resistance to quinupristin-dalfopristin (Bauer-Kirby zone size <14 mm). Chloramphenicol was restarted and the patient improved slowly over a period of 16 days. Our indigenous VRE had limited exposure to quinupristin-dalfopristin in the recent past; however, resistance emerged with the first commercial use of this agent in our burn treatment center. High-dose chloramphenicol treatment did not appear to impair engraftment of cultured epithelial autografts (CEA) in this patient.

Topics: Adult; Burns; Chloramphenicol; Cross Infection; Drug Resistance, Multiple, Bacterial; Enterococcus faecium; Graft Survival; Gram-Positive Bacterial Infections; Humans; Male; Skin Transplantation; Vancomycin Resistance; Virginiamycin

We describe an outbreak of vancomycin-resistant Enterococcus faecium (VRE) on the haematology ward of a Dutch university hospital. After the occurrence of three consecutive cases of bacteraemia with VRE, strains were genotyped and found to be identical. During the next 4 months an intensive surveillance programme identified 21 additional patients to be colonized with VRE, while two more patients developed bacteraemia. A case-control study was carried out to identify risk factors for VRE acquisition. In comparison with VRE-negative control patients (n=49), cases (n=24) had a longer stay on the ward during the year preceding the outbreak (25.8 versus 10.1 d, P=0.02), more cases with acute myeloid leukaemia [11 versus 4, odds ratio (OR) 9.5, 95% confidence interval (CI95) 2.4-32.2] and higher grades of mucositis (P=0.03). Logistic regression analysis identified antibiotic use within 1 month before admission (OR 13.0, CI95 2.1-80.5, P=0.006) and low albumin levels at baseline (OR 1.2, CI95 1.1-1.3, P=0.02) to be independent risk factors. Four patients with VRE-bacteraemia were successfully treated with quinupristin/dalfopristin (Synercid). Control of the outbreak was achieved by step-wise implementation of intensive infection control measures, which included the cohorting of patients, allocation of nurses and reinforcement of hand hygiene.

Topics: Adult; Anti-Bacterial Agents; Bacteremia; Case-Control Studies; Cross Infection; Drug Therapy, Combination; Enterococcus faecium; Female; Gram-Positive Bacterial Infections; Hematology; Hospital Departments; Humans; Infection Control; Length of Stay; Logistic Models; Male; Middle Aged; Patient Isolation; Risk Assessment; Serum Albumin; Vancomycin Resistance; Virginiamycin

Data regarding clinical administration, outcomes, and costs of quinupristin-dalfopristin treatment in 48 patients with serious gram-positive infections in a large teaching hospital were analyzed retrospectively. Thirty-six patients had vancomycin-resistant Enterococcus faecium (VREF) infections, 10 had methicillin-resistant Staphylococcus aureus (MRSA) or Staphylococcus epidermidis (MRSE) infections, and 2 were treated empirically Overall, 67% of the patients were clinically cured, and 56% had bacteriologic eradication; overall response rate was 48%. Patients with VREF bacteremia had the highest clinical cure (82%) and bacteriologic eradication (73%) rates. Mortality rate was 31%, but 6 of 15 patients who died were treated successfully with quinupristin-dalfopristin. Length of hospital stay was significantly shorter among patients who lived versus those who died (p<0.05). Similarly, the mean hospital cost/patient was significantly lower in patients who lived than in those who died ($35,244 vs $122,922). Quinupristin-dalfopristin is effective in the treatment of both VREF and MRSA or MRSE infections in patients who fail to respond to, or are intolerant of, vancomycin.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Cost-Benefit Analysis; Drug Resistance, Microbial; Female; Gram-Positive Bacterial Infections; Humans; Length of Stay; Male; Middle Aged; Retrospective Studies; Vancomycin Resistance; Virginiamycin

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.

Topics: Adolescent; Anti-Bacterial Agents; Child; Child, Preschool; Drug Therapy, Combination; Enterococcus faecium; Female; Gram-Positive Bacterial Infections; Humans; Immunocompromised Host; Infant; Infant, Newborn; Liver Transplantation; Male; Treatment Outcome; Virginiamycin

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.

Topics: Arthralgia; Drug Therapy, Combination; Gram-Positive Bacterial Infections; Humans; Muscular Diseases; Pain; Retrospective Studies; Risk Factors; Virginiamycin

Topics: Acetyltransferases; Amino Acid Sequence; Bacterial Proteins; Drug Therapy, Combination; Enterococcus faecium; Genes, Bacterial; Gram-Positive Bacterial Infections; Humans; Molecular Sequence Data; Reverse Transcriptase Polymerase Chain Reaction; United Kingdom; Virginiamycin

Vancomycin-resistant enterococci (VRE) have recently emerged as an increasing concern in the management of severe infections. Treatment of these life-threatening infections has been limited to quinupristin-dalfopristin and, more recently, linezolid therapy. We report the first case, to our knowledge, of vancomycin-resistant Enterococcus faecium vertebral osteomyelitis treated successfully with quinupristin-dalfopristin. We review the recent epidemiology of VRE and briefly outline the pharmacology and pharmacokinetics of quinupristin-dalfopristin.

Topics: Aged; Anti-Bacterial Agents; Enterococcus faecium; Female; Gram-Positive Bacterial Infections; Humans; Osteomyelitis; Vancomycin Resistance; Virginiamycin

We tested 165 enterococcal isolates, biased toward vancomycin resistant (VR) isolates, collected during recent years from fecal samples of healthy subjects and clinical specimens of hospitalized patients (mostly from United States and some from Europe) for susceptibility to 19 antimicrobials. Nosocomial isolates, whether VR or not, were more often highly resistant to aminoglycosides and clindamycin than fecal isolates from healthy community volunteers and more often resistant to erythromycin, chloramphenicol, trimethoprim, levofloxacin and, for E. faecium, ampicillin (93 vs. 0%). Resistance rates were similar between nosocomial and community-fecal isolates for minocycline, rifampin and quinupristin-dalfopristin (Q-D). None of the 165 enterococci tested hybridized with aph(2'')-Ic and aph(2'')-Id probes for recently described gentamicin resistance genes and 37 of the 39 isolates with high level resistance (HLR) to gentamicin hybridized with an intragenic aac(6')-aph(2'') probe. Of the two newer drugs tested, daptomycin MIC90s were 0.25 microg/mL for E. faecalis and 1 microg/mL for E. faecium, regardless of their vancomycin resistance level or source. For Q-D, none of 28 E. faecium from community based healthy subjects in the USA and 7 of 66 E. faecium from hospitalized patients in the United States were resistant. Among these 7 Q-Dr United States isolates and 7 Q-Dr isolates from Europe (MICs of Q-D of 4-8 microg/mL), none hybridized with vat(D) (formerly satA) and vat(E) (formerly satG) DNA probes, indicating the involvement of other mechanism/s of resistance in these isolates. We also demonstrated that an intragenic probe of the gene ace from E. faecalis showed specific hybridizations to all E. faecalis isolates, suggesting the usefulness of this gene for identification of this species.

Topics: Adhesins, Bacterial; Anti-Bacterial Agents; DNA, Bacterial; Drug Resistance, Microbial; Enterococcus faecalis; Feces; Genes, Bacterial; Gentamicins; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests; Molecular Probes; Species Specificity; Vancomycin; Virginiamycin

The occurrence of resistance to the streptogramin quinupristin-dalfopristin in Enterococcus faecium isolates from chickens on the Eastern Seaboard, was evaluated. Quinupristin-dalfopristin resistance was found in 51 to 78% of E. faecium isolates from the food production environment. The high level of resistance in this organism suggests that this reservoir of resistance may compromise the therapeutic potential of quinupristin-dalfopristin.

Topics: Animal Husbandry; Animals; Chickens; Drug Resistance, Microbial; Drug Therapy, Combination; Enterococcus faecium; Environmental Microbiology; Gram-Positive Bacterial Infections; Virginiamycin

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.. Retrospective analysis.. University of Pittsburgh Medical Center.. 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.. 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.. 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.. Hyperbilirubinemia in these patients was likely multifactorial and most frequently due to sepsis and prior graft injury.

Topics: Adult; Aged; Bilirubin; Biopsy; Enterococcus faecalis; Female; Gram-Positive Bacterial Infections; Humans; Hyperbilirubinemia; Liver; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Virginiamycin

A 44-year-old man was treated successfully for vancomycin-resistant Enterococcus faecium (VREF) ventriculitis with intrathecal quinupristin-dalfopristin 1 mg, 2 mg, and 4 mg, and other intravenous antibiotics. Cerebrospinal fluid samples were collected before and after the 1-mg and 2-mg doses to determine the concentrations of quinupristin-dalfopristin and its active metabolites. Concentrations were above the minimum inhibitory concentration for VREF immediately after unclamping the extraventricular drain and were quantifiable for at least 7 hours.

Topics: Adult; Cerebrospinal Fluid Shunts; Encephalitis; Enterococcus faecalis; Gram-Positive Bacterial Infections; Humans; Male; Microbial Sensitivity Tests; Vancomycin Resistance; Virginiamycin

Topics: Animals; Anti-Bacterial Agents; Drug Resistance, Multiple; Drug Therapy, Combination; Gram-Positive Bacterial Infections; Gram-Positive Cocci; Humans; Virginiamycin

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.. 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).

Topics: Anti-Bacterial Agents; Drug Resistance, Multiple; Drug Therapy, Combination; Gram-Positive Bacterial Infections; Gram-Positive Cocci; Humans; Microbial Sensitivity Tests; Virginiamycin

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.

Topics: Anti-Bacterial Agents; Cross Infection; Drug Approval; Drug Resistance, Multiple; Drug Therapy, Combination; Gram-Positive Bacterial Infections; Gram-Positive Cocci; Humans; Multicenter Studies as Topic; Pneumonia; Randomized Controlled Trials as Topic; Soft Tissue Infections; Virginiamycin

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.

Topics: Animals; Anti-Bacterial Agents; Drug Resistance, Multiple; Drug Synergism; Drug Therapy, Combination; Gram-Positive Bacterial Infections; Gram-Positive Cocci; Humans; Lactams; Microbial Sensitivity Tests; Virginiamycin

The steady increase in resistant organisms is related to the widespread use of antibiotics in community and hospital settings. New therapeutic options are needed, including treatments for infections caused by antibiotic-resistant gram-positive organisms. Quinupristin-dalfopristin, the first formulation of a distinct class of antibiotics known as the streptogramins, has activity against a range of gram-positive bacteria that are usually resistant to other agents, including vancomycin-resistant Enterococcus faecium. The pharmacodynamic (postantibiotic effect) and pharmacokinetic characteristics of quinupristin-dalfopristin allow dosing at eight- to 12-hour intervals. The safety profile of the formulation is generally favorable, with no demonstrable ototoxicity, nephrotoxicity, bone marrow suppression, or cardiovascular adverse effects. Reversible arthralgias, myalgias, and peripheral venous irritation are the formulation's major side effects. A potential for drug interactions exists because quinupristin-dalfopristin significantly inhibits the cytochrome P450-3A4 enzyme system. Quinupristin-dalfopristin has been shown to be effective in the management of documented severe infections caused by vancomycin-resistant E. faecium, nosocomial pneumonia, and infections related to the use of intravascular catheters.

Topics: Drug Therapy, Combination; Gram-Positive Bacterial Infections; Humans; Virginiamycin

Topics: Acetamides; Anti-Bacterial Agents; Bacteremia; Bone Marrow Transplantation; Drug Administration Schedule; Drug Therapy, Combination; Enterococcus faecium; Follow-Up Studies; Gram-Positive Bacterial Infections; Humans; Leukemia, Myeloid, Acute; Linezolid; Male; Middle Aged; Oxazoles; Oxazolidinones; Postoperative Complications; Treatment Failure; Treatment Outcome; Vancomycin Resistance; Virginiamycin

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.. Quinupristin/dalfopristin was administered according to the manufacturer's recommendations. Clinical and laboratory data were recorded for each patient.. 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.. 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.

Topics: Adolescent; Anti-Bacterial Agents; Child; Child, Preschool; Drug Therapy, Combination; Enterococcus faecium; Female; Gram-Positive Bacterial Infections; Humans; Infant; Male; Treatment Outcome; Vancomycin Resistance; Virginiamycin

Topics: Aged; Anti-Bacterial Agents; Drug Therapy, Combination; Enterococcus faecium; Female; Gram-Positive Bacterial Infections; Humans; Hyponatremia; Virginiamycin

Central nervous system infections involving vancomycin-resistant Enterococcus faecium (VREF) are infrequently described and pose significant therapeutic difficulties, because these organisms are intrinsically resistant to many antibiotics. We describe the use of intrathecal quinupristin/dalfopristin to treat a VREF-associated infection in a neuro--surgical patient.

Topics: Acetamides; Anti-Bacterial Agents; Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Therapy, Combination; Enterococcus faecium; Fatal Outcome; Female; Gram-Positive Bacterial Infections; Humans; Hydrocephalus; Injections, Intravenous; Injections, Intraventricular; Injections, Spinal; Linezolid; Middle Aged; Oxazoles; Oxazolidinones; Subarachnoid Hemorrhage; Tomography, X-Ray Computed; Vancomycin; Ventriculoperitoneal Shunt; Virginiamycin

We report the activity of the new glycylcycline antimicrobial agent GAR-936 against 37 clinical isolates of vancomycin-resistant enterococci (including organisms carrying the vanA, vanB, vanC-1, and vanC-2/3 genes), 26 clinical isolates of methicillin-resistant S. aureus and 30 clinical isolates of high-level penicillin-resistant S. pneumoniae. All isolates of vancomycin-resistant enterococci, methicillin-resistant S. aureus, and penicillin-resistant S. pneumoniae were inhibited by < or = 1, < or = 2, or < or = 0.25 microg/ml of GAR-936, respectively. Time kill experiments using vancomycin-resistant enterococci did not demonstrate synergy or antagonism between 2 microg/ml of GAR-936 and 0.25 microg/ml of quinupristin/dalfopristin.

Topics: Anti-Bacterial Agents; Drug Resistance, Microbial; Drug Synergism; Drug Therapy, Combination; Enterococcus; Gram-Positive Bacterial Infections; Humans; Methicillin Resistance; Microbial Sensitivity Tests; Minocycline; Penicillin Resistance; Staphylococcus aureus; Streptococcus pneumoniae; Tigecycline; Vancomycin Resistance; Virginiamycin

Quinupristin-dalfopristin is a streptogramin combination active against multiply resistant Enterococcus faecium. Among 45 E. faecium isolated from patients in various French hospitals, only two strains were intermediate (MIC = 2 microgram/ml) and one, E. faecium HM1032, was resistant (MIC = 16 microgram/ml) to quinupristin-dalfopristin, according to British Society for Antimicrobial Chemotherapy and National Committee for Clinical Laboratory Standards approved breakpoints. The latter strain contained the vgb and satA genes responsible for hydrolysis or acetylation of quinupristin and dalfopristin, respectively, and an ermB gene (also previously referred to as ermAM) encoding a ribosomal methylase. The two intermediate strains had an LS(A) phenotype characterized by resistance to lincomycin (L), increased MICs (>/=8 microgram/ml) of dalfopristin (streptogramin A [S(A)]), and susceptibility to erythromycin and quinupristin. This phenotype was also detected in eight other strains susceptible to quinupristin-dalfopristin. No genes already known and conferring resistance to dalfopristin by acetylation or active efflux were detected in these LS(A) strains. Nineteen other strains resistant to erythromycin but susceptible to the quinupristin-dalfopristin combination displayed elevated MICs of quinupristin after induction (from 16 to >128 microgram/ml) and contained ermB genes. The effects of ermB, vgb, and satA genes on the activity of the streptogramin combination were tested by cloning these genes individually or in various combinations in recipient strains susceptible to quinupristin-dalfopristin, E. faecium HM1070 and Staphylococcus aureus RN4220. The presence of both the satA and vgb genes (regardless of the presence of an ermB gene) was necessary to confer full quinupristin-dalfopristin resistance to the host. The same genetic constructs were introduced into E. faecium BM4107 which displays a LS(A) phenotype. Addition of the satA or vgb gene to this LS(A) background conferred resistance to quinupristin-dalfopristin.

Topics: Acetyltransferases; Anti-Bacterial Agents; Bacterial Proteins; Drug Resistance, Microbial; Enterococcus faecium; Genes, Bacterial; Genotype; Gram-Positive Bacterial Infections; Hemeproteins; Humans; Methyltransferases; Microbial Sensitivity Tests; Plasmids; Polymerase Chain Reaction; Staphylococcus aureus; Virginiamycin

Using checkerboard and time-kill assays, we evaluated the in vitro activity of quinupristin-dalfopristin (RP 59500) alone and in combination with five other antimicrobial agents against 12 clinical strains of vancomycin-resistant Enterococcus faecium (VREF). In time-kill studies, six VREF strains exhibited synergism with the combination of quinupristin-dalfopristin and doxycycline and three exhibited synergism with quinupristin-dalfopristin plus ampicillin-sulbactam. Combinations of quinupristin-dalfopristin with these and other agents warrant further clinical evaluation for the treatment of serious VREF infections.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Carbon-Oxygen Ligases; Drug Synergism; Enterococcus faecium; Genotype; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests; Time Factors; Vancomycin; Vancomycin Resistance; Virginiamycin

Topics: Anti-Bacterial Agents; Clinical Trials as Topic; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Oxazoles; Oxazolidinones; Streptococcal Infections; Streptococcus pyogenes; Vancomycin Resistance; Virginiamycin

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Bacteremia; Enterococcus faecium; Fluoroquinolones; Gram-Positive Bacterial Infections; Humans; Male; Middle Aged; Portasystemic Shunt, Transjugular Intrahepatic; Vancomycin Resistance; Virginiamycin

Topics: Anti-Bacterial Agents; Cross Infection; Drug Resistance, Multiple; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Randomized Controlled Trials as Topic; Staphylococcus aureus; Streptococcus pyogenes; United Kingdom; Virginiamycin

Topics: Clinical Trials as Topic; Costs and Cost Analysis; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Enterococcus faecium; Fees, Pharmaceutical; Gram-Positive Bacterial Infections; Humans; Infusions, Intravenous; Vancomycin Resistance; Virginiamycin

From 125 separate cloacal cultures from three turkey flocks fed virginiamycin, 104 Enterococcus faecium and 186 Enterococcus faecalis isolates were obtained. As the turkeys aged, there was a higher percentage of quinupristin-dalfopristin-resistant E. faecium isolates, with isolates from the oldest flock being 100% resistant. There were no vancomycin-resistant enterococci. Results of pulsed-field gel electrophoresis (PFGE) indicated there were 11 PFGE types of E. faecalis and 7 PFGE types of E. faecium that were in more than one group of flock cultures.

Topics: Animals; Anti-Bacterial Agents; Drug Resistance, Microbial; Enterococcus faecalis; Enterococcus faecium; Gram-Positive Bacterial Infections; Turkeys; Virginiamycin

Topics: Adult; Anti-Bacterial Agents; Drug Resistance, Microbial; Drug Therapy, Combination; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Injections, Intraventricular; Male; Vancomycin; Ventriculoperitoneal Shunt; Virginiamycin

We describe three cases of Enterococcus faecium sepsis arising in immunocompromised patients, severely ill with other conditions, who were treated with the new injectable streptogramin RP59500. There are still few reports of clinical experience with this drug. All had bacteriological resolution, with one patient recovering fully. Although two of the three patients died, this was due to underlying disease in one case and a gram-negative superinfection in another. Quinupristin/dalfopristin therapy was not associated with significant adverse effects in any of the patients.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Enterococcus faecium; Female; Gram-Positive Bacterial Infections; Humans; Male; Middle Aged; Opportunistic Infections; Virginiamycin

Topics: Anti-Bacterial Agents; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Infant, Newborn; Meningitis, Bacterial; Virginiamycin

This investigation used checkerboard and time-kill assays to evaluate the in vitro activity of RPR 106972 (45% pristinamycin IB and 55% pristinamycin IIB) alone and in combination with vancomycin or ampicillin +/- gentamicin against multidrug-resistant enterococci. The checkerboard procedure resulted in synergistic or additive effects in 91% of the isolates with the combination of RPR 106972 plus vancomycin versus 68% with RPR 106972 plus ampicillin. The addition of gentamicin to either combination resulted in synergistic or additive results in 100% of the isolates. Inhibitory activity was observed with the time-kill assay with mean change in log10 CFU/mL at 24 h of -0.31 for RPR 106972, 3.3 for vancomycin, -0.46 for RPR 106972 plus vancomycin, and -0.35 for RPR 106972 plus vancomycin and gentamicin. No antagonism was noted with any of the combinations. RPR 106972 demonstrates good inhibitory activity against Enterococcus faecium and may prove useful in the treatment of enterococcal infections.

Topics: Ampicillin; Anti-Bacterial Agents; Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Synergism; Drug Therapy, Combination; Enterococcus; Enterococcus faecalis; Enterococcus faecium; Gentamicins; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests; Vancomycin; Virginiamycin

An orally administered streptogramin (RPR 106,972) and a parenteral streptogramin (quinupristin/dalfopristin) were evaluated against a collection of 2481 recent clinical isolates of gram-positive cocci. The isolates were gathered from ten North American medical centres during the winter months of 1996-1997. In spite of minor differences, both streptogramins had essentially identical spectra of activity which included many erythromycin-resistant isolates. Previously proposed interpretative criteria for quinupristin/dalfopristin disc diffusion susceptibility tests were confirmed.

Topics: Academic Medical Centers; Anti-Bacterial Agents; Drug Resistance, Microbial; Enterococcus; Erythromycin; Gram-Positive Bacterial Infections; Gram-Positive Cocci; Humans; Microbial Sensitivity Tests; North America; Staphylococcus; Streptococcus; Virginiamycin

Topics: Aged; Doxycycline; Drug Resistance, Microbial; Drug Synergism; Drug Therapy, Combination; Endocarditis, Bacterial; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Male; Rifampin; Vancomycin; Virginiamycin

Quinupristin/dalfopristin and RPR 106972 were active in vitro against a wide range of aerobic Gram-positive organisms including Enterococcus faecium. However, most isolates of Enterococcus faecalis were resistant or of intermediate sensitivity. Against Staphylococcus aureus quinupristin/dalfopristin was more active but for all other species the range of activity of the two drugs was the same or RPR 106972 was more active. RPR 106972 was also more active against the respiratory pathogens Haemophilus influenzae and Moraxella catarrhalis. Quinupristin/dalfopristin MICs for isolates of H. influenzae (1-8 mg/L) clustered around the breakpoint. There were differences in the quality of growth, but little difference in MICs or zone diameters was obtained on three different media: Mueller-Hinton (MHA), Iso-Sensitest (ISA), and Diagnostic Sensitivity Test (DST) agars. The addition of blood to the medium increased MICs 2- to 4-fold, with MHA showing the greatest increase, and reduced zone diameters around quinupristin/dalfopristin discs by 3-4 mm, with the greatest effect on ISA.

Topics: Anti-Bacterial Agents; Culture Media; Drug Therapy, Combination; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Haemophilus Infections; Haemophilus influenzae; Humans; Microbial Sensitivity Tests; Moraxella catarrhalis; Neisseriaceae Infections; Respiratory Tract Infections; Virginiamycin

Topics: Adult; Anti-Bacterial Agents; Bacteremia; Drug Resistance, Microbial; Drug Resistance, Multiple; Echocardiography; Enterococcus faecium; Gram-Positive Bacterial Infections; HIV Infections; Humans; Male; Microbial Sensitivity Tests; Vancomycin; Virginiamycin

Topics: Adult; Aged; Ampicillin; Anti-Bacterial Agents; Coronary Artery Bypass; Diabetes Mellitus, Type 1; Drug Hypersensitivity; Endocarditis; Enterococcus faecalis; Gentamicins; Gram-Positive Bacterial Infections; Humans; Male; Methicillin; Methicillin Resistance; Microbial Sensitivity Tests; Penicillins; Renal Dialysis; Staphylococcal Infections; Staphylococcus aureus; Superinfection; Vancomycin; Virginiamycin; Wound Infection

Topics: Anti-Bacterial Agents; Drug Resistance, Microbial; Endocarditis, Bacterial; Enterococcus faecium; Female; Gram-Positive Bacterial Infections; Humans; Middle Aged; Prosthesis-Related Infections; Vancomycin; Virginiamycin

Using a checkerboard assay, ampicillin, vancomycin, and RP 59500, each in combination with chloramphenicol, were tested for synergy against 23 isolates of vancomycin-resistant enterococci. Additive effects were seen in 62.5% of the isolates when exposed to chloramphenicol plus RP 59500. Additive effects were observed in 20% and 15% of isolates with chloramphenicol plus vancomycin or ampicillin, respectively. No antagonism was noted.

Topics: Ampicillin; Anti-Bacterial Agents; Chloramphenicol; Cross Infection; Drug Resistance, Microbial; Drug Synergism; Drug Therapy, Combination; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; In Vitro Techniques; Microbial Sensitivity Tests; Penicillins; Vancomycin; Virginiamycin

Topics: Anti-Bacterial Agents; Drug Combinations; Drug Resistance, Microbial; Enterococcus; Enterococcus faecalis; Enterococcus faecium; Gram-Positive Bacterial Infections; Vancomycin; Virginiamycin

A 46-year-old woman was admitted to the hospital with severe peripheral vascular disease, requiring multiple vascular surgical procedures. During the sixth hospital week, after prior therapy with multiple antibiotics, Enterococcus faecium was isolated as the only organism from an operating room culture of an infected aortic graft. Histological examination of the graft showed infiltration with polymorphonuclear leukocytes. Subsequently, cultures of an infected inguinal wound yielded Enterococcus faecium with mixed bacterial growth. Both isolates of Enterococcus faecium were resistant to all available antimicrobials, including ampicillin, vancomycin, tetracycline, chloramphenicol, and ciprofloxacin. Compassionate use therapy with quinupristin/dalfopristin (RP59500) was administered for 25 days, the patient's clinical condition improved, and wound healing occurred. Transient elevation of serum alkaline phosphatase was noted. This case demonstrates successful eradication of deep VREF infection by quinupristin/dalfopristin with good tolerance of prolonged therapy.

Topics: Anti-Bacterial Agents; Arteries; Coronary Artery Bypass; Drug Resistance, Microbial; Enterococcus faecium; Female; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests; Middle Aged; Postoperative Complications; Vancomycin; Virginiamycin

Vancomycin-resistant Enterococcus faecium (VREF) collected between July 1991 and February 1994 were tested in vitro against RP 59500 and ramoplanin using agar dilution and standard macro broth dilution procedures. Colony counts were determined at 0, 4, and 24 h. RP 59500 had an MIC range of < or = 0.5-8 micrograms/ml with an MIC90 of 2 micrograms/ml and a MBC range of < or = 0.5-16 micrograms/ml with an MBC90 of 16 micrograms/ml. Ramoplanin had an MIC range of < or = 0.125-1 microgram/ml with an MBC range of < or = 0.125-4 micrograms/ml. The MIC90 for ramoplanin was 1 microgram/ml and the MBC90 was 4 micrograms/ml for the tested isolates. Against these isolates of E. faecium, RP 59500 was bactericidal at 8x MIC, a potentially achievable level using a high drug dosage. Ramoplanin was bactericidal at 2x MIC.

Topics: Anti-Bacterial Agents; Colony Count, Microbial; Depsipeptides; Drug Resistance, Microbial; Enterococcus faecium; Genes, Bacterial; Gram-Positive Bacterial Infections; Humans; Kinetics; Microbial Sensitivity Tests; Peptides, Cyclic; Phenotype; Vancomycin; Virginiamycin

Topics: Adult; Aged; Anti-Bacterial Agents; Enterococcus faecium; Female; Gram-Positive Bacterial Infections; Humans; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Peritonitis; Virginiamycin

Topics: Child; Drug Resistance, Microbial; Enterococcus faecium; Gentamicins; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests; Vancomycin; Virginiamycin