PHA 046 Antimicrobial Agents PDF

Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________...

Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ Lesson title: Antimicrobial Agents Materials: Book, Pen and SAS Lesson Objectives: References: At the end of the lesson, you should be able to: Burton's Microbiology for the Health 1. Classify the mechanism of actions of antibacterial, antifungal, Sciences; Paul Engelkirk, Paul G. Engelkirk, antiprotozoal, anthelmintic and antiviral agents Janet L. Duben-Engelkirk Lippincott Williams 2. Recognize occurrence of antimicrobial resistance & Wilkins, 29 Aug 2014 3. Create interventions to prevent antimicrobial resistance Productivity Tip: In the previous modules, you encountered the different microorganisms and understood their metabolism and growth. In this module, you can now connect those knowledge to this topic – identifying drugs or agents that target microbial diseases. A very fundamental topic as future pharmacist as this module will help you as you to dispense certain prescription drugs. Many drugs to memorize but it’ll be worth it. A. LESSON PREVIEW/REVIEW Introduction (2 mins) Another aspect of controlling the growth of microorganisms involves the use of drug to treat (and hopefully to cure) infectious diseases in other words, using drugs to control the growth of pathogen in vivo. Although we most often hear the term chemotherapy used in conjunction with cancer, it actually refers to the use of any chemical (drug) to treat any disease or condition. The chemicals (drugs) used to treat diseases are referred as chemotherapeutic agents. By definition, a chemotherapeutic agent is any drug used to treat any condition or disease. For thousands of years, people have been discovering and using herbs and chemicals to cure infectious diseases. Native which doctors in Central and South America long ago discovered that the herb, ipecac, aided in treatment of dysentery, and that a quinine extract of cinchona bark was effective in treating malaria. During the 16 th and 17 centuries the alchemists of Europe searched for ways to cure smallpox, syphilis and many other diseases that were rampant during the period of history. Unfortunately, many of the mercury and arsenic chemicals that were used frequently caused more damage to the patient than to the pathogen. The chemotherapeutic agents used to treat infectious diseases are collectively referred to as antimicrobial agents thus it is any chemical (drug) used to treat an infectious disease, either by inhibiting or by killing pathogens in vivo. Drugs used to treat bacterial diseases are called antibacterial agents, whereas those used to treat fungal diseases are called antifungal agents. Drugs used to treat protozoal diseases are called antiprotozoal agents, and those used to treat viral diseases are called antiviral agents. Characteristics of and Ideal Antimicrobial Agent Good to know! The ideal antimicrobial agent should: Unfortunately, most 1. Kill or inhibit growth of pathogens antimicrobial agents 2. Cause no damage to the host have some side 3. Cause no allergic reaction in the host effects, produce 4. Be stable when stored in solid or liquid form allergic reactions, or 5. Remain in specific tissues in the body long enough to be effective permit development 6. Kill the pathogen before they mutate and become resistant to it of resistant mutant pathogens. This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ This module is consists of five topics, classifying antimicrobial agents: I. Antibacterial agents II. Antifungal agents III. Antiprotozoal agents IV. Anthelmintic agents V. Antiviral agents Activity 1: What I Know Chart, Part 1 (5 mins) Instructions: In this chart, reflect on what you know now. Do not worry if you are or not of your answers. This activity simple serves to get started on thinking about our topic. Answer only the first column, “what I know”. Leave the third column “what I learned” blank at this time. What I Know Questions: What I Learned (Activity 4) What is susceptible? What is inhibition? What is a drug of choice? B.MAIN LESSON Activity 2: Content Notes THE HISTORY OF CHEMOTHERAPY By definition, an antibiotic is a substance produced by a microorganism that is effective in killing or inhibiting the growth of other microorganisms. Although all antibiotics are antimicrobial agents not all antimicrobial agents are antibiotics, therefore, the terms are not synonyms, and care should be taken to use the terms correctly. Antibiotics are produced by certain moulds and bacteria, usually those that live in soil. The antibiotics produced by soil organism give them a selective advantage in the struggle in the struggle for the available nutrients in the soil. Penicillin and cephalosporins are examples of antibiotics produced by moulds, bacitracin, erythromycin, and chloramphenicol are examples of antibiotics produced by bacteria. Although originally produced by microorganisms, many antibiotics are now synthesized or manufactured in pharmaceutical laboratories. Also many antibiotics have been chemically modified to kill a wider variety of pathogens or reduce side effects; these modified antibiotics are called semisynthetic antibiotics. Semisynthetic antibiotics include semisynthetic penicillins, such as ampicillin and carbenicillin. Antibiotics are primarily antibacterial agents and are used to treat bacterial diseases. PAUL EHRLICH ‒ Father of Chemotherapy ‒ He coined the term selective toxicity and chemotherapy Selective toxicity: means that the drug is harmful to a pathogen without being harmful to the host Chemotherapy: the use of drugs to treat a disease This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ ALEXANDER FLEMING ‒ Discovered Penicillin in 1928 ‒ In 1928, Alexander Fleming observed that the growth of the bacterium Staphylococcus aureus was inhibited in the area surrounding the colony of a mold that had contaminated a Petri plate HOWARD WALTER FLOREY AND ERNST BORIS CHAIN, ‒ Purified penicillin and demonstrated its effectiveness in the treatment of various bacterial infections. SELMAN WAKSMAN ‒He isolated streptomycin (the first antituberculosis drug) and subsequently discovered antibiotics such as chloramphenicol, tetracycline, and erythromycin in soil samples. SPECTRUM OF ANTIMICROBIAL ACTIVITY NARROW SPECTRUM ‒ drugs that are effective against few types of bacteria. ‒ Advantage: will cause less resistance of the bacteria as well as it will deal only with specific bacteria ‒ Disadvantage: can be used only if the causative organism is identified. BROAD SPECTRUM ‒ drugs that are effective against several different classes of bacteria. Both gram positive and negative ‒ Advantage: there is less need to identify the infecting pathogen before treatment. ‒ Disadvantages: Children increased risk of developing childhood asthma and may give rise to drug resistance EXTENDED-SPECTRUM - Effective against gram-positive organism and a significant number of gram-negative organisms BACTERICIDAL – means killing of microorganism BACTERIOSTATIC – inhibition of metabolism and reproduction of microorganism Good to Know! When are bactericidal antibiotics preferable to bacteriostatic antibiotics? 1. Immunocompromised patients 2. Infections that are immediately life-threatening 3. Infections that are protected from the host’s immunity THE ACTION OF ANTIMICROBIAL DRUGS To be acceptable, an antimicrobial agent must inhibit or destroy the pathogen without damaging the host. To accomplish this, the agent must target a metabolic process or structure possessed by the pathogen but not possessed by the host. The five most common mechanisms of action of antimicrobial agents are as follows: 1. Inhibiting Cell Wall Synthesis 2. Inhibiting Protein Synthesis 3. Injuring the Plasma Membrane 4. Inhibiting Nucleic Acid Synthesis 5. Inhibiting the Synthesis of Essential Metabolites This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ 1. Inhibiting Cell Wall Synthesis TARGETS: Penicillin-binding proteins PBP 1a and 1b are transpeptidases involved in peptidoglycan synthesis associated with cell elongation. PBP 2 a transpeptidase involved in maintaining the rod shape of bacilli. PBP 3 transpeptidase required for septum formation during cell division. PBP 4 through 6 are carboxypeptidases responsible for the hydrolysis of D alanine–D-alanine terminal peptide bonds of the cross-linking peptides. 2. Inhibiting Protein Synthesis - Binds to 30s ribosomes Aminoglycoside Tetracycline - Binds to 50s ribosomes Chloramphenicol Erythromycin/Macrolides Lincosamides 3. Injuring the Plasma Membrane TARGET: - Lipopolysaccharide, - inner and outer membranes 4. Inhibiting Nucleic Acid Synthesis - A number of antibiotics interfere with the processes of DNA replication and transcription in microorganisms. These drugs block bacterial topoisomerase or RNA polymerase 5. Inhibiting the Synthesis of Essential Metabolites Targets: - Folic acid synthesis enzyme - Mycolic acid synthesis enzyme TEST TO GUIDE CHEMOTHERAPY 1. DISK DIFFUSION METHOD Kirby-Bauer test - A bacterial culture is inoculated on an agar medium, and filter paper disks impregnated with chemotherapeutic agents are overlaid on the culture. - After incubation, the diameter of the zone of inhibition is used to determine whether the organism is sensitive, intermediate, or resistant to the drug. - Minimal inhibitory concentration (MIC) is the lowest concentration of drug capable of preventing microbial growth; MIC can be estimated using the E test. This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ 2. BROTH DILUTION TESTS - In a broth dilution test, the microorganism is grown in liquid media containing different concentrations of a chemotherapeutic agent. - The lowest concentration of a chemotherapeutic agent that kills bacteria is called the minimum bactericidal concentration MULTIDRUG THERAPY - two or more drugs may be used simultaneously to kill all the pathogens and to prevent resistant mutant pathogens from emerging Possible reasons for using two or more antimicrobials simultaneously instead of a single drug are as follows: 1. To give prompt treatment in desperately ill patients suspected of having serious microbial infections. 2. To delay the emergence of microbial mutants’ resistant to one drug in chronic infections by the use of a second or third non-cross-reacting drug. 3. To treat mixed infections, particularly those after massive trauma or those involving vascular structures. 4. To achieve bactericidal synergism or to provide bactericidal action. Disadvantages 1. The physician may believe that because several drugs are already being given, everything possible has been done for the patient, leading to relaxation of the effort to establish a specific diagnosis. 2. The more drugs that are administered, the greater the chance for drug reactions to occur or for the patient to become sensitized to drugs. 3. The cost is unnecessarily high. 4. Antimicrobial combinations usually accomplish no more than an effective single drug. 5. Very rarely, one drug may antagonize a second drug given simultaneously Pharmacological Drug Interactions (Enhancement of Drug Effects) 1. Addition: (1+1=2) the combined action is equivalent to the sum of the actions of each drug when used alone Example: Bactericidal + Bacteriostatic Trimethoprim & Sulfamethoxazole inhibit different steps in synthesis of folic acid, resulting in the suppression of bactericidal growth 2. Synergism: (1+1=3) the combined action is significantly greater than the sum of both effects Example: Bacteriostatic + Bacteriostatic Penicillin & Gentamicin are synergistic in their antipseudomonal activities 3. Potentiation: (1+0=2) the effect of one drug is greatly increased by the intake of another drug itself without notable effect Example: B lactam antibiotic + B lactamase inhibitor - Amoxicillin + Clavulanic Acid = Co-Amoxiclav (Augmentin) - Ticarcillin + Clavulanic Acid = Timentin - Ampicillin + Sulbactam = Unasyn - Pipercillin + Tazobactam = Piper-Tazo, Tazoan, Piptaz 4. Antagonism: (1+1=0) the combined action is less than that of the more effective agent when used alone Example: Bactericidal + Bacteriostatic Penicillin + Chloramphenicol This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ UNDESIRABLE EFFECTS OF ANTIMICROBIAL AGENTS 1. Whenever an antimicrobial agent is administered to a patient, any organisms within that patient that are susceptible to the agent will die, but resistant one will survive. 2. The patient may become allergic to the agent. 3. Many antimicrobial agents are toxic to humans, and some are so toxic that they are administered only for serious diseases for which no other agents are available. 4. With prolonged use, broad spectrum antibiotics may destroy the indigenous microbiota of the mouth, intestine, or vagina. RESISTANCE TO ANTIMICROBIAL DRUGS Antimicrobial resistance These days, it is quite common to hear about drug- resistant bacteria or “superbugs” as they have been labeled by the press. Although superbugs can refer to an organism that is resistant to only one antimicrobial agent, the term usually refers to multidrug resistant organisms. Infection caused by superbugs are more difficult to treat. Especially troublesome superbugs. It is important to note that bacteria are not the only microbes that have developed resistance to drugs. Certain viruses (including HIV, herpes simplex viruses, and influenza viruses), fungi (both yeasts and moulds), parasitic protozoa, and helminths have also developed resistance to drugs. Parasitic protozoa that have become resistant include strains of P. falciparum, Trichomonas vaginalis, Leishmania spp and Giardia lamblia. Mechanisms by which Bacteria Become Resistant to Antimicrobial Agents 1. Enzymatic Destruction or Inactivation of the Drug The ability of bacteria to produce an enzyme that destroys or inactivates the drug - Example: Penicillin antibiotics - penicillinase resistant (MRSA) 2. Prevention of Penetration to the Target Site within the Microbe A chromosomal mutation can result in an alteration in the structure of the cell membrane, which in turn can change the permeability of the membrane. If the drug is no longer able to pass through the cell membrane, it cannot reach its target (e.g., a ribosome or the DNA of the cell), and the organism is now resistant to the drug 3. Alteration of the Drug’s Target Site A structural change to those targets can prevent drug binding, rendering the drug ineffective. Examples include: 3.1. Alteration of Penicillin binding protein (PBP) providing resistance to beta-lactam antibiotics 3.2. The ribosome subunits providing resistance to macrolides, tetracyclines, and aminoglycosides; 3.3. The lipopolysaccharide structure providing resistance to polymyxins 4. Rapid Efflux (Ejection) of the Antibiotic - The inhibition of the accumulation of an antimicrobial drug, which then prevents the drug from reaching its cellular target. - Example: Tetracycline This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ ESPECIALLY TROUBLESOME “SUPERBUGS” ∙ Methicillin Resistant Staphylococcus aureus (MRSA) ∙ Methicillin Resistant Staphylococcus epidermidis (MRSE) ∙ Streptococcus pyogenes ∙ Streptococcus pneumonia ∙Vancomycin-resistant Enterococcus spp.(VRE) ∙ Pseudomonas aeruginosa ∙ Clostridium difficile ∙ Acinetobacter baumannii ∙ Klebsiella pneumonia ∙ Multidrug-resistant M. tuberculosis (MDR-TB β-lactamases At the heart of every penicillin and cephalosporin molecule is a double-ringed structure, which in penicillins resembles a “house and garage”. The “garage” the beta-lactam ring. Some Penicillinases bacteria produce enzymes that destroy the B-lactam ring; these enzymes are known as B- lactamases. It destroy the β-lactam ring in Penicillins. When the B-lactam ring is destroyed, the antibiotic no longer works. Thus, an organism that produces a B-lactamases is resistant to antibiotics containing B-lactam ring (collectively An organism that referred to as B-lactam antibiotic or B-lactam). There are two types of B-lactamases: produces penicillinase is Penicillinase and Cephalosporinase: resistant to penicillin. To combat the effect of beta-lactamases, drug companies have developed special drugs that combined B-lactam antibiotic with B-lactamase inhibitor B-lactamase inhibitor The β-lactam inhibitor irreversibly binds to and inactivates the β-lactamase, thus Cephalosporinases enabling the companion drug to enter the bacterial cell and disrupt cell wall synthesis. It destroy the β-lactam ring -Examples: in Cephalosporins. ∙ Clavulanic acid (clavulanate) combined with amoxicillin (Augmentin) ∙ Clavulanic acid (clavulanate) combined with ticarcillin (Timentin) An organism that produces ∙ Sulbactam combined with ampicillin (Unasyn) cephalosporinase is resistant ∙ Tazobactam combined with piperacillin (Zosyn) to Cephalosporins. This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ ANTIMICROBIAL STEWARDSHIP This refers to interventions designed to promote the optimal use of antibiotic agents, including drug choice, dosing, route, and duration of administration (WHO). National Antimicrobial Stewardship (AMS) Program (Philippines) It is the concerted implementation of systematic, multi-disciplinary, multi-prolonged interventions in both public and private hospitals in the Philippines to improve appropriate use of antimicrobials, which is essential for preventing the emergence and spread of antimicrobial resistance. AIMS: 1. Promote rational and optimal antimicrobial therapy 2. Improve patient outcomes and decrease healthcare costs by reducing unnecessary antimicrobial use, adverse drug events, and mortality and morbidity from infections (including secondary infections by resistant pathogens); 3. Foster awareness on the global and country situation on the threat of AMR and the compelling need to address it; 4. Effect positive behaviour and/or institutional changes through educational and persuasive interventions towards improving the use of antimicrobials by the prescribers, dispensers, other healthcare professionals, and patients; 5. Establish multi-disciplinary leadership and commitment, clinical governance and accountability in SOME STRATEGIES IN THE WAR AGAINST antimicrobial management to ensure that interventions DRUG RESISTANCE are sustainable and well-supported with necessary technical and financial resources; 1. Education 6. Create an environment where healthcare professionals are 2. Patients should never pressure clinicians to supported with monitoring tools and systems prescribe antimicrobial agents to implement antimicrobial management; 3. It is important that clinicians not allow 7. Conduct research aiming to analyse the progress and themselves to be pressured by patients. challenges on implementing hospital 4. Clinicians should prescribe an inexpensive, antimicrobial stewardship program; and, narrow spectrum drug whenever the laboratory 8. Prevent or slow down the emergence of AMR. result demonstrate that such a drug effectively kills the pathogen. 5. Patients must take their antibiotics in the exact manner in which they are prescribed. 6. It is critical that clinicians prescribe the appropriate amount of antibiotic necessary to cure the infection. 7. Patients should always destroy any excess medications and should never keep antibiotics in their medicine cabinet. 8. Unless prescribed by a clinician, antibiotics should never be used in a prophylactic manner—such as to avoid ―traveler’s diarrhea‖ when traveling to a foreign country. 9. Healthcare professionals must practice good infection prevention and control procedure. This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ I. ANTIBACTERIAL AGENTS Mechanism of Action of Antibacterial Agents 1. Inhibiting Cell Wall Synthesis 2. Inhibiting Protein Synthesis 3. Injuring the Plasma Membrane 4. Inhibiting Nucleic Acid Synthesis 5. Inhibiting the Synthesis of Essential Metabolites This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ 1. INHIBITION OF CELL WALL SYNTHESIS 1.1 Beta-lactam antibiotics 1.2 Polypeptides / Glycopeptides 1.1 BETA-LACTAM ANTIBIOTICS The β-lactam antibacterial block the crosslinking of peptide chains during the biosynthesis of new peptidoglycan in the bacterial cell wall. They are able to block this process because the β-lactam structure is similar to the structure of the peptidoglycan subunit component that is recognized by the crosslinking transpeptidase enzyme, also known as a penicillin binding protein (PBP). This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ A. PENICILLINS Penicillins are referred to as B-lactam drugs because their molecular structure includes a four-sided ring structure known as B-lactam ring (shown below). Penicillins interfere with the synthesis of bacterial cell walls and have maximum effect on bacteria that actively dividing. They are bactericidal drugs. *The active nucleus common in all penicillin: 6-aminopenicillanic acid Classification of Penicillins 1. Natural Penicillins 2. Penicillinase resistant/ Antistaphylococcal Penicillins 3. Aminopenicillins 4. Extended Spectrum/Anti-Pseudomonal Penicillins 1. Natural Penicillins - Disadvantage: Narrow spectrum and susceptibility to penicillinases Penicillin G - Benzylpenicillin - Intravenous Penicillin V - Phenoxymethylpenicillin - Oral 2. Penicillinase-resistant Penicllins - They are commonly used for Staphylococcus aureus infections, especially for penicillinase producing strains. - Narrow-spectrum against gram-positive bacteria only, including strains producing penicillinase Methicillin - 2,6-dimethoxyphenylpenicillin - formerly used against S. aureus however the bacteria developed resistance and is referred as Methicillin- resistant Staphylococcus aureus Nafcillin - 2-ethoxy-1-phenylpenicillin Isoxazolyl Penicillins (Oxacillin, Cloxacillin,Dicloxacillin) 3. Aminopenicillins - effective against many gram-negative bacteria as well as gram-positive ones, although they are not resistant to penicillinases. Ampicillin - Prodrugs: Hetacillin, Bacampicillin, Cyclacillin, Pivampicillin Amoxicillin - better GI absorption than ampicillin This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ 4. Extended Spectrum Penicillin Carboxypenicillins - Carbenicillin and Ticarcillin - have even greater activitycagainst gram-negative bacteria and have the special advantage of activity against Pseudomonas aeruginosa Ureidopenicillins - Mezlocillin, Azlocillin, Piperacillin - These broader-spectrum penicillins are modifications of the structure of ampicillin BETA-LACTAMASE INHIBITORS Beta-lactamase inhibitors have no antibacterial activity rather they inactivate beta-lactamases - Class I inhibitors that have a heteroatom leaving group at position 1 (e.g., clavulanic acid and sulbactam, tazobactam) - Class II inhibitors that do not (e.g., the carbapenems). Clavulanic acid - Antibiotic isolated from Streptomyces clavuligeris Sulbactam - 1,1-dioxopenicillanic acid Tazobactam - It is a more potent –lactamase inhibitor than sulbactam and has a slightly broader spectrum of activity than clavulanic acid. B. CEPHALOSPORINS The cephalosporins are also B-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 first, second, third, fourth and fifth cephalosporins. Each of this generation have specific targets, see table below. *The active nucleus common in all cephalosporin: 7-aminocephalosporanic acid This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ First Generation Second Generation Third Generation Fourth Generation Fifth Generation Primarily against Gram- Increased activity Less active against Increased activity Effective against gram- positive bacteria against Gram- negative Gram-positive bacteria against Gram-negative negative bacteria and (Narrow-spectrum) bacteria but most active against bacteria MRSA members of the (Extended-spectrum) (Expanded-spectrum) Enterobactericeae family and P. aeruginosa (Broad-spectrum) Cephadroxil Cefaclor Cefdinir Cefepime Ceftaroline Cefazolin Cefamandole Cefditoren Cefpirome Cephalexin Cefonicid Cefixime Cephalothin Cefuroxime Cefoperazone Cephaloridine Cefprozil Cefotaxime Cephapirin Loracarbef Cefpodoxime Cephradine Cefoxitin Ceftibuten Cefotetan Ceftizoxime Cefmetazole Ceftriaxone *Cefuroxime ‒ is the first of a series of a-methoximinoacyl– substituted cephalosporins that constitute most of the third generation agents available for clinical use C. CARBAPENEMS Carbapenems, including imipenem, are. Among the most powerful antibacterial agents in use today. They target the cell envelope and have excellent activity against a broad spectrum of bacteria, including many aerobic Gram-positive bacteria, most aerobic Gram-negative bacteria and most anaerobe. - Thienamycin ‒ a novel -lactam antibiotic first isolated and identified by researchers at Merck from fermentation of cultures of Streptomyces cattleya - Meropenem ‒ second-generation carbapenem that, to date, has undergone the most extensive clinical evaluation ‒ Meropenem is not hydrolyzed by DHP-I and is resistant to most -lactamases, including a few carbapenemases that hydrolyze carbapenem - Imipenem ‒ N-formimidoylthienamycin ‒ cleaved by dihydropeptidase ‒ In combination with Cilastatin, DHP inhibitor ‒ Imipenem + Cilastatin (Tienam) D. MONOBACTAM - It is a synthetic antibiotic that has only a single ring and is therefore known as monobactam - The beta-lactam ring is not fused to another ring - Aztreonam (Azactam) ‒ the first new member of the new class of antibiotics. Magic bullet for pseudomonas ‒ It binds with high affinity to PBP 3 in Gram negative bacteria only This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ ‒ Tigemonam ‒ In contrast to the poor oral bioavailability of aztreonam, the oral absorption of tigemonam is excellent 1.2 POLYPEPTIDE ANTIBIOTICS Glycopeptides including vancomycin, target the cell envelope. They have excellent activity against most aerobic and anaerobic Gram-positive bacteria. Unfortunately, these popular drugs have several drawbacks. Bacteria, especially enterococci, are becoming resistant to these drugs and they have a number of toxic side effects. Bacitracin ‒ MOA: Block transport of peptidoglycan subunits across cytoplasmic membrane which inhibits mucopeptide cell wall synthesis of G (+) bacteria ‒ Isolated from a wound on girl named, Margaret Tracy. ‒ Its use is restricted to topical application for superficial infections. Vancomycin ‒ MOA: Large molecules that bind to the peptide chain of peptidoglycan subunits, blocking transglycosylation and transpeptidation ‒ isolated from Streptomyces orientalis ‒ DOC for Pseudomembranous colitis caused by Clindamycin ‒ Adverse effect: Redman's syndrome (diphenhydramine before administering; slow IV infusion/drip) ‒ Teixobactin, discovered in 2015, represents a new class of antibiotics called acyldepsipeptides. ‒ It inhibits cell wall synthesis in gram-positive bacteria and mycobacteria. ‒ It is produced by a soil bacterium, Eleftheria terrae ANTIMYCOBACTERIAL ANTIBIOTICS ISONIAZID ‒ MOA: inhibits the synthesis of mycolic acids, which are components of cell walls only of the mycobacteria. ETHAMBUTOL ‒ Effective only against mycobacteria. ‒ MOA: The drug inhibits incorporation of mycolic acid into the cell wall, making the cell wall weaker ‒ Its principal use is as the secondary drug to avoid resistance problems. 2. INHIBITION OF PROTEIN SYNTHESIS 2.1 BINDS TO 30S RIBOSOMAL SUBUNIT A. Aminoglycosides Aminoglycosides are bactericidal broad-spectrum drugs that inhibit bacterial protein synthesis. They are a group of antibiotics in which aa are linked by glycosidic bonds. The major factor that limits their use is their toxicity. Aminoglycosides are effective against wide variety of aerobic Gram-negative, but are ineffective against anaerobes. They are used to treat infections with members of the Family Enterobacteriaceae. ‒ Sources “mycin”- derived from Streptomyces “micin”- derived from Micromonospora This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ ‒ Examples i.Streptomycin ▪ Uses: TB (2nd line), Zoonotic infections (Tularemia, Brucellosis, Plague) ▪ S/E: Congenital deafness ii.Amikacin ▪ Narrowest therapeutic index, least resistance iii.Neomycin ▪ Use: hepatic encelopathy (overproduction of NH3; antibiotic kill the NH3 forming bacteria) iv.Tobramycin v.Gentamicin vii.Netilmicin MOA: Causes mismatches between codons and anticodons, leading to faulty proteins that insert into and disrupt cytoplasmic membrane Characteristics A: allergic reaction M:muscular blockade/ neuromuscular agent: I: inactivated in the presence of Beta lactamase in vitro. N: nephrotoxic O: ototoxic B. Tetracycline Tetracyclines are broad-spectrum drugs that can exert their effect by targeting bacterial ribosomes. It contains four fused rings with a system of conjugated double bonds. They are bacteriostatic. Tetracyclines are effective against a wide variety of bacteria. ‒ MOA: Blocks association of tRNAs with ribosome ‒ Adverse drug reactions include gastric discomfort, deposition in the bones and primary dentition causing discoloration and hypoplasia of the teeth and a temporary stunting of growth, hepatotoxicity, phototoxicity (demeclocycline), vestibular problems (minocycline) 2.2 BINDS TO 50S RIBOSOMAL SUBUNIT A. Macrolides ‒ Common chemical characteristics 1. A large lactone ring 2. A ketone group 3. A glycosidically linked amino sugar ‒ MOA: Blocks peptide bond formation between amino acids ‒ Bacteriostatic ‒ Prototype: Picromycin ‒ Erythromycin isolated from S. erythreus formerly Ilotycin ‒ Clarithromycin ▪ methylerythromycin ‒ Azithromycin ▪ Once a day (OD) This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ B. Lincosamides ‒ Resemble sulfonamides in antibacterial spectrum ‒ For abdominal and female genitourinary tract infections caused by B. fragilis ‒ MOA: Blocks peptide bond formation between amino acids ‒ Clindamycin ▪ isolated from Streptomyces lincolnensis ▪ 7-chloro-7-deoxylincomycin ▪ AE: Pseudomembranous colitis C. Chloramphenicol ‒ isolated from Streptomyces venezuelae ‒ MOA: Blocks peptide bond formation between amino acids ‒ Bacteriostatic ‒ Precautions and monitoring: a. Bone marrow suppression (dose-related) b. Aplastic anemia (non-dose related) c. Gray Baby Syndrome (neonates) D. STREPTOGRAMINS ‒ it is effective in the treatment against VRSA, MRSA, VRE ‒ Synercid (prototype), combination of two peptides : Dalfopristin and Quinupristin ‒ S/E: Arthralgia-myalgia syndrome ‒ CYP450 inhibitor E. OXAZOLIDINONES ‒ MOA: Interferes with the formation of the initiation complex between 50S and 30S subunits and other factors. ‒ They are unique in their target: ‒ Binding to the 50s ribosomal unit close to the point where it interfaces with the 30s subunit. Check how far you are already! Mechanism of Action of Antibacterial Agents o Inhibition of Cell Wall synthesis o Inhibition of Protein Synthesis 3. INJURY TO THE PLASMA MEMBRANE o Injuring the Plasma Membrane o Inhibition of Nucleic Acid Synthesis A. LIPOPEPTIDES o Inhibition of the Synthesis of Essential Metabolites Daptomycin ‒ produced by a Streptomyces roseosporus ‒ Its used to treat certain systemic and life-threatening infections caused by Gram-positive organisms ‒ It was removed from WHO List of Essential Medicines in 2019 Polymixin B and Colistin (Polymixin E) ‒ Basic polypeptides ‒ Cationic, surface-active compounds that disrupt the permeability of both outer and cytoplasmic membranes of gram(-) bacteria This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ 4. INHIBITION OF NUCLEIC ACID SYNTHESIS A. RIFAMYCINS ‒ MOA: Inhibits bacterial RNA polymerase activity and blocks transcription, killing the cell ‒ Narrow spectrum with activity against gram-positive and limited numbers of gram-negative bacteria. Also active against Mycobacterium tuberculosis. ‒ Combination therapy for treatment of tuberculosis B. FLUOROQUINOLONES ‒ MOA: Inhibits the activity of DNA gyrase (topoisomerase II and IV) and blocks DNA replication, killing the cell ‒ 1,4-dihydro-4-oxo-3-pyridinecarboxylic acid moiety (essential for antibacterial activity) ‒ Broad spectrum against gram-positive and gram-negative bacteria ‒ Bactericidal ‒ Wide variety of skin and systemic infections Nalidixic acid (1st gen) 🡺 Prototype Ciprofloxacin (2nd gen) Ofloxacin (2nd gen) Levofloxacin (3rd gen) Moxifloxacin (4th gen) 5. INHIBITION OF THE SYNTHESIS OF ESSENTIAL METABOLITES FOLIC ACID SYNTHESIS ENZYME A. SULFONAMIDES (SULFAMETHOXAZOLE) and SULFONES (DAPSONE) - MOA: Inhibits the enzyme involved in production of dihydrofolic acid (see illustration below) - AE: – Crystalluria – Steven-Johnson Syndrome – Kernicterus – Anemia Sulfonamides are usually used with dihydrofolate reductase inhibitors (eg. Trimethoprim) 1.DOC for UTI - Sulfamethoxazole and trimethoprim/Cotrimoxazole (Bactrim®) 2. DOC for Pneumocystis carinii - Bactrim; alternative drug: Pentamidine (aromatic diamide) 3. Burn therapy - Silver sulfadiazine and Mafenide (Flammazine®) 4. Conjunctivitis - Sodium sulfacetamide 5. Chloroquine-resistant malaria - Quinine + pyrimethamine + sulfadoxime (Fansidar®) B. TRIMETHOPRIM - MOA: Inhibits the enzyme involved in the production of tetrahydrofolic acid (see illustration above) -Sulfamethoxazole, a sulfonamide that is a structural analog of PABA, competitively inhibits the synthesis of dihydrofolic acid from PABA -Trimethoprim, a8 structural analog of a portion of dihydrofolic acid, competitively inhibits the synthesis of tetrahydrofolic acid. This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ MYCOLIC ACID SYNTHESIS ENZYME A. ISONIAZID ‒ INH, Isonicotinic Acid Hydrazide ‒ MOA: Interferes with the synthesis of mycolic acid ‒ A/E: Peripheral neuritis B. ETHAMBUTOL/EMB ‒ MOA: This drug is thought to block the assembly of arabinogalactan polysaccharide by inhibition of an arabinotranferase enzyme. C. PYRAZINAMIDE ‒ Moa: Unknown ‒ cidal for actively dividing TB bacillus ‒ Previous: “sterilizing agent” ‒ Use: Active TB ‒ S/E: Most hepatotoxic Asymptomatic hyperuricemia (gouty arthritis) Rash Photosensiivity ANTILEPROSY LEPROSY – known as Hansen’s disease is an infection caused by slow-growing bacteria called Mycobacterium leprae. It can affect the nerves, skin, eyes, and lining of the nose (nasal mucosa). Treatment: DAPSONE/ACEDAPSONE – Sulfur derivative – MOA: inhibit folic acid synthesis (competitive antagonist of PABA) – Use: for erythema nodosum leprosum – Side effects: Skin rash, Methemoglobinemia, Hemolysis in G6PDpatients CLOFAZIMINE – MOA: Bind to guanine bases of bacterial DNA – Use: Leprosy – S/E: Red-orange skin discoloration Erythema nodosum leprosum (nodules on skin) Rescue drug; THALIDOMIDE This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ II. ANTIFUNGAL AGENTS ANTIFUNGAL AGENTS It is much 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 the three ways: CLASSIFICATION OF ANTIFUNGAL DRUGS 1. Agents affecting fungal sterol 2. Agents affecting fungal cell walls 3. Agents inhibiting nucleic acids 1. AGENTS AFFECTING FUNGAL STEROL A. POLYENES ‒ MOA: Pore formation; binds to ergosterol present in the cell membrane disrupting membrane function, allowing electrolytes to leak out from the cell, resulting in cell death i. Amphotericin B (Streptomyces nodosus) ‒ DOC for severe systemic mycoses such as histoplasmosis, coccidiodomycosis, blastomycosis, life threatening invasive aspergillosis ‒ MOA: Amphotericin B is believed to interact with membrane sterols (ergosterol in fungi) to produce an aggregate that forms a transmembrane channel. Intermolecular hydrogen bonding interactions among hydroxyl, carboxyl, and amino groups stabilize the channel in its open form, destroying symport activity and allowing the cytoplasmic contents to leak out ii.Nystatin (Streptomyces noursei) (Mycostatin) ‒ Used un the treatment of candida infections of the skin, vagina, and alimentary tract: iii.Natamycin (Streptomyces natalensis) B. AZOLES ‒ MOA: Inhibits fungal CP450 => inhibits ergosterol synthesis. A cytochrome P450-class enzyme, lanosterol 14a demethylase, is the likely target for the azoles. i. IMIDAZOLES ∙ iconazole (Daktarin, Monistat, Micatin) - This is an antifungal that acts by inhibiting lanosterol C14-demethylase, an important enzyme in sterol synthesis - For superficial mycoses ∙ Tioconazole (Trosyd) - Used for the treatment of vulvovaginal candidiasis. ∙ Clotrimazole (Canesten) - For superficial mycoses ∙ Ketoconazole (Nizoral) - Oral: less toxic than amphotericin B for many systemic mycoses; liver damage has been reported - Topical: used to treat dermatomycoses. - adverse effect: Hepatotoxic; antiadrogenic effect (inhibits testosterone/gynecomastia, low sperm count, and low libido) This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ ii. TRIAZOLES ∙ Itraconazole (Inox, Sporanox) - Lacks the endocrinologic effects of ketoconazole. - Itraconazole is more effective and better tolerated than is ketoconazole ∙ Fluconazole (Diflucan) - Excellent penetrability into the CSF - DOC for Cryptococcal meningitis NEWER ANTIFUNGALS i.Voriconazole ‒ New promising broad spectrum Antifungal, is expected to replace amphotericin B for treatment of many systemic mycoses. ‒ It is able to penetrate BBB. ‒ is more potent than itraconazole against Aspergillus spp. ii. Posaconazole ‒ which is used to treat Aspergillus and Candida systemic fungal infections C. ALLYLAMINES ‒ MOA: Inhibition of squalene epoxidase shuts down the biosynthesis of ergosterol and causes an accumulation of squalene, which destabilizes the fungal cell membrane. ∙ Terbinafine (Lamisil) ∙ Naftifine (Naftin) ∙ Tolnaftate (Tinactin) ‒ Common alternative to miconazole as a topical agent for the treatment of athlete’s foot. 2. AGENTS AFFECTING FUNGAL CELL WALLS ‒ MOA: inhibition of Beta-glucan results in an incomplete cell wall and results in lysis of the fungal cell. ∙ Echinocandins – Caspofungin (Cancidas) Effective against Candida spp. and Pneumocystis jiroveci, which causes a pneumonia often seen in AIDS patients. 3. AGENTS INHIBITING NUCLEIC ACIDS FLUCYTOSINE ‒ Pyrimidine analog ‒ MOA: Inhibits DNA and RNA synthesis ‒ Used only in combination with Amphotericin B for the treatment of systemic mycoses and meningitis caused by Cryptococcus neoformans and Candida ‒ This is an important antifungal agent which inhibits DNA synthesis and is active only on yeasts (candida and Cryptococcus This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ OTHER ANTIFUNGAL DRUGS GRISEOFULVIN (Penicillium griseofulvum) ‒ MOA: Interacts with the microtubule within the fungus and inhibit mitosis (metaphase), thereby inhibits fungal reproduction ‒ Absorption is increased with fatty acids ‒ Side effect: Disulfiram like reactions ‒ DOC for Dermatophytoses (Ringworm Infections) ∙ UNDECYLENIC ACID ‒ A fatty acid that has anti-fungal property against athlete’s foot, although it is not effective as tolnaftate or the imidazoles. ∙ PENTAMIDINE ISETHIONATE ‒ Is used in the treatment of Pneumocystis pneumonia, a frequent complication of AIDS. The drug’s mode of action is unknown, but it appears to bind to DNA. III. ANTIPROTOZOAL AGENTS ANTIPROTOZOAL AGENTS Antiprotozoal drugs are usually quite toxic to the host and work (a) interfering with DNA and RNA synthesis (eg. Chloroquine, Pentamidine and Quinacrine) or (b) interfering with protozoal metabolism (eg. Metronidazole). 1. CINCHONA ALKALOIDS QUININE – Reserved for malarial strains resistant and to other agents – AE: Abortifacient and Cinchonism 2 7-CHLORO-4-AMINOQUINOLINES CHLOROQUINE – DOC for erythrocytic falciparum malaria AMIODAQUINE –for P. falciparum (curative) and Plasmodium vivax 2. 8-AMINOQUINOLINES PRIMAQUINE – Only for exoerythrocytic stages of malaria – Only agent that can lead to radical cures of the P. vivax & ovale – Gametocidal for all 4 plasmodia species – Side effect: Hemolytic anemia in G6PD deficiency. 3. 9-AMINOACRIDINES QUINACRINE – Primarily used in the treatment of giardiasis, but is also effective against tapeworm and malaria, and topically, against leishmaniasis – Should not be given with primaquine because of inc. toxicity MEFLOQUINE – For multi-drug resistant forms of Plasmodium falciparum This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ 4. METRONIDAZOLE – Metronidazole is one of the most widely used antiprotozoan drugs – It’s unique in that it acts not only against parasitic protozoa but also against obligately anaerobic bacteria – It is effective in giardiasis, trichominiasis, amoebiasis – DOC for Trichomonas vaginalis 5. TINIDAZOLE – Tinidazole, a drug similar to metronidazole, is effective in treating giardiasis, amebiasis, and trichomoniasis. 6. NITAZOXANIDE – The first to be approved for the chemotherapy of diarrhea caused by Cryptosporidium hominis. – It’s active in treating giardiasis and amebiasis. – Because it interferes with an enzyme used in the anaerobic conversion of pyruvic acid to acetyl-CoA, it is also used to treat some bacterial infections. 7. MILTEFOSINE – Miltefosine, first developed as an anticancer drug, is a core drug listed by the World Health Organization to treat leishmaniasis – This drug inhibits cytochrome oxidase in mitochondria PENTAMIDINE – Used for Kala azar, Espundia –Treatment of pneumonia caused by the opportunistic pathogenic protozoan P. carinii, a frequent secondary invader associated with AIDS – Alternative treatment for Trypanosoma brucei – T. cruzi: American Sleeping sickness (Chaga’s Disease) ∙ spread the insect known as Reduvid/Assassin/Kissing bug ∙ DOC: NIFURTIMOX and BENZIDAZOLE ‒ T. brucei: African Sleeping sickness ∙ T. brucei gambiense: Western and central African Sleeping Sickness ∙ T. brucei rhodesiense: Eastern and Southern African Sleeping Sickness ∙ DOC: MELARSOPROL SURAMIN – Good synergist action with melarsoprol – a high–molecular-weight bisurea derivative containing six sulfonic acid groups as their sodium salts – Use for African sleeping sickness (east) STIBOGLUCONATE – DOC for Visceral leishmaniasis Check how far you are already! Antimicrobial Agents o Antibacterial agents o Antifungal agents o Antiprotozoal agents o Anthelmintic agents o Antiviral agents This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ IV. ANTHELMINTIC AGENTS ANTHELMINTIC AGENTS The word helminth means parasitic worm. Although helminths are not microorganisms, the various procedures used to diagnose helminth infections are performed in the Parasitology Section of the Clinical Microbiology Laboratory. These procedures often involve the observation of microscopic stages ---eggs and larvae – in the life cycles of these parasites. Helminths infect humans, other animals, and plants but only helminth infection of humans are discussed here. Helminths are multicellular, eukaryotic organisms in the Kingdom Animalia. The two major divisions of helminths are roundworms (nematodes) and flatworms. The flatworms are further divided into tapeworms (cestodes) and flukes (trematodes). CHEMOTHERAPY FOR NEMATODES i. ALBENDAZOLE – Inhibits microtubule synthesis by decreasing glucose uptake – DOC for Echinococcus ii. MEBENDAZOLE (ANTIOX ) – Inhibits microtubule synthesis and depletes glucose inducing paralysis of the worm – DOC for Ascaris, Pinworm, Whipworm iii. PYRANTEL PAMOATE – Depolarizing neuromuscular agent (nicotinic receptors) spastic paralysis of the worm. – Targets: Ascaris, hookworm and enterobius infestations iv. PIPERAZINE – Flaccid paralysis of helminth (Blocks response of helminth muscle to Ach) – Targets: Ascaris and pinworm v. IVERMECTIN – Targets GABA receptors => paralysis – Drug for Strongiloides vi. THIABENDAZOLE – Also affects microtubular aggregation vii. DIETHYLCARBAMAZINE – DOC for Bancroftian filariasis CHEMOTHERAPY FOR TREMATODES i. PRAZIQUANTEL – Increases membrane permeability to calcium contraction vacuolization parasite death This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ CHEMOTHERAPY FOR CESTODES i. NICLOSAMIDE – Inhibits oxidative phosphorylation in mitochondria of cestodes – For intestinal cestodes only: T. saginata, D latum, H. nana METRIFONATE ‒ It inhibits cholinesterases (organophosphate) ‒ Effective only for Schistosoma haematobium ‒ Mixed infection of S. haematobium and S. mansoni = metrifonate + oxamniquine V. ANTIVIRAL AGENTS ANTIVIRAL AGENTS Antiviral agents are the newest weapons in antimicrobial methodology. Until the 1960s, there were no drugs for the treatment of viral diseases. Antiviral agents are particularly difficult to develop and use because viruses are produced within the host cells. ANTIVIRAL DRUGS CLASSIFICATION 1. Entry and Fusion Inhibitors 2.Uncoating, Genome Integration Inhibitors 3. Nucleic Acid Synthesis Inhibitors 4. Assembly and Exit Inhibitors 5. Interferons 1. ENTRY AND FUSION INHIBITORS ‒ Drugs that block the initial steps in viral infection — absorption and penetration—are entry inhibitors ‒ The first of this class of drugs to target HIV infection step is maraviroc ‒ Entry of HIV into the cell can also be blocked by fusion inhibitors, such as enfuvirtide ‒ This is a synthetic peptide that blocks fusion of the virus and cell by mimicking a region of the gp41 HIV-1 envelope ‒ Enfuvirtide: binds to gp41 and inhibits the fusion HIV-1 to CD4+ cells ‒ Maraviroc: blocks the binding of the gp120 HIV protein to CCR5 on macrophage surface to prevent viral entry ‒ Enfuvirtide and maraviroc block the entry of HIV into cells 2. UNCOATING, GENOME INTEGRATION INHIBITORS AMANTADINE AND RIMANTADINE. – Prevent the uncoating of virus – Amantadine and rimantadine are no longer recommended as prophylaxis or treatment for influenza A viruses. RALTEGRAVIR AND ELVITEGRAVIR – competitive inhibitors of integrase 3. NUCLEIC ACID SYNTHESIS INHIBITORS ACYCLOVIR – is used for treating herpes infections, especially genital herpes. – It’s an especially useful treatment in immunosuppressed individuals. – Acyclovir is selectively used by the viral enzyme thymidine kinase – This drug competitively inhibits the RNS virus’s reverse transcriptase This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ FAMCICLOVIR AND GANCICLOVIR – Are derivatives of acyclovir and have a similar mode of action. RIBAVIRIN – Resembles the nucleoside guanine and accelerates the already high mutation rate of RNA viruses until the accumulation of errors reaches a crisis point, killing the virus. – MOA: Monophosphorylated form inhibits IMP dehydrogenase Triphosphate inhibits viral RNA polymerase and end- capping of viral RNA – It is used to treat hepatitis C infections, Lassa fever, and Hantavirus ADEFOVIR DIPIVOXIL ‒ A nucleotide analog, has been introduced for patients whose hepatitis B infections are resistant to lamivudine ‒ This drug competitively inhibits the virus’s reverse transcriptase CIDOFOVIR – Another nucleoside analog which is currently used to treat cytomegalovirus infection of the eye NEVIRAPINE – Non-nucleoside inhibitor – block RNA synthesis by other mechanisms. 4. ASSEMBLY AND EXIT INHIBITORS SAQUINAVIR for HIV BOCEPREVIR AND TELAPREVIR for hepatitis C infections – Protease inhibitors ZANAMIVIR (Relenza®), OSELTAMIVIR (Tamiflu®), and PERAMIVIR (Rapivab®). – Neuraminidase inhibitors – Inhibit neuraminidases of influenza A and B (enzymes that prevent clumping of virions so that more particles are available for infecting host cells) – Decreases likelihood that the virus will penetrate uninfected cells – Clinical uses: prophylaxis mainly, but may decrease duration of flu symptoms by 2–3 days 5. INTERFERONS Interferons are classified as cytokines Alpha interferon is currently a drug of choice for viral hepatitis B,D, and C infections. The production of interferons can be stimulated by a recently introduced antiviral, imiquimod. This drug is often prescribed to treat genital warts. This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ I. ANTIRETOVIRAL AGENTS HIV is treated with antiretroviral medicines, which work by stopping the virus replicating in the body. This allows the immune system to repair itself and prevent further damage. A. NRTI ((Nucleoside Reverse Transcriptase Inhibitors) - Abacavir - Lamivudine - Didanosine - Zalcitabine - Zidovudine - Stavudine Are components of most combination drug regimens used in HIV infection Are used together with a protease inhibitor (PI) Highly active antiretroviral therapy (HAART) has often resulted in ↓ viral RNA, reversal of the decline in CD4 cells, and ↓ opportunistic infections *Ziduvodine recommended for the management of adult patients with symptomatic HIV infection who have history of confirmed Pneumocystis carinii pneumonia MOA: Phosphorylated nonspecifically to a triphosphate that can inhibit reverse transcriptase (RT) by competing with natural nucleotides and can also be incorporated into viral DNA to cause chain termination. Resistance occurs by mutations (multiple) in the gene that codes for RT. This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ Agents Side effects Zidovudine, AZT Hematotoxicity (major and dose-limiting), neutropenia, nausea, insomnia, Didanosine, DDI Pancreatitis (major and dose-limiting) Lamivudine, Least toxic of the NRTIs, but some GI effects and neutropenia Emtricitabine Active in hepatitis B (lamivudine) B. NNRTIs (Non- Nucleoside Reverse Transcriptase Inhibitors) - Nevirapine - Delavirdine - Efavirenz RTIs that do not require metabolic activation: nevirapine, efavirenz Are not myelosuppressant it inhibits reverse transcriptase at a site different from the one NRTIs bind to Additive or synergistic if used in combination with NRTIs and/or PIs C. PROTEASE INHIBITORS - Saquinavir - Ritonavir - Indinavir (Side effect: Crystalluria 🡺 maintain hydration) - Atazanavir - Nelfinavir (can cross BBB) - Fosamprenavir MOA: Aspartate protease (pol gene encoded) is a viral enzyme that cleaves precursor polypeptides in HIV buds to form the proteins of the mature virus core. The enzyme contains a dipeptide structure not seen in mammalian proteins. PIs bind to this dipeptide, inhibiting the enzyme. Resistance occurs via specific point mutations in the pol gene, such that there is not complete cross-resistance between different PIs. D. FUSION INHIBITOR - Enfuvirtide II. DRUG FOR RESPIRATORY SYNCYTIAL VIRUS ∙ Ribavirin is approved for severe lower respiratory infections caused by respiratory syncytial virus ONLY III. DRUG FOR HERPETIC KERATITIS (TOPICAL AGENTS) - Idoxuridine - Trifluridine - Vidarabine IV. DRUG FOR HERPES & VARICELLA - Systemic treatment - Acyclovir - Valacyclovir - Famciclovir - Penciclovir - Docosanol This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ V. Drug For Cytomegalovirus (CMV) - Ganciclovir - Valganciclovir VI. ANTI-INFLUENZA AGENTS - Amantadine - Rimantadine - Oseltamivir - Zanamivir Amantadine MOA: Prevent the penetration of the intact virus into the host cell Activity 3: Skill-building Activities (100 mins) Instructions: Create a diagram to classify agents as antibacterial agents, antifungal agents, antiprotozoal agents, anthelmintic agents and antiviral agents. This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ Activity 4: What I Know Chart, part 2 (2 mins) Instruction: To review what was learned from this session, please go back to “What I Learned” column. Notice and reflect on any changes in your answers. Activity 5: Check for Understanding (12 mins) Instruction: Now it’s time for you to figure this one out on your own! Take time to read, analyze and answer the following questions. I. Write the letter of your answer in CAPITAL LETTER in the space provided ___ 1. All are protein synthesis inhibitors, EXCEPT: a. Vancomycin b. Erythromycin c. Streptomycin d. Chloramphenicol ___ 2. Which of the following is associated with gray baby syndrome? a. Rifampicin b. Vancomycin c. Erythromycin d. Chloramphenicol ___ 3. Which of the following is a beta-lactamase inhibitor? a. Penicillin b. Clavulanate c. Vancomycin d. None of the above ___ 4. Which of the following is a polypeptide antibiotic? a. Imipenem b. Neomycin c. Ethambutol d. Vancomycin ____5. Which of the following Inhibits microtubule synthesis and depletes glucose inducing paralysis of the worm? a. Ivermectin b. Praziquantel c. Albendazole d. Mebendazole ____6. Which of the following is a protease inhibitor? a. Abacavir b. Saquinavir c. Enfuvirtide d. Ganciclovir This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ ____7. Which of the following causes flaccid paralysis to helminth? a. Piperazine b. Metrifonate c. Thiabenzole d. Praziquantel ____8. Which of the following antifungal agents is taken with fatty acids to increase absorption? a. Flucytosine b. Griseofulvin c. Ketoconazole d. Amphotericin B ____9. The antimalarial drug that has gametocidal effect a. Quinacrine b. Primaquine c. Mefloquine d. Chloroquine ____10. Treatment of choice for American trypanosomiasis a. Tinidazole b. Nifurtimox c. Iodoquinol d. Pentamidine II. Evaluate the case As a clinical pharmacist, you helped the physician in assessing the patient’s medical condition. The patient came to you to look into her allergy. After tedious assessment of interviewing the patient together with the physician, the patient did not have any history of allergies especially in food. The patient was prescribed on a 7-day antibacterial treatment, yet on the first dose of taking Cefuroxime 500mg tablet the patient experienced nausea, rhinitis and self-limited cutaneous eruptions. 1. In your assessment the patient is basically allergic to which type of drug? Which type of drug would you recommend to her physician to give? _______________________________________________________________________________________________________________________________ _______________________________________________________________________________________________________________________________ 2. How will you create prevention of antibacterial resistance? _______________________________________________________________________________________________________________________________ _______________________________________________________________________________________________________________________________ This document is the property of PHINMA EDUCATION  Course Code: PHA 046 (Pharmaceutical Microbiology and Parasitology) Student Activity Sheet # 4 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ C. LESSON WRAP-UP Activity 6: Thinking about Learning (5 mins) A. Work Tracker: You are done with this session! Let’s track your progress. Shade the session number you just completed. P1 P2 1 2 3 4 5 6 7 8 9 10 B. Think about your Learning: Tell me about your thoughts. Today’s topic is all about the History of pharmacy and drug discovery. What surprised you about the lesson today? Explain why. _________________________________ ______________________________________ ______________________________________ ______________________________________ ______________________________________ ______________________________________ ______________________________________ _________ FAQs 1. Does chemotherapy refers to magic bullets? Ans: Yes, Paul Ehrlich began his search for chemicals that would destroy bacteria yet would not damage normal body cells and referred it “magic bullets.” He had tested several compounds in the search to treat syphilis. He discovered arsenic compound that proved effective treating for syphilis, the compound was referred as “compound 606” or its technical name as Arsphenamine. 2. Was the first antibiotic discovered Penicilin? Ans. Yes, Alexander Fleming accidentally discovered the first antibiotic when he noticed that growth of containment Penicillium notatum mould colonies on his culture plate was inhibiting growth of Staphylococcus bacteria. This document is the property of PHINMA EDUCATION