Cubicin® (daptomycin for injection) Rx only
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CUBICIN and other antibacterial drugs, CUBICIN should be used only to treat or prevent infections caused by bacteria.
CUBICIN contains daptomycin, a cyclic lipopeptide antibacterial agent derived from the fermentation of Streptomyces roseosporus. The chemical name is N -decanoyl-L-tryptophyl-D-asparaginyl-L-aspartyl-L-threonylglycyl-L-ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl- threo -3-methyl-L-glutamyl-3-anthraniloyl-L-alanine ε1-lactone. The chemical structure is:
The empirical formula is C72H101N17O26; the molecular weight is 1620.67. CUBICIN is supplied as a sterile, preservative-free, pale yellow to light brown, lyophilized cake containing approximately 900 mg/g of daptomycin for intravenous (IV) use following reconstitution with 0.9% sodium chloride injection. The only inactive ingredient is sodium hydroxide, which is used in minimal quantities for pH adjustment. Freshly reconstituted solutions of CUBICIN range in color from pale yellow to light brown.
Daptomycin is an antibacterial agent of a new class of antibiotics, the cyclic lipopeptides. Daptomycin is a natural product that 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 retains potency against antibiotic-resistant Gram-positive bacteria, including isolates resistant to methicillin, vancomycin, and linezolid.
Daptomycin exhibits rapid, concentration-dependent bactericidal activity against Gram-positive organisms in vitro. This has been demonstrated both by time-kill curves and by MBC/MIC ratios (minimum bactericidal concentration/minimum inhibitory concentration) 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 antibiotic. Daptomycin binds to bacterial membranes and causes a rapid depolarization of membrane potential. This loss of membrane potential causes inhibition of protein, DNA, and RNA synthesis, which results in bacterial cell death.
Mechanism of Resistance
At this time, no mechanism of resistance to daptomycin has been identified. Currently, there are no known transferable elements that confer resistance to daptomycin.
Cross-resistance has not been observed with any other antibiotic class.
Interactions with Other Antibiotics
In vitro studies have investigated daptomycin interactions with other antibiotics. Antagonism, as determined by kill curve studies, has not been observed. In vitro synergistic interactions of daptomycin with aminoglycosides, β-lactam antibiotics, and rifampin have been shown against some isolates of staphylococci (including some methicillin-resistant isolates) and enterococci (including some vancomycin-resistant isolates).
Complicated Skin and Skin Structure Infection (cSSSI) Studies
The emergence of daptomycin non-susceptible isolates occurred in 2 infected patients across the set of Phase 2 and pivotal Phase 3 clinical trials. In one case, a non-susceptible S. aureus was isolated from a patient in a Phase 2 study 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 enrolled in a salvage trial.
S. aureus Bacteremia/Endocarditis and Other Post-Approval Studies
In subsequent clinical trials, non-susceptible isolates were recovered. S. aureus was isolated from a patient in a compassionate-use study and from 7 patients in the S. aureus bacteremia/endocarditis study (see PRECAUTIONS). An E. faecium was isolated from a patient in a VRE study.
Daptomycin has been shown to be active against most isolates of the following microorganisms both in vitro and in clinical infections, as described in the INDICATIONS AND USAGE section.
Aerobic and facultative Gram-positive microorganisms:
Enterococcus faecalis (vancomycin-susceptible isolates only)
Staphylococcus aureus (including methicillin-resistant isolates)
Streptococcus dysgalactiae subsp. equisimilis
The following in vitro data are available, but their clinical significance is unknown. Greater than 90% of the following microorganisms demonstrate an in vitro MIC less than or equal to the susceptible breakpoint for daptomycin versus the bacterial genus. The efficacy of daptomycin in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.
Aerobic and facultative Gram-positive microorganisms:
Enterococcus faecalis (vancomycin-resistant isolates)
Enterococcus faecium (including vancomycin-resistant isolates)
Staphylococcus epidermidis (including methicillin-resistant isolates)
Susceptibility Testing Methods
Susceptibility testing by dilution methods requires the use of daptomycin susceptibility powder. The testing of daptomycin also requires the presence of physiological levels of free calcium ions (50 mg/L of calcium, using calcium chloride) in Mueller-Hinton broth medium.
Quantitative methods are used to determine antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure1, 2 based on a broth dilution method or equivalent using standardized inoculum and concentrations of daptomycin. The use of the agar dilution method is not recommended with daptomycin2. The MICs should be interpreted according to the criteria in Table 3.
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable.
Table 3. Susceptibility Interpretive Criteria for Daptomycin
|Pathogen||Broth Dilution MICThe 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 35ºC for 20 to 24 hours.|
|Note: S, Susceptible; I, Intermediate; R, Resistant.|
| Staphylococcus aureus ||≤1||()||()|
| (methicillin-susceptible and methicillin-resistant)|
| Streptococcus pyogenes, Streptococcus agalactiae, ||≤1||()||()|
| and Streptococcus dysgalactiae subsp. equisimilis |
| Enterococcus faecalis ||≤4||()||()|
| (vancomycin-susceptible only)|
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 daptomycin2, 3.
Standardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the procedures. Standard daptomycin powder should provide the range of values noted in Table 4. Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within bacteria; the specific strains used for microbiological quality control are not clinically significant.
Table 4. Acceptable Quality Control Ranges for Daptomycin to Be Used in Validation of Susceptibility Test Results
|Quality Control Strain||Broth Dilution MIC RangeThe 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 ranges for 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 35ºC for 20 to 24 hours.|
| Enterococcus faecalis ATCC 29212||1−4|
| Staphylococcus aureus ATCC 29213||0.25−1|
| Streptococcus pneumoniae ATCC 49619This organism may be used for validation of susceptibility test results when testing Streptococcus spp. other than S. pneumoniae.||0.06−0.5|
The mean (SD) pharmacokinetic parameters of daptomycin at steady-state following IV administration of 4 to 12 mg/kg q24h to healthy young adults are summarized in Table 1.
Daptomycin pharmacokinetics were generally linear and time-independent at doses of 4 to 12 mg/kg q24h. Steady-state trough concentrations were achieved by the third daily dose. The mean (SD) steady-state trough concentrations attained following 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) µg/mL, respectively.
Table 1. Mean (SD) CUBICIN Pharmacokinetic Parameters in Healthy Volunteers at Steady-State
|Pharmacokinetic ParametersAUC0-24, area under the concentration-time curve from 0 to 24 hours; t½, terminal elimination half-life; Vss, volume of distribution at steady-state; CLT, plasma clearance; Cmax, maximum plasma concentration.|
|DoseDoses of CUBICIN in excess of 6 mg/kg have not been approved.||AUC0-24||t1/2||Vss||CLT||Cmax|
| 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)|
Daptomycin is reversibly bound to human plasma proteins, primarily to serum albumin, in a concentration-independent manner. The overall mean binding ranged from 90 to 93%.
In clinical studies, mean serum protein binding in subjects with 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 (87.6%), including those receiving hemodialysis (85.9%) and continuous ambulatory peritoneal dialysis (CAPD) (83.5%). The protein binding of daptomycin in subjects with hepatic impairment (Child-Pugh 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 0.10 L/kg and was independent of dose.
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. In in vitro studies, daptomycin was not metabolized by human liver microsomes. It is unlikely that daptomycin will inhibit or induce the metabolism of drugs metabolized by the P450 system.
In 5 healthy young adults after infusion of radiolabeled 14C-daptomycin, the plasma total radioactivity was similar to the concentration determined by microbiological assay. In a separate study, no metabolites were observed in plasma on Day 1 following administration of CUBICIN at 6 mg/kg to subjects. Inactive metabolites have been detected in urine, as determined by the difference in total radioactive concentrations and microbiologically active concentrations. 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 kidney. 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 dose was recovered from feces (collected for up to 9 days) based on total radioactivity.
Because renal excretion is the primary route of elimination, dosage adjustment is necessary in patients with severe renal insufficiency (CLCR <30 mL/min) (see DOSAGE AND ADMINISTRATION).
Population derived pharmacokinetic parameters were determined for infected patients (complicated skin and skin structure infections and S. aureus bacteremia) and noninfected subjects with varying degrees of renal function ( Table 2). Plasma clearance (CLT), elimination half-life (t1/2), and volume of distribution (Vss) were similar in patients with complicated skin and skin structure infections compared with those with S. aureus bacteremia. Following the administration of CUBICIN 4 mg/kg q24h, the mean CLT 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 steady-state systemic exposure (AUC), t1/2, and Vss increased with decreasing renal function, although the mean AUC was not markedly different for patients with CLCR 30–80 mL/min compared with those with normal renal function. The mean AUC for patients with CLCR <30 mL/min and for patients on hemodialysis (dosed post-dialysis) was approximately 2 and 3 times higher, respectively, than for patients with normal renal function. Following the administration of CUBICIN 4 mg/kg q24h, the mean Cmax ranged from 60 to 70 µg/mL in patients with CLCR ≥30 mL/min, while the mean Cmax for patients with CLCR <30 mL/min ranged from 41 to 58 µg/mL. The mean Cmax ranged from 80 to 114 µg/mL in patients with mild-to-moderate renal impairment and was similar to that of patients with normal renal function after the administration of CUBICIN 6 mg/kg q24h. In patients with renal insufficiency, both renal function and creatine phosphokinase (CPK) should be monitored more frequently. CUBICIN should be administered following the completion of hemodialysis on hemodialysis days (see DOSAGE AND ADMINISTRATION for recommended dosage regimens).
Table 2. Mean (SD) Daptomycin Population Pharmacokinetic Parameters Following Infusion of 4 mg/kg or 6 mg/kg to Infected Patients and Noninfected Subjects with Varying Degrees of Renal Function
|4 mg/kg||4 mg/kg||4 mg/kg||4 mg/kg||6 mg/kg||6 mg/kg|
|Note: CLCR, creatinine clearance estimated using the Cockcroft-Gault equation with actual body weight; 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 steady-state; Cmin,ss, trough concentration at steady-state; NA, not applicable.|
|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||10.75 (8.36)||0.12 (0.05)||9.9 (4.0)||466 (177)||637 (215)||12.4 (5.6)|
|(CLCR 50−80 mL/min)||N=64||N=64||N=64||N=64||N=29||N=29|
|Moderate Renal Impairment||14.70 (10.50)||0.15 (0.06)||8.5 (3.4)||560 (258)||868 (349)||19.0 (9.0)|
|(CLCR 30−<50 mL/min)||N=24||N=24||N=24||N=24||N=15||N=14|
|Severe Renal Impairment||27.83 (14.85)||0.20 (0.15)||5.9 (3.9)||925 (467)||1050, 892||24.4, 21.4|
|(CLCR <30 mL/min)||N=8||N=8||N=8||N=8||N=2||N=2|
|Hemodialysis||29.81 (6.13)||0.15 (0.04)||3.7 (1.9)||1244 (374)||NA||NA|
The pharmacokinetics of daptomycin were evaluated in 10 subjects with moderate hepatic impairment (Child-Pugh Class B) and compared with 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 administering CUBICIN to patients with mild-to-moderate hepatic impairment. The pharmacokinetics of daptomycin in patients with severe hepatic insufficiency 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 administering CUBICIN.
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 IV dose, the mean total clearance of daptomycin was reduced approximately 35% and the mean AUC0-∞ increased approximately 58% in elderly subjects compared with young healthy subjects. There were no differences in Cmax. No dosage adjustment is warranted for elderly patients with normal renal function.
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, sex, and renal function. Following administration of a single 4 mg/kg IV dose based on total body weight, the plasma clearance of daptomycin normalized to total body weight was approximately 15% lower in moderately obese subjects and 23% lower in extremely obese subjects compared with nonobese controls. The AUC0-∞ of daptomycin increased approximately 30% in moderately obese and 31% in extremely obese subjects compared with nonobese controls. The differences were most likely due to differences in the renal clearance of daptomycin. No dosage adjustment of CUBICIN is warranted in obese subjects.
The pharmacokinetics of daptomycin in pediatric populations (<18 years of age) have not been established.
Drug-drug interaction studies were performed with CUBICIN and other drugs that are likely to be either coadministered or associated with overlapping toxicity.
In a study in which 15 healthy adult subjects received a single dose of CUBICIN 6 mg/kg IV, aztreonam 1 g IV, and both in combination, the Cmax and AUC0-∞ of daptomycin were not significantly altered by aztreonam; the Cmax and AUC0-∞ of aztreonam also were not significantly altered by daptomycin. No dosage adjustment of either antibiotic is warranted when coadministered.
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, the mean Cmax and AUC0-∞ of daptomycin increased 12.7% and 8.7%, respectively, when administered with tobramycin. The mean Cmax and AUC0-∞ of tobramycin decreased 10.7% and 6.6%, respectively, when administered with CUBICIN. These differences were not statistically significant. The interaction between daptomycin and tobramycin with a clinical dose of CUBICIN is unknown. Caution is warranted when CUBICIN is coadministered with tobramycin.
In 16 healthy subjects, concomitant administration of CUBICIN 6 mg/kg q24h for 5 days followed by a single oral dose of warfarin (25 mg) had no significant effect on the pharmacokinetics of either drug and did not significantly alter the INR (International Normalized Ratio) (see PRECAUTIONS, Drug Interactions).
In 20 healthy subjects on a stable daily dose of simvastatin 40 mg, administration of CUBICIN 4 mg/kg IV q24h for 14 days (N=10) was not associated with a higher incidence of adverse events than in subjects receiving placebo once daily (N=10) (see PRECAUTIONS, Drug Interactions).
Concomitant administration of probenecid (500 mg 4 times daily) and a single dose of CUBICIN 4 mg/kg IV did not significantly alter the Cmax and AUC0-∞ of daptomycin. No dosage adjustment of CUBICIN is warranted when CUBICIN is coadministered with probenecid.
In animals, daptomycin administration has been associated with effects on skeletal muscle with no changes in cardiac or smooth muscle. Skeletal muscle effects were characterized by degenerative/regenerative changes and variable elevations in 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 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 doses higher than those associated with skeletal myopathy. Deficits in the dogs’ patellar reflexes were seen within 2 weeks of the start of treatment at 40 mg/kg (9 times the human Cmax at the 6 mg/kg q24h dose), with some clinical improvement noted within 2 weeks of the cessation of dosing. However, at 75 mg/kg/day for 1 month, 7/8 dogs failed to regain full patellar reflex responses within the duration of 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 cessation of dosing. However, recovery of peripheral nerve function was evident.
Tissue distribution studies in rats have shown that daptomycin is retained in the kidney but appears to only minimally penetrate across the blood-brain barrier following single and multiple doses.
Complicated Skin and Skin Structure Infections
Adult patients with clinically documented cSSSI ( Table 10) were enrolled in two randomized, multinational, multicenter, investigator-blinded studies comparing CUBICIN (4 mg/kg IV q24h) with either vancomycin (1 g IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 4 to 12 g IV per day). 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. Patients could switch to oral therapy after a minimum of 4 days of IV treatment if clinical improvement was demonstrated.
One study was conducted primarily in the United States and South Africa (study 9801), and the second (study 9901) was conducted at non-US sites only. Both studies 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 studies. The majority (89.7%) of patients received IV medication exclusively.
The efficacy endpoints in both studies 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 11.
Table 10. Investigator’s Primary Diagnosis in the cSSSI Studies (Population: ITT)
|Study 9801||Study 9901||Pooled|
|Wound Infection||99 (37.5%)/116 (43.6%)||102 (37.8%)/108 (37.0%)||201 (37.6%)/224 (40.1%)|
|Major Abscess||55 (20.8%)/43 (16.2%)||59 (21.9%)/65 (22.3%)||114 (21.3%)/108 (19.4%)|
|Ulcer Infection||71 (26.9%)/75 (28.2%)||53 (19.6%)/68 (23.3%)||124 (23.2%)/143 (25.6%)|
|Other InfectionThe majority of cases were subsequently categorized as complicated cellulitis, major abscesses, or traumatic wound infections.||39 (14.8%)/32 (12.0%)||56 (20.7%)/51 (17.5%)||95 (17.8%)/83 (14.9%)|
Table 11. Clinical Success Rates by Infecting Pathogen, Primary Comparative cSSSI Studies (Population: Microbiologically Evaluable)
|Pathogen||CUBICIN||ComparatorVancomycin or anti-staphylococcal semi-synthetic penicillins.|
|n/N (%)||n/N (%)|
|Methicillin-susceptible Staphylococcus aureus (MSSA)
||170/198 (85.9)||180/207 (87.0)|
|Methicillin-resistant Staphylococcus aureus (MRSA)||21/28 (75.0)||25/36 (69.4)|
| Streptococcus pyogenes ||79/84 (94.0)||80/88 (90.9)|
| Streptococcus agalactiae ||23/27 (85.2)||22/29 (75.9)|
| Streptococcus dysgalactiae subsp. equisimilis ||8/8 (100)||9/11 (81.8)|
| Enterococcus faecalis (vancomycin-susceptible only)||27/37 (73.0)||40/53 (75.5)|
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 study. In this study, 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 [anti-staphylococcal semi-synthetic penicillin 2 g IV q4h (nafcillin, oxacillin, cloxacillin, or flucloxacillin) or vancomycin 1 g IV q12h, both 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 anti-staphylococcal semi-synthetic penicillin and 53 vancomycin). Thirty-five patients treated with anti-staphylococcal semi-synthetic penicillins 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) and 85 (36%) had surgical procedures within 30 days of onset of the S. aureus bacteremia. Eighty-eight patients (38%) had bacteremia caused by MRSA. Entry diagnosis was based on the modified Duke criteria and included 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.
There were 182 patients with bacteremia and 53 patients with infective endocarditis as assessed by the Adjudication Committee in the ITT population, including 35 with right-sided and 18 with left-sided endocarditis. The 182 patients with bacteremia included 121 with complicated 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 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 included 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 MSSA, serum creatinine <2.5 mg/dL, and were without evidence of extrapulmonary sites of infection were considered to have uncomplicated RIE.
The co-primary efficacy endpoints in the study 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 12.
Eighteen (18/120) patients in the CUBICIN arm and 19/116 patients in the comparator arm died during the study. These include 3/28 CUBICIN-treated and 8/26 comparator-treated patients with endocarditis, as well as 15/92 CUBICIN-treated and 11/90 comparator-treated patients with bacteremia. Among patients with persisting or relapsing S. aureus infections, 8/19 CUBICIN-treated 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 (15.8%) CUBICIN-treated patients (12 with MRSA and 7 with MSSA) and 11/115 (9.6%) comparator-treated patients (9 with MRSA treated with vancomycin and 2 with MSSA treated with anti-staphylococcal semi-synthetic penicillin). Among all failures, 6 CUBICIN-treated patients and 1 vancomycin-treated patient developed increasing MICs (reduced susceptibility) by central laboratory testing on 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 PRECAUTIONS).
Table 12. Adjudication Committee Success Rates at Test of Cure (Population: ITT)
|Population||CUBICIN 6 mg/kg|
|ComparatorComparator: vancomycin (1 g IV q12h) or anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, flucloxacillin; 2 g IV q4h), each with initial low-dose gentamicin|
CUBICIN − Comparator
|Overall||53/120 (44.2%)||48/115 (41.7%)||2.4% (−10.2, 15.1)95% Confidence Interval|
| MSSA||33/74 (44.6%)||34/70 (48.6%)||−4.0% (−22.6, 14.6)
| MRSA||20/45 (44.4%)||14/44 (31.8%)||12.6% (−10.2, 35.5)|
|Entry DiagnosisAccording to the modified Duke criteria4|
| Definite or Possible Infective||41/90 (45.6%)||37/91 (40.7%)||4.9% (−11.6, 21.4)|
| Not Infective Endocarditis||12/30 (40.0%)||11/24 (45.8%)||−5.8% (−36.2, 24.5)|
| Uncomplicated Bacteremia||18/32 (56.3%)||16/29 (55.2%)||1.1% (−31.7, 33.9)
| Complicated Bacteremia||26/60 (43.3%)||23/61 (37.7%)||5.6% (−17.3, 28.6)|
| Right-Sided Infective||8/19 (42.1%)||7/16 (43.8%)||−1.6% (−44.9, 41.6)|
| Uncomplicated Right-Sided||3/6 (50.0%)||1/4 (25.0%)||25.0% (−51.6, 100.0)|
| Infective Endocarditis|
| Complicated Right-Sided||5/13 (38.5%)||6/12 (50.0%)||−11.5% (−62.4, 39.4)|
| Infective Endocarditis|
| Left-Sided Infective||1/9 (11.1%)||2/9 (22.2%)||−11.1% (−55.9, 33.6)|
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