History of Antibiotics and the emergence of Microbial Resistance
- 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.
What is an Antibiotic?
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.
What is the MIC value of an antibiotic?
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.
What is the Clinical Dose of an antibiotic?
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
What is a Bacteriostatic Antibiotic?
An antibiotic which exhibits a bacteriostatic effect at the clinical dose is referred to as a ‘Bacteriostatic Antibiotic’.
What is a Bactericidal Antibiotic?
An antibiotic which exhibits a bactericidal effect at the clinical dose is referred to as a ‘Bactericidal Antibiotic’.
Which Antibiotics are Bacteriostatic at the clinical dose?
Which Antibiotics are Bactericidal at the clinical dose?
Graph the Bacteriostatic versus Bactericidal Effects of Antibiotics
What is the Bacteriostatic Effect of Antibiotics?
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.
What is the Bactericidal Effects of antibiotics?
When administered at the clinical dose, a bactericidal antibiotic inhibits the survival of the microorganism (kills the microorganism).
What is the prerequisite for an antibiotic to be able to exhibit a static or cidal effect?
Susceptibility of the bacterial strain to the antibiotic is a prerequisite for the antibiotic’s ability to exhibit its static/cidal effect.
What four factors are involved in determining the effect (static or cidal) of an antibiotic?
- Concentration (or Dose) *Most important
- Mechanism of Action *Second most important...tells us how the drug works
- Microbial Susceptibility/Resistance
- Microbial Species
Bacteriostatic vs. Bactericidal Effect of an Antibiotic: Is it possible for all antibiotics to exhibit a bactericidal effect regardless of their mechanisms of action?
Yes absolutely! All antibiotics, at a high enough dose, will exhibit bactericidal effects
Bacteriostatic vs. Bactericidal Effect of an Antibiotic: Is it possible for all antibiotics to exhibit both bacteriostatic AND bactericidal effects against a bacterial strain?
- 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.
Bacteriostatic vs. Bactericidal Effect of an Antibiotic: Is it possible for an antibiotic to exhibit only a bactericidal effect against a bacterial strain (no static effect, even at lower concentrations) ?
- 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).
Bacteriostatic vs. Bactericidal Effect of an Antibiotic: Is it possible for an antibiotic, which is known to be ‘bactericidal’ against a particular bacterial species, to suddenly become ‘bacteriostatic’ against a strain of that species at the same clinical dose?
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
How is a clinical dose of an antibiotic determined? How do practitioners decide which dose to pick for the clinical dose?
- 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.
Is it possible to predict the effect of a clinical dose if we know the mechanism of action of an antibiotic?
No...not really. These things are not easy to predict. For example, compare tetracyclines and aminoglycosides.
If we know the effect of the antibiotic, can we predict the mechanism of action of the antibiotic?
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.
What are the clinical implications of the static versus cidal effects of antibiotics? How do practitioners know whether to use a static versus cidal antibiotic?
- 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.
antibiotics should be used for the treatment of mild infections
with bacterial infections should be treated with bactericidal
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
What is a narrow-spectrum antibiotic and when should they be used?
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).
What is a broad-spectrum antibiotic and when should they be used?
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.
What is Combination Antimicrobial Therapy?
Combination Antimicrobial Therapy involves the use of a combination of two or more antibiotics/antibacterial agents for the treatment of an infection.
What are the Advantages and Disadvantages of using Combination Antimicrobial Therapy?
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.
Evaluation of the Antimicrobial activity of drug combinations: What is Synergism?
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.
Evaluation of the Antimicrobial activity of drug combinations: What is Antagonism?
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.
Evaluation of the Antimicrobial activity of drug combinations: What is Indifference?
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.
What is the FIC Index?
The interaction between two antimicrobial agents
can be expressed by the Fractional Inhibitory Concentration
What is the FBC Index?
The Fractional Bactericidal Concentration
can be determined by substituting MBCs (Minimum Bactericidal Concentration) for MICs (Minimum Inhibitory Concentration)
in the equations below.
What are the mathematical requirements for determining Synergism, Antagonism & Indifference?
for combinations of two drugs requires an FIC or FBC index of 0.5 or less
for combinations of two drugs is marked by an FIC or FBC index of 4 or more
for combinations of two drugs requires an FIC or FBC index between 0.5 and 4
Which mechanism, Synergism, Antagonism or Indifference would be worth the money to find drugs that do it?
What are some Mechanisms of Synergistic Action?
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).
What are some Mechanisms of Antagonistic Action?
- 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: What is the scope of the problem?
- 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.
. 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.
of MDR-type strains
What are the contributing factors to Microbial Resistance?
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
Why would the availability of antibiotics as ‘OTC products’ in some parts of the world (outside the U.S.) affect Microbial Resistance in the United States?
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.
What are the Mechanisms of Microbial Resistance to Antimicrobial Therapy?
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).
Development of Altered Metabolic Pathways in order to bypass the metabolic reaction that is inhibited by the drug
- Alteration in Target Accessibility by reducing permeability or increasing efflux of the drug
- (e.g., Tetracyclines, Aminoglycosides).
*(Note: A combination of two or more
of the aforementioned mechanisms can exist in a single bacterial strain
What are the origins of Microbial Resistance?
There are two origins of Microbial Resistance:
1) Non-genetic Origin (e.g. non-multiplying organisms)
2) Genetic Origin
What are the two types of Genetic Microbial Resistance? What mechanism could counteract these types of Microbial Resistance? What are the Mechanisms of the transfer of R-Factors?
: 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
: 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
What is Microbial Cross-Resistance?
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.
What is Microbial Co-Resistance?
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.
What is the difference between Microbial Cross Resistance and Microbial Co-Resistance?
- 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.
Classification of Antibiotics: Inhibitors of Bacterial Cell Wall Synthesis
Classification of Antibiotics: Inhibitors of Protein Synthesis
- Pleuromutilins (Retapamulin)
Classification of Antibiotics: Inhibitors of Nucleic Acid Synthesis
Classification of Antibiotics: Disruptors of Cell Membrane Permeability
- Cyclic Lipopeptides
Classification of Antibiotics: Antifolates
Classification of Antibiotics: Antituberculosis Agents
no names specifically listed