Amoxicillin-Clavulanate Dosing in Stage 3 CKD
For patients with Stage 3 CKD (CrCl 30-59 mL/min), amoxicillin-clavulanate should be dosed at 875 mg orally every 12 hours, administered after dialysis sessions if the patient is on dialysis, with careful monitoring for drug accumulation. 1
Standard Dosing Framework
Stage 3A CKD (CrCl 45-59 mL/min): Use standard dosing of 875 mg orally every 12 hours without adjustment, as renal clearance remains adequate 2
Stage 3B CKD (CrCl 30-44 mL/min): Continue 875 mg orally every 12 hours, but monitor closely for signs of amoxicillin accumulation, as total body clearance decreases more significantly for amoxicillin than clavulanic acid in this range 2
Critical Pharmacokinetic Considerations
The ratio of amoxicillin to clavulanic acid area under the curve increases substantially as renal function declines—from 4.9:1 at GFR 75 mL/min to 11.9:1 at GFR 10-35 mL/min—meaning amoxicillin accumulates disproportionately compared to clavulanic acid 2. This differential accumulation pattern is crucial because:
- Amoxicillin's total body clearance decreases more dramatically than clavulanic acid's as GFR declines 2
- Non-renal clearance of both components is preserved even in severe renal impairment, allowing for less aggressive dose reduction than might be expected 3
- The volume of distribution and systemic availability remain independent of renal function 2
Timing Considerations for Dialysis Patients
If the patient progresses to requiring hemodialysis, both amoxicillin and clavulanic acid are significantly removed during dialysis sessions (fractional removal 0.64 and 0.65, respectively), with dialysis clearances of 77.1 mL/min and 92.8 mL/min 3. Therefore:
- Administer doses immediately after dialysis sessions to prevent drug removal and ensure adequate concentrations 4, 3
- The half-life during dialysis shortens dramatically to 2.3 hours for amoxicillin and 1.19 hours for clavulanic acid 3
High-Dose Strategy for Resistant Organisms
For ESBL-producing organisms in Stage 3 CKD patients, consider escalating to 2875 mg amoxicillin with 125 mg clavulanic acid twice daily, down-titrating every 7-14 days based on clinical response 5. This aggressive approach has demonstrated success in breaking resistance patterns, though it requires:
- Close monitoring for adverse effects given the high amoxicillin load
- Verification that the patient can tolerate the increased pill burden
- Regular assessment of renal function to detect any decline 5
Common Pitfalls to Avoid
Do not reduce the dose below 875 mg every 12 hours in Stage 3 CKD, as smaller doses may significantly compromise efficacy, particularly for concentration-dependent killing 4. The absorption half-life of amoxicillin increases in renal impairment, which partially compensates for decreased clearance 6.
Avoid combining with other nephrotoxic agents such as aminoglycosides, NSAIDs, or contrast media, as Stage 3 CKD patients have limited renal reserve 1. Even though amoxicillin-clavulanate itself is not directly nephrotoxic, the combination increases risk of acute kidney injury.
Monitor for drug interactions in patients on multiple medications, as altered metabolism in renal failure increases toxicity risk even for hepatically-metabolized drugs 4.