Antibiotics and Antibiotic Resistance PDF

ANTIBIOTICS AND ANTIBIOTIC RESISTANCE Antibiotics – biochemical substances produced by microorganisms that inhibit the growth of, or kill, other microorganisms. Many drugs are now completely synthetic or the natural drug is manipulated to change its structure called semi synthetics. There is a la...

ANTIBIOTICS AND ANTIBIOTIC RESISTANCE Antibiotics – biochemical substances produced by microorganisms that inhibit the growth of, or kill, other microorganisms. Many drugs are now completely synthetic or the natural drug is manipulated to change its structure called semi synthetics. There is a large number of antimicrobial agents available for treating diseases caused by microorganisms. Such drugs are now an essential part of modern medical practice. The antimicrobial agents used in medical practice are aimed at eliminating the infecting microorganisms or at preventing the establishment of an infection. To be of therapeutic use, an antimicrobial agent must exhibit selective toxicity; it must exhibit greater toxicity to the infecting pathogens than to the host organism Characteristics of an antibiotic It should be toxic to the infecting organism while harmless to the host cells and the microbiota of the host. It should stay in toxic form for a sufficient amount of time to affect the infecting microorganism. If it changes to another form or is broken down in the body, it may not be useful. Sufficient amounts of it should reach the site of infection to kill the infecting agent. The infecting agent should be sensitive to it. Broad-spectrum antibiotics are active against several types of microorganisms (e.g., tetracyclines are active against gram-negative rickettsiae. mycoplasma and chlamydia) while narrow-spectrum antibiotics act against only one type of microorganism (eg, vancomycin is active against gram-positive staphylococcus only). Antibiotics may be bactericidal, that is, they kill the bacteria, or may be bacteriostatic, that is, they inhibit the growth of bacteria but do not kill them. In the latter type, the bacteria can grow when the drug is withdrawn. TYPES OF ANTIBIOTICS BASED ON MECHANISM OF ACTION Inhibition of cell wall synthesis : Antibiotics such as Penicillins and cephalosporins act by inhibiting transpeptidase and hence inhibit cell wall synthesis. They bind to the penicillin-binding proteins (PBP) which are cell surface receptors. Due to the absence of a rigid cell wall. the bacterial cell cannot withstand the osmotic pressure and hence ruptures. Inhibition of protein synthesis : Bacteria have 30S and 50S ribosomes which differ from host cell ribosomes. Protein synthesis inhibitors take advantage of this difference. They act by misreading messenger RNA and inhibiting the formation of the initiation complex. Drugs that act on 30S ribosomes are: Aminoglycosides (gentamicin, amikacin) Tetracycline (blocks the aminoacyl transfer RNA (RNA) Drugs that act on 50S ribosomes are: Chloramphenicol, which blocks the action of peptidyl transferase, thereby preventing the formation of new peptides Macrolides (erythromycin, clarithromycin and azithromycin), which bind to the 50S ribosome. thereby preventing translocation Other antibiotics with similar action-clindamycin. streptogramin and linezolid Inhibition of nucleic acid synthesis : This may take place in three ways. 1. Inhibition of precursor synthesis: Sulphonamides These are structural analogues to para-amino benzoic acid (PABA) required for folic acid synthesis. Trimethoprim This inhibits dihydrofolate reductase. 2. Inhibition of DNA synthesis: Fluoroquinolones They inhibit the DNA gyrase (topoisomerase) enzyme. 3 Inhibition of mRNA synthesis: Rifampicin acts by blocking RNA polymerase and thereby, mRNA synthesis.  Action on bacterial cell membrane: 1.Polymyxin destroys the phospholipid component of the cell membrane and acts on Pseudomonas and Acinetobacter. 2.Daptomycin disrupts the cell membrane of gram- positive cocci and acts against staphylococci and enterococci. ANTIBIOTIC RESISTANCE Antimicrobial resistance refers to development of resistance to an antimicrobial agent by a microorganism. It can be of two types acquired intrinsic Acquired Resistance this refers to the emergence of resistance in bacteria that are ordinarily susceptible to antimicrobial agents, by acquiring the genes coding for resistance. Most of the antimicrobial resistance shown by bacteria belong to this category. The emergence of resistance is a major problem worldwide in antimicrobial therapy. Infections caused by resistant microorganisms often fail to respond to the standard treatment l, resulting in prolonged illness, higher healthcare expenditures, and a greater risk of death.  Overuse and misuse of antimicrobial agents is the single most important cause of developmental og acquired resistance. The evolution of resistant strains is a natural phenomenon, which can occur among bacteria especially when an antibiotic is overused. Use of the particular antibiotic poses selective pressure in a population of bacteria which in turn promotes resistant bacteria to thrive and the susceptible bacteria to die off. thus the resistant bacterial populations flourish in areas of high antimicrobial use, where they enjoy a selective advantage over susceptible populations. The resistant strains spread in the environment and transfer the genes coding for resistance to other unrelated bacteria. Other factors favouring the spread of antimicrobial resistance include- Poor infection control practices in hospitals- e.g. poor hand hygiene practices can facilitate transmission of resistant strains. inadequate sanitary conditions. inappropriate food-handling. irrational use of antibiotics by doctors, not following antimicrobial susceptibility report. Uncontrolled sale of antibiotics over the counters without a prescription. Intrinsic Resistance It refers to the innate ability of a bacterium to resist a class of antimicrobial agents due to its inherent structural or functional characteristics, (e.g. gram-negative bacteria are resistant to vancomycin). this imposes only little threat to the world as very few organisms show intrinsic resistance Mutational and Transferable Drug Resistance In presence of selective antibiotic pressure, bacteria acquire new genes mainly by two broad methods: Mutational Resistance Resistance can develop due to mutation of the resident genes. It is typically seen in Mycobacterium tuberculosis, developing resistance to anti-tubercular drugs. Mutational drug resistance differs from transferable drug resistance Usually, it is a low level resistance, developed to one drug at a time; which can be overcome by using combination of different classes of drugs. That is why multidrug therapy is used in tuberculosis using 4-5 different classes of drugs, such as isoniazid, rifampicin, pyrazinamide, ethambutol and streptomycin. Transferable Drug Resistance In contrast, transferable drug resistance is plasmid coded and usually transferred by conjugation or rarely by transduction, or transformation The resistance coded plasmid ( called R plasmid) can carry multiple genes, each coding for resistance to one class of antibiotic. thus, it results in a high degree of resistance to multiple drugs, which cannot be overcome by using combination of drugs. Mechanism of Antimicrobial Resistance Bacteria develop antimicrobial resistance by several mechanisms. 1. Decreased Permeability across the Cell Wall Certain bacteria modify their cell membrane porin channels; either in their frequency, size, or selectivity; thereby preventing the antimicrobials from entering into the cell. This strategy has been observed in many gram-negative bacteria, such as Pseudomonas, Enterobacter and Klebsiella species against drugs, such as imipenem, aminoglycosides and quinolones. 2. Efflux Pumps Certain bacteria possess efflux pumps which mediate expulsion of the drug(s) from the cell, soon after their entry; thereby preventing the intracellular accumulation of drugs. This strategy has been observed in: Escherichia coli and other Enterobacteriaceae against tetracyclines, chloramphenicol. Staphylococci against macrolides and streptogramins. Staphylococcus aureus and Streptococcus pneumoniae against fluoroquinolones. 3. By Enzymatic Inactivation Certain bacteria can inactivate the antimicrobial agents by producing various enzymes, such as: Beta lactamase enzyme production (observed in both gram-positive and gram-negative bacteria): It breaks down the beta lactam rings, there by inactivating the Beta lactam antibiotics Aminoglycoside modifying enzymes like (acetyltransferases, adenylyltransferase, and phosphotransferases, produced by both gram-negative and gram-positive bacteria)-they destroy the structure of aminoglycosides. Chloramphenicol acetyltransferase: It is produced by members of Enterobacteriaceae; it destroys the structure of chloramphenicol. 4.By Modifying the Target Sites Modification of the target sites of antimicrobial agents (which are within the bacteria) is a very important mechanism. It is observed in: MRSA (Methicillin-resistant Staphylococcus aureus): ln these strains, the target site of penicillin i.e. penicillin binding protein(PBP)gets altered toPBP-2a. The altered PBP do not sufficient to bind beta-lactam antibiotics and therefore prevent them from inhibiting the cell wall synthesis. Streptomycin resistance in Mycobacterium tuberculosis: It is due to modification of ribosomal proteins or 16S rRNA. Rifampicin resistance in Mycobacterium tuberculosis due to mutations in RNA polymerase. Quinolone resistance seen in many gram-positive bacteria, particularly S. aureus and S. pneumoniae due to mutations in DNAgyrase enzyme. Vancomycin resistance in enterococci (VRE): These strains have a change in the target site of vancomycin(i.e. D-alanine D-alanine side chain peptidoglycan)