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Antibacterials: Protein Synthesis Inhibitors Flashcards

1
Q

Protein synthesis inhibitors general MOA

A

Bind to and interfere with ribosomes

Selective toxicity as bacterial ribosomes (70S: 30S + 50S subunit) differs from mammalian ribosomes (80s) but closely resembles mammalian mitochondrial ribosome

Mostly bacteriostatic - reversible inhibition of growth (except aminoglycosides)

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2
Q

Tetracyclines MOA and antibacterial spectrum

A

Doxycyline
Minocycline
Tetracycline

Broad-spectrum –> against many aerobic and anaerobic gram positive and gram negative bacteria

Entry via passive diffusion and energy-dependent transport unique to bacterial inner cytoplasmic membrane –> susceptible cells concentrate drugs intracellularly –> bind reversibly to 30S subunit to ribosome –> prevent attachment of aminoacyl tRNA –> bacteriostatic

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3
Q

Tetracycline mechanisms of resistance

A

Widespread resistance - usually plasmas mediated

1) Impaired influx or increased efflux by active plasmid-encoded protein pump
2) Production of proteins that interfere binding to ribosome
3) Enzymatic inactivation

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4
Q

Tetracyclines clincial applications

A

Most common use = treat severe acne and rosacea

Empiric therapy of community-acquired pneumonia (outpatients)

Useful at treating atypical pneumonias (mycoplasma, chlamydia, legionella) –> cannot use cell synthesis inhibitors for these

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

Syphilis in patients allergic to penicillin

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5
Q

Tetracyclines PK

A

Variable oral absorption –> decreased by divalent and trivalent cations***
–> Avoid dairy products and antacids are they both have divalent cations which can chelate with the drug

Doxycycline - is lipid soluble –> preferred for parenteral administration and good choice for STDs and prostatitis***

Concentrate in liver, kidney, spleen and skin (therefore used to treat acne, rosacea)

Excreted mainly in urine except doxycycline (mainly via bile)

Can cross placenta and excreted in breast milk –> Teratogenic***

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6
Q

Tetracyclines AE

A

Discoloration and hypoplasia of teeth, stunting of growth –> binds to Ca2+ in teeth and bones –> avoided in pregnancy can not given to children under 8y***

Fatal hepatotoxicity (in pregnancy, with high doses or in patients with hepatic insufficiency)

Photosensitisation***

Gastric distress

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7
Q

Tetracycline contraindications

A

Avoid dairy products and antacids as they both have divalent cations which can chelate with the drug and mess with oral absorption

Pregnancy category D as it is teratogenic

Not given to children under 8y

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8
Q

Glycylcyclines antibacterial spectrum

A

Tigecycline

Tetracycline derivative –> binds to 30S ribosome subunit and inhibit protein synthesis

Broad spectrum against MDR gram positive, some gram negative and anaerobic bacteria

Little resistance –> not subject to same resistant mechanisms as tetracyclines (exceptions = efflux pumps of Proteus & Pseudomonas species)

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9
Q

Glycylcyclines

A

Tigecycline

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

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10
Q

Glycylcyclines contraindication

A

Not given in pregnancy and children less that 8y

Black box warning = increased risk of mortality observed with tigecycline compares to other antibiotic used to treat serious infections (not due to AE but because they do not work as well against serious infections)***

FDA recommends using other drugs to treat patients with serious infections

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11
Q

Glycylcyclines PK

A

IV only - very good tissue and intracellular penetration

Mainly bile and fecal elimination

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12
Q

Aminoglycosides MOA and antibacterial spectrum

A 
Aminkacin 
Gentamycin 
Tobramycin 
Streptomycin 
Neomycin

Most active against aerobic gram negative bacteria***

Passively diffuse across membrane of gram negative organisms –> actively transported across cytoplasmic membrane –> covalently bind 30S subunit before the ribosome forms –> irreversible inhibition of initiation complex –> misreading of mRNA and blockade of translation

Are bactericidal

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13
Q

Aminoglycosides PD

A

Postantibiotic effect + concentration dependent killing = once-daily dosing

Concentration dependent killing = higher the peak concentration the drug can achieve, the more effective it will be in killing the bacteria

Not time-dependent killing like most antibiotics = how long antibiotic is above MIC is important, increasing concentrations will just lead to more side effects

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14
Q

Aminoglycosides mechanisms of resistance

A

Main mechanism = plasmid-associated synthesis of enzymes that modify and inactivate drug by acetylation, phosphorylation and adenylation

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15
Q

Aminoglycosides clinical applications

A

Used mostly in combination

Empiric therapy of serious infections (septicimea, nocosomial respiratory tract infections, complicated UTIs)

Neomycin - for bowel surgery

DOC for empiric therapy of infective endocarditis in combination with vancomycin

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16
Q

Aminoglycosides PK and AE

A

Parenteral only (except neomycin - can be topical)
Once-daily dose
High levels in renal cortex and inner ear
99% excreted in urine

AEs are both time and concentration dependent:
Ototoxicity*
Nephrotoxicity*
Neuromuscular blockade (contraindicated in myasthenia gravis)
Teratogen (contraindicated in pregnancy - category D)***

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17
Q

Oral neomycin clinical applications

A

Aminoglycoside antibiotic

Used as adjunct in treatment of hepatic encephalopathy

18
Q

Treatment options for hepatic encephalopathy

A 
Oral neomycin 
Lactulose - not an antibiotic 
Oral vancomycin 
Oral metronidazole 
Rifaximin
19
Q

Lactulose MOA, AE

A

Nonabsorbable disaccharide (not an antibiotic)

MOA: degraded by intenstinal bacteria to lactic acid + other organic acids –> acidification of gut lumen –> favours formation of NH4+ from NH3 –> NH4 is trapped in colon and excreted in feces –> reduces plasma ammonia concentrations

Is also a prebiotic and osmotically active laxative

AE: osmotic diarrhea, flatulence, abdominal cramping

Can be used to treat hepatic encephalopathy

20
Q

Macrolides MOA and antibacterial spectrum

A

Erthyromycin
Clarithromycin
Azithromycin
Telithromycin

Reversibly bind to 23S rRNA of 50S subunit –> block translocation –> bacteriostatic (bactericidal at high conc)

Binding site is identical or close to that of clindamycin and chloramphenicol

Mainly active against gram positive bacteria (some activity against gram negatives) –> slightly wider than that of penicillins

Erythromycin has a slightly less broad spectrum

21
Q

Macrolides mechanisms of resistance

A

Usually plasmid encoded mechanisms

Production of esterase that hydrolyse drugs (by enterobacteriaceae)

Modification of ribosomal subunit binding site - by chromosomal mutation or by methylation

22
Q

Macrolides clinical applications

A

Used in empiric therapy of community-acquired pneumonia (outpatient and in combination with b-lactam for inpatients)

Useful at treating atypical pneumonias

Treatment of upper respiratory and soft-tissue infections

Erythomycin = DOC for whooping cough (B.pertussis)

Common substitute for patients with penicillin allergy

23
Q

Macrolides PK

A

Clarithromycin, azithromycin, telithromycin = improved oral absorption, longer half-life, increased bioavailability compared to erythromycin

Clarithromycin, erythromycin, telithromycin = inhibit CYP P450 enzymes**

24
Q

Macrolides AE

A

GI irritating

Hepatic abnormalities

QT prolongation - common in patients with underlying cardiac conditions

25
Macrolides contraindications
Statins - due to inhibition of CYP P450 enzymes Telithromycin - don't use for minor illnesses --> fatal hepatotoxicity, exacerbations of myasthenia gravis
26
Chloramphenicol MOA and AE
Enters cells via active transport process --> binds reversibly to 50S ribosomal subunit --> inhibits peptidyltransferase --> potent inhibitor of protein synthesis --> bacteriostatic Can inhibit protein synthesis in mitochondrial ribosomes --> bone marrow toxicity AE: - Bone marrow depression --> dose-related reversible depression or severe irreversible aplastic anemia - Grey baby syndrome (cyanosis) due to drug accumulation*** (pregnant mother might be given the drug and it can lead to this in newborns)
27
Chloramphenicol antibacterial spectrum and clinical applications
Very broad spectrum Activity against gram positive and negative bacteria including Rickettisae and anaerobes Never given systemically for minor infections due to toxicity. Used to treat life-threatening infections with no alternatives, for serious infections resistant to less toxic drugs or when it is much better at penetrating to site of infection compared to other drugs Active against many VRE Topical treatment of eye infections (mainly outside US)
28
Chloramphenicol resistance
Presence of factor that codes for chloramphenicol acetyltransferase --> inactivates drug
29
Chloramphenicol PK
Inhibits hepatic oxidases (CYP3A4 and CYP2C9) --> many drug-drug interactions***
30
Clindamycin MOA and resistance
Same MOA as macrolides --> Reversibly bind to 50S subunit --> block translocation --> mainly bacteriostatic Resistance due to: - mutation of ribosomal receptor site - modification of receptor - enzymatic inactivation of drug Most gram negative aerobes and enterococci are intrinsically resistant Cross resistant with macrolides
31
Clindamycin antibacterial spectrum and clinical applications
Mainly used against gram positive anaerobes. Also active against bacteroides and gram positive aerobes Used to treat: - anaerobic infections (bacteroides infections, abscesses, abdominal infections) - skin and soft tissue infections*** (streptococci and staphylococci and some MRSA because it also covers gram negatives)*** - In combination with pyrimethamine as an alternative treatment for toxoplasmosis of brain - Alternative for prophylaxis in penicillin-allergic patients*** - General rules: treat infections caused by anaerobes above the diaphragm PK: good penetration (including abscesses and bones)
32
Clindamycin AE
Potentially fatal pseudomembranous colitis (superinfection of C.difficile)*** GI irritation - 20% have diarrhea Skin rashes in 10% Neutropenia and impaired liver function
33
Streptogramins MOA
Quinupristin Dalfopristin Bind to separate sites on 50S ribosome subunit Given as a combination - act synergistically to have bactericidal effect Long post antibiotic effect
34
Streptogramins antibacterial spectrum and clinical applications
Gram positive cocci and MDR bacteria (streptococci, PRSP, MRSA, E.faecium) Restricted to treatment of infections causes by drug resistant Staphylococci or VRE
35
Streptogramins PK and AE
Penetrates macrophages and PNMs Inhibitors of CYP3A4**** AE: Infusion related venous irritation, arthralgia, myalgia
36
Linezolid MOA and resistance
Inhibits formation of 70S complex by binding to unique site on 23S rRNA of 50S subunit --> bacteriostatic (but bactericidal against streptococci and clostridium perfringens) MOA: similar to ahminoglycosides but they bind to 30S Resistance mechanisms: - Decreased binding to target site - Point mutation in rRNA - No cross-resistance with other drug classes
37
Linezolid antibacterial spectrum and clinical applications
Acts against most gram positive organisms including MRSA and VRE*** Moderate activity against mycobacterium tuberculosis Used to treat multi-drug resistant infections
38
Linezolid PK, AE and contraindications
PK 100% oral bioavailvity Widely distributed - including CSF Weak reversible MOA inhibitor*** ``` AE Long term use can cause - bone marrow suppression (esp. thrombocytopenia) - optic and peripheral neuropathy - lactic acidosis - serotonin syndrome ``` Contraindications: since it is a reversible, non-selective MOA inhibitor --> potential to interact with adrenergic and serotonergic drugs***
39
Fidaxomicin
Binds to RNA polymerase --> inhibits bacterial protein synthesis Narrow spectrum macrocyclic antibiotic - activity against gram positive aerobes and anaerobes especially Clostridia Used to treat C.difficile colitis in adults*** PK: When given orally, fecal concentrations are high AE: Main effects seem to be GI disorders. Safety and effectiveness in patients under 18y has not been established
40
Mupirocin
Monoxycarbolic acid antibiotic --> binds to bacterial isoleucyl tRNA synthesise --> inhibition of protein synthesis Activity against most gram positive cocci including MRSA and most streptococci (not enterococci) Clinical applications: - Only topical/intranasal activity against MRSA*** - Topically: treatment of impetigo or secondary infected traumatic skin lesions - Intranasal: eradication of nasal colonisation with MRSA in adult patients and healthcare AE: - Resistance develops if used for long periods of time - Mainly local and dermatologic effects (burning, deem, tenderness, dry skin, pruritus)

Pharmacology (20 decks)

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