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 Dedication
In memory of my parents, Ann and Wayne Southwick, and to my children Ashley, Peter, Robyn,
and Karli. And finally to my beautiful wife Kathie Southwick for her loving encouragement and
continual support.
 Contents

Contributors

Preface

Acknowledgments

1. Anti-Infective Therapy
Frederick S. Southwick, MD

2. Sepsis
Frederick S. Southwick, MD

3. The Febrile Patient

Frederick S. Southwick, MD

4. Pulmonary Infections
Frederick S. Southwick, MD

5. Eye, Ear, Nose, and Throat Infections

Frederick S. Southwick, MD

6. Central Nervous System Infections

Frederick S. Southwick, MD

7. Cardiovascular Infections
Frederick S. Southwick, MD

8. Gastrointestinal and Hepatobiliary Infections

Frederick S. Southwick, MD

9. Genitourinary Tract Infections and Sexually Transmitted Diseases

Frederick S. Southwick, MD

10. Skin and Soft Tissue Infections

P. Daniel Lew, MD and Frederick S. Southwick, MD
11. Osteomyelitis, Prosthetic Joint Infections, Diabetic Foot Infections, and
Septic Arthritis
P. Daniel Lew, MD and Frederick S. Southwick, MD

12. Parasitic Infections: A Global Challenge

Frederick S. Southwick, MD

13. Emerging Bacterial Infections (Including Zoonotic Pathogens and

Biological Weapons)
Frederick S. Southwick, MD

14. Serious Viral Illnesses in the Adult Patient

Sankar Swaminathan, MD

15. Infections in the Immunocompromised Host

Frederick S. Southwick, MD

16. HIV Infection

Bernard Hirschel, MD

Index
 Contributors

Bernard Hirschel, MD
Professor of Medicine
Division of Infectious Diseases
University of Geneva
Geneva, Switzerland

P. Daniel Lew, MD
Honorary Professor of Medicine
Geneva University
Geneva, Switzerland

Frederick S. Southwick, MD
Professor of Medicine
Department of Medicine
University of Florida College of Medicine
Gainesville, Florida

Sankar Swaminathan, MD
Don Merrill Rees Presidential Endowed Chair
Professor of Medicine
Chief of Infectious Diseases
University of Utah School of Medicine
Salt Lake City, Utah
 Preface
In 2003, when the first edition of this book was published, national magazines and newspapers
were declaring the end of the antibiotic era. Their warning continues to apply in 2019. The
incidence of infections due to multidrug-resistant (MDR) bacteria continues to rise and now
MDR infections represent a major cause of preventable harm in our hospitals. Clostridium
difficile colitis has spread to many of our most vulnerable patients as a consequence of continued
use of broad-spectrum antibiotics that allow this pathogen to overgrow and release cytotoxins
into the gastrointestinal tract. HIV remains a challenge throughout the world particularly in the
African continent.
Viruses and bacteria continue to emerge as threats to humans including MARS, Ebola virus,
and Zika virus. As a consequence of global warming the tick season has progressively
lengthened increasing the incidence of Lyme disease, Ehrlichia, and other tick-borne illnesses.
And global warming promises to increase the spread of other insect-borne infections including
malaria, Chikungunya virus, and Dengue fever.
As never before clinicians require a solid understanding of infectious diseases and a logical
and cost-effective approach to their diagnosis and treatment. In the United States the cost of
health care has become prohibitively high consuming over 18% of our gross domestic product
(GDP), and many of the anti-infectives required to treat MDR infections are extremely
expensive. Furthermore, these infections are associated with prolonged hospitalizations and a
higher risk of permanent harm or death. The era of the indiscriminate use of broad-spectrum
antibiotics is over. Antibiotic stewardship programs are now restricting the use of many of these
agents with the hopes of slowing the progressive selection of MDR bacteria and viruses. A
fundamental understanding of infectious diseases will allow the clinician to proactively order
high yield diagnostic tests and prescribe the proper anti-infective agents bypassing the need to
interact with the antibiotic stewardship program.
But how can the busy clinician and health professions student achieve this goal? Infectious
Diseases: A Clinical Short Course is designed to be read in 30 days. Below the title of each
chapter is a recommended time for completion. Key points are highlighted using text boxes to
encourage review and to enhance studying for specialty board and maintenance of certification
exams (MOCs). Tables summarize critical clinical presentations, antibiotic dosing and cost, anti-
infective toxicities, and figures demonstrate visually the spectrum of activity of each antibiotic.
Real cases are included in each chapter to illustrate the clinical presentation of each disease and
each case report is followed by an illness script (summary statement) to enhance pattern
recognition and improve diagnostic expertise. Chapter 2, “Sepsis,” has been completely rewritten
to reflect the 2016 consensus report. Chapter 3, “The Febrile Patient,” now includes a unique
approach to effective diagnosis and management that applies manufacturing value stream
mapping, illness scripts, tiered differential diagnosis, and Bayes’ theorem to more efficiently and
effectively arrive at the correct diagnosis for each infectious disease. This chapter describes how
“less is often more” and highlights the dangers of ordering excessive numbers of low-yield tests.
Chapter 4, “Pulmonary Infections,” highlights the use of respiratory multiplex PCR and the
discovery that the majority of pneumonias are viral in origin; the leading viral causes being the
common cold viruses, rhinovirus, and coronavirus. The latest diagnostic and therapeutic
approaches to tuberculosis are reviewed. Diagnosis and management recommendations follow
closely the Infectious Diseases of America (IDSA) guidelines. Chapters 5 and 6 update the
approaches to ENT, eye infections, and central nervous system infections. The more liberal use
of corticosteroids to blunt the excessive inflammatory response associated with meningitis is
now emphasized.
The recent IDSA guidelines for the treatment of endocarditis are included in Chapter 7 as are
the very recent IDSA guidelines for the management of C. difficile colitis in Chapter 8. Chapter 9
includes the latest CDC guidelines for sexually transmitted diseases, and Chapter 10 includes a
more logical classification of soft tissue infections that in turn encourages a more effective and
timely approach to differentiating infections that require surgical debridement. Chapter 11 covers
the latest IDSA guidelines for the management of prosthetic joint infections as well as a
comprehensive approach to the diagnosis and management of osteomyelitis.
Chapter 12 provides updates for the diagnosis and treatment of parasitic diseases and
includes life cycle diagrams that allow a clearer understanding of the epidemiology and clinical
presentations of these infections. Chapter 13 reviews the latest recommendations for zoonotic
emerging bacterial infections including Lyme disease, babesiosis, and rickettsial diseases.
Chapter 14 reviews serious viral infections other than HIV and now includes material on the
emerging viral pathogens—Ebola virus, MERS, and Zika virus—and also reviews the latest anti-
viral agents for influenza, herpes simplex, and CMV. Chapter 15 includes the latest IDSA
guidelines on the outpatient management of neutropenia and fever. This chapter also reviews the
increased risk for opportunistic infections associated with biological cytokine and lymphocyte
inhibitors that are now being widely prescribed for many inflammatory disorders. Finally,
Chapter 16 provides a succinct and timely update of the latest medications, diagnostic, and
treatment recommendations for HIV infection.
On completing this whirlwind tour of infectious diseases, the busy clinician and health
profession student will possess the knowledge and understanding to more judiciously prescribe
anti-infectives and to more efficiently and effectively diagnose and manage infectious diseases.
With this knowledge you can improve the health and wellbeing of your patients and save lives.
 Acknowledgments
I want to thank Morton Swartz, the former Chief of Infectious Diseases at the Massachusetts
General Hospital, for inspiring my love of infectious diseases, and Drs. James McGuigan, the
former Chairman of the Department of Medicine at the University of Florida, and Tom Stossel,
Professor of Medicine at the Harvard Medical School, who have patiently mentored me
throughout my career. I also thank Dr. Hernan Prieto, Assistant Professor of Orthopedics at the
University of Florida for his up-to-date information on prosthetic joint infections. I appreciate the
excellent and timely contributions by my colleagues and friends, Drs. Daniel Lew, Sankar
Swaminathan, and Bernard Hirschel. Finally, I want to thank James Shanahan of McGraw-Hill
for his continued support and guidance.
Chapter 1: Anti-Infective Therapy

Frederick S. Southwick

INTRODUCTION
GUIDING QUESTIONS

1. Are we at the end of the antibiotic era?

2. Why are “superbugs” continuing to increase in our hospitals?

3. How do bacteria become resistant to antibiotics?

4. How can the continued selection of highly resistant organisms be prevented?

5. Is antibiotic treatment always the wisest course of action?

6. Does one antibiotic cure all infections?

7. What are the strategies that underlie optimal antibiotic usage?

8. How is colonization distinguished from infection, and why is this distinction important?

Despite dire warnings in the 1990s that we were approaching the end of the antibiotic era, the incidence of
antibiotic-resistant bacteria has continued to rise. The proportions of penicillin-resistant and macrolide-
resistant Streptococcus pneumoniae, hospital-acquired methicillin-resistant Staphylococcus aureus
(MRSA), and community-acquired S. aureus (cMRSA) as well as vancomycin-resistant enterococci (VRE)
strains continue to steadily increase in many hospitals. Clostridium di icile colitis has reached epidemic
proportions and multiresistant Acinetobacter and Pseudomonas are everyday realities in most of our
hospitals. The pharmaceutical industry has been slow to develop new anti-infective agents to overcome
these highly resistant bacteria, and when they have been successful, the prices charged for these new
medications are consistently high. As never before, it is critical that health care providers understand the
principles of proper anti-infective therapy and use anti-infective agents judiciously. These agents need to
be reserved for treatable infections—not used to calm the patient or the patient’s family. Too o en
caregivers treat patients with antibiotics at the first sign of fever, and despite evidence suggesting a viral
infection and negative bacterial cultures they continue this treatment for prolonged periods.

Physicians unschooled in the principles of microbiology utilize anti-infective agents just as they would
prescribe other classes of medications, such as anti-inflammatory agents, antihypertensive medications,
and cardiac drugs. They use one or two broad-spectrum antibiotics to treat all patients with suspected
infections, and fail to consult an expert in infectious disease or utilize well-established guidelines to assist
in the proper management of anti-infective therapy.

Many excellent broad-spectrum antibiotics can e ectively treat most bacterial infections without requiring
a specific causative diagnosis. However, overuse of empiric broad-spectrum antibiotics has resulted in the
selection of highly resistant pathogens. A simplistic approach to anti-infective therapy and establishment
of a fixed series of simple rules concerning the use of these agents is unwise and has proved harmful to
patients. This approach ignores the remarkable adaptability of bacteria, fungi, and viruses. It is no
coincidence that these more primitive life forms have survived for millions of years, far longer than the
human race.

KEY POINTS

ABOUT ANTI-INFECTIVE THERAPY

1. Too o en, antibiotics are prescribed to fulfill the patient’s expectations, rather than to treat a true
bacterial infection.

2. A single antibiotic cannot meet all infectious disease needs.

3. Physicians ignore the remarkable adaptability of bacteria, fungi, and viruses at their patient’s peril.

4. Anti-infective therapy is dynamic and requires a basic understanding of microbiology.

5. The “shotgun” approach to infectious diseases must end, or we may truly experience the end of the
antibiotic era.

The rules for the use of anti-infective therapy are dynamic and must take into account the ability of these
pathogens to adapt to the selective pressures exerted by the overuse of antibacterial, antifungal, and
antiviral agents. The days of the “shotgun” approach to infectious diseases must end, or more and more
patients will become infected with multiresistant organisms that cannot be treated. In recognition of these
challenges antibiotic stewardship programs that limit the access to costly broad-spectrum antibiotics are
now mandated in all U.S. hospitals. Only through the judicious use of anti-infective therapy combined with
infection control measures can we hope to slow the arrival of the end of the antibiotic era.

ANTIBIOTIC RESISTANCE: GENETIC MODIFICATIONS LEADING TO

ANTIMICROBIAL RESISTANCE
To understand why antibiotics must be used judiciously, the physician needs to understand how bacteria
are able to adapt to their environment. Point mutations can develop in the DNA of bacteria as they
replicate. These point mutations as well as multiple resistance genes are found in bacteria that are part of
our natural environment and have existed for millions of years; however, these genes are of no survival
advantage unless the bacteria are placed under selective pressures. In the case of a mutation that renders a
bacterium resistant to a specific antibiotic, exposure to the specific antibiotic allows the bacterial clone
that possesses the antibiotic resistance mutation to grow, while bacteria without the mutation die and no
longer compete for nutrients. Thus, the resistant strain becomes the dominant bacterial flora.
Nonpathogenic environmental bacteria as well disease-causing bacteria can transfer antibiotic-resistant
genes by three mechanisms:

1. Conjugation. Bacteria o en contain circular, double-stranded DNA structures called plasmids. These
circular DNA structures lie outside the bacterial genome (Figure 1-1). Plasmids o en carry resistance
(“R”) genes. Through a mechanism called “conjugation,” plasmids can be transferred from one
bacterium to another. The plasmid encodes for the formation of a pilus on the donor bacteria’s outer
surface. The pilus attaches to a second bacterium and serves as bridge for the transfer of the plasmid
DNA from the donor to the recipient bacterium. Using this mechanism, a single resistant bacterium can
transfer resistance to other bacteria.
Figure 1-1
Mechanisms by which bacteria transfer antibiotic resistance genes.

2. Transduction. Bacteriophages are protein-coated DNA segments that attach to the bacterial wall and
inject DNA in a process called “transduction.” These infective particles can readily transfer resistance
genes to multiple bacteria.

3. Transformation. Donor bacteria can also release linear segments of chromosomal DNA, which is then
taken up by recipient bacteria and incorporated into the recipient’s genome. This process is called
“transformation,” and the naked DNA capable of incorporating into the genome of recipient bacteria as
a transposon or as an insertion sequence (Figure 1-1). Natural transformation most commonly occurs in
Streptococcus, Haemophilus, and Neisseria species. Transposons and insertion sequences can transfer
multiple antibiotic resistance genes in a single event and have been shown to be responsible for high-
level vancomycin resistance in enterococci.

KEY POINTS

ABOUT ANTIBIOTIC RESISTANCE

 1. Bacteria can quickly alter their genetic makeup by

a. point mutation.

b. transfer of DNA by plasmid conjugation.

c. transfer of DNA by bacteriophage transduction.

d. transfer of naked DNA by transposons or insertion sequences transformation.

2. The ability of bacteria to share DNA provides a survival advantage, allowing them to quickly adapt to
antibiotic exposure.

3. Biochemical alterations leading to antibiotic resistance include

a. degradation or modification of the antibiotic.

b. reduction in the bacterial antibiotic concentration by inhibiting entry or by e lux pumps.

c. modification of the antibiotic target.

4. Under the selection pressure of antibiotics, the question is not whether, but when resistant bacteria will
take over.

Thus, bacteria possess multiple ways to transfer their DNA, and they promiscuously share genetic
information. Virtually any part of a bacterium’s genome can be transferred, and this promiscuity provides a
survival advantage, allowing bacteria to quickly adapt to their environment.

BIOCHEMICAL MECHANISMS FOR ANTIMICROBIAL RESISTANCE

What are some of the proteins that these resistant genes encode for, and how do they work?

The mechanisms by which bacteria resist antibiotics can be classified into three major groups:

Degradation or modification of the antibiotic

Reduction in the bacterial antibiotic concentration

Modification of the antibiotic target

Degradation or modification of the antibiotic

β-Lactamases

Many bacteria synthesize one or more enzymes called β-lactamases that inactivate antibiotics by breaking
the amide bond on the β-lactam ring. Transfer of β-lactamase activity occurs primarily through plasmids
and transposons.

There are four major classes of β-lactamases (A, C, and D are serine proteases while the B class are zinc-
activated metalloproteases). Some preferentially break down penicillins (e.g., TEM-1 in Escherichia coli,
Pseudomonas, and Enterobacteraciae, and SHV-1 in E. coli and Klebsiella); others preferentially destroy
specific cephalosporins or carbenicillin. Extended-spectrum β-lactamases (ESBL, example: SHV-2) readily
destroy most cephalosporins, but are susceptible to β-lactamase inhibitors such as clavulanate. Other
classes of β-lactamases are resistant to clavulanate (CTX-M family and AmpC). Another major concern has
been the spread of bacteria that produce β-lactamases called carbapenemases that inactivate the
carbapenems (e.g., Klebsiella-producing carbapenemase, KPC, Oxa-type enzymes produced by
Acinetobacter).

Gram-negative bacilli produce a broader spectrum of β-lactamases than do gram-positive organisms, and
therefore infections with gram-negative organisms more commonly arise in patients treated for prolonged
periods with broad-spectrum antibiotics. In some instances, β-lactamase activity is low before the
bacterium is exposed to antibiotics; however, following exposure, β-lactamase activity is induced (AmpC
production can increase 10–100 fold). Enterobacter is a prime example. This gram-negative bacterium may
appear sensitive to cephalosporins on initial testing. Following cephalosporin treatment, β-lactamase
activity increases, resistance develops, and the patient’s infection relapses. For this reason, third-
generation cephalosporins are not recommended for serious Enterobacter infections.

Other enzyme modifications of antibiotics

Erythromycin is readily inactivated by an esterase that hydrolyzes the lactone ring of the antibiotic. This
esterase has been identified in E. coli. Other plasmid-mediated erythromycin-inactivating enzymes have
been discovered in Streptococcus species and S. aureus. Chloramphenicol is inactivated by
chloramphenicol acetyltransferase, which has been isolated from both gram-positive and gram-negative
bacteria. Similarly, aminoglycosides can be inactivated by acetyltransferases. Bacteria also inactivate this
class of antibiotics by phosphorylation and adenylation.

These resistance enzymes are found in many gram-negative strains and are increasingly detected in
enterococci, S. aureus, and Staphylococcus epidermidis.

Reduction in the bacterial antibiotic concentration

Interference with antibiotic entry

For an antibiotic to work, it must be able to penetrate the bacterium and reach its biochemical target.
Gram-negative bacteria contain an outer lipid coat that impedes penetration by hydrophobic reagents
(such as most antibiotics). The passage of hydrophobic antibiotics is facilitated by the presence of porins—
small channels in the cell walls of gram-negative bacteria that allow the passage of charged molecules.
Mutations leading to the loss of porins can reduce antibiotic penetration and lead to antibiotic resistance in
many gram-negative bacteria including Klebsiella, Acinetobacter, and Pseudomonas (loss of the OprD
channel). Following prolonged exposure to vancomycin, MRSA can develop a thickened cell wall requiring
higher vancomycin concentrations to inhibit bacterial growth (vancomycin intermediate S. aureus, VISA).

Production of e lux pumps

Transposons have been found that encode for an energy-dependent pump that can actively pump
tetracycline out of bacteria. Active e lux of antibiotics has been observed in many enteric gram-negative
bacteria, and this mechanism is used to resist tetracycline (TetA), macrolide (mef), aminoglycosides, and
fluoroquinolone antibiotic treatment (MexXY). S. aureus, S. epidermidis, Streptococcus pyogenes, group B
streptococci, and S. pneumoniae also can utilize energy-dependent e lux pumps to resist antibiotics.

Modification of the antibiotic target

Alterations of cell wall precursors

Alteration of cell wall precursors is the basis for VRE. Vancomycin and teicoplanin binding requires that D-
alanine–D-alanine be at the end of the peptidoglycan cell wall precursors of gram-positive bacteria.
Resistant strains are found predominantly in Enterococcus faecium and less commonly in Enterococcus
faecalis containing the vanA or vanB transposon that encodes a protein that synthesizes D-alanine–D-
lactate instead of D-alanine–D-alanine at the end of the peptidoglycan precursor. Loss of the terminal D-
alanine markedly reduces vancomycin and teicoplanin binding, allowing the mutant bacterium to survive
and grow in the presence of these antibiotics. Fortunately, the transfer of these transposons to S. aureus is
exceedingly rare.

Changes in target enzymes

Penicillins and cephalosporins bind to specific proteins called penicillin-binding proteins (PBPs) in the
bacterial cell wall. Penicillin-resistant S. pneumoniae demonstrate decreased numbers of PBPs or PBPs
that bind penicillin with lower a inity, or both. Decreased penicillin binding reduces the ability of the
antibiotic to kill the targeted bacteria.

The basis for antibiotic resistance in MRSA is production of a low-a inity PBP2a encoded by the mecA gene.
Mutations in the target enzymes dihydropteroate synthase and dihydrofolate reductase respectively cause
sulfonamide and trimethoprim resistance. Single amino-acid mutations that alter DNA gyrase function can
result in resistance to fluoroquinolones.

Alterations in ribosomal binding site

Tetracyclines, macrolides, lincosamides, and aminoglycosides all act by binding to and disrupting the
function of bacterial ribosomes (see the descriptions of individual antibiotics later in this chapter). A
number of resistance genes encode for enzymes that methylate adenine residues on bacterial ribosomal
RNA, inhibiting antibiotic binding to the ribosome (e.g., erm gene methylates the macrolide ribosomal
binding site). Ribosomal resistance to gentamicin, tobramycin, and amikacin is less common because these
aminoglycosides have several binding sites on the bacterial ribosome and require multiple bacterial
mutations before their binding is blocked.

CONCLUSIONS
Bacteria can readily transfer antibiotic-resistant genes. Bacteria have multiple mechanisms to destroy
antibiotics, lower the antibiotic concentration, and interfere with antibiotic binding. Under the selective
pressures of prolonged antibiotic treatment, the question is not whether, but when resistant bacteria will
take over.

ANTI-INFECTIVE AGENT DOSING

The pharmacokinetic characteristics that need to be considered when administering antibiotics include
absorption (when dealing with oral antibiotics), volume of distribution, metabolism, and excretion. These
factors determine the dose of the drug and the time interval of administration. To e ectively clear a
bacterial infection clinicians also need to be familiar with pharmacodynamic characteristics of each anti-
infective agent: their mechanisms of action and their biological e ects. Depending on the class of
antibiotics, serum levels of the antibiotic need to be maintained above the minimum inhibitory
concentration (MIC) for a significant period. For each pathogen, the MIC is determined by serially diluting
the antibiotic into liquid medium containing 104 bacteria per milliliter. Inoculated tubes are incubated
overnight until broth without added antibiotic has become cloudy or turbid as a result of bacterial growth.
The lowest concentration of antibiotic that prevents active bacterial growth—that is, the liquid media
remains clear—constitutes the MIC (Figure 1-2). Automated analyzers can now quickly determine, for
individual pathogens, the MICs for multiple antibiotics, and these data serve to guide the physician’s choice
of antibiotics.

Figure 1-2
Understanding the minimum inhibitory concentration and the minimal bactericidal concentration.

Clinical laboratories utilize MIC combined with studies examining achievable antibiotic levels
(pharmacokinetics and pharmacodynamics) in humans to determine whether an organism is sensitive,
intermediate, or resistant to a specific antibiotic. This value is called the breakpoint or cuto , and is the
concentration (MIC) above which there is a high likelihood of treatment success, and below which there is
considerable risk of failure. At the present time, di erent countries and di erent organizations utilize
di erent criteria to determine breakpoints, and experts strongly recommend the acceptance of an
international standard for calculating breakpoints.
The mean bactericidal concentration (MBC) is determined by taking each clear tube and inoculating a plate
of solid medium with the solution. Plates are then incubated to allow colonies to form. The lowest
concentration of antibiotic that blocks all growth of bacteria—that is, no colonies on solid medium—
represents the MBC. Because this method is technically cumbersome, this value is now rarely determined.

Successful cure of an infection depends on multiple host factors in addition to serum antibiotic
concentration. However, investigators have attempted to predict successful treatment by plotting serum
antibiotic levels against time. Two parameters have found to correlate with cure in both animal and human
studies (Figure 1-3): time above the MIC (T > MIC), and the ratio of the area under the curve (AUC) to the MIC
(AUC/MIC).

Figure 1-3
Pharmacokinetics of a typical antibiotic. Dashed area shows the area under the curve above the MIC. Peak
is also called the Cmax.

Cure rates for β-lactam antibiotics are maximized by maintaining serum levels above the MIC for >50% of
the time. Peak antibiotic concentrations are of less importance for these antibiotics, and serum
concentrations above eight times the MIC are of no benefit other than to enhance penetration into less
permeable body sites.

Unlike β-lactam antibiotics, aminoglycosides and fluoroquinolones demonstrate concentration-dependent

killing. In vitro studies show that these antibiotics demonstrate greater killing the higher their
concentrations exceed the MIC. High peak levels of these antibiotics are more e ective than low peak levels
for curing infections. Therefore, for treatment with aminoglycosides and fluoroquinolones AUC/MIC is most
helpful for maximizing e ectiveness. For fluoroquinolones, best outcomes in community-acquired
pneumonia may be achieved when the AUC/MIC is >34.

Maintenance of a high AUC/MIC has recently been shown to be a critical factor for preventing the
development of antibiotic resistance particularly in Pseudomonas aeruginosa and other nonfermenting
gram-negative bacteria (Acinetobacter baumannii, Stenotrophomonas maltophilia, and Burkholderia
cepacia). This serum antibiotic concentration has been called the mutant protection concentration (MPC).
For P. aeruginosa, an AUC/MIC of approximately 200 is required. To prevent the development of
fluoroquinolone resistance to S. pneumoniae, in vitro studies have suggested that AUC/MIC should be >50.

KEY POINTS

ABOUT ANTIBIOTIC DOSING

1. Absorption, volume of distribution, metabolism, and excretion all a ect serum drug levels and
represent the pharmacokinetic characteristics of the anti-infective agent.

2. A pharmacodynamic characteristic that needs to be considered when choosing an anti-infective agent

is the minimum inhibitory concentration (MIC).

3. To maximize success with β-lactam antibiotics, serum antibiotic levels should be above the MIC for at
least 50% of the time (T > MIC > 50%).

4. To maximize success with aminoglycosides and fluoroquinolones, high-peak concentration and high
AUC/MIC ratio are recommended.

5. Development of resistance can be prevented by

a. administering su iciently high doses of antibiotics to achieve very high AUC/MIC ratios, 50–200
depending on the organism, called the mutant protection concentration (MPC).

b. short courses of antibiotic, ideally 5 days or less.

In nature, intrinsic resistance is found in 1 out of every 106 organisms; therefore, the likelihood of selecting
for a resistant pathogen also depends on the concentration of bacteria in the infected organ. In pneumonia
and intra-abdominal infections, bacterial counts are o en ≥109; therefore, achieving a high AUC/MIC is
most important for these infections. In patients with sepsis as well as for infections caused by
Pseudomonas, many experts recommend utilizing two antibiotics (double coverage) in order to increase
the likelihood of killing the resistant bacterial population.

A third factor that increases the likelihood of resistance is the duration of exposure to an anti-infective
agent. The number of resistant bacteria remains low early in the course of antibiotic treatment; however,
when the AUC/MIC is insu iciently high within 4–5 days, resistant bacteria begin to increase in
concentration. The longer the exposure, the greater the likelihood resistant bacteria will predominate.
Many experts now agree that from the standpoint of resistance, antibiotic regimens of 5 days or less would
be ideal. In the normal host, neutrophils work in concert with antibiotics to kill infecting organisms. And
when the concentration of organisms drops to 102–103/g of tissue, neutrophils alone are capable of
eradicating the infection. In many instances, 5 days of antibiotic treatment will reduce bacterial
concentrations to this level allowing neutrophils to clean up the remaining pathogenic bacteria.

BASIC STRATEGIES FOR ANTIBIOTIC THERAPY

The choice of antibiotics should be carefully considered. A step-by-step logical approach is helpful (Figure
1-4). Given the complexity of these decisions, to assure that each of these factors is considered a
mandatory checklist for the treatment of severely ill-hospitalized patients promises to increase survival
and reduce antibiotic resistance (Figure 1-5).

Figure 1-4
Algorithm for the initial use of anti-infective therapy.
Figure 1-5
Antibiotic checklist.
1. Decide Whether the Patient Has a Bacterial Infection

One test that has traditionally been used to di erentiate an acute systemic bacterial infection from a
viral illness is the peripheral white blood cell (WBC) count. In patients with serious systemic bacterial
infections, the peripheral WBC count may be elevated and may demonstrate an increased percentage of
neutrophils. On occasion, less mature neutrophils such as band forms and, less commonly,
metamyelocytes are observed on peripheral blood smear. Most viral infections fail to induce a
neutrophil response. Viral infections, particularly Epstein–Barr virus, induce an increase in lymphocytes
or monocytes (or both) and may induce the formation of atypical monocytes. Unfortunately, the
peripheral WBC count is only a rough guideline, lacking both sensitivity and specificity, and serum
procalcitonin concentration has been found to be a far more accurate test for di erentiating bacterial
 from viral infection. In response to bacterial infection, this precursor of calcitonin is synthesized and
released into the serum by many organs of the body; production of interferon (IFN) in response to viral
infection inhibits its synthesis. The serum procalcitonin test can be of prognostic value, serum
procalcitonin levels being particularly high in severe sepsis. Serum levels can also be used to monitor
the response to antibiotic therapy and are expected to decrease as the infection resolves (see Chapter
2).

2. Make a Reasonable Statistical Guess as to the Possible Pathogens

Based on the patient’s symptoms and signs, as well as on laboratory tests, the anatomic site of the
possible infection can o en be determined. For example, burning on urination, associated with pyuria
on urinalysis, suggests a urinary tract infection. The organisms that cause uncomplicated urinary tract
infection usually arise from the bowel flora. They include E. coli, Klebsiella, and Proteus. Antibiotic
treatment needs to cover these potential pathogens. Later chapters review the pathogens commonly
associated with infections at specific anatomic sites and the recommended antibiotic coverage for
those pathogens. These recommendations are based on the Infectious Diseases Society of America
(IDSA) treatment guidelines, and the IDSA treatment guidelines
(http://www.idsociety.org/IDSA_Practice_Guidelines/) should always be consulted to assure that
patients receive the most up-to-date treatment. Renowned experts in the field of infectious diseases
created these guidelines based on careful scrutiny of current clinical and biomedical research.

3. Be Aware of the Antibiotic Susceptibility Patterns in Your Hospital and Community

In patients who develop infection while in hospital (“nosocomial infection), empiric therapy needs to
take into account the antibiotic susceptibility patterns of the flora associated with the hospital and the
floor where the patient became ill. Many hospitals have a high incidence of MRSA, and therefore empiric
antibiotic treatment of a possible staphylococcal infection must include vancomycin, pending culture
results. Other hospitals have a large percentage of Pseudomonas strains that are resistant to
gentamicin, eliminating that antibiotic from consideration as empiric treatment of possible gram-
negative sepsis. In many communities, individuals who have never been hospitalized are today
presenting with so tissue infections caused by cMRSA, and physicians in these communities must
adjust their empiric antibiotic selection (see Chapter 10).

4. Take into Account Previous Antibiotic Treatment

The remarkable adaptability of bacteria makes it highly likely that a new pathogen will be resistant to
previously administered antibiotics. If the onset of the new infection was preceded by a significant
interval when antibiotics were not given, the resident flora may have recolonized with less resistant
flora. However, the reestablishment of normal flora can take weeks, and patients in hospital are likely to
recolonize with highly resistant hospital flora.

5. Take into Consideration Important Host Factors

a. Peripheral WBC count. Patients with neutropenia have a high mortality rate from sepsis. Immediate
broad-spectrum, high-dose intravenous antibiotic treatment is recommended as empiric therapy
for these patients.

b. Age. Elderly patients tend to metabolize and excrete antibiotics more slowly; longer dosing intervals
are therefore o en required. Agents with significant toxicity (such as aminoglycosides) should
generally be avoided in elderly patients because they exhibit greater toxicity.
 c. Hepatic and renal dysfunction. Antibiotics metabolized primarily by the liver should generally be
avoided or reduced in patients with significant cirrhosis. In patients with significant renal
dysfunction, antibiotic doses need to be modified.

d. Duration of hospitalization. Patients who have just arrived in the hospital tend to be colonized with
community-acquired pathogens; patients who have been in the hospital for prolonged periods and
have received several courses of antibiotics tend to be colonized with highly resistant bacteria and
with fungi.

e. Severity of the patient’s illness. The severely ill patient who is toxic and hypotensive requires broad-
spectrum antibiotics; the patient who simply has a new fever without other serious systemic
complaints can usually be observed o antibiotics.

6. Switch to Narrower-Spectrum Antibiotic Coverage Within 3 Days

(Table 1-1, Figure 1-6). Within 3–4 days following the administration of antibiotics, sequential cultures
of mouth flora and genomic analysis of the bowel flora reveal that the numbers and types of bacteria
begin to change significantly. The microbiome found in healthy individuals quickly changes and less
beneficial organisms including resistant gram-negative rods, gram-positive cocci, and fungi begin to
predominate. The more quickly the selective pressures of broad-spectrum antibiotic coverage can be
discontinued, the lower the risk of selecting for highly resistant pathogens. Broad coverage is
reasonable as initial empiric therapy until cultures are available. By the third day, the microbiology
laboratory can generally identify the pathogen or pathogens, and a narrower-spectrum-specific
antibiotic regimen can be initiated. Despite the availability of culture results, clinicians too o en
continue the same empiric broad-spectrum antibiotic regimen, and that behavior is a critical factor in
explaining subsequent infections with highly resistant superbugs. Normal bowel flora has also been
shown to be important for e ective immune and bowel function, and loss of these beneficial organisms
should be minimized whenever possible. Figure 1-6 graphically illustrates the spectrum of available
antibiotics as a guide to the antibiotic choice.

Figure 1-6
Antibiogram of all major antibiotics.