In vitro activities of ME1036 (CP5609), a novel parenteral carbapenem, against methicillin-resistant staphylococci

ME1036, formerly CP5609, is a novel parenteral carbapenem with a 7-acylated imidazo[5,1-b]thiazole-2-yl group directly attached to the carbapenem moiety of the C-2 position. The present study evaluated the in vitro activities of ME1036 against clinical isolates of gram-positive and gram-negative bacteria. ME1036 displayed broad activity against aerobic gram-positive and gram-negative bacteria. Unlike other marketed beta-lactam antibiotics, ME1036 maintained excellent activity against multiple-drug-resistant gram-positive bacteria, such as methicillin-resistant staphylococci and penicillin-resistant Streptococcus pneumoniae (PRSP). The MICs of this compound at which 90% of isolates were inhibited were 2 microg/ml for methicillin-resistant Staphylococcus aureus (MRSA), 2 microg/ml for methicillin-resistant coagulase-negative staphylococci, and 0.031 microg/ml for PRSP. In time-kill studies with six strains of MRSA, ME1036 at four times the MIC caused a time-dependent decrease in the numbers of viable MRSA cells. The activity of ME1036 against MRSA is related to its high affinity for penicillin-binding protein 2a, for which the 50% inhibitory concentration of ME1036 was approximately 300-fold lower than that of imipenem. In conclusion, ME1036 demonstrated a broad antibacterial spectrum and high levels of activity in vitro against staphylococci, including beta-lactam-resistant strains.     

Serum bactericidal activities of high-dose daptomycin with and without coadministration of gentamicin against isolates of Staphylococcus aureus and Enterococcus species

The purpose of this experiment was to evaluate the pharmacokinetics and serum bactericidal titers (SBTs) of daptomycin alone and in combination with gentamicin against strains of Staphylococcus aureus and enterococci to determine if there might be any benefit to the addition of the aminoglycoside. A multiple-dose, randomized crossover study was performed in 11 healthy volunteers to evaluate the steady-state pharmacokinetic profile of 6 mg/kg of body weight daptomycin once daily with or without 1 mg/kg gentamicin every 8 h. SBTs were determined against clinical isolates of nosocomial (MRSA 494) and community-acquired (CA-MRSA 44) methicillin-resistant S. aureus, vancomycin-susceptible Enterococcus faecalis (VSEF 49452), vancomycin-resistant Enterococcus faecium (VREF 80), and quality control strains of methicillin-susceptible S. aureus (ATCC 29213) and vancomycin-susceptible E. faecalis (ATCC 29212). Enhancement of bactericidal activity was evaluated by calculating and comparing the areas under the bactericidal curve (AUBC) for each dosing regimen against each isolate. The area under the concentration-time curve from 0 to 24 h and clearance for daptomycin alone were 645 +/- 91 microg.h/ml and 9.47 +/- 1.4 mg/h/kg, respectively, compared with 642 +/- 69 microg.h/ml and 9.45 +/- 1.0 mg/h/kg for daptomycin plus gentamicin. Daptomycin alone displayed sustained bactericidal activity against five of the six isolates over the entire 24-h dosing interval; bactericidal activity was maintained for 8 h against VREF 80. Mean AUBCs for daptomycin alone ranged from 935 to 1,263 and 36 to 238 against staphylococcal and enterococcal isolates, respectively, compared with 902 to 972 and 34 to 213 against staphylococci and enterococci when coadministered with gentamicin. The results of this study suggest that the addition of gentamicin does not alter the pharmacokinetic profile or enhance the bactericidal activity of daptomycin against staphylococcal or enterococcal isolates.     

Influence of protein binding under controlled conditions on the bactericidal activity of daptomycin in an in vitro pharmacodynamic model

OBJECTIVE: Daptomycin exhibits bactericidal activity against clinically significant Gram-positive bacteria despite being highly bound to human proteins. Evaluations characterizing the effect of protein on daptomycin pharmacodynamics are warranted. METHODS: We utilized an in vitro pharmacodynamic model to simulate daptomycin regimens of 6 mg/kg/day under controlled conditions of pH, calcium and/or protein. Free concentrations were simulated in broth, whereas total concentrations were simulated in broth supplemented with human albumin. Bacterial density was profiled over 48 h for two methicillin-resistant Staphylococcus aureus (MRSA) and two vancomycin-resistant Enterococcus faecium (VREF) clinical isolates. RESULTS: Daptomycin exhibited bactericidal activity against both MRSA isolates, with time to 99.9% killing occurring at 0.5 h and 8 h in broth and in albumin-supplemented broth, respectively. Initial kill was observed against both VREF isolates followed by regrowth. There was no statistical difference (P>0.05) in extent of bacterial kill at 24 or 48 h between the different media. CONCLUSIONS: Although delayed, the extent of kill for daptomycin was unaltered against all isolates in albumin-supplemented broth. Further antimicrobial studies that incorporate protein are warranted to assess the influence of protein in the pharmacodynamic evaluation of antimicrobials.     

Daptomycin is effective in treatment of experimental endocarditis due to methicillin-resistant and glycopeptide-intermediate Staphylococcus aureus

Daptomycin is a lipopeptide antibiotic with potent in vitro activity against gram-positive cocci, including Staphylococcus aureus. This study evaluated the in vitro and in vivo efficacies of daptomycin against two clinical isolates: methicillin-resistant S. aureus (MRSA) 277 (vancomycin MIC, 2 microg/ml) and glycopeptide-intermediate S. aureus (GISA) ATCC 700788 (vancomycin MIC, 8 microg/ml). Time-kill experiments demonstrated that daptomycin was bactericidal in vitro against these two strains. The in vivo activity of daptomycin (6 mg/kg of body weight every 24 h) was evaluated by using a rabbit model of infective endocarditis and was compared with the activities of a high-dose (HD) vancomycin regimen (1 g intravenously every 6 h), the recommended dose (RD) of vancomycin regimen (1 g intravenously every 12 h) for 48 h, and no treatment (as a control). Daptomycin was significantly more effective than the vancomycin RD in reducing the density of bacteria in the vegetations for the MRSA strains (0 [interquartile range, 0 to 1.5] versus 2 [interquartile range, 0 to 5.6] log CFU/g vegetation; P = 0.02) and GISA strains (2 [interquartile range, 0 to 2] versus 6.6 [interquartile range, 2.0 to 6.9] log CFU/g vegetation; P < 0.01) studied. In addition, daptomycin sterilized more MRSA vegetations than the vancomycin RD (13/18 [72%] versus 7/20 [35%]; P = 0.02) and sterilized more GISA vegetations than either vancomycin regimen (12/19 [63%] versus 4/20 [20%]; P < 0.01). No statistically significant difference between the vancomycin HD and the vancomycin RD for MRSA treatment was noted. These results support the use of daptomycin for the treatment of aortic valve endocarditis caused by GISA and MRSA.     

In vitro and in vivo antibacterial activities of CS-023 (RO4908463), a novel parenteral carbapenem

CS-023 (RO4908463, formerly R-115685) is a novel 1beta-methylcarbapenem with 5-substituted pyrrolidin-3-ylthio groups, including an amidine moiety at the C-2 position. Its antibacterial activity was tested against 1,214 clinical isolates of 32 species and was compared with those of imipenem, meropenem, ceftazidime, ceftriaxone, ampicillin, amikacin, and levofloxacin. CS-023 exhibited a broad spectrum of activity against gram-positive and -negative aerobes and anaerobes, including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis, penicillin-resistant Streptococcus pneumoniae (PRSP), beta-lactamase-negative ampicillin-resistant Haemophilus influenzae, and Pseudomonas aeruginosa. CS-023 showed the most potent activity among the compounds tested against P. aeruginosa and MRSA, with MICs at which 90% of isolates tested were inhibited of 4 microg/ml and 8 microg/ml, respectively. CS-023 was stable against hydrolysis by the beta-lactamases from Enterobacter cloacae and Proteus vulgaris. CS-023 also showed potent activity against extended-spectrum beta-lactamase-producing Escherichia coli. The in vivo efficacy of CS-023 was evaluated with a murine systemic infection model induced by 13 strains of gram-positive and -negative pathogens and a lung infection model induced by 2 strains of PRSP (serotypes 6 and 19). Against the systemic infections with PRSP, MRSA, and P. aeruginosa and the lung infections, the efficacy of CS-023 was comparable to those of imipenem/cilastatin and vancomycin (tested against lung infections only) and superior to those of meropenem, ceftriaxone, and ceftazidime (tested against P. aeruginosa infections only). These results suggest that CS-023 has potential for the treatment of nosocomial bacterial infections by gram-positive and -negative pathogens, including MRSA and P. aeruginosa.     

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.     

Bactericidal activities of two daptomycin regimens against clinical strains of glycopeptide intermediate-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and methicillin-resistant Staphylococcus aureus isolates in an in vitro pharmacodynamic model with simulated endocardial vegetations

Daptomycin is an investigational lipopeptide antibiotic active against gram-positive organisms. The mechanism of action is unique, resulting in interference with cell membrane transport. The bactericidal activity of daptomycin was evaluated against glycopeptide-intermediate susceptible Staphylococcus aureus (GISA), vancomycin-resistant Enterococcus faecium (VREF), and methicillin-resistant S. aureus (MRSA) in an in vitro infection model with simulated endocardial vegetations. Simulated regimens of daptomycin at 6 mg/kg/day (D6) and 10 mg/kg/day (D10) were utilized. MICs and MBCs for daptomycin were determined in the absence and in the presence of albumin with the following results (MIC/MBC): for GISA-992, 0.5/1.0 and 16/16; for VREF-590, 2.0/2.0 and 32/32; and for MRSA-494, 0.25/0.25 and 1.0/4.0 microg/ml, respectively. During the first 8 h daptomycin significantly reduced the inoculum for all organisms. Daptomycin at 6 mg/kg/day and 10 mg/kg/day had log(10) CFU/g reductions of 5 and 6, 3.4 and 5, and 6.4 and 6.5 by 8 h for GISA-992, VREF-590, and MRSA-494, respectively. Against both GISA-992 and VREF-590, the D10 regimen achieved the limit of detection at 72 h, with D6 regimens showing slight regrowth. A concentration-dependent killing effect was noted to occur, with daptomycin demonstrating a more rapid and greater kill from the D10 versus the D6 regimen. The results of this study suggest that daptomycin demonstrates significant (P < 0.05) activity against gram-positive organisms in a simulated sequestered infection site.     

In vitro activity of ceftobiprole, daptomycin, linezolid, and vancomycin against methicillin-resistant staphylococci associated with endocarditis and bone and joint infection

We tested the in vitro activity of 4 antimicrobial agents against methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci recovered from patients with endocarditis or bone and joint infection. Ceftobiprole, daptomycin, linezolid, and vancomycin MIC(90) values were 1, 1, 2, and 1 microg/mL, respectively. Ceftobiprole, daptomycin, linezolid, and vancomycin MBC(90) values were 2, 4, > or = 128, and 8 microg/mL, respectively. Ceftobiprole MIC and MBC values were < or = 2 microg/mL for all isolates tested, with the exception of one methicillin-resistant coagulase-negative Staphylococcus spp isolate. Vancomycin lacked bactericidal activity (defined as an MBC/MIC ratio of > or = 32) against 2 methicillin-resistant Staphylococcus aureus (MRSA) isolates from patients with bone and joint infection; one of these isolates was additionally daptomycin nonsusceptible (daptomycin MIC, 2 microg/mL). There was one additional daptomycin nonsusceptible (daptomycin MIC, 2 microg/mL) isolate (MRSA associated with bone and joint infection). Ceftobiprole demonstrated in vitro bactericidal activity against all MRSA and methicillin-resistant coagulase-negative staphylococci tested.     

Daptomycin dose-effect relationship against resistant gram-positive organisms

Daptomycin exhibits in vitro bactericidal activity against clinically significant gram-positive bacteria. We employed pharmacodynamic modeling to determine a once-daily dosing regimen of daptomycin that correlates to pharmacodynamic endpoints for different resistant gram-positive clinical strains. An in vitro pharmacodynamic model with an initial inoculum of 6 log(10) CFU/ml was used to simulate daptomycin regimens ranging in dose from 0 to 9 mg/kg of body weight/day, with corresponding exposures reflecting free-daptomycin concentrations in serum. Bacterial density was profiled over 48 h for two methicillin-resistant Staphylococcus aureus (MRSA-67 and -R515), two glycopeptide intermediate-resistant S. aureus (GISA-992 and -147398), and two vancomycin-resistant Enterococcus faecium (VREF-12366 and -SF12047) strains. A sigmoid dose-response model was used to estimate the effective dose required to achieve 50% (ED(50)) and 80% (ED(80)) bacterial density reduction at 48 h. Daptomycin MICs for study isolates ranged from 0.125 to 4 micro g/ml. Model fitting resulted in an r(2) of >0.80 for all tested isolates. Control growths at 48 h ranged from 7.3 to 8.5 log(10) CFU/ml. Sigmoid relationships were not superimposable between categorical resistant species: ED(50) and ED(80) values were 1.9 and 3.1, 4.2 and 5.6, and 5.4 and 6.8 mg/kg for MRSA, GISA, and VREF isolates, respectively. Doses required to achieve ED(50) and ED(80) values correlated with MIC differences between tested organisms. Corresponding area under the concentration-time curve from 0 to 24 h/MIC exposure ratios demonstrated a wide range of ED(80) values among the tested isolates. Doses ranging between 3 and 7 mg/kg produced significant bactericidal activity (ED(80)) against these multidrug-resistant S. aureus and E. faecium isolates.     

In vitro and in vivo activities of tigecycline (GAR-936), daptomycin,and comparative antimicrobial agents against glycopeptide-intermediate Staphylococcus aureus and other resistant gram-positive pathogens

Tigecycline (GAR-936) and daptomycin are potent antibacterial compounds in advanced stages of clinical trials. These novel agents target multiply resistant pathogenic bacteria. Daptomycin is principally active against gram-positive bacteria, while tigecycline has broad-spectrum activity. When tested by the standard protocols of the National Committee for Clinical Laboratory Standards in Mueller-Hinton broth II, tigecycline was more active than daptomycin (MICs at which 90% of isolates tested are inhibited, 0.12 to 1 and 0.5 to 16 microg/ml, respectively) against staphylococcal, enterococcal, and streptococcal pathogens. Daptomycin demonstrated a stepwise increase in activity corresponding to an increase in the supplemental concentration of calcium. When tested in base Mueller-Hinton broth supplemented with 50 mg of calcium per liter, daptomycin demonstrated improved activity (MIC(90)s, 0.015 to 4 microg/ml). The activity of daptomycin, however, equaled that of tigecycline against the glycopeptide-intermediate Staphylococcus aureus (GISA) strains only when the test medium was supplemented with excess calcium (75 mg/liter). Tigecycline and daptomycin demonstrated in vivo efficacies against GISA, methicillin-resistant S. aureus, and methicillin-susceptible S. aureus strains in an intraperitoneal systemic murine infection model. These data suggest that tigecycline and daptomycin may offer therapeutic options against clinically relevant resistant pathogens for which current alternatives for treatment are limited.     

Synergy of daptomycin with oxacillin and other beta-lactams against methicillin-resistant Staphylococcus aureus

We previously observed marked synergy between daptomycin and both rifampin and ampicillin against vancomycin-resistant enterococci (VRE). Because the synergy between daptomycin and ampicillin was observed for 100% of VRE strains with high-level ampicillin resistance (ampicillin MIC of > or =128 microg/ml), we looked for synergy between daptomycin and other beta-lactams against 18 strains of methicillin-resistant Staphylococcus aureus (MRSA) by employing a time-kill method using Mueller-Hinton broth supplemented to 50 mg of Ca2+/liter. All strains were resistant to oxacillin (16 of 18 strains were resistant at drug concentrations of > or =256 microg/ml), and all strains were susceptible to daptomycin (the MIC at which 90% of the tested isolates were inhibited was 1 microg/ml). Daptomycin was tested at concentrations of 2, 1, 0.5, 0.25, 0.125, and 0.0625 microg/ml alone or in combination with oxacillin at a fixed concentration of 32 microg/ml. Synergy was found for all 18 strains with daptomycin at one-half the MIC in combination with 32 microg of oxacillin/ml, and synergy was found for 11 of 18 strains (61%) with daptomycin at one-fourth the MIC or less in combination with oxacillin. At 24 h, the daptomycin-oxacillin combination with daptomycin at one-half the MIC showed bactericidal activity against all 18 strains, and the combination with one-fourth the daptomycin MIC showed bactericidal activity against 9 of 18 strains. We also used a novel screening method to look for synergy between daptomycin and other beta-lactams. In this approach, daptomycin was incorporated into Ca(2+)-supplemented Mueller-Hinton agar at subinhibitory concentrations, and synergy was screened by comparing test antibiotic Kirby-Bauer disks on agar with and without daptomycin. By this method, daptomycin with ampicillin-sulbactam, ticarcillin-clavulanate, or piperacillin-tazobactam showed synergy comparable to or greater than daptomycin with oxacillin. For seven of the eight strains tested, time-kill studies confirmed synergy between daptomycin and ampicillin-sulbactam with ampicillin in the range of 2 to 8 microg/ml. The combination of daptomycin and beta-lactams may be useful for the treatment of MRSA infection, but further studies are needed to elucidate the mechanisms and to determine the in vivo efficacy of the combination.     

In vitro activities of dalbavancin and 12 other agents against 329 aerobic and anaerobic gram-positive isolates recovered from diabetic foot infections

Tests of dalbavancin's in vitro activity against 209 aerobic and 120 anaerobic isolates from pretreatment diabetic foot infections showed an MIC(90) of < or =0.125 microg/ml against methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), and 120 anaerobes (Clostridium perfringens, other clostridia, Peptoniphilus asaccharolyticus, Finegoldia magna, and Anaerococcus prevotii), compared to respective MIC(90)s for MSSA and MRSA of 0.5 and 1 microg/ml for vancomycin, 4 and 4 microg/ml for linezolid, 0.5 and 0.5 microg/ml for daptomycin, and 0.25 and >8 microg/ml for clindamycin.     

In vitro activity of S-3578, a new broad-spectrum cephalosporin active against methicillin-resistant staphylococci

The in vitro antibacterial activity of S-3578, a new parenteral cephalosporin, against clinical isolates was evaluated. The MICs of the drug at which 90% of the isolates were inhibited were 4 micro g/ml for methicillin-resistant Staphylococcus aureus (MRSA) and 2 micro g/ml for methicillin-resistant Staphylococcus epidermidis, which were fourfold higher than and equal to those of vancomycin, respectively. The anti-MRSA activity of S-3578 was considered to be due to its high affinity for penicillin-binding protein 2a (50% inhibitory concentration, 4.5 micro g/ml). In time-kill studies with 10 strains each of MRSA and methicillin-susceptible S. aureus, S-3578 caused more than a 4-log(10) decrease of viable cells on the average at twice the MIC after 24 h of exposure, indicating that it had potent bactericidal activity. Furthermore, in population analysis of MRSA strains with heterogeneous or homogeneous resistance to imipenem, no colonies emerged from about 10(9) cells on agar plates containing twice the MIC of S-3578, suggesting the low frequency of emergence of S-3578-resistant strains from MRSA. S-3578 was also highly active against penicillin-resistant Streptococcus pneumoniae (PRSP), with a MIC(90) of 1 micro g/ml, which was comparable to that of ceftriaxone. S-3578 also had antibacterial activity against a variety of gram-negative bacteria including Pseudomonas aeruginosa, though its activity was not superior to that of cefepime. In conclusion, S-3578 exhibited a broad antibacterial spectrum and, particularly, had excellent activity against gram-positive bacteria including methicillin-resistant staphylococci and PRSP. Thus, S-3578 was considered to be worthy of further evaluation.     

The in vitro activity of daptomycin against Staphylococcus aureus and Enterococcus species

OBJECTIVE: The purpose of this study was to examine the in vitro activity of daptomycin using an optimal calcium (Ca2+) concentration (50 mg/L) against a diverse collection of enterococcal and Staphylococcus aureus clinical isolates, including glycopeptide-resistant enterococci (GRE) and methicillin-resistant S. aureus (MRSA). METHODS: The activity of daptomycin was compared with the activities of seven other agents against 1483 enterococcal and S. aureus clinical isolates, including 303 GRE and 193 methicillin-resistant S. aureus (MRSA) strains. Susceptibility testing was performed by the NCCLS broth microdilution method, with one exception: Mueller-Hinton (MH) broth was supplemented to a physiological level of 50 mg/L Ca2+ when testing daptomycin. Daptomycin zone diameters were determined by disc diffusion with MH agar plates containing Ca2+ 50 mg/L. RESULTS: All staphylococcal isolates tested, and the majority of enterococcal isolates (96.5%), would be considered susceptible to daptomycin if the breakpoint previously proposed of or = 20 mm, and all of the enterococcal isolates had daptomycin zone diameters > or = 17 mm. CONCLUSIONS: Overall, daptomycin showed potent activity against S. aureus and enterococcal isolates, comparable to quinupristin-dalfopristin and linezolid.     

Efficacy of vancomycin and daptomycin against Staphylococcus aureus isolates collected over 29 years

We investigated vancomycin and daptomycin efficacy for Staphylococcus aureus isolates at our institution by testing 221 methicillin-sensitive and 299 methicillin-resistant isolates recovered from serious infections between 1979 and 2007 using a microdilution method. The MIC₉₀'s for vancomycin remained constant at 2 μg/mL for methicillin-resistant S. aureus (MRSA) and methicillin-sensitive S. aureus (MSSA). For MSSA, the geometric mean vancomycin MICs remained at 1.1 μg/mL but varied from 1.1 to 1.7 for MRSA. Tolerance to vancomycin was seen in 6.5% of MRSA and 10.5% of MSSA. Daptomycin MIC₉₀'s remained at ≤1 μg/mL, and the daptomycin concentration at which 90% of the strains were killed (MBC₉₀) remained at 2 μg/ml. Over 29 years, no trend was detected in vancomycin or daptomycin susceptibilities. Daptomycin had excellent inhibitory and bactericidal activities against all strains throughout the years. Although vancomycin's inhibitory activity was consistent over time, vancomycin-tolerant strains whose presence was not predicted by their MIC were found.     

In vitro activity of daptomycin against methicillin-resistant Staphylococcus aureus, including heterogeneously glycopeptide-resistant strains

The purpose of the present study was to assess the in vitro activity of daptomycin against a well-defined collection of methicillin-resistant Staphylococcus aureus (MRSA) isolates (n = 98), including heterogeneously glycopeptide-resistant MRSA (hGISA) strains. Susceptibility testing was performed by using the Etest system. Daptomycin was potent against both glycopeptide-susceptible and hGISA strains.     

In vitro activities of daptomycin,vancomycin, quinupristin- dalfopristin,linezolid, and five other antimicrobials against 307 gram-positive anaerobic and 31 Corynebacterium clinical isolates

The activities of daptomycin, a cyclic lipopeptide, and eight other agents were determined against 338 strains of gram-positive anaerobic bacteria and corynebacteria by the NCCLS reference agar dilution method with supplemented brucella agar for the anaerobes and Mueller-Hinton agar for the corynebacteria. The daptomycin MICs determined on Ca(2+)-supplemented (50 mg/liter) brucella agar plates were one- to fourfold lower than those determined in unsupplemented media. Daptomycin was highly active (MICs, 8 microg/ml were inhibited by <1 microg of daptomycin per ml. Daptomycin MICs were >or=4 microg/ml for most strains of Clostridium clostridioforme, Clostridium paraputrificum, Clostridium tertium, and Clostridium ramosum; the isolates were generally more resistant to other antimicrobials. Daptomycin was two- to fourfold less active against Actinomyces spp. than vancomycin, quinupristin-dalfopristin, or linezolid. Twenty-nine of 31 strains of Corynebacterium spp., including Corynebacterium jeikeium, Corynebacterium amycolatum, and Corynebacterium pseudodiphtheriticum, were inhibited by 相似文献   

In vitro activity of daptomycin against Staphylococcus aureus and vancomycin-resistant Enterococcus faecium isolates associated with skin and soft tissue infections: first results from India

The in vitro activity of daptomycin and selected comparator agents against Staphylococcus aureus and vancomycin-resistant Enterococcus faecium (VREF) isolates recovered from hospitalized patients with skin and soft tissue infection's was evaluated by Clinical and Laboratory Standards Institute broth microdilution method. Daptomycin was the most active agent against both S. aureus (MIC₉₀, 1 μg/mL; 100% susceptible) and VREF (MIC₉₀, 4 μg/mL; 100% susceptible), making it an excellent therapeutic option.     

Antimicrobial susceptibility of daptomycin and comparator agents tested against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci: trend analysis of a 6-year period in US medical centers (2005-2010)

We evaluated daptomycin activity trends against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE; MIC, ≥8 μg/mL) in a 6-year period (2005–2010) following US regulatory release for clinical use. Consecutive, unique patient strains of clinical significance were collected in 32 US medical centers and susceptibility tested in a central laboratory against daptomycin and various comparator agents by reference broth microdilution methods. A total of 22 858 S. aureus (12 181 [53.3%] MRSA), 4312 Enterococcus faecalis (195 [4.5%] VRE), and 2462 Enterococcus faecium (1867 [75.8%] VRE) were evaluated. Daptomycin susceptibility rates were 99.94%, 99.98%, and 99.68% for S. aureus, E. faecalis, and E. faecium, respectively. Among MRSA (daptomycin MIC_50/90, 0.25/0.5 μg/mL), only 13 (0.11%) daptomycin-non-susceptible (MIC, ≥2 μg/mL) isolates were observed with no MIC creep over the study interval. Daptomycin was very active against vancomycin-resistant E. faecalis (MIC_50/90, 1/2 μg/mL) and E. faecium (MIC_50/90, 2/2 μg/mL). Among VRE, only 4 daptomycin-non-susceptible isolates (all E. faecium) were detected. In conclusion, daptomycin demonstrated sustained activity against an extensive collection of clinical isolates of MRSA and VRE from numerous US medical centers over the last 6 monitored years.     

In Vitro Activity of Cephalosporin RWJ-54428 (MC-02479) against Multidrug-Resistant Gram-Positive Cocci

RWJ-54428 (MC-02479) is a novel cephalosporin that binds to penicillin-binding protein (PBP) PBP 2' (PBP 2a) of methicillin-resistant staphylococci. Its in vitro activity was assessed against 472 gram-positive cocci, largely selected as epidemiologically unrelated isolates with multidrug resistance. The MIC at which 50% of isolates are inhibited (MIC(50)) and MIC(90) of RWJ-54428 for methicillin-resistant Staphylococcus aureus (MRSA) were 1 and 2 microg/ml, respectively, whereas they were 0.5 and 0.5 microg/ml, respectively, for methicillin-susceptible S. aureus. The MIC(50) and MIC(90) were 1 and 4 microg/ml, respectively, for methicillin-resistant coagulase-negative staphylococci (MRCoNS), whereas they were 0.25 and 1 microg/ml, respectively, for methicillin-susceptible isolates. The highest MICs for MRSA and MRCoNS isolates were 2 and 4 microg/ml, respectively. The MIC(50) and MIC(90) of RWJ-54428 for Enterococcus faecalis were 0.5 and 1 microg/ml, respectively, but they were 4 and 8 microg/ml, respectively, for Enterococcus faecium. For penicillin-susceptible, -intermediate, and -resistant pneumococci, the MIC(90)s of RWJ-54428 were 0.03, 0.25, and 0.5 microg/ml, respectively, with the highest MIC for a pneumococcus being 1 microg/ml, recorded for a strain for which penicillin and cefotaxime MICs were 8 and 4 microg/ml. MICs for Lancefield group A, B, C, and G streptococci were < or =0.008 microg/ml; those for viridans group streptococci, including isolates not susceptible to penicillin, were from 0.015 to 0.5 microg/ml. RWJ-54428 did not select resistant mutants of MRSA or enterococci in challenge experiments and has the potential to be useful for the treatment of infections caused by gram-positive cocci.