Is it safe to co‑administer amoxicillin‑clavulanate and azithromycin in a patient with an estimated glomerular filtration rate of 59 mL/min?

Co-Administration of Amoxicillin-Clavulanate and Azithromycin at GFR 59 mL/min

Yes, both amoxicillin-clavulanate and azithromycin can be safely co-administered in a patient with a GFR of 59 mL/min, but amoxicillin-clavulanate requires dose adjustment while azithromycin does not.

Renal Function Classification

• A GFR of 59 mL/min places this patient in Stage 3a chronic kidney disease (CKD), defined as moderately reduced kidney function (GFR 45-59 mL/min/1.73 m²). 1
• This level of renal impairment requires monitoring of kidney function every 3-6 months and careful attention to drug dosing. 1

Amoxicillin-Clavulanate Dosing at GFR 59 mL/min

Reduce the standard dose by extending the dosing interval from every 8 hours to every 12 hours, or reduce each dose by approximately 50%. 2

• For mild-to-moderate infections, use 500 mg/125 mg every 12 hours instead of the standard every 8-hour regimen to account for decreased amoxicillin clearance while maintaining adequate clavulanic acid exposure. 2
• Amoxicillin clearance decreases more significantly than clavulanic acid clearance as renal function declines, with total body clearance of amoxicillin being more affected than clavulanic acid in patients with GFR 35-75 mL/min. 3
• The ratio of amoxicillin to clavulanic acid exposure increases from approximately 4.9 at GFR 75 mL/min to 5.3 at GFR 35-75 mL/min, indicating differential accumulation. 3
• Do not exceed 6 grams of amoxicillin per day to minimize the risk of neurotoxicity from drug accumulation. 2

Azithromycin Dosing at GFR 59 mL/min

No dose adjustment is required for azithromycin at this level of renal function.

• Azithromycin is primarily eliminated through biliary excretion rather than renal clearance, making it safe to use at standard doses even with moderate renal impairment. 1
• Standard dosing of 500 mg on day 1 followed by 250 mg daily for 4 days, or 500 mg daily for 3 days, can be used without modification. 1

Safety Monitoring Requirements

Monitor renal function within 2-3 days if clinical deterioration occurs or if intercurrent illness develops. 4

• Check serum creatinine and electrolytes if the patient develops diarrhea, dehydration, or receives other nephrotoxic medications. 1, 4
• Avoid combining with NSAIDs or other nephrotoxic agents that could further impair amoxicillin clearance and precipitate acute kidney injury. 2
• Temporarily suspend or further reduce the amoxicillin-clavulanate dose if acute illness, dehydration, or contrast administration occurs. 2
• Increase monitoring frequency when GFR is below 60 mL/min, as recommended for all renally cleared medications. 1

Drug Interaction Considerations

There are no significant pharmacokinetic interactions between amoxicillin-clavulanate and azithromycin that would preclude their co-administration.

• Both antibiotics can be used simultaneously without dose adjustment for the azithromycin component. 1
• The combination provides broad-spectrum coverage and is commonly used in clinical practice for community-acquired pneumonia and other mixed infections. 1

Key Clinical Pitfalls to Avoid

• Do not use standard every-8-hour dosing of amoxicillin-clavulanate at GFR 59 mL/min, as this will lead to amoxicillin accumulation and increased risk of adverse effects including crystalluria and neurotoxicity. 2, 3
• Do not assume serum creatinine alone reflects true renal function in elderly patients with reduced muscle mass, as creatinine-based equations may underestimate the degree of renal impairment by one CKD stage in over 30% of cases. 1
• Watch for signs of drug accumulation including confusion, seizures, or other neurological manifestations if therapy extends beyond 7-10 days. 2
• Be vigilant for crystalluria if very high doses are used or if renal function deteriorates further toward GFR 15 mL/min, though this risk is minimal at GFR 59 mL/min. 2