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Ppt chapter 38

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Ppt chapter 38

  1. 1. Chapter 38 Principles of Antimicrobial Therapy Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
  2. 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. 3. Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins Answer • B. Penicillin • Rationale: Penicillin was the first effective antimicrobial agent.
  4. 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. 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
  6. 6. Classification by Mechanism of Action (cont.) Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
  7. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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

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