1 antibacterials: protein synthesis inhibitors

bacteria ribosomes (70S) consist of:

30S & 50S subunits

what are the antibacterials that work on 30S subunit

"TAG"

- Tetracyclines

- Aminoglycosides

- Glycyclines

what are the Tetracyclines

- vibramycin (doxycycline)

- minocin (minocycline)

- tetracycline

spectrum of activity of Tetracyclines

- aerobic gram + (including MRSA)

- aerobic gram -

- spirochetes

- anaerobes

- atypical (ie chlamydia, mycoplasma, rickettsia_

when do we use tetracyclines

primarily skin-skin, CAP, atypicals

- acne

- skin & soft tissue

- respiratory tract

- STDs

- lyme disease

- rocky mountain spotted fever

- leprosy (minocycline)

MOA of tetracyclines

- enter bacterial cell thru passive diffusion or energy-dependent transport

- 30S subunit binding

- prevents tRNA binding to mRNA-ribosome complex --> inhibition of protein synthesis

bacteriostatic

bioavailability of tetracyclines

~ 100%

- administer 1 hr before or 4 hrs after dairy products & antacids (co-admin decreases abx absorption)

metabolism of tetracyclines

- doxy: eliminated via bile in feces (no hepatic/renal)

- tetra: eliminated unchanged in urine (renal adjust)

- minocycline: hepatic & lesser extent kidneys

adverse effects of tetracyclines

- GI disturbance most common

- phototoxic: wear sun protection

- NOT in preg or breastfeeding women, or kids <8 yo (causes tooth discolor & stunt bone growth)

more rare but severe effects of tetracyclines

- assc w pseudotumor cerebri (intracranial htn)

- dizziness, vertigo, tinnitus (esp minocycline)

- blue-black hyperpigmentation of skin & mucosal membr w minocycline

what are the glycylcyclines

tygacil (tigecycline), IV

spectrum of activity of glycylcyclines

- gram + (including MRSA, MSR Streptococci, VRE)

- gram - (including ESBL enterobacteriaceae)

- acinebacter

- many anaerobes like Bacteroides

when do we use glycylcyclines

- complicated skin & soft tissue infections

- complicated intra-abdominal infections

- BBW: higher treatment mortality (use as last line)

MOA of glycylcyclines

same as tetracyclines!

D--D w glycylcyclines

warfarin

adverse effects of glycylcyclines

- N/V (cannot be relieved w Ondansetron)

- risk for hepatotoxicity

- same concerns as tetracycline

what are the aminoglycosides

- amkin (amikacin)

- garamycin (gentamicin)

- neomycin

- zemdri (plazomicin)

- streptomycin

- tobrex, tobi (tobramycin)

spectrum of activity for aminoglycosides

- monotherapy: gram - only

- combo (gentamycin): w Beta lactam (Vanc or Ampicillin) for enterococcus endocarditis

when do we use aminoglycosides

concern for resistant gram neg infections

- usu in synergy

- only monotherapy ijn UTIs!

MOA of aminoglycosides

- bind to 30S ribosomal subunit: interfere w assembly of ribosomal apparatus --> misread genetic code

batericidal

2 dosing schemes of aminoglycosides

traditional dosing

- multiple, lower doses per day

- will order peaks & troughs

extended interval

- larger doses Q12h or > (usu Q24hr- shortest_

- relies on antibiotic effect

- less nephro/ototoxicity

- easier drug monitoring (w random level)

steps for dosing aminoglycosides

step 1: indication, decide on strategy to dose

step 2: calculate CrCl, identify weight

step 3: calc maintenance dose & frequency

step 4: schedule monitoring- peaks/troughs (traditional) vs random level (extended)

what weight do you use for traditional dosing?

ideal body weight

traditional dosing frequency is determined by...

CrCl

traditional dosing: efficacy

for the kill

- 6-8 for gram - (Tobramycin)

- 3-5 for gram + (Gentamycin)

traditional dosing: troughs

nephrotoxicity

irreversible ____ has been assc with HIGH PEAKS

ototoxicuty

if peaks & troughs are both low:

increase dose

if peaks & troughs are both high:

decrease dose

if peak cannot proportion:

must recalculate

advantages to extended interval dosing of aminoglycosides

larger doses, less frequently (post antibiotic effect)

advantages:

- as efficacious

- less nephrotoxicity/ ototoxicity

- convenient & easy

- reduced cost

when to avoid extended interval dosing of aminoglycosides

- renal dysfunction (CrCl < 30 ml/min or dialysis)

- burns > 20%

- cirrhosis/ ascites

- pregnancy

monitoring extended interval dosing of aminoglycosides

- evaluate a RANDOM level at 10 hours after first dose

urban & craig nomogram is used in ____

obstetrics

- 5 mg/kg

adverse effects of aminoglycosides

- monitor for nephro & ototoxicity (deafness can be irreversible)

- risk of neuromuscular paralysis when given w neuromuscular blockers or when high doses given too quick

- renal dose adjust

what are the drugs that work on the 50S subunit

"CLEan"

- clindamycin

- linezolid

- erythromycin

what are the macrolides

- zithromax, zpak (azithromycin); PO, IV, opthalmic

- biaxin (clarithromycin), PO

- E.E.S, ery-tab (erythromycin); PO, IV, opthalmic, topical

spectrum of activity of macrolides

"Jack of all trades but master of NONE"

- gram +

- gram -

- atypicals

- mycobacteria

- spirochetes

NO MRSA. enterococcus, psedomonas, bactereoides

when do we use macrolides

- AECOPD

- mycobacterium avium complex (opportunistic infection prophylaxis)

- STDs

- whooping cough (not as much URI)

- usu: CAP to cover atypicals (Mycoplasma, PNA)

MOA of macrolides

- irreversibly binds to 50S subunit

- inhibits translocation steps of protein synthesis

- bacteriostatic

D--D with macrolides

- with erythromycin: some interaction w other CYP P450 drugs

- QT prolonging agents (also mainly erythromycin)

adverse effects w macrolides

- GI absorption: diarrhea

- some QT prolongation

- azithromycin hepatically eliminated

what macrolide has the longest half life

- azithromycin, due to tissue accumulation (large volume of distrubution)

discuss opthalmic use of macrolides

- prophylaxis of opthalmia neonatorum (gonorrhea & chlamydia)

what are the oxazolidinones

zyvox (linezolid)

spectrum of activity of oxazolidinones

- gram + including MRSA, VRE !!, & mycobacterium TB

when do we use oxazolidinones

- needing coverage for resistant gram + organisms

- avoid for MRSA bacteremia

MOA of oxazolidinones

- 50S subunit, blocks formatino of 70S initiation complex

- bacteriostatic but bactericidal against Strep spp.

drug--food interactions with oxazolidinones

- combined w high tyramine-containing foods, serotogenic agents, and/or monoamine oxidase inhibitors --> serotonin syndrome

adverse effects of oxazolidinones

- GI upset, diarrhea, nausea

- HA

- rash

- myelosuppression when given extended durations (>2 weeks): monitor CBC weekly

- peripheral & optic neuropathy: when used >28 days; monitor for visual disturbances --> perm blindess

what are the lincosamides

- cleocin (clindamycin); PO, IV, topical

spectrum of activity for lincosamides

- aerobic gram + including MRSA & anaerobes

"clinda ABOVE (gram + anaerobes), metronidazole BELOW (gram - anaerobes)

when do we use lincosamides

- skin & soft tissue infections

- acne

MOA of lincosamides

similar to macrolides!

whats important to test when giving lincosamides/ clindamycin

detest!

- erythromycin can induce resistance to clindamycin

- if + detest... we avoid clindamycin

ADME considerations for lincosamides/clindamycin

- good distribution into bone but poor concentration in CSF

- primarily excreted in bile

- low urinary elimination --> do NOT Use this for UTIs

adverse effects of lincosamides/clindamycin

- diarrhea & pseudomembranous colitis

- take w full glass of water to avoid esophageal irritation

- BBW: common cause of C.diff

- assc w severe skin rxns

what are the chloramphenicol drugs

chloromycetin (chloramphenicol), IV

spectrum of activity of chloramphenicol

- broat spectrum

- gram + including MRSA, enterococcus, gram -, bacteroides, atypicals

when do we use chloramphenicol

rarely used due to toxicity profile

- serious infections when nothing else available

MOA of chloramphenicol

- 50S, peptidyl transferase rxn occurs --> protein synthesis inhibition

- bacteriostatic, but depending on organism can be bacteriocidal

adverse effects of chloramphenicol

- BBW: bone marrow toxicity; do NOT use in pt w G6PD deficiency --> hemolytic anemia

- avoid use in breastfeeding females & neonates

what are the streptogramins

synercid (quinupristin/dalfopristin), IV

spectrum of activity for streptogramins

- gram + including enterococcus faecium (including VRE)

what pathogen is covered by synercid?

- pseudomonas

- Enterococcus fatalis

- proteus

- enterococcus faecium!

MOA of streptogramins

- dalfopristin: interferes w addition of amino acids to peptide chain

- quinupristin: incomplete peptide chains being released

combo is bactericidal

pearls: streptogramins

- must be infused via central line

- 1/4 will experience hyperbilirubinemia (competes w bilirubin excretion)

- 50% experience reversible arthralgias & myalgias

which covers pseudomonas

aminoglycosides

which do NOT cover MRSA

macrolides

aminoglycosides

which are bactericidal

aminoglycosides

streptogramins