Worldwide appraisal and update (2010) of telavancin activity tested against a collection of Gram-positive clinical pathogens from five continents

A total of 15,480 Gram-positive pathogens were collected from 89 sites in the United States, Europe, the Asia-Pacific region, and Latin America in 2010. Telavancin was active against indicated Staphylococcus aureus (MIC(50/90), 0.12/0.25 μg/ml), vancomycin-susceptible Enterococcus faecalis (MIC(50/90), 0.5/0.5 μg/ml), and beta-hemolytic (MIC(50/90), 0.06/0.12 μg/ml) and viridans group streptococcus (MIC(50/90), 0.03/0.06 μg/ml) isolates. These MIC results showed potency for telavancin equal to or greater than that of comparators. These in vitro data confirm a continued potent activity of telavancin when tested against contemporary Gram-positive clinical isolates.     

Telavancin activity tested against a contemporary collection of Gram-positive pathogens from USA Hospitals (2007-2009)

This study updates the activity of telavancin against Gram-positive pathogens collected from USA hospitals (2007-2009). Telavancin (MIC_50/90, 0.12/0.25 μg/mL) was active against coagulase-negative staphylococci and methicillin-resistant Staphylococcus aureus (100% susceptible), for which only daptomycin (MIC_50/90, 0.25/0.5 μg/mL; 99% susceptible) and quinupristin/dalfopristin (MIC_50/90, ≤0.25-0.5/0.5 μg/mL; 99% susceptible) exhibited similar activity. Telavancin (MIC_50/90, 0.25/0.5 μg/mL) inhibited 96.5% of Enterococcus faecalis at the Food and Drug Administration breakpoint (MIC, ≤1 μg/mL), where ampicillin (99.9% susceptible), daptomycin (99.9% susceptible), and linezolid (100% susceptible) also demonstrated high-level coverage. Telavancin inhibited, respectively, 100.0% and 91.7% of VanB-phenotype E. faecalis and E. faecium at ≤1 μg/mL, whereas it was less active against VanA strains. Telavancin was uniformly active against Streptococcus pneumoniae and resistant subsets, and demonstrated good potency (MIC₉₀, 0.06-0.12 μg/mL) against other streptococci, regardless of resistance to other drugs. This assessment reveals potent activity of telavancin against Gram-positive isolates collected from USA hospitals with no evidence of emergence of resistance.     

Efficacy of telavancin in the treatment of experimental endocarditis due to glycopeptide-intermediate Staphylococcus aureus

The efficacy of telavancin, a novel lipoglycopeptide, was evaluated in experimental endocarditis in rabbits using two clinical isolates of glycopeptide-intermediate Staphylococcus aureus: ATCC 700788 and HIP 5836. Infected rabbits were treated for 2 days with telavancin (10 mg/kg of body weight once daily intravenously) or vancomycin (1 g twice daily intravenously), administered with a computer-controlled infusion pump system simulating human serum kinetics. Vegetations were harvested at 16 h postinoculation in the control group and at the end of treatment in the drug-treated group. For ATCC 700788, MICs and minimal bactericidal concentrations (MBCs), respectively, were 1 mg/liter and 4 mg/liter for telavancin and 8 mg/liter and 128 mg/liter for vancomycin. For HIP 5836, MICs and MBCs, respectively, were 4 mg/liter and 8 mg/liter for telavancin and 8 mg/liter and 128 mg/liter for vancomycin. Peak and trough levels were 90 microg/ml and 6 microg/ml, respectively, for telavancin and 46 microg/ml and 6 microg/ml, respectively, for vancomycin. In glycopeptide-intermediate S. aureus ATCC 700788, telavancin sterilized 6 of 16 vegetations (37%), whereas vancomycin sterilized 4 of 20 (20%) (P = 0.29) compared with 0 of 17 in the control group. In HIP 5836 experiments, telavancin and vancomycin sterilized 5 of 16 (31%) and 1 of 15 (7%) vegetations (P = 0.17), respectively, compared with none in the control group. Telavancin reduced vegetation titers by 2.0 and 2.3 logs greater than vancomycin for the ATCC 700788 (4.6 [2.0 to 5.8] versus 6.6 [2.0 to 6.9] log CFU/g vegetation; P = 0.05) and HIP 5836 (4.4 [2.0 to 7.4] versus 6.7 [4.5 to 8.7] log CFU/g vegetation; P = 0.09) strains, respectively; these differences did not reach statistical significance. All isolates from vegetations remained susceptible to telavancin after therapy. The results suggest that telavancin may be an effective treatment for endocarditis caused by glycopeptide-intermediate S. aureus.     

In vitro activity of telavancin and comparator antimicrobial agents against a panel of genetically defined staphylococci

The in vitro activity of telavancin was determined for 94 diverse Staphylococcus spp. Telavancin had MIC(90) values of 0.5 μg/mL for methicillin-susceptible, methicillin-resistant, and vancomycin-susceptible Staphylococcus aureus, and coagulase-negative staphylococci isolates. Telavancin MICs were 0.5-1 μg/mL for vancomycin-intermediate S. aureus isolates and 2-4 μg/mL for vancomycin-resistant S. aureus strains.     

Variability in Telavancin Cross-Reactivity among Vancomycin Immunoassays

Telavancin is a semisynthetic lipoglycopeptide with a dual mechanism of action against Gram-positive pathogens. Two brief reports have suggested potential cross-reactivity of telavancin with the vancomycin particle-enhanced turbidometric immunoassay (PETIA). The purpose of this study was to evaluate several commercially available vancomycin immunoassays (fluorescence polarization [FPIA], enzyme-multiplied immunoassays [EMIT], PETIA, and chemiluminescent immunoassay [CMIA]) for cross-reactivity with telavancin. Seven sites were selected to analyze serum samples for vancomycin. Each site received a set of samples (n = 18) which combined drug-free serum with telavancin, 7-OH telavancin metabolite, or vancomycin. Immunoassays demonstrating potential cross-reactivity were further evaluated by sending a duplicate sample set to multiple laboratories. Cross-reactivity was defined as the percent theoretical concentration (reported concentration/theoretical concentration × 100). No cross-reactivity was seen with FPIA or EMIT. Within the theoretical concentration range of 5 to 120 μg/ml of telavancin, the Synchron PETIA system reported vancomycin concentrations ranging from 4.7 to 54.2 μg/ml compared to vancomycin concentrations from 1.1 to 5.6 μg/ml for the Vista PETIA system. The Architect CMIA system reported vancomycin concentrations in the range of 0.27 to 0.97 μg/ml, whereas Advia Centaur XP CMIA reported vancomycin concentrations between 1.6 and 31.6 μg/ml. The Architect CMIA immunoassay had the lowest percent cross-reactivity (0.8 to 5.4%), while the Synchron PETIA immunoassay demonstrated the highest percent cross-reactivity (45.2 to 53.8%). Telavancin samples measured by liquid chromatography-mass spectroscopy were within 93.9 to 122% of theoretical concentrations. Vancomycin concentrations were not measured in any 7-OH telavancin-spiked sample. Vancomycin concentrations measured by liquid chromatography-mass spectroscopy were within 57.2 to 113% of theoretical concentrations. PETIA and CMIA measured vancomycin concentrations in telavancin-spiked samples. Significant variability in percent cross-reactivity was observed for each platform regardless of immunoassay method.     

Worldwide summary of telavancin spectrum and potency against Gram-positive pathogens: 2007 to 2008 surveillance results

Telavancin was approved in the United States and Canada for the treatment of adult patients with complicated skin and skin-structure infections (cSSSI) caused by susceptible Gram-positive isolates. In this study, telavancin and comparator antimicrobial activities were determined against a total of 24?017 clinical isolates, including Staphylococcus aureus, coagulase-negative Staphylococcus spp. (CoNS), Enterococcus spp., and various Streptococcus spp. Overall, telavancin was highly active across all geographic regions for S. aureus (MIC_50/90, 0.12/0.25 μg/mL; 100.0% susceptible), CoNS (MIC_50/90, 0.12/0.25 μg/mL), vancomycin-susceptible Enterococcus faecalis (MIC_50/90, 0.25/0.5 μg/mL; 100.0% susceptible), Enterococcus faecium (MIC_50/90, 0.06/0.12 μg/mL), Streptococcus pneumoniae (MIC_50/90, ≤0.015/0.03 μg/mL), viridans group Streptococcus spp. (MIC_50/90, 0.03/0.06 μg/mL; 100.0% susceptible), and β-hemolytic Streptococcus spp. (MIC_50/90, 0.03/0.12 μg/mL; 99.8% susceptible). Telavancin had potent activity against vancomycin-nonsusceptible, teicoplanin-susceptible (VanB) E. faecalis (MIC_50/90, 0.25/0.5 μg/mL) and E. faecium (MIC_50/90, 0.06/0.25 μg/mL). These in vitro results show continued activity for telavancin, which represents an important alternative available for treating cSSSI.     

Baseline Activity of Telavancin against Gram-Positive Clinical Isolates Responsible for Documented Infections in U.S. Hospitals (2011-2012) as Determined by the Revised Susceptibility Testing Method

Telavancin had MIC₅₀ and MIC₉₀ values of 0.03 and 0.06 μg/ml (100.0% susceptible), respectively, against methicillin-resistant and -susceptible Staphylococcus aureus. Telavancin was active against vancomycin-susceptible Enterococcus faecalis (MIC_50/90, 0.12/0.12 μg/ml; 100% susceptible) and Enterococcus faecium (MIC_50/90, 0.03/0.06 μg/ml), while higher MIC values were obtained against vancomycin-resistant E. faecium (MIC_50/90, 1/2 μg/ml) and E. faecalis (MIC_50/90, >2/>2 μg/ml). Streptococci showed telavancin modal MIC results of ≤0.015 μg/ml, except against Streptococcus agalactiae (i.e., 0.03 μg/ml). This study reestablishes the telavancin spectrum of activity against isolates recovered from the United States (2011-2012) using the revised broth microdilution method.     

Efficacy of Telavancin in a rabbit model of aortic valve endocarditis due to methicillin-resistant Staphylococcus aureus or vancomycin-intermediate Staphylococcus aureus

The activities of telavancin and vancomycin were compared in vitro and in the rabbit model of aortic valve endocarditis against a methicillin-resistant Staphylococcus aureus strain, COL, and a vancomycin-intermediate S. aureus (VISA) strain, HIP 5836. Telavancin was bactericidal in time-kill studies at a concentration of 5 microg/ml against both COL and HIP5836. Vancomycin was bacteriostatic at 5 microg/ml and bactericidal at 10 microg/ml against COL and was bacteriostatic at 10 microg/ml against VISA strain HIP 5836. Compared to untreated controls, a twice-daily regimen of 30 mg/kg of telavancin reduced mean aortic valve vegetation titers of the COL strain by 4.7 log(10) CFU/g after 4 days of therapy and sterilized 6/11 vegetations compared to 3.4 log(10) CFU/g with 3/10 vegetations sterilized for a regimen of twice-daily vancomycin, 30 mg/kg; these differences were not statistically significant. Telavancin was significantly more effective than vancomycin in the VISA model, producing a 5.5 log(10) CFU/g reduction versus no reduction in CFU with vancomycin. In experiments comparing 2-day regimens of telavancin at 30 mg/kg and 50 mg/kg twice daily, organisms were rapidly eliminated from vegetations, but the effect was not different between the two doses. These results suggest that telavancin may be an effective treatment for endocarditis and other serious staphylococcal infections accompanied by bacteremia, including infections caused by staphylococci not susceptible to vancomycin.     

Telavancin for the treatment of hospital-acquired pneumonia: findings from the ATTAIN studies

Treatment options for hospital-acquired pneumonia caused by Gram-positive organisms are far from ideal. The increase in vancomycin MICs among methicillin-resistant Staphylococcus aureus (MRSA) isolates, and the slow bactericidal action and poor lung penetration of vancomycin have driven the search for an alternative agent. Telavancin, a once-daily lipoglycopeptide, displays strong bactericidal activity against S. aureus. Two large Phase III randomized trials have recently compared intravenous telavancin (10mg/kg every 24?h) with vancomycin (1?g intravenously every 12?h) for 7–21 days for the treatment of hospital-acquired pneumonia caused by Gram positives. No significant differences were observed in the cure rates in the all-treated (n = 1503), the clinically evaluable (n = 654) and the microbiologically evaluable (n =480) populations. Telavancin performed better than vancomycin in patients with monomicrobial S. aureus pneumonia (84.2 vs 74.3%; 95% CI: 0.7–19.1), with MRSA (81.8 vs 74.1%; 95% CI: –3.5 to 19.3), and with strains having vancomycin MICs ≥1µg/ml (87.1 vs 74.3; 95% CI: 0.5–23). The rate of adverse events, including serious adverse events, was similar in both groups, with a slightly higher rate of serum creatinine increase in the telavancin-treated group. Based on these results, telavancin (already approved for this indication by the EMA) could certainly be added to the current treatment options, particularly in patients with MRSA pneumonia.     

Update on the telavancin activity tested against European staphylococcal clinical isolates (2009-2010)

This study evaluated telavancin activity against 3868 Staphylococcus aureus and 1003 coagulase-negative staphylococci (CoNS) collected from 33 European hospitals (2009-2010). Studies of telavancin potency included analysis of strains with decreased susceptibility to glycopeptides. Telavancin (MIC_50/90, 0.12/0.25 μg/mL) showed high activity against S. aureus and CoNS, regardless of the stratification analysis performed (year sampled, infection source, or methicillin susceptibility). In addition, telavancin (MIC_50/90, 0.25/0.5 μg/mL) retained activity against S. aureus isolates with higher vancomycin (MIC, 2 μg/mL) or teicoplanin (MIC, 2-8 μg/mL) MIC results. Overall, telavancin exhibited higher potency (at least 2-fold greater) than tested comparators (vancomycin, daptomycin, and linezolid) against European staphylococci. Alongside published clinical data, the telavancin in vitro activity observed against these pathogens supports this drug as an option for treating S. aureus infections in Europe, including those infections caused by strains with decreased susceptibility to vancomycin and/or teicoplanin.     

Comparative surveillance study of telavancin activity against recently collected gram-positive clinical isolates from across the United States

Telavancin is an investigational, rapidly bactericidal lipoglycopeptide antibiotic that is being developed to treat serious infections caused by gram-positive bacteria. A baseline prospective surveillance study was conducted to assess telavancin activity, in comparison with other agents, against contemporary clinical isolates collected from 2004 to 2005 from across the United States. Nearly 4,000 isolates were collected, including staphylococci, enterococci, and streptococci (pneumococci, beta-hemolytic, and viridans). Telavancin had potent activity against Staphylococcus aureus and coagulase-negative staphylococci (MIC range, 0.03 to 1.0 microg/ml), independent of resistance to methicillin or to multiple agents. Telavancin activity was particularly potent against all streptococcal groups (MIC(90)s, 0.03 to 0.12 microg/ml). Telavancin had excellent activity against vancomycin-susceptible enterococci (MIC(90), 1 microg/ml) and was active against VanB strains of vancomycin-resistant enterococci (MIC(90), 2 microg/ml) but less active against VanA strains (MIC(90), 8 to 16 microg/ml). Telavancin also demonstrated activity against vancomycin-intermediate S. aureus and vancomycin-resistant S. aureus strains (MICs, 0.5 microg/ml to 1.0 microg/ml and 1.0 microg/ml to 4.0 microg/ml, respectively). These data may support the efficacy of telavancin for treatment of serious infections with a wide range of gram-positive organisms.     

In vitro activity of telavancin against resistant gram-positive bacteria

The in vitro activity of telavancin was tested against 743 predominantly antimicrobial-resistant, gram-positive isolates. Telavancin was highly active against methicillin-resistant staphylococci (MIC(90), 0.5 to 1 microg/ml), streptococci (all MICs, < or =0.12 microg/ml), and VanB-type enterococci (all MICs, < or =2 microg/ml). Time-kill studies demonstrated the potent bactericidal activity of telavancin.     

Telavancin In Vitro Activity against a Collection of Methicillin-Resistant Staphylococcus aureus Isolates,Including Resistant Subsets,from the United States

Telavancin had MIC₅₀, MIC₉₀, and MIC₁₀₀ values of 0.03, 0.06, and 0.12 μg/ml, respectively, against methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), and non-multidrug-resistant (non-MDR) and MDR subsets. MRSA with elevated MIC values for vancomycin (2 to 4 μg/ml) or daptomycin (1 to 2 μg/ml) had telavancin MIC₅₀ (0.06 μg/ml) values 2-fold higher than those of isolates with lower MIC results (MIC₅₀, 0.03 μg/ml). However, telavancin had MIC₉₀ and MIC₁₀₀ results of 0.06 and 0.12 μg/ml (100% susceptible), respectively, regardless of the MRSA subset.     

Evaluation of telavancin activity versus daptomycin and vancomycin against daptomycin-nonsusceptible Staphylococcus aureus in an in vitro pharmacokinetic/pharmacodynamic model

Daptomycin-nonsusceptible (DNS) Staphylococcus aureus strains have been reported over the last several years. Telavancin is a lipoglycopeptide with a dual mechanism of action, as it inhibits peptidoglycan polymerization/cross-linking and disrupts the membrane potential. Three clinical DNS S. aureus strains, CB1814, R6212, and SA-684, were evaluated in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model with simulated endocardial vegetations (starting inoculum, 10(8.5) CFU/g) for 120 h. Simulated regimens included telavancin at 10 mg/kg every 24 h (q24h; peak, 87.5 mg/liter; t(1/2), 7.5 h), daptomycin at 6 mg/kg q24h (peak, 95.7 mg/liter; t(1/2), 8 h), and vancomycin at 1 g q12h (peak, 30 mg/liter; t(1/2), 6 h). Differences in CFU/g between regimens at 24 through 120 h were evaluated by analysis of variance with a Tukey's post hoc test. Bactericidal activity was defined as a ≥3-log(10) CFU/g decrease in colony count from the initial inoculum. MIC values were 1, 0.25, and 0.5 mg/liter (telavancin), 4, 2, and 2 mg/liter (daptomycin), and 2, 2, and 2 mg/liter (vancomycin) for CB1814, R6212, and SA-684, respectively. Telavancin displayed bactericidal activities against R6212 (32 to 120 h; -4.31 log(10) CFU/g), SA-684 (56 to 120 h; -3.06 log(10) CFU/g), and CB1814 (48 to 120 h; -4.9 log(10) CFU/g). Daptomycin displayed initial bactericidal activity followed by regrowth with all three strains. Vancomycin did not exhibit sustained bactericidal activity against any strain. At 120 h, telavancin was significantly better at reducing colony counts than vancomycin against all three tested strains and better than daptomycin against CB1814 (P < 0.05). Telavancin displayed bactericidal activity in vitro against DNS S. aureus isolates.     

Intrapulmonary distribution of intravenous telavancin in healthy subjects and effect of pulmonary surfactant on in vitro activities of telavancin and other antibiotics

Steady-state concentrations of telavancin, a novel, bactericidal lipoglycopeptide, were determined in the plasma, pulmonary epithelial lining fluid (ELF), and alveolar macrophages (AMs) of 20 healthy subjects. Telavancin at 10 mg of drug/kg of body weight/day was administered as a 1-h intravenous infusion on three successive days, with bronchoalveolar lavage performed on five subjects, each at 4, 8, 12, and 24 h after the last dose. Plasma samples were collected before the first and third infusions and at 1, 2, 3, 4, 8, 12, and 24 h after the third infusion. The plasma telavancin concentration-time profile was as reported previously. Telavancin (mean +/- standard deviation) penetrated well into ELF (3.73 +/- 1.28 microg/ml at 8 h and 0.89 +/- 1.03 microg/ml at 24 h) and extensively into AMs (19.0 +/- 16.8 microg/ml at 8 h, 45.0 +/- 22.4 microg/ml at 12 h, and 42.0 +/- 31.4 microg/ml at 24 h). Mean concentrations in AMs and plasma at 12 h were 45.0 microg/ml and 22.9 microg/ml (mean AM/plasma ratio, 1.93), respectively, and at 24 h were 42.0 microg/ml and 7.28 microg/ml (mean AM/plasma ratio, 6.67), respectively. Over the entire dosing interval, telavancin was present in ELF and AMs at concentrations up to 8-fold and 85-fold, respectively, above its MIC 90 for methicillin-resistant Staphylococcus aureus (0.5 microg/ml). Pulmonary surfactant did not affect telavancin's in vitro antibacterial activity. Telavancin was well tolerated. These results support the proposal for further clinical evaluation of telavancin for treating gram-positive respiratory infections.     

Comparative activity of the new lipoglycopeptide telavancin in the presence and absence of serum against 50 glycopeptide non-susceptible staphylococci and three vancomycin-resistant Staphylococcus aureus

BACKGROUND: Telavancin, a new multifunctional lipoglycopeptide antibiotic, exhibits broad-spectrum Gram-positive activity against a variety of pathogens. We examined the effects of human serum and antimicrobial concentrations on the activity of telavancin against glycopeptide-intermediate staphylococcal species (GISS), heteroresistant GISS (hGISS) and three vancomycin-resistant Staphylococcus aureus (VRSA) compared with vancomycin, quinupristin/dalfopristin, linezolid and daptomycin. METHODS: MIC and MBCs were performed against all antimicrobials. Time-kill experiments were performed using two strains of GISS (Mu50; NJ992) and VRSA (VRSAMI; VRSAPA) at 1, 2, 4, 8, 16 and 32x MIC. Telavancin and daptomycin were evaluated in the presence and absence of serum. RESULTS: All GISS and hGISS were susceptible to the tested agents with telavancin and quinupristin/dalfopristin demonstrating the lowest MIC, followed by daptomycin, linezolid and vancomycin. Against VRSA, daptomycin and quinupristin/dalfopristin had the lowest MIC, followed by linezolid, telavancin and vancomycin. In the presence of serum, telavancin and daptomycin MICs increased 1- to 4-fold. Concentration-dependent activity was demonstrated by telavancin and daptomycin, in the presence and absence of serum. Telavancin and daptomycin were bactericidal against GISS and performed similarly in the presence of serum. Quinupristin/dalfopristin demonstrated bactericidal activity at clinically achievable concentrations, whereas linezolid was bacteriostatic. CONCLUSIONS: Telavancin demonstrated concentration-dependent bactericidal activity against GISS, hGISS and VRSA at concentrations equal to or above 4x MIC, which corresponds to therapeutic levels against GISS and clinically achieved concentrations against the VRSA. Similar to daptomycin, telavancin activity was diminished in the presence of serum but bactericidal activity was maintained. Further investigation with telavancin against GISS, hGISS and VRSA is warranted.     

Pharmacodynamics of telavancin (TD-6424), a novel bactericidal agent, against gram-positive bacteria

Telavancin (TD-6424) is a novel lipoglycopeptide that produces rapid and concentration-dependent killing of clinically relevant gram-positive organisms in vitro. The present studies evaluated the in vivo pharmacodynamics of telavancin in the mouse neutropenic thigh (MNT) and mouse subcutaneous infection (MSI) animal models. Pharmacokinetic-pharmacodynamic studies in the MNT model demonstrated that the 24-h area under the concentration-time curve (AUC)/MIC ratio was the best predictor of efficacy. Telavancin produced dose-dependent reduction of thigh titers of several organisms, including methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA), penicillin-susceptible and -resistant strains of Streptococcus pneumoniae, and vancomycin-resistant Enterococcus faecalis. The 50% effective dose (ED50) estimates for telavancin ranged from 0.5 to 6.6 mg/kg of body weight (administered intravenously), and titers were reduced by up to 3 log10 CFU/g from pretreatment values. Against MRSA ATCC 33591, telavancin was 4- and 30-fold more potent (on an ED50 basis) than vancomycin and linezolid, respectively. Against MSSA ATCC 13709, telavancin was 16- and 40-fold more potent than vancomycin and nafcillin, respectively. Telavancin, vancomycin, and linezolid were all efficacious and more potent against MRSA ATCC 33591 in the MSI model compared to the MNT model. This deviation in potency was, however, disproportionately greater for vancomycin and linezolid than for telavancin, suggesting that activity of telavancin is less affected by the immune status. The findings of these studies collectively suggest that once-daily dosing of telavancin may provide an effective approach for the treatment of clinically relevant infections with gram-positive organisms.     

Effects of the oral,direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays

Summary. Introduction: Rivaroxaban is an oral direct factor Xa inhibitor developed for prophylaxis and treatment of thromboembolic disorders. Laboratory monitoring is not necessary but the dose‐dependent effects on common reagents and assay procedures are largely unknown. Objectives: To investigate the effect of rivaroxaban on commonly used coagulation assays. Materials and Methods: Rivaroxaban was added to plasma from healthy subjects in the concentration range 0–1000 μg L^?1 and analyzed using different reagents for activated partial thromboplastin time (APTT), prothrombin time (PT), antithrombin, fibrinogen and activated protein C (APC) resistance assays. Results: At an expected peak concentration of rivaroxaban in clinical use, the APTTs were almost invariably prolonged but at lower concentrations the effect was weak. The concentration needed to double the APTT varied between 389 ± 106 and 617 ± 149 μg L^?1 for different reagents. The PT assays showed a marked degree of difference. In general, the Quick PT type assays were more sensitive compared with the Owren type PT assays. The results from antithrombin assays were dependent on the type of reagent, with the Xa‐based assay being sensitive for rivaroxaban with an estimated increase of 0.09 IU mL^?1 per 100 μg L^?1 rivaroxaban. There were only minor effects on fibrinogen assays based on thrombin reagents. The APTT‐based assay for APC resistance is affected in a dose‐dependent manner whereas an assay based on the activation of coagulation at the prothrombinase level was unaffected. Conclusions: Different assays, and even different reagents within an assay group, display variable effects by therapeutic concentrations of rivaroxaban.     

In Vitro Pharmacodynamics of Human Simulated Exposures of Telavancin against Methicillin-Susceptible and -Resistant Staphylococcus aureus with and without Prior Vancomycin Exposure

Telavancin is a lipoglycopeptide with potent activity against methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-susceptible S. aureus (MSSA). The activity of telavancin against MRSA and MSSA after prior vancomycin exposure was studied in an in vitro pharmacodynamic model. Two clinical MRSA and two MSSA isolates, all with vancomycin MICs of 2 μg/ml, were subjected to humanized free drug exposures of vancomycin at 1 g every 12 h (q12h) for 96 h, telavancin at 750 mg q24h for 96 h, and vancomycin at 1 g q12h for 72 h followed by telavancin at 750 mg q24h for 48 h (120 h total). The microbiological responses were measured by changes from 0 h in log₁₀ CFU/ml at the end of experiments and area under the bacterial killing and regrowth curves over 96 h (AUBC₀₋₉₆). The control isolates grew to 8.8 ± 0.3 log₁₀ CFU/ml. Initially, all regimens caused −4.5 ± 0.9 reductions in log₁₀ CFU/ml by 48 h followed by slight regrowth over the following 48 to 72 h. After 96 h, vancomycin and telavancin achieved −3.7 ± 0.9 and −3.8 ± 0.8 log₁₀ CFU/ml changes from baseline, respectively (P = 0.74). Sequential exposure to telavancin after vancomycin did not result in additional CFU reductions or increases, with ultimate log₁₀ CFU/ml reductions of −4.3 ± 1.1 at 96 h and −4.2 ± 1.3 at 120 h (P > 0.05 for all comparisons at 96 h). The AUBC_0–96 was significantly smaller for the regimen of telavancin for 96 h than for the regimens of vancomycin for 96 h and vancomycin followed by telavancin (P ≤ 0.04). No resistance was observed throughout the experiment. Against these MRSA and MSSA isolates with vancomycin MICs of 2 μg/ml, telavancin was comparable with vancomycin and its activity was unaffected by prior vancomycin exposure.     

Therapeutic drug monitoring of tobramycin: once-daily versus twice-daily dosage schedules

Objective: To evaluate the effect of dosage regimen (once-daily vs. twice-daily) of tobramicyn on steady-state serum concentrations and toxicity. Materials and methods: Patients undergoing treatment with iv tobramycin (4 mg/kg/day) were randomised to two groups. Group OD ( n=22) received a once-daily dose of tobramycin and group TD (n=21) received the same dose divided into two doses daily. Tobramycin serum concentrations (peak and trough) were measured by enzyme multiplied immunoassay. The renal and auditorory functions of the patients were monitored before, during and immediately after treatment. Results: The two groups were comparable with respect to sex, age, body weight and renal function. No statistically significant differences were found in mean daily dose, duration of treatment, or cumulative dose. Trough concentrations were < 2 μg/ml in the two groups (100%). Peak concentrations were > 6 μg/ml in 100% of the OD group and in 67% of the TD group ( P< 0·01). Mean peak concentrations were markedly different: 11·00±2·89 μg/ml in OD vs. 6·53±1·45 μg/ml in TD ( P< 0·01). The pharmacokinetics parameters were: K_e, (0·15±0·03/h in OD vs. 0·24±0·06/h in TD), t_1/2, (4·95±1·41 h in OD vs. 3·07±0·71 h in TD), V_d (0·35±0·11 l/kg in OD vs. 0·33±0·09 l/kg in TD), Cl (0·86±0·29 ml/min/kg in OD vs. 1·28±0·33 ml/min/kg in TD). Increased serum creatinine was observed in 73% of patients in OD versus 57% of patients in TD, without evidence of nephrotoxicity. In TD group, three patients developed decreased auditory function, of which one presented with an auditory loss of –30 dB, whereas in the OD group only one patient presented decreased auditory function. Conclusion: This small study suggests that a once-daily dosing regimen of tobramycin is at least as effective as and is no more and possibly less toxic than the twice-daily regimen. Using a single-dose therapy, peak concentration determination is not necessary, only trough samples should be monitored to ensure levels below 2 μg/ml.