Formative 2 Flashcards
Salmonella strain isolated from pt was resistant to tetracycline, ampicillin, sulfisoxazole, gentamicin, tobramycin, streptomycin and ceftriaxone. Therefore:
Strain is likely to carry a plasmid.
Large number of resistance in one strain is usually due to
Presence of a plasmid
Do phages have antibiotic resistant genes?
None found so far
Target of Fluoroquinolones
Gram (-) infections
Penicillins target
Gram (+) infections
Ampicillin targets
Gram (+) and some Gram (-)
Salmonella is
Gram (-)
Ceftriaxone
3rd Generation Cephalosporin Broad Gram (-) coverage
Sulfisoxazole
Mimics PABA
Competitively inhibits dihydropteroate synthase
Bacterial Protein Synthesis
- Initiate Process (Aminoglycosides/Linezolid
- Add tRNA (tetracycline)
- Add peptides: translocate (Chloramphenicol, Macrolides, Clindamycin)
Gentimicin
Aminoglycoside so blocks initiation of protein synthesis
Binds to 30s
Misread proteins will increase permeability of cell membrane
Bactericidal
Tobramycin
Aminoglycoside
Streptomycin
Aminoglycoside
Aminoglycosides treat
Gram (-) infections
Streptomycin can be used for
Tuberculosis
Aminoglycosides have synergestic effects with
Beta-lactams
Vancomycin/Gentamicin
Endocarditis
Ampicillin/Gentamicin
Newborn Meningitis
Tetracycline
Transported into bacterial cells
Binds 30s ribosome
Prevents attachment of tRNA
Which drug should not be taken with antacids or milk?
Tetracyclines
Chelation with cations
Hfr strains are generated by which of the following mechanisms?
Chromosomal integration of F
- F integrates into the bacterial chromosome using IS elements for homology
- IS element serves as a source of homology for homologous recombination leading to integration
HFr Conjugation
recombination of chromosomal DNA fragments are transferred to recipient after F plasmid transfer
IS element
IS element – insertion sequence, simplest transposon, provide regions of homology with chromosome to allow recombination
Phage Conversion
Involves phage gene affecting the phenotype of a bacterium
Transformation
Direct uptake of DNA from surrounding environment
Conjugation
Transfer from one cell to another via pilus
DNA transferred via plasmids
Plasmids
Small DNA molecule within a cell
Physically separated from chromosomal DNA
Can replicate independently
Can contain genes for antibiotic resistance, toxins
Can be transferred from one bacteria to another
Transduction
Transfer of DNA via a bacteriophage
-Virus that infects bacteria
Virus picks up DNA, transfers to another bacteria
Generalized Transduction
Virus infects bacteria
Multiplies, randomly picks up host DNA
Host DNA transferred to other bacteria
Specialized Transduction
Transfer of specific genes
Virus DNA inserts into host DNA (lysogeny)
When bacteriophage DNA excised, packaged into virus with specific host DNA
Transduction occurs via
Lytic or Lysogenic Cycles
Generalized Transduction via
Lytic Cycle
Nuclear material enters bacteria
Multiplies, lyses cell
Releases progeny viruses
Specialized Transduction via
Lysogenic Cycle
Nuclear material enters cell
Incorporates into host DNA
May later become excised (enter lytic phase)
Why lysogeny matters
Genes for some bacterial toxins are transferred to non-toxic strains via lysogeny
Transposons are
DNA segments within bacterial DNA
Transposons can be
Excised and reintegrated in new locations in DNA
Once transposon is excised, it can also be moved to
plasmid, which transfers to other bacteria
Mycobacteria
Mycolic acids in cell wall
Lipid-rich cell wall that is “acid-fast”
M. Leprae (Leprosy)
Obligate IC organism
Cannot be cultured
Cool temps: skin, extremities, face
Granulomatous inflammation
M. Leprae infects
Skin and superficial nerves
Tuberculoid Leprosy
Mild (infection contained)
Lepromatous Leprosy
Severe (weak cell-mediated response)
Tuberculoid Leprosy
Patches of hypopigmented skin
Loss of sensation over affected area
Strong cell-mediated Th1 response contains infection
Lesions show granulomas, few bacteria
M. Leprae
Leprosy Dx
Acid-fast organisms on skin biopsy
Tuberculoid Leprosy Tx
Dapsone and Rifampin (6 months)
Lepromatous Leprosy Tx
Dapsone, rifamipin, clofazimine (years)
Dapsone
Competes with bacterial para-aminobenzoic acid (PABA)
Inhibits dihydropteroate synthase
Disrupts folic acid pathways (like sulfonamides)
Also used for pneumocystis jirovecii (like sulfonamides)
Hemolysis in G6PD (like sulfonamides)
Rarely can cause agranulocytosis (ANC=0)
Sulfonamides
Disrupt folic acid pathways
Pneumocystis jirovecii
Hemolysis in G6PD
Hypopigmented anesthetic skin patch over R side face. C/o occasional ‘electric current’-like sensation radiating from her R elbow to hand. Stain shows acid-fast bacilli. Which drug for first-line treatment?
Dapsone
Dapsone is first-line therapy for
leprosy
Isoniazid
Do not use with antacids or dairy
Ethambutol
Inhibits synthesis of mycobacterial cell wall glycan
Well absorbed and distributed
CNS level variable, but usually reaches therapeutic level
Most excreted in urine– accumulates in renal failure
Dose-dependent optic neuritis, decreased acuity, loss of red-green differentiation
Resistance– Rapid, use in combination
Isoniazid (INH)
Mechanism
Blocks synthesis of Mycolic Acids for mycobacterial cell wall
Bactericidal in growing cells only
Pharmacokinetics
Well absorbed and distributed after oral administration
CNS levels 20-100% of serum level; Intracellular = extracellular
Metabolism key factor in pharmacokinetics– acetylated in the liver
Genetic differences (polymorphism) in acetylation
Fast acetylators may require higher doses
“Fast” acetylators–50% of US Blacks and Whites, most Asians, Native Americans
t1/2 for “Fast acetylators < 1 hrs, “slow” acetylators– t1/2 > 3 hrs
Excretion– Urine (INH and acetylated product)
Alter dosing in hepatic, not renal disease
Clinical use
Prophylaxis– Used alone for TB exposure, tuberculin convertors
Combination chemotherapy for TB– With ethambutol, rifampin, or pyrazinamide
Adverse effects
Dose- and duration-dependent
Hepatotoxicity– Increases with age of patient,
more common in alcoholics, maybe during pregnancy
Peripheral and central neuropathy– Treat with pyridoxine (Vitamin B6)
Resistance– Can develop rapidly, or is already present
10% of isolates in US resistant
Higher in Caribbean, Asia (approaching 20%)
Deletion of katG gene in mycobacterium
Pyrazinamide
Oral, absorbed, distributed
Bacteriostatic
Activated by mycobacterium, blocks membrane functions
Rapid resistance if used as monotherapy
Causes hyperuricemia (gouty arthritis) in up to 40%
1-5% incidence of hepatotoxicity
Contraindicated in pregnancy
Streptomycin
Was only for severe (life-threatening) cases, now used more frequently
PK, adverse effects typical of aminoglycoside
Interferon γ assay
Interferon γ assay – M.tb antigens + whole blood → activated T cells produce INF-γ → ELISA
Pt diagnosed with miliary tuberculosis. Which test would best confirm latent infection of immediate family members?
Positive interferon-gamma blood test
Il-12 triggers
Differentiation of T cells into Th1 cells
Activated Th1 cells produce
Interferon gamma
Interferon gamma is important for
response to IC infections
BCG vaccine
live attenuated M. bovis, best for children, not in US
Interferon-gamma blood test is specific for
M. tuberculosis
Detection of acid-fast bacilli in sputum indicates
active infection
Tuberculin test resulting in an erythema 15 mm in diameter or more is
Positive
M. Tuberculosis Transmission
Transmission – respiratory droplets → taken up by alveolar macros via LAM – mannose binding and opsonization → prevention of phagosome-lysosome fusion and oxidant breakdown → spread through lymph and blood to marrow, spleen, kidney, CNS
M. Tuberculosis lipoarabinomannan binds to
macrophage mannose receptor
Opsonization occurs via
C3B (component of complement system)
Capsules
Capsules – protection/phagocytosis evasion
Cord factor
Cord factor – cytotoxic to neutros by disrupting mitochondrial membranes
Virulence factor
Bacterial features that allow evasion of host defenses
Listeria is found in
Unpasteurized milk products
Listeria can
Cross the placenta and infect the fetus
Concentration-Dependent Cell Killing
Concentration-dependent (aminoglycosides, fluoroquinolones)
Peak serum concentration relates to extent of killing (continues to increase above MBC)
Higher peak values result in increased efficacy and decreased development of resistance
Gentimicin
Aminoglycoside
Efficacy of aminoglycosides is related to their
Peak concentration
Aminoglycosides elicit a
post-antibiotic effect
Post-antibiotic effect
continued killing or suppression of bacteria after the drug concentrations have fallen below MBC
Aminoglycosides are rapidly cleared into the urine, and thus
have short half-lives
Aminoglycosides used to be administered 3 or 4 times daily to maintain their plasma concentrations. That was effective for bacterial killing, but by maintaining high systemic concentrations for extended periods of time the adverse effects of aminoglycosides
Nephrotoxicity
Ototoxicity
were more common and severe
Pseudomonas infection Extended spectrum penicillin prescribed Gentamicin ordered for combination chemo Gentamicin administered as a single 30-min infusion daily This is appropriate b/c gentamicin
Exhibits concentration-dependent killing
Piperacillin
Antipseudomonal Penicillin
- Greater porin channel penetration
- More gram (-) coverage vs. aminopenicillins
Pseudomonas
Gram (-)
Ampicillin administered
orally
Piperacillin administered
IV
Most penicillins have similar half-lives
Short: (1/2-1 hour)
Piperacillin
is one of the most expensive penicillins
Piperacillin
Anti-Pseudomonal Penicillin
Susceptible to beta-lactamases
Given with beta-lactamase inhibitor (tazobactam)
