Pharmacodynamics of telavancin studied in an in vitro pharmacokinetic model of infection

The antibacterial effects of telavancin, vancomycin, and teicoplanin against six Staphylococcus aureus strains (1 methicillin-susceptible S. aureus [MSSA] strain, 4 methicillin-resistant S. aureus [MRSA] strains, and 1 vancomycin-intermediate S. aureus [VISA] strain) and three Enterococcus sp. strains (1 Enterococcus faecalis strain, 1 Enterococcus faecium strain, and 1 vancomycin-resistant E. faecium [VREF] strain) were compared using an in vitro pharmacokinetic model of infection. Analyzing the data from all five vancomycin-susceptible S. aureus (VSSA) strains or all 4 MRSA strains showed that telavancin was superior in its antibacterial effect as measured by the area under the bacterial kill curve at 24 h (AUBKC(24)) and 48 h (AUBKC(48)) in comparison to vancomycin or teicoplanin (P < 0.05). Telavancin was also superior to vancomycin and teicoplanin in terms of its greater early killing effect (P < 0.05). Against the three Enterococcus spp. tested, telavancin was superior to vancomycin in terms of its AUBKC(24), AUBKC(48), and greater early bactericidal effect (P < 0.05). Dose-ranging studies were performed to provide free-drug area under the concentration-time curve over 24 h in the steady state divided by the MIC (fAUC/MIC) exposures from 0 to 1,617 (7 to 14 exposures per strain) for 5 VSSA, 4 VISA, and the 3 Enterococcus strains. The fAUC/MIC values for a 24-h bacteriostatic effect and a 1-log-unit drop in the viable count were 43.1 ± 38.4 and 50.0 ± 39.0 for VSSA, 3.2 ± 1.3 and 4.3 ± 1.3 for VISA, and 15.1 ± 8.8 and 40.1 ± 29.4 for the Enterococcus spp., respectively. The reason for the paradoxically low fAUC/MIC values for VISA strains is unknown. There was emergence of resistance to telavancin in the dose-ranging studies, as indicated by subpopulations able to grow on plates containing 2× MIC telavancin concentrations compared to the preexposure population analysis profiles. Changes in population analysis profiles were less likely with enterococci than with S. aureus, and the greatest risk of changed profiles occurred for both species at fAUC/MIC ratios of 1 to 10. Maintaining a fAUC/MIC ratio of >50 reduced the risk of subpopulations able to grow on antibiotic-containing media emerging. These data help explain the clinical effectiveness of telavancin against MRSA and indicate that telavancin may have clinically useful activity against Enterococcus spp., and perhaps also VISA, at human doses of 10 mg/kg of body weight/day. In addition, they support a clinical breakpoint of sensitive at ≤1 mg/liter for both S. aureus and Enterococcus spp.     

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.     

Impact of high-inoculum Staphylococcus aureus on the activities of nafcillin, vancomycin, linezolid, and daptomycin, alone and in combination with gentamicin, in an in vitro pharmacodynamic model

We evaluated the impact of high (9.5 log10 CFU/g) and moderate (5.5 log10 CFU/g) inocula of methicillin-susceptible and -resistant Staphylococcus aureus (MSSA and MRSA, respectively) on the activities of nafcillin, linezolid, vancomycin, and daptomycin, alone and in combination with gentamicin in an in vitro pharmacodynamic model with simulated endocardial vegetations over 72 h. Human therapeutic dosing regimens for nafcillin, daptomycin, vancomycin, linezolid, and gentamicin were simulated. At a moderate inoculum, nafcillin (MSSA only), vancomycin, and daptomycin demonstrated equivalent and significant (P < 0.01) bactericidal (99.9% kill) activities (decreases of 3.34 +/- 1.1, 3.28 +/- 0.4, and 3.34 +/- 0.8 log10 CFU/g, respectively). Bactericidal activity was demonstrated at 4 h for nafcillin and daptomycin and at 32 h for vancomycin. Linezolid demonstrated bacteriostatic activity over the course of the study period. At a high inoculum, daptomycin exhibited bactericidal activity against both MSSA and MRSA by 24 h (decrease of 5.51 to 6.31 +/- 0.10 log10 CFU/g). Nafcillin (versus MSSA), vancomycin, and linezolid (MSSA and MRSA) did not achieve bactericidal activity throughout the 72-h experiment. The addition of gentamicin increased the rate of 99.9% kill to 8 h for daptomycin (P < 0.01) and 48 h for nafcillin (MSSA only) (P = 0.01). The addition of gentamicin did not improve the activity of vancomycin or linezolid for either isolate for the 72-h period. Overall, high-inoculum Staphylococcus aureus had a significant impact on the activities of nafcillin and vancomycin. In contrast, daptomycin was affected minimally and linezolid was not affected by inoculum.     

In vitro activities of LTX-109, a synthetic antimicrobial peptide, against methicillin-resistant, vancomycin-intermediate, vancomycin-resistant, daptomycin-nonsusceptible, and linezolid-nonsusceptible Staphylococcus aureus

LTX-109 and eight other antimicrobial agents were evaluated against 155 methicillin-resistant Staphylococcus aureus (MRSA) isolates, including strains resistant to vancomycin and strains with decreased susceptibility to daptomycin and linezolid, by microdilution tests to determine MICs. Time-kill assays were performed against representative MRSA, vancomycin-intermediate S. aureus (VISA), and vancomycin-resistant S. aureus (VRSA) isolates. LTX-109 demonstrated a MIC range of 2 to 4 μg/ml and dose-dependent rapid bactericidal activity against S. aureus. This activity was not influenced by resistance to other antistaphylococcal agents.     

Pharmacodynamics of TD-1792, a novel glycopeptide-cephalosporin heterodimer antibiotic used against Gram-positive bacteria, in a neutropenic murine thigh model

TD-1792 is a novel glycopeptide-cephalosporin heterodimer investigational antibiotic that displays potent bactericidal effects against clinically relevant Gram-positive organisms in vitro. The present studies evaluated the in vivo pharmacokinetics (PK) and pharmacodynamics (PD) of TD-1792 in the neutropenic murine thigh infection animal model. TD-1792, dosed subcutaneously (SC), produced dose-dependent reduction in the thigh bacterial burden of several organisms, including methicillin-susceptible and -resistant strains of Staphylococcus aureus and Staphylococcus epidermidis (MSSA, MRSA, MSSE, MRSE, respectively), penicillin-susceptible strains of Streptococcus pneumoniae (PSSP), Streptococcus pyogenes, and vancomycin-intermediate-susceptible Staphylococcus aureus (VISA). In single-dose efficacy studies, the 1-log(10) CFU kill effective dose (ED(1-log kill)) estimates for TD-1792 ranged from 0.049 to 2.55 mg/kg of body weight administered SC, and the bacterial burden was reduced by up to 3 log(10) CFU/g from pretreatment values. Against S. aureus ATCC 33591 (MRSA), the total 24-h log(10) stasis dose (ED(stasis)) and ED(1-logkill) doses for TD-1792 were 0.53 and 1.11 mg/kg/24 h, respectively, compared to 23.4 and 54.6 mg/kg/24 h for vancomycin, indicating that TD-1762 is 44- to 49-fold more potent than vancomycin. PK-PD analysis of data from single-dose and dose-fractionation studies for MRSA (ATCC 33591) demonstrated that the total-drug 24-h area under the concentration-time curve-to-MIC ratio (AUC/MIC ratio) was the best predictor of efficacy (r(2) = 0.826) compared to total-drug maximum plasma concentration of drug-to-MIC ratio (Cmax/MIC ratio; r(2) = 0.715) and percent time that the total-drug plasma drug concentration remains above the MIC (%Time>MIC; r(2) = 0.749). The magnitudes of the total-drug AUC/MIC ratios associated with net bacterial stasis, a 1-log(10) CFU reduction from baseline and near maximal effect, were 21.1, 37.2, and 51.8, respectively. PK-PD targets based on such data represent useful inputs for analyses to support dose selection decisions for clinical studies of patients.     

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.     

In vitro activities of a novel cephalosporin, CB-181963 (CAB-175), against methicillin-susceptible or -resistant Staphylococcus aureus and glycopeptide-intermediate susceptible staphylococci

We examined the activity of CB-181963, a novel cephalosporin, against methicillin-resistant Staphylococcus aureus (MRSA) (n = 200), methicillin-susceptible S. aureus (MSSA) (n = 50), glycopeptide-intermediate Staphylococcus species (GISS) (n = 47), and VRSA (n = 2) isolates. CB-181963 exhibited MIC profiles similar to those of linezolid against MRSA and GISS; however, activity against MSSA was similar to that of vancomycin. Time-kill study results of investigations of activity against MRSA, MSSA, and GISS at 24 h were as follows: CB-181963 activity = vancomycin activity > linezolid activity (P < 0.001); CB-181963 = quinupristin-dalfopristin = vancomycin > linezolid (P < 0.05); CB-181963 > linezolid (P = 0.003); and CB-181963 = quinupristin-dalfopristin = vancomycin. CB-181963 may provide an alternative treatment for multidrug-resistant staphylococci.     

Antimicrobial activities of ceragenins against clinical isolates of resistant Staphylococcus aureus

The rise in the rates of glycopeptide resistance among Staphylococcus aureus isolates is concerning and underscores the need for the development of novel potent compounds. Ceragenins CSA-8 and CSA-13, cationic steroid molecules that mimic endogenous antimicrobial peptides, have previously been demonstrated to possess broad-spectrum activities against multidrug-resistant bacteria. We examined the activities of CSA-8 and CSA-13 against clinical isolates of vancomycin-intermediate S. aureus (VISA), heterogeneous vancomycin-intermediate S. aureus (hVISA), as well as vancomycin-resistant S. aureus (VRSA) and compared them to those of daptomycin, linezolid, and vancomycin by susceptibility testing and killing curve analysis. We also examined CSA-13 for its concentration-dependent activity, inoculum effect, postantibiotic effect (PAE), and synergy in combination with various antimicrobials. Overall, the MICs and minimal bactericidal concentrations of CSA-13 were fourfold lower than those of CSA-8. Time-kill curve analysis of the VRSA, VISA, and hVISA clinical isolates demonstrated concentration-dependent bactericidal killing. An inoculum effect was also observed when a higher starting bacterial density was used, with the time required to achieve 99.9% killing reaching 1 h with a 6-log10-CFU/ml starting inoculum, whereas it was>or=24 h with a 8- to 9-log10-CFU/ml starting inoculum with 10x the MIC (P相似文献   

Clinical relevance of hetero-VRSA in surgical infections

Vancomycin was used increasingly for treating methicillin-resistant Staphylococcus aureus(MRSA) infection. Recently MRSA strains which showed low-level resistance to vancomycin were isolated. Vancomycin-intermediate Staphylococcus aureus(VISA) show a vancomycin minimum inhibitory concentration(MIC) of 8 micrograms/ml. VISA appear to be rare. The vancomycin resistance phenotype is reported to be unstable in such isolates. To detect heterogeneously resistant VRSA(hetero-VRSA. MIC 1 to 4 micrograms/ml), we need to use population analysis and growth on Mu3 agar plate, because MIC cannot confirm hetero-VRSA. Hetero-VRSA is not so rare(about 0-47%). Hetero-VRSA may be responsible for failure of vancomycin therapy, but its mechanism remains unclear. Until it becomes better understood, the clinical relevance cannot be assessed.     

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.     

Comparative activity of cloxacillin and vancomycin against methicillin-susceptible Staphylococcus aureus experimental endocarditis

OBJECTIVES: To compare the activity of cloxacillin and vancomycin against methicillin-susceptible Staphylococcus aureus and to determine how rapidly their bactericidal activity occurs in cardiac vegetations. METHODS: In vitro and in vivo studies using an experimental model of endocarditis in rabbits. Animals were treated for 1, 2 or 3 days with cloxacillin 200 mg/kg intramuscularly three times a day or vancomycin 25 mg/kg intravenously twice a day. RESULTS: Cloxacillin and vancomycin at concentrations 4- and 16-fold the MIC produced a modest decrease in the number of microorganisms at 4 h. After 24 h, cloxacillin produced a decrease in the counts of staphylococci from 2.19 to 4.84 log10 cfu/mL of inoculum. Only concentrations of vancomycin from 16- to 32-fold the MIC resulted in equivalent decreases. After 24 h of treatment, both antibiotics were equally effective in preventing mortality of rabbits. Cloxacillin produced a greater decrease in the number of staphylococci than vancomycin (3.50+/-2.18 log10 cfu/g vegetation and 6.25+/-1.28 log10 cfu/g vegetation, respectively; P<0.05) and 41% of rabbits had sterile vegetations in comparison with none with vancomycin (P=0.035). After 48 and 72 h of treatment, both antimicrobials exhibited equivalent activity. CONCLUSIONS: Vancomycin was less rapidly bactericidal than cloxacillin in vivo.     

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.     

In vivo pharmacodynamics of torezolid phosphate (TR-701), a new oxazolidinone antibiotic, against methicillin-susceptible and methicillin-resistant Staphylococcus aureus strains in a mouse thigh infection model

Torezolid phosphate (TR-701) is the phosphate monoester prodrug of the oxazolidinone TR-700 which demonstrates potent in vitro activity against Gram-positive bacteria, including methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA). The pharmacodynamics of TR-701 or TR-700 (TR-701/700) against S. aureus is incompletely defined. Single-dose pharmacokinetic studies were conducted in mice for TR-701/700. Forty-eight-hour dose range and 24-hour dose fractionation studies were conducted in a neutropenic mouse thigh model of S. aureus infection using MRSA ATCC 33591 to identify the dose and schedule of administration of TR-701/700 that was linked with optimized antimicrobial effect. Additional dose range studies compared the efficacies of TR-701/700 and linezolid for one MSSA strain and one community-associated MRSA strain. In dose range studies, TR-701/700 was equally bactericidal against MSSA and MRSA. Mean doses of 37.6 and 66.9 mg/kg of body weight/day of TR-701/700 resulted in stasis and 1 log CFU/g decreases in bacterial densities, respectively, at 24 h, and mean doses of 35.3, 46.6, and 71.1 mg/kg/day resulted in stasis and 1 and 2 log CFU/g reductions, respectively, at 48 h. Linezolid administered at doses as high as 150 mg/kg/day did not achieve stasis at either time point. Dose fractionation studies demonstrated that the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) was the pharmacodynamic index for TR-701/700 that was linked with efficacy. TR-701/700 was highly active against MSSA and MRSA, in vivo, and was substantially more efficacious than linezolid, although linezolid's top exposure has half the human exposure. Dose fractionation studies showed that AUC/MIC was the pharmacodynamic index linked with efficacy, indicating that once-daily dosing in humans is feasible.     

In vitro activities of daptomycin, vancomycin, linezolid, and quinupristin-dalfopristin against Staphylococci and Enterococci, including vancomycin- intermediate and -resistant strains

The in vitro activity of daptomycin was compared with those of vancomycin, linezolid, and quinupristin-dalfopristin against a variety (n = 203) of gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and S. epidermidis (MRSA and MRSE, respectively), vancomycin-resistant enterococci (VRE), and vancomycin-intermediate S. aureus (VISA). Overall, daptomycin was more active against all organisms tested, except Enterococcus faecium and VISA, against which its activity was similar to that of quinupristin-dalfopristin. In time-kill studies with MRSA, MRSE, VRE, and VISA, daptomycin demonstrated greater bactericidal activity than all other drugs tested, killing > or =3 log CFU/ml by 8 h. Daptomycin may be a potential alternative drug therapy for multidrug-resistant gram-positive organisms and warrants further investigation.     

Comparative activity of garenoxacin and other agents by susceptibility and time-kill testing against Staphylococcus aureus, Streptococcus pyogenes and respiratory pathogens

OBJECTIVES: Garenoxacin is a novel des-F(6)quinolone that has shown excellent antimicrobial activity against a wide range of clinically important microorganisms. In this study, its activity was examined, in comparison with that of other antimicrobial agents, by susceptibility and time-kill testing against Staphylococcus aureus, Streptococcus pyogenes and respiratory pathogens. METHODS: Overall, 200 bacterial strains were tested. The antimicrobial activity of garenoxacin was compared with that of ciprofloxacin, levofloxacin, moxifloxacin, amoxicillin, co-amoxiclav, cefuroxime, cefotaxime, ceftriaxone, imipenem, erythromycin and clarithromycin. In addition, the bactericidal activity of garenoxacin, moxifloxacin, levofloxacin and ciprofloxacin was evaluated by time-kill analysis against four strains each of staphylococci [two methicillin-susceptible (MSSA) and two methicillin-resistant (MRSA)], pneumococci (two penicillin-susceptible and two penicillin-resistant) and Streptococcus pyogenes (two erythromycin-susceptible and two erythromycin-resistant). Antibiotics were tested at concentrations 1-8 x MIC. RESULTS: MIC90 values of garenoxacin for the MSSA and MRSA strains were 0.03 and 2 mg/L, respectively. Among all the quinolones tested, garenoxacin yielded the lowest MIC values against all pneumococci (MIC90 0.12 mg/L) irrespective of macrolide resistance; the rank order of activity was garenoxacin> moxifloxacin>levofloxacin>ciprofloxacin. Excellent activity was shown also against Haemophilus influenzae (MIC90 or= 3 log10 decrease in viable counts (cfu/mL) within 3 h at 4 x MIC, whereas a moderate, slower killing rate was observed versus streptococci. CONCLUSIONS: This investigational des-F(6)quinolone represents a promising alternative for the treatment of respiratory tract infections.     

Efficacy of human simulated exposures of ceftaroline administered at 600 milligrams every 12 hours against phenotypically diverse Staphylococcus aureus isolates

Ceftaroline exhibits bactericidal activity against Gram-positive pathogens, including methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus, as well as common Gram-negative pathogens. This study evaluated the efficacy of human simulated exposures of ceftaroline against S. aureus in both the neutropenic and immunocompetent mouse thigh infection models. Twenty-six S. aureus isolates (4 MSSA, 22 MRSA) with ceftaroline MICs ranging from 0.125 to 4 μg/ml were collected. All isolates were tested in the neutropenic model and a subset of 13 MRSA isolates were tested in the immunocompetent model. Two hours after inoculation, a ceftaroline regimen that simulated the percentage of the dosing interval that free-drug concentrations remained above the MIC of the infecting organism (fT>MIC) of humans administered ceftaroline at 600 mg every 12 h (q12h) infused over 1 h was given. The change in log(10) CFU/ml after 24 h of treatment was analyzed relative to the 0- and 24-h controls for neutropenic and immunocompetent mice, respectively. The human simulated regimen resulted in efficacy against all isolates tested in both infection models. In the neutropenic model, a 0.95 to 3.28 log(10) CFU/ml reduction was observed when compared with the 0-h control, whereas for the immunocompetent model, all isolates obtained a >1 log(10) CFU/ml reduction (log(10) CFU/ml reduction range: 1.06 to 2.43) in bacterial density. Irrespective of immune competency, a reduction in bacterial density was observed at the highest MIC of 4 μg/ml (fT>MIC of 27.5%). Human simulated exposures of ceftaroline 600 mg q12h provided predictable efficacy against all tested S. aureus isolates in the mouse thigh model independent of immune status. These data support the clinical utility of ceftaroline against S. aureus, including MRSA, with MICs of ≤4 μg/ml.     

In vitro activities of daptomycin-, vancomycin-, and teicoplanin-loaded polymethylmethacrylate against methicillin-susceptible, methicillin-resistant, and vancomycin-intermediate strains of Staphylococcus aureus

The objective of this study was to evaluate the antibacterial effects of polymethylmethacrylate (PMMA) bone cements loaded with daptomycin, vancomycin, and teicoplanin against methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-intermediate Staphylococcus aureus (VISA) strains. Standardized cement specimens made from 40 g PMMA loaded with 1 g (low-dose), 4 g (middle-dose) or 8 g (high-dose) antibiotics were tested for elution characteristics and antibacterial activities. The patterns of release of antibiotics from the cement specimens were evaluated using in vitro broth elution assay with high-performance liquid chromatography. The activities of broth elution fluid against different Staphylococcus aureus strains (MSSA, MRSA, and VISA) were then determined. The antibacterial activities of all the tested antibiotics were maintained after being mixed with PMMA. The cements loaded with higher dosages of antibiotics showed longer elution periods. Regardless of the antibiotic loading dose, the teicoplanin-loaded cements showed better elution efficacy and provided longer inhibitory periods against MSSA, MRSA, and VISA than cements loaded with the same dose of vancomycin or daptomycin. Regarding the choice of antibiotics for cement loading in the treatment of Staphylococcus aureus infection, teicoplanin was superior in terms of antibacterial effects.     

Activities of trovafloxacin and ampicillin-sulbactam alone or in combination versus three strains of vancomycin- intermediate Staphylococcus aureus in an in vitro pharmacodynamic infection model

The recent isolation of clinical strains of methicillin-resistant Staphylococcus aureus (MRSA) with intermediate susceptibility (MICs, 8 microg/ml) to vancomycin (vancomycin-intermediate S. aureus [VISA]) emphasizes the importance of developing novel antimicrobial regimens and/or agents for future treatment. We studied the activities of ampicillin-sulbactam and trovafloxacin alone or in combination against three unique strains of VISA in an in vitro infection model. Two VISA strains were trovafloxacin susceptible (MICs, < or =2 microg/ml); one VISA strain was trovafloxacin resistant (MIC, 4 microg/ml). Trovafloxacin was administered to simulate a dose of 200 or 400 mg every 24 h. Ampicillin-sulbactam was administered to simulate a dose of 3 g every 6 h. Samples were removed from the infection models over 48 h, and reductions in colony counts were compared between regimens. Trovafloxacin (200 mg) produced rapid killing of a control MRSA strain over the 48-h experiment but produced only slight killing of all three VISA strains. The higher dose of trovafloxacin improved killing but did not produce bactericidal activity at 48 h. Ampicillin-sulbactam produced rapid bactericidal activity against all four strains tested, and colony counts at 8 h were at the limits of detection. However, regrowth occurred by 48 h for each strain. The combination of ampicillin-sulbactam and trovafloxacin provided additive activity against two of the three VISA strains. In conclusion, trovafloxacin or ampicillin-sulbactam alone did not provide adequate activity against the VISA strains for the 48-h evaluation period, but the combination could help improve activity against some strains of VISA.     

In-vitro and in-vivo activity of cefpirome (HR 810) against methicillin-susceptible and -resistant Staphylococcus aureus and Streptococcus faecalis

With cefpirome (HR 810) the MICs for both methicillin-resistant Staphylococcus aureus (MRSA) and for Streptococcus faecalis were 8.0 mg/l. At 4 x MIC, cefpirome killed MRSA as rapidly as did vancomycin while for enterococci, cefpirome, vancomycin or ampicillin alone were not bactericidal. However, all agents were bactericidal when combined with 2 mg/l of gentamicin, although gentamicin combined with cefpirome showed a smaller decrease in cfu/ml than the combination with ampicillin or vancomycin. A mouse thigh infection model was developed in which the thigh muscle was infected with bacteria and either no therapy or concurrent antibiotic therapy was initiated. On the subsequent day, the entire thigh muscle was quantitatively cultured. In this model, the numbers of enterococci at the infection site at 24 h were reduced by 2.1 logs with no treatment, 2.6 with cefpirome (25 mg/kg/day), 2.8 with ampicillin (150 mg/kg/day), and 2.7 with vancomycin (25 mg/kg/day). For MRSA the reductions were 1.1 logs with no therapy, 2.8 with vancomycin, and 3.0 with cefpirome. The apparent enhanced in-vivo activity of cefpirome for MRSA argues for further evaluation of this antibiotic for treatment of MRSA and other Gram-positive cocci, including enterococci.     

Comparative efficacy of daptomycin, vancomycin, and cloxacillin for the treatment of Staphylococcus aureus endocarditis in rats and role of test conditions in this determination.

The in vivo efficacy of daptomycin, a new cell wall-active anti-gram-positive-bacterial agent, was compared to those of cloxacillin and vancomycin in a rat model of Staphylococcus aureus endocarditis. Both methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) strains were used. When therapy was initiated early (8 h) after infection, at the time when valvular bacterial counts were relatively low (approximately 10(6) CFU/g of vegetation), 3 days of therapy was found to be effective against the MSSA strains whatever the antibiotic regimen. In contrast, when the onset of therapy was delayed up to 15 h after infection, so that higher bacterial counts could develop on the valves (approximately 10(9) CFU/g of vegetation), a longer period of treatment (6 days) was required to cure infection. Under these conditions after 3 days of therapy, daptomycin was more effective than cloxacillin and vancomycin against the MSSA strains. Similarly, daptomycin showed a greater activity than vancomycin against the MRSA strain after 3 days of treatment, but after 6 days both antibiotics were equally effective. Decreasing doses of daptomycin showed decreasing activity: 10 mg/kg of body weight every 12 h (q12h) was better than 5 mg/kg q12h, whereas 5 mg/kg q24h (providing drug levels in blood detectable only during the first 12 h) failed to cure infection. In vitro, daptomycin was highly bactericidal at high concentrations (25 and 60 micrograms/ml, corresponding to peak levels in serum after doses of 5 and 10 mg/kg, respectively) and bacteriostatic at lower concentrations (0.5 to 2.5 micrograms/ml, corresponding to trough levels in serum). In conclusion, against low-bacterial-count S. aureus endocarditis, daptomycin showed an efficacy similar to those of vancomycin and cloxacillin. Against high-bacterial-count S. aureus endocarditis, daptomycin showed a higher bactericidal activity than cloxacillin (against the MSSA strains) and vancomycin (against both the MSSA and MRSA strains).