Basic concepts in choosing the right antimicrobial agent for therapy

1. General principles of
antimicrobial therapy
Class notes
Dr. Abialbon Paul

2. List of principles
• Selective toxicity
• Role of Pharmacokinetics
• Bacteriostatic vs Bactericidal
• Concentration dependent vs
Time dependent killing
• Post antibiotic effect
• Combination therapy
• Spectrum of action
• Superinfections
• Prophylactic therapy
• Empirical therapy
• Microbial sensitivity
• Mechanisms of resistance
• Host factors
• Disease states
• Organ function
• Adverse effects
• Drug interactions
• Cost factors
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3. Selectivity
• Target receptors/enzymatic processes selective to the pathogen
so that damage to the host is minimized
• Selectivity is relative, complete selectivity is not seen in the real
world
• Anticancer drugs and anti viral drugs tend to have more toxicity
because of homology of targets between host and pathogen
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Host
Pathogen

4. Targeting pathogens
4No need to memorize now

5. Pharmacokinetics
• ABSORBTION
• Oral route: non life threatening infections
• Intravenous route: serious life threatening infections
• Topical: localized infection
• DISTRIBUTION
• The drug must reach the required site of action at adequate dose in
adequate amounts in the active form for sufficient time
• Drugs are preferred depending on the organ involved
• Pus cavities are avascular; low concentrations of antibiotics are
achieved. Incision and drainage of pus is done prior to antibiotics.
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6. Pharmacokinetics
• Metabolism & Excretion
• Drugs are excreted either by the hepatic or renal system or both
• Drug levels increase in organ dysfunction
• Requires dose reduction or appropriate drug selection in hepatic or
renal disease
• Hence in renal dysfunction, drugs excreted by renal system require
dose reduction or change to a drug metabolized predominantly by
hepatic system (and vice versa)
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7. Bactericidal or Bacteriostatic
• -static drugs stop multiplication, body’s immune system clears
• -cidal drugs kill bacteria; hence preferred in
immunocompromised
• Classifications are not absolute
• Larger doses of –static drugs can become –cidal
• Combination of –static drugs can become –cidal
• Clinical relevance in combination therapy (see later)
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9. Concentration / Time dependent killing
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[Drug]
%Kill
0
20
40
60
80
100
Non-Concentration-Dependent
Concentration-Dependent
Time Above MBC
%Kill
0
20
40
60
80
100
Non-Time-Dependent
Time-Dependent

10. Concentration dependent
• Max kill depends on
concentration achieved
• High doses as shorter
infusions or lesser frequency
are better
• Has post antibiotic effect
Time dependent
• Max kill depends on time
achieved
• Optimal doses as longer
infusions or at higher
frequency
• No post antibiotic effect
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Conc.
Time Time
Conc.
Minimum bactericidal
concentration

11. Post antibiotic effect
• Also referred as HIT & RUN
• Antibiotic effect persists even after drug concentrations have
fallen below MIC (Minimum Inhibitory Concentration)
• Various mechanisms, common in Gram +ve
• Seen in drugs showing concentration dependent killing
• Decides the dosing regime (Once a day dosing is preferred)
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12. Spectrum of action
Broad spectrum
• Acts on wider class of
pathogens (e.g. Gram+ve &
gram-ve; Gram-ve &
anaerobics etc.)
• Used when unsure of
pathogen involved (empirical)
or in mixed infections
• Higher risk of superinfections
and resistance
Narrow spectrum
• Acts on a single class or a
single species of bacteria
(e.g. Gram+ve)
• Used when pathogen is
known and microbial
susceptibility is known
• Lesser risk of superinfection
and resistance
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13. Superinfections (Supra-infections)
• Infections caused by pathogenic strains present among normal
flora manifests because of generalized suppression of normal
flora by antibiotic
• Commonly seen with broad spectrum antibiotics
• Might arise in any site with normal flora (commonly in GIT)
• Major infections are: Intestinal candidiasis, Staph enterocolitis,
Pseudomembranous colitis
• (Read about probiotics)
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14. Microbial sensitivity
• Quantified in terms of minimum inhibitory concentration (MIC)
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Growth inhibited at lower
concentration of antibiotic
SUSCEPTIBLE
Growth inhibited at intermediate
concentrations of antibiotic
INTERMEDIATE SENSITIVITY
Growth inhibited at very
high concentrations of
antibiotic or not inhibited
RESISTANT

15. Development of resistance
• Only pathogens susceptible to chemotherapy and immune
system will be eradicated
• Resistant organisms get a growth advantage when susceptible
organisms are eradicated
• This means, theoretically, every antibiotic exposure is a chance
for development of resistance as antibiotics put a pressure
(survival of fittest) for selection of resistant organisms
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16. Mechanisms of resistance development
• Non genetic (Temporary)
• Genetic (Permanent)
1) Inactivation of drug by microbial enzymes
2) Decreased accumulation of drug by the microbe either by
-↑efflux -by P glycoprotein like protein or
-↓uptake -by porin like channel blockade
3) Reduced affinity of the target macromolecule for the
drug.
-Modified target in pathogen not affected by drug
-Increased production of target molecules
-Development of altered metabolic pathways to bypass target
4) Formation of biofilm
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17. Combination therapy
• Synergistic (1+1>2); Additive (1+1=2); Antagonistic (1+1<2)
• Combination of 2 –static drugs are usually addictive (exception
Sulfonamide with Trimethoprim is synergistic)
• Combination of 2 –cidal drugs with different MOA is additive or
synergistic
• Combination of –cidal + -static is ANTAGONISTIC (rarely additive if
organism is less sensitive to -cidal)
• e.g. Penicillin + Tetracycline ANTAGONISTIC
• but Rifampicin + Dapsone in leprosy is additive
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18. Combination therapy
• For enhanced therapeutic effect
• Lowers the dose of individual doses, hence reduces toxicity
• Delays appearance of resistance
• Mixed infections (to increase spectrum)
• Empirical therapy
• Serious infections
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19. Prophylactic therapy
• Treating patients at RISK
• Patients undergoing invasive procedure/ surgery
• Patients exposed to infectious agents/ patients
• Patients travelling to endemic countries
• Principles
• always directed towards a specific pathogen,
• no resistance should develop during the period of drug use,
• prophylactic drug use should be of limited duration,
• conventional therapeutic doses should be employed, and
• prophylaxis should be employed only in situations of documented drug
efficacy.
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20. Empirical therapy
• Patient is INFECTED but organism and susceptibility not known
• “In the mean time” – until investigation reports are available
• Principles
• Establish infection, evidence of infection and probable site
• Obtain samples for investigations BEFORE antibiotic initiation
• Consider most common microbiological diagnosis
• Determine need for empirical therapy
• Initiate antibiotics (Consider site, broad spectrum and host factors)
• Review investigations (change or continue)
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21. Host factors
• Organ systems
• Renal dysfunction (refer pharmacokinetics)
• Hepatic function
• Age
• Immune function
• Immunocompromised have poor outcome
• Tend to develop more resistance
• -cidal drugs preferred
• Tend to have mixed infections and atypical infections
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22. Host factors
• Toxicity
• Dose related toxicity
• Dose adjustments based on lab parameters and weight
• Hypersensitivity (Immune mediated)
• Idiosyncratic reactions
• Rare and unpredictable reactions
• Possibly because of genetically altered pharmacokinetics
• Host with previous antibiotic exposure
• Tend to have resistant organisms
• Community vs Hospital acquired
• Community acquired organisms are likely to be susceptible while hospital
acquired organisms are likely to be resistant
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23. Adverse reactions
• Certain categories have adverse effects on specific systems
• Ototoxic effect of aminoglycosides
• Anaphalactoid reactions, Red man syndrome by vancomycin due to
diffuse histamine release
• Renal toxicity and neuromuscular blockade by aminoglycosides
• Damage to cartilage by fluoroquinolones
• Hematopoietic toxicity by chloramphenicol
• Consider the side effect profile while choosing the drug
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24. A patient treated for months with large doses of broad spectrum antibiotics
would be most likely to develop which of the following?
A. Bleeding in joints
B. Bony abnormalities
C. Decreased night vision
D. Neurologic deficits
E. Scurvy
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Explanation:
The correct answer is A. To answer this question you have to identify two pieces of information.
First, you have to recognize that it is about vitamin deficiency acquired by antibiotic therapy (vitamin K is
made by bacteria in the gut) and then recognize the deficiency syndrome that would be produced
(bleeding tendency secondary to the inability to make clotting factors II, VII, IX, X, and proteins C and S).
The other vitamin/syndrome associations are as follows:
Vitamin D deficiency can lead to bony abnormalities (choice B).
Vitamin A deficiency can result in decreased night vision (choice C).
Vitamin B12 and thiamine deficiency can lead to neurological defects (choice D).
Vitamin C deficiency can lead to scurvy (choice E).

25. Drug interactions
• Broad spectrum antibiotics + warfarin
• Potentiation of bleeding tendency caused by warfarin
• Antibiotics + Oral contraceptive pills
• Possibility of contraceptive failure
• Possibility due to decrease in the entero-hepatic circulation of
estrogens
• Tetracyclines + Milk
• Reduced efficacy due to calcium chelation
• And many others…
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26. Cost of therapy
• Practical importance
• Higher costing antibiotics might result in lower adherence;
inadequate dosing and/or duration
• Consider the cost of entire therapy rather than a single unit of
drug
• e.g. Treatment with co-amoxiclav is cheap but requires treatment for 7-
10 days while azithromycin is costly but requires treatment for 3 days.
• Might vary depending on the brand chosen and disease
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27. Minimizing resistance
• Only use chemotherapeutic agents when they are clearly
indicated
• Use a narrow-spectrum drug known to be effective against the
pathogen, which is present
• Use an effective dose of the chemotherapeutic agent
• Ensure that the duration of chemotherapy is adequate
• Use older chemotherapeutic drugs whenever possible
• Use multiple drugs in combination chemotherapy when the
pathogen is noted to develop resistance to an individual drug
rapidly
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