抗微生物药物（英文ppt）

Chapter 21: Antimicrobial Medications Important Point: Antimicrobial Chemotherapeutics q “The prognosis for people with common diseases such as bacterial pneumonia and severe staphylococcal infection was grim before the discovery and widespread availability of penicillin in the 1940s.” q “Physicians were able to identify the cause of the disease, but they were generally unable to recommend treatments other than bed rest.” q Early history of Antimicrobial Chemotherapeutic Agents: q 1910: Salvarsan (an arsenic compound) by Paul Ehlrich q 1928: Penicillin (a mold product-first antibiotic discovered) by Alexander Fleming q 1932: Sulfanilamide (sulfa drug) by Gerhard Domagk q 1941: Purification of Penicillin by Ernst Chain and Howard Florey q post-WWII: Widespread availability Penicillin G Antibiotic Discovery It is easy to identify antibiotic-producing microorganism, the hard part is finding antibiotics that are sufficiently Selectively Toxic. Post-microbe modified antibiotics are called Semisynthetic antibiotics. Selective Toxicity means that the agent is more toxic against bacteria than against, e.g., humans. Antimicrobal Chemotherapy Terms Distinguishing Antibiotics q Antibiotics (as well as synthetic antimicrobials) differ in terms of q The organism they are or were isolated from. q Their chemical structure. q Their (chemo)Therapeutic index. q Bacteriostasis versus bacteriostatic. q Their spectrum of activity. q Their pharmacokinetics (tissue distribution, metabolism, and excretion). q Their site of action in bacterial cells. q Interaction with other chemotherapeutics. q Potential for evolution to resistance. q Mechanism of toxicity to the host. q Cost. Distinguishing Antibiotics q Antibiotics (as well as synthetic antimicrobials) differ in terms of q The organism they are or were isolated from. q Their chemical structure. q Their (chemo)Therapeutic index. q Bacteriostasis versus bacteriostatic. q Their spectrum of activity. q Their pharmacokinetics (tissue distribution, metabolism, and excretion). q Their site of action in bacterial cells. q Interaction with other chemotherapeutics. q Potential for evolution to resistance. q Mechanism of toxicity to the host. q Cost. Antibiotics Sources Distinguishing Antibiotics q Antibiotics (as well as synthetic antimicrobials) differ in terms of q The organism they are or were isolated from. q Their chemical structure. q Their (chemo)Therapeutic index. q Bacteriostasis versus bacteriostatic. q Their spectrum of activity. q Their pharmacokinetics (tissue distribution, metabolism, and excretion). q Their site of action in bacterial cells. q Interaction with other chemotherapeutics. q Potential for evolution to resistance. q Mechanism of toxicity to the host. q Cost. Family Tree of Penicillins Antibiotics are chemotherapeutic antimicrobials that are isolated from microorganisms. Compare: “Synthetic drug.” Some Penicillin Derivatives Methicillin -Induced Lysis Vancomycin Cell-Wall Synthesis Inhibitors Distinguishing Antibiotics q Antibiotics (as well as synthetic antimicrobials) differ in terms of q The organism they are or were isolated from. q Their chemical structure. q Their (chemo)Therapeutic index. q Bacteriostasis versus bacteriostatic. q Their spectrum of activity. q Their pharmacokinetics (tissue distribution, metabolism, and excretion). q Their site of action in bacterial cells. q Interaction with other chemotherapeutics. q Potential for evolution to resistance. q Mechanism of toxicity to the host. q Cost. Therapeutic Index q It is relatively trivial to identify antibiotics. q The trick is to identify antibiotics that are selectively toxicharming the pathogen but not the host. q We employ a concept called the Therapeutic Index as a measure of the degree of selective toxicity. q The therapeutic index is the ratio of the toxic dosage to the therapeutic dosage. q That is, (Lowest dose toxic to patient) (Dose normally used for therapy). q The greater the ratio (or difference) of these two numbers, the easier it is to find a dosage that kills the pathogen without harming the host. Therapeutic Index Therapeutic Index Therapeutic Index = Toxic Dose/Therapeutic Dose Drug Dosage (per Kg Body Weight) Small Ratio (dangerous) Moderate Ratio High Ratio (safe) Most desirable. Distinguishing Antibiotics q Antibiotics (as well as synthetic antimicrobials) differ in terms of q The organism they are or were isolated from. q Their chemical structure. q Their (chemo)Therapeutic index. q Bacteriostatic versus bactericidal. q Their spectrum of activity. q Their pharmacokinetics (tissue distribution, metabolism, and excretion). q Their site of action in bacterial cells. q Interaction with other chemotherapeutics. q Potential for evolution to resistance. q Mechanism of toxicity to the host. q Cost. Bactericidal agents outright kill bacteria. Bacteriostatic agents inhibit growth but dont kill. They rely on body defenses to clear the infection. Removal of agent results in return of growth of any remaining bacteria. Bactericidal agents are preferable particularly if the body otherwise has trouble clearing the bacteria. Distinguishing Antibiotics q Antibiotics (as well as synthetic antimicrobials) differ in terms of q The organism they are or were isolated from. q Their chemical structure. q Their (chemo)Therapeutic index. q Bacteriostasis versus bacteriostatic. q Their spectrum of activity. q Their pharmacokinetics (tissue distribution, metabolism, and excretion). q Their site of action in bacterial cells. q Interaction with other chemotherapeutics. q Potential for evolution to resistance. q Mechanism of toxicity to the host. q Cost. Spectrum of Activity Narrow-Spectrum Antimicrobial Wide-Spectrum Antimicrobial Spectrum of Activity Wide-Spectrum Antimicrobial Broad-spectrum antibiotics are useful if one must begin treatment before identifying either a pathogen or its antibiotic susceptibility. However, broad- spectrum antibiotics are more likely to destroy normal flora, resulting in superinfections. Distinguishing Antibiotics q Antibiotics (as well as synthetic antimicrobials) differ in terms of q The organism they are or were isolated from. q Their chemical structure. q Their (chemo)Therapeutic index. q Bacteriostasis versus bacteriostatic. q Their spectrum of activity. q Their pharmacokinetics (tissue distribution, metabolism, and excretion). q Their site of action in bacterial cells. q Interaction with other chemotherapeutics. q Potential for evolution to resistance. q Mechanism of toxicity to the host. q Cost. Penetration of the antibiotic to infected tissues is kind of important, and antibiotics differ in where and to what degree they penetrate. Anitibiotics differ in terms of how the body modifies or destroys them, e.g., liver vs. kidneys. Ultimately, antibiotics are not retained within the body indefinitely, and the dosage and rate of administration allows a balance of uptake and excretion. Concentrations at the site of action should remain high throughout the treatment period, though not so high that the host is poisoned. Fluctuation of Antibiotic Levels with Time Time of ingestion of dose #3. Distinguishing Antibiotics q Antibiotics (as well as synthetic antimicrobials) differ in terms of q The organism they are or were isolated from. q Their chemical structure. q Their (chemo)Therapeutic index. q Bacteriostasis versus bacteriostatic. q Their spectrum of activity. q Their pharmacokinetics (tissue distribution, metabolism, and excretion). q Their site of action in bacterial cells. q Interaction with other chemotherapeutics. q Potential for evolution to resistance. q Mechanism of toxicity to the host. q Cost. Finding Targets Drug-Finding Ability as Function of Host-Pathogen Similarity # Biochemical Differences from Mammalian Host Number Drug Targets or Drugs with High Chemotherapeutic Index Too-Few Genes & share host Metabolism Too Biochemically similar as fellow Eukaryotes Basically they are Us! Different domain from Us! Targets of Antibacterial Drugs Targets of Antibacterial Drugs Yes, do know the five indicated sites of action. No, do not memorize the specific antibiotics from this figure. Ribosomal Targets Tetracyclines Tetracycline Distinguishing Antibiotics q Antibiotics (as well as synthetic antimicrobials) differ in terms of q The organism they are or were isolated from. q Their chemical structure. q Their (chemo)Therapeutic index. q Bacteriostasis versus bacteriostatic. q Their spectrum of activity. q Their pharmacokinetics (tissue distribution, metabolism, and excretion). q Their site of action in bacterial cells. q Interaction with other chemotherapeutics. q Potential for evolution to resistance. q Mechanism of toxicity to the host. q Cost. Combination of Drugs q For antibiotics “A” and “B” used in combination: q Actual killing rate = A + B Additive q Actual killing rate A + B Synergistic q Actual killing rate A + B Synergistic q Actual killing rate A + B Antagonistic q Typically bacteriostatic agents are antagonistic to bactericidal agents. q Bacteriocidal agents can be synergistic (think of the latter as one antibiotic weakens more bacteria than it kills, making the not-killed bacteria more susceptible to additional insult by the second antibiotic). q Additive means that the two (or more) antibiotics neither hinder nor help each others ability to kill. q Also relevant to rates of mutation to resistance. Synergistic means greater than the sum of the parts. Antagonistic means less than the sum of the parts. Mutation to Resistance The number of resistant bacteria is dependent on the rate of mutation to resistance. Rational for Combining Drugs What you want is a rate of mutation to multiple drug resistance that is less than than the reciprocal of the pathogen population size (and then some accounting for lack of environmental homogeneity). Consequence of Not Combining If this were cancer than each “bump” would represent the end of remission. In a homogeneou s population this would be the last cancer cell / virus / pathogen alive. Consequence of Not Combining So, hence, multi-drug anti-cancer chemotherap y or combination therapy against HIV or TB. Not Maintaining Course Obviously this is not what you want to happen. Distinguishing Antibiotics q Antibiotics (as well as synthetic antimicrobials) differ in terms of q The organism they are or were isolated from. q Their chemical structure. q Their (chemo)Therapeutic index. q Bacteriostasis versus bacteriostatic. q Their spectrum of activity. q Their pharmacokinetics (tissue distribution, metabolism, and excretion). q Their site of action in bacterial cells. q Interaction with other chemotherapeutics. q Potential for evolution to resistance. q Mechanism of toxicity to the host. q Cost. Acquired Antibiotic Resistance Innate or Intrinsic Resistance means that the antibiotic targets simply are missing from a bacterium, e.g., lack of cell wall = penicillin resistance. Alternatively there exist a number of non-intrinsic (acquired) mechanisms that can lead to antibiotic resistance. Acquired Antibiotic Resistance Acquired resistance can occur by alteration of target by chromosomal mutation. Or acquisition on plasmid encoding resistance genes. Resistance in Simpler Terms BA By-pass Altered target Efflux ImpermeabilityInactivation Chromosomal vs. R Plasmid Encoded BA By-pass Altered target Efflux ImpermeabilityInactivation Chromosomal mutation R plasmid R plasmid Distinguishing Antibiotics q Antibiotics (as well as synthetic antimicrobials) differ in terms of q The organism they are or were isolated from. q Their chemical structure. q Their (chemo)Therapeutic index. q Bacteriostasis versus bacteriostatic. q Their spectrum of activity. q Their pharmacokinetics (tissue distribution, metabo