Bridges: Antibiotics - Protein synthesis inhibitors
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| Inhibit bacterial cell wall synthesis | Beta-lactams
Vancomycin
Bacitracin
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| Anti-metabolic activity | Sulfonamides
Trimethoprim
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| Inhibition of bacterial protein synthesis. | Aminoglycosides
Tetracyclins
Chloramphenicol
Macrolides
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| Inhibit bacterial nucleic acid syntheses | Fluoroquinolones
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| Which drug classes target the bacterial ribosome? | Aminoglycosides
Tetracyclins
Macrolides
Chloramphenicol
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| This class is of protein synthesis inhibitors are bacteriocidal | Aminoglycosides
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| Classes that work on the 50s unit | Macrolides
Streptogramins
Chloramphenicol
Lincosamides
Oxazolidinones
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| Classes that work on the 30s unit | Aminoglycosides
Tetracyclins
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| Animoglycoside that is topically OTC | Neomycin
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| Aminoglycosides are frequently used in | Serious infxn from aerobic G-
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| Use is limited due to | Toxicity
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| Used in combination with... | Beta-lactams
Vancomycin
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| Why does it work best in aerobics G-? | Uptake of the drug requires O2 dependent transport system
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| Frequently used for infxns due to... | PEPS
Pseudomonas (DoC)
Enterobacter
Proteus
Serratia
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| Can also be used to treat | Invasive enterococcal infxn
Serious staph. infxn
Y. pestis and Francisella tularenis
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| Clinical applications of aminoglycosides | -Serious infxns-
Septicemia
Nosocomial RTI
Complicated UTI
Osteomyelitis
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| When are aminoglycosides discontinued? | Once the organism is identified and susceptibility is known
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| Aminoglycoside MoA | Irreversibly binds to 30s ribosome
1. interferes with initiation complex formation
2. Causes misreading of mRNA
3. Restricts polysome formation
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| What contributes to the bacteriocidal nature? | Concentration-dependent killing
Long PAE
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| AG uptake into G- | Diffuse across the outer membrane via porin channels
Cross the inner membrance via O2 dependent active transport
Inner membrane potential drives transport
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| What can block the transport of AG? | Anaerobic environment
Low extracellular pH
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| Aminoglycoside resistance | Inactivation of drug by microbial enzymes
(aminoglycoside modifying enzymes)
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| Aminoglycoside kinetics | Very polar compounds
Don't cross the membrane well
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| Aminoglycoside pharmacokinetics | Concentrated in the proximal tubular cells
Largely eliminated by GF
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| What must you do in renal compromised pts? | Adjust the dose/dosing frequency
Blood levels are very important
Must adjust dose relative to creatintine clearance
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| Advantages of consolidated therapy | Comparable efficacy
Decreased nephrotoxicity
Long PAE
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| Toxicity is dependent on | Concentration and time above threshold
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| Consolidation therapy is not recommended for what situations? | Pregnant pts
Osteomyelitis
Infective endocarditis
Pts recieving concurrent ototoxins
Pts undergoing solid organ transplantation
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| Aminoglycosides therapeutic index | Narrow
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| Primary toxicities of aminoglycosides | Nephrotoxicity
Ototoxicity
Neuromuscular blockade
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| Which of these are reversible/irreversible? | -Reversible-
Nephrotoxicity
Neuromuscular blockade
-Irreversible-
Ototoxicity
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| Makes nephrotoxicity and ototoxicity more likely | Therapy > 5 days
In elderly pts
In pts with renal dysfunction
Tox incidence related to drug concentration
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| Nephrotoxicity | Reversible
Involves an acute tubular necrosis
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| The most important result of nephrotoxicity | Decreased AG excretion
-Increased AG plasma levels
-Predisposes to ototoxicity
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| AGs accumulate and are retained in.. | Proximal tubular cells
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| Results of AG accumulation | Impairs renal concentrating ability
Mild proteinuria
Appearance of hyalin and granular casts
GFR decreases
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| 2 drugs that are nephrotoxic | Amphotericin B
Cyclosporine
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| Why is ototoxicity is difficult to determine? | May occur after drug is stopped
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| Where do AGs accumulate in the ear? | Perilymph and endolymph in the inner ear
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| Ototoxicity manifestations | Tinnitus
High freq. hearing loss
Vestibular damage
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| What is special about ototoxicity? | Irreversible
Damage accumulates with repeat courses
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| This class of drugs may enhance ototoxicity. | Loop diuretics
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| Absolute contraindication for AG use | Pts with Myasthenia gravis
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| What may be seen with neuromuscular blockade? | Acute respiratory paralysis
May enhance effects skeletal muscle relaxants
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| Mechanism of NM blockade | May inhibit prejunctional relase of acetylcholine
Reduce postsynaptic sensitivity
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| Streptomycin use | Limited by resistance and advent of newer AGs
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| Streptomycin used alone to treat... | Tularemia and plague (DoC)
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| Streptomycin used in combination to treat | Tuberculosis
Brucellosis (DoC with doxy)
Endocarditis (w/ cillin)
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| Gentamycin | One of the most frequently used
Generally chosen first
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| Gentamycin used in combination for... | (used with cillin)
Pseudomonas (DoC)
Enterococcal (DoC)
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| Amakacin primarily used for | Pseudomonas
Other serious infxns caused by *organisms resistant to other AGs*
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| Amikacin has | The broadest spectrum
Resistance to inactivating enzymes
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| What makes amikacin more effective than other AGs? | There is only one site susceptible to enzyme anabolism
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| Neomycin is... | Not used systemically
Used topically
The most toxic AG
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| Only time Neomycin is used orally/systemically | To sterilize the gut
When organisms are resistant to other agents
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| Tetracycline (class) spectrum | G+, G-, aerobic, anaerobic
Intracellular bacteria
-Chlamydia, Rickettsia, Mycoplasm p.)
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| Doxycycline and minocycline | 2 of the most widely prescribed drugs
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| Doxycycline | One of the most active and clinically used
Preferred in pts with poor renal fxn
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| Minocycline | Meningococcal carrier state
Crosses the blood-brain-barrier
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| Tetracyclines are Docs or alternatives for | Mycoplasma p
Chlamydia
Rickettsiae
Lyme Dz
Plague, tularemia, brucellosis, malaria prophylaxis
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| Tetracycline (group) MoA | Reversibly binds to 30s
Prevents tRNA binding to acceptor site
Prevents addition of amino acids to growing peptide
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| How does it get into the cell? | Passive diffusion (porin Om in G-)
Active transport (plasma membrane)
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| Why are tetracyclins and penicillina antagonistic? | Tetra's stop bacterial growth
Penicillions need bacterial growth
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| Primary mechanism of resistance to tetras | Efflux pumps
*Ribosome protection*
-Proteins interfere with binding and dislodge drug form ribosome
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| This provides a cross-resistance among tetracyclines except for | Tigrecyclin
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| Tetracycline pharmacokinetics | GI absorption is variable
For stable chelates with cations
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| DD interactions | Milk
Antacids
Pepto-Bismol
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| Tetracycline that gets into the CSF | Minocycline
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| Chelates with Ca effecting | Bones and teeth
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| Don't give to which patient population? | Pregnant women
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| Tetracycline elimination | Eliminated by the kidneys
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| Which 3 tetras are less dependent on the kidneys for excretion? | Doxy, mino, and Tige
Excreted by the bile
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| Tigecycline spectrum of action | Very broad spectrum antibiotic
Effective in resistant organisms
(MRSA, Staph epi, PRSP, VRE)
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| What makes tigecycline so useful? | Not susceptible to efflux pumps and ribosome protection
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| Tigecyclin route of administration and excretion | IV
Poor oral absorption
Biliary excretion
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| Tigecycline uses | Complicated skin and skin structure infxn
Intraabdominal infxn
Community-acquired pneumonia
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| Tetracycline adverse effects | GI
Boney structures and teeth
Liver tox
Local Tissus Tox
Photosensitivity
Vestibular reactions
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| Tetracycline AE: GI | Oral dosing can cause GI distress
NVD
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| Tetracycline AE: Bone | Bind Ca, esp. in newly formed bone of young kids
Kids may develop permanent brown discoloration
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| What increases the risk of permanent brown discoloration? | Use in the last half of pregnancy and up to 8 y/o
Crosses the placenta and accumulates in fetus
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| Tetracycline AE: Liver Tox | Rare but fatal
Occurs more commonly with tetra and mino
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| Tetracycline AE: Local tissue tox | Directly irritating to tissues
IV: thromboplebitis
IM: painful
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| Tetracycline AE: Photosensitivity | Fair skin pts ate major risk
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| Tetracycline AE: Vestibular Rxn | May be produced by Mino
Ataxia
Dizziness
NV
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| Tetracycline AE: Superinfections | Pseudomembranous colitis
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| Precautions with Tetracyclines | Don't give to:
Pregnant pts
kids <8
Discard unused drugs as it may cause Fanconi syndrome
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| Drug classes that act on the 50s | Chloramphenicol
Macrolides
Lincosamides
Streptogramins
Oxazolidinones
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| Chloramphenicol | Rarely used
Serious toxicity limits use
Reserved for life-threatening infxn due to resistance or allergies to safer drugs
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| Chloramphenicol occasionally used for | Rickettsial infxn
Menengitis
Anaerobic infxn
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| Chloramphenicol spectrum and MoA | Broad spectrum
-Aerobic, anaerobic, G+, G-
Reversibly binds to inhibit peptidyl transferase
(Peptide bond formation)
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| Chloramphenicol Toxicity | Hematological Toxicity
Bone marrow suppression
-anemia, leukocytopenia, thrombocytopenia
Dose dependent and reversible
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| Chloramphenicol: Idiosyncratic response | Serious and fatal
Aplastic anemia-> fatal pancytopenia
Rare; does NOT containdicate
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| Chloramphenicol: Idiosyncratic drug reaction | Abnormal
Rare and unpredictable
Occurs sporadically
Not related to dose
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| Chloramphenicol: Adverse Effects | Gray syndrome/gray baby syndrome
-Gray color, shock, hypothermia, vomiting, flaccidity
Can be fatal in 2 days
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| Gray baby syndrome: Mechanism | Lack of glucuronyl transferare activity
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| Macrolides | Good substitute for penicillins
G+ activity
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| Clarithromycin and Azrithromycin: Spectrum | G+ and some G-
Camylobacter jejuni
H. pylori
Shingella spp
E. Coli
Meisseria gonorrhoeae
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| Macrolides are DoC for | Kids and pregnant women
Pts allergic to penicillin
Preferred for community-acquired RTIs
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| Restrictions for macrolide use in CAP | Uncomplicated pneumonia not requiring hospitalization
No sig. comorbidities
No ABx use in past 3 mo.
No sig. macrolide-resistant strains locally
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| Macrolides also DoC for... | Mycoplasma p
Chlamydia
Bordetella
Campylobacter
Mycobacterium avian complex (MAC)
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| Macrolides: Mechanism of Action | Bacteriostatic
Inhibits peptide chain elongation
(translocation or peptidyl tRNA from A to P site is inhibited
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| Macrolides: Resistance | Efflux pumps
Ribosome modification
-Alters macrolide binding site on the bacterial ribosome
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| Macrolides: Pharmacokinetics | New macrolides are more acid-stable
Clarithro: less freq dosing
Azithro has 1/2 life ~70hrs
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| Macrolides: Drug interactions | **Inhibit CYP3A4**
P450 inhibition
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| Macrolides: Toxicity (Primarily seen with Erythromycin) | GI
-Anorexia, NVD
-Epigastric distress
Cholestatic hepatitis
-Fever, jaundice, impaired liver fxn
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| Lincosamides Clindamycin: Spectrum and Clinical use | Anaerobic, strept, staph infxns
DoC for C. perfringens
Aerobic G- bacilli are intrinsically resistant
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| Lincosamides Clindamycin: Mechanism of Action | Binds close to erythromycin and chloramphenicol binding sites
Inhibits peptide bond formation
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| Lincosamides Clindamycin: Resistance | Alterations of ribosomal binding site
-Cross resistance with erythro
Metabolism of drug
G- intrinsic resistance
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| Lincosamides Clindamycin: Pharmacokinetics | Does not cross BBB
Penetrates into bone (high levels)
Actively transported into PMN leukocytes and macrophages (high levels)
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| Lincosamides Clindamycin: Adverse effects | Severe diarrhea
-May cause antibiotic associated diarrhea
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| Lincosamides Clindamycin and pseudomembranous colitis | Clindamycin classically assoc. with this disorder
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| Streptogramins Quinupristin + Dalfopristin: Spectrum | G+ bacteria
-Staph resistant to:
Methacillin, quinolones, vanc
-Strept. pneumonia resistant to Pens
Vanc-resistant E. farcium
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| Streptogramins Quinupristin + Dalfopristin: Principle Clinical Use | Drug resistant G+ cocci infxn
-Skin and soft tissue
Serious or life-threatening VRE
Complicated skin infxn
-MSSA and S. pyrogenes
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| Streptogramins Quinupristin + Dalfopristin: Mechanism of Action | Q: binds same site as macrolides
D: directly interferes with polypeptide chain formation
Binds near Q, enhances binding of Q
Bactericidal
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| Streptogramins Quinupristin + Dalfopristin: Resistance | D: enzymatic inactivation, efflux pumps
Q: binding site mods by methylase, enzymatic inactivation
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| Streptogramins Quinupristin + Dalfopristin: Drug Interactions | **POTENT CYP3A4 inhibitor**
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| Streptogramins Quinupristin + Dalfopristin: Adverse Effects | Pain and phlebitis at infusion site
Severe arthalgias and myalgias
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| Oxazolidinones Linezolid: Spectrum | Similar to quinupristin+dalfopristin (G+) plus e. faecalis
Should be reserved for MDR G+
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| Oxazolidinones Linezolid: Clinical Use | Hospital and community AP
-Strep pneumoniae
Tx of skin and soft tissue
-Complicated/uncomplicated
-MRSA & MSSA
VR enterococcus
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| Oxazolidinones Linezolid: Mechanism of Action | Block formation of initiation complex
Mostly bacteriostatic
-Cidal to strep.
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| Oxazolidinones Linezolid: Resistance and Pharmacokinetics | R: mutation or rRNA binding site
P: MAO inhibitor
Weak, reversible
Tyramine rich foods can cause sudden and severe high BP
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| Oxazolidinones Linezolid: Adverse Effects | Myelosuppression
-Thrombocytopenia (most common effect)
Anemia, Leukopenia
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