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.,
Current Post-Doctoral Fellow
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.
