Activity Of Linezolid Research Articles

A1.10 Urinary bactericidal activity of linezolid against gram-positive cocci in comparison with other oral antibiotics

A1.10 Urinary bactericidal activity of linezolid against gram-positive cocci in comparison with other oral antibiotics

In Vitro and In Vivo Synergistic Activities of Linezolid Combined with Subinhibitory Concentrations of Imipenem against Methicillin-Resistant Staphylococcus aureus

Indifference or moderate antagonism of linezolid combined with other antibiotics in vitro and in vivo have mainly been reported in the literature. We have assessed the in vitro activities of linezolid, alone or in combination with imipenem, against methicillin-resistant Staphylococcus aureus (MRSA) strains using the dynamic checkerboard and time-kill curve methods. Linezolid and low concentrations of imipenem had a synergistic effect, leading us to evaluate the in vivo antibacterial activity of the combination using the rabbit endocarditis experimental model. Two MRSA strains were used for in vivo experiments: one was a heterogeneous glycopeptide-intermediate clinical S. aureus strain isolated from blood cultures, and the other was the S. aureus COL reference strain. Animals infected with one of two MRSA strains were randomly assigned to one of the following treatments: no treatment (controls), linezolid (simulating a dose in humans of 10 mg/kg of body weight every 12 h), a constant intravenous infusion of imipenem (which allowed the steady-state concentration of about 1/32 the MIC of imipenem for each strain to be reached in serum), or the combination of both treatments. Linezolid and imipenem as monotherapies exhibited no bactericidal activity against either strain. The combination of linezolid plus imipenem showed in vivo bactericidal activity that corresponded to a decrease of at least 4.5 log CFU/g of vegetation compared to the counts for the controls. In conclusion, the combination exhibited synergistic and bactericidal activities against two MRSA strains after 5 days of treatment. The combination of linezolid plus imipenem appears to be promising for the treatment of severe MRSA infections and merits further investigations to explore the mechanism underlying the synergy between the two drugs.

Linezolid disposition after standard dosages in critically ill patients undergoing continuous venovenous hemofiltration: A report of 2 cases

Linezolid is a new oxazolidinone antibiotic active against most Gram-positive microorganisms the renal elimination of which accounts for about 30% to 35% of all the clearance. Its pharmacokinetic ability was assessed during continuous venovenous hemofiltration (CVVH) in 2 anuric patients with severe postsurgical intraabdominal infections who were receiving standard dosages (600 mg intravenously twice a day). Blood samples for quantification of linezolid in plasma and in filtrate were collected after more than 4 days of therapy before dosing and at 0, 0.5, 1, 2, 3, 5, 7, 9, and 11 hours after the morning 1-hour intravenous infusion, and concentrations were determined by means of high-performance liquid chromatography. Linezolid was partially cleared by CVVH in both the patients (hemofiltration clearance [CL CVVH ] = 0.38 and 0.35 mL/min/kg), with high sieving coefficient values (0.76 to 0.92). Efficacious plasma exposure for time-dependent antibacterial activity of linezolid, either in terms of trough levels above minimum inhibitory concentration (MIC) at which 90% of the isolates are inhibited (Cmin >MIC90 ) or of area under the plasma concentration time curve to MIC90 ratio (AUC/MIC90 ) >100 hours, was ensured during CVVH in both patients. However, despite similar CL CVVH , significant interindividual pharmacokinetic variability was found in the 2 patients (AUC during the observational period [AUC 0-tau ] 334.71 versus 109.34 mg/L x h), mainly owing to substantial differences in non-CVVH-related clearance of linezolid (total CL, 0.55 versus 1.21 mL/min/kg). Our findings indicate that linezolid, although partially removed, does not warrant dosage modification during the first 48 hours when CVVH (with polysulfide hemofilter) at standard 2,000 mL/h substitution flow rate in predilution is applied to anuric patients. Thereafter, this choice is a reasonable one with the exception of those patients who have other features of linezolid toxicity and in which non-CVVH-related clearance might be impaired, although further evaluations are warranted.

Impact of High-InoculumStaphylococcus aureuson 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.

Comparative In Vitro Activities of Linezolid, Telithromycin, Clarithromycin, Levofloxacin, Moxifloxacin, and Four Conventional Antimycobacterial Drugs against Mycobacterium kansasii

Mycobacterium kansasii is one of the most pathogenic and frequent nontuberculous mycobacteria isolated from humans. Patients with adverse drug reactions, resistant isolates, or suboptimal response require alternative treatment regimens. One hundred forty-eight consecutive clinical isolates of M. kansasii were tested for antimicrobial susceptibilities by the BACTEC 460 system (NCCLS) with two different inoculation protocols, one conventional and one alternative. In the alternative protocol, the inoculum 12B vial was incubated until the growth index was between 250 and 500. Four conventional antimycobacterial drugs (isoniazid, rifampin, streptomycin, and ethambutol) were studied with standard critical concentrations. The in vitro activities of linezolid, telithromycin, clarithromycin, levofloxacin, and moxifloxacin were determined by measuring radiometric MICs. All isolates tested were identified as M. kansasii genotype I and were resistant to isoniazid at a concentration of 0.4 mug/ml. One hundred twenty isolates (81.1%) were inhibited by 1 microg of isoniazid per ml. A high level of resistance to isoniazid (>10 microg/ml) was observed in six isolates (4.1%). Only five strains (3.4%) were resistant to rifampin (>1 microg/ml). All isolates studied were susceptible to streptomycin and ethambutol. The MICs at which 90% of the isolates were inhibited (in micrograms per milliliter) were as follows: linezolid, 1 (range, < or =0.25 to 2); telithromycin, >16 (range, 4 to >16); clarithromycin, 0.5 (range, < or =0.03 to 1); levofloxacin, 0.12 (range, 0.12 to 0.25); and moxifloxacin, 0.06 (range, < or =0.06 to 0.12). The susceptibility testing results with both inoculation protocols showed perfect correlation. In conclusion, all M. kansasii isolates showed decreased susceptibility to isoniazid, but resistance to rifampin was infrequent. Quinolones, especially moxifloxacin, were the most active antimicrobial agents tested, followed by clarithromycin. Linezolid also showed good activity against these microorganisms, but telithromycin's in vitro activity was poor.

Action of Fluoroquinolones and Linezolid on Logarithmic- and Stationary-Phase Culture of Mycobacterium tuberculosis

Background: The new challenges involved in the chemotherapy of tuberculosis make it necessary to find novel drugs, especially ones that are useful in the latent phase of the disease. Methods: We evaluated the activity of linezolid and fluoroquinolones against logarithmic- and stationary-phase Mycobacterium tuberculosis. Results: We observed that linezolid exhibits antibacterial action, although slowly, in both situations. Quinolones with an 8-methoxy group exhibit greater activity than levofloxacin in logarithmic growth phases, whereas levofloxacin exhibits greater activity in stationary-phase growth. Conclusion: The study of the activity of drugs against the M. tuberculosis microorganism in the latent phase is one of the most important tools available in the fight against the tuberculosis epidemic, and both linezolid and the new fluoroquinolones appear to be promising drugs.

Activity of OPT-80, a Novel Macrocycle, Compared with Those of Eight Other Agents against Selected Anaerobic Species

Agar dilution MIC was used to compare activities of OPT-80, linezolid, vancomycin, teicoplanin, quinupristin/dalfopristin, amoxicillin/clavulanate, imipenem, clindamycin, and metronidazole against 350 gram-positive and -negative anaerobes. OPT-80 was active against gram-positive strains only, especially Clostridium spp. (85 strains tested, including 21 strains of C. difficile), with MICs ranging between </=0.016 and 0.25 microg/ml.

In vivo efficacy of linezolid in combination with gentamicin for the treatment of experimental endocarditis due to methicillin-resistant Staphylococcus aureus

Indifference or even antagonism has mainly been reported with combinations including linezolid. The presence of in vitro antagonism is not always correlated with in vivo failure. The purpose of this study was to evaluate the in vivo activity of linezolid combined with gentamicin using a methicillin-resistant Staphylococcus aureus (MRSA) endocarditis experimental model. A human-like pharmacokinetic simulation was used for linezolid and gentamicin to improve the extrapolation of the results to human therapy. Contrary to the antagonism previously described in vitro, linezolid combined with gentamicin exhibited bactericidal activity on the two strains with a decrease of at least 4 log 10 cfu/g of vegetation compared with controls. These data suggest that linezolid plus gentamicin could be an appropriate combination for the treatment of severe MRSA infections.

New drugs for Gram-positive uropathogens

Complicated urinary tract infections (UTIs) are frequent nosocomial infections. The bacterial spectrum encompasses Gram-negative but also Gram-positive pathogens in up to 30–40%. The existing treatment for Gram-positive pathogens is not always optimal. Antimicrobials for the treatment of Gram-positive uropathogens comprise older agents, such as aminopenicillins with or without β-lactamase inhibitors and vancomycin, as well as newer fluoroquinolones, such as levofloxacin or gatifloxacin. However, resistant bacteria such as vancomycin-resistant enterococci (VRE) or methicillin-resistant Staphylococcus aureus (MRSA) (except vancomycin-resistant) are generally also not susceptible to the fluoroquinolones. Therefore new agents need to be assessed in the treatment of UTI. Daptomycin and linezolid are new antimicrobial agents with good efficacy against Gram-positive uropathogens as shown by their minimal inhibitory concentrations. In a phase II study the urinary bactericidal activity of linezolid versus ciprofloxacin in volunteers showed comparable activity of both drugs against fluoroquinolone susceptible Gram-positive uropathogens, whereas linezolid was also as active against fluoroquinolone resistant ones. The pharmacokinetics and the mode of action of these two antibiotics are discussed together with some clinical data in the context of therapeutic use in patients with complicated UTIs.

Activity of linezolid against Gram-positive cocci isolated in French hospitals as determined by three in-vitro susceptibility testing methods

In total, 844 strains of Gram-positive cocci were collected from six university hospitals in France between September 1999 and January 2000. MICs of linezolid were determined: (i) for all strains by agar dilution (method A); (ii) by broth microdilution (method B) for staphylococci and enterococci; (iii) by Etest (method E) for beta-haemolytic streptococci and Streptococcus pneumoniae. Susceptibility to other antibiotics was determined by the disk diffusion method. MIC50 and MIC90 values were identical (2 mg/L) for methicillin-susceptible Staphylococcus aureus (n = 179) by methods A and B. Linezolid was active against methicillin-resistant S. aureus (n = 117), with an MIC90 of 2 mg/L (methods A and B), but with a lower MIC50 of 1 mg/L by method A. Of the 200 coagulase-negative staphylococci, 56.5% were methicillin-resistant and 43.5% were methicillin-susceptible. Linezolid had similar in-vitro activity by methods A and B (MIC50 and MIC90 values of 1-2 mg/L), irrespective of methicillin susceptibility. The MIC90 of linezolid for all enterococci (150 Enterococcus faecalis and 50 Enterococcus faecium) was 2 mg/L by both methods. MICs of linezolid for beta-haemolytic streptococci had a narrow range of 0.5-2 mg/L (method A) and 0.125-2 mg/L (method E). Pneumococci (n = 118), including 67 penicillin G-intermediate and -resistant strains, were all inhibited by linezolid 2 mg/L (MIC90 of 2 mg/L by methods A and E). No strain had an MIC of > 2 mg/L by agar dilution or Etest, or of > 4 mg/L by broth microdilution. Overall, the study confirmed the good in-vitro activity of linezolid and the very narrow range of MICs for Gram-positive cocci susceptible or resistant to other antibiotics, irrespective of the method used.

In vitro activities of Daptomycin, Linezolid, and Quinupristin-Dalfopristin against a challenge panel of Staphylococci and Enterococci, including vancomycin-intermediate staphylococcus aureus and vancomycin-resistant Enterococcus faecium.

We assessed the in vitro activities of daptomycin, linezolid, and quinupristin-dalfopristin (QD) against a contemporary challenge panel of 88 staphylococcal and 90 enterococcal isolates. The staphylococci selected included vancomycin-intermediate Staphylococcus aureus (VISA), methicillin-resistant S. aureus, and coagulasenegative staphylococci. Enterococcal isolates included vancomycin-resistant Enterococcus faecium (VREF) containing either vanA, vanB1, or vanD. The MICs of daptomycin, linezolid, and QD were determined using commercial broth microdilution panels. All three VISA isolates were susceptible to daptomycin, linezolid, and QD. QD was the most active agent against staphylococcal isolates (MIC50 < or = 0.5 microg/ml and MIC90 = 1 microg/ml), including those with decreased susceptibility to vancomycin. QD was also the most active agent against VREF (MIC90 < or = 0.5 microg/ml). No differences were seen for susceptibility of vanA, vanB1, and vanD VREF strains for daptomycin, linezolid, or QD. Daptomycin was the most effective against E. faecalis. On the basis of manufacturer-suggested interpretive criteria, 92% of isolates were susceptible (MIC90 = 4 microg/ml). All isolates tested were susceptible to at least one antimicrobial agent for which interpretive criteria have been defined. Population analysis of three S. aureus isolates for which the daptomycin MICs were 8 microg/ml showed a pattern of homogeneous resistance.

Bactericidal activities of daptomycin, quinupristin-dalfopristin, and linezolid against vancomycin-resistant Staphylococcus aureus in an in vitro pharmacodynamic model with simulated endocardial vegetations.

In search of treatment alternatives against vancomycin-resistant S. aureus (VRSA), an in vitro pharmacodynamic model with simulated endocardial vegetations incorporating protein and a high inoculum was used to simulate daptomycin, linezolid, quinupristin-dalfopristin, and vancomycin against the Michigan VRSA strain. Daptomycin and quinupristin-dalfopristin exhibited the greatest bacterial reductions, and all tested agents except vancomycin exhibited bactericidal activity against the VRSA.

In vitro activity of newer antibiotics against Corynebacterium jeikeium, Corynebacterium amycolatum and Corynebacteriumurealyticum

The in vitro activity of ciprofloxacin, erythromycin, telithromycin, teicoplanin, linezolid and quinupristin–dalfopristin was tested against human derived pathogenic corynebacteria. The MICs of these antibiotics were measured using the agar dilution method against 31 strains of Corynebacterium jeikeium, 58 Corynebacterium amycolatum (including 33 multidrug-resistant strains) and 64 Corynebacterium urealyticum clinical strains. A high resistance rate to ciprofloxacin and erythromycin was found in the three species. Telithromycin was much more active than erythromycin (MIC 90 of erythromycin ≥128 mg/l for all three species; MIC 90 of telithromycin: 4 mg/l for C. jeikeium, 64 mg/l for C. amycolatum and 1 mg/l for C. urealyticum). There were no teicoplanin-resistant (MIC 90 1, 0.5 and 1 mg/l, respectively) or linezolid-resistant strains (MIC 90 1, 0.2 and 0.5 mg/l, respectively). Quinupristin–dalfopristin was active against most strains with an activity similar to linezolid, but three C. jeikeium and one C. amycolatum showed MICs ≥4 mg/l. Telithromycin showed much better activity against corynebacteria than older macrolides. Synercid and linezolid were active against most isolates tested, including multidrug resistant strains.

Influence of ethylene-Oxy spacer group on the activity of linezolid: Synthesis of potent antibacterials possessing a thiocarbonyl group

The influence of an ethylene-oxy spacer element between the heterocycle and the aromatic ring in linezolid is reported. The introduction of such spacer group generated compounds with inferior antibacterial activity. However, the conversion of the acetamide group present in the linezolid analogues to either thiocarbamate or thioacetamide functionality restored the activity. The synthesis of linezolid analogues possessing the ethylene-oxy spacer group along with SAR studies with different heterocycles and preparation of some thiocarbonyl compounds possessing potent antibacterial property are presented.

In vitro activities of linezolid combined with other antimicrobial agents against Staphylococci, Enterococci, Pneumococci, and selected gram-negative organisms.

The activities of linezolid, an oxazolidinone antibacterial agent active against gram-positive organisms, alone and in combination with 35 antimicrobial agents were tested in vitro against methicillin-sensitive (n = 1 to 2 strains) and methicillin-resistant (n = 8 to 10) Staphylococcus aureus strains; vancomycin-sensitive (n = 6) and vancomycin-resistant (n = 6 to 8) Enterococcus faecalis strains; vancomycin-sensitive (n = 5) and vancomycin-resistant (n = 6) Enterococcus faecium strains; penicillin-sensitive (n = 2 to 5), penicillin-intermediate (n = 5 to 6), and penicillin-resistant (n = 5 to 6) Streptococcus pneumoniae strains; Escherichia coli (n = 6); and Klebsiella pneumoniae (n = 6). The fractional inhibitory concentration indices of linezolid in combination with other antimicrobial agents for the organisms tested were generated on checkerboard broth microdilution plates prepared by a semiautomated method. Of 1,380 organism-drug combinations, 1,369 (99.2%) combinations of linezolid with 28 antimicrobial drugs were indifferent, 9 combinations (0.65%) of linezolid with 6 drugs (amoxicillin, erythromycin, imipenem, sparfloxacin, teicoplanin, and tetracycline) were synergistic, and 2 combinations (0.15%) of linezolid with 2 drugs (ofloxacin and sparfloxacin) were antagonistic. Overall, the in vitro data demonstrated that linezolid combined with other antimicrobial agents primarily produces an indifferent response, with infrequent occurrences of synergism and antagonism.

Worldwide assessment of linezolid's clinical safety and tolerability: comparator-controlled phase III studies.

Linezolid, an oxazolidinone antibiotic, has 100% oral bioavailability and favorable activities against gram-positive pathogens including multidrug-resistant staphylococci, enterococci, and pneumococci. Safety assessments were conducted for 2,046 linezolid-treated patients and 2,001 comparator drug-treated patients from seven controlled clinical trials comparing the activities of linezolid and comparator drugs against nosocomial and community-acquired pneumonia, skin and skin structure infections, and methicillin-resistant staphylococcal infections. Drug-related adverse events were primarily transient. The most frequent (> or = 2%) adverse events caused by linezolid and the comparator drugs were diarrhea (4.3 and 3.2%, respectively; P = 0.074), nausea (3.4 and 2.3%, respectively; P = 0.036), and headache (2.2 and 1.3%, respectively; P = 0.047). Treatment discontinuations due to drug-related events (2.4 and 1.9%, respectively), serious adverse events (11.4 and 10.6%, respectively), and deaths (4.8 and 4.9%, respectively) were similar. No clinically significant drug-related hematologic events were reported, and laboratory safety data were comparable. In the first 6 months of postmarketing surveillance, hematologic abnormalities were reported in 0.1% of linezolid-treated patients, but no irreversible blood dyscrasias were documented. The risk for transient, reversible hematologic effects from treatment with linezolid should be considered together with the clinical benefits associated with its use.

In vitro activity of linezolid against slowly growing nontuberculous Mycobacteria.

MICs of linezolid in broth microdilutions were tested against 341 slowly growing nontuberculous mycobacteria (NTM) belonging to 15 species. The proposed linezolid susceptibility MICs for all Mycobacterium marinum, Mycobacterium szulgai, Mycobacterium kansasii, Mycobacterium malmoense, and Mycobacterium xenopi isolates and for 90% of Mycobacterium gordonae and Mycobacterium triplex isolates were </=8 micro g/ml. Linezolid has excellent therapeutic potential against most species of NTM.

Activity of linezolid against anaerobic bacteria

Minimal inhibition concentrations (MICs) were determined for linezolid (LZD) and compared with those of reference antibiotics against 265 anaerobes. For the Bacteroides fragilis group, MIC range for LZD was 2–4 mg/l. Strains resistant to the other antibiotics were detected including one strain of B. fragilis showing high level resistance to metronidazole (64 mg/l). LZD MIC 50 was 4 mg/l for prevotella and 1 mg/l for fusobacteria. LZD MICs were <1 mg/l for porphyromonas and veillonellae and ≤4 mg/l for all Gram-positive anaerobes. For all anaerobes, resistance rates were 1, 2.4, 9.8 and 17% for imipenem, amoxycillin–clavulanic acid, metronidazole and clindamycin, respectively. As no strains resistant to LZD were detected, this antibiotic seems a promising candidate to treat infections caused by anaerobes.

In vitro activity of linezolid alone and in combination with gentamicin, vancomycin or rifampicin against methicillin-resistant Staphylococcus aureus by time-kill curve methods.

The in vitro activity of the oxazolidinone linezolid was studied alone and in combination with three antibiotics acting on different cellular targets. Oxazolidinones are bacterial protein synthesis inhibitors that act at a very early stage by preventing the formation of the initiation complex. Combinations of linezolid with gentamicin, vancomycin or rifampicin were evaluated against four methicillin-resistant Staphylococcus aureus strains, using killing curves in conjunction with scanning electron microscopy. Time-kill curves were performed over 24 h using an inoculum of 5 x 10(6)- 1 x 10(7) cfu/mL. Linezolid was studied at concentrations of 1 x, 4 x and 8 x MIC, with partner drugs at 8 x MIC. Addition of linezolid resulted in a decrease of antibacterial activity for gentamicin and vancomycin, and linezolid was antagonistic to the early bactericidal activity of gentamicin. Linezolid, in combination with rifampicin, showed an additive interaction for susceptible strains and inhibited rifampicin-resistant variants. Linezolid plus rifampicin appeared to be the most active combination against methicillin-resistant S. aureus strains in time-kill experiments.

Activity of daptomycin against susceptible and multidrug-resistant Gram-positive pathogens collected in the SECURE study (Europe) during 2000-2001.

Antibiotic resistance was prevalent in Gram-positive pathogens collected from 40 sites in 15 European countries during 2000-2001. Among Staphylococcus aureus, 27.3% of all isolates submitted were resistant to oxacillin and ranged from 0% of isolates from the Netherlands to 36.9% of isolates from Portugal. The overall prevalence of vancomycin-resistant Enterococcus faecium was 25.1%, with Italy submitting the largest percentage of resistant isolates (60.6%). For Streptococcus pneumoniae, 9.4% of all isolates collected were resistant to penicillin with variation by country from 0% in the Netherlands to 20.7% in Portugal. Multidrug resistance (MDR), defined as concurrent resistance to three or more antimicrobials of different chemical classes, was observed in 24.6% of S. aureus, 19.6% of E. faecium and 3.6% of S. pneumoniae. The directed spectrum agents daptomycin, linezolid and quinupristin-dalfopristin were active in vitro against all isolates regardless of their resistance to other agents. Daptomycin and quinupristin-dalfopristin (MIC(90)s 0.5 mg/L) were equally active against oxacillin-resistant S. aureus compared with linezolid (MIC(90) 2 mg/L). The activities of daptomycin, quinupristin-dalfopristin and linezolid were not affected by resistance to vancomycin in E. faecium (MIC(90)s of 4, 2 and 2 mg/L, respectively). Daptomycin was more active against penicillin-resistant S. pneumoniae (MIC(90) 0.25 mg/L) than was quinupristin-dalfopristin (MIC(90) 0.5 mg/L) or linezolid (MIC(90) 2 mg/L). Daptomycin was highly active against clinically important Gram-positive pathogens, including those that were multiply resistant to currently available agents. The results of this study provide a benchmark of the activity of daptomycin against contemporary European isolates and will serve as a baseline to monitor future changes in the susceptibility of these organisms to daptomycin.