ppt chapter 38

Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Chapter 38

Principles of Antimicrobial Therapy

Chapter 38

Principles of Antimicrobial Therapy


Question Question

• The first effective antimicrobial drug was

– A. Sulfa

– B. Penicillin

– C. Tetracycline

– D. Cephalosporin


AnswerAnswer

• B. Penicillin

• Rationale: Penicillin was the first effective antimicrobial agent.


Classification by Susceptible Organism 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 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.)Classification by Mechanism of Action (cont.)


Inhibition of Bacterial Cell Wall Synthesis 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 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 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 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 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 Question

• The most common location of resistant bacteria is

– A. Inner city apartments

– B. Homeless shelters

– C. Jails

– D. Hospitals


AnswerAnswer

• D. Hospitals

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


Antimicrobial Resistance 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 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.)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 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.)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) 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 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)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 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 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 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 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 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.)Drug Susceptibility (cont.)

• Disk diffusion test: This is the most commonly performed test to determine drug susceptibility.


Drug Susceptibility (cont.)Drug Susceptibility (cont.)

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


Drug SpectrumDrug 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.)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 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 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 InfectionSite 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 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.


QuestionQuestion

• ___________ is prescribing antibiotics before identification of the pathogen.

– A. Empiric therapy

– B. Standard of care

– C. Prophylactic therapy

– D. Inoculation therapy


AnswerAnswer

• 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 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.)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.

ppt chapter 38

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