A 65-year-old man weighing 80 \text{ kg} is admitted to the intensive care unit with a sev… — USMLE Step 3

A 65-year-old man weighing $80 \text{ kg}$ is admitted to the intensive care unit with a severe, drug-resistant gram-negative bacteremia. The infectious disease consultant recommends starting a continuous intravenous infusion of a novel bactericidal antibiotic. The target steady-state plasma concentration ( $C_{ss}$ ) for efficacy is $5 \text{ mg/L}$ .

The population pharmacokinetic parameters for this antibiotic in healthy individuals with normal renal function (creatinine clearance $\approx 120 \text{ mL/min}$ ) are:
- Volume of distribution ( $V_d$ ): $1.5 \text{ L/kg}$
- Systemic clearance ( $CL$ ): $0.6 \text{ L/hr/kg}$

The drug is eliminated entirely unchanged in the urine, and its systemic clearance is directly proportional to creatinine clearance. The patient's estimated creatinine clearance is $60 \text{ mL/min}$ . The patient's extracellular fluid volume is clinically normal.

Based on these parameters, which of the following represents the most appropriate loading dose and continuous maintenance infusion rate for this patient?

Loading dose $600 \text{ mg}$ ; maintenance infusion $120 \text{ mg/hr}$ Answer
B
Loading dose $600 \text{ mg}$ ; maintenance infusion $240 \text{ mg/hr}$
C
Loading dose $300 \text{ mg}$ ; maintenance infusion $120 \text{ mg/hr}$
D
Loading dose $300 \text{ mg}$ ; maintenance infusion $240 \text{ mg/hr}$
E
Loading dose $120 \text{ mg}$ ; maintenance infusion $24 \text{ mg/hr}$

Answer

The correct dosing regimen is a loading dose of

600 \text{ mg}

and a maintenance infusion of

120 \text{ mg/hr}

The required loading dose is determined strictly by the volume of distribution (

V_d

) and the desired steady-state plasma concentration (

C_{ss}

), utilizing the formula:

\text{Loading Dose} = V_d \times C_{ss}

. For an

80 \text{ kg}

patient, the total

V_d

120 \text{ L}

. Thus, the loading dose is

120 \text{ L} \times 5 \text{ mg/L} = 600 \text{ mg}

. Because the patient's extracellular fluid volume is normal, the

V_d

is unchanged by his renal failure, meaning the loading dose requires no adjustment. The maintenance infusion rate is dictated by systemic clearance (

CL

) and target

C_{ss}

, utilizing the formula:

\text{Maintenance Rate} = CL \times C_{ss}

. The normal clearance for an

80 \text{ kg}

patient would be

48 \text{ L/hr}

. However, because this drug is exclusively renally cleared and the patient's creatinine clearance (

60 \text{ mL/min}

) is

50\%

of normal (

120 \text{ mL/min}

), the patient's actual clearance is halved to

24 \text{ L/hr}

. Therefore, the appropriate maintenance infusion rate is

24 \text{ L/hr} \times 5 \text{ mg/L} = 120 \text{ mg/hr}

Step-by-Step Solution

Calculate the patient's total volume of distribution (

V_d

Total

V_d = 1.5 \text{ L/kg} \times 80 \text{ kg} = 120 \text{ L}

The total fluid volume into which the drug distributes must be determined to calculate the loading dose.

Calculate the required loading dose.

Loading dose =

V_d \times C_{ss} = 120 \text{ L} \times 5 \text{ mg/L} = 600 \text{ mg}

The loading dose rapidly fills the volume of distribution to achieve the target concentration immediately. It is not affected by renal impairment as long as extracellular volume is normal.

Calculate the patient's adjusted systemic clearance (

CL

Normal total

CL = 0.6 \text{ L/hr/kg} \times 80 \text{ kg} = 48 \text{ L/hr}

. Patient

CL = 48 \text{ L/hr} \times (60 / 120) = 24 \text{ L/hr}

The maintenance dose must be adjusted for renal impairment since the drug is exclusively renally cleared and the patient's creatinine clearance is 50% of normal.

Calculate the required maintenance infusion rate.

Maintenance infusion rate = Adjusted

CL \times C_{ss} = 24 \text{ L/hr} \times 5 \text{ mg/L} = 120 \text{ mg/hr}

The maintenance infusion must exactly match the patient's specific rate of drug elimination to maintain the target steady-state plasma concentration.

Key Concept

In patients with renal impairment, the loading dose of a drug typically remains unchanged (as it depends on the volume of distribution), while the maintenance dose must be proportionally decreased (as it depends on clearance).

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