Antibiotics

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[edit] Classes of Antibiotics

[edit] Inhibitors of bacterial cell wall

β-LACTAM ANTIBIOTICS: These include Penicillins, Cephalosporins, Monobactams and Carbapenems.

All β-lactams are characterized by the same mechanisms of action. The key structure responsible for the antibacterial activity is the β-lactam. They work by inhibiting peptidoglycan synthesis. Peptidoglycan is a dimer formed by N-acetyl muramic acid (NAM) and N-acetyl glucosamide (NAG). β-lactams, by binding to specific penicillin-binding proteins (PBPs) located inside the bacterial cell wall, they inhibit the third and last stage of bacterial cell wall synthesis. Cell lysis is then mediated by bacterial cell wall autolytic enzymes such as autolysins

[edit] Bacteriostatic and Bactericidal Agents

Bacteriostatic agents inhibit the growth of microorganisms without killing the agent. They leave the body’s immune system to process bacteria and remove them from the body. Bacteriostatic agents are sufficient for patients with a competent immune system and should not be used for immunodeficient patients. An example is chloramphenicol.

Bactericidal agents kill the microorganism. An example is penicillin.

Bactericidal agents Bacteriostatic agents
Aminoglycosides *: gentamicin Chloramphenicol
β-lactams: penicillins, cephalosporins, carbapenems Macrolide
Fluoroquinolones Tetracycline
Vancomycin Clindamycin
Isoniazid (only active against Mycobacterium) Sulphonamides
Rifampin (active against other bacteria)
* Note: except for aminoglcosides, most antibiotics that
inhibit protein synthesis are bacteriostatic

Bactericidal antibiotics are those able to reach bactericidal concentration in the body. This is important because increasing the dose of a drug in vitro will finally kill the microorganism but the question is if this dose can be tolerated in vivo. Thus, bactericidal is referred to as antibiotics that reach blood concentration exceeding the minimal bactericidal concentration (MBC).

Bacteriostatic antibiotics are also defined s those able to reach the blood above the minimal inhibitory concentration (MIC).

However, the above classification isn’t so strict because antibiotics like penicillin can be bactericidal for S. pneumonia, whiles it is typically bacteriostatic for enterococcus (extremely resistant to antibiotic therapy). Chloramphenicol is also a typical example of bacteriostatic agent (seldom used because of its toxic effect especially at the bone marrow), but behave as a bactericidal agent for microorganisms like H. influenzae, Pneumococcus, Meningococcus, all of which are etiological agents of meningitis.

[edit] MIC and MBC

MIC (minimal inhibitory concentration): is the minimal concentration capable of inhibiting the growth of bacteria. We use vials with various concentrations of antibiotics and we check the multiplication of bacteria after 24 hours.

MBC (minimal bactericidal concentration): is the minimal concentration required to kill 99.9% of the bacterial population. It is useful for meningitis, endocarditis, and sepsis (infection of neutropenic patients).

The MBC and MIC are essential because you have to release a concentration of the drug high enough and higher than the MIC. Also, the drug must reach the site of infection at concentration toxic for the bacteria.

In order for a drug to be bactericidal in the body, concentrations that exceed the MIC must be reached. Generally, penicillin is bactericidal for streptococcus but bacteriostatic for enterococcus feacalis and faecium, which are naturally resistant to penicillins.

Resistant bacteria might be susceptible if the dose of the same antibiotic is increased in vitro. But we also have to consider if such a high dose can be reached in the human body. If the concentration is too high, then we have to consider the bacteria as resistant. In this way, a laboratory test helps us determine if a bacterial strain is resistant or not to antibiotics. Thus, the MIC and MBC refer to drug concentrations that can be reached in the patient.

[edit] Time-dependent bactericidal activity

The longer the drug stays above the MIC, the higher the efficacy. E.g., β-lactams and vancomycin. The most suitable way to administer this type of drug is by continuous infusion or frequent administration.

[edit] Concentration-dependent bactericidal activity

e.g.: aminoglycosides, fluoroquinolones.

Killing increases when the concentration of the drug is many times above the MIC. It is important for the concentration of the drug to be extremely above the MIC, this is due to the post-antibiotic effect. Aminoglycosides, for example, are capable of staying bound to the target for a long time, even if they disappear from the plasma, they remain bound to the target for long (high avidity), and their antibiotic activity continues for long despite the decrease in plasma levels.
So it is better to give a single high dose of aminoglycosides, i.e., one dose per day, instead of three doses per day. And the single high dose is associated with lower toxicity compared to fractionated dosing.

[edit] Contraindications

  • Tetracyclines: have high affinity for the bones and can alter intrauterine growth
  • Fluoroquinolones: chondrotoxic
  • Chloramphenicol: impair bone marrow development
  • Trimethoprim (Sulfamethasoxole): can cause an altered development of bone marrow; antagonist to DHFR.