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Ppt chapter 38
- 1. Chapter 38
Principles of Antimicrobial
Therapy
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
- 2. Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
Question
• The first effective antimicrobial drug was
– A. Sulfa
– B. Penicillin
– C. Tetracycline
– D. Cephalosporin
- 3. Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
Answer
• B. Penicillin
• Rationale: Penicillin was the first effective
antimicrobial agent.
- 4. 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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
- 5. 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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
- 7. 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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
- 8. 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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
- 9. 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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
- 10. 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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
- 11. 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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
- 12. Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
Question
• The most common location of resistant bacteria is
– A. Inner city apartments
– B. Homeless shelters
– C. Jails
– D. Hospitals
- 13. Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
Answer
• D. Hospitals
• Rationale: Hospitals are more likely than any other
location to harbor resistant bacteria.
- 14. 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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
- 15. 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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
- 16. 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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
- 17. 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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
- 18. 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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
- 19. 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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
- 20. 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
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
media.
– Patients at increased risk of infections, be
immunized.
- 21. 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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
- 22. 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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
- 23. 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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
- 24. 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
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
- 25. 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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
- 26. 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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
- 27. Drug Susceptibility (cont.)
• Disk diffusion
test: This is the
most commonly
performed test to
determine drug
susceptibility.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
- 28. Drug Susceptibility (cont.)
• Broth dilution
procedure: The
bacteria are
inoculated into a
liquid medium
containing
graduated
concentrations of
the test
antimicrobial.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
- 29. 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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
- 30. 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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
- 31. Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
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.
- 32. 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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
- 33. 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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
- 34. 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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
- 35. Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
Question
• ___________ is prescribing antibiotics before
identification of the pathogen.
– A. Empiric therapy
– B. Standard of care
– C. Prophylactic therapy
– D. Inoculation therapy
- 36. Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
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.
- 37. 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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
- 38. 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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins