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`UK BACTERIAL
`
`ENDOCARDITI8 WORKSHOPS
`
`October/November 1998
`
`The British Society for Antimicrobial Chemotherapy (BSAC), in collaboration with the Association of Medical
`Microbiologists (AMM) and the Hospital Infection Society (HIS), is holding a series of educational workshops
`focusing on bacterial endocarditis.
`
`Dulwich — Monday 19 October
`Darlington — Wednesday 21 October
`Chester — Thursday 22 October
`
`Bristol — Friday 23 October
`Derby — Wednesday 28 October
`Peterborough — Thursday 5 November
`
`Reading — Tuesday 10 November
`Dublin — Date to be advised
`
`Stirling — Date to be advised
`
`Registration Fee: £25.00 (BSAC/AMM/HIS members), £100.00 (non-members)
`The meetings will commence with a buffet lunch at 12 noon. The workshops will begin at 1.00pm and will close at
`approximately 4.30pm.
`
`To register or for further information please contact:
`
`Organising Secretariat: Nicole Robert/Kate Auty
`Gardiner—Caldwell Communications Ltd
`
`Victoria Mill, Windmill Street, Macclesfield, Cheshire SK11 7HQ, UK
`Tel: +44 (0)1625 664200 Fax: +44 (0)1625 664016
`
`Association of Medical Microfitologists
`
`The Journal of Antimicrobial Chemotherapy
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`_]AC
`
`The Journal of Antimicrobial Chemotherapy
`
`Volume 42 Number 2 August 1998
`
`Contents
`
`Leading articles
`Antibiotic resistance
`R. G. Finch
`
`Extended—spectrum fl-Iactamases in Pseudomonas aeruginosa
`P. Nordmann and M. Guibert
`
`Original articles
`Interactions of plaunotol with bacterial membranes
`T. Koga, H. Watanabe, H. Kawada, K. Takahashi, Y. Utsui, H. Domon, C. lshii, T. Narita and H. Yasuda
`
`In-vitro activity of Iytic peptides, inhibitors of ion transport systems and ionophorous antibiotics against
`Pneumocystis carinii
`O. Cirioni, A. Giacometti, F. Barchiesi and G. Scalise
`
`Influence of ciprofloxacin and other antimicrobial drugs on different Escherichia coli strains in
`continuous-flow cultures under aerobic and anaerobic conditions
`H. Bernhardt, K. Schulz, K=Zimmermann and M. Knoke
`
`Increasing resistance of planktonic and biofilm cultures of Burkholderia cepacia to ciprofloxacin and
`ceftazidime during exponential growth
`M. Desai, T. Buh/er, P. H. Wellerwand M. Ft. W. Brown
`
`Comparison of the modified Stokes’ method of susceptibility testing with results obtained using MIC
`methods and British Society of Antimicrobial Chemotherapy breakpoints
`P. E. Gosden, J. M. Andrews, K. E. Bowker, H. A. Holt, A. P. MacGowan, D. S. Reeves, J. Sunder/and
`and R. Wise
`
`In-vitro investigation of the antibacterial activity of agents which may be used for the oral treatment of
`lung infections in CF patients
`Ft. M. E. Flichards, V. E. S. Hamilton and M. H. Thomas
`
`The effects of increasing levels of quinolone resistance on in—vitro activity of four quinolones
`K. S. Thomson and C. C. Sanders
`
`Glycopeptide tolerance in Staphylococcus aureus
`J. May, K. Shannon, A. King and G. French
`
`Activated cell-wall synthesis is associated with vancomycin resistance in methicillin-resistant
`Staphylococcus aureus clinical strains Mu3 and Mu5O
`H. Hanaki, K. Kuwahara—Arai, S. Boyle—Vavra, H. S. Daum, H. Labischinski and K. Hiramatsu
`
`The effect of a component of tea (Camellia sinensis) on methicillin resistance, PBP2’ synthesis, and
`fl-lactamase production in Staphylococcus aureus
`T. S. Yam, J. M. T. Hamilton—Mil/er and S. Shah
`
`In-vitro susceptibility of Cryptococcus neoformans isolates to fluconazole and itraconazole
`K. G. Davey, E. M. Johnson, A. D. Holmes, A. Szekely and D. W. Warnock
`
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`The effect of dicloxacillin and fusidic acid on the extracellular and intracellular killing of Staphylococcus aureus
`8. L. Nielsen and F. T. Black
`
`Bacterial concentrations in pus and infected peritoneal tluid—implications for bactericidal activity of antibiotics
`C. Konig, H.-P. Simmen and J. Blaser
`
`221
`
`227
`
`Efficacy and safety of teicoplanin plus rifampicin in the treatment of bacteraemic infections caused by
`Staphylococcus aureus
`E. P. F. Yzerman, H. A. M. Boelens, M. Vogel and H. A. Verbrugh
`ST‘ }
`Brief reports
`Diethylcarbamazine-related antimicrobial activity in Mycobacterlum tuberculosls—infected blood
`L. W. Kitchen, C. M. Weston and S. P. Day
`
`in—vitro antibiotic susceptibility and molecular analysis of anaerobic bacteria isolated in Cape Town,
`South Africa
`
`C. L. Koch, P. Derby and V. Ft. Abratt
`
`Sub—MlCs of sanfetrinem promote the interaction of human polymorphonuclear granulocytes with a
`multiply resistant strain of Klebslella pneumonlae
`A. M. Cufflni, V. Tulllo, A.
`l. Palarchio, A. Bonino and N. A. Carlone
`
`Voriconazole against fluconazole—susceptible and resistant candida isolates: in—vitro efficacy compared
`with that of itraconazole and ketoconazole
`
`M. H. Nguyen and C. Y. Yu
`
`Comparison of four antibiotics in a murine model of necrotizing cutaneous infections caused by toxigenic
`Streptococcus pyogenes and Staphylococcus aureus
`N. Barg
`
`Comparative grepafloxacin phototoxicity in mouse skin
`K. Owen
`
`Correspondence
`Current MIC breakpoints may understate the potential efficacies of carbapenems for treatment of patients
`with infections caused by strains of Streptococcus pneumoniae that are resistant or of intermediate
`susceptibility to penicillin
`J. Ft’. Edwards, J. S. Bradley and K. P. Klugman
`
`Study on the in—vitro activity of LY333328 against Gram—positive cocci
`M. L. Mezzatesta, G. Bonfiglio, L. De Angelis, 8. Stefani and G. Russo
`
`Activities of cefepime and five other antibiotics against nosocomial PER—1—type andlor OXA—10-type
`fi—lactamase—producing Pseudomonas aeruglnosa and Acinetobacter spp.
`H. Vahaboglu, S. Sar/bas, H. Akbal, Fl. Ozturk and A. Yucel
`
`Evaluation of the activities of two—drug combinations of rifampicin, polymyxin B and ampicillinlsulbactam against
`Acinetobacter baumannii
`‘
`C. Tasclni, F. Menlchettl, S. Bozza, A. Del Favero and F. Bistoni
`
`A study of the mechanisms involved in imipenem resistance in Pseudomonas aeruglnosa isolates from Japan
`Fl. A. Stunt, C. J. Thomson, D. J. Payne and S. G. B. A-myes
`
`Emergence of resistance to third—generation cephalosporins amongst Salmonella typhlmurium isolates in
`Greece: report of the first three cases
`L. S. Tzouvelekis, M. Gazoull, A. Markogiannakis, E. Paraskaki, N. J. Legakls and E. Tzelepi
`
`Isolation of glycopeptide resistant Streptococcus gallolyticus strains with vanA, vanB, and both vanA
`and vanB genotypes from faecal samples of veal calves in The Netherlands
`D. Mevlus, L. Devrlese, P. Butaye, P. Vandamme, M. Verschure and K. Veldman
`
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`Activity of nisin against Streptococcus pneumoniae, in vitro, and in a mouse infection model
`B. P. Goldstein, J. Wei, K. Greenberg and R. Novick
`
`An isocratic high performance liquid chromatography (HPLC) assay for moxifioxacin, a new
`8-methoxyquinolone
`C. M. Tobin, J. Sunderland, L, 0. White, A. P. MacGowan and D. S. Reeves
`
`Book reviews
`
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`Journal of Antimicrobial Chemotherapy (1998) 42, 253—256
`
`JAC
`
`Voriconazole against fluconazole-susceptible and resistant candida
`isolates: in-vitro efficacy compared with that of itraconazole and
`ketoconazole
`
`M. Hong Nguyen“"’* and Christine Y. Yu“
`
`“Department of Medicine, Division of Infectious Disease, University of Florida College of Medicine,
`PO Box 100277, JHMHC, Gainesville, FL 32610; 1’ VA Medical Center, Gainesville, FL, USA
`
`We compared the in-vitro activity of fluconazole, itraconazole, ketoconazole and voriconazole
`against 67 blood isolates of Candida spp. exhibiting a wide range of fluconazole Mlcs (0.125 to
`>64 mg/L). Voriconazole was the most potent in vitro, followed by itraconazole, ketoconazole
`and fluconazole.
`itraconazole and voriconazole had in-vitro activity against fluconazole-
`susceptible and -resistant candida isolates. Higher itraconazole and voriconazole Mlcs were
`observed in isolates exhibiting higher fluconazole Mlcs, suggesting cross-resistance. itra-
`conazole and voriconazole Mlcs of 216 mg/L were observed only in Candida albicans and
`Candida tropicalis. Candida krusei and Candida glabrata exhibited itraconazole Mlcs of 0.5-1
`mg/L and voriconazole Mlcs of 0.25-0.5 mg/L.
`
`Introduction
`
`Voriconazole is a new triazole antifungal agent which acts
`by inhibiting cytochrome P450 sterol 14a-demethylase, an
`enzyme involved in ergosterol biosynthesis. Voriconazole
`has potent in-vitro and in—vivo activity against Aspergillas
`spp. and other moulds.” Although voriconazole has
`in-vitro activity against
`fluconazole-resistant Candida
`albicans, Candida krusei and Candida glabrata,“ its
`activity against other Candida spp. that are fluconazole—
`resistant in vitro is unknown. Furthermore, the in-vitro
`
`activity of voriconazole has not been compared with that
`of itraconazole and ketoconazole. The goal of this study
`was
`to compare the in-vitro activity of
`fluconazole,
`itraconazole, ketoconazole and voriconazole against a
`large number of candida isolates;
`the isolates studied
`exhibited a wide range of fluconazole MICS.
`
`Materials and methods
`
`Sixty—seven blood isolates of Candida spp. collected during
`a prospective study of candidaemia were tested.6 These
`isolates exhibited fluconazole MICs ranging from 0.125
`to >64 mg/L. These included C. albicans (24 isolates),
`Candida tropicalis (17), C. glabrata (12), Candida para-
`psilosis (8), C. krusei (3) and Candida lusitaniae (3). C.
`
`parapsilosis ATCC 90018, C. albicans ATCC 90028 and
`90029 and C. glabrata ATCC 90030 were incorporated into
`each set of experiments as quality control isolates.
`The susceptibility testing was performed by a macro-
`dilution method adhering to the National Committee
`for Clinical Laboratory Standards (NCCLS) protocol.7
`Fluconazole (Pfizer Central Research, Groton, CN, USA)
`stock solutions of 2000 mg/L were prepared with sterile
`distilled water. Voriconazole (Pfizer Central Research,
`Groton, CN, USA) stock solutions of 4000 mg/L were
`prepared with dimethylsulphoxide (DMSO); subsequent
`dilutions were performed in water. Stock solutions of
`ketoconazole and itraconazole (Janssen Research Foun-
`dation, Beerse, Belgium) were prepared with 0.2 N HCl
`and DMSO,
`respectively;
`subsequent drug dilutions
`were performed according to the manufacturer’s protocol.
`The concentrations of drugs tested were: 0.125—64 mg/L
`for fluconazole; 0.015—16 mg/L for itraconazole and vori-
`conazole; and 0.03—16 mg/L for ketoconazole. Each
`Candida sp. was tested simultaneously against fluconazole,
`itraconazole, ketoconazole and voriconazole.
`
`Results and discussion
`
`itraconazole, ketoconazole and vori-
`The fluconazole,
`conazole MlCs for the ATCC isolates were: 0.5, 0.125, 0.06
`
`H }§!?ri;i§‘{i.3§:Lg%§4déé;i§;x;‘ +i—s5Vi—3i9S40S105i;S E”.....;l. .guy;i..;t.»i..;..;lc;.;;;.;1.;d;. nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnH
`
`_
`__
`._
`......................
`.
`_
`© 1998 The British Society for Antimicrobial Chemotherapy
`
`........................ .,C_FA,m...Ah_é66.h.._'.P_§2mSm776 ______
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`M. H. Nguyen and C. Y. Yu
`
`and 0.015 mg/L, respectively, for ATCC 90018; 0.5, 0.125,
`0.06 and 0.03 mg/L, respectively for ATCC 90028; 0.5,
`0.125, 0.03 and 0.03 mg/L, respectively, for ATCC 90029;
`16, 0.125, 0.03 and 0.03 mg/L, respectively, for ATCC
`90030.
`
`The MIC ranges, MIC50s, MIC90s and geometric mean
`MICs of ketoconazole,
`fluconazole,
`itraconazole and
`
`voriconazole for specific Candida spp. are presented in
`Table I. Using the fluconazole breakpoint values proposed
`by the NCCLS,8 69% (46/67) of Candida spp. were
`susceptible, 9% (6/67) dose—dependently susceptible and
`22% (15/67) resistant to fluconazole in virro. Using the
`itraconazole breakpoints,8 40% (27/67) were susceptible,
`40% (27/67) dose—dependently susceptible and 20%
`(13/67) resistant to itraconazole in vitro.
`To our knowledge, this is the first published study to
`compare the in-vitro efficacy of voriconazole, itraconazole
`and ketoconazole against a large number of Candida spp.
`with a wide range of fluconazole MICs. We included in
`our study not only fluconazolc—resistant C. albicans and
`C. krasei, but also C.
`tropicalis, C. parapsilosis and C.
`lasitaniae. We demonstrated that voriconazole was the
`
`most potent of the azole agents against the Candida spp.
`
`followed by
`tested (geometric mean of 0.12 mg/L),
`itraconazole
`(geometric mean of
`0.30 mg/L)
`and
`ketoconazole (geometric mean of 0.75 mg/L).
`both
`Voriconazole
`had
`in-vitro
`activity
`against
`fluconazole-susceptible and —resistant Candida spp. For
`fluconazole—susceptible isolates, voriconazole was signifi-
`cantly more potent than itraconazole and ketoconazole:
`the geometric mean MIC of voriconazole (0.04 mg/L) was
`significantly lower than that of itraconazole (0.17 mg/L;
`P < 0.001) and that of ketoconazole (0.43 mg/L; P
`< 0.001)
`(Table II). Moreover, 91% (42/46) of the
`fluconazole-susceptible Candida spp. exhibited voricona-
`zole MICs of $0.125 mg/L, whereas only 52% (24/46)
`exhibited itraconazole MICs $0.125 mg/L, and 48%
`(21/46) exhibited ketoconazole MICs $0.125 mg/L.
`For fiuconazole—resistant or dose—dependently suscept-
`ible isolates, voriconazole also demonstrated good in-vitro
`activity. Sixty—two percent
`(13/21) of
`these isolates
`exhibited voriconazole MICs of $0.5 mg/L, whereas only
`43% (9/21) exhibited itraconazole MICs of $0.5 mg/L, and
`19% (4/21) exhibited ketoconazole MICS of $0.5 mg/L.
`As previously noted, C. krusei and C. glabrata, species
`often associated with fluconazole resistance, were sus-
`
`Table I. In-vitro activity of ketoconazole, fluconazole, itraconazole and voriconazole against Candida spp.
`
`Species
`
`C. albicans
`
`n
`
`24
`
`C. tropicalis
`
`17
`
`C. glabrata
`
`12
`
`C. parapsilosis
`
`C. lusitaniae
`
`Antimicrobial
`
`48 h MIC (mg/L)
`
`agent
`
`range
`
`50%
`
`90%
`
`geometric mean
`
`ketoconazole
`fluconazole
`itraconazole
`voriconazole
`ketoconazole
`fluconazole
`itraconazole
`voriconazole
`ketoconazole
`fluconazole
`itraconazole
`voriconazole
`ketoconazole
`fluconazole
`itraconazole
`voriconazole
`ketoconazole
`fluconazole
`itraconazole
`voriconazole
`ketoconazole
`fluconazole
`itraconazole
`voriconazole
`
`0.03—> 16
`O.125—>64
`0.06—>16
`$0.015—>16
`0.03—>16
`0.5—>64
`0.015—>16
`$0.015—>16
`0.03—1
`2-32
`0.25—1
`0.06—0.5
`0.03—1
`0.5—>64
`0.125—0.5
`0.015—1
`0.5~1
`>64
`0.25—0.5
`0.5
`0.03—0.5
`0.125—32
`0.125—0.5
`0.015—0.5
`
`8
`0.5
`0.125
`$0.015
`4
`8
`0.25
`0.125
`1
`8
`0.5
`0.125
`0.125
`2
`0.125
`0.03
`0.5
`>64
`0.5
`0.5
`0.03
`2
`0.125
`0.015
`
`>16
`>64
`0.5
`0.25
`>16
`>64
`>16
`>16
`1
`32
`1
`0.25
`1
`32
`0.25
`0.25
`0.5
`>64
`0.5
`0.5
`0.5
`32
`0.5
`0.5
`
`1.10
`1.30
`0.22
`0.06
`1.75
`9.02
`0.54
`0.33
`0.47
`8.00
`0.56
`0.16
`0.19
`3.35
`0.19
`0.06
`0.63
`64.07
`0.40
`0.50
`0.08
`1.99
`0.20
`0.06
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`Candida susceptibility to voriconazole in vitro
`
`Table II. Geometric means, MICSO and MIG,“ for fluconazole—susceptible and -resistant Candida species against
`itraconazole, ketoconazole and voriconazole
`
`Geometric mean MIC (range) forllfiuconazolez
`
`M1C50/MIC.;0 (mg/L) for fluconazole:
`
`susceptible
`isolates
`
`resistant
`
`isolates
`
`susceptible
`isolates
`
`resistant
`isolates
`
`0.17
`0.13
`0.13
`
`0.46
`0.18
`—
`
`1.39
`3.97
`2.51
`1.00
`0.25
`0.40
`
`2.51
`11.36
`3.06
`1.00
`1.00
`0.63
`
`1.14
`5.64
`1.68
`0.25
`0.50
`0.50
`
`0.125/0.5
`0.125/0.25
`0.125/0.25
`0.5/0.5
`0.125/0.25
`—
`
`0.25/16
`0.5/16
`0.5/16
`0.5/1
`0.125/0.25
`—
`
`0.03/0.125
`0.015/0.06
`0.06/0.125
`0.125/0.25
`0.03/0.06
`—
`
`1/16
`16/16
`1/16
`1/1
`0.125/0.5
`0.5/0.5
`
`4/16
`8/16
`8/16
`1/1
`1/1
`0.5/0.5
`
`0.5/16
`16/16
`0.25/16
`0.25/0.5
`0.25/1
`0.5/0.5
`
`Azole agent
`
`Itraconazole
`
`all Candida spp.
`C. albicans
`
`C. tropicalis
`C. glabrata
`C. parapsilosis
`C. krusei
`Ketoconazole
`
`all Candida spp.
`C. albicans
`
`C. tropicalis
`C. glabrata
`C. parapsilosis
`C. krasei
`Voriconazole
`
`all Candida spp.
`C. albicans
`
`C. tropicalis
`C. glabrata
`C. parapsilosis
`C. krusei
`
`NS, not significant.
`
`ceptible in vitro to itraconazole,°"” to voriconazole“ with
`MICs of 0.25—0.5 mg/L, and to ketoconazole with MICS of
`0.5-1 mg/L (Table II).
`there was cross-
`Despite these promising results,
`resistance between fluconazole and voriconazole for some
`
`Candida spp. For example, isolates with higher flucon-
`azole MICs were associated with higher voriconazole
`MICS (P < 0.001, linear regression). There was also cross-
`resistance between fluconazole,
`itraconazole and keto-
`
`the higher fluconazole MICS were associated
`conazole:
`with higher
`itraconazole and ketoconazole MICs
`(P
`< 0.001, and 0.003, respectively). This pattern of cross-
`resistance has been previously described, and may result
`from the similar mechanisms of actions of these agents.9*“’
`Six (38%) of the 16 Candida spp. with fluconazole MICs
`of >64 mg/L displayed itraconazole MICs of 216 mg/L
`and ketoconazole MICs of 28 mg/L. All of these isolates
`had voriconazole MICs of 216 mg/L. In our study, these
`high levels of resistance to multiple azole agents (MICs
`2 8 mg/L) were seen only for C. albicans and C. tropicalis
`isolates. Fluconazole-resistant C. krusei, C. glabrata, C.
`parapsilosis and C. lusitaniae isolates, on the other hand,
`did not display high—level
`resistance to itraconazole,
`ketoconazole and voriconazole.
`
`In conclusion, voriconazole has potent in—vitro activity
`against Candida
`spp.,
`including
`those
`that were
`dose—dependently lluconazole—susceptible or fluconazole-
`resistant. This finding suggests that voriconazole might be
`effective in the treatment of refractory candidosis caused
`by fluconazole-resistant strains. However, cross—resistance
`with fluconazole exists in a small subset of Candida spp.
`Given the high oral bioavailability and the well tolerated
`nature of voriconazole, this drug may become an impor-
`tant addition to the armamentarium of systemic antifungal
`agents. This promise, however, requires to be confirmed in
`the clinical setting.
`
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`Received 17 October 1997; returned 21 January 1998; revised 12
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