Medical microbiology Flashcards

Question

Why is aciclovir so effective and safe?

Answer 1

HSV thymidine kinase (TK) has 100x the affinity for ACV compared with cellular phosphokinases Aciclovir triphosphate has 30x the affinity for HSV DNA polymerase compared with cellular DNA polymerase Aciclovir triphosphate is a highly polar compound - difficult to leave or enter cells (but aciclovir is easily taken into cells prior to phosphorylation) DNA chain terminator

Answer 2

Treatment of encephalitis Treatment of genital infection suppressive therapy for recurrent genital herpes Varicella zoster virus Treatment of chickenpox Treatment of shingles Prophylaxis of chickenpox CMV/EBV Prophylaxis only Shingles (zoster)

Answer 3

Active for CMV - reactivated infection or prophylaxis in organ transplant recipients congenital infection in newborn retinitis in immunosuppressed Structurally similar to aciclovir CMV does not encode TK but has UL97 kinase Inhibits CMV DNA polymerase

Answer 4

CMV, because it doesnt have the tyrosine kinase needed to activate the drug in the first step.

Answer 5

Foscarnet: Selectively inhibits viral DNA/RNA polymerases and RTs No reactivation required Binds pyrophosphate binding site – a structural mimic used for CMV infection in the immunocompromised e.g. pneumonia in solid organ and bone marrow transplants. May be used because of ganciclovir resistance (TK mutants) Cidofovir Chain terminator - targets DNA polymerase Competes with dCTP Monophosphate nucleotide analog Prodrug – phosphorylated by cellular kinases to di-phosphate drug active against CMV; but MUCH MORE nephrotoxic Treatment of retinitis in HIV disease

Answer 6

Two main mechanisms Thymidine Kinase mutants DNA polymerase mutants If occurs in TK, drugs not needing phosphorylation are still effective (e.g. foscarnet, cidofovir) If occurs in DNA polymerase, all drugs rendered less effective VERY RARE in immune competent patients (low viral load)

Answer 7

Envelope protein, gp120 with transmembrane gp41 Membrane associated matrix protein Gag 17 Nucleocapsid protein Gag p24 Reverse transcriptase Viral envelope ds RNA genome

Answer 8

1. Attachment with binding of viral gp120 via CD4 and CCRX 2. Reverse transcription of RNA into ds DNA 3. Integration into host chromosome of proviral 4. Transcription of viral genes 5. Translation of viral mRNA into viral proteins 6. Virus assembly and release by budding 7. Maturation

Answer 9

1. Anti-reverse transcriptase inhibitors nukes -nucleoside/nucleotide RT inhibitors non-nukes -non-nucleotide RT inhibitors (allosteric) 2. Protease inhibitors - multiple types 3. Integrase inhibitors – POL gene - protease, reverse transcriptase and integrase (IN) with the 3´end encoding for IN (polynucleotidyl transferase) 4. Fusion inhibitors – gp120/41 - biomimetic lipopeptide Treatment-HAART (combination of drugs to avoid resistance)

Answer 10

Nukes AZT - Zidovudine Synthetic analogue of nucleoside thymidine – when converted to tri-nucleotide by cell enzymes, it blocks RT by - competing for natural nucleotide substrate dTTP incorporation into DNA causing chain termination Others ddI, ddC, d4T, and 3TC (2′,3′-dideoxy-3′-thiacytidine

Answer 11

Non-competitive inhibitor of HIV-1 RT | Synergistic with NRTI’s such as AZT because of different mechanism

Answer 12

PEP – within 72 hours post exposure - take for 28 days. 2x NRTIs + integrase inhibitor ``` PrEP – pre-exposure - blocks transmission 2x NRTIs (Truvada) two tablets 2 – 24 hours before sex, one 24 hours after sex and a further tablet 48 hours after sex - called ‘on-demand’ or ‘event based’ dosing ``` ``` 2 x NRTIs = Combination of Nucleoside RTIs emtricitabine (guanosine analog) + tenofovir (adenosine analog) ```

Answer 13

Use of single agents leads to rapid development of resistance The drug binding site is altered in structure by as few as one amino acid substitution Mutation rate - high Viral load – high resistance

Answer 14

Selection pressure and mutation frequency Increased mutation rate seen in HIV. They form a quasispecies within an individual patient:- A viral swarm The error rate in copying viral genome by reverse transcriptase enzyme is 1 base per 10 4-5 incorporations; lacks proof reading capacity. So, for HIV with 10 9-10 viruses produced every day, ALL possible viral variants would be produced Hence use of combinations of antivirals e.g. HAART

Answer 15

Amantadine Inhibit virus uncoating by blocking the influenza encoded M2 protein when inside cells and assembly of haemagglutinin Now rarely used Zanamivir and Oseltamivir (Tamiflu) Inhibits virus release from infected cells via inhibition of neuraminidase Oseltamivir –oral Zanamivir- inhaled or IV - less likely for resistance to develop

Answer 16

target and inhibit NA at highly conserved site (reduce chances of resistance via mutation) prevent release of sialic acid residues from the cell receptor preventing virus budding and release and spread to adjacent cells. Neuraminidase inhibitors

Answer 17

Resistance sometimes only requires a single amino acid change - seen recently with swine flu (H1N1) and Tamiflu (oseltamivir) Point mutation (H275Y; tyrosine replacing histidine) Seen in immunocompromised patients; shed virus for weeks/months Likely to be selected from among quasispcies during treatment Transmissible and virulent Remains sensitive to zanamivir;

Answer 18

Hep B specific Hep B immunoglobulin (passive immunity) + vaccination within 48 hours (HBV treatment includes antivirals 3TC/NRTIs) Hep C interferon- + ribavarin (anti-viral) for 6 months within first 2 months of exposure 90% cure rate - now direct acting antivirals ``` HIV 80% protection i.e. no sero-conversion must be FAST – hours antiviral drug treatment – 28 days 2xNRTI + protease or integrase inhibitor ```

Answer 19

9.6 Kb RNA virus, enveloped; Flaviviridae family; identified in 1989 transmitted via blood – infectious (mother to baby) increasingly common – high risk groups – drug users 20% +ve; – needles (sex?) major cause of chronic liver disease estimated 170 million people infected worldwide occupational risk groups – healthcare workers needle-stick risk – 3% to sero-conversion; chronic carriage almost certain (85%) long incubation – 1 - 6 months vaccination NOT available prevalence in UK - ~6000 per year ( 95% are i/v drug users) early treatment facilitates resolution

Answer 20

Block RNA synthesis by inhibiting inosine 5'-monophosphate (IMP) dehydrogenase – this blocks the conversion of IMP to XMP (xanthosine 5'-monophosphate) and thereby stops GTP synthesis and, consequently, RNA synthesis Treat: RSV and HepC (in combination with pegylated interferon)

Answer 21

relatively new class of medication acts to target specific steps in the HCV viral life cycle shorten the length of therapy, minimize side effects, target the virus itself, improve sustained virologic response (SVR) rate. structural and non-structural proteins - replicate and assemble new virions HCV - first chronic viral infection to be cured without IFN or ribavirin. All the major HCV-induced enzymes - NS2-3 and NS3-4A proteases, NS3 helicase and NS5B RNA-dependent RNA polymerase (RdRp) are essential for HCV replication and are potential drug targets. DAA with different viral targets, are synergistic in combinations

Answer 22

``` Because they are self limiting. Can give vaccinations for them. rabies dengue Common cold viruses Ebola HPV Arbovirsues ```

Answer 23

B-lactams (penicillins, cephalosporins) and vancomycin.

Answer 24

Bacteria acquire genes, and if you select with antibiotics for these clones of bacteria that have acquired the genes, they then spread throughout the population.

Answer 25

Widely used and misused drugs 20-50% questionable use In hospitals - 30% of drug budget ~25% of patients have received antibiotics within the previous 24h In ITU, 50% of patients are on antibiotics 50 million prescriptions per year 80% of human use is in the community 50% - respiratory infections 15% - urinary tract infections

Answer 26

Natural products of fungi and bacteria - soil dwellers - natural antagonism and selective advantage - kill or inhibit the growth of other microorganisms most derived from natural products by fermentation, then modified chemically :increase in pharmacological properties Increase in antimicrobial effect Some totally synthetic - e.g. sulphonamides

Answer 27

Alexander Fleming Diffusion of penicillin into agar caused lysis of S.aureus. The plate had been left in a room for several weeks at a temperature that allowed growth of mould without overgrowth of the bacteria.

Answer 28

Selective Toxicity Due to the differences in structure and metabolic pathways between host and pathogen Harm microorganisms, not the host Target in microbe, not host (if possible) Difficult for viruses (intracellular), fungi and parasites Variation between microbes

Answer 29

active dose (MIC) versus toxic effect narrow for toxic drugs - e.g. aminoglycosides, vancomycin ototoxic, nephrotoxic -the dose between when a drug can stop becoming therapeutic, and start causing host damage.

Answer 30

Maintains flora - complex interactions Competition between flora Limits growth of competitors and PATHOGENS

Answer 31

bacterial or pathogen overgrowth e.g. Antibiotic Associated Colitis : (clindamycin, broad-spectrum lactams, fluoroquinolones) - pseudomembranous colitis Clostridium difficile (part of normal flora of 3% of population), causes pseudomembranous colitis of colon, so colon cannot absorb water, causing diarrhoea. Ulcerations-inflammation Severe diarrhoea Serious hospital cross infection risks.

Answer 32

``` Immunity Antibiotics and immunity of individual result in bacteria clearance. Immunosuppression e.g. cancer chemotherapy, transplantations, myeloma, leukaemias, HIV with low CD4 Neutropenics, asplenics, renal disease, diabetes, alcoholics, Babies, elderly., ……….. ```

Answer 33

Classified by:- Type of activity Structure Target site for activity

Answer 34

Bactericidal: Kill bacteria Used when the host defense mechanisms are impaired Required in endocarditis, kidney infection Bacteriostatic: Inhibit bacteria Used when the host defense mechanisms are intact Used in many infectious diseases Varies for drug and species and concentration

Answer 35

Broad Spectrum Antibiotics: Effective against many types Example: Cefotaxime Narrow Spectrum Antibiotics: Effective against very few types Example: Penicillin G

Answer 36

Antbiotics can be altered pharmacologically to have enhanced effect on some bacteria. Go from being first generation, to second generation, to third generations.

Answer 37

Duff antibiotics have diff structures. Structural mimics of natural substrates for enzymes B-lactams have a beta lactam ring, mimics the active structure in penicillin.

Answer 38

Infolding of plasma membrane, capsule, cell wall, DNA coiled into nucleoid, basal body, ribosomes, cytoplasm, plasma membrane, pili, cytoplasmic inclusion,

Answer 39

1. Cell wall synthesis, eg, cycloserine, vancomycin, teichoplanin, penicillin. 2. Folic acid metabolism, trimethoprim, sulfonamides. 3. Cell membrane, colistin, daptomycin. 4. Protein synthesis 50S inhibitors, erythromycin, clindamycin 30S inhibitors, tetracycline, streptomycin, getamicin. 5. DNA and RNA processing Quinolones, -DNA gyrase, DNA directed RNA polymerase. 6. Forming free radicals, Metroonidazole, nitrodurantoin.

Answer 40

Gram positive - Peptidoglycan on outside of membrane - Peptidoglycan makes majority of cell wall, but also contains lipoteichoic acids, and integral proteins. Gram negative -peptidoglycan found in periplasmic space between outer and inner membrane. To get to it, you need porins, and selective transport mechanisms, found in outer membrane. -Different structure of cell wall between them both.

Answer 41

To make peptidoglycan, there are two dimers, one with 5 peptide amino acids attatched. This contains to D-ALA, D-ALA terminal amino acids. An inhibitor like cycloserine inhibits reactions involved in incorporation of alanine into cell wall precursor. An enzyme in the bacterial cell breaks off the terminal D-ALA, and attaches the remaining D-ALA to adjacent chain, causing the formation of peptidoglycan. Vancomycin inhibitor binds to the terminal D-ALA D-ala residues, and prevents incorporation of sub unit into growing peptido glycan chain. Bacitracin prevents dephosphorylation of phospholipid carrier which prevents regeneration of carrier necessary for synthesis to continue. Penicillins and cephalosporins (beta-lactams) bind to and inhibit enzymes which catalyse this link. Peniclilin forms covalent enzyme-inhibitor complex with transpeptidase, as it is a structural mimic of the 5 amino peptide chain. Antibiotics are often structural mimics of natural substrates for bacterial enzymes.

Answer 42

bacteria can make their own folic acid. So we can inhibit this process, sulfonamides and dapsone block the first enzyme. Trimethoprim antibiotic blocks the enzyme dihydrofolate reductase. Gives the bacteria selective toxicity.

Answer 43

Treatment of bacterial infections Prophylaxis - close contacts of transmissible infections carriage rates ( ~80% in outbreaks) e.g. meningitis - prevention of infection e.g. tuberculosis - peri-operative cover for gut surgery - people with  susceptibility to infection. Inappropriate use - viral sore throats - patient pressure

Answer 44

This will depend upon the age, weight, renal and liver function of the patient and the severity of infection Depend on the susceptibility of the organism Will also depend upon properties of the antibiotic i.e. enough to give a concentration higher than the MIC (minimum inhibitory concentration) ! at the site of infection

Answer 45

BEFORE an organism identified in life-threatening infections e.g. endocarditis, septicaemia Polymicrobial infections e.g. abscess, G.I. perforation anaerobes and aerobes Less toxic doses of an individual drug possible Synergy e.g. penicillin and gentamicin Co-trimoxazole (sulphonamides + trimethoprim) reduce antibiotic resistance e.g. Tuberculosis

Answer 46

Basic penicillins e.g. benzylpenicillin(PenG), penicillin V Active against streptococci, pneumococci, meningococci, treopnemes. Most strains of Staphylococcus aureus are resistant. Anti-staphylococcal penicillins e.g. flucloxacillin narrow spectrum, G+ves, beta-lactamase resistant, less potent that PenG Not MRSA Pen G benzlypenicillin (G= gold standard); not acid stable i/v or i/m good for some G-ves as well as G+ves penV phenoxymethlypenicillin oral (more acid stable than penG) less active v G-ves, but same activity v G+ves as PenG Broader spectrum penicillins e.g. ampicillin Spectrum of activity is similar to basic penicillins but also includes some Gram-negative organsims and also enterococci Anti-pseudomonal penicillins e.g. piperacillin extended spectrum beta-lactam antibiotic also G+ve, G-ve, anaerobes Beta-lactam/beta-lactamase inhibitor combinations e.g. co-amoxiclav (Augmentin) Spectrum like amoxicillin plus activity against some Gram-negatives and Staph aureus

Answer 47

~ 25,000 people die every year across Europe because of infections related to Antimicrobial Resistance (AMR) In USA, MDR infections cost the health-care system ~20 billion US$ annually and generate more than 8 million additional hospital days Antibiotic resistance: Increases mortality challenges control of infectious diseases threatens a return to the pre-antibiotic era increases the costs of health care jeopardizes health-care gains to society

Answer 48

Drug resistant bacteria are NOT MORE pathogenic We just have fewer antibiotic options for treatment

Answer 49

1. Altered or new target e.g. Ribosome Porin PBPs – peptidoglycan synthesis DNA gyrase RNA polymerase Mcr1 & colistin 2. Drug inactivation e. g. beta-lactamase 3. Metabolic by-pass e.g. vancomycin D-ala-D-lac 4. Efflux pump 5. Overproduction of target - trimethoprim 6. Intrinsic impermeability Mechanisms of resistance Natural resistance Genetic Mechanisms - acquired Non-Genetic Mechanisms (growth phases)

Answer 50

Directed at antibiotic itself - Degrading the drug Modifying the drug New or Altered target antibiotic no longer binds e.g. PBPs - PBP2a in MRSA Altered transport Actively pumping drug out - efflux pump porins no longer influx drug Metabolic by-pass metabolic change D-ala-D-lac and vancomycin

Answer 51

Drug must reach target - natural barriers, porins, export pump G+ve peptidoglycan - highly porus - no barrier to diffusion G-ves outer membrane - barrier resistance advantage Porins single mutation - multiple resistance

Answer 52

``` Chromosome-mediated Due to spontaneous mutation: in the target molecule in the drug uptake system Mutants are SELECTED ; they are NOT induced ``` Plasmid-mediated Common in Gram-negative rods Transferred via conjugation Multidrug resistance The mutant is out there-we select it. As bacteria are constantly mutating. Genetic mechanisms of resistance Production of drug-inactivating enzymes Altered target structures – new or mutations Alteration of membrane permeability Altered influx or efflux - new pumps or mutations or altered gene expression

Answer 53

Mechanism for genetic heterogeneity and evolution Rapid, cross-species Virulence (toxins), drug resistance, antigens (immune evasion) 1. Transformation - fragment of DNA from another bacterial cell enters bacterial chromosome. 2. Transduction - Fragment of DNA from another bacterial cell (former phage host, is transmitted into bactera) 3. Conjugation - Sex pili form, allow the transfer of bacterial DNA.

Answer 54

Gram + ve ß-lactamase (Penicillinase), destroys beta lactam ring Alteration of the transpeptidase enzyme (PBP) Gram - ve ß -Lactamase (Penicillinase), destroys beta lactam ring. Alteration of porins Augmentin/co-amoxiclav - combination of both - binds to and inactivates beta lactamases. No antibacterial activity of its own.

Answer 55

1. Porin mutates or new porin type Multi-resistant, so beta lactam cannot enter bacteria 2. PBP - mutates or bacteria acquires a new PBP (penicillin binding protien) 3. Bacteria acquires a beta lactamase enzyme.

Answer 56

Produce penicillinases / beta lactamases that cleave the beta lactam ring - penicillin is inactivated Acquire alternative forms of / or mutations in penicillin binding proteins (PBPs) - penicillin can’t bind Acquire alternative forms of / mutations in porins, - penicillin cannot get into cell Acquire alternative forms of / mutations in efflux pumps - penicillins are pumped out faster

Answer 57

vancomycin

Answer 58

Acquisition of van operon by transposition | -Makes D-ala, D-lactate, prevents vancomycin binding.

Answer 59

Inaccessibility to drugs (e.g., abscess, TB lesion) Stationary phase/vegetations and biofilms (non-susceptible to inhibitors of cell wall synthesis)

Answer 60

1. Control use not in animal feeds complete course [DOTS for TB] appropriate prescribing 2. New or modified drugs few in past 25 years 3. Combination therapy different targets overcome mutation rates 4. Infection control individual - ward - society Re-establish susceptible fora?

Medical microbiology Flashcards

(84 cards)