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FELLOWSHIP PROGRAM 2011
 

The Antibiotic Pharmacodynamic Research Institute
at the University of Minnesota College of Pharmacy
Minneapolis, MN

 

Director:  John Rotschafer, PharmD, FCCP

Professor, University of Minnesota College of Pharmacy

Description of the fellowship program
The fellowship program, sponsored by the Antibiotic Pharmacodynamic Research Institute and the University of Minnesota College of Pharmacy is a two-year experience designed to provide participants with a background in antimicrobial pharmacokinetics/pharmacodynamics and research skills. The fellowship was recognized in infectious diseases and pharmacodynamics by the American College of Clinical Pharmacy. Upon completion of the program, fellows have the training necessary to build a career as an independent researcher. Most post-doctoral candidates will need training to master the necessary lab/microbiology skills for this fellowship. Necessary training will be provided.

Dr. John Rotschafer, the director of the fellowship program is Professor of Experimental and Clinical Pharmacology at the University of Minnesota, College of Pharmacy. Dr. Rotschafer has trained 19 fellows, who have achieved successful careers in both the pharmaceutical and health care industries as well as academics.

The Institute has a proven track record of obtaining grants for research, largely from the pharmaceutical industry. With the recent acquisition of a thermal cycler and gel apparatus, and the use of an image analyzer, the Institute is poised to integrate pharmacodynamic data with microbial genomics.

The majority of fellows who have completed the program have received PharmD degrees from a U.S. college of pharmacy. In addition to research-related activities (which consume 50-60% of the fellow’s time), fellows participate in the education of PharmD students through lecturing and TA responsibilities in a didactic course in infectious diseases. Fellows also become involved in the peer review process and will present and publish data from research projects.

To apply, please send a letter indicating your interest, a copy of your curriculum vitae, three letters of recommendation, and an official transcript.

For more information, please contact:
John Rotschafer, PharmD, FCCP
University of Minnesota College of Pharmacy
Department of Experimental and Clinical Pharmacology
9-157 Weaver-Densford Hall
308 Harvard Street SE
Minneapolis, MN 55455
p/ 612.624.2183

Former Fellows

1. George Bailey, Pharm.D. Professor, Albany College of Pharmacy

2. Bruce Ackerman, Pharm.D. Associate Professor, Philadelphia College of Pharmacy

3. Irving Steinberg, Pharm.D. Associate Professor (ASHP Fellow Infectious Diseases)
University of Southern California

4. Humphrey Zokufa, Pharm.D. Director: Health Support Services (Fulbright Scholar)
Eastern Cape: Provincial Head Office, Bisho, South Africa

5. Mark Garrison, Pharm.D. Associate Professor, Washington State University

6. Kyle Vance-Bryan, Pharm.D. Vice President, Clinical Outcomes (ACCP Fellow Infectious Diseases) Prime Therapeutics

7. Richard Zabinski, Pharm.D. Director, Pharmaceutical Care (ASHP Fellow Infectious Diseases) United Health Care

8. Karla J. Walker, Pharm.D. Director Clinical Toxicology, MedTox Laboratories

9. Karl J. Kelly, Pharm.D. Associate Professor (ACCP Fellow Infectious Diseases) Idaho State University

10. Beth Ostergaard, Pharm. D. Clinical Liaison, Novartis Pharmaceutic

11. Janet K. Raddatz, Pharm. D Clinical Liaison, Ortho-McNeil

12. Dell Mather, Pharm. D. Director, Pharmacoeconomic Outcomes, Prime Therapeutics

13. Anh Thu Dang Hoang, Pharm. D. Senior Medical Writer, Sudler and Hennessey

14. Marnie Peterson, Pharm. D., Ph. D. Assistant Professor, Dept. of Microbiology & College of Pharmacy, University of Minnesota

15. David Wright, Pharm. D. Director of Professional Education & Scientific Affairs
Ortho Mc Neil Pharmaceuticals

16. GiGi Brown, Pharm. D. Health Science Liaison, Ortho Mc Neil Pharmaceuticals

17. Khalid Ibrahim, Pharm. D., Global New Products Manger; Business Franchise ID, Novartis Pharma AG

18. Brent Gunderson, Pharm. D. Senior Pharmacist, Prime Therapeutics

19. Elizabeth Hermsen, Pharm.D., Antimicrobial Specialist and Research Associate, The University of Nebraska Medical Center, Omaha, Nebraska

20. Jeremy Schafer, Pharm.D., Senior Pharmacist, Prime Therapeutics

21. Isaac Mitropoulos, Pharm.D., Anti-Infectives Scientific Affairs Liaison, Ortho-McNeil Janssen Scientific Affairs, LLC

22. Mary Ullman, Pharm.D., Current Post-Doctoral Fellow

Description of the Antibiotic Pharmacodyanmic Research Institute

The post-doctoral fellow(s) is surrounded by an abundance of resources allowing the candidates to achieve maximal potential. The following is a description of the computer, library and laboratory available for use by the post-doctoral fellow(s):

Laboratory
The Antibiotic Pharmacodynamic Research Institute is located at the University of Minnesota in the new McGuire Translational Research Facility. The fully equipped, 700 square foot, laboratory is available for the post-doctoral fellow’s use. Office space is available outside of the laboratory and includes a desk and cabinet space, two Dell computers, an HP LaserJet printer and an HP fax machine. There is currently one laboratory microbiologist/medical technologist to assist in post-doctoral infectious diseases research projects. The laboratory is equipped with two analytical scales, two CO2 incubators, two Bactron IV anaerobic chambers, a Bio-Tek Precision 2000 automated pipetting system, a WASP 2 spiral plater and an aCOLyte automated colony counter, an autoclave, laminar flow and ventilation hoods, a refrigerator/freezer, a lab oven, various centrifuges, an ultra-low temperature freezer, a pH meter, an Eppendorf thermalcycler, and a gel tank with power source. Other equipment includes laboratory glassware, peristaltic pumps, stir/hot plates, vortex mixers, pipettes, and custom-made glass vessels in a variety of sizes for pharmacodynamic modeling.


Additional Laboratory Resources
Genomics equipment belonging to the College of Pharmacy is available for our use. This equipment includes a bioimaging system and a spectrophotometer. Many of the research laboratories within the college utilize high performance liquid chromatography and use of that instrumentation could be arranged.



Library
The University of Minnesota’s Diehl Hall Biomedical Library is conveniently located within the Academic Health Center complex and has one of the most complete collections of medical resource information found in the United States.

Computer Support
Post-doctoral fellows will have their own desktop PC. The office space has wireless access for to the university’s server allowing for rapid Internet service. A variety of word-processing programs, spreadsheets, and graphics packages are also available as well as software for one compartment, multiple compartment, and non-compartment pharmacokinetic analysis.

Personnel
John C. Rotschafer, Pharm.D., F.C.C.P., Professor, College of Pharmacy, University of Minnesota; Director, Antibiotic Pharmacodynamic Research Institute and Antibiotic Pharmacokinetics Consult Services, University of Minnesota.
Laurie Baeker Hovde, MT (ASCP), Antibiotic Pharmacodynamic Research Institute
Other faculty within the Department of Experimental and Clinical Pharmacology

Introduction to Pharmacodynamics and Pharmacodynamic Modeling

The Antibiotic Pharmacodynamic Research Institute utilizes a well-established method to pharmacodynamically model the interaction between bacteria and antibiotic. The model we developed in our laboratory is capable of studying single or combination antibiotic therapy against a particular pathogen under aerobic or anaerobic conditions in a carefully controlled environment. More specifically, the model can be manipulated to simulate a variety of pharmacokinetic (volume of distribution, half life, peak concentration, etc.) and pharmacodynamic (AUC, peak to MIC ratios, time concentration remains above MIC, etc.) parameters. The availability of meaningful pharmacodynamic parameters with well-defined endpoints can help clinicians make objective antibiotic choices. Clinical antibiotic trials tend to be extremely conservative, resulting in over-treatment to minimize the possibility of clinical failure. In the model, we need not be concerned with clinical outcome and can, therefore, design experiments without regard for potential failure. The model can reproduce the desired pharmacodynamic parameters consistently. All of the modeling techniques have already been developed and are common procedures in our laboratory.

Data gleaned from appropriately designed in vitro experiments can quickly depict an antibiotic as a time- or concentration-dependent killer of a specific microorganism. Phenomena such as the PAE, the effect of protein binding on drug activity, and relative activity in aerobic and anaerobic environments are easily studied. Work done with in vitro models is intended to be and should be complementary to work done with in vivo systems. Demonstrating that pharmacodynamic data are reproducible in vitro, in animals, and in clinical trials will help determine optimal antibiotic dosing. In summary, the in vitro pharmacodynamic model is a cost-effective and rapid means to gather preliminary information on antibiotic activity and to explore pharmacodynamic parameters under a variety of conditions.

The In vitro Pharmacodynamic Model

The model utilized in our laboratory consists of a sealed glass chamber filled with broth and fitted with input and output tubing. Bacteria and antibiotic are introduced into the chemostat. First-order elimination kinetics are created by bolus dosing drug into the chamber to achieve the desired peak concentration and then pumping antibiotic-free media into the system at a specified rate using a peristaltic pump. An equal volume of antibiotic-containing media is displaced creating the desired antibiotic half-life. Simulating elimination of two compounds with different half-lives is accomplished by pumping media containing the compound with the longer half-life and drug-free media into the model simultaneously at appropriate rates.



“Dynamic” versus “Static”
This “dynamic” method, where antibiotic concentration changes over time, as in the human host, has several advantages over tests done under “static” conditions. With standard MIC testing, bacterial growth is read as inhibited or not inhibited at 24 hours. With an in vitro pharmacodynamic model, viable bacteria are enumerated at many time points during the course of the experiment, giving a better indication of the time-kill profile. Additionally, static models do not adequately test the impact of changing antibiotic concentrations over time on bacterial kill. Static models cannot usually determine if the agent is a concentration- or time-dependent killer of the bacteria in question and cannot fully explore pharmacodynamic parameters. As such, they provide only limited information and insight into the correct dose. Table 1 offers examples of critical information that can be provided by in vitro pharmacodynamic models.

Table 1. Valuable pharmacodynamic data that can be provided by in vitro testing.
1. Bacterial susceptibility data
2. Resistance frequency, mechanism of resistance
3. Activity: Concentration-dependent or -independent
4. Pharmacodynamic outcome parameter and range of values
5. Effect of protein binding, including which protein drug binds to
6. Effect of aerobic versus anaerobic environment
7. ± synergy with other antibiotics
8. pH effect
9. Inoculum effect
10. Glycocalyx effect
11. Bacterial toxin release profile

Advantages of In Vitro Models
Animal models are another source of valuable pharmacodynamic data. In vitro models are meant to be complementary to animal models and offer certain advantages. For example, the lack of an immune system effect with the in vitro model can lend clarity to the antibiotic-bacteria interaction. Also, it is possible to simulate conditions in vitro that are not possible in animals. Because of this, in vitro models may be better suited to reduce the covariance in the traditional pharmacodynamic outcome parameters T>MIC, Cmax/MIC and AUC/MIC compared to animal models.

Pharmacodynamics and Drug Development
Identifying pharmacodynamic parameters is becoming an important part of the new drug development process. Characterizing an antibiotic as a concentration or time dependent killer of the bacteria in question and understanding the pharmacodynamic parameters that best predict activity can be combined with toxicology data to design rational dosage regimens in humans and reduce cost and time in the antibiotic development process. In addition, identifying optimal pharmacodynamic parameters, as well as other variables influencing activity, and using the information to determine the most effective dosing regimen in pre-clinical testing will increase the likelihood of establishing clinical efficacy in Phase III/IV trials and beyond. In vitro models are particularly useful in sorting though covariance among outcome parameters. The ability of in vitro pharmacodynamic models to explore the predictive value of a variety of pharmacodynamic parameters rapidly and relatively inexpensively can play an important role in the early stages of a drug’s development.

Research in our Laboratory
We are interested in characterizing the in vitro pharmacodynamics of antibiotics in development. In general, we conduct studies that systematically evaluate the pharmacodynamic profile of the agent. Initial phases are designed to test the influence of a range of Cmax/MIC, AUC/MIC and T>MIC values. Additionally, the agent is characterized as a concentration- or time-dependent killer of different bacterial species. Activity and optimal pharmacodynamic parameters often differ for antibiotic-bacteria combinations; as a result, we test antibiotics between and among species of bacteria. Subsequent phases compare the activity of the antibiotic to other antimicrobials, both within and outside the chemical class, and the influence of other factors including pH, inoculum size, presence of oxygen for facultative species, and combination therapy on overall effect.

Conclusion
Antibiotic pharmacodynamics, by providing objective data on the nature of the interaction between antimicrobial and bacteria, can help to identify optimal doses of drug. Such data, when duplicated in in vitro and animal models, can help streamline the drug development process and provide evidence to administrative agencies on potential uses. In addition, with appropriate clinical validation, antibiotic pharmacodynamics could be used to improve outcomes. Clinical practitioners would undoubtedly welcome measures that could predict the success rate of an antibiotic in their patient population. Our laboratory has a history of generating meaningful pharmacodyanmic data and is committed to continue our research with the goal of improving antimicrobial chemotherapy through developing the pharmacodynamic profile of antibiotics.

References From Our Laboratory
Hermsen ED, Hovde LB, Sprandel KA, Rodvold KA, Rotschafer JC Levofloxacin plus Metronidazole Administered Once Daily versus Moxifloxacin Monotherapy against a Mixed Infection of Escherichia coli and Bacteroides fragilis in an In Vitro Pharmacodynamic Model. Antimicrob Agents Chemother. 2005 Feb;49(2):685-689.

Ibrahim KH, Gunderson BW, Hermsen ED, Hovde LB, Rotschafer JC Pharmacodynamics of Pulse Dosing versus Standard Dosing: In Vitro Metronidazole Activity against Bacteroides fragilis and Bacteroides thetaiotaomicron. Antimicrob Agents Chemother, 2004 Nov;48(11):4195-4199

Hermsen ED, Hovde LB, Hotchkiss JR, Rotschafer JC Increased Killing of Staphylococci and Streptococci by Daptomycin Compared with Cefazolin and Vancomycin in an In Vitro Peritoneal Dialysate Model. Antimicrob Agents Chemother, 2003 Dec;47(12): 3764-3767

In Vitro Pharmacodynamic Analysis of Single Daily Dosing Versus Conventional Dosing of Gentamicin Administered with Penicillin against Enterococcus faecalis.
Ross GH, Hovde LB, Ibrahim YH, Rotschafer JC Pharmacotherapy, 2001 Dec; 21(12): 1479-85

Pharmacodynamics of Trovafloxacin and Levofloxacin Against Bacteroides fragilis in an In Vitro Pharmacodynamic Model. Peterson ML, Hovde LB, Wright DH, Brown GH, Hoang AD, Rotschafer JC Antimicrobial Agents and Chemotherapy, 2002 Jan; 46(1): 203-10

Comparative Pharmacodynamics of Three Newer Fluoroquinolones versus Six Strains of Staphylococci in an In Vitro Model under Aerobic and Anaerobic Conditions.
Wright DH, Gunderson BW, Hovde LB, Ross GH, Ibrahim KH, Rotschafer JC Antimicrobial Agents and Chemotherapy, 2002 May; 46(5): 1561-3

Microbiologic Effectiveness of Time- or Concentration-based dosing strategies in Streptococcus pneumoniae. KH Ibrahim, LB Hovde, GH Ross, BW Gunderson, DH Wright, JC Rotschafer
Diagnostic Microbiology and Infectious Disease 44 (2002): 265-271

Comparison of Linezolid Activities under Aerobic and Anaerobic Conditions against Methicillin Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococcus faecium.
BW Gunderson, KH Ibrahim, CA Peloquin, LB Hovde, JC Rotschafer. Antimicrobial Agents and Chemotherapy, Jan. 2003, Vol. 47, No. 1, p. 398-399

Synergistic Activity of Colistin and Ceftazidime Against Multiantibiotic-Resistant Pseudomonas aeruginosa in an In Vitro Pharmacodynamic Model. BW Gunderson, KH Ibrahim, LB Hovde, TL Fromm, MD Reed, JC Rotschafer. Antimicrobial Agents and Chemotherapy, Mar. 2003, Vol. 47, No. 3, p. 905-909

Mutation Prevention Concentration of Ceftriaxone, Meropenem, Imipenem, and Ertapenem Against Three Strains of Streptococcus pneumoniae. LB Hovde, SE Rotschafer, KH Ibrahim, B Gunderson, ED Hermsen, JC Rotschafer. Diagnostic Microbiology and Infectious Disease 45 (2003): 265-267

Ross GH, Wright DH, Hovde LB, Peterson ML, Rotschafer JC Fluoroquinolone resistance in anaerobic bacteria following exposure to levofloxacin, trovafloxacin, and sparfloxacin in an in vitro pharmacodynamic model. Antimicrob Agents Chemother. 2001 Jul;45(7):2136-40.

Ross GH, Hovde LB, Ibrahim KH, Ibrahim YH, Rotschafer JC. Comparison of once-daily versus twice-daily administration of cefdinir against typical bacterial respiratory tract pathogens. Antimicrob Agents Chemother. 2001 Oct;45(10):2936-8.3. Peterson ML, Hovde LB, Wright DH, Brown GH, Hoang AD, Rotschafer JC. Pharmacodynamics of trovafloxacin and levofloxacin against Bacteroides fragilis in an in vitro pharmacodynamic model. Antimicrob Agents Chemother. 2002 Jan;46(1):203-10.

Ross GH, Hovde LB, Ibrahim YH, Rotschafer JC. In vitro pharmacodynamic analysis of single daily dosing versus conventional dosing of gentamicin administered with penicillin against Enterococcus faecalis. Pharmacotherapy. 2001 Dec;21(12):1479-85.

Wright DH, Gunderson BW, Hovde LB, Ross GH, Ibrahim KH, Rotschafer JC. Comparative pharmacodynamics of three newer fluoroquinolones versus six strains of staphylococci in an in vitro model under aerobic and anaerobic conditions. Antimicrob Agents Chemother. 2002 May;46(5):1561-3.

Peterson ML, Hovde LB, Wright DH, et al. Fluoroquinolone resistance in Bacteroides fragilis following sparfloxacin exposure. Antimicrobial Agents & Chemotherapy 1999; 43:2251-5.

Madaras-Kelly KJ, Larsson AJ, Rotschafer JC. A pharmacodynamic evaluation of ciprofloxacin and ofloxacin against two strains of Pseudomonas aeruginosa. Journal of Antimicrobial Chemotherapy 1996; 37:703-10.

Madaras-Kelly KJ, Ostergaard BE, Hovde LB, Rotschafer JC. Twenty-four-hour area under the concentration-time curve/MIC ratio as a generic predictor of fluoroquinolone antimicrobial effect by using three strains of Pseudomonas aeruginosa and an in vitro pharmacodynamic model. Antimicrobial Agents & Chemotherapy 1996; 40:627-32.

Madaras-Kelly KJ, Moody J, Larsson A, Baeker Hovde L, Rotschafer JC. Characterization of synergy between ofloxacin, ceftazidime, and tobramycin against Pseudomonas aeruginosa. Chemotherapy 1997; 43:108-17.

Larsson AJ, Walker KJ, Raddatz JK, Rotschafer JC. The concentration-independent effect of monoexponential and biexponential decay in vancomycin concentrations on the killing of Staphylococcus aureus under aerobic and anaerobic conditions. Journal of Antimicrobial Chemotherapy 1996; 38:589-97.

Zabinski RA, Walker KJ, Larsson AJ, Moody JA, Kaatz GW, Rotschafer JC. Effect of aerobic and anaerobic environments on antistaphylococcal activities of five fluoroquinolones. Antimicrobial Agents & Chemotherapy 1995; 39:507-12.

Walker KJ, Larsson AJ, Zabinski RA, Rotschafer JC. Evaluation of antimicrobial activities of clarithromycin and 14-hydroxyclarithromycin against three strains of Haemophilus influenzae by using an in vitro pharmacodynamic model. Antimicrobial Agents & Chemotherapy 1994; 38:2003-7.

Zabinski RA, Vance-Bryan K, Krinke AJ, Walker KJ, Moody JA, Rotschafer JC. Evaluation of activity of temafloxacin against Bacteroides fragilis by an in vitro pharmacodynamic system. Antimicrobial Agents & Chemotherapy 1993; 37:2454-8.

 

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