Optimizing Antimicrobial Therapy of Sepsis and Septic Shock
Optimizing Antimicrobial Therapy of Sepsis and Septic Shock
A substantial body of literature suggests that optimization of dosing strategies can improve pathogen clearance and clinical responses in infection. However, to date, data on the impact of pharmacokinetic (PK) optimization on mortality in serious infections, particularly septic shock, remain sparse.
For β-lactam antibiotics, the key PK parameter for optimization of pathogen clearance is the fractional time above the minimal inhibitory concentration (fT > MIC) of the pathogen. There are relatively few studies that examine the role of fT > MIC in serious human infections. They suggest that high fT > MIC (>60–100%) is associated with better bacterial eradication and clinical cure.
Continuous infusion of certain antibiotics, which generates 100% fT > MIC for sensitive pathogens, compared with intermittent administration (i.e., piperacillin-tazobactam, meropenem, ceftazidime), resulted in improved clinical cure, shorter hospitalization, and lower mortality in the subset of the most critically ill patients, many of whom would have had septic shock.
At least two meta-analyses of continuous infusion of β-lactams in human infection have been published. Neither showed an overall beneficial effect of continuous infusion; however, both yielded intriguing insights. Each study commented on the trend toward greater beneficial effects in those studies with high baseline mortality risk, an observation that is congruent with our underlying hypothesis that the benefit of PK optimization of dosing strategies on mortality should exist primarily in septic shock.
As a whole, these data support the use of high-end daily dosing at short intervals or extended infusions and continuous infusions where possible. These data also suggest the need for studies of continuous infusion β-lactam therapy in the highest risk septic shock patients who are most likely to benefit.
For fluoroquinolones and aminoglycoside antibiotics, the key PK parameter for optimization of pathogen clearance is the area under the curve divided by the MIC of the pathogen normalized to 24 hours (AUC24/MIC), although peak/maximum concentration divided by the MIC (Cmax/MIC) is a closely related value.
Experimental animal models and human studies suggest that an AUC24/MIC of >87 to 125 for fluoroquinolones (depending on the individual drug and clinical syndrome) during the course of therapy yields optimal pathogen clearance and clinical cure. Unfortunately, there are no human data linking fluoroquinolone PK indices to survival or mortality and no studies of septic shock have yet been reported. Similarly, peak/MIC ratios of >10 to 12 have been shown to be associated with improved clinical and microbiologic cure rates with aminoglycosides.
Vancomycin is another antibiotic whose efficacy is most closely related to concentration-dependent pharmacokinetic indices. Retrospective studies of methicillin-resistant S. aureus (MRSA) bacteremia and pneumonia reported better microbiological and clinical outcomes in patients who had vancomycin AUC24/MIC of 400. This has been shown to be independently associated with survival in a retrospective study of MRSA septic shock.
Antimicrobial pharmacokinetic indices have been linked to clinical and microbiologic response in a variety of studies, but the ones showing an association with survival are more limited. To the extent that such studies exist, they tend to show a survival advantage in critically ill patients, particularly in those with septic shock.
Pharmacokinetic Optimization
A substantial body of literature suggests that optimization of dosing strategies can improve pathogen clearance and clinical responses in infection. However, to date, data on the impact of pharmacokinetic (PK) optimization on mortality in serious infections, particularly septic shock, remain sparse.
Time-dependent Killing Agents
For β-lactam antibiotics, the key PK parameter for optimization of pathogen clearance is the fractional time above the minimal inhibitory concentration (fT > MIC) of the pathogen. There are relatively few studies that examine the role of fT > MIC in serious human infections. They suggest that high fT > MIC (>60–100%) is associated with better bacterial eradication and clinical cure.
Continuous infusion of certain antibiotics, which generates 100% fT > MIC for sensitive pathogens, compared with intermittent administration (i.e., piperacillin-tazobactam, meropenem, ceftazidime), resulted in improved clinical cure, shorter hospitalization, and lower mortality in the subset of the most critically ill patients, many of whom would have had septic shock.
At least two meta-analyses of continuous infusion of β-lactams in human infection have been published. Neither showed an overall beneficial effect of continuous infusion; however, both yielded intriguing insights. Each study commented on the trend toward greater beneficial effects in those studies with high baseline mortality risk, an observation that is congruent with our underlying hypothesis that the benefit of PK optimization of dosing strategies on mortality should exist primarily in septic shock.
As a whole, these data support the use of high-end daily dosing at short intervals or extended infusions and continuous infusions where possible. These data also suggest the need for studies of continuous infusion β-lactam therapy in the highest risk septic shock patients who are most likely to benefit.
Concentration-sependent Killing Agents
For fluoroquinolones and aminoglycoside antibiotics, the key PK parameter for optimization of pathogen clearance is the area under the curve divided by the MIC of the pathogen normalized to 24 hours (AUC24/MIC), although peak/maximum concentration divided by the MIC (Cmax/MIC) is a closely related value.
Experimental animal models and human studies suggest that an AUC24/MIC of >87 to 125 for fluoroquinolones (depending on the individual drug and clinical syndrome) during the course of therapy yields optimal pathogen clearance and clinical cure. Unfortunately, there are no human data linking fluoroquinolone PK indices to survival or mortality and no studies of septic shock have yet been reported. Similarly, peak/MIC ratios of >10 to 12 have been shown to be associated with improved clinical and microbiologic cure rates with aminoglycosides.
Vancomycin is another antibiotic whose efficacy is most closely related to concentration-dependent pharmacokinetic indices. Retrospective studies of methicillin-resistant S. aureus (MRSA) bacteremia and pneumonia reported better microbiological and clinical outcomes in patients who had vancomycin AUC24/MIC of 400. This has been shown to be independently associated with survival in a retrospective study of MRSA septic shock.
Antimicrobial pharmacokinetic indices have been linked to clinical and microbiologic response in a variety of studies, but the ones showing an association with survival are more limited. To the extent that such studies exist, they tend to show a survival advantage in critically ill patients, particularly in those with septic shock.