In vitro activity of the orally bioavailable ceftibuten/VNRX-7145 (VNRX-5236 etzadroxil) combination against a challenge set of Enterobacterales pathogens carrying molecularly characterized β-lactamase genes.

OBJECTIVES: This study assessed the activity of ceftibuten, ceftibuten combined with the active form (VNRX-5236) of the β-lactamase inhibitor VNRX-7145 and comparators against a challenge set of Gram-negative pathogens.
METHODS: Two hundred and five Enterobacterales carrying plasmid AmpC (53 isolates), ESBL (50), KPC (50), OXA-48-like (49) or OXA-48-like with KPC (3) encoding genes were selected. Susceptibility was determined by broth microdilution. VNRX-5236 and avibactam were tested at a fixed concentration of 4 mg/L.
RESULTS: Ceftibuten/VNRX-5236 (MIC50/90 0.12/1 mg/L) MIC values were 256-fold lower than those of ceftibuten (MIC50/90 32/256 mg/L) for all Enterobacterales and 2- to 4-fold lower than those of ceftazidime/avibactam (MIC50/90 0.5/2 mg/L). For isolates producing a plasmid-encoded AmpC, VNRX-5236 decreased ceftibuten MIC (MIC50/90 0.12/1 mg/L) by at least 512-fold compared with ceftibuten (MIC50/90 128/>256 mg/L). Ceftibuten/VNRX-5236 (MIC50/90 0.06/0.12 mg/L) and meropenem (MIC50/90 ≤0.03/0.06 mg/L; 100% susceptible) showed comparable activities against ESBL isolates and these agents had MIC90 values 4- to 8-fold lower than that of ceftazidime/avibactam (MIC50/90 0.25/0.5 mg/L; 100% susceptible). Ceftibuten/VNRX-5236 (MIC50/90 0.12/0.5 mg/L) had the lowest MIC for KPC producers, followed by ceftazidime/avibactam (MIC50/90 2/4 mg/L; 98.0% susceptible). The same MIC90 values were obtained for ceftibuten/VNRX-5236 (MIC50/90 0.25/1 mg/L) and ceftazidime/avibactam (MIC50/90 1/1 mg/L; 100.0% susceptible) for isolates carrying blaOXA-48-like. VNRX-5236 decreased the ceftibuten MIC at least 16-fold for three isolates carrying blaOXA-48-like and blaKPC.
CONCLUSIONS: VNRX-5236 rescued the in vitro activity of ceftibuten against Enterobacterales carrying common serine β-lactamases, including ESBL, AmpC and the KPC and OXA-48-like carbapenemases. Ceftibuten/VNRX-5236 may have potential as an oral treatment for infections caused by resistant Enterobacterales, while sparing carbapenems.

Introduction

The emergence and spread of Enterobacterales producing ESBL and carbapenemase enzymes have threatened the utility of agents within the β-lactam class for treating infections caused by these organisms. A report from the US CDC estimated that, in 2017, 197 400 infections in hospitalized patients were caused by ESBL-producing Enterobacterales and 9100 of those patients died. A report from the ECDC documented that between 14.6% and 15.1% of Escherichia coli isolates were resistant to third-generation cephalosporins during 2015–19. This phenotype was reported to be present in 31% of Klebsiella pneumoniae during the same period. Although carbapenem resistance remains low among E. coli, 8% of K. pneumoniae showed this phenotype in Europe, whereas 2.3%, 16.2% and 15.5% of K. pneumoniae were carbapenem resistant in the USA, Latin America and Asia-Pacific regions during 2019, respectively.

β-Lactamase inhibitors (BLIs) have long been used to restore the activity of β-lactams against isolates producing β-lactamases. However, approved β-lactam/BLI combinations possess limitations due to their lack of coverage against important β-lactamase enzymes and/or lack of oral bioavailability. The only oral BLI, clavulanic acid, was approved for use with amoxicillin in 1984, but it exhibits no useful activity against AmpC cephalosporinases, most oxacillinases or carbapenemases. The orally bioavailable etzadroxil prodrug, VNRX-7145, is under clinical development in combination with ceftibuten, a third-generation oral cephalosporin. VNRX-7145 undergoes biotransformation to the active inhibitor, VNRX-5236, which is a new broad-spectrum cyclic boronate BLI. This study assessed the in vitro activity of ceftibuten alone, the investigational ceftibuten/VNRX-5236 combination and comparator agents against a challenge set of MDR Gram-negative pathogens.

Materials and methods

Bacterial isolates

A set of 198 non-duplicate single-patient Enterobacterales (11 species) isolates were collected from patients in European and US medical centres in 2015–16 through the SENTRY Antimicrobial Surveillance Program (Table 1). Seven isolates collected from Latin American and Asia-Pacific hospitals were added, for an overall total of 205 isolates studied. These isolates were selected for their plasmid AmpC (53 isolates), ESBL (50), KPC (50), OXA-48-like (49) or OXA-48-like in combination with KPC (3) encoding genes (see below). Identification was confirmed for these Enterobacterales by MALDI-TOF MS (Bruker Daltonics, Bremen, Germany).

Table 1.

Antimicrobial activity of agents tested against the main organisms and organism groups

Organism/group (no. of isolates)	No. of isolates and cumulative % inhibited at MIC (mg/L) of:																													MIC50	MIC90
	≤0.008	0.015	0.03		0.06		0.12			0.25		0.5		1		2	4	8	16		32		64		128		256		>a
Enterobacteriaceae (205)b
ceftibuten							4 2.0			2 2.9		6 5.9		3 7.3		19 16.6	25 28.8	24 40.5	18 49.3		27 62.4		18 71.2		28 84.9		17 93.2		14 100.0	32	256
ceftibuten/VNRX-5236c		12 5.9	17 14.1		38 32.7		52 58.0			35 75.1		29 89.3		11 94.6		2 95.6	5 98.0	1 98.5	0 98.5		0 98.5								3 100.0	0.12	1
AmpC (53)
ceftibuten																	1 1.9	1 3.8		2 7.5	4 15.1		4 22.6		18 56.6			12 79.2	11 100.0	128	>256
ceftibuten/VNRX-5236c		1 1.9	1 3.8		8 18.9			19 54.7			1277.4		5 86.8		4 94.3	0 94.3	1 96.2	0 96.2		0 96.2	0 96.2								2 100.0	0.12	1
ESBL (50)
ceftibuten									4 8.0		2 12.0		5 22.0		1 24.0	8 40.0	11 62.0	11 84.0		3 90.0	4 98.0		1 100.0							4	16
ceftibuten/VNRX-5236c		9 18.0	8 34.0			18 70.0			11 92.0		2 96.0		1 98.0		0 98.0	1 100.0														0.06	0.12
KPCd (50)
ceftibuten																7 14.0	7 28.0	10 48.0		5 58.0	13 84.0		3 90.0		2 94.0			2 98.0	1 100.0	16	64
ceftibuten/VNRX-5236c		1 2.0		4 10.0		5 20.0			16 52.0		10 72.0		9 90.0		1 92.0	0 92.0	3 98.0	1 100.0												0.12	0.5
OXA-48-likee (49)
ceftibuten													1 2.0		2 6.1	4 14.3	6 26.5	2 30.6		7 44.9		4 53.1		10 73.5		8 90.0		3 95.9	2 100.0	32	128
ceftibuten/VNRX-5236c		1 2.0		4 10.2		7 24.5			6 36.7		11 59.2		12 83.7		5 93.9	1 95.9	1 98.0	0 98.0		0 98.0		0 98.0							1 100.0	0.25	1
OXA-48 and KPCf (3)
ceftibuten																				1 33.3		2 100.0								–	–
ceftibuten/VNRX-5236c													2 66.7		1 100.0															–	–

Represents an MIC >256 mg/L for ceftibuten alone or >32 mg/L for ceftibuten/VNRX-5236.

Includes C. freundii (4 isolates), Enterobacter cloacae (8), E. coli (71), Hafnia alvei (1), Klebsiella oxytoca (3), K. pneumoniae (106), Pluralibacter gergoviae (1), Proteus mirabilis (6), Providencia stuartii (1), Raoultella ornithinolytica (2) and Serratia marcescens (2).

VNRX-5236 was tested at a fixed concentration of 4 mg/L. VNRX-5236 is the active BLI of the orally available VNRX-7145 product.

Includes KPC-2, KPC-3, KPC-4 and KPC-6 encoding gene variants.

Includes OXA-48, OXA-163, OXA-232 and OXA-244 encoding gene variants.

Includes a K. pneumoniae carrying blaOXA-48 and blaKPC-3 (ceftibuten/VNRX-5236 MIC 0.5 mg/L), a K. pneumoniae carrying blaOXA-232 and blaKPC-2 (ceftibuten/VNRX-5236 MIC 0.5 mg/L) and a C. freundii species complex carrying blaOXA-48 and blaKPC-2 (ceftibuten/VNRX-5236 MIC 1 mg/L).

Antimicrobial susceptibility testing

Isolates were tested for susceptibility by broth microdilution following CLSI M07 guidelines. MIC values of comparator agents were interpreted using CLSI and EUCAST breakpoint criteria., Ceftibuten breakpoints published by EUCAST were applied to ceftibuten/VNRX-5236 for comparative purposes of in vitro testing results only, since no breakpoints were available for ceftibuten/VNRX-5236 during the preparation of this manuscript. Frozen-form broth microdilution panels were manufactured by JMI Laboratories (North Liberty, IA, USA) using fresh cation-adjusted Mueller–Hinton broth. VNRX-5236 and avibactam BLI agents were provided by Venatorx Pharmaceuticals Inc. (Malvern, PA, USA) and tested at a fixed concentration of 4 mg/L. Quality assurance was performed by concurrently testing CLSI-recommended quality control reference strains E. coli ATCC 25922, K. pneumoniae ATCC 700603 and ATCC BAA-1705, Pseudomonas aeruginosa ATCC 27853 and Staphylococcus aureus ATCC 29213. This study was performed prior to the formal CLSI approval of quality control MIC ranges for ceftibuten/VNRX-5236; however, all MIC values obtained for ATCC BAA-1705 were within the currently approved range.

Characterization of resistance mechanisms by next-generation sequencing

Total genomic DNA was extracted using a fully automated Thermo Scientific™ KingFisher™ Flex Magnetic Particle Processor (Cleveland, OH, USA), which was used as input material for library construction. DNA libraries were prepared using the Nextera™ library construction protocol (Illumina, San Diego, CA, USA) following the instructions of the manufacturer and were sequenced on MiSeq Sequencer platforms (Illumina) at JMI Laboratories. FASTQ format sequencing files for each sample set were assembled independently using de novo assembler SPAdes 3.11.1. An in-house software was applied to align the assembled sequences against a curated database containing known β-lactamase resistance genes with the purpose of screening. Isolates classified within the AmpC or ESBL group carried exclusively plasmid-encoded AmpC or ESBL genes only. Similarly, those isolates carrying blaKPC were classified as KPC, whereas those carrying blaOXA-48-like genes were categorized accordingly. A K. pneumoniae carrying blaOXA-48 and blaKPC-3, a K. pneumoniae carrying blaOXA-232 and blaKPC-2 and a Citrobacter freundii species complex carrying blaOXA-48 and blaKPC-2 were included and analysed as a separate group. In addition, some isolates classified within the KPC and OXA-48-like subsets also carried ESBL and/or plasmid AmpC genes. Information related to β-lactamase gene content can be found in Table S1 (available as Supplementary data at JAC Online).

Results and discussion

Overall, ceftibuten/VNRX-5236 inhibited 94.6% of isolates in the challenge set at ≤1 mg/L (Table 1). Eight isolates displayed ceftibuten/VNRX-5236 MIC values of 2–8 mg/L and carried carbapenemases (blaOXA-48 or blaKPC) with multiple ESBL genes, except for two isolates, each with blaCMY-2 or blaSHV-26 (first-generation BLI resistant). Two E. coli (both carrying blaCMY-42) and one K. pneumoniae (blaOXA-48 and blaDHA-1) displayed a ceftibuten/VNRX-5236 MIC of >32 mg/L. These three isolates showed an MDR phenotype, including a carbapenem-resistant Enterobacterales (CRE) phenotype by the K. pneumoniae (Table S1).

The ceftibuten/VNRX-5236 (MIC50/90 0.12/1 mg/L) MIC values were 256-fold lower than those of ceftibuten alone (MIC50/90 32/256 mg/L; 40.5% susceptible) for all Enterobacterales and 2- to 4-fold lower than those of ceftazidime/avibactam (MIC50/90 0.5/2 mg/L) (Tables 1 and 2). Meropenem (MIC50/90 0.25/32 mg/L; 58.5–64.9% susceptible) and piperacillin/tazobactam (MIC50/90 >64/>64 mg/L; 34.1–38.0% susceptible) had limited activity against this challenge set, as did all other comparators, including oral agents (≤29.9% susceptible) (Table 2).

Table 2.

Antimicrobial activity of ceftibuten, ceftibuten/VNRX-5236 and comparator agents against selected Enterobacterales and resistant subsets

Antimicrobial agent	MIC (mg/L)			CLSIa				EUCASTa
	MIC50	MIC90	range	%S	%I	%R		%S	%I	%R
Enterobacterales (205)
ceftibutenb	32	256	≤0.12 to >256	40.5	8.8	50.7		7.3		92.7
ceftibuten/VNRX-5236b	0.12	1	≤0.015 to >32					94.6		5.4
ceftazidime/avibactam	0.5	2	0.06 to 32	98.5		1.5		98.5		1.5
piperacillin/tazobactam	>64	>64	0.5 to >64	38.0	10.7	51.2		34.1		65.9
ceftazidime	64	>256	0.25 to >256	7.8	7.3	84.9		4.9	2.9	92.2
cefepime	16	>256	≤0.12 to >256	27.8	10.2e	62.0		22.9	9.3	67.8
meropenem	0.25	32	≤0.03 to >64	58.5	6.3	35.1		64.9	8.3	26.8
levofloxacin	16	>16	0.03 to >16	22.4	5.9	71.7		22.4	5.9	71.7
trimethoprim/sulfamethoxazole	>4	>4	≤0.5 to >4	29.9		70.1		29.9	4.4	65.7
AmpC (53)
ceftibutenb	128	>256	4 to >256	3.8	3.8	92.5		0.0		100.0
ceftibuten/VNRX-5236b	0.12	1	≤0.015 to >32					94.3		5.7
ceftazidime/avibactam	0.25	2	0.06 to 32	96.2		3.8		96.2		3.8
piperacillin/tazobactam	8	>64	1 to >64	73.6	15.1	11.3		67.9		32.1
ceftazidime	32	256	4 to >256	1.9	5.7	92.5		0.0	1.9	98.1
cefepime	0.5	4	≤0.12 to 32	83.0	11.3e	5.7		79.2	11.3	9.4
meropenem	≤0.03	0.06	≤0.03 to 2	98.1	1.9	0.0		100.0	0.0	0.0
levofloxacin	0.5	>16	0.03 to >16	50.9	9.4	39.6		50.9	9.4	39.6
trimethoprim/sulfamethoxazole	1	>4	≤0.5 to >4	52.8		47.2		52.8	0.0	47.2
ESBL (50)
ceftibutenb	4	16	≤0.12 to 64	84.0	6.0	10.0		24.0		76.0
ceftibuten/VNRX-5236b	0.06	0.12	≤0.015 to 2					98.0		2.0
ceftazidime/avibactam	0.25	0.5	0.06 to 2	100.0		0.0		100.0		0.0
piperacillin/tazobactam	4	64	0.5 to >64	76.0	18.0	6.0		68.0		32.0
ceftazidime	16	128	0.25 to >256	20.0	18.0	62.0		12.0	8.0	80.0
cefepime	16	128	1 to >256	14.0	20.0e	66.0		2.0	20.0	78.0
meropenem	≤0.03	0.06	≤0.03 to 0.25	100.0	0.0	0.0		100.0	0.0	0.0
levofloxacin	16	>16	0.03 to >16	22.0	4.0	74.0		22.0	4.0	74.0
trimethoprim/sulfamethoxazole	>4	>4	≤0.5 to >4	32.0		68.0		32.0	2.0	66.0
KPCc (50)
ceftibutenb	16	64	2 to >256	48.0	10.0	42.0		0.0		100.0
ceftibuten/VNRX-5236b	0.12	0.5	≤0.015 to 8					92.0		8.0
ceftazidime/avibactam	2	4	0.25 to 16	98.0		2.0		98.0		2.0
piperacillin/tazobactam	>64	>64	16 to >64	2.0	4.0	94.0		0.0		100.0
ceftazidime	256	>256	8 to >256	0.0	2.0	98.0		0.0	0.0	100.0
cefepime	64	>256	1 to >256	2.0	4.0e	94.0		2.0	0.0	98.0
meropenem	16	>64	0.06 to >64	6.0	10.0	84.0		16.0	26.0	58.0
levofloxacin	16	>16	0.25 to >16	4.0	8.0	88.0		4.0	8.0	88.0
trimethoprim/sulfamethoxazole	>4	>4	≤0.5 to >4	18.4		81.6		18.4	10.2	71.4
OXA-48-liked (49)
ceftibutenb	32	256	0.5 to >256	30.6	14.3	55.1		6.1		93.9
ceftibuten/VNRX-5236b	0.25	1	≤0.015 to >32					93.9		6.1
ceftazidime/avibactam	1	1	0.12 to 2	100.0		0.0		100.0		0.0
piperacillin/tazobactam	>64	>64	64 to >64	0.0	6.1	93.9		0.0		100.0
ceftazidime	128	256	0.5 to >256	10.2	4.1	85.7		8.2	2.0	89.8
cefepime	128	>256	0.5 to >256	10.2	6.1e	83.7		6.1	6.1	87.8
meropenem	8	32	0.12 to 64	30.6	14.3	55.1		44.9	8.2	46.9
levofloxacin	16	>16	0.03 to >16	12.2	2.0	85.7		12.2	2.0	85.7
trimethoprim/sulfamethoxazole	>4	>4	≤0.5 to >4	16.3		83.7		16.3	6.1	77.6
OXA-48-like and KPCf (3)
ceftibutenb	–	–	16 to 32
ceftibuten/VNRX-5236b	–	–	0.5 to 1
ceftazidime/avibactam	–	–	0.5 to 4
piperacillin/tazobactam	–	–	>64
ceftazidime	–	–	32 to 256
cefepime	–	–	64 to >256
meropenem	–	–	32 to >64
levofloxacin	–	–	8 to >16
trimethoprim/sulfamethoxazole	–	–	>4

MIC values were interpreted using CLSI and EUCAST criteria (2021), where breakpoints are available.

VNRX-5236 was tested at a fixed concentration of 4 mg/L; ceftibuten/VNRX-5236 used the EUCAST ceftibuten breakpoints for Enterobacterales infections originating in the urinary tract (susceptible ≤1 mg/L/resistant >1 mg/L; based on a once-daily 400 mg oral dose of ceftibuten) for comparison purposes of in vitro testing results only; VNRX-5236 is the active BLI of the orally bioavailable etzadroxil prodrug, VNRX-7145.

Includes KPC-2, KPC-3, KPC-4 and KPC-6 encoding gene variants.

Includes OXA-48, OXA-163, OXA-232 and OXA-244 encoding gene variants.

Intermediate interpreted as susceptible-dose dependent.

Includes a K. pneumoniae carrying blaOXA-48 and blaKPC-3 (ceftibuten/VNRX-5236 MIC 0.5 mg/L), a K. pneumoniae carrying blaOXA-232 and blaKPC-2 (ceftibuten/VNRX-5236 MIC 0.5 mg/L) and a C. freundii species complex carrying blaOXA-48 and blaKPC-2 (ceftibuten/VNRX-5236 MIC 1 mg/L).

When tested against the subset of isolates producing plasmid-encoded AmpC, VNRX-5236 in combination with ceftibuten (MIC50/90 0.12/1 mg/L) decreased MIC values by at least 512-fold compared with ceftibuten alone (MIC50/90 128/>256 mg/L) (Tables 1 and 2). Ceftibuten/VNRX-5236 (MIC50/90 0.12/1 mg/L; 94.3% inhibited at ≤1 mg/L), ceftazidime/avibactam (MIC50/90 0.25/2 mg/L; 96.2% susceptible) and meropenem (MIC50/90 ≤0.03/0.06 mg/L; 98.1%–100% susceptible) were active in vitro against isolates producing plasmid-encoded AmpC. Other agents tested had suboptimal activities against this subset (Table 2).

Ceftibuten/VNRX-5236 (MIC50/90 0.06/0.12 mg/L; 98.0% inhibited at ≤1 mg/L) and meropenem (MIC50/90 ≤0.03/0.06 mg/L; 100% susceptible) had similar MIC values for the subset of ESBL isolates, with MIC90 values 4- to 8-fold lower than that of ceftazidime/avibactam (MIC50/90 0.25/0.5 mg/L; 100% susceptible) (Table 2). All but four KPC-producing strains were inhibited by ≤1 mg/L ceftibuten/VNRX-5236 (MIC50/90 0.12/0.5 mg/L; 92.0% inhibited at ≤1 mg/L) (Table 1). Ceftazidime/avibactam (MIC50/90 2/4 mg/L; 98.0% susceptible) was also highly active against the subset of KPC producers (Table 2). Similarly, ceftibuten/VNRX-5236 (MIC50/90 0.25/1 mg/L; 93.9% inhibited at ≤1 mg/L) and ceftazidime/avibactam (MIC50/90 1/1 mg/L; 100.0% susceptible) were both active against the subset of isolates carrying blaOXA-48-like and both agents had MIC90 values of 1 mg/L. Moreover, VNRX-5236 decreased the ceftibuten MIC at least 16-fold when tested against three isolates carrying both blaOXA-48-like and blaKPC genes, with all three isolates exhibiting ceftibuten/VNRX-5236 MICs of 0.5–1 mg/L (Table 1).

Ceftibuten/VNRX-5236 demonstrated potent activity overall and against each of these important subsets of clinical isolates, inhibiting all but 5.4% of strains at ≤1 mg/L, regardless of β-lactamase content. The challenge set of isolates carried the most common β-lactamase encoding genes, including the blaCTX group that is currently carried by the vast majority of E. coli and K. pneumoniae isolates resistant to third-generation cephalosporins. In addition, ceftibuten/VNRX-5236 showed potent activity against isolates producing (co-producing) the serine carbapenemases KPC and OXA-48-like, which have become prevalent worldwide and endemic in certain regions., The orally bioavailable ceftibuten/VNRX-7145 combination may be a valuable option for treating infections caused by MDR Enterobacterales carrying ESBL, AmpC and/or serine carbapenemase genes. Pending results from clinical efficacy and safety studies, this combination may provide the convenience of switching to oral administration with the accordingly recognized benefits.

It is important to note that the isolates included in this study were selected solely based on the presence of specific β-lactamases and do not represent the true distribution of these organisms and resistance mechanisms in clinical or community settings. Also, isolates carrying genes encoding Ambler class B carbapenemases were excluded due to the known lack of inhibition by VNRX-5236. Moreover, the data presented here did not assess resistance mechanisms other than the presence of β-lactamase encoding genes. These additional mechanisms of resistance or a combination thereof probably could explain the elevated MIC values (i.e. >32 mg/L) observed for ceftibuten/VNRX-5236 against a small number of isolates in this challenge set. The investigational BLI VNRX-5236 rescued the in vitro activity of ceftibuten against Enterobacterales carrying common β-lactamases. This combination may have potential clinical utility when treating patients with infections caused by resistant Enterobacterales, while sparing the use of carbapenem agents.

Funding

This study was performed by JMI Laboratories and supported by Venatorx Pharmaceuticals Inc., which included funding for services related to preparing this manuscript. Discovery and development of VNRX-7145 are supported by NIH R01 grant 1R01AI111539 and by NIAID contract HHSN272201600029C.

Transparency declarations

JMI Laboratories was contracted to perform services in 2020 for Affinity Biosensors, Allergan, Amicrobe, Inc., Amplyx Pharma, Artugen Therapeutics USA, Inc., Astellas, Basilea, Beth Israel Deaconess Medical Center, BIDMC, bioMerieux, Inc., BioVersys Ag, Bugworks, Cidara, Cipla, Contrafect, Cormedix, Crestone, Inc., Curza, CXC7, Entasis, Fedora Pharmaceutical, Fimbrion Therapeutics, Fox Chase, GlaxoSmithKline, Guardian Therapeutics, Hardy Diagnostics, IHMA, Janssen Research & Development, Johnson & Johnson, Kaleido Biosciences, KBP Biosciences, Luminex, Matrivax, Mayo Clinic, Medpace, Meiji Seika Pharma Co., Ltd, Melinta, Menarini, Merck, Meridian Bioscience Inc., Micromyx, MicuRx, N8 Medical, Nabriva, National Institutes of Health, National University of Singapore, North Bristol NHS Trust, Novome Biotechnologies, Paratek, Pfizer, Prokaryotics Inc., QPEX Biopharma, Rhode Island Hospital, RIHML, Roche, Roivant, Salvat, Scynexis, SeLux Diagnostics, Shionogi, Specific Diagnostics, Spero, SuperTrans Medical LT, T2 Biosystems, The University of Queensland, Thermo Fisher Scientific, Tufts Medical Center, Universite de Sherbrooke, University of Iowa, University of Iowa Hospitals and Clinics, University of Wisconsin, UNT System College of Pharmacy, URMC, UT Southwestern, Venatorx, Viosera Therapeutics and Wayne State University. There are no speakers’ bureaus or stock options to declare.

Supplementary data

Table S1 is available as Supplementary data at JAC Online.

Click here for additional data file.