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ID Exam 2
Antibiotics
| Question | Answer |
|---|---|
| What is the function of a Cell wall? | to provide a semi-permeable barrier; to protect from osmotic pressure from the environment; to prevent digestion from host enzymes |
| Similarities b/w gram (-) and gram (+) cell walls: | Contain peptidoglycan and membrane proteins |
| Differences b/w gram (-) and gram (+) cell walls: | Gram (+)--> thick peptidoglycan Gram (-)--> Contain PORINS and a outer membrane layer -impermeable and doenst allow things to get inside, there are porins (water channels) that allow for certain substances to get into the bacteria |
| Strength and rigidity from the polymers that make up the peptidoglycan layer comes from the? | cross-linking via penta-glycine chains ** G (N-acetylgycosamide (NAG)) **M (N-acetylmyramic acid (NAM)) G and M attach via glycosidic bonds |
| Overvierw of the Peptidoglycan Biosynthesis: | 1. Starting Point (Glucose-6-Phosphate) 2. Udipine-NAG--> Udipine-NAM 3. Binding of the NAG-NAM to the Pentapeptide (5 amino acids) and to the BP (Bactoprenol) 4 and 5. Slanted line on graph (is the penta-glycel chain) attached to the NAG-NAM monomer 6. Translocation of monomer outside of the bacterial cell via the BP 7. Monomer attaches to an existing polymer to lengthen the polymer chain Lastly seen in step 3: polymer cross-linking via the pentaglycine chain |
| 3 main steps of peptidoglycan biosynthesis: | 1. Synthesis of NAM-NAG monomer 2. Manomer translocation and polymerization 3. Polymer crosslinking |
| What is bactoprenol? | A lipid carrier that can freely move across the lipid barrier |
| Biosynthesis of Peptidoglycan (Step 1: Synthesis of NAM-NAG monomer: | Steps A and B--> synthesis of UDP-NAG and UDP-NAM pentapeptide Steps C: Synthesis of NAM-NAG monomer |
| Step 1 Biosynthesis of NAM-NAG monomer Ramsinghani takeawy: The UDP- NAM pentapeptide consists of 5 amino acids but differ when its a gram (+) or a gram (-) what is the difference? Unique structure in UDP-NAM is? | In gram (+) L-Lysine (amino acid #3) In gram (-) L-Lys is DAP (di-phenolic acid) -Lactate |
| Step 2 Biosynthesis of peptidoglycan (Monomer translocation and polymerization)--> | Comes out and monomer will attach to an existing polymer and will have attachment and another unit of NAG-NAM |
| Step 3 Biosynthesis of peptidoglycan (Polymer crosslinking)--> | most important step where our B lactam antibiotics will work. The enzyme transpeptidase--> will form a peptide linkage **(1)Attachess on the 4th D-alanine of your pentapeptide (2) 5th pentapetide leaves (3) Pentaglycine will attack on the 4th D-alanine and would then "relieve" the transpeptidase so that it repeat the crosslinking elsewhere (release and repeat) |
| What is the MOA of Bactoprenol | Bactoprenol circles back into the cell membrane and becomes BP-phosphate |
| What is the SOA of Bacitracin and its MOA? | SOA is Bactoprenol MOA "recycling of Bactoprenol" (1 phosphate has to be removed so that de-phosphorylation is inhibited by Bacitracin |
| What is the MOA of Vancomycin? | "interfere with the elongating the NAM-NAG polymer" inhibits the polymerization; inhibiting attachment of the NAM-NAG monomer to an existing polymer (works at Step 2 of the Biosynthesis of peptidoglycan) |
| What is the MOA of B-lactams? | inhibiting the cross-linking of the polymers (works at Step 3 of the Biosynthesis of the peptidoglycan) |
| B-lactam anbtibiotics: What needs to occur to get the formation of B-lactam rings? | Propanoic acid (carboxylic group and amino group at the 3rd carbon amino group attacks the carboxylic group and have cyclization; 3-aminopropanoic acid (HOOC-CH2 (alpha carbon)--CH2 (beta carbon)--NH2 |
| Structure of Penicillins: What is the alternative name of a PCN? | B-lactam ring fused to a 5-member ring containing a SULFUR; -(Penam) |
| Structure of a cephalosporin: What is the alternative name of a Cephalosporin? | Fused to a 6-member ring and a double bond -(Cefem) |
| Structure of a carbapenem: | B-lactam ring fused to a 5-member ring contains a CARBON instead of a sulfur with a double bond in the 5-member ring as compared to a PCN which contains a sulfur but no double bond |
| Structure of a monobactam: | No other ring is fused; only contains a B-lactam ring |
| Which of the following statements about the bacterial cell wall are correct? | Gram (+) bacteria have a thick peptidoglycan layer Gram (-) bacteria have porins |
| B-lactam antibiotics interfere with: | cross-linking the NAM-NAG polymers |
| What are some classification of drugs that will interfere with cell wall synthesis or repair will be toxic to bacteria and will spare the mammalian cell? Are they Bacteriostatic or Bactericidal? | B-lactam antibiotics/ some cyclic peptide antibiotics -Bactericidal (kill the bacteria) |
| PCN has stuctural similarity to D-Alanine/D-alanine. How does this help inhibit the synthesis of peptidoglycan? | Transpeptidase will get confused b/w the D-alanine/D-alanine and the PCN structure since they share STRUCTURAL SIMILARITIES |
| What are the fundamental requirements of PCN drug activity? | 1. a highly constrained fused B-lactam structure 2. Carboxylic acid at C-2 (pKa 2.4) (**this ionzies at physioligcial pH 3. Structural amide side chian (needed for activity) |
| Walk me through the Peptidoglycan cross-linking steps: | Transpeptidase attaches to the 4th D-alanine using its active site Serine (CH2OH) through a nucleophile attack on the 4th D-alanine Next step is 5th D-alanine is removed. Lastly is pentaglycine attack on the 4th D-alanine and form a crosslink and our Penicillin binding protein (serine) will be taken out of that complex to do another round of cross-linking_ |
| What is the MOA of B-lactam antibiotics? | inhibit bacterial cell wall synthesis by binding to one or more PCN Binding proteins (PBP) which in turn prevents the final cross-linking (tenspeptidation) in peptidoglycan synthesis in bacterial cell walls |
| Because of the structural simliarities of our B-lactams to the D-alanine/D-alanine ___________ gets fooled ant attacks PCN of our B-lactam antibioitics. It cannot come out from that complex because its ________ bonded to B-lactam hence the inhibition of the biosynthesis | transpeptidase; covalently |
| What structure does Transpeptidase covalently bind to that is causing the steric hinderance? | Substituted amide group |
| What makes PCN have selective toxicity to bacteria? | bacterial cell wall |
| Which of the statements is true about B-lactam antibiotics and bacteria? | Some bacteria can become resistant to B-lactam antibiotics |
| What are the mechanisms of Bacterial resistance to B-lactams | 1. Alteration of penicillin binding proteins (PBP) (alteration of target and cant bind to inhibit the cross-linking rxn) 2. Ineffective penetration of drug to site of action (efflux or cant get through) 3. Alteration of drug by B-lactamase |
| MOR (Mechanism of resistance) 1. Resistance arising from altered Penicillin Binding proteins (PBP) arises from: | 1. Intrinsic resistance due to structural differences in PBP (*** Enterococcys faecium---> PBP-5) **(this has low affinity binding protein and wont be effective for our drug causing intrinsic resistance 2. Acquired resistance due to homologous recombination (Transfer of DNA in transposons transferred to bacteria that can produe resistance to B-lactam drugs (decreasing effectiveness) |
| Give me 2 prime examples of decreased affinity for B-lactam antibiotics: | 1. Methicillin resistant Staphylococcus aureus (MRSA)--> gene MecA (encodies for an additional PBP2a) 2. Penicillin resistant Streptococcus Pneumoniae (PRSP)--> PBP2x **(PBP continues to do the cross-linking) Remember--> important exmaples is penicllin resistant and strep pneumoniae (produces a lower affinty PBP2x where B-lactams will not be efficient |
| Resistance arising from Ineffective Penetration of drug to SOA, how does this occur? | Reduced permeability due to changes in PORINS (Enterococcus species, and Pseudomonas aeruginosa) **Remember these have low affinty porins |
| What is the prime reason for the ineffectiveness of B-lactams with low affinity porins in P. aeruginosa and Enterococcus spp.? | Doesn't allow drug to get in; if somehow the drug does get it, it can be effluxed out. Prime example is the MexAB |
| These low affinity porin bacteria posses enhanced efflux systems, what are they called and give examples of bacteria they are seen in? What do they have in common? | MexAB-OprF efflux transporter (Type of transport that throws the drug out; Seen in: Pseudomonas aeruginosa, E. coli, and N. gonorrhea They are all gram (-) |
| Resistance arising from alteration of drug by B-lactamases. What is the role of B-lactamase? | B-lactamases contain an active site serine (CH2OH) that can attack on the carbonyl carbon of our B-lactam drugs and can cause the OPENING OF THE RING) making our antibiotic inactive and ineffective |
| B-lactamases also go by what other names? | Penicillinases, cephalosporinases, carbapenemases |
| Enterobnacteriacea have what kind of B-lactamase? | Extended Spectrum B-Lactamases (ESBL) |
| What is the only drug class that is effective against ESBL? | Carbapenems |
| A PCN is _______ to B-lactamase if it is hydrolyzed by B-lactamase | sensitive |
| B-lactamase inhibiitors have structural similarity to _____. What advantage does this provide? | PCN Enzyme will be engaged and will spare the PCN |
| What structure is missing between a PCN and a B-lactamase inhibitor? ***Test question | The B-lactamase inhibitiors are missing the R-group substituted Amide group |
| What are the available B-lactamase inhibitors? | Clavulanic Acid; Sulbactam; Tazobactam |
| What are your PCN/B-lactamase inhibitor combinations and brand names? | Amoxicillin/Clavulaanate (Augmentin) Ticarcillin/Clavulanate (Timentin) Ampicillin/Sulbactam (Unasyn) Piperacillin/Tazobactam (Zosyn) |
| Do the B-lactamase inhibitors have antibiotic activity? why or why not? | No because they lack the requirement of the substituted amide side chain which is required for activity |
| How is B-lactamase inhibited? | B-lactamase's active site serine attacks the B-lactam ring of Clavulanic acid and becomes trapped within the complex via irreverisble inhibition **know that B-lactamase is getting acetylated by the inhibitor and our PCN is saved |
| What is another way to prevent B-lactamase aside from using a B-lactamase inhibitor? | Modification of R-group of PCN *** using a BULKY, ORTHO-SUBSTITUTED R GROUP which creates steric hinderance to the B-lactamase activity **steric hinderance won't allow for the B-lactamase to reach the point of the CARBONYL CARBON |
| Examples given by Ramsinghani include a _____ ring with ortho subsituted ________ | Phenyl ring; OCH3 |
| How can the degradatio of PCN by B-lactamase be prevented? | By using a B-lactamase inhibitor By have a bulky ortho-substututed R group in PCN structure |
| What classification do these antibiotics belong to? Penicillin G, Penicillin V? | Natural Penicillins |
| What classification do these antibiotics belong to? (Nafcillin, Oxcacillin, Coxacillin, Dicloxacillin? | Antistaphylococcal Penicillins |
| What classification do these antibiotics belong to? Ampicillin, Amoxicillin? | Amino Penicillins |
| What classification do these antibiotics belong to? Ticarcillin, Piperacillin? | AntiPseudomonal Penicillins |
| PK properites of PCN's | A: Oral BA vaires; some have ACID INSTABILITIES D: Rapidly distributed in the extracellular fluid of most tissues (CSF variable, increases in meningitis M: none (No CYP-related interactions E: Kidney (rapid 1/2 life: 30 min (90% tubular secretion/ 10% glomerular filtration; Caution with renal insufficency--> may lead to seizures |
| Natural Penicillin--> Benzylpenicllin (Penicillin G) describe please? | one of the first PCN to be used; rapidly degraded in stomach--> poor oral BA so used parenterally; salts with K+ (IV) -salts with organic bases (procain, benzathine (Form depots) Depots--> given in the thigh to provide long term antibiotic effect |
| What is the use of Benzylpenicillin? Why use salt forms? | They are used as treatment for syphilis (Hard to get IV injections so we use depots that provide long term PCN therapy Salt forms are not very soluble and will aggregate into depots |
| What is the issue of PCN in acids (in the GI), what happens to our drug? | in the presence of acid, the (-) chanrged oxygen makes a nucelophilic attack on B-lactam ring causing rearrangement--> opening of the B-lactam ring--> degradation of PCN structure |
| How we protect our PCNs from acid degradation is through the addition of a _____ _______ R group. How do they work? | Electron withdrawing; R-group pulls away the electron cloud from Oxygen so that it won't be able to attach to the B-lactam ring and preventing it from opening and degrading. |
| This PCN contains an electron withdrawing group that allowed for a PO formulation that is acid stable with a % absorption of intact drug of 60-70%. | Phenoxymethylpenicillin (Penicillin V) |
| What is the spectrum of activity for Natural Penicillins such as Penicillin V and G? Are they sensitive or resistant to B-lactamase? | Against mostly gram (+) bacteria; sensitive |
| Methicillin, the first _________-__________ PCN to be used clinically and was used as a narrow-spectrum for penicillinase producing Staph aureus | Penicillinase-resistant |
| What caused the resistance to all B-lactam antibiotics? | Production of PBP2a causing methicillin resistance |
| Is Methicillin still used clinically? | NOT CLINICALLY USED ANYMORE due to high toxicity |
| Can B-lactams be used to fight against MSSA? | Yes |
| These drugs are examples of Anti-staphylococcal PCNS What unique structure do they have in common? | Oxacillin, Coxacillin, and Dicloxacillin, Nafacillin -substituted Oxazole ring (bulky ortho-substituted R-grp) that provides steric hinderance and resistance to B-lactamase |
| Which of the Anti-staphylococcal PCNs have stability towards Acid (or acid resistant)? and what structure gives the acid resistance? | Cloxacillin and Dicloxacillin -The Chloro Electron withdrawing group (-Cl) allowing them to be given as oral meds |
| Which of the Anti-staphylococcal PCNs do not have Acid resistance? | Nafcillin and Oxacillin -Do not contain an Electron withdrawing group so are given Parenteral |
| Nafcillin is given parenteral but is a vesicant, what did Ramsinghani want us to know about this? | Drug is given in the vein but if it gets out will cause burning and necrosis of the surrounding tissue |
| Uses of the Anti-Staphylococcal PCNS are for __________ ________ Staph. infections; For ______ but not MRSA | Penicillinase producing; MSSA |
| Remind me of the amino penicillins we have and what kind of bacterial spectrum they cover? What structure do they have that is unique for this class of PCS? | Ampicillin and Amoxicillin -Amino group in the side chain (Electron-withdrawing--> NH3+ when ionized) given oral -R group is polar so its able to get into the Gram (-) porins making it a broad spectrum antibiotic |
| Are Aminopenicillins sensitive to penicillinase? If so, how do they combat this? | Yes since they lack the bulky, ortho substituted group; -Formulated with a B-lactamase inhibitor |
| If you were to choose between Amoxicillin and Ampicillin, which would you choose and why? **Possible test question | Amoxicillin is more rapildy and completely abosrbed from GI than Ampicillin -Peak serum conc. is 2-2.5 x higher than ampicillin |
| Next class are your anti-Pseudomonal PCNs, what are your drugs? What is their antibiotic Spectrum? | Ticarcillin and Piperacillin They are acid unstable so they are given parenteral Spectrum: broad (effective against gram (+) and (-) bacteria but sensitive to B-lactamase |
| How do we combat the sensitivity to B-lactamase in our Anti-pseudomoal PCNs? | -Ticarcillin (CARBOXYpenicillin) paired with Clavulanate since it lacks the steric hinderance structure -Piperacillin (UREIDOpeniciilin) paired with Tazobactam |
| What unique structure that Ramsinghani pointed out is present in Ticarcillin? | Contains 2 Na+ (sodiums) aka "disodium salt" |
| What unique structure that Ramsinghani pointed out is present in Piperacillin? | UREIDO (N-CO-NH) Its thought that it provides additional points of interaction to Peniciilin binding proteins) making it a very potent PCN |
| Remember: Which structural feature makes PCN resistant to stomach acid? | Electron-withdrawing R group |
| How can allergic reactions to PCN occur? | PCN do not cause allergy by themselves (they react with body proteins and form compelxes becoming ANTIGENIC and presented as MHC (Modified human proteins) **PCNs are haptens |
| This type of PCN allergy is immediate with a rapid onset within 0.5 to 1 hour after administration. Symptoms? | Type 1, IgE-mediated (anaphylaxis) -Reaction type (swelling, broncho-constriction, hypotension) |
| This type of PCN allergy is non-immediate with a delayed onset within 24-48 hours after administration. Symptoms? | Type 4, Cell-mediated Drug rash, itching |
| Pts found allergic to PCN should _______ receive PCN again What is the exception? | NOT; De-sensitization protocol |
| Adverse effects of PCN include? | GI UPSET, DIARRHEA, taste disturbace; Acute interstitial nephritis, RASH/ALLERGIC RXN/ANAPHYLAXIS/SEIZURES with accumulation, DRESS, and bone marrow suppression w/ prolonged use |
| PCNs have an adverse effect of DRESS, what does it stand for and mean? | Drug reaction with eosinophilia and systemic symptoms -This can mean involvement or injury and damage to multiple organ systems such as the liverk kidney, lung, and the myocardium |
| How can PCNS cause seizures? | If the pt has renal insufficiency, this can cause the active drug to bind and inhibit GABA receptors and prevent the NT inhibitor from doing its job causing increased neurotransmission and result in seizures |
| Drug Interaction: What effects do PCNs have on other drugs? | -PCN can increase serum conc. of MTX (compete or delay or reduce excretion of MTX) -Increase the anticoagulant effect of Warfarin (increased risk of bleeding) |
| Drug Interaction: What effects do other drugs have on PCN? | -Probenacid can increase levels of PCN by interfering with renal excretion -TCN (Tetracyclines) may decrease effectiveness of PCN |
| A pt started on Augmentin reports a rash on the trunk next day. This pt is experiencing: | delayed onset allergic reaction; Type IV hypersensitivty |
| Explain the selective toxicity of B-lactam antibiotics? | Cell wall |
| Explain the MOA of B-lactam antibiotics? | D-ala-D-ala; Transpeptidase inhibtion |
| Describe how bacteria resist B-lactam antibiotics? | Alteration of PBP;Influx/Efflux; B-lactamase |
| Describe how the R-group affects: A: resistance to stomach acid B: Resistance to B-Lactamase C: Spectrum of activity | A. Electron withdrawing group B. B-lactamase inhibitor; Bulky C. Narrow broad, extended spectrum |
| What is the MOA of Cephalosporin? | Inhibition of transpeptidase activity thereby preventing PEPTIDOGLYCAN CROSS-LINKING |
| What are the MOR (Mechanisms of Resistance) to Cephalosporin? | -Alteration of Target (PBP) -Inefficient pentration to active site -Alteration of drug structure |
| Can allergic reactions occur with Cephalosporin? | Yes, similar with PCN but occur less frequently **Avoid cephalosporins in a pt with Type I hypersensitivity to PCN |
| Pts with ______________ (type IV) allergy to PCN may be given certain cepahlosporins | delayed-onset |
| What is the general structure of a Cephalosporin? | "Cefems" contain the b-lactam ring and a dihydrothiazine ring |
| What are the 3 SAR's for Cephalosporins? | 1. alpha notation at NH2 (improved stability under acidic conditions (oral formulation) due to NH2 being an electron withdrawing 2. X-->OCH3 (improved antibacterial activity; increased B-lactamase resistance (Cephamycins) 3. Methoxime (or related oxime) at alpha--> improved B-Lactamase resistance (especially with z-oxime) |
| What is the importance of a Z-oxime in Cephalosporins? | Z oximes point towards the B-lactam ring providing steric hinderance to B-lactamase. E-oximes point away from the B-lactam ring (no steric hinderance) |
| Classification of Cephalosporin generations and coverage: | 1st gen--> primarily G+, some G- 2nd gen--> some G+, H. influenza and some G- 3rd gen--> less G+, BUT VERY ACTIVE G- 4th gen--> less active G+, most G- 5th gen--> very active G+, MRSA, less G- |
| First generation Cephalosporins include? Formulation? | Cefazoline (IV); Cephalexin, Cefadroxil (PO) |
| Second generation Cephalosporins include? Formulation? | Cefuroxime, Cefotetan*, Cefoxitin* (IV); Cefprozil, Cefuroxime axetil (PO) *(Cefotetan and Cefoxitin are Cefamycins meaning they contain Methoxy groups) |
| Third generation Cephalosporins include? Formulation? | Cefotaxime, Ceftazidime, Ceftriaxone (IV); Cefdinir, Cefditoren, Cefpodoxime, Ceftibuten (PO) |
| Fourth generation Cephalosporins include? Formulation? | Cefepime (IV) |
| Fifth generation Cephalosporins include? Formulation? | Ceftaroline (IV) |
| Which of the following describes the antibacterial spectrum of activity of ceftriaxone as compared to cefazolin? | G+ less; G- more |
| Some cephalosporins are well distributed, which can enter the CSF? | Cefotaxime, Ceftriaxone, Cefepime |
| Cefotaxime _______ in vivo. | deacteylates; Contains an acetoxy (ester can break down and end up with hydroxymethyl and interact with COOH and form a lactone (since we lose that COOH, drug becomes inactive |
| Cefazolin (Ancef) given IV is used for _______ _______; whereas Cephalexen (Keflex) given PO is used for _________ _____ , _____ infections; First generation Cephalosporins do NOT _________ CNS | -Surgical Prophylaxis -Localized Staph, Strep -penetrate |
| Cephalexin contains an amino group with a phenyl ring on its side group, what protection does this give? | prevent the attack onto the carbonyl carbon of the B-lactam ring and its stable in acid so you can give it PO |
| 2nd gen: Cefuroxime (Zinacef) is IV due to no electron withdrawing group but does contain a Z-_________ (facing towards the B-lactam. What protection does this provide? | Methoxime; steric hinderance and resitance to B-lactamase |
| Cefprozil (Cefzil) can be given PO. What structure does it contain that provide protection? | Contains an Aspartic acid and phenylanine and a electron withdrawing group allowing it to be PO |
| Cefprozil's Aspartic acid and phenyl ring which is present in the suspension may not always be metabolized in pts with ___________ _____ | Phenoketourea; USe caution since some pts cant metabolize phenylalanine; *** (Aspartic acid and phenylalanine make a di-peptide also used as an artificial sweetener) |
| Cefuroxime axetil (Ceftin), given as PO contains what kind of unique structures? | contain Axetil (COO) as well as esters; allows the drug to be lipophilc and given as PO |
| 2nd gen Cephalosporins Cefoxitin (Mefoxin) and Cefotetan (Cefotan) contain a ______ group at C-7 that provides increased stability towards B-lactamase. Both of these are given (IV) | methoxy |
| Cefotetan (Cefotan) not only contains a methoxy at C-7 but aslo contains an MTT. What is the role of this structural group? | Useful activity against anaerobes (Bacteroides fragilis) |
| What is the effect of MTT group in Cephalosporins? | Can cause B-lactam bond hydrolysis--> which may be accompaned by isomerization of 2,3-OLEFINIC linakge if X is a good leaving group such as MTT. Can lead to hypoprotrombinemia, disulfiram-like rxn |
| What is disulfiram? | This is used for treatatin alcoholism. When one consumes alcohol--> its converted to ADH--> ALDH---> acetic acid. But with disulfirum, it causes a disturbance in that metabolism and you get the bad effects (build up of acetylaldehyde (toxic), flushing, HA, palpitations, tachycardia, etc |
| Cephalosporins containing an MTT (methylthiotetrazole) should not be administered to pts on ______ _______ ________ or heparin therapy; Counsel pt to avoid _______ | -oral anti-coagulants -Alcohol |
| What are the common structure seen in all 3rd gen cephalosporins? | 1. Aminothiazole (anti gram (-) 2. Methoxime (B-lactamase resistance) |
| What are your 3rd gen antibiotics and brand names? | Cefotaxime (Claforan) IV Cefdinir (Omnicef) PO Cetriaxone (Rocephin) IV Cefpodoxime proxetil (Vantin) PO |
| 1. Cefotaxime (Claforan) contains a ___ (inactive lactone) 2. Cefinir (Omnicef) contains a _____ 3. Ceftriaxone (Rocephin) contains a CO2H which can bind to _____ to become more soluble 4. Cefpodoxime proxetil (Vantin) contains ______ | 1. metabolically unstable acetoxy 2. Vinyl group (=CH2) 3. Na+ 4. Esters |
| Of the 3rd gen cephalosporins which can penetrate the CNS which is useful in treatin meningitis | Ceftriaxone and Cefotaxime |
| What are some important points about Ceftriaxone? | -eliminated via renal and biliary excretion; Does not need to be renally or liver dosed -Do not co-administer with Ca2+ containing solutions (can cause precipitates sich as with Lactated ringers) -Neonates (contraindicated in hyperbilliubinemic neonates (Jaundice)--> can cause biliary sludging |
| Based on the structure of Ceftazidime (Fortaz, Tazicef), what do we know about its coverage? | -given IV (due to quaternary amine); the charge allows it to be solubilize and enter the gram (-) porins -B-lactamase resistance due to Z-oxime -Gram (-) due to the aminothiazine ring -Does not have CNS penetration due to charge -contains a CO2H (coverage for Psudomonas) |
| Based on the structure of Ceftolozane-Tazobactam, what do we know about it? Uses? | Parenteral (Quaternary amine) -Activity against G + and G- (such as P. Aeruginosa) due to Aminothiazine ring -Side chain off of Pyrazole ring contributes to B-lactamase resistance via steric hinderance -Used for COMPLICATED UTI and Intra-abdominal infections (w/ metronidazole |
| 4th gen Cephalosporin: Cefepime. Activity against? Unique groups? charged groups? | Activity against Strep spp, Staph (MSSA) and gram (-) -Z-methoxyimine group (resistance to B-lactamase) -N-methylpyrrollidinium ion (improves penetration into gram (-) bacteria such as p.aeruginosa |
| 5th gen Cephalosporin: Ceftaroline Fosamil: properties? structures? uses? | Fos--> contains phosphate; PRODRUG; has excellent activity against normal and mutated PBPs such as PBP-2a, PBP2x; -uses (MRSA infections, drug-resistant s. Pneumonia infections) -given IV |
| List off the Carbapenems: MOA of Carbapenems: | Imipenem, Meropenem; Meropenem-vaborbactam, Ertapenem (Invanz) MOA: inhibition of peptidoglycan cross-linking; bind to a variety of PBPs, but NOT PBP-2a (not active against MRSA) |
| Tell me about the SARs of Carbapenems: Drug choice for which kind of bacteria? | -contain a C instead of S (making it very potent) -C-3 side chain--> giving broad spectrum of activity -Hydroxyethyl group at C-6; trans C5,C6--> resistance to MOST B-Lactamase (Trans instead of Cis seen in PCN) -DOC--> ESBL-producing bacteria |
| Generla PK knowledge of Carbapenems include: | -poor oral absorption (Stability issues for extended infusions with meropenem and imipenem -metabolism (none, except imipenem (not metabolized so decrease the dose) E: decrease dose and/or extend interval in renal impairment |
| Imipenem unique structures and metabolism knowledge: *Test question | -Contains FORMAMINO group on side chain -Metabolized in kidney by RENAL DEHYDROPEPTIDASE I |
| Imipenem must be formulated with _________ (Primaxin) | Cilastatin (to prevent the enzyme (renal dehydropeptidase I) from opening the B-lactam ring and protect Imipenem |
| ADRs of Imipenem include: | At high concentration, can cause SEIZURES in pts with CNS disease or renal insufficiency *just like PCN can prevent GABA from binding |
| Meropenem (Merrem) and Ertapenem (Invanz) both contain a _____ ______ at C-4 which confers resistance to ______ ________ and therefore are used as single agents. Incidence of seizures is less than with _______ | methyl group; renal dehydropeptidase; imipenem |
| Ertapenem has 95% Plasma Protein Binding extending its half-life due to its COOH R-group therefore its _____ ______ dosing due to high binding with albumin. | once daily |
| Meropenem can be formulated with Vabormactam forming _________. Vaborbactam is a ________ B-lactamase inhibitor | Vabormere; NON-B-LACTAM *use of Vabormere potentiates Meropenem’s bactericidal action against KPC producing bacteria |
| What unique element is contained within VaBorbactam? | BORON |
| What is the use of Meropenem + Vaborbactam (Vabomere)? | cUTI (complicated UTI) and pyelonephritis |
| Imipenem is degraded by renal dehydopeptidase. What structural feature protects other carbapenems from such degradation? | The 4-methyl group |
| What are some examples of Carbapenem Drug interactions? | Imipenem/Cilastatin: Concurrent use w/ cyclosporin, ganciclovir--> leads to increased CNS toxicity (seizures) -use of valproic acid w/carbapenems would lead to a loss of anticonvulsant effects -Carbapenems and Probenacid would lead to a decrease in abx excretion |
| What do we need to know about the monobactam Aztreonam? | -researchers found out you dont need a fused ring for essential activity -Contains sulfamic acid (SO3Na)--> spatial positioning as the COO- group in PCN -a-methyl at C2 (Z-oxime)--> resistance to B-lacatamse -Aminothiazole (G (-)) -Totally SYNTHETIC (made in the lab) |
| MOA of Aztreonam and Sulfamic acid group use? | Similar with PCN but has STRONG affinity to PBP-3 Sulfamic group (SO3Na) gives anti-pseudomonas activity especially for cystic fibrosis caused by pseudomonas -Its use is for severe infections caused by gram (-); NOT for G (+) |
| ROA of Aztreonam | Parenteral; IM; Oral inhalation |
| Are there causes for concern with Cross-allergenicity of PCN with other B-lactams? | -Within the PCNs (complete) With Cephalosporins: can occur but rare; more likely with 1st and 2nd gen, than 3rd or 4th gen. (remember R group similarities) -With Carbapenems (0.9-11%) |
| Are there causes for concern with Monobactam cross-allergenicity? | no known cases of cross-allergenicity; It is possible with AZTREONAM and CEFTAZIDIME (due to identical side chains) |
| A pt with Type IV allergy is to be treated for a gram (-) infection. Which of the following are good options for this pt? | Ceftriaxone and Aztreonam |
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