Daptomycin: a comparison of two intravenous formulations.

Daptomycin is a cyclic lipopeptide antibacterial agent with potent bactericidal activity against a broad range of Gram-positive organisms. In 2003, daptomycin for injection received approval from the US Food and Drug Administration (FDA) for the treatment of patients with complicated skin and skin structure infections (cSSSIs); in 2006, it was approved for the treatment of patients with Staphylococcus aureus bacteremia, including those with right-sided infective endocarditis caused by methicillin-susceptible and methicillin-resistant isolates. In 2016, the FDA approved a new formulation of daptomycin for injection (daptomycin RF) for the same indications. The efficacy and safety of daptomycin for injection have been established in pivotal clinical trials, and the findings of nonclinical studies indicate that both formulations of daptomycin for injection are equivalent. Herein we refer to the new daptomycin formulation as daptomycin RF to distinguish it from the original formulation. Daptomycin RF provides clinicians and clinical pharmacists with a product that offers improved stability and more rapid, in-vial reconstitution with either sterile or bacteriostatic water for injection, while maintaining the same antibacterial coverage. Here we discuss the rationale for and the potential value of daptomycin RF, and briefly review the similarities and differences between the original formulation of daptomycin and daptomycin RF.

A retrospective study of outcomes of device-associated osteomyelitis treated with daptomycin.

BACKGROUND: Daptomycin appears well tolerated and effective for osteomyelitis treatment. However, limited data exist regarding daptomycin use for treatment of device-associated osteomyelitis (DAO). METHODS: We used a retrospective, observational database (Cubicin® Outcomes Registry and Experience [CORE® 2007-2009]) that assessed patients treated with daptomycin to evaluate the characteristics of patients with DAO, outcomes after daptomycin treatment, and safety of daptomycin in this setting. Information from 54 institutions for patients with prosthetic joint infection (PJI) and other hardware-associated osteomyelitis (OHAO) who received daptomycin from January 2007 to December 2008 with follow-up data in 2009 was collected using a standardized data collection form. RESULTS: Eighty-two patients receiving daptomycin were identified in CORE 2007-2009; 48 patients (59 %) had follow-up data. Sixty-seven percent of patients had received a previous antibiotic. Surgical intervention was similar between the 2 groups: PJI, 22 of 27 (82 %) and OHAO, 17 of 21 (81 %). However, device removal or replacement was more frequent in the PJI patients (17 of 27, 63 %) than in the OHAO patients (8 of 21, 38 %). Clinical success was reported in 22 of 27 (82 %; 95 % confidence interval [CI], 62-94 %) patients with PJI and 18 of 21 (86 %; 95 % CI, 64-97 %) patients with OHAO at follow-up (13-402 days). Adverse events occurred in 8 of 50 (16 %) patients in the safety population and did not differ by daptomycin dose. CONCLUSION: Daptomycin appeared effective and well tolerated in patients with DAO, including PJI or OHAO.

Comparative Effectiveness of Vancomycin Versus Daptomycin for MRSA Bacteremia With Vancomycin MIC >1 mg/L: A Multicenter Evaluation.

PURPOSE: Clinical studies comparing vancomycin with alternative therapy for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia are limited. The objective of this study was to compare outcomes of early daptomycin versus vancomycin treatment for MRSA bacteremia with high vancomycin MICs in a geographically diverse multicenter evaluation. METHODS: This nationwide, retrospective, multicenter (N = 11), matched, cohort study compared outcomes of early daptomycin with vancomycin for MRSA bloodstream infection (BSI) with vancomycin MICs 1.5 to 2 µg/mL. Matching variables, based on propensity regression analysis, included age, intensive care unit (ICU), and type of BSI. Outcomes were as follows: (1) composite failure (60-day all-cause mortality, 7-day clinical or microbiologic failure, 30-day BSI relapse, or end-of-treatment failure (EOT; discontinue/change daptomycin or vancomycin because of treatment failure or adverse event]); (2) nephrotoxicity; and (2) day 4 BSI clearance. FINDINGS: A total of 170 patients were included. The median (interquartile range) age was 60 years (50-74); the median (range) Acute Physiology and Chronic Health Evaluation II score was 15 (10-18); 31% were in an ICU; and 92% had an infectious disease consultation. BSI types included endocarditis/endovascular (39%), extravascular (55%), and central catheter (6%). The median daptomycin dose was 6 mg/kg, and the vancomycin trough level was 17 mg/L. Overall composite failure was 35% (59 of 170): 15% due to 60-day all-cause mortality, 14% for lack of clinical or microbiologic response by 7 days, and 17% due to failure at end of therapy (discontinue/change because of treatment failure or adverse event). Predictors of composite failure according to multivariate analysis were age >60 years (odds ratio, 3.7; P < 0.01) and ICU stay (odds ratio, 2.64; P = 0.03). Notable differences between treatment groups were seen with: (1) end of therapy failure rates (11% vs 24% for daptomycin vs vancomycin; P = 0.025); (2) acute kidney injury rates (9% vs 23% for daptomycin vs vancomycin; P = 0.043); and (3) day 4 bacteremia clearance rates for immunocompromised patients (n = 26) (94% vs 56% for daptomycin vs vancomycin; P = 0.035). IMPLICATIONS: Results from this multicenter study provide, for the first time, a geographically diverse evaluation of daptomycin versus vancomycin for patients with vancomycin-susceptible MRSA bacteremia with vancomycin MIC values >1 µg/mL. Although the overall composite failure rates did not differ between the vancomycin and daptomycin groups when intensively matched according to risks for failure, the rates of acute kidney injury were significantly lower in the daptomycin group. These findings suggest that daptomycin is a useful therapy for clinicians treating patients who have MRSA bacteremia. Prospective, randomized trials should be conducted to better assess the potential significance of elevated vancomycin MIC.

Duration of prior vancomycin therapy and subsequent daptomycin treatment outcomes in methicillin-resistant Staphylococcus aureus bacteremia.

The association between varying durations of previous vancomycin therapy and subsequent daptomycin success rates was evaluated in a subset of patients with methicillin-resistant Staphylococcus aureus bacteremia from the Cubicin® Outcomes Registry and Experience 2005-2009 (n=159). Previous vancomycin exposure did not adversely affect daptomycin outcomes; success rates were 81% in patients treated with first-line daptomycin and 89%, 83%, and 88%, respectively, in patients with 1-3days, 4-6days, and ≥7days of previous vancomycin exposure (P=0.5).

Clinical Outcomes of Daptomycin for Vancomycin-resistant Enterococcus Bacteremia.

PURPOSE: In light of recent evidence suggesting enhancement of daptomycin activity against vancomycin-resistant Enterococcus (VRE) by ampicillin and other ß-lactam antibiotics, we evaluated the safety profile and clinical efficacy of daptomycin with and without concomitant ß-lactam antimicrobials in the treatment of VRE (faecium or faecalis) bacteremia from multiple centers across the United States. METHODS: Data were collected retrospectively as part of a larger multicenter registry (The Cubicin Outcomes Registry and Experience). Efficacy and clinical outcomes in patients with VRE bacteremia who received at least 3 days of daptomycin with or without concomitant ß-lactams were analyzed. Although all the cases involved daptomycin-susceptible VRE, additional analysis was performed to examine whether the adjunctive ß-lactam would play a more pivotal role in cases where the daptomycin MIC was in the upper limit of the susceptibility range, indicating that daptomycin monotherapy efficacy may be relatively compromised compared with cases with lower daptomycin MICs. FINDINGS: Two hundred sixty-two patients from 33 hospitals were evaluated. Most patients had at least one significant comorbidity, such as solid-organ or bone marrow transplantation (16%), neutropenia (36%), dialysis dependency (20%), or critical illness (36%) requiring care in an intensive care unit. Overall treatment success was 86% (n = 225/262), and treatment success for patients taking concomitant ß-lactams was 86% (n = 105/122). Logistic regression identified treatment failure to be associated with sepsis (odds ratio = 3.42; P = 0.009) and an elevated daptomycin MIC (3-4 µg/mL) (odds ratio = 3.23, P = 0.013). No significant increase in clinical failure was seen among patients with elevated daptomycin MIC who received concomitant ß-lactam therapy (clinical success, 88% vs 79% for MIC ≤2 vs 3-4 µg/mL, respectively; P = 0.417). Of 262 patients, 33 (13%) experienced ≥1 adverse event possibly related to daptomycin (increased creatine kinase in 8 patients). IMPLICATIONS: Overall, daptomycin was effective and well tolerated for VRE bacteremia, with lower effectiveness noted with daptomycin MIC of 3 to 4 µg/mL. Concomitant ß-lactam therapy with daptomycin may improve clinical outcomes in this setting. Further studies are needed to characterize the potential benefit of concomitant ß-lactams with daptomycin.

Daptomycin experience in patients with human immunodeficiency virus and resistant gram-positive infections.

OBJECTIVES: This study was conducted to evaluate the clinical experience with daptomycin in the treatment of resistant gram-positive infections (GPIs) in patients with HIV infection. METHODS: Using a retrospective, multicenter, and observational registry study, investigators assessed outcomes following daptomycin therapy in 78 patients (62 efficacy evaluable) infected with HIV and with resistant GPIs. RESULTS: Overall, success rates by infection type were bacteremia 91% (20 of 22), endocarditis 91% (10 of 11), and bone/joint 100% (9 of 9). Success by pathogen was 93% (39 of 42), 93% (14 of 15), and 100% (5 of 5) for methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and methicillin-resistant coagulase-negative staphylococci, respectively. Daptomycin appeared to be well tolerated, with 9% having an adverse event possibly related to daptomycin and 4% discontinuing daptomycin. CONCLUSIONS: In HIV-infected patients, daptomycin appears to be a useful agent for treating resistant GPIs.

Outcomes and metrics for antimicrobial stewardship: survey of physicians and pharmacists.

We conducted a survey to compare antimicrobial stewardship outcomes considered to be most important with those used in practice as metrics. Respondent opinion of important outcomes compared with those collected as metrics were antimicrobial use (15% vs 73%), antimicrobial cost (10% vs 73%), appropriateness of antimicrobial use (56% vs 51%), infection-related mortality rate (34% vs 7%), and antibiotic-associated length of stay (22% vs 12%). Patient outcomes are important to many practitioners but are rarely used as metrics.

Assessing appropriateness of antimicrobial therapy: in the eye of the interpreter.

To address the increase of drug-resistant bacteria and widespread inappropriate use of antimicrobials, many healthcare institutions have implemented antimicrobial stewardship programs to promote appropriate use of antimicrobials and optimize patient outcomes. However, a consensus definition of appropriate use is lacking. We conducted a multicenter observational study to compare 4 definitions of appropriateness--a study site-specific definition, use supported by susceptibility data, use supported by electronic drug information resources (Clinical Pharmacology/Micromedex), or study site principal investigator (PI) opinion-among patients receiving 1 or more of 13 identified antimicrobials. Data were collected for 262 patients. Overall, appropriateness with the 4 definitions ranged from 79% based on PI opinion to 94% based on susceptibility data. No single definition resulted in consistently high appropriate use for all target antimicrobials. For individual antimicrobials, the definitions with the highest rate of appropriate use were Clinical Pharmacology/Micromedex support (6 of 7 antimicrobials) and susceptibility data (5 of 7 antimicrobials). For specific indications, support from susceptibility data resulted in the highest rate of appropriate use (4 of 7 indications). Overall comparisons showed that appropriateness assessed by PI opinion differed significantly compared with other definitions when stratified by either target antimicrobial or indication. The significant variability in the rate of appropriate use highlights the difficulty in developing a standardized definition that can be used to benchmark judicious antimicrobial use.

Breaking down the barriers: challenges with development and implementation of an industry-sponsored antimicrobial stewardship data collection and analysis tool.

Partnership between clinicians and the pharmaceutical industry with a focus on antimicrobial stewardship research initiatives is a necessary step toward meeting the shared goals of combating inappropriate antimicrobial use, improving patient outcomes, and minimizing resistance development. Achieving these goals requires outcomes-focused data collection and monitoring tools for antimicrobial stewardship programs (ASP) that consider real-world data about how antimicrobials are used to treat patients. Here we highlight the experiences and challenges associated with the development and implementation of an industry-sponsored electronic antimicrobial stewardship data collection and analysis tool (AS-DCAT). The benefits and risks of the industry-sponsored AS-DCAT from the perspectives of the sponsoring company and participating sites are discussed. Barriers encountered as well as general considerations and recommendations for preventing or overcoming those barriers for future studies and tool development are provided.

Daptomycin for methicillin-resistant Staphylococcus aureus diabetic foot infections.

BACKGROUND: Diabetic foot infection (DFI) is a serious, difficult-to-treat infection, especially when caused by methicillin-resistant Staphylococcus aureus (MRSA). Vancomycin has been the standard treatment for MRSA infection, but lower response rates in MRSA skin infections have been reported. This analysis assessed the outcome and safety of daptomycin therapy in patients with a DFI caused by MRSA. METHODS: Using the Cubicin Outcomes Registry and Experience and the European Cubicin Outcomes Registry and Experience (2006-2009), 79 patients with MRSA DFI were identified and included in this analysis. RESULTS: In the 74 evaluable patients, daptomycin was administered at a median dose of 4.8 mg/kg primarily every 24 hours (85.1%) and for a median of 15.0 days. Overall, 77.0% of the patients (57 of 74) received initial therapy with activity against MRSA; however, of patients receiving daptomycin as second-line therapy (n = 31), only 45.2% were treated with an antibiotic agent active against MRSA. The overall clinical success and treatment failure rates were 89.2% and 10.8%, respectively. Success with daptomycin therapy was higher in patients who had surgery and in those whose initial therapy was daptomycin. Eleven patients had 14 adverse events, two of which were possibly related to daptomycin use and led to discontinuation. CONCLUSIONS: In a large real-world cohort of patients with MRSA DFI, daptomycin therapy was shown to be generally well tolerated and effective. The use of an anti-MRSA antibiotic agent should be considered when implementing first-line antibiotic drug therapy for DFI in countries where MRSA is common to avoid inappropriate empirical treatment and potential negative effects on outcomes.

Daptomycin use in neutropenic patients with documented gram-positive infections.

PURPOSE: The goal of this study was to describe the outcomes associated with daptomycin treatment of documented gram-positive infections in patients with neutropenia. METHODS: All patients with neutropenia (≤500 cells/m(3)) and at least one documented gram-positive culture from 2006-2009 were identified from a retrospective, multicenter, and observational registry (Cubicin(®) Outcome Registry and Experience (CORE(®))). Investigators assessed patient outcome (cured, improved, failed, nonevaluable) at the end of daptomycin therapy. All patients were included in the safety analysis. RESULTS: The efficacy population had 186 patients; 159 (85 %) patients had either cure (n = 108, 58 %) or improved (n = 51, 27 %) as an outcome. Success rates (cure plus improved) by the lowest WBC during daptomycin were 98/116 (84 %) for ≤100 cells/m(3) and 61/70 (87 %) for 101-499 cells/m(3), P = 0.6. Most patients had cancer; 135/186 (73 %) had hematological malignancy; 26/186 (14 %) had solid tumors, and 9 (5 %) had both. One hundred fifty-six (84 %) patients received other antibiotics before daptomycin treatment; 82 % vancomycin, of which 31 % failed vancomycin. The most common infections were bacteremia (78 %), skin and skin structure infections (8 %), and urinary tract infections/pyelonephritis (6 %). The most common pathogens were vancomycin-resistant Enterococcus faecium (47 %), methicillin-resistant Staphylococcus aureus (20 %), and coagulase-negative staphylococci (19 %). The median (min, max) initial daptomycin dose was 6 mg/kg (3.6, 8.3). The median (min, max) daptomycin duration of therapy was 14 days (1, 86). Possibly related adverse events occurred in 12/209 patients (6 %), and 13 patients (6 %) discontinued daptomycin due to adverse event. CONCLUSIONS: The results suggest that daptomycin appeared useful and well tolerated in neutropenic patients, and the degree of neutropenia did not affect daptomycin success rates. Comparative clinical trials are needed to confirm these findings.

Safety of daptomycin in patients completing more than 14 days of therapy: results from the Cubicin® Outcomes Registry and experience.

Patients with complicated infections may receive daptomycin for extended periods. This retrospective analysis was conducted to describe the safety profile of daptomycin in patients completing >14 days of therapy. In the Cubicin(®) Outcomes Registry and Experience (CORE(®)) 2005-2009, a retrospective, multicentre, observational registry, patients completing >14 days of daptomycin were studied. Investigators assessed adverse events (AEs) using ICH-E2A definitions of seriousness/severity ≤30 days after completing daptomycin. AEs were grouped by onset at ≤14, 15-28 and >28 days after starting daptomycin. In total, 2263 patients received >14 days of daptomycin. The most common indications were complicated skin and skin-structure infection (25.5%) and osteomyelitis (21.7%). Regarding AEs, 205 patients (9.1%) experienced AEs with an onset ≤14 days of therapy, 168 (7.4%) between 15-28 days and 108 (4.8%) >28 days; a total of 389/2263 patients experienced 814 AEs. The most common AE was increased blood creatine phosphokinase (CPK), occurring in 49 patients (2.2%) during ≤14 days of therapy, 32 (1.4%) between 15-28 days and 10 (0.4%) >28 days. In 183/2263 patients (8.1%), 264 AEs were possibly related to daptomycin. Serious AEs occurred in 153/2263 patients (6.8%). Eighty-nine (3.9%) of 2263 patients had daptomycin discontinued due to AEs, with 36 discontinued due to increased CPK. The overall mortality rate was 63/2263 (2.8%); 4 patients died of a possibly related AE. The most common AEs with onset <14 days were similar to those occurring between 15-28 days and >28 days. Daptomycin appears to be safe in patients treated for >14 days.

Multicenter evaluation of the clinical outcomes of daptomycin with and without concomitant ß-lactams in patients with Staphylococcus aureus bacteremia and mild to moderate renal impairment.

Patients with underlying renal disease may be vulnerable to vancomycin-mediated nephrotoxicity and Staphylococcus aureus bacteremia treatment failure. In light of recent data demonstrating the successful use of ß-lactam plus daptomycin in very difficult cases of S. aureus bacteremia, we examined safety and clinical outcomes for patients who received daptomycin with or without concomitant ß-lactams. We identified 106 patients who received daptomycin for S. aureus bacteremia, had mild or moderate renal insufficiency according to FDA criteria, and enrolled in the Cubicin Outcomes Registry and Experience (CORE), a multicenter registry, from 2005 to 2009. Daptomycin treatment success was 81%. Overall treatment efficacy was slightly enhanced with the addition of a ß-lactam (87% versus 78%; P = 0.336), but this trend was most pronounced for bacteremia associated with endocarditis or bone/joint infection or bacteremia from an unknown source (90% versus 57%; P = 0.061). Factors associated with reduced daptomycin efficacy (by logistic regression) were an unknown source of bacteremia (odds ratio [OR] = 7.59; 95% confidence interval [CI] = 1.55 to 37.2), moderate renal impairment (OR = 9.11; 95% CI = 1.46 to 56.8), and prior vancomycin failure (OR = 11.2; 95% CI = 1.95 to 64.5). Two patients experienced an increase in creatine phosphokinase (CPK) that resolved after stopping daptomycin. No patients developed worsening renal insufficiency related to daptomycin. In conclusion, daptomycin appeared to be effective and well tolerated in patients with S. aureus bacteremia and mild to moderate renal insufficiency. Daptomycin treatment efficacy might be enhanced with ß-lactam combination therapy in primary endovascular and bone/joint infections. Additional studies will be necessary to confirm these findings.

Daptomycin experience in critical care patients: results from a registry.

BACKGROUND: Vancomycin is often the drug of choice in critically ill patients with gram-positive infections, although circumstances often prevent its use. In these situations, clinicians are frequently left with limited data regarding alternative agents. OBJECTIVE: To describe patients with reported sepsis receiving daptomycin in a critical care unit. METHODS: This multicenter, noncomparative, noninterventional study identified patients in critical care units, using the Cubicin Outcomes Registry and Experience (CORE) 2005-2009 registry. A descriptive account of patient characteristics, infectious etiology, outcomes at the end of daptomycin therapy, and 30-day mortality is reported. Nonevaluable patients were excluded from the efficacy analysis but included in the safety analysis. RESULTS: We identified 128 patients, 98 (77%) of whom were evaluable for efficacy. Patient characteristics for the efficacy population were 55 (56%) males, 30 (31%) aged 66 years or older, 38 (39%) had creatinine clearance less than 30 mL/min, and 27 (28%) were on dialysis. Common underlying diseases included acute or chronic renal failure 44 (45%), hypertension 40 (41%), and diabetes 27 (28%). Seventy-two (73%) patients were bacteremic. The most common pathogens found were methicillin-resistant Staphylococcus aureus (32%), vancomycin-resistant Enterococcus faecium (21%), and coagulase-negative staphylococci (20%). Prior to daptomycin, antibiotics were used in 84 (86%) patients, most commonly vancomycin (65/84; 77%). The median (range) initial daptomycin dose was 6 mg/kg (3-10) and duration of 10 days (1-58). Overall success rate was 70% (31% cured; 39% improved). Twelve adverse events possibly related to daptomycin were reported in 9 of 128 (7%) patients in the safety population; 4 of these in 4 (3%) patients were serious. The mortality rate within 30 days of completing daptomycin was 42 of 128 (33%) patients. CONCLUSIONS: These data provide preliminary results on the use of daptomycin in critically ill patients with complicated conditions. Controlled studies are needed to best evaluate daptomycin use in these patients.

Safety of daptomycin in patients receiving hemodialysis.

STUDY OBJECTIVE: To determine the safety of daptomycin administered using a variety of doses and dosing frequencies in patients receiving intermittent hemodialysis who had probable or confirmed gram-positive infections. DESIGN: Analysis of data from the Cubicin Outcomes Registry and Experience (CORE), a multicenter, retrospective, observational registry. SETTING: Fifty-four study sites, mostly (46%) large teaching hospitals. PATIENTS: Three hundred ninety-three adults in the CORE registry who received intermittent hemodialysis between 2005 and 2008. MEASUREMENTS AND MAIN RESULTS: The CORE registry is noninterventional and collects standard-of-care data on daptomycin treatment from health care institutions. Of the 393 patients, 370 (94%) could be categorized by daptomycin dosing frequency: every 48 hours (251 patients [64%]), 3 times/week (87 [22%]), and every 24 hours (32 [8%]); the remaining 23 (6%) had unreported dosing frequencies or received a single dose of daptomycin. Three hundred eighty-four patients (98%) received part of their daptomycin therapy as an inpatient and 129 patients (33%) received part of their daptomycin therapy in an intensive care setting. The primary infection type was bacteremia (224 patients [57%]), and the most common pathogen was Staphylococcus aureus (155 patients [39%]). Thirty-eight adverse events possibly related to daptomycin occurred in 28 patients (7%); increased blood creatine kinase level (7 patients [1.8%]) was the most common adverse event. Adverse-event rates were similar across all dosing regimens. CONCLUSION: In these patients undergoing hemodialysis, daptomycin was a well-tolerated treatment for gram-positive infections across several doses and dosing frequencies. Further study in prospective trials is warranted.

Outcomes with daptomycin in the treatment of Staphylococcus aureus infections with a range of vancomycin MICs.

OBJECTIVES: Recent recommendations by the Infectious Diseases Society of America for the treatment of Staphylococcus aureus suggest the use of alternative agents when vancomycin MIC values are >or=2 mg/L. This study examines the outcome of patients treated with daptomycin for S. aureus infections with documented vancomycin MICs. PATIENTS AND METHODS: All patients with skin, bacteraemia and endocarditis infections due to S. aureus with vancomycin MIC values in CORE 2005-08, a retrospective, multicentre, observational registry, were studied. The outcome (cure, improved, failure or non-evaluable) was the investigator assessment at the end of daptomycin therapy. Success was defined as cure or improved. RESULTS: Five hundred and forty-seven clinically evaluable patients were identified with discrete vancomycin MIC values [MIC <2 mg/L: 451 (82%); MIC >or=2 mg/L: 96 (18%)]. The vancomycin MIC groups were well matched for patient characteristics, types of infections, first-line daptomycin use (19%) and prior vancomycin use (58%). Clinical success was reported in 94% of patients. No differences were detected in the daptomycin success rate by the vancomycin MIC group overall or by the infection type. A multivariate logistic regression also failed to identify vancomycin MIC as a predictor of daptomycin failure. Adverse event (AE) rates were not different when analysed by MIC group; both groups had approximately 17% of patients with one AE. CONCLUSIONS: In this diverse population, daptomycin was associated with similar outcomes for patients, regardless of whether the vancomycin MIC was categorized as <2 or >or=2 mg/L. Further studies are warranted.

Daptomycin use in patients with cancer and neutropenia: data from a retrospective registry.

Clinical data for daptomycin in the treatment of neutropenic cancer patients with documented gram-positive infections are limited. For this study, neutropenic patients were identified from an ongoing retrospective registry (Cubicin Outcome Registry and Experience [CORE]; 2006 program year). Clinical outcomes included cure, improved, failed, and nonevaluable response, and were assessed at the end of daptomycin therapy. Patients who had a nonevaluable clinical response were only included in the safety analysis. Eighty-four patients were identified, of which 72 (86%) were clinically evaluable. Thirty-four (47%) evaluable patients had severe neutropenia (less than 100 cells/mm(3)). Hematologic malignancies were most common (82%). Bacteremia was the most common infection (76%), and vancomycin-resistant enterococci (50%), coagulase-negative staphylococci (24%), and Staphylococcus aureus (11%) were the most common pathogens isolated. Sixty-three patients (88%) received prior antibiotics, including vancomycin (83%), cefepime (17%), and linezolid (16%). The overall success rate (cure + improved) was 90%. Success rates stratified by degree of neutropenia were 85% for patients with less than 100 cells/mm(3), 93% for those with 100-499 cells/mm(3), and 100% for those with 500-1,000 cells/mm(3). The median final daptomycin dose was 6 mg/kg (range, 3-8) and the median duration of therapy was 13 days (range, 1-86). Of the 84 patients analyzed for safety, 24 (29%) developed 44 adverse events; only 5 (6%) patients had adverse events possibly related to daptomycin. The results suggest that daptomycin may be useful for specific cases involving neutropenic patients, and comparative clinical trials are feasible.

Safety and clinical outcomes among older adults receiving daptomycin therapy: Insights from a patient registry.

BACKGROUND: Serious gram-positive bacterial infections are an important cause of morbidity and mortality among older adults and can present significant challenges to clinicians. Data evaluating the safety and effectiveness of newer agents in this population are limited. OBJECTIVE: Daptomycin is a lipopeptide with activity against resistant gram-positive organisms. To better understand the overall safety and effectiveness of daptomycin in older adults (≥66 years of age), the authors reviewed the data that were collected as part of an ongoing registry maintained by Cubist Pharmaceuticals, Inc. (Lexington, Massachusetts), the manufacturer of daptomycin. METHODS: The Cubicin Outcomes Registry and Experience (CORE) is a multicenter, retrospective registry designed to collect postmarketing clinical data on patients who received daptomycin. The CORE data collected from 58 institutions across the United States between January 1, 2005, and December 31, 2007, were analyzed to better understand the overall safety profile of daptomycin and the clinical outcomes of older adults who were treated with this agent. Patients were considered to be nonevaluable if the medical record did not contain sufficient information to determine response at the end of therapy. Nonevaluable patients were excluded from the clinical outcome analysis but included in the safety analysis. RESULTS: The registry contained 1073 patients aged ≥66 years who received daptomycin; 23.8% (255/1073) were ≥81 years of age. Overall, 18.1% (194/1073) of patients experienced 324 adverse events, and 6.2% (67/1073) of patients experienced 97 adverse events that were considered possibly related to treatment with daptomycin. The most frequently reported adverse events that were considered possibly treatment related included creatine phosphokinase (CPK) elevations, gastrointestinal disorders, and skin rashes. Among the 67 patients who experienced ≥1 adverse event that was possibly related to daptomycin, 30 discontinued therapy due to the adverse event (13 due to CPK elevation). Overall, 78.7% (844/1073) of patients were considered evaluable for clinical outcomes. The clinical success rate for all evaluable patients was 90.2% (761/844). The success rate for evaluable patients ≥81 years of age (88.6% [171/193]) was comparable to that of the overall population. CONCLUSION: Experience with daptomycin in this group of older adults suggests good tolerability and clinical outcomes that are consistent with the results of other studies published to date.

Clinical outcomes of patients receiving daptomycin for the treatment of Staphylococcus aureus infections and assessment of clinical factors for daptomycin failure: a retrospective cohort study utilizing the Cubicin Outcomes Registry and Experience.

BACKGROUND: Daptomycin is most commonly used as a second-line treatment. Previous studies have not differentiated the effect of prior antibiotic therapy on daptomycin clinical outcomes. OBJECTIVES: The primary objective of this study was to compare clinical outcomes of patients treated with daptomycin as first-line therapy versus after prior antibiotic therapy (specifically, vancomycin). A secondary objective was to identify other factors associated with the clinical failure of daptomycin therapy. METHODS: This was a retrospective cohort study using data from a postlabeling registry database. The effects of relevant patient characteristics on the clinical outcome of individuals treated for Staphylococcus aureus infections with daptomycin were examined in an unblinded approach using univariate and multivariate analyses. Only patients with an evaluable clinical outcome (ie, cure, improvement, failure) and culture-confirmed S aureus infection were included in the analysis cohort. RESULTS: Of 1227 clinically evaluable patients, 250 (20%) received daptomycin as first-line therapy and 977 (80%) received daptomycin after other prior antibiotic therapy. Overall, 53% of patients were male; 64% were aged 31 to 65 years and 26% were aged >or=66 years. Race information was collected beginning in 2007; of the patients studied, 71% were white and 18% were black. The initial daptomycin dose (mean [SD]) overall was 5.1 (1.1) mg/kg and was highest for patients with endocarditis (5.9 [1.2] mg/kg) and lowest for those with uncomplicated skin and skin structure infections (4.4 [0.9] mg/kg). Clinical success, defined as an outcome of cured or improved at the end of daptomycin therapy, was reported for 1140 (93%) of the 1227 evaluable patients. The clinical success rates for first-line therapy with daptomycin and after prior antibiotics were both 93%. Using univariate analysis, 8 variables were associated with clinical failure (receipt of daptomycin in an intensive care unit setting, severe renal dysfunction [creatinine clearance <30 mL/min], dialysis, diabetes mellitus (DM), concomitant antibiotics, bacteremia, endocarditis, and failure of prior vancomycin therapy) and 3 with clinical success (outpatient daptomycin therapy and complicated and uncomplicated skin and skin structure infections). Using the stepwise multivariate regression analysis, only the presence of endocarditis (odds ratio [OR] = 2.56; 95% CI, 1.18-5.54; P = 0.017), bacteremia (OR = 1.77; 95% CI, 1.04-3.02; P = 0.037), severe renal dysfunction (OR = 1.78; 95% CI, 1.05-3.03; P = 0.034), and DM (OR = 1.79; 95% CI, 1.10-2.93; P = 0.02) were identified as factors independently associated with clinical failure of daptomycin therapy. Of the remaining patients, 9% were aged 18 to 30 years and 0.7% were aged 12 to 17 years. CONCLUSIONS: In this retrospective study, after controlling for clinical factors that are associated with suboptimal outcomes, clinical outcomes with daptomycin did not differ whether it was used as first-line therapy or after other antibiotics. Endocarditis, bacteremia, severe renal dysfunction, and DM were associated with higher rates of clinical failure of daptomycin treatment.

Daptomycin for the treatment of surgical site infections.

BACKGROUND: The increasing frequency of methicillin-resistant Staphylococcus aureus (MRSA) as a cause of surgical site infections, and decreased susceptibility to vancomycin, highlight the need for alternative therapies. METHODS: All patients with a surgical site infection enrolled in the Cubicin Outcomes Registry and Experience (CORE 2007 retrospective multicenter registry were studied. Outcome was assessed at the end of daptomycin therapy using protocol-defined criteria. Success was defined as cured or improved. Non-evaluable patients were excluded from the efficacy analysis but were included in the safety analysis. RESULTS: Of 962 patients in the CORE registry in 2007, 104 (11%) had a surgical infection and met the criteria for the efficacy analysis. The overall success rate was 91% (95/104). The distribution of surgical site infections by depth was 36% (38/104) superficial incisional, 36% (38/104) deep incisional, and 27% (28/104) organ/space. Success rates by infection depth were 92% for superficial incisional, 92% deep incisional, and 89% organ/space (P = .9). Success in patients with and without surgery was 89% (49/55) and 94% (46/49) (P = .5). The median final daptomycin dose was 5.5 mg/kg. The median duration of daptomycin therapy was 14 days. Prior antibiotic therapy was given to 79% of patients; 35% failed. Prior vancomycin was used in 45% of patients; 24% failed. Among vancomycin failures, the daptomycin success rate was 91% (10/11). Of those with a positive culture, common pathogens were S. aureus (68%; MRSA 61%) and enterococci (26%; vancomycin-resistant 36%). There were 9 possible treatment-related adverse events (AEs) in 8 of 118 (7%) patients; 2 serious AEs were reported in 1 patient. CONCLUSION: Success rates for patients with a surgical site infection treated with daptomycin were high and did not differ based on the need for surgical intervention. High success rates were achieved in patients with infection caused by MRSA as well as in patients who had failed to respond to previous antibiotic therapies, including vancomycin, regardless of the depth of the infection.