ABSTRACTS
`of the 36th
`lnterscience Conference
`
`on Antimicrobial Agents
`
`and Chemotherapy
`
`an Annual Meeting
`of the American Society for Microbiology
`
`September 15-18, 1996
`
`Ernest N. Morial Convention Center
`New Orleans, Louisiana
`
`Amercan Society for Microbiology
`Washington, D.C.
`
`ACRUX DDS PTY LTD. et al.
`EXHIBIT 1015
`IPR Petition for
`U.S. Patent No. 7,214,506
`
`1 of 4
`
`

`
`© 1996 American Society for Microbiology
`1325 Massachusetts Avenue, N.W.
`Washington, DC 20005-4171
`
`All Rights Reserved
`Printed in the United States of America
`ISBN 1-55581-113-2
`
`2 of 4
`
`

`
`CONTENTS
`
`Abstracts in Order of Subject Category:
`
`Subject Category A ........................................................................................................................................................................ 1
`Pharmacokinetics and Pharmacodynamics in Animals or Humans
`
`Subject Category B ...................................................................................................................................................................... 21
`Animal Models, Pathogenesis of Infectious Diseases, Molecular Basis for Pathogenicity
`
`Subject Category C ...................................................................................................................................................................... 34
`Antimicrobial Resistance and Action: Genetics, Mechanisms, Epidemiology
`
`Subject Category D ...................................................................................................................................................................... 60
`Laboratory Tests (Excluding Viral) for Diagnosing Infections; Methods for Susceptibility Testing
`
`Subject Category E ...................................................................................................................................................................... 81
`In Vitro Antimicrobiai Susceptibility Studies; Surveillance and Detection of Antimicrobial Resistance; Drug
`Interactions and Combinations
`
`Subject Category F ..................................................................................................................................................................... 100
`New Antimicrobials (pre US IND) Including Chemistry and Susceptibility
`
`Subject Category G .................................................................................................................................................................... 143
`Immunology and Host Defenses; Bacterial Vaccines, Immunomodulators, and Immune Response
`
`Subject Category H .................................................................................................................................................................... 163
`Virology: Diagnostics, Pathogenesis, Natural History, Antiviral Drugs, and Vaccines
`
`Subject Category I ...................................................................................................................................................................... 186
`HIV and Other Retroviruses
`
`Subject Category J ..................................................................................................................................................................... 218
`Nosocomial Infections and Surgical Infections and Related Epidemiologic Studies
`
`Subject Category K .................................................................................................................................................................... 249
`Community-Acquired Infections, Including OB GYN and STD Infections, and Related Epidemiologic Studies
`
`Subject Category L, M .............................................................................................................................................................. 280
`Clinical Trials of Antimicrobial Agents & Unique and Instructive Clinical Observations
`
`Subject Category N .................................................................................................................................................................... 293
`Pharmacoeconomics and Managed Care
`
`Subject Index ............................................................................................................................................................................. 327
`
`Participant Index ........................................................................................................................................................................ 337
`
`iii
`
`3 of 4
`
`

`
`Monday, Session 50
`
`ABSTRACTS OF THE 36th ICAAC
`
`F78 KP-103, a Novel Topical Antifungul Trlazole:
`Structure-Activity Relationships of Azolylamine Derivatives.
`H.OGURA*, H.KOBAYASHI, K.NAGAI, T.NISHIDA, T.NAITO,
`Kaken Pharm. Co., LTD.,
`Y.TATSUMI, M.YOKOO and T.ARIKA.
`Kyoto, Japan.
`In a search for an antilungal agent, we have prepared a
`variety of new azolylandne derivatives with general
`formula (I)and
`measured in vitro activity. MIC vaines(pg/ml) were
`shown below.
`
`2
`KP-103 1
`Fun[i
`<0.025 <0.025 <0.025
`C. albicans KC-03
`0.1
`0.2
`Cr. neoformans KC-201 0.05
`A. fumigalus KA-01
`0.2
`0.2
`1.56
`0.78
`1.56
`T. menta~roph~tes KD-04 0.39
`¯ A; SAA_MP broth. B; sahouraud dextrose agar.
`We found that the cyclic amine having methylene group at
`the 3 position is necessary for a broad antifungal specUam and
`a potent activity. KP-103 which has a (2R,3R)-absolute configuration
`and a 4-methylenepipendine moiety, showed the most potent
`activity and significantly lower MIC values than clotrimazole(CTZ).
`
`C’TZ Media’
`4
`3
`0.025 A
`0.05 0.2
`0.78 6.25 0.2
`B
`1.56 50.0
`B
`0.78
`3.13 25.0
`0.39
`B
`
`~
`
`AN~~F~I
`
`F I
`= Jmbm~tuted andn~ iProup
`
`~q.3R rlt~m, .... ,(cid:128)
`
`eac~t,(cid:128) ra~oic
`
`-- N.~.~
`
`"He
`
`F79 In Vitro hJ=tlvity of KP-103, a Novel Toploal /l~Mfungnl Tdmole.
`Y. TATSUMI’, M. YOKOO, T. ARIKA, H, OGURA, It,. NAGAI, and T. NAITO.
`Kakan Pharmaceutical Co. Ltd., Kyoto, Japan, H. YAMAGUCHI, Talkyo Univ.,
`Tokyo, Japan.
`The in vitro ac~vity of KP-103, a triazofe having 4-me~peddlne
`moiety at the C-3 posrdon, was compared ~ that of dotrtmazofe (Cl-Z),
`neticonazole (NCZ), isnoconazole (LCZ), and butlmalkw (B’rF) agalnat
`pathogmtc fungi. M;Cso vafuos Ozo/n’d) were ~’mwn below.
`
`KP-103 CTZ NCZ LCZ
`Fungi (No. of sb’alns)
`0.002
`0,0~13 0.0625 0.25
`C. albicans (44)
`0.78
`0,025
`6.25
`3.13
`M. furfur (6)
`Aspergl//us spp,(15)
`0.0625 2.0
`0.25
`0.002
`0.0078
`0.125
`0.5
`0.25
`T. rubrum (39)
`T. mentagrophytes (28) 0.25
`0.0013
`0.25
`0.25
`¯ A. 0.2M MOPS-beffemd RPMi 1840, pH 7.0; B, Sabouraud dwtlmle
`C, medlum C {Fs~,ar, n J M aL A~ Dram. VK~IoL SUl~l ~ I-e’~, 19"/11}.
`KP-103 was the moat active against C. atbicens and M. fudur among ’din
`tented dt’ugs. Its activity agalnM Trichophyton spp. was almost equal to that
`of CTZ and NCZ, but was weaker than that of LCZ and BTF.
`
`BTF Media"
`>8.0
`A
`12.5
`C
`0.25
`A
`0.0078
`B
`0.0156
`B
`
`Anti- T. menmgrophy~ aC~Nities of the mfemnm drugs were md~ed by
`the addition of human serum and horny rn~edals as reported, while that of
`KP-103 wan not atfoctod. F~, Anti- T. mentngmpytes m,-tlvlty of KP-
`103 on the s~pped human hamy layer was equal to that of LCZ md BTF.
`These results reflocted in vivo efl1,~.._cios,
`In summaw, KP-103 has a broad antifungal spectrum and could keep
`a high activity in the horny layer where fungi reside.
`
`Fg0 Therapeutic Efficacy of KP-103, n Novel Toploal Antlfungal
`Tda=ole, on Expwlmantat Suparflclat Mycosis. Y, TATSUMI’, M. YOKOO,
`T. ARIKA, H. OGURA, K. NAGAI, and 1". NAITO. Kaken Pharmaceutical Co.
`Ltd., Kyoto, Japan, H. YAMAGUCHI, Teikyo Univ., Tokyo, Japan.
`The therapeutic efficacy of KP-103 on dermatomycosis models in guinea
`pig was compared with that of naticonazlee (NCZ), isaoconazole (LCZ),
`butenafine (BTF), and clofrimazole (CTZ). One % SOlution of each drug was
`topically applied once a clay. Two days after last application, skin blocks or
`homogenates were cultured. Rate of complete cure was expressed by the
`percentlge of mycoingically cured animals in infected animals (n=lO).
`
`F’/5
`
`SSY726, a New Triazole Aatifangal Agent: in vitro and in mvo
`Evaluation. K. YOKOYAMA*, L. WANG, end M. MIYAJI.
`Research Center for Pathogenic Fungi and Microbial Toxicoses. Chiba
`University, Chiba, and A IWASA Research Laboratories, SS
`Pharmaceutical Co, Ltd, Narita, and Y. Ikeda Research Laboratories.
`Yoshitomi Pharmaceutical Industries, Ltd, Fukuoka, Japan
`The in vitro and in vivo antifungal activity of SSY726, a new antifungal
`agent, was compared with that of fluconazole (FLCZ) against Candida spp,
`C.ryptococcus neoformans, and Aspergillus spp Minimum inhibitory
`concentration (MIC) was determined to estimate the in vitro activity by the
`twofold agar dilution method. The MIC ranges were as follows: SSY726,
`0.5 - 4 pg/~; FLCZ, 0.5 - 8 with synthetic amino acid medium for fungal
`(SAAMF), SSY726, 128 - >512; FLCZ, 512 - >512 with RPMI-1640
`MOPS medium (RPMI) against C.albicans (30 strains). SSY726, 4 - 256
`p g/mi; FLCZ, 4 - 256 with RPMI against C.neoformans (30 strains).
`SSY726, 32 - >512 pg/m]; FLCZ, 128 - >512 with SAAMF against
`
`A.~’gatus (30 strains).
`e in vivo activity was measured following one time on day 0 (in
`Candida and Crv.~tococcus models) or once a day on five successive days
`(in Aspergillus models) injection of the agent into 5-week old, ICR male
`mice. The efficacy was determined by the dose of agent necessary to
`achieve a certain T/C (treated group/control group) ratio of survival days. In
`the cendidosis model, 0.313 mg/kg of SSY726 or 5 mg/kg of FLCZ was
`required to achieve 300 % of T/C ratio, respectively. In the cryptococcosis
`model, 5 mg/kg of SSY726 or 20 mg/kg of FLCZ achieved 122 % of T/C.
`In the aspergillosis model, no significant difference in efficacy was detected
`between these two agents. Our study suggests that the in vivo efficacy of
`SSY726 is higher than that of FLCZ against Candida and CO,ptococcus.
`
`Efficacy of SSY726 on Systemic Candidosis and Cryptococcosis
`in Neutropenic Mice. M. MATSUMOTO* T. ASAOKA, and A.
`IWASA. Research Laboratories, SS Pharmaceutical Co., Ltd., Narita, and
`Y. IKADA, K. YAMAMOTO, and F. HIRAYAMA. Research
`Laboratories, Yoshitomi Pharmacetical Industries, Ltd., Fukuoka, Japan.
`SSY726:(R)-(-)-3-mcthyl-3-methylsulfonyl- I-(I H- 1, 2, 4 - triazol - ! -yl)
`2-[4-(trifluoromethyl)phenyl]butan-2-ol is a new triazole antifungal agent.
`Its in vivo efficacies on the basis of prolongation of survival were tested in
`comparison with those of fluconazole (FLCZ). SSY726 showed more
`potent activity than FLCZ with a single i.v. treatment on systemic
`candidosis (C.albicans IFM 40009) and cryptococcosis (C.neoformans
`TIMM 1855) in mice. In normal mice, minimum effective doses were
`0.313 mg/kg of SSY726 and 1.25 mg/kg of FLCZ on candidosis, and 20
`mg/kg of SSY726 and over 20 mg/kg of FLCZ on cryptococcosis. In
`neutropenic mice (cyclophosphamide 100 mg/kg i.p. treated: Cy), they
`were 0.313 mg/kg of SSY726 and 5 mg/kg of FLCZ on candidosis, and
`1.25 mg/kg of SSY726 and 20 mg/kg of FLCZ on cryptococcosis. In
`5-fluorouracil treated mice (150 mg/kg i.p.), they were 0.313 mg/kg of
`SSY726 and 5 mg/kg of FLCZ on candidosis. SSY726 efficacy was also
`compared to that of FLCZ after repeated treatments. In normal mice, i.v.
`treatment of SSY726 every two days or daily doses of 1.25 mg/kg for
`eight days showed an e.quivalent effect to that of i.v. daily treatment of 5
`mg/kg FLCZ for eight days. In neutropenic mice (Cy), i.v. treatment of
`SSY726 every four days doses of !.25 mg/kg for eight days showed an
`equivalent effect to that of i.v. daily treatment of 5 mg/kg FLCZ for eight
`days. Thus, SSY726 was more effective than FLCZ in the systemic
`infection with C.albican$ and C.neoformans, especially in neutropenic
`mice.
`
`F’t7
`
`Anticryptococcal Activity of SSY726, a New Triazole Antifuagal
`Agent, in a Murine Pulmonary Infection Model. Y. IKEDA*, K.
`YAMAMOTO, and F. HIRAYAMA. Research Laboratories, Yoshitomi
`Pharmaceutical Industries, LTD., Fukuoka. M. MATSUMOTO, T.
`ASAOKA, and A. IWASA, Central Research Laboratories, SS
`Pharmaceutical Co., LTD., Chiba, Japan.
`SSY726, a new iriazole antifungal agent, was evaluated for
`anticryptococcal activity in normal or neutropenic mice. The leukopenic
`mice with cyclophosphamide (CY, 100 mg/kg, i.p.), 5-fluorouracil (5-FU,
`150 mg/kg, i.p.) or prednisolone (PDN, 50 mg/kgj s.c.), and normal mice
`were inoculated intranasally with 1.7 - 3.0 x 10~ cells of Cryprococcus
`neoformans TIMM 1855. Intravenous treatment with SSY726 or
`fluconazole (FLCZ) was initiated 1 hour after the challenge, and was
`followed by once daily, every two days or every four days for 8 days.
`Therapeutic effect was estimated by the reduction of viable cell counts
`(CFU) in lungs at day 10 after the infection. In once daily for eight
`successive days injection, SSY726 significantly reduced CFU in lungs at
`a dose of 0.31 mg/kg/day in CY- and 5-FU-treated mice, and at a dose of
`5 mg/kg/day in normal and PDN-treated mice. FLCZ reduced CFU in
`lungs at a dose of 5 mg/kg/day and 20 mg/kg/day in CY- and
`5-FU-treated mice, respectively, but did not up to 80 mg/kg/day in normal
`and PDN-treated mice. Every four days treatment with 5 mg/kg/day of
`SSY726 (total dose: 10 mg/kg) showed the effect comparable to once
`daily for eight successive days treatment with 20 mg/kg/day of FLCZ
`(total dose: 160 mg/kg) in CY-treated mice. These results suggest that
`SSY726 is more effective than FLCZ in the therapy of pulmonary
`cryptococcosis in compromised humans.
`
`Rate of complete cure (%)
`
`KP-103 NCZ LCZ
`
`BTF
`
`CTZ
`
`Mycosis models
`
`Treatment
`duration
`(days)
`Tinea corporsis
`10
`Tinea pedis
`lo
`Intordigital ffnea pedis 10
`Skin candidia~s
`3
`
`100
`lOO
`100
`80
`
`90
`100
`10
`N.D.
`30
`lOO
`lOO
`N.D.
`40
`100
`100
`N.D.
`0
`0
`0
`N.D.
`The efficacy of KP-103 on dermatopbylceis models was superior to that
`of NCZ and almost equal to that of LCZ and BTF. KP-103 was effective on
`skin candidiasis, while the other drugs warn not. TO cisdfy the duration of
`retention lime Of the drug in skin alter topical appSce~on, the prophylactic
`effect of KP-103 on dermatophylosis model was examined. KP-103 exerted
`prophylactic effect with go% cure rate at application of 48h before lnfeclion.
`In summary, the excellent efficacy of KP-103 on dermatophytosls and
`skin cendldiasis may be attributed to its high activity and long time retention
`In the horny layer.
`
`113
`
`4 of 4