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Antifungal Therapy
Second Edition

Edited by
Mahmoud A. Ghannoum
John R. Perfect
CRC Press
Taylor & Francis Group
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New York, NY 10017

© 2019 by Taylor & Francis Group, LLC

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Library of Congress Cataloging‑in‑Publication Data

Names: Ghannoum, Mahmoud A. (Mahmoud Afif), editor. | Perfect, John R., 1949- editor.
Title: Antifungal therapy / [edited by] Mahmoud Ghannoum, John R. Perfect.
Description: Second edition. | New York, NY : CRC Press, [2019] | Includes bibliographical references and index.
Identifiers: LCCN 2018033731| ISBN 9781498768146 (hardback : alk. paper) | ISBN 9780429402012 (ebook)
Subjects: | MESH: Mycoses--drug therapy | Antifungal Agents--therapeutic use
Classification: LCC RM410 | NLM WC 450 | DDC 615.7/92--dc23
LC record available at https://lccn.loc.gov/2018033731

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Contents

Preface v
Editors vii
Contributors ix

1 History of antifungals 1
Emily L. Larkin, Ali Abdul Lattif Ali, and Kim Swindell
2 Epidemiology of fungal infections: What, where, and when 11
Frederic Lamoth, Sylvia F. Costa, and Barbara D. Alexander
3 Experimental animal models of invasive fungal infections 49
Christopher L. Hager, Lisa Long, Yoshifumi Imamura, and Mahmoud A. Ghannoum
4 Antifungal drug resistance: Significance and mechanisms 63
Sharvari Dharmaiah, Rania A. Sherif, and Pranab K. Mukherjee
5 Antifungal prophylaxis: An ounce of prevention is worth a pound of cure 87
Aimee K. Zaas
6 Preemptive antifungal therapy: Do diagnostics help? 97
Vidya Jagadeesan, Margaret Powers-Fletcher, and Kimberly E. Hanson
7 The immune response to fungal challenge 115
Jeffery Hu and Jeffery J. Auletta
8 Immunomodulators: What is the evidence for use in mycoses? 131
J. Andrew Alspaugh
9 Fungal biofilms and catheter-associated infections 143
Jyotsna Chandra and Mahmoud A. Ghannoum
10 Polyenes for prevention and treatment of invasive fungal infections 155
Richard H. Drew
11 Flucytosine 177
Richard H. Drew
12 Pharmacology of azole antifungal agents 193
Elizabeth S. Dodds Ashley
13 Echinocandins for prevention and treatment of invasive fungal infections 213
Melissa D. Johnson, John Mohr, and Ahmad Mourad
14 Novel methods of antifungal administration 239
Richard H. Drew
15 Dermatophytosis 257
Mahmoud A. Ghannoum, Iman Salem, and Nancy Isham
16 Invasive candidiasis 273
Richard R. Watkins and Tracy Lemonovich
17 Invasive aspergillosis 287
Frank Esper
18 Management of cryptococcosis 301
John R. Perfect and Ahmad Mourad

iii
iv Contents

19 Management of endemic mycoses 317

John R. Perfect and Ahmad Mourad
20 Human hyalohyphomycoses: A review of human infections due to Acremonium spp., Paecilomyces spp.,
Penicillium spp., Talaromyces spp., and Scopulariopsis spp. 325
Nour Hasan
21 Management of phaeohyphomycosis 337
John R. Perfect and Ahmad Mourad
22 Pneumocystis 347
Kim Swindell
23 Management of mucormycoses 357
John R. Perfect and Ahmad Mourad
24 Antifungal management in risk groups: Solid organ transplant recipients 363
Jasmine Chung, Sylvia F. Costa, and Barbara D. Alexander
25 Prophylaxis and treatment of invasive fungal infections in neutropenic cancer and hematopoietic
cell transplant patients 383
Daniel R. Richardson, Marcie L. Riches, and Hillard M. Lazarus
26 Antifungal use in transplant recipients: Selection, administration, and monitoring 403
Richard H. Drew, Mary L. Townsend, Melanie W. Pound, and Steven W. Johnson
27 Infants: Yeasts are beasts in early life 445
Rachel G. Greenberg and Daniel K. Benjamin Jr.
28 Newer antifungal agents in pediatrics 457
William J. Steinbach
29 Fungal infections in burn patients 473
Nour Hasan
30 Allergic bronchopulmonary aspergillosis 479
Nour Hasan
31 Fungal infections of the genitourinary tract 489
Raymond R. Rackley and Jessica C. Lloyd
32 Mycobiome in health and disease 503
Najla El-Jurdi, Jyotsna Chandra, and Pranab K. Mukherjee

Index 517
Preface
This book is designed to provide a comprehensive but
insightful examination of antifungal therapy in the changing
clinical milieu of modern medicine. It is an update from
the original work almost a decade ago. It is clear that as
medicine advances to treat and cure severe underlying
diseases, the collateral consequences of this management
can be immunosuppression and opportunistic fungal infec-
tions. Furthermore, there are a series of primary fungal
infections, such as dermatophytosis and endemic mycoses,
which continue to plague normal hosts. Additionally, the
pandemic of HIV, which has impacted the entire world, laid
in its immunosuppressive path the rise of invasive mycoses.
It is clear that most clinicians who care for the seriously
sick will be faced at times with the appearance of a fungal
infection and a need to manage its disease. There are many
aspects of invasive mycoses, including genetic susceptibil-
ity, risk factor predictions, diagnosis, epidemiology, and
outcome of underlying diseases, that require a present and
future knowledge base for medical practice. In this book,
we have attempted to focus the presentation on the updated
management aspects of fungal diseases. With the rising
number of fungal infections worldwide and the develop-
ment and clinical use of a variety of antifungal agents, it is
quite clear that the statement: “Amphotericin B is the gold
standard for the invasive mycoses” is no longer true. We
have safer and effective alternative drugs to use. It is our
mission in this book to provide clinicians with a foundation
and insights into current antifungal management and the
second edition has allowed us the ability to revisit the sub-
jects as they have changed over the last decade. The book
has repeated the original list of topics.
First, we approach some general antifungal agent issues,
from the history of antifungal agents, fungal epidemiol-
ogy, antifungal agent preclinical development to drug
resistance. Second, we examine in depth the antifungal
classes of drugs. Third, there is an attempt to provide
clinical management issues and strategies around specific
fungal infections that the clinician may face frequently or
rarely, depending on the patient population in their prac-
tice. In these sections, there are insights provided into
dosing, choice of drugs, concerns about complications,
and outcomes, which are evidence-based but mixed with
personal opinions and experiences. Fungal infections are
treated “one patient at a time,” and there is no “cookbook
recipe” that fits all patients all the time. In fact, the under-
lying disease simply gets in the way too often or our
evidence-based material is either weak or non-existent.
Finally, we conclude with the management of several risk
groups, or unique patient populations or infection sites,
and their fungal infections. It is not an exhaustive list but
provides illustrative exposure to these patients. It also lays
the ground work/foundation for the principles of man-
aging other risk groups which occur today or may occur
tomorrow.
Fungal diseases have risen to prominence over the last
50 years. They have paralleled the technological advances
in the care of serious medical diseases. Fungi, as eukaryotic
organisms, play an interesting role in the human condition.
They have been harnessed to help make our bread and bev-
erages. In fact, we eat some of them and, during the traffic of
life, we are constantly exposed to millions of them. During
health, they are rarely a problem for us and after death they
degrade us. Many of our critical exposures for health and
fungi come between these stations of life. It is in this arena
as a “human petri dish” that fungal disease raises its ugly
consequences. It is the hope of these authors that this book
reveals the tools, strategies, and insights to manage these
irritating, costly, and life-threatening infections, and they
have updated them to meet the rapidly changing clinical
landscape. At times, it may seem the patient is defenseless
against these marauders, but, in fact, present antifungal
therapy is very good and applied early and correctly can
make a difference in patient outcome. This success story is
told in the following pages. In this second edition, we have
made an effort to insightfully update the fast-moving field
over the last decade, so all available tools and principles are
recognized. Vulnerable patients continue to integrate into
the fabric of modern medicine; thus, invasive fungal dis-
eases consistently follow these patients. From the specialists
to the generalists, we must “all be in” when it comes to suc-
cessful management of fungal diseases.
Mahmoud A. Ghannoum
John R. Perfect
v
Editors
Mahmoud A. Ghannoum, PhD, MBA, FIDSA, FAAM
joined Case Western Reserve University and University
Hospitals Case Medical Center in 1996 from prior positions
at the UCLA School of Medicine and Kuwait University.
Dr. Ghannoum has spent his entire academic career studying
medically important fungi encompassing different fungal
pathogens including Candida, Aspergillus, and Cryptococcus,
the major causes of fungal infections. He has published more
than 350 peer-reviewed articles addressing various aspects of
superficial and systemic fungal infections. More recently, he
published the first study describing the oral mycobiome of
healthy individuals. He has published extensively in the area
of fungal pathogenesis with special focus on virulence factors
including phospholipase B, germination, adhesion, and bio-
film formation, both in vitro and in vivo. Dr. Ghannoum is
a professor and director of the Center for Medical Mycology
at Case Western Reserve University and University Hospitals
Case Medical Center. This center of excellence, which he
directs, is a multidisciplinary center that combines basic and
translational research investigating fungi from the test tube
to the bedside. He has performed several studies investigat-
ing the mechanisms underlying Candida pathogenesis. He is
the recipient of the Freedom to Discover Award from Bristol-
Myers Squibb and the Rhoda Benham Award from the
Medical Mycological Society of the Americas. He served as a
chairman of the Subcommittee on Antifungal Susceptibility
Testing, Clinical Laboratory Standards Institute, and was
selected as a “Most Interesting Person” by Cleveland Magazine
in 2013. Dr. Ghannoum is an entrepreneur-scientist who has
launched a number of companies focusing on the treatment
of biofilm infections and microbial dysbiosis as it relates to
gut health. He coined the term ‘Mycobiome’.
John R. Perfect, MD, is James B. Duke Professor of Medicine
at Duke University Medical Center, a faculty member of the
Duke University Interdisciplinary Program in Genetics, and
director of the Duke University Mycology Research Unit.
He is chief of the Division of Infectious Diseases in the
Department of Medicine at Duke Medical Center. Dr. Perfect
is a diplomat of the American Board of Internal Medicine and
American Board of Infectious Diseases. After receiving an
undergraduate degree in biology from Wittenberg University,
Dr. Perfect went on to receive a medical degree from the
Medical College of Ohio at Toledo. He then completed an
internship at the Riverside Methodist Hospital in Columbus,
Ohio; a residency in internal medicine at the University of
Michigan Medical Center in Ann Arbor; and a fellowship in
infectious diseases at Duke University Medical Center. He is
a fellow of the American Society for Microbiology and the
Infectious Diseases Society of America. Dr. Perfect is also
a fellow of the American Association for Advancement of
Science and member of International Society for Human and
Animal Mycology, and Immunocompromised Host Society
(ISHAM). He is president of the Mycoses Study Group and
Educational Research Consortium and president-elect of
ISHAM. Dr. Perfect has served on numerous committees
and advisory boards. He received the Rhoda Benham Award
from Medical Mycology Society of the Americas and the
Lucille Georg Award from ISHAM. Dr. Perfect’s research
interests focus on the understanding of fungal pathogene-
sis through the study of Cryptococcus neoformans as well as
clinical studies on the epidemiology, diagnosis, and manage-
ment of invasive mycoses.
vii
Contributors

Barbara D. Alexander Jyotsna Chandra

Department of Medicine/Infectious Diseases Department of Dermatology
Duke University Medical Center Center of Medical Mycology
Durham, North Carolina University Hospitals Cleveland Medical Center
Case Western Reserve University
Ali Abdul Lattif Ali Cleveland, Ohio
Rudolph H. Raabe College of Pharmacy
Ohio Northern University Jasmine Chung
Ada, Ohio Division of Medicine/Infectious Diseases
Duke University Medical Center
Durham, North Carolina
J. Andrew Alspaugh
and
Department of Medicine
Department of Infectious Diseases,
Duke University School of Medicine
Singapore General Hospital, Singapore
and
Department of Molecular Genetics and
Microbiology Sylvia F. Costa
Duke University School of Medicine Department of Medicine/Infectious Diseases
Durham, North Carolina Duke University Medical Center
Durham, North Carolina

Elizabeth S. Dodds Ashley

Division of Infectious Diseases and Sharvari Dharmaiah
International Health Center for Medical Mycology
Duke University University Hospitals Cleveland Medical Center
Durham, North Carolina Case Western Reserve University
Cleveland, Ohio

Jeffery J. Auletta
Hematology/Oncology/BMT & Infectious Diseases Richard H. Drew
Nationwide Children’s Hospital Duke University School of Medicine
and Durham, North Carolina
Clinical Pediatrics and
The Ohio State University College of Medicine Campbell University College of Pharmacy and Health
The James Comprehensive Cancer Center Sciences
Columbus, Ohio Buies Creek, North Carolina

Daniel K. Benjamin, Jr. Najla El-Jurdi

Department of Pediatrics
Duke University Medical Center
and
Duke Clinical Research Institute
Durham, North Carolina
Division of Hematology/Oncology
Department of Medicine
University Hospitals Cleveland Medical Center
Case Western Reserve University
Cleveland, Ohio

ix
x Contributors

Frank Esper Melissa D. Johnson

Center for Pediatric Infectious Diseases Division of Infectious Diseases
Cleveland Clinic Children’s Hospital Department of Medicine
Cleveland, Ohio Duke University Medical Center
Durham, North Carolina
Mahmoud A. Ghannoum
Center for Medical Mycology Steven W. Johnson
University Hospitals Cleveland Medical Center Campbell University College of Pharmacy and Health
Case Western Reserve University Sciences
Cleveland, Ohio Buies Creek, North Carolina
and
Rachel G. Greenberg Novant Health Forsyth Medical Center
Department of Pediatrics Winston-Salem, North Carolina
Duke University Medical Center
and Frederic Lamoth
Duke Clinical Research Institute Service of Infectious Diseases and Institute of Microbiology
Durham, North Carolina Lausanne University Hospital
Lausanne, Switzerland
Christopher L. Hager
Center for Medical Mycology Emily L. Larkin
University Hospitals Cleveland Medical Center Center for Medical Mycology
Case Western Reserve University Department of Dermatology
Cleveland, Ohio University Hospitals Case Medical Center
Case Western Reserve University
Kimberly E. Hanson Cleveland, Ohio
Department of Clinical Microbiology
ARUP Laboratories
and Hillard M. Lazarus
Department of Infectious Diseases Department of Medicine
University of Utah Case Western Reserve University
Salt Lake City, Utah Cleveland, Ohio

Nour Hasan Tracy Lemonovich

Department of Pediatric Infectious Disease Division of Infectious Diseases and HIV Medicine
University Hospitals Cleveland Medical Center University Hospitals Cleveland Medical Center
Cleveland, Ohio Case Western Reserve University
Cleveland, Ohio
Jeffery Hu
Case Western Reserve University School of Medicine
Jessica C. Lloyd
Cleveland, Ohio
Section of Female Pelvic Medicine and Reconstructive
Surgery
Yoshifumi Imamura
Glickman Urology and Kidney Institute
Department of Molecular Microbiology and Immunology
Cleveland Clinic Lerner College of Medicine of Case
Nagasaki University Graduate School of Biomedical Sciences
Western Reserve University
Nagasaki, Japan
Cleveland, Ohio

Nancy Isham
Center for Medical Mycology Lisa Long
University Hospitals Cleveland Medical Center Center for Medical Mycology
Case Western Reserve University University Hospitals Cleveland Medical Center
Cleveland, Ohio Case Western Reserve University
Cleveland, Ohio
Vidya Jagadeesan
Clinical Microbiology John Mohr
ARUP Laboratories Medical Affairs Strategic Solutions, LLC
Salt Lake City, Utah Acton, Massachusetts
 Contributors xi

Ahmad Mourad Marcie L. Riches

Division of Infectious Diseases Division of Hematology/Oncology
Department of Medicine Department of Internal Medicine
Duke University Medical Center The University of North Carolina at Chapel Hill
Durham, North Carolina Chapel Hill, North Carolina

Iman Salem
Pranab K. Mukherjee
Center for Medical Mycology
Department of Dermatology
University Hospitals Cleveland Medical Center
Center of Medical Mycology
Case Western Reserve University
University Hospitals Cleveland Medical Center
Cleveland, Ohio
Case Western Reserve University
Cleveland, Ohio
Rania A. Sherif
Center for Medical Mycology
John R. Perfect University Hospitals Cleveland Medical Center
Division of Infectious Diseases Case Western Reserve University
Department of Medicine Cleveland, Ohio
Duke University Medical Center
Durham, North Carolina William J. Steinbach
Department of Pediatrics
and
Melanie W. Pound
Department of Molecular Genetics & Microbiology
Campbell University College of Pharmacy and Health
Duke University Medical Center
Sciences
Durham, North Carolina
Buies Creek, North Carolina
and
Kim Swindell
New Hanover Regional Medical Center
Martinsburg, Pennsylvania
Wilmington, North Carolina

Mary L. Townsend
Margaret Powers-Fletcher Campbell University College of Pharmacy and Health
Department of Pathology and Laboratory Medicine Sciences
College of Medicine Buies Creek, North Carolina
University of Cincinnati and
Cincinnati, Ohio Durham Veterans Administration Health Care
System
Durham, North Carolina
Raymond R. Rackley
Surgery
Richard R. Watkins
Glickman Urology and Kidney Institute
Division of Infectious Diseases
Cleveland Clinic Lerner College of Medicine of Case
Cleveland Clinic Akron General
Western Reserve University
Akron, Ohio
Cleveland, Ohio
and
Northeast Ohio Medical University
Daniel R. Richardson Rootstown, Ohio
Division of Hematology/Oncology
Department of Internal Medicine Aimee K. Zaas
The University of North Carolina at Chapel Hill Division of Infectious Diseases
Chapel Hill, North Carolina Duke University Medical Center
Durham, North Carolina
 1
History of antifungals

EMILY L. LARKIN, ALI ABDUL LATTIF ALI, AND KIM SWINDELL

Introduction 1 Second generation azoles 3

Early treatments 1 Third generation azoles 4
Antifungals for the treatment of invasive infections 2 Echinocandin antifungals 4
Polyenes 2 New antifungals underdevelopment 5
Nystatin 2 Topical antifungals 5
Amphotericin B 2 Future agents 5
Azole antifungals 3 References 6
Early azoles 3

INTRODUCTION EARLY TREATMENTS

Over the past decades, the incidence and diversity of fun-
gal infections has grown in association with an increasing
number of immunocompromised patients. The human
immunodeficiency virus (HIV) epidemic, technological
improvements in the fields of solid organ transplantation
medicine, stem cell transplantation, neonatology, coupled
with the advent of new immunosuppressive drugs have col-
lectively attributed to an increase in the incidence of sys-
temic fungal infections, including those caused by Candida,
Aspergillus, Cryptococcus, Coccidioides, Pneumocystis, and
Zygomycetes species. More recently, other species have
begun to rival Candida albicans as major causative agents
of fungal disease. For example, fluconazole-resistant non-
albicans Candida species, such as C. glabrata, are now more
prevalent in some hospitals [1,2]. Likewise, molds, such as
Scedosporium, Fusarium, Rhizopus, and Mucor species, are
now increasingly responsible for superficial and systemic
mycoses in humans [3,4].
Healthcare professionals must carefully consider the
expanded role of medically important fungi in order to
provide optimal treatment of fungal infections in immu-
nocompromised patient populations. Coincidently, novel
therapies that target host defenses, fungal biofilm physiol-
ogy, and emerging resistances must be developed in order
to keep pace with changes in the etiology and the resistance
patterns of fungal pathogens.
Antifungal therapies evolved slowly during the early years
of the past century. For example, from the beginning of
the twentieth century until after World War II, potas-
sium iodide was the standard treatment for cutaneous
fungal infections, including actinomycosis, blastomyco-
sis, sporotrichosis, and tinea [5]. First derived from sea
algae, potassium iodide was considered to exert a direct
antifungal effect, although the complete mechanism of
action remains unclear [6–8]. Contemporarily, radiation
was used to treat severe tinea capitis infections, often with
significant complications, including skin cancer and brain
tumors [9].
In the 1940s, Mayer et al. [10] demonstrated that sulfon-
amide drugs, such as sulfadiazine, exhibited both fungistatic
and fungicidal activities against Histoplasma capsulatum
[11]. This discovery led to the formation and the use of sul-
fonamide derivatives for the treatment of blastomycosis,
nocardiosis, and cryptococcosis [12–14].
Griseofulvin, a compound derived from Penicillium gris-
eofulvum, has been widely used to treat superficial fungal
infections since its isolation in 1939 [15]. In 1958, Gentles
[16] reported the successful treatment of ringworm in guinea
pigs using oral griseofulvin.
These successful attempts to develop novel and effective
antifungal drugs encouraged the further study and discov-
ery of new agents.

1
2 History of antifungals
ANTIFUNGALS FOR THE TREATMENT
OF INVASIVE INFECTIONS
Polyenes
In 1946, polyene antifungals (Figure 1.1), which are effective
against organisms with sterol-containing cell membranes
(e.g., yeast, algae, and protozoa), were developed from the
fermentation of Streptomyces [17,18]. These drugs disrupt
the fungal cell membrane by binding to ergosterol, the main
cell fungal membrane sterol moiety. As a result, holes form
in the membrane allowing leakage of essential cytoplasmic
materials, such as potassium, leading to cell death. From the
1950s until the advent of effective azole compounds in the
1960s, polyene antifungal agents were standard therapy for
systemic fungal infections [19].
NYSTATIN
In 1949, while conducting research at the Division
of Laboratories and Research of the New York State
Department of Health, Elizabeth Lee Hazen and Rachel
Fuller Brown discovered nystatin, a polyene derived from
Streptomyces noursei [20–22]. In 1955, Sloane [23] reported
topical nystatin to be particularly effective for treatment of
noninvasive moniliasis (candidiasis), a frequent complica-
tion observed in children enrolled in early chemothera-
peutic leukemia trials underway during this period [24].
2015
(a)
2006 Posaconazole
2002 Voriconazole
1992 Itraconazole
1990 Fluconazole
1981 Ketoconazole
Late 1960s Clotrimazole, miconazole, and econazole
1959 Chlormidazole
1944 Benznidazole
Figure 1.1 Historical development of the antifungal agents, including novel antifungals: (a) azoles, (b) polyenes, and
(c) echinocandins (1,3-β-glucan synthase inhibitors).
Nystatin exhibited good activity against Candida and mod-
est activity against Aspergillus species.
In aqueous solutions, nystatin forms aggregates that
are toxic to mammalian cells both in vitro and in vivo. The
insolubility and toxicity precluded its use as an intravenous
therapy for systemic mycoses.
Subsequently, (NyotranOR), a more soluble liposomal
nystatin formulation with reduced toxicity was developed
[25]. The liposomal formulation consists of a freeze-dried,
solid dispersion of nystatin mixed with a dispersing agent,
such as a poloxamer or polysorbate [26,27]. The dispersing
agent prevents aggregate formation in solution, increasing
the drug’s solubility and decreasing toxicity while main-
taining efficacy [27,28]. Liposomal nystatin has good activ-
ity in vitro against a variety of Candida species, including
some amphotericin B–resistant isolates [28].
Studies by Oakley et al. [29] showed that NyotranOR
was more effective than liposomal amphotericin against
Aspergillus species. Although the liposomal form of nystatin
was less toxic than conventional nystatin, unacceptable
infusion-related toxicity unfortunately caused a halt in the
development of this drug [30–32].
AMPHOTERICIN B
Amphotericin B is a fungicidal polyene antibiotic and, like
other members of the polyene class, is effective against
organisms with sterol-containing cell membranes [19].
Underdevelopment:
VT-1161, VT-1129, and VT-1158
Lipid-amphotericin
1995–1997
B formulations
Isavuconazole (b)
1958 Amphotericin B
1955 Nystatin
Underdevelopment:
CD101 and SCY-078
(c)
2006 Anidulafungin
2005 Micafungin
2002 Caspofungin

Amphotericin B was extracted from Streptomyces nodosus,
a filamentous bacterium, at the Squibb Institute for Medical
Research in 1955 and subsequently served as the standard
treatment for many invasive fungal infections [33].
Amphotericin B provided activity against invasive
Aspergillus superior to that of previously available antifun-
gal agents [33,34]. Amphotericin B continues to be effective
for the treatment of fluconazole-resistant fungal infec-
tions [19,30]. Like other polyenes, amphotericin B exhibits
dose-dependent toxicities including renal impairment and
hypokalemia [19,30,34,35]. Renal toxicity associated with
polyene antibiotics is believed to be mediated by the drug
interaction with cholesterol within the mammalian cell
membrane, resulting in pore formation, abnormal electro-
lyte flux, decrease in adenosine triphosphate (ATP), and
eventually a loss of cell viability [19].
In the early 1980s, several research groups developed a new
liposomal amphotericin B formulation. Graybill et al. [36]
published the first extensive study investigating the treat-
ment of murine cryptococcosis with liposome-associated
amphotericin B. The tissues of Crytococcus-infected mice
treated with the liposome-associated formulation were
demonstrated to have lower tissue fungal burden than the
tissues of similarly-infected mice treated with conventional
amphotericin B. Liposome-associated amphotericin B dem-
onstrated increased efficacy attributed to the ability to treat
with higher doses (due to its lesser toxicity) than was possi-
ble with amphotericin B deoxycholate (conventional ampho-
tericin B formulation) [36,37].
In the past decades, three novel liposomal formula-
tions of amphotericin B have been approved for use in the
United States: amphotericin B colloidal dispersion (ABCD;
AmphocilOR or AmphotecOR), amphotericin B lipid complex
(ABLC; AbelcetOR), and small unilamellar vesicle liposomal
formulation (L-AmB; AmbisomeOR).
The development of lipid-based amphotericin B formu-
lations afforded significant advantages in treatment of sys-
temic fungal infections, including decreased toxicity and
improved tolerance [38–40].
Despite the introduction of newer antifungal agents for
the treatment of systemic mycoses, amphotericin B remains
the standard treatment for many severe, invasive fungal
infections. However, because of toxicities associated with
its intravenous use, along with the expanded availability of
safer treatment options, it is frequently reserved for patients
who have severe, life-threatening invasive fungal infections
or who are unable to tolerate alternative antifungal agents.
Azole antifungals
Progress in the development of new antifungal agents
lagged behind that of antibacterial antibiotics. The delay can
be explained by two factors: (i) before the HIV/AIDS period,
the occurrence of fungal infections was believed to be too
low to warrant aggressive research by the pharmaceutical
industry; and (ii) the apparent lack of a highly selective fun-
gal target not present in other mammalian cells limited the
Antifungals for the treatment of invasive infections 3
number of potential pharmacologic mechanisms not associ-
ated with shared pathogen–host cell toxicity [19,41].
The discovery of the azole antifungal drugs (Figure 1.1)
was seminal in the history of antifungal development. Until
the discovery of azoles, amphotericin B was the only avail-
able agent to treat disseminated fungal infections includ-
ing invasive aspergillosis—although not without concerns
regarding nephrotoxicity and administration.
Azoles inhibit the synthesis of ergosterol, the major ste-
rol in the fungal cell membrane, via inhibition of the cyto-
chrome P450 enzyme, lanosterol demethylase [41,42]. This
inhibition results in disruption of cell membrane integrity
with eventual death.
EARLY AZOLES
In 1944, Woolley [43] described the antifungal activity of
the first azole, benzimidazole. Descriptions of the antifun-
gal properties of substituted benzimidazole were followed
by the discovery of chlormidazole [44–46].
In the late 1960s, clotrimazole was developed in
Germany by Bayer [17]. Miconazole and econazole were
developed subsequently by Janssen Pharmaceutica, Antwerp,
Belgium [46]. The early imidazoles, such as clotrimazole,
miconazole, and tioconazole, showed good topical antifun-
gal activity, but were of limited value for treating systemic
infections.
SECOND GENERATION AZOLES
In 1981, the Food and Drug Administration (FDA) approved
the systemic use of ketoconazole, an imidazole derivative
synthesized and developed by Janssen Pharmaceutica,
Antwerp, Belgium [45]. Ketoconazole was also avail-
able commercially as an anti-dandruff shampoo, branded
(NizoralOR) by the same company. For almost a decade,
ketoconazole was regarded as the standard oral agent for
treatment of fungal infections, including chronic muco-
cutaneous candidiasis [47]. Mendes et al. [48] considered
azole derivatives as the drugs of choice for the treatment
of eumycetomas. The oral formulation of ketoconazole is
now regarded as a treatment option only when all others fail
[49]. There are serious hepatic issues that can develop with
its use. In fact, it was taken off the market across Europe
and in Australia in 2013 [50]. Its topical formulation is still
in use because it does not share the same toxicity concerns
as its oral counterpart.
In 1978, Pfizer developed fluconazole, a drug suitable
for oral and intravenous treatment of superficial and sys-
temic fungal infections [47,48,51]. Fluconazole was shown
to have a good safety profile and was approved for the treat-
ment of oropharyngeal, esophageal, vaginal, peritoneal, and
genito-urinary candidal infections, disseminated candi-
diasis, and cryptococcal meningitis. Unlike ketoconazole,
fluconazole is highly water soluble and can be administered
parenterally. Recently, the utility of fluconazole has been
limited by the emergence of resistant organisms, such as
C. krusei and C. glabrata, against which fluconazole has
poor activity [52,53].
4 History of antifungals
In 1992, the FDA approved itraconazole, a broad spec-
trum triazole antifungal agent developed by Janssen
Pharmaceutica (SporanoxOR). Itraconazole was shown to be
less toxic than previous azoles, with a spectrum of activ-
ity broader than that of ketoconazole [52,53]. Consequently,
itraconazole has replaced ketoconazole as the treatment of
choice for invasive aspergillosis [52].
Although the discovery of fluconazole and itraconazole
represented a major advancement in the management of
systemic fungal infections, these triazole antifungal agents
have some important limitations [54,55]. Fluconazole
activity has a narrow spectrum, targeting mainly yeast
(Cryptococcus neoformans, C. albicans) and dimorphic
fungi, with no activity against molds [56,57]. In compari-
son, itraconazole has a broader spectrum that includes
activity against Aspergillus species and some yeast strains
that are intrinsically resistant to fluconazole, such as C. krusei
and C. glabrata [56,57].
THIRD GENERATION AZOLES
Voriconazole, a derivative of fluconazole, is a synthetic
third-generation triazole developed in the late 1980s by
Pfizer Pharmaceuticals, Antwerp, Belgium [58,59] and
approved by the FDA in May 2002. Voriconazole is more
active than fluconazole and itraconazole against Candida
species [60]. The activity of voriconazole against filamen-
tous fungi, particularly Aspergillus, was found to be supe-
rior to that of amphotericin B [57,58]. Voriconazole is now
considered the gold standard for the treatment of aspergil-
losis [61–63].
Posaconazole, a hydroxylated analogue of itraconazole,
was developed by the Schering-Plough Research Institute
and approved for use in 2006 [64]. Posaconazole is effec-
tive against opportunistic and endemic fungi, such as
Aspergillus spp., Zygomycetes, and Candida species [64,65].
Posaconazole has been shown to be superior to ampho-
tericin B, fluconazole, and itraconazole against most com-
mon fungal pathogens in in vitro and animal studies [66].
It is approved for prophylaxis of invasive fungal infections
(aspergillosis and candidiasis) in immunocompromised
patients and for the treatment of oropharyngeal candidiasis.
Recently, a delayed-release formula was created that allows
patients to be dosed once to twice daily in the hospital or at
home [67].
Isavuconazole (Basilea Pharmaceutica, Antwerp,
Belgium) and marketed by Astellas Pharma was approved
by the FDA in 2015 for the treatment of invasive asper-
gillosis and invasive mucormycosis in adults [68]. It is
a broad-spectrum antifungal affective against Candida
species, Aspergillus, some Zygomycetes, C. neoformans,
Cryptococcus, and several other molds, including Mucorales
[69]. It has been shown to be as effective as voriconazole and
is highly water soluble, unlike voriconazole and posacon-
azole. This allows for it to be administered without a cyclo-
dextrin vehicle. Cyclodextrin vehicles are associated with
nephrotoxicity and, since isavuconazole and its inactive,
prodrug form isacuconazonium sulfate do not require this
vehicle, this antifungal is associated with lower toxicity in
humans.
Azoles underdevelopment that show great promise
are several compounds by Viamet Pharmaceuticals [70].
VT-1161, VT-1129, and VT-1598 are all azoles that have
been molecularly altered to substantially reduce the inter-
actions these azoles have with cytochrome P450 and to
increase their half-lives [70,71]. Since azoles effects on cyto-
chrome P450 is the main driving force behind drug-drug
interactions of azoles, Viamet’s compounds have markedly
less drug-drug complications leading to their ability to be
used in more circumstances than previously allowed [72].
VT-1161 was recently evaluated in phase II clinical tri-
als for both vaginal candidiasis and onychomycosis, while
VT-1129 and VT-1598 are still undergoing in vitro and in
vivo testing [73].
Echinocandin antifungals
The advent of echinocandins (Figure 1.1), was heralded
by the development and approval of caspofungin acetate
(Cancidas; Merck & Co., Inc.) for the treatment of candi-
diasis in 2002 [66]. The echinocandins are a group of large,
semisynthetic, cyclic lipopeptides discovered in the 1970s.
Large molecular weight may explain their poor absorption
through the digestive tract. Therefore, all three commer-
cially available echinocandin compounds—caspofungin
acetate, micafungin, and anidulafungin—are used only
intravenously [74,75]. Echinocandins inhibit synthesis of
1,3-ß-D-glucan, an essential component of the fungal cell
wall [76]. The synthesis of caspofungin acetate based on
pneumocandin B0 requires chemical modification at two
sites of the peptide core, reduction of a primary amide to
an amine, and condensation of the hemiaminal moiety with
ethylenediamine [76].
Caspofungin acetate (CancidasOR) is fungicidal against
yeasts and dimorphic fungi such as C. albicans, includ-
ing triazole-resistant isolates, and fungistatic against
Aspergillus species [77]. Aspergillus fumigatus is unable to
sustain polarized growth in the presence of multiple doses
of caspofungin, leading to significant fungal cell death in
tissues [74,78]. Isham and Ghannoum [79] concluded that
voriconazole demonstrated greater in vitro inhibitory activ-
ity than caspofungin against the non-albicans isolates.
Micafungin (MycamineOR, Astellas Pharma, Japan)
and anidulafungin (EraxisOR, Pfizer, Inc., New York) were
approved for use in 2006. Micafungin was first isolated from
the culture broth of Coleophoma empedri [80]. It is a novel
water-soluble lipopeptide derived by semisynthetic modifi-
cation of FR901379, a naturally occurring cyclic hexapep-
tide with a fatty acryl side chain and is similar in structure
to echinocandins and pneumocandins [80,81]. Micafungin
is useful in the treatment of infections due to azole-resistant
Candida [82].
Anidulafungin is a derivative of a naturally occurring
candin, echinocandin B, produced by Aspergillus nidulans
or A. rugulosis [83]. Cilofungin was the first semisynthetic

derivative of echinocandin B to be evaluated in clinical tri-
als; however, the trials were discontinued due to associated
nephrotoxicity. Further structure modification of cilofun-
gin led to the synthesis of anidulafungin [83].
The newest echinocandin underdevelopment is CD101
(Cidara Therapeutics), which is more stable and, thus, has
a longer half-life than the previous echinocandins [84].
This stability also leads to the ability for CD101 to be used
topically [85]. This allows for its use in skin and vaginal
infections as well as systemic infections. Like the other echi-
nocandins, there is no oral formulation. It is in clinical trials
for vaginal and invasive candidiasis [85,86].
New antifungals underdevelopment
SCY-078 (Scynexis, Inc., New Jersey), another 1,3-β-glucan
synthase inhibitor that continues to be evaluated in clinical
trials, unlike echinocandins, is an orally bioavailable triter-
pene with a spectrum of activity similar to echinocandins
[87,88]. SCY-078 has been demonstrated to have similar in
vitro efficacy as echinocandins with regard to several spe-
cies of Candida and Aspergillus including those that are
resistant [88].
There are also a couple novel antifungals with unique
mechanisms of action: APX001 (previously E1210; Amplyx
Pharmaceuticals Inc., San Diego, CA) and F901318 (F2G
Ltd., Manchester, UK). APX001 inhibits Gwp1p, an enzyme
involved in the glycosylphophtidylinositol-anchoring
pathway, which causes the cell wall to weaken [89]. While
humans contain a homolog to Gwp1p, APX001 does not
inhibit the mammalian version and, therefore, this drug
has demonstrated low toxicity in in vivo models [89,90].
APX001 has demonstrated effectiveness against both yeast
and molds, including Candida, Aspergillus, and Fusarium
[91–94]. APX001 has begun undergoing clinical trials to fur-
ther evaluate its safety, pharmacokinetics and tolerability.
F901318 impedes pyrimidine biosynthesis by inhibit-
ing the fungal enzyme dihydroorotate dehydrogenase [95].
This new antifungal is ineffective against Candida spe-
cies but is highly active against molds such as Aspergillus,
Scedosporium, and Lomentospora, including azole-resistant
types [95–97]. Like APX001, humans have their own version
of dihydroorotate dehydrogenase, which is not inhibited by
F901318, indicating that it will have a low toxicity that has
been demonstrated in in vivo models [95]. Clinical trials to
evaluate its tolerability and safety have been undertaken.
The development of the new antifungals that belong to
triazole and echinocandin classes as well as novel antifun-
gals will provide clinicians new alternatives for the treat-
ment of invasive and resistant systemic fungal infections.
TOPICAL ANTIFUNGALS
Superficial fungal infections, such as cutaneous and muco-
sal candidiasis, dermatophytoses, and tinea versicolor are
among the most frequently encountered infections world-
wide [98,99]. These infections are commonly caused by
Future agents 5
Candida, Trichophyton, Microsporum, and Malassezia spe-
cies and most often involve the skin, nails, buccal or vaginal
mucosa, or eyes [98]. Historically, compounds such as gen-
tian violet and Balsam of Peru were used for topical antifun-
gal therapy. However, in the past decades, fungistatic azole
drugs with imidazole- and triazole-containing compounds
(e.g., miconazole and itraconazole, respectively) have been
the mainstay of topical antifungal therapy [100,101]. The
advent of fungicidal allylamines (e.g., terbinafine) has
improved treatment outcomes, as cure rates are higher
with fungicidal drugs. Other new agents such as topical
echinocandins (caspofungin), ciclopirox, efinaconazole,
and tavaborole offer additional options for the treatment of
superficial fungal infections [102–104].
FUTURE AGENTS
Powerful historical precedents support the use of antibody-
based therapies to treat infectious diseases [105,106].
However, although still in the early stages of development,
newer approaches to the treatment of fungal infections will
likely include the consideration of the host immune system
and the interplay of drugs and host immunomodulators
[107,108].
Immunomodulator therapies can be categorized as either
pathogen specific or pathogen nonspecific [107]. Pathogen-
specific immunomodulators include antibody reagents and
vaccines, whereas cytokines, antimicrobial peptides, and
probiotics are considered pathogen nonspecific immu-
nomodulators [109]. Studies have shown immune sera to
be protective in animal models of systemic candidiasis
[107,109–115].
The immunodominant fungal antigen heat shock pro-
tein 90 (HPS90), expressed on the cell surfaces of yeasts and
certain malignant cells, has been investigated as a potential
target for antibody therapy [116,117]. MycograbOR (NeuTec
Pharma, Antwerp, Belgium), a human recombinant mono-
clonal antibody against HSP90, was shown to have synergistic
activity with amphotericin B, fluconazole, and caspofungin
in vitro against a broad spectrum of Candida species [118–
120]. MycograbOR consists of an antigen-binding variable
domain of heavy and light chains linked together to create
a recombinant protein that can be expressed in Escherichia
coli. This drug demonstrated activity in clinical trials and
looked like it would be an excellent addition to the antifun-
gal armamentarium [119,121]. Unfortunately, the Committee
for Medicinal Products for Human Use released an opinion
against the use of the product in combination [120]. The
main reason for this negative opinion was because the pro-
tein could fold incorrectly and aggregate [120]. Alterations
to the protein have been made to fix this issue; however, the
new molecule, Mycgrab C28Y, does not increase survival
rates compared to amphotericin B alone.
Other new antifungal agents under study include natu-
rally derived molecules with antifungal properties, such
as the antifungal proteins secreted by fungus, bacteria, or
derived from plants such as Clitoria ternatea [122–125].
6 History of antifungals
Antifungal proteins interfere with the physiological proper-
ties of fungus leading to fungal cell death [122–125].
The history of antifungal agents continues to evolve, and
no doubt will produce novel agents that, it is hoped, will
target the organism as well as the host immunity.
REFERENCES
1. Li L, Redding S, Dongari-Bagtzoglou A. Candida
glabrata, an emerging oral opportunistic pathogen.
J Dent Res 2007;86(3):204–215.
2. Bille J, Marchetti O, Calandra T. Changing face of
health-care associated fungal infections. Curr Opin
Infect Dis 2005;8:314–319.
3. Castagnola E, Cesaro S, Giacchino M, et al. Fungal infec-
tions in children with cancer: A prospective, multicenter
surveillance study. Pediatr Infect Dis J 2006;25:634–639.
4. Bethge WA, Schmalzing M, Stuhler G, et al.
Mucormycoses in patients with hematologic
malignancies: An emerging fungal infection.
Haematologica 2005;90:ECR22.
5. Richardson MD, Warnock DW (Eds.). Fungal
Infection: Diagnosis and Management, 3rd ed.
Malden, MA: Blackwell Publishing, 1993.
6. Frankenberg BE, Litvineko AN. Treatment of cervico-
facial actinomycosis with massive doses of potassium
iodide. Stomatologiia (Mosk) 1952;6(4):26–30.
7. Dostrovsky A, Rauitschek F, Paz ZE, et al. The
treatment of tinea capitis with oral potassium
iodide. J Invest Dermatol 1960;34:347–349.
8. Urabe H, Nagashima T. Mechanism of antifun-
gal action of potassium iodide on sporotrichosis.
Dermatol Int 1969;8:36–39.
9. Shore RE, Moseson M, Xue X, et al. Skin cancer
after X-ray treatment for scalp ringworm. Radiat Res
2002;157:410–418.
10. Mayer RL, Eisman PC, Geftic S, et al. Sulfonamides
and experimental histoplasmosis. Antibiot
Chemother 1956;6:215–225.
11. Mahgoub ES. Treatment of actinomycetoma with
sulphamethoxazole plus trimethoprim. Am J Trop
Med Hyg 1972;21(3):332–335.
12. Lamb JH. Combined therapy in histoplasmosis
and coccidioidomycosis; methyltestosterone and
meth-dia-mer-sulfonamides. AMA Arch Derm
Syphilol 1954;70:695–712.
13. Webster BH. Pulmonary nocardiosis; a review with a
report of seven cases. Am Rev Tuber Pulmonary Dis
1956;73:485–500.
14. Weed LA, Andersen HA, Good CA, et al.
Nocardiosis; clinical, bacteriologic and pathological
aspects. New Engl J Med 1955;253:1137–1143.
15. Oxford AE, Raistrick H, Simonart P. Studies in
the biochemistry of micro-organisms: Griseoful-
vin, C(17)H(17)O(6)Cl, a metabolic product of
penicillium griseo-fulvum dierckx. Biochem J
1939;33(2):240–248.
16. Gentles JC. Experimental ringworm in guinea
pigs: Oral treatment with griseofulvin. Nature
1958;182(4633):476–477.
17. Whiffen AJ, Bohonos N, Emerson RL. The produc-
tion of an antifungal antibiotic by streptomyces
griseus. J Bacteriol 1946;52(5):610–611.
18. Steffen C, Dupree MT. The introduction of griseoful-
vin. Skin Med 2004;3(2):105–106.
19. Ghannoum MA, Rice LB. Antifungal agents: Mode
of action, mechanisms of resistance, and correlation
of these mechanisms with bacteria resistance. Clin
Microbiol Rev 1999;12(4):501–517.
20. Fromtling RA. Overview of medically important
antifungal azole derivatives. Clin Microbiol Rev
1988;1:187–219.
21. Brown R, Hazen EL. Present knowledge of nystatin,
an antifungal antibiotic. Trans N Y Acad Sci
1957;19(5):447–456.
22. Brown R, Hazen EL. Nystatin. Ann NY Acad Sci
1960;89:258–266.
23. Sloane MB. A new antifungal antibiotic, mycostatin
(nystatin), for the treatment of moniliasis: A prelimi-
nary report. J Invest Dermatol 1955;24(6):569–571.
24. Mehta RT, Hopfer RL, Gunner LA, et al. Formulation,
toxicity, and antifungal activity in vitro of liposome-
encapsulated nystatin as therapeutic agent for
systemic candidiasis. Antimicrob Agents Chemother
1987;31:1897–1900.
25. Arikan S, Rex JH. Lipid-based antifungal agents:
Current status. Curr Pharm Des 2001;7:395–417.
26. Ng AW, Wasan KM, Lopez-Berestein G. Development
of liposomal polyene antibiotics: An historical per-
spective. J Pharm Pharm Sci 2003;6(1):67–83.
27. Silva L, Coutinho A, Fedorov A, et al. Nystatin-
induced lipid vesicles permeabilization is strongly
dependent on sterol structure. Bioch Biophys Acta
2006;1758(4):452–459.
28. Gupta AK, Sauder DN, Shear NH. Antifungal
agents: An overview. Part II. J Am Acad Dermatol
1994;30:677–698.
29. Oakley KL, Moore CB, Denning DW. Comparison
of in vitro activity of liposomal nystatin against
aspergillus species with those of nystatin, ampho-
tericin B (AB) deoxycholate, AB colloidal dis-
persion, liposomal AB, AB lipid complex, and
itraconazole. Antimicrob Agents Chemother
1999;43(5):1264–1266.
30. Kleiberg M. What is the current and future status of
conventional amphotericin B? Int J Antimic Agents
2006;27(Suppl. 1):12–16.
31. Boswell GW, Buell D, Bekersky I. AmBiosome (lipo-
somal amphotericin B): A comparative review. J Clin
Pharmacol 1998;38:583–592.
32. Larson JL, Wallace TL, Tyl RW, et al. The reproduc-
tive and developmental toxicity of the antifungal
drug NyotranOR (liposomal nystatin) in rats and rab-
bits. Toxicol Sci 2000;53:421–429.

33. Peer ET. Case of aspergillosis treated with ampho-
tericin B. Dis Chest 1960;38:222–230.
34. Procknow JJ. Treatment of opportunistic fungus
infections. Lab Invest 1962;11:1217–1230.
35. Plihal V, Jedlickova Z, Viklicky J, et al. Multiple
bilateral pulmonary aspergillomata. Thorax
1964;19:104–111.
36. Graybill JR, Craven PC, Taylor RL, et al. Treatment
of murine cryptococcosis with liposome-associated
amphotericin B. J Infect Dis 1982;145(5):748–752.
37. Graybill JR. Lipid formulations for amphotericin B:
Does the emperor need new clothes? Ann Int Med
1996;124(10):921–923.
38. Graybill JR. The future of antifungal therapy. Clin
Infect Dis 1996;22(Suppl. 2):S166–S178.
39. Boswell GW, Buell D, Bekersky I. AmBisome (lipo-
somal amphotericin B): A comparative review. J Clin
Pharmacol 1998;38:583–592.
40. Bekersky I, Fielding RM, Dressler DE, et al.
Pharmacokinetics, excretion, and mass balance of
liposomal amphotericin B (AmBisome) and ampho-
tericin B deoxycholate in humans. Antimicrob Agents
Chemother 2002;46(3):828–833.
41. Ghannoum MA. Future of antimycotic therapy.
Dermatol Ther 1997;3:104–111.
42. Maertens JA. History of the development of azole
derivatives. Clin Microbiol Infect 2004;10(suppl.
1):1–10.
43. Woolley DW. Some biological effects produced by
benzimidazole and their reversal by purines. J Biol
Chem 1944;152:225–232.
44. Jerchel D, Fischer H, Fracht M. Zur darstel-
lung der benzimidazole. Liebigs Ann Chem
1952;575:162–173.
45. Holt RJ. Topical pharmacology of imidazole antifun-
gals. J Cutan Pathol 1976;3(1):45–59.
46. Herrling S, Sous H, Kruppe W, et al. Experimental
studies on a new combination effective against
fungi. Arzneimittelforschung 1959;9:489–494.
47. Hume AL, Kerkering TM. Ketoconazole. Drug Intell
Clin Pharm 1983;17(3):169–174.
48. Mendes PR, Negroni R, Bonifaz A, et al. New
aspects of some endemic mycoses. Med Mycol
2000;38(Suppl. 1):237–241.
49. United States Food and Drug Administration. FDA
drug safety communication: FDA limits usage of
Nizoral (ketoconazole) oral tablets due to potentially
fatal liver injury and risk of drug interactions and
adrenal gland problems, 2013. [Online.] https://www.
fda.gov/drugs/drugsafety/ucm362415.htm.
50. Gupta AK, Lyons DCA. The rise and fall of oral keto-
conazole. J Cutan Med Surg 2015;19(4):352–357.
51. Richardson K. Taking a drug to market. Sci Publ
Affairs 1990;5(3):11–14.
52. Richardson K, Cooper K, Marriott MS, et al.
Discovery of fluconazole, a novel antifungal agent.
Rev Infect Dis 1990;12(Suppl. 3):S267–S271.
References 7
53. Sheehan DJ, Hitchcock CA, Sibley CM. Current and
emerging azole antifungal agent. Clin Microbiol Rev
1999;12:40–79.
54. Coleman JM, Hogg GG, Rosenfeld JV, et al. Invasive
central nervous system aspergillosis: Cure with
liposomal amphotericin B, itraconazole, and radical
surgery—Case report and review of the literature.
Neurosurgery 1995;36(4):858–863.
55. United States Food and Drug Administration.
Hepatotoxicity labelling for sporanox (itraconazole)
oral solution, 2002. [Online.] http://www.fda.gov/
cder/foi/label/2002/20657s8lbl.pdf.
56. Nolte FS, Parkinson T, Falconer DJ, et al. Isolation
and characterization of fluconazole- and ampho-
tericin B-resistant Candida albicans from blood
of two patients with leukemia. Antimicrob Agents
Chemother 1997;41(1):196–199.
57. Dismukes WE. Antifungal therapy: Lessons
learned over the past 27 years. Clin Infect Dis
2006;42:1289–1296.
58. Marriott MS, Richardson K. The discovery and
mode of action of fluconazole. In: Formtling RA
(Ed.). Fluconazole, a Significant Advance in the
Management of Human Fungal Disease. Barcelona,
Spain: J. R. Prous Science Publishers, 1987:81–92.
59. Pappas PG, Rex JH, Sobel JD, et al. Guidelines
for treatment of candidiasis. Clin Infect Dis
2004;38:161–189.
60. Lewis RE, Wiederhold NP, Klepser ME. In vitro
pharmacodynamics of amphotericin B, itraconazole,
and voriconazole against aspergillus, fusarium, and
scedosporium spp. Antimicrob Agents Chemother
2005;49(3):945–951.
61. Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment
of aspergillosis: Clinical practice guidelines of the
infectious diseases society of America. Clin Infect Dis
2008;46:327–360.
62. Consigny S, Dhedin N, Datry A. Successful voricon-
azole treatment of disseminated Fusarium infection
in an immunocompromised patient. Clin Infect Dis
2003;37:311–313.
63. Marco F, Pfaller MA, Messer S, et al. In vitro activi-
ties of voriconazole (UK-109,496) and four other
antifungal agents against 394 clinical isolates
of Candida spp. Antimicrob Agents Chemother
1998;42(1):161–163.
64. Farowski F, Vehreschild JJ, Cornely OA.
Posaconazole: A next-generation triazole antifungal.
Future Microbiol 2007;2:231–243.
65. Chiou CC, Groll AH, Walsh TJ. New drugs and novel
targets for treatment of invasive fungal infections in
patients with cancer. Oncologist 2000;5(2):120–135.
66. Sun QN, Fothergill AW, McCarthy DI, et al. In vitro
activities of posaconazole, itraconazole, voricona-
zole, amphotericin B, and fluconazole against 37
clinical isolates of zygomycetes. Antimicrob Agents
Chemother 2002;46(5):1581–1582.
8 History of antifungals
67. United States Food and Drug Administration. Center for
Drug Evaluation and Research: Application Number:
205596Orig1s000 Summary review, 2014. [Online.]
https://www.accessdata.fda.gov/drugsatfda_docs/
nda/2014/205596Orig1s000SumR.pdf.
68. Mullard A. FDA approvals for the first 6 months of
2015. Nat Rev Drug Discov 2015;14:517.
69. Pettit NN, Carver PL. Isavuconazole: A new option
for the management of invasive fungal infections.
Ann Pharmacother 2015;49(7):825–842.
70. Moriyama B, Gordon LA, McCarthy M, et al.
Emerging drugs and vaccines for candidemia.
Mycoses 2014;57(12):718–733.
71. Schell WA, Jones AM, Garvey EP, et al. Fungal
CYP51 inhibitors VT-1161 and VT-1129 exhibit
strong in vitro activity against Candida glabrata and
C. krusei isolates clinically resistant to azole and
echinocandin antifungal compounds. Antimicrob
Agents Chemother 2017;61(3):e01817–16.
72. Warrilow AG, Parker JE, Price CL, et al. The investi-
gational drug VT-1129 is a highly potent inhibitor of
cryptococcus species CYP51 but only weakly inhibits
the human enzyme. Antimicrob Agents Chemother
2016;60(8):4530–4538.
73. Chang Y, Yu S, Heitman J, et al. New facets of anti-
fungal therapy. Virulence 2017;8(2):222–236.
74. Morris MI, Villmann M. Echinocandins in the man-
agement of invasive fungal infections, part 2. Am
J of Health Syst Pharm 2006;63(19):1813–1820.
75. Kim R, Khachikian D, Reboli AC. A comparative
evaluation of properties and clinical efficacy of
the echinocandins. Expert Opin Pharmacother
2007;8(10):1479–1492.
76. Denning DW. Echinocandins: A new class of antifun-
gal. J Antimicrob Chemother 2002;49:899–891.
77. Leonard WR Jr, Belyk KM, Conlon DA, et al.
Synthesis of the antifungal beta-1,3-glucan
synthase inhibitor CANCIDAS (caspofungin
acetate) from pneumocandin B0. J Org Chem
2007;72(7):2335–2343.
78. Minassian B, Huczko E, Washo T, et al. In vitro
activity of ravuconazole against zygomycetes, sce-
dosporium and fusarium isolates. Clin Micro Infect
Dis 2003;9:1250–1252.
79. Isham N, Ghannoum MA. Determination of MICs of
aminocandin for Candida spp. and filamentous fungi.
J Clin Microbiol 2006;44(12):4342–4344.
80. Ernst EJ, Roling EE, Petzold CR, et al. In vitro
activity of micafungin (FK-463) against Candida
spp.: Microdilution, time-kill, and postantifungal-
effect studies. Antimicrob Agents Chemother
2002;46(12):3846–3853.
81. van Burik JH, Ratanatharathorn V, Stepan DE, et al.
Micafungin versus fluconazole for prophylaxis
against invasive fungal infections during neutrope-
nia in patients undergoing hematopoietic stem cell
transplantation. Clin Infect Dis 2004;39:1407–1416.
82. Messer A, Diekema DJ, Boyken L, et al. Activities of
micafungin against 315 invasive clinical isolates of
fluconazole-resistant Candida spp. J Clin Microbiol
2006;44:324–326.
83. Ghannoum M, D’Angelo M. Anidulafungin, a potent
antifungal that target Candida and Aspergillus.
Infect Dis Clin Pract 2005;13(4):1–14.
84. Pfaller MA, Messer SA, Rhomberg PR, et al. Activity
of a long-acting echinocandin (CD101) and seven
comparator antifungal agents tested against a
global collection of contemporary invasive fungal
isolates in the SENTRY 2014 antifungal surveil-
lance program. Antimicrob Agents Chemother
2017;61(3):e02045–16.
85. ClinicalTrials.gov. RADIANT: CD101 vs. Standard of
care in subjects with acute vaginal yeast infections,
2016. [Online.] https://clinicaltrials.gov/ct2/show/
NCT02733432.
86. ClinicalTrials.gov. CD101 Compared to caspofun-
gin followed by oral step down in subjects with
candidemia and/or Invasive Candidiasis (STRIVE),
2016. [Online.] https://clinicaltrials.gov/ct2/show/
NCT02734862.
87. ClinicalTrials.gov. Open-label study to evaluate
efficacy and safety of SCY-078 in patients with
refractory or intolerant fungal diseases (FURI),
2017. [Online.] https://clinicaltrials.gov/ct2/show/
NCT03059992.
88. Jimenez-Ortigosa C, Perez WB, Angulo D, et al. De
novo acquisition of resistance to SCY-078 in Candida
glabrata involves FKS mutations that both overlap
and are distinct from those conferring echino-
candin resistance. Antimicrob Agents Chemother
2017;61(9):e00833-17.
89. Watanabe N, Miyazaki M, Horii T, et al. E1210,
a new broad-spectrum antifungal, suppresses
Candida albicans hyphal growth through
inhibition of glycosylphosphatidylinositol
biosynthesis. Antimicrob Agents Chemother
2012;56(2):960–971.
90. Hata K, Horii T, Miyazaki M, et al. Efficacy
of oral E1210, a new broad-spectrum anti-
fungal with a novel mechanism of action, in
murine models of Candidiasis, Aspergillosis,
and fusariosis. Antimicrob Agents Chemother
2011;55(10):4543–4551.
91. Wiederhold NP, Najvar LK, Fothergill AW, et al. The
investigational agent E1210 is effective in treat-
ment of experimental invasive Candidiasis caused
by resistant Candida albicans. Antimicrob Agents
Chemother 2015;59(1):690–692.
92. Castanheira M, Duncanson FP, Diekema DJ, et al.
Activities of E1210 and comparator agents tested
by CLSI and EUCAST broth microdilution methods
against Fusarium and Scedosporium species identi-
fied using molecular methods. Antimicrob Agents
Chemother 2012;56(1):352–357.

93. Pfaller MA, Duncanson F, Messer SA, et al. In
vitro activity of a novel broad-spectrum anti-
fungal, E1210, tested against Aspergillus spp.
determined by CLSI and EUCAST broth microdi-
lution methods. Antimicrob Agents Chemother
2011;55(11):5155–5158.
94. Miyazaki M, Horii T, Hata K, et al. In vitro activity of
E1210, a novel antifungal, against clinically important
yeasts and molds. Antimicrob Agents Chemother
2011;55(10):4652–4658.
95. Oliver JD, Sibley GEM, Beckmann N, et al. F901318
represents a novel class of antifungal drug that
inhibits dihydroorotate dehydrogenase. PNAS
2016;113(45):12809–12814.
96. Buil JB, Rijs AJM, Meis JF, et al. In vitro activity of
the novel antifungal compound F901318 against
difficult-to-treat Aspergillus isolates. J Antimicrob
Chemther 2017;72(9):2548–2552.
97. Wiederhold NP, Law D, Birch M. Dihydroorotate
dehydrogenase inhibitor F901318 has potent in
vitro activity against Scedosporium species and
Lomentospora prolificans. J Antimicrob Chemther
2017;72:1977–1980.
98. Ghannoum MA, Hajjeh RA, Scher R, et al. A large-
scale North American study of fungal isolates from
nails: The frequency of onychomycosis, fungal distri-
bution, and antifungal susceptibility patterns. J Am
Acad Dermatol 2000;43(4):641–648.
99. Thomas J, Jacobson GA, Narkowicz CK, et al.
Toenail onychomycosis: An important global disease
burden. J Clin Pharm Ther 2010;35(5):497–519.
100. Katoh T. Guidelines for diagnosis and treatment
of mucocutaneous candidiasis. Jpn J Med Mycol
2009;50(4):207–212.
101. Iorizzo M, Piraccini BM, Rech G, et al. Treatment of
onychomycosis with oral antifungal agents. Expert
Opin Drug Deliv 2005;2(3):435–440.
102. Bao YQ, Wan Z, Li RY. In vitro antifungal activity
of micafungin and caspofungin against derma-
tophytes isolated from China. Mycopathologia
2013;175(1–2):141–145.
103. Tauber A, Muller-Goymann CC. Comparison of
the antifungal efficacy of terbinafine hydrochlo-
ride and ciclopirox olamine containing formula-
tions against the dermatophyte Trichophyton
rubrum in an infected nail plate model. Mol Pharm
2014;11(7):1991–1996.
104. Saunders J, Maki K, Koski R, et al. Tavaborale, efin-
azconazole, and luliconazole: Three new antimycotic
agents for the treatment of dermatophytic fungi.
J Pharm Pract 2016;30:621–630.
105. Buchwald UK, Pirofski L. Immune therapy for
infectious diseases at the dawn of the 21st
century: The past, present and future role of
antibody therapy, therapeutic vaccination and
biological response modifiers. Curr Pharm Des
2003;9:945–968.
References 9
106. Casadevall A, Scharff MD. Serum therapy revisted:
Animal models of infection and development
of passive antibody therapy. Antimicrob Agents
Chemother 1994;38:1695–1702.
107. Heitman J. Cell biology: A fungal Achilles’ heel.
Science 2005;309:2175–2176.
108. Scorzoni L, de Paula e Silva ACA, Marcos CM, et al.
Antifungal therapy: New advances in the under-
standing and treatment of mycosis. Front Microbiol
2017;8:36.
109. Casadevall A. The third age of antimicrobial therapy.
Clin Infect Dis 2006;42:1414–1416.
110. Franco R, Pacheco R, Lluis C, et al. The emergence
of neurotransmitters as immune modulators. Trends
Immun 2007;28(9):400–407.
111. Burnie JP, Carter TL, Hodgetts SJ, et al. Fungal
heat shock proteins in human disease. FEMS Rev
2006;30(1):53–88.
112. Spellberg B, Ibrahim AS, Yeaman MR, et al. The
antifungal vaccine derived from the recombinant
N terminus of Als3p protects mice against the
bacterium Staphylococcus aureus. Infect Immun
2008;76:4574–4580.
113. Spellberg BJ, Ibrahim AS, Avanesian V, et al. Efficacy
of the anti-Candida rAls3p-N or rAls1p-N vaccines
against disseminated and mucosal candidiasis.
J Infect Dis 2006;194:256–260.
114. Torosantucci A, Bromuro C, Chiani P, et al. A novel
glycol-congate vaccine against fungal pathogens.
J Exp Med 2005;202(5):597–606.
115. Torosantucci A, Chiani P, Bromuro C, et al.
Protection by anti-beta-glucan antibodies is associ-
ated with restricted beta-1,3 glucan binding specific-
ity and inhibition of fungal growth and adherence.
PLoS One 2009;4(4):e5392.
116. Saito K, Dai Y, Ohtsuka K. Enhanced expression of
heat shock proteins in gradually dying cells and their
release from necrotically dead cells. Exp Cell Res
2005;310:229–236.
117. Matthews R, Burnie J. Antibodies against Candida:
Potential therapeutics? Trends Microbiol
1996;4:354–358.
118. Casadevall A. Antibody immunity and invasive fungal
infections. Infect Immun 1995;63:4211–4218.
119. Pachl J, Svoboda P, Jacobs F. A randomized, blinded,
multicenter trial of lipid-associated amphotericin
B alone versus in combination with an antibody-
based inhibitor of heat shock protein 90 in
patients with invasive candidiasis. Clin Infect Dis
2006;42(10):1404–1413.
120. Bugli F, Cacai M, Martini C, et al. Human monoclonal
antibody-based therapy in the treatment of invasive
candidiasis. Clin Dev Immunol 2013;2013:403121.
121. Matthews RC, Rigg G, Hodgetts S. Preclinical assess-
ment of the efficacy of mycograb, a human recom-
binant antibody against fungal Hsp90. Antimicrob
Agents Chemother 2003;47(7):2208–2216.
10 History of antifungals
122. Delgado J, Owens RA, Doyle S, et al. Impact of the
antifungal protein PgAFP from Penicillium chrysoge-
num on the protein profile in Aspergillus flavus. Appl
Microbiol Biotechnol 2015;99(20):8701–8715.
123. Wen C, Guo W, Chen X. Purification and identifi-
cation of a novel antifungal protein secreted by
Penicillium citrinum from the Southwest Indian
Ocean. J Microbiol Biotechnol 2014;24(10):1337–45.
124. Ajesh K, Sreejith K. A novel antifungal protein
with lysozyme-like activity from seeds of
Clitoria ternatea. Appl Biochem Biotechnol
2014;173(3):682–693.
125. Yasmin N, Saleem M. Biochemical characteriza-
tion of fruit-specific pathogenesis-related anti-
fungal protein from Basrai banana. Microbiol Res
2014;169(5–6):369–377.
 2
Epidemiology of fungal infections:
What, where, and when

FREDERIC LAMOTH, SYLVIA F. COSTA, AND BARBARA D. ALEXANDER

Introduction 11 Mucormycosis 20
Aspergillosis 12 Endemic mycoses 21
Non-Aspergillus hyalohyphomycetes 14 Blastomyces 21
Acremonium 14 Coccidioides 22
Fusarium 14 Histoplasma 22
Paecilomyces 16 Paracoccidioides 23
Scedosporium 16 Penicillium marneffei 23
Scopulariopsis 17 Emmonsia 24
Phaeohyphomycoses 18 Sporothrix 24
Alternaria 18 Yeasts 24
Bipolaris 18 Candida 24
Cladophialophora 19 Cryptococcus 26
Curvularia 19 Malassezia 27
Verruconis/Ochroconis 19 Trichosporon 27
Exophiala (Wangiella) dermatitidis and Exophiala Rhodotorula 28
jeanselmei 19 Saccharomyces 28
Exserohilum 20 Geotrichum 28
Fonsecaea 20 Pneumocystis 28
Phialophora 20 References 29
Ramichloridium 20

INTRODUCTION invasive aspergillosis, invasive mucormycosis, cryptococco-

Fungal infections represent an important cause of morbid-
ity worldwide, including localized cutaneous or subcutane-
ous diseases (e.g., onycomycosis, tineas, dermatophytoses,
eumycetomas, hypho- or phaeo-hyphomycoses, keratitis)
and deep-seated or invasive fungal infections (IFIs). While
some systemic fungal diseases, referred to as endemic myco-
ses (e.g., histoplasmosis, blastomycosis, coccidioidomycosis,
paracoccidioidomycosis, penicilliosis) are associated with
specific geographical areas and have the ability to affect
the immunosuppressed as well as immunocompetent host,
the majority of IFIs (e.g., Candida bloodstream infections,
sis, and Pneumocystis pneumonia) affect the frail or immu-
nosuppressed patient and are associated with the highest
mortality. The most common immunosuppressive condi-
tions predisposing to IFIs include neutropenia following
anticancer therapies, and prolonged corticostroid therapy or
immunosuppressive treatments following allogeneic hema-
topoietic stem cell transplantation (HSCT) or solid organ
transplantation (SOT). IFIs are increasingly reported pos-
sibly as a consequence of active screening and improved
diagnostic methods, but also due to an ever-enlarging at-risk
population [1]. Surveillance data, though not perfect and
likely still reflecting underdiagnosis and underreporting of

11
12 Epidemiology of fungal infections: What, where, and when
these entities, indicate that over the past several decades,
there has been an increasing incidence of IFIs due to yeasts,
such as Candida spp. and Cryptococcus spp., and molds,
such as Aspergillus spp. and fungi of the order Mucorales [2].
Epidemiologic trends also suggest that other filamentous
hyphomycetes, such as Fusarium spp., Scedosporium spp.,
and Paecilomyces spp., are becoming more common [3].
Emergence of these rare fungal pathogens, which often
exhibit multiresistance to antifungals, is an increasing con-
cern. This chapter reviews the epidemiology of the most
common fungal infections including the typical clinical
manifestations associated with each fungal pathogen.
ASPERGILLOSIS
Aspergillus is a ubiquitous hyalohyphomycete (mold with
nonpigmented, regularly septate hyphae) found in soil, dust,
compost, rotted plants, and other organic debris including
foods and spices [4,5]. About 339 species are known [6]
and divided into 20 sections, though only a few have been
reported as pathogenic to humans. The more commonly
reported human pathogens include Aspergillus of the sec-
tion Fumigati (Aspergillus fumigatus), Flavi (A. flavus), Nigri
(A. niger), and Terrei (A. terreus). Of these, A. fumigatus
is the most common species to cause invasive disease, and
A. flavus is the second most commonly reported. Though
A. terreus is less common, it is resistant to amphoteri-
cin B and has historically been associated with an excep-
tionally high mortality [7–10]. Aspergillus of section Usti
(e.g., A. calidoustus) with intrinsic pan-azole resistance
has emerged as a new opportunistic pathogen in patients
receiving azole prophylaxis [11,12]. Other Aspergillus spe-
cies such as A. versicolor and A. nidulans are occasionnally
reported [4]. Moreover, some species belonging to the sec-
tion Fumigati (A. lentulus, A. udagawae, N. pseudofischeri),
Flavi (A. alliaceus), or Nigri (A. tubingensis) are increasingly
recognized and may be misidentified in clinical practice.
These cryptic species represent 3%–10% of all Aspergillus
clinical isolates and some, such as A. lentulus or A. udaga-
wae, may also exhibit intrinsic resistance to triazoles and
other antifungal drug classes [13–15].
Aspergillus grows best at 37°C, forming hyaline hyphae
with asexual reproduction by conidia that give each species
a distinctive colony color. Conidia are easily aerosolized
and, when small airborne conidia (2–3 μm for A. fumigatus)
are inhaled, they can settle deep in the lungs where coloni-
zation and a variety of clinical syndromes may develop. The
type of host plays a role in the clinical spectrum of disease,
as the host’s immune response and the ability of Aspergillus
to invade and destroy tissue determine the clinical presen-
tation. In patients with asthma, the inflammatory condition
of allergic bronchopulmonary aspergillosis (ABPA) may
develop. Allergic sinusitis is also a feature of Aspergillus that
can set up a fungus ball or aspergilloma in lungs with pre-
formed cavities. Those with underlying chronic lung disease
can progress to chronic necrotizing aspergillosis or present
with tracheobronchitis. In immunocompromised hosts,
invasive disease may develop as invasive pulmonary asper-
gillosis, invasive sinusitis, or dissemination to extrapulmo-
nary sites [4,16].
ABPA arises from a hypersensitivity reaction to Aspergillus
antigens. Patients with asthma or cystic fibrosis may
develop ABPA late in the course of their disease [17–19].
In patients with cystic fibrosis (CF), one study has shown
lung function to deteriorate over time in those CF patients
with ABPA compared with CF controls [20]. Similarly,
patients with bronchiectasis and evidence of ABPA have
been shown to have worse lung function when compared to
those with bronchiectasis without ABPA [21]. The diagno-
sis of ABPA is suspected on clinical findings and confirmed
by radiologic and serologic results. Impaired mucous clear-
ance, productive cough with mucous plugs or brown specks,
mucoid impaction, and episodic bronchial obstruction are
characteristics of ABPA. Those with chronic disease may
present with bronchiectasis and fibrosis. Imaging with com-
puted tomography (CT) may show pulmonary infiltrates or
bronchiectasis, and laboratory findings, such as growth of
Aspergillus in culture or immunologic response with skin
reactivity to Aspergillus antigens, support the diagnosis.
Allergic fungal sinusitis tends to arise in patients with
atopy, history of allergic rhinitis/sinusitis, nasal polyps, and
sometimes, asthma [4,22]. Direct microscopy often reveals
thick green mucus or mucopurulent secretions, crusting,
or the presence of polyps. Histologic examination of tissue
biopsy demonstrates thick allergic mucin, hyaline, septate
hyphae without invasion of tissue, and a chronic inflamma-
tory response. Growth in culture of the offending mold and
high levels of IgE aid in the diagnosis of this entity.
Aspergilloma, or fungus ball, is the most common
form of pulmonary involvement due to Aspergillus [4,16].
It usually develops in a preformed pulmonary cavity (e.g.,
a consequence of prior tuberculosis or bronchiectasis) or
in the paranasal sinuses and consists of masses of mycelia,
inflammatory cells, debris, and mucus [23]. The aspergil-
loma can remain asymptomatic for a prolonged period of
time, though some patients with pulmonary aspergilloma
may experience hemoptysis, ranging from mild to severe,
secondary to bleeding from bronchial blood vessels. A fun-
gus ball in the sinus cavity can likewise remain asymptom-
atic, evolve to cause allergic-type presentation, or invade
the contiguous tissue. The latter may occur in patients who
are immunosuppressed with hematologic malignancy, dia-
betes, chronic steroid use, SOT, and AIDS [24]. Invasion
of tissue and bone may progress to invasion of adjacent
structures, such as the orbit or the brain. The clinical pre-
sentation is variable and requires a high index of suspicion,
along with imaging, tissue histology, and culture to estab-
lish the diagnosis.
Endobronchial fungal infections are being increas-
ingly described with the use of surveillance flexible

bronchoscopy [25]. Presentation can range from mild
mucosal inflammation to central airway obstruction with
invasive disease. In lung transplant recipients, ulcerative
or pseudomembranous tracheobronchitis, including infec-
tion of the anastomotic site, has been described [26,27].
Chronic necrotizing pulmonary aspergillosis is due
to locally destructive invasion of lung parenchyma by
Aspergillus without distal invasion or dissemination to
other organs [4,16]. Patients usually have chronic underly-
ing lung diseases, such as chronic obstructive pulmonary
disease (COPD), and present with fever, cough productive
of sputum, and weight loss over a period of several months.
In immunocompromised patients (neutropenia, cortico-
steroid use, transplant recipients, hematologic malignancy,
cytotoxic chemotherapy, AIDS), invasive pulmonary asper-
gillosis (IPA) may develop, remaining largely asymptomatic
early on or presenting with non-specific signs, such as fever,
cough and dyspnea. Pleuritic chest pain and hemoptysis
may also be present, as can altered mental status and respi-
ratory failure. IPA is characterized by being more invasive
than chronic necrotizing aspergillosis as it includes inva-
sion of small vessels with hemorrhage and/or infarction and
the possibility of dissemination [4,16,28]. Radiologically,
alveolar infiltrates, either bilateral or diffuse, nodules,
cavitation, and pleural effusion can be present. Review of
the baseline chest CT findings from 235 patients with IPA,
who participated in the global multicenter trial comparing
voriconazole with amphotericin B for treatment of inva-
sive aspergillosis (IA) revealed that, at presentation, most
patients (94%) had one or more macronodules [29]. In
patients with neutropenia and IPA, the CT scan may have a
nodule surrounded by ground glass attenuation, the classic
halo sign. As this occurs early, it allows the presumption of
IPA diagnosis to be made prior to cavitation. However, this
lesion is transitory and by the first week, three-fourths of
the CT halo signs disappear. With recovery of the neutro-
phil count, an air crescent sign (representing early cavita-
tion) may be seen, which is highly indicative of IPA [30]. In
addition to radiological signs, serological markers, such as
circulating galactomannan or 1,3-β-d-glucan in serum or
galactomannan in bronchoalveolar lavage fluid, are impor-
tant diagnostic tools as microbiological documentation of
Aspergillus spp. by standard culture methods is often lack-
ing [31,32]. Molecular methods (PCR) targeting ribosomal
rRNA (18S) or the internal transcribed spacer (ITS) are also
adjunctive tools for the diagnosis of invasive aspergillosis [33].
Pre-emptive strategies that combine screening with these
markers coupled with chest CT are common practice for the
early diagnosis and management of high-risk onco-hema-
tological patients [34]. Guidelines have been established by
the European Organization for Research and Treatment
of Cancer (EORTC) and Mycoses Study Group (MSG) to
assess the probability of invasive aspergillosis on the basis
of host criteria, clinical and radiological signs, and micro-
biology results [35].
Aspergillosis 13
Patients who are immunocompromised can have dis-
semination of Aspergillus to the central nervous system
(CNS) [28,36,37]. At-risk immunocompromised individuals
are posttransplant and hematologic malignancy patients,
but aspergillosis of the CNS has also been reported in AIDS,
chronic asthma with steroid use, burn patients, patients
with hepatic failure, and infections in the postoperative
period. Cultures from non-CNS sites (most of which are
from lung) are positive for Aspergillus in approximately
half the patients with CNS aspergillosis [37]. Pathology
reports from a series of CNS aspergillosis cases diagnosed
by autopsy described hemorrhagic necrosis, abscesses, large
hemorrhages, bland nonhemorrhagic infarctions, myelitis,
mycotic aneurysm, basilar meningitis, sino-orbital disease,
carotid artery invasion and thrombosis, dural abscesses, as
well as findings of minimal inflammation in CNS lesions
[37]. Imaging studies of patients with cerebral aspergillosis
reveal three general patterns: single or multiple infarcts, ring
lesions (single or multiple) consistent with abscess forma-
tion after infarction, and dural or vascular infiltration aris-
ing from the paranasal sinuses or orbits. Other findings on
imaging include mycotic aneurysm and contrast enhance-
ment of affected parenchyma, as well as hemorrhagic trans-
formation of infarcted areas [38]. Galactomannan detection
in cerebrospinal may be an important adjunctive tool for
the diagnosis of cerebral aspergillosis.
The cumulative incidence of IA in the United States for
two of the highest populations at risk, HSCT and SOT recip-
ients, has been reported from the Transplant-Associated
Infection Surveillance Network (TRANSNET) multicenter
studies [39,40]. In the HSCT population, Aspergillus now
exceeds Candida as the most common invasive fungal
pathogen with a cumulative incidence at 12 months of 1.6%
and a one-year overall mortality rate of 75% [39]. In the SOT
population, the 12-month cumulative incidence of IA was
lower (0.7%) as was the mortality rate (41%) [40].
In the Prospective Antifungal Therapy (PATH) Alliance
Registry, a cohort of 960 cases of proven/probable inva-
sive aspergillosis reported from 2004 to 2008 in North
America, 48.3% of patients had hematologic malignancies
and 29.2% were SOT recipients, 33.8% were neutropenic
and 27.9% were HSCT recipients [41]. The lung was the
most common site of infection (76% of cases). Most com-
mon sites of extrapulmonary aspergillosis were the tra-
cheobronchial tree, sinuses, skin/soft tissues and central
nervous system. Among patients with a positive culture,
A. fumigatus accounted for 72.6% of cases, followed by
A. flavus (9.9%), A. niger (8.7%) and A. terreus (4.3%).
In 25% of cases, the diagnosis of invasive aspergillosis
relied on a positive galactomannan and/or histopathologic
examination of tissue biopsy without Aspergillus growth
in culture. The proportion of cases for which a positive
galactomannan in serum or bronchoalveolar lavage (BAL)
is the only microbiologic diagnostic criterion was as high
as 50%–80% in recent cohort studies [42,43].
14 Epidemiology of fungal infections: What, where, and when
Studies have also evaluated risk factors for IA in trans-
plant populations [44–46]. Factors associated with devel-
opment of early IA (≤40 days posttransplant) in the HSCT
population included older age at transplant, underlying
disease other than chronic myelogenous leukemia in the
chronic phase (aplastic anemia, myelodysplastic syndrome,
and multiple myeloma), the type of transplant (receipt
of T-cell depleted or CD-34–selected stem cell products
or cord blood), prolonged neutropenia, cytomegalovirus
(CMV) disease, and receipt of corticosteroids for treatment
of acute graft-versus-host disease (GvHD). Risk factors for
IA following engraftment (days 41–180) in the HSCT popu-
lation included older age at the time of transplant, receipt of
T-cell depleted or CD-34–selected stem cell products, mul-
tiple myeloma as an underlying disease, delayed engraft-
ment of T-lymphocytes, neutropenia, lymphopenia, grade
II–IV GvHD, treatment with high dose steroids, CMV dis-
ease after day 40, and respiratory viral infections (especially
parainfluenza 3) [44,47]. In the very late period (>6 months)
post HSCT, risk factors for IA included neutropenia, clini-
cally extensive chronic GvHD, CMV disease, and receipt
of an unrelated or HLA-mismatched peripheral blood stem
cell transplant. The outcome of IA was poor independent of
the timing post transplant of IA; survival was approximately
30% at 6 months and 20% at 12 months after the diagnosis of
the infection. Different risk factors have been identified for
IA among the various SOT populations as well. In general,
poor status prior to transplant, severe immunosuppression,
colonization with Aspergillus, and complicated postopera-
tive course are the common risk factors [48–55].
Invasive aspergillosis is also increasingly reported in other
populations, including patients with chronic lung diseases
and prolonged corticosteroid therapy, immune diseases,
liver cirrhosis, severe Influenza infections, or prolonged ICU
stay [56–58]. The disease is often underestimated in these
populations and associated with a high mortality.
NON-ASPERGILLUS
HYALOHYPHOMYCETES
The hyalohyphomycete molds are a heterogeneous group;
however, they do have in common septate, hyaline hyphae
when visualized in tissue [5]. It is important to remem-
ber that fungal hyphae of the various hyalohyphomycetes
(including Aspergillus) as seen in direct specimen examina-
tion and tissue preparation are indistinguishable. Culture
of infected tissue or body fluid is, therefore, required to
definitively identify the invading pathogen. Over 30 non-
Aspergillus hyalohyphomycetes have been implicated in
human disease including, most commonly, species of
Acremonium, Fusarium, Paecilomyces, and Scedosporium
(Table 2.1) [59]. Several of the non-Aspergillus hyalohypho-
mycetes are unique in their capability of producing adven-
titial forms that are able to sporulate in vivo, which permits
release of propagules into the bloodstream and dissemination
to other organs [60].
Acremonium
Acremonium is a mold found in soil, decaying vegetation, and
food that can be pathogenic to plants, insects, and humans.
Human infection has been reported with Acremonium alaba-
mense, A. falciforme, A. kiliense, A. roseogriseum, A. strictum,
A. potronii, A. curvulum, A. artrogriseum, and A. recifei.
In immunocompetent individuals, Acremonium has
been implicated in cases of keratitis and endophthalmi-
tis either following trauma or laser in situ keratomileusis
(Lasik) [61–64]. It has also been reported as causing cuta-
neous and subcutaneous dermal infections, eumycetoma,
onychomycosis, osteomyelitis, peritonitis in patients under-
going continuous ambulatory peritoneal dialysis (CAPD),
prosthetic valve endocarditis, and CNS infection [65–69].
In immunocompromised patients, dialysis fistula infec-
tions, peritonitis, pneumonia, cerebritis, and disseminated
infection have been reported [5,60,70–76]. Although rare,
Acremonium eumycetoma has also been reported in SOT
recipients [77]. Given the presence of adventitial forms,
Acremonium can disseminate through the bloodstream to
distant sites [78–82]. The portal of entry may be either the
lungs or gastrointestinal tract or skin, with dissemination
at times producing endophthalmitis, meningitis, or funge-
mia with sepsis and end organ damage. Recently, a cluster of
A. kiliense fungemia in 3 HSCT recipients, possibly related
to intravascular catheter infections, has been described in
Greece [83].
Fusarium
Members of the genus Fusarium are ubiquitous fila-
mentous fungi commonly found as soil saprophytes and
plant pathogens. Characterized by canoe-shaped mac-
roconidia, Fusarium solani is the most frequent cause of
human infections, followed by F. oxysporum, F. verticil-
loides and F. moniliforme. Human disease ranges from
mycotoxicosis, caused by ingestion of fusarial toxins, to
infections, which may be superficial, localized, or dis-
seminated [5,70,84]. These infections are particularly dif-
ficult to treat because of common resistance to multiple
antifungal drug classes. In onco-hematological patients, a
cutaneous port of entry, such as onychomycosis or inter-
digital intertrigo, may precede disseminated infection in
as many as 2/3 of cases [85].
In the US, Fusarium spp. are responsible for about
3% of IFIs among HSCT recipients, ranking fourth after
invasive aspergillosis, candidiasis and mucormycosis [39].
However, in tropical areas, such as Brasil, invasive fusari-
osis may account to up to 35% of invasive fungal diseases
[86]. A particularity of disseminated fusariosis is the high
proportion of fungemia, which is observed in about 40%
of cases [87,88].
In a multicenter study involving 9 centers, 61 bone mar-
row transplant (BMT) patients with fusariosis were reported.
The overall incidence was 5.97 cases/1000 transplants [88].
 Non-Aspergillus hyalohyphomycetes 15

Table 2.1 Currently documented agents of hyalohypmycoses

Acremonium spp Emmonsia Parva Paecilomyces variotii Trichoderma spp

A. alabamense Engyodontium album Purpureocillium lilacinum T. harzianum
A. atrogriseum Fusarium spp Rasamsonia argillacea T. longibrachiatum
A. curvulum F. chlamydosporum Penicillium spp Tritirachium oryzae
A. falciforme F. dimerum P. chrysagenum Verticillium serrae
A. kilinse F. incarnatum P. citrinum Volutella cinerescens
A. potronii F. moniliforme P. commune
A. roseogriseum F. napiforme P. decumbens
A. strictum F. nivale P. expansum
Aphanoascus fulvescens F. nygamai P. marneffei a
Arthrographis kalrae F. oxysporum Phaeoacremonium parasiticum
Beauveria spp F. pallidoroserum P. inflatipes
B. alba F. proliferatum P. rubrigenum
B. bassiana F. solani Phialemonium obovatum
Cephaliophora irregularis F. veriticillioides Phialemonium curvatum
Chrysonilia sitophila Gymnascella dankaliensis Polycytella hominis
Chrysosporium spp Lecythophora hoffmannii Schizophyllum commune
C. pannicola Lecythophora mutabilis Scedosporium spp
C. zonatum Metarhizium anisopliae S. apiospermum
Coprinus cinereus Myceliophthora thermophila Lomentospora prolificans
Cylindrocarpon spp Onychocola canadensis Scopulariopsis spp
C. destructans Ovadendron sulphureoochraceum S. brevicaulis
C. lichenicola Neocosmospora vasinfecta Scytalidium dimidiatum
C. vaginae
Source: Munoz, P. et al., Am. J. Transplant., 4, 636–643, 2004.
Note: List not inclusive.
a Most authorities refer to disease as penicilliosis.

Fifty-four patients were allogeneic and seven were autolo-
gous BMT recipients. Disseminated infection with metastatic
skin lesions was the most frequent presentation (75%) fol-
lowed by fungemia alone (11%). Lung infiltrates were seen
in 64% and sinusitis in 36% of the cases. Presenting symp-
toms included fever (92%) and papular or nodular skin
lesions with or without central necrosis [88,89]. At the time
of diagnosis, 46% of the patients were neutropenic, and
most had acute or chronic GvHD. There was a trimodal
distribution of infection: an “early peak” was seen prior
to engraftment (median posttransplant day 16), a “second
peak” was seen late (median posttransplant day 64), and a
“very late” third peak was observed after posttransplant day
360. Mortality was very high at 75%–90%, and median sur-
vival after diagnosis was 13 days, with only 13% of patients
alive at 90 days [89]. Persistent neutropenia and corticoste-
roid treatment were significant prognostic factors [88,89].
A recent study identified treatment with antithymocyte
globulin, acute myeloid leukemia and hyperglycemia as
independent risk factors for invasive fusariosis in the early
phase after allogeneic HSCT, while an association with
non-myeloblative conditioning regimen, severe GvHD
and previous invasive mold disease was found during the
later phase [90].
A study of Fusarium infection conducted in Israel
reported a slightly different clinical scenario, with 76%
patients considered immunocompetent [91]. These tended
to be older patients who had ischemic heart disease, diabe-
tes, peripheral vascular disease, and chronic renal failure as
the underlying disease. Of the mycologic data available, 10
infections were with Fusarium oxysporum, 8 were F. solani,
and 4 were F. dimerum. The proportion of disseminated and
localized disease was about equal in immunocompetent and
immunosuppressed patients, and as in the BMT popula-
tion, skin ulcerations were a common clinical presentation.
Risk factors for infection were hematologic malignancy,
immunosuppression, burns, other disseminated infec-
tions, and chronic renal failure. Mortality was 11% during
hospitalization, significantly lower than that reported in the
BMT series.
Isolated outbreaks of Fusarium keratitis associated with
contact lenses have been reported from several states in the
United States [92]. Most outbreaks have been traced to con-
taminated contact lens fluids [93]. Fusarium has also been
isolated from a hospital water reservoir during an outbreak
of fusariosis [94]. The epidemiologic investigation deter-
mined that aerosolization occurring during showers consti-
tuted the potential source of infection.
16 Epidemiology of fungal infections: What, where, and when
Paecilomyces
Paecilomyces species are isolated from soil and decaying
plant matter and are often implicated in decay of food and
cosmetics. The two most common species are Paecilomyces
lilacinus, which has been reassigned to a new genus as
Purpureocillium lilacinum, and P. variotii, both rarely patho-
genic for humans. In immunocompetent hosts, these organ-
isms have been reported as the cause of keratitis after corneal
implants, endophthalmitis, onychomycosis, skin infections,
peritonitis in CAPD patients, pneumonitis, sinusitis, and
endocarditis following valve replacement [95–97]. A case of
pulmonary fungus ball by Paecilomyces in an immunocom-
petent individual has also been reported [98]. P. variotii was
also reported as a cause of outbreak of fungal peritonitis in
patients undergoing peritoneal dialysis following contami-
nation of fluid bags by dust [99,100]. Immunosuppressed
patients may also present with Paecilomyces infection. It has
been reported as causing infection in patients with chronic
granulomatous disease (CGD), including cellulitis, osteo-
myelitis, pneumonitis, and splenic abscess, and pneumonia,
and lung abscess in patients with hairy cell leukemia, CGD,
and CF [98,101]. Disseminated disease appears to occur pre-
dominantly in immunosuppressed hosts.
Paecilomyces variotii has been reported in a multiple
myeloma patient who had undergone autologous HSCT
6 months prior to presentation. Fever was the predominant
symptom, and P. variotii was isolated from line and periph-
eral blood cultures [102]. P. variotii has also been recovered
from the cerebral spinal fluid (CSF) of a patient with meta-
static breast cancer and multiple enhancing brain lesions
on magnetic resonance imaging (MRI) [103]. CSF param-
eters were abnormal, and numerous fungal cells and septate
hyphae were seen on mycological examination. Importantly,
disseminated P. variotii infection has also been reported
breaking through voriconazole prophylaxis in a neutrope-
nic child with relapsed leukemia [104]. The clinical presen-
tation consisted of persistent fever with a pink macular and
nodular rash on the child’s forearms and face.
Purpureocillium lilacinum has been isolated from many
sites of infection. In a large study from Spain, 119 cases were
reported from 1964 to 2004 [105]. Most cases of P. lilacinum
were onychomycosis (51.3%) followed by cutaneous and sub-
cutaneous infection (35.3%). For cutaneous infections, risk
factors included SOT, HSCT, surgery, primary immunode-
ficiency, and AIDS. Lesions presented as painful red nod-
ules that sometimes progressed to excoriated nodules and
draining pustules. Severe onychomycosis, as with Fusarium
spp., may constitute a risk factor for invasive disease since
the toenail may serve as a portal of entry and provide con-
tiguous or lymphangitic spread [106]. Cases of oculomycosis
presenting as scleritis, keratitis, and endophthalmitis have
also been reported, with lens implantation, diabetes, prior
scleritis, surgery, and immunosuppression constituting risk
factors [105,107,108].
An outbreak of invasive P. lilacinum was reported in
severely neutropenic patients due to contaminated skin
lotion [109,110]. Neutropenic patients in a laminar flow
ward presented with cutaneous lesions that erupted either
during the neutropenic period or shortly thereafter.
Invasive disease occurred in 36% of patients treated with
chemotherapy for leukemia or lymphoma and in 100% of
BMT recipients. Moisturizing skin lotion was found to
be contaminated with the organism. P. lilacinum causing
cutaneous lesions have also been reported in SOT, ste-
roid users, and patients with CGD [111]. Lesions may be
papular, pustular, nodular, or ulcerated, and located on
any part of the skin.
Scedosporium
Species of the genus Scedosporium are frequently encoun-
tered in soil from rural areas, parks, potted plants, from
compost, manure of cattle and fowl, polluted waters and
sewage, and occasionally from hospital air during construc-
tion [5,70,71,112]. Infections are caused by species of the
Scedosporium apiospermum complex (including S. apiosper-
mum, S. boydii and its sexual form Pseudallescheria boydii,
and S. auranthiacum). S. prolificans, actually reassigned to
a new genus as Lomentospora prolificans, has occasionally
been designated as a dematiaceous mold and is characterized
by resistance to virtually all antifungal classes [113]. The first
case of L. prolificans infection was reported in 1984 [114].
Since that time, multiple cases have been reported in the lit-
erature, with fairly large case series from Spain, Australia,
and the United States [115–118]. SOT recipients, especially
lung-transplant recipients, seem to be particularly suscep-
tible to Scedosporium colonization and infection [119–121].
In one series, approximately 66% of the patients with L. pro-
lificans infection were receiving amphotericin B prior to the
infection [122]. In a series from a tertiary care cancer cen-
ter, the incidence of Scedosporium infection increased from
0.82 cases per 100,000 patient-inpatient days (1993–1998) to
1.33 cases per 100,000 patient-inpatient days, with all cases
of S. prolificans presenting as breakthrough infections after
the year 2000 [123]. In a series of 162 cases of L. prolificans
infections, major risk factors were malignancy (45%), cystic
fibrosis (11%) and SOT (8%) [124]. Most common clinical
presentations were disseminated infections (44%), pulmo-
nary infections (29%) and bone and joint infections (10%).
Fungemia was present in 70% of cases of systemic infections
and overall mortality was 47%. The increase in S. prolificans
infections may be linked to the increasing use of antifungal
prophylaxis, which in turn may select for this opportunistic
pathogen that is notoriously resistant to practically all anti-
fungal agents.
It is important to note that both S. apiospermum
complex and L. prolificans may simply colonize body
sites without overt disease, or they may produce a vari-
ety of clinical syndromes in a wide range of hosts. For
example, S. apiospermum has been isolated as a colonizer
from the airways of CF patients, and S. prolificans has
been reported to colonize airways and external auditory
canals [116,117,125–129]. Patients in these reports had the
Another random document with
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that, if the thief does not restore the stolen property, he will be a
dead man within a month.34.1
Similarly in Nias, an island to the west of
Thieves cursed in Sumatra, when a thief cannot be found he is
Nias.
cursed, and to give weight to the curse a dog is
burned alive. While the animal is expiring in torments, the man who
has been robbed expresses his wish that the thief may likewise die
in agony; and they say that thieves who have been often cursed do
die screaming.34.2 Curses are also employed for
Thieves cursed
among the Sea
the same purpose with excellent effect by the Sea
Dyaks of Borneo. Dyaks of Borneo. On this point a missionary bears
the following testimony. “With an experience of
nearly twenty years in Borneo, during which I came into contact with
thousands of the people, I have known of only two instances of theft
among the Dyaks. One was a theft of rice. The woman who lost the
rice most solemnly and publicly cursed the thief, whoever it might be.
The next night the rice was secretly left at her door. The other was a
theft of money. In this case, too, the thief was cursed. The greater
part of the money was afterwards found returned to the box from
which it had been abstracted. Both these incidents show the great
dread the Dyak has of a curse. Even an undeserved curse is
considered a terrible thing, and, according to Dyak law, to curse a
person for no reason at all is a fineable offence.
“A Dyak curse is a terrible thing to listen to. I have only once heard
a Dyak curse, and I am sure I do not want to do so again. I was
travelling in the Saribas district, and at that time many of the Dyaks
there had gone in for coffee-planting; indeed, several of them had
started coffee plantations on a small scale. A woman told me that
some one had over and over again stolen the ripe coffee-berries
from her plantation. Not only were the ripe berries stolen, but the
thief had carelessly picked many of the young berries and thrown
them on the ground, and many of the branches of the plants had
been broken off. In the evening, when I was seated in the public part
of the house with many Dyak men and women round me, we
happened to talk about coffee-planting. The woman was present,
and told us of her experiences, and how her coffee had been stolen
by some thief, who, she thought, must be one of the inmates of the
house. Then she solemnly cursed the thief. She began in a calm
voice, but worked herself up into a frenzy. We all listened horror-
struck, and no one interrupted her. She began by saying what had
happened, and how these thefts had gone on for some time. She
had said nothing before, hoping that the thief would mend his ways;
but the matter had gone on long enough, and she was going to curse
the thief, as nothing, she felt sure, would make him give up his evil
ways. She called on all the spirits of the waters and the hills and the
air to listen to her words and to aid her. She began quietly, but
became more excited as she went on. She said something of this
kind:
“ ‘If the thief be a man, may he be unfortunate in
Curses on a man all he undertakes! May he suffer from a disease
thief.
that does not kill him, but makes him helpless—
always in pain—and a burden to others. May his wife be unfaithful to
him, and his children become as lazy and dishonest as he is himself.
If he go out on the war-path, may he be killed, and his head smoked
over the enemy’s fire. If he be boating, may his boat be swamped
and may he be drowned. If he be out fishing, may an alligator kill him
suddenly, and may his relatives never find his body. If he be cutting
down a tree in the jungle, may the tree fall on him and crush him to
death. May the gods curse his farm so that he may have no crops,
and have nothing to eat, and when he begs for food, may he be
refused, and die of starvation.
“ ‘If the thief be a woman, may she be childless,
Curses on a woman or if she happen to be with child let her be
thief.
disappointed, and let her child be still-born, or,
better still, let her die in childbirth. May her husband be untrue to her,
and despise her and ill-treat her. May her children all desert her if
she live to grow old. May she suffer from such diseases as are
peculiar to women, and may her eyesight grow dim as the years go
on, and may there be no one to help her or lead her about when she
is blind.’
“I have only given the substance of what she said; but I shall never
forget the silence and the awed faces of those who heard her. I left
the house early next morning, so I do not know what was the result
of her curse—whether the thief confessed or not.”36.1
 The ancient Greeks seem to have made a very
Thieves cursed in liberal use of curses as a cheap and effective
ancient Greece.
mode of protecting property, which dispenses the
injured party from resorting to the tedious, expensive, and too often
fruitless formalities of the law. These curses they inscribed on tablets
of lead and other materials and deposited either in the place which
was to be protected from depredation or in the temple of the god to
whose tender mercies the criminal was committed. For example, in a
sacred precinct dedicated to Demeter, Persephone, Pluto and other
deities of a stern and inflexible temper at Cnidus, a number of leaden
tablets were found inscribed with curses which consigned the
malefactors of various sorts to the vengeance of the two Infernal
Goddesses, Demeter and her daughter. “May he or she never find
Persephone propitious!” is the constantly repeated burden of these
prayers; and in some of them the sinner is not only excommunicated
in this world but condemned to eternal torments in the world
hereafter. Often the persons who launched these curses were ladies.
One irate dame consigns to perdition the thief who had stolen her
bracelet or the defaulter who had failed to send back her
underclothes.36.2 Another curse, engraved on a marble slab found at
Smyrna, purports that if any man should steal one of the sacred
vessels of a certain goddess or injure her sacred fish, he may die a
painful death, devoured by the fishes.36.3 Sometimes, apparently,
these Greek imprecations were as effective in reclaiming sinners as
Dyak curses are to this day. Thus we read of a curious dedication to
a lunar deity of Asia Minor, by name Men Aziottenos, which declares
how one Artemidorus, having been reviled by a couple of rude
fellows, cursed them in a votive tablet, and how one of the culprits,
having been punished by the god, made a propitiatory offering and
mended his wicked ways.37.1 To prevent people
Landmarks
protected by gods
from encroaching on their neighbours’ land by
and curses. removing the boundary stones, the Greeks
committed landmarks to the special protection of
the great god Zeus;37.2 and Plato dwells with unction on the double
punishment, divine and human, to which the sinner exposed himself
who dared to tamper with these sacred stones.37.3 The Romans
went even further, for they created a god for the sole purpose of
looking after landmarks, and he must have had his hands very full if
he executed all the curses which were levelled not only at every man
who shifted his neighbour’s boundary stone, but even at the oxen
which he employed to plough up his neighbour’s land.37.4 The
Hebrew code of Deuteronomy pronounced a solemn curse on such
as removed their neighbour’s landmarks;37.5 and Babylonian kings
exhausted their imagination in pouring out a flood of imprecations
against the abandoned wretch who thus set at naught the rights of
property in land.37.6 King Nebuchadnezzar in particular, before he
was turned out to grass, appears to have distinguished himself by
the richness and variety of his execrations, if we may judge by a
specimen of them which has survived. A brief extract from this
masterpiece may serve to illustrate the king’s style of minatory
eloquence. Referring to the bold bad man, “be it shepherd or
governor, or agent or regent, levy master or magistrate,” whosoever
he might be, who “for all days to come, for the future of human
habitations,” should dare to tamper with the land which his Majesty
had just marked out, “Ninib, lord of boundaries and boundary-stones,
tear out his boundary stone. Gula, great lady, put lingering illness
into his body, that dark and light red blood he may pour out like
water. Ishtar, lady of countries, whose fury is a flood, reveal
difficulties to him, that he escape not from misfortune. Nusku, mighty
lord, powerful burner, the god, my creator, be his evil demon and
may he burn his root. Whoever removes this stone, in the dust hides
it, burns it with fire, casts it into water, shuts it up in an enclosure,
causes a fool, a deaf man, an idiot to take it, places it in an invisible
place, may the great gods, who upon this stone are mentioned by
their names, curse him with an evil curse, tear out his foundation and
destroy his seed.”38.1
In Africa also superstition is a powerful ally of
Superstition as an the rights of private property. Thus the Balonda
ally of the rights of
private property in place beehives on high trees in the forest and
Africa. protect them against thieves by tying a charm or
“piece of medicine” round the tree-trunks. This
proves a sufficient protection. “The natives,” says Livingstone,
“seldom rob each other, for all believe that certain medicines can
inflict disease and death; and though they consider that these are
only known to a few, they act on the principle that it is best to let
them all alone. The gloom of these forests strengthens the
superstitious feelings of the people. In other quarters, where they are
not subjected to this influence, I have heard the chiefs issue
proclamations to the effect, that real witchcraft medicines had been
placed at certain gardens from which produce had been stolen; the
thieves having risked the power of the ordinary charms previously
placed there.”38.2
The Wanika of East Africa “believe in the power
The Wanika of East and efficacy of charms and amulets, and they
Africa.
wear them in great variety; legs, arms, neck, waist,
hair, and every part of the body are laden with them, either for the
cure or prevention of disease; for the expulsion or repulsion of evil
spirits; and to keep at bay snakes, wild animals, and every other evil.
They hang painted calabashes from the baobab at their hut doors to
keep away thieves; shells, dolls, eggs scratched over with Arabic
characters by the Wana Chuoni (sons of the book) of the coast, are
placed about their plantations and in their fruit-trees, and they
believe that death would overtake a thief who should disregard them.
A charm bound to the leg of a fowl is ample protection for the village.
There is no doubt that, superstitious as the people are, they dread
running great risks for the sake of small gains, and so these charms
answer their purpose.”39.1 Among the Boloki of the
The Boloki of the
Congo.
Upper Congo, when a woman finds that the
cassava roots, which she keeps soaking in a
water-hole, are being stolen, she takes a piece of gum copal, and
fixing it in the cleft of a split stick she puts it on the side of the hole,
while at the same time she calls down a curse on the thief. If the thief
is a man, he will henceforth have no luck in fishing; if she is a
woman, she will have no more success in farming.39.2 The Ekoi of
Southern Nigeria protect their farms against thieves by bundles of
palm leaves to which they give the name of okpata. Should any one
steal from a farm thus protected, he will fall sick and will not recover
unless he gives a certain dance, to which the name of okpata is also
applied.39.3
 In the mountains of Marrah, a district of Darfur,
Guardian spirits houses, goods, and cattle are protected against
(damzogs) of
property in Darfur. thieves by certain fierce and dangerous guardian-
spirits called damzogs, which can be bought like
watch dogs. Under the guardianship of such a spiritual protector the
sheep and cows are left free to wander at will; for if any one were
rash enough to attempt to steal or kill one of the beasts, his hand
with the knife in it would remain sticking fast to the animal’s throat till
the owner came and caught the rascal. An Arab merchant, travelling
in Darfur, received from a friend the following account of the way to
procure one of these useful guardians. “At the time when I first
began to trade, my friend, I often heard that damzogs could be
bought and sold, and that to procure one I must apply to the owner
of a damzog, and discuss the price with him. When the bargain is
concluded, it is necessary to give a large gourd of milk to the seller,
who takes it to his house, where are his damzogs. On entering he
salutes them, and goes and hangs up his vase to a hook, saying,
—‘One of my friends—such a one—very rich, is in fear of robbers,
and asks me to supply him with a guardian. Will one of you go and
live in his house? There is plenty of milk there, for it is a house of
blessing, and the proof thereof is, that I bring you this kara of milk.’
The damzogs at first refuse to comply with the invitation. ‘No, no,’
say they, ‘not one of us will go.’ The master of the hut conjures them
to comply with his desires, saying, ‘Oh! let the one that is willing
descend into the kara.’ He then retires a little, and presently one of
the damzogs is heard to flop into the milk, upon which he hastens
and claps upon the vase a cover made of date-leaves. Thus stopped
up he unhooks the kara, and hands it over to the buyer, who takes it
away and hangs it on the wall of his hut, and confides it to the care
of a slave or of a wife, who every morning comes and takes it,
emptying out the milk, washing it and replenishing it, and hanging it
up again. From that time forward the house is safe from theft or
loss.” The merchant’s informant, the Shereef Ahmed Bedawee, had
himself purchased one of these guardian spirits, who proved most
vigilant and efficient in the discharge of his duties; indeed his zeal
was excessive, for he not only killed several slaves who tried to rob
his master, but did summary execution on the Shereef’s own son,
when the undutiful young man essayed to pilfer from his father’s
shop. This was too much for the Shereef; he invited a party of friends
to assist him in expelling the inflexible guardian. They came armed
with guns and a supply of ammunition, and by raking the shop with
repeated volleys of musketry they at last succeeded in putting the
spirit to flight.40.1
Amongst the Nandi of British East Africa nobody
The curses of dares to steal anything from a smith; for if he did,
smiths and potters.
the smith would heat his furnace, and as he blew
the bellows to make the flames roar he would curse the thief so that
he would die. And in like manner among these people, with whom
the potters are women, nobody dares to filch anything from a potter;
for next time she heated her wares the potter would curse him,
saying, “Burst like a pot, and may thy house become red,” and the
thief so cursed would die.41.1 In Loango, when a
Charms to protect
property in West
man is about to absent himself from home for a
Africa. considerable time he protects his hut by placing a
charm or fetish before it, consisting perhaps of a
branch with some bits of broken pots or trash of that sort; and we are
told that even the most determined robber would not dare to cross a
threshold defended by these mysterious signs.41.2 On the coast of
Guinea fetishes are sometimes inaugurated for the purpose of
detecting and punishing certain kinds of theft; and not only the culprit
himself, but any person who knows of his crime and fails to give
information is liable to be punished by the fetish. When such a fetish
is instituted, the whole community is warned of it, so that he who
transgresses thereafter does so at his peril. For example, a fetish
was set up to prevent sheep-stealing and the people received
warning in the usual way. Shortly afterwards a slave, who had not
heard of the law, stole a sheep and offered to divide it with a friend.
The friend had often before shared with him in similar enterprises,
but the fear of the fetish was now too strong for him; he informed on
the thief, who was brought to justice and died soon after of a
lingering and painful disease. Nobody in the country ever doubted
but that the fetish had killed him.41.3 Among the Ewe-speaking tribes
of the Slave Coast in West Africa houses and household property
are guarded by amulets (võ-sesao), which derive their virtue from
being consecrated or belonging to the gods. The crops, also, in
solitary glades of the forest are left under the protection of such
amulets, generally fastened to long sticks in some conspicuous
position; and so guarded they are quite safe from pillage. By the side
of the paths, too, may be seen food and palm-wine lying exposed for
sale with nothing but a charm to protect them; a few cowries placed
on each article indicate its price. Yet no native would dare to take the
food or the wine without depositing its price; for he dreads the
unknown evil which the god who owns the charm would bring upon
him for thieving.42.1 In Sierra Leone charms, called greegrees, are
often placed in plantations to deter people from stealing, and it is
said that “a few old rags placed upon an orange tree will generally,
though not always, secure the fruit as effectually as if guarded by the
dragons of the Hesperides. When any person falls sick, if, at the
distance of several months, he recollects having stolen fruit, etc., or
having taken it softly as they term it, he immediately supposes
wangka has caught him, and to get cured he must go or send to the
person whose property he had taken, and make to him whatever
recompense he demands.”42.2
Superstitions of the same sort have been
Charms to protect transported by the negroes to the West Indies,
property in the West
Indies. where the name for magic is obi and the magician
is called the obeah man. There also, we are told,
the stoutest-hearted negroes “tremble at the very sight of the ragged
bundle, the bottle or the egg-shells, which are stuck in the thatch or
hung over the door of a hut, or upon the branch of a plantain tree, to
deter marauders.… When a negro is robbed of a fowl or a hog, he
applies directly to the Obeah-man or woman; it is then made known
among his fellow blacks, that obi is set for the thief; and as soon as
the latter hears the dreadful news, his terrified imagination begins to
work, no resource is left but in the superior skill of some more
eminent Obeah-man of the neighbourhood, who may counteract the
magical operations of the other; but if no one can be found of higher
rank and ability; or if, after gaining such an ally, he should still fancy
himself affected, he presently falls into a decline, under the incessant
horror of impending calamities. The slightest painful sensation in the
head, the bowels, or any other part, any casual loss or hurt, confirms
his apprehensions, and he believes himself the devoted victim of an
invisible and irresistible agency. Sleep, appetite and cheerfulness
forsake him; his strength decays, his disturbed imagination is
haunted without respite, his features wear the settled gloom of
despondency: dirt, or any other unwholesome substance, becomes
his only food, he contracts a morbid habit of body, and gradually
sinks into the grave.”43.1 Superstition has killed him.
Similar evidence might doubtless be multiplied,
Conclusion. but the foregoing cases suffice to shew that
among many peoples and in many parts of the
world superstitious fear has operated as a powerful motive to deter
men from stealing. If that is so, then my second proposition may be
regarded as proved, namely, that among certain races and at certain
times superstition has strengthened the respect for private property
and has thereby contributed to the security of its enjoyment.
 IV.
MARRIAGE

I pass now to my third proposition, which is, that

Superstition as a among certain races and at certain times
prop of sexual
morality. superstition has strengthened the respect for
marriage, and has thereby contributed to a stricter
observance of the rules of sexual morality both among the married
and the unmarried. That this is true will appear, I think, from the
following instances.
Among the Karens of Burma “adultery, or
Adultery or fornication, is supposed to have a powerful
fornication
supposed by the influence to injure the crops. Hence, if there have
Karens to blight the been bad crops in a village for a year or two, and
crops. the rains fail, the cause is attributed to secret sins
of this character, and they say the God of heaven
and earth is angry with them on this account; and all the villagers
unite in making an offering to appease him.” And
Pig’s blood used to when a case of adultery or fornication has come to
expiate the crime.
light, “the elders decide that the transgressors
must buy a hog, and kill it. Then the woman takes one foot of the
hog, and the man takes another, and they scrape out furrows in the
ground with each foot, which they fill with the blood of the hog. They
next scratch the ground with their hands and pray: ‘God of heaven
and earth, God of the mountains and hills, I have destroyed the
productiveness of the country. Do not be angry with me, do not hate
me; but have mercy on me, and compassionate me. Now I repair the
mountains, now I heal the hills, and the streams and the lands. May
there be no failure of crops, may there be no unsuccessful labours,
or unfortunate efforts in my country. Let them be dissipated to the
foot of the horizon. Make thy paddy fruitful, thy rice abundant. Make
the vegetables to flourish. If we cultivate but little, still grant that we
may obtain a little.’ After each has prayed thus, they return to the
house and say they have repaired the earth.”45.1 Thus, according to
the Karens adultery and fornication are not simply moral offences
which concern no one but the culprits and their families: they
physically affect the course of nature by blighting the earth and
destroying its fertility; hence they are public crimes which threaten
the very existence of the whole community by cutting off its food
supplies at the root. But the physical injury which these offences do
to the soil can be physically repaired by saturating it with pig’s blood.
Some of the tribes of Assam similarly trace a
Disastrous effects connexion between the crops and the behaviour of
ascribed to sexual
crime in Assam, the human sexes; for they believe that so long as
Bengal, and the crops remain ungarnered, the slightest
Annam.
incontinence would ruin all.45.2 Again, the
inhabitants of the hills near Rajamahal in Bengal imagine that
adultery, undetected and unexpiated, causes the inhabitants of the
village to be visited by a plague or destroyed by tigers or other
ravenous beasts. To prevent these evils an adulteress generally
makes a clean breast. Her paramour has then to furnish a hog, and
he and she are sprinkled with its blood, which is supposed to wash
away their sin and avert the divine wrath. When a village suffers from
plague or the ravages of wild beasts, the people religiously believe
that the calamity is a punishment for secret immorality, and they
resort to a curious form of divination to discover the culprits, in order
that the crime may be duly expiated.45.3 The Khasis of Assam are
divided into a number of clans which are exogamous, that is to say,
no man may marry a woman of his own clan. Should a man be found
to cohabit with a woman of his own clan, it is treated as incest and is
believed to cause great disasters; the people will be struck by
lightning or killed by tigers, the women will die in child-bed, and so
forth. The guilty couple are taken by their clansmen to a priest and
obliged to sacrifice a pig and a goat; after that they are made
outcasts, for their offence is inexpiable.46.1 The Orang Glai, a savage
tribe in the mountains of Annam, similarly suppose that illicit love is
punished by tigers, which devour the sinners. If a girl is found with
child, her family offers a feast of pigs, fowls, and wine to appease the
offended spirits.46.2
The Battas of Sumatra in like manner think that if an unmarried
woman is with child, she must be given in marriage at once, even to
 a man of lower rank; for otherwise the people will
Similar views held be infested with tigers, and the crops in the fields
by the Battas of
Sumatra. will not be abundant. They also believe that the
adultery of married women causes a plague of
tigers, crocodiles, or other wild beasts. The crime of incest, in their
opinion, would blast the whole harvest, if the wrong were not
speedily repaired. Epidemics and other calamities that affect the
whole people are almost always traced by them to incest, by which is
to be understood any marriage that conflicts with their customs.46.3
The natives of Nias, an island to the west of Sumatra, imagine that
heavy rains are caused by the tears of a god weeping at the
commission of adultery or fornication. The punishment for these
crimes is death. The two delinquents, man and woman, are buried in
a narrow grave with only their heads projecting above ground; then
their throats are stabbed with a spear or cut with a knife, and the
grave is filled up. Sometimes, it is said, they are buried alive.
However, the judges are not always incorruptible and the injured
family not always inaccessible to the allurement of gain; and
pecuniary compensation is sometimes accepted as a sufficient salve
for wounded honour. But if the wronged man is a chief, the culprits
must surely die. As a consequence, perhaps, of this severity, the
crimes of adultery and fornication are said to be far less frequent in
Nias than in Europe.47.1
Similar views prevail among many tribes in
Similar views Borneo. Thus in regard to the Sea Dyaks we are
among the tribes of
Borneo. told by Archdeacon Perham that “immorality
among the unmarried is supposed to bring a
plague of rain upon the earth, as a punishment inflicted by Petara. It
must be atoned for with sacrifice and fine. In a
Excessive rains function which is sometimes held to procure fine
thought by the
Dyaks to be caused weather, the excessive rain is represented as the
by sexual offences. result of the immorality of two young people.
Petara is invoked, the offenders are banished from
their home, and the bad weather is said to cease. Every district
traversed by an adulterer is believed to be accursed of the gods until
the proper sacrifice has been offered.”47.2 When rain pours down day
after day and the crops are rotting in the fields, these Dyaks come to
the conclusion that some people have been secretly indulging in
lusts of the flesh; so the elders lay their heads together and
adjudicate on all cases of incest and bigamy, and purify the earth
with the blood of pigs, which appears to these
Blood of pigs shed savages, as sheep’s blood appeared to the
to expiate incest
and unchastity. ancient Hebrews, to possess the valuable property
of atoning for moral guilt. Not long ago the
offenders, whose lewdness had thus brought the whole country into
danger, would have been punished with death or at least slavery. A
Dyak may not marry his first cousin unless he first performs a special
ceremony called bergaput to avert evil consequences from the land.
The couple repair to the water-side, fill a small pitcher with their
personal ornaments, and sink it in the river; or instead of a jar they
fling a chopper and a plate into the water. A pig is then sacrificed on
the bank, and its carcase, drained of blood, is thrown in after the jar.
Next the pair are pushed into the water by their friends and ordered
to bathe together. Lastly, a joint of bamboo is filled with pig’s blood,
and the couple perambulate the country and the villages round
about, sprinkling the blood on the ground. After that they are free to
marry. This is done, we are told, for the sake of the whole country, in
order that the rice may not be blasted by the marriage of cousins.48.1
Again, we are informed that the Sibuyaus, a Dyak tribe of Sarawak,
are very careful of the honour of their daughters, because they
imagine that if an unmarried girl is found to be with child it is
offensive to the higher powers, who, instead of always chastising the
culprits, punish the tribe by visiting its members with misfortunes.
Hence when such a crime is detected they fine the lovers and
sacrifice a pig to appease the angry powers and to avert the
sickness or other calamities that might follow. Further, they inflict
fines on the families of the couple for any severe accident or death
by drowning that may have happened at any time within a month
before the religious atonement was made; for they regard the
families of the culprits as responsible for these mishaps. The fines
imposed for serious or fatal accidents are heavy; for simple wounds
they are lighter. With the fear of these fines before their eyes parents
keep a watchful eye on the conduct of their daughters. Among the
Dyaks of the Batang Lupar river the chastity of the unmarried girls is
not so strictly guarded; but in respectable families, when a daughter
proves frail, they sacrifice a pig and sprinkle its blood on the doors to
wash away the sin.48.2 The Hill Dyaks of Borneo abhor incest and do
not allow the marriage even of cousins. In 1846 the Baddat Dyaks
complained to Mr. Hugh Low that one of their chiefs had disturbed
the peace and prosperity of the village by marrying his own
granddaughter. Since that disastrous event, they said, no bright day
had blessed their territory; rain and darkness alone prevailed, and
unless the plague-spot were removed, the tribe would soon be
ruined. The old sinner was degraded from office, but apparently
allowed to retain his wife; and the domestic brawls between this ill-
assorted couple gave much pain to the virtuous villagers.49.1
Among the pagan tribes of Borneo in general,
Incest punished but of Sarawak in particular, “almost all offences
with death by the
pagan tribes of are punished by fines only. Of the few offences
Borneo. which are felt to require a heavier punishment, the
one most seriously regarded is incest. For this
offence, which is held to bring grave peril to the whole house,
especially the danger of starvation through failure of the padi crop,
two punishments have been customary. If the guilt of the culprits is
perfectly clear, they are taken to some open spot on the river-bank at
some distance from the house. There they are thrown together upon
the ground and a sharpened bamboo stake is driven through their
bodies, so that they remain pinned to the earth. The bamboo, taking
root and growing luxuriantly on this spot, remains as a warning to all
who pass by; and, needless to say, the spot is looked on with horror
and shunned by all men. The other method of punishment is to shut
up the offenders in a strong wicker cage and to throw them into the
river. This method is resorted to as a substitute for the former one,
owing to the difficulty of getting any one to play the part of
executioner and to drive in the stake, for this involves the shedding
of the blood of the community. The kind of incest most commonly
committed is the connection of a man with an adopted daughter, and
(possibly on account of this frequency) this is the kind which is most
strongly reprobated.… The punishment of the incestuous couple
does not suffice to ward off the danger brought by them upon the
community. The household must be purified with the blood of pigs
and fowls; the animals used are the property of the offenders or of
their family; and in this way a fine is imposed. When any calamity
threatens or falls upon a house, especially a great rising of the river
which threatens to sweep away the house or the tombs of the
household, the Kayans are led to suspect that incestuous
intercourse in their own or in neighbouring houses has taken place;
and they look round for evidences of it, and sometimes detect a case
which otherwise would have remained hidden. It seems probable
that there is some intimate relation between this belief and the
second of the two modes of punishment described above; but we
have no direct evidence of such connection. All the other peoples
also, except the Punans, punish incest with death. Among the Sea
Dyaks the most common form of incest is that between a youth and
his aunt, and this is regarded at least as seriously as any other
form.”50.1
Nor is it the heinous crime of incest alone which
Evil and confusion in the opinion of the Sea Dyaks endangers the
supposed by the
Dyaks to be whole community. The same effect is supposed to
wrought by follow whenever an unmarried woman is found
fornication. with child and cannot or will not name her seducer.
“The greatest disgrace,” we are told, “is attached
to a woman found in a state of pregnancy, without being able to
name her husband; and cases of self-poisoning, to avoid the shame,
are not of unusual occurrence. If one be found in this state, a fine
must be paid of pigs and other things. Few even of the chiefs will
come forward without incurring considerable responsibility. A pig is
killed, which nominally becomes the father, for want, it is supposed,
of another and better one. Then the surrounding neighbours have to
be furnished with a share of the fine to banish the Jabu, which exists
after such an event. If the fine be not forthcoming, the woman dare
not move out of her room, for fear of being molested, as she is
supposed to have brought evil (kudi) and confusion upon the
inhabitants and their belongings.”50.2
The foregoing accounts refer especially to the
Similar beliefs and tribes of Borneo under British rule; but similar
customs among the
tribes of Dutch ideas and customs prevail among the kindred
Borneo. tribes of Dutch Borneo. Thus the Kayans or
Bahaus in the interior of the island believe that adultery is punished
by the spirits, who visit the whole tribe with failure of the crops and
other misfortunes. Hence in order to avert these evil consequences
from the innocent members of the tribe, the two culprits, with all their
possessions, are first placed on a gravel bank in the middle of the
river, in order to isolate or, in electrical language, to insulate them
and so prevent the moral or rather physical infection from spreading.
Then pigs and fowls are killed, and with the blood priestesses smear
the property of the guilty pair in order to disinfect it. Finally, the two
are placed on a raft, with sixteen eggs, and allowed to drift down
stream. They may save themselves by plunging into the water and
swimming ashore; but this is perhaps a mitigation of an older
sentence of death by drowning, for young people still shower long
grass stalks, representing spears, at the shamefaced and dripping
couple.51.1 Certain it is, that some Dyak tribes used to punish incest
by fastening the man and woman in separate baskets laden with
stones and drowning them in the river. By incest they understood the
cohabitation of parents with children, of brothers with sisters, and of
uncles and aunts with nieces and nephews. A Dutch resident had
much difficulty in saving the life of an uncle and niece who had
married each other; finally he procured their banishment to a distant
part of Borneo.51.2 The Blu-u Kayans, another tribe in the interior of
Borneo, believe that an intrigue between an unmarried pair is
punished by the spirits with failure of the harvest, of the fishing, and
of the hunt. Hence the delinquents have to appease the wrath of the
spirits by sacrificing a pig and a certain quantity of rice.51.3 In Pasir, a
district of Eastern Borneo, incest is thought to bring dearth,
epidemics, and all sorts of evils on the land.51.4 In the island of
Ceram a man convicted of unchastity has to smear every house in
the village with the blood of a pig and a fowl: this is supposed to wipe
out his guilt and ward off misfortunes from the village.51.5
When the harvest fails in Southern Celebes, the
Failure of the crops Macassars and Bugineese regard it as a sure sign
and other disasters
thought to be that incest has been committed and that the spirits
caused by incest in are angry. In the years 1877 and 1878 it happened
Celebes. that the west monsoon did not blow and that the
rice crop in consequence came to nothing; moreover many buffaloes
died of a murrain. At the same time there was in the gaol at Takalar a
prisoner, who had been formerly accused of incest. Some of the
people of his district begged the Dutch governor to give the criminal
up to them, for according to the general opinion the plagues would
never cease till the guilty man had received the punishment he
deserved. All the governor’s powers of persuasion were needed to
induce the petitioners to return quietly to their villages; and when the
prisoner, having served his time, was released shortly afterwards, he
was, at his own request, given an opportunity of sailing away to
another land, as he no longer felt safe in his own country.52.1 Even
when the incestuous couple has been brought to
Disastrous effects justice, their blood may not be shed; for the people
supposed to follow
from shedding the think that, were the ground to be polluted by the
blood of incestuous blood of such criminals, the rivers would dry up
couples on the and the supply of fish would run short, the harvest
ground.
and the produce of the gardens would miscarry,
edible fruits would fail, sickness would be rife among cattle and
horses, civil strife would break out, and the country would suffer from
other widespread calamities. Hence the punishment of the guilty is
such as to avoid the spilling of their blood: usually they are tied up in
a sack and thrown into the sea to drown. Yet they get on their
journey to eternity the necessary provisions, consisting of a bag of
rice, salt, dried fish, coco-nuts, and other things, among which three
quids of betel are not forgotten.52.2 We can now perhaps understand
why the Romans used to sew up a parricide in a sack with a dog, a
cock, a viper, and an ape for company, and fling him into the sea.
They probably feared to defile the soil of Italy by spilling upon it the
blood of such a miscreant.52.3 Amongst the Tomori of Central
Celebes a person guilty of incest is throttled; no drop of his blood
may fall on the ground, for if it did, the rice would never grow again.
The union of uncle with niece is regarded by these people as incest,
but it can be expiated by an offering. A garment of the man and one
of the woman are laid on a copper vessel; the blood of a sacrificed
animal, either a goat or a fowl, is allowed to drip on the garments,
and then the vessel with its contents is set floating down the river.53.1
Among the Tololaki, another tribe of Central Celebes, persons who
have defiled themselves with incest are shut up in a basket and
drowned. No drop of their blood may be spilt on the ground, for that
would hinder the earth from ever bearing fruit again.53.2 Among the
Bare’e-speaking Toradjas of Central Celebes in general the penalty
for incest, that is for the sexual intercourse of parents with children or
of brothers with sisters, is death. But whereas the death-sentence for
adultery is executed with a spear or a sword, the death-sentence for
incest is usually executed among the inland tribes by clubbing or
throttling; for were the blood of the culprits to drip on the ground, the
earth would be rendered barren. The people on the coast put the
guilty pair in a basket, weight it with stones, and fling it into the sea.
This prescribed manner of putting the incestuous to death, we are
informed, makes the execution very grievous. However, the writers
who furnish us with these particulars and who have lived among the
people on terms of intimacy for many years, add that “incest seldom
occurs, or rather the cases that come to light are very few.”53.3 In
some districts of Central Celebes, the marriage of cousins, provided
they are children of two sisters, is forbidden under pain of death; the
people think that such an alliance would anger the spirits, and that
the rice and maize harvests would fail. Strictly speaking, two such
cousins who have committed the offence should be tied together,
weighted with stones, and thrown into water to drown. In practice,
however, the culprits are spared and their sin expiated by shedding
the blood of a buffalo or a goat. The blood is mixed with water and
sprinkled on the rice-fields or poured on the maize-fields, no doubt in
order to appease the angry spirits and restore its fertility to the tilled
land. The natives of these districts believe that were a brother and
sister to commit incest, the ground on which the tribe dwells would
be swallowed up. If such a crime takes place, the guilty pair are tied
together, their feet weighted with stones, and thrown into the sea.54.1
When it rains in torrents, the Galelareese of
Excessive rains, Halmahera, another large East Indian island, say
earthquakes, and
volcanic eruptions that brother and sister, or father and daughter, or
supposed to be in short some near kinsfolk are having illicit
produced by incest relations with each other, and that every human
in Halmahera.
being must be informed of it, for then only will the
rain cease to descend. The superstition has repeatedly caused blood
relations to be accused, rightly or wrongly, of incest. Further, the
people think that alarming natural phenomena, such as a violent
earthquake or the eruption of a volcano, are caused by crimes of the
same sort. Persons charged with such offences are brought to
Ternate; it is said that formerly they were often drowned on the way
or, on being haled thither, were condemned to be thrown into the
volcano.54.2 In the Banggai Archipelago, to the east of Celebes,
earthquakes are explained as punishments inflicted by evil spirits for
indulgence in illicit love.54.3
In some parts of Africa, also, it is believed that
Breaches of sexual breaches of sexual morality disturb the course of
morality thought to
blight the fruits of nature, particularly by blighting the fruits of the
the earth and earth; and probably such views are much more
otherwise disturb widely diffused in that continent than the scanty
the course of nature
in Africa. and fragmentary evidence at our disposal might
lead us to suppose. Thus, the negroes of Loango,
in West Africa, imagine that the commerce of a man with an
immature girl is punished by God with drought and consequent
famine until the transgressors expiate their transgression by dancing
naked before the king and an assembly of the people, who throw hot
gravel and bits of glass at the pair as they run the gauntlet. The rains
in that country should fall in September, but in 1898 there was a long
drought, and when the month of December had nearly passed, the
sun-scorched stocks of the fruitless Indian corn shook their rustling
leaves in the wind, the beans lay shrivelled and black on the ruddy
soil, and the shoots of the sweet potato had flowered and withered
long ago. The people cried out against their rulers for neglecting their
duty to the primeval powers of the earth; the priests of the sacred
groves had recourse to divination and discovered that God was
angry with the land on account of the immorality of certain persons
unknown, who were not observing the traditions and laws of their
God and country. The feeble old king had fled, but the slave who
acted as regent in his room sent word to the chiefs that there were
people in their towns who were the cause of God’s wrath. So every
chief called his subjects together and caused enquiries to be made,
and then it was discovered that three girls had broken the customs of
their country; for they were with child before they had passed
through what is called the paint-house, that is, before they had been
painted red and secluded for a season in token that they had
attained to the age of puberty. The people were incensed and
endeavoured to punish or even kill the three girls; and the English
writer who has recorded the case has thought it worth while to add
that on the very morning when the culprits were brought before the
magistrate rain fell.55.1 Amongst the Bavili of Loango, who are
divided into totemic clans, no man is allowed to marry a woman of
his mother’s clan; and God is believed to punish a breach of this
marriage law by withholding the rains in their due season.56.1 Similar
notions of the blighting influence of sexual crime appear to be
entertained by the Nandi of British East Africa; for we are told that
when a warrior has got a girl with child, she “is punished by being put
in Coventry, none of her girl friends being allowed to speak to or look
at her until after the child is born and buried. She
Sexual purity is also regarded with contempt for the rest of her
required of those
who handle corn or life and may never look inside a granary for fear of
enter a granary. spoiling the corn.”56.2 Among the Basutos in like
manner “while the corn is exposed to view, all
defiled persons are carefully kept from it. If the aid of a man in this
state is necessary for carrying home the harvest, he remains at
some distance while the sacks are filled, and only approaches to
place them upon the draught oxen. He withdraws as soon as the
load is deposited at the dwelling, and under no pretext can he assist
in pouring the corn into the basket in which it is preserved.”56.3 The
nature of the defilement which thus disqualifies a man from handling
the corn is not mentioned, but we may conjecture that unchastity
would fall under this general head. For amongst the Basutos after a
child is born a fresh fire has to be kindled in the dwelling by the
friction of wood, and this must be done by a young man of chaste
habits; it is believed that an untimely death awaits him who should
dare to discharge this holy office after having lost his innocence.56.4
In Morocco whoever enters a granary must first remove his slippers
and must be sexually clean. Were an unclean person to enter, the
people believe not only that the grain would lose its blessed
influence (baraka), but that he himself would fall ill. A Berber told Dr.