Infectious Agents of Heart Disease Flashcards
Infectious endocarditis-most common etiological agents
• the most common etiological agents are members of normal microbiota
• Staphylococcus aureus – anterior nares
• Coagulase-negative staphylococci (e.g. S. epidermidis) – skin
• viridans streptococci (e.g. S. sanguis, S. mutans, S. mitis) – oral
cavity
• enterococci (E. faecalis, E. faecium) – GI tract
• Access to endocardium provided by transient bacteremia
Properties of successful IE pathogens
• able to survive antimicrobial components of serum
• able to adhere avidly to endocardium
• dextran (exopolysaccharide) – viridans streptococci
• adhesins (surface proteins; FimA, GspB, PblA, PblB) that
mediate attachment to platelets and fibrin – viridans streptococci
• fibrinogen-binding adhesins (ClfA, coagulase) – S. aureus
Life in a vegetation
-heterogeneous matrix of deposited bacteria, platelets, fibrin, other matrix ligands
-protection from immune cells
-bacteria can achieve high densities
• limitations on nutrient exchange, high cell density – bacteria are not growing rapidly
Implications for antibiotic therapy
- Bactericidal activity
- parental administration for sustained activity
- long-term treatment required
Structure of Bacteria-cell wall
cell wall defines shape of bacteria
- spheres (cocci)
- single cells
- pairs (diplococci)
- chains (streptococci)
- tetrads (micrococci)
- grapelike clusters (stapylcocci)
- rods (bacilli) coccobacilli–>long rods
- spirals–comma-shaped(Vibrio)–>4–>20coils (Spirochetes)
gram positive vs gram negative-cell wall
- Gram Positive Thick Peptidoglycan
* Gram Negative Thin Peptidoglycan - Crosslinked to the Outer Membrane (Outer Membrane:Permeability barrier)
Antibiotic therapy of IE-overview
Cell wall agents: • cefazolin, ceftriaxone, penicillin • vancomcyin • daptomycin
Protein synthesis inhibitors:
• gentamicin
RNA synthesis inhibitors:
• rifampicin
β-lactam antibiotics mechanism
- block peptidoglycan cross linking
- Four basic types of β-lactam – modification at “R” groups alters properties of the antibiotic
Mechanisms of resistance to β-lactam antibiotics
Mutations in PBPs that prevent binding of β-lactam antibiotics (modification of antibiotic target)
• Most common mechanism of -lactam resistance found in Gram-positive bacteria, such as Streptococcus and methicillin-resistant Staphylococcus aureus (MRSA)
peptidoglycan inhibitors: Glycopeptides (vancomycin)
mechanism of action?
effective on what?
used for what infections?
-Glycopeptides are glycosylated, cyclic non-ribosomally synthesized peptide
antibiotics
- Mechanism of action: Vancomycin binds to D-Ala-D-Ala at the end of peptide side chain in peptidoglycan precursors, blocking PBPs from catalyzing transglycosylation/transpeptidation steps of peptidoglycan synthesis
- Effective on many Gram-positives, not effective on Gram-negative bacteria due to permeability barrier of Gram-negative outer membrane
- Used for β-lactam resistant infections (e.g. MRSA) or in patients w/ β -lactam hypersensitivity
vancomycin mechanism of resistance?
genes found where?
often associated with what bacteria?
- Mechanism of resistance: Modification of antibiotic target - bacteria acquire genes encoding machinery to produce altered peptidoglycan structure that lacks D-Ala-D-Ala groups (contain D-Ala-D-Lac in place of D-Ala-D-Ala); vancomycin is unable to bind efficiently to these modified precursors
- Genes encoding vancomycin resistance are usually found on plasmids or transposons that can be easily transferred to other bacteria
- Vancomycin resistance often associated with enterococci in hospital settings (VRE – vancomycin-resistant enterococci)
Daptomycin spectrum? mechanism of action? uses?
- Daptomycin: Lipopeptide (lipid-modified peptide)
- Bactericidal, narrow spectrum (Gram-positive bacteria)
- Mechanism of action: thought to bind to and disrupt the cytoplasmic membrane, possibly via loss of membrane potential, leading to death
- used for infections caused by antibiotic-resistant bacteria because it employs a novel mechanism of action that retains activity against resistant bacteria
Rifampin spectrum? mechanism? resistance mechanisms? uses?
-Bactericidal, narrow spectrum (Gram-positive bacteria)
-Mechanism of action: binds to and inhibits RNA polymerase to prevent gene expression (inhibits transcription of DNA into RNA)
-Resistant mutants arise due to point mutations in the target of the drug
(RpoB subunit of RNA polymerase)
-Not generally used as monotherapy – use in combinations for synergy
which protein synthesis inhibitors target 30S function?
mechanism? spectrum of action? adverse effects? resistance?
- Aminoglycosides (e.g. gentamicin): Bactericidal
- Mechanism of action: bind irreversibly to 30S ribosomal subunit and cause misreading (incorporation of incorrect amino acid into growing protein) and premature release of ribosome from mRNA
- Not good for monotherapy: do not penetrate many Gram-positives well
- However, usually used in combination with a cell-wall-active agent to enhance penetration (synergy)
- Adverse effects: Ototoxic and nephrotoxic
- Mechanism of resistance: Enzymatic modification of the antibiotic (transferases catalyze addition of adenyl, acetyl, or phosphoryl group) to prevent aminoglycoside binding to the ribosome
Summary of Infectious Agents of Heart Disease
- the most common etiological agents of IE are Gram-positive members of normal microbiota that gain access via transient bacteremias
- factors that promote adherence to heart valves (dextran, cell surface proteins) are important virulence determinants
- bacteria live at high density and low growth rates in “vegetations” that restrict access to immune cells
- Antibiotics that target the Gram-positive cell wall are the primary therapeutics - bactericidal
