Combinations of antibiotics and chemotherapeutics
Definition & Classification
Antibiotics are chemicals of natural origin produced by microorganisms of various species (bacteria and fungi) capable of stopping growth (bacteriostatic effect) or killing (bactericidal effect) bacteria. Industrial production, which made therapeutic use of penicillin (the first antibiotic discovered in 1920) possible in the 1940s, has evolved in such a way that all antibiotics available for clinical use are of synthetic (in this case, it is more appropriate to speak about chemotherapy) or semi-synthetic origin.
Antibiotics and chemotherapeutics can be classified according to many criteria; the most used correspond to its bacterial effect (bacteriostatic VS bactericides) and its chemical structure:
- BETA-LACTAMICS: its chemical structure is distinguished by a beta-lactam ring in its structure. Examples: Penicillin and derivatives, cephalosporins, cephamycins, carbapenems, monobactams, beta-lactamase inhibitors.
- AMINOGLUCOIDS: its chemical structure consists of amino sugars linked by glycosides to a hexagonal cyclic alcohol with amino (aminocyclitol) groups. Examples: spectinomycin, gentamicin, amikacin, neomycin, kanamycin, etc.
- QUINOLONES: Its chemical structure consists of two rings, with nitrogen in position 1, a carbonyl group in position 4 and a carboxyl-group in position 3. Examples: nalidixic acid, pipemidic / fluorinated quinolones: pefloxacin, ciprofloxacin, norfloxacin , Sparfloxacin.
- POLYMYXINES: Its chemical structure consists of cationic, basic peptides. Examples: polymyxin B and E
- TETRACYCLINES: Its chemical structure consists of 4 rings in the hydronaphthacen core. Examples: oxytetracycline and doxycycline.
- MACROLIDES: Its chemical structure consists of a macrocyclic lactose ring formed by many members, to which one or more deoxy-sugars are to be joined. Examples: erythromycin, clarithromycin, roxythromycin and azithromycin (azalide)
- SULFONAMIDES: its chemical structure consists of a nucleus of benzene with amino groups. Examples: sulfamethoxazole and sulfisoxazole.
- PHENICOLES: Its chemical structure comes from a dichloroacetic acid derivative to which a benzene ring is attached. Examples: chloramphenicol and thiamphenicol.
Antagonism and Synergy
Combinations of antibiotics and / or chemotherapeutics are usually used for the treatment of certain infections. This strategy can have two objectives:
- Avoid a mechanism of resistance.
- Reach bactericidal concentration.
A combination of antibiotics and / or chemotherapeutics acted synergistically or antagonistically depends on the antibiotics and / or chemotherapeutics combined and the bacterial strain on which it acts.
Antagonism occurs when the combined effect of two medicines is less than the sum of the effects of each medicine. This antagonism is evident as a decrease of bacterial or bacteriostatic activity in the in vitro studies or in the healing effect in vivo. Some examples of antagonism between antibiotics observed, both in vitro and in vivo, are: penicillin and chloramphenicol, penicillin and tetracycline, gentamicin and tetracycline, among others.
Combinations of antibiotics and / or chemotherapeutic agents that presents antagonism in vitro or in the experimental model should be avoided as possible, with the condition that what happens in humans may be totally different. One of the combinations that should be prohibited in clinical practice is the use of penicillin-tetracycline and possibly penicillin-chloramphenicol in purulent meningitis, since it has proved ineffective when there is this antagonistic effect among them, and may also cause other problems such as resistance.
It is the property of certain combinations of antibiotics capable of producing a bactericidal effect superior to that exerted by each of them separately. Combinations of antibiotics that act at different levels of the bacterial structure are synergistic. Attached is an action plan of the different groups of antibiotics and / or chemotherapeutics:
Combinations of antibiotics and / or chemotherapeutic agents should never be performed unless they have been shown to have a synergistic effect in the laboratory. Once this has been demonstrated, the clinical efficacy of the chosen combination should be tested.
Some examples of antimicrobial combinations that have synergy are:
- Betalactamics + Quinolones:
- Mechanism of action:
- Betalactamics: act by inhibiting the last stage of bacterial cell wall synthesis. They are the largest family of antimicrobials and the most widely used in clinical practice.
- Quinolones: they act by inhibiting the DNA gyrase, they present a broad spectrum, but their action is more effective against Gram -.
Its combined use is recommended for persistent or complicated infections. One of the first references to the use of this combination is trovafloxacin and a beta-lactam that showed synergy against P.aeruginosa. The rapid occurrence of resistance in the quinolones group, which is the main drawback for its use, makes its use combined with beta-lactams recommended.
Tetracyclines + Aminoglycosides:
Although the synergy has been shown to occur more in groups of antibiotics with similar actions: bactericidal + bactericidal or bacteriostatic + bacteriostatic, as in the case of the group previously described: two bactericides (Betalactamics + Quinolones) with synergistic action, there are also mixed combinations such as tetracyclines and aminoglycosides that have been shown to have good synergism.
Mechanism of action:
Both inhibit protein synthesis but in different ways.
- Tetracyclines are bacteriostats that exert their action by inhibiting bacterial protein synthesis by their reversible binding to the 30S ribosomal unit and thus block the binding of the aminoacyl-tRNA to the acceptor site in the ribosome-RNA complex.
- Aminoglycosides are bactericidal antibiotics that bind to the 30S ribosomal unit, preventing the beginning of reading or introducing errors. In addition, they act directly on the membrane, hence its bactericidal action.
An example of this combination is doxycycline together with gentamicin or streptomycin, indicated for the treatment of Brucella abortus in veterinary and human medicine. The combined use, in addition to the synergistic action, reduces the toxicity that can occur in the treatment with aminoglycosides because it allows reducing the dose of the same ones. In addition, because of their oral malabsorption, aminoglycosides must be administered parenterally while tetracyclines have a good oral absorption, this is an advantage because the disadvantages of the combined use of two parenteral antibiotics are reduced: possible incompatibility of the molecules to be administered in the same syringe, more punctures (if they were necessary to administer them separately), request of more material, among others.