The Oral β-Lactamase SYN-004 (Ribaxamase) Degrades Ceftriaxone Excreted into the Intestine in Phase 2a Clinical Studies
John F Kokai-Kun, Tracey Roberts, Olivia Coughlin, Eric Sicard, Marianne Rufiange, Richard Fedorak, Christian Carter, Marijke H Adams, James Longstreth, Heidi Whalen, Joseph Sliman, John F Kokai-Kun, Tracey Roberts, Olivia Coughlin, Eric Sicard, Marianne Rufiange, Richard Fedorak, Christian Carter, Marijke H Adams, James Longstreth, Heidi Whalen, Joseph Sliman
Abstract
SYN-004 (ribaxamase) is a β-lactamase designed to be orally administered concurrently with intravenous β-lactam antibiotics, including most penicillins and cephalosporins. Ribaxamase's anticipated mechanism of action is to degrade excess β-lactam antibiotic that is excreted into the small intestine. This enzymatic inactivation of excreted antibiotic is expected to protect the gut microbiome from disruption and thus prevent undesirable side effects, including secondary infections such as Clostridium difficile infections, as well as other antibiotic-associated diarrheas. In phase 1 clinical studies, ribaxamase was well tolerated compared to a placebo group and displayed negligible systemic absorption. The two phase 2a clinical studies described here were performed to confirm the mechanism of action of ribaxamase, degradation of β-lactam antibiotics in the human intestine, and were therefore conducted in subjects with functioning ileostomies to allow serial sampling of their intestinal chyme. Ribaxamase fully degraded ceftriaxone to below the level of quantitation in the intestines of all subjects in both studies. Coadministration of oral ribaxamase with intravenous ceftriaxone was also well tolerated, and the plasma pharmacokinetics of ceftriaxone were unchanged by ribaxamase administration. Since ribaxamase is formulated as a pH-dependent, delayed-release formulation, the activity of ribaxamase in the presence of the proton pump inhibitor esomeprazole was examined in the second study; coadministration of these drugs did not adversely affect ribaxamase's ability to degrade ceftriaxone excreted into the intestine. These studies have confirmed the in vivo mechanism of action of ribaxamase, degradation of β-lactam antibiotics in the human intestine (registered at ClinicalTrials.gov under NCT02419001 and NCT02473640).
Keywords: beta-lactamases; ceftriaxone; clinical trials; dysbiosis; gut microbiome; oral administration; protection.
Copyright © 2017 Kokai-Kun et al.
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References
- Kinross JM, Darzi AW, Nicholson JK. 2011. Gut microbiome-host interactions in health and disease. Genome Med 3:14. doi:10.1186/gm228.
- Konkel L, Danska J, Mazmanian S, Chadwick L. 2013. The environment within: exploring the role of the gut microbiome in health and disease. Environ Health Perspect 121:a276–a281. doi:10.1289/ehp.121-A276.
- Britton RA, Young VB. 2014. Role of the intestinal microbiota in resistance to colonization by Clostridium difficile. Gastroenterology 146:1547–1553. doi:10.1053/j.gastro.2014.01.059.
- Chalmers JD, Akram AR, Singanayagam A, Wilcox MH, Hill AT. 2016. Risk factors for Clostridium difficile infection in hospitalized patients with community-acquired pneumonia. J Infect 73:45–53. doi:10.1016/j.jinf.2016.04.008.
- Crowther GS, Wilcox MH. 2015. Antibiotic therapy and Clostridium difficile infection—primum non nocere—first do no harm. Infect Drug Resist 8:333–337. doi:10.2147/IDR.S87224.
- Johanesen PA, Mackin KE, Hutton ML, Awad MM, Larcombe S, Amy JM, Lyras D. 2015. Disruption of the gut microbiome: Clostridium difficile infection and the threat of antibiotic resistance. Genes (Basel) 6:1347–1360. doi:10.3390/genes6041347.
- Stevens V, Dumyati G, Fine LS, Fisher SG, van Wijngaarden E. 2011. Cumulative antibiotic exposures over time and the risk of Clostridium difficile infection. Clin Infect Dis 53:42–48. doi:10.1093/cid/cir301.
- Alverdy JC, Chang EB. 2008. The re-emerging role of the intestinal microflora in critical illness and inflammation: why the gut hypothesis of sepsis syndrome will not go away. J Leukoc Biol 83:461–466.
- Bjorksten B. 2004. Effects of intestinal microflora and the environment on the development of asthma and allergy. Springer Semin Immunopathol 25:257–270. doi:10.1007/s00281-003-0142-2.
- Finegold SM. 2008. Therapy and epidemiology of autism: clostridial spores as key elements. Med Hypotheses 70:508–511. doi:10.1016/j.mehy.2007.07.019.
- Nicholson JK, Holmes E, Wilson ID. 2005. Gut microorganisms, mammalian metabolism and personalized health care. Nat Rev Microbiol 3:431–438. doi:10.1038/nrmicro1152.
- Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA. 2005. Diversity of the human intestinal microbial flora. Science 308:1635–1638. doi:10.1126/science.1110591.
- Lozupone CA, Stombauch JI, Gordon JI, Jansson JK, Knight R. 2012. Diversity, stability, and resilience of the human gut microbiota. Nature 489:220–230. doi:10.1038/nature11550.
- Azvolinsky A. 2015. Antibiotics and the gut microbiome. Scientist. LabX Media Group, Midland, Ontario, Canada: .
- Knecht H, Neulinger SC, Heinsen FA, Knecht C, Schilhabel A, Schmitz RA, Zimmermann A, dos Santos VM, Ferrer M, Rosenstiel PC, Schreiber S, Friedrichs AK, Ott SJ. 2014. Effects of beta-lactam antibiotics and fluoroquinolones on human gut microbiota in relation to Clostridium difficile associated diarrhea. PLoS One 9:e89417. doi:10.1371/journal.pone.0089417.
- Nord CE, Kager L, Heimdahl A. 1984. Impact of antimicrobial agents on the gastrointestinal microflora and the risk of infections. Am J Med 76:99–106. doi:10.1016/0002-9343(84)90250-X.
- Smits WK, Lyras D, Lacy DB, Wilcox MH, Kuijper EJ. 2016. Clostridium difficile infection. Nat Rev Dis Primers 2:16020. doi:10.1038/nrdp.2016.20.
- Theriot CM, Young VB. 2015. Interactions between the gastrointestinal microbiome and Clostridium difficile. Annu Rev Microbiol 69:445–461. doi:10.1146/annurev-micro-091014-104115.
- Forslund K, Sunagawa S, Kultima JR, Mende DR, Arumugam M, Typas A, Bork P. 2013. Country-specific antibiotic use practices impact the human gut resistome. Genome Res 23:1163–1169. doi:10.1101/gr.155465.113.
- Hung YP, Lin HJ, Wu CJ, Chen PL, Lee JC, Liu HC, Wu YH, Yeh FH, Tsai PJ, Ko WC. 2014. Vancomycin-resistant Clostridium innocuum bacteremia following oral vancomycin for Clostridium difficile infection. Anaerobe 30:24–26. doi:10.1016/j.anaerobe.2014.07.009.
- van Schaik W. 2015. The human gut resistome. Philos Trans R Soc Lond B Biol Sci 370:20140087. doi:10.1098/rstb.2014.0087.
- Blair JM, Webber MA, Baylay AJ, Ogbolu DO, Piddock LJ. 2015. Molecular mechanisms of antibiotic resistance. Nat Rev Microbiol 13:42–51. doi:10.1038/nrmicro3380.
- Boyle DP, Zembower TR. 2015. Epidemiology and management of emerging drug-resistant gram-negative bacteria: extended-spectrum beta-lactamases and beyond. Urol Clin North Am 42:493–505. doi:10.1016/j.ucl.2015.05.005.
- Miller WR, Munita JM, Arias CA. 2014. Mechanisms of antibiotic resistance in enterococci. Expert Rev Anti Infect Ther 12:1221–1236. doi:10.1586/14787210.2014.956092.
- Kong KF, Schneper L, Mathee K. 2010. Beta-lactam antibiotics: from antibiosis to resistance and bacteriology. APMIS 118:1–36. doi:10.1111/j.1600-0463.2010.02598_1.x.
- Hayton WL, Schandlik R, Stoeckel K. 1986. Biliary excretion and pharmacokinetics of ceftriaxone after cholecystectomy. Eur J Clin Pharmacol 30:445–451. doi:10.1007/BF00607958.
- Karachalios G, Charalabopoulos K. 2002. Biliary excretion of antimicrobial drugs. Chemotherapy 48:280–297.
- Maudgal DP, Maxwell JD, Lees LJ, Wild RN. 1982. Biliary excretion of amoxicillin and ceftriaxone after intravenous administration in man. Br J Clin Pharmacol 14:213–217. doi:10.1111/j.1365-2125.1982.tb01964.x.
- Harmoinen J, Mentula S, Heikkila M, van der Rest M, Rajala-Schultz PJ, Donskey CJ, Frias R, Koski P, Wickstrand N, Jousimies-Somer H, Westermarck E, Lindevall K. 2004. Orally administered targeted recombinant beta-lactamase prevents ampicillin-induced selective pressure on the gut microbiota: a novel approach to reducing antimicrobial resistance. Antimicrob Agents Chemother 48:75–79. doi:10.1128/AAC.48.1.75-79.2004.
- Harmoinen J, Vaali K, Koski P, Syrjanen K, Laitinen O, Lindevall K, Westermarck E. 2003. Enzymic degradation of a β-lactam antibiotic, ampicillin, in the gut: a novel treatment modality. J Antimicrob Chemother 51:361–365. doi:10.1093/jac/dkg095.
- Pitout JD. 2009. IPSAT P1A, a class A beta-lactamase therapy for the prevention of penicillin-induced disruption to the intestinal microflora. Curr Opin Investig Drugs 10:838–844.
- Tarkkanen AM, Heinonen T, Jogi R, Mentula S, van der Rest ME, Donskey CJ, Kemppainen T, Gurbanov K, Nord CE. 2009. P1A recombinant beta-lactamase prevents emergence of antimicrobial resistance in gut microflora of healthy subjects during intravenous administration of ampicillin. Antimicrob Agents Chemother 53:2455–2462. doi:10.1128/AAC.00853-08.
- Stiefel U, Nerandzic MM, Koski P, Donskey CJ. 2008. Orally administered beta-lactamase enzymes represent a novel strategy to prevent colonization by Clostridium difficile. J Antimicrob Chemother 62:1105–1108. doi:10.1093/jac/dkn298.
- Kaleko M, Bristol JA, Hubert S, Parsley T, Widmer G, Tzipori S, Subramanian P, Hasan N, Koski P, Kokai-Kun J, Sliman J, Jones A, Connelly S. 2016. Development of SYN-004, an oral beta-lactamase treatment to protect the gut microbiome from antibiotic-mediated damage and prevent Clostridium difficile infection. Anaerobe 41:58–67. doi:10.1016/j.anaerobe.2016.05.015.
- Kokai-Kun JF, Bristol JA, Setser J, Schlosser M. 2016. Nonclinical safety assessment of SYN-004: an oral β-lactamase for the protection of the gut microbiome from disruption by biliary-excreted, intravenously administered antibiotics. Int J Toxicol 35:309–316. doi:10.1177/1091581815623236.
- Roberts T, Kokai-Kun JF, Coughlin O, Lopez BV, Whalen H, Bristol JA, Hubert S, Longstreth J, Lasseter K, Sliman J. 2016. Tolerability and pharmacokinetics of SYN-004, an orally administered beta-lactamase for the prevention of Clostridium difficile-associated disease and antibiotic-associated diarrhea, in two phase 1 studies. Clin Drug Invest 36:725–734. doi:10.1007/s40261-016-0420-0.
- AstraZeneca Pharmaceuticals LP. 2008. Nexium prescribing information. AstraZeneca Pharmaceuticals LP, Wilmington, DE.
- Blume H, Donath F, Warnke A, Schug BS. 2006. Pharmacokinetic drug interaction profiles of proton pump inhibitors. Drug Safety 29:769–784. doi:10.2165/00002018-200629090-00002.
- Drawz SM, Bonomo RA. 2010. Three decades of beta-lactamase inhibitors. Clin Microbiol Rev 23:160–201. doi:10.1128/CMR.00037-09.
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