NDA No. 21-572 SN007
`
`Cubicin
`
`Cubist Pharmaceuticals, Inc.
`
`
`Microbiology Portion of the Package Insert
`
`Page 1 of 4
`Clinical Microbiology Review
`March 7, 2006
`
`
`Changes to the Microbiology Portion of the Package Insert by this Reviewer are indicated as
`follows: added text is italicized, bolded, and underlined while deleted text is stricken
`through.
`
`MICROBIOLOGY
`Daptomycin is an antibacterial agent of a new class of antibiotics, the cyclic lipopeptides.
`Daptomycin is a natural product which 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 using broth dilution methodology.
`
`In vitro studies have demonstrated additive or indifferent interactions of daptomycin with
`other antibiotics. Antagonism, as determined by kill curve studies, has not been
`observed. In vitro synergistic interactions occurred with aminoglycosides and β-lactam
`antibiotics against some isolates of staphylococci and enterococci, including some MRSA
`isolates.
`
`
`
`Mechanism of Action
`The mechanism of action of daptomycin is distinct from any other antibiotic. Daptomycin
`binds to bacterial membranes and causes a rapid depolarization of membrane potential.
`The loss of membrane potential leads to inhibition of protein, DNA, and RNA synthesis,
`which results in bacterial cell death.
`
`Resistance
`Mechanisms 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:
`Cross-resistance has not been observed with any other class of antibiotic.
`Other:
`The emergence of resistance to daptomycin occurred in 2 of more than 1000 (<0.2%)
`infected subjects across the entire set of Phase 2 and 3 clinical trials. In one case, a
`resistant S. aureus was isolated from a patient in a Phase 2 study who received
`daptomycin at less than the protocol-specified dose for the initial 5 days of therapy. In
`the second case, a resistant E. faecalis was isolated from a patient with an infected
`chronic decubitus ulcer enrolled in a salvage trial.
`
`

`

`Page 2 of 4
`Clinical Microbiology Review
`March 7, 2006
`
`
`
`
`
`NDA No. 21-572 SN007
`Cubicin
`Cubist Pharmaceuticals, Inc.
`
`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 strains isolates only)
`Staphylococcus aureus (including methicillin-resistant strains isolates)
`Streptococcus agalactiae
`Streptococcus dysgalactiae subsp. equisimilis
`Streptococcus pyogenes
`
`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:
`Corynebacterium jeikeium
`Enterococcus faecalis (vancomycin-resistant strains isolates)
`Enterococcus faecium (including vancomycin-resistant strains isolates)
`Staphylococcus epidermidis (including methicillin-resistant strains isolates)
`Staphylococcus haemolyticus
`
`Susceptibility Testing Methods
`Susceptibility testing by dilution methods requires the use of daptomycin susceptibility
`powder. The testing also requires presence of physiological levels of free calcium ions
`(50 mg/L calcium chloride) in Mueller-Hinton broth medium. and a minimum of 28 mg/L
`calcium chloride in Mueller-Hinton agar medium.
`
`Dilution technique
`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 procedure2, 3. Standardized procedures are based on a
`dilution method (broth or agar) or equivalent with standardized inoculum concentrations
`and standardized concentrations of daptomycin powder. The MIC values should be
`interpreted according to the criteria in Table 3. Agar dilution has not been validated for
`daptomycin.
`
`Diffusion technique
`Quantitative methods that require measurement of zone diameters have not been shown
`to provide reproducible estimates of the susceptibility of bacteria to daptomycin1.
`The disk diffusion method does not reliably differentiate isolates with reduced
`susceptibility to daptomycin (MIC >2 µg/mL) from susceptible isolates (MIC <
`1µg/mL). Therefore, disk diffusion testing is not recommended.
`
`

`

`NDA No. 21-572 SN007
`Cubicin
`Cubist Pharmaceuticals, Inc.
`
`Table 3. Susceptibility Interpretive Criteria for Daptomycin
`
`
`
`
`
`Page 3 of 4
`Clinical Microbiology Review
`March 7, 2006
`
`Pathogen
`
`Staphylococcus aureus
`(methicillin-susceptible and
`methicillin-resistant)
`Streptococcus pyogenes,
`Streptococcus agalactiae, and
`Streptococcus dysgalactiae
`subsp. equisimilis
`Enterococcus faecalis
`(vancomycin-susceptible
`only)
`
`Minimal inhibitory
`concentration (µg/mL)a
`S
`I
`R
`≤1
`(b)
`(b)
`
`≤1
`
`(b)
`
`(b)
`
`≤4
`
`(b)
`
`(b)
`
`
`a. The MIC interpretive criteria for S. aureus and E. faecalis are applicable only to tests performed by
`broth microdilution 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 microdilution 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.
`b. The current absence of data on daptomycin resistant strains isolates precludes defining any categories
`other than “Susceptible”. Strains 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 pathogen is likely to be inhibited if the
`antimicrobial compound in the blood reaches the concentrations usually achievable.
`
`Quality Control
`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.
`Agar dilution has not been validated for daptomycin.
`
`

`

`NDA No. 21-572 SN007
`Cubicin
`Cubist Pharmaceuticals, Inc.
`
`Table 4. Acceptable Quality Control Ranges for Daptomycin to Be Used in Validation of
`Susceptibility Test Results
`
`Page 4 of 4
`Clinical Microbiology Review
`March 7, 2006
`
`
`
`
`
`QC Strain
`
`Enterococcus faecalis
`ATCC 29212
`
`Staphylococcus aureus
`ATCC 29213
`
`Streptococcus pneumoniae
`ATCC 49619b
`
`Minimum Inhibitory
`Concentration Range
`(MIC in μg/mL)a
`1-8
`
`0.25-1
`
`0.06-0.5c
`
`
`
`a. Quality control ranges reflect MICs obtained when Mueller-Hinton broth is supplemented with
`calcium to a final concentration of 50 mg/L.
`b. This organism may be used for validation of susceptibility test results when testing Streptococcus
`spp. other than S. pneumoniae.
`c. This quality control range for S. pneumoniae is applicable only to tests performed by broth
`microdilution using cation adjusted Mueller-Hinton broth with 2-5% lysed horse blood inoculated
`with a direct colony suspension and incubated in ambient air at 35ºC for 20 to 24 hours.
`
`
`
`REFERENCES
`
`National Committee for Clinical Laboratory Standards. Performance standards for
`antimicrobial disk susceptibility tests; approved standard-eighth edition. NCCLS
`document M2-A8, Villanova (PA). 2003 January.
`Clinical Laboratory Standards Institute. Methods for dilution antimicrobial
`susceptibility test for bacteria that grow aerobically; approved standard-seventh
`edition. CLSI document M7-A7, Wayne (PA). 2006 January.
`Clinical Laboratory Standards Institute. Performance standards for antimicrobial
`susceptibility testing; sixteenth informational supplement. CLSI document M100-
`S16, Wayne (PA). 2006 January.
`
`
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Jim Vidra
`3/8/2006 10:02:43 AM
`
`