Chapter 12: Drugs, Microbes, Host- The Elements Of Chemotherapy PDF

Chapter 12: Drugs, Microbes, Host- The Elements of Chemotherapy © McGraw Hill 1  Principles of Antimicrobial Therapy Goal of antimicrobial chemotherapy: administer a drug to an infected person that destroys the infective agent...

Chapter 12: Drugs, Microbes, Host- The Elements of Chemotherapy © McGraw Hill 1  Principles of Antimicrobial Therapy Goal of antimicrobial chemotherapy: administer a drug to an infected person that destroys the infective agent without harming the host’s cells Antimicrobial drugs are produced naturally or synthetically The “perfect drug” does not exist, but by balancing drug characteristics against one another, a satisfactory compromise can usually be achieved © McGraw Hill 2  The Ideal Antimicrobial Drug TABLE 12.1 Characteristics of the Ideal Antimicrobial Drug Selectively toxic to the microbe but nontoxic to host cells Microbicidal rather than microbistatic Remains potent long enough to act and is not broken down or excreted prematurely Is not subject to the development of antimicrobial resistance Complements or assists the activities of the host's defenses Remains active even when diluted in body fluids and tissues Readily delivered to the site of infection Reasonably priced Does not disrupt the host's health by causing allergies or predisposing the host to other infections © McGraw Hill 3  Origins of Antimicrobial Drugs 1 Antibiotics are common metabolic products of aerobic bacteria and fungi Bacteria in genera Streptomyces and Bacillus Molds in genera Penicillium and Cephalosporium By inhibiting the other microbes in the same habitat, antibiotic producers have less competition for nutrients and space © McGraw Hill 4  TABLE 12.2 Selected Microbial Sources of Antibiotics Producer Genus Type of Microbe Drugs Formed Penicillins Penicillium Mold Griseofulvin Cephalosporium Mold Cephalosporins Micromonospora Bacteria Gentamicin Bacitracin Bacillus Bacteria Polymyxin B Chromobacterium Bacteria Aztreonam Streptomycin Erythromycin Tetracycline Streptomyces Filamentous bacteria Vancomycin Chloramphenicol Amphotericin B © McGraw Hill 5  TABLE 12.3 Terminology of Chemotherapy Chemotherapeutic Any chemical used in the treatment, relief, or prophylaxis of a drug disease. Prophylaxis* Use of a drug to prevent potential for infection in a person at risk. Antimicrobial The use of chemotherapeutic drugs to control infection chemotherapy* Antimicrobials All inclusive term for any antimicrobial drug, regardless of its origin Substances produced by the natural metabolic processes of some Antibiotics* microorganisms that can inhibit or destroy other microorganisms Drugs that are chemically modified in the laboratory after being Semisynthetic drugs isolated from natural sources Antimicrobial compounds synthesized entirely in the laboratory Synthetic dugs through chemical reactions Narrow spectrum Antimicrobials effective against a limited array of microbial types; (limited spectrum) for example, a drug effective mainly on gram-positive bacteria Antimicrobials effective against a wide variety of microbial types; Broad spectrum for example, a drug effective against both gram-positive and gram- (extended spectrum) negative bacteria © McGraw Hill 6  The Spectrum of an Antimicrobial Drug Spectrum – range of activity of a drug Narrow-spectrum drugs– effective on a small range of microbes Target a specific cell component found only in certain microbes (Bacitracin) Medium or Broad-spectrum drugs– greatest range of activity Target cell components common to most pathogens (Ampicillin, medium; tetracycline, broad) © McGraw Hill 7  Antimicrobial Spectrum Drugs have a range of pathogens on which they will work, which is known as the antimicrobial spectrum. – Broad-spectrum drugs affect many taxonomic groups. – Narrow-spectrum drugs affect only a few pathogens. © McGraw Hill 8  Interactions Between Drugs and Microbes Antimicrobial drugs should be selectively toxic – drugs should kill or inhibit microbial cells without simultaneously damaging host tissues As the characteristics of the infectious agent become more similar to the vertebrate host cell, complete selective toxicity becomes more difficult to achieve and more side effects are seen © McGraw Hill 9  Mechanisms of Drug Action Five major components that are useful drug targets in an actively dividing cell: 1. Inhibition of cell wall synthesis 2. Breakdown of the cell membrane structure or function 3. Interference with functions of DNA and RNA 4. Inhibition of protein synthesis 5. Blockage of key metabolic pathways © McGraw Hill 10  Actions of Drugs on Microbial Groups TABLE 12.4 General Actions of Drugs on Microbial Groups Microbe Type Drug Groups/Examples Effects of Drugs Bacteria Penicillins Cell wall damage and lysis Cephalosporins Cell wall damage and lysis Bacitracin Cell wall damage and lysis Aminoglycosides Inhibit ribosomal protein synthesis Macrolides Erythromycin Inhibit ribosomal protein synthesis Vancomycin Cell wall damage and lysis Inhibit protein synthesis on Tetracyclines ribosomes Inhibit protein synthesis on Chloramphenicol ribosomes Block replication of DNA Stops Fluoroquinolones mRNA synthesis Rifampin Stops mRNA synthesis Sulfa drugs Inhibit folic acid metabolism Trimethoprim Inhibit folic acid metabolism © McGraw Hill 11  Actions of Drugs on Microbial Groups TABLE 12.4 General Actions of Drugs on Microbial Groups Microbe Type Drug Groups/Examples Effect of Drugs Fungi Amphotericin B Loss of membrane permeability Azoles Loss of membrane permeability Flucytosine Inhibits DNA and RNA synthesis Buildup of toxic wastes in the Protozoa Quinines parasite's cells Metronidazole Buildup of toxic free radicals Helminths Bendazoles Inhibit glucose metabolism Diethylcarbamide Kills larval forms Piperazine Paralyzes muscular system Niclosamide Loosens worm hold Ivermectin Inhibits neuromuscular system Viruses Oseltamivir Prevents viral budding Cyclovirs Stop viral replication Blocks formation of DNA from RNA Azidothymidine strand © McGraw Hill 12  Major Targets of Drugs on Bacterial Cells © McGraw Hill 13  1. Antimicrobial Drugs That Affect the Bacterial Cell Wall Most bacterial cell walls contain peptidoglycan Penicillins and cephalosporins block synthesis of peptidoglycan, causing the cell wall to lyse Active on young, growing cells Penicillins that do not penetrate the outer membrane and are less effective against gram-negative bacteria Broad spectrum penicillins and cephalosporins can cross the cell walls of gram-negative bacteria © McGraw Hill 14  Effects of Penicillin on Gram(+) Cell Walls © McGraw Hill 15  2. Antimicrobial Drugs That Disrupt Cell Membrane Function A cell with a damaged membrane dies from disruption in metabolism or lysis These drugs have specificity for a particular microbial group, based on differences in types of lipids in their cell membranes Polymyxins interact with phospholipids and cause leakage, particularly in gram-negative bacteria Amphotericin B and nystatin form complexes with sterols on fungal membranes which causes leakage © McGraw Hill 16  Effects of Drugs on Membranes: Polymyxin © McGraw Hill 17  3. Drugs That Affect Nucleic Acid Synthesis May block synthesis of nucleotides, inhibit replication, or stop transcription Chloroquine binds and cross-links the double helix; quinolones inhibit DNA helicases Antiviral drugs that are analogs of purines and pyrimidines insert in viral nucleic acid, preventing replication © McGraw Hill 18  4. Drugs That Block Protein Synthesis Ribosomes of eukaryotes differ in size and structure from prokaryotes; antimicrobics usually have a selective action against prokaryotes; can also damage the eukaryotic mitochondria Aminoglycosides (streptomycin, gentamycin) insert on sites on the 30S subunit and cause misreading of mRNA Tetracyclines block attachment of tRNA on the A acceptor site and stop further synthesis © McGraw Hill 19  Targets on the Prokaryotic Ribosome mRNA is misread, protein is incorrect. © McGraw Hill 20  Targets on the Prokaryotic Ribosome Formation of peptide bonds is blocked. © McGraw Hill 21  Targets on the Prokaryotic Ribosome Prevent initiation and block ribosome assembly © McGraw Hill 22  Targets on the Prokaryotic Ribosome tRNA is blocked, no protein is synthesized. Access the text alternative for slide images. © McGraw Hill 23  Targets on the Prokaryotic Ribosome Ribosome is prevented from translocating. © McGraw Hill 24  5. Drugs that Affect Metabolic Pathways Competitive inhibition (metabolic analogs)– drug competes with normal substrate for enzyme’s active site Metabolic analog drugs are “dead-end” and cannot function as required. As the enzyme is no longer able to produce a needed product, cellular metabolism slows or stops Examples: sulfonamides, trimethoprim, retrovir © McGraw Hill 25  5. Drugs that Affect Metabolic Pathways Synergistic effect – the effects of a combination of antibiotics are greater than the sum of the effects of the individual antibiotics Example: Sulfonamides and trimethoprim combined block enzymes required for tetrahydrofolate synthesis needed for DNA and RNA synthesis © McGraw Hill 26  Competitive Inhibition as a mode of action The metabolic pathway needed to synthesize tetrahydrofolic acid (THFA) contains two enzymes that are chemotherapeutic targets. Under normal circumstances, PABA acts as a substrate for the enzyme pteridine synthetase, the product of which is needed for the eventual production of folic acid. © McGraw Hill 27  Competitive Inhibition as a mode of action © McGraw Hill 28  Survey of Major Antimicrobial Drug Groups ~280 different antimicrobial drugs classified into 24 drug families Antibacterial drugs that act on the cell wall Penicillin and its relatives Cephalosporin group of drugs Carbapenems and monobactams Miscellaneous cell wall inhibitors (non-beta-lactam) Antibiotics that damage bacterial cell membranes Drugs that act on DNA or RNA © McGraw Hill 29  Survey of Major Antimicrobial Drug Groups Drugs that interfere with protein synthesis Aminoglycoside drugs Tetracycline antibiotics Chloramphenicol Macrolides and related antibiotics Drugs that block metabolic pathways © McGraw Hill 30  Antibacterial Drugs that Act on the Cell Wall Beta-lactam antimicrobials - all contain a highly reactive 3 carbon, 1 nitrogen ring Primary mode of action is to interfere with cell wall synthesis Greater than ½ of all antimicrobic drugs are beta-lactams Penicillins and cephalosporins most prominent beta-lactams Structure of pencillin G © McGraw Hill 31  Subgroups and Uses of Penicillins Penicillins G and V most important natural forms Penicillin is the drug of choice for gram-positive cocci (streptococci) and some gram-negative bacteria (meningococci and syphilis spirochete) Semisynthetic penicillins – ampicillin and amoxicillin have broader spectra – Gram-negative infections Beta-lactamase or Penicillinase-enzyme produced by some bacteria making them resistant. Methicillin, nafcillin, and cloxacillin developed Primary problems – allergies and resistant strains of bacteria © McGraw Hill 32  Chemical Structure and functions of Semisynthetic Penicillins © McGraw Hill 33  Cephalosporins Account for one-third of all antibiotics administered Synthetically altered beta-lactam structure Relatively broad-spectrum, resistant to most penicillinases, and cause fewer allergic reactions Some are given orally; many must be administered parenterally (injected into muscle or vein) Generic names have root – cef, ceph, or kef © McGraw Hill 34  The Structure of Cephalosporins 4 generations exist: each group more effective against gram-negatives than the one before with improved dosing schedule and fewer side effects First generation – cephalothin, cefazolin – most effective against gram-positive cocci and few gram-negative Second generation – cefaclor, cefonacid – more effective against gram-negative bacteria Third generation – cephalexin, ceftriaxone – broad-spectrum activity against enteric bacteria with beta- *New improved versions of lactamases drugs are referred to as new Fourth generation – cefepime – widest “generations.” range; both gram- negative and gram- positive © McGraw Hill 35  Additional Beta-lactam Drugs Carbapenems Imipenem – broad-spectrum drug for infections with aerobic and anaerobic pathogens; low dose, administered orally with few side effects Monobactams Aztreonam – narrow-spectrum drug for infections by gram- negative aerobic bacilli; may be used by people allergic to penicillin © McGraw Hill 36  Non Beta-lactam Cell Wall Inhibitors Vancomycin – narrow-spectrum, most effective in treatment of Staphylococcal infections in cases of penicillin and methicillin resistance or if patient is allergic to penicillin; toxic and hard to administer; restricted use Bacitracin – narrow-spectrum produced by a strain of Bacillus subtilis; used topically in ointment Isoniazid (INH) – works by interfering with mycolic acid synthesis; used to treat infections with Mycobacterium tuberculosis © McGraw Hill 37  Antibiotics That Damage Bacterial Cell Membranes Polymixins, narrow-spectrum peptide antibiotics with a unique fatty acid component Produced by Bacillus polymyxa Indicated for drug-resistant Pseudomonas aeruginosa and severe UTI Can be toxic to the kidney © McGraw Hill 38  Drugs that Act on DNA or RNA Fluoroquinolones – work by binding to DNA gyrase and topoisomerase IV Broad spectrum effectiveness Concerns have arisen regarding the overuse of quinoline drugs CDC is recommending careful monitoring of their use to prevent ciprofloxacin-resistant bacteria © McGraw Hill 39  Drugs That Interfere with Protein Synthesis Aminoglycosides Products of various species of soil actinomycetes Relatively broad-spectrum : inhibit protein synthesis by binding to one ribosomal subunit Useful against aerobic gram-negative rods and certain gram-positive bacteria Streptomycin – bubonic plague, tularemia, TB Streptomycin Gentamicin – less toxic, used against gram- negative rods Newer – tobramycin and amikacin, used against gram-negative bacteria © McGraw Hill 40  Drugs That Interfere with Protein Synthesis Tetracycline Antibiotics Broad-spectrum, block protein synthesis by binding ribosomes Treatment for STDs, Rocky Mountain spotted fever, Lyme disease, typhus, acne, and protozoa Generic tetracycline is low in cost but limited by its side effects Figure 10.11B: The staining of teeth associated with tetracycline use. © McGraw Hill 41  Drugs That Interfere with Protein Synthesis Chloramphenicol Potent broad-spectrum drug with unique nitrobenzene structure Blocks peptide bond formation and protein synthesis Entirely synthesized through chemical processes Very toxic, restricted uses, can cause irreversible damage to bone marrow Typhoid fever, brain abscesses, rickettsial, and chlamydial infections © McGraw Hill 42  Drugs That Interfere with Protein Synthesis Macrolides and Related Antibiotics Erythromycin –lactone ring with sugars; attaches to ribosomal 50s subunit Broad-spectrum, fairly low toxicity Taken orally for Mycoplasma pneumonia, legionellosis, Chlamydia, pertussis, diphtheria and as a prophylactic prior to intestinal surgery For penicillin-resistant – gonococci, syphilis, acne Newer semi-synthetic macrolides – clarithromycin, azithromycin © McGraw Hill 43  Antibiotics and their affect on protein synthesis. © McGraw Hill 44  Drugs That Block Metabolic Pathways Most are synthetic Sulfonamides (or sulfa drugs ) the most important Narrow-spectrum; block the synthesis of folic acid by bacteria Sulfisoxazole – shigellosis, UTI, protozoan infections Silver sulfadiazine – burns, eye infections Trimethoprim – given in combination with sulfamethoxazole – UTI © McGraw Hill 45  Drugs That Block Metabolic Pathways Newly Developed Class of Antibiotics Formulated from pre-existing drug classes Three new drug types: Fosfomycin trimethamine – a phosphoric acid effective as alternate treatment for UTIs; inhibits cell wall synthesis Synercid – effective against Staphylococcus and Enterococcus that cause endocarditis and surgical infections; used when bacteria is resistant to other drugs; inhibits protein synthesis Daptomycin – directed mainly against gram-positive; disrupts membrane function © McGraw Hill 46  Drugs That Block Metabolic Pathways Ketolides – telithromycin (Ketek), new drug with different ring structure from Erythromycin (macrolide) Used for respiratory tract infection resistant to macrolides Oxazolidinones – linezolid (Zyvox); synthetic antimicrobial that blocks the interaction of mRNA and ribosome Used to treat methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) © McGraw Hill 47  Antifungal Drugs The cells of fungi are eukaryotic, which presents special problems in chemotherapy The great majority of chemotherapeutic drugs are designed to act on bacteria and are generally ineffective in combating fungal infections A drug that is toxic to fungal cells also capable of harming human cells There are five main groups of drugs that have been developed to specifically treat fungal infections © McGraw Hill 48  Five Antifungal Drug Groups 1. Macrolide polyenes – bind to fungal membranes and cause loss of selective permeability 2. Griseofulvin – stubborn cases of dermatophyte infections, nephrotoxic 3. Synthetic azoles – broad-spectrum Ketoconazole, clotrimazole, miconazole 4. Flucytosine – analog of cytosine; cutaneous mycoses; with amphotericin B for systemic mycoses 5. Echinocandins – damage cell walls Capsofungin © McGraw Hill 49  Antiparasitic Chemotherapy Antimalarial drugs Quinine chloroquine primaquine mefloquine Antiprotozoan drugs Antihelminthic drugs © McGraw Hill 50  Antiviral Chemotherapeutic Agents Selective toxicity is almost impossible due to obligate intracellular parasitic nature of viruses Most designed to block a step of virus cycle: 1. Block penetration into host cell 2. Block replication, transcription, or translation of genetic material Nucleotide analogs Acyclovir – herpesviruses Ribavirin – a guanine analog – RSV, hemorrhagic fevers AZT – thymine analog – HIV 3. Prevent maturation of viral particles Protease inhibitors – HIV © McGraw Hill 51  Antiviral Chemotherapeutic Agents Inhibition of viral entry or release 1. Prevents binding of viral receptors to cell and blocks fusion with virus. 2. Covers up cell receptors; Virus cannot adhere. 3. Drug blocks final budding and release of new viruses © McGraw Hill 52  Antiviral Chemotherapeutic Agents Inhibition of Nucleic Acid Synthesis 4. Nucleotide analogs terminate DNA replication 5. Reverse transcriptase inhibitors, blocks viral DNA synthesis 6. Reverse transcriptase inhibitors, drug attaches to RT binding site © McGraw Hill 53  Antiviral Chemotherapeutic Agents Inhibition of HIV Insertion, Assembly, Release 7. Integrase inhibitor 8. Protease inhibitors © McGraw Hill 54  The Acquisition of Drug Resistance Drug-resistance is an adaptive response in which microorganisms begin to tolerate an amount of drug that would ordinarily be inhibitory Result of genetic versatility and adaptability of microbial populations Can be intrinsic and acquired Acquisition of resistance is the main problem for microbial chemotherapy © McGraw Hill 55  How Does Drug Resistance Develop? Newly acquired after: 1. Spontaneous mutations in critical chromosomal genes 2. Acquisition of new genes or sets of genes via transfer from another species (intermicrobial transfer) Transfer of resistance (R) factors (plasmids) encoded with drug resistance Transposons duplicated and inserted from one plasmid to another or from a plasmid to the chromosome © McGraw Hill 56  Transfer of Drug Resistance 1. Transformation 2. Conjugation 3. Transduction © McGraw Hill 57  Mechanisms of Acquired Drug Resistance 1. Drug inactivation Inactivation of a drug like penicillin by penicillinase or beta- lactamase, enzymes that cleaves a portion of the molecule and renders it inactive. © McGraw Hill 58  Mechanisms of Acquired Drug Resistance 2. Decreased permeability The receptor that transports the drug is altered, so that the drug cannot enter the cell. © McGraw Hill 59  Mechanisms of Acquired Drug Resistance 3. Activation of drug pumps Specialized membrane proteins are activated and continually pump the drug out of the cell. © McGraw Hill 60  Mechanisms of Acquired Drug Resistance 4. Change in drug binding site Binding site on target (ribosome) is altered so drug has no effect. © McGraw Hill 61  Mechanisms of Acquired Drug Resistance 5. Use of alternate metabolic pathway The drug has blocked the usual metabolic pathway (green), so the microbe circumvents it by using an alternate, unblocked pathway that achieves the required outcome (red). © McGraw Hill 62  Natural Selection and Drug Resistance Large populations of microbes likely to include drug resistant cells due to prior mutations or transfer of plasmids – no growth advantage until exposed to drug If exposed, sensitive cells are inhibited or destroyed while resistance cells will survive and proliferate. Eventually population will be resistant – natural selection © McGraw Hill 63  TABLE 12.8 Strategies to Limit Drug Resistance of Microorganisms Drug Usage Physicians have the responsibility for making an accurate diagnosis and prescribing the correct drug therapy. Compliance with physicians' guidelines: The patient should take the correct dosage, by the best route, for the appropriate period. This diminishes the selection for mutants that can resist low drug levels and ensures elimination of the pathogen. Combined therapy with two or more drugs together increases the chances that at least one of the drugs will be effective and that a strain resistant to one drug will be eliminated by the other. © McGraw Hill 64  TABLE 12.8 Strategies to Limit Drug Resistance of Microorganisms Drug Research Research focuses on developing shorter-term, higher- dose antimicrobials that are more effective, less expensive, and have fewer side effects. Pharmaceutical companies continue to seek new antimicrobial drugs with structures that are not readily inactivated by microbial enzymes or drugs with modes of action that are not readily circumvented. © McGraw Hill 65  TABLE 12.8 Strategies to Limit Drug Resistance of Microorganisms Long-Term Strategies Proposals to reduce the abuse of antibiotics range from educational programs for medical workers to requiring justification for prescribing certain types of antibiotics. Especially valuable antimicrobials may be restricted in their use to only one or two types of infections. The addition of antimicrobials to animal feeds must be curtailed worldwide. Government programs that make effective therapy available to low-income populations should be increased. Vaccines should be used whenever possible to provide alternative protection. © McGraw Hill 66  Interactions Between Drugs and Hosts Estimate that 5% of all persons taking antimicrobials will experience a serious adverse reaction to the drug – side effects Major side effects: Direct damage to tissue due to toxicity of drug (ex: liver and kidney) Allergic reactions Disruption in the balance of normal flora- superinfections possible Tetracycline causes permanent brownish discoloration of tooth enamel © McGraw Hill 67  Role of Antimicrobials in Superinfections a) A primary infection in the throat is treated with an oral antibiotic b) The drug is carried to the intestine and is absorbed into the circulation c) The primary infection is cured, but drug-resistant pathogens have survived and create an intestinal superinfection © McGraw Hill 68  Major Adverse Reactions to Common Drugs TABLE 12.9 Major Adverse Toxic Reactions to Common Drug Group Antimicrobial Drug Primary Damage or Abnormality Produced Antibacterials Penicillin G Skin allergy Ampicillin Diarrhea and enterocolitis Inhibition of prothrombin synthesis Cephalosporins Decreased circulation Nephritis Diarrhea and enterocolitis Tetracyclines Discoloration of tooth enamel Reactions to sunlight (photosensitization) Chloramphenicol Injury to red and white blood cell precursors Aminoglycosides (streptomycin, Diarrhea and enterocolitis; loss of hearing, dizziness, gentamicin) kidney damage Azithromycin Heart arrhythmias © McGraw Hill 69  Selecting an Antimicrobial Drug Consideration must be given to at least three factors: 1. The nature of the microorganism causing the infection Specimens should be taken before antimicrobials are initiated 2. The degree of the microorganism’s susceptibility (sensitivity) to various drugs Essential for groups of bacteria commonly showing resistance Kirby-Bauer Disc Diffusion Test Etest® Tube dilution test. Used to determined the minimum inhibitory concentration (MIC), The smallest concentration of drug in the series that visibly inhibits microbial growth 3. The overall medical condition of the patient © McGraw Hill 70  Kirby-Bauer Tests a) Example and evaluation of an agar diffusion sensitivity test. If the test bacterium is sensitive to a drug, a zone of inhibition develops around its disc. The larger the size of this zone, the greater is the bacterium's sensitivity to the drug. The diameter of each zone is measured in millimeters and evaluated for susceptibility or resistance by means of a comparative standard (R, I, or S). © McGraw Hill 71  Kirby-Bauer Tests b) Zone of inhibition, Vancomycin on Staphylococcus aureus c) Pseudomonas is well known for its resistance to multiple drugs © McGraw Hill Lisa Burgess/McGraw-Hill Education 72  E-Test® Diffusion Test © McGraw Hill Sirirat/Shutterstock 73  Tube Dilution Test Used to determined the minimum inhibitory concentration (MIC), The smallest concentration of drug in the series that visibly inhibits microbial growth © McGraw Hill © Kathy Park Talaro 74  Comparing MICs for Common Drugs and Pathogens TABLE 12.10 Comparing MICs (μg/ml) for Common Drugs and Pathogens Sulfameth Bacterium Penicillin G Ampicillin Tetracycline Cefaclor oxazole Staphylococcus aureus 4 0.05 3 0.3 4 Enterococcus faecalis 3.6 1.6 100 0.3 60 Neisseria gonorrhoeae 0.5 0.5 5 0.8 0.2 Escherichia coli 100 12 3 1—4.0 3 Pseudomonas >500.0 >200.0 >100.0 >100.0 4 aeruginosa Salmonella species 12 10 10 1 0.8 Clostridium perfringens 0.16 NA NA 3 12 NA = not available © McGraw Hill 75  The MIC and Therapeutic Index In vitro activity of a drug is not always correlated with in vivo effect If therapy fails, a different drug, combination of drugs, or different administration must be considered Best to chose a drug with highest level of selectivity but lowest level toxicity – measured by therapeutic index (TI) – the ratio of the dose of the drug that is toxic to humans as compared to its minimum effective dose High index is desirable Drug companies recommend dosages that will inhibit the microbes but not adversely affect patient cells. © McGraw Hill 76