Clinico-pharmacological characteristic of amoxicillin:
An important task of modern pharmacology of antibiotics is to fight infectious agents whose resistance to antimicrobial agents is due to beta-lactamase. For this purpose, apply antibiotics potentiated inhibitors of beta-lactamase. The drug Amoxil is considered in terms of the main areas of combating antibiotic resistance. The data on clinical efficacy Trifamoksa IBL, discussed the prospects of its application.
- Amoxicillin drug has optimal pharmacokinetic characteristics (Generic Amoxil 500 mg)– bioavailability, the rate of absorption, distribution in enteral use. Half-life, in Vol. h. in enteral use; has high activity against pneumococci, even a high level of resistance of the latter, which is observed in some regions, can be partially overcome by increasing the dose of an antibiotic; exhibits higher compared with ampicillin bactericidal activity against other sensitive aminopenicillins strains in Vol. h. by parenteral administration of antibiotics.
Basic mechanisms and ways to overcome antibiotic resistance:
- There are several basic mechanisms of formation of microbial resistance to antibiotics. Among the most highly specific inactivation considered antimicrobials enzymes produced by both gram-positive and gram-negative bacteria. An example of this mechanism of resistance is the destruction of penicillins and / or cephalosporins, beta-lactamases or aminoglycoside group “modifying” enzymes. Other relevant mechanisms of resistance – modification of the “target” of antibiotics, antibiotic concentrations decrease due to lower permeability of the bacterial cell wall, as well as under the influence of bacterial “pumps” – (efflux-pump) are regarded as less specific.
It is believed that penicillin binding proteins that are targets of the beta-lactam antibiotics that have a lot in common beta-lactamases c. In the evolution of enzymes, the synthesis of peptidoglycan and destroy beta-lactam antibiotics, emerged as an independent group.
Basic information of beta-lactamase in the review of Bush K. In a modified form. Presently known beta-lactamase (over 300 types) are divided into four molecular classes within which the enzymes are characterized by certain common properties and amino acid homology. According to the structure of the active site of beta-lactamase classes A, C and D are serine enzymes type, class B – for metalloenzymes (Zn-beta-lactamase).
In practical terms when describing the beta-lactamase is necessary to take them into account the following parameters:
- the ability to destroy specific antibiotics;
- sensitivity to inhibitors of beta-lactamase;
- localization (chromosomes and / or plasmids) gene.
There are two main directions overcome antibiotic resistance among bacteria that produce beta-lactamase:
Synthesis of beta lactamase resistant antibiotics. Examples are oxacillin, cefazolin (resistant staphylococcal effect “penicillinases”), cephalosporins III-IV generations (stability to beta-lactamases broad spectrum of gram-negative bacteria), and, of course, carbapenems is active against the beta-lactamase strains most relevant pathogens;
the use of combinations of antibiotics with beta-lactamase inhibitors, which are intended to increase (restore) the activity of antibiotics against bacteria producing hydrolyzing enzymes.
Dynamics of antibiotic resistance show that microorganisms gradually (usually in direct proportion to the intensity of use of an antibiotic) acquire the ability to overcome the protection inherent in the structure of the antimicrobial agent in its creation. And this is achieved not only through the creation of new mechanisms of stability (modification of “targets”, efflux), but due to production more aggressive types of beta-lactamase. Unfortunately, this negative process progresses. If in 1970 it was described 14 types of beta-lactamase, by 2000 their number reached 283. A striking example of the consequences of such aggression is almost complete helplessness to cephalosporins III generation beta-lactamase mutants a wide range of Gram-negative bacteria – enzymes, extended spectrum. Even seemingly insurmountable protection carbapenems begins to take under the pressure of a previously unknown metallo-beta-lactamase. From this point of view seems more predictable protective effect of beta-lactamase inhibitors, prolonging “clinical life” of a number of useful, but initially unprotected antibiotics.
Inhibitors are effective against beta-lactamase plasmid localization mainly produced many important pathogens, except plasmid enzyme class D. The chromosomal beta-lactamase classes B and C are resistant to clinically used inhibitors (products of chromosomal beta-lactamase is most common in hospital strains a number of gram-negative bacteria – enterobacteria, Pseudomonas aeruginosa, Klebsiella and some others).
In general, clavulanate, sulbactam and tazobactam approximately equally aminopenicillins potentiate the effect against Gram-negative bacteria, increasing it from 5 to 40-60%. However sulbactam has several advantages over other inhibitors: firstly, it is more resistant to most of the beta-lactamase plasmids and even chromosomal beta-lactamase I group; secondly, it possesses a bactericidal activity against Bacteroides fragilis and Acinetobacter spp. Interestingly, beta-lactamase inhibitors potentiate the action of penicillin is not only a result of the blockade of the enzyme, but also due to antiinokulyatsionnogo effect, enhance bactericidal properties of PMN, as well as a kind of “post-beta -laktamazotormoznogo” effect. The latter differ from the known steps postantibioticski antibiotics and retained against certain microorganisms, such as strains of H. influenzae and K. Pneumoniae, up to 5 hours or more. When combined with sulbactam and cefoperazone aminopenicillins increased activity against the causative agent of another problem in the surgical wards – Stenotophomonas maltophilia. At the same time bactericidal activity of aztreonam, cefoperazone and cefepime against this microorganism is enhanced by the addition thereto of clavulanate and tazobactam. Thus, the use of combinations of antibiotics with different beta-lactamase inhibitors would, in our view, enhance the ability of antibiotics.
Another feature of the sulbactam is in its pharmacokinetics, determining achieve an adequate level of inhibitor in humans (data obtained from healthy volunteers) with standard dosing “protected” penicillins. It is shown that the average concentration of tazobactam and sulbactam especially in vivo exceed desired levels by NCCLS criteria of sensitivity, whereas the concentration of clavulanate reach only 65% of the required.
Thus, sulbactam has pharmacodynamic and pharmacokinetic properties, capable of providing the best possible protection of penicillins hydrolysing enzymes produced initial sensitivity to them strains of microorganisms.
From this perspective, a very promising new drug protected amoxicillin, wherein the beta-lactamase inhibitor used not clavulanate and sulbactam.