Drug Mech: Antibiotics 1

• Antibiotics have been described as the single most
• important therapeutic discovery in the history of medicine.

They have revolutionized our ability to curb death and disease from infectious microorganisms (the ‘Miracle’ Drugs).

• Their overuse and misuse have led to the emergence
• and spread of microbial resistance.

An antibiotic, also referred to as an antibacterial agent, is a molecule (synthetic or a natural product) capable of selectively inhibiting the growth or survival of one or more species of microorganisms at very low concentrations.

The MIC value of an antibiotic is the Minimum Inhibitory Concentration of the antibiotic which completely prevents the growth or survival of a microorganism in a standard assay.

In other words, the MIC value measures the potency of an antibiotic.

• High MIC = low potency.
• Low MIC = high potency.

The clinical dose is usually expected to achieve a plasma concentration of ~4 to 8 times the MIC value of the antibiotic. The clinical dose must be associated with minimum or no toxicity to the patient (kill the infection, not the patient).

• The general rule is that antibiotics should always be tailored to the patient via:
• 1) the type of antibiotic
• 2) the disease state

An antibiotic which exhibits a bacteriostatic effect at the clinical dose is referred to as a ‘Bacteriostatic Antibiotic’.

An antibiotic which exhibits a bactericidal effect at the clinical dose is referred to as a ‘Bactericidal Antibiotic’.

• Tetracyclines
• Sulfonamides

• Penicillins
• Aminoglycosides
• Polypeptides
• Quinolones

When administered at the clinical dose, a bacteriostatic antibiotic inhibits cell division (growth) of the microorganism. As a result, the microorganism survives but will stop multiplying.

When administered at the clinical dose, a bactericidal antibiotic inhibits the survival of the microorganism (kills the microorganism).

Susceptibility of the bacterial strain to the antibiotic is a prerequisite for the antibiotic’s ability to exhibit its static/cidal effect.

• Concentration (or Dose) *Most important
• Mechanism of Action *Second most important...tells us how the drug works
• Microbial Susceptibility/Resistance
• Microbial Species

Yes absolutely! All antibiotics, at a high enough dose, will exhibit bactericidal effects.

• Yes!
• The majority of antibiotics have both a static and cidal dose.
• The static dose is always lower than the cidal dose.
• Some antibiotics only have a cidal dose.

• Yes...but only for a few antibiotics.
• Remember that first and foremost, the bacterial cell has to be susceptible to the antibiotic used.
• Only a few antibiotics are cidal only. Why? Because their mechanism of action is devastating to the cell. Think of antibiotics that inhibit bacterial cell wall synthesis. The bacterial cell cannot survive that, and therefore, the effects are cidal.
• A great example is polypeptides (polymixin B & E).

Yes...because of Microbial Resistance. However, the cell must have two binding sites (or two biological targets) in the cell, and only one binding site must work.

• The general rule is to tailor the treatment of the patient by two things:
• 1) the type of antibiotic
• 2) the disease state
• Practitioners may do the following to decide which dose to pick for the clinical dose:
• Look at differences between the cidal and the static dose of the antibiotic. If the cidal dose is way higher than the static dose, the the cidal dose will be toxic to the patient. Therefore, pick the static dose!

For example, Tetracyclines have two doses (a static and a cidal dose), but the static dose is much less toxic to the patient.

No...not really. These things are not easy to predict. For example, compare tetracyclines and aminoglycosides.

No...not really. For example, compare penicillins to aminoglycosides. They have a completely different mechanism of action, yet, they both produce the same effect at the clinical dose.

• Patients with severe or life-threatening infections
• should be treated with bactericidal antibiotics. Remember, it's always better to kill a microorganism than to inhibit growth.

Bacteriostatic antibiotics should be used for the treatment of mild infections.

Immunocompromised patients with bacterial infections should be treated with bactericidal antibiotics.

Bacteriostatic antibiotics should only be used to treat infections in immunocompetent patients.

Patients should not skip doses or stop taking an antibiotic prematurely (regardless of whether the antibiotic is bacteriostatic or bactericidal).

A narrow-spectrum antibiotic is effective only against a limited number of bacterial species/strains.

The use of narrow-spectrum antibiotics contributes significantly to minimizing the emergence of microbial resistance to antibiotic therapy (they should always be recommended whenever possible).

A broad-spectrum antibiotic is effective against a large number of bacterial species/strains, which usually would include both Gram-positive and Gram-negative bacteria.

To help minimize the emergence of microbial resistance, broad-spectrum antibiotics should be used only when it is absolutely necessary.

Combination Antimicrobial Therapy involves the use of a combination of two or more antibiotics/antibacterial agents for the treatment of an infection.

ADVANTAGES OF USING COMBINATION THERAPY include:

Provide a broad-spectrum empiric (Initial) antimicrobial therapy in seriously ill patients.

Treat polymicrobial (mixed) infections such as intra-abdominal abscesses.

Obtain enhanced antimicrobial activity against a specific infection (Synergism). The agents used in the combination must have different mechanisms of action or different targets in the bacterial cell.

DISADVANTAGES OF COMBINATION ANTIMICROBIAL THERAPY include:

Increased overall toxicity.

Increased cost to patient.

Antagonism (some combinations may be antagonistic).

Emergence of microbial resistance through selection of resistant bacterial species/strains.

When the inhibitory or killing effects of two or more antimicrobial agents used together are significantly greater than expected from their effects when used individually, synergism is said to result.

Synergism is marked by a fourfold or greater reduction in the MIC or MBC (Minimum Bactericidal Concentration) of each drug when used in combination versus when used alone.

Antagonism occurs when the combined inhibitory or killing effects of two or more antimicrobial agents are significantly less than expected from their effects when used individually.

Indifference occurs when the combined inhibitory or killing effects of two or more antimicrobial agents are more or less the same as their effects when used individually.

The interaction between two antimicrobial agents can be expressed by the Fractional Inhibitory Concentration (FIC) Index:

The Fractional Bactericidal Concentration (FBC) Index can be determined by substituting MBCs (Minimum Bactericidal Concentration) for MICs (Minimum Inhibitory Concentration) in the equations below.

Synergism for combinations of two drugs requires an FIC or FBC index of 0.5 or less.

Antagonism for combinations of two drugs is marked by an FIC or FBC index of 4 or more.

Indifference for combinations of two drugs requires an FIC or FBC index between 0.5 and 4.

Synergism!

1) Blockade of Sequential Steps in a Metabolic Sequence (e.g., trimethoprim-sulfamethoxazole combination).

2) Inhibition of Enzymatic Inactivation (e.g., the combination of a b-lactamase-sensitive penicillin and a b-lactamase inhibitor). (Note: a b-Lactamase is an enzyme produced by certain bacterial species in order to destroy a b-Lactam antibiotic)

• 3) Enhancement of Antimicrobial Agent Uptake by Bacterial Cells (e.g., the combination of a
• penicillin and an aminoglycoside; the combination of the antifungal agents amphotericin B and flucytosine).

• 1) Inhibition of Cidal Activity by Static Agents (e.g., the combination of a penicillin and a
• tetracycline). Please keep in mind that this type of inhibition depends primarily on the mechanisms of action of the static/cidal agents and does not
• always occur (e.g., the combination of a tetracycline and an aminoglycoside is not antagonistic).

• 2) Induction of Enzymatic Inactivation. For
• example, some Gram-negative bacteria possess inducible b-lactamases. b-Lactam antibiotics, such as imipenem, cefoxitin, and ampicillin, are
• potent inducers of b-lactamase production. If an inducing agent is combined with a b-lactam antibiotic which is b-lactamase-sensitive (such as piperacillin), antagonism may result.

• Microbial resistance to antimicrobial therapy is an increasingly important public health concern and a factor in virtually all hospital-acquired (nosocomial)
• infections and many community-acquired infections.

Microbial resistance is evolutionary. It has been recognized since the introduction of penicillin nearly 80 years ago, and will continue to be a problem as long as we continue to use antibiotics and antimicrobial agents.

Rapid emergence and dissemination of MDR-type strains.

1. The ability of infectious organisms to adapt quickly to new environmental conditions (none of them is facing extinction!!).

2. Microbes, generally unicellular, have a small number of genes. Even a single random gene mutation can have a large impact on their properties (unlike multicellular organisms).

• 3. Microbes replicate very rapidly. As a result,
• they can evolve rapidly.

• 4. A mutation that helps a microbe survive in the
• presence of an antibiotic or antimicrobial agent will quickly become predominant throughout the microbial population.

5. Microbes commonly acquire genes, including those encoding for resistance, by direct transfer from members of their own species or from other unrelated microbial species.

6. Widespread and inappropriate use of antibiotics (the CDC estimates at least 50 million unnecessary courses of antibiotics prescribed each year in the United States).

Examples of inappropriate use of antibiotics include:

• -Treatment of viral infections
• -Improper dosage
• -Lack of adequate bacteriological information regarding the infecting organism
• -The use of antibiotics in animal feed as growth promoters
• -The availability of antibiotics as ‘OTC products’ in
• some parts of the world (outside the U.S.)

7. Patient noncompliance.

The simple answer is it's a small world. Between modern transportation and global travel, bugs affecting people in other countries can affect tourists from the U.S. and be brought back to our country.

If antibiotics are used as OTC products in other countries, that would pretty much guarantee a higher rate of inappropriate usage of antibiotics, which would cause a higher rate of microbial resistance to microorganisms. Thus, if a U.S. tourist brings one of these "super bugs" back to the states, it could add to the microbial resistance here.

Drug Inactivation by Enzymes (e.g., inactivation of b-Lactam antibiotics by bacterial b-Lactamases).

Target Modification by chromosomal mutations (e.g., b-Lactams, Aminoglycosides, Quinolones, Trimethoprim).

• Alteration in Target Accessibility by reducing permeability or increasing efflux of the drug
• (e.g., Tetracyclines, Aminoglycosides).

Development of Altered Metabolic Pathways in order to bypass the metabolic reaction that is inhibited by the drug (e.g., Sulfonamides).

*(Note: A combination of two or more of the aforementioned mechanisms can exist in a single bacterial strain)

There are two origins of Microbial Resistance:

1) Non-genetic Origin (e.g. non-multiplying organisms)

2) Genetic Origin

Chromosomal Resistance: caused by a spontaneous mutation that occurs on the bacterial chromosome. This type of resistance becomes predominant in the microbial population through the process of Selection of resistant strains (which results from the use of antibiotics). Chromosomal mutations lead mainly to ‘Target Modification’ as the resistance mechanism.



Extrachromosomal Resistance: caused by the transfer of R-Factors from one bacterial cell to another. R-Factors are plasmids which contain genes that encode for resistance. Transfer of R Factors leads mainly to ‘Drug Inactivation by Enzymes’ as the resistance mechanism.

What are the Mechanisms of the transfer of R-Factors?

• 1) Transformation
• 2) Transduction
• 3) Conjugation
• 4) Transposition

1) Classical Cross-Resistance

• A single resistance mechanism confers resistance
• to a single class of antimicrobials.

2) Cross-Resistance Between Two or More Classes of Antimicrobials which can occur by one or a combination of the following two mechanisms:

• -Overlapping Targets
• For example, methylation of a single adenine residue in ribosomal RNA confers resistance to three classes of antibiotics which are chemically unrelated (Macrolides, Lincosamides, and Streptogramins), due to overlapping targets on the bacterial ribosome.

• -Active Efflux
• This energy-dependent export system confers low level resistance to a wide variety of antimicrobials. The broad substrate specificities of the pumps account for decreased susceptibility to many antibiotics, such as Tetracyclines, Aminoglycosides, b-Lactams, Fluoroquinolones, and Sulfonamides, among others.

Results from the presence of several resistance mechanisms, in the same strain, each conferring resistance to a given class of antimicrobials.

Interestingly, the corresponding resistance genes are often adjacent (physically linked) and express in a coordinated fashion.

Because of the co-expression of the various genes, the use of any antibiotic that is a substrate for one of the resistance mechanisms will co-select for resistance to other classes of antimicrobials and thus for maintenance of the entire gene set.

• Cross-Resistance is more common that Co-Resistance...and good thing because Co-Resistance is the nasty resistance.
• Co-resistance is MDR = Multi-Drug Resistance. In essence, Co-resistance happens when a single bacterial strain that is physically linked together has co-expressed genes (located on plasmid) and get transferred from one species to another. For example, NDM-1 is an example of Co-resistance. The genes are physically linked at each one encodes for a different mechanism of resistance.

• b-Lactams
• Vancomycin
• Cycloserine
• Bacitracin
• Fosfomycin
• Dalbavancin
• Telavancin

• Tetracyclines
• Aminoglycosides
• Macrolides
• Lincosamides
• Chloramphenicol
• Streptogramins
• Linezolid
• Pleuromutilins (Retapamulin)

• Quinolones
• Rifamycins

• Polypeptides
• Cyclic Lipopeptides

• Sulfonamides
• Trimethoprim

no names specifically listed