Biotherapeutic Agents and Infectious Diseases, 1st Edition
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ISBN 978-1-4757-4652-5 ISBN 978-1-59259-711-6 (eBook)
DOI 10.1007/978-1-59259-711-6
© 1999 Springer Science+Business Media New York
Originally published by Humana Press Inc. in 1999
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Preface
Extensive use of antimicrobials for over 50 years has resulted in the
proliferation and establishment in our environment of microorgan-
isms that carry genes coding for a variety of resistance mechanisms. As
the world population expands and populations become more mobile,
resistant pathogens may rapidly spread from country to country.
Intra- and interspecies transfer of genetic material further enhances
the risks of contracting an infection with a resistant pathogen. New
approaches to treat, and more importantly to prevent, infectious dis-
eases are mandatory if we are to avoid areturn to the times when
common infections carried a substantial risk for disease or death.
It has been long recognized that the body has a variety of natural
defenses to combat invasion by pathogens. Elucidation of these
defense mechanisms has the potential to lead to new modalities for use
in treatment of infectious diseases. Vaccines are one example of a way
to enhance host defenses. Another under intensive investigation is the
endogenous antimicrobial peptides. Biotherapeutic Agents and Infectious
Diseases examines a third modality for the prevention and treatment of
infectious diseases: the use of whole, living microorganisms with in
vive antagonistic activities against specific pathogens. The goal of this
approach is the restoration or enhancement of the normal protective
ability of the microbial flora to resist pathogen establishment and pro-
liferation. This activity (variously called colonization resistance, bar-
rier effect, bacterial interference, or bacterial antagonism) can be
perturbed by disease, surgery, or antimicrobial therapy, with resulting
risk for intestinal or vaginal infections. Less commonly, virulent patho-
gens may be able to overwhelm this colonization resistance directly. In
any event, introduction of a microorganism that is able to mimic the
activities of the normal flora or have other beneficial activities in
impeding pathogen growth may be helpful.
The consumption of crude mixtures of living microorganisms in the
form of fermented foods has long been associated with beneficial
effects on human health and longevity. Gradually it became appreci-
ated that any therapeutic effect of these products largely resulted from
v
vi Preface
the microorganism present rather than the food itself. With time, vari-
ous single and defined mixtur es of microorganisms, mostly lactic acid-
producing microbes, were introduced commercially as antidiarrheal
agents, but controlled studies to define their efficacy have been lack-
ing. The terms "probiotic" and "biotherapeutic agent" have been used
to describe these products. Probiotic is a more general term for micro-
organisms having general beneficial effects on the health of animals or
humans. "Biotherapeutic agents" is a term used for microorganisms
having therapeutic effects in humans. This book is limited to a discus-
sion of biotherapeutic agents.
An impetus for recent widespread interest in biotherapeutic agents
came from scientific studies showing that two biotherapeutic agents
were useful in Clostridium difficile disease. This was the first example,
arising from large clinical trials, of the successful use of a biotherapeutic
agent for treatment of a severe, life-threatening infection. Another
impetus is the growing frequency of pathogens resistant to antimicro-
bials and the recognition of the need to explore alternative methods to
prevent and treat infections. Resistant microbes are selected, and these
thrive in the presence of antimicrobials; the key to solving the problem
they present is to minimize population exposure to these agents. Two
examples are offered to illustrate the potential contribution of
biotherapeutic agents in decreasing antibiotic use. The first is the
obvious usefulness of an effective biotherapeutic agent to prevent
traveler's diarrhea, which would obviate most of the use of
Ciprofloxacin or other antibiotics in travelers with diarrhea. To date,
no biotherapeutic agent has shown striking efficacy, so more work is
needed in this area. A second example is one in which a combination
of a biotherapeutic agent, S. boulardii, and an antibiotic, vancomycin,
was used to treat recurrent C. difficile diarrhea and colitis. The subse-
quent 50% decrease in recurrence of the disease in the group thus
treated compared to the antibiotic-placebo group points to the poten-
tial application of biotherapeutic agents as adjuncts to antimicrobial
therapy. In this example, yeast treatment alleviated the need for
retreatment with vancomycin or metronidazole.
The aims of Biotherapuetic Agents and Infectious Diseases are to pro-
vide a concise review and discussion of the applications of
biotherapeutic agents to human therapy and to present the saHent
scientific underpinnings necessary for an understanding of their
potential in therapy. The chapters are written by investigators pres-
ently active in the discovery, development, and application of
biotherapeutic agents. We have confined our book' s scope to the appli-
Preface Vll
cations in human therapy and by focusing on agents that have been
tested in controlled clinical studies. Research needed to better define
the potential of therapy using biotherapeutic agents is discussed, as
weH as the potential risks of this innovative method of therapy for
infectious diseases. We also consider the potential of genetic
approaches to the engineering of biotherapeutic agents for maximum
in vivo production of bioactive substances in the intestine or vagina.
The audience for this book will be pharmacists, internists, gastroen-
terologists, specialists in infectious diseases, gynecologists, microbi-
ologists,andrepresentativesofthepharmaceuticalindustry,especially
those involved in the discovery of agents for the treatment of infectious
diseases.
Acknowledgment
The editors would like to acknowledge Sharon Andrews, goddess of
the hard drive, for her valuable assistance with manuscript preparation.
Gary W. Eimer
Lynne V. McFarland
Christina M. Surawicz
Contents
Preface ......................................................................................................... v
Contributors .............................................................................................. xi
1 • Quality Control and Regulatory Issues for Biotherapeutic
Agents ............................................................................................ 1
Lynne V. McFarland
2 • Mechanisms of Action of Biotherapeutic Agents ..................... 27
Jean-Paul Buts
3 • Pharmacokinetics of Biotherapeutic Agents ............................. 47
Steven W. Martin, Anne C. Heatherington, and Gary W. EImer
4 • Influences on the Normal Microbial Flora ................................ 85
Kerstin Orrhage and Carl Erik Nord
5 • Immunological Effects of Biotherapeutic Agents .................. 121
Phillippe Marteau and Christophe Cellier
6 • Biotherapeutic Agents in the Prevention of Antibiotic-
Associated Diarrhea ................................................................ 145
Christina M. Surawicz
7 • Biotherapeutic Agents for Clostridium difficile-Associated
Disease ....................................................................................... 159
Lynne V. McFarland
8 • Biotherapeutic Agents in the Management of Pediatric
Diarrheal Disease ..................................................................... 195
Jose M. Saavedra
9 • Biotherapeutic Agents and Adult Diarrhea ............................ 207
S. Salminen, E. Isolauri, and E. Salminen
10 • Biotherapeutic Agents as Therapy for Vaginitis .................... 221
J. D. Sobel
11 • Biotherapeutic Agents to Prevent Cystitis in Women .......... 245
Gregor Reid, Vladimir Smeianov, and Andrew W. Bruce
IX
x Contents
12 • Risks of Biotherapeutic Agents .................................................. 263
Christina M. Surawicz and Lynne V. McFarland
13 • Future Directions for Research on Biotherapeutic Agents:
Contribution of Genetic Approaches on Lactic Acid
Bacteria ........................................................................................ 269
Gerard Corthier and Pierre Renault
Index ........................................................................................... ............. 305
Contributors
ANDREW W. BRucE • Division of Urology, University ofToronto, Canada
JEAN-PAUL BUTS • Division of Pediatric Gastroenterology, Department of
Pediatrics, Cliniques Universitaires St-Luc, Catholic Universityof
Louvain, Brussels, Begium
CHRISTOPHE CELLIER • Gastroenterology Department, Laennec Hospital,
Paris, France
GERARD CORTHIER • Fonctions des Bacteries Intestinales, UEPSD-FBI,
Jouy-en Josas, France
GARY W. ELMER • Department of Medicinal Chemistry, School of
Pharmacy, University of Washington, Seattle, WA
ANNE C. HEATHERINGTON • Department of Pharmacokinetics and Drug
Metabolism, Amgen Ine., Thousand Oaks, CA
E. ISOLAURI • Department of Pediatries, Turku University Hospital,
Turku, Finland
PHILIPPE MARTEAU • Department of Gastroenterology, University of Paris,
France
STEVEN W. MARTIN • Department of Pharmacokineties and Drug
Metabolism, Amgen Ine., Thousand Oaks, CA
LYNNE V. McFARLAND • Department of Medicinal Chemistry, University
ofWashington, Seattle, WA
CARL ERIK NORD • Department of Immunology, Mierobiology, Pathology,
and Infeetious Diseases, Karolinska Institute, Huddinge University
Hospital, Huddinge, Sweden
KERSTIN ORRHAGE • Department of Immunology, Mierobiology,
Pathology, and Infeetious Diseases, Karolinska Institute, Huddinge
University Hospital, Huddinge, Sweden
GREGOR REID • Lawson Research Institute, London, Ontario, Canada; and
Department of Microbiology and Immunology, The University of
Western Ontario, London, Ontario, Canada
PIERRE RENAuLT • Charge de Recherches, Genetique Microbienne, INRA,
Jouy-en Josas, Franee
JOSE M. SAAVEDRA • Department of Gastroenterology and Nutrition,
Johns Hopkins Children's Center, Baltimore, MD
Xl
Xll Contributors
E. SALMINEN •Department of Oncology, Turku University Hospital,
Turku, Finland
S. SALMINEN • Department of Biochemistry and Food Chemistry,
University of Turku, Finland
VLADIMIR SMEIANOV • Lawson Research Institute, London, Ontario,
Canada
J. D. SOBEL • Division of Infectious Diseases, Wayne State University
School of Medicine, Detroit Medical Center, Detroit, MI
CHRISTINA M. SURAWICZ • Department of Medicine, Universityof
Washington, Harborview Medical Center, Seattle, WA
CHAPTER 1
Quality Control and Regulatory Issues
for Biotherapeutic Agents
Lynne V. McFarland
On a long journey, the true reward comes not at the end,
but is gathered piece by piece during the trek itself.
1. Introduction
Biologie organisms that show promise as therapeutics have several
routes for development, which begin in the microbiology laboratory
and end in the medical marketplace. This chapter describes the regula-
tions regarding biotherapeutics, and presents the differences between
biotherapeutic agents and the other designations for biologics (dietary
supplements, medical foods, and functional foods). In addition, the
developmental pathway for a biotherapeutic agent and requirements
for drug approval in the United States will be described. Finally,
quality control and manufacturing concerns will be addressed. In this
chapter, the goal is to describe how a microorganism goes from being
just "an interesting bug on a Petri plate" to joining the arsenal of
approved drugs and biologics for the treatment and prevention of
disease.
2. Regulations for Biotherapeutics
One of the more difficult decisions for a scientist, company, or
manufacturer of a biotherapeutic agent is early in the development
phase. The decision is wh ich developmental pathway should be taken
for a specific potential therapeutic biologie; as a result of this decision,
there will be vast differences in the degree of scientific proof required,
time and expense of development, the targeted market population, and
the degree of reputability that is achieved at the end of the develop-
Fram: Biotherapeutic Agents and Infectious Diseases
Edited by G. W. EImer, L. McFarland, and C. Surawicz
© Humana Press Inc., Totowa, NJ
1
2 McFarland
mental proeess. Historieally, mieroorganisms that seem to have prom-
ise in the prevention or treatment of diseases were not subjected to
extensive scientifie studies and may have been sold as over-the-eounter
preparations. Some eompanies opted to follow a more diffieult path-
way, and they developed these mieroorganisms as new "drugs" under
their individual eountry's regulatory guidelines. The most rigorous
pathway is the development as a biotherapeutie agent with the same
requirements for approval through regulatory agencies as any new mo-
leeular entity, that is, like all other approval drugs. There is another
option, whieh beeame available after the passage of the 1994 Dietary
Supplement Health and Edueation Act (DSHEA). Biologie agents may
also be used as dietary supplements und er the DSHEA, but there ean be
no claims that the biologie actually treats or prevents a specifie disease.
Only limited health claims may be made, and thus, the degree of scien-
tifie proof is less than with true biotherapeutie agents. The least rigorous
of all pathways is to add the biologie agent to foods already on the
market and classify it as a "functional food." The area of funetional
foods is not defined by eurrent Food and Drug Administration (FDA)
regulations; they are more eommonly found in Europe and Asia. Fune-
tional foods may not make any health claims and therefore are of limited
seientifie value in the USo
2.1. Biotherapeutic Agents
Biotherapeutie agents are organisms that have been developed in
a nearly identieal pathway to any approved drug through the FDA
regulations and guidelines (see Table 1). The ehoiee of this develop-
ment plan involves eomplete studies of tolerability, toxieity studies,
anima I models, early dosing studies, human volunteer studies, and
at least two large, well-eontrolled phase 3 clinieal trials. Onee these
studies are finished, the eompany submits a "drug" applieation to
the FDA, ealled a biologie lieense applieation (BLA). The FDA eommit-
tee will review this information and give its approval or rejection.
This approved biologie may be used as a preseription or over-the-
counter preparation. The advantage of this long and rigorous route
is that a biotherapeutie agent ean make claims about treating or pre-
venting specifie diseases. Beeause the biologie has undergone similar
tests and studies to any approved new drug, it holds the same high
esteem and reputability as other drugs used by physicians. Biothera-
peutie agents are regulated by laws found in the Code of Federal
Regulations relating to labeling (21 CFR § 610.60-65), manufacturing
(21 CFR § 607 and 21 CFR § 210), and development (21 CFR § 600,
Table 1
Characteristics of Biotherapeutic Agents, Dietary Supplements, Functional Foods, and Medical Foods
Biotherapeutic Dietary Functional Medical
agent supplement food a food
Medical claim To treat or prevent Structure or function None Specific dietary
a specific disease only requirement
Federal FDCA of 1938 DSHEA of 1994, 21 FDCA of 1938 seetion Orphan Drug Act of
regulations seetion 21 CFR CFR Part 101 201 1988
Degree of High Low None Medium
scientific proof
Clinical trials Yes No No No
required
w Targeted Yes No No Yes
population
Safety Adverse reactions No adulterations Safe from filth and Adverse reactions
from placebo- contaminants from postmarketing
controlled trials studies
Examples UltraLevure® , Lactinex® (L. acidophilus Yogurt with L. None
Perenterol® and L. bulgaris), acidophilus, or B.
(5. boulardii) Infloran berna (B. bifidum and
bifidum, L. acidophilus), Acidophilus milk
Bioflorin (Enterococcus
faecium SF68)
aFunctional foods are found in Europe, Canada, and Asia. They are not currently regulated by the FDA.
Abbreviations used in table: CFR = Code of Federal Regulations, DSHEA = Dietary Supplement Health and Education Act,
FDCA = Food, Drug and Cosmetic Act.
4 McFarland
Fig. 1. Biotherapeutic agent examples.
21 CFR § 200 and 21 CFR § 312) (1). Deviations or violations from
these regulations are handled by the FDA. Examples of biotherapeutie
agents available in Europe are shown in Fig. 1.
2.2. Dietary Supplements
In the past, dietary supplements have included essential nutrients
(vitamins), minerals, and proteins, were regarded as foods, and did
not include biologie organisms. However, with the passage of the
Quality Control and Regulatory Issues 5
DSHEA, the US Congress expanded the meaning to include a wider
variety of items (herbai produets, "natural" products, such as melato-
nin and dehydroepiandrosterone [DHEA], enzymes, and biologie mi-
eroorganisms). The DSHEA established a formal definition of "dietary
supplement" with the following eriteria:
1. It is a product (other than tobacco) that is intended to supplement
the diet that bears or contains one or more of the following dietary
ingredients: a vitamin, a mineral, an herb or other botanical, an amino
acid, a dietary substance for use by humans to supplement the diet
by increasing the total daily in take, or a concentrate, metabolite, constit-
uent, extract, or combinations of these ingredients.
2. It is intended for ingestion in pill, capsule, tab let, or liquid form.
3. It is not represented for use as a conventional food or as the sole item
of a meal or diet.
4. It is labeled as a "dietary supplement."
5. It includes products, such an approved new drug, certified antibiotic,
or licensed biologie that was marke ted as a dietary supplement or
food before approval, certification, or license (unless the Secretary of
Health and Human Services waives this provision) (21 CFR § 341).
Thus, biologies that had been on the market in health food stores
and sold before Oetober 15, 1994 eould be eonsidered dietary
supplements.
What is the advantage of classifying a biologie as a dietary supple-
ment? Although dietary supplements eannot make a claim to treat
or prevent speeifie diseases, the regulations allow what is ealled
"structure or funetion" claims. These claims must not be made about
the use of a dietary supplement to diagnose, prevent, mitigate, treat,
or eure a specifie disease. Four types of claims are permitted:
1. Claims, which states a benefit related to a classical nutrient defi-
ciency disease.
2. Role, which describes the role a dietary supplement is intended to
affect in the structure or function of the human body.
3. Characterization, which describes the documented mechanism in-
volved in maintaining such a function and structure.
4. Well-being, wh ich describes the general well-being from consumption
of a dietary supplement.
Examples of these types of claims include: "for general well-being,"
"for improved functioning of the intestinal tract" (listed on a probiotie
preparation), "helps maintain normal structure and development of
the bones" Oisted on a calcium supplement), and "reduces eholesterol
if a low-fat diet is followed at the same time" (on a Lactobacillus species
6 MeFarland
preparation). Like other foods, dietary supplement produets must
bear ingredient labeling with the name and quantity of eaeh dietary
ingredient, excluding inert ingredients. The label must also identify
the product as a dietary supplement and must provide nutrition
labeling (quantity per serving for eaeh ingredient). The degree of
scientific proof for these structure/function claims is signifieantly less
than for biotherapeutic agents. The FDA requires that manufacturers
have "substantiation" that claims are truthful and not misleading,
but no scientific clinical trials are required (21 CFR § 343 [r] section
403 [rD. This degree of scientifie substantiation is one of the eritical
differenees between a dietary supplement and an approved biothera-
peutie agent. Although this law was passed in 1994, there is still mueh
debate about the provisions and speeifie guidelines (2,3).
The area of safety is limited to adulteration provisions if one or
more of its ingredients presents "a significant or unreasonable risk
of illness or injury" when used as directed on the label or und er
normal eonditions of use (21 CFR § 342).
Violations or deviations from these regulations are, in theory, und er
the power of the FDA. However, limited manpower and operating
budgets have foreed the Federal Trade Commission (FTC) to provide
the only realistic federal enforcement arm for dietary supplements.
The most common violation is false health claims on labels.
Examples of biologie organism preparations that may be considered
dietary supplements include lyophilized powders containing Lactoba-
eillus speeies, Bifidobaeterium bifidium, Bacillus lieheniformis, or a combi-
nation of these organisms (Fig. 2). The strueture/funetion claims on
these preparations usually state "for use to restore intestinal health"
or "will eontribute to good health." Thus, the use of microorganisms
as dietary supplements may arrive in the marketplaee more quiekly,
but will have mueh less scientific reputability regarding the strength
or real effectiveness of the organism on specifie diseases.
2.3. Functional Foods
When a biologie is added to a food already on the market, it may
be eonsidered a "functional food." This is an area of eonfusion, beeause
this use of a biologie has also been called nutraceutical (pharmaceuti-
cal companies prefer this name) and also functional foods (food indus-
trial manufacturers prefer this name), but the use of the microorganism
is identieal. These funetional foods have been defined as "any modi-
fied food or food ingredient that may provide a health benefit beyond
the traditional nutrients it contains." Although usually meant for
