"The U.S. Food and Drug Administration today approved Dotarem (gadoterate meglumine) for use in magnetic resonance imaging (MRI) of the brain, spine and associated tissues of patients ages 2 years and older.
Dotarem is a gadolinium-based"...
Mechanism Of Action
Daptomycin is an antibacterial drug [see Microbiology].
Based on animal models of infection, the antimicrobial activity of daptomycin appears to correlate with the AUC/MIC (area under the concentration-time curve/minimum inhibitory concentration) ratio for certain pathogens, including S. aureus. The principal pharmacokinetic/pharmacodynamic parameter best associated with clinical and microbiological cure has not been elucidated in clinical trials with CUBICIN.
CUBICIN Administered Over A 30-Minute Period
The mean and standard deviation (SD) pharmacokinetic parameters of daptomycin at steady-state following intravenous (IV) administration of CUBICIN over a 30-minute period at 4 to 12 mg/kg q24h to healthy young adults are summarized in Table 7.
Table 7: Mean (SD) Daptomycin Pharmacokinetic
Parameters in Healthy Volunteers at Steady-State
|AUC0-24 (mcg•h/mL)||t½h||Vss (L/kg)||CLT (mL/h/kg)||Cmax (mcg/mL)|
|4 (N=6)||494 (75)||8.1 (1.0)||0.096 (0.009)||8.3 (1.3)||57.8 (3.0)|
|6 (N=6)||632 (78)||7.9 (1.0)||0.101 (0.007)||9.1 (1.5)||93.9 (6.0)|
|8 (N=6)||858 (213)||8.3 (2.2)||0.101 (0.013)||9.0 (3.0)||123.3 (16.0)|
|10 (N=9)||1039 (178)||7.9 (0.6)||0.098 (0.017)||8.8 (2.2)||141.1 (24.0)|
|12 (N=9)||1277 (253)||7.7 (1.1)||0.097 (0.018)||9.0 (2.8)||183.7 (25.0)|
|*CUBICIN was administered by IV infusion over a 30-minute
†Doses of CUBICIN in excess of 6 mg/kg have not been approved.
‡AUC0-24, area under the concentration-time curve from 0 to 24 hours; t½, elimination half-life; VSS, volume of distribution at steady-state; CLT, total plasma clearance; Cmax, maximum plasma concentration.
Daptomycin pharmacokinetics were generally linear and time-independent at CUBICIN doses of 4 to 12 mg/kg q24h administered by IV infusion over a 30-minute period for up to 14 days. Steady-state trough concentrations were achieved by the third daily dose. The mean (SD) steady-state trough concentrations attained following the administration of 4, 6, 8, 10, and 12 mg/kg q24h were 5.9 (1.6), 6.7 (1.6), 10.3 (5.5), 12.9 (2.9), and 13.7 (5.2) mcg/mL, respectively.
CUBICIN Administered Over A 2-Minute Period
Following IV administration of CUBICIN over a 2-minute period to healthy volunteers at doses of 4 mg/kg (N=8) and 6 mg/kg (N=12), the mean (SD) steady-state systemic exposure (AUC) values were 475 (71) and 701 (82) mcg·h/mL, respectively. Values for maximum plasma concentration (Cmax) at the end of the 2-minute period could not be determined adequately in this study. However, using pharmacokinetic parameters from 14 healthy volunteers who received a single dose of CUBICIN 6 mg/kg IV administered over a 30-minute period in a separate study, steady-state Cmax values were simulated for CUBICIN 4 and 6 mg/kg IV administered over a 2-minute period. The simulated mean (SD) steady-state Cmax values were 77.7 (8.1) and 116.6 (12.2) mcg/mL, respectively.
Daptomycin is reversibly bound to human plasma proteins, primarily to serum albumin, in a concentration-independent manner. The overall mean binding ranges from 90 to 93%.
In clinical studies, mean serum protein binding in subjects with creatinine clearance (CLCR) ≥ 30 mL/min was comparable to that observed in healthy subjects with normal renal function. However, there was a trend toward decreasing serum protein binding among subjects with CLCR < 30 mL/min (88%), including those receiving hemodialysis (86%) and continuous ambulatory peritoneal dialysis (CAPD) (84%). The protein binding of daptomycin in subjects with moderate hepatic impairment (Child-Pugh Class B) was similar to that in healthy adult subjects.
The volume of distribution at steady-state (Vss) of daptomycin in healthy adult subjects was approximately 0.1 L/kg and was independent of dose.
In in vitro studies, daptomycin was not metabolized by human liver microsomes.
In 5 healthy adults after infusion of radiolabeled 14C-daptomycin, the plasma total radioactivity was similar to the concentration determined by microbiological assay. Inactive metabolites were detected in urine, as determined by the difference between total radioactive concentrations and microbiologically active concentrations. In a separate study, no metabolites were observed in plasma on Day 1 following the administration of CUBICIN at 6 mg/kg to subjects. Minor amounts of three oxidative metabolites and one unidentified compound were detected in urine. The site of metabolism has not been identified.
Daptomycin is excreted primarily by the kidneys. In a mass balance study of 5 healthy subjects using radiolabeled daptomycin, approximately 78% of the administered dose was recovered from urine based on total radioactivity (approximately 52% of the dose based on microbiologically active concentrations), and 5.7% of the administered dose was recovered from feces (collected for up to 9 days) based on total radioactivity.
Population-derived pharmacokinetic parameters were determined for infected patients (complicated skin and skin structure infections [cSSSI] and S. aureus bacteremia) and noninfected subjects with various degrees of renal function (Table 8). Total plasma clearance (CLT), elimination half-life (t1/2), and volume of distribution at steady-state (Vss) in patients with cSSSI were similar to those in patients with S. aureus bacteremia. Following administration of CUBICIN 4 mg/kg q24h by IV infusion over a 30- minute period, the mean CLCR was 9%, 22%, and 46% lower among subjects and patients with mild (CLCR 50–80 mL/min), moderate (CLCR 30– < 50 mL/min), and severe (CLCR < 30 mL/min) renal impairment, respectively, than in those with normal renal function (CLCR > 80 mL/min). The mean steadystate systemic exposure (AUC), t1/2, and Vss increased with decreasing renal function, although the mean AUC for patients with CLCR 30–80 mL/min was not markedly different from the mean AUC for patients with normal renal function. The mean AUC for patients with CLCR < 30 mL/min and for patients on dialysis (CAPD and hemodialysis dosed post-dialysis) was approximately 2 and 3 times higher, respectively, than for patients with normal renal function. The mean Cmax ranged from 60 to 70 mcg/mL in patients with CLCR ≥ 30 mL/min, while the mean Cmax for patients with CLCR < 30 mL/min ranged from 41 to 58 mcg/mL. After administration of CUBICIN 6 mg/kg q24h by IV infusion over a 30-minute period, the mean Cmax ranged from 80 to 114 mcg/mL in patients with mild to moderate renal impairment and was similar to that of patients with normal renal function.
Table 8: Mean (SD) Daptomycin Population
Pharmacokinetic Parameters Following Infusion of CUBICIN 4 mg/kg or 6 mg/kg to
Infected Patients and Noninfected Subjects with Various Degrees of Renal
|Renal Function||Pharmacokinetic Parameters*|
|t½† (h) 4 mg/kg||Vss (L/kg) 4 mg/kg||CLT † (mL/h/kg) 4 mg/kg||AUC 0 -∞† (mcg•h/mL) 4 mg/kg||AUC (mcg•h/mL) 6 mg/kg||Cmin,ss‡ (mcg/mL) 6 mg/kg|
|Normal||9.39 (4.74)||0.13 (0.05)||10.9 (4.0)||417 (155)||545 (296)||6.9 (3.5)|
|(CLCR > 80 mL/min)||N=165||N=165||N=165||N=165||N=62||N=61|
|Mild Renal Impairment (CLCR50-80 mL/min)||10.75 (8.36) N=64||0.12 (0.05) N=64||9.9 (4.0) N=64||466 (177) N=64||637 (215) N=29||12.4 (5.6) N=29|
|Moderate Renal Impairment (CLCR 30- < 50 mL/min)||14.70 (10.50) N=24||0.15 (0.06) N=24||8.5 (3.4) N=24||560 (258) N=24||868 (349) N=15||19.0 (9.0) N=14|
|Severe Renal Impairment (CLCR < 30 mL/min)||27.83 (14.85) N=8||0.20 (0.15) N=8||5.9 (3.9) N=8||925 (467) N=8||1050, 892 N=2||24.4, 21.4 N=2|
|Hemodialysis||30.51 (6.51) N=16||0.16 (0.04) N=16||3.9 (2.1) N=16||1193 (399) N=16||NA||NA|
|CAPD||27.56 (4.53) N=5||0.11 (0.02) N=5||2.9 (0.4) N=5||1409 (238) N=5||NA||NA|
|Note: CUBICIN was administered over a 30-minute period.
*CLCR, creatinine clearance estimated using the Cockcroft-Gault equation with actual body weight; CAPD, continuous ambulatory peritoneal dialysis; AUC0-∞, area under the concentration-time curve extrapolated to infinity; AUCss, area under the concentration-time curve calculated over the 24 -hour dosing interval at steadystate; Cmax, trough concentration at steady-state; NA, not applicable.
†Parameters obtained following a single dose from patients with complicated skin and skin structure infections and healthy subjects.
‡Parameters obtained at steady-state from patients with S. aureus bacteremia.
Because renal excretion is the primary route of elimination, adjustment of CUBICIN dosage interval is necessary in patients with severe renal impairment (CL < 30 mL/min) [see DOSAGE AND ADMINISTRATION].
The pharmacokinetics of daptomycin were evaluated in 10 subjects with moderate hepatic impairment (Child-Pugh Class B) and compared with those in healthy volunteers (N=9) matched for gender, age, and weight. The pharmacokinetics of daptomycin were not altered in subjects with moderate hepatic impairment. No dosage adjustment is warranted when CUBICIN is administered to patients with mild to moderate hepatic impairment. The pharmacokinetics of daptomycin in patients with severe hepatic impairment (Child-Pugh Class C) have not been evaluated.
No clinically significant gender-related differences in daptomycin pharmacokinetics have been observed. No dosage adjustment is warranted based on gender when CUBICIN is administered.
The pharmacokinetics of daptomycin were evaluated in 12 healthy elderly subjects ( ≥ 75 years of age) and 11 healthy young controls (18 to 30 years of age). Following administration of a single 4 mg/kg dose of CUBICIN by IV infusion over a 30-minute period, the mean total clearance of daptomycin was approximately 35% lower and the mean AUC0-∞ was approximately 58% higher in elderly subjects than in healthy young subjects. There were no differences in Cmax [see Use in Specific Populations].
The pharmacokinetics of daptomycin were evaluated in 6 moderately obese (Body Mass Index [BMI] 25 to 39.9 kg/m²) and 6 extremely obese (BMI ≥ 40 kg/m²) subjects and controls matched for age, gender, and renal function. Following administration of CUBICIN by IV infusion over a 30-minute period as a single 4 mg/kg dose based on total body weight, the total plasma clearance of daptomycin normalized to total body weight was approximately 15% lower in moderately obese subjects and 23% lower in extremely obese subjects than in nonobese controls. The AUC0-∞ of daptomycin was approximately 30% higher in moderately obese subjects and 31% higher in extremely obese subjects than in nonobese controls. The differences were most likely due to differences in the renal clearance of daptomycin. No adjustment of CUBICIN dosage is warranted in obese patients.
The pharmacokinetics of daptomycin in pediatric populations ( < 18 years of age) have not been established [see Nonclinical Toxicology].
In Vitro Studies
In vitro studies with human hepatocytes indicate that daptomycin does not inhibit or induce the activities of the following human cytochrome P450 isoforms: 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4. It is unlikely that daptomycin will inhibit or induce the metabolism of drugs metabolized by the P450 system.
In a study in which 15 healthy adult subjects received a single dose of CUBICIN 6 mg/kg IV and a combination dose of CUBICIN 6 mg/kg IV and aztreonam 1 g IV, administered over a 30-minute period, the Cmax and AUC0-∞ of daptomycin were not significantly altered by aztreonam.
In a study in which 6 healthy adult males received a single dose of CUBICIN 2 mg/kg IV, tobramycin 1 mg/kg IV, and both in combination, administered over a 30-minute period, the mean Cmax and AUC0-∞ of daptomycin were 12.7% and 8.7% higher, respectively, when CUBICIN was coadministered with tobramycin. The mean Cmax and AUC0-∞ of tobramycin were 10.7% and 6.6% lower, respectively, when tobramycin was coadministered with CUBICIN. These differences were not statistically significant. The interaction between daptomycin and tobramycin with a clinical dose of CUBICIN is unknown.
In 16 healthy subjects, administration of CUBICIN 6 mg/kg q24h by IV infusion over a 30-minute period for 5 days, with coadministration of a single oral dose of warfarin (25 mg) on the 5th day, had no significant effect on the pharmacokinetics of either drug and did not significantly alter the INR (International Normalized Ratio).
In 20 healthy subjects on a stable daily dose of simvastatin 40 mg, administration of CUBICIN 4 mg/kg q24h by IV infusion over a 30-minute period for 14 days (N=10) had no effect on plasma trough concentrations of simvastatin and was not associated with a higher incidence of adverse events, including skeletal myopathy, than in subjects receiving placebo once daily (N=10) [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
Concomitant administration of probenecid (500 mg 4 times daily) and a single dose of CUBICIN 4 mg/kg by IV infusion over a 30-minute period did not significantly alter the Cmax or AUC0-∞ of daptomycin.
Daptomycin belongs to the cyclic lipopeptide class of antibacterials. Daptomycin has clinical utility in the treatment of infections caused by aerobic, Gram-positive bacteria. The in vitro spectrum of activity of daptomycin encompasses most clinically relevant Gram-positive pathogenic bacteria.
Daptomycin exhibits rapid, concentration-dependent bactericidal activity against Gram-positive bacteria in vitro. This has been demonstrated both by time-kill curves and by MBC/MIC (minimum bactericidal concentration/minimum inhibitory concentration) ratios using broth dilution methodology. Daptomycin maintained bactericidal activity in vitro against stationary phase S. aureus in simulated endocardial vegetations. The clinical significance of this is not known.
Mechanism Of Action
The mechanism of action of daptomycin is distinct from that of any other antibacterial. Daptomycin binds to bacterial cell membranes and causes a rapid depolarization of membrane potential. This loss of membrane potential causes inhibition of DNA, RNA, and protein synthesis, which results in bacterial cell death.
Mechanism Of Resistance
The mechanism(s) of daptomycin resistance is not fully understood. Currently, there are no known transferable elements that confer resistance to daptomycin.
Complicated Skin And Skin Structure Infection (cSSSI) Trials
The emergence of daptomycin non-susceptible isolates occurred in 2 infected patients across the set of Phase 2 and pivotal Phase 3 clinical trials of cSSSI. In one case, a non-susceptible S. aureus was isolated from a patient in a Phase 2 trial who received CUBICIN at less than the protocol-specified dose for the initial 5 days of therapy. In the second case, a non-susceptible Enterococcus faecalis was isolated from a patient with an infected chronic decubitus ulcer who was enrolled in a salvage trial.
S. Aureus Bacteremia/Endocarditis And Other Post-Approval Trials
In subsequent clinical trials, non-susceptible isolates were recovered. S. aureus was isolated from a patient in a compassionate-use trial and from 7 patients in the S. aureus bacteremia/endocarditis trial [see Clinical Trials]. An E. faecium was isolated from a patient in a vancomycin-resistant enterococci trial.
Interactions With Other Antibacterials
In vitro studies have investigated daptomycin interactions with other antibacterials. Antagonism, as determined by kill curve studies, has not been observed. In vitro synergistic interactions of daptomycin with aminoglycosides, β-lactam antibacterials, and rifampin have been shown against some isolates of staphylococci (including some methicillin-resistant isolates) and enterococci (including some vancomycin-resistant isolates).
Activity In Vitro And In Vivo
Daptomycin has been shown to be active against most isolates of the following Gram-positive bacteria both in vitro and in clinical infections, as described in Indications and Usage (1).
Enterococcus faecalis (vancomycin-susceptible
Staphylococcus aureus (including methicillin-resistant isolates)
Streptococcus dysgalactiae subsp. equisimilis
The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following Gram-positive bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for daptomycin versus the bacterial genus (Table 9). However, the efficacy of CUBICIN in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.
Enterococcus faecalis (vancomycin-resistant isolates)
Enterococcus faecium (including vancomycin-resistant isolates)
Staphylococcus epidermidis (including methicillin-resistant isolates)
Susceptibility Testing Methods
When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility tests for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized broth test method with the broth adjusted to a calcium content of 50 mg/L. The use of the agar dilution method is not recommended with daptomycin2,3. The MICs should be interpreted according to the criteria listed in Table 9.
Table 9: Susceptibility Interpretive Criteria for
|Pathogen||Broth Dilution MIC* (mcg/mL)|
|Staphylococcus aureus (methicillin-susceptible and methicillin-resistant)||≤ 1||(†)||(†)|
|Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus dysgalactiae subsp. equisimilis||≤ 1||(†)||(†)|
|Enterococcus faecalis (vancomycin-susceptible only)||≤ 4||(†)||(†)|
|Note: S, Susceptible; I, Intermediate; R, Resistant.
*The MIC interpretive criteria for S. aureus and E. faecalis are applicable only to tests performed by broth dilution using Mueller-Hinton broth adjusted to a calcium content of 50 mg/L; the MIC interpretive criteria for Streptococcus spp. other than S. pneumoniae are applicable only to tests performed by broth dilution using Mueller- Hinton broth adjusted to a calcium content of 50 mg/L, supplemented with 2 to 5% lysed horse blood, inoculated with a direct colony suspension and incubated in ambient air at 35° C for 20 to 24 hours.
†The current absence of data on daptomycin-resistant isolates precludes defining any categories other than “Susceptible.” Isolates yielding test results suggestive of a “Non-Susceptible” category should be retested, and if the result is confirmed, the isolate should be submitted to a reference laboratory for further testing.
A report of “Susceptible” indicates that the antimicrobial is likely to inhibit the growth of the pathogen if the antimicrobial compound reaches the concentration at the infection site necessary to inhibit growth of the pathogen.
Quantitative methods that require measurement of zone diameters have not been shown to provide reproducible estimates of the susceptibility of bacteria to daptomycin. The use of the disk diffusion method is not recommended with daptomycin3,4.
Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test2,3. Standard daptomycin powder should provide the ranges of MIC values noted in Table 10.
Table 10: Acceptable Quality Control Ranges for
Daptomycin to Be Used in Validation of Susceptibility Test Results
|Quality Control Strain||Broth Dilution MIC Range* (mcg/mL)|
|Enterococcus faecalis ATCC 29212||1-4|
|Staphylococcus aureus ATCC 29213||0.12-1|
|Streptococcus pneumoniae ATCC 49619†||0.06-0.5|
|*The quality control ranges for S. aureus and E.
faecalis are applicable only to tests performed by broth dilution using
Mueller-Hinton broth adjusted to a calcium content of 50 mg/L; the quality
control range for Streptococcus pneumoniae is applicable only to tests performed
by broth dilution using Mueller-Hinton broth adjusted to a calcium content of 50
mg/L, supplemented with 2 to 5% lysed horse blood, inoculated with a direct
colony suspension and incubated in ambient air at 35° C for 20 to 24 hours.
†This strain may be used for validation of susceptibility test results when testing Streptococcus spp. other than S. pneumoniae.
Animal Toxicology And/Or Pharmacology
In animals, daptomycin administration has been associated with effects on skeletal muscle. However, there were no changes in cardiac or smooth muscle. Skeletal muscle effects were characterized by microscopic degenerative/regenerative changes and variable elevations in creatine phosphokinase (CPK). No fibrosis or rhabdomyolysis was evident in repeat-dose studies up to the highest doses tested in rats (150 mg/kg/day) and dogs (100 mg/kg/day). The degree of skeletal myopathy showed no increase when treatment was extended from 1 month to up to 6 months. Severity was dose-dependent. All muscle effects, including microscopic changes, were fully reversible within 30 days following the cessation of dosing.
In adult animals, effects on peripheral nerve (characterized by axonal degeneration and frequently accompanied by significant losses of patellar reflex, gag reflex, and pain perception) were observed at daptomycin doses higher than those associated with skeletal myopathy. Deficits in the dogs' patellar reflexes were seen within 2 weeks after the start of treatment at 40 mg/kg/day (9 times the human Cmax at the 6 mg/kg/day dose), with some clinical improvement noted within 2 weeks after the cessation of dosing. However, at 75 mg/kg/day for 1 month, 7 of 8 dogs failed to regain full patellar reflex responses within a 3-month recovery period. In a separate study in dogs receiving doses of 75 and 100 mg/kg/day for 2 weeks, minimal residual histological changes were noted at 6 months after the cessation of dosing. However, recovery of peripheral nerve function was evident.
Tissue distribution studies in rats showed that daptomycin is retained in the kidney but appears to penetrate the blood-brain barrier only minimally following single and multiple doses.
Target organs of daptomycin-related effects in 7-week-old juvenile dogs were skeletal muscle and nerve, the same target organs as in adult dogs. In juvenile dogs, nerve effects were noted at lower daptomycin blood concentrations than in adult dogs following 28 days of dosing. In contrast to adult dogs, juvenile dogs also showed evidence of effects in nerves of the spinal cord as well as peripheral nerves after 28 days of dosing. No nerve effects were noted in juvenile dogs following 14 days of dosing at doses up to 75 mg/kg/day.
Administration of daptomycin to 7-week-old juvenile dogs for 28 days at doses of 50 mg/kg/day produced minimal degenerative effects on the peripheral nerve and spinal cord in several animals, with no corresponding clinical signs. A dose of 150 mg/kg/day for 28 days produced minimal degeneration in the peripheral nerve and spinal cord as well as minimal to mild degeneration of the skeletal muscle in a majority of animals, accompanied by slight to severe muscle weakness evident in most dogs. Following a 28-day recovery phase, microscopic examination revealed recovery of the skeletal muscle and the ulnar nerve effects, but nerve degeneration in the sciatic nerve and spinal cord was still observed in all 150 mg/kg/day dogs.
Following once-daily administration of daptomycin to juvenile dogs for 28 days, microscopic effects in nerve tissue were noted at a Cmax value of 417 mcg/mL, which is approximately 3-fold less than the Cmax value associated with nerve effects in adult dogs treated once daily with daptomycin for 28 days (1308 mcg/mL).
Neonatal dogs (4 to 31 days old) were more sensitive to daptomycin-related adverse nervous system and/or muscular system effects than either juvenile or adult dogs. In neonatal dogs, adverse nervous system and/or muscular system effects were associated with a Cmax value approximately 3-fold less than the Cmax in juvenile dogs, and 9-fold less than the Cmax in adult dogs following 28 days of dosing. At a dose of 25 mg/kg/day with associated Cmax and AUCinf values of 147 mcg/mL and 717 mcg·h/mL, respectively (1.6 and 1.0-fold the adult human Cmax and AUC, respectively, at the 6 mg/kg/day dose), mild clinical signs of twitching and one incidence of muscle rigidity were observed with no corresponding effect on body weight. These effects were found to be reversible within 28 days after treatment had stopped.
At higher dose levels of 50 and 75 mg/kg/day with associated Cmax and AUCinf values of ≥ 321 mcg/mL and ≥ 1470 mcg·h/mL, respectively, marked clinical signs of twitching, muscle rigidity in the limbs, and impaired use of limbs were observed. Resulting decreases in body weights and overall body condition at doses ≥ 50 mg/kg/day necessitated early discontinuation by PND19.
Histopathological assessment did not reveal any daptomycin-related changes in the peripheral and central nervous system tissue, as well as in the skeletal muscle or other tissues assessed, at any dose level.
No adverse effects were observed in the dogs that received daptomycin at 10 mg/kg/day, the NOAEL, with associated Cmax and AUCinf values of 62 mcg/mL and 247 mcg·h/mL, respectively (or 0.6 and 0.4- fold the adult human Cmax and AUC, respectively at the 6 mg/kg dose).
Complicated Skin And Skin Structure Infections
Adult patients with clinically documented complicated skin and skin structure infections (cSSSI) (Table 11) were enrolled in two randomized, multinational, multicenter, investigator-blinded trials comparing CUBICIN (4 mg/kg IV q24h) with either vancomycin (1 g IV q12h) or an anti-staphylococcal semisynthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 4 to 12 g IV per day). Patients could switch to oral therapy after a minimum of 4 days of IV treatment if clinical improvement was demonstrated. Patients known to have bacteremia at baseline were excluded. Patients with creatinine clearance (CLCR ) between 30 and 70 mL/min were to receive a lower dose of CUBICIN as specified in the protocol; however, the majority of patients in this subpopulation did not have the dose of CUBICIN adjusted.
Table 11: Investigator's Primary Diagnosis in the
cSSSI Trials (Population: Intent-to-Treat)
|Primary Diagnosis||Patients (CUBICIN / Comparator*)|
N=264 / N=266
N=270 / N=292
N=534 / N=558
|Wound Infection||99 (38%) / 116 (44%)||102 (38%) / 108 (37%)||201 (38%) / 224 (40%)|
|Major Abscess||55 (21%) / 43 (16%)||59 (22%) / 65 (22%)||114 (21%) / 108 (19%)|
|Ulcer Infection||71 (27%) / 75 (28%)||53 (20%) / 68 (23%)||124 (23%) / 143 (26%)|
|Other Infection†||39 (15%) / 32 (12%)||56 (21%) / 51 (18%)||95 (18%) / 83 (15%)|
|*Comparator: vancomycin (1 g IV q12h) or an
anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin,
or flucloxacillin; 4 to 12 g/day IV in divided doses).
†The majority of cases were subsequently categorized as complicated cellulitis, major abscesses, or traumatic wound infections.
One trial was conducted primarily in the United States and South Africa (study 9801), and the second was conducted at non-US sites only (study 9901). The two trials were similar in design but differed in patient characteristics, including history of diabetes and peripheral vascular disease. There were a total of 534 patients treated with CUBICIN and 558 treated with comparator in the two trials. The majority (89.7%) of patients received IV medication exclusively.
The efficacy endpoints in both trials were the clinical success rates in the intent-to-treat (ITT) population and in the clinically evaluable (CE) population. In study 9801, clinical success rates in the ITT population were 62.5% (165/264) in patients treated with CUBICIN and 60.9% (162/266) in patients treated with comparator drugs. Clinical success rates in the CE population were 76.0% (158/208) in patients treated with CUBICIN and 76.7% (158/206) in patients treated with comparator drugs. In study 9901, clinical success rates in the ITT population were 80.4% (217/270) in patients treated with CUBICIN and 80.5% (235/292) in patients treated with comparator drugs. Clinical success rates in the CE population were 89.9% (214/238) in patients treated with CUBICIN and 90.4% (226/250) in patients treated with comparator drugs.
The success rates by pathogen for microbiologically evaluable patients are presented in Table 12.
Table 12: Clinical Success Rates by Infecting Pathogen
in the cSSSI Trials (Population: Microbiologically Evaluable)
|Pathogen||Success Rate n/N (%)|
|Methicillin-susceptible Staphylococcus aureus (MSSA)†||170/198 (86%)||180/207 (87%)|
|Methicillin-resistant Staphylococcus aureus (MRSA)†||21/28 (75%)||25/36 (69%)|
|Streptococcus pyogenes||79/84 (94%)||80/88 (91%)|
|Streptococcus agalactiae||23/27 (85%)||22/29 (76%)|
|Streptococcus dysgalactiae subsp. equisimilis||8/8 (100%)||9/11 (82%)|
|Enterococcus faecalis (vancomycin-susceptible only)||27/37 (73%)||40/53 (76%)|
|*Comparator: vancomycin (1 g IV q12h) or an
anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin,
or flucloxacillin; 4 to 12 g/day IV in divided doses).
†As determined by the central laboratory.
S. Aureus Bacteremia/Endocarditis
The efficacy of CUBICIN in the treatment of patients with S. aureus bacteremia was demonstrated in a randomized, controlled, multinational, multicenter, open-label trial. In this trial, adult patients with at least one positive blood culture for S. aureus obtained within 2 calendar days prior to the first dose of study drug and irrespective of source were enrolled and randomized to either CUBICIN (6 mg/kg IV q24h) or standard of care [an anti-staphylococcal semi-synthetic penicillin 2 g IV q4h (nafcillin, oxacillin, cloxacillin, or flucloxacillin) or vancomycin 1 g IV q12h, each with initial gentamicin 1 mg/kg IV every 8 hours for first 4 days]. Of the patients in the comparator group, 93% received initial gentamicin for a median of 4 days, compared with 1 patient ( < 1%) in the CUBICIN group. Patients with prosthetic heart valves, intravascular foreign material that was not planned for removal within 4 days after the first dose of study medication, severe neutropenia, known osteomyelitis, polymicrobial bloodstream infections, creatinine clearance < 30 mL/min, and pneumonia were excluded.
Upon entry, patients were classified for likelihood of endocarditis using the modified Duke criteria (Possible, Definite, or Not Endocarditis). Echocardiography, including a transesophageal echocardiogram (TEE), was performed within 5 days following study enrollment. The choice of comparator agent was based on the oxacillin susceptibility of the S. aureus isolate. The duration of study treatment was based on the investigator's clinical diagnosis. Final diagnoses and outcome assessments at Test of Cure (6 weeks after the last treatment dose) were made by a treatment-blinded
Adjudication Committee, using protocol-specified clinical definitions and a composite primary efficacy endpoint (clinical and microbiological success) at the Test of Cure visit. A total of 246 patients ≥ 18 years of age (124 CUBICIN, 122 comparator) with S. aureus bacteremia were randomized from 48 centers in the US and Europe. In the ITT population, 120 patients received CUBICIN and 115 received comparator (62 received an anti-staphylococcal semi-synthetic penicillin and 53 received vancomycin). Thirty-five patients treated with an anti-staphylococcal semi-synthetic penicillin received vancomycin initially for 1 to 3 days, pending final susceptibility results for the S. aureus isolates. The median age among the 235 patients in the ITT population was 53 years (range: 21 to 91 years); 30/120 (25%) in the CUBICIN group and 37/115 (32%) in the comparator group were ≥ 65 years of age. Of the 235 ITT patients, there were 141 (60%) males and 156 (66%) Caucasians across the two treatment groups. In addition, 176 (75%) of the ITT population had systemic inflammatory response syndrome (SIRS) at baseline and 85 (36%) had surgical procedures within 30 days prior to onset of the S. aureus bacteremia. Eighty-nine patients (38%) had bacteremia caused by methicillinresistant S. aureus (MRSA). Entry diagnosis was based on the modified Duke criteria and comprised 37 (16%) Definite, 144 (61%) Possible, and 54 (23%) Not Endocarditis. Of the 37 patients with an entry diagnosis of Definite Endocarditis, all (100%) had a final diagnosis of infective endocarditis, and of the 144 patients with an entry diagnosis of Possible Endocarditis, 15 (10%) had a final diagnosis of infective endocarditis as assessed by the Adjudication Committee. Of the 54 patients with an entry diagnosis of Not Endocarditis, 1 (2%) had a final diagnosis of infective endocarditis as assessed by the Adjudication Committee.
In the ITT population, there were 182 patients with bacteremia and 53 patients with infective endocarditis as assessed by the Adjudication Committee, including 35 with right-sided endocarditis and 18 with left-sided endocarditis. The 182 patients with bacteremia comprised 121 with complicated S. aureus bacteremia and 61 with uncomplicated S. aureus bacteremia.
Complicated bacteremia was defined as S. aureus isolated from blood cultures obtained on at least 2 different calendar days, and/or metastatic foci of infection (deep tissue involvement), and classification of the patient as not having endocarditis according to the modified Duke criteria. Uncomplicated bacteremia was defined as S. aureus isolated from blood culture(s) obtained on a single calendar day, no metastatic foci of infection, no infection of prosthetic material, and classification of the patient as not having endocarditis according to the modified Duke criteria. The definition of right-sided infective endocarditis (RIE) used in the clinical trial was Definite or Possible Endocarditis according to the modified Duke criteria and no echocardiographic evidence of predisposing pathology or active involvement of either the mitral or aortic valve. Complicated RIE comprised patients who were not intravenous drug users, had a positive blood culture for MRSA, serum creatinine ≥ 2.5 mg/dL, or evidence of extrapulmonary sites of infection. Patients who were intravenous drug users, had a positive blood culture for methicillin-susceptible S. aureus (MSSA), had serum creatinine < 2.5 mg/dL, and were without evidence of extrapulmonary sites of infection were considered to have uncomplicated RIE.
The coprimary efficacy endpoints in the trial were the Adjudication Committee success rates at the Test of Cure visit (6 weeks after the last treatment dose) in the ITT and Per Protocol (PP) populations. The overall Adjudication Committee success rates in the ITT population were 44.2% (53/120) in patients treated with CUBICIN and 41.7% (48/115) in patients treated with comparator (difference = 2.4% [95% CI -10.2, 15.1]). The success rates in the PP population were 54.4% (43/79) in patients treated with CUBICIN and 53.3% (32/60) in patients treated with comparator (difference = 1.1% [95% CI -15.6, 17.8]).
Adjudication Committee success rates are shown in Table 13.
Table 13: Adjudication Committee Success Rates at Test
of Cure in the S. aureus Bacteremia/Endocarditis Trial (Population: ITT)
|Population||Success Rate n/N (%)||Difference: CUBICIN-Comparator (Confidence Interval)|
|CUBICIN 6 mg/kg||Comparator*|
|Overall||53/120 (44%)||48/115 (42%)||2.4% (-10.2, 15.1)†|
|Methicillin-susceptible S. aureus||33/74 (45%)||34/70 (49%)||-4.0% (-22.6, 14.6)‡|
|Methicillin-resistant S. aureus||20/45 (44%)||14/44 (32%)||12.6% (-10.2, 35.5)†|
|Definite or Possible Infective Endocarditis||41/90 (46%)||37/91 (41%)||4.9% (-11.6, 21.4)‡|
|Not Infective Endocarditis||12/30 (40%)||11/24 (46%)||-5.8% (-36.2, 24.5)‡|
|Uncomplicated Bacteremia||18/32 (56%)||16/29 (55%)||1.1% (-31.7, 33.9);|
|Complicated Bacteremia||26/60 (43%)||23/61 (38%)||5.6% (-17.3, 28.6)¶|
|Right-Sided Infective Endocarditis||8/19 (42%)||7/16 (44%)||-1.6% (-44.9, 41.6)¶|
|Uncomplicated Right-Sided Infective Endocarditis||3/6 (50%)||1/4 (25%)||25.0% (-51.6, 100.0)¶|
|Complicated Right-Sided Infective Endocarditis||5/13 (39%)||6/12 (50%)||-11.5% (-62.4, 39.4)¶|
|Left-Sided Infective Endocarditis||1/9 (11%)||2/9 (22%)||-11.1% (-55.9, 33.6)¶|
|*Comparator: vancomycin (1 g IV q12h) or an
anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin,
or flucloxacillin; 2 g IV q4 h), each with initial low-dose gentamicin.
†95% Confidence Interval
‡97.5% Confidence Interval (adjusted for multiplicity)
§According to the modified Duke criteria5
¶99% Confidence Interval (adjusted for multiplicity)
Eighteen (18/120) patients in the CUBICIN arm and 19/116 patients in the comparator arm died during the trial. These comprise 3/28 CUBICIN-treated patients and 8/26 comparator-treated patients with endocarditis, as well as 15/92 CUBICIN-treated patients and 11/90 comparator-treated patients with bacteremia. Among patients with persisting or relapsing S. aureus infections, 8/19 CUBICIN-treated patients and 7/11 comparator-treated patients died.
Overall, there was no difference in time to clearance of S. aureus bacteremia between CUBICIN and comparator. The median time to clearance in patients with MSSA was 4 days and in patients with MRSA was 8 days.
Failure of treatment due to persisting or relapsing S. aureus infections was assessed by the Adjudication Committee in 19/120 (16%) CUBICIN-treated patients (12 with MRSA and 7 with MSSA) and 11/115 (10%) comparator-treated patients (9 with MRSA treated with vancomycin and 2 with MSSA treated with an anti-staphylococcal semi-synthetic penicillin). Among all failures, isolates from 6 CUBICIN-treated patients and 1 vancomycin-treated patient developed increasing MICs (reduced susceptibility) by central laboratory testing during or following therapy. Most patients who failed due to persisting or relapsing S. aureus infection had deep-seated infection and did not receive necessary surgical intervention [see WARNINGS AND PRECAUTIONS].
2. Clinical and Laboratory Standards Institute (CLSI). Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard—ninth edition. CLSI Document M07-A9; Wayne, PA. 2012.
3. Clinical and Laboratory Standards Institute (CLSI). Performance standards for antimicrobial susceptibility testing; twenty-second informational supplement. CLSI Document M100-S22; Wayne, PA. 2012.
4. Clinical and Laboratory Standards Institute (CLSI). Performance standards for antimicrobial disk susceptibility tests; approved standard—eleventh edition. CLSI Document M02-A11; Wayne, PA. 2012.
5. Li JS, Sexton DJ, Mick N, Nettles R, Fowler VG Jr, Ryan T, Bashore T, Corey GR. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 2000;30:633–638.
Last reviewed on RxList: 7/25/2016
This monograph has been modified to include the generic and brand name in many instances.
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