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