Pharmacology- 3 Prof. Basel A Abdel-Wahab ANTIBIOTICS I&II Prof. Basel A Abdel-Wahab Professor of Clinical Pharmacology and Toxicology Pharmacology-3 Prof. Basel A Abdel-Wahab INTRODUCTION Chemotherapy: • The term chemotherapy was first used by Ehrlich (1904) to describe the use of synthetic chemicals to destroy infective agents. Selective toxicity: • The antimicrobial agent must produce toxic effect on the organism at concentrations that considered safe to the host. • Selective toxicity depends on the existence of biochemical differences between the parasite and the host. • The selective toxicity depends on the mechanisms of actions of the antimicrobial agent. Antibiotics: • Chemical substances produced by living microorganisms that destroy or suppress the growth of other microorganisms. • The term is now applied to the use of chemicals (natural or synthetic) that inhibit the growth of malignant cells in the body. Classification of Chemotherapeutic agents are divided into: A) Antimicrobial agents (Antibacterial, Antifungal and Antiviral). B) Antiparasitic agents (Anthelmintics and Antiprotozoal). C) Antineoplastic agents (anticancer). Agents. Pharmacology-3 Prof. Basel A Abdel-Wahab ANTIBACTERIAL AGENTS Classification of Antibacterial agents: Antimicrobial agents can be classified by different classifications I. According to the Spectrum against bacteria: 1) Drugs act mostly against Gram +Ve organisms e.g. B-lactam antibiotics (Penicillin G,V), Erythromycin, Macrolides, Vancomycin. 2) Drugs act mostly against Gram -Ve organisms e.g. Aminoglycoside antibiotics, polymyxins. 3) Drugs act against Gram +Ve and Gram -Ve organisms (Broad spectrum) e.g. Broad-spectrum penicillins, Cephalosporins, chloramphenicol and Tetracyclines. Pharmacology-3 Prof. Basel A Abdel-Wahab II According to the ultimate fate of the organism 1) Bacteriostatic drugs which temporarily inhibit the growth of the microorganism. 2) Bactericidal drugs which cause death of the microorganism This classification is somewhat not precise, and the distinction disappears when the concentration of the antibiotic is high, or a different microorganism is considered e.g. 1.Erythromycin: is bactericidal only at high concentrations; 2. Chloramphenicol: is primarily bacteriostatic although it may be bactericidal to certain species such as H-influenzae, N-meningitidis. Pharmacology-3 Prof. Basel A Abdel-Wahab N.B: • When a bacteriostatic drug is used the defense mechanisms of the host (humoral or cellular immunity) are relied on to destroy the microorganism whose multiplication is stopped by the drug. • In infections that cannot be controlled by host defense mechanisms as in infective Endocarditis or when the immune system is compromised by disease or drugs, **bactericidal drugs should be used and treatment with bacteriostatic drugs results in relapse as soon as treatment is discontinued. • Concurrent use of bacteriostatic with bactericidal drugs is not advisable, as they antagonize the action of each other on the bacteria. • If bactericidal drugs are most potent with actively dividing cells, then the inhibition of growth induced by a bacteriostatic drug should result in an overall reduction of efficacy when the drug is used in combination with a bactericidal drug. Pharmacology- 3 Prof. Basel A Abdel-Wahab III. According to the Mechanism of action: The most common classification based on the chemical structure and the proposed mechanisms of action are as follows: 1) Inhibition of bacterial cell wall synthesis: Cell walls of different bacteria vary in their composition, but all possess a common ground substance, “Peptidoglycan” which has great strength and provides the bacterial surface with the rigidity necessary to protect the underlying cytoplasmic membrane from osmotic shock. Peptidoglycan units composed of: 1) short peptide chain 2) Amino sugar (Nacetylgucosamine or N-acetyl muramic acid). Cell wall is made by transpeptidation among peptidoglycan units. Pharmacology- 3 Prof. Basel A Abdel-Wahab Any drug which impairs the structure or synthesis of this peptidoglycan will lead to damage of membrane, consequently lysis of the cell (Bactericidal action). Peptidoglycan is specific to the bacterial cell (not present in mammalian cells) and its inhibition is, therefore, a highly selective process. Examples of drugs acting by this mechanism are: Penicillins, Cephalosporins, Bacitracin, Vancomycin, cycloserine. Pharmacology- 3 Prof. Basel A Abdel-Wahab 2) Inhibition of the function of cytoplasmic membrane: The bacterial cytoplasmic membrane acts as an osmotic barrier and as a medium for the selective transport of nutrients into the bacterial cell. The antibacterial action depends on the increase in the permeability of the cytoplasmic membrane by a mechanism similar to the surface-active detergents. These effects are relatively non-specific. Examples of drugs acting by this mechanism are Polymyxin, Amphotericin B, Nystatin (Antifungal). Pharmacology-3 Prof. Basel A Abdel-Wahab 3) Inhibition of bacterial Protein Synthesis: Ribosomal DNA plays an essential role in the cellular protein synthesis. The subunits of bacterial ribosomes (30 S and 50 S subunits) are sufficiently different from mammalian cell ribosomes (40 S and 70 S subunits). Agents that selectively bind with the 30, 50S subunits can inhibit protein synthesis in bacterial cells without having major effect on mammalian cells. Examples of drugs acting by this mechanism are - Aminoglycosides, Tetracyclines, (30-S inhibitors) Chloramphenicol, Erythromycins, Lincomycins (50 s inhibitors). Pharmacology-3 Prof. Basel A Abdel-Wahab Pharmacology-3 Prof. Basel A Abdel-Wahab 4) Inhibition of some Metabolic Processes: (Competition for an essential metabolite): Many antibacterial compounds produce their effects by interfering with substances that are essential for bacterial growth. Example, the bacteriostatic action of sulphonamides is due to competition with p-aminobenzoic acid for the bacterial enzyme responsible for the conversion of p-aminobenzoic acid to folic acid. Pharmacology-3 Prof. Basel A Abdel-Wahab 4) Inhibition of bactereial Nucleic acid Synthesis: Some antimicrobial drugs form complex with DNA and block mRNA formation. e.g. 1. Quinolones inhibit DNA supercoiling by inhibiting the bacterial enzyme DNA gyrase (Topoisomerase II). 2. Rifampin inhibits RNA synthesis in bacteria by inhibiting DNAdependent RNA polymerase. Pharmacology-3 Prof. Basel A Abdel-Wahab RESISTANCE TO ANTIBACTERIAL AGENTS When penicillin was introduced, it soon became clear that some bacterial strains become resistant to its action. This problem has become of great importance in relation to most antibiotics and as each new agent has been introduced a period of maximum effectiveness has generally been followed by the appearance of increasing proportions of resistant strains. Bacterial resistance is the capacity of bacteria to withstand the effects of antibiotics or biocides that are intended to kill or control them. Neisseria gonorrhea, which causes gonorrhea, the antibiotics penicillin and tetracycline that were used against it in the 1980s, but are no longer effective against it. Eg: Gram-negative organisms are inherently resistant to vancomycin. The term "multiple resistance" (MR) or "multi-resistance" is used when a bacterial strain is resistant to several different antimicrobials or antimicrobial classes. For instance, multidrug resistant tuberculosis is simultaneously resistant to a number of antibiotics belonging to different chemical classes. Pharmacology-3 Prof. Basel A Abdel-Wahab Biochemical Mechanisms of Resistance to antibacterial agents 1- Microorganisms produce enzymes that destroy the active drug e.g. B-lactamases which inactivate penicillin, acetyl-transferases which inactivate chloramphenicol, adenylating and acetylating enzymes which inactivate aminoglycosides. 2- Microorganisms change their permeability to the drug, thereby reducing its uptake by the bacterium e.g. resistance of susceptible organisms to tetracyclines, polymyxins and aminoglycosides. This can be partly overcome by the simultaneous presence of a cell wall active drug e.g. penicillin. Pharmacology-3 Prof. Basel A Abdel-Wahab 3- Microorganisms develop modification of the drug binding sites or target enzymes e.g. in case of sulphonamides the target enzyme may lose its affinity for the drug while retaining its affinity for its substrate PABA. 4- Active replication of bacteria is usually required for most antibacterial drug actions. Consequently, microorganisms that are metabolically inactive may be resistant to drugs. However, their offsprings are fully susceptible. **A notable example is mycobacteria which often survive in tissues for many years and do not multiply. Such organisms are resistant to treatment and cannot be eradicated by drugs. However, if they start to multiply, e.g. following corticosteroid treatment, they are fully susceptible to the same drug. Pharmacology-3 Prof. Basel A Abdel-Wahab Pharmacology-3 Prof. Basel A Abdel-Wahab Adverse reactions of antibacterial agents The untoward reactions produced by antibacterial agents include toxic effects and hypersensitivity . Antibiotics also cause unique reactions that result from alterations in the microbial flora of the host. All individuals who receive broad spectrum antibiotics or combination of antibiotics undergo alteration in normal microbial population of intestinal, upper respiratory and genitourinary tracts; some develop “superinfection”. Superinfection is defined as the appearance of bacteriological and clinical evidence of a new infection during the chemotherapy of a primary one. It is relatively dangerous because it is responsible for new infection by Enterobacteriaceae, pseudomonas and candida which are difficult to be treated. Pharmacology-3 Prof. Basel A Abdel-Wahab COMBINATION OF ANTIMICROBIAL AGENTS Indications for clinical use of the combination (Advantages of combination): 1) Treatment of mixed bacterial (aerobic and anerobic) infections, examples: intra-abdominal infection, hepatic and brain abscesses and genital tract infections. 2) Therapy of severe infections in which a specific cause is unknown. 3) Enhancement of antibacterial activity in the treatment of specific infections. In some cases a combination of two antimicrobial agents may produce synergistic effect which leads to: i- Reduction in the dosage of one or both. ii- Rapid or complete bactericidal effect which is not achieved with either drug alone. 4) Prevention of emergence of resistant microorganisms e.g. treatment of tuberculosis. Synergism : Antibiotic synergism can occur in several types of situations and the mechanisms involved include: Pharmacology-3 Prof. Basel A Abdel-Wahab 1- Sequential block of microbial metabolic pathway by two drugs i.e. blocking successive steps. 1.Sulfonamides compete with paraaminobenzoic acid (PABA) for the synthesis of folic acid. 2.Trimethoprim affects the next step by inhibiting the enzyme dihydrofolate reductase that reduces dihydrofolate to tetrahydrofolate; both steps are essential for the synthesis of nucleic acids. The simultaneous use of trimethoprim and sulfonamides produce more complete inhibition of growth than either component alone and can be used for treatment of infections caused by microorganisms that may be resistant to sulfonamides alone Pharmacology-3 Prof. Basel A Abdel-Wahab 2- One drug inhibits an enzyme that destroys the second drug. Clavulinic acid or sulbactum inhibits b-lactamase or penicillanase and can protect Amoxicillin or Ticarcillin from inactivation by b-lactamase producing microorganisms. This approach may allow successful treatment of infection by micro organisms that produce b-lactamase as H.influenzae 3- One drug may enhance the uptake of a second drug through the microbial cell wall or cell membrane. e.g. Penicillin and cephalosporins which are inhibitors of cell wall synthesis may enhance the penetration of aminoglycosides which then act on the ribosomes and accelerate the bactericidal effect. Aminoglycosides and B-lactam antibiotics are used in treatment of enterococcal endocarditis, pseudomonas infections and others. Pharmacology-3 Prof. Basel A Abdel-Wahab Disadvantages of combinations of antimicrobial agents. a) The risk of toxicity from two or more agents. b) Increased cost. c) Antagonism of antibacterial effect may result when bacteriostatic and bactericidal agents are given concurrently; well-documented clinical examples are relatively rare, (pneumococcal meningitis treatment by penicillin is more effective by penicillin alone than by penicillin plus chlortetracycline). d) Antimicrobial combination often produces effects no more than those of an effective single drug Pharmacology-3 Prof. Basel A Abdel-Wahab Prophylaxis of Infections with Antibiotics Chemoprophylaxis has been employed primarily for 3 purposes: 1-To protect healthy persons from invasion by specific microorganism to which they are exposed e.g.the use of penicillin G to prevent infection with group A streptococci or to prevent gonorrhea after contact with infected person. 2-To prevent secondary bacterial infections in patients who are at risk as those receiving cancer chemotherapy or having organ transplantation. 3-To prevent endocarditis in patients with valvular or cardiac lesions who are undergoing dental, surgical or other procedures that produce a high incidence of bacteremia. 4. To prevent wound infection after surgical procedures use chemoprophylaxis in selected operative procedures:a-In dirty and contaminated surgical procedures as surgery of GIT. b-In surgical procedures involving the insertion of prosthetic implants as prosthetic cardiac valves or artificial orthopedic devices Pharmacology-3 Prof. Basel A Abdel-Wahab Failure of antibiotic therapy (Misuses of antibiotics) 1- Treatment of non-bacterial infections e.g. treatment of virus disease by antibiotics. 2- Therapy of fever of undetermined origin. 3- Improper dosage. 4- Improper choice of antibacterial agent e.g. using a bacteriostatic drug in cases where a bactericidal agent is needed e.g. endocarditis 5- Omission of surgical drainage for purulent exudate (pus) or necrotic or avascular tissues. For example, patients with empyema often fail to be cured by the administration of large doses of an effective drug until drainage of the involved area is done. Thank You….
