What is the structure of penicillin?
1. Thiazolidine ring
2. B-lactam ring
What is the mechanism of action of B-lactams?
-interact with enzymes localized in cell membrane whose action is to build the cell wall
-prevents peptidoglycan synthesis (Gm +)
What is the dose of antibiotics limited by?
What is the minimum inhibitory concentration (MIC) of an antibiotic?
the lowest concentration of antibiotic that, under certain in vitro test conditions, inhibits further bacterial growth
What is the minimum bactericidal concentration (MBC) of an antibiotic?
lowest concentration that kills bacteria
In which diseases is the bactericidal effect thought to be important (relative to bacteriostatic effect)?
-endocarditis (only bacterial infection for which bacterial effect is absolutely necessary for a cure)
-meningitis or osteomylitis
What is Penicillin G?
-first form of penicillin used in humans
-most destroyed by gastric acid, so given IV
What is penicillin V?
-add a phenoxy group to side chain of penicillin G
-can be given orally b/c it resists acid
What does probenecid do?
-delays excretion of penicillin at renal tubules
-Musher has never used it, doesn't think its necessary
Where does penicillin go in the body (distribution)?
-distributes to EFC (22% of lean body weight)
How rapidly is penicillin excreted (clearance)?
T1/2 = 20 minutes
-excreted via kidney
By percentage of body weight, how much ECF do we have?
22% (15 liters)
Why does penicillin only distribute to ECF?
-cell membranes exclude it
What conditions are associated with greatly increased ECF?
-cirrhosis w/ ascites
-renal failure *doses of abx need to be adjusted to reflect this
How is penicillin excreted?
*keep creatinine clearance and kidney failure in mind
Why is the peak concentration of penicillin much lower than expected?
-half life of 20 minutes
-infusion takes 20-30 minutes
How should penicillin be administered? Why?
-IV at close intervals, usually 4hrs
-Keeps concentration above MIC about 2/3 of the time
if you double the dose of IV penicillin, you only add ___________ of coverage
20 min (= one half-life)
So, if you want to increase the concentration of penicillin, how do you do it?
-shorten the dosing interval
-doubling dose will only add 20 min of coverage
How is nafcillin excreted?
-Kidney AND liver
What are the pharmakinetic advantages and disadvantages of amoxicillin over penicillin?
-lower peak concentration
-level above MIC may be more sustained because drug is being absorbed in GI tract as its being excreted
-nearly 100% is absorbed in GI tract
What are procaine and benzathine penicillin designed for?
-slow absorption from injection site
What are the three factors that determine the outcome of treatment with antibiotics?
1) time that tissue levels exceed MIC
2) peak level of concentration (sometimes binding is irreversible above certain concentration)
3) area under the curve above MIC. (ex. both duration and height of level of quinolones)
Beta-lactams. Must exceed MIC for ______ of treatment period.
Antibiotic resistance may arise by __________ or by acquisition of ___________.
What are the general mechanisms of bacterial resistance to antibiotics?
1) make an enzyme that disrupts Abx at active site.
2) alter site at which abx act
3) generate new pathway that bypasses the one blocked by abx (MRSA)
4) alter entrance of antibiotic into bacterium (porins)
5) increase rate with which abx is pumped out of the bacterium
Resistance of pneumococci to beta-lactam antibiotics is of concern in ______________, not in pneumonia, sinusitis or otitis media
meningitis (antibiotic passage across blood-brain barrier)
What are bacterial porins?
1. Porins are protein channels of outer membrane
2. Transport polar molecules into periplasmic space; from there, diffuse through cell wall into cytoplasm
3. Mechanism only for gram negative rods; Gram positive bacteria do not have them
Which -cillins are resistant to B-lactamase?
What drug is usually used against methicillin-susceptible S. aureus?
Which drugs is MRSA resistant to?
-cephalosporins (except ceftaroline)
What is the half life of Amoxicillin?
What types of organisms is ampicillin good against?
Gm (-) organisms
What is piperacillin used against?
-Gm (-) rods
**widely used in TMC, especially with B-lactamase inhibitor (tazobactam)
What are the B-lactamase inhibitors?
What is Augmentin made of?
-Amoxicillin + Clavulanic acid (b-lactamase blocker)
Can Augmentin be used against MRSA?
What is Unasyn?
-Ampicillin + sulbactam
What is Zosyn?
Piperacililn + tazobactam
What are the adverse effects of penicillin?
-skin rash (10%)
What is the structure of cephalospornis?
-four membered ring attached to a six membered ring
-side chain on four-membered ring
What are the first generation cephalosporins?
-Cephalexin (oral cefazolin)
What is Cefazolin used against?
-non-MRSA Staph aureus
-Group A strep, & other soft tissue infections
-Gm (-) rods
**no effect against enterococcus
What is antibiotic prophylaxis for surgery?
-give abx before surgery so that it is in the tissues at the time of surgery
What is cephalexin?
-oral version of cefazolin
What are the third generation of cephalosporins?
-cefpodoxime (Vantin) = oral
What are third generation cephalosporins effective against?
-Gram negative rods (except Pseudomonas)
What is the half life of Ceftriaxone?
*can be given every 24 hours
What cephalosporins are good against pseudomonas?
-ceftaroline (5G) (MRSA)
Does penicillin cross the blood brain barrier?
Not very well
Inflammation decreases the rate at which the choroid plexus pump removes _________ from CSF, so, during meningitis, antibiotic levels persist whereas in the absence of meningitis they are rapidly cleared.
Does ceftriaxone cross the blood-brain barrier?
-good for meningitis
What is Cefpodoxime?
-Oral 3rd generation cephalosporin
What are the fourth generation cephalosporins?
When is cefepime used?
-like ceftriaxone, but with a good effect against pseudomonas
*really only used for pseudomonas
What is ceftaroline?
-"fifth generation" cephalosporin
-has all properties of cefepime, but ALSO active against MRSA
What are ESBL bacteria?
-extended spectrum beta lactamase
-resistant to all beta-lactamases (penicillins & cephalosporins)
Many cephalosporins have capacity to induce bacterial production of _____________.
What are the side effects and drug reactions of cephalosporins?
-most common is skin rash
-drug fever is #2
-don't give ceph if pt has had life threatening rxn to penicillin)
Which penicillins are good against pseudomonas?
How do we treat syphilis?
How do we know which antibiotics are carbapenems?
-they all end in penem
What is Primaxin?
-Compination of imipenem and cilastatin
How do carbapenems work?
-bind all known penicillin binding proteins EXCEPT PBP2a (MRSA)
Are carbapenems effective against bacteria with beta-lactamases?
*carbapenemases have appeared though
Are carbapenems effective against E. faecalis?
Are carbapenems effective against MRSA?
Are carbapenems effective against pseudomonas?
What is Aztreonam useful against?
What element do aminoglycosides require?
How do aminoglycosides work?
Irreversibly bind to 30s ribosomal subunit at interface of 30s and 50s subunits
What is an example of synergism involving aminoglycosides?
-Aminoglycosides + B-lactams
-B-lactam alters cell wall, allows high concentrations of aminoglycoside to enter cell
-fights Enterococcus and other Gm (+) bacteria
What class of abx is streptomycin?
What was streptomycin first developed as?
an antituberculosis agent
What kind of bacteria is streptomycin good against?
Gm (-) rods
*limited by rapid selection to resistance
What are the adverse effects of all aminoglycosides?
-CN 8 damage
***dosage must be reduced in renal insufficiency
What organ clears aminoglycosides?
What bugs is gentamicin good against?
-nearly all communit Gm (-) rods and most nosocomial
What is a good initial therapy for serious UTI?
What class of drug is gentamicin?
Why is it ok if aminoglycoside levels are not above the MIC for the majority of time?
-irreverisbly binds ribosome
-bacteriocidial capability depends on peak concentration, NOT time above MIC
What class of drug is Amikacin?
What is Amikacin used for?
-nosocomial or comm acquired Gm (-) infection
When are aminoglycosides used?
-againsed Gm (-) rod infections but generally only if not susceptible to other drugs (fear of toxicity)
Vancomycin resistant bacteria have gene ______ which encodes formation of terminal ________ instead of D-ala; thus vancomcyin does not bind.
What is vancomycin good against?
-NOT better than penicillins in staph infection s that are methicillin susceptible
-works on pretty much everything except VRE
Why do we need to measure Vancomycin levels when giving to patients?
-It distributes to fat as well
-need to base dosage on TOTAL body mass, not just lean mass
What drug is added to vancomycin for synergy against Staph aureus?
Do not use vancomycin for "empiric" therapy unless:
-infection is serious AND
-there is good reason to believe that it is due to an organism that will be resistant to other Abx
(T/F) Every pneumococcus is susceptible to vancomycin.
*but still give ceftriaxone b/c vanc can't cross BBB as well
What is Panton-Valentine Toxin?
-seen in CA-MRSA
-causes necrotic lesions of skin and mucos
**produced from genetic material of a bacteriophage
-know that all pneumococci produce it
-if we block its production, pneumococci are no longer virulent
-animal studies show cure to pneumococcal disease if they have antibody to it
-inhibits PMN function
What toxicities do we watch for with Polymyxins?
-Nephro and neurotoxic
What are Polymyxins good against?
Gm (-) rods, especially ones that are resistant to other abx
What drugs are Polymyxins?
What drugs are the advanced macrolides?
Macrolides are ________for Staph aureus. __________for pneumococcus, Haemophilus
How do macrolides prevent biofilm production by pseudomonas?
Why are macrolides used in CF patients?
-it prevents biofilm production by pseudomonas
What are the two clinically important forms of resistance to macrolides?
-efflux pump (mef gene)
-Erythromycin ribosome methylation, alters attachment site (erm gene)
What is azithromycin useful against?
-Mycobacterium avium-intracellulare (MAC)
Why are macrolides good against intracellular pathogens?
-they are taken up by macrophages
What are the adverse effects of Macrolides?
-prolonged Q-T interval
-sudden death (VERY rare)
What class of drug is Clindamycin?
What is clyindamycin effective against?
-Gm (+) bacteria
-most anaerobic bacteria
In which clinical scenarios is clindamycin useful?
-w/ penicillin in Streptococcal gangrene (necrotizing fasciitis (group A))
What drug is most likely to cause C. diff colitis?
What is the black box warning on Ketolides for?
What is linezolid effective against?
-Gm (+) organisms
-S. aureus & MRSA
-Coag (-) staph
What are the adverse effects of linezolid?
-bone marrow suppression, especially platelets
What drug is used for N. meningitis prophylaxis of nasal carriage in an outbreak situation?
Why can't rifampin be used as a single drug?
rapid emergence of resistance
What is Rifabutin used for?
Mycobacterium avium/intracellular (MAC)
When is rifampin used?
-Difficult staph associated with foreign body (prosthetics)
-Coating of impregnating implantable devices
What are the adverse effects of rifampin?
-turns urine and tears orange
-Stains soft contact lenses
What are the tetracyclines?
What are tetracyclines effective against?
-Haemophilus & moraxella
-Staph aureus including MRSA
-Legionella, mycoplasma, chlamydia
-Rickettsiae, ehrlichia, anaplasma
What is Septra/Bactrim?
-combination of sulfamethoxazole plus trimethoprim
How does sulfamethoxazole work?
-inhibits synthesis of tetrahydrofolic acid (needed for synthesis of thymidine)
What bugs are sulfa drugs and trimethoprim effective against?
-S. aureus soft tissue infections (including MRSA)
-Group A strep in vitro, poor in vivo though (strep break down human tissue to get thymidine)
What are the recommended clinical uses for sulfa/trimethoprim?
-pneumonia caused by Pneumocystis jiroveci
What are the adverse effects of sulfa/trimethoprim?
-Stevens Johnson syndrome (idiosyncratic)
-Renal insufficiency (dose-related)
How are quinolones given?
-orally, they are well absorbed
*except in surgical pt's who cannot swallow
What bugs are quinolones good against?
-Gram (-) rods
-good against biofilms
What clinical scenarios are quinolones used?
What antibiotic is causing problems because farmers are adding it to animal feed?
What's a super awesome treatment against biofilm formation?
-combination of quinolone with rifampin
What are the adverse effects of quinolones?
-prolonged Q-T interval (be careful in conjunction w/ Ca channel blockers)
-Tendonitis & achilles rupture
-Drug-drug interaction; increased risk of bleeding in pt's on warfarin (vitamin K)
**prophylaxis in pt's w/ prolonged neutropenia or cirrhosis, ascites, and prior spont. bacterial peritonitis
What drug is in the class of Lipopeptides?
What class of drug is Daptomycin?
What class of drug is Daptomycin?
Why can't we use daptomycin to treat pneumonia?
-it is inactivated by surfactant
What is Daptomycin good against?
-S. aureus and MRSA
What are the adverse effects of Daptomycin?
-elevation of enzymes indicating muscle damage (Cr. phosphokinase)
What class of antibiotics ends in "-vancin"?
What is the mechanism of action of Lipoglycopeptides?
1) block peptidoglycan synthesis (same as vanc)
2) alter cell membrane (dame as daptomycin)
What is metronidazole good against?
What are the adverse effects of metronidazole?
-causes a bad taste in the mouth
What is fidaxomycin used to treat?
-C. diff ONLY
-better than vanc (lower rate of relapse)
What are the two topical antibiotics?