Bruno Fantin

Critical influence of resistance to streptogramin B-type antibiotics on activity of RP 59500 (quinupristin-dalfopristin) in experimental endocarditis due to Staphylococcus aureus.

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.

In vivo activities and penetration of the two components of the streptogramin RP 59500 in cardiac vegetations of experimental endocarditis.

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. Images

Fusidic acid alone or in combination with vancomycin for therapy of experimental endocarditis due to methicillin-resistant Staphylococcus aureus.

The usefulness of fusidic acid, alone or combined with vancomycin, was investigated for the therapy of experimental endocarditis caused in rabbits by a methicillin-resistant strain of Staphylococcus aureus. In vitro killing curves showed an indifferent interaction between the two antibiotics. In vivo, vancomycin alone was as effective as a vancomycin-fusidic acid combination (P < 0.05 versus control animals). No resistance to fusidic acid emerged during combination therapy. Fusidic acid alone was not effective. Resistance emerged in 5 of 12 animals treated with fusidic acid alone and was responsible for antibacterial failure. Fusidic acid alone was effective (P < 0.001) and did not select resistant strains if therapy was started when animals retained a smaller inoculum. We concluded that the vancomycin-fusidic acid combination exhibited no advantage over vancomycin alone in this model.

Influence of low-level resistance to vancomycin on efficacy of teicoplanin and vancomycin for treatment of experimental endocarditis due to Enterococcus faecium.

Emergence of vancomycin-resistant strains among enterococci raises a new clinical challenge. Rabbits with aortic endocarditis were infected with Enterococcus faecium BM4172, a clinical strain resistant to low levels of vancomycin (MIC, 16 micrograms/ml) and susceptible to teicoplanin (MIC, 1 micrograms/ml), and against its susceptible variant E. faecium BM4172S obtained in vitro by insertional mutagenesis (MICs, 2 and 0.5 micrograms/ml, respectively). Control animals retained 8 to 10.5 log10 CFU/g of vegetation. We evaluated in this model the efficacy of vancomycin (30 mg/kg of body weight; mean peak and trough serum levels, 27 and 5 micrograms/ml, respectively), teicoplanin (standard dose, 10 mg/kg; mean peak and trough levels, 23 and 9 micrograms/ml, respectively; and high dose, 20 mg/kg; mean peak and trough levels, 63 and 25 micrograms/ml, respectively), gentamicin (6 mg/kg; mean peak and trough levels, 8.6 and less than 0.1 micrograms/ml, respectively), alone or in combination, given every 12 h intramuscularly for 5 days. Teicoplanin standard dose was as active as vancomycin against both strains. Vancomycin was not effective against E. faecium BM4172 but was highly effective against E. faecium BM4172S (7.5 +/- 1.1 log10 CFU/g of vegetation versus 4.9 +/- 1.0 log10 CFU/g of vegetation for vancomycin against E. faecium BM4172 and E. faecium BM4172S, respectively; P = 0.0012). A high dose of teicoplanin was more effective than vancomycin against E. faecium BM4172 (4.4 +/- 1.8 log10 CFU/g of vegetation versus 7.5 +/- 1.1 log10 CFU/g of vegetation for teicoplanin high dose and vancomycin, respectively; P less than 0.05). Against E. faecium BM4172 glycopeptide-gentamicin combinations were the most effective regimens in vitro and in vivo (2.8 +/- 0.7 and 3.5 +/- 1.3 log10 CFU/g of vegetation for vancomycin plus gentamicin and teicoplanin standard dose plus gentamicin, respectively; P < 0.05 versus single-drug regimens). We concluded that high-dose teicoplanin or the combination of a glycopeptide antibiotic plus gentamicin was effective against experimental infection due to E. faecium with low-level resistance to vancomycin.

Ferritinemia during type 1 Gaucher disease: mechanisms and progression under treatment.

BACKGROUNDnEarlier results highlighted hyperferritinemia during type-1 Gaucher disease (GD), but its potential mechanisms and long-term progression remained unexamined.nnnMETHODSnWe analyzed the clinical, biological and iron characteristics of type-1 GD patients, before and after starting enzyme-replacement therapy (ERT). Iron parameters under ERT were subjected to linear-regression analyses.nnnRESULTSnSerum ferritin (median 739 [46-2371] μg/L) was determined for 54 patients (21 (39%) males; median age 32 [range 12-73] years) before ERT; it exceeded 300 μg/L in 47 (87%), while the other iron parameters always remained normal: transferrin saturation coefficient (26 [16-42]), serum iron at 13 [6-22] mmol/L and transferrin at 2.4 [2,3] g/L. Four patients had mild elevation of liver transaminases, with C-reactive protein >20mg/l in two. The absence of hemolysis was accompanied by a median bilirubin of 9 μmol/L and lactate dehydrogenase at 250 IU/L; diabetes and lipid anomalies were not observed. Clinical, biological and iron parameters at GD diagnosis were comparable for the 12 and 42 patients with ferritinemia ≤400 and >400 μg/L, respectively. Ferritinemia was measured at least once for 46 patients after ERT onset (median treatment duration 90 [3-204] months). At study closure, median serum ferritin was 187.5 [11-1560] μg/L, exceeding 300 μg/L in 15 (33%) patients, while the other iron parameters were normal. Among the latter, only the mean±SD ferritinemia slope decreased significantly under ERT (-1.9±0.3%/month; p<0.001).nnnCONCLUSIONnHyperferritinemia is a specific GD characteristic and serum ferritin monitoring could be informative during follow-up.

Bone events and evolution of biologic markers in Gaucher disease before and during treatment.

IntroductionKnown biomarkers of Gaucher-disease activity are platelets, chitotriosidase, angiotensin-converting enzyme (ACE), tartrate-resistant acid phosphatase (TRAP) and ferritin. The aim of this study was to retrospectively evaluate the frequency of bone events (BE) and biomarker changes during two periods: diagnosis to first enzyme-replacement therapy (ERT) and the latter to the closing date.MethodsBE of 62 treated patients, among the 73-patient cohort followed at Beaujon Hospital, Clichy, France, were described with Kaplan-Meier curves, and linear-mixed models were used to analyze their biomarker changes and the influence of several covariates (splenectomy, diagnosis year, genotype, age at diagnosis and sex).ResultsBE occurred before (54 events in 21 patients), but also during, ERT (12 events in 10 patients), with respective frequencies (95% confidence interval) at 10 years of 22.4% (13.3 to 36.3) and 20.0% (10.2 to 36.9). Biomarker slope changes before and during ERT differed significantly for platelets (+190/mm3/year and 7,035/mm3/year, respectively; P < 0.0001) and ferritin (+4% and -14%; P < 0.0001). High ferritin levels and low platelet counts at ERT onset were significantly associated with BE during ERT (P = 0.019 and 0.039, respectively). Covariates significantly influenced biomarker changes (baseline and/or slope): splenectomy affected platelets (baseline and changes), TRAP changes and chitotriosidase changes; diagnosis date influenced ACE and TRAP baseline values; and genotype influenced chitotriosidase baseline and changes.ConclusionsPlatelet counts and ferritin levels and their slope changes at ERT onset seem to predict BE during treatment. Biomarker baseline values and changes are dependent on several covariables.

Complications infectieuses liées aux chambres implantables : caractéristiques et prise en charge

Totally implanted access port-related infections are responsible for their own morbidity and mortality. Main risk factors of totally implanted access port-related infections are total parenteral nutrition, young age, difficulties during insertion, poor general status and neutropenia. Recent guidelines defined intravascular catheter-related infections. This relies on a strict clinical and microbiological work-up including simultaneous culture of blood drawn from the catheter and a peripheral vein. The search for local or general complications is mandatory: clinical and possibly echographic assessments are therefore needed. Depending on the context and the type of microorganism, this evaluation may include transoesophageal echocardiography and search for suppurative thrombosis in case of catheter-related bloodstream infection caused by Staphylococcus aureus. Indeed, intravascular complications in this setting are frequent. Catheter removal is mandatory in case of local complication (tunnel infection or port pocket abscess), septic thrombosis, infective endocarditis, osteomyelitis, septic shock or infection related to specific pathogens (S. aureus, Candida spp., Pseudomonas aeruginosa). Otherwise, retention of the catheter might be proposed given results from recent studies including antibiotic lock therapy associated with systemic antibiotic. Future studies must focus on defining more precisely the factors associated with salvage therapy failure including host, pathogens virulence factors and biofilm formation.

Impact of imiglucerase on the serum glycosylated-ferritin level in Gaucher disease

Gaucher disease (GD) is a lysosomal storage disorder, caused by deficient activity of the enzyme glucocerebrosidase, which can be treated by enzyme-replacement therapy (ERT). No prognostic marker can predict long-term complications of GD but several markers are used in therapeutic monitoring: chitotriosidase, total serum ferritin (TSF), angiotensin-converting enzyme (ACE) and tartrate-resistant acid phosphatase (TRAP). They all increase with disease progression and generally decrease under ERT. This study was undertaken to investigate ferritin glycoforms, i.e., glycosylated ferritin (GF) and non-glycosylated ferritin (NGF) concentrations, as potential markers for the follow-up of GD therapy. GF and NGF determinations for GD patients followed in a single center between 1996 and 2007 were analyzed using two approaches: (1) the serum levels of 12 untreated patients were compared with those of 10 patients after 48 months on ERT; (2) the evolution of serum levels under ERT in 15 patients were analyzed using linear/logarithmic mixed models. TSF and NGF levels did not differed significantly between untreated patients and those on ERT (TSF: 524.5 (range 221.0-2045.0) μg/L vs. 410.5 (range 115.0-1587.0) μg/L, respectively, p=0.72; NGF: 340.0 (range 182.8-1717.8) μg/L vs. 199.9 (range 77.1-649.8) μg/L, p=0.09). The percent GF was significantly lower in untreated patients than in those on ERT (27.0% (range 8.0-51.0) vs. 43.5% (range 22.0-80.0) respectively; p=0.02). The percent GF increased significantly during ERT (slope=0.156% [95% confidence interval (CI), 0.03; 0.29] per month, p=0.01) regardless of whether NGF and TSF significantly decreased during ERT (slope=-1.4% per month [95%CI, -1.9%; -1.0%], p<0.0001; slope=-1.1% [95%CI, -1.6%; -0.6%] per month, p<0.0007, respectively). Thus, GF is low in untreated GD patients. GF and NGF changed significantly under ERT and might be of clinical value for GD management under treatment.

Tuberculous cerebral vasculitis: Retrospective study of 10 cases

BACKGROUNDnTuberculous cerebral vasculitis is a complication of tuberculous meningitis. This study was undertaken to determine the epidemiological characteristics, context, diagnostic means and outcomes under treatment of tuberculous cerebral vasculitides.nnnMETHODSnAll consecutive patients diagnosed with tuberculous cerebral vasculitis were identified from the databases of three Internal Medicine, one Neurology and one Infectious Disease Departments in three suburban Parisian hospitals.nnnRESULTSnWe describe 10 cases: five men and five women (median age 33.5 [range: 27-55] years). Two were infected with the human immunodeficiency virus. Nine patients had tuberculous meningitis, eight with extraneurological involvement. The following manifestations led to the diagnosis: motor deficit, acute confusional state, headaches, involvement, coma and/or seizures. The cerebral vasculitis revealed tuberculosis in three patients, but tuberculosis was already known when vasculitis was diagnosed for the seven others. The cerebral computed-tomography scan showed cerebral infarctions in five patients, hydrocephalus and tuberculomas in four, while magnetic resonance imaging detected infarctions and leptomeningitis in nine patients, pachymeningitis in one, hydrocephalus and tuberculomas in seven. Therapy combined antituberculous agents with oral corticosteroids for all patients, preceded by a methylprednisolone pulse for five patients. Outcome was favorable for nine patients.nnnCONCLUSIONnWe described the non-negligible frequency of tuberculous cerebral vasculitides, their clinical manifestations and their potential severity, and the diagnostic and monitoring contributions of magnetic resonance imaging and magnetic resonance angiography.

Flow Cytometry as a Tool To Determine the Effects of Cell Wall-Active Antibiotics on Vancomycin-Susceptible and -Resistant Enterococcus faecalis Strains

ABSTRACT Flow cytometry and confocal microscopy were used to study the effects of vancomycin, daptomycin, telavancin, and PA1409, a new investigational vancomyquine, on the morphology, membrane potential, and permeability of glycopeptide-susceptible and -resistant Enterococcus faecalis strains. Daptomycin exerted the most pronounced effects on bacterial size and bacterial permeability against susceptible and resistant strains.