Showing papers on "Dalfopristin published in 1999"

The efficacy and safety of quinupristin/dalfopristin for the treatment of infections caused by vancomycin-resistant Enterococcus faecium

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

Treatment of hospitalized patients with complicated Gram-positive skin and skin structure infections: two randomized, multicentre studies of quinupristin/dalfopristin versus cefazolin, oxacillin or vancomycin

Abstract: Quinupristin/dalfopristin (Synercid), the first injectable streptogramin antibiotic available for the treatment of complicated gram-positive skin and skin structure infections, was compared with standard comparators (cefazolin, oxacillin or vancomycin) in one USA and one international trial. These two randomized, open-label trials of virtually identical design enrolled a total of 893 patients (450 quinupristin/dalfopristin, 443 comparator). The majority of patients had erysipelas, traumatic wound infection or clean surgical wound infection. Staphylococcus aureus was the most frequently isolated pathogen in both treatment groups and polymicrobial infection was more common in the quinupristin/dalfopristin group than in the comparator group. The clinical success rate (cure plus improvement) in the clinically evaluable population was equivalent between the two treatment groups (68.2% quinupristin/dalfopristin, 70.7% comparator; 95% CI, -10.1, 5.1) despite a shorter mean duration of treatment for quinupristin/dalfopristin patients. In the bacteriologically evaluable population, by-patient and by-pathogen bacteriological eradication rates were somewhat lower for quinupristin/dalfopristin (65.8% and 66.6%, respectively) than for the comparator regimens (72.7% and 77.7%, respectively). The lower bacteriological response rates in the quinupristin/dalfopristin group were, in part, due to a higher rate of polymicrobial infections and a higher incidence of patients classified as clinical failure, a category which included premature discontinuation of treatment because of local venous adverse events. The bacteriological eradication rate for quinupristin/dalfopristin was higher in monomicrobial infections than in polymicrobial infections (72.6% versus 63.3%, respectively), whereas the corresponding rate for the comparator regimens was lower for monomicrobial infections than polymicrobial infections (70.8% versus 83.1%). This finding was not unexpected, since the spectrum of quinupristin/dalfopristin is focused on gram-positive pathogens and additional antibiotics to treat gram-negative bacteria were not required per protocol. The systemic tolerability of both treatment regimens was qualitatively similar. A higher rate of drug-related venous adverse events was reported for quinupristin/dalfopristin (66.2%) than for the comparator regimen (28.4%). Premature discontinuation of study drug was primarily due to adverse clinical events for quinupristin/dalfopristin (19.1%), whereas the most common reason for discontinuation among those receiving the comparator regimens was treatment failure (11.5%). Quinupristin/dalfopristin is an effective alternative for the treatment of hospitalized patients with complicated skin and skin structure infections due to quinupristin/ dalfopristin-susceptible gram-positive organisms, including methicillin- and erythromycin-resistant S. aureus.

Antimicrobial treatment of chronic osteomyelitis.

Abstract: Chronic osteomyelitis has been a difficult problem for patients and the treating physicians. Appropriate antibiotic therapy is necessary to arrest osteomyelitis along with adequate surgical therapy. Factors involved in choosing the appropriate antibiotic(s) include infection type, infecting organism, sensitivity results, host factors, and antibiotic characteristics. Initially, antibiotics are chosen on the basis of the organisms that are suspected to be causing the infection. Once the infecting organism(s) is isolated and sensitivities are established, the initial antibiotic(s) may be modified. In selecting specific antibiotics for the treatment of osteomyelitis, the type of infection, current hospital sensitivity resistance patterns, and the risk of adverse reactions must be strongly appraised. Antibiotic classes used in the treatment of osteomyelitis include penicillins, beta-lactamase inhibitors, cephalosporins, other beta-lactams (aztreonam and imipenem), vancomycin, clindamycin, rifampin, aminoglycosides, fluoroquinolones, trimethoprim-sulfamethoxazole, metronidazole, and new investigational agents including teicoplanin, quinupristin/dalfopristin, and oxazolidinones. Traditional treatments have used operative procedures followed by 4 to 6 weeks of parenteral antibiotics. Adjunctive therapy for treating chronic osteomyelitis may be achieved by using beads, spacers, or coated implants to deliver local antibiotic therapy and/or by using hyperbaric oxygen therapy (once per day for 90-120 minutes at two to three atmospheres at 100% oxygen).

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

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

Prevalence of resistance to MLS antibiotics in 20 European university hospitals participating in the European SENTRY surveillance programme

Abstract: Macrolide, lincosamide and streptogramin (MLS) antibiotics are chemically distinct inhibitors of bacterial protein synthesis. Resistance to MLS antibiotics may be constitutive or inducible. The purpose of this study is to update our understanding of the prevalence of different forms of MLS resistance in Europe. The analysis of 3653 clinical pneumococcal, staphylococcal and enterococcal isolates exhibited an average percentage of 21.3% and 6.2% intermediate and high-level penicillin-resistant Streptococcus pneumoniae, 21.8% methicillin-resistant S t a p h y l o- coccus aureus and 11% vancomycin-resistant Enterococcus faecium. Geographical differ- ences in erythromycin and clindamycin resistance in isolates of S. pneumoniae and S. aureus strongly reflect geographical variations in susceptibility to penicillin and methicillin, respec- tively. A very narrow range of MICs was obtained with quinupristin/dalfopristin, with no S. pneumoniae, S. aureus and E. faecium isolate having an MIC of >4 mg/L, indicating a possible role of quinupristin/dalfopristin in the treatment of infections by multi-resistant Gram-positive bacteria.

Optimal treatment of complicated skin and skin structure infections

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

Costs of treating infections caused by methicillin-resistant staphylococci and vancomycin-resistant enterococci.

Abstract: Infection with methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant Enterococcus faecium (VREF) increases the risk of mortality and results in prolonged hospitalization and high utilization of costly treatment modalities. Measures to prevent the spread of MRSA (and possibly VREF) include patient isolation and decontamination, hygiene measures, ward closure, and screening of patients and staff for carriage. In seriously ill patients, the increased use of vancomycin for the treatment of MRSA can lead to the emergence of VREF colonization/infection. Quinupristin/dalfopristin is effective in the treatment of MRSA infections, including nosocomial pneumonia, skin and soft tissue infection, and septicaemia. In the treatment of nosocomial pneumonia, clinical success rates were equivalent between quinupristin/dalfopristin and vancomycin. In the context of a hospital policy which emphasizes effective hygiene measures and the prudent use of antibacterials, quinupristin/dalfopristin is an effective antimicrobial that can help to control the high costs associated with multiresistant MRSA and VREF infections.

Safety and tolerability of quinupristin/dalfopristin: administration guidelines

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

Effects of genes encoding resistance to streptogramins A and B on the activity of quinupristin-dalfopristin against Enterococcus faecium.

Abstract: In recent years, enterococci have become one of the most common causes of nosocomial infections, while certain strains have acquired resistance to all available antimicrobial agents, including aminoglycosides, penicillins, and glycopeptides. Quinupristin-dalfopristin is an antimicrobial combination developed for the treatment of infections due to vancomycin-resistant Enterococcus faecium (20). This antimicrobial belongs to the streptogramin class which includes naturally synthesized antibiotics composed of two chemically distinct factors, streptogramins A (SA) and streptogramins B (SB). Quinupristin-dalfopristin is a semisynthetic injectable streptogramin mixture of quinupristin (SB) and dalfopristin (SA) in a 30:70 ratio (9). Binding of these factors to the 50S ribosomal subunit causes inhibition of protein synthesis (37). Alone, each factor has a moderate bacteriostatic activity, but in combination, they often display a bactericidal synergistic effect (9). This is related to the synergistic binding of the factors to their ribosomal target site. Each factor binds a different site on the peptidyltransferase domain of the ribosome, but the binding of SA causes a conformational change which increases the affinity of SB for its target (36). Since SA and SB are chemically unrelated and have different binding sites, the mechanisms of resistance to these two streptogramin types are different. In E. faecium, an acetyltransferase encoded by the satA gene inactivates streptogramins A (31). After completion of this work, a new satG gene encoding a putative acetyltransferase which appeared to be prevalent in E. faecium was reported (39). Both genes are related to the acetyltransferase genes vat (7), vatB (2), and vatC (4) reported in staphylococci. Resistance to streptogramins B is due either to hydrolysis of the antibiotic mediated by the vgb gene (12, 23) initially reported in Staphylococcus aureus (6) or to modification of the ribosomal target by a 23S rRNA methylase encoded by the ermB gene (24, 38). Other staphylococcal genes such as vga and vgaB conferring resistance to SA by a putative efflux mechanism (3, 5) or msrA encoding a protein which participates in the active efflux of macrolides and SB (34) have not been reported in enterococci. Because of the synergism displayed by the two streptogramin types, it has been suggested that acquisition of isolated resistance to dalfopristin or quinupristin could have no or only partial negative impact on the antimicrobial activity of the combination (13, 25). In fact, it has been shown that inhibitory synergy between the two factors is maintained in vitro against E. faecium strains resistant to quinupristin by synthesis of a ribosomal methylase (19). However, the consequences of inactivation of dalfopristin or quinupristin or the outcome of combined mechanisms of resistance on the activity of quinupristin-dalfopristin have not been systematically analyzed. We have studied the activity of quinupristin-dalfopristin against 45 clinical strains of E. faecium isolated from patients in different French hospitals in relation to the mechanisms of resistance to quinupristin and dalfopristin. Recombinant plasmids containing the three streptogramin resistance genes well characterized in enterococci, ermB, satA, and vgb alone or in all possible combinations, were also constructed. The plasmids were introduced into E. faecium and S. aureus to evaluate the impact of the various resistance mechanisms on the activity of quinupristin-dalfopristin.

Comparative in-vitro activities of moxifloxacin, trovafloxacin, quinupristin/dalfopristin and linezolid against staphylococci.

Abstract: 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.

Prospective, randomized dose-ranging open phase II pilot study of quinupristin/dalfopristin versus vancomycin in the treatment of catheter-related staphylococcal bacteremia.

Abstract: 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.

Current and future management of infections due to methicillin-resistant staphylococci infections: the role of quinupristin/dalfopristin.

Abstract: 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.

Quinupristin/dalfopristin: therapeutic potential for vancomycin-resistant enterococcal infections

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

Synergy Testing of Vancomycin-Resistant Enterococcus faecium against Quinupristin-Dalfopristin in Combination with Other Antimicrobial Agents

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

Methods for administration of antibiotics

Abstract: The invention provides methods for administering a therapeutically effective amount of daptomycin while minimizing skeletal muscle toxicity. The methods provide daptomycin administration at a dosing interval of 24 hours or greater. This long dosing interval minimizes skeletal muscle toxicity and allows for higher peak concentrations of daptomycin, which is related to daptomycin's efficacy. The invention also provides methods of administering lipopeptide antibiotics other than daptomycin while minimizing skeletal muscle toxicity by administering a therapeutically effective amount of the lipopeptide antibiotic at a dosage interval that does not result in muscle toxicity. The invention also provides methods of administering quinupristin/dalfopristin while minimizing skeletal muscle toxicity by administering a therapeutically effective amount of quinupristin/dalfopristin at a dosage interval that does not result in muscle toxicity.

Activities of new antimicrobial agents (trovafloxacin, moxifloxacin, sanfetrinem, and quinupristin-dalfopristin) against Bacteroides fragilis group: comparison with the activities of 14 other agents.

Abstract: The antimicrobial activities of trovafloxacin, moxifloxacin, sanfetrinem, quinupristin-dalfopristin, and 14 other antimicrobial agents against 218 Bacteroides fragilis group strains were determined. A group of 10 imipenem-resistant strains were also tested. Imipenem, meropenem, and sanfetrinem had the lowest MICs of all of the β-lactams. Quinupristin-dalfopristin inhibited all of the strains at 2 μg/ml. Overall, the MICs of trovafloxacin and moxifloxacin for 90% of the strains tested were 1 and 2 μg/ml, respectively.

In-vitro activity of 29 antimicrobial agents against penicillin-resistant and -intermediate isolates of Streptococcus pneumoniae

Abstract: Antibiotic resistance among isolates of Streptococcus pneumoniae is increasing worldwide. Optimal therapy, though unknown, should be guided by in-vitro susceptibility testing. Currently, vancomycin is the only approved antibiotic that is universally active against multiresistant S. pneumoniae. In-vitro activities were determined for 29 antimicrobial agents against 22 penicillin-intermediate S. pneumoniae (PISP) and 16 penicillin-resistant S. pneumoniae (PRSP) isolates. MICs were determined in cation-adjusted Mueller-Hinton broth with 3% lysed horse blood in microtitre trays. Antimicrobial classes tested included cephalosporins, penicillin, aminopenicillins, macrolides, quinolones, carbapenems and other antimicrobial agents. Among the classes of antimicrobial agents tested, wide differences in susceptibility were demonstrated for both PISP and PRSP. Of the cephalosporins, ceftriaxone and cefotaxime demonstrated the best in-vitro activity for both PISP and PRSP. Of the quinolones, clinafloxacin and trovafloxacin showed the greatest in-vitro activity. Rifampicin and teicoplanin demonstrated excellent in-vitro activity. Promising in-vitro results of newer agents, such as quinupristin/dalfopristin, ramoplanin, teicoplanin and linezolid may justify further evaluation of these agents in clinical trials.

Pharmacokinetics of Quinupristin-Dalfopristin in Continuous Ambulatory Peritoneal Dialysis Patients

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

Quinupristin/dalfopristin attenuates the inflammatory response and reduces the concentration of neuron-specific enolase in the cerebrospinal fluid of rabbits with experimental Streptococcus pneumoniae meningitis

Abstract: The inflammatory response following initiation of antibiotic therapy and parameters of neuronal damage were compared during intravenous treatment with quinupristin/dalfopristin (100 mg/kg as either a short or a continuous infusion) and ceftriaxone (10 mg/kg/h) in a rabbit model of Streptococcus pneumoniae meningitis. With both modes of administration, quinupristin/dalfopristin was less bactericidal than ceftriaxone. However, the concentration of proinflammatory cell wall components (lipoteichoic acid (LTA) and teichoic acid (TA)) and the activity of tumour necrosis factor (TNF) in cerebrospinal fluid (CSF) were significantly lower in the two quinupristin/dalfopristin groups than in ceftriaxone-treated rabbits. The median LTA/TA concentrations (25th/75th percentiles) were as follows: (i) 14 h after infection: 133 (72/155) ng/mL for continuous infusion of quinupristin/dalfopristin and 193 (91/308) ng/mL for short duration infusion, compared with 455 (274/2042) ng/mL for ceftriaxone (P = 0.002 and 0.02 respectively); (ii) 17 h after infection: 116 (60/368) ng/mL for continuous infusion of quinupristin/dalfopristin and 117 (41/247) ng/mL for short duration infusion, compared with 694 (156/2173) ng/mL for ceftriaxone (P = 0.04 and 0.03 respectively). Fourteen hours after infection the median TNF activity (25th/75th percentiles) was 0.2 (0.1/1.9) U/mL for continuous infusion of quinupristin/dalfopristin and 0.1 (0.01/3.5) U/mL for short duration infusion, compared with 30 (4.6/180) U/mL for ceftriaxone (P = 0.02 for each comparison); 17 h after infection the TNF activity was 2.8 (0.2/11) U/mL (continuous infusion of quinupristin/dalfopristin) and 0.1 (0.04/6.1) U/mL (short duration infusion), compared with 48.6 (18/169) U/mL for ceftriaxone (P = 0.002 and 0.001). The concentration of neuron-specific enolase (NSE) 24 h after infection was significantly lower in animals treated with quinupristin/dalfopristin: 4.6 (3.3/5.7) microg/L (continuous infusion) and 3.6 (2.9/4.7) microg/L (short duration infusion) than in those treated with ceftriaxone (17.7 (8.8/78.2) microg/L) (P = 0.03 and 0.009 respectively). In conclusion, antibiotic treatment with quinupristin/dalfopristin attenuated the inflammatory response within the subarachnoid space after initiation of antibiotic therapy. The concentration of NSE in the CSF, taken as a measure of neuronal damage, was lower in quinupristin/dalfopristin-treated rabbits than in ceftriaxone-treated rabbits.

Bacterial Pathogens Isolated from Patients with Bloodstream Infections in Latin America, 1997: Frequency of Occurrence and Antimicrobial Susceptibility Patterns from the SENTRY Antimicrobial Surveillance Program.

Abstract: We report the antimicrobial susceptibility of 736 organisms isolated from bloodstream infections in 10 Latin American medical centers during the first six months of 1997. The data presented here is from the SENTRY Antimicrobial Surveillance Program, a comprehensive surveillance study involving 72 medical centers worldwide. The isolates ivere tested for in in vitro susceptibility to 35 antimicrobial agents by the broth microdilution method. The five most frequently isolated species were (n/%): Staphylococcus aureus (1 65/22.4%), Escherichia coli(118/16.0%), coagulase-negative staphylococci (CoNS - 115/15.6%), Pseudomonas aeruginosa (51/6.9%), Klebsiella spp. (46/ 6.3%). Susceptibility to oxacillin was 70.9% for S. aureus and only 33.9% for CoNS. Vancomycin was active against all of staphylococci, while teicoplanin was active against 99.4% of S. aureus and only 90.4% of CoNS. The new fluoroquinolones sparfloxacin, gatifloxacin, and trovafloxacin, and the streptogramin, quinupristin/dalfopristin, were very active against these species. Only one vancomycin-resistant enterococcus was detected; however, high-level aminoglycoside resistance rates were common (66.7%). E. coli and Klebsiella spp. showed low susceptibilities for cefotaxime (90.7% and 41.3%) and for cefoxitin (85.6% and 78.3% respectively), indicating a high frequency of isolates that produce ESBL and/or stably derepressed ampC enzymes. These strains, phenotypically consistent with extended-spectrum beta-lactamase (ESBL) production, were typed using ribotyping and pulsed-field gel electrophoresis. The most active compounds (M IC90 in µg/mL /% susceptibility) against P. aeruginosa were meropenem (2 /94.1%), followed by amikacin (>32 / 86.3%), and piperacillin alone or with tazobactam (128/84.3%). Ceftazidime and cefepime showed similar activity (70.6% susceptibility) and levofloxacin was the most active fluoroquinolone (MI C50 l 0.5; 76.5% susceptibility) against this gram-negative species. These results show the unique pattern of bloodstream isolates for Latin America and they demonstrate the present utility of several classes of compounds against emerging antimicrobial-resistant species in this region.

Plasmid-mediated coresistance to streptogramins and vancomycin in Enterococcus faecium HM1032.

Abstract: Enterococcus faecium has emerged as a major cause of nosocomial infections. Correspondingly, this species has become increasingly resistant to a broad range of antimicrobial agents, including aminoglycosides, penicillins, and glycopeptides (4). Quinupristin-dalfopristin, an injectable streptogramin, is proposed as an alternative drug for severe infections caused by multiply resistant E. faecium and in many cases could represent the only therapy available (3). We have isolated from urine a strain of E. faecium, HM1032, which was resistant to both vancomycin and quinupristin-dalfopristin, and we have studied the localization of the genetic determinants for these resistances. E. faecium HM1032 was resistant to erythromycin (MIC > 128 μg/ml), quinupristin-dalfopristin (MIC = 16 μg/ml), vancomycin (MIC >128 μg/ml), and tetracycline. We found that resistance to macrolides and vancomycin was related to the presence of an ermAM (ermB)-like gene and a vanA gene, respectively, as shown by PCR experiments (2, 6). Resistance to quinupristin-dalfopristin was due to inactivation of quinupristin and dalfopristin (MICs = 64 μg/ml), as suggested by a microbiological screen test, Gots’ test, and confirmed in PCR experiments by amplification of vgb- and satA-like genes responsible for acetylation and hydrolysis of quinupristin and dalfopristin, respectively. The nucleotide sequences of amplicons were nearly identical to those of the prototype satA and vgb genes (1, 5). The resistances could not be transferred by mating on filters to E. faecium HM1070, a plasmid-free recipient strain, except for tetracycline resistance, which transferred with a frequency of 10−6 per donor colony. Transformation of E. faecium HM1070 with plasmid extracts of E. faecium HM1032 yielded clones coresistant to vancomycin, quinupristin-dalfopristin (MIC = 8 μg/ml), and erythromycin. However, the transformants inactivated dalfopristin but not quinupristin. One of the transformants, E. faecium HM1070SR, was studied further, and PCR experiments indicated that the strain contained the vanA, ermAM, and satA genes but not the vgb gene. Total DNA, plasmid DNA of E. faecium HM1032, and plasmid DNA of E. faecium HM1070SR were analyzed by agarose gel electrophoresis and hybridization with vanA, ermAM, vgb, and satA probes (Fig. ​(Fig.1).1). E. faecium HM1032 contained at least six plasmids, three of which were present in E. faecium HM1070SR. The ermAM, satA, and vanA genes were localized on the same large plasmid (>60 kb), while the vgb gene was apparently chromosomal in the wild-type strain (lack of hybridization to plasmid bands with hybridization to the region with linearized DNA, including fragments of chromosomal DNA) and absent from the transformant. After plasmid digestion with EcoRI, vanA, satA, and ermAM probes hybridized to EcoRI fragments, of 5.5, 10, and 10 kb, respectively (data not shown). FIG. 1 Analysis of non-digested genomic DNA (lane 1) and plasmid DNA (lane 2) from E. faecium HM1032 and of nondigested plasmid DNA from the transformant E. faecium HM1070SR (lane 3) by agarose gel electrophoresis and hybridization. (A) Agarose gel electrophoresis ... Although uncommon, quinupristin-dalfopristin resistance in glycopeptide-resistant E. faecium has already been reported for human and animal isolates from Germany, the United Kingdom, and the United States (3, 7, 8). The presence of genes responsible for glycopeptide and streptogramin resistance linked on the same plasmid is an additional cause of concern if this plasmid happened to disseminate. Although we were unable to transfer by conjugation this resistance plasmid to a recipient strain, transformation experiments showed that the combination of genes for resistance to vancomycin and streptogramins borne by this plasmid was sufficient to confer resistance to both antibiotics.

Study to assess the reliability of a disc diffusion method for determining the sensitivity of gram-positive pathogens to dalfopristin/quinupristin.

Abstract: A standardized method of disc testing the sensitivity of gram-positive pathogens to dalfopristin/quinupristin was developed, and then 'field tested' in ten centres in the UK. For a 15 microg disc, zone diameter breakpoints of 20 mm and 15 mm are suggested when organisms are tested on Iso-Sensitest agar and Iso-Sensitest agar supplemented with 5% whole horse blood, respectively.

Modified time–kill assay against multidrug-resistant Enterococcus faecium with novel antimicrobial combinations

Abstract: This study used a modified time-kill assay to compare the in-vitro activity of chloramphenicol and quinopristin/dalfopristin combined with vancomycin, ampicillin or gentamicin against multidrug-resistant Enterococcus faecium. The assay uses standardized time-kill methods with the following modifications: centrifugation of the test tubes at 1-2 h intervals, removal of supernatant and resuspension of bacteria in media containing antibiotic concentrations corresponding to simulated steady-state serum concentrations. None of the agents, alone or in combination, produced bactericidal or synergic activity. The modified time-kill assay more closely simulates in-vivo conditions and may provide a better qualitative assay to determine the interaction between antimicrobial agents and bacteria.

Quinupristin-Dalfopristin Is Active against Toxoplasma gondii

Abstract: Synercid and each of its components (quinupristin and dalfopristin) were examined for their activities against Toxoplasma gondii. In vitro, intracellular replication of tachyzoites was inhibited by synercid and each of its two components. The 50% inhibitory concentrations of synercid, quinupristin, and dalfopristin were 1.6, 2.7, and 6.3 microg/ml, respectively. Thus, synercid was markedly more active than its components. Treatment of acutely infected mice with 100 or 200 mg of synercid per kg of body weight per day administered intraperitoneally for 10 days resulted in survival of 50% (P = 0.0002) and 100% (P < 0.0001) of infected mice, respectively, whereas all control mice died by day 18. In contrast, treatment with 200 mg of either quinupristin and dalfopristin per kg per day alone resulted in only 20% survival; treatment with 50 mg of either drug per kg per day resulted only in the prolongation of time to death. These results suggest that synercid may be useful for treatment of toxoplasmosis in humans.

Susceptibility of penicillin-resistant and penicillin-susceptible Streptococcus pneumoniae to newer antimicrobial agents

Abstract: Agar dilution minimum inhibitory concentration (MIC) methodology, according to NCCLS guidelines, was used to test the activity of three glycopeptides (LY 333328 [LY], vancomycin [VAN], and teicoplanin [TEI]), four fluoroquinolones (trovafloxacin [TRO], BAY 12-8039 [BAY], ciprofloxacin [CIP], and ofloxacin [OFL]), five macrolide-lincosamide-streptogramin antibiotics (erythromycin [ERY], azithromycin [AZI], miocamycin [MOM], clindamycin CLN], and quinupristin-dalfopristin [SYN] against 126 Streptococcus pneumoniae strains, isolated in Lozano Blesa Hospital of Zaragoza (Spain). MIC50/MIC90 (microg/ml) values for penicillin-susceptible (PS), penicillin-intermediate (PI) and penicillin-resistant (PR) strains show an excellent antipneumococcal activity of LY 333326--a new glycopeptide, for the fluoroquinolones trovafloxacin and moxifloxacin [BAY 12-8039], and for quinupristin/dalfopristin, regardless of the resistance phenotype of the strains.