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Kristine Cannon, Brendan Byrne, Jennifer Happe, Kaiyu Wu, Linda Ward, Laurent Chesnel, Thomas Louie, Enteric microbiome profiles during a randomized Phase 2 clinical trial of surotomycin versus vancomycin for the treatment of Clostridium difficile infection, Journal of Antimicrobial Chemotherapy, Volume 72, Issue 12, December 2017, Pages 3453–3461, https://doi.org/10.1093/jac/dkx318
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Abstract
The effects of surotomycin (CB-183,315, MK-4261), a bactericidal cyclic lipopeptide, and vancomycin, the current standard-of-care for Clostridium difficile infection (CDI), on intestinal pathogens and microbiota were evaluated parallel to a Phase 2 randomized, double-blind clinical trial.
The single-centre cohort included 26 patients receiving surotomycin [125 or 250 mg twice daily (n = 9 each)] or oral vancomycin [125 mg four times daily (n = 8)] for 10 days. Faecal samples were collected at days 0–42 to quantify both C. difficile by conventional culture and the major components of the microbiome by quantitative PCR.
Surotomycin 250 mg twice daily or vancomycin 125 mg four times daily reduced faecal C. difficile counts from ∼105–107 log10 cfu/g at baseline to ≤ 102 cfu/g by days 4–10 of treatment. Day 10 counts of C. difficile in 3/9 patients receiving surotomycin 125 mg twice daily remained detectable, including one patient who failed to achieve clinical cure. Bacteroidetes and Prevotella mean counts increased 0.7 log10 or remained unchanged with surotomycin 125 and 250 mg twice daily, respectively, whereas vancomycin reduced counts by 2.5–3.2 log10 (P < 0.02). Vancomycin reduced Firmicutes counts by 2.5–2.8 log10; surotomycin moderately suppressed these microbes in a dose-dependent manner.
In this Phase 2 trial substudy, compared with vancomycin 125 mg four times daily, surotomycin 250 mg twice daily is as active in vivo against C. difficile, but was more sparing of microbiota. Surotomycin is no longer in development due to failed Phase 3 efficacy results.
Introduction
The objective of antimicrobial treatment of Clostridium difficile infection (CDI) is to kill or inhibit the pathogen in the intestinal lumen, thereby arresting the production of C. difficile toxins, while at the same time minimizing further damage to the normal intestinal microbiota, a strategy that prevents subsequent recurrence of infection.1,2
Currently, vancomycin and fidaxomicin are the only antibiotics approved for the treatment of CDI, with metronidazole also used in accordance with its approval for anaerobic bacterial infections. Vancomycin and metronidazole are highly effective in reducing C. difficile counts during treatment of CDI, but are damaging to other components of the microbiome such as Bacteroidetes, and Clostridium cluster IV and XIVa microbes.3–5 The dysbiosis of intestinal microbiota caused by vancomycin, metronidazole and broad-spectrum antibiotics leads to an increased risk of CDI recurrence.6 In contrast, fidaxomicin, a macrocyclic antibiotic, appears to be sparing of the three main normal microbiota groups while simultaneously suppressing C. difficile counts during treatment. This sparing of microbiota is associated with a higher sustained response rate observed with fidaxomicin as compared with vancomycin treatment for CDI.5,7,8
Despite the introduction of fidaxomicin, the number of treatments available for CDI therapy remains critically limited. Alternative narrow-spectrum treatments under development include surotomycin (CB-183, 315, MK-4261),9 in addition to cadazolid10 and ridinilazole (formerly SMT 19999).11 Surotomycin (an orally administered, minimally absorbed, selective bactericidal cyclic lipopeptide) demonstrated potent activity in vitro against C. difficile (MIC90 = 0.5 mg/L) and other Gram-positive bacteria, including Enterococcus spp. (E. faecium, E. faecalis and VRE).9,12 Surotomycin demonstrated poor activity against facultative and obligate anaerobic Gram-negative organisms including the Bacteroides fragilis group, Prevotella spp., Porphyromonas spp., Fusobacterium spp., Veillonella spp. and Acidaminococcus spp.12–15 The surotomycin development programme hypothesized that the preservation of these bacteria would reduce CDI recurrence.
In Phase 1 studies, surotomycin was well tolerated following single oral doses of up to 4 g and multiple doses of up to 1 g twice daily for 14 days in healthy volunteers.15 Surotomycin undergoes minimal systemic absorption and the faeces is the primary route of elimination following oral administration.16 Furthermore, in a Phase 2 clinical trial, surotomycin demonstrated greater efficacy at achieving sustained response compared with vancomycin (clinicaltrials.gov reference: NCT01085591).17 To further evaluate the factors contributing to an improved sustained response, this single-centre substudy evaluated the impact of surotomycin on the normal intestinal microbiota compared with vancomycin by quantitative PCR (qPCR), the in vivo activity of surotomycin against C. difficile (spores and vegetative cells) and if antibiotic resistant organisms are selected during treatment.
Surotomycin ultimately failed to meet the primary efficacy endpoint of a Phase 3 trial18 and the surotomycin development programme has been discontinued. Herein, we report results of the Phase 2 substudy to determine if findings could have been predictive of outcomes, which could be useful to guide future studies.
Patients and methods
Ethics
This research was conducted in accordance with the Declaration of Helsinki, Good Clinical Practices and applicable regulatory requirements. The study protocol, consent forms and patient information were reviewed and approved according to local regulations, Institutional Review Boards and Research Ethics Boards before trial initiation. All patients provided written informed consent to participate.
Study design and participants
This single-centre cohort was composed of a subset of a randomized, double-blind, single-dummy, active-controlled, dose-ranging, parallel-group, Phase 2 trial of surotomycin versus vancomycin in patients with CDI (protocol number LCD-DR-09-03).17 The multicentre study was conducted between April 2010 and May 2011. The inclusion criteria, randomization process and blinding procedure for the main Phase 2 trial were previously described in detail.17 Briefly, patients ≥18 years of age with non-severe or severe CDI were enrolled in the US and Canada. The patients were randomized 1:1:1 to receive surotomycin 125 mg twice daily, surotomycin 250 mg twice daily or vancomycin 125 mg four times daily for 10 days. All patients, study staff and sponsors remained blinded to treatment assignments for the duration of the study. The cohort used in the substudy included 26 patients treated with surotomycin [125 mg twice daily (n = 9) or 250 mg twice daily (n = 9)] or oral vancomycin [125 mg four times daily (n = 8)] for 10 days at the Foothills Medical Centre, Calgary, Canada.
Faecal sample collection
Faecal samples, 5 g undiluted and 2.5 g in 2.5 mL brain heart infusion broth with 10% glycerol, were collected at day 0 (baseline) and at days 4, 10 (end of treatment), 14, 17, 21, 24, 28 and 40 ± 2. The faecal samples were subsequently frozen at –80 °C for qPCR testing and for screening of targeted antibiotic-resistant organisms. Prior to freezing, 1 g of faecal sample was diluted 10−2, 10−4, 10−6 onto cefoxitin cycloserine fructose agar (CCFA) to quantify total counts of C. difficile. An additional 1 g aliquot was mixed with 1 mL of 100% ethyl alcohol and incubated for 1 h at room temperature for quantitative C. difficile spore shock cultures on CCFA. C. difficile cell cytotoxicity neutralization assay toxin titres were determined by serial 2-fold dilutions of faecal filtrates onto Vero cell monolayers with antibody neutralization (Techlab, Blackburg, VA, USA).
qPCR microbiome profiles
Bacterial DNA from 200–400 mg faecal samples (exact amount determined) was extracted using the QIAamp DNA Stool Mini extraction kit (Mississauga, Ontario, Canada). The samples were added to lysis buffer along with 200 mg of zirconium beads (0.2 mm diameter) and bead-beaten for 2 min. Purified genomic DNA (gDNA) was eluted off the columns with 200 μL molecular grade water and checked for purity and concentration using a NanoDrop 2000 spectrophotometer (Thermo, Wilmington, DE, USA). Yield (ng of DNA/mg stool) was calculated before storing at –20 °C for later analysis.
Real-time qPCR was performed using a BioRad (Hercules, CA, USA) iQ5 Detection System (software version 2.0). Amplification and detection was carried out in 96-well plates with SYBR Green 2x PCR Master Mix (BioRad). Each sample (20 ng of total gDNA) was probed with 10 different sets of primers targeting the 16S rRNA gene of the target groups. The primers used were published probes for B. fragilis group, Bacteroides/Prevotella, Clostridium coccoides subgroup (Cluster XIV), Clostridium leptum subgroup (Cluster IV), Enterobacteriaceae, Veillonella spp., Desulfovibrio spp., Bifidobacterium spp., Enterococcus spp. and Lactobacillus spp. (Table 1).
Target group/sequence . | Standard . | Reference . |
---|---|---|
Bacteroides fragilis groupa (Bacteroides) | ||
forward-GAAGGTCCCCCACATTG | Bacteroides fragilis | 27 |
reverse-CAATCGGAGTTCTTCGTG | 28 | |
Bacteroides/Prevotella | ||
forward-GTAGGGGTTCTGAGAGGA | Prevotella oris | probeBase pB-45 |
reverse-AGCTGCCTTCGCAATCGG | probeBase pB-47 | |
Clostridium coccoides (Cluster XIV) | ||
forward-ACTCCTACGGGAGGCAGC | Ruminococcus productus | probeBase pB-963 |
reverse-GCTTCTTAGTCARGTACCG | probeBase pB-159 | |
Clostridium leptum (Cluster IV) | ||
forward-GCACAAGCAGTGGAGT | Clostridium leptum | 29 |
reverse-CTTCCTCCGTTTGTCAA | 29 | |
Enterobacteriaceae | ||
forward-CATTGACGTTACCCGCAGAAGAAGC | Escherichia coli | 27 |
reverse-CTCTACGAGACTCAAGCTTGC | 27 | |
Veillonella spp. | ||
forward-A(C/T)CAACCTGCCCTTCAGA | Veillonella parvula | 30 |
reverse-CGTCCCGATTAACAGAGCTT | 30 | |
Desulfovibrio spp. | ||
forward-GGTACCTTCAAAGGAAGCAC | Desulfovibrio vulgaris | 30 |
reverse-GGGATTTCACCCCTGACTTA | Hildenborough | 30 |
Bifidobacterium spp. | ||
forward-CGCGTCYGGTGTGAAAG | Bifidobacterium bifidum | 31 |
reverse-CCCCACATCCAGCATCCA | 31 | |
Enterococcus spp. | ||
forward-CCCTTATTGTTAGTTGCCATCATT | Enterococcus faecium | 30 |
reverse-ACTCGTTGTACTTCCCATTGT | 30 | |
Lactobacillus spp. | ||
forward-TCCTACGGGAGGCAGCAGT | Lactobacillus acidophilus | 32 |
reverse-TGGAAGATTCCCTACTGC | probeBase pB-195 |
Target group/sequence . | Standard . | Reference . |
---|---|---|
Bacteroides fragilis groupa (Bacteroides) | ||
forward-GAAGGTCCCCCACATTG | Bacteroides fragilis | 27 |
reverse-CAATCGGAGTTCTTCGTG | 28 | |
Bacteroides/Prevotella | ||
forward-GTAGGGGTTCTGAGAGGA | Prevotella oris | probeBase pB-45 |
reverse-AGCTGCCTTCGCAATCGG | probeBase pB-47 | |
Clostridium coccoides (Cluster XIV) | ||
forward-ACTCCTACGGGAGGCAGC | Ruminococcus productus | probeBase pB-963 |
reverse-GCTTCTTAGTCARGTACCG | probeBase pB-159 | |
Clostridium leptum (Cluster IV) | ||
forward-GCACAAGCAGTGGAGT | Clostridium leptum | 29 |
reverse-CTTCCTCCGTTTGTCAA | 29 | |
Enterobacteriaceae | ||
forward-CATTGACGTTACCCGCAGAAGAAGC | Escherichia coli | 27 |
reverse-CTCTACGAGACTCAAGCTTGC | 27 | |
Veillonella spp. | ||
forward-A(C/T)CAACCTGCCCTTCAGA | Veillonella parvula | 30 |
reverse-CGTCCCGATTAACAGAGCTT | 30 | |
Desulfovibrio spp. | ||
forward-GGTACCTTCAAAGGAAGCAC | Desulfovibrio vulgaris | 30 |
reverse-GGGATTTCACCCCTGACTTA | Hildenborough | 30 |
Bifidobacterium spp. | ||
forward-CGCGTCYGGTGTGAAAG | Bifidobacterium bifidum | 31 |
reverse-CCCCACATCCAGCATCCA | 31 | |
Enterococcus spp. | ||
forward-CCCTTATTGTTAGTTGCCATCATT | Enterococcus faecium | 30 |
reverse-ACTCGTTGTACTTCCCATTGT | 30 | |
Lactobacillus spp. | ||
forward-TCCTACGGGAGGCAGCAGT | Lactobacillus acidophilus | 32 |
reverse-TGGAAGATTCCCTACTGC | probeBase pB-195 |
RT qPCR, real-time quantitative PCR; R indicates a purine nucleotide; Y indicates a pyrimidine nucleotide.
Bacteroides fragilis primer also targeted other members of the Bacteroides genus and not strictly B. fragilis. B. fragilis group and Bacteroides are used interchangeably throughout this publication.
Target group/sequence . | Standard . | Reference . |
---|---|---|
Bacteroides fragilis groupa (Bacteroides) | ||
forward-GAAGGTCCCCCACATTG | Bacteroides fragilis | 27 |
reverse-CAATCGGAGTTCTTCGTG | 28 | |
Bacteroides/Prevotella | ||
forward-GTAGGGGTTCTGAGAGGA | Prevotella oris | probeBase pB-45 |
reverse-AGCTGCCTTCGCAATCGG | probeBase pB-47 | |
Clostridium coccoides (Cluster XIV) | ||
forward-ACTCCTACGGGAGGCAGC | Ruminococcus productus | probeBase pB-963 |
reverse-GCTTCTTAGTCARGTACCG | probeBase pB-159 | |
Clostridium leptum (Cluster IV) | ||
forward-GCACAAGCAGTGGAGT | Clostridium leptum | 29 |
reverse-CTTCCTCCGTTTGTCAA | 29 | |
Enterobacteriaceae | ||
forward-CATTGACGTTACCCGCAGAAGAAGC | Escherichia coli | 27 |
reverse-CTCTACGAGACTCAAGCTTGC | 27 | |
Veillonella spp. | ||
forward-A(C/T)CAACCTGCCCTTCAGA | Veillonella parvula | 30 |
reverse-CGTCCCGATTAACAGAGCTT | 30 | |
Desulfovibrio spp. | ||
forward-GGTACCTTCAAAGGAAGCAC | Desulfovibrio vulgaris | 30 |
reverse-GGGATTTCACCCCTGACTTA | Hildenborough | 30 |
Bifidobacterium spp. | ||
forward-CGCGTCYGGTGTGAAAG | Bifidobacterium bifidum | 31 |
reverse-CCCCACATCCAGCATCCA | 31 | |
Enterococcus spp. | ||
forward-CCCTTATTGTTAGTTGCCATCATT | Enterococcus faecium | 30 |
reverse-ACTCGTTGTACTTCCCATTGT | 30 | |
Lactobacillus spp. | ||
forward-TCCTACGGGAGGCAGCAGT | Lactobacillus acidophilus | 32 |
reverse-TGGAAGATTCCCTACTGC | probeBase pB-195 |
Target group/sequence . | Standard . | Reference . |
---|---|---|
Bacteroides fragilis groupa (Bacteroides) | ||
forward-GAAGGTCCCCCACATTG | Bacteroides fragilis | 27 |
reverse-CAATCGGAGTTCTTCGTG | 28 | |
Bacteroides/Prevotella | ||
forward-GTAGGGGTTCTGAGAGGA | Prevotella oris | probeBase pB-45 |
reverse-AGCTGCCTTCGCAATCGG | probeBase pB-47 | |
Clostridium coccoides (Cluster XIV) | ||
forward-ACTCCTACGGGAGGCAGC | Ruminococcus productus | probeBase pB-963 |
reverse-GCTTCTTAGTCARGTACCG | probeBase pB-159 | |
Clostridium leptum (Cluster IV) | ||
forward-GCACAAGCAGTGGAGT | Clostridium leptum | 29 |
reverse-CTTCCTCCGTTTGTCAA | 29 | |
Enterobacteriaceae | ||
forward-CATTGACGTTACCCGCAGAAGAAGC | Escherichia coli | 27 |
reverse-CTCTACGAGACTCAAGCTTGC | 27 | |
Veillonella spp. | ||
forward-A(C/T)CAACCTGCCCTTCAGA | Veillonella parvula | 30 |
reverse-CGTCCCGATTAACAGAGCTT | 30 | |
Desulfovibrio spp. | ||
forward-GGTACCTTCAAAGGAAGCAC | Desulfovibrio vulgaris | 30 |
reverse-GGGATTTCACCCCTGACTTA | Hildenborough | 30 |
Bifidobacterium spp. | ||
forward-CGCGTCYGGTGTGAAAG | Bifidobacterium bifidum | 31 |
reverse-CCCCACATCCAGCATCCA | 31 | |
Enterococcus spp. | ||
forward-CCCTTATTGTTAGTTGCCATCATT | Enterococcus faecium | 30 |
reverse-ACTCGTTGTACTTCCCATTGT | 30 | |
Lactobacillus spp. | ||
forward-TCCTACGGGAGGCAGCAGT | Lactobacillus acidophilus | 32 |
reverse-TGGAAGATTCCCTACTGC | probeBase pB-195 |
RT qPCR, real-time quantitative PCR; R indicates a purine nucleotide; Y indicates a pyrimidine nucleotide.
Bacteroides fragilis primer also targeted other members of the Bacteroides genus and not strictly B. fragilis. B. fragilis group and Bacteroides are used interchangeably throughout this publication.
Samples were run in duplicate at a final volume of 20 μL with 0.3 μM final concentration of each primer and 5 μL of 4 ng/μL template gDNA. Internal controls (positive, negative and water controls) were run with each plate to control for potential inter-experiment differences. Amplifications were carried out using the following two-step template ramping profile: 1 cycle at 95 °C for 300 s, followed by 49 cycles of 95 °C for 30 s, 52–60 °C for 30 s and 72 °C for 30 s.
A melt step was added to determine amplification specificity. The specificity of the primers was first determined and optimized by using purified template DNA from reference strains for each of the 10 groups of bacteria. Melt curve analysis was also performed to ensure specificity of the primer sets. DNA extracted from reference strains, Enterococcus faecalis ATCC 29212, Bacteroides thetaiotaomicron ATCC 29741 and B. fragilis ATCC 25285, were included in each run to ensure reproducibility and consistency. The limit of detection for each assay was determined with concentrations of purified reference strain DNA (0.00002–20 ng). This range was also used to generate each standard curve using 10-fold dilutions (at least 5 standard dilutions).
To estimate the amounts of target bacterial DNA from faecal DNA extractions the threshold cycle values were first converted into genomic DNA copies using the standard curve generated from each qPCR run. For construction of standard curves, a series of 10-fold dilutions between 10−2 and 10−6 target genomes from reference species were prepared and run with samples.
Susceptibility testing
MICs of surotomycin for C. difficile strains recovered from samples collected at baseline and at recurrence were determined according to CLSI M11-A8 2012 guidelines with adjustment of Ca2+ to 50 mg/L. After overnight thaw, faecal samples in brain heart infusion broth with 10% glycerol final concentration were screened for VRE, ESBL and AmpC-positive Gram-negative bacilli by overnight selective broth amplification cultures followed by plating and four-quadrant streaking onto selective agars. Samples showing any colonies of target organisms were reprocessed quantitatively to a final dilution of 10−2, 10−3, 10−5 or 10−7 onto m-Enterococcus agar with 6 mg/L vancomycin or MacConkey agar containing 2 mg/L cefazolin, 2 mg/L ceftriaxone or no added cephalosporin. Susceptibility testing for ESBL- and AmpC-producing organisms was performed according to CLSI M100-S23, based on potentiation of susceptibility to the β-lactam agent by inhibitor for ESBLs and lack thereof for presumed AmpC-producing organisms.
Quantification of faecal antibiotic concentrations by LC-MS/MS and by microbiological activity in faecal filtrates by bioassay
Three faecal sample timepoints, days 4, 10 and 14, were tested if sample was provided. Faecal samples were tested by liquid chromatography with LC-MS/MS at Tandem Laboratories, Salt Lake City, UT, USA. Faecal filtrate concentrations were measured in triplicate using Staphylococcus epidermidis ATCC 12228 as the indicator organism in 1.2% Brucella agar supplemented with 5% horse blood and 50 μg/mL calcium.
Statistical methods
The quantitative bacterial counts and calculated colony forming units (cfu) per gram of target organism group by qPCR were log-transformed and expressed as 16S rDNA copies/g faeces, after which changes in each time of collection were compared between surotomycin and vancomycin treatments, using Wilcoxon signed-rank tests for non-parametric data (GraphPad Prism v. 6; GraphPad, San Diego, CA, USA). A paired two-tailed t-test was performed between day samples of the different treatment arms. A P value of < 0.05 was considered statistically significant. Additionally, summary statistics of means and SDs were calculated for the data.
Results
Substudy population demographics
The demographics of the patients enrolled in this substudy are shown in Table 2. β-Lactam, lincosamide/macrolide, metronidazole and ciprofloxacin exposure, similar in each group, preceded development of CDI. Subjects with a prior CDI occurrence received a treatment course of metronidazole. Concomitant antimicrobial exposure during the study period was observed in one patient in the surotomycin 250 mg group who received co-trimoxazole treatment for 6 days; additionally, one patient in the vancomycin group received trimethoprim 200 mg twice daily for 16 days as treatment for urinary tract infection.
Characteristics . | Surotomycin 125 mg twice daily (n = 9) . | Surotomycin 250 mg twice daily (n = 9) . | Vancomycin 125 mg four times daily (n = 8) . |
---|---|---|---|
Gender | |||
female | 6 (66.7) | 6 (66.7) | 4 (50) |
male | 3 (33.3) | 3 (33.3) | 4 (50) |
Race | |||
Caucasian | 8 (88.9) | 7 (77.8) | 8 (100) |
First Nation | 1 (11.1) | 0 | 0 |
Asian | 0 | 2 (22.2) | 0 |
BMI, mean (SD), kg/m2 | 26.2 (5.4) | 23.8 (4.1) | 23.4 (3.0) |
Systemic concomitant antibiotic usea | 0 (0) | 1 (11.1) | 1 (12.5) |
Severity of CDIb | |||
severe | 0 (0) | 0 (0) | 0 (0) |
non-severe | 9 (100) | 9 (100) | 8 (100) |
Number of prior CDI episodes | |||
0 | 5 (55.6) | 7 (77.8) | 5 (62.5) |
1 | 4 (44.4) | 2 (22.2) | 3 (37.5) |
UBM on day 1,c mean (SD) | 7.0 (1.7) | 7.8 (2.1) | 8.1 (2.1) |
BI/NAP1/027 strain-positive | 1 (11.1) | 1 (11.1) | 1 (12.5) |
Characteristics . | Surotomycin 125 mg twice daily (n = 9) . | Surotomycin 250 mg twice daily (n = 9) . | Vancomycin 125 mg four times daily (n = 8) . |
---|---|---|---|
Gender | |||
female | 6 (66.7) | 6 (66.7) | 4 (50) |
male | 3 (33.3) | 3 (33.3) | 4 (50) |
Race | |||
Caucasian | 8 (88.9) | 7 (77.8) | 8 (100) |
First Nation | 1 (11.1) | 0 | 0 |
Asian | 0 | 2 (22.2) | 0 |
BMI, mean (SD), kg/m2 | 26.2 (5.4) | 23.8 (4.1) | 23.4 (3.0) |
Systemic concomitant antibiotic usea | 0 (0) | 1 (11.1) | 1 (12.5) |
Severity of CDIb | |||
severe | 0 (0) | 0 (0) | 0 (0) |
non-severe | 9 (100) | 9 (100) | 8 (100) |
Number of prior CDI episodes | |||
0 | 5 (55.6) | 7 (77.8) | 5 (62.5) |
1 | 4 (44.4) | 2 (22.2) | 3 (37.5) |
UBM on day 1,c mean (SD) | 7.0 (1.7) | 7.8 (2.1) | 8.1 (2.1) |
BI/NAP1/027 strain-positive | 1 (11.1) | 1 (11.1) | 1 (12.5) |
Data are presented as n (%) unless otherwise indicated. CDI, C. difficile infection; modified intent-to-treat population, enrolled and randomized patients who received any amount of study drug; UBM, unformed bowel movement.
Any antibiotic received from first dose of study drug to the end of follow-up.
Severity defined using the modified Zar criteria.33
Does not include patients using a collection device. Number of UBMs at baseline was not recorded in the database.
Characteristics . | Surotomycin 125 mg twice daily (n = 9) . | Surotomycin 250 mg twice daily (n = 9) . | Vancomycin 125 mg four times daily (n = 8) . |
---|---|---|---|
Gender | |||
female | 6 (66.7) | 6 (66.7) | 4 (50) |
male | 3 (33.3) | 3 (33.3) | 4 (50) |
Race | |||
Caucasian | 8 (88.9) | 7 (77.8) | 8 (100) |
First Nation | 1 (11.1) | 0 | 0 |
Asian | 0 | 2 (22.2) | 0 |
BMI, mean (SD), kg/m2 | 26.2 (5.4) | 23.8 (4.1) | 23.4 (3.0) |
Systemic concomitant antibiotic usea | 0 (0) | 1 (11.1) | 1 (12.5) |
Severity of CDIb | |||
severe | 0 (0) | 0 (0) | 0 (0) |
non-severe | 9 (100) | 9 (100) | 8 (100) |
Number of prior CDI episodes | |||
0 | 5 (55.6) | 7 (77.8) | 5 (62.5) |
1 | 4 (44.4) | 2 (22.2) | 3 (37.5) |
UBM on day 1,c mean (SD) | 7.0 (1.7) | 7.8 (2.1) | 8.1 (2.1) |
BI/NAP1/027 strain-positive | 1 (11.1) | 1 (11.1) | 1 (12.5) |
Characteristics . | Surotomycin 125 mg twice daily (n = 9) . | Surotomycin 250 mg twice daily (n = 9) . | Vancomycin 125 mg four times daily (n = 8) . |
---|---|---|---|
Gender | |||
female | 6 (66.7) | 6 (66.7) | 4 (50) |
male | 3 (33.3) | 3 (33.3) | 4 (50) |
Race | |||
Caucasian | 8 (88.9) | 7 (77.8) | 8 (100) |
First Nation | 1 (11.1) | 0 | 0 |
Asian | 0 | 2 (22.2) | 0 |
BMI, mean (SD), kg/m2 | 26.2 (5.4) | 23.8 (4.1) | 23.4 (3.0) |
Systemic concomitant antibiotic usea | 0 (0) | 1 (11.1) | 1 (12.5) |
Severity of CDIb | |||
severe | 0 (0) | 0 (0) | 0 (0) |
non-severe | 9 (100) | 9 (100) | 8 (100) |
Number of prior CDI episodes | |||
0 | 5 (55.6) | 7 (77.8) | 5 (62.5) |
1 | 4 (44.4) | 2 (22.2) | 3 (37.5) |
UBM on day 1,c mean (SD) | 7.0 (1.7) | 7.8 (2.1) | 8.1 (2.1) |
BI/NAP1/027 strain-positive | 1 (11.1) | 1 (11.1) | 1 (12.5) |
Data are presented as n (%) unless otherwise indicated. CDI, C. difficile infection; modified intent-to-treat population, enrolled and randomized patients who received any amount of study drug; UBM, unformed bowel movement.
Any antibiotic received from first dose of study drug to the end of follow-up.
Severity defined using the modified Zar criteria.33
Does not include patients using a collection device. Number of UBMs at baseline was not recorded in the database.
Clinical outcomes and changes in pathogen counts
At baseline, C. difficile was recovered from 25/26 patients and C. difficile toxin was detected in 19/26 patients. Clinical cure was achieved in 25/26 patients; one patient receiving surotomycin 125 mg twice daily was considered a clinical protocol failure. In this patient, C. difficile culture at days 8 and 11 showed 105 and 106.5 cfu/g total counts, respectively. In all other samples, serial quantitative cultures of C. difficile showed that surotomycin and vancomycin exposure significantly reduced C. difficile counts by the end of treatment (day 10) (Table 3). The quantity of vegetative C. difficile cultured from samples collected at the end of treatment from patients receiving surotomycin 125 mg twice daily appeared to be on average ∼10-fold higher compared with counts from patients dosed with surotomycin 250 mg twice daily or vancomycin 125 mg four times daily (P = 0.08). By 4 days after the end of treatment (day 14), counts of C. difficile had risen such that no difference was observed between baseline and end of treatment in patients receiving surotomycin 125 mg twice daily (P = 0.38). Apparent spore counts were 2.5–3.0 log10 lower than total counts and were significantly reduced by all treatments by day 10 (P ≤ 0.02). Recurrence of CDI was observed in 4/8 patients receiving surotomycin 125 mg twice daily at days 13, 20, 24 and 34; in 3/9 patients receiving surotomycin 250 mg twice daily at days 23, 27 and 28; and in 1/8 patients receiving vancomycin 125 mg four times daily at day 16. Comparing 8 subjects who suffered recurrences with 17 who did not, 8/8 recurrent subjects’ C. difficile counts rose prior to and at recurrence of CDI to a C. difficile mean count of 6.7 log10 with median toxin cell cytotoxicity neutralization assay titres of 2000 (range 20 − 4000). Of 17 subjects who did not suffer a recurrence, C. difficile counts in the post-treatment period remained generally low, or showed transient rises in 1/3 of subjects and toxin was detected in 4/17 subjects between days 23 and 35 with titres of 200, 200, 1000 and 4000 (P < 0.0005 comparing differences in toxin re-expression in recurrent versus non-recurrent subjects in the post-treatment period).
. | Mean log10 cfu/g ± SD . | ||||||
---|---|---|---|---|---|---|---|
Genera/treatment . | Day 0 . | Day 4 . | Day 10 . | Day 14 . | Day 21 . | Day 28 . | Day 42 . |
C. difficile vegetative cells | |||||||
SUR 125 mg 2× dailya | 5.4 ± 2.1 | 2.3 ± 0.6 | 3.1 ± 1.9* | 4.4 ± 2.3 | 2.9 ± 1.5 | 2.6 ± 0.7 | 3.4 ±2.9 |
SUR 250 mg 2× dailyb | 6.4 ± 0.9 | 2.9 ± 1.2 | 2.0 ± 0.6* | 2.0 ± 0.0 | 3.6 ± 2.3 | 3.9 ± 2.3 | 2.7 ±1.3 |
VAN 125 mg 4× dailyc | 5.8 ± 2.0 | 2.6 ± 1.1 | 2.0 ± 0.0* | 2.0 ± 0.0 | 1.8 ± 0.4 | 2.9 ± 1.1 | 3.4 ± 1.9 |
C. difficile spores | |||||||
SUR 125 mg 2× daily | 4.0 ± 1.4 | 2.4 ± 1.7 | 2.2 ± 0.5* | 3.3 ± 1.5 | 3.3 ± 1.5 | 3.4 ± 1.6 | 3.2 ± 1.8 |
SUR 250 mg 2× daily | 4.4 ± 1.4 | 1.5 ± 1.0 | 2.4 ± 1.2* | 2.4 ± 0.7 | 4.0 ± 1.2 | 3.6 ± 1.8 | 2.7 ± 1.7 |
VAN 125 mg 4× daily | 4.1 ± 1.7 | 2.2 ± 1.4 | 2.1 ± 0.4* | 2.7 ± 1.5 | 3.6 ± 1.0 | 3.2 ± 1.3 | 2.9 ± 1.3 |
B. fragilis group (Bacteroides) | |||||||
SUR 125 mg 2× daily | 7.7 ± 1.8 | 7.9 ± 1.9 | 8.6 ± 1.7 | 8.5 ± 1.9 | 8.5 ± 2.2 | 8.7 ± 2.0 | 8.4 ± 1.3 |
SUR 250 mg 2× daily | 8.2 ± 1.3 | 8.1 ± 1.4 | 8.2 ± 1.3 | 8.3 ± 1.7 | 8.6 ± 1.1 | 8.5 ± 1.6 | 6.6 ± 2.6 |
VAN 125 mg 4× daily | 8.2 ± 2.0 | 5.9 ± 0.9* | 5.5 ± 0.9* | 6.2 ± 1.7* | 6.9 ± 0.8 | 7.7 ± 1.6 | 6.9 ± 2.0 |
Bacteroides/Prevotella | |||||||
SUR 125 mg 2× daily | 7.8 ± 1.6 | 7.9 ± 2.2 | 8.5 ± 1.7 | 8.5 ± 1.8 | 8.6 ± 1.9 | 8.5 ± 1.7 | 8.2 ± 1.6 |
SUR 250 mg 2× daily | 8.2 ± 1.4 | 8.0 ± 1.3 | 8.0 ± 1.8 | 8.7 ± 1.1 | 8.8 ± 1.0 | 8.3 ± 2.0 | 7.3 ± 1.8 |
VAN 125 mg 4× daily | 7.9 ± 2.1 | 5.7 ± 1.8* | 4.8 ± 1.8* | 6.0 ± 1.5* | 6.9 ± 1.4 | 7.5 ± 1.5 | 6.6 ± 2.0 |
C. coccoides | |||||||
SUR 125 mg 2× daily | 7.8 ± 1.5 | 6.6 ± 1.1 | 6.8 ± 0.7* | 7.8 ± 1.1 | 9.1 ± 0.3 | 8.6 ± 0.4 | 8.1 ± 0.8 |
SUR 250 mg 2× daily | 7.5 ± 1.2 | 6.0 ± 1.2* | 6.0 ± 0.6* | 6.5 ± 1.1 | 8.4 ± 0.6 | 8.3 ± 0.7 | 8.5 ± 0.8 |
VAN 125 mg 4× daily | 8.1 ± 1.4 | 6.6 ± 1.9 | 5.6 ± 0.6* | 6.4 ± 1.9 | 8.5 ± 0.5 | 8.8 ± 0.4 | 8.5 ± 0.7 |
C. leptum | |||||||
SUR 125 mg 2× daily | 6.4 ± 1.6 | 4.6 ± 1.0* | 5.5 ± 1.2 | 5.4 ± 1.7 | 6.1 ± 1.9 | 6.4 ± 0.6 | 5.9 ± 1.4 |
SUR 250 mg 2× daily | 6.1 ± 1.3 | 4.0 ± 1.4* | 4.3 ± 1.4* | 4.5 ± 1.1* | 5.2 ± 1.5 | 5.8 ± 0.9 | 5.9 ± 1.7 |
VAN 125 mg 4× daily | 6.0 ± 1.5 | 4.3 ± 2.1* | 3.4 ± 0.5* | 3.8 ± 1.0* | 5.6 ± 0.8 | 6.2 ± 1.4 | 5.5 ± 1.1 |
Enterobacteriaceae | |||||||
SUR 125 mg 2× daily | 7.7 ± 1.6 | 9.1 ± 0.4* | 9.4 ± 0.2* | 8.9 ± 0.6 | 8.2 ± 0.3 | 8.2 ± 0.2 | 7.3 ± 1.0 |
SUR 250 mg 2× daily | 8.5 ± 1.1 | 9.3 ± 0.4* | 9.2 ± 0.7 | 8.5 ± 1.4 | 8.4 ± 0.8 | 7.8 ± 1.0 | 8.0 ± 1.2 |
VAN 125 mg 4× daily | 8.4 ± 1.3 | 8.2 ± 1.4 | 8.4 ± 0.7 | 8.6 ± 0.9 | 8.4 ± 0.6 | 8.1 ± 0.8 | 8.1 ± 1.2 |
Enterococcus | |||||||
SUR 125 mg 2× daily | 5.1 ± 0.7 | 4.6 ± 0.4 | 4.6 ± 0.2 | 4.8 ± 0.5 | 6.3 ± 1.1 | 4.5 ± 0.8 | 3.1 ± 0.8 |
SUR 250 mg 2× daily | 5.8 ± 1.1 | 4.9 ± 0.8 | 4.4 ± 0.8 | 4.6 ± 0.3 | 5.5 ± 1.3 | 4.7 ± 0.6 | 3.8 ± 0.4 |
VAN 125 mg 4× daily | 5.4 ± 0.5 | 5.0 ± 1.0 | 4.5 ± 0.3 | 5.3 ± 1.0 | 5.3 ± 0.6 | 4.5 ± 1.4 | 4.2 ± 0.7 |
Lactobacillus | |||||||
SUR 125 mg 2× daily | 7.2 ± 0.6 | 7.2 ± 0.8 | 7.8 ± 0.7 | 7.8 ± 0.7 | 7.9 ± 0.3 | 8.3 ± 0.3 | 7.8 ± 0.8 |
SUR 250 mg 2× daily | 7.8 ± 0.9 | 7.2 ± 0.4 | 7.4 ± 0.7 | 7.1 ± 0.4 | 7.4 ± 0.5 | 7.6 ± 0.4 | 7.3 ± 0.8 |
VAN 125 mg 4× daily | 7.6 ± 0.8 | 7.6 ± 0.6 | 7.8 ± 0.7 | 8.1 ± 0.3 | 7.6 ± 0.6 | 7.5 ± 0.9 | 7.2 ± 1.1 |
Bifidobacteria | |||||||
SUR 125 mg 2× daily | 6.1 ± 1.1 | 4.9 ± 1.2 | 5.5 ± 1.4 | 6.1 ± 1.4 | 7.4 ± 0.2 | 6.1 ± 1.3 | 5.6 ± 1.2 |
SUR 250 mg 2× daily | 6.9 ± 1.1 | 5.8 ± 1.0 | 6.4 ± 1.3 | 6.2 ± 0.4 | 6.4 ± 1.2 | 6.0 ± 1.0 | 5.7 ± 1.4 |
VAN 125 mg 4× daily | 7.1 ± 0.5 | 5.7 ± 1.6 | 4.5 ± 0.4 | 5.9 ± 1.8 | 7.2 ± 0.9 | 6.7 ± 0.9 | 5.7 ± 1.2 |
Veillonella | |||||||
SUR 125 mg 2× daily | 6.7 ± 1.0 | 7.3 ± 0.7 | 7.3 ± 1.0 | 6.8 ± 1.6 | 6.4 ± 0.8 | 5.4 ± 1.3 | 5.2 ± 0.8 |
SUR 250 mg 2× daily | 7.5 ± 1.0 | 7.1 ± 1.1 | 6.7 ± 1.1 | 6.6 ± 1.0 | 6.0 ± 1.6 | 6.0 ± 1.8 | 6.2 ± 2.0 |
VAN 125 mg 4× daily | 7.7 ± 1.1 | 7.6 ± 1.3 | 7.9 ± 0.4 | 7.3 ± 0.9 | 7.2 ± 1.5 | 6.6 ± 0.8 | 5.7 ± 0.8 |
Desulfovibrio | |||||||
SUR 125 mg 2× daily | 3.8 ± 1.4 | 4.0 ± 1.8 | 4.2 ± 2.1 | 4.5 ± 1.7 | 5.3 ± 2.0 | 4.0 ± 3.7 | 3.6 ± 2.8 |
SUR 250 mg 2× daily | 4.0 ± 1.6 | 3.6 ± 1.7 | 3.8 ± 1.5 | 3.9 ± 2.0 | 3.8 ± 2.0 | 4.0 ± 2.1 | 2.4 ± 1.0 |
VAN 125 mg 4× daily | 3.5±1.3 | 3.6±0.7 | 3.5±1.4 | 3.5±1.4 | 2.8±0.6 | 3.6±0.9 | 4.1±1.3 |
. | Mean log10 cfu/g ± SD . | ||||||
---|---|---|---|---|---|---|---|
Genera/treatment . | Day 0 . | Day 4 . | Day 10 . | Day 14 . | Day 21 . | Day 28 . | Day 42 . |
C. difficile vegetative cells | |||||||
SUR 125 mg 2× dailya | 5.4 ± 2.1 | 2.3 ± 0.6 | 3.1 ± 1.9* | 4.4 ± 2.3 | 2.9 ± 1.5 | 2.6 ± 0.7 | 3.4 ±2.9 |
SUR 250 mg 2× dailyb | 6.4 ± 0.9 | 2.9 ± 1.2 | 2.0 ± 0.6* | 2.0 ± 0.0 | 3.6 ± 2.3 | 3.9 ± 2.3 | 2.7 ±1.3 |
VAN 125 mg 4× dailyc | 5.8 ± 2.0 | 2.6 ± 1.1 | 2.0 ± 0.0* | 2.0 ± 0.0 | 1.8 ± 0.4 | 2.9 ± 1.1 | 3.4 ± 1.9 |
C. difficile spores | |||||||
SUR 125 mg 2× daily | 4.0 ± 1.4 | 2.4 ± 1.7 | 2.2 ± 0.5* | 3.3 ± 1.5 | 3.3 ± 1.5 | 3.4 ± 1.6 | 3.2 ± 1.8 |
SUR 250 mg 2× daily | 4.4 ± 1.4 | 1.5 ± 1.0 | 2.4 ± 1.2* | 2.4 ± 0.7 | 4.0 ± 1.2 | 3.6 ± 1.8 | 2.7 ± 1.7 |
VAN 125 mg 4× daily | 4.1 ± 1.7 | 2.2 ± 1.4 | 2.1 ± 0.4* | 2.7 ± 1.5 | 3.6 ± 1.0 | 3.2 ± 1.3 | 2.9 ± 1.3 |
B. fragilis group (Bacteroides) | |||||||
SUR 125 mg 2× daily | 7.7 ± 1.8 | 7.9 ± 1.9 | 8.6 ± 1.7 | 8.5 ± 1.9 | 8.5 ± 2.2 | 8.7 ± 2.0 | 8.4 ± 1.3 |
SUR 250 mg 2× daily | 8.2 ± 1.3 | 8.1 ± 1.4 | 8.2 ± 1.3 | 8.3 ± 1.7 | 8.6 ± 1.1 | 8.5 ± 1.6 | 6.6 ± 2.6 |
VAN 125 mg 4× daily | 8.2 ± 2.0 | 5.9 ± 0.9* | 5.5 ± 0.9* | 6.2 ± 1.7* | 6.9 ± 0.8 | 7.7 ± 1.6 | 6.9 ± 2.0 |
Bacteroides/Prevotella | |||||||
SUR 125 mg 2× daily | 7.8 ± 1.6 | 7.9 ± 2.2 | 8.5 ± 1.7 | 8.5 ± 1.8 | 8.6 ± 1.9 | 8.5 ± 1.7 | 8.2 ± 1.6 |
SUR 250 mg 2× daily | 8.2 ± 1.4 | 8.0 ± 1.3 | 8.0 ± 1.8 | 8.7 ± 1.1 | 8.8 ± 1.0 | 8.3 ± 2.0 | 7.3 ± 1.8 |
VAN 125 mg 4× daily | 7.9 ± 2.1 | 5.7 ± 1.8* | 4.8 ± 1.8* | 6.0 ± 1.5* | 6.9 ± 1.4 | 7.5 ± 1.5 | 6.6 ± 2.0 |
C. coccoides | |||||||
SUR 125 mg 2× daily | 7.8 ± 1.5 | 6.6 ± 1.1 | 6.8 ± 0.7* | 7.8 ± 1.1 | 9.1 ± 0.3 | 8.6 ± 0.4 | 8.1 ± 0.8 |
SUR 250 mg 2× daily | 7.5 ± 1.2 | 6.0 ± 1.2* | 6.0 ± 0.6* | 6.5 ± 1.1 | 8.4 ± 0.6 | 8.3 ± 0.7 | 8.5 ± 0.8 |
VAN 125 mg 4× daily | 8.1 ± 1.4 | 6.6 ± 1.9 | 5.6 ± 0.6* | 6.4 ± 1.9 | 8.5 ± 0.5 | 8.8 ± 0.4 | 8.5 ± 0.7 |
C. leptum | |||||||
SUR 125 mg 2× daily | 6.4 ± 1.6 | 4.6 ± 1.0* | 5.5 ± 1.2 | 5.4 ± 1.7 | 6.1 ± 1.9 | 6.4 ± 0.6 | 5.9 ± 1.4 |
SUR 250 mg 2× daily | 6.1 ± 1.3 | 4.0 ± 1.4* | 4.3 ± 1.4* | 4.5 ± 1.1* | 5.2 ± 1.5 | 5.8 ± 0.9 | 5.9 ± 1.7 |
VAN 125 mg 4× daily | 6.0 ± 1.5 | 4.3 ± 2.1* | 3.4 ± 0.5* | 3.8 ± 1.0* | 5.6 ± 0.8 | 6.2 ± 1.4 | 5.5 ± 1.1 |
Enterobacteriaceae | |||||||
SUR 125 mg 2× daily | 7.7 ± 1.6 | 9.1 ± 0.4* | 9.4 ± 0.2* | 8.9 ± 0.6 | 8.2 ± 0.3 | 8.2 ± 0.2 | 7.3 ± 1.0 |
SUR 250 mg 2× daily | 8.5 ± 1.1 | 9.3 ± 0.4* | 9.2 ± 0.7 | 8.5 ± 1.4 | 8.4 ± 0.8 | 7.8 ± 1.0 | 8.0 ± 1.2 |
VAN 125 mg 4× daily | 8.4 ± 1.3 | 8.2 ± 1.4 | 8.4 ± 0.7 | 8.6 ± 0.9 | 8.4 ± 0.6 | 8.1 ± 0.8 | 8.1 ± 1.2 |
Enterococcus | |||||||
SUR 125 mg 2× daily | 5.1 ± 0.7 | 4.6 ± 0.4 | 4.6 ± 0.2 | 4.8 ± 0.5 | 6.3 ± 1.1 | 4.5 ± 0.8 | 3.1 ± 0.8 |
SUR 250 mg 2× daily | 5.8 ± 1.1 | 4.9 ± 0.8 | 4.4 ± 0.8 | 4.6 ± 0.3 | 5.5 ± 1.3 | 4.7 ± 0.6 | 3.8 ± 0.4 |
VAN 125 mg 4× daily | 5.4 ± 0.5 | 5.0 ± 1.0 | 4.5 ± 0.3 | 5.3 ± 1.0 | 5.3 ± 0.6 | 4.5 ± 1.4 | 4.2 ± 0.7 |
Lactobacillus | |||||||
SUR 125 mg 2× daily | 7.2 ± 0.6 | 7.2 ± 0.8 | 7.8 ± 0.7 | 7.8 ± 0.7 | 7.9 ± 0.3 | 8.3 ± 0.3 | 7.8 ± 0.8 |
SUR 250 mg 2× daily | 7.8 ± 0.9 | 7.2 ± 0.4 | 7.4 ± 0.7 | 7.1 ± 0.4 | 7.4 ± 0.5 | 7.6 ± 0.4 | 7.3 ± 0.8 |
VAN 125 mg 4× daily | 7.6 ± 0.8 | 7.6 ± 0.6 | 7.8 ± 0.7 | 8.1 ± 0.3 | 7.6 ± 0.6 | 7.5 ± 0.9 | 7.2 ± 1.1 |
Bifidobacteria | |||||||
SUR 125 mg 2× daily | 6.1 ± 1.1 | 4.9 ± 1.2 | 5.5 ± 1.4 | 6.1 ± 1.4 | 7.4 ± 0.2 | 6.1 ± 1.3 | 5.6 ± 1.2 |
SUR 250 mg 2× daily | 6.9 ± 1.1 | 5.8 ± 1.0 | 6.4 ± 1.3 | 6.2 ± 0.4 | 6.4 ± 1.2 | 6.0 ± 1.0 | 5.7 ± 1.4 |
VAN 125 mg 4× daily | 7.1 ± 0.5 | 5.7 ± 1.6 | 4.5 ± 0.4 | 5.9 ± 1.8 | 7.2 ± 0.9 | 6.7 ± 0.9 | 5.7 ± 1.2 |
Veillonella | |||||||
SUR 125 mg 2× daily | 6.7 ± 1.0 | 7.3 ± 0.7 | 7.3 ± 1.0 | 6.8 ± 1.6 | 6.4 ± 0.8 | 5.4 ± 1.3 | 5.2 ± 0.8 |
SUR 250 mg 2× daily | 7.5 ± 1.0 | 7.1 ± 1.1 | 6.7 ± 1.1 | 6.6 ± 1.0 | 6.0 ± 1.6 | 6.0 ± 1.8 | 6.2 ± 2.0 |
VAN 125 mg 4× daily | 7.7 ± 1.1 | 7.6 ± 1.3 | 7.9 ± 0.4 | 7.3 ± 0.9 | 7.2 ± 1.5 | 6.6 ± 0.8 | 5.7 ± 0.8 |
Desulfovibrio | |||||||
SUR 125 mg 2× daily | 3.8 ± 1.4 | 4.0 ± 1.8 | 4.2 ± 2.1 | 4.5 ± 1.7 | 5.3 ± 2.0 | 4.0 ± 3.7 | 3.6 ± 2.8 |
SUR 250 mg 2× daily | 4.0 ± 1.6 | 3.6 ± 1.7 | 3.8 ± 1.5 | 3.9 ± 2.0 | 3.8 ± 2.0 | 4.0 ± 2.1 | 2.4 ± 1.0 |
VAN 125 mg 4× daily | 3.5±1.3 | 3.6±0.7 | 3.5±1.4 | 3.5±1.4 | 2.8±0.6 | 3.6±0.9 | 4.1±1.3 |
P < 0.05 compared with baseline (day 0). Lower limit of quantification = 2.0 log10 cfu/g, values below the lower limit of quantification are presented as 2.0 log10 cfu/g; SUR, surotomycin; VAN, vancomycin.
Surotomycin 125 mg twice daily, number of cultures: day 0, n = 9; day 4, n = 9; day 10, n = 8; day 14, n = 7; day 21, n = 3; day 28, n = 4; day 42, n = 3.
Surotomycin 250 mg twice daily, number of cultures: day 0, n = 9; day 4, n = 9; day 10, n = 8; day 14, n = 7; day 21, n = 7; day 28, n = 5; day 42, n = 5.
Vancomycin 125 mg four times daily, number of cultures: day 0, n = 8; day 4, n = 8; day 10, n = 8; day 14, n = 7; day 21, n = 4; day 28, n = 6; day 42, n = 6.
. | Mean log10 cfu/g ± SD . | ||||||
---|---|---|---|---|---|---|---|
Genera/treatment . | Day 0 . | Day 4 . | Day 10 . | Day 14 . | Day 21 . | Day 28 . | Day 42 . |
C. difficile vegetative cells | |||||||
SUR 125 mg 2× dailya | 5.4 ± 2.1 | 2.3 ± 0.6 | 3.1 ± 1.9* | 4.4 ± 2.3 | 2.9 ± 1.5 | 2.6 ± 0.7 | 3.4 ±2.9 |
SUR 250 mg 2× dailyb | 6.4 ± 0.9 | 2.9 ± 1.2 | 2.0 ± 0.6* | 2.0 ± 0.0 | 3.6 ± 2.3 | 3.9 ± 2.3 | 2.7 ±1.3 |
VAN 125 mg 4× dailyc | 5.8 ± 2.0 | 2.6 ± 1.1 | 2.0 ± 0.0* | 2.0 ± 0.0 | 1.8 ± 0.4 | 2.9 ± 1.1 | 3.4 ± 1.9 |
C. difficile spores | |||||||
SUR 125 mg 2× daily | 4.0 ± 1.4 | 2.4 ± 1.7 | 2.2 ± 0.5* | 3.3 ± 1.5 | 3.3 ± 1.5 | 3.4 ± 1.6 | 3.2 ± 1.8 |
SUR 250 mg 2× daily | 4.4 ± 1.4 | 1.5 ± 1.0 | 2.4 ± 1.2* | 2.4 ± 0.7 | 4.0 ± 1.2 | 3.6 ± 1.8 | 2.7 ± 1.7 |
VAN 125 mg 4× daily | 4.1 ± 1.7 | 2.2 ± 1.4 | 2.1 ± 0.4* | 2.7 ± 1.5 | 3.6 ± 1.0 | 3.2 ± 1.3 | 2.9 ± 1.3 |
B. fragilis group (Bacteroides) | |||||||
SUR 125 mg 2× daily | 7.7 ± 1.8 | 7.9 ± 1.9 | 8.6 ± 1.7 | 8.5 ± 1.9 | 8.5 ± 2.2 | 8.7 ± 2.0 | 8.4 ± 1.3 |
SUR 250 mg 2× daily | 8.2 ± 1.3 | 8.1 ± 1.4 | 8.2 ± 1.3 | 8.3 ± 1.7 | 8.6 ± 1.1 | 8.5 ± 1.6 | 6.6 ± 2.6 |
VAN 125 mg 4× daily | 8.2 ± 2.0 | 5.9 ± 0.9* | 5.5 ± 0.9* | 6.2 ± 1.7* | 6.9 ± 0.8 | 7.7 ± 1.6 | 6.9 ± 2.0 |
Bacteroides/Prevotella | |||||||
SUR 125 mg 2× daily | 7.8 ± 1.6 | 7.9 ± 2.2 | 8.5 ± 1.7 | 8.5 ± 1.8 | 8.6 ± 1.9 | 8.5 ± 1.7 | 8.2 ± 1.6 |
SUR 250 mg 2× daily | 8.2 ± 1.4 | 8.0 ± 1.3 | 8.0 ± 1.8 | 8.7 ± 1.1 | 8.8 ± 1.0 | 8.3 ± 2.0 | 7.3 ± 1.8 |
VAN 125 mg 4× daily | 7.9 ± 2.1 | 5.7 ± 1.8* | 4.8 ± 1.8* | 6.0 ± 1.5* | 6.9 ± 1.4 | 7.5 ± 1.5 | 6.6 ± 2.0 |
C. coccoides | |||||||
SUR 125 mg 2× daily | 7.8 ± 1.5 | 6.6 ± 1.1 | 6.8 ± 0.7* | 7.8 ± 1.1 | 9.1 ± 0.3 | 8.6 ± 0.4 | 8.1 ± 0.8 |
SUR 250 mg 2× daily | 7.5 ± 1.2 | 6.0 ± 1.2* | 6.0 ± 0.6* | 6.5 ± 1.1 | 8.4 ± 0.6 | 8.3 ± 0.7 | 8.5 ± 0.8 |
VAN 125 mg 4× daily | 8.1 ± 1.4 | 6.6 ± 1.9 | 5.6 ± 0.6* | 6.4 ± 1.9 | 8.5 ± 0.5 | 8.8 ± 0.4 | 8.5 ± 0.7 |
C. leptum | |||||||
SUR 125 mg 2× daily | 6.4 ± 1.6 | 4.6 ± 1.0* | 5.5 ± 1.2 | 5.4 ± 1.7 | 6.1 ± 1.9 | 6.4 ± 0.6 | 5.9 ± 1.4 |
SUR 250 mg 2× daily | 6.1 ± 1.3 | 4.0 ± 1.4* | 4.3 ± 1.4* | 4.5 ± 1.1* | 5.2 ± 1.5 | 5.8 ± 0.9 | 5.9 ± 1.7 |
VAN 125 mg 4× daily | 6.0 ± 1.5 | 4.3 ± 2.1* | 3.4 ± 0.5* | 3.8 ± 1.0* | 5.6 ± 0.8 | 6.2 ± 1.4 | 5.5 ± 1.1 |
Enterobacteriaceae | |||||||
SUR 125 mg 2× daily | 7.7 ± 1.6 | 9.1 ± 0.4* | 9.4 ± 0.2* | 8.9 ± 0.6 | 8.2 ± 0.3 | 8.2 ± 0.2 | 7.3 ± 1.0 |
SUR 250 mg 2× daily | 8.5 ± 1.1 | 9.3 ± 0.4* | 9.2 ± 0.7 | 8.5 ± 1.4 | 8.4 ± 0.8 | 7.8 ± 1.0 | 8.0 ± 1.2 |
VAN 125 mg 4× daily | 8.4 ± 1.3 | 8.2 ± 1.4 | 8.4 ± 0.7 | 8.6 ± 0.9 | 8.4 ± 0.6 | 8.1 ± 0.8 | 8.1 ± 1.2 |
Enterococcus | |||||||
SUR 125 mg 2× daily | 5.1 ± 0.7 | 4.6 ± 0.4 | 4.6 ± 0.2 | 4.8 ± 0.5 | 6.3 ± 1.1 | 4.5 ± 0.8 | 3.1 ± 0.8 |
SUR 250 mg 2× daily | 5.8 ± 1.1 | 4.9 ± 0.8 | 4.4 ± 0.8 | 4.6 ± 0.3 | 5.5 ± 1.3 | 4.7 ± 0.6 | 3.8 ± 0.4 |
VAN 125 mg 4× daily | 5.4 ± 0.5 | 5.0 ± 1.0 | 4.5 ± 0.3 | 5.3 ± 1.0 | 5.3 ± 0.6 | 4.5 ± 1.4 | 4.2 ± 0.7 |
Lactobacillus | |||||||
SUR 125 mg 2× daily | 7.2 ± 0.6 | 7.2 ± 0.8 | 7.8 ± 0.7 | 7.8 ± 0.7 | 7.9 ± 0.3 | 8.3 ± 0.3 | 7.8 ± 0.8 |
SUR 250 mg 2× daily | 7.8 ± 0.9 | 7.2 ± 0.4 | 7.4 ± 0.7 | 7.1 ± 0.4 | 7.4 ± 0.5 | 7.6 ± 0.4 | 7.3 ± 0.8 |
VAN 125 mg 4× daily | 7.6 ± 0.8 | 7.6 ± 0.6 | 7.8 ± 0.7 | 8.1 ± 0.3 | 7.6 ± 0.6 | 7.5 ± 0.9 | 7.2 ± 1.1 |
Bifidobacteria | |||||||
SUR 125 mg 2× daily | 6.1 ± 1.1 | 4.9 ± 1.2 | 5.5 ± 1.4 | 6.1 ± 1.4 | 7.4 ± 0.2 | 6.1 ± 1.3 | 5.6 ± 1.2 |
SUR 250 mg 2× daily | 6.9 ± 1.1 | 5.8 ± 1.0 | 6.4 ± 1.3 | 6.2 ± 0.4 | 6.4 ± 1.2 | 6.0 ± 1.0 | 5.7 ± 1.4 |
VAN 125 mg 4× daily | 7.1 ± 0.5 | 5.7 ± 1.6 | 4.5 ± 0.4 | 5.9 ± 1.8 | 7.2 ± 0.9 | 6.7 ± 0.9 | 5.7 ± 1.2 |
Veillonella | |||||||
SUR 125 mg 2× daily | 6.7 ± 1.0 | 7.3 ± 0.7 | 7.3 ± 1.0 | 6.8 ± 1.6 | 6.4 ± 0.8 | 5.4 ± 1.3 | 5.2 ± 0.8 |
SUR 250 mg 2× daily | 7.5 ± 1.0 | 7.1 ± 1.1 | 6.7 ± 1.1 | 6.6 ± 1.0 | 6.0 ± 1.6 | 6.0 ± 1.8 | 6.2 ± 2.0 |
VAN 125 mg 4× daily | 7.7 ± 1.1 | 7.6 ± 1.3 | 7.9 ± 0.4 | 7.3 ± 0.9 | 7.2 ± 1.5 | 6.6 ± 0.8 | 5.7 ± 0.8 |
Desulfovibrio | |||||||
SUR 125 mg 2× daily | 3.8 ± 1.4 | 4.0 ± 1.8 | 4.2 ± 2.1 | 4.5 ± 1.7 | 5.3 ± 2.0 | 4.0 ± 3.7 | 3.6 ± 2.8 |
SUR 250 mg 2× daily | 4.0 ± 1.6 | 3.6 ± 1.7 | 3.8 ± 1.5 | 3.9 ± 2.0 | 3.8 ± 2.0 | 4.0 ± 2.1 | 2.4 ± 1.0 |
VAN 125 mg 4× daily | 3.5±1.3 | 3.6±0.7 | 3.5±1.4 | 3.5±1.4 | 2.8±0.6 | 3.6±0.9 | 4.1±1.3 |
. | Mean log10 cfu/g ± SD . | ||||||
---|---|---|---|---|---|---|---|
Genera/treatment . | Day 0 . | Day 4 . | Day 10 . | Day 14 . | Day 21 . | Day 28 . | Day 42 . |
C. difficile vegetative cells | |||||||
SUR 125 mg 2× dailya | 5.4 ± 2.1 | 2.3 ± 0.6 | 3.1 ± 1.9* | 4.4 ± 2.3 | 2.9 ± 1.5 | 2.6 ± 0.7 | 3.4 ±2.9 |
SUR 250 mg 2× dailyb | 6.4 ± 0.9 | 2.9 ± 1.2 | 2.0 ± 0.6* | 2.0 ± 0.0 | 3.6 ± 2.3 | 3.9 ± 2.3 | 2.7 ±1.3 |
VAN 125 mg 4× dailyc | 5.8 ± 2.0 | 2.6 ± 1.1 | 2.0 ± 0.0* | 2.0 ± 0.0 | 1.8 ± 0.4 | 2.9 ± 1.1 | 3.4 ± 1.9 |
C. difficile spores | |||||||
SUR 125 mg 2× daily | 4.0 ± 1.4 | 2.4 ± 1.7 | 2.2 ± 0.5* | 3.3 ± 1.5 | 3.3 ± 1.5 | 3.4 ± 1.6 | 3.2 ± 1.8 |
SUR 250 mg 2× daily | 4.4 ± 1.4 | 1.5 ± 1.0 | 2.4 ± 1.2* | 2.4 ± 0.7 | 4.0 ± 1.2 | 3.6 ± 1.8 | 2.7 ± 1.7 |
VAN 125 mg 4× daily | 4.1 ± 1.7 | 2.2 ± 1.4 | 2.1 ± 0.4* | 2.7 ± 1.5 | 3.6 ± 1.0 | 3.2 ± 1.3 | 2.9 ± 1.3 |
B. fragilis group (Bacteroides) | |||||||
SUR 125 mg 2× daily | 7.7 ± 1.8 | 7.9 ± 1.9 | 8.6 ± 1.7 | 8.5 ± 1.9 | 8.5 ± 2.2 | 8.7 ± 2.0 | 8.4 ± 1.3 |
SUR 250 mg 2× daily | 8.2 ± 1.3 | 8.1 ± 1.4 | 8.2 ± 1.3 | 8.3 ± 1.7 | 8.6 ± 1.1 | 8.5 ± 1.6 | 6.6 ± 2.6 |
VAN 125 mg 4× daily | 8.2 ± 2.0 | 5.9 ± 0.9* | 5.5 ± 0.9* | 6.2 ± 1.7* | 6.9 ± 0.8 | 7.7 ± 1.6 | 6.9 ± 2.0 |
Bacteroides/Prevotella | |||||||
SUR 125 mg 2× daily | 7.8 ± 1.6 | 7.9 ± 2.2 | 8.5 ± 1.7 | 8.5 ± 1.8 | 8.6 ± 1.9 | 8.5 ± 1.7 | 8.2 ± 1.6 |
SUR 250 mg 2× daily | 8.2 ± 1.4 | 8.0 ± 1.3 | 8.0 ± 1.8 | 8.7 ± 1.1 | 8.8 ± 1.0 | 8.3 ± 2.0 | 7.3 ± 1.8 |
VAN 125 mg 4× daily | 7.9 ± 2.1 | 5.7 ± 1.8* | 4.8 ± 1.8* | 6.0 ± 1.5* | 6.9 ± 1.4 | 7.5 ± 1.5 | 6.6 ± 2.0 |
C. coccoides | |||||||
SUR 125 mg 2× daily | 7.8 ± 1.5 | 6.6 ± 1.1 | 6.8 ± 0.7* | 7.8 ± 1.1 | 9.1 ± 0.3 | 8.6 ± 0.4 | 8.1 ± 0.8 |
SUR 250 mg 2× daily | 7.5 ± 1.2 | 6.0 ± 1.2* | 6.0 ± 0.6* | 6.5 ± 1.1 | 8.4 ± 0.6 | 8.3 ± 0.7 | 8.5 ± 0.8 |
VAN 125 mg 4× daily | 8.1 ± 1.4 | 6.6 ± 1.9 | 5.6 ± 0.6* | 6.4 ± 1.9 | 8.5 ± 0.5 | 8.8 ± 0.4 | 8.5 ± 0.7 |
C. leptum | |||||||
SUR 125 mg 2× daily | 6.4 ± 1.6 | 4.6 ± 1.0* | 5.5 ± 1.2 | 5.4 ± 1.7 | 6.1 ± 1.9 | 6.4 ± 0.6 | 5.9 ± 1.4 |
SUR 250 mg 2× daily | 6.1 ± 1.3 | 4.0 ± 1.4* | 4.3 ± 1.4* | 4.5 ± 1.1* | 5.2 ± 1.5 | 5.8 ± 0.9 | 5.9 ± 1.7 |
VAN 125 mg 4× daily | 6.0 ± 1.5 | 4.3 ± 2.1* | 3.4 ± 0.5* | 3.8 ± 1.0* | 5.6 ± 0.8 | 6.2 ± 1.4 | 5.5 ± 1.1 |
Enterobacteriaceae | |||||||
SUR 125 mg 2× daily | 7.7 ± 1.6 | 9.1 ± 0.4* | 9.4 ± 0.2* | 8.9 ± 0.6 | 8.2 ± 0.3 | 8.2 ± 0.2 | 7.3 ± 1.0 |
SUR 250 mg 2× daily | 8.5 ± 1.1 | 9.3 ± 0.4* | 9.2 ± 0.7 | 8.5 ± 1.4 | 8.4 ± 0.8 | 7.8 ± 1.0 | 8.0 ± 1.2 |
VAN 125 mg 4× daily | 8.4 ± 1.3 | 8.2 ± 1.4 | 8.4 ± 0.7 | 8.6 ± 0.9 | 8.4 ± 0.6 | 8.1 ± 0.8 | 8.1 ± 1.2 |
Enterococcus | |||||||
SUR 125 mg 2× daily | 5.1 ± 0.7 | 4.6 ± 0.4 | 4.6 ± 0.2 | 4.8 ± 0.5 | 6.3 ± 1.1 | 4.5 ± 0.8 | 3.1 ± 0.8 |
SUR 250 mg 2× daily | 5.8 ± 1.1 | 4.9 ± 0.8 | 4.4 ± 0.8 | 4.6 ± 0.3 | 5.5 ± 1.3 | 4.7 ± 0.6 | 3.8 ± 0.4 |
VAN 125 mg 4× daily | 5.4 ± 0.5 | 5.0 ± 1.0 | 4.5 ± 0.3 | 5.3 ± 1.0 | 5.3 ± 0.6 | 4.5 ± 1.4 | 4.2 ± 0.7 |
Lactobacillus | |||||||
SUR 125 mg 2× daily | 7.2 ± 0.6 | 7.2 ± 0.8 | 7.8 ± 0.7 | 7.8 ± 0.7 | 7.9 ± 0.3 | 8.3 ± 0.3 | 7.8 ± 0.8 |
SUR 250 mg 2× daily | 7.8 ± 0.9 | 7.2 ± 0.4 | 7.4 ± 0.7 | 7.1 ± 0.4 | 7.4 ± 0.5 | 7.6 ± 0.4 | 7.3 ± 0.8 |
VAN 125 mg 4× daily | 7.6 ± 0.8 | 7.6 ± 0.6 | 7.8 ± 0.7 | 8.1 ± 0.3 | 7.6 ± 0.6 | 7.5 ± 0.9 | 7.2 ± 1.1 |
Bifidobacteria | |||||||
SUR 125 mg 2× daily | 6.1 ± 1.1 | 4.9 ± 1.2 | 5.5 ± 1.4 | 6.1 ± 1.4 | 7.4 ± 0.2 | 6.1 ± 1.3 | 5.6 ± 1.2 |
SUR 250 mg 2× daily | 6.9 ± 1.1 | 5.8 ± 1.0 | 6.4 ± 1.3 | 6.2 ± 0.4 | 6.4 ± 1.2 | 6.0 ± 1.0 | 5.7 ± 1.4 |
VAN 125 mg 4× daily | 7.1 ± 0.5 | 5.7 ± 1.6 | 4.5 ± 0.4 | 5.9 ± 1.8 | 7.2 ± 0.9 | 6.7 ± 0.9 | 5.7 ± 1.2 |
Veillonella | |||||||
SUR 125 mg 2× daily | 6.7 ± 1.0 | 7.3 ± 0.7 | 7.3 ± 1.0 | 6.8 ± 1.6 | 6.4 ± 0.8 | 5.4 ± 1.3 | 5.2 ± 0.8 |
SUR 250 mg 2× daily | 7.5 ± 1.0 | 7.1 ± 1.1 | 6.7 ± 1.1 | 6.6 ± 1.0 | 6.0 ± 1.6 | 6.0 ± 1.8 | 6.2 ± 2.0 |
VAN 125 mg 4× daily | 7.7 ± 1.1 | 7.6 ± 1.3 | 7.9 ± 0.4 | 7.3 ± 0.9 | 7.2 ± 1.5 | 6.6 ± 0.8 | 5.7 ± 0.8 |
Desulfovibrio | |||||||
SUR 125 mg 2× daily | 3.8 ± 1.4 | 4.0 ± 1.8 | 4.2 ± 2.1 | 4.5 ± 1.7 | 5.3 ± 2.0 | 4.0 ± 3.7 | 3.6 ± 2.8 |
SUR 250 mg 2× daily | 4.0 ± 1.6 | 3.6 ± 1.7 | 3.8 ± 1.5 | 3.9 ± 2.0 | 3.8 ± 2.0 | 4.0 ± 2.1 | 2.4 ± 1.0 |
VAN 125 mg 4× daily | 3.5±1.3 | 3.6±0.7 | 3.5±1.4 | 3.5±1.4 | 2.8±0.6 | 3.6±0.9 | 4.1±1.3 |
P < 0.05 compared with baseline (day 0). Lower limit of quantification = 2.0 log10 cfu/g, values below the lower limit of quantification are presented as 2.0 log10 cfu/g; SUR, surotomycin; VAN, vancomycin.
Surotomycin 125 mg twice daily, number of cultures: day 0, n = 9; day 4, n = 9; day 10, n = 8; day 14, n = 7; day 21, n = 3; day 28, n = 4; day 42, n = 3.
Surotomycin 250 mg twice daily, number of cultures: day 0, n = 9; day 4, n = 9; day 10, n = 8; day 14, n = 7; day 21, n = 7; day 28, n = 5; day 42, n = 5.
Vancomycin 125 mg four times daily, number of cultures: day 0, n = 8; day 4, n = 8; day 10, n = 8; day 14, n = 7; day 21, n = 4; day 28, n = 6; day 42, n = 6.
Microbiota shifts
The mean log10 cfu/g ± SD of microbiota bacterial groups are shown in Table 3. Figure 1 shows mean counts of bacterial groups over time to assess the differential impact of the three treatment arms on specific bacterial groups. Figure 1(a) shows that both doses of surotomycin did not adversely affect Bacteroidetes or Prevotella counts. However, significant reduction of these groups was observed during vancomycin treatment at days 10 (P = 0.018 and 0.006, respectively) and 14 (P = 0.046 and 0.048, respectively) compared with baseline levels. This reduction did not recover by day 42. Figure 1(b) presents the effect of antibiotic exposure on the Firmicutes [C. coccoides (Clostridial cluster XIVa) and C. leptum (Clostridial cluster IV)] groups. Treatment with both doses of surotomycin and with vancomycin reduced Firmicutes counts, and the reduction was most pronounced during vancomycin treatment. Dose-dependent suppression of Firmicutes was observed with surotomycin treatment. Firmicutes recovered over a 7–10 day period. Treatment effects on Bifidobacterium spp. and Lactobacillus spp. are shown in Figure 1(c). Surotomycin treatment at both dosages reduced Bifidobacteria counts by ∼0.5 log10 and vancomycin decreased counts by ∼2 log10, but these differences were not significant (P values not shown). Lactobacillus counts were unchanged by all treatments, showing similar counts at baseline, end of treatment and after the end of treatment. Figure 1(d) shows the effect of treatments on Gram-negative enterics, including Enterobacteriaceae, Veillonella and Desulfovibrio species. High counts of Enterobacteriaceae and Veillonella associated with surotomycin appeared to decrease over time following the end of treatment on day 10, possibly reflecting the re-establishment of the protective microbiota. Mean enterococcal counts remained in the 104–106 cfu/g range in all groups over time.
Antimicrobial susceptibility of microflora
MICs of all C. difficile isolates tested for surotomycin and vancomycin were in the ranges 0.25–1 mg/L and 0.5–1 mg/L, respectively, with no change in susceptibility between baseline and recurrence MICs. As patients who suffered recurrences were treated with vancomycin, faecal samples were not further assessed, accounting for the reduction in numbers of tested samples.
Faecal acquisition of MRSA or VRE was not observed in any study patient. Overall, 11/26 (42%) patients were found to harbour/acquire ESBL (n = 2)/AmpC (n = 9) coliforms during the treatment interval in 4/9, 5/9 and 2/8 patients treated with surotomycin 125 mg twice daily, surotomycin 250 mg twice daily and vancomycin, respectively. The majority of ESBL/AmpC-positive isolates were present in low numbers (102–106 cfu/g) and were transient in nature. As this cohort of patients consisted of outpatients, the acquisition or clonal expansion of antibiotic-resistant microbes should have excluded transfer from the hospital environment or other patients.
Pharmacokinetics
Surotomycin and vancomycin concentrations in faecal filtrates measured by microbiological assay (Table 4) were consistently lower compared with results generated by LC-MS. Vancomycin concentrations are consistent with previously reported values.19 Day 4 versus day 10 samples were comparable for both treatments, indicating achievement of steady-state concentrations.
Treatment . | Faecal filtrate antibiotic concentration (μg/mL, mean ± SD) versus LC-MS detection of faecal antibiotic concentration (μg/g, mean ± SD) . | |||||
---|---|---|---|---|---|---|
day 4 . | day 10 . | day 14 . | ||||
bioassay . | LC-MS . | bioassay . | LC-MS . | bioassay . | LC-MS . | |
SUR 125 mg 2× daily (n = 9) | 174 ± 97 | 585 ± 282 | 204 ± 101 | 569 ± 263 | 85 ± 101 | 366 ± 609 |
SUR 250 mg 2× daily (n = 8) | 350 ± 180 | 1432 ± 797 | 401 ± 193 | 1368 ± 442 | 75 ± 63 | 352 ± 302 |
VAN 125 mg 4× daily (n = 8) | 902 ± 335 | 998 ± 768 | 1069 ± 342 | 1533 ± 510 | 142 ± 206 | 757 ± 898 |
Treatment . | Faecal filtrate antibiotic concentration (μg/mL, mean ± SD) versus LC-MS detection of faecal antibiotic concentration (μg/g, mean ± SD) . | |||||
---|---|---|---|---|---|---|
day 4 . | day 10 . | day 14 . | ||||
bioassay . | LC-MS . | bioassay . | LC-MS . | bioassay . | LC-MS . | |
SUR 125 mg 2× daily (n = 9) | 174 ± 97 | 585 ± 282 | 204 ± 101 | 569 ± 263 | 85 ± 101 | 366 ± 609 |
SUR 250 mg 2× daily (n = 8) | 350 ± 180 | 1432 ± 797 | 401 ± 193 | 1368 ± 442 | 75 ± 63 | 352 ± 302 |
VAN 125 mg 4× daily (n = 8) | 902 ± 335 | 998 ± 768 | 1069 ± 342 | 1533 ± 510 | 142 ± 206 | 757 ± 898 |
SUR, surotomycin; VAN, vancomycin.
Treatment . | Faecal filtrate antibiotic concentration (μg/mL, mean ± SD) versus LC-MS detection of faecal antibiotic concentration (μg/g, mean ± SD) . | |||||
---|---|---|---|---|---|---|
day 4 . | day 10 . | day 14 . | ||||
bioassay . | LC-MS . | bioassay . | LC-MS . | bioassay . | LC-MS . | |
SUR 125 mg 2× daily (n = 9) | 174 ± 97 | 585 ± 282 | 204 ± 101 | 569 ± 263 | 85 ± 101 | 366 ± 609 |
SUR 250 mg 2× daily (n = 8) | 350 ± 180 | 1432 ± 797 | 401 ± 193 | 1368 ± 442 | 75 ± 63 | 352 ± 302 |
VAN 125 mg 4× daily (n = 8) | 902 ± 335 | 998 ± 768 | 1069 ± 342 | 1533 ± 510 | 142 ± 206 | 757 ± 898 |
Treatment . | Faecal filtrate antibiotic concentration (μg/mL, mean ± SD) versus LC-MS detection of faecal antibiotic concentration (μg/g, mean ± SD) . | |||||
---|---|---|---|---|---|---|
day 4 . | day 10 . | day 14 . | ||||
bioassay . | LC-MS . | bioassay . | LC-MS . | bioassay . | LC-MS . | |
SUR 125 mg 2× daily (n = 9) | 174 ± 97 | 585 ± 282 | 204 ± 101 | 569 ± 263 | 85 ± 101 | 366 ± 609 |
SUR 250 mg 2× daily (n = 8) | 350 ± 180 | 1432 ± 797 | 401 ± 193 | 1368 ± 442 | 75 ± 63 | 352 ± 302 |
VAN 125 mg 4× daily (n = 8) | 902 ± 335 | 998 ± 768 | 1069 ± 342 | 1533 ± 510 | 142 ± 206 | 757 ± 898 |
SUR, surotomycin; VAN, vancomycin.
Discussion
For the past two decades clinical research has focused on the development of more selective antimicrobial agents for the treatment of CDI. Declining clinical response rates to metronidazole treatment,20 emergence of more pathogenic strain types and higher CDI recurrence rates in patients with prior recurrences have been driving forces to find alternatives to metronidazole and vancomycin.21–24 The need for the simultaneous arrest of C. difficile proliferation and toxin production while preserving the protective normal microbiota has been the mission of candidate agents in the development pipeline. Tolevamer, a C. difficile toxin binding agent, failed to achieve clinical success,25 but findings supported the concept of preserving the residual normal microbiota to reduce recurrence risk in patients who did respond to initial treatment.4 Failure to achieve clinical success in the majority of tolevamer recipients also underscored the importance of killing the pathogen, rather than relying solely on binding and neutralizing C. difficile toxins.
During the development of fidaxomicin, differences in the composition of the microflora between vancomycin and fidaxomicin recipients suggested that preservation of Bacteroides spp., as well as Clostridial cluster XIVa and cluster IV microbes observed with fidaxomicin treatment, but which were each markedly impaired during vancomycin treatment, imputed a role for these microbial groups in preventing recurrences of CDI.8 In this substudy of the surotomycin Phase 2 dose-ranging clinical trial, surotomycin treatment spared the Bacteroides/Prevotella groups, whereas vancomycin significantly suppressed these bacteria. Compared with vancomycin, surotomycin appeared also to be suppressive of the Firmicutes, but to a lesser extent than vancomycin, and in a dose-dependent manner. Taken together, if microbiota groups are equal contributors to colonization resistance, surotomycin could be considered intermediate in microbiota-sparing properties between fidaxomicin and vancomycin. At the 250 mg twice-daily dosage of surotomycin, the microflora sparing effect is hypothesized to be largely dependent on Bacteroidetes group microbes. However, despite suppression of microbiota groups during treatment, the speed of recovery (resilience) of the microbiota after antibiotic treatment ceases may also play a role in preventing recurrences. Extrapolating these Phase 2 substudy observations to the Phase 3 clinical trials,18 in which a 3.6%–3.8% reduction in recurrence was observed, favouring surotomycin over vancomycin, it is possible to support a contention that the Phase 2 substudy observations are predictive of outcomes. Based on studies to date, the relative contributions of microbial groups to colonization resistance remain to be elucidated. In support of a role for Firmicutes for the prevention of CDI recurrences, the initial results from a mainly Firmicutes composition (SER 109) faecal microbiota transplant were in favour of a role, but a subsequent negative study raised concerns that there is more to be learned.26 Additional microbial ecological studies performed during the evaluation of other candidate CDI treatments would add to the literature on the relative role of different microbiota groups in host ecological defence.
In support of a hypothesis that reductions in C. difficile counts in faecal samples could be predictive of clinical cure of diarrheal disease, treatment of CDI with either surotomycin 250 mg twice daily or with vancomycin 125 mg four times daily, each for 10 days, resulted in comparable reductions of C. difficile numbers at or near the limit of detection at days 4, 10 and 14. Surotomycin 125 mg twice daily was less effective in the same period. These findings supported the Phase 3 clinical trial dose selection of 250 mg surotomycin twice daily (NCT01598311 and NCT01597505) and appeared to be predictive of comparable clinical responses.17,18
The current strategy to achieve high sustained clinical cure rates for new anti-CDI agents is challenging. A small percentage difference in the clinical cure rate is additive to the difference in the recurrence rate. Should a treatment be a few percentage points less effective in achieving clinical cure, the treatment would have to make up the difference with lower rates of recurrence to be comparably effective. Following the unfavourable Phase 3 data on achieving a superior sustained clinical cure, the surotomycin development programme was discontinued, but knowledge gained from the programme can be used in the conduct of future studies.
The patient population enrolled to this substudy was largely representative of the global population in the Phase 2 trial. However, the substudy population lacked African-American patients and patients with severe CDI. Additionally, the number of patients reporting systemic antibiotic use, positive for BI/NAP1/027 strain infection and not experiencing a previous CDI episode were under-represented in this substudy compared with the global population. These differences in demographics, in addition to the small number of individuals assessed in the substudy, may limit how representative the current results are. However, the results presented herein do suggest a link between surotomycin in vivo activity against C. difficile, preservation of bacterial groups present in the healthy gut microbiome and clinical outcomes.
Acknowledgements
These data were presented in part at the 23rd European Congress of Clinical Microbiology and Infectious Diseases, London, 2012, Abstract #2250, p. 180.
Funding
This work was funded by Merck & Co., Inc., Kenilworth, NJ, USA. Medical writing and editorial assistance was funded by Merck & Co., Inc., Kenilworth, NJ, USA.
Transparency declarations
Medical writing and editorial assistance was provided by Dan Rigotti, PhD and Cara L. Hunsberger of StemScientific, Lyndhurst, NJ, an Ashfield Company, part of UDG Healthcare plc, and Edward Rochford, PhD of Complete Medical Communications, Hackensack, NJ, USA. T. L. received research funding as an investigator from Optimer Pharmaceuticals Inc., Cubist Pharmaceuticals Inc. and Actelion Pharmaceuticals Inc.; and received payment for participating in a scientific advisory board sponsored by Cubist Pharmaceuticals Inc. L. C. is a current employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock and/or stock options. K. C., B. B., J. H., K. W. and L. W. have nothing to disclose.
Author contributions
K. C. substantially contributed to acquisition of the data, analysis of the data, interpretation of the results, drafting the manuscript and critically reviewing or revising the manuscript for important intellectual content. B. B. substantially contributed to acquisition of the data, drafting the manuscript and critically reviewing or revising the manuscript for important intellectual content. J. H. substantially contributed to acquisition of the data, drafting the manuscript and critically reviewing or revising the manuscript for important intellectual content. K. W. substantially contributed to acquisition of the data, drafting the manuscript and critically reviewing or revising the manuscript for important intellectual content. L. W. substantially contributed to conception, design or planning the study, acquisition of the data, drafting the manuscript and critically reviewing or revising the manuscript for important intellectual content. L. C. substantially contributed to conception, design or planning the study, interpretation of the results, drafting the manuscript and critically reviewing or revising the manuscript for important intellectual content. T. L. substantially contributed to conception, design or planning the study, acquisition of the data, analysis of the data, interpretation of the results, drafting the manuscript and critically reviewing or revising the manuscript for important intellectual content.