Effect of MMX® mesalamine coadministration on the pharmacokinetics of amoxicillin, ciprofloxacin XR, metronidazole, and sulfamethoxazole: results from four randomized clinical trials

Abstract

BackgroundMMX® mesalamine is a once daily oral 5-aminosalicylic acid formulation, effective in induction and maintenance of ulcerative colitis remission. Patients on long-term mesalamine maintenance may occasionally require concomitant antibiotic treatment for unrelated infections.AimTo evaluate the potential for pharmacokinetic interactions between MMX mesalamine and amoxicillin, ciprofloxacin extended release (XR), metronidazole, or sulfamethoxazole in four open-label, randomized, placebo-controlled, two-period crossover studies.MethodsIn all four studies, healthy adults received placebo once daily or MMX mesalamine 4.8 g once daily on days 1–4 in one of two treatment sequences. In studies 1 and 2, subjects also received a single dose of amoxicillin 500 mg (N=62) or ciprofloxacin XR 500 mg (N=30) on day 4. In studies 3 and 4, subjects received metronidazole 750 mg twice daily on days 1–3 and once on day 4 (N=30); or sulfamethoxazole 800 mg/trimethoprim 160 mg twice daily on days 1–3 and once on day 4 (N=44).ResultsMMX mesalamine had no significant effects on systemic exposure to amoxicillin, ciprofloxacin, or metronidazole; the 90% confidence intervals (CIs) around the geometric mean ratios (antibiotic + MMX mesalamine: antibiotic + placebo) for maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) fell within the predefined equivalence range (0.80–1.25). Sulfamethoxazole exposure increased by a statistically significant amount when coadministered with MMX mesalamine; however, increased exposure (by 12% in Cmax at steady state; by 15% in AUC at steady state) was not considered clinically significant, as the 90% CIs for each point estimate fell entirely within the predefined equivalence range. Adverse events in all studies were generally mild.ConclusionMMX mesalamine may be coadministered with amoxicillin, ciprofloxacin, metronidazole, or sulfamethoxazole, without affecting pharmacokinetics or safety of these antibiotics.ClinicalTrials.gov identifiersNCT01442688, NCT01402947, NCT01418365, and NCT01469637.

Human gut microbiota plays a role in the metabolism of drugs

“…one , in vitro study with C. perfringens or rat caecal contents also confirmed the formation of these metabolites 82 N-(2-hydroxyethyl)-oxamic acid and acetamide were detected in small amounts in the urine of patients treated with metronidazole 83 . according to four randomized clinical trials, coadministration of mesazalamine was found to have no effect on the pharmacokinetics of metronidazole 84 .…”

Influence of antibiotic treatment on the detection of S. aureus in whole blood following pathogen enrichment

“…For comparison, we chose CIP, which is widely prescribed by general practitioners for the treatment of pneumonia, suspected gastrointestinal infections, or infections of the genitourinary tract [46,47], as well as CLI, which is commonly used for the treatment of skin and soft tissue infections in outpatient care [48]. All antibiotics were applied to achieve concentrations equivalent to mean plasma levels reported in the literature [26,27,[29][30][31][32]. We used an established manual pathogen enrichment kit, since it allows for intervention at multiple steps of the pre-analytical protocol, while protocols provided by other suppliers are fully integrated systems, which process blood samples automatically and do not allow for pathogen quantification at individual stages of the pre-analytical protocol.…”

“…To investigate whether weakening or disruption of bacterial cell walls by antibiotic pretreatment would influence subsequent pathogen enrichment and, consequently, PCR-based quantification of pathogen DNA, S. aureus was spiked into whole blood and incubated for 4 h as described above to ensure logarithmic growth. Subsequently, [28,29] Ciprofloxacin (CIP) prevents replication of bacterial DNA by inhibiting DNA gyrase [30,31] Clindamycin (CLI) inhibits bacterial protein synthesis by binding to 50S ribosomal subunits [32] final concentrations of 15 μg/mL vancomycin (VAN), 20 μg/mL piperacillin (PIP), 1 μg/mL ciprofloxacin (CIP), or 2 μg/mL clindamycin (CLI), respectively (Table 1), were added, and incubation was continued for another 90 min at 37°C with gentle agitation. Subsequent pathogen enrichment and DNA extraction were performed as described below.…”

Gut Microbiota-Mediated Drug-Antibiotic Interactions

“…The metabolites have also been found in the urine of human patients treated with metronidazole (Koch et al, 1981). Mesalamine treatment does not affect the pharmacokinetics of metronidazole (Pierce et al, 2014). , is dependent on metabolism of gut bacteria.…”