Chair, Pharmacokinetics Special Emphasis Panel
Thomas Lodise, Pharm D, PhD
Albany College of Pharmacy and Health Sciences
Professor, Department of Pharmacy Practice

The Pharmacokinetics Special Emphasis Panel (PK SEP) is dedicated to enhancing our current understanding of antimicrobial exposure-response relationships in patients with invasive infections. Similar to other ARLG special emphasis panels and committees, the PK SEP supports the mission of the ARLG by reviewing proposals, assigning scientific merit scores, and serving as a resource in prioritizing the network’s scientific agenda. The panel’s purpose is to ensure that state-of-the-art pharmacokinetic/pharmacodynamic (PK/PD) methods are used to design innovative pharmacologic strategies that optimize the utility of the existing antibacterial agents in our armamentarium for implementation into clinical practice.

The PK SEP concentrates on development of innovative dosing regimens for antibacterial agents prioritized by the U.S. Centers for Disease Control and Prevention (CDC), U.S. Food and Drug Administration (FDA), and the National Institutes of Health (NIH) to combat antibacterial resistance. In addition, the PK SEP is most interested in identifying optimal dosing schemes for patient populations typically underrepresented in Phase III clinical trials, but likely to be encountered in clinical practice.

With support from the PK SEP, the ARLG is pioneering practice-changing research. Panel chair, Tom Lodise, PharmD, PhD, highlights three studies below:

PROVIDE: Prospective Observational Evaluation of the Association between Initial Vancomycin Exposure and Failure Rates among Adult Hospitalized Patients with MRSA Bloodstream Infection.
Recently published in Clinical Infectious Diseases, PROVIDE was a multi-center prospective study to evaluate the relationship between day-2 vancomycin exposure profiles and outcomes in patients infected with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia.Vancomycin is the most commonly administered antibiotic in United States hospitals and has been a mainstay for treatment of MRSA infections for decades, yet optimal dosing of vancomycin is unclear. For serious MRSA infections, current guidelines recommend targeting an area under the concentration time curve to minimum inhibitory concentration ratio (AUC/MIC) ≥400. Despite widespread clinical adoption of these recommendations, optimal exposure targets remain controversial.

The study took place in 14 hospitals across the United States. The primary outcome was treatment failure, defined as 30-day mortality or a positive blood culture at ≥7 days. Secondary outcomes included acute kidney injury (AKI), defined as a ≥1.5-fold increase in serum creatinine. Of the 265 eligible patients, treatment failure occurred in 18% and AKI in 26% of patients. Overall, higher day-2 vancomycin exposures for patients with MRSA bacteremia were not associated with a lower incidence of treatment failure but were associated with higher rates of AKI.  Patients with day 2 area under the curve (AUC) exposures ≤515 experienced the best global outcomes (no treatment failure and no AKI).

The results from PROVIDE have important implications for clinical practice and indicate that clinicians should reassess the balance of benefits and risks of targeting higher day-2 exposures for patients with MRSA bacteremia.  Most importantly, the findings suggest that vancomycin dosing should be guided by the AUC and day-2 AUCs should be maintained below 515 to maximize efficacy and minimize risk of AKI. Moving forward, further study is needed to define the lower bound of the therapeutic range

PROVIDE results heavily informed the draft vancomycin consensus guidelines by the American Society of Health-System Pharmacists ASHP. Based in large part on PROVIDE, the guidelines now recommend monitoring vancomycin AUCs vs. troughs in clinical practice.

ACUMIN: Acute Care Unit Minocycline

The ACUMIN study is examining the PK of intravenous (IV) minocycline in critically-ill patients with Gram-negative infections in the intensive care unit (ICU). Minocycline is a tetracycline derivative first approved in the United States as both oral and IV formulations in the 1970s. A new IV formulation of minocycline became available in 2015 and is approved by the FDA for the treatment of patients with infections due to Gram-positive and Gram-negative pathogens, including Acinetobacter baumannii.

A. baumannii is a healthcare-associated pathogen and a major cause of pneumonia, bacteremia, and wound infection among critically ill patients. A. baumannii is intrinsically resistant to many commercially available antibiotics. It also has a remarkable capacity to develop resistance to commonly used antibiotics like carbapenems, aminoglycosides, and fluoroquinolones. As a result, the terms ‘multi-drug resistant (MDR)’ and ‘extensively drug resistant’ are often used to characterize the different patterns of resistance exhibited by A. baumannii. Infections due to MDR A. baumannii is a growing world-wide problem and is classified as a serious public health threat by the CDC. Fortunately, minocycline is highly active against A. baumannii, including MDR strains, and is well tolerated, making it a potential treatment option for MDR A. baumannii infections.

While there is longstanding clinical use experience with minocycline in patients, PK studies are limited and were conducted in the 1970s in healthy volunteers. In addition, no published minocycline PK data exists in critically ill patients staying in the ICU.

ACUMIN is designed to address this PK knowledge gap by developing a population PK model to describe the plasma exposure profile of minocycline in ICU patients following a single 200-mg IV infusion over 60 minutes. Results of ACUMIN will inform optimal dosing of minocycline in the critically ill patient population. More importantly, this study will determine if dosing adjustments for the approved FDA minocycline dosing regimen are needed based on weight and estimated renal function. ACUMIN enrollment is complete and data analyses will start in fall 2019.

COMBINE: Efficacy and Safety of Ceftazidime-Avibactam in Combination with Aztreonam

COMBINE focuses on the use of ceftazidime-avibactam in combination with aztreonam (ATM) for patients with metallo-β-lactamase (MBL) – producing Gram-negative infections. Metallo-β-lactamases are carbapenemases and have the ability to inactivate all β-lactams except ATM. Infections due to MBL-producing Gram-negative bacteria (GNB) are increasing worldwide and are a major public health concern as there are limited treatment options available. Furthermore, none of the recently approved antibiotics have notable activity against MBL-producing GNB. Several antibiotics with activity against MBL-producing GNB are being developed, but none are anticipated to be available until at least 2021. This underscores the demand of redeploying our existing agents in innovative ways to meet the needs of patients today.

One strategy that is serving as a “bridge” treatment for MBL-producing GNB infections is ceftazidime-avibactam (AVYCAZ) combined with ATM. Although the precise mechanism of improved bacterial killing activity with AVYCAZ combined with ATM is not completely understood, it is likely attributable to maximal saturation of the diverse penicillin binding proteins present in GNB, flooding of periplasm with β-lactams, and maximal binding of available β-lactamases.  Aztreonam is not inactivated by MBLs but many MBL-bearing GNB co-harbor extended spectrum beta-lactamases (ESBLs) that inactivate ATM. In the combination of ATM with AVYCAZ, AVI inhibits the ESBLs and other beta-lactamases that are often present in MBL-producing GNB, allowing ATM, which is unaffected by MBLs, to effectively bind to its target site of action (i.e., bacterial penicillin binding proteins).

Before uniform adoption of this treatment, it is critical to identify the optimal combination of AVYCAZ with ATM regimens associated with maximal efficacy and safety due to the potential of cumulative toxicity from use of two beta-lactam antibiotics simultaneously. To identify the optimal treatment regimens, an in-vitro PK/PD study using the hollow fiber infection model (HFIM) system was conducted to determine the optimal AVYCAZ combined with ATM treatment regimens that result in maximal bacterial kill and resistance suppression. The HFIM studies were selected to determine optimal combination regimens as they are an integral part of the drug development process and are used to inform dose and schedule selection for Phase III clinical trials. They are particularly useful in situations when there are limited clinical data available to define optimal therapy, especially when there is interest in studying humanized drug exposure profiles, treatment durations, and starting bacterial burdens that mirror clinical practice.

In these HFIM experiments the two combination regimens that showed maximal bacterial killing and resistance suppression over 7 days were:

• AVYCAZ 2.5 g IV as a 2-hour infusion every 8 hours combined with ATM 2g IV as a 2-hour infusion every six hours, and
• AVYCAZ combined with ATM, each administered as a continuous infusion (CI) (AVYCAZ 7.5 g/day CI combined with ATM 8g/day CI).

The ARLG, in consultation with the PK SEP, believe it is of paramount importance to establish the safety and PK of these regimens in humans. Although AVYCAZ and ATM appear to be safe and well-tolerated, there are no available data on safety when these antibiotics are used in combination. Mild-to-moderate elevations in liver enzymes are common with ATM; however, these elevations are usually self-limiting and do not require ATM discontinuation. It is unclear if AVYCAZ combined with ATM will further exacerbate liver enzyme elevations or lead to other adverse events due to the potential of cumulative toxicity from dual-β-lactam treatment. There are also no published PK data of these antibiotics when administered concurrently, and it is therefore unknown if use of these agents in combination will lead to an altered PK profile of each agent due to inhibition of renal or other compensatory clearance mechanisms. Therefore, a Phase I study using healthy volunteers was launched to assess the safety and PK profile of AVYCAZ combined with ATM relative to its standalone counterparts.

This Phase I study is currently underway at the Duke Early Phase Clinical Research Unit. It is an open-label, single center study in 48 healthy adult male and female participants age 18-45 years old. Eligible subjects are admitted to the Phase I unit and assigned into one of six dosing cohorts. Four treatment cohorts are single-agent dosing cohorts and include AVYCAZ per label dosing, AVYCAZ as a CI, ATM per label dosing, and ATM as a CI. Single-drug treatment cohorts are being conducted to collect baseline safety and PK data. The remaining two cohorts are the two optimal AVYCAZ combined with ATM regimens identified from the HFIM experiments. Participants will stay in the study unit for a minimum of one week. Cohorts 1-4 will be completed prior to Cohorts 5 and 6.

Safety is being closely monitored using daily assessments of adverse events, vital signs, and clinical laboratory safety tests. Serial blood and urine samples are being collected for PK evaluation.  The target completion for enrollment is December 2019 with data analysis completed in early 2020.

 Future Plans

As ARLG moves forward, the PK SEP will continue to support the mission of the ARLG by reviewing proposals, assigning scientific merit scores, and serving as a resource in prioritizing the ARLG scientific agenda. The panel will continue to ensure that the best PK/PD methods are used to derive optimal treatment strategies with maximal efficacy and safety for implementation into clinical practice. The SEP will also work to ensure the populations most likely to be encountered in clinical practice are included when designing future studies.

Congratulations to the ARLG’s co-principal investigators, Vance Fowler, MD, MHS, Duke University, and Henry “Chip” Chambers, MD, UCSF, as well as a number of other ARLG investigators who have been recognized as world experts in Staphylococcus aureus by Expertcape.

In addition, Dr. Fowler  was recognized as the number one world expert in bacteremia by Expertscape. Other ARLG leaders, such as Robert Bonomo, MD, David Paterson, MD, Ralph Corey, MD, and Tom Holland, MD, ranked high on the list.

Congratulations to Robert Bonomo, MD, ARLG Laboratory Center Co-Director, who was named a Distinguished University Professor at Case Western Reserve University (CWRU) during its fall convocation on August 28, 2019. CWRU awards the title of “Distinguished University Professor”— a permanent, honorific title, to acknowledge contributions of full-time, tenured faculty with exceptional records of research, scholarship, teaching, and service.

Bonomo, a professor of medicine, pharmacology, molecular biology, and microbiology at the CWRU School of Medicine, has dedicated his research career to addressing the mounting problem of antibiotic resistance. “Infections previously brought under control can resurface in resistant and more virulent new forms,” he said, “allowing disease to proliferate — potentially unchecked.”

Among his investigations, Bonomo works to uncover the genetic and amino acid determinants of bacterial enzymes that create multi-resistance to such widely used antibiotics as penicillins and cephalosporins. Nailing down these sequences and using an integrated approach can lead to new medications that overcome the antibiotic resistance, and his work is paying off. Because of his collaboration with colleagues at CWRU and elsewhere, five new antimicrobials have been approved to date. “We’re always trying to stay a step ahead of the bacteria,” he said. “Evolution rewards organisms that adapt to their environments, including those that fend off antibiotics, so there is a fundamental natural mechanism that we have to overcome.” Bonomo said his teaching and mentoring are as meaningful to him as his research. “Providing intellectual prep for the next generation helps ensure that future patients live longer, healthier lives,” he said. “Nothing can be more crucial than that.”

Read the complete article from CWRU.

Support your ARLG colleagues who will be presenting at the 29th European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) in Amsterdam, Netherlands from April 13-16, 2019.