Flashcards in Protein Synthesis inhibitors: Chloramphenicol Deck (28):
The next drug within the protein synthesis inhibitors is Chloramphenicol. What is the MOA and resistance?
--inhibitor of protein synthesis
--can inhibit protein synthesis in mammalian mitochondrial ribosomes which can lead to bone marrow toxicity
--production of chloramphenicol acetyltransferase (a plasmid encoded enzyme that inactivates the drug)
--changes in membrane permeability
What is the spectrum of activity and clinical applications of chloramphenicol?
Bacteriostatic Broad Spectrum
Aerobic and Anaerobic Gram - and +
Tx of serious infections resistant to other less toxic drugs or when its penetrability to the site of infection is clinically superior to other drugs to which the organism is susceptible (bacteroides, H. influenzae, N. Meningitides, Salmonella and Rickettsia)
Effective against vancomycin-resistant enterococci
Topical treatment of ear and eye infection (use declining due to cases of aplastic anemia)
What are the pharmacokinetics of chloramphenicol?
Given orally, IV or topically
--widely distributed to virtually all tissues including the CNS and CSF
What are the drug interactions of chloramphenicol?
Inhibits CYP 450s that metabolize other drugs, half lives are prolonged and serum concentrations of phenytoin, tolbutamide, chlorpropamide and warfarin are increased
Antagonize bactericidal drugs such as penicillins or aminoglycosides
What are the adverse effects of chloramphenicol?
GI disturbances: n/v/d
Bone Marrow Depression: causes a dose related reversible suppression of red cell production at high doses
Gray Baby Syndrome (cyanosis): infants lack an effective glucuronic acid conjugation required for the degradation of chloramphenicol therefore drug may accumulate resulting in gray baby syndrome (vomiting, flaccidity, hypothermia, gray color, shock)
The next two drugs to discuss are protein synthesis inhibitors but are called Lincosamides. The first is Clindamycin. What is the MOA and resistance?
inhibits protein synthesis by binding to 50S subunit of bacterial ribosome
--cross resistance to macrolides and is mainly due to either mutation of the ribosomal receptor site, modification of the receptor by a constitutively expressed methylase, or enzymatic inactivation of the drug.
--gram - aerobic organisms and enterococci are resistant
What is the spectrum of activity for clindamycin?
Activity against gram + aerobic bacteria (staph and strep)
Gram - anaerobic bacteria (bacteroides)
Tx: of skin and soft tissue infections caused by strep and staph
Tx: anaerobic infections caused by bacteroides and other anaerobes
Tx: clindamycin + aminoglycoside or cephalosporin in penetrating wounds of gut and abdomen
In combination with primaquine, clindamycin is an effective alternative for?
Cotrimoxazole for moderate to moderatley severe Pneumocystis Jiroveci pneumonia (PCP) in AIDS patients
Used in combo with pyrimethamine for AIDS related toxo of the brain
Clindamycin is used as a prophylaxis of endocarditis in valvular disease patients who are undergoing?
Dental procedures and who are allergic to penicillin
How can clindamycin be given?
Orally or IV and penetrates well into most tissues
(Abscesses and bone)
What are adverse effects of clindamycin?
Diarrhea, Nausea, and Skin Rashes
Potentially fatal pseudomembranous Colitis: highest risk of all antimicrobial agents for the development of diarrhea and colitis due to C. Difficile
Impaired Live Function and Neutropenia
The second Lincosamide in addition to Clindamycin is Linezolid. What is the MOA and resistance?
--unique binding site, located on 23S ribosomal RNA of the 50S subunit
--results in no cross resistance with other drug classes
--caused by mutation of the binding site
What is the spectrum of activity for linezolid?
Gram + including staph, strep and enterococci
Gram + anaerobic cocci
Gram - rods including corynebacteria and listeria monocytogenes
Activity against M. Tuberculosis
What is the clinical applications of linezolid?
Use against vancomycin resistant enterococcus faecium (VRE), Nocosomial Pneumonia caused by staph (including MRSA) or strep pneumonia
Gram + infections
Treats multi drug resistant infections, the use of linezolid is mainly restricted to this role
What are the pharmacokinetics of linezolid?
not 100% bioavailable after oral administration
Available for IV use
Not an inducer or inhibitor of CYP 450 enzymes
Weak, reversible inhibitor of MAO (potential to interact with adrenergic and serotonergic drugs)
What are the adverse effects of linezolid?
Well tolerated for short administration with the main complaints being GI, headache or rash
1. Inhibition of MAO
2. Long term administraion: can result in reversible myelosuppression and also optic and peripheral neuropathy and lactic acidosis
Moving on to the next protein synthesis inhibitors are the Streptogramins (Quinupristin-Dalfopristin). What is the MOA and resistance?
Comb of two stretogramins 30:70 ratio
--act to inhibit protein synthesis by binding to separate sites on the 50S ribosome
Uncommon but due to modification of the quinupristin binding site, enzymatic inactivation of dalforpistin or increased efflux of the drugs.
What is the spectrum of activity and clinical applications of Streptogramins?
Bactericidal for most organisms except Enterococcus Faecium (slowly killed)
Active against gram + cocci : streptococci, penicillin resistant S. pneumonia, MRSA and E. faecium
Use is restricted to the tx of infections caused by staph or by vancomycin resistant strains of E. faecium
What are the pharmacokinetics of Streptogramins?
Excellent penetration into macrophages and PMNs
Significant inhibitors of CYP3A4
What are the adverse effects of Streptogramins?
--pain at the infusion site and arthalgia-myalgia syndrome
GI effects and CNS effects
Moving on to some miscellaneous drugs in the protein synthesis inhibitors. The first is Fidaxomicin. What is the MOA and resistance?
--narrow spectrum, macrocyclic antibiotic that inhibits bacterial protein synthesis by binding to the sigma subunit of RNA polymerase
What is the spectrum of activity and clinical applications of Fidaxomicin?
Gram + aerobes and anaerobes
Lacks activity against Gram - bacteria
Esp active against C. difficile
Approved by the FDA for tx of C. difficile colitis in adults (much more expensive then vancomycin so therefore most ppl use vanco)
What are the pharmacokinetics for Fidaxomicin?
Systemic absorption is negligible but fecal concentrations are high (why its great for tx c. diff)
What are the adverse effects of Fidaxomicin?
Lack of systemic effects appears to be well tolerated
GI complaints most important adverse effect
Safety in teens and kids has not be established
The next protein synthesis inhibitor that is miscellaneous is Mupirocin. What is the MOA and resistance?
Active against gram + cocci including methicillin sensitive and resistance S. aureus and most streptococci
Works by binding to bacterial isoleucyl transfer RNA synthetase resulting in inhibition of protein synthesis
What is the spectrum of activity and clinical applications for Mupirocin?
Active against gram positive cocci including MSSA and MRSA
Approved to be used via intranasal route for the eradication of nasal colonization with MRSA in adult patients and healthcare workers
Topically for the tx of impetigo or secondary infected traumatic skin lesions due to S. aureus or S. pyogenes
What are the pharmacokinetics for Mupirocin?
Administered either intranasal route or topically