Pharmacokinetics/Pharmacodynamics

suggesting cutoffs of about 40% for carbapenems, 50% for penicillins, and 50%–75% for cephalosporins

prolonged or continuous infusions. Many institutions have adopted the practice of prolonged infusions.

This is supported by quasi-experimental and retrospective studies showing improved outcomes such as

improved clinical cure, improved microbiological cure, and reduced morbidity and mortality. However,

between PD modeling studies and controlled clinical trials; patient variability, dosing variability, and

consider is resolving AKI and timely dose adjustment of β-lactam antibiotics because delayed dose

adjustments have been associated with in-hospital mortality (Open Forum Infect Dis 2024;11:ofae059).

Aminoglycosides: Aminoglycoside bacterial killing is based on the ratio between the maximum

drug concentration and the MIC for the bacterial pathogen (Cmax/MIC), or concentration-dependent

killing. Efficacy was noted when patients were pooled from four controlled clinical trials and peak

concentrations, MIC values, and clinical response were evaluated. Peak-to-MIC ratios of 8–10 resulted in

around a 90% clinical response (J Infect Dis 1987;155:93-9). In patients with gram-negative bacteremia,

early therapeutic peak concentrations were a significant discriminating factor for mortality. According

to these and other data, once-daily aminoglycoside dosing has been used. Taking advantage of high

peak concentrations maximizes the PD of aminoglycosides. Variability in the Vd of aminoglycosides in

critically ill patients, together with concern for ARC in this population, raises issues about appropriately

dosing these agents, especially in critically injured trauma patients, whose drug concentrations can be

undetectable for more than 12 hours (J Trauma 2000;49:869-87) and larger loading doses and more

frequent monitoring may be warranted.

Vancomycin: The PD parameter that best describes vancomycin efficacy is the AUC/MIC. Several

studies have evaluated the free 24-hour AUC/MIC (fAUC0-24/MIC), or the AUC × 50% protein binding/

MIC. Current guidelines use the available literature to recommend an AUC/MIC of 400 or greater for

of vancomycin of 20–35 mg/kg based on actual body weight are recommended to expedite achieving

these target serum concentrations and PD goals while decreasing the chance of subtherapeutic serum

concentrations during the initial days of therapy. The guidelines recommending continuous infusion

regimens are an acceptable alternative when conventional dosing is unable to achieve the target AUC.

They also note the intravenous access issues presented for critically ill patients when continuous

infusion regimens are employed (Clin Infect Dis 2020:71;1361-4). Specifically, vancomycin has been

demonstrated to be Y-site incompatible with multiple β-lactams, moxifloxacin, propofol, phenytoin,

methylprednisolone, and furosemide—all medications that are commonly used in the ICU setting.

As such, clinicians should closely monitor vancomycin coadministration with other medications. Of

interest is a retrospective study of vancomycin-associated nephrotoxicity in critically ill patients. In

this study, intermittent dosing was associated with a significantly higher risk of nephrotoxicity than

dosing may be required in critically ill patients. Doses as high as 20 mg/kg administered as often as

every 6 hours were needed to optimize PK variables in critically injured trauma patients being treated

for ventilator-associated pneumonia (J Trauma Acute Care Surg 2012;72:1478-83).

Fluoroquinolones: Similar to the efficacy of aminoglycosides, the efficacy of the fluoroquinolones is based

on a Cmax/MIC (10 or greater), and they exhibit a post-antibiotic effect against gram-negative and gram-

positive bacteria. PD studies have shown that the fAUC0-24/MIC is associated with bacterial eradication.

In one study of lower respiratory tract infections treated with ciprofloxacin, an AUC0-24/MIC of 125

was associated with the percent probability for clinical cure of 80% (Antimicrob Agents Chemother

1993;37:1073-81). However, it is difficult to incorporate these PD variables into fluoroquinolone dosing

in individual critically ill patients. Measuring fluoroquinolone serum concentrations is not routine;

therefore, it is difficult to determine whether the PD targets have been met in an individual patient.