PROTEIN SYNTHESIS INHIBITORS Flashcards Preview

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Flashcards in PROTEIN SYNTHESIS INHIBITORS Deck (45):
1

PROTEIN SYNTHESIS INHIBITORS

• 1) Tetracyclines
• 2) Glycylcyclines
• 3) Aminoglycosides

• 4) Macrolides
• 5) Chloramphenicol

• 6) Clindamycin
• 7) Streptogramins
• 8) Linezolid
• 9) Mupirocin

Bind to and interfere with ribosomes

Bacterial ribosome (70S) differs from mammalian (80S) but closely resembles mammalian mitochondrial ribosome

• Mostly bacteriostatic

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DOXYCYCLINE

MINOCYCLINE

TETRACYCLINE

TETRACYCLINES

"DMT" binds to the THIRTY-S subunit

-broad spectrum

-bacterioSTATIC

-activity against many aerobic and anaerobic Gram +ve and -ve organisms 

MOA: 

• Entry via passive diffusion & energy-dependent transport unique to bacterial inner cytoplasmic membrane

• Susceptible cells concentrate drug intracellularly

• Bind reversibly to 30S subunit of ribosome, preventing binding of aminoacyl tRNA

3

TETRACYCLINS - RESISTANCE

3 main mechanisms:

• Impaired influx or increased efflux by active protein pump

• Production of proteins that interfere with binding to ribosome

• Enzymatic inactivation

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TETRACYCLINS - CLINICAL APPLICATIONS

-Most common use = severe acne & rosacea
• Used in empiric therapy of community-acquired

pneumonia (outpatients)

• Can be used for infections of respiratory tract, sinuses, middle ear, urinary tract, & intestines

Syphilis (patients allergic to penicillin)

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TETRACYCLINE IS DOC FOR

 

DOC FOR

• Chlamydia
• Mycoplasma pneumoniae

• Lyme disease
• Cholera
• Anthrax prophylaxis

• Rickettsia (Rocky Mountain Spotted Fever, typhus)

 

Used in combination for:

• H.pylori eradication
• Malaria prophylaxis and treatment
• Treatment of plague, tularemia, brucellosis

6

TETRACYCLINE PK

 

• Variable oral absorption (decreased by divalent & trivalent cations)

Doxycycline (lipid soluble) = preferred for parenteral admin. and good choice for STD’s and prostatitis

Minocycline = reaches high concentrations in all secretions (useful for eradication of meningococcal carrier state)

• Concentrate in liver, kidney, spleen & skin

• Excreted primarily in urine except doxycycline (primarily via bile)

• TERATOGENIC – all cross placenta & are excreted into breast milk (FDA category D)

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TETRACYCLINES - AE

• Gastric effects / superinfections (nausea, vomiting, diarrhea)

Discoloration & hypoplasia of teeth, stunting of growth (generally avoided in pregnancy & not given in children under 8y)

• Fatal hepatotoxicity (in pregnancy, with high doses,

patients with hepatic insufficiency)

• Exacerbation of existing renal dysfunction
• Photosensitization
• Dizziness, vertigo (esp. doxycycline & minocycline)

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TIGECYCLINE

is a GLYCYLCYCLINE

-is STRUCTURALLY similar to tetracyclines

-antibacterial spectrum: Broad-spectrum against multidrug-resistant Gram- positive, some Gram-negative & anaerobic organisms

RESISTANCE: 

Little resistance

• Not subject to same resistant mechanisms as tetracyclines (exceptions = efflux pumps of Proteus & Pseudomonas species)

 

CLINICAL APPLICATIONS:

Treatment of complicated skin, soft tissue and intra- abdominal infections

 

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GLYCYLCYCLINES - TIGECYCLINE

BLACK BOX WARNING

1) Increased risk of mortality has been observed with tigecycline compared with other antibiotics when used to treat serious infections

FDA recommends considering the use of alternative antimicrobials when treating patients with serious infections

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GENTAMICIN

AMIKACIN

NEOMYCIN

TOBRAMYCIN

STREPTOMYCIN

"G-ANTS" - AMINOGLYCOSIDES

fight against AEROBIC gram -NEGATIVE

• Bactericidal
• Associated with serious toxicities
• Largely replaced by safer antibiotics

MOA: 

• Passively diffuse across membranes of Gram-negative organisms

• Actively transported (O2-dependent) across cytoplasmic membrane

--> therefore are most active against AEROBIC GRAM -VE BACTERIA

• Bind to 30S ribosomal subunit prior to ribosome formation leading to:

  • 1) misreading of mRNA, &
  • 2) inhibition of translocation

PHARMACODYNAMICS;

Postantibiotic effect + Concentration-dependent killing

Once-daily dosing

--> Concentration-dependent (aminoglycosides)

 

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GLYCYLCYCLINES - PK/AE

 

IV only
• Excellent tissue & intracellular penetration • Primarily biliary/fecal elimination

Adverse effects
• Well tolerated
• AE similar to tetracyclines

Contraindications

Pregnancy & children <8y

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AMINOGLYCOSIDES - RESISTANCE

3 principal mechanisms:
1) Plasmid-associated synthesis of enzymes that

modify and inactivate drug

2) Decreased accumulation of drug

3) Receptor protein on 30S ribosomal subunit may be deleted or altered due to mutation

13

CONCENTRATION DEPENDENT VS TIME-DEPENDENT KILLING

• Concentration-dependent (aminoglycosides)

• Time-dependent (penicillins, cephalosporins)

A image thumb
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AMINOGLYCOSIDES - CLINICAL APPLICATIONS 

-Used mostly in COMBINATION

Empiric therapy of serious infections eg, septicemia, nocosomial respiratory tract infections, complicated UTI’s, endocarditis etc

• Once organism is identified aminoglycosides are normally

discontinued in favor of less toxic drugs

DOC: 

1) Empiric therapy of infective endocarditis in combination with either a penicillin or (more commonly) vancomycin

2) Streptomycin is the drug of choice for Plague (Y.Pestis)

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TREATEMENT FOR THE PLAGUE

-the plague (yersinia pestis) is treated with STREPTOMYCIN

A image thumb
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ORAL NEOMYCIN

AMINOGLYCOSIDE

• Used as adjunct in treatment for hepatic encephalopathy

Alternative treatment options for hepatic encephalopathy:

1) Lactulose
2) Oral vancomycin
3) Oral metronidazole

4) Rifaximin

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HEPATIC ENCEPHALOPATHY

-treated with ORAL NEOMYCIN 

Alternative treatment options for hepatic encephalopathy:

Lactulose
• Oral vancomycin
• Oral metronidazole

• Rifaximin

 

18

LACTULOSE

-Nonabsorbable disaccharide

MOA

• Degraded by intestinal bacteria  lactic acid + other organic acids

--> acidification of gut lumen

--> favors formation of NH4+ from NH3

--> NH4+ is trapped in colon effectively reducing plasma ammonia concentrations

Other Effects

• Prebiotic (suppression of urase producing organisms)

• Osmotically active laxative

Adverse Effects

• Osmotic diarrhea
• Flatulence
• Abdominal cramping

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AMINOGLYCOSIDES PK + AE

Like sticking the "sai" from sketchy into your EAR as well as KIDNEY

 

PK: 

Parenteral admin. only (except neomycin - topical)
Once-daily admin.
• Well distributed (excluding CSF, bronchial secretions)
High levels in renal cortex & inner ear
• 99% excreted in urine (reduce dose in renal insufficiency)

AE: 

Both time- and concentration-dependent

• Ototoxicity

• Nephrotoxicity

• Neuromuscular blockade (myasthenia gravis =

contraindicated)

• Pregnancy (contraindicated unless benefits outweigh risks – FDA Category D)

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ERYTHROMYCIN

CLARITHROMYCIN

AZITHROMYCIN

TELITHROMYCIN

 

Mainly used to treat Gram-positive infections

Bacteriostatic (bactericidal at high conc.)

MOA: 

• Reversibly bind to 50S subunit inhibiting translocation

• Binding site is identical or close to that for clindamycin & chloramphenicol

ANTIBACTERIAL SPECTRUM: 

Most active against Gram-positive bacteria (some activity against Gram-negatives)

• Spectrum is slightly wider than that of penicillins

• Azithromycin, clarithromycin & telithromycin have broader spectrum than erythromycin

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MACROLIDES - RESISTANCE

 

3 main mechanisms (usually plasmid encoded):

  1. • Reduced membrane permeability or active efflux
  2. • Production of esterase that hydrolyze drugs (by enterobacteriaceae)
  3. • Modification of ribosomal binding site (by chromosomal mutation or by a methylase)

• Complete cross-resistance between erythromycin, azithromycin, & clarithromycin

• Partial cross-resistance with clindamycin & streptogramins

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MACROLIDES - CLINICAL APPLICATION

• Used in empiric therapy of community-acquired pneumonia (outpatient & in combination with B-lactam for inpatients)

• DOC for Mycoplasma pneumoniae

• Treatment of upper respiratory tract & soft-tissue infections (eg, Staph, H.influenzae, S.pneumoniae, enterococci)

• Erythromycin = DOC for whooping cough (B.pertussis)

 

Is a common substitute for patients with penicillin allergy

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WHOOPING COUGH TREATMENT

ERYTHROMYCIN (macrolide) 

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Mycoplasma Pneumonia treatment

macrolide

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MACROLIDES PK + AE

 

PK: 

• Clarithromycin, azithromycin, telithromycin = improved oral absorption, longer t1/2, increased bioavailability compared to erythromycin

• Azithromycin & telithromycin = greater tissue penetration compared to other macrolides

• Erythromycin, clarithromycin & telithromycin = CYP P450 inhibition (NOT azithromycin)****

AE:

• GI irritation
• Hepatic abnormalities (erythromycin & azithromycin) • QT prolongation
• Severe reactions are rare (anaphylaxis, colitis)

 

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MACROLIDE CONTRAINDICATIONS 

Macrolides always standing on the static (statins) telephone poles (TELI) --> fatal hepatotoxicity, exacerbation of myasthenia gravis  

 

CONTRAINDICATIONS:

1) Statins (due to macrolides inhibiting CYP P450)

2) Telithromycinfatal hepatotoxicity, exacerbations of myasthenia gravis, & visual disturbances --> don’t use for minor illnesses

27

CHLORAMPHENICOL

Potent inhibitor of protein synthesis
• VERY Broad-spectrum (aerobic & anaerobic Gram-positive & -

negative organisms)

• Bacteriostatic (usually)

Toxicity limits use to life-threatening infections with no alternatives

MOA: 

Enters cells via ACTIVE TRANSPORT process
Binds reversibly to 50S ribosomal subunit (site adjacent

to site of action of macrolides & clindamycin)

• Can inhibit protein synthesis in mitochondrial ribosomes

ADVERSE EFFECTS 

--> bone marrow toxicity --> reversible or APLASTIC ANEMIA

 

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CHLORAMPHENICOL ANTIBACTERIAL SPECTRUM + CLINICAL APPLICATIONS

Very broad spectrum
• Activity against Gram-positive and negative bacteria, including Rickettisae & anaerobes
N.meningitidis, H.influenzae, Salmonella & bacteroides = highly susceptible

• Never given systemically for minor infections (due to adverse effects)

CLINICAL APPLICATIONS: 

1) Serious infections resistant to less toxic drugs

2) When chloramphenicols penetrability to site of

infection is clinically superior to other drugs

3) Active against many VRE

4) Topical treatment of eye infections (mainly outside US)

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CHLORAMPHENICAL PK + AE

 

Chloram"chemical" --> inhibits hepatic oxidases, and does BONE MARROW DEPRESSION b/c is such a strong chlorine chemical, also TURNS YOU GREY!!! 

• Oral, IV or topical
• Wide distribution (readily enters CSF)
• Inhibits hepatic oxidases (3A4 & 2C9)

AE: 

• GI distress
Bone marrow depression

  • dose-related reversible depression
  • severe irreversible aplastic anemia

Gray baby syndrome (cyanosis), due to drug accumulation

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CLINDAMYCIN

"give it to 50 (for 50S subunit)  y/o's and then they get C diff 

--> used for gut anaerobic bact

 

MOA = same as macrolides (binds to 50S subunit)

• Mainly bacteriostatic

• Primarily used against Gram-positive anaerobic bacteria. Also active against bacteroides

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CLINDAMYCIN RESISTANCE

Due to:

  1. • mutation of ribosomal receptor site
  2. • modification of the receptor
  3. • enzymatic inactivation of drug

• Most Gram-negative aerobes & enterococci are intrinsically resistant

• Cross-resistant with macrolides

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CLINDAMYCIN - CLINICAL APPLICATIONS

1) Anaerobic infections (eg, bacteroides infections, abscesses, abdominal infections)

2) Skin and soft tissue infections (streptococci and staphylococci, and some MRSA)

3) In combination with primaquine as an alternative in PCP (pneumocystis pneumonia) 

4) In combination with pyrimethamine as an alternative treatment for toxoplasmosis of brain

5) Prophylaxis of endocarditis in valvular patients allergic to penicillin

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CLINDAMYCIN - PK + AE

• Oral or IV
• Good penetration (including abscesses and bones)

AE:

• Potentially fatal pseudomembranous colitis (superinfection of C.difficile)

• GI irritation (~ 20% people experience diarrhea)

• Skin rashes (~10 %)
• Neutropenia & impaired liver function

34

QUINUPRISTIN

DALFOPRISTIN

PRISTIN = STREPTOGRAMINS

Given as a combination (act synergistically to have

bactericidal action)

• Long postantibiotic effect

Mechanism of action

• Bind to separate sites on 50S bacterial ribosome

• Resistance is uncommon

ANTIBACTERIAL SPECTRUM: 

1) Gram-positive cocci

2) Multi-drug resistant bacteria (streptococci, PRSP, MRSA, E.faecium)

 

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QUINUPRISTIN

DALFOPRISTIN

CLINICAL APPLICATIONS:

STREPTOGRAMINS

Restricted to treatment of infections caused by drug- resistant

1) Staphylococci or

2) VRE

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STREPTOGRAMINS PK + AE

• IV only
• Penetrates macrophages & polymorphonucleocytes

Inhibitors of CYP 3A4

AE: 

• Infusion related (venous irritation, arthralgia & myalgia)

• GI effects
• CNS effects (headache, pain)

37

LINEZOLID

LINEZOLID --> LINE --> looks like a 7, so know it that it binds to the 70S and the Z looks like a "+" sign so for gram +ve species. Line's are STATIC 

• Bacteriostatic (cidal against streptococci & Clostridium perfringens)

Mechanism of action

• Inhibits formation of 70S initiation complex

• Binds to unique site on 23S ribosomal RNA of 50S subunit

RESISTANCE: 

-Decreased binding to target site
-No cross-resistance with other drug classes

ANTIBACTERIAL SPECTRUM: 

Most Gram-positive organisms (staphylococci, streptococci, enterococci, Corynebacterium, Listeria monocytogenes)

• Moderate activity against mycobacterium tuberculosis

 

38

LINEZOLID CLINICAL APPLICATIONS

treatment of MULTI-DRUG RESISTANT INFECTIONS 

39

LINEZOLID PK + AE 

PK: 

-Oral (100% bioavailable) & IV
• Widely distributed (including CSF)

Weak reversible inhibitor of MAO

AE: 

• Well tolerated for short admin. (GI, nausea, diarrhea, headaches, rash)

Long-term admin. can cause:

Reversible myelosuppression*****
Optic & peripheral neuropathy, & lactic acidosis***

40

LINEZOLID CONTRAINDICATIONS

Reversible, nonselective inhibitor of MAO

--> potential to interact with adrenergic and serotonergic drugs

41

FIDAXOMICIN

"FEDEX"-OMI-SIN --> if you want to fedex you sin, only a narrow time (narrow spectrum) for you to do that. Is anaerobic inside the fedex box, binds to the RNA polymerase to get delivered --> treats C DIFF!!! and you MUST BE 18 Y/O to use credit card to ship!!! 

Narrow spectrum macrocyclic antibiotic
• Activity against Gram-positive aerobes and

anaerobes especially Clostridia
• No activity against Gram-negative bacteria

MOA: Inhibits bacterial protein synthesis by binding to RNA polymerase

CLINICAL APPLICATOINS: treatment of C. diff colitis (in adults)

-when administered orally, systemic absorptoin is negligible but fecal concentrations are high 

AE: 

Main effects appear to be gastrointestinal disorders

• The safety and effectiveness of fidaxomicin in patients < 18 years of age have not been established. *** watch this age

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TREATMENT OF C. DIFF COLITIS IN AN ADULT

FIDAXOMICIN

-patient must be AT LEAST 18 y/o

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MUPIROCIN

MUCOUS IS IN!!! --> use it for INTRANASAL MRSA, or topically applied for impetigo, binds to bacterial isoleucyl transfer-RNA synthetase 

Antibiotic belonging to monoxycarbolic acid class
• Activity against most Gram-positive cocci, including

MRSA and most streptococci (but not enterococci)

Only topical/intranasal agent with activity against MRSA

MOA: 

Binds to bacterial isoleucyl transfer-RNA synthetase resulting in the inhibition of protein synthesis

CLINICAL APPLICATIONS: 

A) Intranasal:
• Eradication of nasal colonization with MRSA in

B) Topically:

adult patients and healthcare workers

• Treatment of impetigo or secondary infected traumatic skin lesions due to S.aureus or S.pyogenes

AE: 

• Resistance develops if used for long periods of time

Mainly local and dermatologic effects (eg, burning,

edema, tenderness, dry skin, pruritus)

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MUPIROCIN 

CLINICAL APPLICATIONS

Intranasal:

  • Eradication of nasal colonization with MRSA in  adult patients and healthcare workers

Topically:

  • Treatment of impetigo or secondary infected traumatic skin lesions due to S.aureus or S.pyogenes

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TREATMENT OF IMPETIGO or secondary infected traumatic skin lesion d/t S. aureus or S. pyogenes

MUPIROCIN