**3.4 Dosing and modality of administration**

Maximizing the dose in patients with sepsis and septic shock is a judicious attitude. This strategy is based upon the known increased volume of distribution that can occur in patients with sepsis due to the administration of fluid and the action of inflammatory cytokines [46, 47] and that higher clinical success rates have been reported in patients with higher peak concentrations of antimicrobials [48, 49]. Continuous infusions of antibiotics as compared with intermittent dosing regimens remain investigational at this time [50].

The meta-analysis of Chen CH, et al. [51] (9 RCTs plus 4 retrospective studies, 1957 participants) compared continuous and intermittent groups. A significant difference was showed with mortality which was higher in the subgroup of continuous infusion (OR 1.433, 95% CI: 1.139–1.801). In this same group, length of stay in ICU was shorter and antibiotic duration was longer but without significance [(OR 0.834, 95% CI: 0.542–1.282) and (OR 1.055, 95% CI: 0.659–1.689) respectively] [51].

However, authors were unable to recommend continuous infusion of intravenous antibiotics better than traditional intermittent infusions of antibiotics at routine clinical care.

In general, the choice of the administration modality depends above all on the PK/PD characteristics of the antibiotic. Time-dependent antibiotics (eg betalactamins, vancomycin) their bactericide are based on the time of contact with the


*¶Aminoglycosides and fluoroquinolones are generally used in combination with another agent. Source: Reference [52, 53]*

*Δmeans that the recommended dosage corresponds to that of colistin base, the conversion is: 1 mg colistin base = 2.67 mg colistimethate = 33.3 IU. Thus 2.5 to 5 mg / kg / day of colistin base correspondsabout 6 to 12 million IU of colistimethate. ◊ For severe hepatic dysfunction: loading dose is the same (100 mg) followed by 25 mg IV every 12 hours.*

**Table 3.**

*Dosage of most common prescribed systemic antibiotics in ICU adults with normal renal function.*

microorganism at doses above the MIC. Therefore the administration of this type of antibiotic in continuous infusion or in multiple doses is preferred. On the other hand, dose-dependent antibiotics (eg aminosia, colistin), whose effectiveness depends on the peak concentration reached, their administration at a single or twice dose is preferred.

Dosing of the most common prescribed antimicrobials in ICU patients with normal renal function is summarized in the **Table 3.** When renal function impair, antibiotic's doses should be adjusted according to the creatinine clearance.

The follow up of infection's indices is mandatory, including complete blood count and additional cultures. Results should prompt modification of antibiotic choice if a better and safer regimen can be substituted and/or investigations directed towards source control.

#### **3.5 Eradication of septic focus**

It should be undertaken in timely manner when they feasible since undrained foci of infection may not respond to antibiotics alone. Typical examples are: infected catheter which must be removed (obviously after the establishment of another vascular access), plumonary abscess and chest wall, obstructive pyelonephritis which indicates percutaneous nephrostomy, cholecystectomy, peritonitis to be cleaned in the operative room, dermo-hypoderma which require debridement or amputation of soft tissues, etc.

Expert opinions recommend not exceeding 6 to 12 hours since the identification of septic focus and its eradication in order to facilitate access to antibiotics and thus improve survival.

#### **3.6 De-escalation and duration of antibiotics**

Antibiotics started for sepsis should be reassessed daily for potential discontinuing if sepsis is ruled out or narrowing if more data becomes available [54]. While there is no consensus on de-escalation criteria, most experts use follow-up clinical (improved vital signs), laboratory and imaging data, and a fixed course of broadspectrum therapy (eg, 3 to 5 days). After culture and susceptibility results return and/or after patients clinically improve, antimicrobial therapy may be narrowed to a few days. When possible, antimicrobial therapy should also be pathogen/ susceptibility-directed. However, since no pathogen is identified (almost in 50% of patients), de-escalation of empiric therapy requires a component of clinical judgment. For example, vancomycin is typically discontinued, if no *Staphylococcus* is cultured.

Concerning the duration of antibiotic therapy, it must be reasoned and reassessed on a case-by-case basis. Often duration of 7 to 10 days is sufficient [55]. For certain cases, this duration must be prolonged up to even three weeks (mainly septicaemic presentations with metastatic locations (endocarditis, osteomyelitis, large abscess), a lack of clinical improvement within the usual timeframes, deep infections with *Candida* or *aspergillus,* some viral infections (Herpes or cytomegalovirus), isolation of extensively drug resistant (XDR) Gram-negative bacilli, immune disorders [56].

#### **3.7 Role of procalcitonin**

PCT appears to be a more relevant marker in diagnostic for bacterial infections. Its serum level increases in case of severe bacterial or parasitic infection with a sensitivity comparable to that of PCR but with better specificity. The importance

#### *Empiric Antimicrobial Therapy in Critically Ill Septic Patients DOI: http://dx.doi.org/10.5772/intechopen.98327*

of its serum level at the time of initial treatment would be also correlated with a subsequent poor prognosis of patients.

Although many institutions and guidelines support the use of procalcitonin to limit antibiotic (empiric or therapeutic) use in critically ill patients with suspected infection or documented infection, the evidence to support this practice is limited. Other studies suggest that procalcitonin may distinguish infectious from noninfectious conditions and may therefore facilitate the decision to de-escalate empiric therapy [57, 58].

In addition, studies of the kinetics of PCT were more interesting and useful than studies of a static value of unadjusted PCT. MDT is a favorable marker to assess changes in clinical symptoms and patient prognosis. MDT may improve the judgment of disease severity in patients with sepsis or septic shock, thereby improving the ability of clinicians to accurately assess disease prognosis [59]. Hence, we suggest that PCT be assessed daily or at default every 48 hours for critical septic patients.
