General Principles of Antimicrobial Chemotherapy

MS-I Core Pharmacology

General Principles of Antimicrobial Therapy

Reading Assignment

Reading Katzung Chapter 51, pp.901-913

Reading objectives: Apply the five steps in the “Approach to Empiric

Therapy” to a clinically-relevant case scenario. Describe a “rule of thumb” for duration of

antimicrobial therapy in febrile patients.

PPT Learning Objectives

1. Describe “selective toxicity”.

2. Apply the five key things to consider in selection of antibiotics to a clinically-relevant case scenario.

3. Apply one combination and one single broad-spectrum antibiotic to be used for empiric therapy to a clinically-relevant case scenario.

4. Explain how “selective toxicity” is critical for antibiotic action giving 3 possible ways target action is distinguished from host action.

5. Apply 4 general sites of antibiotic action to a clinically-relevant case scenario.

Conceptual Overview Part 1

I. Selecting anti-microbials

II. Empiric therapy

III. Achieving selective toxicity

IV. Sites of anti-microbial action

V. Narrow- versus broad-spectrum

Chemotherapy The use of chemicals against invading organisms (e.g.,

bacteria). The term is used for both treatment of infection and cancer.

Antibiotic A chemical that is produced by a microorganism and has

the ability to harm other microbes. Selective toxicity

The ability of a drug (chemical) to injure a target cell or organism without injuring other cells or organisms that should not be injured.

I. Selection of antimicrobial agents Selection of the most appropriate

antimicrobial agents require knowledge of: The organism’s identity and its sensitivity

to a particular agent. The site of infection The safety of the agent Patient factors The cost of therapy

Follow guidelines:

Most infectious disease physicians follow CDC sites for outbreaks, guidelines, and resistance development on a regular basis http://www.cdc.gov/CDCForYou/public_health

_professionals.html Guidelines and protocols—for example Many medical societies create guidelines. For

infectious diseases it is the IDSA whose website is: http://www.idsociety.org

II. Empiric therapy

Empiric (or presumptive) therapy is use of antimicrobial agents before the pathogen for a particular illness is known.

It is often based on experience with a particular clinical entity.

It is justified if evidence demonstrates that early intervention will improve outcome.

Approach to Empiric Therapy (See page 902 K&T and Reading objective)

1. Clinical diagnosis

2. Obtain specimens for lab

3. Microbiologic diagnosis

4. Is ET necessary?

5. Institute treatment

III. Selective toxicity

Kill the germs not the patient

How is “selective toxicity” achieved?

Disruption of thebacterial cell wall

Inhibition of an enzyme

unique to bacteria

Disruption of bacterial

protein synthesis

Characteristics of Selective Toxicity

1. Unique target must be present in pathogen, absent in host.

2. Target must be structurally different in pathogen than in host.

3. Or target must be more important in pathogen than in host.

I. Disruption of the bacterial cell wall Unlike mammalian cells, bacteria are encased in

a rigid cell wall. If it were not for cell wall, bacteria would absorb

water, swell, and then burst. Several families of drugs such as penicillins,

cephalosporins, act to weaken the cell wall and thereby promote bacterial lysis.

Since mammalian cells have no cell wall, drugs directed at this structure do not affect the host.

IV. Sites of Antibiotic action

Structure of Bacterial Cell Wall

II. Inhibition of an enzyme unique to bacteria The sulfonamides provide an excellent example. The enzyme that the sulfonamides inhibit is

needed by bacteria for production of folic acid, a compound required for synthesis of essential molecules (DNA, RNA, and protein).

The folic acid used by mammalian cells is acquired directly from dietary sources.

In contrast, bacteria lack the ability to take up folic acid from their environment.

Inhibition of an enzyme unique to bacteria

In bacteria

para-aminobenzoic acid (PABA)

Folic acid

Sulfonamides suppress bacterial growth by inhibitingan enzyme required to synthesize folic acid from PABA.

Since mammalian cells do not synthesize folic acid, toxicityof sulfonamides is selective for microbes.

Sulfonamides

Dihydropteroate synthase

Dihydrofolate reductase

Inhibition of sequential steps in the synthesis of tetrahydrofolic acid

(compete with PABA)

III. Disruption of bacterial protein synthesis Synthesis of proteins employs cellular

components called ribosomes.

IV. Inhibition of nucleic acid DNA gyrase

V. Inhibition of membrane function Fungal membranes

Sites of antibiotic action (cont’d)

V. Classification of antimicrobial drugs Narrow Spectrum

Gram-positive cocci and gram-negative bacilli

Penicillin G and V Penicillinase-resistant penicillins: nafcillin,

methicillin Vancomycin Erythromycin Clindamycin

Gram-negative aerobes Aminoglycosides (e.g., gentamicin) Cephalosporins (e.g., 2nd generation)

V. Classification of antimicrobial drugs Broad Spectrum

Gram-positive & negative microorganisms Broad-spectrum penicillins such as ampicillin Extended-spectrum penicillins such as

carbenicillin Cephalosporins (third generation) Tetracyclines Imipenem Trimethoprim Sulfonamides: sulfamethoxazole Fluoroquinolones: ciprofloxacin, norfloxacin

MIC and MBC

An anti-microbial should be present in concentrations such that it can either inhibit bacterial growth (above minimal inhibitory concentration; MIC) or

Kill the organism (above the minimal bactericidal concentration; MBC).

Learning Objectives Part Two

6. List the 3 things (in a phrase each) that determine an anti-microbial’s effectiveness against organisms.

7. Apply the possible relationship of resistance to mechanisms controlling active transport across a bacteria’s cell membrane to a clinically-relevant case scenario.

8. Describe how efflux pumps can confer resistance to antibiotics and give 3 antibiotic classes affected by such resistance.

9. Apply superinfection to a clinically-relevant case scenario.

Learning Objectives Part Two10. Apply 3 principal factors to consider in

choosing an appropriate antibiotic to a clinically-relevant case scenario.

11. Describe 3 particular conditions in which a primary drug of choice would not be used.

12. Apply conditions when sulfonamides should not be used to a clinically-relevant case scenario.

13. Apply 2 reasons to use antibiotic combinations to a clinically-relevant case scenario.

Learning Objectives Part Two14. Apply a synergistic interaction of 2

antimicrobials to a clinically-relevant case scenario.

15. Apply an antagonistic interaction of 2 antimicrobials to a clinically-relevant case scenario.

Conceptual overview part 2

I. Susceptibility versus resistance

II. Superinfection

III. Selection of anti-microbials

IV. Combinations of anti-microbials

V. Disadvantages & prophylactic use

I. FACTORS THAT DETERMINE THE SUSCEPTIBILITY & RESISTANCE OF MICROORGANISMS TO ANTIMICROBIAL AGENTS

1. Failure of drug to reach its target

2. Drug inactivation

3. Target alteration

Failure of drug to reach its target The outer membrane of gram-negative

bacteria is a barrier that excludes large polar molecules from entering the cell.

Small polar molecules, including many antibiotics, enter the cell through protein channels called porins.

Slow drug entry into a cell via a porin Mutation can cause loss or blockage of a

favored porin

Failure of drug to reach its target If the target is intracellular and the drug

requires active transport across the cell membrane, resistance can result from mutations that inhibit this transport mechanism.

Example: Gentamicin Targets the ribosome Is actively transported across the cell

membrane using energy provided by the membrane electrochemical gradient.

Failure of drug to reach its target Gentamicin, continued;

The electrochemical gradient is generated by specific enzymes that couple electron transfer and oxidative phosphorylation. A mutation in the above pathway or

anaerobic conditions slows entry of gentamicin into the cell, resulting in resistance.

Failure of drug to reach its target Bacteria also have efflux pumps that can

transport drugs, such as the following, out of cells. – Resistance:

Tetracyclines Chloramphenicol Fluoroquinolones Macrolides Beta-lactam antibiotics

Failure of drug to reach its target

Sometimes an antibiotic is metabolized in the body and sometimes not.

For example, lower urinary tract antibiotics must get through blood into urine intact to have effect.

Drug inactivation Bacterial resistance to aminoglycosides

and b-lactam antibiotics usually results from production of enzymes that modify or destroy the antibiotic, respectively.

A variation in this mechanism Sometimes the prodrug depends on the

bacteria to convert to an active form. For example, Mycobacterium tuberculosis

converts isoniazid, if it loses that ability then resistance develops.

Drug Resistance (Handout)

Rapid Development of Resistance to Newly Introduced Antibacterial Agents

Agent Year of FDA Approval First Reported Resistance

Penicillin 1943 1949

Streptomycin 1947 1947

Tetracycline 1952 1956

Methicillin 1960 1961

Gentamicin 1967 1969

Vancomycin 1972 1987

Cefotaxime 1981 1981 (AmpC -lactamase)

1983 (ESBL)

Which antibiotics promote resistance? All antimicrobial drugs promote the emergence

of drug-resistant organisms. However, some agents are more likely to promote

resistance than others. Since broad-spectrum antibiotics kill off more

competing organisms than do narrow-spectrum drugs, emergence of resistance is facilitated most by the broad-spectrum drugs.

II. Superinfection A special example of the emergence of drug

resistance. Defined as a new infection that appears during

the course of treatment for a primary infection. A new infection can develop because antibiotic use

can eliminate the inhibitory influence of normal flora, thereby allowing a second infectious agent to flourish.

More common with broad-spectrum agents.

III. Selection of antibiotics Therapeutic objectives- three principle factors:

1. The identity of the infecting organism

2. Drug sensitivity of the infecting organism

3. Host factors such as site of infection and the status of host defenses.

Drug of choice: Greater efficacy Lower toxicity Narrow spectrum

Selection of antibiotics Alternative agents should be used only when the

first choice drug is inappropriate in conditions such as:

Allergy to the drug of choice Inability of the drug of choice to penetrate to the site

in infection Unusual susceptibility of the patient to a toxicity of

the first-choice drug

Other host factors Age

Use of sulfonamides in newborns can produce kernicterus,a severe neurologic disorder caused by displacement of

bilirubin from plasma proteins.

Tetracyclines bind to developing teeth, causing discoloration.

IV. Therapy with antibiotic combinations Reasons to use combinations:

Initial therapy of severe infection Mixed infections Prevention of resistance Decreased toxicity Enhanced antibacterial action

Therapy with antibiotic combinations Antimicrobial effects

When two antibiotics are used together, the result may be: Additive Potentiative (synergistic) Antagonistic

1. Additive response Is one in which the antimicrobial effect of the

combination is equal to the sum of the effects of the two drugs alone (e.g. two bacteriostatic agents with the same mechanism of action are used).

Therapy with antibiotic combinations Antimicrobial effects

2. Potentiative (synergistic) interaction: Is one in which the effect of the combination is

greater than the sum of the effects of the individual agents.

One of the two drugs must show at least 4-fold increase in antibacterial activity (or a decrease in MIC to ¼).

Three Mechanisms of Antibiotic Synergism1. Blockade of sequential steps in metabolic

sequence (e.g. Trimethoprim-sulfamethoxazole for folic acid production (see above)

2. Inhibition of enzymatic inactivation: Beta-lactams and Beta-lactamase inhibitor like sulbactam.

3. Enhancement of AB uptake: Penicillins increase uptake of aminoglycosides in staphylococci, enterococci etc.

Therapy with antibiotic combinations Antimicrobial effects

3. Antagonism A combination of two antibiotics may be less

effective than one of the agents by itself (usually static agents are antagonistic to cidal agents; eg., chloramphenicol vs. penicillin in the treatment of Pneumococcal meningitis).

Other example: Tetracycline (bacteriostatic) plus penicillin (bactericidal)

Concave!

Convex!

Therapy with antibiotic combinations Initial therapy of severe infection

The most common indication for use of multiple antibiotics is initial therapy for severe infections of unknown etiology, especially in the neutropenic host.

Once the identity of the infecting microbe is known, drug selection can be adjusted accordingly.

Samples for culture should be obtained before drug therapy is initiated.

Therapy with antibiotic combinations Mixed infections

Infections that may be caused by more than one microbe.

Common in brain abscesses, pelvic infections, and infections resulting from perforation of abdominal organs.

Prevention of resistance Although use of multiple antibiotics is

usually associated with promotion of drug resistance, there is one disease – tuberculosis – in which drug combinations are employed.

Caldwell’s helpful memory listCategory Prominent

exampleBrief MOA Helpful

pnemonics

Penicillins Amoxicillin Bind to PBP End in “cillin”

Tetracyclines Tetracycline At 30S ribo End in “cycline”

Aminoglycosides Streptomycin Affects protein syn.

Mycin or micin

Quinolones Levofloxacin DNA gyrase inhibitors

End in “oxacin”

Cephalosporins Cefaclor Protein synthesis

Start with Cef or ceph (loracarbef)

Macrolides Erythromycin 50S ribosome End in mycin