1. How do Antibiotics work?
Antibiotics are drugs that selectively attack bacteria. Their effectiveness lies in the fact that they act on structures or metabolic pathways that are unique to bacteria and do not exist in human cells, thus minimizing toxicity.
A. Betalactams
Examples: Penicillins, Cephalosporins, Carbapenems, Monobactams.
Mechanism of action: They inhibit the synthesis of the bacterial cell wall. They bind to "Penicillin-Binding Proteins" (PBPs), which are the enzymes (transpeptidases) responsible for building peptidoglycan, the main component of the wall. Without an intact cell wall, the bacteria cannot withstand the osmotic pressure and dies (bactericidal effect).
Special considerations: They are most effective against actively growing bacteria. Its spectrum varies greatly between different "generations" and types.
Check your Understanding
Ask: If a beta-lactam needs a building wall to act, would it be useful to combine it with an antibiotic that stops bacterial growth (bacteriostatic)?
Answer: Generally not. The combination could be antagonistic, since the bacteriostatic stops the growth and, therefore, the construction of the wall, removing the target of action of the beta-lactam.
B. Macrolides and Lincosamides
Examples: Azithromycin, Clarithromycin, Erythromycin (Macrolides); Clindamycin (Lincosamide).
Mechanism of action: They inhibit protein synthesis. They bind to the 50S subunit of the bacterial ribosome, blocking the exit of the tunnel through which the new protein must pass. This stops the production of essential proteins for the bacteria (bacteriostatic effect).
Special considerations: They have good intracellular penetration, being useful for atypical pathogens (e.g. *Mycoplasma*, *Chlamydia*). Clindamycin has excellent activity against anaerobes and gram-positive cocci.
Check your Understanding
Ask: Why don't macrolides affect our cells?
Answer: Because human ribosomes are different (80S, composed of 60S and 40S subunits). This structural difference is the key to the drug's selectivity.
C. Fluoroquinolones
Examples: Ciprofloxacin, Levofloxacin.
Mechanism of action: They interfere with the replication and repair of bacterial DNA. They inhibit two key enzymes: DNA gyrase (in gram-negatives) and topoisomerase IV (in gram-positives). These enzymes are necessary to unwind and separate DNA during cell division. By blocking them, breaks occur in the DNA that are lethal for the bacteria (bactericidal effect).
Special considerations: Its use in pediatrics is restricted by concerns about arthropathy in immature animals, although the risk in humans appears to be low. They are reserved for specific infections where the benefit outweighs the risk (e.g. *Pseudomonas aeruginosa* in cystic fibrosis).
Check your Understanding
Ask: What type of effect (bactericidal or bacteriostatic) would you expect from a drug that causes irreparable DNA damage?
Answer: A bactericidal effect. DNA damage is a lethal injury that the bacteria cannot overcome, leading to cell death.
D. Other Important Groups
- Aminoglycosides (Gentamicin): They bind to the 30S subunit of the ribosome, causing misreading of the mRNA. They produce defective proteins that alter the cell membrane. They are bactericidal. They require oxygen-dependent transport, so they are not active against anaerobes.
- Glycopeptides (Vancomycin): They inhibit cell wall synthesis in a step prior to beta-lactams. They bind directly to the peptidoglycan precursors (D-Ala-D-Ala), preventing their incorporation into the wall. They are bactericidal and active only against gram-positives, since they are large molecules that cannot cross the outer membrane of gram-negatives.
- Sulfonamides and Trimethoprim (Cotrimoxazole): They sequentially block the bacterial folic acid synthesis pathway, which is essential for producing DNA. Humans are not affected because we obtain folic acid from the diet, we do not synthesize it. Generally bacteriostatic separately, bactericidal in combination.
2. The Fight of Bacteria: Resistance Mechanisms
Bacteria are experts at survival. They have developed ingenious strategies to evade the action of antibiotics. Understanding these mechanisms is essential to choosing the appropriate treatment.
A. Enzymatic Inactivation of the Antibiotic
The bacteria produces an enzyme that destroys or modifies the antibiotic, inactivating it before it reaches its target.
Classic example: The beta-lactamases. They are enzymes that break the beta-lactam ring, which is the active nucleus of penicillins and cephalosporins.
- Resistant to: Penicillins (Amoxicillin, Ampicillin), 1st and 2nd generation Cephalosporins. Extended Spectrum Beta-lactamases (ESBL) can inactivate even 3rd and 4th generation cephalosporins.
- Sensitive to (Strategies to overcome it):
- Combination with beta-lactamase inhibitors: Amoxicillin/clavulanate, Ampicillin/sulbactam. The inhibitor "distracts" the enzyme.
- Beta-lactamase stable antibiotics: Cephalosporins of higher generations, Carbapenems (Imipenem, Meropenem), which are very resistant to most beta-lactamases (except carbapenemases).
- Antibiotics from other families: Macrolides, Quinolones, Aminoglycosides (if the germ is sensitive).
B. Modification of the Diana Site
The bacteria alters the structure of where the antibiotic should bind, like changing the lock so that the key no longer fits.
Key examples:
- *Methicillin-Resistant Staphylococcus aureus* (MRSA): It acquires the *mecA* gene, which codes for an altered PBP (PBP2a). No beta-lactams (penicillins, cephalosporins) can bind to this new PBP.
- Macrolide resistance: Mutation of the *erm* gene that methylates the ribosome at the antibiotic binding site.
- Resistance to quinolones: Mutations in the *gyrA* and *parC* genes that encode DNA gyrase and topoisomerase IV.
Therapeutic options:
- For MRSA: Vancomycin, Clindamycin, Cotrimoxazole, Doxycycline (depending on local sensitivity).
- For resistance to macrolides due to ribosomal modification: It usually confers cross resistance to lincosamides (clindamycin). A different family should be looked for (e.g. beta-lactams, if the germ is sensitive).
C. Efflux Pumps and Permeability Reduction
The bacteria can actively expel the antibiotic or close the entry doors so that it does not reach the necessary concentration inside.
Efflux Pumps: They are membrane proteins that actively recognize and expel antibiotics out of the cell. They can be specific for a drug or broad spectrum (MDR - Multi-Drug Resistance pumps).
Permeability Reduction: Typical of gram-negative bacteria such as *Pseudomonas aeruginosa*. They close or modify their porin channels in the outer membrane, preventing the entry of antibiotics such as carbapenems.
- Resistant to: Tetracyclines, Macrolides, Quinolones (efflux). Beta-lactams, Aminoglycosides (loss of porins).
- Sensitive to (Strategies): It's complicated. Sometimes increasing the dose of the antibiotic can overcome the efflux. For the loss of porins, drugs that do not use that entry route or seeking alternatives from other families are required. The choice depends on the antibiogram.
3. Test yourself: Final Evaluation
4. Bibliography and Resources
- Nelson. Treaty of Pediatrics. 21st Edition. Elsevier.
- Red Book: 2024-2027 Report of the Committee on Infectious Diseases. 33rd Edition. American Academy of Pediatrics.
- Clinical Practice Guides on Pediatric Infections of the Spanish Society of Pediatric Infectology (SEIP).
- Principles and Practice of Pediatric Infectious Diseases. 6th Edition. Long, Prober, Fischer & Kimberlin. Elsevier.
- Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th Edition. Elsevier.
- European Committee on Antimicrobial Susceptibility Testing (EUCAST). Clinical breakpoints and dosing. (www.eucast.org)