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Biotech / Medical : Microcide Pharmaceuticals (MCDE) -- Ignore unavailable to you. Want to Upgrade?

To: scaram(o)uche who wrote (163)	8/29/1999 1:23:00 PM
From: scaram(o)uche	Read Replies (1) \| Respond to of 186

Session: Novel b-Lactams and b-Lactamase Inhibitors Location: Exhibit Hall Session Date: Sunday, 9/26/99 Session Time: 1:30 pm - 3:00 pm Design, Synthesis and In vitro Antibacterial Properties of Novel 3-Heteroarylthio Cephems with Anti-MRSA Activity; Amino Acid Prodrug Approach to Solubility Improvement T. Glinka, R. Frith, S. Halas, G. Nudelman, C. Whitehead, A. Cho, J. Crawford, M. Ludwikow, T. Calkins, S. Chamberland, M. Price, S. Hecker, V. Lee Microcide Pharmaceuticals Inc.: Mountain View, CA The desirable antibacterial properties of cephalosporin MC-02,479 (RWJ-54428) (Glinka, et al., 37th ICAAC #167, 1997) discovered recently at Microcide can be attributed to the cephem 3-(pyrid-4-ylthio) substituent as well as the aminoethylthiomethyl appendage attached to the pyridine ring. The pyridine substituent also provides a protonation site which, at acidic pH, allows solubility sufficient for intravenous administration. We have further explored related 3-heteroarylthio cephems in which the aminoethylthio subsituent is attached to a variety of other heterocycles. As a result, we have identified a wide range of novel analogs of MC-02,479 with high antibacterial activity against b-lactam resistant Gram-positive organisms, including MRSA. The pH-solubility profiles of these novel analogs do not achieve desired solubility levels at acceptable pH. A prodrug approach, employing a cleavable alanyl derivative of the aminothiazole moiety, was used to improve the solubility of MC-03,791. In vivo evaluation of its prodrug MC-03,971 showed excellent bioavailability of the parent cephalosporin.

To: scaram(o)uche who wrote (163)	8/29/1999 1:25:00 PM
From: scaram(o)uche	Respond to of 186

Session: Novel b-Lactams and b-Lactamase Inhibitors Location: Exhibit Hall Session Date: Sunday, 9/26/99 Session Time: 1:30 pm - 3:00 pm Design, Synthesis, and SAR of Water-Soluble Dibasic Cephalosporins Active against Resistant Gram-Positive Bacteria A. Cho, M. Ludwikow, N. Liu, A. Fan, T. Glinka, Z.J. Zhang, M. Price, S. Chamberland, V.J. Lee, S.J. Hecker Microcide Pharmaceuticals: Mountain View, CA We recently reported the discovery of MC-02,479, a new cephalosporin displaying potent activity against sensitive and resistant Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) (Glinka, et al., 37th ICAAC, Abstract #F176, 1997) The compound bears a basic 4-pyridyl group at the C(3) position that is protonated at acidic pH, affording sufficient solubility for intravenous administration. In the current work, we have explored other non-basic aromatic motifs at C(3), which required appending an additional basic functionality within the structural framework for solubilization. Several strategies were pursued, including modification of the appendage on the C(3)-heterocycle, attachment of a basic group to the C(7)-oxime, and replacement of the C(7)-heterocycle. The latter approach afforded MC-03,260, which displays excellent solubility (>20 mg/ml at pH 4.5) while retaining good potency (MIC90 vs. MRSA 4 mg/ml, ED50 against S. aureus Smith 0.3 mg/kg).

To: scaram(o)uche who wrote (163)	8/29/1999 1:27:00 PM
From: scaram(o)uche	Respond to of 186

Session: Novel b-Lactams and b-Lactamase Inhibitors Location: Exhibit Hall Session Date: Sunday, 9/26/99 Session Time: 1:30 pm - 3:00 pm Pilot Study of RWJ-54428 (MC-02,479): Correlation of Broth Microdilution Susceptibility Testing Results with Disk Diffusion Zone Diameters B. Foleno1, J.J. Hilliard1, D.A. Montenegro1, J. Blais2, S. Chamberland2, M. Dudley2, M. Hoang2, G. Miller2, K. Bush1 1R. W. Johnson PRI: Raritan, NJ; 2Microcide Pharmaceuticals: Mountain View, CA RWJ-54428 (MC-02,479) is a novel cephalosporin with good antibacterial activity against Gram-positive pathogens, including MRSA, methicillin-resistant coagulase negative staphylococci, multi-drug-resistant streptococci and vancomycin-susceptible and -resistant enterococci. To begin development of a disk for diagnostic use, broth microdilution MICs and zone diameters for RWJ-54428 against 157 isolates were measured in two laboratories. Disks were prepared with 2.5, 5.0 or 10 mg of RWJ-54428 by dissolving the cephalosporin in 95% ethanol, drying either in air for 1 hour or for 30 minutes at 45oC, and storing at 4oC, -20oC or -70oC. Results: MIC Zone Diameter (mm) for Disk Content Organism N (mg/ml) 2.5 mg 5.0 mg 10 mg Staphylococci 66 £0.06 - 4 12 - 35 17 - 37 21 - 42 Streptococci 26 £0.06 - 0.5 19 - 40 20 - 41 23 - 45 Enterococci 35 £0.06 - 8 6 - 25 6 - 28 13 - 31 Gm negatives 30 1 - >128 6 - 15 6 - 19 6 - 22 Correlation Coefficient* 0.89 0.90 0.91 *Linear regression analysis only for organisms with MIC endpoints Zone sizes were largest for the most sensitive streptococci. Regression statistics were similar for all disks tested. The 5.0 and 10 mg disks were stable (£ 1 mm diameter change in repetitive testing against S. aureus ATCC 25923) over a period of at least 3 weeks. Additional studies will be needed to determine the susceptibility breakpoint for this cephalosporin. Either a 5.0 mg or 10 mg disk is a good candidate for further development.

To: scaram(o)uche who wrote (163)	8/29/1999 1:29:00 PM
From: scaram(o)uche	Respond to of 186

Session: Inhibitors of Bacterial and Fungal Efflux Pumps Location: Exhibit Hall Session Date: Monday, 9/27/99 Session Time: 3:00 pm - 4:30 pm Targeting Efflux Pumps in Pseudomonas aeruginosa O. Lomovskaya1, A. Lee1, M. Warren1, J. Galazzo1, R. Fronko1, M. Lee1, S. Chamberland1, S. Hecker1, V. Lee1, H. Ishida2, K. Hoshino2 1Microcide Pharmaceuticals, Inc.: Mountain View, CA; 2Daiichi Pharmaceutical Co, Ltd.: Tokyo, Japan We present the first report on identification and characterization of bacterial multi-drug resistance (MDR) pump inhibitors through high-throughput screening of small molecule libraries. Whole-cell assays were implemented to search for efflux pump inhibitors (EPIs) of the three MDR pumps (MexAB-OprM, MexCD-OprJ, MexEF-OprN) that contribute to fluoroquinolone resistance in clinical isolates of P. aeruginosa. Secondary assays were developed to identify leads with exquisite activity as inhibitors. Both pump-selective and broad-spectrum EPIs, which are active against all three known Mex pumps from P. aeruginosa and their close E. coli pump homolog (AcrAB-TolC), were discovered. Broad-spectrum EPIs decreased significantly the intrinsic resistance of P. aeruginosa to fluoroquinolones [16-fold for levofloxacin (LVFX)]. Acquired resistance due to overexpression of efflux pumps was also decreased (32 to 64-fold reduction in MIC for LVFX). Similarly, 32 to 64-fold reduction in MICs in the presence of EPIs was observed for strains with overexpressed pumps and various target mutations conferring resistance to LVFX (e.g., gyrA, parC). We also compared the frequencies of emergence of LVFX-resistant variants in the wild-type strain at 4xMIC of LVFX (1 mg/ml) when LVFX was used alone or in combination with EPI. In case of LVFX alone, the frequency was 10-6-10-7 cfu/ml. In contrast, with an EPI, the frequency is below the level of detection (<10-11). In summary, the inhibition of efflux pumps 1) decreased intrinsic resistance significantly, 2) reversed acquired resistance, and 3) resulted in decreased frequency of emergence of P. aeruginosa strains that are highly resistant to fluoroquinolones.

To: scaram(o)uche who wrote (163)	8/29/1999 1:34:00 PM
From: scaram(o)uche	Respond to of 186

Session: Inhibitors of Bacterial and Fungal Efflux Pumps Location: Exhibit Hall Session Date: Monday, 9/27/99 Session Time: 3:00 pm - 4:30 pm Inhibitors of Efflux Pumps in Pseudomonas aeruginosa Potentiate the Activity of the Fluoroquinolone Antibacterial Levofloxacin T.E. Renau1, R. Leger1, E.M. Flamme1, J. Sangalang1, M.W. She1, R. Yen1, C.L. Ford1, K.M. Mathias1, S. Chamberland1, S.J. Hecker1, V.J. Lee1, T. Ohta2, K. Nakayama2 1Microcide Pharmaceuticals, Inc.: Mountain View, CA; 2Daiichi Pharmaceutical Co. Ltd.: Tokyo, Japan P. aeruginosa is an opportunistic pathogen characterized by intrinsic resistance to a wide variety of antimicrobial agents, a property that has been attributed in part to the activity of several efflux systems. We embarked on a program to identify broad-spectrum efflux pump inhibitors in P. aeruginosa in order to potentiate the activity of the fluoroquinolone antibacterial agent levofloxacin. To identify potential inhibitors, we screened against specifically engineered strains of P. aeruginosa that over-expressed each of the known pumps. Follow-up studies were implemented to confirm that the inhibitors were indeed blocking the efflux pumps. One of the compounds identified from this effort was MC-207,110, a low molecular weight dipeptide amide. The compound had minimal intrinsic antibacterial activity (MIC = 256 µg/mL) but potentiated the activity of levofloxacin 8-fold at 10 µg/mL. The overall in vitro biological profile and structural simplicity of MC-207,110 led to its choice as the lead compound in our program. We began an extensive medicinal chemistry effort to optimize the biological and physicochemical properties of this lead. Herein we describe a portion of our work in this area and disclose the first known class of broad-spectrum efflux pump inhibitors in P. aeruginosa.

To: scaram(o)uche who wrote (163)	8/29/1999 1:35:00 PM
From: scaram(o)uche	Respond to of 186

Session: Inhibitors of Bacterial and Fungal Efflux Pumps Location: Exhibit Hall Session Date: Monday, 9/27/99 Session Time: 3:00 pm - 4:30 pm Efflux Pump Inhibitors (EPIs) Enhance the Activity of Antimicrobial Agents against a Broad Selection of Bacteria J. Blais, D. Cho, K. Tangen, C. Ford, A. Lee, O. Lomovskaya, S. Chamberland Microcide Pharmaceuticals, Inc.: Mountain View, California The in vitro activity profile of a series of new agents that are devoid of intrinsic antimicrobial activity but enhance the activity of several classes of drugs against clinically relevant pathogens through the inhibition of active efflux is presented. EPIs were combined with a variety of antibiotics and tested against a wide selection of gram-negative isolates, including several Enterobacteriaceae and Pseudomonadaceae, and gram-positive isolates, including Staphylococci, Enterococci, and Streptococci. Specific pump deletion mutants and mutants overexpressing pumps were used to characterize the activity of these new agents in combination with several antibiotics against the Mex pumps in P. aeruginosa, the AcrAB pump system in E. coli and Salmonella, and Acr homologs in H. influenzae. Significant synergy was observed with combinations of fluoroquinolones or macrolides and EPIs in Enterobacteriaceae and Pseudomonadaceae. For example the MIC90 of levofloxacin for a population of 50 clinical isolates of P. aeruginosa was 8-fold lower in the presence of these efflux pump inhibitors (EPIs), shifting from 8 to 1 µg/ml or from resistant to susceptible according to the NCCLS susceptibility breakpoints for levofloxacin. In time-kill studies, the combination of EPIs and levofloxacin was synergistically bactericidal against P. aeruginosa. EPIs also enhanced the activity of fluoroquinolones and macrolides in several gram-positive isolates. In summary, EPIs significantly enhance the activity of antimicrobial agents against several pathogenic bacteria and may be clinically useful agents.

To: scaram(o)uche who wrote (163)	8/29/1999 1:37:00 PM
From: scaram(o)uche	Respond to of 186

Session: Inhibitors of Bacterial and Fungal Efflux Pumps Location: Exhibit Hall Session Date: Monday, 9/27/99 Session Time: 3:00 pm - 4:30 pm Prevalence of Efflux Pumps among Clinical Isolates of Fluoroquinolone-Resistant Pseudomonas aeruginosa D. Cho, J. Blais, K. Tangen, C. Ford, A. Lee, O. Lomovskaya, S. Chamberland, G.H. Miller Microcide Pharmaceuticals, Inc.: Mountain View, CA Active efflux plays an important role in intrinsic and acquired resistance of Pseudomonas aeruginosa to a wide variety of antimicrobial agents. There are three well-characterized efflux systems involved in multidrug resistance in P. aeruginosa: MexAB-OprM, MexCD-OprJ, and MexEF-OprN. Another efflux system, MexXY has also recently been reported. We determined the frequency of efflux-mediated resistance in 409 recent clinical isolates of P. aeruginosa obtained from 12 countries (USA, Japan, Thailand, Canada, Greece, China, France, Argentina, UK, Venezuela, Turkey, and Spain). Efflux pump profiles were based upon susceptibility to 10 antibiotics (piperacillin, carbenicillin, ceftazidime, aztreonam, imipenem, meropenem, chloramphenicol, erythromycin, ciprofloxacin, and levofloxacin) and response to broad-spectrum and pump-specific efflux pump inhibitors (EPIs). 56 laboratory mutants with known genotypes and varied pump expression were used to establish criteria for each pump profile. The MexAB profile was the most prevalent among these isolates (296 or 72%) while the MexAB/MexCD profile was observed in 9% (36) of the isolates. The remaining isolates were divided as follows: 17 (4%) AB/EF, 15 (4%) AB/CD/EF, 14 (3%) CD, 9 (2%) CD/EF, 3 (<1%) EF, and 19 (5%) other pumps (responding to a broad-spectrum EPI only). Breakdown of profiles by geographic origin revealed significant variation in pump profiles from region to region. For example, the MexAB profile was found in only 27% of isolates from China but in 96% of isolates from Japan. These results show that Mex-type efflux pumps are highly prevalent among worldwide isolates of fluoroquinolone-resistant P. aeruginosa.

To: scaram(o)uche who wrote (163)

8/29/1999 1:49:00 PM

From: scaram(o)uche

Respond to of 186

sorry, I can't get the table to cut and paste......

Session: Inhibitors of Bacterial and Fungal Efflux Pumps
Location:
Exhibit Hall
Session Date:
Monday, 9/27/99
Session Time:
3:00 pm - 4:30 pm

Potentiation of Levofloxacin (Levo) by a Broad-Spectrum Efflux Pump Inhibitor
(EPI) in Mouse Models of Infection Caused by Pseudomonas aeruginosa

D. Griffith, O. Lomovskaya, V. Lee, M. Dudley
Microcide Pharmaceuticals, Inc.: Mountain View, CA

We have previously shown that overexpression of the MexAB-OprM efflux pump in PA
results in reduced efficacy with Levo and ciprofloxacin. A prototypical lead for a series
of broad-spectrum EPIs for Mex-type pumps in PA with MexAB-OprM
over-expressed (Levo MIC alone/+10 mg/L of EPI =2/0.125 mg/L) was tested in the
neutropenic mouse thigh and mouse sepsis models. In the neutropenic mouse thigh
model, mice were treated with Levo 30mg/kg q4h alone or with varying doses and
dosing intervals of the EPI. The CFU/thigh were determined at varying time points up to
24h after inoculation. In the sepsis model, mice were treated with varying doses of Levo
alone, or in combination with 25 or 50 mg/kg of the EPI. Results in the neutropenic
mouse thigh model (see Table) showed dose-related potentiation with more rapid effects with more frequent EPI dosing. In the sepsis model,
co-administration of the EPI reduced the Levo dose required for 50% survival (ED50) at
72h from 100 mg/kg to 69 and 28 mg/kg for the 25 and 50 mg/kg EPI dose groups,
respectively. These data show that Levo activity against PA in vivo can be potentiated
by inhibition of efflux pumps associated with drug resistance.

To: scaram(o)uche who wrote (163)	8/29/1999 1:50:00 PM
From: scaram(o)uche	Respond to of 186

Session: Inhibitors of Bacterial and Fungal Efflux Pumps Location: Exhibit Hall Session Date: Monday, 9/27/99 Session Time: 3:00 pm - 4:30 pm Inhibitors of Fungal Efflux Pumps O. Lomovskaya1, M. Warren1, A. Mistry1, A. Staley1, J. Galazzo1, H. Fuernkranz1, M. Lee1, G. Miller1, D. Sanglard2 1Microcide Pharmaceuticals, Inc.: Mountain View, CA; 2Inst. of Microbiol.: Lausanne, Switzerland Multi-Drug Resistance (MDR) pumps in C. albicans modulate their susceptibility to many antifungal agents. These pumps may also be implicated as the cause of the high intrinsic non-susceptibility of many Candida species to azoles. We have screened synthetic compounds and natural products for inhibitors of CDR-type pumps (ABC transporters) in C. albicans and C. glabrata. Several chemical types of fungal efflux pump inhibitors (FEPIs) were identified. Their specific mode-of-action was verified by secondary assays that demonstrated that: 1) FEPIs reversed pump-mediated resistance to antifungal agents active against different cellular targets (azoles, terbinafine, rhodamine 6G) and did not potentiate antifungals that are not substrates of efflux pumps (amphotericin B); 2) FEPIs did not have significant activity against containing deletions of efflux pumps genes; 3) FEPIs completely reversed resistance in recombinant S. cerevisiae strains overexpressing efflux pumps from C. albicans or C. glabrata; and 4) FEPIs increased intracellular accumulation of the efflux pump substrate Rhodamine 6G and inhibited its efflux from preloaded cells. These inhibitors did not have significant activity against MDR-pumps of the Major Facilitator family (BenR from C. albicans and C. glabrata), however they were active against multiple CDR-pumps in multiple Candida species. A single compound can reverse CDR-mediated azole resistance in C. albicans (64-128-fold reduction in MIC of fluconazole [FLU] or SCH-56592 [SCH]) and reduce intrinsic resistance in C. glabrata (8-16-fold reduction in MIC of FLU or SCH). Thus, broad-spectrum FEPIs may significantly enhance the clinical efficacy of azoles against various Candida species.

To: scaram(o)uche who wrote (163)	8/29/1999 1:51:00 PM
From: scaram(o)uche	Respond to of 186

Session: Inhibitors of Bacterial and Fungal Efflux Pumps Location: Exhibit Hall Session Date: Monday, 9/27/99 Session Time: 3:00 pm - 4:30 pm Impact of MC-510,027, a Fungal Efflux Pump Inhibitor, on the Susceptibility of Clinical Isolates of Candida spp. to Antifungal Agents S. Chamberland, J. Blais, D.P. Cotter, M.K. Hoang, J. Galazzo, A. Staley, M. Lee, G.H. Miller Microcide Pharmaceuticals, Inc.: Mountain View, CA Resistance to azoles is often mediated by overexpression or modification of their primary target (14-alpha demethylase) or overexpression of efflux pumps capable of reducing the intracellular concentration of drug. We have identified a natural product (MC 510027) that acts as a fungal efflux pump inhibitor (FEPI). Combinations of MC-510,027 and itraconazole (Itra), fluconazole (Flu), terbinafine (Terb) or Sch 56592 (Sch) were tested against 139 recent clinical isolates of 9 species of Candida. MICs were determined using a broth microdilution assay in RPMI. MC-510,027 is devoid of significant antifungal activity. The effect of MC-510,027 on the susceptibility of clinical isolates to antifungal agents is summarized below: Yeast (n) MIC90 (µg/ml) to drug alone or with MC-510,027 (+) Itra Itra + SCh SCh + Flu Flu + Terb Terb+ C. albicans (92) >8 0.03 >8 0.002 >128 8 >32 4 C. glabrata (19) >8 1 8 1 128 16 >32 16 C. tropicalis (11) >8 0.008 >8 0.002 >128 1 >32 4 Candida spp.* (17) 4 0.125 4 0.06 >128 16 >32 >32 * Candida spp. include: 8 C. krusei, 3 C. parapsilosis, 2 C. guillermondii, 2 C. pseudotropicalis, 1 C. lipolytica and 1 C. stellatoidea. MC-510,027 enhanced the activity of azoles in all species of Candida tested, even though their relative intrinsic susceptibility varied over a wide range. These data indicate that drug efflux plays an important role in both intrinsic and acquired resistance to azoles and terbinafine in recent clinical isolates of Candida. Inhibition of fungal efflux pumps may lead to a significant increase in susceptibility to currently used antifungal agents.

To: scaram(o)uche who wrote (163)	8/29/1999 1:52:00 PM
From: scaram(o)uche	Respond to of 186

Session: Inhibitors of Bacterial and Fungal Efflux Pumps Location: Exhibit Hall Session Date: Monday, 9/27/99 Session Time: 3:00 pm - 4:30 pm Pharmacodynamic Assessment of Efflux- and Target-Based Resistance to Fluconazole (FLU) on Efficacy against C. albicans in a Mouse Kidney Infection Model K. Sorensen, E. Corcoran, S. Chen, D. Clark, V. Tembe, O. Lomovskaya, M. Dudley Microcide Pharmaceuticals, Inc.: Mountain View, CA Mechanisms for reduced in vitro susceptibility of C. albicans to azoles include target- or efflux-based mechanisms. It is not known whether these mechanisms working alone or in combination result in similar levels of resistance to FLU in vivo. Strains of C. albicans with a >2,000-fold range in susceptibility to FLU due to drug efflux or target over-expression/modification were tested in neutropenic CFW mice. An inoculum of ca. 104 CFU was administered IV followed 2h later by a single dose of FLU. Kidneys were harvested at 24h and CFU/kidney determined. Results (see table) showed that reduction in CFU with comparable FLU dose:MIC Efflux Pump/Target Status of Test Strain FLU MICs mg/ml) Difference in Log CFU/kidney vs. No Rx According to Indicated Dose:MIC Ratio: <1 to 5 6 to 25 >25 D CDR1/D CDR2/D BEN/D FLU1 0.06 no data -0.99 -1.75 D CDR1/D CDR2 0.125 -0.49 -1.90 -2.02 Wild-type 0.25-1 0.08 to -1.93 -0.98 to -2.18 -1.99 to -2.69 BEN over-expression 8 -0.46 to -0.48 -1.43 no data BEN over-expression/target modification 64 0.06 to -0.40 no data no data CDR1/CDR2 over-expression 128 0.01 to -0.12 no data no data (or AUC:MIC) ratios did not vary according to resistance mechanism. These data show that reduced in vitro susceptibility due to efflux- and/or target-based mechanisms is associated with diminished FLU efficacy in vivo; however, similar levels of efficacy in vivo can be restored by a proportional increase in FLU dose to attain target dose (or AUC):MIC ratios. These data have implications for combination therapy with agents that potentiate azole activity against drug-resistant strains.

To: scaram(o)uche who wrote (163)

8/29/1999 1:58:00 PM

From: scaram(o)uche

Respond to of 186

[sorry, can't get table to cut and paste]

Session: Pharmacodynamics and Efficacy of Antibiotics in
Gram-positive Infections
Location:
Exhibit Hall
Session Date:
Tuesday, 9/28/99
Session Time:
1:30 pm - 3:00 pm

The Novel Cephalosporin RWJ-54428 (MC-02,479) is Active against
Vancomycin-Intermediate S. aureus (VISA) in the Neutropenic Mouse Thigh
Model

D. Griffith, S. Chen, C. Liu, E. Corcoran, V. Tembe, K. Huie, J. Blais, S.
Chamberland, M.N. Dudley
Microcide Pharmaceuticals, Inc.: Mountain View, CA

The emergence of infections due to VISA has created an urgent need for new agents.
RWJ-54428 has previously been shown to have activity in vitro against many
drug-resistant gram-positive bacteria, including VISA. The pharmacodynamics of
subcutaneous doses of RWJ-54428 and vancomycin (V) for 2 VISA strains (HIP-5836;
HIP-5827; MICs in mg/ml for V and RWJ-54428 = 8, 8 and 0.5, 1, respectively) was
studied in the neutropenic mouse thigh model. The V dosage regimen was adjusted to
produce 24h free drug serum AUC:MIC and % of 24h free drug exceeding MIC
(%T>MIC) comparable to that for V 500 mg q 6h in humans. For RWJ-54428,
regimens that produced a 10-fold range in 24h dose and 5-fold range in %T>MIC were
tested. Results for HIP-5836 / HIP-5827 at 24 h:

In this model, RWJ-54428 dosage regimens that produced a free serum AUC:MIC ³ 41
or %T>MIC ³ 35% resulted in greater killing of these VISA strains than that observed
with V exposures mimicking dosage regimens in humans.

To: scaram(o)uche who wrote (163)	8/29/1999 1:59:00 PM
From: scaram(o)uche	Read Replies (1) \| Respond to of 186

Session: Pharmacodynamic Studies of Drug-resistant Bacteria (with minilecture) Location: 132/133 Session Date: Wednesday, 9/29/99 Session Time: 8:30 am - 11:00 am Presentation Time: 9:30 am - 9:45 am Pharmacokinetic-Pharmacodynamic (PK-PD) Indices for Vancomycin (V) Treatment of Susceptible (VSSA) and Intermediate (VISA) S. aureus in the Neutropenic Mouse Thigh Model M. Dudley, D. Griffith, E. Corcoran, C. Liu, K. Sorensen, V. Tembe, D. Cotter, S. Chamberland, S. Chen Microcide Pharmaceuticals, Inc.: Mountain View, CA Recent infections with VISA in the clinic have raised questions concerning the adequacy of current V regimens to treat these strains. We compared the PK-PD indices associated with bacterial killing of strains of VISA and VSSA over 24h in the neutropenic mouse thigh model. V doses of 7.5-1,200mg/d were given in 2-12 divided doses (i.e., 14 regimens/strain) over 24h. PK-PD indices for free drug AUC:MIC; % of 24h free serum V concentrations exceed MIC (%T>MIC) and Cmax:MIC were determined for each strain and modeled to change in log CFU/thigh at 24h using the modified Hill equation. All strains grew well in mice, with subpopulations of VISA maintained in untreated mice over 24h. Reduction in log CFU/thigh was best described using either V AUC:MIC or Cmax:MIC as independent variables (see Table). The maximum extent of killing (Emax) by V of PK:PD Indices VSSA (n=3) (MIC=0.5-1mg/L) VISA (n=2) (MIC=8) For AUC:MIC Modeling: Emax , D Log CFU/thigh vs. no Rx 0.72 to 3.3 1.0, 2.4 AUC:MIC @50% Emax 86 to 460 23, 32 For Cmax:MIC Modeling: Emax , D Log CFU/thigh vs. no Rx 0.59 to 4.0 2.5, 3.1 Cmax:MIC @50% Emax 15 to 91 4.4, 9.5 VISA strains occurred at lower values of AUC:MIC and Cmax:MIC than that for VSSA. These data show that although V MICs are elevated in VISA strains, comparable levels of bacterial killing of VISA by V in this model are obtained at a lower PK-PD intensity than with VSSA. These findings may have implications for the management of infections due to VISA.