GENERAL PRINCIPLE OF ANTIBIOTICS AND ANTIMICROBIAL THERAPY
Eduard Jirkovský, Přemysl Mladěnka
Content
DEFINITION ... 2
STRUCTURE OF BACTERIAL CELL ... 2
CLASSIFICATION OF ATB ACCORDING TO MECHANISM OF ACTION ... 3
CLASSIFICATION OF ATB ACCORDING TO TYPE OF ACTION ... 4
ANTIMICROBIAL RESISTANCE ... 4
WAYS OF TRANSFERE OF ANTIBIOTIC RESISTANCE GENES ... 5
MECHANISMS OF ANTIBIOTIC RESISTANCE ... 5
COMBINATION OF ANTIBIOTICS ... 5
ANTIBIOTIC PROPHYLAXES ... 5
TYPE OF ANTIBIOTIC THERAPY ... 6
REFERENCES ... 6
Definition
• Antibiotics (ATB) are drugs produced by various microorganisms to inhibit or kill other microorganisms.
• Today this term include also synthetic antimicrobial drugs.
• Synthetic antimicrobial drugs were called originally (bacterial) chemotherapeutics. However, this term should not be used further because nowadays the meaning of the term
“chemotherapeutics” include also anticancer and antiparasital therapy.
Structure of bacterial cell
Fig. 1. Structural differences between bacterial prokaryotic cell (A) a human eukaryotic cell (B)..
• single cell prokaryotic organism
• does not content nucleus and mitochondria
• plasmids are extrachromosomal DNA particle
• in contrast to viruses, bacterial cell contents ribosomes
• in contrast to mammalian cells, bacterial cell envelope is composed from the cytoplasmatic wall and the cell wall. Cell wall protects bacteria against external environment and loss of structural integrity caused by higher internal turgor pressure
➢ Cell wall is composed by peptidoglycans (murein). It is a heteropolymer (polysaccharide) made up of linear backbone consisting of alternating N-Acetylmuramic acid (NAM)
and N-acetylglucosamine (NAG) residues in equal amounts which are cross-linked by peptide chains.
➢ Cell wall of G-negative bacteria have a thin peptidoglycan layer (approx. 5-10 % of cell wall) and thick lipid layer. They are not dyeable by crystal violet during Gram staining test (pink colour).
➢ Cell wall of G-positive bacteria contains almost 95 % of murein layer (40x thicker than in G-) in contrast to absence of the lipid layer. They stain purple during Gram staining test.
Classification of ATB according to mechanism of action
• agents inhibiting bacterial cell wall synthesis
➢ β-lactams
➢ glycopeptides
• agents interacting with bacterial cell wall permeability
➢ polymyxins
➢ daptomycin
• agents interacting with function of ribosomal subunits
➢ tetracyclines
➢ aminoglycosides
➢ amphenicols
➢ macrolides
➢ lincosamides
➢ oxazolidinones
➢ pleuromutilins
• agents interacting with nucleic acids
➢ ansamycins
➢ chinolones
➢ fidaxomycin
• agents interacting with folate synthesis
➢ sulfonamides
➢ trimetoprime
• others
➢ nitroimidazols
➢ nitrofuranoin
Classification of ATB according to type of action
• bactericidal – such ATB kills bacteria
➢ Primary bactericidal are ß-lactams, aminoglycosides, glycopeptides, peptides (polymyxin), fluorochinolone and nitroimidazols
• bacteriostatic – such ATB stops bacteria from reproducing but not necessary kills them
➢ Primary bacteriostatic are tetracyclines, macrolides, chloramfenicole, lincosamides and sulfonamides.
➢ Patients cured by bacteriostatic agents must have uncompromised immune host defense mechanisms to be able to eradicate the bacteria.
Bactericidal ATB are drug of choice for
• life threatening infections
• patients with immunodeficiency
• infections where host defense mechanisms are not involved/ineffective
The division of ATB to bacteriostatic and bactericidal is not absolute. Many bacteriostatic ATBs are often cidal at higher concentrations.
A bactericidal ATB should relieve patient’s symptoms within 24-48 hours, otherwise is possible that the infection is caused by a microbe resistant to the chosen ATB.
Antimicrobial resistance
• primary antibiotic resistance – bacteria are insensitive for the chosen ATB due to their natural property
• acquired antibiotic resistance - develops during drug administration
➢ mutation resistance (chromosomal) is the result of a spontaneous mutation of the chromosome (frequency 10-12-10-7); for rifampicin therapy is more frequent (10-7-10-5)
➢ transferable resistance (plasmid-mediated) – majority of the resistance to antibiotics in clinical practice, plasmids can replicate independently of chromosomes and could transfer the resistance genes between bacteria (even of different species).
• every use of ATBs is risk for development of antimicrobial resistance. Of major importance is use of ATB in suboptimal doses, voluntary discontinuation of ATB therapy and use of ATB on primary resistant species
Ways of transfere of antibiotic resistance genes
• transduction – the plasmid DNA is enclosed in a bacterial virus (bacteriophage) which transfers plasmids between individual bacteria. Important in the transmission of resistance genes between strains of staphylococci and streptococci.
• transformation – free DNA molecules in the bacteria environment are incorporated into recipient bacterial DNA by mean of normal homologous recombination. Only few bacterial species could accept DNA in this ways under natural conditions. Generally the way of the lowest clinical importance.
• conjugation – transfer of the resistance genes (chromosomal or extrachromosomal DNA) involves cell-to-cell contact of bacteria via sex pili (proteinaceous surcace tubules). During this process one or more resistance genes could be transferred. Generally for bacteria of the same species. Way of the major clinical importance in antibiotic resistance.
Mechanisms of antibiotic resistance
• a drug could not achieve its molecular
• a drug could not cross the cell wall
• lack of energy for active drug transport in anaerobic conditions
• presence and/or induction of efflux transporter
• inactivation of the drug
• modification of drug’s target structure – mutation of genes for gyrase, ribosomal subunits, penicillin binding protein (PBP)
Combination of antibiotics
• rational synergistic combination increase treatment effectivity
• combination of bactericidal and static ATB is generally unsuitable
• decrease incidence of the resistance
• increase risk of drugs toxicities and manifestation of adverse effects
• standard combination for treatment of H. pylori and tuberculosis
Antibiotic prophylaxes
• routine initiation of antibiotic therapy after surgical and dental procedures, organ transplantation etc. to prevent microbial contamination and infection
• often controversial, a lack of precise guidelines for specific situations; based mainly on in- house experiences
• clinical benefit proven for bigger surgical procedures (e.g. abdominal surgery, joint replacement surgery, bigger dental surgery etc.)
• unsubstantiated approach after common injuries, fractures etc. or installation of central port for i.v. administration
Type of antibiotic therapy
• empiric – based on general experiences with individual infections
• rational – based on the results of microbial cultivation and ATB sensitivity test
• combined – use of broad-spectrum ATB in the first step, further adjustment according to results of microbial cultivation
REFERENCES
Brunton L, Chabner B & Knollman B. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12th edition. Mc Graw-Hill: New York, 2011.
Jindrák V, Hedlová, Urbášová P et al. Antibiotická politika a prevence infekcí v nemocnici.
Mladá fronta:Praha, 2014.
Rang HP, Dale MM, Ritter JM, Moore PK. Pharmacology 5th edition. Churchill Livingstone:
Edinburgh, 2003.
