Antibacterials: Protein Synthesis Inhibitors Flashcards
Protein synthesis inhibitors general MOA
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)
Tetracyclines MOA and antibacterial spectrum
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
Tetracycline mechanisms of resistance
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
Tetracyclines clincial applications
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
Tetracyclines PK
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***
Tetracyclines AE
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
Tetracycline contraindications
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
Glycylcyclines antibacterial spectrum
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)
Glycylcyclines
Tigecycline
Treatment of complicated skin, soft-tissue and intra-abdominal infections
Glycylcyclines contraindication
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
Glycylcyclines PK
IV only - very good tissue and intracellular penetration
Mainly bile and fecal elimination
Aminoglycosides MOA and antibacterial spectrum
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
Aminoglycosides PD
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
Aminoglycosides mechanisms of resistance
Main mechanism = plasmid-associated synthesis of enzymes that modify and inactivate drug by acetylation, phosphorylation and adenylation
Aminoglycosides clinical applications
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
Aminoglycosides PK and AE
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)***
Oral neomycin clinical applications
Aminoglycoside antibiotic
Used as adjunct in treatment of hepatic encephalopathy
Treatment options for hepatic encephalopathy
Oral neomycin Lactulose - not an antibiotic Oral vancomycin Oral metronidazole Rifaximin
Lactulose MOA, AE
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
Macrolides MOA and antibacterial spectrum
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
Macrolides mechanisms of resistance
Usually plasmid encoded mechanisms
Production of esterase that hydrolyse drugs (by enterobacteriaceae)
Modification of ribosomal subunit binding site - by chromosomal mutation or by methylation
Macrolides clinical applications
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
Macrolides PK
Clarithromycin, azithromycin, telithromycin = improved oral absorption, longer half-life, increased bioavailability compared to erythromycin
Clarithromycin, erythromycin, telithromycin = inhibit CYP P450 enzymes**
Macrolides AE
GI irritating
Hepatic abnormalities
QT prolongation - common in patients with underlying cardiac conditions
Macrolides contraindications
Statins - due to inhibition of CYP P450 enzymes
Telithromycin - don’t use for minor illnesses –> fatal hepatotoxicity, exacerbations of myasthenia gravis
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)
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)
Chloramphenicol resistance
Presence of factor that codes for chloramphenicol acetyltransferase –> inactivates drug
Chloramphenicol PK
Inhibits hepatic oxidases (CYP3A4 and CYP2C9) –> many drug-drug interactions***
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
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)
Clindamycin AE
Potentially fatal pseudomembranous colitis (superinfection of C.difficile)***
GI irritation - 20% have diarrhea
Skin rashes in 10%
Neutropenia and impaired liver function
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
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
Streptogramins PK and AE
Penetrates macrophages and PNMs
Inhibitors of CYP3A4**
AE: Infusion related venous irritation, arthralgia, myalgia
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
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
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***
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
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)
