Generality
Macrolides constitute a class of antibiotics of natural origin.
The progenitor of this class is erythromycin, obtained from cultures of Streptomyces erythraeus .
Macrolides are the drugs of choice for treating certain types of infections in patients who have experienced allergic reactions to penicillins, since they have a similar spectrum of action.
Macrolides possess bacteriostatic activity (ie they inhibit bacterial growth), but at high concentrations they can also become bactericidal (ie they are able to kill bacterial cells).
Drugs belonging to this class of antibiotics include erythromycin, clarithromycin, azithromycin and spiramycin .
Indications
For what it uses
As mentioned above, macrolides possess an action spectrum that can be comparable to that of medium-spectrum penicillins.
Macrolides are administered mainly orally, sometimes in the form of gastroresistant pharmaceutical formulations, since they are unstable in the acidic environment of the stomach.
They are mainly used for the treatment of systemic minor infections of the respiratory system, mammary glands, liver, kidneys and prostate.
More specifically, macrolides can be used to treat:
- Infections of the upper and lower respiratory and soft tissues caused by Gram-positive bacteria, such as Streptococcus pyogenes and Streptococcus pneumoniae ;
- Infections of the upper and lower respiratory tract and otitis of the middle ear caused by Haemophilus influenzae (usually in association with a sulfonamide);
- Mycoplasma pneumonia;
- Infections with Mycobacterium avium complex (MAC) in AIDS patients (usually, in combination with rifabutin, an antibiotic belonging to the class of rifamycins);
- Legionnaire's disease;
- Prophylaxis of bacterial endocarditis caused by Streptococcus viridans ;
- Gonorrhea;
- Pelvic inflammatory disease (Pelvic Inflammatory Disease or PID) caused by mixed infections from organisms without a bacterial cell wall, such as Chlamydia trachomatis .
Furthermore, clarithromycin can be used in a mixture of drugs used to treat gastric ulcer caused by Helicobacter pylori infections .
Action mechanism
Macrolides exert their antibiotic action by interfering with the protein synthesis of bacteria.
Protein synthesis in bacterial cells occurs thanks to specific organelles called ribosomes.
The ribosomes consist of ribosomal RNA (rRNA) and proteins, associated with each other to form two subunits:
- The 30S subunit, consisting of 21 proteins and one RNA molecule (16S);
- The 50S subunit, consisting of 34 proteins and two RNA molecules (23S and 5S).
The task of these organelles is to bind and translate the messenger RNA (mRNA) that comes from the cell nucleus and to synthesize the proteins for which it encodes.
Macrolides are capable of binding to the 50S ribosomal subunit. More precisely, these antibiotics bind in two very specific regions of the 23S ribosomal RNA molecule.
The macrolide-RNA 23S bond prevents the RNA itself from completing protein synthesis, thereby inhibiting bacterial growth.
Resistance to macrolides
Bacteria can develop resistance against macrolides, making changes to their structure or activating particular mechanisms, including:
- Modifications to the structure of the bacterial ribosomal RNA, in this way the binding of the macrolide to the same RNA is prevented;
- Activation of a process by which the antibiotic is expelled from the bacterial cell;
- Production of specific bacterial enzymes (esterases) that break the lactone ring by inactivating it.
The intrinsic resistance of Gram-negative bacteria, on the other hand, appears to be due to the lack of penetration of the drug into the bacterial cell.
Interactions
The interactions between drugs with the use of macrolides are quite common and arise due to the competition for hepatic metabolism by cytochrome P3A4.
The drugs with which macrolides can establish interactions are:
- Ergotamine and its semisynthetic derivative bromocriptine, drugs used in the treatment of migraine;
- Theophylline, used to treat bronchial asthma;
- Carbamazepine, an anticonvulsant used in antiepileptic therapy;
- Warfarin, an oral anticoagulant;
- Digoxin, a drug used to increase the strength of cardiac contraction;
- Oral contraceptives;
- Ciclosporin, an immunosuppressive drug used in the prevention of transplant rejections;
- Astemizole and terfenadine, antihistamine drugs;
- Midazolam and triazolam, benzodiazepine drugs;
- Methylprednisolone, a glucocorticoid.
The possible interactions between these drugs and macrolides can be very dangerous for patients, as there could be an increase in the plasma concentration of the drug, which in turn can translate into an increase in toxicity.
Interactions with astemizole and terfenadine can lead to serious cardiovascular adverse effects.
Side effects
Generally, the side effects that can occur during macrolides therapy are in the gastrointestinal tract, liver and bile.
More precisely, macrolides can cause:
- Abdominal cramps;
- Gastrointestinal disorders;
- Dose-dependent cholestatic jaundice which can also be very serious.
In the event of the onset of severe cholestatic jaundice, macrolide therapy should be stopped immediately and - to continue the anti-infective treatment - other types of antibiotics should be given, such as penicillins, cephalosporins or lincosamides.
ketolides
The research in the field of macrolide antibiotics has developed a lot, this has led to the synthesis of new molecules characterized by a wider spectrum of action and able to induce fewer side effects, ketolides.
Ketolides are mainly used for the treatment of bacterial respiratory infections caused by bacteria resistant to macrolides.
Telithromycin belongs to this new class of drugs.
