Staphylococcal Skin Infections
Conditions
Keywords
Complicated Skin and Skin Structure Infections (cSSSI), Methicillin-resistant Staphylococcus aureus (MRSA), Daptomycin, Vancomycin, Antibiotics
Brief summary
This was a real-world, prospective, open-label, multicenter study in which participants were randomized (1:1) to receive intravenous (IV) vancomycin or IV daptomycin. The purpose of this study is to compare infection-related hospital length of stay, along with a number of participant-reported outcomes, between participants with complicated skin and soft tissue infection treated with daptomycin and vancomycin.
Detailed description
Eligible participants will be recruited within 24 hours of hospital admission for cSSSI due to suspected or documented Methicillin-resistant Staphylococcus Aureus (MRSA), and who are anticipated to require IV antibiotics effective against MRSA and at least 3 days of hospitalization for management of cSSSI. The primary objective is to compare infection-related hospital length of stay between participants treated with daptomycin and vancomycin. Secondary objectives were to compare participant reported outcomes (pain symptoms and Health Related Quality of Life), 30 day cSSSI-related hospital readmission rates, and cSSSI-related medical resource utilization and costs between participants treated with daptomycin and vancomycin.
Interventions
DRUGDaptomycin
DRUGVancomycin
Sponsors
Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* ≥18 years of age * Primary reason for hospitalization is skin and skin structure infection of a complicated nature (for example, cellulitis/erysipelas, major cutaneous abscess, or wound infection) that requires IV antibiotic treatment for an anticipated 3 to14 days and hospitalization for management 1. Further defined as infections either involving deeper soft tissue or requiring significant surgical intervention or infections in which the participant has a significant underlying disease state that complicates the response to treatment 2. Are suspected or documented to be caused by MRSA 3. At least 3 of the following clinical signs and symptoms associated with the cSSSI: i. Pain; tenderness to palpation; ii. Elevated temperature (\>37.5°Celsius \[99.5° Farenheit\] oral or \>38° Celsius \[100.2° Farenheit\] rectal); iii. Elevated white blood count (WBC) \>10,000/millimeters cubed (mm\^3); iv. Swelling and/or induration; erythema; v. Purulent or seropurulent drainage or discharge * Physician determination that vancomycin or daptomycin would be the initial treatment of choice for the cSSSI under study (or meets institutional criteria for use of vancomycin or daptomycin) * Informed consent obtained and signed * Less than 24 hours post hospital admission
Exclusion criteria
* Participants with known bacteremia, osteomyelitis, septic arthritis, or endocarditis * Conditions where surgery (in and of itself) constitutes curative treatment of the infection (for example, amputation, incision and drainage) * cSSSIs which can be managed with an oral antibiotic * Participants where hospitalization is expected to be \<48 hours * Nosocomial infection * Participants with necrotizing infections or concomitant gangrene * Use of systemic antibacterial therapy for the infection for \> 24 hours within 48 hours prior to the start of study drug unless (a) the infecting Gram-positive pathogen was resistant in vitro to the therapy or (b) the therapy was administered for 3 or more days with either worsening or no improvement in the infection * Pathogens identified at study entry to be nonsusceptible to daptomycin or vancomycin * Participants with neutropenia or compromised immune function (that is, severe neutropenia \[absolute neutrophil count \<500 cells per microliter (μL)\] or is anticipated to develop severe neutropenia during the study period due to prior or planned therapy) * Renal insufficiency (calculated creatinine clearance \[CLcr\] \<30 milliliters per minute or on dialysis) * Known to be allergic or intolerant to daptomycin or vancomycin * Pregnant or nursing mothers * Suspected implanted device or prosthetic as source of infection * Is considered unlikely to comply with study procedures or to be available for follow-up contact
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Infection-Related Hospital Length of Stay | Baseline (Day 0) through the End of Hospital Stay (up to Day 14) | Infection Related Hospital Length of Stay (IRLOS) is defined as the number of hours of hospitalization associated with antibiotic treatment of the complicated skin and skin structure infections (cSSSI) beginning at initiation of study-antibiotic administration and ending at discontinuation of all antibiotic therapy for cSSSI or at hospital discharge (whichever occurred first). This included continued hospitalization for treatment of adverse events resulting from use of the study antibiotic or subsequent antimicrobial therapy. The mean number of hours for each treatment group is presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline to Hospital Discharge in Pain According to the Brief Pain Inventory-Short Form (BPI-SF) | Baseline (Day 0), End of Hospital Stay (up to Day 14) | Pain was measured as the amount of pain experienced right now by the participant using an 11-point numerical rating scale adapted from Brief Pain Inventory-Short Form (BPI-SF). Participants were asked to rate pain in his or her skin infection from 0 to 10, where 0 is no pain and 10 is pain as bad as he or she could imagine. Change from baseline to hospital discharge is presented; a negative value represents a decrease in pain. |
| Mean Change From Baseline to Hospital Discharge in Participant-reported Health-related Quality of Life (HRQoL) | Baseline (Day 0), End of Hospital Stay (up to Day 14) | Health-related quality of life (HRQoL) was measured using the EuroQol-5 Dimensions, 5 Level (EQ-5D-5L) multi-attribute questionnaire. The 5 dimensions measured were: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The participant's health state was expressed by a descriptive profile of a 5 digit number. The EQ-5D health states were converted into a single summary index (from 0 to 1, with 0 representing death, to 1 representing perfect health) by applying weights to each of the levels in each dimension. Change from baseline to hospital discharge is presented; positive values represent an increase in health utility. |
| Participant Global Impression of Improvement (PGI-I) at Hospital Discharge | End of Hospital Stay (up to Day 14) | PGI-I assessments of improvement were measured by asking participants: How is your skin infection today compared to how it was yesterday? Scores were calculated based on response to the single item, where 1 = improved a lot; 2 = improved moderately; 3 = improved a little; 4 = no change; 5 = worsened a little; 6 = worsened moderately; 7 = worsened a lot. Mean PGI-I scores are presented at hospital discharge; lower values represent greater improvement. |
| 30-day cSSSI-related Hospital Readmission Rates | End of Hospital Stay (up to Day 14) through 30 days post hospital discharge | Hospital readmission rates were defined as readmission to an inpatient hospital facility within 30 days of hospital discharge for management of cSSSI relapse or treatment of adverse events related to cSSSI treatment. It did not include all-cause readmissions (for completeness, all-cause readmissions are reported in the descriptive tables). Participants were asked if they had been readmitted to the hospital since their discharge and whether the admission was specifically for their skin infection. The number of participants who were re-hospitalized for skin infection or side effects due to skin infection medication within 30 days since the initial hospital discharge (Day 14) is presented. |
| cSSSI-related Medical Resource Utilization and Costs | Baseline (Day 0) through 30 days post hospital discharge | Direct medical costs were based on utilization of health resources. Unit cost data were obtained from sources external to the trial and assigned to corresponding medical resource utilization observed within the trial to estimate costs of care. cSSSI-related costs were reported from a societal perspective, and further broken down into a health care system perspective. The health care system perspective includes hospital and outpatient costs. The societal perspective includes the health care system perspective plus participant and caregiver time loss from work and participant and caregiver out-of-pocket expenses. Total cost (including both total inpatient and total post-discharge costs) per participant is presented. |
Countries
Puerto Rico, United States
Participant flow
Pre-assignment details
One participant enrolled in the study but was lost to follow up prior to being randomized to either treatment arm (daptomycin or vancomycin). This participant did not receive study drug and was not included in further analysis. No further details are available for this participant.
Participants by arm
| Arm | Count |
|---|---|
| Daptomycin Daptomycin 4 milligrams per kilogram (mg/kg) was administered intravenously once a day until end of antibiotic therapy for cSSSI or until hospital discharge, whichever occurred first. Investigators treated participants according to their usual decision-making and discretion. | 118 |
| Vancomycin Vancomycin was reconstituted per the manufacturer's instructions and was dosed and administered intravenously until end of antibiotic therapy for cSSSI or until hospital discharge, whichever occurred first. Investigators treated participants according to their usual decision-making and discretion. | 106 |
| Total | 224 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | No IRLOS-No adverse event treatment date | 0 | 1 |
| Overall Study | No IRLOS-No in-patient end date reported | 3 | 6 |
| Overall Study | No IRLOS-non trial antibiotic used | 1 | 2 |
| Overall Study | No IRLOS-randomized, not treated | 2 | 4 |
| Overall Study | Participant randomized, not treated | 1 | 0 |
| Overall Study | Site data not available | 3 | 2 |
Baseline characteristics
| Characteristic | Daptomycin | Vancomycin | Total |
|---|---|---|---|
| Age, Customized 18-29 Years Old | 16 participants | 10 participants | 26 participants |
| Age, Customized 30-39 Years Old | 22 participants | 17 participants | 39 participants |
| Age, Customized 40-49 Years Old | 30 participants | 21 participants | 51 participants |
| Age, Customized 50-59 Years Old | 26 participants | 32 participants | 58 participants |
| Age, Customized 60-69 Years Old | 14 participants | 21 participants | 35 participants |
| Age, Customized 70+ Years Old | 10 participants | 5 participants | 15 participants |
| Sex: Female, Male Female | 54 Participants | 49 Participants | 103 Participants |
| Sex: Female, Male Male | 64 Participants | 57 Participants | 121 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 15 / 118 | 9 / 106 |
Outcome results
Primary
Infection-Related Hospital Length of Stay
Infection Related Hospital Length of Stay (IRLOS) is defined as the number of hours of hospitalization associated with antibiotic treatment of the complicated skin and skin structure infections (cSSSI) beginning at initiation of study-antibiotic administration and ending at discontinuation of all antibiotic therapy for cSSSI or at hospital discharge (whichever occurred first). This included continued hospitalization for treatment of adverse events resulting from use of the study antibiotic or subsequent antimicrobial therapy. The mean number of hours for each treatment group is presented.
Time frame: Baseline (Day 0) through the End of Hospital Stay (up to Day 14)
Population: The primary analytic sample (subset of the entire sample) comprised participants receiving at least 1 dose of study drug with complete data to calculate the primary outcome, IRLOS. As the end of the IRLOS depended upon the participant's course of treatment, no static set of items were answered to determine if a participant had complete data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Daptomycin | Infection-Related Hospital Length of Stay | 91.46 Hours | Standard Deviation 57.81 |
| Vancomycin | Infection-Related Hospital Length of Stay | 93.23 Hours | Standard Deviation 60.78 |
Secondary
30-day cSSSI-related Hospital Readmission Rates
Hospital readmission rates were defined as readmission to an inpatient hospital facility within 30 days of hospital discharge for management of cSSSI relapse or treatment of adverse events related to cSSSI treatment. It did not include all-cause readmissions (for completeness, all-cause readmissions are reported in the descriptive tables). Participants were asked if they had been readmitted to the hospital since their discharge and whether the admission was specifically for their skin infection. The number of participants who were re-hospitalized for skin infection or side effects due to skin infection medication within 30 days since the initial hospital discharge (Day 14) is presented.
Time frame: End of Hospital Stay (up to Day 14) through 30 days post hospital discharge
Population: The primary analytic sample (subset of the entire sample) comprised participants receiving at least 1 dose of study drug with complete data to calculate the primary outcome, IRLOS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Daptomycin | 30-day cSSSI-related Hospital Readmission Rates | 5 participants |
| Vancomycin | 30-day cSSSI-related Hospital Readmission Rates | 2 participants |
Secondary
cSSSI-related Medical Resource Utilization and Costs
Direct medical costs were based on utilization of health resources. Unit cost data were obtained from sources external to the trial and assigned to corresponding medical resource utilization observed within the trial to estimate costs of care. cSSSI-related costs were reported from a societal perspective, and further broken down into a health care system perspective. The health care system perspective includes hospital and outpatient costs. The societal perspective includes the health care system perspective plus participant and caregiver time loss from work and participant and caregiver out-of-pocket expenses. Total cost (including both total inpatient and total post-discharge costs) per participant is presented.
Time frame: Baseline (Day 0) through 30 days post hospital discharge
Population: The primary analytic sample (subset of the entire sample) comprised participants receiving at least 1 dose of study drug with complete data to calculate the primary outcome, IRLOS.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Daptomycin | cSSSI-related Medical Resource Utilization and Costs | Health Care System Perspective | 10441.30 dollars (United States) | Standard Deviation 7952.4 |
| Daptomycin | cSSSI-related Medical Resource Utilization and Costs | Societal Perspective | 11085.57 dollars (United States) | Standard Deviation 8120.2 |
| Vancomycin | cSSSI-related Medical Resource Utilization and Costs | Health Care System Perspective | 9894.34 dollars (United States) | Standard Deviation 6620.51 |
| Vancomycin | cSSSI-related Medical Resource Utilization and Costs | Societal Perspective | 10397.24 dollars (United States) | Standard Deviation 6827.55 |
Secondary
Mean Change From Baseline to Hospital Discharge in Pain According to the Brief Pain Inventory-Short Form (BPI-SF)
Pain was measured as the amount of pain experienced right now by the participant using an 11-point numerical rating scale adapted from Brief Pain Inventory-Short Form (BPI-SF). Participants were asked to rate pain in his or her skin infection from 0 to 10, where 0 is no pain and 10 is pain as bad as he or she could imagine. Change from baseline to hospital discharge is presented; a negative value represents a decrease in pain.
Time frame: Baseline (Day 0), End of Hospital Stay (up to Day 14)
Population: The primary analytic sample (subset of the entire sample) comprised participants receiving at least 1 dose of study drug with complete data to calculate the primary outcome, IRLOS. Participants also had evaluable BPI-SF data at baseline and at hospital discharge.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Daptomycin | Mean Change From Baseline to Hospital Discharge in Pain According to the Brief Pain Inventory-Short Form (BPI-SF) | -2.08 units on a scale | Standard Deviation 3.13 |
| Vancomycin | Mean Change From Baseline to Hospital Discharge in Pain According to the Brief Pain Inventory-Short Form (BPI-SF) | -2.54 units on a scale | Standard Deviation 3.46 |
Secondary
Mean Change From Baseline to Hospital Discharge in Participant-reported Health-related Quality of Life (HRQoL)
Health-related quality of life (HRQoL) was measured using the EuroQol-5 Dimensions, 5 Level (EQ-5D-5L) multi-attribute questionnaire. The 5 dimensions measured were: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The participant's health state was expressed by a descriptive profile of a 5 digit number. The EQ-5D health states were converted into a single summary index (from 0 to 1, with 0 representing death, to 1 representing perfect health) by applying weights to each of the levels in each dimension. Change from baseline to hospital discharge is presented; positive values represent an increase in health utility.
Time frame: Baseline (Day 0), End of Hospital Stay (up to Day 14)
Population: The primary analytic sample (subset of the entire sample) comprised participants receiving at least 1 dose of study drug with complete data to calculate the primary outcome, IRLOS. Participants also had evaluable EQ-5D data at baseline and at hospital discharge.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Daptomycin | Mean Change From Baseline to Hospital Discharge in Participant-reported Health-related Quality of Life (HRQoL) | 0.12 units on a scale | Standard Deviation 0.2 |
| Vancomycin | Mean Change From Baseline to Hospital Discharge in Participant-reported Health-related Quality of Life (HRQoL) | 0.18 units on a scale | Standard Deviation 0.21 |
Secondary
Participant Global Impression of Improvement (PGI-I) at Hospital Discharge
PGI-I assessments of improvement were measured by asking participants: How is your skin infection today compared to how it was yesterday? Scores were calculated based on response to the single item, where 1 = improved a lot; 2 = improved moderately; 3 = improved a little; 4 = no change; 5 = worsened a little; 6 = worsened moderately; 7 = worsened a lot. Mean PGI-I scores are presented at hospital discharge; lower values represent greater improvement.
Time frame: End of Hospital Stay (up to Day 14)
Population: The primary analytic sample (subset of the entire sample) comprised participants receiving at least 1 dose of study drug with complete data to calculate the primary outcome, IRLOS. Participants also had evaluable PGI-I data at hospital discharge.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Daptomycin | Participant Global Impression of Improvement (PGI-I) at Hospital Discharge | 2.05 units on a scale | Standard Deviation 1.16 |
| Vancomycin | Participant Global Impression of Improvement (PGI-I) at Hospital Discharge | 1.80 units on a scale | Standard Deviation 0.94 |