protein cell wall inhibitors - 30s and 50s Flashcards
where does protein synthesis takes place
in ribosomes
what are the components and features of the bacterial ribosome
50s and 30s subunits and has three binding sites for tRNA (A,P,E sites)
which abx target 30s subunits
aminoglycosides and tetracyclines
which abx target 50s subunits
macrolides, clindamycin, linezolid
what is the moa of tetracyclines
enter susceptible organisms via passive diffusion and energy dependent transport protein mechanism -> concentrate intracellularly in susceptible organism -> bind irreversibly to 30s subunit of bacterial ribosome -> prevent binding of tRNA to A site of mRNA-ribosome complex -> inhibit bacterial protein synthesis
what is the type of activity of tetracyclines
bacteriostatic
what is the spectrum of activity for tetracyclines
broad coverage for gram pos, gram neg, atypical and spirochete
inadequate activity for pseudomonas and proteus
is tetracycline suitable for pregnancy and lactation and why
no it is category D as it crosses placenta barrier
what is the absorption for tetracyclines
adequately absorbed after oral ingestion, best on empty stomach
what is the important counselling points for tetracyclines
take on empty stomach
avoid dairy products as it contains Ca or any other substances that contains divalent or trivalent cations (Mg, Fe, Al) as it can cause formation of non absorbable chelates which decreases absorption
what is the distribution of tetracyclines
well distributed in bile, kidney, liver, gingival fluid, skin
where kind of tissue does tetracyclines bind to
binds to tissues undergoing calcification like bones and teeth or tumors with high Ca content
what are the drugs that are tetracyclines
tetracyclines, doxycycline, minocycline
route, indication and excretion of tetracycline
PO
chlamydia, mycoplasma pneumoniae, vibrio chloerae, plague due to yersinia pestis
kidney
route, indication and excretion of doxycycline
PO, IV
chlamydia, mycoplasma pneumoniae, vibrio chloerae, plague due to yersinia pestis, rickettsial, acne, CAP, strep pneumoniae, influenzae, skin and tissue infections by MRSA
kidney, unchanged in bile and urine
completely absorbed from GIT
route, indication and excretion of doxycycline
PO, IV
chlamydia, mycoplasma pneumoniae, vibrio chloerae, plague due to yersinia pestis, rickettsial, acne, CAP, strep pneumoniae, influenzae, skin and tissue infections by MRSA
kidney, unchanged in bile and urine
completely absorbed from GIT
route, indication and excretion of minocycline
PO
chlamydia, mycoplasma pneumoniae, vibrio choloerae, plague due to yersinia pestis, severe acne, influenzae, klebsiella
kidney, extensively metabolised in liver before excretion
what are the mechanisms of resistance to tetracyclines
- efflux pumps
- ribosomal protection through synthesis of Tet(O) and Tet(M) proteins which dislodges tetracycline from 30S subunit
what are the adverse effects of tetracyclines
- gastric discomfort (take on empty stomach, drink plenty of fluids, do not take right before bed)
- effects on calcified tissues (discolouration of teeth, temporary stunting of growth)
- hepatotoxicity
- phototoxicity
- vestibular dysfunction (dizziness, vertigo, tinnitus esp with minocycline)
- renal (less renal toxicity with doxycycline)
- superinfection due to prolonged use (like CDAD, pseudomembranous colitis)
what are the c/i for tetracyclines
not for pregnant or breastfeeding or children <8, extra caution for patient with myasthenia gravis
what is myasthenia gravis
chronic autoimmune neuromuscular disease
what are the ddi for tetracyclines
enhances effects of sulfonylureas which can cause hypoglycemia
enhances effects of digoxin, lithium and theophylline which have narrow therapeutic index
decrease effectiveness of oral contraceptives
enhances effect of oral anticoagulant warfarin
which class is tigecycline derived from and what structure is it similar to
derived from tetracycline, structure similar to minocycline
how is tigecycline’s activity affected due to molecular alterations from minocycline
route, indication, csf, excretion
IV (poor oral F)
MRSA, MDR strep, VRE, ESBL (carbapenem resistant strains), complicated skin or skin structure infections, intra abdominal, CAP, not active against pseudomonas and proteus
10% in uninflamed meninges
not extensively metabolised, primarily cleared by biliary or fecal, no renal dose adjustments but yes hepatic adjustments
is tigecycline good for blood stream infections why
no it penetrates well into tissues but have low plasma conc
what is the moa of aminoglycosides
diffuse through aq porin channels in outer membrane of gram neg bacteria and is transported across the inner membrane by active transport which is energy dependent and requires aerobic conditions and can be enhanced by beta lactams -> distorts structure of ribosomes by binding to them and blocks formation of initiation complex -> causes misreading of codons as wrong amino acyls tRNAs can bind to A site without matching the codon of mRNA present at that site -> inhibit translocation
what is the activity of aminoglycosides
rapidly bactericidal and concentration dependent killing with PAE
why are aminoglycosides rapidly bactericidal
largely cationic which affects cell membrane by causing fissures in cell membrane to form
what is the type of activity of aminoglycosides
rapidly bactericidal and conc dependent killing with PAE, less effective in anaerobic environment
what is the spectrum of activity for aminoglycosides
broad spectrum against gram pos and gram neg
what are the indications for aminoglycosides
aerobic gram neg (enterobacter - klebsiella, ecoli; MDR pseudomonas and acinetobacter and TB), aerobic mycobacteria, aerobic gram pos with beta lactams
freq used for empiric therapy for serious infections (septicemia, complicated uti, nosocomial resp tract infections) -> usually discontinued once causative microbe identified
what is the rationale behind administering aminoglycosides with beta lactams
- to expand empiric spectrum of activity to ensure presence of at least one drug against a suspected pathogen
- for synergistic bacterial killing
- prevent emergence of resistance to individual agents
what is the distribution of aminoglycosides
penetration into most body fluids variable
low distribution into fatty tissue -> dosing based on lean body mass and not total body weight
csf conc low even in inflamed meninges
can cross placenta barrier and cause accumulation in fetal plasma and amniotic fluid
what are the drugs that are aminoglycosides
gentamicin, tobramycin, amikacin, streptomycin, neomycin
route, indication and excretion for gentamicin
IV, IM, IT, ophthalmic, topical
gram pos cocci (but not mono abx)
serious gram neg bacilli
gram neg enterobacteriaceae (klebsiella, pseudomonas, proteus) with penicillin/ ceftriaxone
gram pos enterococcal endocarditis
route, indication and excretion for gentamicin
IV, IM, IT, ophthalmic, topical
gram pos cocci (but not mono abx)
serious gram neg bacilli
gram neg enterobacteriaceae (klebsiella, pseudomonas, proteus) or MDR gram neg with penicillin/ ceftriaxone
gram pos enterococcal endocarditis with penicillin
renal, excreted unchanged in urine, renal dose adjustments required
route, indication and excretion for tobramycin
IV, IM, inhalation, ophthalmic, ointment, solution
pseudomonas (along with anti pseudomonal abx)
ineffective against mycobacteria
poor activity against enterococci with penicilin
renal excreted unchanged in urine, renal dose adjustments required
route, indication and excretion for amikacin
IV, IM, IT
gram neg pseudomonas, proteus, gentamicin resistant ecoli and klebsiella
gram pos enterococci (but less effective than gentamicin)
mycobacterium TB
renal, excreted unchanged in urine, renal dose adjustments required
route, indication and excretion for streptomycin
IM
enterococcal endocarditis with penicillin if resistant to gentamicin
with other abx for mycobacterial diseases
plague by yersinia pestis
renal, unchanged in urine, renal dose adjustments required
route, indication and excretion for neomycin
PO, topical
klebsiella, e coli
staph aureus, enterococci faecalis
topical for skin infections, oral for bowel prep for surgery
97% unchanged in feces
which aminoglycoside has the widest spectrum of activity
amikacin
which aminoglycoside is the most toxic
neomycin
what are the c/i for neomycin
hypersensitivity to neomycin or other aminoglycosides, intestinal obstruction, ulcerative GI disease
why is neomycin not given parenterally
severe nephrotoxicity
what are the adverse effects of aminoglycosides
ototoxicity, nephrotoxicity, neuromuscular paralysis, hypersensitivity
why can aminoglycosides cause ototoxicity and what are the risks between the different aminoglycosides
streptomycin: ++ for vestibular, + for cochlear
gentamicin: ++ for vestibular, + for cochlear
amikacin: + for vestibular, ++ for cochlear
abx can accumulate in endolymph and perilymph of inner ear, deafness may be irreversible
why can aminoglycosides cause nephrotoxicity
retention of aminoglycosides by proximal tubular cells disrupts calcium mediated transport process thus leading to kidney damage
why can aminoglycosides cause neuromuscular paralysis
rapid increase in conc or concurrent administration with neuromuscular blockers
which aminoglycoside can cause hypersensitivity
topical neomycin can cause skin rash and contact dermatitis
what should you monitor when using aminoglycoside
avoid/ limit use if renal impairment, hearing defects, myasthenia gravis
avoid/ limit use with other nephrotoxic drugs like amphotericin B, vancomycin, NSAIDs, neuromuscular blockers
TDM
renal function tests (urea, Cr, electrolytes)
what are the factors predisposing to nephro and ototoxicity
dose, duration more than 5 days, other nephrotoxic drugs, age, genetic
what are the mechanisms of resistance to aminoglycosides
- efflux pumps
- gram neg bacteria producing aminoglycosides inactivating enzymes
- alteration of 30S subunit by bacteria
- inhibition of aminoglycoside uptake by bacteria
what is the moa of macrolides
inhibits protein synthesis by reversibly binding to the 50S ribosomal unit and inhibit translocation step as the nascent peptide chain at A site of the transferase reaction cannot move to peptidyl donor (P) site
what are the drugs that are macrolides
erythromycin, clarithromycin, azithromycin
what are the structural modifications of the macrolides and what is the benefit
clarithromycin is the methylated form of erythromycin
azithromycin has a 15C lactone ring with added methylated N group which reduces the inhibitory effect on cyp
structural modifications to clarithromycin and azithromycin from erythromycin improves acid stability, tissue penetration and broadens the spectrum of activity
what are the indications for macrolides
alternative to penicillin if allergy to beta lactams, atypical microbes (legionella, mycoplasma, chlamydia), resp tract infections (CAP), diphtheria, h pylori, mycobacteria
what are the implications of inhibitory effects on cyp
give rise to ddi
what is the absorption of macrolides affected by
absorption of erythromycin and azithromycin affected by food (given with or after food)
what is the distribution of macrolides like
distribute to most body tissues, poor cns penetration, azithromycin has higher distribution in phagocytes than plasma
route, indication, distribution, excretion of erythromycin
IV, PO (destroyed by gastric acid, either enteric coated or esterified)
gram pos, gram neg, atypicals, strep pneumoniae
diffuse readily into intracellular fluids except csf, increased penetration wit inflammed meningitis
hepatic metabolism, excreted in bile
limitation of erythromycin
no effect on fungi, yeast, virus
route, indication, distribution, excretion of clarithromycin
PO
gram pos, gram neg, atypicals (legionella, pylori), mycobacteria
extensive tissue distribution, conc higher in tissues than in serum
hepatic metabolism, excreted in bile and urine
benefits of clarithromycin
most active out of the three macrolides against gram pos, gram neg and mycobacterium
more effective against atypicals compared to erythromycin
wider spectrum than penicillin (all three are common substitutes)
better GI tolerance as stable in stomach acid and readily absorbed
limitations of clarithromycin
no effect on fungi, yeast, virus
route, indication, distribution, excretion of azithromycin
PO
atypicals, CAP due to influenzae and moraxella catarrhalis, STD due to chlamydia or gonorrhoea, common bacterial enteric pathogens (campylobacter, shigella, salmonella, vibrio cholerae)
extensively distributed in tissues, higher drug conc in tissue than plasma
excreted in bile, unchanged in feces
benefits of azithromycin
more stable in stomach acid and more readily absorbed
wider spectrum than pencillin (all three are common substitute)
limitations of azithromycin
no effect on fungi, yeast, virus
what are the adverse effects of macrolides
- GI distress and motility (less with azithromycin and clarithromycin due to structural modifications)
- hepatotoxicity
- ototoxicity (transient deafness assoc with erythromycin, irreversible sensorineural hearing loss with azithromycin)
- QT prolongation
what is the c/i for macrolides
hepatic dysfunction as erythromycin and azithromycin can accumulate in liver
can macrolides be used in pregnancy
yes
erythromycin and azithromycin category B, clarithromycin category C
used for chlamydia, gonorrhea, gram pos urti, premature rupture of membranes, cases of beta lactamase allergy
what are the ddi of macrolides
interfere with cyp and inhibit hepatic metabolism which can result in toxic accumulation (warfarin, digoxin, corticosteroids)
what are the mechanisms of resistance to macrolides
- increased efflux pumps (pump out after abx enters cell but protein synthesis unaffected)
- acquisition of erm gene which results in ribosomal methylation which alters 50S subunit
what is clindamycin ineffective against
gram neg aerobes
what are the indications for clindamycin
gram pos (MRSA, streptococcus, penicillin resistant anaerobes), alternative to penicillin, anaerobic infections of skin and soft tissues (bacteriodes, clostridiodes), acne vulgaris, bacterial vaginosis
what is the moa of clindamycin
bind exclusively to 50S ribosomal subunit
what happens if clindamycin given with macrolides like erythromycin
binding of clindamycin occurs close proximity to erythromycin which means can antagonise each others actions and cross resistance due to erm methylases can also occur
route, distribution, excretion of clindamycin
IV, PO with very good F, topical solution/gel/lotion, vaginal cream
distributes well into all bodily fluids including bones, poor csf penetration, excellent bond and salivary gland penetration
hepatic metabolism, excreted as bioinactive metabolites
what are the c/i of clindamycin
UC, pseudomembranous colitis
what bacteria is always resistant to clindamycin
clostridiodes difficile
what are the adverse effects of clindamycin
esophageal irritation, GI effects (D/V), skin rash, CDAD
how to manage esophageal irritation caused by clindamycin
take with a full glass of water, avoid taking before bed
what are the mechanisms of resistance to clindamycin
- alteration of 50S subunit by AA substitution
- alteration in 23S ribosomal RNA unit by methylation of erm gene
what is the difference between clindamycin and macrolides in terms of efflux pumps
clindamycin is not a substrate for efflux pumps
what is linezolid mostly used for
treatment of MDR strains
can linezolid be used for gram neg and why
no because the gram neg bacteria are intrinsically resistant to linezolid as the efflux pumps will remove them faster than it can accumulate
what are the indications for linezolid
gram pos (staphylococcus, streptococcus, enterococcus, listeria monocytogenes), strains that are resistant to other agents like MRSA, VRE, VRSA, penicillin resistant, MDR gram pos cns infections
route, distribution and excretion of linezolid
IV, PO with good F (well absorbed after oral administration can take without regard to food)
widely distributed throughout body, good csf penetration
metabolised via nonenzymatic oxidation into two inactive metabolites, 80% of dose in urine, no renal or hepatic dose adjustments
what are the adverse effects of linezolid
- GI effects (N,D, headache, rash)
- bone marrow suppression (>10d use can cause thrombocytopenia, monitor blood counts)
- serotonin syndrome
- irreversible peripheral neuropathies and optic neuritis (>28d use)
what are the c/i of linezolid
not for treatment of catheter site infections or blood stream infections, not within two weeks of MAOIs, avoid tyramine rich food and serotonergi drugs
what are the mechanisms of resistance to linezolid
mutations in 23S RNA unit
why does linezolid cause serotonin syndrome and what can be done
linezolid possess nonselective monoamine oxidase inhibitory activity and this will occur if given concomitantly with selective serotonin reuptake inhibitors or MAOi, condition is reversible if discontinue drug and avoid tyramine and histamine rich food as can affect adrenergic pathways
what are examples of tyramine rich foods
aged cheese, cured/ smoked meats, draft beers, fava beans, soy products
