抗菌疗法的原则(英文)Foundations-in-Microbiology课件.ppt

1、Variola virus(Smallpox)Random microbe of the week!2Principles of Antimicrobial Therapy Administer a drug to an infected person that destroys the infective agent without harming the hosts cells Antimicrobial drugs are produced naturally or synthetically345Origins of Antimicrobial Drugs Antibiotics ar

2、e 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 space67Interactions Between Drug and

3、 Microbe 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 achi

4、eve and more side effects are seen8Mechanisms of Drug Action1.Inhibition of cell wall synthesis2.Breakdown of cell membrane structure or function3.Inhibition of nucleic acid synthesis,structure or function4.Inhibition of protein synthesis5.Blocks on key metabolic pathways91011The Spectrum of an Anti

5、microbic Drug Spectrum range of activity of a drug Narrow-spectrum effective on a small range of microbes Target a specific cell component that is found only in certain microbes Broad-spectrum greatest range of activity Target cell components common to most pathogens(ribosomes)12Antimicrobial Drugs

6、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 are less effective against gram-negativ

7、e bacteria Broad spectrum penicillins and cephalosporins can cross the cell walls of gram-negative bacteria1314Antimicrobial 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 gr

8、oup,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 leakage1516 Drugs That Affect Nucleic Acid Synt

9、hesis 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 replication17Drugs That Block Pro

10、tein 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 T

11、etracyclines block attachment of tRNA on the A acceptor site and stop further synthesis1819Drugs that Affect Metabolic Pathways Sulfonamides and trimethoprim block enzymes required for tetrahydrofolate synthesis needed for DNA and RNA synthesis Competitive inhibition drug competes with normal substr

12、ate for enzymes active site Synergistic effect the effects of a combination of antibiotics are greater than the sum of the effects of the individual antibiotics202122Survey of Major Antimicrobial Drug Groups Antibacterial drugs Antibiotics Synthetic drugs Antifungal drugs Antiprotozoan drugs Antivir

13、al drugsAbout 260 different antimicrobial drugs are classified in 20 drug familiesAntibacterial 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 of all antimi

14、crobic drugs are beta-lactams Penicillins and cephalosporins most prominent beta-lactams2324Penicillin and Its Relatives Large diverse group of compounds Could be synthesized in the laboratory More economical to obtain natural penicillin through microbial fermentation and modify it to semi-synthetic

15、 forms Penicillium chrysogenum major source All consist of 3 parts:Thiazolidine ring Beta-lactam ring Variable side chain dictating microbial activity252627Subgroup and Uses of Penicillins Penicillins G and V most important natural forms Penicillin is the drug of choice for gram-positive cocci(strep

16、tococci)and some gram-negative bacteria(meningococci and syphilis spirochete)Semisynthetic penicillins ampicillin,carbenicillin,and amoxicillin have broader spectra Gram-negative infections Penicillinase-resistant methicillin,nafcillin,cloxacillin Primary problems allergies and resistant strains of

17、bacteria28Cephalosporins 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 Generic names have roo

18、t cef,ceph,or kef29Cephalosporins 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 ce

19、faclor,cefonacid more effective against gram-negative bacteria Third generation cephalexin,ceftriaxone broad-spectrum activity against enteric bacteria with beta-lactamases Fourth generation cefepime widest range;both gram-negative and gram-positive3031Additional Beta-lactam Drugs Carbapenems Imipen

20、em 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 penicillin32Non Beta-lactam Cell Wall Inhibitors

21、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 topicall

22、y in ointment Isoniazid(INH)works by interfering with mycolic acid synthesis;used to treat infections with Mycobacterium tuberculosisAntibiotics That Damage Bacterial Cell Membranes Polymixins,narrow-spectrum peptide antibiotics with a unique fatty acid component Treat drug resistant Pseudomonas aer

23、uginosa and severe UTI 33Drugs 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

24、bacteria3435Drugs That Interfere with Protein Synthesis Aminoglycosides composed of one or more amino sugars and an aminocyclitol(6C)ring;binds ribosomal subunit Products of various species of soil actinomycetes in genera Streptomyces and Micromonospora Broad-spectrum,inhibit protein synthesis,espec

25、ially useful against aerobic gram-negative rods and certain gram-positive bacteria Streptomycin bubonic plague,tularemia,TB Gentamicin less toxic,used against gram-negative rods Newer tobramycin and amikacin gram-negative bacteria3637Tetracycline Antibiotics Broad-spectrum,block protein synthesis by

26、 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 effects3839Chloramphenicol Potent broad-spectrum drug with unique nitrobenzene structure Blocks peptide bond formation and protein synt

27、hesis Entirely synthesized through chemical processes Very toxic,restricted uses,can cause irreversible damage to bone marrow Typhoid fever,brain abscesses,rickettsial,and chlamydial infections4041Macrolides and Related Antibiotics Erythromycin large lactone ring with sugars;attaches to ribosomal 50

28、s 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,azithromycin4243Drugs That

29、 Block Metabolic Pathways Most are synthetic;most important are sulfonamides,or sulfa drugs-first antimicrobic drugs Narrow-spectrum;block the synthesis of folic acid by bacteria Sulfisoxazole shigellosis,UTI,protozoan infections Silver sulfadiazine burns,eye infections Trimethoprim given in combina

30、tion with sulfamethoxazole UTI,PCPStructure of sulfonamides4445Newly Developed Classes of Antimicrobials 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

31、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 function46Newly Developed Classes of Antimicrobials Ketolides telitromy

32、cin(Ketek),new drug with different ring structure from Erythromycin;used for infection when 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 r

33、esistant Enterococcus(VRE)47Agents to Treat Fungal Infections Fungal cells are eukaryotic;a drug that is toxic to fungal cells also toxic to human cells Five antifungal drug groups:Macrolide polyene Amphotericin B mimic lipids,most versatile and effective,topical and systemic treatments Nystatin top

34、ical treatment Griseofulvin stubborn cases of dermatophyte infections,nephrotoxic Synthetic azoles broad-spectrum;ketoconazole,clotrimazole,miconazole Flucytosine analog of cytosine;cutaneous mycoses or in combination with amphotericin B for systemic mycoses Echinocandins damage cell walls;capsofung

35、in4849Antiparasitic Chemotherapy Antimalarial drugs quinine,chloroquinine,primaquine,mefloquine Antiprotozoan drugs metronidazole(Flagyl),quinicrine,sulfonamides,tetracyclines Antihelminthic drugs immobilize,disintegrate,or inhibit metabolism Mebendazole,thiabendazole broad-spectrum inhibit function

36、 of microtubules,interferes with glucose utilization and disables them Pyrantel,piperazine paralyze muscles Niclosamide destroys scolex50Antiviral Chemotherapeutic AgentsSelective toxicity is almost impossible due to obligate intracellular parasitic nature of virusesBlock penetration into host cellB

37、lock replication,transcription,or translation of viral genetic materialNucleotide analogs Acyclovir herpesvirusesRibavirin a guanine analog RSV,hemorrhagic feversAZT thymine analog HIVPrevent maturation of viral particlesProtease inhibitors HIV5152Drugs for Treating Influenza Amantadine,rimantidine

38、restricted almost exclusively to influenza A viral infections;prevent fusion of virus with cell membrane Relenza and tamiflu slightly broader spectrum;blocks neuraminidase in influenza A and B53Antiherpes Drugs Many antiviral agents mimic the structure of nucleotides and compete for sites on replica

39、ting DNA Acyclovir Zovirax Valacyclovir Valtrex Famiciclovir Famvir Peniciclovir Denavir Oral and topical treatments for oral and genital herpes,chickenpox,and shingles54Drugs for Treating HIV Infections and AIDS Retrovirus offers 2 targets for chemotherapy:Interference with viral DNA synthesis from

40、 viral RNA using nucleoside reverse transcriptase inhibitors(nucleotide analogs)Interference with synthesis of DNA using nonnucleoside reverse transcriptase inhibitors Azidothymidine(AZT)first drug aimed at treating AIDS,thymine analog55Interferons(INF)Human-based glycoprotein produced primarily by

41、fibroblasts and leukocytes Therapeutic benefits include:Reduces healing time and some complications of infections Prevents or reduces symptoms of cold and papillomavirus Slows the progress of certain cancers,leukemias,and lymphomas Treatment of hepatitis C,genital warts,Kaposis sarcoma56The Acquisit

42、ion of Drug Resistance Adaptive response in which microorganisms begin to tolerate an amount of drug that would ordinarily be inhibitory;due to genetic versatility or variation;intrinsic and acquired Acquired resistance:Spontaneous mutations in critical chromosomal genes Acquisition of new genes or

43、sets of genes via transfer from another species Originates from resistance factors(plasmids)encoded with drug resistance,transposons5758Mechanisms of Drug Resistance Drug inactivation by acquired enzymatic activity penicillinases Decreased permeability to drug or increased elimination of drug from c

44、ell acquired or mutation Change in drug receptors mutation or acquisition Change in metabolic patterns mutation of original enzyme5960Natural Selection and Drug Resistance Large populations of microbes likely to include drug resistant cells due to prior mutations or transfer of plasmids no growth ad

45、vantage until exposed to drug If exposed,sensitive cells are inhibited or destroyed while resistance cells will survive and proliferate.Eventually population will be resistant selective pressure natural selection Worldwide indiscriminate use of antimicrobials has led to explosion of drug resistant m

46、icroorganisms61A model of natural selection for drug resistance6263Interactions Between Drug and Host 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 Allergic r

47、eactions Disruption in the balance of normal flora-superinfections possible64656667Considerations in Selecting an Antimicrobial Drug Identify the microorganism causing the infection Test the microorganisms susceptibility(sensitivity)to various drugs in vitro when indicated The overall medical condit

48、ion of the patient68Identifying the Agent Identification of infectious agent should be attempted as soon as possible Specimens should be taken before antimicrobials are initiated69Testing for Drug Susceptibility Essential for groups of bacteria commonly showing resistance Kirby-Bauer disk diffusion

49、test E-test diffusion test Dilution tests minimum inhibitory concentration(MIC)smallest concentration of drug that visibly inhibits growth Provide profile of drug sensitivity70717273The MIC and Therapeutic Index In vitro activity of a drug is not always correlated with in vivo effect If therapy fail

50、s,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 the ratio of the dose of the drug that is toxic to humans as compared to its minimum effective dose Hi