General principles of antimicrobial therapy

Class notesDr. Abialbon Paul

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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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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

Host

Pathogen

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Targeting pathogens

No need to memorize now

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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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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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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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Concentration / Time dependent killing

[Drug]

% K

ill

0

20

40

60

80

100

Non-Concentration-DependentConcentration-Dependent

Time Above MBC

% K

ill

0

20

40

60

80

100

Non-Time-DependentTime-Dependent

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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

Conc.

Time Time

Conc.

Minimum bactericidal concentration

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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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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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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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Microbial sensitivity

• Quantified in terms of minimum inhibitory concentration (MIC)

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 inhibitedRESISTANT

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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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Mechanisms of resistance development• Non genetic (Temporary) • Genetic (Permanent)

1) Inactivation of drug by microbial enzymes2) Decreased accumulation of drug by the microbe either by -↑efflux -by P glycoprotein like protein or

-↓uptake -by porin like channel blockade3) 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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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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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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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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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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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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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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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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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 jointsB. Bony abnormalitiesC. Decreased night visionD. Neurologic deficitsE. Scurvy

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).

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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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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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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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