Optimizing Amoxicillin/Clavulanic Acid Dosing Regimens in Patients on Maintenance High-Flux Hemodialysis

Amoxicillin/clavulanic acid (AMC) is frequently prescribed in maintenance HD patients, mainly for treating community-acquired respiratory tract infections. As this β-lactam antibiotic exhibits a time-dependent killing, amoxicillin (AMX) concentrations exceeding the minimal inhibitory concentration (MIC) at least 50% of treatment time are recommended,1Turnidge J.D. The pharmacodynamics beta-lactams.Clin Infect Dis. 1998; 27: 10-22Crossref PubMed Scopus (498) Google Scholar while clavulanic (CLA) should suffice to inhibit β-lactamases prolonged period time.2Murbach V. Dhoyen N. Linger L. Monteil H. Jehl F. Evidence true post-beta-lactamase-inhibitor effect against Klebsiella pneumoniae and Haemophilus influenzae.Clin Microbiol Infect. 2001; 7: 661-665Abstract Full Text PDF (16) In patients with preserved kidney hepatic function, pharmacokinetic studies revealed that total body clearance (CL) AMX CLA comparable, allowing fixed-dose drug combination. However, since renal much higher than (71% vs 28%), different dosage adjustments may be needed patients.3Horber F.F. Frey F.J. Descoeudres C. Murray A.T. Reubi F.C. Differential impaired function on kinetics amoxicillin.Antimicrob Agents Chemother. 1986; 29: 614-619Crossref (27) such removes both compounds, but available data refer older using low-flux dialyzers.4Davies B.E. Boon R. Horton C.E. Pharmacokinetics amoxycillin haemodialysis following intravenous administration Augmentin.Br J Clin Pharmacol. 1988; 26: 385-390Crossref Scholar, 5Francke E.L. Appel G.B. Neu H.C. Kinetics long-term dialysis.Clin Pharmacol Ther. 1979; 31-35Crossref (14) 6Slaughter R.L. Kohli Brass Effects hemodialysis pharmacokinetics amoxicillin/clavulanic combination.Ther Drug Monit. 1984; 6: 424-427Crossref (7) lack updated setting more efficient scarce PK/PD (pharmacokinetic/pharmacodynamic) makes AMC dosing challenging. We therefore aimed characterize population PK model intermittent high-flux HD, also investigating predictors interindividual variability. With model, we assessed probability target attainment regimens, aiming propose optimized strategies. This single-center prospective observational study included from 26 (Tables S1 S2) receiving regimens (Table S3; Item S1). Inter- intradialytic blood samples were taken (Fig S1) measure plasma CLA. A was developed nonlinear mixed effects by fitting observed concentration-time data. Different covariates added stepwise fashion; those improving model’s goodness-of-fit retained. Next, each proposed regimen simulated 1,000 virtual over 1-week Monte Carlo simulations. For patient, set random values used any factor has inherent uncertainty, based generating distributions possible outcome values. these simulations, (PTA) regimen. Since there no universally accepted CLA, only accumulation studied.7Sanchez Navarro A. New formulations acid: pharmacodynamic review.Clin Pharmacokinet. 2005; 44: 1097-1115Crossref (28) 2-compartmental between-participant variability distribution volume central compartment (V1), CL, dialysis extraction ratio (ER), fitted best measured (n = 247) compounds 1) (goodness-of-fit plots Figs S2 S3).Table 1Parameter Estimates Final Model CLAParameterTypical Value (%RSE) AMXTypical CLAFixed effectsKa, h-10.78 (29)1.14 (22)F, %65.1 (12)37.0 (33)CL, mL/min64 (21) Residual diuresis <500 mL/d12 (18) ≥500 mL/d22 (17)V1, L11.3 (12)16.2 (14)V2, L12.5 (7)7.4 (26)Q2, mL/min180 (27)66.7 (67)ER, flow rate 300 mL/min, % 74 (12)78 (17)t1/2 interdialytic, haSecondary parameters, which calculated estimated parameters model.2.9 mL/d10.8 mL/d6.1t1/2 intradialytic, model.0.62 mL/d0.56 mL/d0.53Random variabilityV1, L0.141 (45)CL, mL/min0.289 (42)0.344 (39)ER, %0.357 (43)Random error / residual unexplained variabilitybResidual proportional additive model.Additive error1.37 (57)0.030 (21)Proportional error0.0301 (51)0.0773 (21)Abbreviations: Ka, absorption constant; F, bioavailability; clearance; Vx, (x or 2) peripheral compartment; Q2, intercompartmental between V1 V2; ER, ratio; t1/2, terminal half-life; RSE, relative standard estimate.a Secondary model.b model. Open table new tab Abbreviations: estimate. Within an individual estimates ER highly correlated. Dialyzer high (74%, AMX; 78%, CLA). AMX, associated CL (P 0.03), (QB) < 0.001). Accordingly, kept final S4). significantly improved S5). All strategies S6 S7) achieved adequate (PTA > 90%) showed time, profiles accumulation, not even 1, Fig S4, Table S8).Figure 1Concentration-time graph Black line indicates median prediction; gray area shows 95% prediction interval. Scenarios (A) 500 mg/125 mg orally every 24 hours (+ during [HD], post-HD); (B) 12 (administration (C) 8 pre- (D) starting dose mg/200 intravenously (IV), mg/100 IV (E) IV, (F) post-HD). PTA targeting MIC mg/L greater EUCAST (European Committee Antimicrobial Susceptibility Testing) guidelines.View Large Image Figure ViewerDownload Hi-res image Download (PPT) performed current practice QB dialyzers. resulted 74% (QB mL/min) versus previously reported 17% 26% 8; 250-300 mL/min)5Francke 44% 1; 190 mL/min)6Slaughter Estimated (12-22 64 is, however, still lower individuals (208-237 215 mL/min).3Horber results interdialytic half-life (t1/2) 3-fold 6- 10-fold t1/2 1 hour normal function. Furthermore, almost double oligoanuric compared mL/d (10.8 6.1 hours), 2.9 influenced diuresis, as found.3Horber Scholar,4Davies Aside elimination, distribution. Total volumes similar healthy controls (ie, 0.26-0.41 L/kg [AMX] 0.22-0.25 [CLA]).3Horber Scholar,8Todd P.A. Benfield P. acid. An update its antibacterial activity, properties therapeutic use.Drugs. 1990; 39: 264-307Crossref (151) bioavailability (65.1% 37% CLA) (80%-85% 60% ± 23% CLA), possibly owing fluid overload delayed gastric emptying reduced splanchnic bowel surface area9Corsonello Abbatecola A.M. Fusco S. et al.The impact interactions polypharmacy antimicrobial therapy elderly.Clin 2015; 21: 20-26Abstract (24) population. conclusion, primarily considering toxicity dose-dependent within range.10Amoxicillin. Drugs.com. Updated January 12, 2020. Accessed October 10, https://www.drugs.com/amoxicillin.htmlGoogle conclude after loading would reach sufficient exposure minimizing significant AMX. Considering dialyzer clearance, scheduled postdialysis. Designed study: PDC, PDP, WVB, SE; collaborated patient recruitment acquisition: FV, SD, NV, KDS; popPK modeling: PJC; analyzed data: KDS, SE, PJC. Each author contributed important intellectual content manuscript drafting revision agrees personally accountable individual’s own contributions ensure questions pertaining accuracy integrity portion work, one directly involved, appropriately investigated resolved, including documentation literature if appropriate. supported unrestricted scientific grant Fresenius Medical Care (2017-2020), had role design; collection, analysis, interpretation data; writing report; decision submit report publication. authors declare they have relevant financial interests. indebted K. Rokegem, Inion, I. Dewettinck, E. De Man, T. Mertens, Lobbestael, M. Van Landschoot, G. Tanushi, Hoet, Dirven, Soetens, B. Claeys, Dejonghe, Snijkers, Reyntjens their assistance clinical study, Vooren Caeneghem laboratory analyses. Received July 15, Evaluated 3 external peer reviewers, direct editorial input Statistics/Methods Editor, Associate Editor-in-Chief. Accepted revised form December 28, .pdf (3.1 MB) Help pdf files Supplementary File (PDF)Figures S1-S4; S1; Tables S1-S8.