General Rules of Antimicrobial Therapy

Choice of Antimicrobial

• Patient characteristics
• Cost
• Maximize benefit/risk ratio
• Ideal - bacteriologic diagnosis
• Sensitivity test Petri dish /w antibacterial disks [CR?]
• Best guess
• Mixed infections
• Life-threatening -- combos and broad spectrum till pathogens identified
• Use narrow spectrum if possible
• Use bactericidal drugs if possible

Antimicrobial sensitivity patterns

• Routine monitoring aids local ad hoc choices
• Variation by locale
• Published tables

TABLE: Facultative pathogens, common infections, and antimicrobial therapy

Name and Synonyms  Usual Site of      Typical Infections  Effective          
                   Infection                              Antibiotics        

Staphylococcus     Skin, upper        Boils, infected     Flucloxacillin,    
aureus, Coagulase  respiratory tract  wounds, mastitis,   clindamycin,       
positive                              purulent            (when sensitive,   
staphylococcus                        parotitis,          benzylpenicillin), 
                                      suppurative          erythromycin,     
                                      pneumonia,          vancomycin         
                                      antibiotic-induced                     
                                      enterocolitis,                         
                                      food poisoning,                        
                                      infections                             
                                      associated with                        
                                      foreign bodies,                        
                                      osteomyelitis                          

S. intermedius     Skin, urinary      cystitis, pyoderma  amoxacillin/clavul 
(dogs)             tract infections                       anic acid,         
                                                          oxacillin,         
                                                          enrofloxacillin,   
                                                          cephalothin        

                                                                             

Prophylaxis and Viral Infections

• Avoid general prophylaxis
• Target prophylaxis
• Hospital strains - often resistant
• Timing important

Selection Pressure

• Varies with drug
• Piperacillin < Ampicillin
• Broad spectrum drugs > narrow spectrum

Acquired Cross-Resistance Among Antimicrobials

• Also called parallel resistance
• Difference among members of same group of drugs
• Shift to which antimicrobial if resistance?
• Sensitivity testing -- prototype drug?
• Cross resistance common
  • tetracyclines
  • sulfonamides
  • neomycin and kanamycin (sub group of aminoglycosides)
  • natural and aminopenicillins if due to penicllinase
  • ampicillin and amoxicillin
  • all beta-lacams if "methicillin-resistant"
• Not common or predictable
  • aminoglycosides
  • beta-lactams in general

Pharmacokinetic Considerations

Absorption

• Drug
• Route
• Formulation
  • highly soluble
  • poorly soluble
  • Example - trihydrate & sodium salts of ampicillin
• Tailor to target infection & site

Distribution

• Barriers
• Difficult sites
  • CNS
  • eye
  • mammary gland
  • prostate
  • testis
  • intracellular
  • inflammatory "capsule"

Elimination

• Function of primary eliminating mechanism
• If slow -- accumulation & toxicity
• If fast -- insufficient concentration

Administration

• Route
• Dose form
• Dose
• Regimen

Route

• Considerations
  • cidal vs. static
  • MIC
  • Post-antibiotic effect
  • Induced resistance
• IV
  • Serious infections
  • bolus
  • infusion
• PO
  • Usually easy
  • Most common
  • Vomiting?
  • Bioavailability
• IM / SC
  • Widely used
  • Drug residues in food
  • Dose form
  • NO for Irritants / vesicants
• Topical
  • Not penetrate well
  • Avoid with strong allergens, e.g., beta-lactams
• Patient Tolerance
  • Topical -- ointment vs cream
  • GI distrubance
  • IV/IM > PO for serious allergic reactions
  • IV best for highly irritating drugs

Dosage

• Organism
• Site of infection
• Nature of infection (chronic / acute)
• Dose form
• Route of administration
• Regimen -- Dose / Dose interval
• Patient characteristics
  • age
  • species
• Therapeutic drug monitoring

Dose form

• Ampicillin - trihydrate vs sodium
  • Note relation to MICs
  • Ampicillin: Sodium vs trihydrate salt

  Regimen

  • Same daily dose
    • Ampicillin sodium q12h
    • Ampcillin sodium q8h
    • Ampicillin sodium q6h

  Duration of Treatment

  • As long as necessary
  • Norms for certain diseases
  • Client education
  • Acute vs chronic

  Antibiotic Combinations

  • Immunocompromised
  • Initial therapy severely ill patients
  • Guide initial choices for combinations
  • Clinical trial -- "gold standard"
  • Cidal / static

  Cidal/Static in Combination Antimicrobial Therapy

  The guiding principle is that one should not combine a "cidal" antibiotic with a "static" anibiotic in the therapy of the SAME PATHOGEN.

  /p>

    Efficacy of Combinations Against   
               Klebsiella              
  
                   Add--   Syner--  Ant-
                    %        %        %
  
  Cephalothin [c]                      
  plus --                              
  
  Kanamycin [c]      9       90      0    
  Gentamicin [c]     5       95      0    
  
  Chloramphenicol [s]                  
  plus --                              
  
  Kanamycin [c]      26      36     38    
  Gentamicin [c]     13      51     36    
  
  Add = Additive        Syner =   Synergistic
  Ant =   Antagonistic                         
  [c] = cidal     [s] = static         
  D'Alessandri et al., '76             
  
  
  

  ---

  • Cidal + static often antagonistic
  • Immunocompromised patients
  • Difficulty in showing antagonism in vivo

  Measuring Effects of Combinations In Vitro

  • 48 well plate
  • MIC
  • FIC
  • Assays to determine interaction

  Categories for Combination of Antimicrobials

  • Group I -- Bactericidal
    • Rapidly growing organisms
    • beta-lactams, aminoglycosides
  • Group II -- Bacteriostatic
    • tetracyclines
    • sulfonamides
    • lincosamides
    • macrolides
  • Effect of growth rate on antimicrobial action
  • Rule
    • Group I + Group I -- often synergistic
    • Group I + Group II -- often antagonistic
  • Exceptions
    • Mixed infections
    • Location of organism
    • Growth rate of organism
  • Increased deaths with combination
    • Lepper & Dowling '51, bacterial meningitis;
      Pen G alone 30% deaths
      Pen G + Chlortet 79% deaths

  Problems Created by Misuse of Antimicrobials

  • Facilitation of Development of Resistance
    • Imporoper dosage
    • Improper interval
    • Insufficient duration
    • Poor choice of drug
    • Use when not needed / prophylaxis
  • Development of Hypersensitivity
  • Superinfections
    • Importance of commensal organisms
    • Broad spectrum
    • Too long therapy
    • Interference with body defenses
  • Tissues residues
    • Public Health
    • Nurslings
  • Drug failure
  • Death of patient

  Properties of an Ideal Chemotherapeutic Agent

  1. be selective and have effective antimicrobial activity;
  2. be bactericidal and not easily induce bacterial resistance;
  3. have a satisfactory therapeutic ratio;
  4. not act as a sensitizing agent or disturb vital organs or functions;
  5. have antibacterial efficacy that is not reduced by body fluids, exudates, plasma proteins, or tissue enzymes;
  6. be water soluble and stable at room temperature (especially important in drugs used for mass therapy);
  7. have efficacy via various routes of administration, especially PO;
  8. achieve and maintain, with cost-effective doses, cidal levels in blood, tissue, and body fluids, e.g. CSF;
  9. produce bactericidal concentrations of drug in urinary tract;
  10. be neither carcinogenic nor have carcinogenic metabolites;
  11. be quickly cleared from the edible tissues and products of food producing animals; and
  12. have reasonable cost.

  Study Questions

  1. You should be able to list and discuss major problems created by the misuse of chemotherapeutic agents. What is the mechanism by which the misuse could contribute to each of the problems you mention? Do these apply to all categories of chemotherapeutic agents (e.g., antiparasitics or anticancer drugs?)
  2. How does one select a chemotherapeutic agent to use, initially, in a given case? For this question, focus on how one decides on the basis of efficacy only, ignoring safety and cost. These will be considered in separate steps. Be able to discuss at least two different means.
  3. What is an important consideration, in addition to the effect on the pathogen(s), that one must consider in the decision of whether to use a "broad" versus a "narrow" spectrum antimicrobial?
  4. Be able to discuss at least 3 factors that influence the decision as to which route is most appropriate for a certain antimicrobial agent and a given infectious episode?
  5. Why would experts recommend that for treatment of serious bacterial infections with intravenous therapy bactericidal drugs may be given by bolus, but bacteriostatic drugs should be given by infusion?
  6. Why is it of value to know whether a drug is "cidal" (bactericidal) or "static" (bacteriostatic) in its action against microorganisms? Be able to discuss the application of the "rules" for combining antimicrobial drugs including situations in which the rules are less applicable.
  7. What is meant by the terms Minimum Inhibitory Concentration (MIC), Minimum Bactericidal Concentration (MBC), Fractional Inhibitory Concentration (FIC)? What relevance do these values have to the determination of the dose that should be given to a patient?
  8. Is a total dose of a given antimicrobial drug "base" per day the most important consideration or must one consider dose interval, route, and dose form as well? Be able to discuss this issue and to provide a graphical example. (Note: drug "base" refers to the active portion of the drug preparation. For example, penicillin is available as the salt of potassium, sodium, procaine, and benzathine. Dosing penicillin on a mg/kg basis assuming that the active ingredient constitutes the same proportion of the total in all cases would constitute a serious error. Think about the difference between forumula weight and molecular weight.)
  9. Be able to discuss and apply the principles of antibacterial therapy contained in this document. When applying these principles on in-class and take-home exams, you should be able to explicitly identify the concept involved.
  10. You should be able to list 8 of the 12 properties of an ideal chemotherapeutic agent. Be able to describe why each of the factors is important and how it would contribute to more effective therapy.

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  Gordon L. Coppoc, DVM, PhD
  Professor of Veterinary Pharmacology
  Head, Department of Basic Medical Sciences
  School of Veterinary Medicine
  Purdue University
  West Lafayette, IN 47907-1246
  Tel: 317-494-8633Fax: 317-494-0781
  Email: coppoc@vet.purdue.edu
  
  Last modified 11:44 AM on 3/27/96 GLC