MG - infectious diseases and oncology 3

Lecture 4 - Antibiotics: inhibitors of protein synthesis

what are the steps of transcription in the protein synthesis

initiation: RNA polymerase binds to the promotor of DNA

promoter escape: RNA polymerase to escape the promoter so that it can enter into the elongation step

elongation: RNA polymerase traverses the template strand of the DNA and base pairs with the nucleotides on the template(noncoding) strand > mRNA transcript

termination: the hydrogen bonds of the RNA-DNA helix break

what are the steps of translation of the protein synthesis

amino acids are linked together in a specific order

activation: the amino acid is covalently bonded to the tRNA

initiation: the small subunit of the ribosome binds to the 5’end of the mRNA with the help of initiation factors

elongation: the next aminoacyl-tRNA in line binds to the ribosome along with GTP and an elongation factor

termination: the A site of the ribosome faces a stop codon

post-translation events

protein folding

proteolysis

other modifications: addition of chemical groups, formation of covalent bonds

aminoglycosides

MOA: poly-cations > disrupt the membrane of gram negative bacteria, there is irriversible binding to the 30S subunit(inhibition, irreversible ribosome damage, misreading(nonsense proteins, pores on the membranes))

effect is concentration-dependent

long post antibacterial effect, resulting in dose 1 dd

spectrum: only aerobe (oxygen dependent transport into the cell) gram positive and negative and mycobacteria

PK: no CNS penetration, no oral absorption, iv/im, cumulation in kidney and inner ear

side effects of aminoglycosides

saturable, active cumulation: kidney epithelial cells, cochlear hair cells.

oto- and vestibular toxicity

neuromuscular blockade: decrease in ACh release

nephrotoxicity: reversible at the beginning, decrease in kidney function

embryo-fetal toxicity: no administration to pregnant

resistance aminoglycoside

production of transferase enzyme > inactivation

impaired entry of aminoglycosides into the cell

the receptor on the 30S ribosomal subunit deleted or altered

indications of standard aminoglycosides(gentamycin, tobramycin, netilmicin, amikacin)

monotherapy: urinary infections

combination with b-lactams, glycopeptides: increases efficacy, indicated for severe infections, sepsis and endocarditis

local: eyedrops and ointments

inhalation: CF(tobramycin)

gentamycin indications

nosocmial pneumonia or hospital acquired pneumonia

urogenital infections

severe eye infections

infections associated with severe burns

sepsis

amikacin indications

nosocomial pneumonia(severe)

intraabdominal infections

recurrent, complicated urinary infections

skin and soft tissue infections

sepsis

bacterial endocarditis

post-op intraabdominal infections

(generally in combinaiton with other AB)

tobramycin indications

local: ocular infections

inhalational: chronic P. aeruginosa infection in the case of CF

systemic: complicated UTI, peritonitis, bacterial pneumonia, severe skin and subcutaneous inffections

streptomycin

aminoglycoside

old agent, very ototoxic

indication: TBC, brucellosis, tularemia, plague

neomycin

aminoglycoside

only local application

ear and eye drops

oral for lowering GI flora

tetracyclines

MOA: bind to the 30S subunit, preventing tRNA from binding, bacteriostatic

spectrum: broad: gram positive, negative, anaerobe, spirochetes, intracellular pathogens, protozoans

PK: differences in absorption, complex forming with metals, mainly calcium is of importance, bound to plasma proteins, distributed well, poor to the CNS, cross placenta and in breastmilk, excreted in bile and urine

SE: nausea, vomiting, diarrhea, alteration of normal flora, esophageal ulceration, calcium binding, vestibular disturbances, sensitivity to sun/UV light, impair hepatic function, neprhotoxicity(in the case of expired product)

indications doxycycline

cutaneous infections, respiratory infections, H. pylori, Gonorrhoea, gynecology, dental practice, STDs, cholera, malaria prophylaxis, atypical mycobacteria, borrelia, rare infections

tetracycline (the drug)

food reduces the absorption

preparations for mouth and throat remedy

capsules, eye drops, creams and ointments

minocycline

similar to doxycycline

less preferred (often)

ervacycline

used for complicated intraabdominal infections

broad spectrum: MRSA, CRE

clinical trails ongoing

tigecycline

glycilcycline

derivative of tetracycline, same MOA

effective against resistant strains

indication: complicated skin and soft tissue infection, complicated intraabdominal infections

only if there is no alternative

SE: similar to tetracyclines with the addition of thrombocytopenia

chloramphenicol

MOA: effect on the 50S subunit by inhibition of the peptidyl-transferase

spectrum: wide > gram positive, negative, aerobe, anaerobe and intracellular

strong resistance

PK: great absorption and distribution(incl CNS and abscesses)

• metabolized in the liver

• CYP inhibitor

SE: dose dependent bone marrow suppresion, grey baby syndrome, aplastic anemia, dysbacteriosis

indications: bacterial eye infections

• brain and eye abscesses

• meningitis

• rickettsiosis

macrolides

eryhtromycin, clarithromycin, azithromycin

MOA: binding to the 50S subunit inhibiting the elongation by inhibition of the tRNA transfer from the A to the P site and the peptidyl transferase inhibition

bacteriostatic effect

binding spot is MLSb, this is the same binding spot as some others resulting in the possibility of cross-resistance

spectrum: gram positive coccus, gram negative coccus, corynebacterium, hemophilus sp. bordetalla, legionella, Chlamydia

resistance: MRSA, enterococcus, enterobacteriaceae(natural), pneumococcus, S. aureus

indications - broad spectrum

• upper respiratory tract infections(sinusitis, pharyngitis, tonsillitis, acute otitis media

• lower respiratory tract infections(acute bronchitis, mild to moderate CAP

• skin infections

• uncomplicated Chlamydia

• gonnorhea, urethritis

PK: good absorption, good distribution, goes into breastmilk and through placenta, long PAE

SE: GI, metal taste(clarithromycin), allergy, QT interval prolongation, teratogenic?

clindamycin

lincosamide

MOA: same as macrolides

spectrum: broad > gram positive coccus and gram positive and negative anaerobes

PK: good oral absorption and distribution, metabolism in liver

indications:

• infection of the lower respiratory tract

• infections of skin and soft tissues

• infections of small pelvis and female genital tract

• intraabdomnial infections

• bone and joint infections

• chronic sinusitis

• tonsillitis

side effects: dysbacteriosis, skin rash, liver enzymes increase in the blood panel

linezolid

oxazolidinones

MOA: binding to the 50S subunit(inhibits initiation, unique binding spot), bacteriostatic, rare resistance

spectrum: gram positive coccus, rod and anaerobe

indications: pneumonia and complicated skin and soft tissue infections.

administration should be in hospital setting

PK: good absorption, good CNS penetration, excretion via bile and kidneys

SE: bone marrow suppression, GI disturbances, MAO inhibitor, decrease in sperm number, increase in transaminase enzyme

fucidin acid

unknown MOA

spectrum: gram positive, mainly staphylococcus, corynebacterium

indications: mainly used locally

• non-severe superficial and non-extensive primary skin infections caused by microorganisms

systemic indications

• staphylococcal infections > pneymonia, sepsis, osteomyelitis, skin infections

mupirocin

MOA: inhibits isoleucine tRNA synthase in bacteria, combined inhibition of protein synthesis and RNA synthesis, bacteriostatic

spectrum: gram positive(mainly coccus)

indications: superficial skin infections, elimination of staphylococci in the nose

drugs with good oral absorption

tetracyclines, macrolides, lincosamides

commonly used antibiotic in dental practice due to good penetration into bones

clindamycin

special indication: elimination of staphylococci in the nose before surgeries

mupirocin

choose the “backup” antibiotic, which is active against MRSA, VRSA and VRE

linezolid

possible side effects macrolides

GI disturbances, diarrhea, metal taste in mouth, allergy

what might be a danger of chronic clindamycin administration

pseudomembranosus colitis

why is chloramphenicol only rarely used today

resistance is common, might cause aplastic anemia

which of the antibiotics have broad spectrum

tetracyclines, macroludes, clindamycin, chloramphenicol