CENTER FOIR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`21-572
`
`Microbiology Review(s)
`
`

`

`NDA No. 21-5722
`Cubicin
`Cubist Pharmaceuticals, Inc.
`
`Page 1 of4
`
`Division of Anti-Infective Drug Products
`Clinical Microbiological Review # 1
`
`NDA: 21-572
`2003
`
`Dates Completed: September 5,
`
`Applicant (NDA):
`Cubist Pharmaceuticals, Inc.
`
`65 Hayden Avenue
`Lexington, MA 02421
`781-860-8660
`
`Therapeutic Type: Daptomycin for injection
`
`Submissions Reviewed: NDA 21,572
`
`Providing for: Treatment of complicated skin structure infections (cSSSI)
`
`Product Name(s):
`Proprietary: Cubicin R
`Non-proprietary: Daptomycin
`
`Chemical name: N-decanoyl-L-tryptophyl-L—asparaginyl-L-aspanyl-L-
`threonylglycyl-I.-omithy1-L—aspartyl-D-alany]-L-aspartylg1ycyl-D-seryl-
`three-3-methyl~L-glutamyl-3~anthraniloyl-L-alanine El-lactone.
`
`Structural formula:
`
`Hi:JJ\(co,n
`“00:5.th
`Wi:if“
`
`/
`
`12
`
`

`

`NDA No. 21-572
`Cubicin
`Cubist Pharmaceuticals, Inc.
`
`Page 2 of4
`
`Molecular formula: C72H101N17026; the molecular weight is 1620.67.
`
`Dos‘age form: Four mg/kg administered over a 30~minute period by
`intravenous infusion in 0.9% sodium chloride injection, USP once every
`24 hours for 7-14 days.
`
`Route(s) of administration: Injection
`
`Pharmacological Category: Anti-Infective
`
`Dispensed: Rx
`
`X
`
`OTC
`
`Initial Submission Dates
`
`-
`
`Received by CDER: September 12, 2003
`Received by Reviewer: September 12, 2003
`Review Completed: September 12, 2003
`
`Related Documents: NDA 21,572; IND 57,693
`
`Remarks:
`
`This is an amendment to the original review ofthe clinical microbiology
`portion of an NDA submission from Cubist Pharmaceutical, Inc. for
`Cubicin. This drug is intended to treat complicated skin and skin
`structure infections caused by S. aureus (methicillin-susceptible and —
`resistant strains), Streptococcus agalactiae, Streptococcus pyogenes,
`Streptococcus dysgalactiae subsp. equisimilis,
`~—
`"j"
`‘ and Entero'coccusfaecalis (vancomycin-susceptible strains
`only). However, based on discussion within the review team and as
`
`negotiated with the Applicant, the
`has been
`excluded as a pathogen for the indication.
`
`O
`
`‘
`
`This review addresses the modification of the breakpoints for the
`Stre’ptowcci species listed in the product package insert. The original
`susceptible breakpoint negotiated with Cubist Pharmaceuticals, Inc. of
`-—--
`for Streptococci have been renegotiated to 50.5 pg/mL, since
`"‘"
`is now deleted from the indications section of the
`
`the
`
`package insert. It is concluded by the review team that this organism is
`not a pathogen for complicated skin and skin structure infections. Thus
`we need to change the breakpoint to reflect the susceptibility of the -
`pathogens to be approved in the indications section of the package insert
`for daptomycin.
`
`M if
`
`

`

`NDA No. 2l-572
`Cubicin
`Cubist Pharmaceuticals, Inc.
`
`Page 3 of4 -
`
`The basis of our argument rests upon the following points:
`Analysis ofthe in vitro spectrum of activity as presented in the
`original review does not support the breakpoint of F“
`unless the
`"‘
`is included in the
`
`analysis.
`
`However, it has been determined by the review team that the
`—
`should be excluded from the analysis because they
`are not considered pathogens for the indication of complicated skin
`and skin structure infections sought by the Applicant.
`Analysis of the in vitro spectrum of activity dataset excluding
`’-
`supports the breakpoint of 50.5 pg/mL.
`In addition to this dataset, the surveillance information clearly
`supports a breakpoint of 50.5 ug/mL. Evaluation of this data
`shows that the vast majority ofpathogens had MICs less than 0.5
`pg/mL. Thus, pathogens with Mle greater than 0.5 pg/mL are
`rare.
`
`Although pharmacoldnetic/phannacodynamic studies were
`performed, the majority of the studies were performed with
`Streptococcus pneumoniae, an organism not sought as a pathogen
`for the proposed indication. Some studies were performed with S.
`pyogenes; these data are used to provide part of the information
`necessary to make decisions on breakpoints. These data are not the
`final arbitrators of breakpoint determinations but augment existing
`evidence.
`
`Evaluation of‘the clinical data was also performed to determine the
`final breakpoint for Streptococci species. If we look at
`Microbiological Review #1 and specifically at Table 47 (page 5'9)
`which describes clinical and microbiological success rates by MIC,
`we clearly see that there are no clinical or microbiological
`experiences to support a breakpoint of
`--
`In fact we
`have little evidence to demonstrate the efficacy of daptomycin for
`pathogens with susceptible Mle of 0.5 ug/mL. Most of these data
`demonstrate clinical and microbiological efficacy for pathogens
`_with Mle of50.25 ug/mL. Since a majority ofthe clinical and
`microbiological experiences are with Mle at this dilution, and the
`error of the assay can be :t one tube dilution, the breakpoint
`supported by the data is $0.5 ug/mL. This is consistent with the
`practice of setting breakpoints that are one dilution higher than the
`clinical and microbiological experiences.
`These arguments were conveyed to the Applicant in a
`teleconference dated September 1 l, 2003_ at which time final
`agreement was reached that the breakpoint of $0.5 pg/mL would
`be established for Streptococci species. They conceded the
`discussion and sent their final product package insert with the
`susceptib‘lzelbreakpoint of 50.5 pg/rnL.
`
`

`

`NDA No. 21-572
`Cubicin
`
`Cubist Pharmaceuticals, Inc.
`
`Conclusions/Recommendations:
`
`Page 4 of4
`
`The Microbiology portion of this submission is approvable but with the
`indicated changes to the Microbiology Section of the Package Insert.
`Specifically, the susceptible breakpoint of 50.5 ug/mL for the Streptococci
`species listed in the indications section of the package insert and as
`described in the Microbiology section should be adopted.
`'
`‘
`
`Peter Coderre PhD.
`
`Microbiology Reviewer ‘
`
`Albert T. Sheldon, Jr._Ph.D.
`Microbiology Team Leader
`
`Cc: Original NDA No. 021-572
`Microbiologist, RFD-520
`File name: 21572-Strept BPs.doc N21572_RD#2.doc
`
`Smicro/ATSheldon
`m1 Initialed 6/10/03. W2 Inltlaled 8f27l03 ATS: Final lnltlaled
`
`BIIOSATS
`
`DepDir/LGavrilovich
`
`Cc: Original NDA#21-572
`HFD-473
`
`HFD-SZO’DepDir/LGavrilovich
`HFD-SZO/Smicro/ATSheldon
`
`HFD—SZO/Micro
`l-lFD-520/MO/
`HFD-SZO/Pharm/
`HFD-520/Chem/
`HFD-SZO/CSO/
`HFD-SZO
`-
`
`HFD-SOZ
`HFD-635-
`
`'
`
`-
`
`\
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/s/
`
`_
`
`'
`Albert Sheldon
`9/12/03 11:24:28 AM
`MI CROBIOLOGI ST
`
`Lillian Gavrilovich
`9/12/03 11:34:59 AM
`MEDICAL OFFICER
`
`ii
`
`

`

`NDA No. 21—572
`Cubicin
`
`Cubist Pharmaceuticals, Inc.
`
`Page I of l 14
`'
`
`Division of Anti-Infective Drug Products
`Clinical Microbiological Review # 1
`'
`
`NDA: 21-572
`
`Dates Completed: September 5, 2003'-
`
`Applicant (NDA):
`Cubist Pharmaceuticals, Inc.
`
`65 Hayden Avenue
`Lexington, MA 0242]
`781-860-8660
`
`Therapeutic Type: Daptomycin for injection
`
`Submissions Reviewed: NDA 21,572
`
`Providing for: Treatment of complicated skin structure infections (cSSSl)
`
`Product Name(s):
`- Proprietary: Cubicin R
`Non-proprietary: Daptomycin
`
`Chemical name: N-decanoyl-L-tryptophyl—L-asparaginyl-L-aspartyl-L-threonylglycyl—L-
`omithy]-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo~3-methyl-L-glutamyl-3-
`anthraniloyl-L~alanine El-lactone.
`.
`
`Structural formula:
`
` HN
`
`ch
`
`o
`
`HN
`
`'\n/‘\
`
`o
`
`O
`
`NH
`
`HN
`
`H
`
`O
`
`NH‘
`
`

`

`NDA No. 2l-572
`Cubicin
`Cubist Pharmaceuticals, Inc.
`
`'
`
`Page 2 or I I4
`
`Molecular formula: C72H101N17025; the molecular weight is 1620.67.
`
`Dosage form:_Four mngg administered over a 30-minute period by intravenous infusion in
`0.9% sodium chloride injection, USP once every 24 hours for 7-14 days.
`
`Route(s) of administration: Injection
`
`'
`
`'
`
`_
`
`Pharmacological Category: Anti-Infective
`
`Dispensed: Rx
`
`X
`
`OTC
`
`.
`Initial Submission Dates
`Received by CDER: December 19, 2002
`Received by Reviewer: December 30, 2002
`Review Completed: September 5, 2003
`
`Related Documents: IND 57,693
`
`Remarks:
`
`This is' a review of the clinical microbiology portion of an NDA submission from Cubist
`Pharmaceutical, Inc. for Cubicin. This drug is intended to treat complicated skin and
`skin structure infections caused by S. aureus (methicillin-susceptible and —resistant
`strains), Streplococcus agalacn'ae, Streprococcus pyogenes, Streptococcus afiisgalacn'ae
`subsp. equisimilis,
`'
`..._
`‘ and Enlerococcusfaecalis
`(vancomycin-susceptible strains only).
`'
`
`Conclusions/Recommendations:
`
`The Microbiology portion of this submission is approvable but with the indicated changes
`to the Microbiology Section of the Package Insert.
`‘
`
`ii ii
`
`

`

`Page 3-0T 1 I4
`
`TABLE OF CONTENTS
`
`NDA No. 21-572
`Cubicin
`Cubist Pharmaceuticals, Inc.
`
`I
`
`INTRODUCTION
`
`PRECLINICAL EFFICACY
`
`In vitro
`
`Mechanism of Action.
`Spectrum of Daptomycin Activity.
`Mechanisms of Resistance.
`Post-Antibiotic Effect (PAE).
`Synergy Studies.
`
`In vivo
`
`-'
`
`‘_ "
`_
`
`9
`_
`
`25
`
`30
`
`37
`
`4
`
`4
`
`4
`4
`'
`
`21
`25
`25
`
`27
`
`50
`
`34
`
`41
`
`41
`41
`42
`42
`
`50
`50
`
`52
`53
`
`81
`82
`84
`86
`
`87
`
`95
`
`Comparative Pharmacokinetics in Different Species.
`Human Pharmacokinetics.
`
`Pharmacodynamics.
`Animal Models of Efficacy.
`
`CLINICAL EFFICACY
`
`46
`
`Clinical Laboratory Susceptibility Test Methods.
`Disk Diffusion Testing.
`Broth Dilution Testing.
`Quality Control Studies (MIC and Disk diffusion).
`Provisional Susceptibility Testing Interpretive Criteria
`Correlation of Provisional Interpretative Criteria with
`Clinical and Microbiological Outcomes.
`Overview of Primary Comparative cSSSl Studies
`Analysis of Outcomes by Specific Comparator Agents
`Primary Efficacy Outcome
`52
`Clinical Success Rates by Pathogen
`Pathogen Eradication Rates
`Establishment of In Vitro Susceptibility Testing
`Interpretative Criteria
`Breakpoint Discussion for Staphylococcus aureus
`~ Breakpoint Discussion for Streptococcus sp.
`Breakpoint Discussion for Enterococcus faecalis
`
`\
`
`REFERENCES
`
`MICROBIOLOGY PORTION OF THE PACKAGE INSERT
`
`"\M.
`
`INTRODUCTION
`
`

`

`NDA No. 2l-572
`Cubicin
`Cubist Pharmaceuticals, Inc.
`
`Page 4.of l 14
`
`Daptomycin is a lipopeptide antibiotic derived from Streptomyces roseospor that represents
`a new class of agents. The spectrum of activity is similar to those ofvancomycin and
`teicoplanin, and has bactericidal activity against most Gram~positive pathogens including
`the clinically significant species of staphylococci, streptococci, and enterococci. The
`characteristics of daptomycin that distinguish it from vancomycin and teicoplanin are its
`concentration-dependent bactericidal activity against enterococci and staphylococci, its
`novel mechanism of action and its requirement for ionized calcium. The Applicant has
`provided the microbiology data that they believe will help to support their request for the
`following indication:
`
`Complicated skin and skin structure infection caused by S. aureus (methicillin-
`susceptible and —resistant strains), Streptococcus agaiactiae, Streptococcus
`pyogenes, Streptococcus ajtsgaloctioe subsp. equisimilis,
`.——-.
`.——_.
`i and Enterococcusfaecalis (vancomycin- susceptible strains only).
`
`The Applicant also proposes the interpretative criteria presented in Table l for the
`following pathogens that cause complicated skin and skin structure infections.
`
`Table ]: Provisional interpretive criteria for susceptibility to daptomycin
`
`[
`
`PRECLINICAL EFFICACY (IN VITR0)
`MECHANISM OF ACTION
`
`Daptomycin inserts directly into the cytoplasmic membrane of Gram-positive cells [1].
`This action is calcium-dependent and results in dissipation of the membrane potential [2,
`3]. Depolarization of the membrane is followed rapidly by the arrest of bacterial DNA,
`RNA, and protein synthesisgnd cell death. The conditions, rates and dose responses
`
`

`

`NDA No. 21-572
`Cubicin
`Cubist Pharmaceuticals, Inc.
`
`'
`
`Page gen 14
`
`associated with daptomycin-induced depolarization are consistently associated with its
`bactericidal activity. A possible mechanism for the depolarization has been demonstrated
`through the release of potassium ions from bacterial cells exposed to daptomycin. An early
`report suggested that daptomycin acts through the inhibition of lipoteichoic acid synthesis
`[4, 5]; however, data that are more recent indicate that event is secondary to membrane
`depolarization [6].
`"
`
`Binding and fractionation studies using MC-daptomycin in S. aureus and human tissue
`culture cells suggest that daptomycin inserts tightly into the membrane of Gram-positive
`pathogens, but is only loosely associated with the membranes of mammalian cells [9, 10].
`
`Upon binding, daptomycin gradually dissipates the membrane potential of S. aureus,
`requiring 30 to 60 minutes for full depolarization compared to less than 5 minutes for the
`pore-fonning antibiotic nisin. Viability decreased in parallel to the changes-in potential.
`
`The Applicant has provided data that further support the mechanism of action. These data
`can be found in of the Microbiology Section 6.1 of the briefing package.
`
`Effects of miscellaneous factors on activity
`The antibacterial activity of daptomycin requires the presence of free (ionized) calcium.
`This requirement cannot be met by other inorganic or organic cations [8, 27]. A solution of
`50 mg/L calcium has a free (ionized) calcium concentration of1.l mM, which is close to
`the normal range for human serum (1.15 - 1.31 mM)[7]. Current NCCLS standards specify
`that Mueller-Hinton Broth (MHB) used for susceptibility testing should contain 25 mg/L
`calcium [1 7]; the proposed standard for daptomycin testing is 50 mg/L calcium [13]. These
`studies indicate that daptomycin M1Cs are more accurate and reproducible when the media
`contain 50 mg/L calcium and are artifactually elevated 2- to 8-fold when the media contain
`25 mg/L calcium [60, 63, 64].
`
`Table 2 displays the distribution, median, and geometric mean of the daptomycin MICs at
`the two calcium concentrations for each of three major genera of Gram-positive pathogens
`(staphylococci, streptococci, and enterococci). Using the proposed standard media for
`susceptibility testing (MHB supplemented with 50 mg/L calcium), >99% of staphylococci
`were inhibited by l ug/ml of daptomycin; >99% of streptococci by 0.5 ug/ml; and 92% of
`enterococci by 2 rig/ml.
`
`As noted above, the current NCCLS standard media for susceptibility testing are Mueller-
`l—linton broth or agar supplemented with 25 mg/L calcium [17]. On the basis of the data
`presented from the Applicant and similar results from other laboratories, the proposed
`NCCLS recommendation is that daptomycin susceptibility testing of rapidly growing,
`aerobic Gram- positive organisms be performed using Mueller-Hinton broth media with 50
`mg/L calcium. This level of supplementation provides a physiologic concentration of free
`(ionized) calcium and ensures that in vitro susceptibility measurements are accurate and
`reproducible Media typically used for susceptibility testing of anaerobes, eg., Brucella
`blood2agar, are also deficientin Ca2+ ions and must be supplemented to physiological levels
`of Ca2+ ions for use with daptomycin
`
`

`

`NDA No. 21-572
`Cubicin
`Cubist Pharmaceuticals, Inc.
`
`'
`
`Page 6 of l 14
`
`Table 2: Distribution of daptomycin Mle for three different genera of bacteria tested in
`MHB with two different levels of calcium'supplementation'
`Enrerococcus spp.
`Daptomycin MIC
`Staphylococcus spp.
`Streptococcus spp.
`(N=550)
`(pg/ml)
`(N= 1,094)
`(N= 1.096)
`No. of strains at each MlC when tested m'th different calcium supplementh
`25 mg/L
`50 mg/L
`25 mg/L
`50 mg/L
`25mg/l.
`50 mg/L
`1
`14
`109
`232
`130
`51
`5
`6
`1
`
`>16
`16
`8
`4
`2
`1
`0.5
`0.25
`0.12
`0.06
`0.03
`0.016
`0.008
`Median MlC
`Geometric mean MlC
`
`2
`2
`39
`741
`251
`53
`5
`
`1
`
`1
`0.81
`
`1
`3
`12
`155
`597
`82
`216
`28
`1
`1
`
`'
`
`3
`16
`339
`656
`73
`5
`1
`1
`
`‘
`
`1
`1
`2
`6
`38
`351
`430
`114
`140
`13
`
`4
`40
`172
`201
`106
`18
`6
`2
`1
`
`‘
`
`. 1
`
`-
`
`4
`3.34
`
`0.25 ‘
`0.30
`
`0.5
`0.38
`
`0.12
`0.13
`
`1
`1.12
`
`a. Cation-adjusted Mueller-Hinton Broth vn'th calcium supplemented to 25 or 50 mg/L as indicated.
`
`The Applicant has supplied additional data that explain the effects of calcium that can be
`found 111 the Microbiology Section 6.4 ofthe briefing package.
`
`Daptomycin powder is stable for at least 2 years at refrigerated temperatures (4°C:3°C).
`Daptomycin in water or phosphate buffer
`solutions stored frozen (-20°C) was. stable
`for at least three months with little degradation (as determined by
`~—-
`
`I The Applicant has supplied evidence for the stability of daptomycin in various
`microbiological broth media used for susceptibility testing and assessed at concentrations
`of 2 and 8 pg/ml. Daptomycin showed good stability in the presence of 5% lysed horse
`blood over the course of the experiments.
`
`Daptomycircis appreciably bound to serum proteins (approx. 90%). As expected,
`susceptibility testing of daptomycin in the presence of serum proteins was associated with
`an increase in the MIC.
`
`Further data on the effects of serum proteins was provided by the Applicant in
`Microbiology section 6.4 of the briefing package.
`
`The in virro antibacterial activity of daptomycin is reduced by increases in the inoculum
`density. The effect of the inoculum density on the activity of daptomycin against isolates of
`S. aureus, 5. epidennidis and E. faecalis was studied by several independent investigators
`[21, 29]. The daptomycin MIC of these isolates increase 2- to 8-fold as the inoculurn
`density increased from 103 1649‘ CFU/ml (Table 3).
`
`

`

`NDA No. 21-572
`Cubicin
`Cubist Pharmaceuticals, Inc.
`
`-
`
`Page ion 14
`
`Table 3: Effect ofinoculum density of the in vitro activity of daptomycin
`'
`'
`Logic lnoculum Density (CPU/ml)
`
`isolate
`
`(Antibiotic Susceptibility)
`
`S. pneumoniae $51. #25 (Pen-S)'
`S. pneumoniae SSL#27 (Pen-R)
`Slaphylococcus aureus #784 (Meth-R)
`Staphylococcus aureus SSL#758 (Meth-R)
`Staphylococcus spp.” SSL#638
`(Van-l)
`S. aureus ATCC 29212 (Meth-S)
`£r1/er0coccus faecium SSL#50] (Van-R)
`E. faecalis ATCC 292l3 (Van-S)
`
`3
`
`0.25
`0.5
`l
`1
`l
`0.5
`0.125
`l
`
`_
`
`,
`
`4
`
`0.5
`l
`2
`l
`l
`l
`0.5
`2
`
`5
`MIC 11ng _
`l_
`l
`2
`2
`2
`2
`2
`4
`
`6
`
`l
`I
`8
`8
`4
`8
`4
`8
`
`Tested in MB agar supplemented with 5% sheep blood. incubated in C01
`a.
`b. Coagulase-negative staphylococci
`
`Bactericidal activity
`Time-kill curves illustrating the bactericidal activity of daptomycin against S. aureus and
`E. faecalis are shown in Figure 3. For S. aureus (including MRSA), daptomycin (at 2x to
`4x MIC) achieves a 3-logtcn reduction in viable organisms in less than 30 min. Daptomycin
`is bactericidal within 1 hour at 4leC against VRE. Vancomycin is generally
`bacteriostatic against enterococci using the same methodology.
`
`Figure 3: Bactericidal effects of daptomycin
`
`igure 6-] l: Bactericidal effects of daptomycin
`
`
`
`Rdmtx Thin-z: an! Alder. (lined Mtcutuu‘mpx Nubian-12!»: [6?]
`
`Fuchs et a]. [82] determined the bactericidal activity of daptomycin as compared to those
`of vancomycin, quinupristin/dalfopristin and linezolid against 108 isolates of staphylococci
`(3 GISA, 25 MRSA, 4O MRSE, 25 MSSA, 4 M8813 and 11 S. haemolyzicus). Eighty-three
`percent ofthe isolates showed MBC/MIC ratio of l (Mle =MBCs); 15% showed
`MBC/MIC ratio= 2 (within 1 dilution), and 2 isolates (one MRSA, and one MRSE) showed
`MBC/MIC ratio = 4 (2 dilutions apart). The compilation ofMlC and MBC data from this
`study is shown in Table 6-16.
`Recently Cha er a] [31] investigated the bactericidal activity of daptomycin, linezolid, and
`quinupristin/dalfopristin agmsr the first reported isolate of VRSA [78] in an in vitro
`
`
`
`
`
`BESTPOSSIBLECOPY
`
`

`

`NDA No. 21-572
`Cubicin
`Cubist Pharmaceuticals, Inc.
`
`Page 8 of 1 l4
`
`pharmacodynamic model with simulated endocardial vegetations (Figure 2). Daptomycin
`and quinupristin/dalfopristin achieved 99.9% kill against the VRSA isolate by 8 hours (first
`timepoint analyzed) and maintained bactericidal activity for the duration of the experiments
`(i.e. 72 hours). Linezolid did not achieve 99.9% kill until 24 hours, vancomycin had no
`activity against the isolate.
`
`Figure 2: Bactericidal effects of daptomycin, linezolid,‘ and quinupristinjdafopristin
`against vancomycin-resistant S. aureus.
`
`.
`
`igure (>12: Time-kill kinetics nfdaptnmycin. linezolid. and quinuprisfin/dalfopristin
`againsl vancomycin-resistant S. aureus
`
`‘2‘
`
`togfictnq
`
`(he-n cannot
`Vaneemvem
`
`Gull-c: am i: am: -r\~c1r
`
`L nelclvd
`
`0
`
`‘2
`
`4':
`
`3:
`
`‘5
`
`U:
`
`‘Rcstezge (Lia/1:; til-kit 2'0: [Ml
`
`Using MBC/MIC ratios, Snydman el al. determined that daptomycin was bactericidal for
`82% (14/17) ofE.faecium (VRE) strains [76]. Similar findings were obtained by Fuchs et
`01. against 44 enterococcal isolates (16 E. faecalis, 9 vancomycin-resistant, 7 vancomycin-
`susceptible; and 28 E. faecium, l9 vancomycin-resistant, 9 vancomycin~susceptible3132].
`Time-kill studies determining the bactericidal activity of daptomycin against enterococci
`showed that daptomycin is bactericidal against enterococci, with a rate of kill for VRE that
`appears to be slower than that observed for MRSA. Akins and Rybak, using the
`pharmacodynamic in vitro model demonstrated bactericidal aetivity of daptomycin against
`an E. faecium (VRE) isolate [81].
`
`Transmission Electron Microscopy (TEM) was used to better assess the early structural
`effects of daptomycin on S. aureus strain 42 MRSA exposed to four concentrations of
`daptomycin [33]. Cells exposed to 2 11ng demonstrated no killing and begin to recover
`and grow at approximately 2hr. Cells exposed to 4 pg/ml showed killing during the first
`hour.
`
`."‘.
`
`Table 4: Mle and MBCs of daptomycin and 3 comparator agents against 108
`Staphylococci-isolates
`
`

`

`1
`
`—]
`
`_
`
`-
`
`.
`
`‘
`
`.
`
`25
`
`25
`
`3
`
`4
`
`40
`
`S. aureus
`(glycopeptide
`intermediate-
`susceptible; GISA)
`S. epidemidis
`(methicillin-
`susceptible)
`
`S. epidermidis
`(methicillin-
`resistant)
`
`l - 2
`Daptomycin
`1 - 2
`Vancomycin
`>16 - >64
`Linezolid
`l - >16
`Quinupristin/dalfopristin
`l - 4
`Daptomycin
`l - 2
`Vancomycin
`16 - >32
`Linezolid
`>4 - >16
`Quinupristin/dalfopristin
`l - 2
`Daptomycin
`l - >4
`Vancomycin
`8,0 - >32
`Linezolid
`] - >8
`Quinupristin/dalfopristin
`1 - 2
`Daptomycin
`l - 1
`Vancomycin
`32 - >128
`Linezolid
`l - >32
`Quinupristin/dalfopristin
`l - 4
`Daptomycin
`1 - 2
`Vancomycin
`1 - >128
`Linezolid
`l - >32
`Quinupristin/dalfopristin
`l - 2
`Daptomycin
`1 - 2
`Vancomycin
`l - >64
`Linezolid
`1 - >16
`J
`L
`Quinupristin/dalfoptistin
`a. MBC/MlC < 4 is interpreted as bactericidal activity; MBC/MlC > 4 is interpreted as lack of bactericidal activity
`
`NDA No. 21-572
`Cubicin
`
`Cubist Pharmaceuticals, Inc.
`
`Page 9 of 1 14
`
`No. of
`Strains
`._
`
`~
`
`Antimicrobial
`Agent
`
`MIC Range
`(pg/ml)
`
`_
`
`MBC Range MBC/MIC'
`(pg/ml)
`(dilutions)
`
`Species
`(resistance
`phenotype)
`S. aureus
`(methicillin-
`susceptible)
`
`S. aureus
`(methicillin-
`resistant)
`
`-
`
`S. haemolyricus
`
`ll
`
`-
`
`SPECTRUM 0F ACTIVITY OF DAPTOMYCIN
`Daptomycin is a potent antibiotic with a spectrum of activity that includes many cliirically
`significant Species of aerobic and anaerobic Gram-positive pathogens. The in vitro activity
`of daptomycin has been assessed against more than 21,000 clinical isolates from
`throughout the US and Europe. These studies include a series of carefully controlled, large-
`scale profiling surveys using standard NCCLS recommended methodology [1 7], except
`that microdilution was performed using MH broth supplemented with‘SO mg/L calcium
`chloride, as recommended by NCCLS for daptomycin susceptibility testing (Table 3, pp.
`118-119, Document M100--SlZ [13]). As_detai1ed below (see Section 6.4.1), accurate in
`vitro assessment of daptomycin activity rcquires‘physiologic levels of free (ionized)
`calcium.
`
`The Applicant has provided a table (Table 5) which summarizes the spectrum of activity of
`daptomycin.
`
`Table 5: Summary of the spectrum 01' activity of daptomycin
`
`

`

`NDA No. 21-572
`Cubicin
`
`Cubist Pharmaceuticals, Inc.
`
`Species of Microorganism
`
`Aerobes (Gram-positive)
`Bacitius anthracis
`
`Bacillus spp.
`Corynebacteriumjeikeium
`Other Corynebacterittm spp.
`Enlerococcus avium
`Entcrococcus casseli avus
`
`Enterococcusfaecalis (Susceptibility not specified)
`Enterococcusfaecalis (Vancomycin-susceptible)
`Enterococcusfaecalis
`(Vancomycin-resistant)
`Enterococcusfaecalis (Vancomycin-interrnediate)
`Enterococcusfaecium (Susceptibility not specified)
`Enterococcusfaecium (Vancomycin-susceptible)
`Enterucoccusfaecium (V ancomycin-resistant)
`Enterococcusfaecium (Vancomycin-intermediate)
`Enterococcus gallinarum
`Enterococcus spp. (Vancomycin-susceptible)
`Enterococcus spp. (Vancomycin-intermediate)
`Enterococcus spp. (Vancomycin-t'esistant)
`Enterococcus spp.
`(Susceptibility not specified)
`Lactobacillus spp. (grown aerobically)
`Lactococcus coprophilus
`Leuconostoc spp.
`Listeria monocytogenes
`Pediococcus pentosaceus
`Staphylococcus aureus (methicillin-susceptible; MSSA)
`Staphylococcus aureus (methicillin-tesistant; MRSA)
`Staphylococcus aureus (vancomycin-intetrncdiate; VISA)
`Staphylococcus aureus (vancomycin-resistant; VRSA)
`Staphylococcus epidermidis (methicillin-susceptible;
`Staphylococcus epidemidt's (methicillin—tesistant; MRSE)
`Staphylococcus
`spp.(vancomycin-intennediate)
`Staphylococcus haemolytt'cus
`Staphylococcus saprophyticus
`Staphylococcus spp., coagulase negative (methicillin-
`susceptible)
`Staphylococcus spp., coagulase negative (methicillin-
`resistant)
`-
`c.
`.
`Streptococcus agalactiae (Group B)
`Streptococcus anginosus
`Streptococcus B—hemolytic (not grouped or speciated)
`Streptococcus bovt‘s
`Streptococcus gordom't'
`Streptococcus t'ntermedt'us
`Streptococcus milleri
`Streptococcus mitis
`Streptococcus oralis
`Streptococcus pneumoniae (penicillin susceptibility not
`specified)
`_
`Streptococcus pneumoniae (penicillin-susceptible)
`“V-- s..-
`Species of Microorganism
`
`'
`
`N
`
`13
`
`68
`42
`10
`
`951
`4310
`131
`
`875
`590
`525
`
`11
`216
`
`18
`109
`
`15
`
`32
`
`2440
`1378
`
`101
`105
`
`102
`36
`1101
`
`1779
`
`983
`
`100
`12
`
`49
`16
`30
`428
`
`1894
`N
`
`Page 10 013114
`
`MIC Range
`lug/ml)
`
`Mle
`(HEJml)
`
`F
`
`:1
`
`2.0
`
`0.25
`0.06
`
`0.25 - 1.0
`0.5 - 1.0
`0.5 - 2.0
`
`1.0-4.0
`1.0-2.0
`1.0-4.0
`
`MIC90
`(pg/ml)
`
`2.0
`
`0.25 - 0.5
`0.25
`
`0.25 - 4.0
`0.5 - 2.0
`0.5 - 4
`
`1.0 - 8.0
`2.0 - 4.0
`2.0 - 4.0
`
`<0.5 - 2.0
`
`4.0 - 4.0
`
`4.0-4.0
`1.0-1.0
`
`4.0 - 4.0
`4.0 -4.0
`
`4.0
`
`4.0
`
`0.125-0.5
`0.125-1.0
`
`0.125-1.0
`O.l3-l.0
`
`'D
`0.13-0.25
`0.13-0.25
`
`0.125 - 0.25
`0.5 - 0.5
`0.12 - 0.25
`
`0.5
`0.25
`0.25 - 0.25
`
`0.25 - 0.5
`0.5 - 0.5
`0.25 - 0.5
`
`0.25 - 0.5
`
`0.5-1.0
`
`0.125 - 0.5
`
`0.25 - 0.5
`
`0.25 - 0.5
`0.5 4 0.5
`0.5 - 0.5
`
`0.125 - 0.25
`
`0.03 - 0.12
`
`MIC”
`
`0.5-1.0
`1.0-1.0
`1.0-1.0
`0.25-0.5
`
`0.125 _- 0.25
`MIC”
`
`.1
`l.v
`
`MlCllange
`
`

`

`NDA No. 21-572
`Cubicin
`Cubist Pharmaceuticals, Inc.
`
`-
`
`Page 11 _of114
`
`638
`454
`950
`
`10
`18
`2
`1
`59
`593
`
`18
`19
`
`Streptococcus pneumoniae' (penicillin-intermediate)
`Streptococcus pneumoniae (penicillin-resistant)
`Streptococcus pyogenes (Group A)
`
`Streptococcus salivarius
`Slreptococcus sanguis
`Streptococcus parasanguis
`Streptococcus vestibularis
`Streptococcus spp., Group C, F, and G
`V iridans Streptococcus Group (not speciated)
`
`.
`
`Anaerobes (G ram-positive)
`Clostridium diflicile
`Clostridium innocuum
`
`CIostridium perfringens
`Clostridium ramosum
`Other Clostridium species
`Laclobacillus species
`PeptoStrep/ococcus asaccharolyticus
`PeptoStreptococcus magnus
`PeptoStreptococcus micros
`Propionibactert’um spp.
`Total [N]
`
`(#me
`
`‘1'.
`
`1
`
`(pg/ml)
`
`(tug/ml)
`
`0.12 - 0.25
`0.12 - 0.25
`0.015 - 0.06
`
`~
`0.5 - 0.5
`~
`—
`0.03 - 0.06
`0.25 - 0.5
`
`0.25 - 1.0
`0.125 - 1.0
`0.06 - 0.12
`
`-
`1.0 - 1.0
`-
`-
`0.06 - 0.06
`1.0 - 1.0
`
`“
`
`‘
`
`-
`
`‘
`
`1 1
`15
`25
`37
`10
`7
`7
`-
`15 L4/
`21,703
`
`0.5
`2.0
`
`0.5
`16.0
`0.5
`1.0
`0.02
`-
`-
`0.5
`
`1.0
`4.0
`
`0.5
`16.0
`2.0
`16.0
`0.06
`-
`-
`2.0
`
`Daptomycin possesses potent in vitro activity against the most common aerobic Gram-positive
`pathogens [14, 15, 63, 71, 72, 75, 76], including staphylococci and enterococci resistant to
`methicillin, vancomycin, linezolid, and/or quinupristin-dalfopristin (e.g., MSSA, MRSA, MRSS,
`GlSA, VSE, VRE). The two recently reported isolates of vancomycin-resistant S. aureus (VRSA)
`[18, 78] are susceptible to daptomycin with a MIC of 0.5 and 1 pg/ml [23, 79]. Table 6 presents
`the in vitro activity of daptomycin against 4,429 S. aureus isolates, including 1,378 MRSA, and
`3,371 coagulase-negative staphylococci. Daptomycin was active against all isolates of S. aureus,
`with a MIC range of =0.01 5-2 pg/ml. Based on the SECURE studies; the M1C9o for all S. aureus is
`0.5ug/m1 (see Table 6). Resistance to methicillin did not affect the potency of daptomycin.
`Daptomycin was also very active against coagulase-negative Staphylococcus spp. including S.
`epidermidis, with M1C900f0.5 pg/ml [Table 6].
`
`Over the past several years, staphylococcal isolates with reduced susceptibility to glycopeptides
`have emerged [19]. In general, these isolates have also been resistant to methicillin and other [3—
`lactam antibiotics. The Applicant has provided data that shows daptomycin has potent
`antimicrobial activity against the glycopeptide intermediate-susceptible staphylococci (GISE).
`This data can be found in Microbiology Section 6.2 of the briefing package.
`
`Table 6: Activity of Daptomycin against Staphylococci
`
`

`

`NDA No. 21-572
`Cubicin
`Cubist Pharmaceuticals, Inc.
`
`Page 12-of114
`
`MIC Range
`ug/ml
`
`V‘t
`
`Mng
`pg/ml
`0.125 -0.5
`0.125 - 1.0
`0.25
`
`Mic90
`nyml
`012510
`013-r0
`025-05
`
`013-025
`013-025
`025-05
`
`0.125 - 0.25
`0.5 - 0.5
`0.12 - 0.25
`0.25 - 0.5
`0.25
`
`0.25 - 0.5
`0.25 - .25
`0.5 ~ 0.5
`
`0.25 - 0.5
`0.5 - 0.5
`0.25 - 0.5
`0.5 - 1.0
`0.5
`
`1-22!
`
`N
`
`2440
`1378
`601
`
`8 2
`
`101
`105
`40.
`4
`102
`36
`1101
`1779
`103
`7800
`
`Species of Microorganism
`
`.S‘Ianhylococcus aureus (rriethicillini-susceptible) (MSSA)
`Staphylococcus aureus (methicillin-resistant) (MRSA)
`Staphylococcus aureus (methicillin not specified)
`Staphylococcus aureus (vancomycin-intermediate) (VISA)
`Staphylococcus aureus (vancomycimresistant) (VRSA)
`Staphylococcus epidermidis (methicillin-susceptible) (MSSE)
`Staphylococcus epidermidis (methicillin-resistant) (MRSE)
`Staphylococcus cpidenm‘dis (methicillin not specified)
`Staphylococcus spp., (vancomycin- intermediate)
`Staphylococcus haemolytr‘cus
`Staphylococcus saprophyticus'
`Staphylococcus spp., coagulase negative (methicillin-susceptible)
`Staphylococcus spp., coagulase negative (methicillin-resistant)
`Staphylococcus spp., coagulase negative (methicillin not specified)
`Total
`
`Recently. daptomycin was tested against a set of 57 S. aureus and 31 coagulase-negative
`staphylococci with reduced vancomycin susceptibility obtained between 1996 and 2001 .
`[20]. The results are diSplayed in Table 7. The susceptibility of vancomycin-resistant
`clinical isolates of S. aureus to daptomycin is displayed in Table 8.
`
`Table 7: Distribution of Daptomycin MIC against Staphylococci Collected from Project
`lCARE Hospitals
`
`No. of Isolates with Daptomycin MIC (pg/m1)
`0.25
`0.5
`4
`a
`
`8
`
`3
`
`2
`
`1
`
`2
`
`1 0
`
`‘“
`
`NU!
`
`#Species (vancomycin susceptibility) Vancomycin N
`MIC
`
`'=012
`
`S. aureus
`
`intermediate (VISA)
`ecreased (DSV)
`
`Susceptible (VS)
`Coagulase-Negative Staphylococci
`Intermediate (VISA)
`Decreased (DSV) ‘
`Susceptible (VS)
`
`Shaded area represents MIC”
`
`57
`
`3
`16
`
`38
`31
`
`1
`l6
`14
`
`8 pg/ml
`4 pg/ml
`
`2pymt
`
`8 pg/ml
`4 pg/ml
`2 ug/ml
`
`Table 8: Daptomycin Susceptibility against Vancomycin—Resistant Staphylococcus aureus
`Isolate (VRSA)
`Strain (Geographical Source)
`
`Daptomycin MIC
`pg/ml
`1.0
`
`Vancomycin MlC
`uwml
`>128
`
`0.5
`
`>64
`
`S. aureus (Michigan)
`
`S. aureus (Pennsylvania) 1
`
`i!
`
`

`

`NDA No. 21-572
`Cubicin
`Cubist Pharmaceuticals, Inc.
`
`Page 14 OH 14
`
`enterococci, including 5,397 E.faecalis 1,999 E. faecium, 11 E. gallinarum, 10 E. avium, 1
`E. casselifiavus and 349 other Enlerococcus spp. Based on the SECURE studies, the
`MlC9o for vancoinycin- susceptible and -resistant E. faecalis is 2 pg/ml (Table 6). In
`general, daptomycin was slightly more active against E. faecalis than against E. faecium.
`The Applicant asserts that these data support the selection of provisional susceptible
`breakpoint of 8 pg/ml for E. faecalis as detailed in Table 1.
`
`Table 10: Activity of Daptornycin against Enterococci
`Species of Microorganism
`N
`MIC Range
`pg/ml ‘
`
`Enlerococcus avium
`Enlerococcus casseliflavus
`Enlerococcusfaecalis
`(vancomycin-susceptible)
`Emerococcusfaecalis
`(vancomycin-intennediate)
`Enlerococcusfaecalis
`(vancomycin-resistant)
`.Enlerococcusfaecalis
`(susceptibility not specified)
`Enlerococcus faecium
`(vancomycin-susceptible)
`Enlerococcus faecium
`(vancomycin-intermediate)
`Enlerococcus faecium
`(‘-'ar‘comycin-rcsistant)
`Enrerococcusfaecr'um
`(susceptibility not specified)
`Enterococcus gallinarum
`Enrerococcus spp.
`(vancomycin—susceptible)
`Enterococcus spp.
`(vancomycin-intennediate)
`Enrcrococcus spp.
`(vancomycin-resistam)
`Emerococcus spp.
`(susceptibility not specified)
`
`Total [N]
`
`..
`
`w.
`
`10
`1
`
`i-
`5-
`
`4310
`
`5
`
`131
`
`951
`
`590
`
`9
`
`525
`
`875
`ll
`
`MIC”
`pg/ml
`-
`-
`
`MIC”
`pg/ml
`-
`-
`
`0.5 - 1.0
`
`0.5 - 2.0
`
`‘
`
`-
`
`-
`
`0.5 - 2.0
`
`0.5 - 4
`
`0.25 1.0
`
`0.25 - 4.0
`
`1.0 - 2.0
`
`2.0 - 4.0
`
`-
`
`-
`
`1.0 - 4.0
`
`2.0 - 4.0
`
`1.0 - 4.0
`-
`
`1.0 - 8.0
`-
`
`216
`
`'
`
`‘
`
`<0.5 - 2.0
`
`l0 - 4.0
`
`6
`
`18
`
`109
`
`7,767
`
`-
`
`.
`
`-
`
`-
`
`J \
`
`4.0 - 4.0
`
`4.0 - 4.0
`
`1.0 - 1.0
`
`4.0 - 4.0
`
`The Applicant has provided a table (Table 11) demonstra