Macrolides, Ketolides, Streptogramins and Lincosamides

Question 1

Mechanism of Action: Clindamycin
Macrolides:
--Erythromycin
--Clarithromycin
--Azithromycin

Answer 1

• Inhibits protein synthesis by binding to 50S subunit

- Generally bacteriostatic, may be bacteriocidal at high concentrations

Question 2

Mechanisms of Resistance: Clindamycin

Answer 2

Altered 50S target
Active efflux pump
Drug inactivation

Question 3

Spectrum of Activity: Clindamycin

Answer 3

• Gram positive aerobes (not enterococcus), some CA-MRSA

- Anaerobes: not C. diff

Question 4

Indications: Clindamycin

Answer 4

Anaerobic infections outside of the CNS

Skin and soft tissue infection (pen-allergies, CA-MRSA)

Question 5

Adverse Effects: Clindamycin

Answer 5

Most common:
Nausea, vomiting,
diarrhea, dyspepsia
Most severe: 
C. diff- one of the worst inducers
Rare:
cytopenia

Question 6

Bioavailability: Clindamycin

Answer 6

Available IV and PO

Rapidly and completely absorbed (90%); food has minimal effect on absorption

Question 7

Distribution: claritrhomycin

Answer 7

Good concentrations in most tissues

Does not penetrate the CNS

Question 8

Is clindamycin metabolized by the kidneys or liver?

Answer 8

Clindamycin primarily metabolized by the liver (85%)

Question 9

Is clindamycin removed from circulation during hemodialysis

Answer 9

No

Question 10

Does erythromycin show time- or concentration- dependent killing?

Answer 10

Time-dependent killling

Question 11

Does clarithromycin show time- or concentration- dependent killing?

Answer 11

Time-dependent killing

Question 12

Does azithromycin show time- or concentration- dependent killing?

Answer 12

Concentration-dependent killing

Question 13

Clindamycin: time or conc.- dependent

Answer 13

Time

Question 14

Mechanism of Resistance: Macrolides

Answer 14

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

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®

Question 15

Spectrum of Activity: Macrolides

Answer 15

G+ aerobes: MSSA, S.pneumo (not PRSP), all other strep, Bacillus spp., Corynebacterium spp.

G- aerobes: H. flu (not erythro), M. catarrhalis, Neisseria spp.
Does NOT have activity against any Enterobacteriaceae

Anaerobes – activity against upper airway anaerobes

Atypical Bacteria – all macrolides have excellent activity against atypical bacteria including:
Legionella – DOC*
Chlamydophila (psittacosis) and Chlamydia spp.
Mycoplasma spp.

Other Bacteria – Bordetella, Brucella, Pasteurella, H.pylori (combination tx), Mycobacterium avium complex (MAC – only azithromycin and clarithomycin), M. chelonae,

Question 16

List the macrolides–> best to worst activity against G+ aerobes

Answer 16

Clarithro>Erythro>Azithro

Question 17

List the macrolides–> best to worst activity against G- aerobes

Answer 17

Azithro>Clarithro>Erythro

Question 18

Absorption of Erythromycin

Answer 18

Erythromycin – variable absorption (15 to 45%); food may decrease the absorption

Question 19

Absorption of Clarithromycin

Answer 19

Clarithromycin – acid stable and well-absorbed (55%) regardless of presence of food

Question 20

Absorption of Azithromycin

Answer 20

Azithromycin –acid stable; bioavailability = 37% regardless of presence of food

Question 21

Distribution: Macrolides

Answer 21

Distributes to most tissues, clarithromycin and azithromycin have higher distributions

None cross the BBB

Question 22

How are erythromycin and clarithromycin eliminated?

Answer 22

Erythromycin is excreted in bile and metabolized by CYP450

Clarithromycin is metabolized and also partially eliminated by the kidney (18% of parent and all metabolites)

Question 23

Which macrolide does not inhibit CYP450 enzymes?

Answer 23

Azithromycin

Question 24

Indications: Macrolides

Answer 24

Respiratory tract infections
Uncomplicated skin infections
STDs
Mycobacterium avium complex (MAC)
Alternative for PCN-allergic  patients

Question 25

Adverse Effects: Macrolides

Answer 25

``` Most common: Nausea, vomiting, diarrhea, dyspepsia Rare: Cholestatic hepatitis Thrombophlebitis - depends on dilution of dose Prolonged QTc Transient/reversible tinnitus ```

Question 26

Quinupristin/Daltopristin (Synercid®): MOA

Answer 26

``` Inhibits protein synthesis by binding to 50S subunit -Generally bactericidal ```

Question 27

Mech. of Resistance: Quin/Dalt

Answer 27

Alterations in ribosomal binding sites (erm) Enzymatic inactivation Active transport out of the cell

Question 28

Spectrum: Quin/Dalt

Answer 28

G+: MSSA, Coag. negative staph Strep pneumo, incl. pen-R, Group strep, viridans strep E. faecium, incl. VRE Corynebacterium, bacillus, listeria, actinomyces Clostridium spp, excl. diff, peptococcus, peptostreptococcus

Question 29

Indication: Quin/Dalt

Answer 29

VRE bacteremia

Question 30

Adverse Effects: Quin/Dalt

Answer 30

``` Most common: Venous irritation Nausea, vomiting, diarrhea Rare: Rash Myalgias Arthralgias ```

Question 31

Bioavailability for Quin/Dalt?

Answer 31

None, only available parenterally

Question 32

Quin/Dalt: Time- or concentration- dependent killing

Answer 32

Concentration

Question 33

Post-antibiotic effect in gram-positive bacteria?

Answer 33

2 to 8 hours for S. aureus; | 8.5 hours for VSE; 0.2 to 3.2 hours for VRE

Question 34

Distribution: Quin/Dalt

Answer 34

Most tissues; does not penetrate CSF

Question 35

Quin/Dalt Elimination

Answer 35

Hepatic and biliary

Question 36

Which aspect of quin/dalt metabolism should be considered when it's being co-administered with other drugs?

Answer 36

Quin/dalt inhibits cyp450 3A4

Question 37

Adverse effects of quin/dalt

Answer 37

``` Most common: Venous irritation Nausea, vomiting, diarrhea Rare: Rash Myalgias Arthralgias ```