A pharmacokinetic-pharmacodynamic assessment of oral antibiotics for pyelonephritis

J W S Cattrall,I F Trocóniz,J Freeman,E Asín-Prieto,A Kirby

doi:10.1007/s10096-019-03679-9

Abstract

Antibiotic resistance to oral antibiotics recommended for pyelonephritis is increasing. The objective was to determine if there is a pharmacological basis to consider alternative treatments/novel dosing regimens for the oral treatment of pyelonephritis. A systematic review identified pharmacokinetic models of suitable quality for a selection of antibiotics with activity against Escherichia coli. MIC data was obtained for a population of E. coli isolates derived from patients with pyelonephritis. Pharmacokinetic/pharmacodynamic (PK/PD) simulations determined probability of target attainment (PTA) and cumulative fraction response (CFR) values for sub-populations of the E. coli population at varying doses. There are limited high-quality models available for the agents investigated. Pharmacokinetic models of sufficient quality for simulation were identified for amoxicillin, amoxicillin-clavulanic acid, cephalexin, ciprofloxacin, and fosfomycin trometamol. These antibiotics were predicted to have PTAs ≥ 0.85 at or below standard doses for the tested E. coli population including cephalexin 1500 mg 8 hourly for 22% of the population (MIC ≤ 4 mg/L) and ciprofloxacin 100 mg 12 hourly for 71% of the population (MIC ≤ 0.06 mg/L). For EUCAST-susceptible E. coli isolates, doses achieving CFRs ≥ 0.9 included amoxicillin 2500 mg 8 hourly, cephalexin 4000 mg 6 hourly, ciprofloxacin 200 mg 12 hourly, and 3000 mg of fosfomycin 24 hourly. Limitations in the PK data support carrying out additional PK studies in populations of interest. Oral antibiotics including amoxicillin, amoxicillin-clavulanic acid, and cephalexin have potential to be effective for a proportion of patients with pyelonephritis. Ciprofloxacin may be effective at lower doses than currently prescribed.

Highlights

IntroductionPyelonephritis is a bacterial infection of the renal pelvis and kidney
Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.University of Leeds, Leeds LS2 9JT, UK 2 Pharmacometrics & Systems Pharmacology Research Unit, Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain 3 IdiSNA, Navarra Institute for Health Research, Pamplona, Spain 4 Leeds Teaching Hospitals NHS Trust, Leeds LS9 7TF, UK 5 Department of Microbiology, Old Medical School, Leeds General Infirmary, Leeds LS1 3EX, UKPyelonephritis is a bacterial infection of the renal pelvis and kidney
Several models had to be adapted from intravenous administration to simulate single-multiple oral administrations of the antibiotic

Summary

Introduction

Pyelonephritis is a bacterial infection of the renal pelvis and kidney. It is a life-threatening infection that can lead to renal scarring and impairment of kidney function [1]. Estimates of outpatient pyelonephritis rates in females are 12–13 cases per 10,000 population annually [1]. The predominant aetiological agent of pyelonephritis is Escherichia coli in up to 84% of cases [1]. International guidelines (IDSA, ESCMID) recommend outpatient management of pyelonephritis with oral ciprofloxacin, levofloxacin, or oral trimethoprim-sulfamethoxazole [2]. Antibiotic resistance to these antibiotics within populations of E. coli is increasing and complicates treatment for pyelonephritis [2]. Despite a wide range of alternative oral antibiotics having activity against E. coli, the use of orally available cephalexin, fosfomycin, mecillinam, nitrofurantoin, and

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