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You are teaching a course at the YMCA as part of your role as community health nurse. The question about the role of antibiotics arises, and you receive several questions about antibiotic resistance.

How would you describe ..

Actions in the community that have led to increased antibiotic resistance?

Actions in the healthcare community (by prescribers and non-prescribers) that have led to increased antibiotic resistance?

Which pages in the textbook were utilized for this response?

Attached is chapter 83, 84 and 85 of the textbook

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Jacqueline Rosenjack Burchum, DNSc, FNP-BC, CNE
Associate Professor, College of Nursing
Department of Advanced Practice and Doctoral Studies
University of Tennessee Health Science Center
Memphis, Tennessee
Laura D. Rosenthal, RN, DNP, ACNP-BC, FAANP
Associate Professor, College of Nursing
University of Colorado, Anschutz Medical Campus
Denver, Colorado
3251 Riverport Lane
St. Louis, Missouri 63043
ISBN 978-0-323-51227-5
Copyright © 2019, Elsevier Inc. All Rights Reserved.
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or
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Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance
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This book and the individual contributions contained in it are protected under copyright by the Publisher
(other than as may be noted herein).
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and
using any information, methods, compounds or experiments described herein. Because of rapid advances
in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be
made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or
contributors for any injury and/or damage to persons or property as a matter of products liability,
negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas
contained in the material herein.
Previous editions copyrighted 2016, 2013, 2010, 2007, 2004, 2001, 1998, 1994, 1990.
International Standard Book Number: 978-0-323-51227-5
Executive Content Strategist: Sonya Seigafuse
Senior Content Development Manager: Luke Held
Content Development Specialist: Jennifer Wade
Publishing Services Manager: Jeff Patterson
Senior Project Manager: Jodi M. Willard
Design Direction: Paula Catalano
Printed in Canada
Last digit is the print number: 9 8
1 Orientation to Pharmacology 1
2 Application of Pharmacology in Nursing Practice 5
3 Drug Regulation, Development, Names, and
Information 14
Pharmacokinetics 24
Pharmacodynamics 44
Drug Interactions 55
Adverse Drug Reactions and Medication Errors 63
Individual Variation in Drug Responses 74
9 Drug Therapy During Pregnancy and
Breast-Feeding 82
10 Drug Therapy in Pediatric Patients 90
11 Drug Therapy in Older Adults 94
SECTION 1 Introduction
12 Basic Principles of Neuropharmacology 100
13 Physiology of the Peripheral Nervous System 105
SECTION 2 Cholinergic Drugs
14 Muscarinic Agonists and Antagonists 118
15 Cholinesterase Inhibitors and Their Use in
Myasthenia Gravis 131
16 Drugs That Block Nicotinic Cholinergic
Transmission: Neuromuscular Blocking Agents 139
SECTION 3 Adrenergic Drugs
17 Adrenergic Agonists 147
18 Adrenergic Antagonists 159
19 Indirect-Acting Antiadrenergic Agents 174
SECTION 4 Introduction
20 Introduction to Central Nervous System
Pharmacology 179
SECTION 5 Drugs for Neurodegenerative Disorders
21 Drugs for Parkinson Disease 182
22 Drugs for Alzheimer’s Disease 199
23 Drugs for Multiple Sclerosis 206
SECTION 6 Neurologic Drugs
24 Drugs for Seizure Disorders 223
25 Drugs for Muscle Spasm and Spasticity 250
SECTION 7 Drugs for Pain
26 Local Anesthetics 259
27 General Anesthetics 265
28 Opioid Analgesics, Opioid Antagonists, and
Nonopioid Centrally Acting Analgesics 274
29 Pain Management in Patients With Cancer 300
30 Drugs for Headache 318
SECTION 8 Psychotherapeutic Drugs
31 Antipsychotic Agents and Their Use in
Schizophrenia 330
32 Antidepressants 352
33 Drugs for Bipolar Disorder 376
34 Sedative-Hypnotic Drugs 384
35 Management of Anxiety Disorders 399
36 Central Nervous System Stimulants and
Attention-Deficit/Hyperactivity Disorder 406
SECTION 9 Drug Abuse
37 Substance Use Disorders I: Basic Considerations 417
38 Substance Use Disorders II: Alcohol 424
39 Substance Use Disorders III: Nicotine and
Smoking 435
40 Substance Use Disorders IV: Major Drugs of Abuse
Other Than Alcohol and Nicotine 443
41 Diuretics 459
42 Agents Affecting the Volume and Ion Content of
Body Fluids 471
43 Review of Hemodynamics 476
44 Drugs Acting on the Renin-Angiotensin-Aldosterone
System 482
Calcium Channel Blockers 497
Vasodilators 505
Drugs for Hypertension 510
Drugs for Heart Failure 529
Antidysrhythmic Drugs 546
Prophylaxis of Atherosclerotic Cardiovascular
Disease: Drugs That Help Normalize Cholesterol
and Triglyceride Levels 568
Drugs for Angina Pectoris 591
Anticoagulant, Antiplatelet, and Thrombolytic
Drugs 604
Management of ST-Elevation Myocardial
Infarction 633
Drugs for Hemophilia 640
Drugs for Deficiency Anemias 648
Hematopoietic Agents 663
57 Drugs for Diabetes Mellitus 674
58 Drugs for Thyroid Disorders 711
59 Drugs Related to Hypothalamic and Pituitary
Function 723
60 Drugs for Disorders of the Adrenal Cortex 732
61 Estrogens and Progestins: Basic Pharmacology and
Noncontraceptive Applications 739
62 Birth Control 753
63 Drug Therapy for Infertility 770
64 Drugs That Affect Uterine Function 778
65 Androgens 789
66 Drugs for Erectile Dysfunction and Benign Prostatic
Hyperplasia 797
86 Bacteriostatic Inhibitors of Protein Synthesis:
Tetracyclines, Macrolides, and Others 1050
87 Aminoglycosides: Bactericidal Inhibitors of Protein
Synthesis 1061
88 Sulfonamides and Trimethoprim 1068
89 Drug Therapy for Urinary Tract Infections 1076
90 Antimycobacterial Agents: Drugs for Tuberculosis,
Review of the Immune System 809
Childhood Immunization 820
Immunosuppressants 836
Antihistamines 844
Cyclooxygenase Inhibitors: Nonsteroidal
Anti-Inflammatory Drugs and Acetaminophen 852
72 Glucocorticoids in Nonendocrine Disorders 871
73 Drug Therapy for Rheumatoid Arthritis 881
74 Drug Therapy for Gout 894
75 Drugs Affecting Calcium Levels and Bone
Mineralization 900
Disease 925
77 Drugs for Allergic Rhinitis, Cough, and Colds 948
78 Drugs for Peptic Ulcer Disease 956
79 Laxatives 972
80 Other Gastrointestinal Drugs 981
81 Vitamins 996
82 Drugs for Weight Loss 1007
Anthelmintics 1183
Antiprotozoal Drugs I: Antimalarial Agents 1189
Antiprotozoal Drugs II: Miscellaneous Agents 1199
Ectoparasiticides 1206
101 Basic Principles of Cancer Chemotherapy 1212
102 Anticancer Drugs I: Cytotoxic Agents 1226
103 Anticancer Drugs II: Hormonal Agents, Targeted
Drugs, and Other Noncytotoxic Anticancer
Drugs 1245
76 Drugs for Asthma and Chronic Obstructive Pulmonary
Leprosy, and Mycobacterium avium Complex
Infection 1081
Miscellaneous Antibacterial Drugs: Fluoroquinolones,
Metronidazole, Daptomycin, Rifampin, Rifaximin,
and Fidaxomicin 1097
Antifungal Agents 1102
Antiviral Agents I: Drugs for Non-HIV Viral
Infections 1113
Antiviral Agents II: Drugs for HIV Infection and
Related Opportunistic Infections 1133
Drug Therapy for Sexually Transmitted
Infections 1167
Antiseptics and Disinfectants 1176
Drugs for the Eye 1272
Drugs for the Skin 1284
Drugs for the Ear 1304
Additional Noteworthy Drugs 1311
Complementary and Alternative Therapy 1328
109 Management of Poisoning 1343
110 Potential Weapons of Biologic, Radiologic, and
Chemical Terrorism 1349
Canadian Drug Information 1359
83 Basic Principles of Antimicrobial Therapy 1014
84 Drugs That Weaken the Bacterial Cell Wall I:
Penicillins 1029
85 Drugs That Weaken the Bacterial Cell Wall II:
Cephalosporins, Carbapenems, Vancomycin,
Telavancin, Aztreonam, and Fosfomycin 1039
Prototype Drugs and Their Major Uses 1363
To my son, Jade Charmagan, BSN, RN. Congratulations, and welcome to the world
of nursing!
For Ashley, Christine, Courtney, Erica, Laura B., Laura P., and Stacy—my official
support team in life.
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About the Authors
Laura D. Rosenthal, RN, DNP,
ACNP-BC, FAANP, has been a
registered nurse since graduating
with her Bachelor of Science in
Nursing degree from the University of Michigan in 2000. She
completed her Master of Science
in Nursing degree in 2006 at Case
Western Reserve University in
Cleveland, Ohio. She finished her
nursing education at the University
of Colorado, College of Nursing,
graduating with her Doctor of
Nursing Practice degree in 2011.
Her background includes practice
in acute care and inpatient medicine. While working as a nurse
practitioner at the University of Colorado Hospital, she assisted
in developing one of the first fellowships for advanced practice
clinicians in hospital medicine.
Dr. Rosenthal serves as an associate professor at the University of Colorado, College of Nursing, where she teaches
within the undergraduate and graduate programs. She received
the Dean’s Award for Excellence in Teaching in 2013. She
serves on the board of the Colorado Nurses Association, remains
a member of the NP/PA committee for the Society of Hospital
Medicine, and volunteers as a Health Services RN for the Red
Cross. In her spare time, Dr. Rosenthal enjoys running, skiing,
and fostering retired greyhounds for Colorado Greyhound
Jacqueline Rosenjack Burchum,
DNSc, FNP-BC, CNE, has been
a registered nurse since 1981 and
a family nurse practitioner since
1996. She completed her Doctor
of Nursing Science degree in 2002.
Dr. Burchum currently serves
as an associate professor for the
University of Tennessee Health
Science Center (UTHSC) College
of Nursing. She is credentialed as a
certified nurse educator (CNE) by
the National League for Nursing.
She is a two-time recipient of
the UTHSC Student Government
Association’s Excellence in Teaching Award and a recipient of
the 2014 UT Alumni Association’s Outstanding Teacher Award.
Dr. Burchum was also the 2016–2017 Faculty Innovation Scholar
for the UTHSC Teaching and Learning Center.
Dr. Burchum has a special interest in online teaching and
program quality. To this end, she serves as an on-site evaluator
for the Commission on Collegiate Nursing Education (CCNE),
a national agency that accredits nursing education programs.
In addition, she is a peer reviewer for Quality Matters, a program
that certifies the quality of online courses.
As a nurse practitioner, Dr. Burchum’s primary interests
have centered on addressing the needs of vulnerable populations.
She is a member of the National Organization for Nurse
Practitioner Faculties, Sigma Theta Tau International Honor
Society, the American and Tennessee Nurses Associations, and
the National League for Nursing.
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Contributors and Reviewers
Joshua J. Neumiller, PharmD, CDE, FASCP
Assistant Professor of Pharmacotherapy
Washington State University
Spokane, Washington
Chapter 57
Laura Brennan, MS, RN
Assistant Professor
Elmhurst College
Elmhurst, Illinois
Lisa Miklush, PhD, RNC, CNS
Adjunct Faculty
Nursing Department
Gonzaga University
Spokane, Washington
Joan Parker Frizzell, PhD, CRNP, ANP-BC
Associate Professor
School of Nursing and Health Sciences
La Salle University;
Nurse Practitioner
Roxborough Memorial Hospital
Philadelphia, Pennsylvania
Janet Czermak Russell MA, MS, APN-BC
Associate Professor of Nursing
Nursing Department
Essex County College
Newark, New Jersey
James Graves, PharmD
Clinical Pharmacist
University of Missouri Inpatient Pharmacy
Columbia, Missouri
Carin Tripodina, EdD, MS, RN, CPN, CNE
Assistant Professor of Nursing
Nursing Department
American International College
Springfield, Massachusetts
Ellen Ketcherside, RN, MA
Nursing Professor
Allied Health Department
Mineral Area College
Park Hills, Missouri
Jennifer J. Yeager, PhD, RN
Assistant Professor
Department of Nursing
Tarleton State University
Stephenville, Texas
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Pharmacology pervades all phases of nursing practice and
relates directly to patient care and education. Yet despite its
importance, many students—and even some teachers—are often
uncomfortable with the subject. Why? Because traditional texts
have stressed memorizing rather than understanding. In this text,
the guiding principle is to establish a basic understanding of
drugs, after which secondary details can be learned as needed.
This text has two major objectives: (1) to help you, the
nursing student, establish a knowledge base in the basic science
of drugs, and (2) to show you how that knowledge can be
applied in clinical practice. The methods by which these goals
are achieved are described in the following sections.
To understand drugs, you need a solid foundation in basic
pharmacologic principles. To help you establish that foundation,
this text has major chapters on the following topics: basic
principles that apply to all drugs (Chapters 4 through 8), basic
principles of drug therapy across the life span (Chapters 9
through 11), basic principles of neuropharmacology (Chapter
12), basic principles of antimicrobial therapy (Chapter 83),
and basic principles of cancer chemotherapy (Chapter 101).
To understand the actions of a drug, it is useful to understand
the biologic systems influenced by the drug. Accordingly, for
all major drug families, relevant physiology and pathophysiology are reviewed. In almost all cases, these reviews are presented
at the beginning of each chapter rather than in a systems review
at the beginning of a unit. This juxtaposition of pharmacology,
physiology, and pathophysiology is designed to help you
understand how these topics interrelate.
Within each drug family we can usually identify a prototype—a
drug that embodies the characteristics shared by all members
of the group. Because other family members are similar to the
prototype, to know the prototype is to know the basic properties
of all family members.
The benefits of teaching through prototypes can be appreciated with an example. Let’s consider the nonsteroidal antiinflammatory drugs (NSAIDs), a family that includes aspirin,
ibuprofen [Motrin], naproxen [Aleve], celecoxib [Celebrex],
and more than 20 other drugs. Traditionally, information on
these drugs is presented in a series of paragraphs describing
each drug in turn. When attempting to study from such a list,
you are likely to learn many drug names and little else; the
important concept of similarity among family members is easily
lost. In this text, the family prototype—aspirin—is discussed
first and in depth. After this, the small ways in which individual
NSAIDs differ from aspirin are pointed out. Not only is this
approach more efficient than the traditional approach, it is
also more effective in that similarities among family members
are emphasized.
Pharmacology is exceptionally rich in detail. There are many
drug families, each with multiple members and each member
with its own catalog of indications, contraindications, adverse
effects, and drug interactions. This abundance of detail confronts
teachers with the difficult question of what to teach and
confronts students with the equally difficult question of what
to study. Attempting to answer these questions can frustrate
teachers and students alike. Even worse, basic concepts can
be obscured in the presence of myriad details.
To help you focus on essentials, two sizes of type are used
in this text. Large type is intended to say, “On your first exposure
to this topic, this is the core of information you should learn.”
Small type is intended to say, “Here is additional information
that you may want to learn after mastering the material in
large type.” As a rule, we reserve large print for prototypes,
basic principles of pharmacology, and reviews of physiology
and pathophysiology. We use small print for secondary information about the prototypes and for the discussion of drugs that
are not prototypes. This technique allows the book to contain
a large body of detail without having that detail cloud the big
picture. Furthermore, because the technique highlights essentials,
it minimizes questions about what to teach and what to study.
The use of large and small print is especially valuable for
discussing adverse effects and drug interactions. Most drugs are
associated with many adverse effects and interactions. As a rule,
however, only a few of these are noteworthy. In traditional texts,
practically all adverse effects and interactions are presented,
creating long and tedious lists. In this text, we use large print
to highlight the few adverse effects and interactions that are
especially characteristic; the rest are noted briefly in small
print. Rather than overwhelming you with long and forbidding
lists, this text delineates a moderate body of information that
is truly important, thereby facilitating comprehension.
This book contains two broad categories of information:
pharmacology (the basic science about drugs) and therapeutics
(the clinical use of drugs). To ensure that content is clinically
relevant, we use evidence-based treatment guidelines as a basis
for deciding what to stress and what to play down. Unfortunately, clinical practice is a moving target. Guidelines change
when effective new drugs are introduced and when clinical
trials reveal new benefits or new risks of older drugs, and so
we need to work hard to keep this book current. Despite our
resource that includes interactive self-study modules, a
collection of interactive learning resources, and a media-rich
library of supplemental resources.
• The Study Guide, which is keyed to the book, includes
study questions; critical thinking, prioritization, and delegation questions; and case studies.
best efforts, the book and clinical reality may not always agree:
Some treatments discussed here will be considered inappropriate
before the 11th edition is published. Furthermore, in areas
where controversy exists, the treatments discussed here may
be considered inappropriate by some clinicians right now.
• The Instructor Resources for the tenth edition are available
online and include TEACH® for Nurses Lesson Plans, a Test
Bank, a PowerPoint Collection, and an Image Collection.
The principal reason for asking you to learn pharmacology
is to enhance your ability to provide patient care and education.
To show you how pharmacologic knowledge can be applied
to nursing practice, nursing implications are integrated into
the body of each chapter. That is, as specific drugs and drug
families are discussed, the nursing implications inherent in
the pharmacologic information are noted side-by-side with the
basic science.
To facilitate access to nursing content, nursing implications
are also summarized at the end of most chapters. These summaries serve to reinforce the information presented in the
chapter body. These summaries have been omitted in chapters
that are especially brief or that address drugs that are infrequently used. However, even in these chapters, nursing
implications are incorporated into the main chapter text.
Thanks to its focus on essentials, this text is especially well
suited to serve as the primary text for a course dedicated
specifically to pharmacology. In addition, the focused approach
makes it a valuable resource for pharmacologic instruction
within an integrated curriculum and for self-directed learning
by students, teachers, and practitioners.
How is this focus achieved? Four primary techniques are
employed: (1) teaching through prototypes, (2) using standard
print for essential information and small print for secondary
information, (3) limiting discussion of adverse effects and drug
interactions to information that matters most, and (4) using
evidence-based clinical guidelines to determine what content
to stress. To reinforce the relationship between pharmacologic
knowledge and nursing practice, nursing implications are
integrated into each chapter. To provide rapid access to nursing
content, nursing implications are summarized at the end of
most chapters using a nursing process format. In addition, key
points are listed at the end of each chapter. As in previous
editions, the tenth edition emphasizes conceptual material—
reducing rote memorization, promoting comprehension, and
increasing reader friendliness.
Pharmacology can be an unpopular subject due to the vast
and rapidly changing area of content. Often, nursing students
feel that pharmacology is one of the most difficult classes to
master. We hope that this book makes the subject of pharmacology easier and more enjoyable for you to understand
by allowing you to focus on the most important umbrella
concepts of pharmacology as they relate to nursing care and
the safety of patients.
Lehne’s Pharmacology for Nursing Care has been revised cover
to cover to ensure that the latest and most accurate information
is presented. Three new features have been added to help
promote our focus on the most useful and most critical information for nursing students:
• Prototype Drugs: This content, which appeared in an
end-of-book appendix in previous editions, has been moved
into the book’s chapters as a new, easy-to-find feature.
• Safety Alerts: This eye-catching new feature draws the
reader’s attention to important safety concerns related to
contraindications, adverse effects, pregnancy categories,
and more.
• Patient-Centered Care Across the Life Span: New
tables in many chapters highlight care concerns for
patients throughout their lives, from infancy to older
In addition, the popular Special Interest Topics of past editions
have been thoroughly revised to allow for the most current
research. Canadian trade names have been updated and
continue to be identified by a maple-leaf icon.
We would like to acknowledge the support of our colleagues
at Elsevier, including Executive Content Strategist Sonya
Seigafuse, Executive Content Strategist Lee Henderson, Content
Development Specialist Jennifer Wade, and Senior Project
Manager Jodi Willard.
Finally, we would like to express our gratitude to Richard
A. Lehne for his dedication to this book for eight editions. We
are honored to be able to continue his work.
• Online Evolve Resources accompany this edition and
include Downloadable Key Points, Review Questions
for the NCLEX® Examination, Unfolding Case Studies,
and more. These resources are available at http://evolve
• Pharmacology Online for Lehne’s Pharmacology for
Nursing Care, tenth edition, is a dynamic online course
Jacqueline Rosenjack Burchum
Laura D. Rosenthal
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Basic Principles of
Antimicrobial Therapy
Selective Toxicity, p. 1015
Achieving Selective Toxicity, p. 1015
Classification of Antimicrobial Drugs, p. 1015
Classification by Susceptible Organism, p. 1015
Classification by Mechanism of Action, p. 1015
Acquired Resistance to Antimicrobial Drugs, p. 1016
Microbial Mechanisms of Drug Resistance, p. 1017
Mechanisms By Which Resistance Is Acquired,
p. 1018
Relationships Between Antibiotic Use and
Emergence of Drug-Resistant Microbes, p. 1018
Superinfection, p. 1019
Antimicrobial Stewardship, p. 1019
Selection of Antibiotics, p. 1019
Empiric Therapy Before Completion of Laboratory
Tests, p. 1019
Identifying the Infecting Organism, p. 1023
Determining Drug Susceptibility, p. 1024
Host Factors That Modify Drug Choice, Route of
Administration, or Dosage, p. 1024
Host Defenses, p. 1024
Site of Infection, p. 1024
Other Host Factors, p. 1025
Dosage and Duration of Treatment, p. 1025
Modern antimicrobial agents had their debut in the 1930s and
1940s and have greatly reduced morbidity and mortality from
infection. As newer drugs are introduced, our ability to fight
infections increases even more. However, despite impressive
advances, continued progress is needed. There remain organisms
that respond poorly to available drugs; there are effective drugs
whose use is limited by toxicity; and there is, because of
evolving microbial resistance, the constant threat that currently
effective antibiotics will be rendered useless.
Here we focus on two principal themes. The first is microbial
susceptibility to drugs, with special emphasis on resistance. The
second is clinical usage of antimicrobials. Topics addressed
include criteria for drug selection, host factors that modify drug
use, use of antimicrobial combinations, and use of antimicrobial
agents for prophylaxis.
Therapy With Antibiotic Combinations, p. 1025
Antimicrobial Effects of Antibiotic Combinations,
p. 1025
Indications for Antibiotic Combinations, p. 1026
Disadvantages of Antibiotic Combinations, p.
Prophylactic Use of Antimicrobial Drugs, p. 1026
Surgery, p. 1026
Bacterial Endocarditis, p. 1026
Neutropenia, p. 1027
Other Indications for Antimicrobial Prophylaxis,
p. 1027
Misuses of Antimicrobial Drugs, p. 1027
Attempted Treatment of Viral Infection, p. 1027
Treatment of Fever of Unknown Origin, p. 1027
Improper Dosage, p. 1027
Treatment in the Absence of Adequate
Bacteriologic Information, p. 1027
Omission of Surgical Drainage, p. 1027
Monitoring Antimicrobial Therapy, p. 1027
Key Points, p. 1028
Box 83.1. Antibiotics in Animal Feed: Dying for a
Hamburger and Chicken Nuggets, p. 1020
Before going further, we need to consider two terms:
antibiotic and antimicrobial drug. In common practice, the
terms antibiotic and antimicrobial drug are used interchangeably, as they are in this book. However, be aware that the
formal definitions of these words are not identical. Strictly
speaking, an antibiotic is a chemical that is produced by one
microbe and has the ability to harm other microbes. Under
this definition, only those compounds that are actually made
by microorganisms qualify as antibiotics. Drugs such as the
sulfonamides, which are produced in the laboratory, would
not be considered antibiotics under the strict definition. In
contrast, an antimicrobial drug is defined as any agent, natural
or synthetic, that has the ability to kill or suppress microorganisms. Under this definition, no distinction is made between
compounds produced by microbes and those made by chemists.
From the perspective of therapeutics, there is no benefit to
distinguishing between drugs made by microorganisms and
drugs made by chemists. Hence, the current practice is to use
the terms antibiotic and antimicrobial drug interchangeably.
Selective toxicity is defined as the ability of a drug to injure
a target cell or target organism without injuring other cells or
organisms that are in intimate contact with the target. As applied
to antimicrobial drugs, selective toxicity indicates the ability
of an antibiotic to kill or suppress microbial pathogens without
causing injury to the host. Selective toxicity is the property
that makes antibiotics valuable. If it weren’t for selective
toxicity—that is, if antibiotics were as harmful to the host as
they are to infecting organisms—these drugs would have no
therapeutic utility.
Achieving Selective Toxicity
How can a drug be highly toxic to microbes but harmless
to the host? The answer lies with differences in the cellular
chemistry of mammals and microbes. There are biochemical
processes critical to microbial well-being that do not take place
in mammalian cells. Hence, drugs that selectively interfere
with these unique microbial processes can cause serious injury
to microorganisms while leaving mammalian cells intact.
Three examples of how we achieve selective toxicity are
discussed next.
Disruption of the Bacterial Cell Wall
Unlike mammalian cells, bacteria are encased in a rigid cell
wall. The protoplasm within this wall has a high concentration
of solutes, making osmotic pressure within the bacterium high.
If it were not for the cell wall, bacteria would absorb water,
swell, and then burst. Several families of drugs (e.g., penicillins,
cephalosporins) weaken the cell wall and thereby promote
bacterial lysis. Because mammalian cells have no cell wall,
drugs directed at this structure do not affect us.
Basic Principles of Antimicrobial Therapy
protein synthesis in bacteria while leaving mammalian protein
synthesis untouched.
Various schemes are employed to classify antimicrobial
drugs. The two schemes most suited to our objectives are
considered here.
Classification by Susceptible Organism
Antibiotics differ widely in their antimicrobial activity. Some
agents, called narrow-spectrum antibiotics, are active against
only a few species of microorganisms. In contrast, broadspectrum antibiotics are active against a wide variety of
microbes. As discussed later in the chapter, narrow-spectrum
drugs are generally preferred to broad-spectrum drugs.
Table 83.1 classifies the major antimicrobial drugs according
to susceptible organisms. The table shows three major groups:
antibacterial drugs, antifungal drugs, and antiviral drugs. In
addition, the table subdivides the antibacterial drugs into
narrow-spectrum and broad-spectrum agents, and indicates
the principal classes of bacteria against which they are active.
Classification by Mechanism of Action
The antimicrobial drugs fall into seven major groups based
on mechanism of action. This classification is shown in Table
83.2. Properties of the seven major classes are discussed
briefly here.
Inhibition of an Enzyme Unique to Bacteria
The sulfonamides represent antibiotics that are selectively toxic
because they inhibit an enzyme critical to bacterial survival
but not to our survival. Specifically, sulfonamides inhibit an
enzyme needed to make folic acid, a compound required by
all cells, both mammalian and bacterial. Because we can use
folic acid from dietary sources, sulfonamides are safe for human
consumption. In contrast, bacteria must synthesize folic acid
themselves (because, unlike us, they can’t take up folic acid
from the environment). Hence, to meet their needs, bacteria
first take up para-aminobenzoic acid (PABA), a precursor of
folic acid, and then convert the PABA into folic acid. Sulfonamides block this conversion. Since mammalian cells do not
make their own folic acid, sulfonamide toxicity is limited to
Disruption of Bacterial Protein Synthesis
In bacteria as in mammalian cells, protein synthesis is done
by ribosomes. However, bacterial and mammalian ribosomes
are not identical, and hence we can make drugs that disrupt
the function of one but not the other. As a result, we can impair
• Drugs that inhibit bacterial cell wall synthesis or activate
enzymes that disrupt the cell wall—These drugs (e.g.,
penicillins, cephalosporins) weaken the cell wall and
thereby promote bacterial lysis and death.
• Drugs that increase cell membrane permeability—Drugs
in this group (e.g., amphotericin B) increase the permeability of cell membranes, causing leakage of intracellular
• Drugs that cause lethal inhibition of bacterial protein
synthesis—The aminoglycosides (e.g., gentamicin) are
the only drugs in this group. We do not know why inhibition of protein synthesis by these agents results in cell
• Drugs that cause nonlethal inhibition of protein synthesis—
Like the aminoglycosides, these drugs (e.g., tetracyclines)
inhibit bacterial protein synthesis. However, in contrast
to the aminoglycosides, these agents only slow microbial
growth; they do not kill bacteria at clinically achievable
• Drugs that inhibit bacterial synthesis of DNA and RNA
or disrupt DNA function—These drugs inhibit synthesis
of DNA or RNA by binding directly to nucleic acids or
by interacting with enzymes required for nucleic acid
synthesis. They may also bind with DNA and disrupt its
function. Members of this group include rifampin, metronidazole, and the fluoroquinolones (e.g., ciprofloxacin).
• Antimetabolites—These drugs disrupt specific biochemical
reactions. The result is either a decrease in the synthesis
of essential cell constituents or synthesis of nonfunctional
Chemotherapy of Infectious Diseases
TABLE 83.1
Classification of Antimicrobial
Drugs by Susceptible Organisms
TABLE 83.2
Narrow Spectrum
Classification of Antimicrobial
Drugs by Mechanism of Action
Drug Class
Gram-Positive Cocci and Gram-Positive Bacilli
Penicillin G and V
Penicillinase-resistant penicillins: oxacillin, nafcillin
Gram-Negative Aerobes
Aminoglycosides: gentamicin, others
Cephalosporins (first and second generations)
Mycobacterium tuberculosis
Broad Spectrum
Gram-Positive Cocci and Gram-Negative Bacilli
Broad-spectrum penicillins: ampicillin, others
Extended-spectrum penicillins: piperacillin, others
Cephalosporins (third and fifth generations)
Tetracyclines: tetracycline, others
Carbapenems: imipenem, others
Sulfonamides: sulfisoxazole, others
Fluoroquinolones: ciprofloxacin, others
Inhibitors of cell wall synthesis
Drugs that disrupt the cell membrane
Amphotericin B
Bactericidal inhibitors of protein synthesis
Bacteriostatic inhibitors of protein synthesis
Drugs that interfere with synthesis or integrity
of bacterial DNA and RNA
Drugs that suppress viral replication
Viral DNA polymerase inhibitors
HIV reverse transcriptase inhibitors
Drugs for HIV Infection
HIV protease inhibitors
Reverse transcriptase inhibitors: zidovudine, others
Protease inhibitors: ritonavir, others
Fusion inhibitors: enfuvirtide
Integrase inhibitors: raltegravir
CCR5 antagonists: maraviroc
HIV fusion inhibitors
HIV integrase inhibitors
HIV CCR5 antagonists
Influenza neuraminidase inhibitors
Drugs for Influenza
Adamantanes: amantadine, others
Neuraminidase inhibitors: oseltamivir, others
bacteria must ultimately be accomplished by host defenses
(i.e., the immune system working in concert with phagocytic
Other Antiviral Drugs
Interferon alfa
Polyene antibiotics: amphotericin B, others
Azoles: itraconazole, others
Echinocandins: caspofungin, others
analogs of normal metabolites. Examples of antimetabolites include trimethoprim and the sulfonamides.
• Drugs that suppress viral replication—Most of these
drugs inhibit specific enzymes—DNA polymerase, reverse
transcriptase, protease, integrase, or neuraminidase—
required for viral replication and infectivity.
When considering the antibacterial drugs, it is useful to distinguish between agents that are bactericidal and agents that
are bacteriostatic. Bactericidal drugs are directly lethal to
bacteria at clinically achievable concentrations. In contrast,
bacteriostatic drugs can slow bacterial growth but do not cause
cell death. When a bacteriostatic drug is used, elimination of
In this section, we discuss bacterial resistance to antibiotics,
which may be innate (natural, inborn) or acquired over time.
Discussion here is limited to acquired resistance, which is a
much greater clinical concern than innate resistance.
Over time, an organism that had once been highly sensitive
to an antibiotic may become less susceptible, or it may lose
drug sensitivity entirely. In some cases, resistance develops to
several drugs. Acquired resistance is of great concern in that it
can render currently effective drugs useless, thereby creating a
clinical crisis and a constant need for new antimicrobial agents.
As a rule, antibiotic resistance is associated with extended hospitalization, significant morbidity, and excess mortality. Organisms
for which drug resistance is now a serious problem include
Enterococcus faecium, Staphylococcus aureus, Enterobacter
species, Pseudomonas aeruginosa, Acinetobacter baumannii,
Klebsiella species, and Clostridium difficile (Table 83.3).
TABLE 83.3
Basic Principles of Antimicrobial Therapy
Drugs for Some Highly Resistant Bacteria
Resistance Mechanism
Alternative Treatments
Mutation and overexpression of PBP5
Production of altered 23S ribosomes
Production of enzymes that inactivate
quinupristin/dalfopristin, altered drug
Production of aminoglycoside-modifying
enzymes, ribosomal mutations
Quinupristin/dalfopristin, daptomycin,
tigecycline, linezolid
Quinupristin/dalfopristin, daptomycin,
Daptomycin, tigecycline, linezolid
Thickening of cell wall and altered
structure of cell wall precursor
Altered structure of cell wall and cell
Production of altered 23S ribosomes
May attempt to test for streptomycin
Quinupristin/dalfopristin, daptomycin,
tigecycline, linezolid, telavancin
Quinupristin/dalfopristin, tigecycline,
linezolid, telavancin
Quinupristin/dalfopristin, daptomycin,
tigecycline, telavancin, ceftobiprole
Quinupristin/dalfopristin, telavancin
Mutation in PBP2a
Ceftriaxone, cefotaxime,
ceftazidime, cefepime
Production of extended-spectrum
Production of carbapenemases, decreased
Carbapenems, tigecycline
Ceftriaxone, cefotaxime,
ceftazidime, cefepime
Production of extended-spectrum
Production of carbapenemases, decreased
Carbapenems, tigecycline
Decreased permeability, increased drug
efflux, production of carbapenemases
Decreased permeability, increased drug
efflux, production of carbapenemases
Reduced drug activation, increased drug
efflux, increased repair of drug-induced
DNA damage
Vancomycin, rifaximin
Polymyxins, tigecycline
Polymyxins, tigecycline
Methicillin-resistant Staphylococcus aureus is discussed in Chapter 84.
Clostridium difficile infection is discussed in Chapter 85.
PBP5, Penicillin-binding protein 5; PBP2a, penicillin-binding protein 2a.
Two of these resistant bacteria—methicillin-resistant Staph.
aureus and C. difficile—are discussed in Chapters 84 and 85,
In the discussion that follows, we examine the mechanisms
by which microbial drug resistance is acquired and the measures
by which emergence of resistance can be delayed. As you read
this section, keep in mind that it is the microbe that becomes
drug resistant, not the patient.
Microbial Mechanisms of Drug Resistance
Microbes have four basic mechanisms for resisting drugs. They
can (1) decrease the concentration of a drug at its site of action,
(2) alter the structure of drug target molecules, (3) produce a
drug antagonist, and (4) cause drug inactivation.
Reduction of Drug Concentration at
Its Site of Action
For most antimicrobial drugs, the site of action is intracellular.
Accordingly, if a bug can reduce the intracellular concentration
of a drug, it can resist harm. Two basic mechanisms are
involved. First, microbes can cease active uptake of certain
drugs—tetracyclines and gentamicin, for example. Second,
microbes can increase active export of certain drugs—
tetracyclines, fluoroquinolones, and macrolides, for example.
Alteration of Drug Target Molecules
Most antibiotics, like most other drugs, must interact with
target molecules (receptors) to produce their effects. Hence,
if the structure of the target molecule is altered, resistance
can result. For example, some bacteria are now resistant to
streptomycin because of structural changes in bacterial ribosomes, the sites at which streptomycin acts to inhibit protein
Antagonist Production
In rare cases, a microbe can synthesize a compound that
antagonizes drug actions. For example, by acquiring the ability
to synthesize increased quantities of PABA, some bacteria
have developed resistance to sulfonamides.
Chemotherapy of Infectious Diseases
Drug Inactivation
Microbes can resist harm by producing drug-metabolizing
enzymes. For example, many bacteria are resistant to penicillin
G because of increased production of penicillinase, an enzyme
that inactivates penicillin. In addition to penicillins, bacterial
enzymes can inactivate other antibiotics, including cephalosporins, carbapenems, and fluoroquinolones.
New Delhi Metallo-Beta-Lactamase 1 (NDM-1) Gene.
Extensive drug resistance is conferred by the NDM-1 gene,
which codes for a powerful form of beta-lactamase. As discussed
in Chapters 84 and 85, beta-lactamases are enzymes that can
inactivate drugs that have a beta-lactam ring. The form of
beta-lactamase encoded by NDM-1 is both unusual and troubling
in that it can inactivate essentially all beta-lactam antibiotics,
a group that includes penicillins, cephalosporins, and carbapenems. As the NDM-1 gene is resistant to carbapenems, it is
also classified as a type of carbapenems-resistant Enterobacteriaceae (CRE).Worse yet, the DNA segment that contains
the NDM-1 gene also contains genes that code for additional
resistance determinants, including drug efflux pumps, and
enzymes that can inactivate other important antibiotics, including
erythromycin, rifampin, chloramphenicol, and fluoroquinolones.
Furthermore, all of these genes are present on a plasmid, a
piece of DNA that can be easily transferred from one bacterium
to another (see Conjugation). Of note, bacteria that have the
NDM-1 gene are resistant to nearly all antibiotics, except for
tigecycline and colistin. Since its discovery in Klebsiella
pneumoniae in 2008, NDM-1 has been found in other common
enteric bacteria, including Escherichia coli, Enterobacter,
Salmonella, Citrobacter freundii, Providencia rettgeri, and
Morganella morganii. Before 2012, only a few cases of NDM-1
infection were reported in the United States and Canada, but
that number is increasing.
Mechanisms By Which Resistance
Is Acquired
How do microbes acquire mechanisms of resistance? Ultimately,
all of the alterations in structure and function discussed previously result from changes in the microbial genome. These
genetic changes may result either from spontaneous mutation
or from acquisition of DNA from an external source. One
important mechanism of DNA acquisition is conjugation with
other bacteria.
Spontaneous Mutation
Spontaneous mutations produce random changes in a microbe’s
DNA. The result is a gradual increase in resistance. Low-level
resistance develops first. With additional mutations, resistance
becomes greater. As a rule, spontaneous mutations confer
resistance to only one drug.
Conjugation is a process by which extrachromosomal DNA
is transferred from one bacterium to another. To transfer
resistance by conjugation, the donor organism must possess
two unique DNA segments, one that codes for the mechanisms
of drug resistance and one that codes for the “sexual” apparatus
required for DNA transfer. Together, these two DNA segments
constitute an R factor (resistance factor).
Conjugation takes place primarily among gram-negative
bacteria. Genetic material may be transferred between members
of the same species or between members of different species.
Because transfer of R factors is not species specific, it is possible
for pathogenic bacteria to acquire R factors from the normal
flora of the body. Because R factors are becoming common
in normal flora, the possibility of transferring resistance from
normal flora to pathogens is a significant clinical concern.
In contrast to spontaneous mutation, conjugation frequently
confers multiple drug resistance. This can be achieved, for
example, by transferring DNA that codes for several different
drug-metabolizing enzymes. Hence, in a single event, a drugsensitive bacterium can become highly drug resistant.
Relationships Between Antibiotic
Use and Emergence of
Drug-Resistant Microbes
Use of antibiotics promotes the emergence of drug-resistant
microbes. Please note, however, that although antibiotics
promote drug resistance, they are not mutagenic and do not
directly cause the genetic changes that underlie reduced drug
sensitivity. Spontaneous mutation and conjugation are random
events whose incidence is independent of drug use. Drugs
simply make conditions favorable for overgrowth of microbes
that have acquired mechanisms for resistance.
How Do Antibiotics Promote Resistance?
To answer this question, we need to recall two aspects of
microbial ecology: (1) microbes secrete compounds that are
toxic to other microbes and (2) microbes within a given ecologic
niche (e.g., large intestine, urogenital tract, skin) compete with
each other for available nutrients. Under drug-free conditions,
the various microbes in a given niche keep each other in check.
Furthermore, if none of these organisms is drug resistant,
introduction of antibiotics will be equally detrimental to all
members of the population and therefore will not promote the
growth of any individual microbe. However, if a drug-resistant
organism is present, antibiotics will create selection pressure
favoring its growth by killing off sensitive organisms. In doing
so, the drug will eliminate the toxins they produce and will
thereby facilitate survival of the microbe that is drug resistant.
Also, elimination of sensitive organisms will remove competition for available nutrients, thereby making conditions even
more favorable for the resistant microbe to flourish. Hence,
although drug resistance is of no benefit to an organism when
there are no antibiotics present, when antibiotics are introduced,
they create selection pressure favoring overgrowth of microbes
that are resistant.
Which Antibiotics Promote Resistance?
All antimicrobial drugs promote the emergence of drug-resistant
organisms. However, some agents are more likely to promote
resistance than others. Because broad-spectrum antibiotics kill
more competing organisms than do narrow-spectrum drugs,
broad-spectrum agents do the most to facilitate emergence of
The Influence of Increased Antibiotic Use on the
Emergence of Resistance
The more that antibiotics are used, the faster drug-resistant
organisms will emerge. Not only do antibiotics promote the
emergence of resistant pathogens, they also promote the
overgrowth of normal flora that possesses mechanisms for
resistance. Because drug use can increase resistance in normal
flora and because normal flora can transfer resistance to
pathogens, every effort should be made to avoid the use of
antibiotics by individuals who don’t actually need them (i.e.,
individuals who don’t have a bacterial infection). Because all
antibiotic use will further the emergence of resistance, there
can be no excuse for casual or indiscriminate dispensing of
these drugs.
www.cdc.gov/drugresistance. The important topic of antibiotic
use in animals is discussed in Box 83.1.
In addition to the CDC campaign, in 2014 the Interagency
Task Force on Antimicrobial Resistance published an update
to its original publication: A Public Health Action Plan to
Combat Antimicrobial Resistance. This updated action plan
discusses four focus areas developed to decrease resistance to
• Focus Area I: Surveillance, Prevention, and Control
of Antimicrobial-Resistant Infections. Goals include
improving the detection, monitoring, and characterization
of drug-resistant infections in humans and animals, as
well as improving the definition, characterization, and
measurement of the impact of antimicrobial drug use.
• Focus Area II: Research. Goals include the facilitation
of basic research on antimicrobial resistance, as well as
the translation of basic research into practice. Support
for epidemiologic studies to identify key drivers of the
emergence and spread of antimicrobial resistance is of
great importance.
• Focus Area III: Regulatory Pathways for New Products. The aims for this focus area include the provision
of information on the development status of antibacterial
drug products and encouragement for further development
of rapid diagnostic tests and vaccines.
• Focus Area IV: Product Development. Goals include
providing a systematic assessment of current and future
needs for antimicrobial resistance products and promoting
the development of drugs targeted to address areas where
unmet needs exist.
Healthcare-Associated Infections
Because hospitals are sites of intensive antibiotic use, resident organisms can be extremely drug resistant. As a result,
healthcare-associated infections (HAIs) are among the most
difficult to treat. According to the Centers for Disease Control
and Prevention (CDC), 1 of every 25 patients will fall
victim to an HAI. Measures to delay emergence of resistant
organisms in hospitals are discussed under Antimicrobial
Superinfection is a special example of the emergence of drug
resistance. A superinfection is defined as a new infection that
appears during the course of treatment for a primary infection.
New infections develop when antibiotics eliminate the inhibitory
influence of normal flora, thereby allowing a second infectious
agent to flourish. When there is normal flora that contains a
resistant organism, the antibiotic will selectively promote the
growth of that specific resistant flora. Although the antibiotic
promotes the overgrowth of resistant flora, it kills off sensitive
strains, thus facilitating the survival of the resistant flora.
Although there is selective overgrowth of the normal flora
with resistance, there is still a decrease in the inhibitory effects
of the sensitive flora.
Because broad-spectrum antibiotics kill off more normal
flora than do narrow-spectrum drugs, superinfections are more
likely in patients receiving broad-spectrum agents. Because
superinfections are caused by drug-resistant microbes, these
infections are often difficult to treat.
Antimicrobial Stewardship
Many organizations have begun to address the issue of antibiotic resistance in healthcare. In 2012, the Infectious Diseases
Society of America (IDSA), in conjunction with the Society
for Healthcare Epidemiology of America (SHEA) and the
Pediatric Infectious Diseases Society (PIDS), released its first
Policy Statement on Antimicrobial Stewardship. The statement
included five recommendations, including suggestions for
monitoring, education, and research to assist in the prevention
of antibiotic resistance. The statement can be found online at
The Get Smart for Healthcare campaign initiated by the
CDC provides information on the proper use of antibiotics
in humans and animals. The campaign has three objectives:
to promote adherence to appropriate prescribing guidelines,
to decrease the demand for antibiotics among healthy
adults and parents of young children, and to increase adherence to prescribed antibiotics. Target audiences include
patient and providers. More information is available at
Basic Principles of Antimicrobial Therapy
When treating infection, the therapeutic objective is to produce
maximal antimicrobial effects while causing minimal harm to
the host. To achieve this goal, we must select the most appropriate antibiotic for the individual patient. When choosing an
antibiotic, three principal factors must be considered: (1) the
identity of the infecting organism, (2) drug sensitivity of the
infecting organism, and (3) host factors, such as the site of
infection and the status of host defenses.
For any given infection, several drugs may be effective.
However, for most infections, there is usually one drug that
is superior to the alternatives (Table 83.4). This drug of first
choice may be preferred for several reasons, such as greater
efficacy, lower toxicity, or more narrow spectrum. Whenever
possible, the drug of first choice should be employed. Alternative
agents should be used only when the first-choice drug is inappropriate. Conditions that might rule out a first-choice agent
include (1) allergy to the drug of choice, (2) inability of the
drug of choice to penetrate to the site of infection, and (3)
heightened susceptibility of the patient to toxicity of the firstchoice drug.
Empiric Therapy Before Completion of
Laboratory Tests
Optimal antimicrobial therapy requires identification of the
infecting organism and determination of its drug sensitivity.
Chemotherapy of Infectious Diseases
BOX 83.1
Drug-resistant infection resulting from the use of antibiotics in
agriculture is a global public health concern. Antibiotics are
employed extensively in the livestock and poultry industries.
Not surprisingly, this practice has created a large reservoir of
drug-resistant bacteria, some of which now infect humans. In
addition to being a direct detriment to health, these infections
pose an even larger threat: the passage of resistance genes to
normal intestinal flora, and then from normal flora to human
The amount of antibiotics given to food animals is staggering. In 2010, animals worldwide received 63,151 tons of
antimicrobials. This is expected to increase by 67% by 2030.
Of antibiotics produced in the United States each year, nearly
80% (13,300 tons) goes to animals. Even more surprisingly,
of the antibiotics that animals receive, only 7.5% (1000 tons)
is given to treat infection. The vast majority—12,300 tons—is
mixed with feed to promote growth. Both uses encourage the
emergence of resistance.
Of the two agricultural uses—growth promotion and treatment
of infection—growth promotion is by far the more controversial.
Few authorities would argue that we shouldn’t give antibiotics
to treat animal infections. In contrast, there are strong arguments
against giving antibiotics to promote growth. The doses employed
for growth promotion are much lower than those used for infection, and hence are more likely to encourage emergence of
resistance. Moreover, since growth can be promoted by other
means, giving antibiotics for this purpose is unnecessary.
Essentially all of the antibiotics used in humans are used
in animals—including fluoroquinolones and third-generation
cephalosporins, agents that are among the most effective we
have. Because all antibiotics are being used, we are hastening
the day when all will be useless.
The story of virginiamycin and Synercid illustrates the
potentially serious consequences of giving antibiotics to farm
animals. Virginiamycin is a mixture of two streptogramins. For
30 years, the drug has been used to promote animal growth. In
1999, a mixture of two similar streptogramins—quinupristin
and dalfopristin, sold as Synercid—was approved for medical
use in the United States. Synercid is an extremely important
drug because it can kill vancomycin-resistant Enterococcus
faecium, a dangerous pathogenic strain that is resistant to all
other antibiotics. Unfortunately, agricultural use of virginiamycin
is likely to shorten Synercid’s useful life: A study of chickens
that were fed virginiamycin indicates that 50% of the birds
carried Synercid-resistant E. faecium. Sooner or later, these birds
will pass these resistant pathogens on to humans—if they haven’t
How can we reduce agriculture-related resistance? If we want
to delay emergence of resistance, and thereby extend the useful
life of our antibiotics, we must limit agricultural use of these
drugs. To this end, the World Health Organization has recommended that all antibiotics used by humans be banned from use
to promote growth in animals. In 2006, 15 countries in the
European Union complied, banning the use of all antibiotics
for growth promotion in livestock. The impact was entirely
positive, assuming the experience in Denmark applies to the
rest of Europe. In the late 1990s, Denmark banned the use of
antibiotics for growth promotion in pigs and chickens, with no
apparent detriment to either animal health or the incomes of
producers. Furthermore, within a few years after these drugs
were discontinued, rates of antibiotic resistance among farm
animals dropped dramatically. For example, resistance to avoparcin dropped from 73% to 5% in less than 5 years.
In the United States, public health and agriculture officials
have discussed and debated the issue for more than 30 years,
but no legislation has been enacted. In June 2013, legislation
was proposed to limit the use of antibiotics in livestock production. The bill was not enacted in 2013 or 2015, but was reintroduced into Congress in March 2017. If enacted, the Preventing
Antibiotic Resistance Act of 2017 would direct the U.S. Food
and Drug Administration (FDA) to restrict the use of antibiotics
critical to human health in livestock production unless they are
used to treat clinically diagnosable diseases.
And there is some hope. In 2005, the FDA took an important
step: For the first time, they banned the agricultural use of a
specific drug. The FDA ruling, which took effect September 12,
2005, banned the use of enrofloxacin [Baytril] in chickens and
turkeys. (Enrofloxacin is a fluoroquinolone similar to ciprofloxacin
[Cipro].) The ban was based on concerns that widespread use
of enrofloxacin in poultry was promoting resistance to ciprofloxacin and other fluoroquinolones in humans. This case is
significant in that it sets a precedent for FDA action against
other animal antibiotics.
Although wide-reaching restrictive rules are not yet in place,
they may, at long last, be forthcoming: In 2012, the FDA posted
its publication The Judicious Use of Medically Important
Antimicrobial Drugs in Food-Producing Animals as a “guidance,”
indicating that it no longer considers giving livestock antibiotics
to promote growth a “judicious use” of these drugs, implying
that it plans to ban the practice. Then, in 2013, the FDA followed
that guideline with one regarding the use of new animal drugs:
New Animal Drugs and New Animal Drug Combination Products
Administered in or on Medicated Feed or Drinking Water of
Food-Producing Animals. The FDA, however, continues to allow
use of antibiotics to treat or prevent the spread of disease—
provided such use is overseen by a veterinarian.
TABLE 83.4
Basic Principles of Antimicrobial Therapy
Antibacterial Drugs of Choice
Drug of First Choice
Some Alternative Drugs
Penicillin G or ampicillin with either
gentamicin or streptomycin
Vancomycin with either gentamicin or streptomycin,
quinupristin/dalfopristin, linezolid, daptomycin
Nitrofurantoin, penicillin, fosfomycin
A penicillinase-resistant penicillin
Vancomycin or daptomycin
A cephalosporin, vancomycin, imipenem, linezolid,
clindamycin, daptomycin, a fluoroquinolone
Linezolid, quinupristin/dalfopristin, tigecycline,
doxycycline, ceftaroline, trimethoprim/
Streptococcus pyogenes (group A) and
groups C and G
Penicillin G with clindamycin,
penicillin V
Vancomycin, erythromycin, clarithromycin,
azithromycin, daptomycin, linezolid, a
Streptococcus, group B
Penicillin G or ampicillin
A cephalosporin, vancomycin, erythromycin,
Streptococcus viridans group
Penicillin G or ampicillin
A cephalosporin, vancomycin
Streptococcus bovis
Penicillin G or ampicillin
A cephalosporin, vancomycin
Streptococcus, anaerobic
Clindamycin, vancomycin
Streptococcus pneumoniae
Penicillin G, penicillin V, amoxicillin
in susceptible strains
Resistant strains: a cephalosporin,
Erythromycin, azithromycin, clarithromycin,
levofloxacin, gemifloxacin, moxifloxacin,
meropenem, imipenem, ertapenem, trimethoprim/
sulfamethoxazole, clindamycin, a tetracycline,
Endocarditis and other severe
Uncomplicated urinary tract infection
Staphylococcus aureus or S. epidermidisa
Penicillinase producing
Methicillin resistant
Neisseria gonorrhoeae (gonococcus)
See Chapter 95
Neisseria meningitides (meningococcus)
Third-generation cephalosporin
Penicillin G, chloramphenicol, a sulfonamide, a
Bacillus anthracis (anthrax)
See Chapter 110
Clostridium difficile
See Chapter 85
Clostridium perfringens
Penicillin G, clindamycin
Metronidazole, chloramphenicol, imipenem,
meropenem, ertapenem
Clostridium tetani
Penicillin G, doxycycline
Corynebacterium diphtheriae
Penicillin G
Listeria monocytogenes
Ampicillin or penicillin G with or
without gentamicin
Campylobacter jejuni
Fluoroquinolones, azithromycin
Gentamicin, a tetracycline
Escherichia coli
Cefotaxime, ceftazidime, cefepime,
Ampicillin with or without gentamicin, ticarcillin/
clavulanic acid, trimethoprim/sulfamethoxazole,
imipenem, meropenem, others
Imipenem, meropenem, cefepime
Trimethoprim/sulfamethoxazole, gentamicin,
tobramycin, amikacin, ciprofloxacin, cefotaxime,
ticarcillin/clavulanic acid, piperacillin/tazobactam,
aztreonam, ceftazidime, tigecycline
Klebsiella pneumoniaea
Cefotaxime, ceftriaxone, cefepime,
Imipenem, meropenem, ertapenem, gentamicin,
tobramycin, amikacin, others
Proteus, indole positive (including
Providencia rettgeri and Morganella
Cefotaxime, ceftriaxone, cefepime,
Imipenem, meropenem, ertapenem, gentamicin, a
fluoroquinolone, trimethoprim/sulfamethoxazole,
Chemotherapy of Infectious Diseases
TABLE 83.4
Antibacterial Drugs of Choice—cont’d
Drug of First Choice
Some Alternative Drugs
Proteus mirabilis
A cephalosporin, ticarcillin, trimethoprim/
sulfamethoxazole, imipenem, meropenem,
ertapenem, gentamicin, others
Salmonella typhi
Ceftriaxone, a fluoroquinolone
Trimethoprim/sulfamethoxazole, ampicillin,
amoxicillin, chloramphenicol, azithromycin
Other Salmonella
Ceftriaxone, cefotaxime, a
Trimethoprim/sulfamethoxazole, chloramphenicol,
ampicillin, amoxicillin
Imipenem, meropenem
Gentamicin, amikacin, cefotaxime, a
fluoroquinolone, trimethoprim/sulfamethoxazole,
aztreonam, others
A fluoroquinolone
Trimethoprim/sulfamethoxazole, ampicillin,
ceftriaxone, azithromycin
Yersinia enterocolitica
A fluoroquinolone, gentamicin, tobramycin,
amikacin, cefotaxime
Imipenem, meropenem
An aminoglycoside, trimethoprim/sulfamethoxazole,
doxycycline, ciprofloxacin, ceftazidime,
ticarcillin/clavulanic acid, piperacillin/tazobactam
Imipenem, ertapenem, meropenem, amoxicillin/
clavulanic acid, ticarcillin/clavulanic acid,
piperacillin/tazobactam, ampicillin/sulbactam,
Bordetella pertussis (whooping cough)
Azithromycin, clarithromycin,
Brucella (brucellosis)
A tetracycline plus rifampin
A tetracycline plus either gentamicin or
streptomycin, trimethoprim/sulfamethoxazole with
or without gentamicin, chloramphenicol with or
without streptomycin, ciprofloxacin plus rifampin
Calymmatobacterium granulomatis
Doxycycline, trimethoprim/sulfamethoxazole, or
Francisella tularensis (tularemia)
See Chapter 110
Gardnerella vaginalis
Metronidazole (PO)
Topical clindamycin or metronidazole, clindamycin
Haemophilus ducreyi (chancroid)
Azithromycin, ceftriaxone
Ciprofloxacin, erythromycin
Haemophilus influenzae
Meningitis, epiglottitis, arthritis, and
other serious infections
Cefotaxime, ceftriaxone
Cefuroxime, chloramphenicol, meropenem
Helicobacter pylori
Clarithromycin plus amoxicillin plus
esomeprazole (a proton pump
Tetracycline plus metronidazole plus bismuth
subsalicylate plus esomeprazole (a proton pump
Legionella species
Azithromycin, clarithromycin
Doxycycline, trimethoprim/sulfamethoxazole,
erythromycin fluoroquinolone
Pasteurella multocida
Penicillin G
Doxycycline, a second- or third-generation
cephalosporin, amoxicillin/clavulanic acid,
Pseudomonas aeruginosaa
Urinary tract infection
Levofloxacin, piperacillin/tazobactam, ceftazidime,
cefepime, imipenem, meropenem, gentamicin,
tobramycin, amikacin, aztreonam
Ceftazidime, ciprofloxacin, imipenem, meropenem,
aztreonam, or cefepime, any one with or without
tobramycin, gentamicin, or amikacin
Other infections
Spirillum minus (rat bite fever)
Piperacillin/tazobactam (or ticarcillin/
clavulanic acid) with or without
tobramycin, gentamicin, or
Penicillin G, ceftriaxone
Doxycycline, streptomycin
TABLE 83.4
Basic Principles of Antimicrobial Therapy
Antibacterial Drugs of Choice—cont’d
Drug of First Choice
Some Alternative Drugs
Streptobacillus moniliformis (rat bite
Penicillin G, ceftriaxone
Doxycycline, streptomycin
Vibrio cholerae (cholera)
A tetracycline
Trimethoprim/sulfamethoxazole, a fluoroquinolone
Yersinia pestis (plague)
See Chapter 110
Mycobacterium tuberculosis
See Chapter 90
Mycobacterium leprae (leprosy)
See Chapter 90
Mycobacterium avium complex
See Chapter 90
Actinomycetes israelii
Penicillin G
Doxycycline, erythromycin, clindamycin
Sulfisoxazole, imipenem, meropenem, amikacin, a
tetracycline, linezolid, ceftriaxone, cycloserine
Chlamydia psittaci
Chlamydia trachomatis
See Chapter 95
Mycoplasma pneumoniae
Erythromycin, clarithromycin,
azithromycin, a tetracycline
A fluoroquinolone
Ureaplasma urealyticum
A tetracycline, clarithromycin, erythromycin,
Chloramphenicol, a fluoroquinolone
Borrelia burgdorferi (Lyme disease)
Doxycycline, amoxicillin, cefuroxime
Ceftriaxone, cefotaxime, penicillin G, azithromycin,
Borrelia recurrentis (relapsing fever)
A tetracycline, penicillin G
Penicillin G
Doxycycline, ceftriaxone
Rocky Mountain spotted fever, endemic
typhus (murine), trench fever, typhus,
scrub typhus, Q fever
Treponema pallidum (syphilis)
Penicillin G
Doxycycline, ceftriaxone
Treponema pertenue (yaws)
Penicillin G
Many of these drugs have resistant strains that must be treated with alternative antibiotics.
However, when the patient has a severe infection, we may
have to initiate treatment before test results are available. Under
these conditions, drug selection must be based on clinical
evaluation and knowledge of which microbes are most likely
to cause infection at a particular site. If necessary, a broadspectrum agent can be used for initial treatment. Once the
identity and drug sensitivity of the infecting organism have
been determined, we can switch to a more selective antibiotic.
When conditions demand that we start therapy in the absence
of laboratory data, it is essential that samples of exudates and
body fluids be obtained for culture before initiation of treatment;
if antibiotics are present at the time of sampling, they can
suppress microbial growth in culture and can thereby confound
Identifying the Infecting Organism
The first rule of antimicrobial therapy is to match the drug
with the bug. Hence, whenever possible, the infecting organism
should be identified before starting treatment. If treatment is
begun in the absence of a definitive diagnosis, positive identification should be established as soon as possible, so as to permit
adjustment of the regimen to better conform with the drug
sensitivity of the infecting organism.
The quickest, simplest, and most versatile technique for
identifying microorganisms is microscopic examination of a
Gram-stained preparation. Samples for examination can be
obtained from exudate, sputum, urine, blood, and other body
fluids. The most useful samples are direct aspirates from the
site of infection.
In some cases, only a small number of infecting organisms
will be present. Under these conditions, positive identification
may require that the microbes be grown out in culture. As
stressed earlier, material for culture should be obtained before
initiating treatment. Furthermore, the samples should be taken
in a fashion that minimizes contamination with normal body
flora. Also, the samples should not be exposed to low temperature, antiseptics, or oxygen.
Chemotherapy of Infectious Diseases
A relatively new method, known as the polymerase chain
reaction (PCR) test or nucleic acid amplification test, can detect
very low titers of bacteria and viruses. Testing is done by using
an enzyme—either DNA polymerase or RNA polymerase—to
generate thousands of copies of DNA or RNA unique to the
infecting microbe. As a result of this nucleic acid amplification,
there is enough material for detection. Microbes that we can
identify with a PCR test include important bacterial pathogens
(e.g., Clostridium difficile, Staphylococcus aureus, Mycobacterium tuberculosis, Neisseria gonorrhoeae, Chlamydia trachomatis, Helicobacter pylori) and important viral pathogens
(e.g., human immunodeficiency virus, influenza virus).
Compared with Gram staining, PCR tests are both more specific
and more sensitive.
Determining Drug Susceptibility
Owing to the emergence of drug-resistant microbes, testing
for drug sensitivity is common. However, sensitivity testing
is not always needed. Rather, testing is indicated only when
the infecting organism is one in which resistance is likely.
Hence, for microbes such as the group A streptococci, which
have remained highly susceptible to penicillin G, sensitivity
testing is unnecessary. In contrast, when resistance is common,
as it is with Staph. aureus and the gram-negative bacilli, tests
for drug sensitivity should be performed. Most tests used today
are based on one of three methods: disk diffusion, serial dilution,
or gradient diffusion.
Before sensitivity testing can be done, we must first identify
the microbe so that we can test for sensitivity to the appropriate
drugs. For example, if the infection is caused by Clostridium
difficile, we might test for sensitivity to metronidazole or
vancomycin. We would not test for sensitivity to aminoglycosides or cephalosporins—because we already know these
drugs won’t work.
Disk Diffusion
The disk-diffusion test, also known as the Kirby-Bauer test,
is performed by seeding an agar plate with a solution of the
infecting organism and then placing on the plate several paper
disks that have been impregnated with different antibiotics.
Because of diffusion, an antibiotic-containing zone becomes
established around each disk. As the bacteria proliferate, growth
will be inhibited around the disks that contain an antibiotic to
which the bacteria are sensitive. The degree of drug sensitivity
is proportional to the size of the bacteria-free zone. Hence, by
measuring the diameter of these zones, we can determine the
drugs to which the organism is more susceptible and the drugs
to which it is highly resistant.
Serial Dilution
In this procedure, bacteria are grown in a series of tubes containing different concentrations of an antibiotic. The advantage of
this method over the disk-diffusion test is that it provides a more
precise measure of drug sensitivity. By using serial dilution, we
can establish close estimates of two clinically useful values:
(1) the minimum inhibitory concentration (MIC), defined as
the lowest concentration of antibiotic that produces complete
inhibition of bacterial growth (but does not kill bacteria); and
(2) the minimum bactericidal concentration (MBC), defined
as the lowest concentration of drug that produces a 99.9%
decline in the number of bacterial colonies (indicating bacterial
kill). Because of the quantitative information provided, serial
dilution procedures are especially useful for guiding therapy
of infections that are unusually difficult to treat.
Gradient Diffusion
The gradient-diffusion procedure is similar to the disk-diffusion
procedure, but provides a more precise indication of MIC.
Like the disk-diffusion test, the gradient-diffusion test begins
with seeding an agar plate with the infecting organism. Then,
a narrow test strip, rather than a disk, is placed on the plate.
Unlike the disk, which is impregnated with just one concentration of an antibiotic, the strip is impregnated with 15 or
so different concentrations of the same antibiotic, such that
there is a concentration gradient that runs from low to high
along the length of the strip. Hence, as antibiotic diffuses
from the strip into the agar, the concentration of drug in the
agar establishes a gradient as well. Bacteria on the plate will
continue to grow until they reach a zone of the plate where
the antibiotic concentration is high enough to inhibit further
growth. The point where the zone of inhibition intersects the
strip, which is calibrated at short intervals along its length,
indicates the MIC.
In addition to matching the drug with the bug and determining
the drug sensitivity of an infecting organism, we must consider
host factors when prescribing an antimicrobial drug. Two host
factors—host defenses and infection site—are unique to the
selection of antibiotics. Other host factors, such as age,
pregnancy, and previous drug reactions, are the same factors
that must be considered when choosing any other drug.
Host Defenses
Host defenses consist primarily of the immune system and
phagocytic cells (macrophages, neutrophils). Without the
contribution of these defenses, successful antimicrobial therapy
would be rare. In most cases, the drugs we use don’t cure
infection on their own. Rather, they work in concert with host
defense systems to subdue infection. Accordingly, the usual
objective of antibiotic treatment is not outright kill of infecting
organisms. Rather, the goal is to suppress microbial growth
to the point at which the balance is tipped in favor of the host.
Underscoring the critical role of host defenses is the grim fact
that people whose defenses are impaired, such as those with
AIDS and those undergoing cancer chemotherapy, frequently
die from infections that drugs alone are unable to control.
When treating the immunocompromised host, our only hope
lies with drugs that are rapidly bactericidal, and even these
may prove inadequate.
Site of Infection
To be effective, an antibiotic must be present at the site of
infection in a concentration greater than the MIC. At some
sites, drug penetration may be hampered, making it difficult to achieve the MIC. For example, drug access can be
impeded in meningitis (because of the blood-brain barrier),
endocarditis (because bacterial vegetations in the heart are
difficult to penetrate), and infected abscesses (because of poor
vascularity and the presence of purulent material). When treating
meningitis, two approaches may be used: (1) We can select a
drug that readily crosses the blood-brain barrier, and (2) we
can inject an antibiotic directly into the subarachnoid space.
When exudate and other fluids hinder drug access, surgical
drainage is indicated.
Foreign materials (e.g., cardiac pacemakers, prosthetic joints
and heart valves, synthetic vascular shunts) present a special
local problem. Phagocytes react to these objects and attempt
to destroy them. Because of this behavior, the phagocytes are
less able to attack bacteria, thereby allowing microbes to
flourish. Treatment of these infections often results in failure
or relapse. In many cases, the infection can be eliminated only
by removing the foreign material.
Other Host Factors
Previous Allergic Reaction
Severe allergic reactions are more common with the penicillins
than with any other family of drugs. As a rule, patients with
a history of severe allergy to the penicillins should not receive
them again. The exception is treatment of a life-threatening
infection for which no suitable alternative is available. In
addition to the penicillins, other antibiotics (sulfonamides,
trimethoprim, erythromycin) are associated with a high incidence
of allergic responses. However, severe reactions to these agents
are rare.
Genetic Factors
As with other drugs, responses to antibiotics can be influenced
by the patient’s genetic heritage. For example, some antibiotics
(e.g., sulfonamides) can cause hemolysis in patients who,
because of their genetic makeup, have red blood cells that are
deficient in glucose-6-phosphate dehydrogenase. Clearly, people
with this deficiency should not be given antibiotics that are
likely to induce red cell lysis.
Genetic factors can also affect rates of metabolism. For
example, hepatic inactivation of isoniazid is rapid in some
people and slow in others. If the dosage is not adjusted accordingly, isoniazid may accumulate to toxic levels in the slow
metabolizers and may fail to achieve therapeutic levels in the
rapid metabolizers.
Success requires that the antibiotic be present at the site of
infection in an effective concentration for a sufficient time.
Dosages should be adjusted to produce drug concentrations
that are equal to or greater than the MIC for the infection
being treated. Drug levels 4 to 8 times the MIC are often
Duration of therapy depends on a number of variables,
including the status of host defenses, the site of the infection,
and the identity of the infecting organism. It is imperative that
antibiotics not be discontinued prematurely. Accordingly,
patients should be instructed to take their medication for the
entire prescribed course, even though symptoms may subside
before the full course has been completed. Early discontinuation
is a common cause of recurrent infection, and the organisms
Basic Principles of Antimicrobial Therapy
Life Stage
Patient Care Concerns
Infants are highly vulnerable to drug toxicity.
Because of poorly developed kidney and
liver function, neonates eliminate drugs
slowly. Use of sulfonamides in newborns can
produce kernicterus, a severe neurologic
disorder caused by displacement of bilirubin
from plasma proteins (see Chapter 88).
The tetracyclines provide another example of
toxicity unique to the young: These
antibiotics bind to developing teeth, causing
Antimicrobial drugs can cross the placenta,
posing a risk to the developing fetus. For
example, when gentamicin is used during
pregnancy, irreversible hearing loss in the
infant may result. Antibiotic use during
pregnancy may also pose a risk to the
expectant mother.
Antibiotics can enter breast milk, possibly
affecting the nursing infant. Sulfonamides,
for example, can reach levels in milk that are
sufficient to cause kernicterus in nursing
newborns. As a general guideline, antibiotics
and all other drugs should be avoided by
women who are breast-feeding.
Older adults
In the older adult, heightened drug sensitivity is
due in large part to reduced rates of drug
metabolism and drug excretion, which can
result in accumulation of antibiotics to toxic
responsible for relapse are likely to be more drug resistant
than those present when treatment began.
Therapy with a combination of antimicrobial agents is indicated
only in specific situations. Under these well-defined conditions,
the use of multiple drugs may be lifesaving. However, it should
be stressed that although antibiotic combinations do have a
valuable therapeutic role, routine use of two or more antibiotics
should be discouraged. When an infection is caused by a single
identified microbe, treatment with just one drug is usually
most appropriate.
Antimicrobial Effects of
Antibiotic Combinations
When two antibiotics are used together, the result may be
additive, potentiative, or, in certain cases, antagonistic. An
additive response is one in which the antimicrobial effect
of the combination is equal to the sum of the effects of
Chemotherapy of Infectious Diseases
the two drugs alone. A potentiative interaction (also called
a synergistic interaction) is one in which the effect of the
combination is greater than the sum of the effects of the individual agents. A classic example of potentiation is produced
by trimethoprim plus sulfamethoxazole, drugs that inhibit
sequential steps in the synthesis of tetrahydrofolic acid (see
Chapter 88).
In certain cases, a combination of two antibiotics may be
less effective than one of the agents by itself, inducing antagonism between the drugs. Antagonism is most likely when a
bacteriostatic agent (e.g., tetracycline) is combined with a
bactericidal drug (e.g., penicillin). Antagonism occurs because
bactericidal drugs are usually effective only against organisms
that are actively growing. Hence, when bacterial growth has
been suppressed by a bacteriostatic drug, the effects of a
bactericidal agent can be reduced. If host defenses are intact,
antagonism between two antibiotics may have little significance.
However, if host defenses are compromised, the consequences
can be dire.
Indications for Antibiotic Combinations
Initial Therapy of Severe Infection
The most common indication for using multiple antibiotics is
initial therapy of a severe infection of unknown etiology,
especially in the neutropenic host. Until the infecting organism
has been identified, wide antimicrobial coverage is appropriate.
Just how broad the coverage should be depends on the clinician’s
skill in narrowing the field of potential pathogens. Once the
identity of the infecting microbe is known, drug selection can
be adjusted accordingly. As discussed earlier, samples for culture
should be obtained before drug therapy starts.
Mixed Infections
An infection may be caused by more than one microbe. Multiple
infectious organisms are common in brain abscesses, pelvic
infections, and infections resulting from perforation of abdominal organs. When the infectious microbes differ from one
another in drug susceptibility, treatment with more than one
antibiotic is required.
Preventing Resistance
Although the use of multiple antibiotics is usually associated
with promoting drug resistance, there is one infectious disease—
tuberculosis—in which drug combinations are employed for
the specific purpose of suppressing the emergence of resistant
bacteria. Why tuberculosis differs from other infections in this
regard is discussed in Chapter 90.
Decreased Toxicity
In some situations, an antibiotic combination can reduce
toxicity to the host. For example, by combining flucytosine
with amphotericin B in the treatment of fungal meningitis, the
dosage of amphotericin B can be reduced, thereby decreasing
the risk of amphotericin-induced damage to the kidneys.
Enhanced Antibacterial Action
In specific infections, a combination of antibiotics can have
greater antibacterial action than a single agent. This is true of
the combined use of penicillin plus an aminoglycoside in the
treatment of enterococcal endocarditis. Penicillin acts to weaken
the bacterial cell wall; the aminoglycoside acts to suppress
protein synthesis. The combination has enhanced antibacterial
action because, by weakening the cell wall, penicillin facilitates
penetration of the aminoglycoside to its intracellular site of
Disadvantages of
Antibiotic Combinations
The use of multiple antibiotics has several drawbacks, including
(1) increased risk of toxic and allergic reactions, (2) possible
antagonism of antimicrobial effects, (3) increased risk of
superinfection, (4) selection of drug-resistant bacteria, and (5)
increased cost. Accordingly, antimicrobial combinations should
be employed only when clearly indicated.
Estimates indicate that between 30% and 50% of the antibiotics
used in the United States are administered for prophylaxis. That
is, these agents are given to prevent an infection rather than to
treat an established infection. Much of this prophylactic use
is uncalled for. However, in certain situations, antimicrobial
prophylaxis is both appropriate and effective. Whenever prophylaxis is proposed, the benefits must be weighed against the
risks of toxicity, allergic reactions, superinfection, and selection
of drug-resistant organisms. Generally approved indications
for prophylaxis are discussed here.
Prophylactic use of antibiotics can decrease the incidence
of infection in certain kinds of surgery. Procedures in which
prophylactic efficacy has been documented include cardiac
surgery, peripheral vascular surgery, orthopedic surgery, and
surgery on the GI tract (stomach, duodenum, colon, rectum,
and appendix). Prophylaxis is also beneficial for women
undergoing a hysterectomy or an emergency cesarean section.
In contaminated surgery (operations performed on perforated
abdominal organs, compound fractures, or lacerations from
animal bites), the risk of infection is nearly 100%. Hence, for
these operations, the use of antibiotics is considered treatment,
not prophylaxis. When antibiotics are given for prophylaxis,
they should be given before the surgery. If the procedure is
unusually long, dosing again during surgery may be indicated.
As a rule, postoperative antibiotics are unnecessary. For most
operations, a first-generation cephalosporin (e.g., cefazolin)
will suffice.
Bacterial Endocarditis
Individuals with congenital or valvular heart disease and those
with prosthetic heart valves are unusually susceptible to bacterial
endocarditis. For these people, endocarditis can develop following certain dental and medical procedures that dislodge
bacteria into the bloodstream. Thus, before undergoing such
procedures, these patients may need prophylactic antimicrobial
medication. However, according to guidelines released by the
American Heart Association, antibiotic prophylaxis is less
necessary than previously believed, and hence should be done
much less often than in the past.
Severe neutropenia puts individuals at high risk of infection.
There is some evidence that the incidence of bacterial infection
may be reduced through antibiotic prophylaxis. However,
prophylaxis may increase the risk of infection with fungi: By
killing normal flora, whose presence helps suppress fungal
growth, antibiotics can encourage fungal invasion.
Other Indications for
Antimicrobial Prophylaxis
For young women with recurrent urinary tract infection,
prophylaxis with trimethoprim/sulfamethoxazole may be helpful.
Oseltamivir (an antiviral agent) may be employed for prophylaxis against influenza. For individuals who have had severe
rheumatic endocarditis, lifelong prophylaxis may be needed.
Antimicrobial prophylaxis is indicated following exposure to
organisms responsible for sexually transmitted diseases (e.g.,
syphilis, gonorrhea).
Misuse of antibiotics is common. According to the CDC, about
50% of antibiotic prescriptions are either inappropriate or
entirely unnecessary. This fact is underscored by the data in
Table 83.5. Ways that we misuse antibiotics are discussed next.
Attempted Treatment of Viral Infection
The majority of viral infections—including mumps, chickenpox,
and the common cold—do not respond to currently available
drugs. Hence, when drug therapy of these disorders is attempted,
patients are exposed to all the risks of drugs but have no chance
of receiving benefits.
Acute upper respiratory tract infections, including the
common cold, are a particular concern. When these infections
are treated with antibiotics, only 1 patient out of 4000 is likely
to benefit. However, the risks remain high: 1 in 4 patients will
get diarrhea, 1 in 50 will get a rash, and 1 in 1000 will need
to visit an emergency department, usually because of a severe
allergic reaction.
Treatment of Fever of Unknown Origin
Although fever can be a sign of infection, it can also signify
other diseases, including hepatitis, arthritis, and cancer. Unless
TABLE 83.5
Basic Principles of Antimicrobial Therapy
the cause of a fever is a proven infection, antibiotics should not
be employed. If the fever is not due to an infection, antibiotics
would not only be inappropriate, they would expose the patient
to unnecessary toxicity and delay correct diagnosis of the fever’s
cause. If the fever is caused by infection, antibiotics could
hamper later attempts to identify the infecting organism.
The only situation in which fever, by itself, constitutes a
legitimate indication for antibiotic use is when fever occurs
in the severely immunocompromised host. Because fever may
indicate infection and because infection can be lethal to the
immunocompromised patient, these patients should be given
antibiotics when fever occurs—even if fever is the only indication that an infection may be present.
Improper Dosage
Like all other medications, antibiotics must be used in the
right dosage. If the dosage is too low, the patient will be
exposed to a risk of adverse effects without benefit of antibacterial effects. If the dosage is too high, the risks of superinfection
and adverse effects become unnecessarily high.
Treatment in the Absence of Adequate
Bacteriologic Information
As stressed earlier, proper antimicrobial therapy requires
information on the identity and drug sensitivity of the infecting
organism. Except in life-threatening situations, therapy should
not be undertaken in the absence of bacteriologic information.
This important guideline is often ignored.
Omission of Surgical Drainage
Antibiotics may have limited efficacy in the presence of foreign
material, necrotic tissue, or exudate. Hence, when appropriate,
surgical drainage and cleansing should be performed to promote
antimicrobial effects.
Antimicrobial therapy is assessed by monitoring clinical
responses and laboratory results. The frequency of monitoring
is directly proportional to the severity of infection. Important
clinical indicators of success are reduction of fever and resolution of signs and symptoms related to the affected organ
system (e.g., improvement of breath sounds in patients with
Examples of Inappropriate Antibiotic Prescriptions
Type of Infection
Prescriptions per Year
Percent Inappropriate
Common cold
18 million
16 million
Antibiotics are ineffective against bronchitis, except in a few
infections or in patients with chronic severe lung disease.
Sore throat
13 million
Antibiotics should be used only in patients with confirmed
strep infection.
13 million
Most cases are viral, not bacterial. In the absence of facial pain
or swelling, antibiotics should be withheld for about 10 days
to see whether symptoms improve without drugs.
Antibiotics are ineffective against the common cold.
Chemotherapy of Infectious Diseases
Various laboratory tests are used to monitor treatment.
Serum drug levels may be monitored for two reasons: to
ensure that levels are sufficient for antimicrobial effects and
to avoid toxicity from excessive levels. Success of therapy is
indicated by the disappearance of infectious organisms from
post-treatment cultures. Cultures may become sterile within
hours of the onset of treatment (as may happen with urinary
tract infections), or they may not become sterile for weeks (as
may happen with tuberculosis).
In antimicrobial therapy, the term selective toxicity refers
to the ability of a drug to injure invading microbes without
injuring cells of the host.
Narrow-spectrum antibiotics are active against only a few
microorganisms, whereas broad-spectrum antibiotics are
active against a wide array of microbes.
Bactericidal drugs kill bacteria, whereas bacteriostatic drugs
only suppress growth.
The emergence of resistance to antibiotics is a major concern
in antimicrobial therapy.
Mechanisms of resistance include increased drug efflux,
altered drug targets, and enzymatic inactivation of drugs.
Bacteria with the NDM-1 gene are resistant to nearly all
available antibiotics.
An important method by which bacteria acquire resistance
is conjugation, a process in which DNA coding for drug
resistance is transferred from one bacterium to another.
Antibiotics do not cause the genetic changes that underlie
resistance. Rather, antibiotics promote the emergence of
drug-resistant organisms by creating selection pressures
that favor them.
Broad-spectrum antibiotics promote the emergence of
resistance more than do narrow-spectrum antibiotics.
In the hospital, we can delay the emergence of antibiotic
resistance in four basic ways: (1) preventing infection, (2)
diagnosing and treating infection effectively, (3) using
antimicrobial drugs wisely, and (4) preventing patient-topatient transmission.
The use of antibiotics to promote growth in livestock is a
major force for promoting emergence of resistance.
Effective antimicrobial therapy requires that we determine
both the identity and drug sensitivity of the infecting
The minimum inhibitory concentration (MIC) of an
antibiotic is defined as the lowest concentration needed to
completely suppress bacterial growth.
The minimum bactericidal concentration (MBC) is defined
as the concentration that decreases the number of bacterial
colonies by 99.9%.
Host defenses—the immune system and phagocytic
cells—are essential to the success of antimicrobial therapy.
Patients should complete the prescribed course of antibiotic
treatment, even though symptoms may abate before the
full course is over.
Although combinations of antibiotics should generally be
avoided, they are appropriate in some situations, including
(1) initial treatment of severe infections, (2) infection with
more than one organism, (3) treatment of tuberculosis,
and (4) treatment of an infection in which combination
therapy can greatly enhance antibacterial effects.
Appropriate indications for prophylactic antimicrobial
treatment include (1) certain surgeries, (2) neutropenia,
(3) recurrent urinary tract infections, and (4) patients at
risk of bacterial endocarditis (e.g., those with prosthetic
heart valves or congenital heart disease).
Important misuses of antibiotics include (1) treatment of
viral infections (e.g., the common cold and most other
acute infections of the upper respiratory tract), (2) treatment
of fever of unknown origin (except in the immunocompromised host), (3) treatment in the absence of adequate
bacteriologic information, and (4) treatment in the absence
of appropriate surgical drainage.
Please visit http://evolve.elsevier.com/Lehne for chapterspecific NCLEX® examination review questions.
Drugs That Weaken the Bacterial
Cell Wall I: Penicillins
Introduction to the Penicillins, p. 1029
Mechanism of Action, p. 1029
Mechanisms of Bacterial Resistance, p. 1029
Chemistry, p. 1031
Classification, p. 1031
Properties of Individual Penicillins, p. 1032
Penicillin G, p. 1032
Penicillin V, p. 1035
Penicillinase-Resistant Penicillins
(Antistaphylococcal Penicillins), p. 1035
Broad-Spectrum Penicillins (Aminopenicillins),
p. 1035
Extended-Spectrum Penicillin (Antipseudomonal
Penicillin), p. 1036
Penicillins Combined With a Beta-Lactamase
Inhibitor, p. 1036
Key Points, p. 1037
Summary of Major Nursing Implications, p. 1037
Box 84.1. Methicillin-Resistant Staphylococcus
aureus, p. 1031
The penicillins are practically ideal antibiotics, because they
are active against a variety of bacteria and their direct toxicity
is low. Allergic reactions are the principal adverse effects.
Owing to their safety and efficacy, the penicillins are widely
Because they have a beta-lactam ring in their structure, the
penicillins are known as beta-lactam antibiotics. The beta-lactam
family also includes the cephalosporins, carbapenems, and
aztreonam (see Chapter 85). All of the beta-lactam antibiotics
share the same mechanism of action: disruption of the bacterial
cell wall.
Mechanism of Action
To understand the actions of the penicillins, we must first
understand the structure and function of the bacterial cell
wall—a rigid, permeable, mesh-like structure that lies outside
the cytoplasmic membrane. Inside the cytoplasmic membrane,
osmotic pressure is very high. Hence, were it not for the rigid
cell wall, which prevents expansion, bacteria would take up
water, swell, and then burst.
Penicillins weaken the cell wall, causing bacteria to take
up excessive amounts of water and rupture. As a result, penicillins are generally bactericidal. However, it is important to
note that penicillins are active only against bacteria that are
undergoing growth and division.
Penicillins weaken the cell wall by two actions: (1) inhibition of transpeptidases and (2) disinhibition (activation) of
autolysins. Transpeptidases are enzymes critical to cell wall
synthesis. Specifically, they catalyze the formation of crossbridges between the peptidoglycan polymer strands that form
the cell wall, and thus give the cell wall its strength (Fig. 84.1).
Autolysins are bacterial enzymes that cleave bonds in the cel…
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