Antimicrobials - Cell Wall synthesis inhibitors Flashcards
CW synth inhibitor generalizations
- maximum selective toxicity (inhib peptidoglycan synth and X-linking)
- inhibit Gram +++»_space; Gram - bc gram + more dependent on peptidoglycan for cell structure integrity
- narrow or extended spectrum
- bactericidal in general –> lysis
- poor penetration of BBB
- oral admin
- renal clearance
Beta lactamase
-multiple types, enzyme outside cell wall, evolved to destroy antibiotic agents
differences b/t gram + / gram - CW
gram + has an inner plasma membrane, outer layer of peptidoglycan with beta lactamases on outside of CW
gram - has an inner and outer phospholipid membrane, in between is peptidoglycan layer. beta lactamases surround peptidoglycan layer
porins
membrane PRO that allow drugs in
Penicillin binding protein
membrane PRO responsible for tansglycosylation and ranspeptidation of peptidoglycan
fosfomycin MOA, PK, spectrum, resistance, toxicity
- structural analog of phosphoenol pyruvate, blocks step 1 PDG synthesis
- well absorbed and distributed, excreted unchanged in urine
- broad spectrum
- rapid resistance
- few adverse effects: diarrhea, vaginitis
fosfomycin uses
single dose oral rx of uncomplicated UTI caused by E faecalis and E coli
D-cycloserine MOA, PK, spectrum, toxicity
MOA: structural analog of D-alanine, blocks step 2 of PDG synthesis
PK: oral, good CNS penetration, active form in urine
-broad spectrum (both gram neg and positive)
-serious CNS effects, dose related and reversible
D cycloserine use
restricted second-line M tuberculosis drug
bacitracin MOA, PK, spectrum, SE
-depletes lipid carrier to PDG synthesis (interferes with recycling of lipid carrier)
-PK: topical application only, poorly absorbed
-narrow spectrum (gram +, neisseria, T. pallidum)
SE: severe nephrotoxicity
-bactericidal
bacitracin uses
skin and ophthalmologic infections, good in combination w polymixin B (membrane inhibitor)
vancomycin structure & MOA
-glycopeptide
-binds D-Ala-D-Ala terminus of pentapeptide
-blocks PDG synthesis by binding the substrate**
rapidly bactericidal for dividing bacterial cultures except enterococci (static)
vancomycin PK
- IV admin (slow) [not IM except intestinal infection]
- rarely oral d/t poor absorption
- distribution excelling (bone, CNS if meninges inflamed)
- renal excretion
vancomycin spectrum
- narrow
- gram + microbes, most MRSA
2 mechanisms of resistance to vancomycin
- VRE: enterococci can have vanA, vanB, or van C genes (can be transferred b/t cell organisms), bacteria make diff cell wall subunits with reduced binding to vanco
- VRSA: S. aureus overexpresses D-Ala-D-Ala
vanco SE
red man syndrome
-ototoxicity and nephrotoxicity
vancomycin clinical uses
-reserved for serious gram + infections resistant to other less toxic drugs as determined by lab culture and sensitivity tests
-MRSA
-po for antibiotic associated C diff
-penicillin resistant S. pneumonia
combination with aminoglycosides = synergistic`
beta lactam antibiotic categories
PCN
cephalosporins
carbapenems
monobactams
structure of beta lactams
-all have B lactam ring (amide in 4 sided ring)
beta lactam antibiotics generalizations
1- inhibitis transpeptidases (PBP)
- activate autolytic enzymes in CW
- bactericidal : bacteria must be dividing
- time dependent action (takes awhile to work)
- R amino groups have pharmacologic properties
beta lactam antibiotics PK
various route of admin
- will distribution except in CNS
- renal excretion unmetabolized (except nafcillin, imipenim)
spectrum beta lactam
gram + aerobes, csme gram - cocci and stones
beta lactam resistance
- production of beta bactamases/peniucillinases
- alteration of targaret PFP (decreased affinity for job)
- alteration of outer membrane PRO, prevents drug from meeting PBP (gram neg)
- increased efflux pump activity
beta lactam SE/toxicity
- allergy (1-10%) of patients, cross sensitization to chemically related drugs not as much as previously thought
- acute/anaphylactic; accelerated shock (30 mins to 2 days), delayed (2 or more days after admin, mild/reversible rash [80-90%])
- minimal toxicity, maximal selective toxicity
- tissue irritation, phlebitis with IV admin
- can lead to super infections
PCN G PK
-short half-life
-acid-labile, parenteral admin**
2 repository forms for IM injections**
PCN V PK
- short 1/2 life, dosing 4 x per day
- acid stable (better oral bioavailability)
- oral admin, absorption 65%
PCN G & V spectrum
- gram + and gram - cocci
- not most gram neg rods/anaerobes
PCN G & V SE
allergies
- stevens-Johnson syndrom
- pcn g: dose dependent neurotox and seizures
clinical uses of PCN G & V
- S. PNA (many resistant)
- viridians group strep
- Neisseria meningitidis
- Clostridium
- treponema pallidum
beta lactamase resistant PCN; group includes
**oxacillin, dicloxacillin
PK of beta lactamase resistant PCN
oaxacillin, dicloxacillin
- most are acid stable
- food interferes with absorption
- can be given parenterally
beta lactamase resistant PCN spectrum/clinical use
penicillinase producing staphylococci and streptococci (methicillin sensitive)
beta lactamase resistant PCN resistance
- MRSA (not d/t B lactamsase prod)
- due to PBP with lower affinity for drugs
beta lactamase resistant PCN adverse effects
- few more than PNC G/V
- some cross-reaction allergies
- oxacillin : hepatitis as high doses
PCN extended spectrum drugs: aminopenicillins
PK
ampicillin, amoxicillin
- spectrum extended vs PCN V/G
- can be destroyed by beta lactamase
- used with beta lactamase inhibitors
acid stable, oral admin, amoxicillin > ampicillin absoprtion (amoxi not affected by food)
t1/2 1.5h, BID/TID
PCN extended spectrum drugs: carboxypenicillins
ticarcillin
- spectrum extended vs PCN V/G
- can be destroyed by beta lactamase
- used with beta lactamase inhibitors
- parenteral admin
- antipsuedomonal
- rarely used alone
PCN extended spectrum drugs: ureidopenicillins
- piperacillin
- spectrum extended vs PCN V/G
- can be destroyed by beta lactamase
- used with beta lactamase inhibitors
- parenteral admin
- anti-pseudomonal
- reserved for serious systemic infections caused by klebsiella or psudomonas infections (often in combo with aminolycoside, to prevent resistance)
aminopenicillins spectrum/uses
non-lactamase producing gram - bacilli: E coli, H influenza, salmonella, shigella (PK superior to PCN V)
beta lactamase inhibitors
MOA
calvulanic acid, sulbactam, tazobactam
MOA: structurally related to PCN, beta lactamase suicide inhibitors (irreversibly inhibit b lactamase)
-poor antibiotic activity alone
-used in fixed concentrations with extended spectrum PCN
augmentin
beta lactamase inhibitor used in fixed concentrations with extended spectrum PCN
-clavulanic acid + amoxicillin
timentin
clavulanic acid & ticarcillin
beta lactamase inhibitor used in fixed concentrations with extended spectrum PCN
cephalosporins
PK
-most widely hospital-rx antibiotics
-similar to PCN in chemical structure and MOA and adverse effects (allergy most common)
4 generation based on spectra of activity
-pk: acidi stability better w 1st gen; not topical application, some orally or IV/IM
cephalosporin bacterial resistance
later gen resistant to beta lactamases
-low affinity PBP, exteded spectrum B lactamases
cephalosporin adverse effects
- overall v safe
- cutaneous allergy, cross-allergy with PCN (not for pt with anaphylaxis to PCN)
- disulfiram-life reaction (antabuse effect) and bleeded d/o with 2nd/3rd gen
- pseudomembranous colitis (CDAC) w 3rd and 4th gen
cephalexin
1st generation cephalosporin
- more acid stability
- broadest spectrum against gram + cocci, effective against gram - bacilli
- prophylaxis against bacterial endocarditis in PCN-allergic pt
cefuroxime
2nd generation cephalosporin
- antabuse effect and bleeding d/o s.e.
- only group with significant activity against anaerobes
ceftriaxone
- can cause CDAC, antabuse effect and bleeding d/o
- use: antipseudomonal and penuococcal, serious gram - infections such as meningitis, PNA, gonorrhea
- prophylaxis against bacterial endocarditis in PCN-allergic pt
cefepime
- can cause CDAC
- antipseudomonal
- high resistance to B lactamases, useful to rx enterobacter and PCN-resistant strep
carbapenems
- imipenem and meropenem
- recent synthetic derivatives of natural prod
- have B lactam ring, same mech as PCN/cephs
carbapenems activity and spectrum
- bind more efficiently with PBP than PCN/Cephs
- penetrate outer membrane of gram - bacteria
- broadest activity of all B lactam drugs
- resistant to degredation by most B lactamases, but induce those than inactivate PCN/cephs
- antagonize action of PCN/cephs
- active against extended spectrum b lactamase prod organisms
carbapenems resistance
-alt of PBP, carbapenemases
carbapenems PK
- parenteral admin
- renal metabolisma nd inactivation of imipenem
- admin with cilastatin, inhibits dehydropeptidases, which rapidly dissolves carbapenems
imipenem PK
-admin with cilastatin, inhibits dehydropeptidases, which rapidly dissolves imipenem (primaxin) (not significant problem for meropenem)
carbapenems SE
cross allergenic rxn to PCN may be present
rare: GI effects, superinfections, neurotox
clinical uses of carbapenems
2nd line therapy for serious nosocomial infections
monobactams MOA PK spectrum SE
aztreonam
- binds PBP, relatively resistant to beta-lactamases
- IM or IV, drug penetrates inflamed CNS
- no significant x-reactivity with PCN
spectrum: narrow–gram - aerobes like pseudomonals (not gram + or anaerobes)
uses for monobactams
-gram - UTI, lower RTI, systemic infections
cell membrane agents -MOA PK -Spectrum/uses -SE
- daptomycin
- MOA: novel cyclic lipopeptide, causes membrane depolarization
- pokes holes in cell membranes in presence of Ca
- bactericidal
- PK: IV admin (90% PRO bound)
- renal elim
spectrum: similar to vanco, but rx of VRE/MRSA
- myopathy
Why are mitochondrial ribosomes susceptible to PRO synthesis inhibitors
mitochondrial ribosomes are more like bacterial ribosomes (30 + 50) than mammalian (40 + 60 S)
Where do most PRO synthesis inhibitors work
50S subunit of the mitochondrial ribosome
tetracyclines MOA
- tetracycline, doxycycline, minocycline
- reversible binding to the 30S subunit of the bacterial ribosome
- blocks aminoacyl tRNAs from entering the A site of the ribosome
tetracyclines selective toxicity/spectrum
- affects 70S mitochondrial ribosomes, not cytoplasmic ribosomes
- very broad spectrum
- generally more active against gram + than -
- bacteriostatic
tetracyclines resistance
- decreased intracellular levels from decreased influx or increased efflux (pump)
- expression of PRO that protect ribosomes from drug
- enzymatic inactivation of drug
- widespread resistance has limited clinical use
tetracyclines PK
- absorption: oral admin yields variable absorption, decreased by divalent and trivalent cations (dairy, antacids, iron), decreased absorption when gastric pH is elevated
- distribution: wide, accumulation in liver, spleen, BM, bones, dentine, and enamel of unerupted teeth; good penetration into CNS and crosses placenta
- elim: excretion via kidneys, some passage into small intest via bile; except: doxycycline not eliminated via kidneys, elminated as an inactive chelate or conjugate in feces (reduced GI complications, lesser impact on normal flora)
- minocycline: metabolized by liver, passed in fecces
clinical uses of tetracycline
- acne
- drug of choice for rx of rickettsial diseases
- chlamydia, mycoplasma pneumoniae, yersinia pestis, borrelia (lyme disease)
- periodontitis: systemic tetracyclines for rx of periodontitis may have limited benefit and limited long-term efficacy; weigh against risk of propagating antibiotic resistance and efficacy of mechanical therapy
tetracyclines adverse effects
- GI irritation and superinfections (including CDAC)
- photosensitivity
- hepatotoxicity
- renal tox
- discoloration of teeth (fetal and childhood sisks, should not be given to pregnant women or to children
tetracyclines drug interactions
- may compromise efficacy of bactericidal antibiotics b//c they work best against dividing cells and tetracyclines slow division
- can alter phamacological activity of drugs (digoxin increased absoprtion, warfarin competition for plasma PRO binding)
