Ppt chapter 38

Chapter 38
Principles of Antimicrobial
Therapy
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Question
• The first effective antimicrobial drug was
– A. Sulfa
– B. Penicillin
– C. Tetracycline
– D. Cephalosporin

Answer
• B. Penicillin
• Rationale: Penicillin was the first effective
antimicrobial agent.

Classification by Susceptible Organism
• A microbe is a unicellular or small multicellular organism.
• Microbes that are capable of producing disease are called
pathogens.
• Types of microbes include bacteria, viruses, protozoa,
some algae and fungi, and some worms (helminths).
• Drugs used to treat infection can be classified according
to the type of microbe they affect.
• The major classifications include antibacterial drugs,
antiviral drugs, antiretroviral drugs, antifungal drugs,
antiparasitic drugs, antiprotozoal drugs, and
antihelminthic drugs.

Classification by Mechanism of Action
• Antimicrobial drugs work in a variety of ways:
– Inhibition of bacterial cell wall synthesis
– Inhibition of protein synthesis
– Inhibition of nucleic acid synthesis
– Inhibition of metabolic pathways (antimetabolites)
– Disruption of cell wall permeability
– Inhibition of viral enzymes
• In addition to being classified by their mechanisms of
action as already listed, antibiotic drugs are further
classified as bacteriostatic or bacteriocidal.

Classification by Mechanism of Action
(cont.)

Inhibition of Bacterial Cell Wall Synthesis
• Bacteria have rigid cell walls containing complex
macromolecules, which are formed through biosynthetic
pathways.
• The osmotic pressure within the cell is very high and
relies on the integrity of the cell wall to resist the
absorption of water.
• Several antimicrobial drugs weaken the cell wall, allowing
the cell to absorb water, a process that causes bacterial
death.
• Penicillins and cephalosporins bind to specific proteins
located within the bacterial cytoplasmic membrane.

Inhibition of Protein Synthesis
• Ribosomes from human cells and those from bacterial
cells are structurally different.
• Tetracyclines bind to the 30S subunit of the bacterial
ribosome and block the attachment of aminoacyl-tRNA.
• Aminoglycoside antibiotics interact with the 30S
ribosomal subunit.
• Erythromycin and clindamycin interfere with translocation
reactions by binding to the 50S subunit of bacterial
ribosomes.
• Chloramphenicol also binds to the 50S ribosomal subunit.

Inhibition of Nucleic Acid Synthesis
• Many bacteria use enzymes for replication that do not
exist in human cells.
• Fluoroquinolones inhibit deoxyribonucleic acid (DNA)
gyrase, an enzyme needed for bacterial DNA replication.
• Inhibition of metabolic pathways (antimetabolites)
• Nucleic acid synthesis is dependent on folic acid (folate).
• Sulfonamides inhibit bacterial folate synthesis by acting
as an antimetabolite.

Disruption of Cell Wall Permeability
• Drugs that disrupt the integrity of the bacterial cell wall
cause the cell to leak components that are vital to its
survival.
• The polyene antimicrobials bind to membrane
components that are present only in microbial cells.
• The imidazole antifungal agents act as selective inhibitors
of enzymes involved in the synthesis of sterols.
• The replication of viruses requires multiple enzymatic
activities.
• Nucleoside analogues and protease inhibitors interrupt
important enzymes required for viral replication.

Selective Toxicity
• An important principle of antimicrobial therapy is
selective toxicity, which is the ability to suppress or kill
an infecting microbe without injury to the host.
• Selective toxicity is achievable because the drug
accumulates in a microbe at a higher level than in human
cells.
• The drug has a specific action on cellular structures or
biochemical processes that are unique to the microbe or
more harmful to the microbe.
• Understanding selective toxicity has made antimicrobial
drugs safe and effective for managing infection in
humans.

Question
• The most common location of resistant bacteria is
– A. Inner city apartments
– B. Homeless shelters
– C. Jails
– D. Hospitals

Answer
• D. Hospitals
• Rationale: Hospitals are more likely than any other
location to harbor resistant bacteria.

Antimicrobial Resistance
• Antimicrobial resistance refers to the resistance of the
microbe to the drug.
• Because of antimicrobial resistance, pharmaceutical
companies are constantly looking for new ways to
eradicate microbes despite the large number of
antimicrobial agents available.
• Antimicrobial resistance is a major problem, especially in
developed countries where antimicrobial agents are used
daily.

Contributing Factors
• Production of drug-inactivating enzymes: This
common mechanism causes resistance to many beta-lactam
antibiotics.
• Changes in receptor structure: These molecules may
undergo changes in their structures.
• Changes in drug permeation and transport: The
organism’s defense starts in the efficiency of its cell wall.
• Development of alternative metabolic pathways:
They act as antimetabolites by interrupting their
metabolic pathway.

Contributing Factors (cont.)
• Emergence of drug-resistant microbes: Ability to
promote the emergence of drug-resistant microbes.
• Spontaneous mutation: A change in the genetic
composition of the microbe that may just be a random
occurrence.
• Conjugation: A form of sexual reproduction in which
two individual microbes join in temporary union to
transfer genetic material.

Factors that Facilitate the Development of
Resistance
• Several factors facilitate the development of resistance.
– Drug concentrations in tissues that are too low to kill
resistant organisms contribute to the development of
resistance.
– The minimum inhibitory concentration (MIC) of a
drug must be present to stop or slow the replication
of the microbe.
– Inadequate tissue concentrations may occur because
of an improper dose of drug or improper length of
time between doses.

Factors that Facilitate the Development of
Resistance (cont.)
• Several factors facilitate the development of resistance.
(cont.)
– Insufficient duration of therapy may allow resistant
organisms to repopulate and re-establish an
infection.
– Patients frequently stop taking antibiotics when they
feel better.
– Prophylactic use of antibiotics may also contribute to
the development of resistant organisms.

Methicillin-Resistant Staphylococcus
Aureus (MRSA)
• In actuality, the pathogen is widely resistant to all of the
antistaphylococcic penicillins, not just methicillin.
• Many strains of MRSA are also resistant to aminoglycosides,
tetracyclines, erythromycin, and clindamycin.
• Closely related to MRSA is methicillin-resistant
Staphylococcus epidermidis (MRSE).
• MRSE frequently colonizes the nasal passages of health care
workers, resulting in the spread of nosocomial infections.
• Vancomycin is the drug of choice to manage infections
caused by MRSA and MRSE.

Penicillin-Resistant Streptococcus
Pneumoniae
• In the past, penicillins have successfully treated
pneumococcal infections.
• Because they are used so frequently, particularly in
children and the elderly, strains of penicillin-resistant
streptococci are emerging.
• To decrease penicillin resistance among Streptococcus
pneumoniae, the CDC suggested that
– Clinicians stop using drugs as prophylaxis for otitis
media.
– Patients at increased risk of infections, be
immunized.

Vancomycin-Resistant Enterococcus (VRE)
• Enterococcus is generally treated with a combination of
antibiotics: an aminoglycoside with a penicillin or an
aminoglycoside with a cephalosporin.
• The penicillin or cephalosporin damages the bacterial cell
wall and allows the aminoglycoside to penetrate the cell.
• Strains of Enterococcus have developed resistance to
penicillin, gentamicin, and vancomycin.

Multiple Drug–Resistant Mycobacterium
Tuberculosis (MDR-TB)
• Multiple drug–resistant TB is increasingly common.
• Although some of the bacilli are inherently resistant,
others develop resistance over the long course of TB
treatment, which can last as long as 2 years.
• The cause of MDR-TB is inadequate drug therapy.
• To decrease the incidence of MDR-TB, multiple drug
therapy is implemented at the onset of treatment,
followed by a decrease in the number of drugs.

Nosocomial Infections
• A nosocomial infection is an infection that originates or
occurs in a hospital or hospital-like setting.
• They occur because the hospital setting has a high
prevalence of pathogens, a high prevalence of
compromised hosts, and an efficient mechanism of
transmission from patient to patient.
• According to the World Health Organization, an estimated
2 million patients per year in the United States acquire a
nosocomial infection.
• Handwashing results in an immediate and profound
reduction in the spread of resistant bacteria.

General Considerations for Selecting
Antimicrobial Therapy
• The most important factor in managing infections is to
“match the drug with the bug.”
• Several factors must be considered when choosing the
drug of choice or an alternative:
– Identification of the pathogen
– Drug susceptibility
– Drug spectrum
– Drug dose
– Time to affect the pathogen
– Site of infection
– Patient assessment

Identification of the Pathogen
• To eradicate an infection, drugs must be specific to the
type of pathogen involved.
• The first step in the identification of the pathogen is
viewing a Gram-stained preparation under a microscope.
• A Gram stain is a simple test done with a dye and a glass
slide.
• A sample of the pathogen is obtained from body fluids,
sputum, blood, or exudates.
• The Gram stain indicates whether the pathogen is gram-positive
or gram-negative type.
• In some cases, the pathogen must be grown in a culture
medium for identification.

Drug Susceptibility
• To choose the right drug for the infection, a drug
susceptibility test is optimal.
• The site of infection is frequently a clue to the causative
agent.
• Prescribing antibiotic treatment before the pathogen has
been definitively identified is called empiric therapy.
• The most common test to identify drug susceptibility is
called a culture and sensitivity.

Drug Susceptibility (cont.)
• Disk diffusion
test: This is the
most commonly
performed test to
determine drug
susceptibility.

Drug Susceptibility (cont.)
• Broth dilution
procedure: The
bacteria are
inoculated into a
liquid medium
containing
graduated
concentrations of
the test
antimicrobial.

Drug Spectrum
• Choosing a drug with the narrowest possible spectrum is
important.
• The range of microbes against which a drug is active is
its spectrum.
• Narrow-spectrum drugs affect only a few
microorganisms, whereas broad-spectrum drugs affect
many microorganisms.
• An alternative to the use of broad-spectrum
antimicrobials is combination therapy.

Drug Spectrum (cont.)
• Combination therapy is used frequently for an initial
severe infection in which the pathogen is unknown.
• Once the pathogen is known, the appropriate drug can be
administered.
• Although combination therapy has many benefits, it also
has many disadvantages compared with monotherapy.

Drug Dose
• Choosing the antimicrobial agent with the lowest
effective dose is important.
• The dose of the antimicrobial agent is adjusted to affect
the MIC at the site of infection.
• Pediatric doses are calculated as mg/kg/day.

Duration
• Choosing the antimicrobial agent that takes the shortest
time to affect the pathogen is equally important.
• The drug must remain at the site of infection at drug
concentrations equal to or greater than MIC.
• The duration of treatment depends on the type of
pathogen, the site of infection, and the presence or
absence of host defenses.
• The duration of antimicrobial treatment is generally 7 to
10 days, but it may be extended to 30 days or more for
infections such as prostatitis.

Site of Infection
• To be effective, a drug must be able to reach the site of
infection at a concentration equal to or greater than the
MIC.
• Achieving this concentration is a particular problem when
the infection is in the meninges because many drugs do
not cross the blood–brain barrier.
• Another difficult site is within an abscess because
abscesses are poorly vascularized, and the presence of
pus impedes drug concentrations.
• Infections that occur in foreign objects, such as
pacemakers or prosthetic joints, are also difficult to treat.

Patient Assessment
• Health status: The type of antimicrobial agent chosen
must reflect the immune status of the patient.
• Life span and gender: Infants and the elderly are the
populations most vulnerable to drug toxicity.
• Environment: The severity of the infection may
influence the environment in which the antimicrobial is
administered.
• Culture and inherited traits: Certain genetic factors
may influence antimicrobial therapy.

Question
• ___________ is prescribing antibiotics before
identification of the pathogen.
– A. Empiric therapy
– B. Standard of care
– C. Prophylactic therapy
– D. Inoculation therapy

Answer
• A. Empiric therapy
• Rationale: Prescribing antibiotic treatment before the
pathogen has been definitively identified is called
empiric therapy.
• When multiple microbes may be the causative agent,
empiric therapy may be started, but a culture of the
infected area should be taken before treatment with
antimicrobial agents is started.

Monitoring Antimicrobial Therapy
• Successful antimicrobial therapy eradicates the infection.
• Some antimicrobial agents have the ability to induce
toxic adverse effects.
• Serum drug levels should be monitored for drugs that
have a high potential for severe adverse effects.
• In addition, serum peak and trough levels may be
measured.

Monitoring Antimicrobial Therapy (cont.)
• The goal is to keep the serum drug level within the
therapeutic margin.
• For patients receiving long-term or high-dose
antimicrobial therapy, other laboratory testing may be
indicated.
• The very young and the very old should also be
monitored closely.

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