Antibiotics dosing in critically ill patients with sepsis and septic shock

A key component of the first-line management of critically ill patients is the administration of early and appropriate IV antibiotic therapy.

An insufficient or otherwise inadequate antibiotic dosing is one of the variables more strongly associated with unfavourable outcomes in critically ill patients.

The antibiotic dosing regimen should be established depending on host factors and properties of antibiotic agents. Antibiotic pharmacokinetics describes the fundamental processes of absorption, distribution, metabolism, and elimination and the resulting concentration-versus-time profile of an agent administered in vivo. The achievement of appropriate target site concentrations of antibiotics is essential to eradicate the relevant pathogen. Suboptimal target site concentrations may have important clinical implications, and may explain therapeutic failures, in particular, for bacteria for which in vitro MICs are high. Antibiotics typically need to reach a site of action outside the plasma. This requires the drug to pass through the capillary membranes. Disease and drug-related factors can contribute to differential tissue distribution.

In patients with septic shock, administering an optimal first dose is probably as equally important as to the timing of administration. This optimal first dose could be described as a loading, or front-loaded dose and is calculated from the volume of distribution (Vd) of the drug and the desired plasma concentration. The Vd of hydrophilic agents (which disperse mainly in water such as beta-lactams, aminoglycosides and glycopeptides) in patients with septic shock may be altered by changes in the permeability of the microvascular endothelium and consequent alterations in extracellular body water. This may lead to lower than expected plasma concentrations during the first day of therapy resulting in sub-optimal achievement of antibiotic levels. In the setting of alterations in the volume of distribution, loading doses and/or a higher overall total daily dose of beta-lactams, aminoglycosides, or glycopeptides are often required to maximize the pharmodynamics ensuring optimal drug exposure to the infection site in patients with  sepsis or septic shock.

Once an appropriate initial loading dose is achieved, the antibiotic regimen should be reassessed, at least daily, because pathophysiological changes may significantly affect drug availability in the critically ill patients. Lower than standard dosages of renally excreted drugs must be administered in the presence of impaired renal function, while higher than standard dosages of renally excreted drugs may be needed for optimal activity in patients with glomerular hyperfiltration. It should be noted that in critically ill patients, plasma creatinine is an unreliable marker of renal function.

Recommended dosing regimens of the most frequently used renally excreted antimicrobials according to renal function

Knowledge of the pharmacokinetic and pharmacodynamic antibiotic properties of each drug including (inhibition of growth, rate and extent of bactericidal action, and post-antibiotic effect) may provide a more rational determination of optimal dosing regimens in terms of the dose and the dosing interval. Optimal use of the pharmacokinetic/pharmacodynamic relationship of antibiotics is important for obtaining good clinical outcomes and reduction of resistance. Dosing frequency is related to the concept of time-dependent versus concentration-dependent killing. Beta-lactams exhibit time-dependent activity and exert optimal bactericidal activity when drug concentrations are maintained above the MIC. Therefore, it is important that the serum concentration exceeds the MIC for appropriate duration of the dosing interval for the antimicrobial and the organism. Higher frequency dosing, prolonged infusions and continuous infusions have been utilized to achieve this effect. Basing on pharmacokinetics/pharmacodynamics principles the traditional intermittent dosing of each agent may be replaced with prolonged infusions of certain beta-lactam antibiotics especially in those critically ill patients with infections caused by Gram-negative bacilli that have elevated but susceptible MICs to the chosen agent.

In contrast, antibiotics such as aminoglycosides exhibit concentration-dependent activity and should be administered in a once daily manner (or with the least possible number of daily administrations) in order to achieve high peak plasma concentrations. With these agents, the peak serum concentration, and not the time the concentration remains above the MIC, is more closely associated with efficacy. In terms of toxicity, aminoglycosides nephrotoxicity is caused by a direct effect on the renal cortex and its uptake saturation. Thus, an extended interval dosing strategy reduces the renal cortex exposure to aminoglycosides and reduces the risk of nephrotoxicity.

Massimo Sartelli