Biliary excretion of amoxycillin and ceftriaxone after intravenous administration in man.

Maudgal, D P; Maxwell, James; Lees, L.; Wild, Richard

doi:10.1111/j.1365-2125.1982.tb01964.x

Cited by 22 publications

(11 citation statements)

References 17 publications

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“…While ciprofloxacin can reach bile concentrations of about twice the serum concentration even in obstructed bile duct,22–24 piperacillin/tazobactam very frequently does not reach bactericidic levels 24. Ceftriaxon can also reach high bile levels,25 but the effect is flawed by the formation of bile sludge,26 whereas amoxycillin shows bile concentrations inferior to serum levels 25. Imipenem/cilastatin shows moderate concentrations in the nonobstructed bile (imipenem diffuses into the bile, while cilastatin is actively secreted into the bile),27 but this effect is abrogated completely by bile obstruction 28.…”

Section: Discussionmentioning

confidence: 99%

Bactobilia after liver transplantation: Frequency and antibiotic susceptibility

et al. 2006

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After liver transplantation (LT), bactobilia occurs frequently in patients, leading in some cases to cholangitis and biliary sepsis. The present study is the first to investigate bactobilia after LT, and it gives an overview of predisposing factors for bactobilia, the microbial spectrum in the bile of LT patients, and the antibiotic susceptibility. A total of 172 endoscopic retrograde cholangiography (ERC) procedures were performed in 66 LT patients between 1 month and 5.8 years after LT. Bile samples were examined microbiologically. Sixty-eight nontransplanted patients without cholestasis, but requiring ERC for other reasons served as a control group. Of 172 samples obtained from LT patients, 126 (73.3%) were positive for microbes. A total of 236 organisms were isolated: 114 (48.3%) gram-positive bacteria, 92 (39.0%) aerobic gram-negative, 8 (3.4%) anaerobes, and 22 (9.3%) fungi. Ciprofloxacin and amoxycillin/clavulanic acid showed the best susceptibility results among oral antibiotics and piperacillin/tazobactam and imipenem/cilastatin among intravenous preparations. In contrast, only 15.7% of non-LT patients showed bactobilia. In conclusion, our study shows that bactobilia is a problem in patients after LT and that it is not only a contamination from endoscopic intervention. Mechanical obstruction, plastic stents, gallstones, and papillotomy increase the risk of bactobilia significantly. In our cohort we had the best antibiotic susceptibility results for positive cultures in LT patients with piperacillin/tazobactam, ciprofloxacin, or amoxycillin/clavulanic acid. Liver Transpl 12:747-753, 2006.

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Section: Discussionmentioning

confidence: 99%

Bactobilia after liver transplantation: Frequency and antibiotic susceptibility

et al. 2006

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“…Beta‐lactamases are naturally occurring enzymes that confer antibiotic resistance by hydrolysing beta‐lactam antibiotics, the most widely used intravenous (IV) broad‐spectrum antimicrobials (Arlington Medical Resources ), many of which are excreted via the bile into the intestinal tract at high concentrations (Maudgal et al . ). In North America and Europe, ceftriaxone (CRO) is the most frequently prescribed IV beta‐lactam (Arlington Medical Resources ) and has been linked to dysbiosis and increased risk of C. difficile infection (Slimings and Riley ; Crowther and Wilcox ; Zycinska et al .…”

Section: Introductionmentioning

confidence: 97%

“…A novel strategy to protect the microbiome from antibiotic-mediated dysbiosis is prophylactic use of a beta-lactamase enzyme to degrade antibiotics in the proximal gastrointestinal (GI) tract before the colonic microbiota are harmed (Kaleko et al 2016). Beta-lactamases are naturally occurring enzymes that confer antibiotic resistance by hydrolysing beta-lactam antibiotics, the most widely used intravenous (IV) broad-spectrum antimicrobials (Arlington Medical Resources 2014), many of which are excreted via the bile into the intestinal tract at high concentrations (Maudgal et al 1982). In North America and Europe, ceftriaxone (CRO) is the most frequently prescribed IV beta-lactam (Arlington Medical Resources 2014) and has been linked to dysbiosis and increased risk of C. difficile infection (Slimings and Riley 2014;Crowther and Wilcox 2015;Zycinska et al 2016).…”

Section: Introductionmentioning

confidence: 99%

SYN-004 (ribaxamase), an oral beta-lactamase, mitigates antibiotic-mediated dysbiosis in a porcine gut microbiome model

et al. 2017

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Aim: To evaluate an antibiotic inactivation strategy to protect the gut microbiome from antibiotic-mediated damage. Methods and Results: SYN-004 (ribaxamase) is an orally delivered betalactamase intended to degrade penicillins and cephalosporins within the gastrointestinal tract to protect the microbiome. Pigs (20 kg, n = 10) were treated with ceftriaxone (CRO) (IV, 50 mg kg À1, SID) for 7 days and a cohort (n = 5) received ribaxamase (PO, 75 mg, QID) for 9 days beginning the day before antibiotic administration. Ceftriaxone serum levels were not statistically different in the antibiotic-alone and antibiotic + ribaxamase groups, indicating ribaxamase did not alter systemic antibiotic levels. Whole-genome metagenomic analyses of pig faecal DNA revealed that CRO caused significant changes to the gut microbiome and an increased frequency of antibiotic resistance genes. With ribaxamase, the gut microbiomes were not significantly different from pretreatment and antibiotic resistance gene frequency was not increased. Conclusion: Ribaxamase mitigated CRO-mediated gut microbiome dysbiosis and attenuated propagation of the antibiotic resistance genes in pigs. Significance and Impact of the Study: Damage of the microbiome can lead to overgrowth of pathogenic organisms and antibiotic exposure can promote selection for antibiotic-resistant micro-organisms. Ribaxamase has the potential to become the first therapy designed to protect the gut microbiome from antibiotic-mediated dysbiosis and reduce emergence of antibiotic resistance.

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“…This occurs even when these antibiotics are delivered intravenously (i.v. ), since a substantial portion of the dose can be excreted in the bile and reach the intestine as a fully functional antibiotic ( 26 – 28 ). This is particularly true for ceftriaxone, a highly effective third-generation cephalosporin, for which more than half of the i.v.…”

Section: Introductionmentioning

confidence: 99%

The Oral β-Lactamase SYN-004 (Ribaxamase) Degrades Ceftriaxone Excreted into the Intestine in Phase 2a Clinical Studies

Kokai‐Kun

Roberts

Coughlin

et al. 2017

Antimicrob Agents Chemother

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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).

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Biliary excretion of amoxycillin and ceftriaxone after intravenous administration in man.

Cited by 22 publications

References 17 publications

Bactobilia after liver transplantation: Frequency and antibiotic susceptibility

Bactobilia after liver transplantation: Frequency and antibiotic susceptibility

SYN-004 (ribaxamase), an oral beta-lactamase, mitigates antibiotic-mediated dysbiosis in a porcine gut microbiome model

The Oral β-Lactamase SYN-004 (Ribaxamase) Degrades Ceftriaxone Excreted into the Intestine in Phase 2a Clinical Studies

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