[3S] Protein Synthesis Inhibitors PPT Flashcards
(120 cards)
1
Q
Selectively inhibit bacterial protein synthesis
A
Protein Synthesis Inhibitors
2
Q
___ ribosomes in bacteria
___ ribosomes in mammalians
A
70S
80S
3
Q
Basis for selective toxicity against microorganisms without causing major effects on mammalian cells
• Differences
• Ribosomal subunits
• Chemical composition
• Functional specificities of component nucleic acids and proteins
A
Protein Synthesis Inhibitors
4
Q
Protein Synthesis Inhibitors MOA
A
• Bacteriostatic
• Bactericidal – Oxazolidinones and Pleuromutilins
5
Q
• Simple and distinctive structure
• Effective orally as well as parenterally
A
Chloramphenicol
6
Q
MOA
Inhibits microbial protein synthesis and is bacteriostatic against most susceptible organisms.
It binds reversibly to the 50S subunit of the bacterial ribosome and inhibits peptide bond formation
A
Chloramphenicol
7
Q
ANTIMICROBIAL ACTIVITY
Active against both aerobic and anaerobic gram-positive and gram-negative organisms.
A
Chloramphenicol
8
Q
ANTIMICROBIAL ACTIVITY
• Bacteriostatic
• Bactericidal - strains of H, influenzae, N. meningitidis, and some strains of Bacteroides
A
Chloramphenicol
9
Q
ANTIMICROBIAL ACTIVITY
Not active against Chlamydia species.
A
Chloramphenicol
10
Q
ANTIMICROBIAL ACTIVITY
Resistance is plasmid-mediated
• formation of chloramphenicol acetyltransferases
A
Chloramphenicol
11
Q
CLINICAL USES
Rickettsial infections: typhus and Rocky Mountain spotted fever
A
Chloramphenicol
12
Q
CLINICAL USES
Alternative to a β-lactam antibiotic for treatment of bacterial meningitis occurring in patients who have major hypersensitivity reactions to penicillin
A
Chloramphenicol
13
Q
PKINETICS: CHLORAMPHENICOL
___ formulation: chloramphenicol succinate (prodrug) -> hydrolyzed to yield free chloramphenicol
A
IV
14
Q
PKINETICS
Widely distributed to virtually all tissues and body fluids, including the central nervous system and cerebrospinal fluid
✔ Concentration in the brain tissue may be equal to that in serum
A
Chloramphenicol
15
Q
PKINETICS
Penetrates cell membranes readily; readily cross the placental and blood-brain barriers
A
Chloramphenicol
16
Q
PKINETICS
Inactived by:
(1) conjugation with glucuronic acid or
(2) reduction to inactive aryl amines
A
Chloramphenicol
17
Q
Chloramphenicol excretion
A
Urine, small amount into bile & feces
18
Q
TOXICITY
- Gastrointestinal disturbances
• Nausea, vomiting, diarrhea - Oral or vaginal candidiasis due to alteration of normal microbial flora
A
Chloramphenicol
19
Q
TOXICITY
- Bone marrow
• Inhibition of red cell maturation
• dose-dependent and reversible
• Aplastic anemia rare idiosyncratic reaction
• usually irreversible
• may be fatal
A
Chloramphenicol
20
Q
TOXICITY: CHLORAMPHENICOL
• Lacks effective glucuronic acid conjugation mechanism for the degradation and detoxification
• Vomiting, flaccidity, hypothermia, gray color, shock, and vascular collapse
A
Gray Baby Syndrome
21
Q
DRUG INTERACTIONS
• Inhibits hepatic drug-metabolizing enzymes
• Increasing the elimination half-lives of drugs
• Phenytoin
• Tolbutamide
• Chlorpropamide
• Warfarin
A
Chloramphenicol
22
Q
Tetracyclines = Bacteriostatic or Bactericidal?
A
Bacteriostatic
23
Q
MOA
Bind reversibly to the 30S subunit of the bacterial ribosome, blocking the binding of aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex and prevents addition of amino acids to the growing peptide
A
Tetracyclines
24
Q
PKINETICS
Absorption:
• _____% for tetracycline and demeclocycline
• _____% for doxycycline and minocycline
A
60–70
95–100
25
Tigecycline & Eravacycline ROA
IV
26
Tetracycline excretion
Feces (?)
27
PKINETICS
Absorption impaired by: by multivalent cations (Ca2+, Mg2+, Fe2+, Al3+); dairy products and antacids, and by alkaline pH.
Tetracyclines
28
PKINETICS
• Wide tissue distribution except CSF
• Cross the placental barrier and excreted in breast milk
• Excreted mainly in bile and urine
• Except : Doxycycline and tigecycline
Tetracyclines
29
PKINETICS
Doxycycline & Tigecycline elimination
Nonrenal mechanisms
30
PKINETICS
Short-acting
tetracycline (oral)
31
PKINETICS
Intermediate-acting
demeclocycline (oral)
32
PKINETICS
Long-acting (Oral & IV)
doxycycline and minocycline
33
PKINETICS
Long half-lives
Tigecycline (IV), Eravacycline (IV), Omadacycline (oral and IV)
34
ANTIBACTERIAL ACTIVITY
Active against gram-positive and gram-negative bacteria
• certain anaerobes, rickettsiae, chlamydiae, and mycoplasmas
Tetracyclines
35
RESISTANCE MECHANISMS
(1) impaired influx or increased efflux by an active transport protein pump
(2) ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome
(3) enzymatic inactivation
Tetracylcines
36
CLINICAL USES
Primary uses:
Mycoplasma pneumoniae (in adults) Chlamydiae
Rickettsiae*
Borrelia sp.*
Vibrios
some spirochetes
Anaplasma phagocytophilum
Ehrlichia sp
Tetracyclines
37
CLINICAL USES
Secondary uses
• community-acquired pneumonia (CAP)
• syphilis
Tetracyclines
38
CLINICAL USES
• Chronic bronchitis
• Leptospirosis
• Acne
Tetracyclines
39
CLINICAL USES
gastrointestinal ulcers caused by H. pylori
tetracycline
40
CLINICAL USES
Lyme disease
Malaria prophylaxis
Treat ameobiasis
doxycycline
41
CLINICAL USES
meningococcal carrier state
minocycline
42
CLINICAL USES
• inhibits the renal actions of antidiuretic hormone
(ADH)
• ADH-secreting tumors
Demeclocycline
43
CLINICAL USES
CONS, gram-positive cocci resistant to methicillin (MRSA strains) and vancomycin (VRE strains)
Tigecycline, eravacycline and omadacycline
44
CLINICAL USES
Streptococci, enterococci, gram-positive rods, Enterobacteriaceae, Acinetobacter sp, anaerobes, rickettsiae, Chlamydia sp, and L. pneumophila; and rapidly growing mycobacteria
Tigecycline, eravacycline and omadacycline
45
TOXICITY
1. Gastrointestinal disturbances
• Nausea, vomiting, and diarrhea
• Esophageal ulceration
• Life-threatening enterocolitis
• Candidiasis (oral and vaginal)
• bacterial superinfections S. aureus or C. difficile.
Tetracyclines
46
TOXICITY
2. Bony structures and teeth
• Fetal exposure
• tooth enamel dysplasia
• irregularities in bone growth
• Younger children
• enamel dysplasia
• crown deformation (permanent teeth)
Tetracylcines
47
TOXICITY
3. Hepatic toxicity
• high doses
• pregnant patients
• preexisting hepatic disease
Tetracylcines
48
TOXICITY
Renal Toxicity: Fanconi Syndrome
outdated tetracyclines
49
TOXICITY
Renal Toxicity: Nephrotoxicity
tetracycline + diuretic
50
TOXICITY
Renal Toxicity: exacerbate preexisting renal dysfunction
Tetracylcines
51
TOXICITY
Photosensitivity
Demeclocycline
52
TOXICITY
Vestibular Toxicity
• Dose-dependent reversible dizziness and vertigo
Doxycycline and minocycline
53
Macrocyclic lactone ring with attached sugars
Macrolides
54
Semisynthetic derivatives of erythromycin
Clarithromycin and azithromycin
55
Macrolides prototype
Erythromycin
56
MOA
Inhibition of protein synthesis occurs via binding to the 50S ribosomal RNA
Macrolides
57
Macrolide antibiotics prolong the electrocardiographic QT interval due to an effect on potassium channels: _____________________________
torsades de pointes arrhythmia
58
MACROLIDES
Absorption impeded by food
Azithromycin
59
MACROLIDES
tissues and phagocytes > plasma
Azithromycin
60
Good oral bioavailability
Distribute to most body tissues
Primarily hepatic metabolism
Macrolides
61
Half-life shortest to longest
Azithromycin, Erythromycin, Clarithromycin
E > C > A
62
ANTIMICROBIAL ACTIVITY
Gram-positive organisms:
pneumococci, streptococci, staphylococci, and corynebacteria
Mycoplasma pneumoniae, L pneumophila, Chlamydia trachomatis, Chlamydophila
psittaci, Chlamydophila pneumoniae, H pylori, Listeria monocytogenes, and certain mycobacteria (Mycobacterium kansasii, Mycobacterium scrofulaceum)
Erythromycin
63
ANTIMICROBIAL ACTIVITY
Gram-negative organisms:
Neisseria sp, Bordetella
pertussis, Bartonella henselae, and Bartonella quintana as well as some Rickettsia species, Treponema pallidum, and Campylobacter species
Erythromycin
64
RESISTANCE MECHANISMS
(1) Reduced permeability of the cell membrane or active efflux
(2) Production (by Enterobacteriaceae) of esterases that hydrolyze macrolides
(3) Modification of the ribosomal binding site (so-called ribosomal protection) by chromosomal mutation or by a macrolide-inducible or constitutive methylase.
Erythromycin
65
T/F: Cross-resistance occurs between erythromycin and the other macrolides
T
66
PKINETICS
Erythromycin excretion
Bile
67
PKINETICS
• Absorbed drug is distributed widely except to the brain and cerebrospinal fluid.
• Taken up by polymorphonuclear leukocytes and macrophages
• Traverses the placenta and reaches the fetus
Erythromycin
68
CLINICAL USES
Corynebacterial and chlamydial infections, M pneumoniae, and L pneumophila, useful as a penicillin substitute in penicillin-allergic individuals with infections caused by staphylococci and streptococci
Erythromycin
69
ADVERSE REACTIONS
Anorexia, nausea, vomiting, and diarrhea; acute cholestatic hepatitis
Erythromycin
70
DRUG INTERACTIONS
theophylline, warfarin, cyclosporine, methylprednisolone, and digoxin
Erythromycin
71
More active against Mycobacterium avium complex; also has activity against M leprae, T gondii, and H influenzae.
Clarithromycin
72
PKINETICS
Clarithromycin metabolism & excretion
Liver and partially eliminated in the urine
73
PKINETICS
14-hydroxyclarithromycin (major metabolite) with antibacterial activity and eliminated in the urine
Clarithromycin
74
ADVERSE REACTION
• Lower incidence of gastrointestinal intolerance
• Similar drug interactions with Erythromycin
Clarithromycin
75
ANTIMICROBIAL ACTIVITY
Active against M avium complex, T gondii, H influenzae, Chlamydia sp
Azithromycin
76
MOA
Penetrates into most tissues (except cerebrospinal fluid) and phagocytic cells extremely well, with tissue concentrations exceeding serum concentrations by 10- to 100-fold
Azithromycin
77
PKINETICS
No drug interactions
Azithromycin
78
Chlorine-substituted derivative of lincomycin
(Streptomyces lincolnensis)
Clindamycin
79
MOA
MOA similar to macrolides but are not chemically
related
Clindamycin
80
ANTIMICROBIAL ACTIVITY
• Streptococci, staphylococci, and pneumococci
• Bacteroides sp and other anaerobes
Clindamycin
81
Gram-negative aerobes are intrinsically resistant
• poor penetration through the outer membrane.
Clindamycin
82
MECHANISM OF RESISTANCE
(1) mutation of the ribosomal receptor site
(2) modification of the receptor by a constitutively expressed methylase
(3) enzymatic inactivation
Clindamycin
83
T/F: Cross-resistance between clindamycin and macrolides is common.
T
84
Clindamycin ROA
Oral & IV
85
Clindamycin metabolism & excretion
Hepatic metabolism, renal and biliary excretion
86
CLINICAL USE
• Treatment of severe anaerobic infections: Bacteroides, Fusobacterium, and Prevotella
• Backup drug against gram-positive cocci: Community-acquired strains of MRSA
Clindamycin
87
CLINICAL USE
• Toxic shock syndrome (with penicillin G) or necrotizing fasciitis
• Penetrating wounds of the abdomen and gut (combined with aminoglycoside or cephalosporin)
Clindamycin
88
CLINICAL USE
• Septic abortion, pelvic abscesses, or pelvic inflammatory disease; and lung and periodontal abscesses
• Prophylaxis of endocarditis in valvular disease (patients allergic to penicillin)
Clindamycin
89
CLINDAMYCIN
• In combination with __________ alternative vs P. jiroveci pneumonia in AIDS patients
• In combination with __________ for AIDS-related toxoplasmosis
primaquine
pyrimethamine
90
TOXICITY
• Gastrointestinal irritation
• Skin rashes
• Neutropenia
• Hepatic dysfunction
• Superinfections C. difficile - pseudomembranous colitis
Clindamycin
91
ANTIMICROBIAL ACTIVITY
Bactericidal except Enterococcus faecium
Quinupristin-dalfopristin
92
ANTIMICROBIAL ACTIVITY
Active against gram-positive cocci, including multidrug-resistant strains of streptococci, penicillin-resistant strains of S pneumoniae, methicillin-susceptible and resistant strains of staphylococci, and E faecium
Quinupristin-dalfopristin
93
MECHANISM OF RESISTANCE
• Modification of the quinupristin binding site (MLS-B type resistance)
• Enzymatic inactivation of dalfopristin
• Efflux
Quinupristin-dalfopristin
94
Quinupristin-dalfopristin ROA & elimination
IV & Fecal route
95
T/F: Quinupristin-dalfopristin
Dose adjustment is necessary for renal failure, peritoneal dialysis, or hemodialysis
F; not necessary
96
Drug interactions due to inhibition of
CYP3A4: warfarin, diazepam, quetiapine, simvastatin, and cyclosporine
Quinupristin-dalfopristin
97
CLINICAL USES
Infections caused by staphylococci or by vancomycin-resistant strains of E faecium
Quinupristin-dalfopristin
98
ADVERSE EFFECTS
Pain at infusion site and arthralgia-myalgia syndrome
Quinupristin-dalfopristin
99
ANTIMICROBIAL ACTIVITY
Active against gram-positive organisms including staphylococci, streptococci, enterococci, gram-positive anaerobic cocci, and gram-positive rods such as corynebacteria, Nocardia sp, and L monocytogenes, and Mycobacterium tuberculosis
Linezolid
100
Bacteriostatic but bactericidal against streptococci
Linezolid
101
MOA
Inhibits protein synthesis by preventing formation of the ribosome complex that initiates protein synthesis.
• Binding site: 23S ribosomal RNA of the 50S subunit
Linezolid
102
T/F: Resistance: mutation of the linezolid binding site on 23S ribosomal RNA
T
103
Linexolid ROA & metabolism
PO & IV; oxidative metabolism -> (2) inactive metabolites
104
CLINICAL USES
vancomycin-resistant E faecium infections, HCAP, CAP, skin and soft tissue infections (gram-positive bacteria)
Linezolid
105
CLINICAL USE
Off-label uses: treatment of MDR-TB and Nocardia infections
Linezolid
106
ADVERSE EFFECTS
thrombocytopenia, anemia, neutropenia; optic and
peripheral neuropathy and lactic acidosis; serotonin syndrome
Linezolid
107
Active moiety of the prodrug tedizolid phosphate
Tedizolid
108
ANTIMICROBIAL ACTIVITY
High potency against gram-positive bacteria (MRSA, VRE, streptococci, gram-positive anaerobes)
Tedizolid
109
PKINETICS
• 91% bioavailability; t1/2: 12 hours
• Higher protein-binding (70–90%) than linezolid (31%)
• Penetrates well into muscle, adipose, and pulmonary tissues
• No dose adjustment for renal or hepatic impairment
Tedizolid
110
CLINICAL USE
skin and soft tissue infection
Tedizolid
111
ADVERSE EFFECT
Lower risk of bone marrow suppression, lower risk of serotonergic toxicity
Tedizolid
112
MOA
binding the 50S ribosome and inhibits bacterial protein synthesis; binding pocket closes around the drug molecule, preventing bacterial transfer RNA from binding appropriately
Lefamulin
113
ANTIMICROBIAL ACTIVITY
Bactericidal: lower respiratory tract infections such as S. pneumoniae, H. influenzae, and atypical pathogens such as L. pneumophila, M. pneumoniae, and C. pneumoniae
Lefamulin
114
ANTIMICROBIAL ACTIVITY
Most aerobic gram-positive organisms, including S. pyogenes, S. aureus, and E. faecium. It may also have activity against certain organisms causing STIs, such as M. genitalium, N. gonorrhoeae, and C. trachomatis
Lefamulin
115
ANTIMICROBIAL ACTIVITY
Lacks activity: E. faecalis, P. aeruginosa, A. baumannii, and the Enterobacteriaceae group of gram-negative organisms
Lefamulin
116
MECHANISM OF RESISTANCE
ribosomal target site alteration and active efflux from the site of action
Lefamulin
117
CLINICAL USE
CAP
Lefamulin
118
Lefamulin ROA & metabolism
PO/IV & hepatic metabolism (CYP3A4)
119
T/F: Lefamulin = Dose adjustment for severe hepatic impairment
T
120
ADVERSE EFFECTS
infusion-site reactions, GI disturbances, congenital malformations
Lefamulin
