An insufficient or inadequate antimicrobial regimen is one of the variables strongly associated with unfavorable outcomes in critically ill patients [5].

Recent Surviving Sepsis Campaign guidelines for the management of severe sepsis and septic shock [6] included three important recommendations about antimicrobial therapy: (1) administration of effective intravenous antimicrobials within the first hour of recognition of septic shock and severe sepsis without septic shock as the goal of therapy; (2) initial empiric anti-infective therapy of one or more drugs that have activity against all likely pathogens that penetrate in adequate concentrations into tissues presumed to be the source of sepsis; (3) antimicrobial regimen should be reassessed daily for potential de-escalation.

Some studies [7–8] showed that modifying an initial inadequate antibiotic therapy, according to microbiological results, in critically ill patients with ventilation aspiration pneumonia (VAP) does not translate into a better outcome. Therefore, the best approach for reducing infection-related mortality in critically ill patients seems to be the initial institution of an adequate and broad-spectrum antibiotic regimen, which should be de-escalated when culture results are available and clinical status can be better assessed, 48–72 h after initiation of empiric therapy. The concept of de-escalation strategy can easily be translated to all critically ill patients. If the empiric therapy is administered in a timely manner by using appropriate agents that lead to rapid bacterial killing, this strategy can minimize the emergence of resistance, optimizing antimicrobial treatment.

We should decide the optimal dosage when starting antimicrobial therapy considering the “dilution effect,” also called the third spacing phenomenon. Low plasma antimicrobial levels can lead to low antimicrobial concentrations in the peritoneal fluid with potentially reduced antimicrobial delivery to the target tissues when administering hydrophilic agents. This includes β-lactams, aminoglycosides, and glycopeptides, which are selectively distributed to the extracellular space. Therefore, higher than standard loading doses of these drugs should be administered to ensure optimal exposure at the infection site whenever treatment is begun in patients with severe sepsis or septic shock [9].

Once appropriate initial treatment is started, it is mandatory to reassess the antimicrobial regimen daily, because the pathophysiological changes of the critically ill patients, may significantly affect drug distribution. Lower than standard dosages of renally excreted drugs should be administered in the presence of impaired renal function. Higher than standard dosages of renally excreted drugs may be needed for optimal exposure in patients with glomerular hyperfiltration [9].

This is crucial for hydrophilic antimicrobials (β-lactams, aminoglycosides, and glycopeptides) and for moderately lipophilic antimicrobials (ciprofloxacin and levofloxacin).

Table 17.1 shows the recommended dosing regimens of the most frequently used renally excreted antimicrobials according to renal function [10].

In the last years, the relevance of pharmacokinetic-pharmacodynamic relationships in optimizing drug exposure has been progressively highlighted in critically ill patients [11]. Different approaches should be pursued according to the mechanism of antimicrobial activity exhibited by each antibiotic [12]. Two patterns of bactericidal activity have been identified: time-dependent activity (where the time that the plasma concentration persists above the minimum inhibitory concentration [MIC] of the etiological agent is considered the major determinant for efficacy) and concentration-dependent activity (where the efficacy is mainly related to the plasma peak concentration in relation to the MIC of the microorganism).

Concentration-dependent antibiotics, such as aminoglycosides and quinolones, are more effective at higher concentrations. These agents show an associated concentration-dependent postantibiotic effect, and bactericidal action continues for a period of time after the antibiotic level falls below the MIC [9]. Concentration-dependent agents administered in high dosage, short-course, once-a-day treatment regimens may promote more rapid and efficient bactericidal action and prevent the development of resistant strains and antibiotic toxicity.