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Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
Chapter 38
Principles of Antimicrobial Therapy
Chapter 38
Principles of Antimicrobial Therapy
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
Question Question
• The first effective antimicrobial drug was
– A. Sulfa
– B. Penicillin
– C. Tetracycline
– D. Cephalosporin
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
AnswerAnswer
• B. Penicillin
• Rationale: Penicillin was the first effective antimicrobial agent.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
Classification by Mechanism of Action (cont.)Classification by Mechanism of Action (cont.)
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
Question Question
• The most common location of resistant bacteria is
– A. Inner city apartments
– B. Homeless shelters
– C. Jails
– D. Hospitals
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AnswerAnswer
• D. Hospitals
• Rationale: Hospitals are more likely than any other location to harbor resistant bacteria.
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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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
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.
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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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
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
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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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
Drug Susceptibility (cont.)Drug Susceptibility (cont.)
• Disk diffusion test: This is the most commonly performed test to determine drug susceptibility.
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Drug Susceptibility (cont.)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
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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
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.
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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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
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.
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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.
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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.
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
QuestionQuestion
• ___________ is prescribing antibiotics before identification of the pathogen.
– A. Empiric therapy
– B. Standard of care
– C. Prophylactic therapy
– D. Inoculation therapy
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
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.
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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.
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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.