Cell Wall Inhibitors Flashcards
Penicillin G & V spectrum
Gram (+) microbes have the greatest activity
gram (-) cocci -> not as good because need to get through cell wall where B-lactamase is waiting
and non-B-lactamase producing anaerobes
Susceptible to B-lactamase activity
B-lactamase resistant penicillins spectrum
Nafcillin, Dicloxacilliin
Against Strep, staph, pneunmococci
No activity against enterococci and anaerobes or gram (-) rods or cocci
Aminopenicillins and extended spectrum penicillins
amoxicillin, ampicillin
similar to penicillin in spectrum
BUT WITH GREATER ACTIVITY AGAINST GRAM (-)
often with B-lactamase inhibitors like clavulanic acid (increases the activity of the abx)
Indication and drug of choice for Penicillin G
Streptococci, Meningococci, PEN- susceptible pneumococci
for Antrax, diptheria, C. difficile, syphillis, meningitis
Indication and drug of choice for Penicillin V
Poor availability -> mild infections
Step. A,C,G (pharyngitis and tonsilitis)
PEN -sensitive S. pneumonaie
Clinical uses for Nafcillin and Dicloxacillin - B-lactamase resistant
Penicillnase producing staph,
MSSA - methicillin susceptible s. aureus
prosthetic valve infection
Aminopenicillins - ampicillin and amoxicillin
drug of choice for pneumococci
shigella and other GI infections
Gonorrhea
Respiratory infections
Ticarcillin, Piperacillin, Azlocillin - extended spectrum
drug of choice for pseudomonas also for shigella and other GI bone and joint infections skin infections also used for lower respiratory and UTI where access is difficult
MoA of penicillins and cephalosporins
Inhibit transpeptidase PBP1a and PBP1b -> prevents D-ala removal on the 5th position
Absorption of Pen G
IV or IM because unstable in gastric acid - destroyed
Absorption of Nafcillin, ticarcillin, piperacillin
IV or IM because poor GI absorption
Pen V, Dicloxacillin, Ampicillin: special consideration when administered
can be given orally but food interferes with absorption
Elimination of Penicillin drugs
All unchanged in the urine Rapid elimination (30mins- 1.5hr) All except for amoxicillin have some biliary excretion Ticarcillin and piperacillin: biliary excretion is increased with renal deficiency
AE for penicillin drugs
Common:
NVD (increased risk with amoxicillin), Allergic reactions, phlebitis- inflammation of veins (Ticarcillin and piperacilin)
Rare:
neutropenia (pen G, nafcillin, piperacillin)
CNS effects (confusion, seizures)
Hyperkalemia (pen G K+)
dizziness, tinnitus, headache (Pen G procaine)
Special considerations for Penicillins
Increased risk of rash with amoxicillin with allopurinol
Pen G and V decrease effectiveness of birth control pills
Colestipol (cholesterol) decrease Pen V absorption
Probenecid (gout) increases plasma levels with pen G and V
Cephalosporins First generation
very active against gram (+) aerobic cocci Pen-sensitive staph and strep NOT active against enterococci little g(-) Cefazolin Cephalexin
Cephalosporins Second generation
active against g(+) aerobic cocci but not as much as 1st gen but has better g(-) mouth but not GI anaerobes Loracarbef Cefonicid cefaclor cefuroxime cefprozil cefazolin (parenteral)
3rd generation cephalosporin
inferior to 2nd and 1st for g(+) good against g(-) broad coverage of enterobacteria NO GI anaerobes cefixime cefotaxime Cefoperaxone (doesn't go to CNS & biliary excretion) Ceftriaxone (biliary excretion- reversible obstructive toxicity)
4th generation cephalosporin
less potent than 1st gen but more than 3rd gen against g(+) EXCELLENT against g(-)
better than 3rd gen!
cefeprime
Cephamycins
Cefoxitin
not “true” 2nd generation
less active against G(+) cocci
CAN GO AGAINST SOME ENTEROBACTERIA
Used: anaerobic/aerobic infections of the skin/ soft tissue
intra-abdominal or gynecological surgical prophylaxis
Clinical use of first generation cephalosporin
uncomplicated, community acquired skin and soft tissue infections and UTI
respiratory infection by PEN sensitive bacteria
surgical wound prophylaxis (parenteral)
Clinical use of 2nd generation cephalosporin
community acquired respiratory infection
uncomplicated UTI by E.coli
clinical use of 3rd generation cephalosporin
hospital acquired gram (-) infections
all kinds of complicated community acquired infections
lyme disease, severe shigella, typhoid fever
clinical use of 4th gen cephalosporin
moderate to sever nosocomial acquired infections
uncomplicated and complicated UTI, skin and soft tissue infections
Pneumonia bacteremia
MoA of cephalosporins
inhibit transpeptidase PBP1a, 1b, PBP3
Ceftobiprole Medocarila
broad spectrum cephalosporin derivative
high affinity for PBP2a for MRSA and PBP2x for resistant strep.
knocks everything down
T1/2 for 1st gen & 4th gen cephalosporins
1-2 hours
4th gen readily penetrate the CNS
T1/2 for 2nd gen & 3rd gen cephalosporins
wide range: 1-8hr
AE for cephalosporins:
Common: NVD, allergic rxns
ceftrioxone - reversible obstructive excretion
Rare: blood cell problems, granulocytopenia (bone marrow suppression), renal tubular necrosis (most are excreted through the kidneys)
Special considerations for cephalosporins
MTT (methytetrathiazole) increased effects of warfarin.
alcohol intolerance because acetaldehyde dehydrogenase
increased nephrotoxicity with ahminoglycosides
probenecid (gout) increase plasma levels
milk protein hypersensitivity
B-lactamase inhibitors
not used separated because have weak abx activity- potent inhibitors of B-lactamases
Drugs:
Clavulinic acid
Sulbactam
Tazobactam
Restore the abx properties of aminopenicillins, piperacillin and ticarcillin.
MoA of B-lactamase inhibitors
covalently bonds with B-lactamases to make table intermediates - > prevents interactions with penicillins
Excretion of B-lactamase inhibitors
they are all excreted in urine Clavulinic acid also secreted as metabolites in lungs and feces sulbactam minor biliary excretion low CNS penetration absorbed in GI tract
names some Carbapenems
Imipenem-cilistatin
Meropenem
Ertapenem
Doripenem
Carbapenem spectrum
broad spectrum - g(-) and g(+) aerobic and anaerobic
better than pen G = better g(+)
not active against MRSA or C.difficile
Use of carbapenem
moderate to severe nosocomial and polymicrobial infections = imipenem, meropenem, doripenem
mild to moderate community acquired infections = ertapenem NOT FOR NOSOCOMIAL
MoA of carbapenems
inhibit PBP activity
affinities for Imipenem: PBP2»PBP1a»PBP3a
Meropenem, Ertapenem: PBP2, PBP3>PBP1a, 1b
Doripenem: high affinity for PBP1a, 1b, PBP2, 3, 4
NO affinity for PBP2a (MRSA) or PBP2x (resistant strep)
Absorption/excretion of Carbapenems
Parenterally - poor stability in GI and poor absorption
Short half life (1hr)
most excreted unchanged in glomerular filtration
How is imipenem excreted?
It is hydrolyzed at the brush borders of renal tubules by dehydropeptidase.
- *must be given with cilistatin (DHPI inhibitor) or else metabolites are NEPHROTOXIC
- also enhances the ability of imipenem
AE of carbapenems
blood and clotting problems with imipenem
seizures with imipenem
okay for pregnancy
special considerations with carbapenems
- cross reactive with other B-lactam abx
- any drug cause causes decrease in glomerular filtration
- increased risk of seizures with imipenem and ganciclovir
- Probenecid increases serum levels with meropenem
- Ertapenem diluted with lidocaine is contraindicated in pots with hypersensitivity to amide local anesthetics
Monobactam spectrum
Gram negative aerobic bacteria that are resistant to B-lactamases
DOES NOT WORK WITH G(+) anaerobic
Clinical use of monobactams
Used as Azetreonam.
UTI’s, lower respiratory infections, skin…
patients with severe allergy to penicillins and cephalosporins
MoA of monobactams
binds to and inhibits PBP3 in g(-) bacteria
changes cell shape structure so that it no longer works`
Absorption/elimination of monobactams
not absorbed by GI tract
glomerular filtration elimination
adjusted to renal failure
AE of monobactams
Elevated liver enzymes
Special considerations for monobactams
B-lactamase inducing abx may increase resistance to Aztreonam
Vancomycin spectrum
G(+) aerobic or anaerobic
not effective against Listeria (which is G+)
Clinical uses of vancomycin
prophylaxis: surgical implant, MSSA or MRSA in hemodialysis, respiratory/GI/ Genitourinary procedures
C. difficile
Staph. enterocolitis
MoA of vancomycin
Binds with high affinity to D-ala, D-ala terminus
DOES NOT interact with PBPps
prevents interaction with transglycosylase blocking growth of peptidoglycan chain
Absorption/ elimination of vancomycin
poor oral absorption ->IV
readily goes into CSF
excreted unchanged in urine -> depends on CrCl
Long half life (6h) with 2-4x MIC, PAE last 2-7hr
watch the CrCl
AE of vancomycin
nephrotoxicity
RED MAN SYNDROME (immediate reaction: severe hypotension and cardiac arrest due to fast IV infusion)
special considerations for vancomycin
increased risk or nephrotoxicity with ahminoglycosides, bacitracin, polymixin B.
flushing with anesthetics
neuromuscular blockade increase with muscular relaxants
Telavancins are…
semi-synthetic analog of vancomycin
Telavancin spectrum
G(+). effective against MSSA and MRSA.
more potent than vancomycin for decreasing biofilm formation.
effective for E. faecium and faecalis
Clinical use of Telavancin
skin and skin structure infections by susceptible strains.
Nosocomial pneumonia
MoA of Telavacin
1) same as vancomycin: binds to D-ala, D-ala terminus to stop inhibiting peptidoglycan chains
2) Lipid side chain acts as a detergent to destroy membrane
Excretion of Telavacin
LONG half life (9hrs) normal renal function
excreted in urine
high plasma protein binding
AE of Telavacin
taste disturbance,
increase serum creatinine, low K
Daptomycin spectrum
aerobic and anaerobic G(+).
effective against stop (MSSA/MRSA) and strep A, D
Clinical use of Daptomycin
same as Telavancin:
skin and skin structure infections.
Nosocomial pneumonia
MoA of Daptomycin
Concentration dependent - Ca++
Daptomycin inserted into the lipid bilayer (creates a channel) and then depolarizes the membrane with K+ efflux resulting in rapid cell death
Daptomycin Elmination
Long half life (8-9 hours) & PAE (5-10hr)
unchanged in urine. clearance decreased in obese pts (highly lipid)
AE of daptomycin
Regular: NVD, injection site, headache, fever,
INSOMINIA
special considerations of daptomycin
interactions with HMG-CoA reductase inhibitors (statins): increases risk for myopathy.
dose change for hemodialysis
Polymyxins examples
Polymyxin B - parenteral
Colistin (topical and oral)
Colistimethate (oral)
spectrum of polymyxins
G(-) esp. for p. aeruginosa
NOT FOR g(-) or g(+) aerobic cocci or g(+) aerobic bacilli
Clinical use for polymyxins
when nothing else works
MoA of polymyxins
binds to and neutralizes LPS (inflammation). reacts with lipid A (part of LPS) to make pore-like structures to disrupt membrane.
Elimination of polymyxins
highly bound to membrane lipids in many tissues-> slow release of drug from bound tissue
half like moderate (3.5-6h)
unchanged in urine
AE of polymyxins
Nephrotoxicity (reversible) tubular necrosis (acute) neuromuscular blockade (like daptomycin and vancomycin)
