What is the recommended dosage of Cloxacillin (generic name) for a patient with a confirmed or suspected bacterial infection, considering factors such as severity of infection, age, weight, and renal function (Impaired renal function)?

Cloxacillin Dosing in Renal Impairment

For patients with impaired renal function, cloxacillin dosing must be significantly reduced from standard regimens, with doses ranging from 3.5-13.1 g/day based on glomerular filtration rate (GFR), rather than the conventional 12 g/day used in normal renal function. 1

Standard Dosing in Normal Renal Function

For adults with preserved renal function and severe methicillin-susceptible Staphylococcus aureus (MSSA) infections:

• Standard dose: 12 g/day administered as either continuous infusion or divided intermittent doses 2, 3
• Alternative regimen: 2 g every 4 hours (12 g/day total) or 3 g every 6 hours (12 g/day total) for intermittent dosing 3
• Continuous infusion of 2 g/day achieves time above MIC (T>MIC) of 50%, while four infusions of 3 g/day achieves T>MIC of 42% 3

Critical Dosing Adjustments for Renal Impairment

The most important factor determining cloxacillin dosing is renal function, as standard doses cause systematic overdosing in 83.9% of ICU patients with renal dysfunction. 2

GFR-Based Dosing Algorithm

Using the validated nomogram for continuous infusion 1:

• GFR 125 mL/min: 13.1 g/day
• GFR 100 mL/min: 10.5 g/day
• GFR 75 mL/min: 7.9 g/day
• GFR 50 mL/min: 5.7 g/day
• GFR 20 mL/min: 3.5 g/day

Severe Renal Impairment (CrCl <10 mL/min)

• Patients with creatinine clearance <10 mL/min (with or without hemodialysis) have significantly increased risk of overdosing even with dose adjustments 2
• Doses should be reduced to the lower end of the nomogram range and therapeutic drug monitoring (TDM) is mandatory 2, 4

Therapeutic Drug Monitoring

Target trough concentration: 20-50 mg/L for total antibiotic activity 2, 1

• TDM is essential in renal impairment, as 83.9% of patients receiving standard 12 g/day dosing are overdosed (median trough 134.3 mg/L) 2
• Plasma concentrations >50 mg/L are associated with increased risk of acute kidney injury (AKI) and neurological toxicity 2, 4
• Continuous infusion produces fewer outlying drug concentrations compared to intermittent dosing 5

Toxicity and Safety Considerations

Neurological Toxicity

• 17.7% of overdosed patients experience neurological side effects including persistent coma and delirium 2
• Risk increases with trough concentrations exceeding 50 mg/L 2

Acute Kidney Injury

• AKI occurs in elderly patients (median age 75 years) receiving high-dose cloxacillin, particularly with concomitant nephrotoxic drugs 4
• 57% of AKI cases had cloxacillin concentrations >50 µg/mL 4
• Most patients (57%) achieve complete renal recovery after cloxacillin discontinuation 4

High-Risk Populations for AKI

• Concomitant gentamicin use (present in 83% of AKI cases) 4
• Diuretics (65% of cases) 4
• ACE inhibitors or ARBs (35% of cases) 4
• Elderly patients 4

Administration Method

Continuous infusion is preferred over intermittent dosing because:

• Produces more consistent plasma concentrations with fewer outliers 5
• Optimizes time-dependent bactericidal activity (T>MIC) 3
• Easier to adjust based on TDM results 1

Monitoring Requirements

• Baseline and serial creatinine clearance measurements using CKD-EPI formula expressed in mL/min (not normalized to body surface area) 1
• Therapeutic drug monitoring at steady state (after 3-5 doses for intermittent dosing, or 24-48 hours for continuous infusion) 2, 5
• Monitor for neurological symptoms (confusion, delirium, coma) especially in patients with renal impairment 2
• Serial renal function assessment particularly when combined with aminoglycosides or other nephrotoxic agents 4

Clinical Pitfalls to Avoid

• Do not use the standard 12 g/day dose without considering renal function - this causes systematic overdosing in renal impairment 2
• Do not rely solely on serum creatinine - calculate actual GFR in mL/min using CKD-EPI formula 1
• Avoid combining with multiple nephrotoxic agents when possible, especially gentamicin, diuretics, and RAAS inhibitors 4
• Do not assume dose adjustments based on creatinine alone are adequate - correlation between creatinine and plasma concentrations is low 5