virginiamycin and Staphylococcal-Infections

Septic arthritis is a rheumatologic emergency as joint destruction occurs rapidly and can lead to significant morbidity and mortality. Accurate diagnosis can be particularly challenging in patients with underlying inflammatory joint disease. This review outlines the risk factors for septic arthritis and summarizes the causative bacterial organisms. We highlight advances in antibiotic management with a focus on new drugs for methicillin-resistant Staphylococcus aureus (MRSA) and discuss the use of adjunctive therapies for treatment of septic arthritis in adults.

Topics: Acetamides; Anti-Bacterial Agents; Arthritis, Infectious; Bacterial Infections; Ceftaroline; Cephalosporins; Daptomycin; Drug Therapy, Combination; Humans; Immunologic Factors; Linezolid; Methicillin-Resistant Staphylococcus aureus; Oxazolidinones; Risk Factors; Staphylococcal Infections; Treatment Outcome; Virginiamycin

After the report of first case of methicillin-resistant Staphylococcus aureus (MRSA) in 1961, MRSA become a major problem worldwide. Over the last decade MRSA strains have emerged as serious pathogens in nosocomial and community settings. Glycopeptides (vancomycin and teicoplanin) are still the current mainstay of therapy for infections caused by MRSA. In the last decade dramatic changes have occurred in the epidemiology of MRSA infections. The isolates with reduced susceptibility and in vitro resistance to vancomycin have emerged. Recently, therapeutic alternatives such as quinupristin/dalfopristin, linezolid, tigecycline and daptomycin have been introduced into clinical practice for treating MRSA infections. Nevertheless, these drugs are only approved for certain indication and resistance has already been reported. In this review, the new information on novel drugs for treating MRSA infections and the resistance mechanisms of these drugs were discussed.

Topics: Acetamides; Anti-Bacterial Agents; Daptomycin; Drug Resistance, Bacterial; Humans; Linezolid; Methicillin-Resistant Staphylococcus aureus; Minocycline; Oxazolidinones; Protein Synthesis Inhibitors; Staphylococcal Infections; Teicoplanin; Tigecycline; Vancomycin; Vancomycin Resistance; Virginiamycin

We review data on the treatment of infections caused by drug-resistant Staphylococcus aureus, particularly methicillin-resistant S. aureus (MRSA). In this review, we cover findings reported in the English language medical literature up to February 2006. Despite the emergence of resistant and multidrug resistant S. aureus, five effective drugs for which little resistance has been observed are in clinical use: vancomycin, quinupristin-dalfopristin, linezolid, tigecycline, and daptomycin. However, vancomycin is less effective for infections with MRSA isolates that have a high minimum inhibitory concentration in the susceptible range. Linezolid looks promising in the treatment of MRSA pneumonia and skin and soft-tissue infections (SSTIs). Daptomycin displays rapid bactericidal activity in vitro, and it has been shown to be noninferior to comparator agents in the treatment of SSTIs and bacteremia. Tigecycline was also noninferior to comparator drugs in the treatment of SSTIs. Clindamycin, trimethoprim-sulfamethoxazole, doxycycline, and minocycline are oral antistaphylococcal agents that may have utility in the treatment of SSTIs and osteomyelitis, but the clinical data for their efficacy is limited. There are four drugs with broad-spectrum activity against Gram-positive organisms at an advanced stage of clinical testing: ceptobiprole and three new glycopeptides with potent bactericidal activity, oritavancin, dalbavancin, and telavancin. Thus, there are currently many effective drugs to treat resistant S. aureus infections and many promising agents in the pipeline. Nevertheless, S. aureus remains a formidable adversary against which there are frequent treatment failures. The next goals are to determine the most appropriate indications and cost-effectiveness of each of these drugs in the treatment strategy against S. aureus.

Topics: Acetamides; Anti-Bacterial Agents; Daptomycin; Drug Resistance, Bacterial; Humans; Linezolid; Methicillin Resistance; Minocycline; Oxazolidinones; Staphylococcal Infections; Staphylococcus aureus; Tigecycline; Vancomycin; Virginiamycin

The advent of vancomycin-resistant enterococci in the 1990s and the threat posed by vancomycin resistance in Staphylococcus aureus led to the development of several new antimicrobial agents active against these pathogens. Quinupristin/dalfopristin was the first such drug to be commercially available but adverse effects have meant that the drug is now rarely used. Linezolid, the first antimicrobial of the oxazolidinone class, has met with more widespread use and has both an intravenous and an oral formulation. Daptomycin is a lipopeptide antimicrobial that is rapidly bactericidal against S. aureus. It is effective in the therapy of S. aureus bloodstream infections but is inactivated by pulmonary surfactant, making it of no use in the therapy of pneumonia. Tigecycline, by contrast, is bacteriostatic against most pathogens but has a broad spectrum of antimicrobial activity and has enhanced penetration into many tissues. Other new antibiotics (dalbavancin, telavancin, ceftobiprole and doripenem) are currently under clinical development and hold promise for widespread clinical use in the next decade.

Topics: Acetamides; Anti-Bacterial Agents; Bacterial Infections; Daptomycin; Humans; Linezolid; Minocycline; Oxazolidinones; Staphylococcal Infections; Streptococcal Infections; Tigecycline; Virginiamycin

Infection by Staphylococcus aureus in critically ill patients is usually associated with antimicrobial resistance and high mortality. A more effective antibiotic treatment is needed to replace older drugs that have limited efficacy. Novel substances active on methicillin-resistant Staphylococcus aureus, which are already available on the market or are still in development, are discussed in this review, with emphasis on nosocomial infections.. A number of new antibiotics are on the market (linezolid, quinupristin-dalfopristin, daptomycin) and there is good evidence regarding their efficacy, especially in methicillin-resistant Staphylococcus aureus infections. Linezolid is, to date, the best alternative in treating nosocomial pneumonia by methicillin-resistant Staphylococcus aureus. It is cost-effective; resistance levels are still very low but there are some concerns regarding its adverse events. Quinupristin-dalfopristin shows good activity in vitro but its efficacy in patients with pneumonia by methicillin-resistant Staphylococcus aureus is modest. Daptomycin is not recommended for pulmonary infections because of its reduced penetration in the lung tissue. Under current phase III trials in patients with nosocomial infections are tigecycline, ceftobiprole, and three new glycopeptides, all with particular activity against methicillin-resistant Staphylococcus aureus.. For the moment, there are limited and rather expensive therapeutic options for the infections by Staphylococcus aureus in the critically ill. No dramatic superiority of the new drugs in comparison to the standard therapies was observed in most of the clinical trials. Better results on the efficacy of the drugs under investigation are expected.

Topics: Acetamides; Aminoglycosides; Anti-Bacterial Agents; Cephalosporins; Clinical Trials as Topic; Critical Illness; Daptomycin; Drug Resistance, Multiple, Bacterial; Glycopeptides; Humans; Linezolid; Lipoglycopeptides; Methicillin Resistance; Minocycline; Oxazolidinones; Staphylococcal Infections; Teicoplanin; Tigecycline; Virginiamycin

This paper reviews recent data on the treatment of infections caused by drug-resistant Staphylococcus aureus, particularly methicillin-resistant S. aureus (MRSA). This review will focus on new findings reported in the English-language medical literature from June 2003 to September 2004.. Despite the emergence of resistant and multidrug-resistant S. aureus, we have three effective drugs in clinical use for which little resistance has been observed: quinupristin-dalfopristin, linezolid, and daptomycin. Linezolid looks particularly promising in the treatment of MRSA pneumonia. Daptomycin displays rapid bactericidal activity in vitro, but, so far, clinical trials have only been conducted for the treatment of skin and soft-tissue infections. There are three drugs with broad-spectrum activity against Gram-positive organisms at an advanced stage of testing: two new glycopeptides with potent bacteriocidal activity and long half-lives (oritavancin and dalbavancin), and tigecycline, a minocycline derivative. These drugs have also shown efficacy in the treatment of skin and soft-tissue infections.. The promising data that have emerged in the last year indicate that we may have six available drugs to treat resistant S. aureus infections within the next few years. The next goal is to determine the appropriate indications and cost-effectiveness of each of these drugs in our treatment strategy against S. aureus and other Gram-positive pathogens.

Topics: Acetamides; Anti-Bacterial Agents; Daptomycin; Drug Resistance, Multiple, Bacterial; Glycopeptides; Humans; Linezolid; Lipoglycopeptides; Minocycline; Oxazolidinones; Staphylococcal Infections; Teicoplanin; Tigecycline; Virginiamycin

Research efforts to discover new compounds active against staphylococci are more than ever justified today. The incidence of methicillin-resistant staphylococci remains very high in hospitals, and the solution provided by glycopeptides is far from being satisfactory. These compounds exhibit mediocre pharmacokinetic and pharmacodynamic properties. Their ease and safety of use are poor. Finally, strains with diminished sensitivity to these antibiotics are beginning to appear. This article examines the opportunities offered by two new anti-staphylococcal agents: quinupristine-dalfopristine (Synercid) and linezolide (not marketed in France).

Topics: Acetamides; Anti-Bacterial Agents; Drug Therapy, Combination; Humans; Linezolid; Oxazolidinones; Staphylococcal Infections; Staphylococcus aureus; 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

INJECTABLE SPECTROGRAMIN: Combination regimens using quinupristin/dafopristin with either gentamicin or vancomycin have powerful bactericidal activities (even against quinupristin-resistant strains) against methicillin-resistant Staphylococcus aureus (MRSA) in a model of experimental endocarditis in the rabbit. In clinical trials, quinupristin/dalfopristin is becoming a therapeutic alternative to consider after failure of conventional antistaphylococcal treatments. NEW GENERATION CEPHALOSPORINS: These new cephalosporins, particularly C-3 pyridinium-thiomethyl-cephalosporins, new (3-dithiocarbamoyl) cephalosporins, and a series of new compounds with high affinity for MRSA PLP2a, are particularly active against MRSA and are unaffected by beta-lactamases. A NEW CARBAPENEM: This new antibiotic has a wide bactericidal effect against Gram-positive organisms and is active against MRSA as well as penicillin-resistant S. pneumoniae. NEW FLUOROQUINOLONE DERIVATIVES: In vitro, these new derivatives have been found to be active against MRSA, pneumococci non-sensitive to ciprofloxacin, and Bacteroides fragilis, Mycobacterium tuberculosis, Chlamydia pneumoniae.

Topics: Anti-Infective Agents; Carbapenems; Cephalosporins; Drug Therapy, Combination; Endocarditis, Bacterial; Fluoroquinolones; Humans; Methicillin Resistance; Staphylococcal Infections; Virginiamycin

The rise in the number of multidrug-resistant gram-positive bacteria that has occurred in recent years has resulted in the development of infections that are difficult to treat, and also in severely restricted treatment options. In particular, the incidence of methicillin-resistant Staphylococcus aureus (MRSA) has increased, with strains shown to cause up to 21% of skin infections and 59.6% of nosocomial pneumonia. Recently, strains of S. aureus with reduced susceptibility to vancomycin (glycopeptide-intermediate S. aureus or GISA) are causing great concern, particularly as vancomycin has been the agent of choice in the treatment of infection caused by MRSA. GISA has been identified in Japan, the USA and Europe. New agents that have anti-MRSA activity are now being investigated. These include the novel streptogramin, quinupristin/dalfopristin. This report examines the activity of quinupristin/dalfopristin against strains of S. aureus and coagulase-negative staphylococci, including multidrug-resistant MRSA and GISA.

Topics: Anti-Bacterial Agents; Bacteremia; Humans; Methicillin Resistance; Staphylococcal Infections; Vancomycin; 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

Gram-positive organisms such as Staphylococcus aureus (including MRSA), coagulase-negative staphylococci, Enterococcus spp., and Streptococcus spp. have in recent years emerged as significant pathogens in hospitals and are now being isolated more frequently than gram-negative bacilli. These organisms are often multidrug resistant. Therefore, alternative agents with potent activity against gram-positive organisms are of considerable interest. In addition to the glycopeptide antibiotic vancomycin and the aminoglycoside antibiotic arbekacin, which can be used in MRSA infections, teicoplanin, RP 59500 and daptomycin are now under basic research in Japan. These antimicrobial agents are very active against gram-positive organisms, including MRSA and appear to be potent agents against infections due to gram-positive cocci, particularly MRSA.

Topics: Daptomycin; Glycopeptides; Humans; Methicillin Resistance; Peptides; Staphylococcal Infections; Staphylococcus aureus; Teicoplanin; Vancomycin; Virginiamycin

A review of the literature suggests the following conclusions: 1) since its first practical use in 1965, namely over the past 10 years, there has been no drop in activity of Gentamicin on Staphylococcus aureus and on numerous other Staphylococcus and/or Micrococcus species. 2) In comparison with the other aminoglycosidic antibiotics employed up to the present, i.e. Streptomycin, Neomycin, Kanamycin, Amminosidine, and Framycetin, Gentamicin has demonstrated a much superior antistaphylococcic activity, and this has also been documented on numerous strains of staphylococci recalcitrant to Kanamycin, Streptomycin, Framycetin and Neomycin. This goes to prove the absence of any cross resistance between Kanamycin, Streptomycin, Framycetin and Neomycin on the one hand and Gentamycin on the other. 3) Along with Rifampicin, certain Cephalosporins (Cephalotine, Cephaloridine) and Pristinamycin-Virgimycin, Gentamicin must undoubtedly be considered a "greater" antibiotic as far as antistaphylococcic activity is concerned. It also has the advantage over other antistaphylococcic-acting antibiotics that only in exceptional cases does it give rise to resistant strains.

Topics: Cephalosporins; Cross Infection; Drug Resistance, Microbial; Framycetin; Gentamicins; Humans; Kanamycin; Microbial Sensitivity Tests; Neomycin; Paromomycin; Rifampin; Staphylococcal Infections; Staphylococcus; Streptomycin; Virginiamycin

An emergency-use program forof Synercid (quinupristin/dalfopristin, Q/D) has been set up following the occurrence of Gram-positive infections with no therapeutic alternatives to the available antibiotic arsenal.. The experience in France is based on a collective of 88 infections analysed in 74 patients. The most frequent clinical indications were: central catheter-related bacteremia, bone and joint infection, endocarditis and, intraabdominal infection. The most frequently causative pathogens were: S. aureus (n = 26, including 24/26 meticillin-resistant), coagulase negative staphylococci (n = 28, including 24/28 meticillin-resistant), enterococci (n = 15), and others (n = 5). Q/D was administered most frequently by central venous infusion, 3 times a day (68/74 patients); the mean and median dose per infusion was 7.4 mg/kg and the mean duration of treatment was 15.6 days. A combined antibiotic therapy was used in 70/74 patients (a glycopeptide in 41/54 staphylococcal infections).. A Clinical success at the end of treatment was obtained in 40/74 patients (54%; CI 42.1%-65.7%) [the analysis included 25 patients (34%) with an indeterminate clinical response, categorized as failures] et and 39/73 patients (53%) at the follow-up [including 22 deaths (30%), categorized as failure at the follow-up]. The end-of-treatment success rate in patients with staphylococcal and enterococcal infections was respectively 30/54 (56%) and 8/15 (53%). The safety analysis indicated that 24/74 patients presented at least one treatment-related intercurrent event (possible or probable relationship), the most frequent ones being digestive disordersturbances, signs of venous intolerance, or diffuse or muscular pain.. Q/D has demonstrated a therapeutic potential in a variety of Gram-positive infections (staphylococcal and enterococcal) in patients with no therapeutic antibiotic alternative, and the type of the intercurrent events reported was consistent with those expected ones in this population of seriously ill patients.

Topics: Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Drug Prescriptions; Drug Resistance, Microbial; Drug Therapy, Combination; Emergencies; Enterococcus; Follow-Up Studies; France; Humans; Rabbits; Staphylococcal Infections; Staphylococcus aureus; Streptococcus; Time Factors; Virginiamycin

Safety and efficacy of quinupristin-dalfopristin (an injectable streptogramin antibiotic) were evaluated in the treatment of a variety of infections due to methicillin-resistant Staphylococcus aureus (MRSA) in patients either intolerant of or failing prior therapy. The influence of resistance phenotypes on treatment outcome was also assessed. This worldwide, multicentre, open-label, non-comparative, emergency-use clinical study enrolled patients with one or more of nine predefined, culture-confirmed infections with MRSA, who had no clinically appropriate alternative antibiotic therapy. The recommended quinupristin-dalfopristin dose was 7.5 mg/kg administered iv every 8 h for a duration judged appropriate by the investigator. There were no restrictions on prior or concomitant treatment with other antibiotics. Clinical, microbiological and laboratory assessments were performed at baseline, during study drug treatment, within 24 h after the last dose, and 7-21 days post-therapy. Ninety patients [age (mean +/- S.D.) 57.4 +/- 18.5 years] with significant underlying medical illnesses were treated at 63 centres in five countries. The most common indications were bone and joint infection (44.4% of patients) and skin and skin structure infection (16.7%). The mean (+/- S.D.) daily dose and treatment duration was 20.2 +/- 2.9 mg/kg/day for 28.5 +/- 22.3 days, most frequently administered every 8 h. The overall success rate (defined as a clinical outcome of either cure or improvement and a bacteriological outcome of eradication or presumed eradication) was 71.1% in the all-treated population (n = 90) and 66.7% in patients who were both clinically and bacteriologically evaluable (n = 27). Success rates for endocarditis, respiratory tract infection and bacteraemia of unknown source were below the population mean. The macrolide-lincosamide-streptogramin type B resistance phenotype did not appear to alter the response rate. The most common non-venous adverse events related to study medication were arthralgias (10.8%), myalgias (8.6%) and nausea (8.6%). Quinupristin-dalfopristin should be considered as a treatment option for infections caused by MRSA, especially in patients intolerant of or failing alternate therapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Confidence Intervals; Drug Therapy, Combination; Emergency Treatment; Female; Humans; Male; Methicillin Resistance; Middle Aged; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome; Virginiamycin

Two different doses of quinupristin/dalfopristin were compared with intravenous vancomycin with regard to the efficacy and safety in the treatment of catheter-related staphylococcal bacteremia. A total of 39 patients were enrolled from 13 centers. For all treated patients with a baseline pathogen, outcome was comparable for all antibiotic study regimens. Discontinuation of the antibiotic for an adverse clinical event occurred in 12% of patients receiving quinupristin/dalfopristin and in 15% of those receiving vancomycin. Quinupristin/dalfopristin may have the potential to serve as an alternative agent in the treatment of catheter-related staphylococcal bacteremia. However, larger prospective randomized trials are required.

Topics: Adult; Aged; Anti-Bacterial Agents; Bacteremia; Catheterization; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Pilot Projects; Prospective Studies; Single-Blind Method; Staphylococcal Infections; Vancomycin; Virginiamycin

We recently demonstrated that oral roxithromycin is as effective as intravenous penicillin G in adults with erysipelas. We therefore evaluated the effectiveness of pristinamycin, an antibiotic which is very active on streptococci and Staphylococcus aureus, in non-necrotizing bacterial dermohypodermitis in adults.. This prospective open study was conducted in one center and included immunocompetent patients with bacterial dermophypodermitis without signs of toxicity or local manifestations suggesting necrotizing fasciitis. Bacteriology tests included direct immunofluorescence for streptococcus (groups A, C, G) on skin biopsies of the lesion before treatment. Patients were treated with pristinamycin (Pyostacine 500, 3 g/day until 10 days after apyrexia), and evaluated clinically on day 0, 2, 6, 8, and 15. Overall treatment effect was assessed on day 15.. The study group included 42 adults (23 woman and 19 men; mean age 64 +/- 3.5 yr). In 39 cases (93%), the bacterial dermohypodermitis was localized on the lower limb. The inflammatory lesion was well delimited, a characteristic feature of erysipelas, in 32 cases (76%). Sample culture, direct immunofluorescence or serology findings demonstrated presence of streptococci in 33 cases (79%). A single treatment with pristinamycin was successful in 36 patients, giving an overall rate of 86%. Drainage of a localized abscess was successful in 5 of 6 patients after initial failure of antibiotic treatment.. This prospective study demonstrated the effectiveness of pristinamycin in non-necrotizing bacterial dermohypodermitis in the adult, especially in erysipelas. Overall effectiveness was comparable with that reported for penicillin G or macrolides in erysipelas.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Erysipelas; Female; Humans; Male; Middle Aged; Prospective Studies; Skin Diseases, Bacterial; Staphylococcal Infections; Streptococcal Infections; Treatment Outcome; Virginiamycin

A prospective double-blind study was conducted in patients hospitalized with a staphylococcal infection. The effects of oxacillin (4-6 g/d) and pristinamycin (2-3 g/d) were compared. These were 52 cutaneous infections and 17 other ones. The results of the two antibiotics effects were not different. Tolerance was appreciated in the 82 patients who entered the study: pristinamycin had fewer (but not significantly different) side effects than oxacillin (3/37 vs 9/45). As pristinamycin is active in vitro on at least 95 p. cent of strains, we concluded that it can be the first choice antibiotic in staphylococcal infections when the oral route is possible.

Topics: Administration, Oral; Adolescent; Adult; Aged; Child; Child, Preschool; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Infant; Male; Middle Aged; Oxacillin; Skin Diseases, Infectious; Staphylococcal Infections; Virginiamycin

Topics: Anti-Bacterial Agents; Bacteremia; Bacterial Typing Techniques; Ceftaroline; Cephalosporins; Drug Resistance, Multiple, Bacterial; Electrophoresis, Gel, Pulsed-Field; Gene Expression; Genes, Bacterial; Humans; Linezolid; Methicillin; Methicillin Resistance; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Phylogeny; Rifampin; Staphylococcal Infections; Tetracycline; Turkey; Vancomycin; Vancomycin Resistance; Virginiamycin

Clonal complex (CC) 9 is a prevalent livestock-associated (LA) MRSA clone in Asia whose pathogenicity in humans remains unknown.. In 2012, we identified a patient with CC9-MRSA infection linked to livestock. After screening 3328 clinical MRSA isolates from a national database, eight isolates (0.24%) collected between 1998 and 2012 were further confirmed to be of CC9. The detailed molecular features of the nine human CC9 strains and phylogenetic relatedness to animal CC9 strains were characterized with WGS. The antibiotic susceptibilities were determined and the clinical information was abstracted from medical records.. WGS grouped the CC9 strains into two clades, which were respectively associated with distinct toxome profiles, resistance gene profiles and staphylococcal cassette chromosomes (SCCmecXII for 7 isolates and SCCmecVT for 2 isolates). The SCCmecXII strains were phylogenetically related to animal CC9-MRSA strains, negative for Panton-Valentine leucocidin and 100% resistant to ciprofloxacin, erythromycin, clindamycin, gentamicin and tigecycline. Four of the seven SCCmecXII isolates were associated with invasive diseases including bacteraemia leading to death (2) and osteomyelitis (2). Two SCCmecXII isolates were from patients with exposure to pigs before development of the MRSA diseases.. The CC9-SCCmecXII MRSA prevailing in pigs in Asia is multidrug resistant and potentially pathogenic to humans. It is critical to continuously monitor the local epidemiology of MRSA and implement effective control measures to limit the spread of LA-MRSA between animals, to humans and in healthcare facilities.

Topics: Adult; Aged; Aged, 80 and over; Animals; Anti-Bacterial Agents; beta-Lactam Resistance; beta-Lactams; Child, Preschool; Ciprofloxacin; Clindamycin; Drug Resistance, Multiple, Bacterial; Erythromycin; Farmers; Female; Gentamicins; Humans; Livestock; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Middle Aged; Minocycline; Staphylococcal Infections; Swine; Swine Diseases; Taiwan; Tigecycline; Virginiamycin

The aim of this study was to evaluate the antimicrobial susceptibility profile of 85 Staphylococcus epidermidis and 84 Staphylococcus haemolyticus strains isolated from blood cultures to oxacillin, vancomycin, tigecycline, linezolid, daptomycin, and quinupristin/dalfopristin over a period of 12 years. S. epidermidis and S. haemolyticus isolated from blood cultures of inpatients, attended at a teaching hospital, were analyzed for the presence of the mecA gene and by SCCmec typing. The minimum inhibitory concentration (MIC) values of tigecycline, linezolid, daptomycin, quinupristin/dalfopristin, and vancomycin were determined. Isolates exhibiting vancomycin MICs of ≥2 μg/ml were typed by pulsed-field gel electrophoresis (PFGE). The rate of mecA positivity was 92.9% and 100% in S. epidermidis and S. haemolyticus, respectively. The most frequent SCCmec types were type III (53.2%) in S. epidermidis and type I (32.1%) in S. haemolyticus. All isolates were susceptible to linezolid and daptomycin, but 7.1% of S. haemolyticus and 2.3% of S. epidermidis isolates were resistant to tigecycline, and 1.2% each of S. haemolyticus and S. epidermidis were resistant and intermediately resistant to quinupristin/dalfopristin, respectively. S. epidermidis exhibited higher vancomycin MICs (40% with MIC of ≥2 μg/ml). Clonal typing of strains with vancomycin MIC of ≥2 μg/ml revealed the presence of different PFGE types of S. epidermidis and S. haemolyticus over a period of up to 4 years (2002-2004, 2005-2008, 2006-2009, 2010-2011). Despite the observation of a high prevalence of mecA, the clinical strains were fully susceptible to vancomycin and to the new drugs linezolid, daptomycin, tigecycline, and quinupristin/dalfopristin. The PFGE types with vancomycin MIC of ≥2 μg/ml exhibited a great diversity of SCCmec cassettes, demonstrating that S. epidermidis and S. haemolyticus may easily acquire these resistance-conferring genetic elements.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Bacterial Typing Techniques; Blood Culture; Brazil; Daptomycin; Drug Resistance, Multiple, Bacterial; Electrophoresis, Gel, Pulsed-Field; Gene Expression; Hospitals, Teaching; Humans; Linezolid; Minocycline; Mutation; Oxacillin; Prevalence; Staphylococcal Infections; Staphylococcus epidermidis; Staphylococcus haemolyticus; Tigecycline; Vancomycin; Virginiamycin

The aims of the present study were to evaluate erythromycin, clindamycin, and streptogramin resistance rates, as well as the phenotypic and genotypic characteristics of erythromycin-resistant staphylococci in a Greek University Hospital. Macrolide, lincosamide, and streptogramin B-type resistance was investigated by double disk diffusion and the D-zone testing, while Minimal inhibitory concentration determination was performed among 656 erythromycin-resistant staphylococcal clinical consecutive isolates, too. The presence of the major genetic determinants ermA, ermB, ermC, and msrA were detected by polymerase chain reaction (PCR). The overall erythromycin resistance rate was 49·70%. One hundred and forty-six of the 322 Staphylococcus aureus were methicillin-resistant S. aureus (MRSA) (45·34%), whereas 176 were methicillin-susceptible S. aureus (54·66%). The macrolides, lincosamides, and streptogramin B-type antibiotics (MLSB)-constitutive phenotype was detected in 126 S. aureus strains (88·7%), whereas the inducible MLSB resistance phenotype was demonstrated in 16 S. aureus (11·3%). The MS phenotype was not detected. ErmC was the most frequently encountered gene responsible for macrolide resistance among S. aureus and coagulase negative staphylococci in this hospital. Pulsed-field gel electrophoresis (PFGE) analysis of SmaI DNA fragments revealed the presence of a single predominant clone among erythromycin-resistant S. aureus. The predominance of constitutive erythromycin resistance is a serious problem and limits the use of clindamycin for severe staphylococcal infections not only in this university hospital, but in many countries worldwide.

Topics: Anti-Bacterial Agents; Clindamycin; Cross Infection; Disk Diffusion Antimicrobial Tests; Drug Resistance, Multiple, Bacterial; Electrophoresis, Gel, Pulsed-Field; Erythromycin; Genes, Bacterial; Genotype; Greece; Hospitals, University; Humans; Microbial Sensitivity Tests; Prevalence; Staphylococcal Infections; Staphylococcus aureus; Streptogramin B; Tertiary Healthcare; Virginiamycin

Quinupristin/dalfopristin (Q/D) is a valuable alternative to vancomycin for the treatment of meticillin-resistant Staphylococcus aureus (MRSA) infections. However, not long after Q/D was approved, bacteria with resistance to this newer antimicrobial agent were reported. To investigate the prevalence of Q/D resistance, a total of 1476 non-duplicate S. aureus isolates, including 775 MRSA, from a Chinese tertiary hospital were selected randomly from 2003 to 2013. Of the 775 MRSA, 3 (0.4%) were resistant to Q/D. All meticillin-susceptible S. aureus were susceptible to Q/D. The prevalence of Q/D resistance among S. aureus was 0.2% (3/1476). The three isolates with Q/D resistance had the same antimicrobial resistance profile, except for cefaclor and chloramphenicol. All three Q/D-resistant MRSA were positive for five streptogramin B resistance genes (ermA, ermB, ermC, msrA and msrB) and two streptogramin A resistance genes (vatC and vgaA) as determined by PCR and DNA sequencing. MRSA WZ1031 belonged to ST9-MRSA-SCCmecV-t899, whilst MRSA WZ414 and WZ480 belonged to ST9-MRSA-SCCmecNT(non-typeable)-t899. ST9 has been reported predominantly in livestock-associated (LA) MRSA in some Asian countries. The three patients with these MRSA isolates were not livestock handlers and did not keep close contact with livestock. The origin of these important LA-MRSA isolates causing human infections is not known. Taken together, Q/D resistance, which was caused by a combination of ermA-ermB-ermC-msrA-msrB-vatC-vgaA, was first found among S. aureus clinical isolates in China. The present study is the first report of the emergence of human infections caused by ST9 LA-MRSA isolates with Q/D resistance.

Topics: Aged; Anti-Bacterial Agents; China; DNA, Bacterial; Drug Resistance, Bacterial; Genes, Bacterial; Genotype; Humans; Middle Aged; Molecular Typing; Polymerase Chain Reaction; Sequence Analysis, DNA; Staphylococcal Infections; Staphylococcus aureus; Virginiamycin

The present study was carried out to assess the frequency of methicillin-resistant staphylococci (MRS) among racehorses (n=209) and veterinary personnel (n=13) as well as environmental surfaces (n=14) at an equine hospital in Adana, Turkey. In addition, species distribution, antimicrobial susceptibility, resistance genes, staphylococcal chromosomal cassette mec (SCCmec) type and clonality of these isolates were also investigated. MRS were identified by 16S rRNA sequencing, and typed by pulsed-field gel electrophoresis (PFGE). As a result, MRS was isolated in horses (48.3%), clinic staff (92.3%) and environmental samples (71.4%). Of the 123 MRS isolates, 118 isolates were identified as Staphylococcus lentus, and the remaining ones were found to be S. sciuri (n=3), S. intermedius (n=1) and S. fleuretti (n=1). All isolates were found to be susceptible against vancomycin, quinupristin-dalfopristin and rifampicin. Additionally, single or various combinations of resistance genes were detected among MRS isolates. SCCmec type II was identified in all isolates. Similar PFGE patterns were observed among MRS isolated from horses, humans, and environmental samples. Since MRS were concurrently isolated from horses and humans it is suggested that cross-transmission of MRS between horses and humans might occur. However, it cannot be ruled out that transmission is human to animal or animal to human.

Topics: Animal Technicians; Animals; Cross Infection; DNA Primers; Electrophoresis, Gel, Pulsed-Field; Genes, MDR; Horse Diseases; Horses; Humans; Methicillin Resistance; Polymerase Chain Reaction; Rifampin; Species Specificity; Staphylococcal Infections; Staphylococcus; Turkey; Vancomycin; Virginiamycin

The aim of this study was to determine whether vancomycin resistant Staphylococcus aureus (VRSA) and vancomycin intermediate susceptible S.aureus (VISA) strains were present among methicillin-resistant S.aureus (MRSA) strains isolated from patients hospitalised at intensive care units (ICU) of hospitals located at different regions of Turkey and to determine the minimum inhibitory concentration (MIC) values of teicoplanin, linezolid, tigecycline, quinupristin-dalfopristin and daptomycin, which are alternative drugs for the treatment of MRSA infections. A total of 260 MRSA clinical strains (isolated from 113 lower respiratory tract, 90 blood, 24 wound, 17 catheter, 13 nasal swabs, two urine and one CSF sample) were collected from nine health-care centers in eight provinces [Ankara (n= 52), Konya (n= 49), Antalya (n= 40), Istanbul (n= 7), Izmir (37), Diyarbakir (n= 15), Van (n= 12), Trabzon (n= 48)] selected as representatives of the seven different geographical regions of Turkey. Methicillin resistance was determined by cefoxitin disk diffusion in the hospitals where the strains were isolated and confirmed by oxacillin salt agar screening at the Refik Saydam National Public Health Agency. Screening for VISA and VRSA was conducted using the agar screening test and E-test. Susceptibility of the MRSA strains to other antibiotics was also determined by E-test method. None of the 260 MRSA strains were determined to be VRSA or VISA. All were susceptible to teicoplanin and linezolid, and susceptibility rates to daptomycin, tigecycline and quinupristin-dalfopristin were 99.6%, 96.9%, and 95%, respectively. Absence of VISA and VRSA among the MRSA strains surveyed currently seemed hopeful, however, continuous surveillance is necessary. In order to prevent the development of VISA and VRSA strains the use of linezolid, tigecycline, quinupristin-dalfopristin and daptomycin should be encouraged as alternative agents of treatment of MRSA infections.

Topics: Acetamides; Anti-Bacterial Agents; Daptomycin; Humans; Intensive Care Units; Linezolid; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Minocycline; Oxazolidinones; Staphylococcal Infections; Teicoplanin; Tigecycline; Turkey; Vancomycin; Vancomycin Resistance; Virginiamycin

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Aqueous Humor; Endophthalmitis; Eye Infections, Bacterial; Humans; Intravitreal Injections; Male; Staphylococcal Infections; Staphylococcus aureus; Vancomycin Resistance; Virginiamycin; Vitreous Body

The aim was to study the changes in the antimicrobial resistance of methicillin-resistant Staphylococcus aureus (MRSA) clones over a 5-year period (from 2000 to 2005) at a representative hospital in Beijing, China.. A total of 100 randomly selected MRSA strains were analyzed using antimicrobial susceptibility testing, pulsed-field gel electrophoresis, spa typing, multilocus sequence typing, SCCmec typing, and PCR for the Panton-Valentine leukocidin virulence factor.. Resistance to rifampin greatly increased from 32% (16/50) to 68% (34/50). High-level mupirocin-resistant isolates were found only in 2005, when four were identified. Intermediate susceptibly to quinupristin-dalfopristin increased from 22% (11/50) to 52% (26/50) between 2000 and 2005. The main antimicrobial resistance profiles changed from TC-GM-CI-EM-CM in 2000 to TC-GM-CI-EM-CM-RI in 2005. The main pulsed-field gel electrophoresis type changed from types C, L, and E in 2000 to types J, F, and N, respectively, in 2005. ST239-MRSA-III was the most predominant clone in 2000 and 2005, whereas ST5-MRSA-II was found only in 2005.. There were increasing levels of antimicrobial resistance and epidemiological changes in the hospital-associated MRSA strains isolated in this facility between 2000 and 2005.

Topics: Anti-Bacterial Agents; Bacterial Toxins; China; Clone Cells; Electrophoresis, Gel, Pulsed-Field; Exotoxins; Hospitals, Urban; Humans; Leukocidins; Methicillin Resistance; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Multilocus Sequence Typing; Respiratory System; Staphylococcal Infections; Staphylococcus aureus; Time Factors; Virginiamycin

Treatment of chronic or recurrent Staphylococcus aureus infections may require using antibiotics with activity against intracellular multiresistant organisms. Quinupristin/dalfopristin (3:7) has been examined in this context.. Quinupristin and dalfopristin were used separately or mixed. Strains used were: (i) methicillin-susceptible and -resistant S. aureus (MSSA and MRSA); (ii) one vat(B) MSSA and msr(A/B) MRSA; (iii) erm(A)+ [MSSA, MRSA, vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA)]; and (iv) one erm(A/B)+ cfr+ MRSA resistant to quinupristin, dalfopristin and their combination. Assessment of activity was determined by: (i) MICs (CLSI method); and (ii) concentration-response curves in broth and after phagocytosis by THP-1 macrophages, with descriptors of the model (Emin) and the pharmacodynamic response [maximal relative efficacy (Emax), relative potency (EC50) and apparent static concentration (Cstatic)].. erm(A)-positive strains were all susceptible to quinupristin/dalfopristin (except strain CM05), with MICs not adversely influenced by acid pH or by the MRSA, VISA or VRSA character of the strain. In concentration-response experiments, quinupristin/dalfopristin showed similar patterns for all strains (except strain CM05), with a >3 log10 cfu decrease in broth and a 1.3 [erm(A) strain] to 2.6 [fully susceptible, vat(B) and msr(A/B) strains] log10 cfu decrease for intracellular bacteria at the maximal extracellular concentration tested (25 mg/L). Maximal extracellular and intracellular activity was obtained for a quinupristin/dalfopristin ratio of 3:7. For strain CM05, quinupristin/dalfopristin was static in all conditions.. Based on historical comparisons with rifampicin, fluoroquinolones, lipoglycopeptides and other antistaphylococcal drugs with a large accumulation in eukaryotic cells, quinupristin/dalfopristin appears to be one of the most active antibiotics against intracellular S. aureus studied in this model so far, largely irrespective of its resistance phenotype.

Topics: Anti-Bacterial Agents; Cell Line; Colony Count, Microbial; Drug Resistance, Bacterial; Humans; Macrophages; Microbial Sensitivity Tests; Microbial Viability; Phagocytosis; Staphylococcal Infections; Staphylococcus aureus; Virginiamycin

The activity of telavancin and comparators was assessed against a contemporary (2007 and 2008) global collection of 10,000 isolates of Staphylococcus aureus. Telavancin was very active against methicillin-susceptible and -resistant S. aureus (MSSA and MRSA, respectively; MIC(50/90) for both, 0.12/0.25 microg/ml; 100.0% susceptible). This agent was 2-, 4-, and 8-fold more potent than daptomycin (MIC(90), 0.5 microg/ml), vancomycin or quinupristin-dalfopristin (MIC(90), 1 microg/ml), and linezolid (MIC(90), 2 microg/ml) against MRSA, respectively. These data show a potent activity of telavancin tested against a current global collection of S. aureus.

Topics: Acetamides; Aminoglycosides; Anti-Bacterial Agents; Daptomycin; Drug Resistance, Bacterial; Humans; In Vitro Techniques; Linezolid; Lipoglycopeptides; Methicillin Resistance; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Oxazolidinones; Staphylococcal Infections; Staphylococcus aureus; Vancomycin; Virginiamycin

Following an initial response to vancomycin therapy, a patient with meticillin-resistant Staphylococcus aureus (MRSA) bacteraemia developed endocarditis, failed a second course of vancomycin and then failed daptomycin therapy. An increase in the vancomycin minimum inhibitory concentrations of four consecutive MRSA blood isolates from 2 microg/mL to 8 microg/mL was shown by Etest. Population analysis of four successive blood culture isolates recovered over the 10-week period showed that the MRSA strain became progressively less susceptible to both vancomycin and daptomycin. Retrospectively, the macro Etest method using teicoplanin indicated a decrease in vancomycin susceptibility in the second blood isolate. The patient improved after treatment with various courses of trimethoprim/sulfamethoxazole, quinupristin/dalfopristin and linezolid. Early detection of vancomycin-heteroresistant S. aureus isolates, which appeared to have clinical significance in this case, continues to be a challenge for the clinical laboratory. Development of suitable practical methods for this should be given priority. Concurrent development of resistance to vancomycin and daptomycin, whilst rare, must be considered in a patient who is unresponsive to daptomycin following vancomycin therapy.

Topics: Acetamides; Anti-Bacterial Agents; Bacteremia; Daptomycin; Drug Resistance, Bacterial; Endocarditis, Bacterial; Humans; Linezolid; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Oxazolidinones; Staphylococcal Infections; Trimethoprim, Sulfamethoxazole Drug Combination; Vancomycin; Virginiamycin

Peritonitis remains a major complication in patients undergoing peritoneal dialysis. The most recent ISPD guidelines for the empiric initial treatment of peritonitis recommend the use of antibiotics that provide coverage against Gram-positive organisms (vancomycin or cefazolin) and Gram-negative organisms (a third-generation cephalosporin or an aminoglycoside). However, there are some situations in which this regimen may not be desirable. Concerns of resistant organisms, changing microbiology, drug toxicity, or difficulties administering therapy may lead a provider to modify the initial regimen. Drug resistant Staphylococcus aureus strains and Enterococcus strains may require administration of newer agents such as linezolid, quinipristin/dalfopristin, or daptomycin. Many centers have reported that, over time, the microbiology at those institutions has been changing. Some centers have reported a significant decrease in gram positive organisms and increase in extended spectrum beta-lactamase (ESBL) organisms. It is important for each center to examine its microbiology to document such trends. Although the currently recommended therapies have low toxicities, it is possible that concerns for untoward side effects in an individual patient may dictate changing the regimen. Finally, there is evidence from many prospective studies that monotherapy with different agents (oral quinolones or cefepime) is efficacious; if ease of therapy is a consideration, these may also be appropriate agents.

Topics: Acetamides; Anti-Bacterial Agents; Daptomycin; Drug Resistance, Bacterial; Humans; Linezolid; Oxazolidinones; Peritoneal Dialysis; Peritonitis; Staphylococcal Infections; Staphylococcus aureus; Virginiamycin

Topics: Aged; Bacteremia; Catheterization, Central Venous; Chronic Disease; Daptomycin; Discitis; Humans; Jugular Veins; Male; Methicillin-Resistant Staphylococcus aureus; Pancreatitis; Rifampin; Staphylococcal Infections; Vancomycin; Virginiamycin

We compared the efficacy of quinupristin/dalfopristin versus vancomycin, alone or in combination with rifampicin, in a rabbit model of methicillin-resistant Staphylococcus aureus-induced arthritis. Vancomycin, alone or in combination with rifampicin, and quinupristin/dalfopristin+rifampicin were significantly more effective than quinupristin/dalfopristin alone.

Topics: Animals; Anti-Bacterial Agents; Arthritis, Infectious; Disease Models, Animal; Drug Therapy, Combination; Methicillin Resistance; Microbial Sensitivity Tests; Rabbits; Rifampin; Staphylococcal Infections; Staphylococcus aureus; Vancomycin; Virginiamycin

To compare pharmacodynamic indices and minimal inhibitory concentrations for vancomycin, gatifloxacin, moxifloxacin, linezolid, and combined quinupristin and dalfopristin for historic and current human coagulase-negative staphylococcus (CoNS) endophthalmitis isolates.. Experimental study.. Fifty-nine CoNS endophthalmitis isolates retrieved from patients at the Bascom Palmer Eye Institute from 1993 through 2006.. Coagulase-negative staphylococcal endophthalmitis isolates were recovered from the microbiology specimen bank, rehydrated, and processed for susceptibility testing using standard microbiological protocols. E tests were used to determine and compare mean inhibitory concentration for 50% of isolates (MIC50) and mean inhibitory concentration for 90% of isolates (MIC90) values. Peak concentration (C(max)) was defined as the maximum attainable aqueous concentration using topical or oral therapy, or both. The MIC50 and MIC90 values for each antibiotic are the minimum concentrations that inhibit 50% and 90% of CoNS endophthalmitis isolates, respectively. Significance was determined by the McNemar test. Pharmacodynamic indices (C(max)/MIC) were calculated using determined MIC values and published intraocular drug concentrations for topical and oral dosing. The pharmacodynamic index was defined as the achievable aqueous humor concentration of an antibiotic divided by the concentration of the antibiotic required to inhibit a specified percentage of microbiologic isolates.. Pharmacodynamic indices for new and conventional antibiotics.. General in vitro susceptibility patterns in descending order were vancomycin (100%), linezolid (100%), quinupristin and dalfopristin (98%), moxifloxacin (48%), and gatifloxacin (47%). The corresponding MIC50 and MIC90 values were vancomycin, 2 microg/ml and 3 microg/ml, respectively; linezolid, 1 microg/ml and 4 microg/ml; quinupristin and dalfopristin, 0.25 microg/ml and 0.5 microg/ml; moxifloxacin, 0.75 microg/ml and > or =32 microg/ml; and gatifloxacin, 2 microg/ml and > or =32 microg/ml. Pharmacokinetic indices (C(max)/MIC90) for topical dosing were all <1. There was a significant difference in the percent of isolates susceptible to combined quinupristin and dalfopristin, vancomycin, and linezolid compared with moxifloxacin and gatifloxacin. There was no statistical significance in CoNS susceptibility between the tested fluoroquinolones.. Vancomycin, linezolid, and combined quinupristin and dalfopristin were more effective in vitro than fluoroquinolones against CoNS in the current study. Reported aqueous concentrations of the antibiotics used in this study failed to provide adequate coverage for 90% of the CoNS endophthalmitis isolates.

Topics: Acetamides; Administration, Oral; Administration, Topical; Anti-Bacterial Agents; Aqueous Humor; Aza Compounds; Biological Availability; Coagulase; Endophthalmitis; Eye Infections, Bacterial; Fluoroquinolones; Gatifloxacin; Humans; Linezolid; Methicillin Resistance; Microbial Sensitivity Tests; Microbiological Techniques; Moxifloxacin; Oxazolidinones; Quinolines; Staphylococcal Infections; Staphylococcus; Vancomycin; Virginiamycin

Our study compared the susceptibility of 136 clinical isolates of Staphylococcus aureus and 119 multidrug-resistant Staphylococcus aureus (MRSA) isolates from Oslo to a range of antibiotics, including the novel antibiotics quinupristin-dalfopristin, linezolid and daptomycin. All isolates were susceptible to daptomycin, linezolid and quinupristin-dalfopristin, although a subgroup was less susceptible to the latter. There was no linkage between reduced susceptibility to daptomycin, linezolid or quinupristin-dalfopristin and resistance to other classes of antimicrobials. In addition, MRSA strains from 2004 have become more sensitive to fucidin and rifampicin. The results can be used to evaluate the appropriateness of breakpoints and to define a baseline for monitoring possible future emergence of resistance to daptomycin, quinupristin-dalfopristin and linezolid in Staphylococcus aureus in Norway.

Topics: Acetamides; Anti-Bacterial Agents; Daptomycin; Humans; Linezolid; Methicillin Resistance; Norway; Oxazolidinones; Staphylococcal Infections; Staphylococcus aureus; Virginiamycin

This study was undertaken to evaluate the in vitro activities of arbekacin-based combination regimens against vancomycin hetero-intermediate Staphylococcus aureus (hetero-VISA). Combinations of arbekacin with vancomycin, rifampin, ampicillin-sulbactam, teicoplanin, or quinupristin-dalfopristin against seven hetero-VISA strains and two methicillin-resistant S. aureus strains were evaluated by the time-kill assay. The combinations of arbekacin with vancomycin, teicoplanin, or ampicillin-sulbactam showed the synergistic interaction against hetero-VISA strains. Data suggest that these arbekacin-based combination regimens may be useful candidates for treatment options of hetero-VISA infections.

Topics: Aminoglycosides; Ampicillin; Anti-Bacterial Agents; Dibekacin; Drug Resistance, Bacterial; Drug Synergism; Humans; In Vitro Techniques; Methicillin Resistance; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus; Sulbactam; Teicoplanin; Vancomycin; Virginiamycin

Methicillin-resistant S. aureus (MRSA) with low susceptibility to glycopeptides is uncommon.. The case of a 50-year-old non-drug addict patient presenting with tricuspid valve infective endocarditis (IE) by MRSA resistant to vancomycin and linezolid is presented. There was response only to quinupristin/dalfopristin. He had a motorcycling accident four years before undergoing right above-the-knee amputation and orthopaedic fixation of the left limb. There were multiple episodes of left MRSA-osteomyelitis controlled after surgery and vancomycin therapy. MRSA isolated from the blood at the time of IE presented with the same profile than the isolated four years earlier. Sequential treatment with teicoplanin-cotrimoxazole and Linezolid associated to vancomycin--rifampicin--cotrimoxazole had no improvement. Infection was controlled after 28 days of therapy with quinupristin/dalfopristin.. The literature presents only a few cases of MRSA IE not susceptible to glycopeptides in not drug addicted patients. This case shows the comparison of a highly-resistant MRSA after previous S. aureus osteomyelitis treated with glycopeptides. This is the first description of successful treatment of resistant-MRSA IE of the tricuspid valve complicated by multiple pulmonary septic infarction with quinupristin/dalfopristin.

Topics: Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Endocarditis, Bacterial; Heart Valve Diseases; Humans; Male; Methicillin Resistance; Middle Aged; Osteomyelitis; Radiography; Staphylococcal Infections; Staphylococcus aureus; Substance-Related Disorders; Tricuspid Valve; Ultrasonography; Virginiamycin

Nosocomial infections after spinal surgery are relatively uncommon but potentially serious. The goal of diagnostic evaluation is to determine the extent of infection and identify the microorganism involved. Neuroimaging provides accurate information on correct topography, localization and propagation of the infection. Microbiological data are able to give aetiological causes. In this patient with severe, chronic polymicrobial spine infection with epidural abscess and CSF fistula due to multidrug-resistant organisms, the cure was achieved with long-term antimicrobial specific therapy with quinupristin-dalfopristin (50 days) and linezolid (100 days) with mild side effects. This positive result was due to combined medical and surgical treatment.

Topics: Acetamides; Anti-Bacterial Agents; Bacteria; Cerebrospinal Fluid; Combined Modality Therapy; Cross Infection; Curettage; Device Removal; Discitis; Epidural Abscess; Female; Fistula; Fluconazole; Fungi; Humans; Internal Fixators; Laminectomy; Linezolid; Lumbar Vertebrae; Meropenem; Methicillin Resistance; Middle Aged; Osteomyelitis; Oxazolidinones; Parkinson Disease; Prosthesis-Related Infections; Reoperation; Skin Diseases; Spinal Diseases; Spinal Stenosis; Staphylococcal Infections; Thienamycins; 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

We report here a 34-year-old woman with complicated severe opportunistic pulmonary infection, who was treated with the newly developed antibiotics quinupristin/dalfopristin (QPR/DPR) and voriconazole. She had received repeated chemotherapy, irradiation of the left lung, autologous and allogeneic bone marrow transplantation (BMT), and segmentectomy of the base of the left lung as treatments for Hodgkin's lymphoma. Although she had been in complete remission (CR), the structure of the left lung was severely degraded. Four years after achieving CR, she developed complicated life-threatening pulmonary infections with methicillin-resistant Staphylococcus epidermidis and Aspergillus niger during outpatient care. Chemotherapies with QPR/DPR for S. epidermidis pneumonia and voriconazole for chronic necrotizing pulmonary aspergillosis (CNPA) improved her symptoms rapidly without any major complications. QPR/DPR and voriconazole are considered effective for patients with life-threatening opportunistic pulmonary infections who have previously been treated with intensive regimens including radiotherapies to the lung.

Topics: Adult; Anti-Bacterial Agents; Antifungal Agents; Aspergillosis; Aspergillus niger; Chronic Disease; Drug Therapy, Combination; Female; Hodgkin Disease; Humans; Lung Diseases, Fungal; Lymphatic Irradiation; Necrosis; Pneumonia, Bacterial; Pyrimidines; Radiation Injuries; Radiography; Staphylococcal Infections; Staphylococcus epidermidis; Triazoles; Virginiamycin; Voriconazole

Topics: Anti-Bacterial Agents; ATP-Binding Cassette Transporters; Bacterial Proteins; Drug Resistance, Bacterial; Electrophoresis, Gel, Pulsed-Field; Greece; Humans; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus hominis; Virginiamycin

In total, 408 staphylococcal isolates were tested for inducible clindamycin resistance (ICR) by the disk-diffusion induction test (D-test). ICR was detected in 5.7% of 105 methicillin-resistant Staphylococcus aureus (MRSA) isolates, 3.6% of 111 methicillin-susceptible S. aureus isolates, 30.8% of 94 methicillin-resistant coagulase-negative staphylococcal (CoNS) isolates, and 11.2% of 98 methicillin-sensitive CoNS isolates. All MRSA isolates that were erythromycin-resistant and clindamycin-susceptible were positive by the D-test. The same results were obtained with an azithromycin instead of an erythromycin disk. All isolates were susceptible to quinupristin-dalfopristin. The cost-benefit of the d-test should be evaluated locally after determining the incidence of the different resistance phenotypes.

Topics: Anti-Bacterial Agents; Clindamycin; Drug Resistance, Bacterial; Erythromycin; Humans; Methicillin Resistance; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus; Turkey; Virginiamycin

We performed in vitro studies to elucidate the bactericidal activity of the antibiotics in an adherent-cell biofilm model. Efficacy studies were performed in a staphylococcal central venous catheter (CVC) infection rat model. Silastic catheters were implanted into the superior cava. Via the CVC the rats were challenged with 1.0 x 10(6) CFU of a live Staphylococcus aureus strain. Twenty-four hours later, the antibiotic-lock technique was started. All animals were randomized to receive daily isotonic sodium chloride solution, quinupristin-dalfopristin (Q/D), linezolid, vancomycin, or ciprofloxacin at the minimal bactericidal concentration (MBC) and at 1,024 microg/ml in a volume of 0.1 ml that filled the CVC. The main outcome measures were MICs and MBCs for both planktonic and adherent cells, quantitative culture of the catheters and surrounding venous tissues, and quantitative peripheral blood cultures. The killing activities of all antibiotics against the adherent bacteria were at least fourfold lower than those against freely growing cells, with the exception of Q/D, which showed comparable activities against both adherent and planktonic organisms. Overall, Q/D at 1,024 microg/ml produced the greatest reduction in the number of cells recovered from the catheters, while at the same concentration, Q/D and vancomycin demonstrated higher activities than ciprofloxacin or linezolid in reducing the number of organisms recovered from the blood cultures. This study points out that treatment outcome of device-related infections cannot be predicted by the results of a standard susceptibility test such as the MIC. Our findings suggest that the clinically used antibiotics cannot eradicate the CVC infection through the antibiotic-lock technique, even at a concentration of 1,024 microg/ml.

Topics: Acetamides; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Biofilms; Catheters, Indwelling; Ciprofloxacin; Disease Models, Animal; Drug Therapy, Combination; Linezolid; Male; Oxazolidinones; Plankton; Rats; Rats, Wistar; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome; Vancomycin; Virginiamycin

Topics: Adult; Anemia; Anti-Bacterial Agents; Drug Administration Schedule; Hip Joint; Humans; Male; Reticulocytes; Staphylococcal Infections; Staphylococcus aureus; 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

To report the successful treatment of vancomycin-resistant Enterococcus (VRE) bacteremia using the combination of quinupristin/dalfopristin and high-dose ampicillin.. A 38-year-old African American woman with relapsed acute myeloid leukemia and neutropenic fever developed VRE bacteremia following 3 successive courses of vancomycin for methicillin-resistant staphylococcal infections. Treatment with linezolid was initiated; however, after 9 days of therapy, blood cultures continued to reveal VRE and the patient became febrile. The patient was subsequently switched to quinupristin/dalfopristin and high-dose ampicillin. The fever resolved and all subsequent blood cultures were negative after the initiation of combination therapy.. The emergence of VRE infections presents a treatment challenge in immunocompromised patients. When treating VRE infections in this patient population, the effectiveness of linezolid and quinupristin/dalfopristin is limited by their bacteriostatic activity when used as monotherapy. Recent in vitro data suggest synergistic activity with quinupristin/dalfopristin when used in combination with other antimicrobials in selected isolates of VRE.. Persistent VRE bacteremia was successfully treated in this neutropenic patient using the combination of high-dose ampicillin and quinupristin/dalfopristin. Case reports and in vitro data suggest that concomitant therapy with high-dose ampicillin may be an effective treatment alternative for VRE infections not responding to standard therapy.

Topics: Adult; Ampicillin; Anti-Bacterial Agents; Bacteremia; Drug Therapy, Combination; Enterococcus faecium; Female; Humans; Leukemia, Myeloid, Acute; Neutropenia; Staphylococcal Infections; Vancomycin Resistance; Virginiamycin

The aim of this study was to determine the in vitro antimicrobial activity of recently licensed quinupristin/dalfopristin and linezolid which have not yet been in clinical use in Turkey against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) strains isolated from various clinical specimens by using the Etest. The results showed that all MRSA strains were fully susceptible to both the new compounds. All strains were inhibited by 1 mg/l quinupristin/dalfopristin (mode MIC 0.38 mg/l) and by 3 mg/l linezolid (mode MIC 1.5 mg/l). Four strains of Enterococcus faecium showed an increase of resistance of 2-3 mg/l to quinupristin/dalfopristin (susceptible mode MIC 0.38 mg/l). With linezolid, all strains except two fell within the range 0.75-2.0 mg/l.

Topics: Acetamides; Anti-Bacterial Agents; Blood; Cerebrospinal Fluid; Drug Resistance, Bacterial; Enterococcus; Humans; Linezolid; Methicillin Resistance; Microbial Sensitivity Tests; Oxazolidinones; Rectum; Respiratory System; Staphylococcal Infections; Staphylococcus aureus; Turkey; Vancomycin Resistance; Virginiamycin; Wounds and Injuries

The growing incidence of infections due to Gram-positive multiresistant germs has stimulated research into new drugs endowed with broader activity, that are useful in case of infections unresponsive to common antibiotics. The case of a 28-year-old man infected with a methicillin resistant Staphylococcus aureus non responder to therapy with glycopeptide antibiotics is reported. At admission the patient presented a septic condition and required mechanical ventilation. Antibiotic therapy was immediately started with teicoplanin+meropenem. Blood culture and bronchial aspirate evidenced a methicillin resistant Staphylococcus aureus with high sensibility to glycopeptide antibiotics. Although this therapy produced a slight improvement in clinical condition and the patient was extubated, fever and leucocytosis associated with a BAL positive to methicillin resistant Staphylococcus aureus, in vitro susceptible to glycopeptides, persisted. Considering the possibility of a non-responder condition of the patient to glycopeptide antibiotics, quinupristin/dalfopristin was added. The streptogramin produced a quick improvement in clinical condition with resolution of sepsis and culture sterilization. The patient improved progressively and was discharged. In conclusion, in our experience the association quinupristin/dalfopristin was effective in the resolution of a critical methicillin resistant Staphylococcus aureus infection non responder to classical treatment with glycopeptide antibiotics that showed a high sensibility in vitro.

Topics: Adult; Anti-Bacterial Agents; Critical Illness; Humans; Male; Methicillin Resistance; Staphylococcal Infections; Thoracic Injuries; Tomography, X-Ray Computed; Virginiamycin; Wounds, Stab

Quinupristin-dalfopristin (Q-D) is a mixture of quinupristin and dalfopristin, which are semisynthetic antibiotics of streptogramin groups B and A, respectively.. We compared the effect of Q-D to that of vancomycin (VCM) in murine models of hematogenous pulmonary infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and VCM-insensitive S. aureus (VISA).. Treatment with Q-D resulted in a significant decrease in the number of viable bacteria in the lungs of mice in an MRSA infection model [Q-D 100 mg/kg, Q-D 10 mg/kg, VCM and control (mean +/- SEM): 2.99 +/- 0.44, 6.38 +/- 0.32, 5.75 +/- 0.43 and 8.40 +/- 0.14 log10 CFU/lung, respectively]. Compared with VCM, high-dose Q-D significantly reduced the number of bacteria detected in the VISA hematogenous infection model [Q-D 100 mg/kg, Q-D 10 mg/kg, VCM and control (mean +/- SEM): 5.17 +/- 0.52, 7.03 +/- 0.11, 7.10 +/- 0.49 and 7.18 +/- 0.36 log10 CFU/lung, respectively]. Histopathological examination confirmed the effect of Q-D.. Our results suggest that Q-D is potent and effective in the treatment of MRSA and VISA hematogenous pulmonary infections.

Topics: Animals; Bacteremia; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Resistance, Microbial; Japan; Lung; Male; Methicillin Resistance; Mice; Mice, Inbred Strains; Pneumonia, Staphylococcal; Specific Pathogen-Free Organisms; Staphylococcal Infections; Staphylococcus aureus; Vancomycin Resistance; Virginiamycin

Topics: Aged; Drug Therapy, Combination; Female; Humans; Oxacillin; Penicillin Resistance; Staphylococcal Infections; Staphylococcus aureus; Vancomycin; Virginiamycin

In search of treatment alternatives against vancomycin-resistant S. aureus (VRSA), an in vitro pharmacodynamic model with simulated endocardial vegetations incorporating protein and a high inoculum was used to simulate daptomycin, linezolid, quinupristin-dalfopristin, and vancomycin against the Michigan VRSA strain. Daptomycin and quinupristin-dalfopristin exhibited the greatest bacterial reductions, and all tested agents except vancomycin exhibited bactericidal activity against the VRSA.

Topics: Acetamides; Anti-Bacterial Agents; Anti-Infective Agents; Colony Count, Microbial; Culture Media; Daptomycin; Drug Therapy, Combination; Endocardium; Linezolid; Microbial Sensitivity Tests; Oxazolidinones; Staphylococcal Infections; Staphylococcus aureus; Vancomycin Resistance; Virginiamycin

We report our experience with quinupristin/ dalfopristin in combination with a glycopeptide in the treatment of severe staphylococcal infections failing previous glycopeptide regimens.. Five patients, affected by persistent bacteremia (n = 2), post-cardiothoracic surgery infection (n = 2) and post-traumatic bone infection (n = 1) due to methicillin-resistant Staphylococcus aureus (MRSA, n = 4) methicillin-resistant coagulase-negative Staphylococcus (MRCNS, n = 1) and unsuccessfully treated with antibiotics including a glycopeptide, were treated with a quinupristin/ dalfopristin and glycopeptide combination.. Three patients were clinically cured; one patient with MRSA thoracic aorta prosthetic infection relapsed after 3 months; one patient was lost to follow-up.. Quinupristin/dalfopristin, in combination with a glycopeptide, is an effective treatment option for severe methicillin-resistant staphylococcal infections failing previous glycopeptide regimens.

Topics: Adult; Aged; Anti-Bacterial Agents; Colony Count, Microbial; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Methicillin Resistance; Microbial Sensitivity Tests; Sampling Studies; Sensitivity and Specificity; Severity of Illness Index; Staphylococcal Infections; Teicoplanin; Treatment Outcome; Vancomycin; Virginiamycin

The E test and broth microdilution showed comparable accuracy for the susceptibility testing of methicillin-resistant S. aureus (MRSA). All of the 109 primary clinical MRSA isolates were fully susceptible to the glycopeptides vancomycin and teicoplanin, the oxazolidinone linezolid, and the streptogramin quinupristin-dalfopristin. Nine out of the 109 MRSA isolates (8.3 percent) demonstrated resistance to moxifloxacin and 5 out of the 109 strains (4.6 percent) were resistant to the topical agent mupirocin. Linezolid and quinupristin-dalfopristin may prove useful alternatives for the treatment of patients with MRSA infections. MRSA isolates should be screened for in vitro susceptibility against mupirocin prior to the topical application.

Topics: Acetamides; Anti-Bacterial Agents; Aza Compounds; Drug Resistance, Bacterial; Fluoroquinolones; Humans; Linezolid; Methicillin Resistance; Microbial Sensitivity Tests; Moxifloxacin; Mupirocin; Oxazolidinones; Quinolines; Staphylococcal Infections; Staphylococcus aureus; Teicoplanin; Vancomycin; Virginiamycin

A rat model was used to investigate the efficacy of quinupristin-dalfopristin (Q-D) in the prevention of vascular prosthetic graft infection due to methicillin-resistant Staphylococcus epidermidis with intermediate resistance to glycopeptides. The in vitro activity of the compound was compared to that of vancomycin by MIC determination and time-kill study. Moreover, the efficacy of collagen-sealed Q-D-soaked Dacron was evaluated in a rat model of graft infection. Graft infections were established in the subcutaneous tissue of the backs of 120 adult male Wistar rats. The in vivo study included a control group, one contaminated group that did not receive any antibiotic prophylaxis, two contaminated groups that received grafts soaked with 10 and 100 micro g of Q-D per ml, respectively, and two contaminated groups that received grafts soaked with 10 and 100 micro g of vancomycin per ml, respectively. Rats that received Dacron grafts soaked with 100 micro g of Q-D per ml showed no evidence of infection (<10 CFU/ml). In contrast, for rats that received Dacron grafts soaked with 10 micro g of Q-D per ml and Dacron grafts soaked with 10 or 100 micro g of vancomycin per ml, the quantitative graft cultures demonstrated 2.2 x 10(2) +/- 1.3 x 10(2), 2.2 x 10(6) +/- 1.9 x 10(5), and 5.6 x 10(2) +/- 0.3 x 10(2) CFU/ml, respectively. Taken together the results of the study demonstrate that the use of Dacron grafts soaked with Q-D can result in significant bacterial growth inhibition and show that this compound is potentially valuable for prevention of vascular prosthetic graft infection.

Topics: Animals; Anti-Bacterial Agents; Blood Vessel Prosthesis; Drug Resistance, Microbial; Male; Microbial Sensitivity Tests; Prosthesis-Related Infections; Rats; Rats, Wistar; Staphylococcal Infections; Staphylococcus epidermidis; Vancomycin Resistance; Virginiamycin

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

Topics: Adult; Aged; Anti-Bacterial Agents; Critical Care; Drug Therapy, Combination; Female; Humans; Male; Methicillin Resistance; Middle Aged; Staphylococcal Infections; Staphylococcus aureus; Staphylococcus epidermidis; Virginiamycin

to investigate the efficacy of quinupristin/dalfopristin in the prevention of prosthetic graft infection in a rat subcutaneous pouch model.. graft infections were established in the subcutaneous tissue of 140 male Wistar rats by implantation of Dacron prostheses followed by topical inoculation with Staphylococcus epidermidis with intermediate resistance to glycopeptides. The study included one group without contamination, one contaminated group without prophylaxis, one contaminated group that received 50mg/l quinupristin/dalfopristin-soaked graft, one contaminated group that received 10mg/kg intraperitoneal levofloxacin, one contaminated group that received 3mg/kg intraperitoneal doxycycline, and two contaminated groups that received 50mg/l quinupristin/dalfopristin-soaked plus 10mg/kg intraperitoneal levofloxacin or 3mg/kg intraperitoneal doxycycline. Each group included 20 animals. The grafts were removed after 7 days and evaluated by quantitative culture.. quinupristin/dalfopristin showed a significantly higher efficacy than levofloxacin and doxycycline, even though quantitative graft cultures for rats that received only quinupristin/dalfopristin-soaked graft showed bacterial growth. Otherwise, the efficacy of levofloxacin was similar to that of doxycycline. Only the group treated with quinupristin/dalfopristin combined with levofloxacin or doxycycline showed no evidence of staphylococcal infection.. quinupristin/dalfopristin as adjunctive topical antibiotic prophylaxis can be useful for the prevention of vascular graft infections caused by staphylococcal strains with high levels of resistance.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotic Prophylaxis; Disease Models, Animal; Doxycycline; Drug Therapy, Combination; Injections, Intraperitoneal; Levofloxacin; Male; Ofloxacin; Polyesters; Prosthesis-Related Infections; Rats; Staphylococcal Infections; Staphylococcus epidermidis; Virginiamycin

The growing interest in methicillin-resistant Staphylococcus aureus (MRSA) has been caused by its increased appearance in hospital and community populations. In our burn centre, an outbreak of MRSA was noticed during an 8-month period. We were able to isolate MRSA in eight patients. DNA analysis by pulsed-field gel electrophoresis (PFGE) demonstrated the development of five different strains during this period. Only two patients developed an infection caused by MRSA colonisation. The infections were proven by positive blood culture or catheter colonisation. One patient developed a clinical vancomycin-resistant sepsis which was treated successfully with the additional application of Quinupristin/Dalfopristin. THIS ANALYSIS SHOWS THAT: (1) the development of MRSA in a burn unit is often created in a single patient by long-term antibiotic therapy and not a result of cross-infection, (2) manifest MRSA infection seldom occurs even in colonised burn patients, and (3) a clinically vancomycin-resistant MRSA infection in burn patients can be treated sufficiently with Quinupristin/Dalfopristin.

Topics: Burn Units; Disease Outbreaks; Drug Therapy, Combination; Germany; Humans; Retrospective Studies; Staphylococcal Infections; Staphylococcus aureus; 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

We describe a patient with early post-surgical infective endocarditis due to methicillin-resistant Staphylococcus aureus, who was unsuitable for surgical reintervention and who failed standard antistaphylococcal therapy, but was successfully cured with a sequential regimen including quinupristin/dalfopristin and linezolid.

Topics: Acetamides; Aged; Aged, 80 and over; Anti-Infective Agents; Cardiovascular Surgical Procedures; Drug Administration Schedule; Drug Therapy, Combination; Endocarditis, Bacterial; Female; Humans; Linezolid; Methicillin Resistance; Mitral Valve Insufficiency; Oxazolidinones; Staphylococcal Infections; Surgical Wound Infection; Virginiamycin

Staphylococcus aureus strains resistant to a variety of antimicrobial agents are often found in the hospital environment and are responsible for many life-threatening infections. The activity of quinupristin/dalfopristin against 84 Staphylococcus aureus bloodstream isolates (both methicillin resistant and methicillin sensitive) was compared to the activity of vancomycin, teicoplanin, erythromycin, oxacillin, clindamycin, gentamicin, rifampicin. The Minimum Inhibitory Concentrations of these agents was evaluated with the Epsilometer Test. Quinupristin/dalfopristin inhibited all methicillin-sensitive strains at 1mg/L, and 75% of methicillin-resistant strains at 1.5mg/L. According to these results, quinupristin-dalfopristin shows promising in-vitro activity and may be a welcome alternative treatment for methicillin-resistant staphylococcal infections, resulting in reduced use of glycopeptides.

Topics: Anti-Bacterial Agents; Bacteremia; Clindamycin; Cross Infection; Erythromycin; Gentamicins; Humans; Methicillin Resistance; Microbial Sensitivity Tests; Oxacillin; Rifampin; Staphylococcal Infections; Staphylococcus aureus; Teicoplanin; Vancomycin; Virginiamycin

MICs and minimum bactericidal concentrations (MBCs) of daptomycin, vancomycin, linezolid and quinupristin-dalfopristin (Q-D) were determined for 108 staphylococcal isolates. All strains were susceptible (MICs) to daptomycin (< or =2.0 mg/L) and Q-D (< or =1.0 mg/L). All but three isolates were susceptible to vancomycin (< or =4.0 mg/L) and all but one methicillin-resistant Staphylococcus aureus strain were susceptible to linezolid (< or =4.0 mg/L). Q-D had the lowest geometric mean MIC (0.29 mg/L) and daptomycin had the lowest geometric mean MBC (0.57 mg/L). Time-kill tests were performed on 25 isolates. Bactericidal activity (>99.9% kill) was observed with daptomycin at 2 mg/L and at 2 x MBC for 92% of strains tested. In comparison, the bactericidal rates for the other drugs at breakpoint concentrations and at 2 x MBC were 72% and 70% for vancomycin, 46% and 60% for Q-D, and 7% and 14% for linezolid. Of the four drugs tested, daptomycin was bactericidal against the most strains and had the most rapid cidal activity.

Topics: Acetamides; Anti-Bacterial Agents; Daptomycin; Drug Therapy, Combination; Linezolid; Methicillin Resistance; Microbial Sensitivity Tests; Oxazolidinones; Staphylococcal Infections; Staphylococcus; Vancomycin; Virginiamycin

We compared the efficacies of quinupristin-dalfopristin (Q-D; 30 mg/kg of body weight every 8 h) and vancomycin (60 mg/kg twice daily), alone or in combination with rifampin (10 mg/kg twice daily), in a rabbit model of methicillin-resistant Staphylococcus aureus knee prosthesis infection. In contrast to vancomycin, Q-D significantly reduced the mean log(10) CFU per gram of bone versus that for the controls. The combination of rifampin with either Q-D or vancomycin was significantly more effective than monotherapy.

Topics: Animals; Anti-Bacterial Agents; Antibiotics, Antitubercular; Drug Synergism; Drug Therapy, Combination; Joint Prosthesis; Methicillin Resistance; Prosthesis-Related Infections; Rabbits; Rifampin; Staphylococcal Infections; Tissue Distribution; Vancomycin; Virginiamycin

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

Topics: Abdominal Abscess; Adult; Aged; Anti-Bacterial Agents; Coagulase; Drug Therapy, Combination; Endocarditis; Female; Heart-Assist Devices; Humans; Male; Methicillin; Methicillin Resistance; Microbial Sensitivity Tests; Middle Aged; Staphylococcal Infections; Staphylococcus aureus; Vancomycin; Virginiamycin

The combination of quinupristin-dalfopristin (Q-D) and gentamicin was tested against two strains of gentamicin- and dalfopristin-susceptible methicillin-resistant Staphylococcus aureus (MRSA). One strain was susceptible to macrolides, lincosamides, and streptogramin B type antibiotics (MLS(B)), and the other was constitutively resistant to these antibiotics by virtue of the ermA gene. The checkerboard method and time-kill curves showed that the combination of Q-D and gentamicin was indifferent. A rabbit endocarditis model simulated the pharmacokinetics achieved in humans receiving intravenous injections of Q-D (7.5 mg/kg of body weight three times a day) and gentamicin (3 mg/kg once daily). For the MLS(B)-susceptible strain, a 4-day regimen reduced mean bacterial titers (MBT) in vegetations from 8.5 +/- 0.8 log CFU/g (control group) to 4.1 +/- 2.6 (gentamicin), 3.0 +/- 0.9 (Q-D), and 2.6 +/- 0.5 log CFU/g (Q-D plus gentamicin). For the strain constitutively resistant to MLS(B), a 4-day regimen reduced MBT in vegetations from 8.7 +/- 0.9 log CFU/g (control group) to 5.0 +/- 2.2 (gentamicin), 5.2 +/- 2.2 (Q-D), and 5.1 +/- 2.4 log CFU/g (Q-D plus gentamicin). The differences between control and treatment groups were significant for both strains (P < 0.0001), although there was no significant difference between treatment groups. No resistant variant was isolated from vegetations, and no significant difference in MBT in vegetations of treatment groups after 1-day regimens was observed. This experimental study found no additive benefit in combining Q-D and gentamicin against dalfopristin- and gentamicin-susceptible MRSA.

Topics: Animals; Drug Therapy, Combination; Endocarditis, Bacterial; Gentamicins; Methicillin Resistance; Microbial Sensitivity Tests; Rabbits; Staphylococcal Infections; Virginiamycin

We evaluated the activities of quinupristin-dalfopristin (Q-D), alone or in combination with rifampin, against three strains of Staphylococcus aureus susceptible to rifampin (MIC, 0.06 microg/ml) and to Q-D (MICs, 0.5 to 1 microg/ml) but displaying various phenotypes of resistance to macrolide-lincosamide-streptogramin antibiotics: S. aureus HM1054 was susceptible to quinupristin and dalfopristin (MICs of 8 and 4 microg/ml, respectively); for S. aureus RP13, the MIC of dalfopristin was high (MICs of quinupristin and dalfopristin for strain RP13, 8 and 32 microg/ml, respectively); and S. aureus HM1054R was obtained after conjugative transfer of macrolide-lincosamide-streptogramin B constitutive resistance to HM1054, and the MIC of quinupristin for this strain was high (MICs of quinupristin and dalfopristin, 64 and 4 microg/ml, respectively). In vitro time-kill curve studies showed an additive effect [corrected] between Q-D and rifampin, at a concentration of four times the MIC, against the three strains. Rabbits with aortic endocarditis were treated 4 days with Q-D, rifampin, or their combination. In vivo, the combination was highly bactericidal and synergistic against strains susceptible to quinupristin (HM1054 and RP13) and sterilized 94% of the animals. In contrast, the combination was neither synergistic nor bactericidal against the quinupristin-resistant strain (HM1054R) and did not prevent the emergence of mutants resistant to rifampin. We conclude that the in vivo synergistic and bactericidal activity of the combination of Q-D and rifampin against S. aureus is predicted by the absence of resistance to quinupristin but not by in vitro combination studies.

Topics: Animals; Anti-Bacterial Agents; Drug Resistance, Microbial; Drug Synergism; Drug Therapy, Combination; Endocarditis, Bacterial; Female; Kinetics; Lincosamides; Macrolides; Microbial Sensitivity Tests; Mutation; Phenotype; Rabbits; Rifampin; Staphylococcal Infections; Staphylococcus aureus; Virginiamycin

Of 3,052 Staphylococcus aureus strains collected by the European SENTRY surveillance study, 35 were found to be nonsusceptible to quinupristin-dalfopristin (MIC of > or =2 mg/liter). These isolates originated from four hospitals in France and one in Spain. In isolates from two Parisian hospitals exhibiting the same SmaI macrorestriction pattern, streptogramin resistance was based on vatA and vgbA. One isolate from a hospital in Lyon and 22 from a hospital in Lille were of the vatB vgaB streptogramin A resistance genotype and possessed ermA and/or ermC. As deduced from the loss of either streptogramin A or streptogramin B resistance determinants in particular isolates, resistance to quinupristin-dalfopristin requires mechanisms conferring resistance to both compounds. The SmaI macrorestriction patterns of strains from hospitals in Lille and Lyon were different; however, similarity analysis suggested a relatedness of 20 methicillin-resistant S. aureus strains from the Lille hospital, a finding confirmed by PCR typing based on three different genomic polymorphisms. These groups of isolates were found to be hetero-glycopeptide-intermediate susceptible S. aureus. Information about the failure of glycopeptide chemotherapy has not been available.

Topics: Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Europe; Humans; Methicillin Resistance; Microbial Sensitivity Tests; Polymerase Chain Reaction; Population Surveillance; Staphylococcal Infections; Staphylococcus aureus; Virginiamycin

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

Topics: Animals; Anti-Bacterial Agents; beta-Lactams; Drug Synergism; Drug Therapy, Combination; Endocarditis, Bacterial; Humans; Rats; Staphylococcal Infections; Virginiamycin

Resistance to macrolides, lincosamides and streptogramin B (MLS) which is expressed either constitutively or inducibly, is mediated by erm genes (erm A, erm B, and erm C in staphylococci). The transposon TN 554, harbouring the erm A gene also encodes spectinomycin resistance. In Turkey, data related to MLS resistance phenotypes of staphylococci are not available. In this study, we screened 500 consecutive clinical isolates of staphylococci isolated in Hacettepe University Hospital, for MLS and spectinomycin resistance by the standard disk diffusion method. All MLS-resistant isolates were further tested for spectinomycin susceptibility by the agar screening method. Of 500 staphylococcal isolates, 368 (73.6%) were susceptible and 132 (26.4%) were resistant to MLS antibiotics. Ninety-one (18.2%) of the resistant isolates exhibited a constitutive resistance pattern, whereas 40 were inducibly resistant. MS (resistance to macrolides and lincosamides only) resistance was detected in only one isolate (0.2%). Of 40 inducibly resistant isolates, 21 were found to be resistant to spectinomycin by both the disk diffusion and agar screening tests, probably indicating a presence of the erm A gene. These results suggest that MLS resistance has been considerably high among clinical isolates of staphylococci in our hospital. On the whole, constitutive resistance was the pattern most frequently encountered. In contrast, MS resistance was very rare. Further epidemiological and molecular investigations are required for clarification of the data presented.

Topics: Anti-Bacterial Agents; Drug Resistance, Microbial; Drug Resistance, Multiple; Hospitals, University; Humans; Lincosamides; Macrolides; Microbial Sensitivity Tests; Phenotype; Staphylococcal Infections; Staphylococcus; Turkey; Virginiamycin

We evaluated the activity of quinupristin-dalfopristin (Q-D) against three clinical strains of Staphylococcus aureus susceptible to Q (MIC, 8 microg/ml) and Q-D (MICs, 0.5 to 1 microg/ml) but displaying various levels of susceptibility to D. D was active against S. aureus HM 1054 (MIC, 4 microg/ml) and had reduced activity against S. aureus RP 13 and S. aureus N 95 (MICs, 32 and 64 microg/ml, respectively). In vitro, Q-D at a concentration two times the MIC (2xMIC) produced reductions of 4.3, 3.9, and 5.8 log(10) CFU/ml after 24 h of incubation for HM 1054, RP 13, and N 95, respectively. Comparable killing was obtained at 8xMIC. Q-D-resistant mutants were selected in vitro at a frequency of 2 x 10(-8) to 2 x 10(-7) for the three strains on agar containing 2xMIC of Q-D; no resistant bacteria were detected at 4xMIC. Rabbits with aortic endocarditis were treated for 4 days with Q-D at 30 mg/kg of body weight intramuscularly (i.m.) three times a day (t.i.d.) or vancomycin at 50 mg/kg i.m. t.i.d. In vivo, Q-D and vancomycin were similarly active and bactericidal against the three tested strains compared to the results for control animals (P < 0.01). Among animals infected with RP 13 and treated with Q-D, one rabbit retained Q-D-resistant mutants that were resistant to Q and to high levels of D (MICs, 64, >256, and 8 microg/ml for Q, D, and Q-D, respectively). We conclude that the bactericidal activity of Q-D against strains with reduced susceptibility to D and susceptible to Q-D is retained and is comparable to that of vancomycin. Acquisition of resistance to both Q and D is necessary to select resistance to Q-D.

Topics: Animals; Disease Models, Animal; Drug Resistance, Microbial; Drug Therapy, Combination; Endocarditis, Bacterial; Microbial Sensitivity Tests; Mutation; Rabbits; Staphylococcal Infections; Staphylococcus aureus; Virginiamycin

Quinupristin-dalfopristin (Q-D) is an injectable streptogramin active against most gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). In experimental endocarditis, however, Q-D was less efficacious against MRSA isolates constitutively resistant to macrolide-lincosamide-streptogram B (C-MLS(B)) than against MLS(B)-susceptible isolates. To circumvent this problem, we used the checkerboard method to screen drug combinations that would increase the efficacy of Q-D against such bacteria. beta-Lactams consistently exhibited additive or synergistic activity with Q-D. Glycopeptides, quinolones, and aminoglycosides were indifferent. No drugs were antagonistic. The positive Q-D-beta-lactam interaction was independent of MLS(B) or beta-lactam resistance. Moreover, addition of Q-D at one-fourth the MIC to flucloxacillin-containing plates decreased the flucloxacillin MIC for MRSA from 500 to 1,000 mg/liter to 30 to 60 mg/liter. Yet, Q-D-beta-lactam combinations were not synergistic in bactericidal tests. Rats with aortic vegetations were infected with two C-MLS(B)-resistant MRSA isolates (isolates AW7 and P8) and were treated for 3 or 5 days with drug dosages simulating the following treatments in humans: (i) Q-D at 7 mg/kg two times a day (b.i.d.) (a relatively low dosage purposely used to help detect positive drug interactions), (ii) cefamandole at constant levels in serum of 30 mg/liter, (iii) cefepime at 2 g b.i.d., (iv) Q-D combined with either cefamandole or cefepime. Any of the drugs used alone resulted in treatment failure. In contrast, Q-D plus either cefamandole or cefepime significantly decreased valve infection compared to the levels of infection for both untreated controls and those that received monotherapy (P < 0.05). Importantly, Q-D prevented the growth of highly beta-lactam-resistant MRSA in vivo. The mechanism of this beneficial drug interaction is unknown. However, Q-D-beta-lactam combinations might be useful for the treatment of complicated infections caused by multiple organisms, including MRSA.

Topics: Animals; Anti-Bacterial Agents; Cefamandole; Cefepime; Cephalosporins; Disease Models, Animal; Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Therapy, Combination; Endocarditis, Bacterial; Humans; Lincosamides; Macrolides; Microbial Sensitivity Tests; Rats; Staphylococcal Infections; Staphylococcus aureus; Time Factors; Virginiamycin

Antibiotic-resistant gram-positive bacteria have become an increasing problem in the last two decades. In order to evaluate the prevalence of antibiotic resistance in staphylococcal bloodstream isolates in Germany, 2,042 staphylococci collected in 21 tertiary-care hospitals were investigated during a 3-year period (March 1996 to March 1999). Altogether, 1,448 S. aureus isolates and 594 coagulase-negative staphylococci (CoNS) that comprised 13 different species were included. Furthermore, the antistaphylococcal activities of quinupristin-dalfopristin were compared with those of eight other compounds by the broth microdilution method. The rates of oxacillin resistance in Staphylococcus aureus, S. epidermidis, S. haemolyticus, and other CoNS were 13.5, 69, 90, and 34%, respectively. In oxacillin-resistant strains high rates of resistance (up to 100%) to erythromycin, clindamycin, ciprofloxacin, and gentamicin were also observed. However, no strain appeared to be resistant to vancomycin or quinupristin-dalfopristin. The streptogramin combination exhibited excellent in vitro activity against all staphylococcal species tested, regardless of the patterns of resistance to other drug classes. In terms of MICs at which 90% of the isolates are inhibited, quinupristin-dalfopristin was 2 times more active against S. aureus isolates, 4 to 16 times more active against S. haemolyticus, and 8 to 32 times more active against S. epidermidis than vancomycin or teicoplanin.

Topics: Anti-Bacterial Agents; Bacteremia; Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Therapy, Combination; Germany; Humans; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus; Virginiamycin

To evaluate the in vitro activity of quinupristin/dalfopristin (Q/D), a streptogramin combination, in comparison with five antibiotics against worldwide clinical isolates of staphylococci.. A multicenter in vitro study was performed using the E test during a period of 3 months (April to June) in 1997 on fresh, clinically significant, non repetitive strains of staphylococci from patients hospitalized in 23 different hospitals in 18 countries tested.. A total of 2132 staphylococcal isolates including methicillin resistant (MR), methicillin susceptible (MS) S. aureus (1003 MS, 462 MR), S. epidermidis (169 MS, 251 MR), S. haemolyticus (28 MS, 46 MR), S. hominis (28 MS, 16 MR), and coagulase negative staphylococci (86 MS, 43 MR) were analyzed. Q/D was highly active against all species tested. MIC90 (mg/L) ranged from 0.5 to 2 depending on the species. Strains had MIC < or = 1 mg/L in 97.6%. For S. aureus, S. epidermidis, S. hominis and other coagulase-negative staphylococci no differences in MIC90 were observed for MS or MR. One dilution difference was observed for S. haemolyticus, which overall was the less susceptible species. Erythromycin resistance was observed among 57- 87% of MR-strains and was lower among MS-strains (18-56%). Erythromycin resistance had no or little influence on MIC of Q/D. In comparison to vancomycin, Q/D was two to four times more active.. The streptogramin combination Q/D showed an excellent in vitro activity against all staphylococcal species tested regardless of the resistance pattern to other drug classes, particularly resistance to methicillin. Q/D was two to four times more active than vancomycin and MIC values varied from 0.5-2 according to the species. The synergy of Q/D was well conserved in macrolide-resistant strains.

Topics: Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Synergism; Drug Therapy, Combination; Erythromycin; Humans; Methicillin Resistance; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus; Vancomycin Resistance; Virginiamycin

The antistaphylococcal activities of four newly developed antibiotics, moxifloxacin (an 8-methoxyfluoroquinolone), trovafloxacin (a naphthyridone), quinupristin/dalfopristin (a semisynthetic streptogramin) and linezolid (an oxazolidinone), were examined and compared with those of ciprofloxacin, vancomycin and teicoplanin, using an agar dilution method. A total of 245 clinical isolates of staphylococci, including a large number of clonally different methicillin-resistant strains, were tested. The new agents tested exhibited wide-spectrum antistaphylococcal activity against both methicillin-susceptible and methicillin-resistant strains. In contrast to the quinolones, the in-vitro activities of quinupristin/dalfopristin, linezolid and the glycopeptides remained almost unchanged, irrespective of the resistance phenotype for methicillin. A number of isolates with elevated quinolone MICs were observed.

Topics: Acetamides; Anti-Bacterial Agents; Aza Compounds; Fluoroquinolones; Humans; Linezolid; Methicillin Resistance; Microbial Sensitivity Tests; Moxifloxacin; Naphthyridines; Oxazoles; Oxazolidinones; Quinolines; Staphylococcal Infections; Staphylococcus; Virginiamycin

A restriction map was made and the DNA sequence was determined for a plasmid, pMC38, derived from the inducible macrolide resistance plasmid pEP2104, that showed constitutive resistance to PMS antibiotics (partial macrolide and streptogramin B antibiotics). A 5. 04 kb SalI-PstI fragment (fragment C) of pMC38, which encoded PMS resistance, was cloned into a shuttle vector, pRIT5, to yield pMR504. The transformant Staphylococcus aureus 4220 (pMR504) exhibited constitutive PMS resistance. Fragment C was subcloned to pUC19 in order to determine the DNA sequence. This sequence was consequently found to contain three open reading frames (ORF1-3), of which ORF3 corresponded to the 63 kDa membrane protein (MsrSA) that expressed PMS resistance. According to DNA sequence comparison of the control region of ORF3 in pMC38 and pEP2104, 44 nucleotides including RBS1 and the leader peptide (MTASMRLK) were deleted on plasmid pMC38. This suggests that the leader peptide is essential for the inducible expression of PMS resistance.

Topics: Anti-Bacterial Agents; ATP-Binding Cassette Transporters; Base Sequence; Cloning, Molecular; Drug Resistance, Microbial; Drug Resistance, Multiple; Erythromycin; Genes, Bacterial; Humans; Microbial Sensitivity Tests; Molecular Sequence Data; Plasmids; Promoter Regions, Genetic; Restriction Mapping; Sequence Alignment; Sequence Analysis, DNA; Staphylococcal Infections; Staphylococcus aureus; Virginiamycin

Topics: Anti-Bacterial Agents; Clindamycin; Drug Resistance, Microbial; Erythromycin; Humans; Lincosamides; Macrolides; Microbial Sensitivity Tests; Staphylococcal Infections; Virginiamycin

A series of 3-descladinosyl-2,3-anhydro-6-O-methylerythromycin A 11, 12-carbamate analogues have been synthesized and evaluated for antibacterial activity. These compounds were found to be potent antibacterial agents against Gram-positive organisms in vitro, many having MIC values below 1 microg/mL for the macrolide-susceptible Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae, as well as improved activity compared to erythromycin A against the inducibly MLS (macrolide, lincosamide, and streptogramin B)-resistant organisms. Structure-activity studies revealed that arylalkyl carbamates with two and four carbon atoms between the aromatic moiety and carbamate nitrogen have the best in vitro activity. All of the C-10 epi analogues evaluated were found to have substantially less activity than the corresponding natural C-10 isomer. Several analogues demonstrated moderate antibacterial activity against the constitutively resistant S.aureus A-5278, S. pneumoniae5979, and S.pyogenes 930. However, despite potent in vitro activity, these analogues showed only moderate in vivo activity in mouse protection studies.

Topics: Animals; Anti-Bacterial Agents; Carbamates; Clarithromycin; Colony Count, Microbial; Drug Evaluation, Preclinical; Drug Resistance, Microbial; Drug Resistance, Multiple; Erythromycin; Haemophilus influenzae; Lincosamides; Macrolides; Mice; Molecular Conformation; Pneumococcal Infections; Staphylococcal Infections; Staphylococcus aureus; Streptococcus pneumoniae; Streptococcus pyogenes; Structure-Activity Relationship; Virginiamycin

A series of 3-descladinosyl-2,3-anhydro-6-O-methylerythromycin A 11, 12-cyclic carbazate analogues was prepared and evaluated for antibacterial activity. These 2,3-anhydro macrolides were found to be potent antibacterial agents in vitro against macrolide-susceptible organisms including Staphylococcus aureus 6538P, Streptococcus pyogenes EES61, and Streptococcuspneumoniae ATCC6303. These compounds were also very active against some organisms that show macrolide resistance (S. aureus A5177, S. pyogenes PIU2584, and S. pneumoniae 5649). The compounds generally showed poor activity against organisms with constitutive MLS resistance. Selected compounds were evaluated in vivo in mouse protection studies. Although most of the compounds tested in vivo showed poor efficacy, two compounds, 38 and 57, were more active than clarithromycin against S. pneumoniae ATCC6303.

Topics: Animals; Anti-Bacterial Agents; Clarithromycin; Drug Evaluation, Preclinical; Drug Resistance, Microbial; Drug Resistance, Multiple; Erythromycin; Lincosamides; Macrolides; Mice; Pneumococcal Infections; Staphylococcal Infections; Staphylococcus aureus; Streptococcus pneumoniae; Streptococcus pyogenes; Structure-Activity Relationship; Virginiamycin

Quinupristin/dalfopristin (RP59500) is a novel streptogramin and a semisynthetic derivative of pristinamycins IA and IIB. The following properties of RP59500 were investigated: (i) its in-vitro activity against 164 hospital isolates of Staphylococcus aureus, 101 of which were methicillin-resistant (MRSA); (ii) its killing effect against 24 MRSA and seven methicillin-susceptible (MSSA) isolates; (iii) its interactions with rifampicin and ciprofloxacin against 18 MRSA isolates, six susceptible to both rifampicin and ciprofloxacin and 12 resistant to both, at 1 x MIC, 2 x MIC and 4 x MIC. Rifampicin and ciprofloxacin were applied at a concentration equal to their mean serum levels in order to establish the clinical relevance of the results. The MIC50, MIC90, MBC50 and MBC90 of quinupristin/dalfopristin were, respectively, < or = 0.015, 2, 0.12 and 2 mg/L for MRSA isolates and < or = 0.015, 0.06, < or = 0.015 and 0.25 mg/L for MSSA isolates. All isolates were inhibited by quinupristin/dalfopristin. Its killing effect varied with concentration and time, being optimal at 4 x MIC and after 24 h growth. Strains surviving 24 h exposure to this agent had much higher MICs than the parent strain, but only a limited number of them became resistant. Quinupristin/dalfopristin at 2 x MIC and 4 x MIC showed in-vitro synergy with rifampicin against highly resistant isolates mainly at 6 h and 24 h of growth involving 50-83% of MRSA isolates, and showed synergy with ciprofloxacin at 24 h involving 42-75% of isolates. The MIC increase in colonies surviving at 24 h was restricted by the presence of rifampicin or ciprofloxacin. In contrast, the above combinations acted synergically over the total number of MRSA strains susceptible to both rifampicin and ciprofloxacin. The above findings show that quinupristin/dalfopristin is a very potent antistaphylococcal agent, and that its activity against MRSA isolates is enhanced when it is combined with rifampicin or ciprofloxacin.

Topics: Anti-Bacterial Agents; Ciprofloxacin; Cross Infection; Dose-Response Relationship, Drug; Drug Interactions; Humans; Methicillin Resistance; Microbial Sensitivity Tests; Rifampin; Staphylococcal Infections; Staphylococcus aureus; Time Factors; Virginiamycin

Topics: Adult; Anti-Bacterial Agents; Endocarditis, Bacterial; Humans; Male; Methicillin Resistance; Staphylococcal Infections; Staphylococcus epidermidis; 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

We evaluated the bactericidal activity of RP 59500 (quinupristin-dalfopristin) against fibrin-platelet clots (FPC) infected with two clinical isolates of Staphylococcus aureus, one constitutively erythromycin and methicillin resistant (S. aureus AW7) and one erythromycin and methicillin susceptible (S. aureus 1199), in an in vitro pharmacodynamic infection model. RP 59500 was administered by continuous infusion (peak steady-state concentration of 6 microg/ml) or intermittent infusion (simulated regimens of 7.5 mg/kg of body weight every 6 h (q6h) q8h, and q12h. FPCs were infected with S. aureus to achieve an initial bacterial density of 10(9) CFU/g. Model experiments were run in duplicate over 72 h. Two FPCs were removed from each model at 0, 12, 24, 36, 48, and 72 h, and the bacterial densities (in CFU per gram) were determined and compared to those of growth control experiments. Additional samples were also removed from the model over the 72-h period for pharmacokinetic evaluation. All regimens significantly (P < or = 0.01) decreased bacterial densities in the infected FPCs for both isolates compared to growth controls. This occurred even though MBCs were equal to or greater than the RP 59500 concentrations achieved in the models. There were no significant differences found between the dosing frequencies and levels of killing when examining each isolate separately. However, examination of the residual bacterial densities (CFU per gram at 72 h) and visual inspection of the overall killing effect (killing curve plots over 72 h) clearly demonstrated a more favorable bactericidal activity against 1199 than against the AW7 isolate. This was most apparent when the q8h and the q12h AW7 regimens were compared to all 1199 treatment regimens by measuring the 72-h bacterial densities (P < or = 0.01). Killing (99.9%) was not achieved against the AW7 isolate. However, a 99.9% kill was demonstrated for all dosing regimens against the 1199 isolate. The area under the concentration-time curve from 0 to 24 h was found to be significantly correlated with reduction in bacterial density for the AW7 isolate (r = 0.74, P = 0.04). No resistance was detected during any experiment for either isolate. RP 59500 efficacy against constitutively erythromycin- and methicillin-resistant S. aureus may be improved by increasing organism exposure to RP 59500 as a function of dosing frequency.

Topics: Anti-Bacterial Agents; Blood Coagulation; Blood Platelets; Drug Administration Schedule; Drug Resistance, Microbial; Erythromycin; Fibrin; Humans; Methicillin Resistance; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus; Virginiamycin

Topics: Anemia, Hemolytic; Anti-Bacterial Agents; Female; Humans; Middle Aged; Osteomyelitis; Reticulocytes; Staphylococcal Infections; Virginiamycin

In an Algerian hospital where pristinamycin (Pt) was extensively used for the treatment of chronic osteomyelitis and for prophylaxis in bone surgery, the prevalence of pristinamycin-resistant (PtR) staphylococci during a five-month period (20%) was higher than that among staphylococci isolated elsewhere in Algeria (4.5%). Analysis of 13 PtR staphylococci isolated in this hospital revealed a diversity of plasmids and genes conferring resistance to Pt and to related antibiotics. Most of the PtR staphylococci were unrelated: they belonged to either different taxa or types. Nevertheless, some of the unrelated staphylococci harboured structurally related plasmids carrying streptogramin resistance genes. Thus, these plasmids may have contributed to the dispersion of these genes.

Topics: Algeria; Anti-Bacterial Agents; Bacteriophage Typing; Bone and Bones; Cross Infection; Disease Outbreaks; DNA Primers; DNA, Bacterial; Drug Resistance, Microbial; Genes, Bacterial; Humans; Microbial Sensitivity Tests; Nucleic Acid Hybridization; Osteomyelitis; Plasmids; Polymerase Chain Reaction; Prevalence; Staphylococcal Infections; Staphylococcus; Virginiamycin

A significant increase in the incidence of isolates of methicillin-resistant Staphylococcus aureus (MRSA), that were also resistant to lincosamides and streptogramin A (LSA-MRSA), was observed in a French university hospital. Twenty-seven isolates from the outbreak were characterised, including 17 isolates from a plastic surgery ward and six control strains of MRSA. The strains were examined by antibiotyping and biotyping, and by three molecular methods: plasmid analysis, ribotyping and insertion sequence (IS) typing with IS256 sequence as a probe. Antibiotyping (five antibiotypes) was discriminatory because of the uncommon resistance phenotype of the epidemic strain. Biotyping (three biotypes), DNA plasmid analysis (four profiles) and ribotyping (two profiles) were poorly sensitive, in contrast to IS-typing (12 profiles). By the latter method, a coefficient of similarity (percentage similarity) compared to the predominant IS profile was calculated. Strains with a coefficient of similarity > or = to 82% were considered as highly related to the epidemic strain, while those with a coefficient of similarity < or = to 40% were regarded as distant. Results obtained with the five markers confirmed that an outbreak of hospital infection had occurred in the plastic surgery ward, with spread of the epidemic strain throughout the hospital.

Topics: Adult; Anti-Bacterial Agents; Bacterial Typing Techniques; Cross Infection; Disease Outbreaks; DNA Probes; DNA, Bacterial; DNA, Ribosomal; Drug Resistance, Microbial; Female; France; Hospital Units; Humans; Lincosamides; Macrolides; Male; Methicillin Resistance; Middle Aged; Nucleic Acid Hybridization; Polymorphism, Restriction Fragment Length; R Factors; Staphylococcal Infections; Staphylococcus aureus; Surgery, Plastic; Virginiamycin

Two oxazolidinones (U100592 and U100766), trovafloxacin, and a streptogramin combination (dalfopristin-quinupristin) were highly active in vitro against Staphylococcus aureus and Staphylococcus epidermidis, including methicillin-resistant strains. Trovafloxacin was more active than ciprofloxacin. Time-kill synergy studies demonstrated indifference for the oxazolidinones combined with vancomycin and rifampin against methicillin-resistant staphylococci. Spontaneous resistance was observed with all agents.

Topics: Acetamides; Anti-Bacterial Agents; Drug Resistance, Microbial; Drug Synergism; Fluoroquinolones; Humans; Linezolid; Microbial Sensitivity Tests; Naphthyridines; Oxazoles; Oxazolidinones; Staphylococcal Infections; Staphylococcus aureus; Staphylococcus epidermidis; Time Factors; Virginiamycin

The susceptibility of clinical isolates of methicillin-susceptible and -resistant staphylococci from cancer patients with central venous catheter bacteremia to quinupristin/dalfopristin, a semisynthetic streptogramin, was determined in vitro. Susceptibility of these isolates to nine other antistaphylococcal antibiotics was also determined for comparison. A total of 197 staphylococcal strains were tested from 1983 to 1992. Quinupristin/dalfopristin was bactericidal against all isolates, independent of their resistance to methicillin. Its activity was similar to that of vancomycin but superior to that of teicoplanin. Quinupristin/dalfopristin may prove to be an important addition to our armamentarium against catheter-related staphylococcal infections.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antitubercular; Bacteremia; Catheterization, Central Venous; Cefamandole; Cephalosporins; Ciprofloxacin; Clindamycin; Daptomycin; Humans; Methicillin; Methicillin Resistance; Microbial Sensitivity Tests; Neoplasms; Novobiocin; Oxacillin; Penicillins; Rifampin; Staphylococcal Infections; Staphylococcus aureus; Staphylococcus epidermidis; Teicoplanin; Vancomycin; Virginiamycin

RP 59500 is a new injectable streptogramin composed of two synergistic components (quinupristin and dalfopristin) which are active against erythromycin-susceptible and -resistant gram-positive pathogens. The present experiments compared the therapeutic efficacy of RP 59500 with that of vancomycin against experimental endocarditis due to either of two erythromycin-susceptible or two constitutively erythromycin-resistant isolates of methicillin-resistant Staphylococcus aureus. RP 59500 had low MICs for the four test organisms as well as for 24 additional isolates (the MIC at which 90% of the isolates were inhibited was < 1 mg/liter) which were mostly inducibly (47%) or constitutively (39%) erythromycin resistant. Aortic endocarditis in rats was produced with catheter-induced vegetations. Three-day therapy was initiated 12 h after infection, and the drugs were delivered via a computerized pump, which permitted the mimicking of the drug kinetics produced in human serum by twice-daily intravenous injections of 7 mg of RP 59500 per kg of body weight or 1 g of vancomycin. Both antibiotics reduced vegetation bacterial titers to below detection levels in ca. 70% of animals infected with the erythromycin-susceptible isolates (P < 0.05 compared with titers in controls). Vancomycin was also effective against the constitutively resistant strains, but RP 59500 failed against these isolates. Further experiments proved that RP 59500 failures were related to the very short life span of dalfopristin in serum (< or = 2 h, compared with > or = 6 h for quinupristin), since successful treatment was restored by artificially prolonging the dalfopristin levels for 6 h. Thus, RP 59500 is a promising alternative to vancomycin against methicillin-resistant S. aureus infections, provided that pharmacokinetic parameters are adjusted to afford prolonged levels of both of its constituents in serum. This observation is also relevant to humans, in whom the life span of dalfopristin in serum is also shorter than that of quinupristin.

Topics: Animals; Drug Resistance, Microbial; Endocarditis, Bacterial; Erythromycin; Female; Methicillin Resistance; Microbial Sensitivity Tests; Rats; Rats, Wistar; Staphylococcal Infections; Staphylococcus aureus; Vancomycin; Virginiamycin

The bactericidal activity and emergence of resistance to RP 59500 (quinupristin/dalfopristin) when it was administered alone and in combination with vancomycin against fibrin clots that have been infected with methicillin-susceptible Staphylococcus aureus ATCC 25923 or methicillin-resistant S. aureus (MRSA) 67 were evaluated in an in vitro pharmacodynamic infected fibrin clot model. Fibrin clots were infected with S. aureus to achieve an inoculum of approximately 10(9) CFU/g. Antibiotics were administered to simulate pharmacokinetics in humans: RP 59500 (7.5 mg/kg of body weight) every 8 h and vancomycin (15 mg/kg) every 12 h over 72 h. Preliminary test tube time-kill experiments with an inoculum of approximately 10(5) CFU/ml suggested that RP 59500 was more rapid in achieving a 99.9% reduction in the number of CFU per milliliter than vancomycin against ATCC 25923 (6.94 versus 24 h; P = 0.0003) and MRSA 67 (6.77 versus 17.03 h; P = 0.004). At a higher inoculum (approximately 10(8) CFU/ml), 99.9% kill was achieved only with the combination regimen against ATCC 25923 and MRSA 67 (10.9 and 10.5 h, respectively), with total reductions of 6.35 and 6.33 log10 CFU/ml over 24 h, respectively. In the fibrin clot model, RP 59500 was more effective than vancomycin in reducing organism titers over 72 h. In the fibrin clot model, the most optimal therapy was the combination regimen.

Topics: Blood Coagulation; Drug Therapy, Combination; Fibrin; Humans; Methicillin Resistance; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus; Thrombosis; Vancomycin; Virginiamycin

In order to determine the microbiological and pharmacokinetic parameters that best predicted the in vivo antistaphylococcal activity of the streptogramin RP 59500 (quinupristin-dalfopristin), we evaluated the activity in rabbit aortic endocarditis of three regimens of quinupristin-dalfopristin against five strains of Staphylococcus aureus with various streptogramin B-type antibiotic resistance phenotypes and susceptible to streptogramin A-type antibiotics. Quinupristin-dalfopristin was as active as vancomycin against three strains that were susceptible to its streptogramin B component quinupristin, including one strain that was inducibly resistant to erythromycin, but had a significantly decreased activity against two strains that were resistant to quinupristin, for all quinupristin-dalfopristin regimens tested (P < 0.05). The area under the concentration-time curve for quinupristin-dalfopristin in plasma divided by the MIC of quinupristin was the only parameter retained by multilinear regression that predicted the in vivo activity of quinupristin-dalfopristin (P = 0.0001), emphasizing the importance of determining the susceptibility to quinupristin in order to predict the in vivo activity of quinupristin-dalfopristin against S. aureus.

Topics: Animals; Drug Resistance, Microbial; Endocarditis, Bacterial; Female; Rabbits; Staphylococcal Infections; Staphylococcus aureus; Vancomycin; Virginiamycin

The bactericidal activity of RP 59500, a semisynthetic streptogramin, was compared with that of vancomycin against Staphylococcus aureus. This activity was evaluated in vitro by the kill curve method and in vivo using a model of mouse septicaemia. In vitro, RP 59500 (MIC = 0.12 mg/L) was more rapidly bactericidal against S. aureus IP 8203 than was vancomycin (MIC = 1 mg/L). In vivo, RP 59500 (120 mg/kg) was bactericidal against staphylococci in the blood of infected mice 1 h after administration, an effect which lasted for up to 7 h, whereas vancomycin at the same dose was bactericidal only 4 h after administration. The serum concentrations of vancomycin were higher than those of RP 59500 for at least 4 h after administration, and the Cmax and AUC of vancomycin were 4.8 and 8.3 times higher, respectively, than those of RP 59500 (Cmax = 13.2 mg/L; AUC0(-1) = 15.2 mg/L/h), although the agents had similar elimination half-lives (about 0.5 h). RP 59500 was also administered to mice as a fractionated dose (30 mg/kg x 4, 40 mg/kg x 3, 60 mg/kg x 2). The onset of its bactericidal effect was delayed by fractionating the dose, but the suppression of bacteria in the blood was prolonged.

Topics: Animals; Anti-Bacterial Agents; Bacteremia; Mice; Mice, Inbred Strains; Microbial Sensitivity Tests; Serum Bactericidal Test; Software; Staphylococcal Infections; Vancomycin; Virginiamycin

High throughput chemical file screening with an enzymatic assay to detect inhibitors of the ErmC methyltransferase enzyme from macrolide-lincosamide-streptogramin B (MLSB) resistant pathogenic bacteria identified low molecular weight compounds that had IC50S (50% inhibitory concentration) in the nMolar to microMolar range. These same inhibitors were assessed in vitro for their capacity to inhibit the liver enzyme, cathechol-O-methyltransferase and the prokaryotic enzyme, EcoRI methylase. Selective inhibitors of the ErmC methyltransferase were tested in tertiary assays to determine their minimal inhibitory concentrations (MICs), as single agents and in combination with the macrolide, azithromycin, against strains of pathogenic bacteria expressing MLSB-resistance. Compounds that were active in vitro, alone or in combination with azithromycin, against strains of macrolide-resistant pathogens were tested in a mouse model of infection using an MLSB-resistant strain of Staphylococcus aureus or a macrolide-susceptible strain of Streptococcus pyogenes.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Drug Resistance, Microbial; Drug Therapy, Combination; Enzyme Inhibitors; Lincosamides; Macrolides; Methyltransferases; Mice; Staphylococcal Infections; Staphylococcus aureus; Streptococcal Infections; Streptococcus pyogenes; Virginiamycin

Topics: Adult; Anti-Bacterial Agents; Bacteremia; Enterobacter cloacae; Fever; Fracture Fixation; Humans; Male; Methicillin Resistance; Staphylococcal Infections; Staphylococcus aureus; Tibial Fractures; Virginiamycin

A plasmid pEP2104 originated from Staphylococcus aureus was clinically isolated in Hungary during 1977. The plasmid mediates inducible resistance to PMS-antibiotics; partial macrolide [the 14-membered macrolides, erythromycin (EM) and oleandomycin and the 16-membered macrolides mycinamicin I (MCM I) and mycinamicin II (MCM II)and type B streptogramin (MKM-B) antibiotics. The sequence of 31 amino acid residues obtained by N-terminal analysis of the 63kDa protein (MsrSA) present in the membrane from 8325(pEP2104) cells whose PMS-resistance was induced by a concentration of 1.35 micrograms EM/ml [EM-induced 8325(pEP2104)], was identical to the corresponding sequence in a membrane protein MsrA related to promoting efflux of [14C]EM [Ross J.I., et al., Mol. Microbiol., 4, 1207 (1990)]. A constitutive PMS-resistant strain 8325(pMC38) was obtained from the 8325( pEP2104) strain in the presence of 1 microgram MCMI/ml. No inactivation of EM in EM-induced 8325(pEP2104) was observed. Moreover, poly (A)-directed polylysine synthesis by a cell-free system containing ribosomes from EM-induced 8325 (pEP2104) cells and S100 from Escherichia coli was inhibited by not only EM but spiramycin and MKM-B [Matsuoka M., et al., Biol. Pharm. Bull., 16, 1288 (1993)]. In addition, ribosomes from both EM-induced 8325 (pEP2104) and 8325(pMC38) strains showed about the same affinity as those from the host stain. NCTC8325. These results suggest, that like MsrA protein, active drug-efflux due to MsrSA protein may be responsible for PMS-resistance. How can the 8325 (pMC38) strain discriminate PMS-antibiotics from most of 16-membered macrolides and lincosamides? A possible explanation is discussed in terms of the pKa-value related to the physicochemical nature of the antibiotics.

Topics: Amino Acid Sequence; Anti-Bacterial Agents; Cell Membrane; Drug Resistance, Microbial; Humans; Hungary; Hydrogen-Ion Concentration; Molecular Sequence Data; Plasmids; Ribosomes; Staphylococcal Infections; Staphylococcus aureus; Virginiamycin

We evaluated the in vivo activity and the diffusion of radiolabelled RP 57669 (RPI) and RP 54476 (RPII), the two components of the injectable streptogramin RP 59500, alone or in combination, in aortic vegetations from experimental endocarditis in rabbits. RPI and RPII demonstrated in vitro bacteriostatic and bactericidal synergy against a clinical strain of Staphylococcus aureus resistant to methicillin and susceptible to erythromycin. In experimental staphylococcal endocarditis, RP 59500 was as effective as vancomycin and significantly more effective than RPI (P < 0.01) and RPII (P < 0.05). Autoradiography studies showed different patterns of distribution into cardiac vegetations infected with Streptococcus sanguis for [14C]RPI and [14C]RPII. [14C]RPI was homogeneously distributed throughout the vegetations whereas [14C]RPII showed a decreasing gradient of concentration between the periphery and the core of the vegetation, with an approximately 2:1 ratio. [14C]RPI diffused approximately 2 to 4 times more than [14C]RPII into the core of the vegetations. Since the injected ratio of RPI and RPII is 30:70 in RP 59500, the actual RPI:RPII ratio in the core of the vegetation may range from 0.8 to 1.7, a ratio which remains compatible with the in vivo synergism demonstrated between the two components.

Topics: Animals; Autoradiography; Culture Media; Drug Synergism; Endocarditis, Bacterial; Female; Humans; Methicillin Resistance; Microbial Sensitivity Tests; Rabbits; Staphylococcal Infections; Staphylococcus aureus; Streptococcal Infections; Streptococcus sanguis; Vancomycin; Virginiamycin

In 1990, over a 6-month period, an increase from 1 to 10% in the incidence of pristinamycin resistance among coagulase-negative staphylococci was observed in four intensive care units of a Parisian hospital. Twenty-three such isolates, as well as 25 pristinamycin-susceptible Staphylococcus epidermidis isolates, were collected and typed by analyzing various bacterial constituents. Two structurally related plasmids of 7.3 and 14.3 kb, carrying the gene vga encoding resistance to pristinamycin, were detected in the 23 pristinamycin-resistant coagulase-negative staphylococci which were identified as S. epidermidis. Although related by numerous common characteristics, 20 of these 23 isolates could be divided into two types, A (17 isolates) and B (three isolates). These types were characterized on the basis of their plasmid contents and hybridization patterns obtained when the EcoRI-digested DNA was probed with plasmid pIP1551 containing an internal fragment of the insertion sequence IS256. These findings suggest that the dissemination of type A epidemic strains was, in large part, responsible for the outbreak.

Topics: Base Sequence; Cross Infection; DNA Probes; Drug Resistance, Microbial; Humans; Immunoblotting; Molecular Sequence Data; Nucleic Acid Hybridization; Paris; Phenotype; Plasmids; Staphylococcal Infections; Staphylococcus epidermidis; Virginiamycin

The activity of RP 59500 against methicillin-resistant Staphylococcus aureus was studied in vitro and in a rabbit model of aortic valve endocarditis. Three strains, 67-O, 529, and Du, ranging from relatively resistant to susceptible to RP 59500 in vitro (mean agar dilution MICs of 0.65, 0.21, and 0.12 mg/L respectively) were used to establish endocarditis, which was treated either with RP 59500, 20 mg/kg im four times a day for four days or with vancomycin, 25 mg/kg iv twice a day for four days. RP 59500 was ineffective for the most resistant strain, 67-O. RP 59500 was effective for the intermediately susceptible strain 529, but vancomycin was more effective. RP 59500 was slightly more effective than vancomycin against the most susceptible strain, Du, but the difference was not statistically significant. These results suggest that strains inhibited by RP 59500 at a concentration of greater than or equal to 0.5 mg/L should probably be considered resistant in this model of infection. RP 59500 was effective in vivo against the two susceptible strains, but overall, vancomycin was the more active drug.

Topics: Animals; Aortic Valve; Drug Combinations; Drug Resistance, Microbial; Endocarditis, Bacterial; Heart Valve Diseases; In Vitro Techniques; Methicillin; Microbial Sensitivity Tests; Rabbits; Staphylococcal Infections; Staphylococcus aureus; Vancomycin; Virginiamycin

RP 59500 is a new semisynthetic injectable streptogramin antibiotic composed of two compounds which interact synergically, RP 57669 and RP 54476, derived from pristinamycin IA and pristinamycin IIB, respectively. The bacteristatic and bactericidal activities of RP 57669 and RP 54476 alone or combined in various proportions were tested by the chequerboard dilution technique. The fractional inhibitory concentration (FIC) index was determined for 14 Staphylococcus aureus isolates (including methicillin- and macrolide-resistant strains) and one culture collection strain. The FIC index was found to be much lower than 0.5, indicating the presence of synergy for all strains tested, whatever their resistance pattern. The ED50 of RP 57669 and RP 54476 in various combinations were also determined in three experimental murine models of septicaemia, caused by either S. aureus or Streptococcus pneumoniae, and a thigh abscess model caused by S. aureus. The combinations which performed best in the model of septicaemia were those in which the RP 57669: RP 54476 ratio ranged from 16:84 to 92:8, while those active against the thigh abscess model had ratios ranging from 8:92 to 84:16. That the drugs were active over a wide range of ratios suggests that synergy will be maintained even if one drug is cleared more rapidly than the other. The combination of 30:70, referred to as RP 59500, was selected for further studies, both in vitro and in various experimental models of infections.

Topics: Abscess; Animals; Drug Resistance, Microbial; Drug Synergism; Humans; In Vitro Techniques; Mice; Microbial Sensitivity Tests; Pneumococcal Infections; Staphylococcal Infections; Staphylococcus aureus; Streptococcus pneumoniae; Thigh; Virginiamycin

Four out of more than 8,200 Staphylococcus aureus strains isolated in Japan between 1961 and 1980 were constitutively resistant to a variety of macrolide antibiotics except tylosin and rokitamycin, but susceptible to lincosamide and streptogramin type B antibiotics (PM). The data obtained by agarose gel electrophoresis, CsCl-ethidium bromide density gradient analysis, diagnosis with ATP-dependent deoxyribonuclease, and a test transducing into a rec- mutant with phage 80L2 propagated on PM-resistant S. aureus all suggested that the determinant for the PM-resistance is located in chromosome.

Topics: Anti-Bacterial Agents; DNA, Bacterial; Drug Resistance, Microbial; Erythromycin; Humans; Lincosamides; Macrolides; Plasmids; Staphylococcal Infections; Staphylococcus aureus; Transduction, Genetic; Virginiamycin

During a period from 1978 to 1989, 413 Staphylococcus aureus strains were isolated at 27 different geographical regions in Hungary; they exhibited an inducible resistance to the 14-membered macrolides and streptogramin type B antibiotics, but not to the 16-membered macrolides and lincosamides: this resistance is referred to as PMS resistance phenotype. The isolates were mostly associated with patients suffering from staphylococcal diseases and with hygienic screenings in hospitals and closed communities. They were rarely isolated from food-poisoning cases, food hygienic screenings, or animal sources. Strains with PMS resistance phenotype were resistant to penicillin (99.0%), tetracycline (78.7%), and chloramphenicol (63.0%); however, they were susceptible to oxacillin. Most of them (94.2%) belonged to the phage type 52-complex. The determinant for PMS phenotype was located on plasmids, which also encoded beta-lactamase production and cadmium ion resistance, but not arsenate resistance. Three types of plasmid with molecular size of 50 kilobases (kb), 23.8 kb, and 16.8 kb, were found among the strains with PMS resistance phenotype, and the 50 kb and 23.8 kb plasmids also encoded mercury resistance. The 16.8 kb and 23.8 kb plasmids belonged to incompatibility group 1.

Topics: Anti-Bacterial Agents; beta-Lactamases; DNA, Bacterial; Drug Resistance, Microbial; Electrophoresis, Agar Gel; Humans; Hungary; Macrolides; Metals; Microbial Sensitivity Tests; Phenotype; R Factors; Staphylococcal Infections; Staphylococcus aureus; Transduction, Genetic; Virginiamycin

Pefloxacin (Pef) is a new quinolone which has been shown to have good in-vitro activity against Staphylococcus aureus, and to reach high tissue concentrations. Its efficacy was compared to that of 2 quinolone derivatives, norfloxacin (Nor) and ciprofloxacin (Cip) and to that of methicillin (Meth), cephalothin (Cep), pristinamycin (Pri) and vancomycin (Van), in an experimental model of S. aureus abscesses. Mice challenged with an intramuscular thigh injection of a calibrated inoculum developed local abscesses. Three S. aureus strains (with different antibiotic resistance profiles (Pase-, Pase+, MethR)) were used. In this model, the antibiotics showing the best ED50 following oral administration, against all three strains were Pef greater than Cip greater than Pri greater than Nor, by subcutaneous administration for the Pase- strain Pef = Cip greater than Cep greater than Van; for the Pase+ strain Pef = Cip greater than Van greater than Meth and for the Pase+ MethR strain: Pef = Cip greater than Van greater than Cep. These data indicate that pefloxacin and ciprofloxacin are highly active in vivo against various strains of S. aureus, and appear to be more potent than norfloxacin, vancomycin, cephalothin and methicillin.

Topics: Abscess; Administration, Oral; Animals; Anti-Bacterial Agents; Cephalothin; Ciprofloxacin; Injections, Subcutaneous; Methicillin; Mice; Norfloxacin; Pefloxacin; Penicillin Resistance; Peptides; Quinolines; Staphylococcal Infections; Staphylococcus aureus; Thigh; Vancomycin; Virginiamycin

Within the framework of this symposium, it is not feasible to present an exhaustive description of the present state of knowledge regarding the sensitivity and resistance of bacterial species to macrolides, lincosamides and streptogramins (MLS). This paper is limited to a description of the evolution of different types of resistance in the light of decisive factors described in previous papers, in order to deduce, if at all possible, trends in future strategy in therapeutics. Only acquired resistance lends itself to epidemiological study, in contrast to natural resistance which is, by definition, characteristic of a species or a genus, and not liable to change. Three groups will therefore be studied in turn: Staphylococcus aureus, streptococci and Bacteroides fragilis. There is as yet insufficient accumulated data to draw conclusions regarding the epidemiology and evolution of MLSB resistance observed in Clostridium perfringens and Corynebacterium diphtheriae, or regarding the high-level resistance to erythromycin due to enzymatic inactivation recently described in Escherichia coli.

Topics: Anti-Bacterial Agents; Bacteroides; Bacteroides Infections; Biological Evolution; Drug Resistance, Microbial; Humans; Lincosamides; Macrolides; Phenotype; Species Specificity; Staphylococcal Infections; Staphylococcus; Staphylococcus aureus; Streptococcal Infections; Streptococcus; Streptococcus pyogenes; Structure-Activity Relationship; Virginiamycin

A number of factors must be taken into consideration when comparing the relative efficacy of macrolides-lincosamides-streptogramins (MLS) in staphylococcal infections: these include their antibacterial activity, their pharmacokinetic characteristics, their tolerance, and the results achieved in clinical practice.

Topics: Anti-Bacterial Agents; Drug Resistance, Microbial; Drug Tolerance; Humans; Lincosamides; Macrolides; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus; Virginiamycin

Topics: Anti-Bacterial Agents; Drug Resistance, Microbial; France; Humans; Lincosamides; Macrolides; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus; Virginiamycin

Pristinamycin is a naturally occurring streptogramin made up of 2 groups of synergistic components (PI and PII). Because these components are not water soluble, use of pristinamycin has up till now been confined to the oral route. Water soluble semisynthetic derivatives of the PIA component, appropriate for parenteral use, have lately been developed. PIA is a peptidic macrolactone. As opening of the lactone results in total loss of biologic activity, semisynthesis must spare this function and preserve the macrocycle. Reactions at 5 gamma and 5 delta yielded 4 families of derivatives. Antimicrobial activity has been studied for more than 80 compounds. Several derivatives are promising as they are water soluble and have in vitro and in vivo (mice) activities similar to those of the original PIA component.

Topics: Animals; Chemical Phenomena; Chemistry; Mice; Microbial Sensitivity Tests; Peptides; Solubility; Staphylococcal Infections; Staphylococcus aureus; Structure-Activity Relationship; Virginiamycin

Topics: Biological Evolution; Disease Outbreaks; France; Humans; R Factors; Staphylococcal Infections; Staphylococcus aureus; Tobramycin; Virginiamycin

Pristinamycin and virginiamycin, two antibiotics belonging to the streptogramin group, are widely used in France against staphylococcal infections. They are mixtures of two different active compounds, pristinamycin I and II, virginiamycine S and M. The present study describes five clinical isolates of Staphylococcus aureus with unusual resistance to these antibiotics. This resistance, whose level is variable according to the strains, concerns both compounds of these antibiotics. It is lost at high frequency spontaneoulsy or after treatment by curing agents, suggesting that the resistance is plasmid mediated. The drug inactivation by the resistant strains supports the hypothesis of an enzymatic mechanism of resistance. Furthermore, this new resistance seems to be linked, in some strains, to either of the two aminoglycoside resistance patterns recently described in S. aureus.

Topics: Anti-Bacterial Agents; Drug Resistance, Microbial; Genetic Variation; Humans; Plasmids; Staphylococcal Infections; Staphylococcus aureus; Virginiamycin

Micrococcin M, micrococcin M1 and eight micrococcin M derivatives, and two peptide antibiotics produced by micrococci and staphylococci were investigated for their antibacterial activity and therapeutic value. These antibiotics appeared to act solely on Gram-positive bacteria, especially on staphylococci and streptococci, in quite low concentrations in vitro and exerting both bacteriostatic and bactericidal effects. Gram-negative bacteria were virtually not susceptible. Resistance to micrococcins developed very rapidly, due to existence of numerous primarily resistant cells in sensitive populations. Complete cross-resistance resulted from acquiring resistance to one of the micrococcin antibiotics. Therapeutic effects are poor, as micrococcins are not absorbed from the injection site or from the intestinal tract after peroral administration. Importance of micrococcins in nature may be high, especially when ecology of normal bacterial flora and carriage of staphylococci and streptococci are concerned.

Topics: Animals; Bacitracin; Bacteriocins; Dogs; Drug Evaluation, Preclinical; Drug Resistance, Microbial; Erythromycin; Male; Mice; Microbial Sensitivity Tests; Micrococcaceae; Mycobacterium avium; Mycobacterium tuberculosis; Staphylococcal Infections; Streptococcal Infections; Time Factors; Virginiamycin

Topics: Adolescent; Anti-Bacterial Agents; Cephalosporins; Child; Child, Preschool; Drug Resistance, Microbial; Fusidic Acid; Gastroenteritis; Gentamicins; Humans; Infant; Otitis; Respiratory Tract Infections; Skin Diseases; Staphylococcal Food Poisoning; Staphylococcal Infections; Sulfamethoxazole; Trimethoprim; Virginiamycin

Topics: Adolescent; Adult; Aged; Child; Chronic Disease; Drug Evaluation; Female; Humans; Kidney Diseases; Male; Microbial Sensitivity Tests; Middle Aged; Regression Analysis; Staphylococcal Infections; Staphylococcus; Urinary Tract Infections; Virginiamycin

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Bronchial Neoplasms; Bronchopneumonia; Drug Combinations; Humans; Male; Middle Aged; Respiratory Tract Infections; Staphylococcal Infections; Tetracycline; Virginiamycin

Topics: Animals; Anti-Bacterial Agents; Bacteriological Techniques; Clostridium; Culture Media; Drug Synergism; Enterobacteriaceae; Haemophilus; Leptospira; Malaria; Mice; Microbial Sensitivity Tests; Mycobacterium; Plasmodium; Protozoan Infections; Staphylococcal Infections; Streptococcal Infections; Toxoplasmosis; Trichomonas; Virginiamycin

Topics: Anti-Bacterial Agents; Dexamethasone; Folliculitis; Furunculosis; Humans; Leg Ulcer; Ointments; Pyoderma; Skin Diseases, Infectious; Staphylococcal Infections; Virginiamycin

Topics: Animals; Anti-Bacterial Agents; Bacteria; Drug Resistance, Microbial; Humans; Mice; Staphylococcal Infections; Staphylococcus; Streptococcal Infections; Virginiamycin

Topics: Anti-Bacterial Agents; Drug Resistance, Microbial; Drug Tolerance; Humans; Male; Middle Aged; Pyoderma; Staphylococcal Infections; Streptococcal Infections; Virginiamycin

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Chronic Disease; Drug Resistance, Microbial; Female; Fractures, Bone; Humans; Male; Middle Aged; Osteomyelitis; Staphylococcal Infections; Staphylococcus; Virginiamycin

Topics: Acne Vulgaris; Anti-Bacterial Agents; Drug Resistance, Microbial; Humans; Leg Ulcer; Staphylococcal Infections; Staphylococcus; Virginiamycin

Topics: Acne Vulgaris; Adult; Anti-Bacterial Agents; Child; Dexamethasone; Eczema; Eczema, Dyshidrotic; Erythema; Female; Humans; Keratosis; Male; Middle Aged; Ointments; Polymyxins; Pyoderma; Skin Diseases; Staphylococcal Infections; Virginiamycin

Topics: Anti-Bacterial Agents; Dermatitis; Drug Resistance, Microbial; Genetics, Microbial; Humans; In Vitro Techniques; Pyoderma; Staphylococcal Infections; Staphylococcus; Virginiamycin

Topics: Anti-Bacterial Agents; Humans; Skin Diseases; Staphylococcal Infections; Virginiamycin

Topics: Anti-Bacterial Agents; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Male; Staphylococcal Infections; Virginiamycin

Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Child; Drug Therapy; Humans; Infant; Ointments; Skin Diseases; Staphylococcal Infections; Virginiamycin

Topics: Animals; Anti-Bacterial Agents; Mice; Staphylococcal Infections; Streptococcal Infections; Virginiamycin

Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Dermatologic Agents; Humans; Staphylococcal Infections; Surgical Wound Infection; Virginiamycin

Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Dermatologic Agents; Sepsis; Staphylococcal Infections; Virginiamycin

Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Dermatologic Agents; Dermatology; Drug Resistance, Microbial; Humans; Staphylococcal Infections; Virginiamycin

Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Brain Abscess; Cerebral Cortex; Humans; Meningitis; Neurosurgery; Spondylitis; Staphylococcal Infections; Surgical Wound Infection; Toxicology; Virginiamycin

Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Dermatologic Agents; Orthopedic Procedures; Orthopedics; Staphylococcal Infections; Virginiamycin

Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Dermatologic Agents; Dermatology; Staphylococcal Infections; Staphylococcal Skin Infections; Virginiamycin

Topics: Anti-Bacterial Agents; Staphylococcal Infections; Virginiamycin