C h a p t e r 1 4
Mechanisms of Infectious Disease
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are interference with a specific step in bacterial cell wall
synthesis (e.g., penicillins, cephalosporins); inhibition of
bacterial protein synthesis (e.g., aminoglycosides, tet-
racyclines); interruption of nucleic acid synthesis (e.g.,
fluoroquinolones, nalidixic acid); and interference with
normal metabolism (e.g., sulfonamides, trimethoprim).
Of great concern is the increasing prevalence of bacte-
ria resistant to the effects of antibiotics. The mechanisms
by which bacteria acquire resistance to antibiotics include
the production of enzymes that inactivate antibiotics, such
as
β
-lactamases; genetic mutations that alter antibiotic
binding sites; alternative metabolic pathways that bypass
antibiotic activity; and changes in the filtration qualities
of the bacterial cell wall that prevent access of antibiot-
ics to the target site in the organism. It is the continuous
search for a “better mousetrap” that makes anti-infective
therapy such a fascinating aspect of infectious diseases.
Antiviral Agents
Until recently, few effective antiviral agents were avail-
able for treating human infections. The reason for this
is host toxicity; viral replication requires the use of
eukaryotic host cell enzymes, and the drugs that effec-
tively interrupt viral replication are likely to interfere
with host cell reproduction as well.
Almost all antiviral compounds are synthetic and,
with few exceptions, their primary target is viral RNA
or DNA synthesis. Like antibiotics, antiviral agents may
be active against RNA viruses only, DNA viruses only,
or occasionally both. A common class of antiviral drugs
is the nucleoside analogs, which include agents such as
acyclovir. These mimic the nucleoside building blocks
of RNA and DNA. During active viral replication, the
nucleoside analogs inhibit the viral DNA polymerase,
preventing duplication of the viral genome and thus
limiting the spread of infectious viral progeny to other
susceptible host cells.
In response to the AIDS epidemic, there has been mas-
sive, albeit delayed, development of antiretroviral agents
capable of targeting the replication of HIV, a retrovirus
(see Chapter 16). These include the nucleoside analogs
such as zidovudine as well as nonnucleoside inhibitors,
which impair the synthesis of the HIV-specific enzyme
reverse transcriptase. This key enzyme is essential for
viral replication and has no counterpart in the infected
eukaryotic host cells. Another class of antiviral agents
developed solely for the treatment of HIV infections
are the protease inhibitors. These drugs inhibit an HIV-
specific enzyme that is necessary for late maturation
events in the virus life cycle.
Antifungal Agents
The target site of the two most important families of
antifungal agents is the cytoplasmic membranes of
yeasts or molds. Fungal membranes differ from human
cell membranes in that they contain the sterol ergos-
terol instead of cholesterol. The polyene family of
antifungal compounds (e.g., amphotericin B, nystatin)
preferentially binds to ergosterol and forms holes in the
cell membrane, causing leakage of the fungal cell con-
tents and, eventually, lysis of the cell. The imidazole
class of drugs (e.g., fluconazole, itraconazole) inhibits
the synthesis of ergosterol, thereby damaging the integ-
rity of the fungal cytoplasmic membrane. Both types of
drugs bind to a certain extent to the cholesterol compo-
nent of host cell membranes and elicit a variety of toxic
side effects in treated patients.
A new class of antifungal agents known as the echi-
nocandins (e.g., caspofungin, micafungin, and anidula-
fungin) inhibit synthesis of the glucan in the cell wall,
preventing the fungal cell wall from cross-linking. The
lack of cross-linking causes the cell wall to become
unstable and eventually lyse. The echinocandins are pri-
marily active against
Candida
and
Aspergillus.
Surgical Interventions
Before the discovery of antimicrobial agents, surgical
removal of infected tissues, organs, or limbs was occa-
sionally the only option available to prevent the demise
of the infected host. Today, medicinal therapy with
antibiotics and other anti-infective agents is an effective
solution for most infectious diseases. However, surgi-
cal intervention is still an important option for cases in
which the pathogen is resistant to available treatments.
Surgical interventions may be used to hasten the recov-
ery process by providing access to an infected site by
antimicrobial agents (drainage of an abscess), cleaning
the site (débridement), or removing infected organs or
tissue (e.g., appendectomy). In some situations, surgery
may be the only means to a complete cure, as in the
case of endocarditis resulting in an infected heart valve,
in which the diseased valve must be replaced with a
mechanical or biologic valve to restore normal function.
In other situations, surgical containment of a rapidly
progressing infectious process such as gas gangrene may
be the only means of saving a person’s life.
SUMMARY CONCEPTS
■■
The goal for treatment of infectious disease is
complete removal of the infectious agent from
the host and restoration of normal physiologic
function to damaged tissues.
■■
Treatment methods include the use of
antimicrobial agents and, when necessary,
surgical interventions that provide access to an
infected site by antimicrobial agents (drainage
of an abscess), clean the site (débridement),
or remove infected organs or tissue (e.g.,
appendectomy).
