[Vaccination strategies for the global eradication of poliomyelitis]. / Stratégies de vaccination pour les dernières étapes de l'éradication mondiale de la poliomyélite.

The world-wide initiative to eradicate poliomyelitis has been remarkably successful since its launch in 1988. According to the WHO, the last wild virus should be isolated in 2005, thus paving the way for the certification of a world free of poliomyelitis in 2008. Discontinuation of poliomyelitis vaccination which constituted the ultimate objective of this campaign has been jeopardised by two recent developments: the characterisation of vaccine-derived polioviruses (VDPV), either circulating or excreted by immunodepressed patients, and renewed concern about the risk of bioterrorism. The threats posed by VDPV have led WHO to recommend that OPV usage be discontinued as soon as possible after eradication certification. This article examines the consequences of these developments and describes possible vaccination strategies to counter these new circumstances.

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

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

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

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

The efficacy and safety of quinupristin/dalfopristin for the treatment of infections caused by vancomycin-resistant Enterococcus faecium. Synercid Emergency-Use Study Group.

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.

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

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.

Evaluation of in vitro activity of quinupristin/dalfopristin and comparator antimicrobial agents against worldwide clinical trial and other laboratory isolates.

This report summarizes the activities of quinupristin/dalfopristin (Q/D) and appropriate comparator antibiotics, including ciprofloxacin, erythromycin, gentamicin, rifampin, teicoplanin, and vancomycin, against selected gram-positive pathogens, including Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus agalactiae, and Streptococcus pyogenes. The study pathogens were obtained from 2 sources: (1) clinical isolates taken from patients participating in Q/D worldwide Phase III comparative and noncomparative (emergency-use program) clinical trials; and (2) other isolates collected from the laboratories of 45 geographically distinct medical centers around the world. Q/D was highly active, with minimum inhibitory concentrations (MICs) < or = 1.0 microg/mL against most isolates, including those known to be resistant to methicillin, vancomycin, or erythromycin. Q/D was active (MICs < or = 1 microg/mL) against 95% of the vancomycin-resistant E. faecium strains, for example, whereas ciprofloxacin was active against 6%. Q/D was equally active against methicillin-susceptible or -resistant S. aureus strains (MIC90=1 microg/mL), as was vancomycin (MIC90=2 microg/mL), whereas ciprofloxacin was much less active against methicillin-resistant strains than against methicillin-susceptible strains (MIC90=32 vs 1 microg/mL). Given its spectrum of activity, Q/D may provide a viable option for the treatment of severe respiratory and skin and skin-structure infections caused by gram-positive bacteria, especially when strains with known or suspected resistance to other commonly used antibiotics are present.

Activity of quinupristin/dalfopristin against gram-positive bacteria: clinical applications and therapeutic potential.

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

Automated analysis of the McKenzie test through color slide digitization and processing.

The McKenzie test is performed to compare the antiinflammatory activity of topical corticosteroids. Each drug induces a local whiteness of the skin called blanching. The blanchings are classically evaluated on the basis of visual score. This paper proposes a new blanching index and a methodology for designing such an index by digitizing and processing color slides. Several indices derived from classical color models are proposed and compared to the visual scores. This work demonstrates the significant improvement of quantitation derived from digitized images with respect to the observer assessment. The difference of chromatic green between the blanching patch and the surrounded healthy skin is proposed for analysis of the McKenzie test.

Inhibition of ex-vivo PAF-induced platelet aggregation by the PAF-antagonist RP 48740: relationship to plasma concentrations in healthy volunteers.

RP 48740, 3-(3-pyridyl)-1H,3H-pyrrolo [1,2-c] thiazole-7-carboxamide, a specific competitive PAF-receptor antagonist in vitro, was given to 29 healthy male volunteers for 7 days. Plasma drug concentrations and ex-vivo PAF-induced platelet aggregation were assessed on Days 1, 4, and 7. RP 48740 had linear pharmacokinetics after single and repeated doses. It caused stable inhibition of PAF-induced platelet aggregation in a dose-dependent manner. The effect disappeared within 24 h, even after 7 days of repeated doses. The effect of RP 48740 displayed a sigmoidal relation to the plasma drug concentration; I50 2.3 (0.3) mg.l-1. There were no clinical or biological adverse reactions to RP 48740 during the study.

Vasodilating mechanism and response to physiological pressor stimuli of acute doses of carvedilol compared with labetalol, propranolol and hydralazine.

There is conflicting evidence regarding the main mechanism of the vasodilating effect with carvedilol at therapeutic doses, and to examine this, single doses of carvedilol 50mg and 100mg were compared with labetalol 400mg, propranolol 160mg, propranolol 80mg plus hydralazine 50mg and placebo in healthy subjects. Dose-response studies (required to increase heart rate or systolic blood pressure by 25 beats/min and 20mm Hg, respectively) were performed with phenylephrine, angiotensin and isoprenaline after each drug, and placebo administration and the effects of physiological pressor stimuli were compared. Phenylephrine systolic pressure dose-response curves were shifted by labetalol (dose ratio 2.4) and both carvedilol doses (dose ratios 50mg 1.9, 100mg 20.2). The slight shift to the right of the angiotensin dose-response curves with hydralazine plus propranolol (dose ratio 1.4) and carvedilol 50mg (dose ratio 1.4) was not significant. beta-Blockade was greatest with propranolol 160mg, followed by carvedilol 100mg, propranolol 80mg plus hydralazine 50mg, carvedilol 50mg and was least with labetalol 400mg (isoprenaline dose ratios required to increase heart rate by 25 beats/min were 55.2, 27.2, 20.2, 14.2, 11.5, respectively). Blood pressure rise with cold pressor and isometric exercise was inhibited most by labetalol. At these acute doses carvedilol displayed some alpha-blockade, but the lower ratio of alpha-blockade to beta-blockade differed from that seen with labetalol, which may account for the different haemodynamic responses at rest and during physiological pressor stimuli with the 2 drugs. There was no definite evidence of direct vasodilator effect.