Protein synthesis inhibitors Flashcards by M D

Clindamycin mechanism of action

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

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clindamycin binding site

50S ribosomal subunit

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is clindaycin bactericidal or bacteriostatic

bacteriostatic typically but bactericidal at high concentrations

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Clindamycins main mechanism of resistance

Altered target sites – encoded by the erm gene, which alters 50S ribosomal binding site; confers high level resistance to macrolides, clindamycin and Synercid® (MLSb resistance)

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erm gene

alters 50S ribosomal binding site; confers high level resistance to macrolides, clindamycin and Synercid® (MLSb resistance)

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mef gene

encodes for an efflux pump that pumps macrolides out of the cell but NOT clindamycin

Confers low level resistance to macrolides, but clindamycin still remains active

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clindamycin’s spectrum of activity

gram + aerobes (MSSA, some MRSA and Streps not PRSP )

anaerobes: including peptostreptococcus, clostridium (except C. diff)

and a few others

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clindamycin absorption

good bioavailability both IV and PO

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

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clindamycin’s distribution

Good serum concentrations with both formulations

Good tissue penetration including bone; minimal CSF penetration

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Clindamcin’s elmination

Clindamycin primarily metabolized by the liver (85%); enterohepatic cycling

Half-life is 2.5 to 3 hours (dosed 6 to 8 hrs)

Clindamycin is NOT removed during hemodialysis (no renal adjustments)

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clindamycin clinical uses

Anaerobic Infections OUTSIDE of the CNS
Pulmonary, intraabdominal, pelvic, diabetic foot and decubitus ulcer infections

Skin & Soft Tissue Infections (good gram+ but pcn might be better)
PCN-allergic patients
Patients with infections due to CA-MRSA

Alternative therapy
C. perfringens, PCP, Toxoplasmosis, malaria, bacterial vaginosis

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clindamycin’s adverse effects on the GI system

Gastrointestinal – 3 to 4% (especially with oral formulation)
Nausea, vomiting, diarrhea, dyspepsia

Clostridium difficile colitis (0.01-10%)– one of worst inducers
Ranges from mild - severe diarrhea
Requires treatment with metronidazole or oral vancomycin

GI side effects occur more commonly with oral administration

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clindamycin adverse effects

Hepatotoxicity - rare
Elevated transaminases

Allergy – rare (rash)

Hematological abnormalities-neutropenia and thrombocytopenia (rare)

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Macrolides that are used clinically

erythromycin, clarithromycin, and azithromycin

erythromycin is the least commonly used due to adverse effects

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Macrolide’s mechanism of action

Inhibit protein synthesis by reversibly binding to the 50S ribosomal subunit

Results in suppression of protein synthesis and bacterial growth is halted

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are Macrolides bacteriostatic or bactericidal?

bacteriostatic except in high concentrations

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Do macrolides have time or concentration depended effects

erythromycin and clarithromycin display time dependent activity

azithromycin is concentration dependent

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2 mechanisms of resistance to macrolides

Active efflux (accounts for 70-80% in US) – 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 (primary resistance mechanism in Europe) – 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

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macrolides spectrum of activity compared to clindamycin

similar gram positive but macrolides also have activity against bacillus and cornynebacterium spp.

clinda has no gram negative aerobe activity but macrolides have some (NOT Enterobacteriaceae)

macrolides have anaerobe and atypical bacteria activity

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which macrolide has the best gram positive activity

clarithro > Erythro > Azithro

which gram negative spp. do macrolides have activity against?

H. influenzae (not erythro), M. catarrhalis, Neisseria spp.

which macrolides have the best gram negative activity

Azithro > Clarithro > Erythro

Macrolides are mainly used for treatment of

atypical bacteria:
Legionella pneumophila – DOC*
Chlamydophila (psittacosis) and Chlamydia spp.
Mycoplasma spp.

all macrolides have excellent activity against them

others: Mycobacterium avium complex (can be used for treatment or prophylaxis

bioavailability of macrolides

Clarithro > azithro > erythro

ways to increase the absorption of 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

absorption of which macrolide is affected by the presence of food in the stomach

erythromycin

macrolide distribution

Extensive tissue and cellular distribution – clarithromycin and azithromycin with higher tissue concentrations Minimal CSF penetration

do macrolides enter the CSF

Not really

macrolide elimination

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)

clinical uses for Macrolides

Respiratory Tract Infections Pharyngitis/ Tonsillitis – PCN-allergic patients Sinusitis,COPD exacerbation, Otitis Media (azithro best if H. influenzae suspected) Community-acquired pneumonia Uncomplicated Skin Infections STDs – Single 1 gram dose of azithro MAC Alternative for PCN-Allergic Patients:

macrolide use in pneumonia

Community-acquired pneumonia – monotherapy in outpatients; with ceftriaxone for inpatients

Macrolide use for Mycobacterium avium complex (MAC)

Azithromycin for prophylaxis; Clarithromycin/ Azithromycin combination for treatment

Macrolide use as an Alternative for PCN-Allergic Patients

Group A Strep upper respiratory infections Prophylaxis of bacterial endocarditis Syphilis and gonorrhea Rheumatic fever prophylaxis

GI adverse effects of macrolides

up to 33% Nausea, vomiting, diarrhea, dyspepsia Most common with erythro; less with clarithromycin and azithromycin (10%) more common that cindamycin but less chance of sever complications from C. diff

side effects of Macrolides

Gastrointestinal Cholestatic hepatitis - rare > 1 to 2 weeks of erythromycin estolate Thrombophlebitis – IV Erythro and Azithro Dilution of dose; slow administration Allergic reactions * Prolonged QTc; aggravated by concomitant drugs that also prolong QTc (e.g. anti‐arrhythmics) Transient /reversible tinnitus or deafness (with long term use) Drug‐drug: e.g., Colchicine: potentially fatal interaction

which protein inhibitors inhibit p450

macrolides: Erythromycin and clarithromycin Quinupristin/Daltopristin (Synercid®) potentially more drug interactions

Streptogramins what is the clinically used drug

Quinupristin/Daltopristin (Synercid®)

what was the target for Quinupristin/Daltopristin (Synercid®)

Developed in response to the need for antibiotics with activity against resistant gram-positive bacteria, namely VRE

Quinupristin/Daltopristin (Synercid®) mechanism of action

Each agent acts individually on 50S ribosomal subunits to inhibit early and late stages of protein synthesis Binds on the 50S ribosome near where the macrolides and clindamycin binding site Bacteriostatic (may be bactericidal against some bacteria)

Quinupristin/Daltopristin (Synercid®) mechanism of resistance

Alterations in ribosomal binding sites (erm) | Enzymatic inactivation

Quinupristin/Daltopristin (Synercid®) spectrum of activity

mainly used for gram positives | includes MRSA, PRSP, and VRE

which protein inhibitor show a post-antibiotic effect

Quinupristin/Daltopristin (Synercid®)

how is Quinupristin/Daltopristin (Synercid®) administered

only IV

Quinupristin/Daltopristin (Synercid®) distribution

penetrates into extravascular tissue, lung, skin/soft tissue not CSF

Quinupristin/Daltopristin (Synercid®) elmination

both agents are hepatically and biliary excreted

Quinupristin/Daltopristin (Synercid®) common clinical uses

VRE (faecium) bacteremia Complicated skin and soft tissue infections due to MSSA or Streptococcus pyogenes Limited data in treatment of catheter-related bacteremia, infections due to MRSA, and community-acquired pneumonia

Quinupristin/Daltopristin (Synercid®) adverse effects

Venous irritation  (66%) – especially when administered through a peripheral vein Gastrointestinal – nausea, vomiting, diarrhea Myalgias, arthralgias – 2% Rash-2.5%

which classes of drugs inhibit protein synethsis by binding to the 50S subunit of the ribosome

Lincosamides (clindamycin) Macrolides Streptogramins (Quinupristin/Daltopristin (Synercid®))

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Protein synthesis inhibitors Flashcards

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