Antibacterials II Flashcards
inhibitors of nuclei acid synthesis?
fluoroquinolones
common: ciprofloxin (cipro) levofloxacin (levaquin) moxifloxacin (avelox) gemifloxacin (factive)
double bonded O and COOH are important
fluoroquinolones:
MoA?
killing?
Mechanisms of resistance?
MoA - inhibit DNA gyrase and topoisomerase
- FQ’s form a complex with gyrase and topoisomerase IV, blocking DNA rep, resulting in DNA release, chromosomal disruption and cell death
BACTERICIDAL, CONCETRATION DEPENDENT KILLING!
(bigger doses less frequently)
mechanism of resistance: altered target site, efflux
fluroquinolones:
spectrum?
uses?
PK/PD?
spectrum - BROAD! (gram +, gram -, atypicals, TB)
Uses - RTI, UTI/prostatitis, GI, osteomyelitis, anthrax, TB
PK/PD - excellent oral absorption, tissue penetration (IV to PO switch)
- Al, Mg, Ca, Fe, Zn impair absorption (di/trivalents)
Fluroquinolones:
adverse SE - regular?
black box? (3)
GI: n, loose stools, altered taste
CNS: HA, lightheadedness, dizziness, nervousness, insomnia
Skin: photosensitivity
Black box:
- tendonitis/rupture, peripheral neuropathy, dysglycemia (blood glucose), QTc prolongation
- generally not recommended in children <18 yr or pregnant women unless benefit is greater than the risk (damage growing cartilage and cause arthropathy - disease of the joints)
- FDA (2016) should be reserved for complicated infections
Inhibitors of 50s ribosomal subunit
- MACROLIDES (erythromycin, clarithromycin, AZITHROMYCIN, fidamicin); Ketolids (telithromycin)
- OXAZOLIDINONES (LINEZOLID, TEDIZOLID)
- LINCOSAMIDES (CLINDAMYCIN)
- CHLORAMPHENICOL
- streptogramins (quinopristin-dalfopristin)
inhibitors of the 30s ribosomal subunit
-AMINOGLYCOSIDES (GENTAMICIN, TOBRAMYCIN, amikacin, streptomycin, plazomicin)
- TETRACYLCINES (tetracycline, DOXYCYCLINE, minocycline, omadacycline (2018), sarecycline (2018)
- glycylcyclines (tigecycline)
chloramphenicol, macrolides, clindamycin, and streptogramins bind to the 50s subunit and block…
peptide bond formation!!
the tetracyclines and aminoglycosides bind to the 30s subunit and prevent….
binding of the incoming charged tRNA unit!
macrolides/ketolides structure is a ….
important one?
macrocyclic lactone ring!
ex. azithromycin (zithromax)
Macrolides inhibit protein synthesis…
killing?
usually bacteriostatic, concentration-independent killing; anti-inflammatory
block elongation and exit of peptides from 50s ribosomal subunit tunnel; produces a defective intermediate, unable to fold correctly
macrolides resistance…
low level?
high level?
low level - efflux pump
high level - target site modification
macrolides spectrum?
BROAD
gram +, neisseria, treponema
drug of choice for atypicals!!!! (mycoplasma, legionella, chlamydia)
**good for intracellular bad
macrolides pharmacology?
erhythromycin - many formulations; erratic absorption, acid labile, excreted in bile; take EMs with food to decrease GI upset
clarithryomycin, azithromycin - better absorbed, higher tissue levels and longer half life!!!!
clinical use of macrolides?
ALTERNATIVES IN PREGNANCY AND PEN ALLERGY!!!
STI - CHLYAMYDIA (azithromycin), gonorrhea!!!!
RTI - phyrungitis, otitis, CAP (azithromycin)!!!!
Treating gastroparesis - stimulates motilin receptors
Macrolide adverse effects?
GI - higher than most classes!!
- erythromycin - 50% have bloating, cramping, n, d
- somewhat less with clark-, lowest with azithromycin
MAY INCREASE QTc INTERVAL! - torsades, block cardiac K+ channels
erthyromycin drug interactions?
VERY POTENT CYP 3A4 INHIBITOR!
(theopylline, warfarin, triazolam, carbamazepine, cyclosporine, simvastatin, lovastatin, sildenafil, many others)
- erthyromycin > clarithromycin > azithromycin
- few or no drug interactions with azithromycin!!!
oxazolidinones (linezolid [zyvox, IV/PO]; tedizolid [sivextro, IV/PO])
relevant chemistry? MOA? Killing? spectrum? therapeutic use?
Relevant chemistry - totally synthetic; originally developed as a MAOI
MoA - inhibits early protein synthesis at initiation complex
- primarily BACTERIOSTATIC, TIME DEPENDENT KILLING
spectrum - narrow (gram +)
use - alt to vanco for MRSA; also used for VRE (vanco resistant enterococci)!!!!!
linezolid and tedizolid (oxazolidinones) Adverse side effects?
GI (most common)!!!
SKIN RASHES - dose related
hematologic (cytopenias; weekly CBC)
neuropathy, optic neuritis
SEROTONIN SYNDROME: a few cases in pts on SSRIs ANTIDEPRESSANTS due to inhibition of MAO by linezolid (FDA WARNING!)
Lincosamides ex.?
clindamycin
lincosamides: clindamycin MoA? killing? MoR? Spectrum?
MoA - binds to 50s, inhibits protein synthesis
BACTERIOSTATIC, TIME-DEPENDENT!
MoR - altered target, decreased binding, efflux
spectrum - BROAD. ; gram positive anaerobes
common uses of lincosamides (clindamycin)
SKIN, SOFT TISSUE, BONE (HIGH BONE LEVELS), INHIBITS TOXIN PRODUCTION
alternative in PEN-ALLERGY!
toxoplasmosis, pneumocytosis
topical for acne, rosacea
adverse effects of lincosamides (clindamycin)
diarrhea, C.diff colitis
hypersensitivity, rash
chloramphenicol Moa? killing? spectrum? therapeutic uses? PK?
Moa: reversibly binds to 50s ribosomal subunit preventing aa from being transferred to growing peptide chain
bacteriostatic for most
BROAD SPECTRUM! many trap +, - aerobes, anaerobes
use - alt in drug allergy!!! (meningitis, brain abscess)
PK - metabolism - extensive hepatic glucoronidation!! drug interactions too
serum monitoring - therapeutic - 15-20 ug/ml
chloramphenicol adverse effects? (3)
- reversible bone marrow suppression (anemia, leukopenia, thrombocytopenia) - concentrations >25 ug/ml
- aplastic anemia
idosncratic - NOT CONCENTRATION RELATED!
may occur weeks to months after completing therapy - CBC twice weekly! - Gray Baby syndrome!!!
- circulatory collapse, cyanosis, acidosis, myocardial depression, coma, death
- newborns lack effect glucoronic acid conjugation mechanisms to metabolize; associated with serum lvls >50ug/ml
aminoglycosides ex.?
gentamicin tobramycin amikacin streptomycin plazomicin
aminoglycosides chemistry?
bacteriocidal!
hexose ring with various amino sugars attached by glycosidic bonds
water soluble, polar
active in alkaline pH (put pus is acidic)
aminoglycosides MoA? killing? MoR? spectrum?
MoA - irreversibly binds to 30s ribosome
RAPIDLY CIDAL, CONCENTRATION DEPENDENT KILLING WITH LONG PAE - post antibiotic effect?
MoR - enzyme modification, altered 30s efflux
spectrum - primarily gram neg; SYNERGISTIC ACTIVITY with cell wall agents for GRAM POS!
aminoglycosides... kinetics? dosing (normal renal)? monitoring? uses?
kinetics: poor absorption, limited tissue, distribution, not metabolized, 100% renal elimination
dosing (normal renal): high dose, extended interval
REQUIRES SERUM CONCENTRATION MONITORING
uses: mainly in combination with other agents:
severe gram neg infections, synergy with gram pos infections, TB!
aminoglycoside toxicity (3)
- nephrotoxicity!!
- ACCUMULATION IN THE PROXIMAL TUBULE (SATURABLE)
- USUALLY GRADUAL, MILD, REVERSIBLE
- INCREASE IN SCR OR TROUGH ACCUMULATION AFTER 5-7 DAYS
- requires dosage modification or d/c
- increased risk with other nephrotoxins - ototoxicity
- 8th nerve damage, destruction of type II hair cells
- VESTIBULAR (vertigo, ataxia) and HEARING (high frequency initially)
- irreversible - NEUROMUSCULAR BLOCKADE!
- associated with rapid, bolus infusion in post surgical pts, neonates (calcium salts can reverse)
tetracyclines and glycylcyclines
primary agents?
new in 2018?
primary agents: tetracycline, DOXYCLCINE, minocycline, TIGECYCLINE
New in 2018: eravacycline, omadacycline, sarecycline
tetracyclines and glycylcyclines
MoA? killling? spectrum? active against what? uses?
MoA:
- bind to 30s ribosome, blocking formation of the initiation complex (same as amino glycosides)
- tigecycline has 5 fold > binding to overcome resistance, not a substrate for efflux pump!
bacteriostatic, time dependent!!
BROAD SPECTRUM!
Tigecycline and new 2018 ervacycline and omadacycline active against many MDR isolates!!
uses: MANY TICK BORNE INFECTIONS!, travelers diarrhea, RTI, STI
tetracyclines and glycylcyclines AE?
GI: n/d, epigastric distress
PHOTOSENSITIVITY
CONTRAINDICATED IN CHILDREN <8YR, PREGNANCY, BREAST FEEDING
- gray-brown to yellow discoloration of teeth and enamel hypoplasia in children; retards bone growth!!!!
TIGECYCLINE BOXED WARNING (2013) - INCREASED RISK OF DEATH!!!
tetracycline and glycylcyclines: drug interactions
Ca, Mg, Al, Fe, NaHCo3, dairy products impair absorption!! (separate doses by > 2h)
MAY DECREASE THE EFFECTS OF ORAL CONTRACEPTIVES!
may potentiate effects of oral anticoagulants
Sulfonamides and trimethoprim (a pyrimidine) are inhibitors of what?
killing???
blocks what?
folate inhibitors
synergisitc, bacteriacidal combination (NEVER USED ALONE! STATIC AND GREATER RESISTANCE)
BLOCKS PURINE PRODUCTION AND NUCLIC ACID SYNTHESIS!
sulfonamides and trimethoprim…
spectrum?
use?
broad spectrum:
many gram pos, neg, pneumocystis, atypical mycobacteria, plasmodium, toxoplasma
common use - UTI!
trimethoprim/ sulfamethoxazole…
PK?
excellent absorption widely distributed hepatic metabolized (acetylation, glucuronidation) long half-life
trimethoprim/ sulfamethoxazole…
ADR?
Warning?
drug interactions?
ADR:
- GI, SKIN (rash, urticaria, photosensitivity)
- hypersensitivity (stevens-johnson, TEN)
- hematologic (bone marrow suppression)
- renal (hyperK+, AKI - acute kidney injury)
WARNING:
- should NOT be used in 3rd trimester or newborns (KERNICTERUS)
- bilirubin displacement from plasma proteins leading to brain damage
drug interactions: CYP 2C8/9 INHIBITOR!
-may increase effects of sulfonylureas, warfarin, anticonvulsants, cyclosporine, methotrexate
nitrofurantoin
MOA?
resistance?
spectrum?
indications?
moa - inhibits several enzyme systems, including acetyl coA, inhibiting metabolism
resistance - low
spectrum - PRIMARILY GRAM NEG!! (E.COLI)
indications - UTI (CYSTITIS)
nitrofurantoin
PK?
WELL ABSORBED! (macrodantin)
- MACROCRYSTALS ABSORBED SLOWER, ALLOWING FEWER GI EFFECTS!
- renal dose adjustment - do not use CrCl <40ml/min
- Mg-containing antacids decrease absorption!!
nitrofurantoin
ADR?
- GI
- RASH
- PULMONARY (<1/100,000)
acute pulm: REVERSIBLE HYPERSENSITIVITY phenomenon
gradual onset of nonproductive cough, dyspnea, interstitial infiltrates on CXR; possible eosinophilia
rapid improvement after drug D/C
chronic pulm: S/Sx similar to acute occurs after 1-6 mos of therapy usually improvement after drug D/C IRREVERSIBLE FIBROSIS, FATALITIES HAVE OCCURRED (VERY RARE)
fluoroquinolones common SE?
GI
CNS stim
photosensitivity
warning - cartilage malformation, tendon rupture, neuropathy, prolonged QT, drug interactions
macrolides common SE?
GI
warning - prolonged QT
drug interactions
lincosamides (clindamycin) common SE?
GI
chloramphenicol common SE?
anemia (conc-related and idiosyncratic aplastic anemia)
bone marrow suppression
gray baby syndrome
oxazolidinones (linezolid) common SE?
GI
CNS
myelosuppression
aminoglycosides common SE?
nephrotoxicity, ototoxicity
tetracylces/glycylcyclines common SE?
GI rash/allergy photosensitivity superinfection warning! not in children - athropathy (disease of joints), teeth discoloration, drug interactions
sulfonamides common SE
GI rash/allergy photosensitivity myelosuppression warning!! do not use in third trimester or newborns, drug interactions
nitrofurantoin common SE?
GI
rash
pulmonary
