Prinicples of antimicrobials

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Principles of Antimicrobial
Dr. Sameh Ahmad Muhamad abdelghany Lecturer Of
Clinical Pharmacology Mansura Faculty of medicine
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INTRODUCTION
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Objectives

1. Review the classification of antimicrobials
2. Define pharmacodynamic principles and their
   relationship to effective antimicrobial therapy
3. Discuss patient and drug related factors that
   influence the selection of the appropriate
   antimicrobial agent
4. Identify monitoring parameters to evaluate
   antimicrobial therapy

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What are Antimicrobials?

• Antimicrobials are drugs that destroy microbes,
  prevent their multiplication or growth, or
  prevent their pathogenic action
• Differ in their physical, chemical, and
  pharmacological properties
• Differ in antibacterial spectrum of activity
• Differ in their mechanism of action

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Classification of Antimicrobials

• According to source
• Natural compounds e.g.penicillin,
  chloramphenicol.
• Synthetic compounds e.g.sulfonamides,
  quinolones.
• Semisynthetic compounds e.g.ampicillin.

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• Accordingto the effect on microorganisms
• Bactericidal agents that kills the microorganism
  e.g. penicillin.
• Bacteriostatic agents arrest growth of the
  microorganism e.g. sulfonamides.

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• Accordingto the effect on microorganisms

• Inhibit cell wall synthesis
• Penicillins
• Cephalosporins
• Carbapenems
• Monobactams (aztreonam)
• Vancomycin
• Inhibit protein synthesis
• Chloramphenicol
• Tetracyclines
• Macrolides
• Clindamycin
• Quinupristin/dalfopristin
• linezolid
• Aminoglycosides

• Alter nucleic acid metabolism
• Rifamycins
• Quinolones
• Inhibit folate metabolism
• Trimethoprim
• Sulfamethoxazole
• Miscellaneous
• Metronidazole
• Daptomycin

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• Different mechanism of action for antimicrobials

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• According to antimicrobial spectrum
• Narrow spectrum drugs
• Drugs affect mainly Gram ve bacteria e.g. benzyl
  penicillin.
• Drugs affect mainly Gram ve bacteria e.g.
  aminoglycosides.
• Extended spectrum drugs
• agents that affect Gram ve Gram ve bacteria.
• Broad spectrum drugs
• agents act on wide range of Gram ve Gram ve
  bacteria and others (protozoa) e.g.
  tetracyclines.

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Antimicrobial therapy

• Empiric
• Infecting organism(s) not yet identified
• More broad spectrum
• Definitive
• Organism(s) identified and specific therapy
  chosen
• More narrow spectrum
• Prophylactic or preventative
• Prevent an initial infection or its recurrence
  after infection

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CLINICAL APPROACHES FOR RATIONAL PRESCRIBING OF
ANTIBIOTICS
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• Confirm the presence of an infection
• CAREFUL history and physical exam including
  relevant laboratory data and signs and symptoms
• Fever
• Is considered a hallmark of most infectious
  diseases.
• defined as elevated temperature gt37.2?C.
• May be present in absence of infection e.g. in
  autoimmune disorders and several malignancies.
• May be absent in presence of infection if the
  immune system is depressed.

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• White blood cell count
• Normal WBC is 4000-10,000 cells/mm3.
• Bacterial infections are associated with elevated
  granulocyte counts (neutrophils, basophils, and
  eosinophils).
• Viral, TB and fungal infections are associated
  with elevated lymphocytic count.
• Parasitic infections and allergic reactions are
  associated with increased eosinophilic count.
• Any swelling or erythema at a particular site
• Purulent drainage from a visible site
• Patient complaints

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• Selection of antimicrobial agents
• Identification of the infecting organism
• Infected body materials (e.g., blood, sputum,
  urine, wound drainage, etc.) must be sampled and
  cultured before initiating treatment.
• Empirical therapy before identification of the
  organism is necessary in the following
  conditions
• In all acutely ill patients with infections of
  unknown origin.
• Infection in a neutropenic patient, or a patient
  with meningitis.

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Culture Results

• Minimum inhibitory concentration (MIC)
• The lowest concentration of drug that prevents
  visible bacterial growth after 24 hours of
  incubation in a specified growth medium
• Organism and antimicrobial specific
• Report organism(s) and susceptibilities to
  antimicrobials
• Susceptible (S)
• Intermediate (I)
• Resistant (R)

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• Culture for micro-organism

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• Patient factors
• In neonates
• The use of chloramphenicol can lead to shock and
  cardiovascular collapse(gray baby syndrome).
• The use of sulfonamides may lead to kernicterus
  (brain damage)
• In growing children
• the use of fluoiroquinolones can lead to
  arthropathy
• - the use of tetracyclines can bind to growing
  bones and teeth resulting in abnormal teeth and
  bone formation.

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• In old age(gt65years)
• The incidence of renal toxicity with
  aminoglycosides is greater than in younger
  patients.
• In immunocompromised patients
• The use of bactericidal agents is necessary , as
  the hosts immune system is not capable of final
  elimination of the bacteria.
• Pregnancy
• Many antibiotics cross the placenta and cause
  adverse effects to the fetus e.g. aminoglycosides
  and tetracyclines.

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• Genetic or metabolic abnormalities
• Glucose-6-phosphate dehydrogenase (G6PD)
  deficiency
• Renal and hepatic function
• Accumulation of drug metabolized and/or excreted
  by these routes with impaired function
• risk of drug toxicity unless doses adjusted
  accordingly
• Renal excretion is the most important route of
  elimination for the majority of antimicrobials

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• Tissue penetration
• The capillary lining in some tissues e.g. brain
  form natural barriers to drug delivery due to
  presence of tight junctions of the capillary
  wall.
• Lipid soluble antibiotics e.g. chloramphenicol
  and metronidazole can cross these barriers in
  normal conditions. Penicillin is ionized at
  physiologic pH and cannot cross these barriers
  unless inflammation is present.
• Poor perfusion of some area
• e.g. diabetic foot, reduces the amount of
  antibiotic reaching this area, making treatment
  is difficult.

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• Determinants of the rational dosing
• Minimum inhibitory concentration (MIC)
•  
• The MIC is the lowest concentration of
  antibiotic in body tissues and fluids that
  inhibits bacterial growth.
• Concentration-dependent killing
• Certain antibiotics(e.g.aminoglycosides) show
  enhanced bacterial killing in concentration above
  the MIC.
• Giving these antibiotics by a single large dose
  per day achieves high peak levels and cause rapid
  killing of bacteria.

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• Time-dependent killing
•  
• depends on the time of the drug concentration to
  remain above the MIC. So, preparations with long
  duration kill more bacteria.
• e.g.ß-lactam antibiotics, macrolides,
  clindamycin, and linezolid
• Post-antibiotic effect (PAE)
• The PAE is a persistent bacterial suppression
  after levels of antibiotic fall below the MIC.
• Antimicrobials with long PAE(e.g. aminoglycosides
  and fluoroquinolones) usually require one dose
  per day.

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Monitoring

• Efficacy and toxicity of antimicrobials
• Clinical assessment
• Improvement in signs and symptoms
• Fever curve, ? WBC
• ? erythema, pain, cough, drainage, etc.
• Antimicrobial regimen
• Serum levels
• Renal and/or hepatic function
• Other lab tests as needed
• Consider IV to PO switch
• Microbiology reports
• Modify antimicrobial regimen to susceptibility
  results if necessary
• Narrow spectrum of antimicrobial if appropriate

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Other Drug Factors

• Adverse effect profile and potential toxicity
• Cost
• Acquisition cost storage preparation
  distribution administration
• Monitoring
• Length of hospitalization readmissions
• Patient quality of life
• Resistance
• Effects of the drug on the potential for the
  development of resistant bacteria in the patient,
  on the ward, and throughout the institution
• Drug Drug interactions

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ADVERSE EFFECTS OF ANTIMICROBIAL AGENTS
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• General adverse effects 
• Hypersensitivity or allergic reactions In form
  of fever, skin rash, arthralgia, cholestatic
  jaundice or hemolysis. More serious reactions are
  agranulocytosis, bone marrow aplasia or
  anaphylactic reaction.
• Reactions related to alterations in normal body
  flora, superinfection or vitamin B deficiency may
  follow the use of broad-spectrum antimicrobials.
  It is due to inhibition of bacterial flora that
  suppresses commensal micro-organisms which
  present in gut or that forms these vitamins,
  respectively.
• Resistance

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• Direct toxic reactions
• resulting from high doses or drug interactions,
  on liver, kidney, GIT, nervous system or CVS.

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SUPERINFECTION (Opportunistic infection)
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• Administration of antimicrobials usually alter
  bacterial flora but with no ill effect in most
  cases however, broad-spectrum antibiotics if used
  for long time may alter or kill bacterial flora.
  So, the bacteria and fungi that are normally
  inhibited by bacterial flora will multiply
  leading to superinfection (its early
  manifestation may by diarrhea).
• caused by staphylococci, Pseudomonas, proteus,
  Candida albicans or Clostridia difficile.

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Cont..

• Superinfection may be vaginal, oral, pharyngeal
  or even systemic infection e.g. staphylococcal
  enterocolitis, candidiasis or Pseudomembranous
  colitis(antibiotic-associated diarrhea).
• Treatment
• Stop the causative agent and give drug, which
  kill the organisms responsible for super
  infection e.g. staphylococcal enterocolitis,
  which is treated by metronidazole or vancomycin
  orally, antifungal nystatin for candidiasis.

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ANTIBIOTIC RESISTANCE
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• Innate resistance
•  
• Is a feature of a particular species of bacteria
  e.g Pseudomonas.
• The gene(s)of resistance can be transferred
  between bacteria by transfer of naked
  DNA(transformation),by conjugation with direct
  cell-to-cellt transfer of extrachromosomal
  DNA(plasmids), or through bacteriophage(transducti
  on)..

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• Acquired resistance
•  
• Occurs when bacteria that were sensitive to
  certain antibiotic become resistant with time.
• Mechanisms responsible
• Production of enzymes that inactivate the drug.
• Alteration of drug binding site.
• Reduction in drug uptake by the organism.
• Development of altered metabolic pathways.

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• Acquired Bacterial Resistance

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Drug-Drug interactions

• Influences the selection of appropriate drug
  therapy, the dosage, and necessary monitoring
• Drug interactions
• ? risk of toxicity or potential for ? efficacy of
  antimicrobial
• May affect the patient and/or the organisms
• Pharmacokinetic interactions
• Alter drug absorption, distribution, metabolism,
  or excretion
• Pharmacodynamic interactions
• Alter pharmacologic response of a drug
• Selection of combination antimicrobial therapy (?
  2 agents) requires understanding of the
  interaction potential

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COMBINATION OF ANTIBIOTICS

• Indications
• To obtain broader spectrum e.g.
  amoxicillinclavulanic acid? co-amoxiclav.
• To obtain synergism e.g. sulfonamides
  trimethoprim ? co-trimoxazole.
• In mixed bacterial infections e.g. diabetic foot
  or peritonitis.
• In serious bacterial infections e.g. bacterial
  meningitis or septicemia.
• To overcome bacterial resistance e.g.TB and
  pseudomonas infection.
• To reduce toxicity of one drug by using smaller
  doses of two drugs.

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Cont.

• Results
• Bactericidalbactericidal ? synergism
• e.g. penicillin with aminoglycosides.
• Bacteriostaticbacteriostatic ? addition
• e.g. tetracyclines with sulfonamides.
• Bactericidalbacteriostatic ?
• Antagonism e.g. penicillin with erythromycin
• Synergism e.g. sulfadiazine with penicillin

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GENERAL PRINCIPLES OF THERAPY WITH ANTIMICROBIALS
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• Antimicrobials should only be given when
  necessary and after antimicrobials susceptibility
  test whenever possible.
• The pharmacokinetics of the drug should be taken
  into consideration e.g. the state of hepatic and
  renal functions of the patient.
• In serious infection it is better to start with a
  parenteral loading of a bactericidal agent to
  avoid emergence of resistant strains by giving
  adequate dosage for sufficient duration and
  adapting proper combination regimens.
• Antimicrobials should be continued for 3 days
  after apparent cure is

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Summary

• Antimicrobials are essential components to
  treating infections
• Appropriate selection of antimicrobials is more
  complicated than matching a drug to a bug
• While a number of antimicrobials potentially can
  be considered, clinical efficacy, adverse effect
  profile, pharmacokinetic disposition, and cost
  ultimately guide therapy
• Once an agent has been chosen, the dosage must be
  based upon the size of the patient, site of
  infection, route of elimination, and other
  factors
• Optimize therapy for each patient and try to
  avoid patient harm
• Use antimicrobials only when needed for as short
  a time period as needed to treat the infection in
  order to limit the emergence of bacterial
  resistance

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Thank you!

• Any Questions?