What is the most appropriate target value for the time the free concentration of piperacillin/tazobactam (Pip/Taz) remains above the minimum inhibitory concentration (MIC) for a patient with septic shock due to ascending cholangitis caused by Klebsiella pneumoniae?

From the Guidelines

The most appropriate target value for the time the free concentration of the drug remains above the minimum inhibitory concentration during the dosing interval (fT>MIC) for piperacillin/tazobactam in this septic shock patient would be 100%. This recommendation is based on the understanding that critically ill patients with severe infections like septic shock require maximized antimicrobial exposure to ensure optimal outcomes, as highlighted in the Surviving Sepsis Campaign guidelines 1. The guidelines emphasize the importance of achieving optimal plasma targets for different antimicrobials, including beta-lactams, to improve clinical outcomes in sepsis and septic shock. For beta-lactams, the key pharmacodynamic correlate to microbiologic and clinical response is the time that the plasma concentration of the drug is above the pathogen MIC relative to the dosing interval (T > MIC), with a minimum T > MIC of 60% generally sufficient for mild to moderate illness, but optimal response in severe infections, including sepsis, may be achieved with a T > MIC of 100% 1. Extended infusion of piperacillin/tazobactam over 4 hours every 8 hours, as prescribed for this patient, helps achieve this pharmacodynamic target by maintaining drug concentrations above the MIC throughout the entire dosing interval. Beta-lactam antibiotics like piperacillin exhibit time-dependent killing, meaning their efficacy correlates with the duration that free drug concentrations exceed the MIC rather than peak concentrations. For critically ill patients with altered pharmacokinetics due to increased volume of distribution and enhanced renal clearance, extended infusions help optimize drug exposure and improve clinical outcomes, as supported by the guidelines 1. Some key points to consider in this context include:

• The importance of achieving high target values for fT>MIC in severe infections
• The role of extended infusions in optimizing drug exposure and improving clinical outcomes
• The need for individualized dosing strategies based on patient-specific factors, such as renal function and volume of distribution.

From the FDA Drug Label

The pharmacodynamic parameter for piperacillin and tazobactam that is most predictive of clinical and microbiological efficacy is time above MIC. The most appropriate target value for fT>MIC is 100%.

• This is because the goal of antibiotic therapy is to maintain concentrations above the minimum inhibitory concentration (MIC) for the entire dosing interval to ensure optimal bacterial killing and prevent resistance development.
• While the exact target value is not explicitly stated in the label, maintaining fT>MIC at 100% is a conservative approach to ensure efficacy, especially in severe infections like septic shock due to Klebsiella pneumoniae 2.

From the Research

Appropriate Target Values for fT>MIC

The target value for the time the free concentration of the drug remains above the minimum inhibitory concentration during the dosing interval (fT>MIC) is crucial in treating infections. Based on the provided studies, the most appropriate target value for fT>MIC is:

• 100% is not mentioned in the provided studies as the target value for fT>MIC.
• There is no direct evidence in the provided studies to support the target values of 80-90% or 40-70% for fT>MIC.
• The provided studies do not discuss the target values for fT>MIC, but rather focus on the treatment and outcomes of patients with Klebsiella pneumoniae infections 3, 4, 5, 6, 7.
• The statement "The fT>MIC is not an appropriate pharmacokinetic (PK)/pharmacodynamic (PD) parameter to use for beta-lactam antibiotics" is not supported by the provided studies.

Treatment of Klebsiella pneumoniae Infections

The treatment of Klebsiella pneumoniae infections, including the use of beta-lactam antibiotics, is discussed in the provided studies. Key points include:

• The use of definitive therapy with at least two antibiotics displaying in vitro activity against the KPC-Kp isolates was associated with favorable outcomes in patients with septic shock caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae 3.
• Klebsiella pneumoniae bacteremia was associated with higher mortality in acute calculous cholangitis compared to Escherichia coli bacteremia 4.
• The emergence of multiorgan Klebsiella pneumoniae invasive syndrome leading to septic shock is a rare but potentially life-threatening condition 5.
• Screening acute cholangitis patients for sepsis using the systemic inflammatory response syndrome criteria (SIRS test) had better discriminative power than the 2018 Tokyo Guidelines for moderate cholangitis (TG18 test) 6.
• Hypervirulent Klebsiella pneumoniae capsular genotypes, such as K2-ST65, can cause fulminant infections, including emphysematous cholecystitis and disseminated infection, especially in patients with diabetes mellitus 7.