Chapter 34. Antimicrobial Chemotherapy

Transcription

1 Chapter 34 Antimicrobial Chemotherapy

2 Chemotherapeutic agents Chemical agents used to treat disease destroy pathogenic microbes or inhibit their growth within host most are antibiotics microbial products or their derivatives that kill susceptible microbes or inhibit their growth

3 The Development of Chemotherapy Paul Ehrlich (1904) selective toxicity dyes African sleeping sickness Sahachiro Hato (1910) arsenic compounds syphilis Gerhard Domagk, and Jacques and Therese Trefouel (1935) sulfonamides and sulfa drugs

4 Penicillin 1896, first discovered by Ernest Duchesne 1928, Alexander Fleming observed penicillin activity on contaminated plate 1939, Florey, Chain, and Heatley effectiveness 1945, Fleming, Florey and Chain received Nobel Prize Figure 34.1

5 Later discoveries 1944, Waksman: Streptomycin tuberculosis 1952, Nobel Prize 1953, chloramphenicol, terramycin, neomycin, and tetracycline isolated

6 General Characteristics selective toxicity therapeutic index ratio of toxic dose to therapeutic dose toxic dose drug level at which drug becomes too toxic for patient (i.e., produces side effects) therapeutic dose drug level required for clinical treatment

7 Activity Bacteriacidal: kill Bacteriastatic: inhibit growth broad-spectrum drugs: attack many different pathogens narrow-spectrum drugs attack only a few different pathogens

8 Antibiotic Production bacteria and fungi are natural producers synthetic chemotherapeutic agents Semisynthetic antibiotics chemically modified less susceptible to pathogen inactivation ampicillin and amoxycillin semisynthetic penicillin G and penicillin V naturally produced

9 Naturally produced chemotherapeutic agents microbial products or their derivatives that kill susceptible microbes or inhibit their growth most are antibiotics

10 Level of antimicrobial activity effectiveness expressed in two ways minimal inhibitory concentration (MIC) lowest concentration of drug that inhibits growth of pathogen minimal lethal concentration (MLC) lowest concentration of drug that kills pathogen

11 Antimicrobial tests Dilution Susceptibility Tests involves inoculating media containing different concentrations of drug Disk Diffusion Tests disks impregnated with specific drugs are placed on agar plates inoculated with test microbe drug diffuses from disk into agar, establishing concentration gradient observe clear zones (no growth) around disks

12 Kirby-Bauer method disk diffusion test sensitivity and resistance determined using tables that relate zone diameter to degree of microbial resistance table values plotted and used to determine if concentration of drug reached in body will be effective

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14 The Etest- strip test The MIC concentration is read from the scale at the point it intersects the zone of inhibition Each strip contains a gradient of antibiotic AB Biodisk, Solna, Sweden

15 Action of Antimicrobial Agents targeting some function necessary for its reproduction or survival targeted function is very specific to pathogen higher therapeutic index

16 Antimicrobial Drugs inhibitors of cell wall synthesis Penicillins, cephalosporins, vancomycin protein synthesis inhibitors metabolic antagonists nucleic acid synthesis inhibition

17 Penicillins- PG synthesis inhibitors inhibit the last step of transpeptidation β-lactam ring resistant organisms β-lactamase (penicillinase) Fig. 34.5

18 Semisynthetic penicillins have a broader spectrum resistance continues to be a problem ~1-5% of adults in US are allergic to penicillin allergy a violent allergic response and death broad-spectrum antibiotics (used to treat penicillinallergic patients)

19 Cephalosporins structurally and functionally similar to penicillins Figure 34.6

20 Vancomycin and Teicoplanin glycopeptide antibiotics vancomycin treatment of antibiotic resistant staphylococcal and enterococcal infections previously considered drug of last resort

21 Protein Synthesis Inhibitors many specifically to the procaryotic ribosome 30S (small) or 50S (large) ribosomal subunit others inhibit a step in protein synthesis aminoacyl-trna binding peptide bond formation mrna reading translocation

22 Aminoglycoside antibiotics contain a cyclohexane ring and amino sugars bind to 30S ribosomal subunit Figure 34.7

23 Tetracyclines broad spectrum and bacteriostatic inhibits bind of aminoacyl-trna molecules to the A site of the ribosome sometimes used to treat acne

24 Macrolide antibiotics 12 ~22-C lactone rings linked to sugar(s) erythromycin broad spectrum and usually bacteriostatic binds to 23S rrna (inhibits peptide chain elongation) used for patients allergic to penicillin Figure 34.9

25 Chloramphenicol chemically synthesized binds to 23s rrna to inhibit peptidyl transferase toxic with numerous side effects only used in life-threatening situations Figure 34.10

26 Metabolic Antagonists Antimetabolites antagonize or block functioning of metabolic pathways by competitively inhibiting the use of metabolites by key enzymes are structural analogs molecules that are structurally similar to, and compete with, naturally occurring metabolic intermediates block normal cellular metabolism

27 Sulfonamides or Sulfa Drugs Structurally related to sulfanilamide, a p- aminobenzoic acid (PABA) analog used for the synthesis of folic acid (precursor for synthesis of purines and pyrimidines) which is made by many pathogens Fig

28 Synergistic Interaction Trimethoprim - synthetic antibiotic that also interferes with folic acid production Figure 34.14

29 Nucleic Acid Synthesis Inhibition block DNA replication inhibition of DNA polymerase inhibition of DNA helicase block transcription inhibition of RNA polymerase Not as selectively toxic as other antibiotics

30 Quinolones broad-spectrum synthetic drugs containing the 4-quinolone ring 1962, nalidixic acid was first synthesized quinolone Ciprofloxacin (Cipro) used to treat anthrax in 911 (2001) U.S. bioterrorist attacks act by inhibiting bacterial DNA-gyrase complex disrupts many cell processes involving DNA

31 Quinolone Inhibition of DNA gyrase action Figure 34.16

32 Factors influencing antimicrobial drugs ability of drug to reach site of infection susceptibility of pathogen to drug ability of drug to reach concentrations in body that exceed MIC of pathogen Modes of administration Oral- some drugs destroyed by stomach acid topical parenteral routes Non-oral routes of administration drug can be excluded by blood clots or necrotic tissue

33 Drug Concentrations in the Blood must be > MIC at infection site to be effective Factors influencing the concentrations amount administered route of administration speed of uptake rate of clearance (elimination) from body

34 Drug Resistance resistance can be transmitted to other bacteria resistance mutants arise spontaneously and are then selected Drug Resistant Superbug a methicillin-resistant S. aureus (MSRA) that developed resistance to vancomycin this VRSA was also resistant to most other antibiotics isolated from foot ulcers on a diabetic patient

35 Figure 34.17

36 Mechanisms of drug resistance (1) Alteration of target enzyme or organelle use of alternative pathways or increased production of target metabolite (2), (3) inactivation of drug chemical modification of drug by pathogen (4) prevent entrance of drug drug can t bind to or penetrate pathogen bacterial decrease in permeability (4) pump drug out Figure 34.18

37 Origin and spread of resistance genes Figure chromosomal genes spontaneous mutations in the drug target R plasmids can be transferred by conjugation, transduction and transformation can carry multiple resistance genes transposons Integrons: may be > 100 kb

38 Preventing drug resistance give drug in high concentrations give two or more drugs at same time use drugs only when necessary possible future solutions continued development of new drugs use of bacteriophages

39 Antibiotic misuse and drug resistance Overuse and misuse of antibiotics Over 90% of colds and upper respiratory infections are caused by viruses Many patients always do not complete their course of medication The use of antibiotics in animal feeds As much as 70% of the antibiotics are added to livestock feed in USA Increase the number of drug resistant bacteria in animal intestinal tracts Box 34.2

40 Superinfection development and spread of drug-resistant pathogens caused by drug treatment, which destroys drug sensitive strains pseudomembranous enterocolitis caused when treatment with certain antibiotics kills intestinal flora, leaving Clostridium difficile to flourish and produce a toxin

41 Antifungal drugs fewer effective agents because of similarity of fungal cells and human cells easier to treat superficial mycoses than systemic infections

42 Treating superficial mycoses polyene antibiotic from Streptomyces Figure disrupts mitotic spindle; may inhibit protein and DNA synthesis disrupt membrane permeability and inhibit sterol synthesis

43 Treating systemic infections binds sterols in membranes 5FC disrupts RNA function Figure 34.20

44 Antiviral Drugs- relatively few because difficult to specifically target viral replication -used to prevent influenza infections -blocks penetration and uncoating of influenza virus Figure 34.21

45 Tamiflu 克流感 anti-influenza agent a neuraminidase (NA) inhibitor not a cure for influenza (to shorten course of illness) Emerging resistant strain

46 inhibits herpes virus enzymes involved in DNA and RNA synthesis and function Figure inhibits herpes virus and cytomegalovirus DNA polymerase inhibits herpes virus DNA polymerase

47 Broad-spectrum anti-dna virus drugs inhibits viral DNA polymerase papovaviruses, adenoviruses, herpesviruses iridoviruses, and poxviruses

48 Anti-HIV drugs Target to reverse transcriptase Target to protease

49 Microbial Vaccines and disease control Chapter

50 Vaccines Vaccine are non-toxic antigens preparation of microbial antigens used to induce protective immunity may consist of killed, living, weakened (attenuated) microbes or inactivated bacterial toxins (toxoids), purified cell material, recombinant vectors or DNA the antigens injected, ingested, or inhaled to induce specific defenses

51 Table 36.4

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53 Table 36.5

54 Acellular or subunit vaccines The use of specific, purified macromolecules derived from pathogenic microbes subunit vaccines capsular polysaccharides recombinant surface antigens inactivated exotoxins (toxoids)

55 Toxoid vaccine

56 Recombinant-Vector Vaccines pathogen genes that encode major antigens inserted into nonvirulent viruses or bacteria which serve as vectors and express the inserted gene released gene products (antigens) can elicit cellular and humoral immunity

57 DNA Vaccines DNA directly introduced into host cell via air pressure or gene gun when injected into muscle cells, DNA taken into nucleus and pathogen s DNA fragment is expressed host immune system responds to foreign proteins produced many DNA vaccine trials are currently being run

58 New directionsthe end of the dreaded syringe Nasal inoculation not for human trials proximity to CNS? Patch vaccine- applied to skin surface Edible vaccinepotato,(tobacco), banana Scientific American

59 Vaccinomics- The Omics study of vaccine To Identify molecular targets for vaccine development

60 Passive immunization protected by injection of antibodies limited duration, however, can be a lifesaver for immunocompromised people or organ transplant recipients diphtheria and tetanus multidrug resistant bacteria

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62 Against bioterrorism 1984 in Dalles, OR Salmonella typhimurium in 10 restaurant salad bars 1996 in Texas intentional release of Shigella dysentariae in a hospital lab break room 2001 in seven eastern U.S. states use of weaponized Bacillus anthracis spores delivered through U.S. postal systems All caused hospitalizations, the anthrax episode resulted in five deaths

63 Biological Weapons Characteristics that favor their use invisible, odorless and tasteless difficult to detect take hours or days before awareness that they have been used fear and panic associated with the anticipation that they were used

64 Table 36.7

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66 Table 36.9

67 Nosocomial Infections result from pathogens that develop within a hospital or other clinical care facility and are acquired by patients while they are in the facility 5-10% of all hospital patients acquire a nosocomial infection usually caused by bacteria that are members of normal microbiota

68 Community-acquired MRSA A recently emergent clinical problem CA-MRSA infections (in contrast to HA-MRSA) are acquired by persons who have not been recently (within the past year) hospitalized or had a medical procedure (such as dialysis, surgery, catheters) The infections in the community are usually manifested as skin infections, such as pimples and boils, and occur in otherwise healthy people

69 Infection sources endogenous pathogen brought into hospital by patient or acquired when patient is colonized after admission exogenous pathogen microbiota other than the patient s autogenous infection caused by an agent derived from microbiota of patient despite whether it became part of patient s microbiota following admission

70 Control, prevention, and surveillance proper training of personnel in basic infection control measures handling of surgical wounds and hand washing monitoring of patient for signs and symptoms of nosocomial infection

71 The hospital epidemiologist individual responsible for developing and implementing policies to monitor and control infections and communicable diseases reports to infection control committee or similar group