Protein Synthesis Inhibitors III- Macrolides, Ketolides, Streptogramins, Lincosamides Flashcards by Ashley Wong

Macrolides

ERYTHROMYCIN (older, not as good)
CLARITHROMYCIN
AZITHROMYCIN

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Macrolides Mech of Action

Reversibly binds 50S ribosomal subunit

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Macrolides- Bactericidal or Bacteriostatic?

Bacteriostatic, but may be bactericidal when present at high concentrations against very susceptible organisms
Erythro & clarithro= time-dependent
Azithro= concentration-dependent

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Mechanisms of Resistance against Macrolide Abx

ACTIVE EFFLUX (primary resistance in U.S.)
ALTERED TARGET SITES (primary resistance in Europe)
CROSS-RESISTANCE OCCURS BETWEEN ALL MACROLIDES

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Macrolides Spectrum of Activity Gram (+) Aerobes

Erythro & clarithro have best activity (Clarithro>Erythro>Azithro)

STAPH AUREUS (MSSA)
STREP PNEUMO

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Macrolides Spectrum of Activity Gram (-) Aerobes

Azithro>Clarithro>Erythro

H. influenze (not erythro)
M. catarrhalis
Neisseria spp.
does not have activity aginst any enterobacteriaceae

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Macrolides Spectrum of Activity Anaerobes and Other bacteria

Anaerobes: activity against upper airway anaerobes

Other: many

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Macrolides Spectrum of Activity Atypical Bacteria

all macrolides have EXCELLENT activity against atypical bacteria including:
LEGIONELLA PNEUMOPHILA- DOC
CHLAMDOPHILA (PSITTACOSIS) AND CHLAMYDIA SPP.
MYCOPLASMA SPP.
UREAPLASMA UREALYTICUM

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Macrolides- Erythromycin Absorption

variable (F= 15-45%)
food may decrease absorption
base- destroyed by gastric acid; enteric coated
esters and ester salts- more acid stable

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Macrolides- Clarithromycin Absorption

well-absorbed and acid stable (F=55%), regardless of presence of food

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Macrolides- Azithromycin Absorption

Acid stable, F= 37% regardless of presence of food

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Macrolides Distribution

extensive

MINIMAL CSF PENETRATION

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Macrolides Elimination

ERYTHRO- EXCRETED IN BILE AND METABOLIZED (CYP450)
CLARITHRO- METABOLIZED/ELIMINATED BY KIDNEY
AZITHRO- ELIMINATED BY BILIARY EXCRETION

NONE OF THE MACROLIDES ARE REMOVED DURING HEMODIALYSIS!!

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Macrolides Clinical Uses

CA-PNEUMONIA- MONOTHERAPY FOR OUTPATIENTS; WITH CEFTRIAXONE FOR INPATIENTS
WITH CEFTRIAXONE FOR CA-BACTERIAL PNEUMONIA FOR "ANTI-INFLAMMATORY EFFECT)
ALTERNATIVE FOR PEN-ALLERGIC PATIENTS:
- Group A Strep URIs
- prophylaxis of bacterial endocarditis
- syph and GC
- rheumatic fever prophylaxis
- Strep sp. and S. pneumo resistant

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Macrolides Drug Interactions

ERYTHROMYCIN & CLARITHROMYCIN ONLY!! Are inhibitors of p450 system and can increase concentrations of:
THEOPHYLLINE
CARBAMAZEPINE
CYCLOSPORINE
PHENYTOIN
WARFARIN
DIGOXIN
VALPROIC ACID
others

NOT AZITHROMYCIN!!!

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Ketolides

TELITHROMYCIN

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Ketolides/Telithromycin Mech of Action

bind to two domains (II & V) on 50S ribosomal subunit; binds 10x more strongly to domain II than macrolides

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Ketolides/Telithromycin- Bactericidal or Bacteriostatic?

Bacteriostatic

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Mechanism of Resistance against Ketolides/Telithromycin

ribosomal binding site alterations

Ketolides/Telithromycin Spectrum of Activity

MACROLIDE-RESISTANT Streptococcus and Staphylococcus

poor activity against H. influenzae

Ketolides/Telithromycin ABSORPTION

F= 57%

unaffected by food

Ketolides/Telithromycin DISTRIBUTION

excellent into tissues and cells

protein binding= 60-70%

Ketolides/Telithromycin ELIMINATION

metabolized by cytochrome p450 (3A4); 1/2 life= 10 hours

no dose adjustment in renal insufficiency

Ketolides/Telithromycin Adverse Effects

Use has been limited
DIARRHEA
HEPATOTOXICITY
DECREASED VISUAL ACUITY
BLURRED VISION
QTc prolongation

Ketolides/Telithromycin Drug Interactions

INHIBITOR OF CYTOCHROME P450 3A4 | - similar drug interactions as erythro and clarithro (digoxin, phnytoin, warfarin, cyclosporin)

Ketolides/Telithromycin Clinical Uses

COMMUNITY-ACQUIRED PNEUMONIA acute bacterial sinusitis acute exacerbations of chronic bronchitis

Streptogramins

Developed in response to need for abx w/ activity against resistan Gram (+) bacteria, namely VRE Synercid is the first available; is a combination of two semi-synthetic pristinamycin derivatives in a 30:70 ratio: QUINUPRISTIN:DALFOPRISTIN

Streptogramins/Synercid MECH OF ACTION

- each agent acts individually on 50S ribosomal subunits to inhibit early and late stages of protein synthesis - binds 50S ribosome near where the macrolides and clindamycin bind

Streptogramins/Synercid- Bactericidal or Bacteriostatic?

Bacteriostatic, may be time-dependent bactericidal against some bacteria PAE exists for Gram (+)

MECHANISMS OF RESISTANCE against Streptogramins/Synercid

alterations in ribosomal binding sites (erm) | enzymatic inactivation

Streptogramins/Synercid Spectrum of Activity

Gram (+): MRSA AND MSSA PRSP ENTEROCOCCUS FAECIUM (INCLUDING VRE) Gram (-): not used Atypical Bacterial: not used

Streptogramins/Synercid Absorption

only available parenterally

Streptogramins/Synercid Distribution

MINIMAL CSF PENETRATION | penetrates into extravascular tissue, lun, skin/soft tissue

Streptogramins/Synercid Elimination

both agents are metabolized

Streptogramins/Synercid Clinical Uses

``` VRE (FAECIUM) BACTEREMIA very expensive ($350/day) ```

Streptogramins/Synercid Drug Interactions

``` CYTOCHROME P450 INHIBITOR, thus Antihistamines Cholesterol-lowering agents immunosuppressive agents Calcium channel blockers others ```

Streptogramins/Synercid Adverse Effects

VENOUS IRRITATION | MYALGIAS, ARTHRALGIAS

Clindamycin

Semisynthetic derivative of lincomycin, but is absorbed better and has a broader spectrum of activity

Clindamycin Mech of Action

Binds exclusively to 50S ribosomal subunit | - binds in close proximity to macrolides and Synercid, may cause competitive inhibition

Clindamycin- Bactericidal or Bacteriostatic?

Bacteriostatic, but can be bactericidal when present at high concentrations against very susceptible organisms

Mechanisms of Resistance against Clindamycin

ALTERED TARGET SITES | ACTIVE EFFLUX- mef gene encodes an efflux pump that pumps macrolides out of the cell BUT NOT CLINDAMYCIN;

Clindamycin Spectrum of Activity

Gram (+): MSSA CA-MRSA Anaerobes: best activity against Above the Diaphragm Anaerobes BACTEROIDES SPP some Clostridium spp. (NOT C-DIF)

Clindamycin Absorption

IV or PO rapidly and completely absorbed food has minimal effect

Clindamycin Distribution

BONE | MINIMAL CSF PENETRATION

Clindamycin Elimination

metabolized by liver | NOT REMOVED DURING HEMODIALYSIS

Clindamycin Clinical Uses

ANAEROBIC INFECTIONS OUTSIDE THE CNS (PULMONARY, OTHERS) SKIN & SOFT TISSUE INFECTIONS - PEN-ALLERGIC PATIENTS - PTS W/ INFECTIONS DUE TO CA-MRSA

Clindamycin Adverse Effects

C-DIF COLITIS Hepatotoxicity- rare Allergy- rare Gastrointestinal