Antimicrobial Drugs PDF

Introduction  It involves the use of drugs to treat (and, hopefully, to cure) infectious diseases.  A chemotherapeutic agent is any chemical (drug) used to treat any condition or disease.  The chemotherapeutic agents used to treat infectious diseases are collectively referred t...

Introduction  It involves the use of drugs to treat (and, hopefully, to cure) infectious diseases.  A chemotherapeutic agent is any chemical (drug) used to treat any condition or disease.  The chemotherapeutic agents used to treat infectious diseases are collectively referred to as antimicrobial agents.  Any chemical (drug) used to treat bacterial diseases are called antibacterial agents, as such antifungal agents, antiprotozoal agents, & antiviral agents.  An antibiotic is a substance produced by a microorganism that is effective in killing or inhibiting the growth of other microorganisms.  The antibiotics produced by soil organisms (moulds and bacteria) give them a selective advantage in the struggle for the available nutrients in the soil.  Ex: From moulds; Penicillin and cephalosporins  Ex: From bacteria: bacitracin, erythromycin, and chloramphenicol  Many antibiotics have been chemically modified to kill a wider variety of pathogens or reduce side effects; these modified antibiotics are called semisynthetic antibiotics.  Ex: semisynthetic penicillins, such as ampicillin and carbenicillin Characteristics of an ideal Antimicrobial agent  Kill or inhibit the growth of pathogens  Cause no damage to the host  Cause no allergic reaction in the host  Be stable when stored in solid or liquid form  Remain in specific tissues in the body long enough to be effective  Kill the pathogens before they mutate and become resistant to it The five most common mechanisms of action of antimicrobial agents are as follows: 1. Inhibition of cell wall synthesis 2. Damage to cell membranes 3. Inhibition of nucleic acid synthesis (either DNA or RNA synthesis) 4. Inhibition of protein synthesis 5. Inhibition of enzyme activity Antibacterial agents  Bactericidal agents: which kill the bacteria.  Bacteriostatic: Drugs which inhibit the growth of bacteria. (Used in patients whose host defense mechanisms are functioning properly) Ex: Sulfa drugs  Narrow spectrum antibiotics: They kill either Gram-positive or Gram-negative Ex: Only for Gram +ve: vancomycin; Only for Gram –ve: colistin and nalidixic acid  Broad spectrum antibiotics: They kill both Gram-positives and Gram-negatives. Ex: Active against both G+ve and G-ve: Major Categories of Antibacterial Agents  Penicillins are referred to as β-lactam drugs because their molecular structure includes a four- sided ring structure known as a β-lactam ring.  Penicillins interfere with the synthesis of bacterial cell walls and have maximum effect on bacteria that are actively dividing. They are bactericidal drugs.  Except for drug-resistant strains, penicillin G is effective against Gram-positive cocci, Gram- positive bacilli, Gram-negative cocci, some anaerobic bacteria and some spirochetes too. Cephalosporins  The cephalosporins are also β –lactam antibiotics and, like penicillin, are produced by moulds.  Also like penicillins, cephalosporins interfere with cell wall synthesis and are bactericidal.  The cephalosporins are classified as  1st Gen: active against Gram-positive bacteria  2nd Gen: Active against Gram-negative bacteria  3rd Gen: Active against G-ve & P. aeruginosa  4th Gen: Active for both G+ve & G-ve & P. aeruginosa Tetracyclines  Tetracyclines are broad-spectrum drugs that exert their effect by targeting bacterial ribosomes.  They are bacteriostatic. Tetracyclines are effective against a wide variety of bacteria, including chlamydias, mycoplasmas, rickettsias, Vibrio cholerae, and spirochetes like Borrelia spp. and T. pallidum. Aminoglycosides  Aminoglcosides are bactericidal broadspectrum drugs that inhibit bacterial protein synthesis.  Aminoglycosides are effective against a wide variety of aerobic Gram- negative bacteria, but are ineffective against anaerobes. They are used to treat infections with members of the family Enterobacteriaceae Macrolides  Macrolides inhibit protein synthesis. They are considered bacteriostatic at lower doses and bactericidal at higher doses.  The macrolides include erythromycin, clarithromycin, and azithromycin. They are effective against chlamydias, mycoplasmas, T. pallidum, and Legionella spp. Fluoroquinolones  Fluoroquinolones are bactericidal drugs that inhibit DNA synthesis.  The most commonly used fluoroquinolone, ciprofloxacin, is effective against members of the family Enterobacteriaceae and P. aeruginosa. Multidrug Therapy  In some cases, a single antimicrobial agent is not sufficient to destroy all the pathogens that develop during the course of a disease; thus, two or more drugs may be used simultaneously to kill all the pathogens and to prevent resistant mutant pathogens from emerging.  In tuberculosis, for example, in which multidrug-resistant strains of Mycobacterium tuberculosis are frequently encountered, four drugs (isoniazid, rifampin, pyrazinamide, and ethambutol) are routinely prescribed, and as many as 12 drugs may be required for especially resistant strains.  Synergism versus Antagonism Synergism  When the use of two antimicrobial agents to treat an infectious disease produces a degree of pathogen killing that is far greater than that achieved by either drug alone, the phenomenon is known as synergism.  Synergism is a good thing! Ex: Trimethoprim and sulfamethoxazole, a combination referred to as co-trimoxazole. Antagonism  When the use of two drugs produces an extent of pathogen killing that is less than that achieved by either drug alone, the phenomenon is known as antagonism. Ex: Antagonism between Bacteriostatic and Bactericidal Antibiotics, Induction of B-lactamase by one agent, renders the second agent ineffective  The extent of pathogen killing is less than that achieved by either drug alone. Antagonism is a bad thing! Antifungal agents  It is much more difficult to use antimicrobial drugs against fungal and protozoal pathogens, because they are eukaryotic cells; thus, the drugs tend to be more toxic to the patient.  Most antifungal agents work in one of three ways:  By binding with cell membrane sterols  By interfering with sterol synthesis  By blocking mitosis or nucleic acid synthesis Antiprotozoal agents  Antiprotozoal drugs are usually quite toxic to the host and work by  Interfering with DNA and RNA synthesis  Interfering with protozoal metabolism Antiviral agents  Antiviral agents are particularly difficult to develop and use because viruses are produced within host cells.  A few drugs have been found to be effective in certain viral infections; these work by inhibiting viral replication within cells.  Certain antiviral agents are administered simultaneously, in combinations referred to as “cocktails.”  Unfortunately, such cocktails are quite expensive and some strains of HIV have become resistant to some of the drugs Drug resistance (“Superbugs”)  Although the term superbug most often refers to multiply resistant bacteria, other types of microbes (e.g., viruses, fungi, protozoa) have also become multiply drug resistant. Resistant to Drugs 1. Intrinsic resistance: Bacteria which are naturally resistant to a particular antimicrobial agent. Ex: mycoplasmas have no cell walls and are, therefore, resistant to any drugs that interfere with cell wall synthesis 2. Acquired resistance: Bacteria which were once susceptible to a particular drug and later become resistant. Ex: Bacteria usually acquire resistance to antibiotics (antimicrobial agents) by one of four mechanisms Mechanisms of antibiotic Resistance Enzymatic Inactivation Enzymatic Inactivation  A β-lactam antibiotic is an antibiotic that contains a β-lactam ring in its molecular structure.  Penicillin and cephalosporin molecule is a double-ringed structure (garage and house), The “garage” is called the β-lactam ring.  The enzymes produced by bacteria to destroy the β-lactam ring is called β- lactamases. When the β–lactam ring is destroyed, the antibiotic no longer works. Thus, an organism is resistant to antibiotics containing the β-lactam ring.  There are two types of β-lactamases: penicillinases and cephalosporinases. Penicillinases destroy the β-lactam ring in penicillins and cephalosporinases destroy the β-lactam ring in cephalosporin.  To combat the effect of β-lactamases, the β-lactam antibiotic with a β-lactamase inhibitor are used (e.g., clavulanic acid, sulbactam, or tazobactam). Altered Target  The target is altered in a way that decreases its affinity for the antimicrobials, the inhibitory effect will be proportionately decreased.  Substitution of a single amino acid at a certain location in a protein can alter its binding to the antimicrobials without affecting its function in the bacterial cell.  Penicillin binding proteins -altered or novel PBPs with low affinity (β-lactams, glycopeptide) Alterations in DNA gyrase, topoisomerase IV (quinolones)