BIO 580 Medical Microbiology Unit 4 - Control of Microbial ...



Unit 4 - Control of Microbial InfectionsWe may not cover all of this information in class, so from time to time I will skip forward.Two ways to control microbial infections:attack the pathogens**chemotherapy – given after exposure, short-termother microbes (bacteriophages)shore up host defenses**immunization – given prior to exposure, longer termimprovements in sanitation, nutrition, and healthI. ChemotherapyA. History of Chemotherapy1854-1915 - Paul Ehrlich - staining magic bullet A chemical with selective toxicity that would kill the pathogen and not human cells would be an effective treatment 1904 - Trypan Red1910 – Salvarsan1935 - Prontosil Red1928 - Fleming - discovery that mold Penicillium would inhibit growth of staphylococci - first antibiotic **1940 - production and purification of penicillin - clinical use on civilians after WW II1944 - streptomycin1950s - Era of antibiotics launched - mainstay of txt against infectious disease since.B. Concerns for Antimicrobial Administration, Distribution, and EliminationRoutes of AdministrationIV - into a vein - IM - into the muscle - oral (PO - per os, Greek - by mouth) - Distribution - what inhibits antimicrobial distribution in the body?barriers – cell membranes, tight cellular junctionspoor circulation, poor penetration of a siteElimination - how antimicrobials are eliminated from the bodyremoved from blood in the kidneys and excreted in the urine metabolized into a different compound, usually an inactive form, by liver.excreted by liver cells into bile and eliminated in the feces.C. How Antimicrobial Agents WorkAntimicrobials are classified by three different classification systems used simultaneously:microbicidal or microbistatic - whether they kill or inhibit the growth-static is reversible, -cidal is notby site of action of the drugby chemical structureAntimicrobial agents organized by site of action - Know site of action for the antibiotics from lab**5 Sites of Action (or targets) of AntimicrobialsCell wall synthesis Cell membrane functionNucleic acid synthesis or replicationBacterial ribosome and protein synthesisMetabolic pathwaysInhibit cell wall (i.e. peptidoglycan)l synthesisCan inhibit peptidoglycan synthesis in two different manners:inhibit synthesis of the linear strands of peptidoglycaninhibit cross-linking between the strands2. Disrupt cell membrane function phospholipids of gram negative bacteriasterols of eucaryotic fungi - ergosterol3. Inhibit nucleic acid synthesis or replicationinhibit DNA gyrase – prevent relaxation of supercoiled DNA during replication inhibit bacterial RNA polymerase mRNA synthInhibit protein synthesis by interfering with bacterial ribosome – either 30S or 50S5. Inhibit metabolic pathwaysEx. Two antimicrobial agents inhibit folic acid synthesis:Antimicrobial agents organized by drug family – Know drug family for the antibiotics from labA. Anti-Bacterial Agents – I will only cover a few of these in classUsually an antibiotic – a natural substance secreted by one microbe that inhibits the growth of another microbe.Inhibitors of cell wall synthesis (Figs. 33.6, 33.8)*Beta-lactams – antibiotics containing a beta-lactam ring a. Penicillins – end in “illin”b. Cephalosporins – begin with “ceph” or “cef” Mode of action – inhibit cell wall synthesis by binding any of a group of membrane proteins collectively called penicillin-binding proteins (PBP) –that are involved in cross-linking the peptides of peptidoglycan activate cell lysis (-cidal)Administration route – IM, IV, PO (some semi-synthetics have been produced to be acid stable)Distribution in the body – cross membranes, incl. BBBMechanism of elimination – kidneys urine (rapid)Special uses –most heavily used family – but only effective against bacteria with cell wallsAdverse side effects – Generally very low toxicity. Type I hypersensitivity (rare), rashes, some bacteria develop ?-lactam resistance during the course of txt.Examples - penicillin, ampicillin, amoxicillin, methicillin cephalothin, cephalexin, cefaclor (highlight the ones from lab)Inhibitors of cytoplasmic membrane functionPolymyxinsMode of action – detergents that disrupt phospholipid structureAdministration – topicalUses – Gram negatives except ProteusExamples – Polymyxin BInhibitors of protein synthesis (Fig. 33.10)Aminoglycosides – end in “mycin” or “micin”Mode of action –1) irreversible binding to 30S subunit of ribosome no initiation complex no protein synthesis. 2) misreading of mRNA defective protein (-cidal)Administration –IV – not well absorbed orally because + charged, don’t cross membranesDistribution – blood and fluids – can’t cross membranesElimination – kidneys urineUses – serious systemic GN in hospitalized patientsSide effects – very toxic – most toxic of all commonly used antibiotics – fine line between therapeutic doses and toxic doses – can result in irreversible damage to inner ear (loss of hearing/balance) and kidneys.Examples – streptomycin (was a major anti-TB drug), gentamicin (broad spectrum), amikacin, neomycinTetracyclines – end in “cline” (although brand names may end in “mycin”, like Vibramycin)Mode of action reversible binding to 30S blocks A site on ribosome (-static)Administration – PO, well-absorbedDistribution - broadly distributed in the body, intracellular.Elimination – through kidneys to urine and bile to fecesUses – very broad spectrum – G+, spirochetes, mycoplasma (don’t have peptidoglycan), intracellular (chlamydia, rickettsia)Side effects:GI upset - partly due to direct irritation of GI by the drug, partly due to rapid drug-induced changes in normal gut microbiota diarrhea.Children – interacts with Ca 2+ in developing bones and teeth, can permanently stain the teeth, so not given to children or pregnant an damage – systemic administration can result in liver and kidney damage.*Added to animal feed - resulting in widespread tetracycline resistanceExamples – tetracycline, oxytetracycline, doxycyclineChloramphenicolMode of action –reversible binding to 50S – prevents action of peptidyl transferase and peptide bond synthesis (-static)Administration – PO, IV, topicalDistribution – crosses membranes incl. brain, eye, and cellularElimination – metabolized in liver inactive form kidneys to urineUses – broad spectrum; G+, G-, aerobes and anaerobes, intracellularSide effects – pretty toxic, used only when other antibiotics are not effective. Disrupts protein synthesis in bone marrow bone marrow suppression, which is dose-dependent and reversible. May also result in aplastic anemia, which is dose independent, irreversible, and fatal. Develops days to weeks after txt stops (rare).Macrolides, lincosamides - mycinMode of action –prevents release of tRNA (-static)Administration – IV, PODistribution – well distributed except into CSF or intracellularElimination – liver bile fecesUses – mainly G+, an alternative to b-lactamsExamples: Macrolide - Erythromycin - best known and most widely used. Binds to 23S rRNA & blocks release of tRNA. Fairly safe, low toxicity, but resistance may develop rapidly during txt.Lincosamide - Clindamycin – inhibits peptide bond formation. Active against many anaerobes. Assoc. with pseudomembranous colitis, caused by an overgrowth of Clostridium difficile in the wake of widespread destruction of normal gut microbiota.Inhibitors of Nucleic Acid SynthesisInhibit DNA replication - QuinolonesMode of Action – inhibit DNA gyrase & topoisomerase (-cidal)Administration - PODistribution – crosses membranesElimination – kidneys urineUses – UTI (esp. ciprofloxacin), systemic infections by Enterobacteriaceae.Side effects – GI, also inhibits cartilage development so not given to children, pregnant or lactating women.Examples - (nalidixic acid), norfloxacin, ciprofloxacinBlock synthesis of mRNA – rifamycinsMode of Action – binds to DNA-dependent RNA polymerase (-cidal)Administration - PODistribution – crosses membranes, reaches high conc in salivaElimination liver __> bile fecesUses mycobacterial infectionsSide effects – rashes and jaundiceExamples - rifampinAntimetabolites - Sulfonamides - syntheticMode of action – structural analogs of para-amino benzoic acid (PABA) results in inhibition of folic acid synthesis (-static)Administration - PODistribution – well absorbed and distributed widely in fluids and tissues.Elimination – inactive compound, kidneys urine.Uses – broad spectrum, G- except . aeruginosa. Standard for UTI in combination with trimethoprim.Side effects – relatively free of toxic effectsExample – Sulfamethoxazole (GantanoleR) B. Anti-Fungal Agents - Fewer in number - Selective toxicity more difficult – superficial infections respond well to topical antifungals but systemic fungal infections are challenging to cure. I will only cover Amphotericin B in classExamples:Azoles – lots of themMode of action – inhibit the synthesis of ergosterolUses – skin and deep systemic mycosesExs. miconazole, ketoconazole, fluconazoleIVPOPO or IV2. Polyenes – produced by StreptomycesEx.NystatinAmphotericin BMode of action -Both bind to ergosterol in the fungal membrane K+ leakage cell deathAdministered -TopicalIVUses - Poor penetration into fluids. Used for serious systemic infections such as cryptococcal meningitis, histoplasmosis.Side effects - Universal febrile high fever, chills, hypotension, nausea, vomiting, dyspnea, tachypnea.Nephrotoxicity permanent kidney damage in 80% of treated patients.Hepatotoxicity, cardiac arrhythmias, cardiac failure3. Griseofulvin – from PenicilliumMode of action – impairs mitotic spindle inhibits fungal cell divisionUses – dermatophytes onlys – a 1st line txt but being replaced by newer antifungals like the azoles.C. Anti-Viral Agents – Development of antiviral chemotherapy has lagged behind the others but has been spurred by HIV/AIDS (1/2 of all antivirals are for HIV). Since viruses use host structures and enzymes for replication, inhibiting viral replication without toxicity to the host is difficult. All are virustatic. I will not cover examples in classTargets for antivirals – in theory, any step from attachment & entry exit.1. Target viral DNA polymerase Ex. Aciclovir (ZoviraxR)Uses – herpes, varicella infections – to prevent reactivation & encephalitis – cannot resolve latent infections – not a cure.Inhibitors of reverse transcriptase - retroviruses including HIV (RNA DNA)Ex. AZT = Azidothymidine (Zidovudine, RetrovirR)Mode of action – analogue of thymidine, interferes with reverse transcription.Administration – POUses – slows the progression of immune failure. Given to pregnant women so they won’t pass HIV to their fetus.Side effects –bone marrow toxicityNever use in monotherapy.3. Inhibitors of viral proteases formation of defective HIVNever use in monotherapy due to risk of developing resistance.Antivirals targeting Influenza virusesEx. Amantadine Mode of action –prevents fusion of viral envelope with cell membrane Administration – PO – 2-4 hrs to peak blood levels.Uses – Txt of influenza A if given w/in 48h. Prophylaxis for high risk patients. Side effects – insomnia, dizziness, headache, psychoses.Ex. OseltamivirMode of action – inhibits neuraminidase Use – also effective against H5N1 (avian influenza)*** Often there is a lot of toxicity with anti microbial drugs!!!Also, development of drug resistance in the microbe is a problem!D. Antimicrobial Resistance1. Perspective (any notes you want to make here)2. Development of antimicrobial resistancePrimary resistance - Modification of existing genetic material via spontaneous mutation - passed vertically from parent to offspringAcquired resistance - genetic material is transferred between individual bacteria = Horizontal Gene Transfer (HGT)transformationtransductionconjugation***3. Relationship between microbial burden, clinical symptoms, and antibiotics (understand well!!!)(sorry the graphs did not copy over very well)patient is symptomaticLevels in the bodynotice some bacteria already present with resistance genes on plasmidLevels in the bodyAntibioticpatient is symptomaticLevels in the bodypatient is symptomaticAntibioticLevels in the bodysymptoms resolvingAntibioticLevels in the bodypatient is symptom freeAntibioticAntibioticpatient is wellLevels in the bodypatient is symptom freeLevels in the bodysymptoms returningLevels in the bodypatient is symptomatic4. The scope of the problem (any notes you want to make)5. Combating antibiotic resistanceDecrease prescription antibiotics to small childrenLarge scale public education effortsRegulate antibiotic use in animal feedWhat about remove antibiotic until bacteria lose the acquired resistance? Once thought that resistance to antibiotics was traded for reduced fitness, so growth rates would be slower – not so, often no reduced fitness.Step up the search for new, very different antimicrobial productsII. ImmunizationUsed to protect individuals prior to exposure. The point of Immunization (how it works) – draw diagramGoal may be to block transmission, prevent symptoms, or eradicate disease.A certain percentage of the population will need to be immune to interrupt disease transmission.The greater the number of persons 1 infected individual can infect, the more difficult the disease will be to control.Requirements of a “Good” Vaccine1. Effectivecorrect and adequate – sufficient duration – herd immunity - boosters - 2. Safeno reversion - no allergies - no contamination - 3. Stablelong shelf-life - refrigeration not required - 4. AffordableTypes of Vaccines - Important1. Live (but attenuated) – whole agent but weakened in the labProsMimics a natural infection – enters at same site, multiplies, providing longer term antigenic stimulationGood instruction of immune response strong antibody (IgG) and cellular responseLong lastingSpreads among close contacts.ConsAgent can mutate and revert to virulent so contraindicated in immunocompromised and pregnantRequires refrigeration to retain potencyExs. Smallpox (heterologous), Influenza nasal (FluMist), MMR, Varicella, yellow fever, OPV (oral polio virus).2. Inactivated (but whole, intact) – produced by killing agent with heat, chemicals, or radiationProsInduces pretty good immune response with IgG and IgANo reversion to virulent, can use in immunocompromisedDoesn’t req. refrigeration, easily stored and transported.Cons Stimulates CMI only poorlyImmunity is not long lasting, req. boostersDoes not spread to close contactsIncreased risk of allergic responses (chemicals)Exs. Influenza injected (TIV), Hep A, IPV, anthrax3. Subunit- instead of whole agent, only the antigens that best stimulate the immune systemPros - Very safeCons – tricky to find the correct antigenExs. Subcellular polysaccharides – Hib, PVC, MCV4 stimulate opsonizing IgG; acellular – aP, HPV; toxoid - D, TTiming of vaccination - Vaccination schedules for various age groups can be found at Childhood Immunizations (Ages 0-6 years) – Updated 2011 - I will only point out a couple of important points1. HepB – Hepatitis B – 3 doses beginning at birth2. RV – Rotavirus – 3 doses beginning at 2 months3. DTaP – Diphtheria-Tetanus-acellular Pertussis – 3 doses beginning at 2 months + booster4. Hib – Haemophilus influenzae type B – 3 doses beginning at 2 months5. PCV – Pneumonococcal (Streptococcus pneumoniae, polysaccharide capsule strains that infect children) – 3 doses beginning at 2 months6. IPV – Inactivated Poliovirus – 2 doses beginning at 2 months + booster7. Influenza – every year beginning at 6 months for TIV, 2 years for LAIV8. MMR – Measles Mumps Rubella – 12 - 15months =+ booster9. Varicella – Chickenpox – 12 – 15 months + booster10. HepA – Hepatitis A – 2 doses beginning at 12 monthsBooster are given age 4-6 yearsRecommended Adult Immunizations – Updated 2011 – see handout for details, I will only point out a couple of important pointsInfluenza – everyone every yearTd/Tdap – Tetanus diphtheria/Tetanus diphtheria acellular pertussis – 1 booster every 10 yearsVaricella – everyone who lacks immunity – 2 dosesHPV – Human papillomoavirus – all females to age 26 – 3 dosesZoster – age 60 – 1 doseMMR – Measles, mumps, rubella – anyone 19-49 who is not immunePneumonococcal – everyone over 65 (those polysaccharide strains of S. pneumoniae that infect adults, different strains than in the childhood vaccine)Hep A, Hep B, Meningococcal – certain “at risk” groupsOthers for overseas travelers, military.There is a lot of mis-information about vaccines and vaccine safety out there. There are sites that I believe to be the most rmation on vaccines and vaccine safety can be found at the following sites:On-line quiz, what vaccinations do you need? Side Effects HYPERLINK "" Adverse Event Reporting System HYPERLINK "" . Attack pathogens using other microbesA. Probiotic Therapy (pro = “for”, bios = “life”)1. Characteristics of good probioticsnon-pathogenicbeneficialacid stablegood attachment mechanismsable to grow2. How probiotics workcompetition for spaceinactivate toxinssecrete antibioticsstimulate nonspecific immunityIV. Phage Therapy Bacteriophages – viruses that specifically infect and kill bacteriaA. History of phage therapyB. How phage therapy worksPhages:can be targeted far more specifically than most drugsare self-replicating - replicate and spread in the body as long as the pathogen target is presentare self-eliminatingevolve with pathogen hosts, resistance is not likely cause few side effects, good for people with allergiesuseful for both treatment and prophylaxiscan be prepared locally and inexpensivelycan be used either independently or in combination with traditional drugs ................
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