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Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 2017 Jul 25;61(8):e00161-17. doi: 10.1128/AAC.00161-17

Differential Activity of the Oral Glucan Synthase Inhibitor SCY-078 against Wild-Type and Echinocandin-Resistant Strains of Candida Species

Michael A Pfaller a, Shawn A Messer a, Paul R Rhomberg a, Katyna Borroto-Esoda b, Mariana Castanheira a,
PMCID: PMC5527608  PMID: 28533234

ABSTRACT

SCY-078 (formerly MK-3118) is a novel orally active inhibitor of fungal β-(1,3)-glucan synthase (GS). SCY-078 is a derivative of enfumafungin and is structurally distinct from the echinocandin class of antifungal agents. We evaluated the in vitro activity of this compound against wild-type (WT) and echinocandin-resistant isolates containing mutations in the FKS genes of Candida spp. Against 36 Candida spp. FKS mutants tested, 30 (83.3%) were non-WT to 1 or more echinocandins, and only 9 (25.0%) were non-WT (MIC, >WT-upper limit) to SCY-078. Among C. glabrata isolates carrying FKS alterations, 84.0% were non-WT to the echinocandins versus only 24.0% for SCY-078. In contrast to the echinocandin comparators, the activity of SCY-078 was minimally affected by the presence of FKS mutations, suggesting that this agent is useful in the treatment of Candida infections due to echinocandin-resistant strains.

KEYWORDS: Candida, SCY, antifungal susceptibility testing, echinocandin resistance

INTRODUCTION

Candidemia and other forms of invasive candidiasis (IC; infection of normally sterile sites and tissues) are, without a doubt, important causes of morbidity, mortality, and excess hospital costs in seriously ill hospitalized individuals (13). It is also recognized that the present era is one of high non-albicans Candida (NAC) prevalence and antifungal resistance (412). NAC species are especially prominent in U.S. medical centers (6, 7, 1012), and a recent publication from France demonstrates that exposure to fluconazole favors bloodstream infection (BSI) with Candida glabrata, C. krusei, and C. tropicalis, and exposure to an echinocandin is predictive of infection with C. glabrata, C. krusei, and C. parapsilosis (8). Notably, the emergence of multi-azole-resistant, echinocandin-resistant, and multidrug-resistant (resistant to 2 or more classes of antifungal agents) strains of these species has been reported in hospitals located in the United States, Europe, and Asia (46, 1315). It is now clear that exposure to azoles and echinocandins sets the stage for IC due to antifungal-resistant NAC species and that infections with echinocandin-resistant and multidrug-resistant strains of Candida are positively associated with treatment failure and all-cause mortality rates (68, 1620).

The emergence of NAC infections secondary to the use of azole antifungal agents for the prevention and treatment of IC has ushered in the echinocandin era of antifungal therapy (2123). The members of the echinocandin class of antifungal agents (anidulafungin, caspofungin, and micafungin) are potent inhibitors of β-(1,3)-glucan synthase (GS), exhibit fungicidal activity against most species of Candida, and have been recommended as first-line agents to treat IC (22, 2428). Although echinocandin-resistant isolates of Candida appear to be concentrated in a relatively small number of large tertiary-care hospitals (4, 14), increased use of both azoles and echinocandins may result in more widespread resistance, especially among NAC species (20). Measures to curb antifungal resistance development include antifungal stewardship, infection prevention measures (6, 29), and alternative treatment strategy development, including novel antifungal compounds (23, 30).

Resistance to echinocandin antifungal agents is acquired during therapy (4, 20), and the resulting mutations in the hot spot (HS) regions of genes encoding the catalytic subunits of GS (FKS1 and FKS2) significantly decrease the sensitivity of the target enzyme to the drug, resulting in higher MIC values and reduced pharmacodynamic and clinical responses (4, 31). Aside from emerging resistance, an important echinocandin limitation is that they must be administered daily by intravenous infusion, potentially prolonging hospital stays for patients undergoing echinocandin therapy and limiting them to inpatient settings in most instances. Given the importance of GS in the viability of Candida spp. (32), developing orally administered GS inhibitors would represent a major step forward by providing a simple therapy transition from the inpatient to the ambulatory setting.

Derivatives of the natural product enfumafungin, a fungal triterpenoid glycoside, are potent inhibitors of GS yet are structurally distinct from the echinocandins (3336). SCY-078 (formerly MK-3118) is a semisynthetic orally bioavailable derivative of enfumafungin with in vitro and in vivo activity against several different species of Candida, Aspergillus, and select non-Aspergillus molds (33, 3740). Importantly, in addition to being orally bioavailable with favorable pharmacodynamic properties (38), SCY-078 has been shown to retain in vitro activity against azole- and echinocandin-resistant strains of Candida (33, 36, 40). Mutations in FKS that result in resistance to the echinocandins are located in domains that may be distinct from those associated with decreased susceptibility to SCY-078, supporting the lack of complete cross-resistance between these agents that has been demonstrated in vitro (33, 38, 40).

The in vitro studies of SCY-078 activity against Candida spp. that have been published thus far demonstrate the excellent potency of SCY-078 against the most common species of Candida, including those with FKS mutations (33, 40). These studies are limited by the inclusion of a relatively small number of isolates of the most common species and the lack of comparison to echinocandins other than caspofungin.

In the present study, we determined the spectrum and potency of SCY-078, anidulafungin, caspofungin, and micafungin against a panel of 11 different species of Candida selected to represent both wild-type (WT) and echinocandin-resistant (ER) strains. All isolates were tested by the Clinical and Laboratory Standards Institute (CLSI) broth microdilution (BMD) method that has been standardized for testing the echinocandins against Candida (4143).

RESULTS AND DISCUSSION

Table 1 summarizes the in vitro susceptibilities of echinocandin WT and ER isolates of Candida spp. to SCY-078 and the 3 echinocandin comparators. Although a recent report highlighted the lack of reproducibility of caspofungin MIC results when tested using the CLSI reference broth microdilution methods (44), results were included in this study. Caspofungin is an important in-class comparator for the echinocandins; furthermore, the testing reported here was generated in a single laboratory, decreasing the issues with reproducibility of the results. In addition, the FKS mutation data included in this study support the categorization of ER as determined by caspofungin testing. The MIC values of SCY-078 ranged from 0.03 to 16 mg/liter depending on the species and echinocandin susceptibility. Whereas the activity of SCY-078 was comparable to that of the 3 echinocandins against WT strains of C. parapsilosis, C. lusitaniae, C. guilliermondii, and C. orthopsilosis, it was 4- to 66-fold less active against WT strains of the other species, reflecting the intrinsic WT susceptibilities of each species to this novel GS inhibitor.

TABLE 1.

MIC distributions of SCY-078 and 3 echinocandins against WT and ER Candida spp. isolates

Species Phenotype (no. of isolates) Modal MICa (range [mg/liter])
SCY-078 Anidulafungin Caspofungin Micafungin
C. albicans WT (61) 0.12 (0.03–0.25) 0.015 (≤0.008–0.06) 0.03 (0.015–0.06) 0.015 (≤0.008–0.06)
ER (8) NM (0.06–2) 0.12 (≤0.008–1) 2 (0.015–2) 0.06 (0.015–2)
C. glabrata WT (39) 0.5 (0.25–1) 0.06 (0.015–0.25) 0.06 (0.03–0.25) 0.015 (≤0.008–0.03)
ER (28) 1 (0.12–16) 1 (0.015–4) 0.5 (0.03–16) 0.06 (≤0.008–4)
C. tropicalis WT (30) 0.25 (0.06–2) 0.015 (≤0.008–0.06) 0.03 (0.015–0.12) 0.03 (0.015–0.06)
ER (1) 2 2 2 2
C. parapsilosis WT (43) 0.25 (0.12–4) 2 (0.5–4) 0.5 (0.25–2) 2 (0.5–2)
C. krusei WT (30) 0.5–1 (0.25–2) 0.03 (0.03–0.25) 0.12 (0.06–0.25) 0.12 (0.06–0.25)
ER (4) 1 (1–4) 0.06 (0.03–0.5) NM (0.06–1) 0.12 (0.06–0.25)
C. dubliniensis WT (19) 0.12 (0.06–0.25) 0.015 (≤0.008–0.06) 0.03 (0.015–0.06) 0.03 (≤0.008–0.06)
ER (1) 0.25 0.5 2 1
C. lusitaniae WT (22) 2 (0.5–4) 0.5 (0.015–1) 0.5 (0.03–0.5) 0.25 (0.03–0.5)
C. guilliermondii WT (23) 2 (1–4) 2 (1–4) 0.5 (0.25–1) 1 (0.5–2)
C. orthopsilosis WT (15) 0.5 (0.06–1) 1 (0.25–1) 0.25 (0.06–0.5) 0.5 (0.12–1)
C. pelliculosa WT (14) 0.25 (0.25–2) 0.015 (≤0.008–2) 0.03 (0.015–0.5) 0.03–0.06 (0.015–1)
ER (1) 1 0.06 0.5 0.5
C. kefyr WT (11) 0.5–1 (0.25–1) 0.06 (0.03–0.06) 0.015 (0.015–0.03) 0.06 (0.03–0.12)
ER (1) 0.06 0.5 0.06 0.25
a

NM, no mode.

It is notable that whereas the increase in modal MIC values between WT and ER strains ranged from 2- to 133-fold for anidulafungin, 4- to 66-fold for caspofungin, and 1- to 66-fold for micafungin, modal MIC values for SCY-078 only increased by 2- to 8-fold across the different species (Table 1 and Fig. 1). Specifically, among the 36 FKS mutants tested, 30 (83.3%) were non-WT to 1 or more echinocandin, whereas only 9 (25.0%) were non-WT (MIC, >WT-upper limit[two 2-fold dilutions higher than the modal MIC value of each WT population]) to SCY-078 (Tables 2 and 3). Among the 25 FKS mutant strains of C. glabrata, 84.0% were non-WT to the echinocandins versus only 24.0% for SCY-078 (Table 3). Isolates of C. glabrata for which the SCY-078 MIC was >2 mg/liter (MIC, >WT-upper limit) all were non-WT and either intermediate or resistant to all three echinocandins (Tables 2 and 3). These isolates harbored a deletion at F659 or mutations L662 and S663 in the HS1 region of FKS2 (Table 3). Whereas FKS mutant strains of C. dubliniensis and C. kefyr were 2- to 8-fold more susceptible to SCY-078 than the echinocandins, 1 strain of C. tropicalis with a mutation in HS1 of FKS1 (F641S) was cross-resistant (MIC, 2 mg/liter) to all 3 echinocandins and SCY-078 (Table 3).

FIG 1.

FIG 1

Activity of SCY-078, anidulafungin, caspofungin, and micafungin against strains displaying FKS mutations. %WT, percent wild type; %NWT, percent non-wild type (for SCY-078, %NWT is the percent exceeding the wild-type upper-limit value [WT-UL; two 2-fold dilutions higher than the modal MIC value of each WT population]).

TABLE 2.

In vitro susceptibilities of Candida spp. to SCY-078 and 3 echinocandin antifungal agentsa

Species (no. of isolates tested) and antifungal agent No. of isolates (no. of mutants) at MIC (mg/liter) of:
≤0.008 0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 8 >8
C. albicans (69)
    SCY-078 3 28 (2) 29 5 (1) 1 (1) 1 2 (2)
    Anidulafungin 27 (1) 28 5 2 4 (3) 1 2 (2)
    Caspofungin 31 (1) 30 1 1 2 (1) 1 (1) 3 (3)
    Micafungin 3 32 (1) 26 4 (1) 2 (2) 2 (2)
C. glabrata (67)
    SCY-078 1 (1) 4 (2) 29 (4) 24 (10) 2 (2) 6 (5) 1 (1)
    Anidulafungin 2 (1) 8 (1) 23 8 4 (3) 3 (3) 7 (5) 6 (6) 6 (6)
    Caspofungin 14 (1) 20 (2) 7 (1) 5 (3) 7 (7) 3 (1) 6 (5) 1 (1) 2 (2) 2 (2)
    Micafungin 2 (1) 22 20 (4) 5 (3) 4 (3) 3 (3) 2 (2) 4 (4) 4 (4) 1 (1)
C. parapsilosis (43)
    SCY-078 1 19 (1) 12 8 2 1
    Anidulafungin 1 15 22 5 (1)
    Caspofungin 11 25 (1) 6 1
    Micafungin 2 17 24 (1)
C. tropicalis (31)
    SCY-078 1 9 15 4 2 (1)
    Anidulafungin 4 17 8 1 1 (1)
    Caspofungin 7 21 1 1 1 (1)
    Micafungin 8 16 6 1 (1)
C. krusei (34)
    SCY-078 2 12 14 (1) 5 1 (1)
    Anidulafungin 22 (1) 9 1 1 1 (1)
    Caspofungin 7 (1) 17 8 1 1 (1)
    Micafungin 12 19 (1) 3 (1)
C. dubliniensis (20)
    SCY-078 3 9 8 (1)
    Anidulafungin 1 8 7 3 1 (1)
    Caspofungin 5 12 2 1 (1)
    Micafungin 1 17 1 1 (1)
C. lusitaniae (22)
    SCY-078 2 2 14 4
    Anidulafungin 2 3 3 4 9 1
    Caspofungin 3 5 6 8
    Micafungin 1 1 4 5 11 1
C. guilliermondii (23)
    SCY-078 2 12 9
    Anidulafungin 3 17 3
    Caspofungin 2 11 10
    Micafungin 1 21 1
C. orthopsilosis (15)
    SCY-078 1 6 7 1
    Anidulafungin 2 4 9
    Caspofungin 3 4 6 2
    Micafungin 1 4 7 3
C. pelliculosa (15)
    SCY-078 8 4 1 2
    Anidulafungin 3 7 2 2
    Caspofungin 4 5 2 1 1 2
    Micafungin 2 5 5 2 1
C. kefyr (12)
    SCY-078 1 (1) 1 5 5
    Anidulafungin 5 6 1 (1)
    Caspofungin 10 1 1 (1)
    Micafungin 2 8 1 1 (1)
a

In vitro susceptibilities were determined by CLSI BMD method and read at a 24-h incubation time.

TABLE 3.

SCY-078 MIC results and those of anidulafungin, caspofungin, and micafungin against selected strains displaying FKS mutations

Organism β-(1,3)-d-glucan synthase mutation(s)a
MIC (mg/liter)
FKS1
FKS2
HS1 HS2 HS1 HS2 SCY-078 Anidulafungin Caspofungin Micafungin
C. albicans F641I WT 2 0.12 0.5 0.06
C. albicans F641S WT 2 0.12 1 0.5
C. albicans S629P WT 0.5 1 2 2
C. albicans L701 M WT 0.25 1 2 2
C. albicans ALT1929 WT 0.06 ≤0.008 0.015 0.015
C. albicans S645P WT 0.06 0.12 2 0.5
C. dubliniensis S645P WT 0.25 0.5 2 1
C. glabrata WT WT F659 deletion WT 16 4 16 2
C. glabrata D632Y WT WT WT 4 2 1 0.12
C. glabrata WT WT F659S WT 4 2 2 0.25
C. glabrata WT WT L662W WT 4 4 2 1
C. glabrata WT WT S663P WT 4 4 2 1
C. glabrata WT WT S663P WT 4 4 4 2
C. glabrata WT WT F659V WT 2 1 0.5 0.12
C. glabrata WT WT S663P WT 2 1 0.5 1
C. glabrata F625S WT WT WT 1 0.25 0.06 0.03
C. glabrata R631S S629P WT WT WT 1 0.5 0.5 0.06
C. glabrata WT WT D648E WT 1 0.5 0.25 0.06
C. glabrata S645P WT 1 2 2 1
C. glabrata WT WT F659Y WT 1 2 2 0.25
C. glabrata WT WT S663P WT 1 1 0.5 0.25
C. glabrata WT WT S663P WT 1 1 0.5 0.5
C. glabrata S629P WT WT WT 1 2 8 2
C. glabrata S629P WT WT WT 1 4 8 2
C. glabrata WT WT S663P WT 1 4 16 4
C. glabrata L630I WT WT WT 0.5 0.03 0.12 ≤0.008
C. glabrata F625Y WT WT WT 0.5 0.25 0.06 0.03
C. glabrata D632V WT WT WT 0.5 0.25 0.25 0.03
C. glabrata WT WT S663F WT 0.5 1 0.5 0.5
C. glabrata WT WT D666E K753Q WT 0.25 0.5 0.5 0.06
C. glabrata WT WT S663F WT 0.25 0.12 0.25 0.12
C. glabrata WT WT WT P1371S 0.12 0.015 0.03 0.03
C. kefyr WT R1344S 0.06 0.5 0.06 0.25
C. krusei NG2034 1 0.03 0.06 0.12
C. krusei L701 M 4 0.5 1 0.25
C. tropicalis F641S WT 2 2 2 2
a

HS1/HS2, hot spots 1 and 2, respectively; WT, wild type.

These data demonstrate the in vitro activity of the novel GS inhibitor SCY-078 compared to the established echinocandin antifungal agents against 11 different species of Candida, including both WT and ER strains. As documented previously (33, 40), ER strains of Candida were included in the WT MIC distribution of SCY-078 (Table 2). This observation suggests that FKS mutations in GS, in general, have less of an effect on the in vitro activity of SCY-078 than the echinocandins. Indeed, Jimenez-Ortigosa et al. (33) demonstrated that kinetic inhibition of product-entrapped GS enzymes isolated from ER strains yielded lower 50% inhibitory concentrations for SCY-078 (MK-3118) than for caspofungin in C. albicans (3- to 5.5-fold) and C. glabrata (3.5- to 62-fold). Similar to Jimenez-Ortigosa et al. (33), we found that 84.0% of FKS mutant strains of C. glabrata were non-WT to the echinocandins versus only 24.0% for SCY-078. Given these findings, it is also notable that Lepak et al. (38) found in an in vivo murine IC model that the static and 1-log kill doses, as well as the total and free-drug area-under-the-curve/MIC pharmacodynamic targets for SCY-078, were numerically lower than those observed for echinocandins, suggesting that this agent will prove to be an oral option for the treatment of Candida infections, including IC.

The in vitro activity of SCY-078 against both WT and ER Candida spp. was assessed using CLSI BMD methods. The potency and spectrum of SCY-078 against this challenging collection of isolates was excellent and less affected by FKS mutations than the echinocandins. These data suggest that SCY-078 will be useful in the treatment of ER candidiasis.

MATERIALS AND METHODS

Organisms.

A total of 351 clinical isolates of Candida were tested, including 307 echinocandin WT strains (61 C. albicans, 39 C. glabrata, 30 C. tropicalis, 43 C. parapsilosis, 30 C. krusei, 19 C. dubliniensis, 22 C. lusitaniae, 23 C. guilliermondii, 15 C. orthopsilosis, 14 C. pelliculosa, and 11 C. kefyr) and 44 ER (non-WT or resistant to one or more echinocandin) strains (8 C. albicans, 28 C. glabrata, 1 C. tropicalis, 4 C. krusei, 1 C. dubliniensis, 1 C. pelliculosa, and 1 C. kefyr) (Table 1). All tested strains were from the SENTRY Antimicrobial Surveillance Program Collection (45). Isolates were identified to species level using a combination of conventional methods, matrix-assisted laser desorption ionization-time of flight mass spectrometry, and DNA sequence analysis as described previously (46, 47). Prior to testing, each isolate was passaged at least twice onto Sabouraud dextrose agar (Remel, Lenexa, Kansas, USA) and CHROMagar Candida medium (Becton Dickinson, Sparks, Maryland, USA) to ensure purity and viability.

Antifungal susceptibility testing.

All isolates were tested for in vitro susceptibility to SCY-078, anidulafungin, caspofungin, and micafungin using CLSI BMD methods (41, 42). The reference powder of SCY-078 was obtained from the manufacturer. Stock solutions were prepared in dimethyl sulfoxide (DMSO), and the final range of SCY-078 and comparator agent concentrations tested was 0.008 to 16 mg/liter.

CLSI BMD testing was performed exactly as outlined in documents M27-S4 (42) and M27-A3 (41) by using RPMI 1640 medium with 0.2% glucose, inocula of 0.5 × 103 to 2.5 × 103 cells/ml, and incubation at 35°C. MIC values for both SCY-078 and the echinocandins were determined visually following 24 h of incubation as the lowest concentration of drug that caused significant growth diminution levels (≥50% inhibition) relative to the growth control, as described by Pfaller et al. (40) and the CLSI (41, 42), respectively.

We used the revised CLSI clinical breakpoint (CBP) values to identify strains of C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, C. krusei, and C. guilliermondii that were susceptible (S), intermediate (I), and resistant (R) to the echinocandins (48) (Table 4). CLSI has not established CBPs for the echinocandins and C. dubliniensis, C. lusitaniae, C. orthopsilosis, C. pelliculosa, and C. kefyr, and it recommends that the previously established epidemiological cutoff values (ECVs) be used to differentiate WT (no acquired resistance mechanisms) from non-WT (may harbor acquired resistance mechanisms) strains of these species (48) (Table 4). Neither CBPs nor ECVs have been determined for SCY-078 and Candida spp. For purposes of comparison, we have used a wild-type-upper-limit value as the susceptibility cutoff value for SCY-078 and each species (49, 50) (Tables 1 and 4).

TABLE 4.

Cutoff values and clinical breakpoints employed for comparison of SCY-078 to anidulafungin, caspofungin, and micafungin against Candida spp.c

Species and antifungal agent Cutoff value (mg/liter)
CBPa (mg/liter)
WT-UL ECVb S I R
C. albicans
    SCY-078 0.5
    Anidulafungin 0.12 ≤0.25 0.5 ≥1
    Caspofungin 0.12 ≤0.25 0.5 ≥1
    Micafungin 0.03 ≤0.25 0.5 ≥1
C. glabrata
    SCY-078 2
    Anidulafungin 0.25 ≤0.12 0.25 ≥0.5
    Caspofungin 0.12 ≤0.12 0.25 ≥0.5
    Micafungin 0.03 ≤0.06 0.12 ≥0.25
C. tropicalis
    SCY-078 1
    Anidulafungin 0.12 ≤0.25 0.5 ≥1
    Caspofungin 0.12 ≤0.25 0.5 ≥1
    Micafungin 0.12 ≤0.25 0.5 ≥1
C. parapsilosis
    SCY-078 1
    Anidulafungin 4 ≤2 4 ≥8
    Caspofungin 1 ≤2 4 ≥8
    Micafungin 4 ≤2 4 ≥8
C. krusei
    SCY-078 4
    Anidulafungin 0.12 ≤0.25 0.5 ≥1
    Caspofungin 0.25 ≤0.25 0.5 ≥1
    Micafungin 0.12 ≤0.25 0.5 ≥1
C. dubliniensis
    SCY-078 0.5
    Anidulafungin 0.12
    Caspofungin 0.12
    Micafungin 0.12
C. lusitaniae
    SCY-078 8
    Anidulafungin 2
    Caspofungin 1
    Micafungin 0.5
C. guilliermondii
    SCY-078 8
    Anidulafungin 4 ≤2 4 ≥8
    Caspofungin 2 ≤2 4 ≥8
    Micafungin 2 ≤2 4 ≥8
C. orthopsilosis
    SCY-078 2
    Anidulafungin 2
    Caspofungin 0.5
    Micafungin 1
C. pelliculosa
    SCY-078 1
    Anidulafungin
    Caspofungin 0.12
    Micafungin
C. kefyr
    SCY-078 4
    Anidulafungin 0.25
    Caspofungin 0.03
    Micafungin 0.12
a

CBP, clinical breakpoint; S, susceptible; I, intermediate; R, resistant. ECVs and CBP values are from Pfaller and Diekema (48).

b

ECV, epidemiologic cutoff value.

c

Cutoff values and clinical breakpoints were determined by 24-h CLSI broth microdilution methods.

Quality control was performed as recommended in CLSI document M27-A3 (41) using C. krusei ATCC 6258 and C. parapsilosis ATCC 22019. All ER isolates were further characterized regarding the presence or absence of a mutation in the HS regions of FKS1 and FKS2 (C. glabrata only) as described previously (45, 51, 52).

ACKNOWLEDGMENTS

We thank S. E. Costello for performing the sequencing of the FKS HS.

This study was sponsored by an investigational grant from Scynexis.

JMI Laboratories, Inc., has also received research and educational grants in 2014 to 2015 from Achaogen, Actavis, Actelion, American Proficiency Institute (API), AmpliPhi, Anacor, Astellas, AstraZeneca, Basilea, Bayer, BD, Cardeas, Cellceutix, CEM-102 Pharmaceuticals, Cempra, Cerexa, Cidara, Cormedix, Cubist, Debiopharm, Dipexium, Dong Wha, Durata, Enteris, Exela, Forest Research Institute, Furiex, Genentech, GSK, Helperby, ICPD, Janssen, Lannett, Longitude, Medpace, Meiji Seika Kasha, Melinta, Merck, Motif, Nabriva, Novartis, Paratek, Pfizer, Pocared, PTC Therapeutics, Rempex, Roche, Salvat, Seachaid, Shionogi, Tetraphase, The Medicines Co., Theravance, ThermoFisher, VenatoRX, Vertex, Wockhardt, Zavante, and some other corporations. In regard to speakers' bureaus and stock options, we have none to declare.

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