Shock Syndromes I

the differences in the benefit with combination therapy according to baseline mortality

risk, showed a significant benefit of combination therapy in those with a mortality risk

greater than 25%. These data suggest that severely ill patients benefit from combination

antibacterial therapy.

iii.

Combination therapy increases the likelihood that at least one drug is effective against the

pathogen, particularly for known or suspected multidrug-resistant organisms such as P.

aeruginosa.

iv.

The 2021 SSC guidelines suggest combination therapy for patients at high risk of multidrug-

resistant pathogens.

Empiric combination therapy should be de-escalated within the first few days of therapy if the

patient has clinical improvement.

As noted in the Pharmacokinetics/Pharmacodynamics chapter, sepsis and septic shock can

significantly affect the probability of attaining the antimicrobial pharmacokinetic/pharmacodynamic

target. Dosing strategies for patients with sepsis should be optimized according to pharmacokinetic/

pharmacodynamic principles.

Most notably, the volume of distribution of hydrophilic antibiotics (e.g., β-lactams,

aminoglycosides, and vancomycin) will be increased. Clearance may either be increased (in the

setting of augmented renal clearance) or decreased (in the presence of end-organ dysfunction).

ii.

A pharmacokinetic/pharmacodynamic study of the first dose of β-lactams in patients with

sepsis and septic shock suggested that the pharmacokinetic/pharmacodynamic target was

attained in less than 50% of the patients given ceftazidime 2 g (28% target attainment),

cefepime 2 g (16%), and piperacillin/tazobactam 4 g/0.5 g (44%). The pharmacokinetic/

pharmacodynamic target was attained in 75% of patients receiving meropenem 1 g. For each

antibiotic, the volume of distribution was higher and the clearance was lower than the values

reported in healthy volunteers.

iii.

A multicenter cross-sectional study of β-lactam concentrations in critically ill patients found

that the minimum pharmacokinetic/pharmacodynamic target of at least 50% of free drug time

above the minimal inhibitory concentration (MIC) (50% fT>MIC) was not achieved in 16%

of patients with an infection. Of importance, achievement of 50% fT>MIC or 100% fT>MIC

was independently associated with a higher likelihood of a positive outcome on multivariable

analysis (OR 1.02; 95% CI, 1.01–1.04 and OR 1.56; 95% CI, 1.15–2.13, respectively).

iv.

These data suggest that a loading dose approach for these antibiotics is necessary for patients

with sepsis and septic shock. In addition, the impact of methods to improve the time that the

free drug concentration is above the MIC should be studied further.

antibiotics. Having a major delay in the second antibiotic dose was independently associated with

increased odds of hospital mortality (OR 1.61; 95% CI, 1.01–2.57) and mechanical ventilation (OR

2.44; 95% CI, 1.24–4.69).

Antimicrobial therapy should be evaluated on a daily basis to determine whether opportunities for

de-escalation or discontinuation exist.

Continued use of broad-spectrum antimicrobial therapy may cause untoward adverse effects

and promote the development of resistance.

ii.

De-escalation may be clear-cut in infections in which a contributive pathogen has been

identified; in such cases, antimicrobial therapy should be reduced to the narrowest-spectrum

agent with adequate activity. However, de-escalation may be more challenging in culture-

negative sepsis.

iii.

Antimicrobials are typically continued for 7–10 days, though longer courses may be

indicated in patients with a poor clinical response, those with bacteremia, or those who are

immunocompromised.