Over the past 100 years, a number of discoveries and inventions in the field of chemistry and medicine can rightfully be attributed to the most significant: vaccines, X-rays, blood substitutes, the discovery of the structure of DNA. But, according to doctors, it was penicillin that became the main medical, chemical and biological discovery of the twentieth century. And what about amoxicillin today?
Amoxicillin a new era
It is believed that the era of antibiotics began in 1941 in the United States, but the first research was started back in 1929, when the microbiologist A. Fleming discovered penicillin in the mold Penicillium notatum. Previous experiments with the reproduction of harmful bacteria have shown that some types of mold are able to destroy others and prevent their further development, primarily streptococci and staphylococci. This phenomenon was called “antibiosis” (from the Greek. “anti” – against and “bios” – life).
The discovery was a real revolution in medicine, but it was still far from a real victory. The path of penicillin from the microbiological laboratory to production on an industrial scale turned out to be quite long. Only towards the end of the Second World War in the United States was it possible to establish mass production of penicillin. Its use led to the fact that the mortality rate from gangrene and sepsis fell to zero, amputations were avoided, the seriously injured recovered quite quickly.
Realizing the full significance of this drug, the discoverer of penicillin, Fleming, Flory and Chain did not patent it, but each country had to get its own penicillin. In the Soviet Union, in wartime conditions, this work was performed by Z. V. Ermolyeva with her like-minded people, and already in 1942 a strain of penicillin similar to the American one was found. In the shortest possible time, its production was established on an industrial scale, and in 1944 it began to enter hospitals and directly to the front.
Fleming, Flory and Cheyne received the Nobel Prize for their discovery in 1945. The real victory over tuberculosis was the discovery of streptomyces in 1944 by the American scientist S. Ya. Waxman. In 1948, Bartz isolated levomycetin, Duggar-chlortetracycline, and in 1949 Brottz received cephalosporin. By 1955 there were already more than 500 antibiotics. About 10,000 compounds of this class have now been discovered and studied, and more than 200 of them have been used in medicine.
And yet, despite the advantages of new antibacterial drugs, penicillin still remains a “long-lived” among them, showing activity against gram-positive and anaerobic microorganisms, while gram-negative microorganisms have a natural resistance to penicillins.
It is unlikely that it will be possible to win a complete victory over the world of microorganisms. In response to the use of antibiotics, microbes resist them. The mechanisms of acquired bacterial resistance to antibiotics include:
- synthesis of enzymes that destroy antibiotics;
- structural or spatial modification of targets for the action of antibiotics;
- violation of the permeability of bacterial cell walls and membranes for antibiotics;
- active removal (efflux mechanism) of antibiotics from the cell using membrane pumps;
- creation of new metabolic pathways.
Natural penicillins have lost their positions before the ability of bacteria to synthesize penicillinases, which break the beta-lactam ring of antibiotics. Plasmid-associated enzymes (penicillinases) are among the main factors determining bacterial resistance. Staphylococci were among the first to “learn” how to synthesize penicillinases. To date, 90% of staphylococcus strains are resistant to natural penicillins.
In this regard, in the 1940s, there was a need to develop penicillins that would be resistant to the action of bacterial (primarily staphylococcal) penicillinases, acting on gram-positive and gram-negative microbes. In addition, it was necessary to take into account such a property of natural antibiotics as their inefficiency when taken orally (they are destroyed in the acidic environment of the stomach).
The first antibiotic resistant to the action of bacterial penicillinases was methicillin. However, methicillin and the following penicillin-resistant penicillins (oxacillin, cloxacillin, dicloxacillin, etc.) were not active against gram-negative microorganisms. Streptococci and pneumococci were found to be more sensitive to natural than to penicillin-resistant penicillins. The only advantage of semi-synthetic penicillins is stability against staphylococcal beta-lactamases, and therefore these drugs are currently considered the drugs of choice for the treatment of staphylococcal infection.
In recent years, staphylococcus strains resistant to oxacillin have been isolated (they are usually also resistant to cephalosporins). The frequency of detection of resistant strains of staphylococcus is 5-15%. In this case, the clinical effect can be achieved by increasing the daily dose of antibiotics (oxacillin to 12-16 g) and their combination with aminoglycosides. Therefore, the scope of application of this group of antibiotics was actually limited to the treatment of infections caused by methicillin-sensitive staphylococci.
Late 1950s: antibiotics, penicillin
In the late 1950s, synthetic penicillins (ampicillin) were obtained, and in 1972–amoxicillin, which differed favorably from ampicillin in its high bioavailability. It was 90% when taken orally and did not depend on food intake, while the bioavailability of ampicillin did not exceed 40% and decreased by 2 times if the drug was used during meals. In addition, amoxicillin was much less likely than ampicillin to have side effects. Ampicillin and amoxicillin were destroyed by bacterial penicillinases, did not act on Pseudomonas aeruginosa, were inferior to benzylpenicillin in antimicrobial activity against streptococci and staphylococci sensitive to the latter. At the same time, their spectrum of action was much wider than that of natural penicillins, which allowed them to be used in infections caused by gram-negative bacteria. The higher activity against pneumococcus was another advantage, thanks to which amoxicillin quickly took a leading position among penicillins.
Then the synthesis of antisynegnoid penicillins was carried out and inhibitors of bacterial β–lactamases were created: clavulanic acid, sulbactam and tazobactam. Anti-pseudomonasal penicillins having an atypical β-lactam ring (ticarcillin, piperacillin, ureidopenicillins) are reserve antibiotics. Clavulanic acid, sulbactam and tazobactam practically do not have their own antibacterial activity, but they are able to inhibit penicillinases. Thus, today such combinations as ampicillin/sulbactam, amoxicillin/ clavunate, amoxicillin/sulbactam, ticarcillin/clavunate, piperacillin/tazobactam can be used.
Many microbes acquire the ability to enzymatically inactivate macrolides, lincosamides, aminoglycosides, others modify the targets of the same classes of drugs, as well as glycopeptides, fluoroquinolones, sulfonamides. Streptococci emit (efflux mechanism) 14–and 15-membered macrolides. There are also systems of multiple antibiotic resistance that provide pathogens with protection from drugs of several groups. The development of resistance to one drug often reduces sensitivity to drugs of other groups.
The combination of amoxicillin (amoxil) with beta-lactamase inhibitors, firstly, restores the activity of the antibiotic against beta–lactamase–producing strains of bacteria initially sensitive to aminopenicillins: staphylococci (penicillin-resistant), H. influenzae, M. catarrhalis, intestinal bacteria and others. Secondly, the addition of inhibitors leads to the appearance of activity against a number of gram-negative microorganisms (Klebsiella spp., Proteus vulgaris, Citobacter) that have natural resistance to aminopenicillins.
Amoxicillin (as well as carbapenems and parenteral cephalosporins of the III–IV generations) remains active against the leading bacterial pathogen of infections of the respiratory system and ENT organs–pneumococcus. The resistance of S. pneumoniae to beta-lactam antibiotics is due to the modification of the penicillin–binding protein (PSB) – the target of action for drugs in the bacterial cell, which leads to an increase in the minimum suppressive concentration (MPC) of drugs and a decrease in clinical efficacy. The combination with β-lactamase inhibitors has little effect on the activity of antibiotics, since its mechanism of resistance to penicillins is not associated with the production of β–lactamases. Therefore, for a reliable clinical effect against pneumococci, amoxicillin concentrations exceeding the MPC for penicillin-resistant strains are necessary. This can only be achieved by increasing its dose. The low toxicity of amoxicillin makes it possible to safely use high doses of this antibiotic.
There is a steady trend of increasing resistance of S. pneumoniae to penicillin in the world, which determines the need to revise the principles of antibacterial therapy for pneumococcal infections. In 1998-2000, a study was conducted in several dozen centers in 26 countries (including Russia), during which the sensitivity of 18,000 strains of the main bacterial pathogens of infections of the respiratory system and ENT organs (S. pneumoniae, H. influenzae and M. catarrhalis) to 23 antibacterial drugs was evaluated. Penicillin resistance (MPC≥2 mg / l) was established in 18.2% of S strains. pneumoniae . The highest activity against pneumococcus among beta–lactam antibiotics was observed in amoxicillin/clavulanate (2000/125 mg) – 97.9%. The activity against pneumococcus in amoxicillin/clavulanate with a standard ratio of active substances was slightly less-95.5%, the activity of amoxicillin and ceftriaxone was 95.1%. The highest efficacy among antibacterial drugs of all groups was observed only in respiratory fluoroquinolones – 98.5–98.9%.
In conclusion, I would like to emphasize once again that, despite the discovery of new classes of antibacterial drugs, amoxicillin holds its position due to its good tolerability, high safety profile, convenient intake regimen, the possibility of implementing step-by-step therapy and low cost.