L8 Pharm: Clindamycin, Macrolides, Streptogramins (Synercid) Flashcards
(42 cards)
What class of drugs are used mainly for ATYPICAL pneumonia, STI,s gram positive cocci and B. pertussis?
What 3 bacteria show atypical pneumonia?
What does the pneumonic MACRO clue you in on?
- MACROLIDES
- for STI (chlamydia)
- gram positive cocci (streptococcal infections in pts. allergic to PCN)
- B. Pertussis
a) Mycoplasma
b) Legionella
c) Chlamydia
MACRO is the toxicity related to using macrocodes
M - motility issues A - Arrhythmia due to prolonged QT! C - Cholestatic Hepatitis R - Rash O - eOsonophilia
Increases serum concentrations of theophylline, oral antigoaluants.
Which two macrolides inhibit C450?
Why not the third?
Clarithromycin & Erythromycin
- NOT AZYTHROMYCIN - eliminated in Bile not in the liver like C & E
Which drug is mainly used for ANAEROBIC infections ABOVE the diaphragm?
Which treats them BELOW the diaphragm? (previous lecture)
- Clindamycin
(bacteroides/ Clostridium)
Also effective for Group A strep (pneumonia)
- METRONIDAZOLE (anaerobic infections below the diaphragm)
TOXICITY: pseudomembranous colitis (C. DIff) + fever + diarrhea
State the following for Clindamycin:
- Spectrum of Activity
- Indication/Clinical use
- Gram positive Aerobes
+ ANAEROBES 9above diaphragm; metronidazole is for below the diaphragm) - Anaerobic infections excluding CNS
- Skin & soft tissue infection (PCN allergic, CA-MRSA)
State the following for Clindamycin:
- Mechanism of Action
- Adverse Effects (main 1, plus 3 rare)
- Inhibits protein synthesis by binding to 50s subunit (bacteriostatic)
- ADVERSE:
- Nausea, vomiting, diarrhea, WORST INDUCER OF C. DIFF!!! (treat with Vanc or Metronidazole)
RARE:
- hepatotoxicity
- neutropenia
- thrombocytopenia
State the following for Macrolides (Erythromycin, Clarithromycin, Azithromycin):
- Spectrum of Activity (main 1 is listed 1st)
- Indication/Clinical use
- ATYPICALS**
(chlamydia, mycoplasma, legionella)
+ pertussis + Strep Infections in people allergic to PCN
Gram positive aerobes
- Gram negative aerobes **(clindamycin doesn’t have activity against this)
2. INDICATIONS/ CLINICAL USE: - Respiratory Tract infections (atypicals)
- Uncomplicated skin infections
- STDs
- MAC***
- Alternative for PCN allergic patients
State the following for Macrolides:
- Mechanism of Action
- Adverse Effects (main 1, plus 3 rare)
- Inhibit protein synthesis by binding to 50s subunit
- Bacteriostatic - Most common: GI side effects (nausea, vomiting, diarrhea)
MACRO M- motility issues A - arrhythmia caused by prolonged QT interval C - Cholestatic Hepatitis R - rash O - eOsinophiluria
RARE:
- allergic reacction
- cholestatic hepatitis
- thrombophlebitis
- Prolonged Qt
- Transiet/reversible TINNITUS
State the following for Streptogramin (Quinupristin/Daltopristin)
- Spectrum of Activity
- Indication/Clinical use (1 main one)
- GRAM POSITIVE BACTERIA
( MSSA, MRSA, coag negative Staph, PRSP, Enterococcus FAECIUM - including VRE)
Clostridium - Indication/Clinical use:
VRE BACTEREMIA!!!
State the following for Streptogramin (Quinupristin/Daltopristin):
- Mechanism of Action
- Adverse Effects (main 1, plus 3 rare)
- Inhibits protein synthesis by binding to 50s subunit
- bacteriostatic - Most common:
- venous irritation
- Nausea, vom, diarrhea (GI irritation)
RARE:
- rash
- myalgias
- arthralgias
What is the MOA of Clindamycin?
Bacteriostatic or Cidal?
- Inhibits protein synthesis by binding exclusively to the 50S ribosomal subunit
- Binds in close proximity to macrolides and Quinupristin/Daltopristin (Synercid)– may cause competitive inhibition - Clindamycin typically displays bacteriostatic activity, but may be bactericidal when present at high concentrations against very susceptible organisms
All protein synthesis inhibitors (except Aminoglycosides) are BACTERIOSTATIC
Remember this from the PCN lecture:
CONCENTRATION DEPENDENT:
- metronidazole
- aminoglycosides
- fluoroquinolones
- AZITHROMYCIN (only macrolide that is conc. dep)
- Daptomycin (lipopeptide)
What are the 5 drugs that are concentration dependent?
- Metronidazole
- Fluoroquinolones
- Aminoglycosides
- Daptomycin
- AZITHROMYCIN (only macrolide)
Conc. dep = extended PAE
(the only exception to this is time dependent SYNERCID)
What is the main MOR for Clindamycin, Synercid, & Macrolides?
Which gene (mer or erm) encodes for this?
The second MOR is ACTIVE efflux encoded by ____ gene. Which drug does not get pumped out by this?
- Altered Target site
- erm gene alters 50s binding site
- confers high level resistance to macrolides, clindamycin and Synercid (MLSb resistance)
2. Active efflux - mef gene! - pumps MACROLIDES out of the cell but NOT clindamycin!!!
What are the gram positive aerobes targeted by Clindamycin? (3)
- Methicillin-susceptible Staphylococcus aureus*, and some CA-MRSA
- Streptococcus pneumoniae (only PSSP) – resistance is developing
- Group and viridans streptococci
BUT REMEMBER THAT IT IS MOSTLY USED FOR ANAEROBES
What are the ANAEROBES targeted by Clindamycin? (8)
What are 3 other bacteria?
- Clostridium (EXCEPT C. DIFF)
- Peptostreptococcus
- Actinomyces
- Propionibacterium
- Clostridium
- some Bacteroides**
- Prevotella
- Fusobacterium
- Pneumocystis Carinii
- Toxoplasmosis Gondii
- Malaria
CLindamycin:
- Absorption:
- available in what forms?
- Does food have an effect? - Distribution
- serum conc. good?
- describe the tissue penetration
- minimal ____ penetration - Elimination
- how is it eliminated?
- is it removed during HD?
- IV AND PO!
- rapid/complete absorption
- food has minimal effect - Distribution
- Good serum concentrations with both formulations
- Good tissue penetration including bone;
**minimal CSF penetration
(common theme for protein synthesis inhibitors- minimal CSF penetration)
- Elimination
- Clindamycin primarily metabolized by the LIVER (85%); enterohepatic cycling
- Half-life is 2.5 to 3 hours
- Clindamycin is NOT removed during hemodialysis (SINCE LIVER METABOLIZES!)
What are the 3 main uses of Clindamycin?
- Anaerobic Infections OUTSIDE of the CNS
- Pulmonary, intra-abdominal, pelvic, diabetic foot and decubitus ulcer infections - Skin & Soft Tissue Infections
- PCN-allergic patients
- Patients with infections due to CA-MRSA - Alternative therapy
- C. perfringens,
- PCP,
- Toxoplasmosis,
- malaria,
- bacterial vaginosis
State the adverse affects of Clindamycin on the following:
- GI
- Worst inducer of _____
(treat with 2 drugs) - Hepatotoxicity (marked by)
- Allergy (1)
- Hematologic abnormalities (2)
- Gastrointestinal
– 3 to 4% (especially with oral formulation)
Nausea, vomiting, diarrhea, dyspepsia
2. Clostridium difficile colitis – one of worst inducers** Ranges from mild - severe diarrhea Requires treatment with a). metronidazole b) oral vancomycin
- Hepatotoxicity - rare
Elevated transaminases* - Allergy –
rare (rash) - Hematological abnormalities-
a) neutropenia and
b) thrombocytopenia (rare)
Macrolides:
Name the 3
Macrolides in clinical use today include
- erythromycin,
- clarithromycin,
- and azithromycin
Erythromycin is a naturally-occurring macrolide derived from Streptomyces erythreus
Structural derivatives include clarithromycin and azithromycin:
- Broader spectrum of activity
- Improved PK properties – better bioavailability, better tissue penetration, - prolonged half-lives
Improved tolerability
- What is the MOA of Macrolides?
- Bacteriostatic or cidal?
- Which 2 have time dependent activity?
- Which is concentration dependent?
- Inhibit protein synthesis by reversibly binding to the 50S ribosomal subunit
- Results in suppression of protein synthesis and bacterial growth is halted - Macrolides typically display BACTERIOSTATIC activity, but may be bactericidal when present at high concentrations against susceptible organisms
- Erythromycin and clarithromycin display time-dependent activity;
- AZITHROMYCIN is concentration-dependent !!!
5 conc. dependent drugs:
- fluroquinolones
- aminoglycosides
- metronidazole
- daptomycin
- AZITHROMYCIN (can give 1 dose)
Conc dep = peak
Time = time spent above the MIC
What are the 2 MOR for Macrolides?
Which genes?
Does cross-resistance for macrocodes exist?
- Active efflux
– MEF gene encodes for an efflux pump that pumps the macrolide out of the cell away from the ribosome; confers low level resistance to macrolides (not clindamycin)
- Altered target sites
– encoded by the ERM gene which alters the macrolide binding site on the ribosome;
– confers high level resistance to all macrolides, clindamycin, and Synercid®
- Cross-resistance occurs between all macrolides
What is the macrolide spectrum of activity for GRAM POSITIVE AEROBES?
(5 total - only 2 more that Clindamycin didn’t have)
Which is most affective (clarity, azithro, erythro?)
Clarithro>Erythro>Azithro
- Methicillin-susceptible Staphylococcus aureus (MSSA)*
- Streptococcus pneumoniae (only PSSP) – resistance is developing
- Group and viridans streptococci
- Bacillus spp.,
- Corynebacterium spp.
(clindamycin did NOT have this activity!)
What is the gram negative coverage of Macrolides? (3)
How is this different from Clindamycin?
Which macrolide is most affective? Least?
No activity against any _______.
Gram-Negative Aerobes: clinda had NO gram negative coverage!
Azithro>Clarithro>Erythro
- H. influenzae (not erythro),
- M. catarrhalis,
- Neisseria spp
- Do NOT have activity against any Enterobacteriaceae (large amount of resistance within this family)
Macrolide’s are used mainly for treating what type of bacteria?
(3 total: it is the DOC for what bacteria?)
What are other bacteria it targets? (1) - which drugs from macrolide class?
A) Atypical Bacteria!!!!
– all macrolides have excellent activity against atypical bacteria including:
- Legionella pneumophila – DOC*
- Chlamydophila (psittacosis) and Chlamydia spp.
- Mycoplasma spp
B) Mycobacterium Avium Complex (MAC)
- only Azithromycin & CLarithromycin
M. chelonae, H.pylori combination tx, (clarithromycin) Bordetella, Brucella, Pasteurella (ELLA)
Anaerobes – activity against upper airway anaerobes
(but rely on clindamycin for anaerobes!)
Absorption:
Food may decrease absorption of which macrolide?
Which drug is acid stable & well absorbed?
Which is acid stable with bioavailability of 37%?
- Erythromycin
- variable absorption (15 to 45%);
Food may decrease the absorption !!!
Base: destroyed by gastric acid; enteric coated
Esters and ester salts: more acid stable
- Clarithromycin – acid stable and well-absorbed (55%) regardless of presence of food
- Azithromycin –acid stable; bioavailability = 37% regardless of presence of food
