HC22: Antimicrobial therapy

Discovery of antibiotics

The first antibiotic was saharsan, to cure Syphilis. This was a very toxic drug. Alexander Fleming discovered penicillin. He came back from a holiday and saw that on the dirty plates he left behind there were certain parts that weren't covered by bacteria. Here, a certain fungus was growing → penicillin. Penicillin was making a molecule which was able to kill bacteria. It took about 10 years until penicillin was used on an industrial level. After the 1980's, there was no new discovery of antibiotics.

Interactions

Antimicrobial therapy should be active against the microorganisms. There are several interactions necessary:

• Antimicrobial therapy «host
• Host «microorganism
• Microorganism «antimicrobial therapy

Antibiotics need to shift this balance in favor of the host. Two terms are very important to describe their effect:

• Pharmacodynamics describe this effect the drug has on the microorganism
• Pharmacokinetics describe the effect the host has on the drug

Pharmacodynamics

Classes of antibiotics

The correct antibiotic depends on the bacterium. Bacteria can be divided in groups:

• Gram positive versus gram negatives
• Aerobe versus anaerobe

Based on this, correct antibiotics can be prescribed:

• Penicillin
  • Gram positive
  • Aerobe and anaerobe
• Meropenem → broad spectrum
  • Gram positive and gram negative
  • Aerobe and anaerobe
• Cefuroxim
  • Gram positive and gram negative
  • Aerobe
• Metronidazol
  • Gram positive and gram negative
  • Anaerobe
• Ciprofloxacin
  • Gram positive and gram negative
  • Aerobe and anaerobe

Mechanism of action:

Different classes of antibiotics influence different parts of the bacteria:

• Antibiotics active on the cell wall: inhibit the crosslinking of peptidoglycans → inhibit the integrity of the cell wall → bacteria can't divide
  • Penicillin
  • Cephalosporine
  • Carbapenem
  • Glycopeptides
    • Vancomycin
• Antibiotics active on the cell membrane
  • Colistin
  • Daptomycin
• Antibiotics active on ribosomes: inhibit protein synthesis
  • Aminoglycosides
  • Tetracycline
  • Macrolides
  • Clindamycin
• Antibiotics that effect DNA synthesis
  • Quinolones/ciprofloxacin
    • Effect DNA gyrase, an enzyme that is important for reading DNA
  • Sulfonamides
    • Blocks folic acid synthesis, an essential building block for bacteria
• Antibiotics active in the cytoplasm
  • Metronidazole/imidazole

Beta-lactams:

There are several beta-lactam antibiotics:

• Penicillin derivatives
  • Penicillin G
  • Flucloxacillin
  • Amoxicillin
  • Amoxicillin + clavulanic acid
• Cephalosporins
  • Cephuroxim
  • Many others

Gram-negative bacteria have a different cell wall than gram-positive bacteria → have a much thinner peptidoglycan layer which cannot contain the colored fluid. Beta-lactams affect the synthesis of peptidoglycans of both gram-positive and gram-negative bacteria → the antibiotics mainly form a problem for bacteria when they are dividing.

The molecular mechanism is as follows:

1. Peptidoglycan chains need to be crosslinked
2. Penicillin is blocking transpeptidase
3. The peptidoglycan chains cannot be crosslinked any longer

Low dosages of penicillin won't affect the bacteria. At a certain dose, there suddenly will be an effect. However, if the dose is increased again, the effect won't become any bigger. This can be shown in a concentration versus effect curve. This curve is different for every class of antibiotics.

Glycopeptides:

Glycopeptides have a different approach than beta lactams. Although they also inhibit the cell wall, they bind to aa-terminus of the peptide blocking the transpeptidase. The pharmacodynamic curve of glycopeptides is almost the same as that of penicillin.

Inhibitors of protein synthesis:

Protein synthesis inhibition occurs on different parts of the ribosome. Aminoglycosides, tetracycline, macrolides and clindamycin all bind to a different part of the ribosome. Their effect is mainly the same.

Inhibitors of DNA synthesis:

Quinolones inhibit the reading of the DNA. Sulfonamides inhibit folic acid synthesis → no precursors can enter.

Choice of antimicrobial agent:

Drugs are either bacteriostatic or bactericidal:

• Bacteriostatic drugs
  • Able to inhibit growth
  • Usually not sufficient to kill the bacteria
  • Antibiotics:
    • Macrolides
    • Tetracyclines
• Bactericidal drugs
  • Used in case of:
    • Infection of the blood stream
      • Sepsis
      • Endocarditis
    • Sites are outside the reach of the immune system
      • CNS
    • Lack of immune cells
      • Granulocytopenia
  • Usually kill the bacteria
  • Antibiotics:
    • Betalactam
    • Aminoglycoside
    • Chinolone

If bacteriostatic drugs are subscribed and then taken away, the bacteria will be able to grow again. This can also happen if bactericidal drugs are given in their MIC (minimal inhibitory concentration) dosage → bacteria will stop dividing temporarily. However, if the antibiotics are washed away in 24 hours, the bacteria will start growing again. These effects can be prevented if the antibiotics are given in a higher dosage. The amount of the dose determines whether the drug is bactericidal or bacteriostatic:

• If the concentration in which the bacteria are killed no matter what is 4 or less times as big as the MIC, the antibiotics are bactericidal
• If the concentration in which the bacteria are killed no matter what is higher, the antibiotics are bacteriostatic

Effect:

Antibiotics cannot be effective in case of:

• No growth
  • In case of inhibitors of cell wall synthesis
• Low pH or low pO2
  • A certain pH is required for the antibiotic to unfold or be activated
• Abscesses, tissue necrosis
  • The antibiotic cannot reach the tissue
  • Molecules in abscesses can bind to antibiotics
• Foreign bodies
  • Catheters, prosthesis
  • Cannot be reached by the immune system itself, but can by bacteria

Case:

A 19-year-old female student enters the ER with:

• Fever, deep shock, diarrhea
• Generalized redness, conjunctivitis
• Menstrual period

She is admitted to the ICU immediately. The diagnosis is toxic shock syndrome, also known as tampon disease. This is caused by staphylococcus aureus.

The shock is caused by massive amounts of toxins which are diffusing into the body, produced by the staphylococcus aureus growing inside the tampon. In 10% of cases, these toxins can act as superantigens. These antigens release a cytotoxic storm from the antigen presenting cells.

Because young women are often well informed, the prevalence of this disease is decreasing. Several forms of treatment are possible:

• Removal of the tampon
  • The main treatment
• IV immunoglobulins
  • To remove the toxin
• Antibiotic blocking of exotoxin production
  • Block the protein synthesis
  • Clindamycin or gentamycin

The population or the aureus is very dense → cell division isn't very important. They mostly are in stationary growth phase. This is why, if exotoxins have a major role in the pathogenesis, it's important to block the protein synthesis → protein synthesis blocking antibiotics need to be prescribed.

The difference between staphylococcal and streptococcal shock syndrome is very important → streptococcal shock syndrome is an invasive infection and has a worse prognosis.

Pharmacokinetics

ADME-phases:

For an antibiotic to reach the site, it has to undergo 4 phases:

• Absorption
  • Forms a problem when the gut is diseased
• Distribution
  • The drug goes to the site of infection
• Metabolism
  • For example the first pass effect in the liver
• Excretion
  • Antibiotics can be excreted in active of inactive form

Drug concentration:

Pharmacists always report the total concentration of the drug. However, this isn't the same as the free concentration:

• The total concentration also includes the antibiotics that have bound to proteins
• The free concentration is the effective concentration → the unbound serum concentration
  • It is the amount that will go to the site of infection

Privileged sites:

There are several privileged target sites which are hard for antibiotics to reach, for example tight junctions to the cerebral fluid. This doesn't form a problem in case of meningitis → the inflammatory response will reduce the diffusion barrier, making it possible for antibiotics to pass.

There also are pumps which can remove the antibiotics from the fluid or can get a higher dose of antibiotics in the brain in case of brain abscesses. Abscesses also need to be treated by removing the excessive fluid.

High concentrations:

If the antibiotic concentration if much higher than the MIC, it won't have an increased effect in comparison to a dosage that is only a little higher. In fact, it may cause side effects. Effects of a too high dosage of penicillin are:

• Gastro-intestinal side effects
• Thrombocytopenia
• Decreased kidney function

Dosage:

The initial dosage is completely dependent on the volume of distribution, the maintenance dosage is dependent on the clearance.

Pharmacokinetics versus pharmacodynamics

Pharmacokinetics are the concentration versus time, pharmacodynamics are the effect versus the concentration. Combined, this results in the effect versus the time curve. This curve is different for every antibiotic, even when the concentration-time curves are similar.

Antibiotics can be divided into groups based on when they have their optimal effect:

• Time/MIC
• Cmax/MIC
• AUC/MIC

Time/MIC:

There are antibiotics whose effect can be measured by their time above MIC → whenever they are above MIC, they are inhibiting/killing the bacteria:

• Beta lactam
• Macrolides
• Clindamycine
• Vancomycine

If the time above MIC is increased, the treatment will improve.

Cmax/MIC:

There also are antibiotics whose effect depends on the Cmax above MIC:

• Aminoglycosides

These antibiotics are dosed once a day, in very high peaks.

AUC/MIC:

Some antibiotics are in between. Their success is best correlated with the AUC above MIC:

• Doxycycline
• Fluoroquinolones

Resistance

Bacteria will try everything to counteract antibiotic mechanisms. They can do multiple things to induce resistance:

• Exclusion barrier
• Altered target
• Enzymatic inactivation

Evolution:

Resistance comes from millions of years of evolution of bacteria creating a resistance against plants, fungi and other microorganisms. Due to selection pression, the strongest, most resistant bacteria survive.

Examples:

2 examples of what bacteria can do to make themselves resistant are:

• ESBL: bacteria can make ESBL to become resistant against antibiotics
  • About 5% of the population carries bacteria which produce ESBL
• NDM-1: an enzyme that makes bacteria resistant to a broad range of beta lactam antibiotics

Staphylococcus aureus:

Staphylococcus aureus is carried by 30% of humans in the nose. This colonized bacteria usually is an MSSA staphyloccocus aureus, which is sensitive to antibiotics like flucoxacillin and cefuroxim. There also are MRSA staphyloccocus aureus (methicillin resistant S. aureus), which are hospital acquired.