Pharmacokinetics–pharmacodynamics, computer decision support technologies, and antimicrobial stewardship: the compass and rudder

Abstract

The first guidelines for conducting antimicrobial stewardship in the hospitalized setting were published in 2007. These guidelines recommend that stewardship programs employ the science of pharmacokinetics–pharmacodynamics (PK-PD) as well as adopting computerized decision support technologies when possible. The United States Food and Drug Administration have adopted PK-PD as a cornerstone in the evaluation of antimicrobial agents during clinical development. The core principles of PK-PD center around describing the relationship between drug exposure indexed to the susceptibility of the infecting bacterial pathogen and patient response. Using such relationships with population pharmacokinetic models and simulation, rational drug and dosing regimens can be selected. But because PK-PD modeling and simulation programs are generally absent in clinical practice, systematic application of this science is missing. Herein we explain advances in technology that allow clinicians to apply PK-PD to optimize the agents and dosing regimens selected for the treatment of hospitalized patients with infection.

Introduction

He who loves practice without theory is like the sailor who boards ship without a rudder and compass and never knows where he may cast.

Leonardo da Vinci

Microbes account for 90% of the cells in the human body; therefore, the administration of antimicrobial agents has a significant impact on our microbiome. While the intended therapeutic effects of antimicrobial agents are undebatable, they must be used judiciously to mitigate the occurrence of undesired collateral consequences in patients (McDonald et al., 2005, Owens Jr, 2005, Owens Jr and Nolin, 2006, Owens Jr et al., 2008). The imprudent use of antimicrobials has contributed to the emergence of resistant organisms such that the Centers for Disease Control and Prevention report more than 2 million infections caused by antibiotic-resistant organisms each year, resulting in approximately 23,000 deaths annually (Centers for Disease Control and Prevention (CDC), 2014, Huttner et al., 2013, Owens Jr and Rice, 2006). Current strategies to counter antimicrobial-resistant organisms include new drug development, infection prevention measures, environmental cleaning strategies, and antimicrobial stewardship. (Owens, 2008b)

Antimicrobial stewardship has been defined as coordinated efforts to ensure that patients receive the right antimicrobial agent, at the right dose, and for the right duration while minimizing adverse drug events and antimicrobial resistance (Dellit et al., 2007, McDonald et al., 2005, Owens Jr, 2005, Owens Jr, 2008b, Owens Jr and Ambrose, 2005, Owens Jr and Nolin, 2006, Septimus and Owens Jr, 2011). The need for shepherding antimicrobial agents was first raised in the 1950s from the noted microbiologist Ernest Jawetz when he wrote “(it is important)… to call attention to the abuse of antibiotics, its causes and results…” (Jawetz, 1956). Over the next several decades, certain notable hospitals researched the best approaches to antimicrobial stewardship, and the numbers of implemented antimicrobial stewardship programs (ASPs) began to slowly multiply (Owens Jr, 2008b, Owens Jr et al., 2009, Pope et al., 2009). Pharmacists and physicians have traditionally coordinated antimicrobial stewardship activities, yet this approach is not feasible at every hospital (Drew et al., 2009, Owens Jr, 2008b, Owens Jr, 2009, Owens Jr et al., 2009, Septimus and Owens Jr, 2011). In 2007, the first guidelines for systematically conducting antimicrobial stewardship in hospitalized patients were put forth by the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) (Dellit et al., 2007, Owens Jr, 2008a). A decade later, governmental regulatory bodies have issued hospital accreditation standards requiring institutions to participate in antimicrobial stewardship. Furthermore, the new Centers for Medicare and Medicaid Services draft guidelines for surveying healthcare facilities report specific goals for antimicrobial stewardship in healthcare settings (Evans et al., 2015). Therefore, it is ostensible that ASPs will be well anchored in healthcare for our foreseeable future.

IDSA/SHEA guidelines on antimicrobial stewardship recommend the use of pharmacokinetics–pharmacodynamics (PK-PD) dose optimization as well as the adoption of computer decision support (CDS) when possible (Barlam et al., 2016, Dellit et al., 2007). PK-PD is the science that describes the relationship between drug exposure indexed to the susceptibility of the infecting bacterial pathogen and patient response (Ambrose et al., 2007). The current paradigm for the development of antimicrobial agents is to use PK-PD to systematically determine the dose and dosing interval for clinical studies (Ambrose, 2011, Ambrose et al., 2012a, Ambrose et al., 2012b, Boucher et al., 2017). Simulations based on population pharmacokinetic models yield patient-specific drug exposures which can be indexed to the minimum inhibitory concentration (MIC) distribution of a suspected or documented pathogen to provide probabilistic outputs. These outputs, when available, can be used to educate the clinician, thereby allowing them to make the most informed decision regarding antimicrobial selection and dose for a given infection. Performing PK-PD analyses in routine patient care settings is not usually done due in part to insufficient access to simulation programs that would allow for the determination of the dosing regimen’s ability to achieve PK-PD targets for efficacy (Ambrose et al., 2012a). Recent advances in technology have made it possible to integrate PK-PD into clinical decision making at the point of care (Bulik et al., 2017a, Bulik et al., 2017b). This is important for many reasons including optimizing the treatment of infections and patient outcomes (Ambrose, 2008), minimizing the development of antimicrobial resistance (Ambrose, 2008, Drusano et al., 2012, Patel et al., 2010), and improving patient safety. For example, dosing mistakes are the most common type of medication error resulting in preventable adverse drug events (Fischer et al., 2003, Gleason et al., 2004, Koppel et al., 2005, Oppenheim et al., 2002, Owens Jr, 2008a). In one study, over 60% of prescribing errors involved incorrect medication doses or improper regimen frequencies (Fischer et al., 2003). The incorporation of PK-PD into clinical decision making at the point of care for antimicrobials will result in a decrease in dosing errors and subsequent adverse drug events.

In concert with the growth of ASPs in the U.S. is a parallel growth of CDS technologies supportive of stewardship activities. CDS technologies range from single-center custom-built or homegrown platforms to large commercial multifunctional CDS programs (Baysari et al., 2016, Evans et al., 1995). A common theme with large commercial multifunctional CDS technologies is that they all seem to have originated with a central focus (e.g., billing, pharmacy, infection control, microbiology laboratory), with antimicrobial stewardship applications developed as afterthoughts. Over time, these large commercial platforms have adapted to the needs of the ASP through the supplementation of more specialized CDS applications. The use of CDS technologies is variable throughout the U.S. as cost, simplicity of use, and functionality relative to the needs of the institution determine the success of a technology. Studies have shown that the most multifunctional, broadly scoped, and knowledge-based systems are the most expensive (upwards of $500,000 annually) (Baysari et al., 2016, Evans et al., 2015, Kullar et al., 2013). Moreover, once a CDS technology is purchased, it is not a guarantee of uptake. For example, a technology may not see widespread usage due to the clinicians being cautious of taking recommendations from a computer-based decision support technology or because the technology is inconvenient relative to the clinician’s workflow. Usage of CDS technologies that require clinicians to log into multiple computer systems to obtain information has been shown to be as low as 50% (King et al., 2007, Rohrig et al., 2008).

In an attempt to increase the exposure of CDS technologies, this review will primarily focus on the commercially available programs intended to enhance antimicrobial stewardship by providing PK- and PK-PD–based dosing and regimen guidance. We will also discuss the emerging developments in the healthcare information technology (IT) field that are making integration of CDS programs possible and convenient.