Daptomycin: first in a new class of antibiotics for complicated skin and soft-tissue infections

With increasing antibiotic resistance reported worldwide, there is an urgent need for novel treatments for infections caused by Gram-positive bacteria. Daptomycin is the first in a new class of antibiotic, the cyclic lipopeptides, with activity against a range of Gram-positive pathogens. US approval of daptomycin for the treatment of complicated skin and soft-tissue infections (cSSTIs) caused by Gram-positive bacteria was gained in 2003, with European approval granted in January 2006. Most Gram-positive clinical isolates tested have proved susceptible to daptomycin, including methicillin- and vancomycin-resistant strains. Daptomycin has a novel mode of action, is rapidly bactericidal in vitro and has a low potential for the development of resistance. Two pivotal phase III studies, in a total of 1092 patients with cSSTIs, demonstrated non-inferiority to currently used antibiotics and a comparable tolerability profile. The unique mode of action of daptomycin is described alongside studies demonstrating its potential in the treatment of cSSTIs and other infections caused by Gram-positive bacteria.     

Antimicrobial activity of daptomycin against multidrug-resistant Gram-positive strains collected worldwide

Daptomycin is a cyclic lipopeptide recently released for clinical use in the treatment of serious Gram-positive infections in hospitalized patients. We evaluated the in vitro activity of daptomycin tested against recently isolated multidrug-resistant Gram-positive clinical strains. A total of 386 isolates were selected from a large collection of strains from more than 70 centers located in Europe, North America, and South America. The strains were tested by reference broth microdilution methods in Mueller-Hinton broth with 50 mg/L Ca++ against daptomycin. Daptomycin was the most potent compound tested against penicillin-resistant Streptococcus pneumoniae with MIC50/90 values at < or =0.12 and 0.25 microg/mL, respectively. Daptomycin was also highly active against vancomycin-resistant enterococci and staphylococcal strains with various resistance patterns. Enterococcus faecium showed higher daptomycin MIC values (MIC90, 4 microg/mL) when compared to E. faecalis (MIC90, 1 microg/mL). In summary, resistance to vancomycin, teicoplanin, quinupristin/dalfopristin, or penicillin among the Gram-positive isolates did not adversely influence daptomycin activity. Daptomycin showed a significant potency and spectrum against Gram-positive species, including multidrug-resistant strains, and may represent a reasonable therapeutic option for infections caused by these important pathogens.     

Daptomycin: a lipopeptide antibiotic for the treatment of serious Gram-positive infections

Infections caused by drug-resistant pathogens are on the rise. Daptomycin, a cyclic lipopeptide with activity against most Gram-positive pathogens, including vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus, is a newly US-FDA approved antimicrobial for complicated skin and skin structure infections (cSSSI). Daptomycin has a unique mechanism of action that results in destruction of the membrane potential. The rapid bactericidal activity of daptomycin makes it an attractive antibiotic for serious Gram-positive infections.     

Antimicrobial activity of daptomycin tested against clinical strains of indicated species isolated in North American medical centers (2003)

Daptomycin is a cyclic lipopeptide approved for use by the US Food and Drug Administration (FDA) for the treatment of complicated skin and skin structure infections caused by Staphylococcus aureus, groups A and B beta-hemolytic streptococci, and vancomycin-susceptible Enterococcus faecalis. We evaluated the daptomycin spectrum against these pathogens by testing 2759 clinical strains consecutively collected in more than 30 hospitals located across the United States and Canada. The isolates were susceptibility tested against daptomycin and many comparators by the reference broth microdilution method. Daptomycin was very active against indicated species with the highest MIC results being 1, 2, and 0.5 microg/mL for S. aureus, E. faecalis, and beta-hemolytic streptococci, respectively. All isolates tested were considered susceptible to daptomycin, according to Clinical and Laboratory Standards Institute and FDA breakpoints, and daptomycin was the most potent (lowest MIC90) among selected antimicrobials commonly used to treat Gram-positive infections. Resistance to oxacillin or vancomycin did not influence daptomycin activity against S. aureus or E. faecalis.     

糖尿病足溃疡处常见病原菌分布与耐药性分析

目的探讨我院糖尿病足溃疡处常见病原菌分布及耐药情况。方法回顾性分析2003-2005年从糖尿病足溃疡处分泌物中分离的129株病原菌及其耐药情况。结果2003-2005年糖尿病足溃疡感染呈上升的趋势;病原菌以革兰阴性菌为主（63.6%）,其次是革兰阳性球菌（31.8%）和真菌（5.4%）;真菌感染呈上升的趋势,以白色念珠菌为主;革兰阴性菌的菌群分布为大肠埃希菌24.8%、变形菌属10.9%、铜绿假单胞菌17.0%、嗜麦芽寡养单胞菌3.1%、其他肠杆菌属7.8%。亚胺培南、头孢哌酮-舒巴坦对革兰阴性菌抗菌活性较高,对其他常用抗菌药物有不同程度的耐药。革兰阳性球菌的菌群分布为金黄色葡萄球菌17.8%,凝固酶阴性葡萄球菌5.4%,肠球菌属7.8%,未见对万古霉素耐药的革兰阳性菌。结论糖尿病足溃疡处感染的病原菌以革兰阴性菌为主,碳青霉烯类及万古霉素仍保持较高抗菌活性;不间断地对糖尿病足感染的病原菌及其耐药性进行监测,可为糖尿病足溃疡感染防治提供依据。     

Daptomycin activity and spectrum: a worldwide sample of 6737 clinical Gram-positive organisms

BACKGROUND: Increasing antimicrobial resistance among bacterial pathogens has prompted attempts to develop new antimicrobial agents active against multidrug-resistant Gram-positive pathogens. OBJECTIVES: To evaluate the in vitro activity of daptomycin against a worldwide collection of clinical bacterial isolates. METHODS: Daptomycin is a novel cyclic lipopeptide recently approved by the United States Food and Drug Administration. Daptomycin and selected comparators were tested against 6737 clinical Gram-positive strains from more than 70 centres located in Europe, North America and South America. RESULTS: The overall distribution of daptomycin MIC values were in the range < or = 0.12-8 mg/L and 99.4% of all strains were inhibited at < or = 2 mg/L. Despite resistances to other antimicrobial agents, >99.9% of staphylococcal isolates were inhibited at < or = 1 mg/L of daptomycin (MIC90 0.5 mg/L for staphylococci). Streptococcal isolates were very susceptible to daptomycin independent of their susceptibility to penicillin. MIC50/90 values were < or = 0.12 and 0.25 mg/L, respectively. Enterococci showed the highest daptomycin MIC values, but all isolates tested were inhibited at < or = 4 mg/L (except for one Enterococcus faecium isolate which showed a daptomycin MIC of 8 mg/L). CONCLUSIONS: Daptomycin exhibited excellent in vitro activity against a wide spectrum of Gram-positive organisms and may represent a therapeutic option for infections caused by multidrug-resistant pathogens worldwide.     

Efficacy and safety of intravenous daptomycin in Japanese patients with skin and soft tissue infections

Daptomycin is a lipopeptide antibiotic active against gram-positive organisms and recently approved for marketing in Japan. This study investigates the efficacy and safety of daptomycin in Japanese patients with skin and soft tissue infections (SSTIs) caused by methicillin-resistant Staphylococcus aureus (MRSA) for regulatory filing in Japan. Overall, 111 Japanese patients with SSTI were randomized in this open-label, randomized, active-comparator controlled, parallel-group, multicenter, phase III study. Patients received intravenous daptomycin 4 mg/kg once daily or vancomycin 1 g twice daily for 7–14 days. Efficacy was determined by a blinded Efficacy Adjudication Committee. Among patients with SSTIs caused by MRSA, 81.8 % (95 % CI, 69.1–90.9) of daptomycin recipients and 84.2 % (95 % CI, 60.4–96.6) of vancomycin recipients achieved a successful clinical response at the test-of-cure (TOC) visit. The microbiological success rate against MRSA at the TOC visit was 56.4 % (95 % CI, 42.3–69.7) with daptomycin and 47.4 % (95 % CI, 24.4–71.1) with vancomycin. Daptomycin was generally well tolerated; most adverse events were of mild to moderate severity. The measurement of daptomycin concentration in plasma revealed that patients with mild or moderate impaired renal function showed similar pharmacokinetics profiles to patients with normal renal function. Clinical and microbiological responses, stratified by baseline MRSA susceptibility, suggested that patients infected with MRSA of higher daptomycin MIC showed a trend of lower clinical success with a P value of 0.052 by Cochran–Armitage test. Daptomycin was clinically and microbiologically effective for the treatment of MRSA-associated SSTIs in Japanese patients.     

Daptomycin for endocarditis and/or bacteraemia: a systematic review of the experimental and clinical evidence

BACKGROUND: Endocarditis and bacteraemia are devastating infections with high mortality. Gram-positive cocci are the most commonly isolated pathogens. In an era of multidrug-resistant pathogens, the evaluation of new treatment options is important. Daptomycin is a cyclic lipopeptide that is active against most of these pathogens. Furthermore, it is a bactericidal antibiotic, a factor that is frequently considered in the choice of treatment of patients with bacteraemia and endocarditis. METHODS: We performed a systematic review of the evidence for the effectiveness of daptomycin in the treatment of patients and animals with endocarditis and/or bacteraemia. We searched PubMed and Scopus databases for relevant studies. Case reports, case series, controlled trials, randomized controlled trials and comparative studies using experimental animal models were included. RESULTS: The most reliable information comes from the single multicentre randomized controlled trial conducted on this issue, which showed that daptomycin is a promising antibiotic for the treatment of patients with Staphylococcus aureus bacteraemia and endocarditis. The experimental models indicate that the combination of daptomycin with rifampicin or gentamicin can improve outcomes further. Finally, in several of the published relevant case reports daptomycin was administered in patients with haematological malignancies. CONCLUSIONS: Daptomycin is a promising antibiotic that has been already approved for the treatment of patients with right-sided endocarditis and bacteraemia. However, the available clinical evidence is limited and further evaluation of the antibiotic is warranted. The commonly reported de novo development of resistance is a major concern that may limit its use. More controlled trials are needed, especially for patients infected with multidrug-resistant Gram-positive cocci, comparing daptomycin with other available treatment options, including glycopeptides and oxazolidinones.     

Daptomycin treatment of Staphylococcus aureus experimental chronic osteomyelitis

BACKGROUND: Infection due to methicillin-resistant Staphylococcus aureus (MRSA) is increasingly common in nosocomial and community settings. Daptomycin is a cyclic lipopeptide anti-infective with activity against MRSA, approved for treatment of complicated skin and skin structure infections. Daptomycin may be useful in systemic or local treatment of chronic osteomyelitis. METHODS: We measured mechanical strength of daptomycin- and vancomycin-loaded polymethylmethacrylate (PMMA), assayed in vivo release of daptomycin and vancomycin from daptomycin- and vancomycin-loaded PMMA, respectively, and compared the efficacy of two systemic doses of daptomycin with that of vancomycin, each with or without the respective anti-infective loaded into PMMA, using a rat model of MRSA chronic osteomyelitis. RESULTS: Neither tensile nor compressive strength of PMMA was impacted by impregnation with these antimicrobials at a concentration of 7.5% by weight. The peak concentrations of daptomycin and vancomycin in rat tibial bone surrounding a 7.5% daptomycin- and vancomycin-loaded 3 mm PMMA bead were 178 and 49 mg/L, respectively. In the treatment of experimental osteomyelitis, rats assigned to no treatment, daptomycin 50 mg/kg subcutaneously twice daily, daptomycin 60 mg/kg subcutaneously twice daily, and vancomycin 50 mg/kg intraperitoneally twice daily had 6.4, 4.1, 4.0 and 4.5 median log10 cfu/g of bone at the end of 21 days of therapy. All systemic anti-infectives studied were more active than was no treatment. Daptomycin- or vancomycin-loaded PMMA did not, however, exhibit microbiological efficacy alone or adjunctively, as assessed 21 days after implantation. CONCLUSIONS: Daptomycin is released from PMMA in vivo at a rate similar to that of vancomycin. Systemic daptomycin is as active as vancomycin in a rat model of chronic MRSA experimental osteomyelitis.     

Pre-clinical experience with daptomycin

Daptomycin is a broad-spectrum, bactericidal agent active against Gram-positive bacteria, acting largely and unusually through membrane depolarization. Activity is markedly affected in vitro by the availability of calcium ions, and its high molecular weight with associated poor diffusion means that conventional disc diffusion testing is not reliable (and as a consequence not available). In order to allow susceptibility categorization, it is recommended that the MIC be determined in the presence of a defined calcium concentration. The activity of daptomycin is concentration-dependent with a prolonged post-antibiotic effect. It has linear pharmacokinetics, with a half-life of 8-9 h, the primary route of excretion is renal, it exhibits serum protein binding of approximately 92% and there is no interaction with the P450 cytochrome. Daptomycin is inactivated by surfactant in the lung and, in consequence, is not recommended for the treatment of respiratory infections. Daptomycin is currently licensed for the treatment of complicated skin and soft tissue infections and for bacteraemia and right-sided endocarditis due to methicillin-susceptible and -resistant Staphylococcus aureus. To date, daptomycin-resistant bacteria have rarely been isolated from patients, although increases in vancomycin MIC may be linked to reduced susceptibility to daptomycin. Close monitoring of resistance is essential to maintain the clinical utility of the drug. Using once-daily dosing, daptomycin has been generally well tolerated; however, weekly monitoring of creatinine phosphokinase is recommended, as myopathy in skeletal muscles has been seen, albeit rarely. The rapid bactericidal action of daptomycin makes it a useful addition to the therapeutic armamentarium for the treatment of Gram-positive infections, providing a valuable alternative to vancomycin when it is inappropriate or resistance is a problem.     

Prospective, open-label investigation of the pharmacokinetics of daptomycin during cardiopulmonary bypass surgery

As methicillin-resistant Staphylococcus aureus (MRSA) becomes more prevalent, vancomycin is becoming increasingly used as a prophylaxis against surgical-site infections for cardiothoracic surgeries. However, vancomycin administration can be challenging, and the pharmacokinetics of alternative antibiotics in this setting are poorly understood. The primary objective of this investigation was to describe the pharmacokinetics of daptomycin in patients undergoing coronary artery bypass graft surgery. We enrolled 15 patients undergoing coronary artery bypass surgery requiring cardiopulmonary bypass. Each subject was administered a single open-label dose of daptomycin (8 mg/kg of body weight) for surgical prophylaxis. Fourteen daptomycin plasma samples were collected. Safety outcomes between subjects who received daptomycin and 15 control subjects who received the standard-of-care antibiotic were compared. The mean maximal concentration of daptomycin (C_max) was 84.4 ± 27.1 μg/ml; the mean daptomycin concentration during the cardiopulmonary bypass procedure was 33.2 ± 11.4 μg/ml and was 30.9 ± 12.7 μg/ml at sternum closure. Mean daptomycin concentrations at 12, 18, 24, and 48 h were 22.7 ± 9.7, 16.2 ± 8.2, 12.0 ± 4.7, and 3.5 ± 2.3 μg/ml, respectively. Mean daptomycin concentrations were consistently above the MIC at which 90% of the tested isolates are inhibited (MIC₉₀) for S. aureus and S. epidermidis during the cardiopulmonary bypass procedure. Daptomycin was not associated with surgical-site infections or differences in adverse events compared to findings for control subjects. We found that a single dose of daptomycin at 8 mg/kg was well tolerated and achieved adequate plasma concentrations against common pathogens associated with surgical-site infections after cardiothoracic surgery. Daptomycin may be considered an alternative surgical prophylaxis antibiotic for patients undergoing cardiothoracic bypass surgery who are unable to receive vancomycin.     

社区糖尿病足病原菌分布及耐药性分析

目的对江西地区社区糖尿病足感染菌及耐药性进行综合评价,为本地区社区糖尿病足感染菌的经验治疗提供依据。方法回顾性分析84例糖尿病足感染患者溃疡处感染菌及耐药性。结果 84例糖尿病足感染患者中68例患者溃疡处分离出82株病原菌,其中有14例分离出2种病原菌。混合感染率为（20.6%）,其中革兰阳性球菌58株,占70.7%,其中金黄色葡萄球菌38株、表皮葡萄球菌11株、粪肠球菌9株;革兰阴性菌22株,占26.8%,其中肠杆菌科细菌共18株（分别为大肠埃希菌12株、变形杆菌1株、阴沟肠杆菌1株、产气肠杆菌1株、肺炎克雷伯杆菌1株）,非发酵菌4株;真菌2株,占2.4%。各种病原菌对常用抗菌药物的耐药率也各不相同。结论糖尿病足感染部分为混合性感染,其致病菌多为多重耐药,为有效治疗糖尿病足感染菌,应结合糖尿病足感染的临床特征,根据药敏结果选择有效抗菌药物,防止滥用抗生素和耐药菌株的出现,提高治愈率。     

The efficacy and safety of daptomycin vs. vancomycin for the treatment of cellulitis and erysipelas

Background: Results from previous trials suggest that daptomycin may result in faster clinical improvement than penicillinase‐resistant penicillins or vancomycin for patients with complicated skin and skin structure infections. Objective: The objective was to evaluate whether daptomycin treatment of cellulitis or erysipelas would result in faster resolution compared with vancomycin. Design: The study was a prospective, evaluator‐blinded, multi‐centre trial. Patients were randomised to receive daptomycin 4 mg/kg once daily or vancomycin according to standard of care for 7–14 days. Patients: Adults diagnosed with cellulitis or erysipelas requiring hospitalisation and intravenous antibiotic therapy were eligible for enrolment. Results: The clinical success rates were 94.0% for daptomycin and 90.2% for vancomycin (95% confidence interval for the difference, ?6.7%, 14.3%). There were no statistically significant differences between treatment arms in the time to resolution or improvement in any of the predefined clinical end‐points. Both daptomycin and vancomycin were well tolerated. Conclusions: There was no difference in the rate of resolution of cellulitis or erysipelas among patients treated with daptomycin or vancomycin. Daptomycin 4 mg/kg once daily appeared to be effective and safe for treating cellulitis or erysipelas.     

A review of linezolid: the first oxazolidinone antibiotic

Resistance of Gram-positive bacterial pathogens, such as Staphylococcus aureus and Enterococcus faecium, to existing antibiotics continues to increase, and new antibiotics with activity against these pathogens are in demand. Linezolid (Zyvox, Pharmacia and Upjohn) is the first agent of a new class of antibiotics called the oxazolidinones. Linezolid possesses excellent microbial activity against a wide variety of Gram-positive pathogens including those resistant to methicillin and vancomycin (Vancocin, Eli Lilly). Linezolid is available for intravenous and oral administration and possesses excellent bioavailability. It exhibits good penetration into pulmonary, as well as skin and related structure tissues, and does not require dosage adjustment in hepatic or renal dysfunction. Linezolid is generally well-tolerated, with the predominant adverse effect manifesting as a duration dependent, reversible thrombocytopenia. Linezolid possesses monoamine oxidase inhibitor activity and caution is warranted with coadministration of adrenergic or seritonergic medications. Clinical trials conducted with linezolid in skin and structure infections, lower respiratory tract infections and vancomycin-resistant enterococcal infections demonstrate that linezolid is an effective therapy. Recent data suggest that linezolid may be superior to vancomycin for the treatment of infections caused by methicillin-resistant S. aureus. Linezolid is an excellent and promising new antibiotic for the treatment of resistant Gram-positive pathogens.     

Daptomycin (LY146032) for prevention and treatment of experimental aortic valve endocarditis in rabbits.

The efficacy of daptomycin (LY146032), a vancomycinlike lipopeptide antibiotic, was compared with that of antibiotics commonly in use for prevention and treatment of experimental aortic valve endocarditis in rabbits. Strains of Staphylococcus aureus. S. epidermidis, Streptococcus sanguis, and Enterococcus faecalis were used to establish endocarditis. A single 10-mg/kg dose of daptomycin and a single 25-mg/kg dose of vancomycin were both effective in prevention of endocarditis produced by strains of S. aureus and S. sanguis. Daptomycin was more effective than vancomycin for prevention of endocarditis caused by the strain of S. epidermidis. A single dose of daptomycin also was more effective in prevention of staphylococcal and enterococcal endocarditis than were single-dose regimens of cefazolin (100 mg/kg) and the combination of ampicillin (30 mg/kg) plus gentamicin (3 mg/kg), respectively. For treatment of endocarditis, daptomycin (10 mg/kg) as a single daily dose was as effective as regimens of either vancomycin or beta-lactam antibiotics for staphylococcal and enterococcal endocarditis. Daptomycin, however, was not as effective as a single daily dose of 600,000 U of procaine penicillin for endocarditis caused by the strain of S. sanguis.     

In vitro effect of the presence of human albumin or human serum on the bactericidal activity of daptomycin against strains with the main resistance phenotypes in Gram-positives

OBJECTIVES: Bactericidal activity depends on antibiotic-bacteria couples, resistance phenotype and theoretically on protein binding. This work explores the influence of protein binding on the bactericidal activity of two antibiotics, daptomycin versus vancomycin, that exhibit, respectively, different C(max) (56 versus 25.5 mg/L), protein binding (91.7% versus 36.9%) and thus theoretical free-drug fractions (4.7 versus 16.1 mg/L). METHODS: The effect of the presence of physiological concentrations of human albumin (4 g/dL) or human serum (90%) on the bactericidal activity of daptomycin was studied against Gram-positive isolates with troublesome resistance phenotypes [multidrug-resistant Streptococcus pneumoniae (MDRSP), methicillin-resistant Staphylococcus aureus (MRSA), heterogeneous vancomycin-intermediate MRSA (MRSA-hVI) and vancomycin-resistant Enterococcus faecium]. Killing curves (final inocula of approximately 10(7) cfu/mL) were performed using daptomycin and vancomycin concentrations similar to the C(max) obtained in serum. RESULTS: Daptomycin was rapidly bactericidal (> or =3 log(10) initial inocula reduction) against S. pneumoniae and S. aureus, regardless of the strain tested or the presence of albumin or human serum (that slightly delayed bactericidal activity). Against vancomycin-susceptible or -resistant enterococci, daptomycin exhibited rapid bactericidal activity, delayed to 8 and 24 h, respectively, by human albumin. Vancomycin exhibited much slower bactericidal activity against MDRSP and methicillin-susceptible or -resistant S. aureus, but was never bactericidal against MRSA-hVI and vancomycin-susceptible or -resistant E. faecium. CONCLUSIONS: Daptomycin exhibited rapid bactericidal activity against the strains of the three Gram-positive species tested, regardless of resistance phenotype or the presence of physiological concentrations of albumin.     

Daptomycin is more efficacious than vancomycin against a methicillin-susceptible Staphylococcus aureus in experimental meningitis

OBJECTIVES: To test the efficacy of daptomycin, a cyclic lipopeptide antibiotic, against a methicillin-susceptible Staphylococcus aureus strain in experimental rabbit meningitis and to determine its penetration into non-inflamed and inflamed meninges RESULTS: Over a treatment period of 8 h, daptomycin (15 mg/kg) was significantly superior to the comparator regimen vancomycin (-4.54 +/- 1.12 log(10)/mL for daptomycin versus -3.43 +/- 1.17 log(10)/mL for vancomycin). Daptomycin managed to sterilize 6 out of 10 CSFs compared with 4 out of 10 for vancomycin. The penetration of daptomycin into inflamed meninges was approximately 5% and approximately 2% into non-inflamed meninges. CONCLUSIONS: The superior bactericidal activity of daptomycin was confirmed in vivo and in time-killing assays in vitro.     

Daptomycin: a rapidly bactericidal lipopeptide for the treatment of Gram-positive infections

Antimicrobial resistance among Gram-positive organisms continues to increase and has reached epidemic proportions in a number of countries and within medical centers worldwide. Daptomycin is a new lipopeptide antibiotic with rapid bactericidal activity against Staphylococcus aureus. It is also active against coagulase-negative staphylococci, enterococci and streptococci. It exerts its effect through cell membrane disruption that results in dissipation of the membrane potential. Daptomycin exhibits a prolonged postantibiotic effect and is well tolerated. In Phase III clinical trials, daptomycin was found to be similar in efficacy to standard therapy in complicated skin and skin structure infections. More recently, it was approved for the treatment of S. aureus bacteremia and right-sided endocarditis. Daptomycin is not indicated for pulmonary infections. Preliminary data suggest that daptomycin may be effective in urinary tract, bone and joint infections. However, randomized clinical trials are needed to confirm these findings. Daptomycin is an effective antimicrobial agent for the treatment of various serious Gram-positive infections, especially those caused by methicillin-resistant S. aureus.     

Daptomycin: a cyclic lipopeptide antimicrobial agent

OBJECTIVES: The aims of this article were: to summarize the pharmacology, pharmacokinetics, and efficacy of daptomycin; to explore its safety profile; and to discuss its current and potential roles as an antimicrobial therapy. METHODS: A literature search was conducted using the MEDLINE (1966-August 2004) and International Pharmaceutical Abstracts (1970-August 2004) databases with the search terms daptomycin, LY146032, and lipopeptide antibiotics. Abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy and documents submitted to the US Food and Drug Administration were also reviewed. RESULTS: Phase III study results suggest no difference in efficacy or tolerability between daptomycin 4 mg/kg IV QD and vancomycin or semisynthetic penicillins for complicated skin and skin-structure infections. Animal studies suggest daptomycin may be useful for the treatment of endocarditis. Daptomycin is not indicated for pneumonia, with poorer outcomes than conventional treatment It is available as an IV medication and exhibits 92% plasma protein binding in vitro. In healthy adult humans, daptomycin has a volume of distribution of 0.1 L/kg and a plasma elimination half-life of approximately 9 hours, and is eliminated primarily by renal excretion (approximately 54%). In patients with reduced renal function, including those receiving hemodialysis and peritoneal dialysis, the dose interval should be 48 hours. No dosage adjustment appears to be necessary for mild to moderate hepatic impairment. The use of daptomycin in patients with severe hepatic impairment has not been assessed. The most commonly reported adverse events include constipation, nausea, injection-site reactions, headache, and diarrhea. Patients should also be monitored regularly for skeletal muscle toxicity. CONCLUSIONS: Daptomycin may be useful for complicated skin and skin-structure infections and gram-positive pathogens resistant to conventional antimicrobials. However, limited data are currently available for duration of treatment beyond 14 days and at doses >4 mg/kg QD.