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97 Cards in this Set
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Respiratory System- Cell Wall Synthesis Inhibitors by Boy Bridges
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Respiratory System- Cell Wall Synthesis Inhibitors by Boy Bridges
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How do Beta-lactams work?
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1.They bind to Penicillin Binding Proteins (PBP)
2.PBP is unable to crosslink peptidoglycan chains 3.Bacteria are unable to synthesize a stable cell wall 4.Weakened cell wall leads to lysis of bacteria from osmotic pressure |
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Name the Penicillins
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penicillin G
penicillin V |
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Antistaphylococcal penicillins
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nafcillin
oxacillin cloxacillin dicloxacillin methicillin |
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Extended-spectrum penicillins
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ampicillin
amoxicillin |
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Antipseudomonal penicillins
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ticarcillin
piperacillin |
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Cephalosporins: First Generation
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Cephalexin
Cefazolin |
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Cephalosporins: Second Generation
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Cefoxitin
Cefaclor Cefprozil |
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Cephalosporins: Third Generation
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Ceftriaxone
Ceftazidime Cefotaxime Cefdinir |
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Cephalosporins: 4th generation
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Cefepime
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Carbapenems
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Imipenem (+ cilastatin)
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Monobactams
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Aztreonam
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Beta-lactamase inhibitors
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Clavulanic acid
Sulbactam Tazobactam |
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Other cell wall/membrane inhibitors
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Vancomycin
Bacitracin |
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What's that important structure of the Gram positive cell wall that we'll pay attention to?
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The thick homogeneous sheath of peptidoglycan (aka murein).
-peptide cross-links predominate -includes teichoic acid and lipoteichoic acid --functions in cell wall maintenance and enlargement during cell division; move cations across the cell envelope; stimulate a specific immune response -gives the cell wall rigidity against osmotic pressure. -drugs prevent this cross-link from forming |
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What's so important about the alanine-alanine?
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it's important for the mechanism of action as well as resistance for drugs.
We first need to change the naturally occurring L-alanine to an unnaturally occurring D-alanine |
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What are the 3 stages of cell wall synthesis?
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Stage 1: occurs in cytoplasm – provides building blocks
Stage 2: occurs as building blocks pass through the plasma membrane 3rd stage: Occurs outside the plasma membrane and involves cross-linking of peptidylglycan strands |
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What does vancomycin do?
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binds (recognizes) to the ala-ala and prevents the cross-links from forming. since the ala-ala has this huge drug on it now, the enzymes used to form the peptide and sugar cross-links can't get in there.
a target-directed mechanism of resistance is here, when the bacteria changes the last amino acid from an alanine to something else, so vancomycin won't recognize it anymore. |
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What does bacitracin do?
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prevents the membrane-bound carrier protein (bactoprenol) from recycling
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What combines 2 amino acids?
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a transpeptidase, a penicillin binding protein. so if you inhibit this PBP, you prevent those amino acid chains from joining together, the cell gets weak from lack of cross-links, and it lyses. this is how penicillin, cephalosporin, etc work.
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How does penicillin work specifically.
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since penicillin is structurally similar to to alanine-alanine, the transpeptidase will bind to THIS instead of the real ala-ala. this is in comparison to the vancomycin which binds to ala-ala.
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What do beta-lactams do?
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-beta-lactams block transpeptidation step …block cross linking of peptidylglycan chains
-All beta-lactam antibiotics bind to PBPs and inhibit cell wall synthesis |
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Describe PBPs (penicillin-binding proteins aka transpeptidases)
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There are a large number of different PBPs
Usually several types in each organism Can be membrane-bound or cytoplasmic Have diverse functions: --catalyze transpeptidase reaction --maintain shape --form septums during division --inhibit autolytic enzymes |
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Beta-lactams are _____-dependent killers.
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Beta-lactams are …“time-dependent” killers
-Effect is directly proportional to amount of TIME the drug concentration at the site of infection is ABOVE the MIC of the organism |
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You want the drug concentration at the site of infection to always...
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be above the MIC between doses
*adding more drug won't kill more bug. massively increasing the amount of drug at the same length of time has no effect on efficacy. it's time-dependent. not concentration dependent. |
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What are the 4 beta-lactams?
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Pencillins
Cephalosporins Monobactams Carbapenems *all share a similar structure. there's a beta- lactam bond between the carboxy and the nitrogen, and this is what the bacteria attacks, and what needs to be in tact for bacterial activity (need that 4-membered ring) |
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What's the R side chain?
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determines spectrum of antibacterial activity and pharmacological properties (e.g., affinity for PBP, resistance to penicillinase, ability to penetrate G- outer membrane, resistance to stomach acid, PK)
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General properties of penicillins
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-A beta-lactam antibiotic
-Prevent cell wall synthesis leading to lysis of the cell -All are bactericidal |
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Pen G vs Pen V
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Pen G
-acid labile -poor oral bioavailability Pen V more stable in acid -so “better” oral availability Remember: V is not IV |
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When to use a penicillin G and why?
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Always consider using a penicillin if …
-the organism is susceptible -can reach the site of infection -the patient is not ALLERGIC Because: -of the low costs -of the low toxicity and large TI |
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What do we use Pen G against?
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Pen G (narrow spectrum)
-mostly gram positives (both cocci and rods) -a few gram negatives (like Neisseriae meningococci and gonococci) -some anaerobes and spirochetes (syphilis) There is acquired resistance for staph a (>90%), strep (5%), most neisseria gonococci |
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Pen G has a wide body distribution, but where doesn't it go?
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since the concentrations in fluids and tissues differ widely, pharmacological sanctuaries exist in the:
-prostate -ocular -CSF (BBB..except during inflammation or meningitis where there's a loss of BBB integrity) |
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What't the halflife like for Pen G, and how can it be altered?
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… short t1/2 (30 min)
Quickly eliminated by renal tubular secretion active transport pump Probenecid can slow the process -blocks renal tubular secretion of penicillin -it is a competitive inhibitor -rarely used for this purpose anymore |
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What is procaine and benzathine used for?
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so you don't turn your pt into a pin cushion (decrease injection frequency)
taken IM, there is a slow release from the injection site, yields low but prolonged drug levels, and they are also known as repository penicillins *works because penicillin is a time-dependent drug. |
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Adverse Effects of Penicillin G
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-Lowest toxicity potential of all antimicrobials
-Allergic (hypersensitivity) Reactions --Most common adverse effect --Most commonly reported medication allergy -----self-reported by at least 10% of patients -----~85 - 90 % are NOT allergic & able to tolerate penicillins -----Can be any of the 4 types of Gell and Coombs hypersensitivity reactions -Manifest with a wide range of symptoms From rash … to anaphylaxis (pretty rare) |
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Tell me, what is Penicilloic Acid?
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Penicilloic acid
-breakdown product of pen G -acts as a hapten -the major determinant --at least 25% due to other minor metabolites |
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Does skin testing always identify an allergic patient?
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No, sir. Skin testing MIGHT identify an allergic patient. The kit may recognize only a particular hapten, so the patient may actually be allergic to a minor metabolite that the kit does not recognize.
*cross-sensitivity with other penicillins |
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What are the non-allergic adverse effects of Penicillin G?
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Diarrhea and GI intolerance
NEUROTOXICITY -Most likely at high concentrations (intrathecal admin or renal failure) Increased CNS activity … SEIZURES Superinfections -more common with broad spectrum agents (e.g. cephlasporins) |
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talk about Penicillin G resistance
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Many G- are resistant (Pen G can’t get in)
Penicillinase production: most common resistance component ( G+ & G- ) Cell lysis cascade not activated (autolysis) certain strep, staph, listeria Mycoplasma don’t have cell walls (no target) For some, transpeptidases are mutated Beta-lactams can’t bind to target (MRSA) |
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What are the two types of beta-lactamase resistance?
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Chromosome encoded
-characteristic of entire species -synthesis may be inducible in the presence of antibiotic Plasmid encoded -characteristic of an individual strain rather than the species -constitutively expressed -most mediate resistance to penicillins and 1st & 2nd generation cephalosporins |
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Where are beta-lactamases for gram positives and gram negatives?
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The attack point is the beta lactam ring ... which is essential for PBP binding ... and antimicrobial effects
In gram positives they are: -Secreted to outside of cell wall -Produced in high concentration in some -Primarily plasmid (R) factor transmitted In gram negatives they are: -In periplasmic space and high concentrations |
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What can ESBLs hydrolyze?
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Extended Spectrum Beta Lactamases
Efficiently hydrolyze: Penicillins Cephalosporins (capable of cleaving later generations) Monobactams (aztreonam) Note: the beta-lactamases we noted previously DO NOT typically cleave later-generation cephalosporins and aztreonam (that’s why they were developed) Primarily seen in gram negative bacilli Klebsiella pneumoniae and E coli most common ESBL producers but many others demonstrated |
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What are our MSSA drugs of choice?
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For Methicillin-Sensitive Staphylococcus Aureus, we shall use oxacillin and nafcillin (but won't work against MRSA because the target is alterned)
Resistant to breakdown by b-lactamase -Contains bulky side chain -doesn’t fit into b-lactamase active site Extends their spectrum to include b-lactamase producing staphylococci |
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Adverse effects of oxacillin and nafcillin?
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Adverse effects similar to Pen G
BUT ... this group may cause: -blood dyscrasias (agranulocytosis) -acute interstitial nephritis -hepatotoxicity (oxacillin only) |
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Which are the extended spectrum penicillins?
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ampicillin and amoxicillin
Penetrate gram negatives more readily, so often used for G- infections E coli, N. meningitidis Broad spectrum -Not effective against beta-lactamase producers -Beta-lactamase inhibitors extend spectrum Administered by most routes but .... -Amoxicillin has better bioavailability than Amp -Amox: one of the oral pens that food does not interfere with absorption |
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What do we use these extended spectrum penicillins?
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HELPSS:
H influenzae, E. coli, Listeria sp., Proteus, Salmonella, Shigella (Amp) Clinical uses include things such as: -Pneumonia, UTIs, Otitis, Sinusitis -Ampicillin is frequently used (synergistic) with an aminoglycoside (Gentamycin) for broad range coverage in serious infections -Ampicillin is DOC for Listeria meningitis |
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Synergy between antibiotics
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Single agents:
bacteriostatic or not effective Drug combination: bactericidal *also can give extended coverage |
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What are the antipseudomonal penicillins
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ticarcillin and puperacillin
Sensitive to b-lactamase breakdown -b-lactamase inhibitors may be added to extend spectrum Spectrum is similar to that of ampicillin but extends to include other gram negatives -Spectrum is Pen G + HELPSS + Pseudomonas*, Klebsiella, and Serratia |
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Clinical Uses of Ticarcillin & Piperacillin
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Due to the ease of resistance emergence with Pseudomonas
-These agents are often used in combination with an aminoglycoside ... Clinical uses: -Useful in a wide range of infections like pneumonia, UTIs, peritonitis -Often used in immunocompromised pts Piperacillin – broadest spectrum of the penicillins when used in combo with b-lactamase inhibitor (tazobactam) |
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Adverse Effects of Ticarcillin & Piperacillin
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Adverse effects ... like that of Pen G but …
-Superinfection more likely -Can potentiate aminoglycoside-associated nephrotoxicity -Sodium overload potential --Look out for pts with CHF or renal insufficiency --Parenteral preps contain sodium |
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Resistance and antipseudomonal penicillins...
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Since they act on both G+ & G- ... more resistance mechanisms may be involved
Gram positive mechanisms -beta lactamases outside cell wall -changes in PBP (target) Gram negative mechanisms -Change in entry through porins -Beta lactamases (periplasmic space) -Efflux pump |
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As you go up in generations, the effectiveness of cephalosporins against gram negatives...
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increases.
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As you go up in generations, the effect of cephalosporins on gram positives...
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decreases.
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General Properties of cephalosporins
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-Mechanism of action same as penicillins … bactericidal
-Kinetics determined by R groups (different generations) … some orally effective -Most drugs eliminated by kidneys … a few are more dependent on metabolism -Spectrum … generally like ampicillin (G+ & HELPSS) ... but varies with generation -Not active against enterococcus or MRSA |
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Cephalosporin resistance
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Resistance – similar to penicillins
-Penicillinases and cephalosporinases -In general … cephs are more resistant to breakdown by these enzymes --Klebsiella, E Coli, Pseudomonas, Enterobacter, (ESBL can breakdown penicillins & cephs) |
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Cephalosporins Adverse effects
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ALLERGIC reactions
-Cephs < pens; Some cross-sensitivity (~10%) Some unique AEs (generation specific) Superinfections – cephs account for large % of reported cases (due to very frequent use) |
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Clinical indications of cephalosporins
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Can be useful alternative for penicillin allergic patients (if mildly allergic)
Often the greatest expenditures of hospital pharmacy (especially 3rd generation) Frequently used for surgical prophylaxis (especially 1st generation) |
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Cephalosporin generalizations
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-Gram negative coverage 3>2>1
-Gram positive coverage 1>2>3 -All are more resistant to b-lactamases than penicillins (all act on MSSA) --Resistance to beta lactamases increase from 1st to 4th generation -Half-life increases with generation (3>2>1) -Renal elimination but 1>2>3 -CSF entry almost exclusively 3rd & 4th gen *there are lots of exceptions |
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Hypoprothrombinemia
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cephalosporin adverse effect:
Coagulation abnormalities Disturbs synthesis of vitamin K-dependent clotting factors |
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Alcohol intolerance
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CephalosporinsAdverse Effects:
disulfiram-like reaction Disulfiram is an agent that inhibits alcohol dehydrogenase, causing an increase of acetaldehyde, the agent that causes hangovers Due to methylthiotetrazole (MTT) group Cefotetan (2nd generation) Cefoperazone (3rd generation) |
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Primary use for 1st generation cephalosporins
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-UTIs caused by Klebsiella and Pen/sulf resistant organisms
-staphylococcal or streptococcal infections; cellulitis or soft tissue infections -PO: not for serious systemic infections -Alternative for pts allergic to antistaphylococcal penicillins (eg oxacillin, nafcillin) -Prophylaxis of surgical procedures (CEFAZOLIN) |
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Primary use for 2nd generation cephalosporins
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UTIs,
soft tissue infections, bone infections, surgical prophylaxis |
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Primary use for 3rd generation cephalosporins
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Nosocomial G- infections ... often in combination with AGs
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1st Generation Cephalosporins
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Kinetics similar to penicillin
Orally active Short half-life and never crosses the BBB (can’t be used for bacterial meningitis) very active against G+ plus Proteus, E. coli, Klebsiella (Pen G + PEcK) Not effective against ... MRSA, enterococcus or pseudomonas |
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What is the drug of choice for surgical phrophylaxis?
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cefazolin
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Adverse effects of first generation
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-Generally pretty safe
-Adverse effects similar to pens -~ 1-10% cross-allergenicity with pens -Blood dyscrasias --neutropenia, thrombocytopenia, hypoprothrombinemia (admin Vit K1) |
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Kinetics of 2nd generation of cephalosporins
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Elimination half-life longer than 1st gen
All renally eliminated Do not achieve adequate levels in CSF (don't cross BBB) |
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Generalizations of 2nd generation cephalosporins
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-Like 1st generation … plus extended G- coverage
less effective on G+ more effective on G- --G+ + H. influenza, Enterobacter, Neisseria, Proteus, E. coli, Klebsiella --(G+ HEN PEcK) -No activity against ... enterococci, MRSA, or pseudomonas |
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Clinical use of 2nd generation cephalosporins
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Primarily used to treat
-sinusitis, bronchitis, otitis media -lower respiratory tract infections -mixed anaerobic infectionseg, peritonitis or diverticulitis -surgical prophylaxis (no advantage over 1st gen) -Lyme disease -Gonorrhea |
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Adverse effects of 2nd gen cephalosporins
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-Allergic reactions
-Blood dyscrasias (anemia, eosinophilia) -Pseudomembranous colitis (a superinfection) |
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What are the backbones of alternating sugars?
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N-acetylglucosamine- NAG
N-acetylmuramic acid- NAM the amino acids hang below this. a bridge of glycines connects adjacent amino acid chains |
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What are some characteristics of 3rd generation cephalosporins?
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-mostly given parenterally
-readily cross the BBB -longer half life -excretion eliminated renally (except cetriaxone which is biliary) -less effective on gram pos -more effective on gram neg (pseudomonas, klebsiella DOC, e.coli DOC) |
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are 3rd generation cephalosporins the DOC for gonorrhea and lyme disease?
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yeah.
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So what's the difference between 3rd and 4th generation?
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not much. 4th just has a wider spectrum, and more resistant to beta-lactamases.
more effective against pseudomonas, staph a, strep pneumo, haemophilus, and neisseria |
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What's an important point that we should know about imipenem?
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it's bactericidal to almost all bacteria (but it's not a good DOC for a lot of things)
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What is the MoA of imipenem?
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similar to pens and cephs (binds to penicillin binding protein to prevent crosslinking)
-also it has a significant post anitbody effect (PAE). The lingering effect after the drug is dropped below the minimal inhibitory concentration. |
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What's the primary use of imipenem?
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organisms resistant to other antimicrobials (eg extended spectrum beta lactamase-producing microbes)
-so you use this when all the other drugs aren't working, so it's not usually a DOC. -empiric treatment of serious nosocomial and mixed infections caused by MDR aerobic and anaerobic enteric bacilli. |
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What are the clinical uses of imipenem?
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mixed infections (on those pts on other antimicrobials, and the immunocompromised)
gram neg pneumonia and bacteremia, complicated UTIs, serious infections by pseudomonas |
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ok, so imipenem is the DOC for what
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enterobacter infections
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what is cilastatin
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cilastatin inhibits the dipeptidase enzyme that slows down the breakdown (metabolism) of the imipenem (in the kidney) so it can achieve therapeutic concentrations.
this is necessary because imipenem usually has a short half life when broken down in the kidney *this has nothing to do with blocking excretion. it's about blocking metabolism. |
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what do you take with imipenem to fight against pseudomonas resistance?
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aminoglycoside
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What are the adverse effects of imipenem?
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-NVD most common
-seizures (especially if CNS lesions present or renal insufficiency) -hypersensitivity (< 3%) --cross reactive with pens |
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What is the magic bullet for gram negatives?
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monobactams (aztreonam)
-same mechanism of action as other beta-lactams, but only binds to a PBP present in gram negatives |
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are monobactams an alternative to aminiglycosides?
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yeah. the spectrum more closely resembles AGs.
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other monobactam details...
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-high degree of resistance to beta-lactamses (ie penicillinases and cephalosporinases)
-active against many MDR strains -used for tx of serious g- infections -no cross sensitivity with pens or cephs (use in allergic pts) |
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and that's it for cell wall synthesis inhibitors
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now onto beta lactamase inhibitors and the 'others' and we're done
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so what does clavulanic acid do?
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prevents the breakdown of amoxacillin (for example) by competing for its binding with beta-lactamase (which wants to break it down). clavulanic acid has little to no antimicrobial effect, so it doesn't compete with amox for that, but it will keep amox from being broken down by beta lactamases, by inactivating it.
-it looks like penicillin and irreversibly binds to beta lactamase. |
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are beta lactamases inhibitors active against plasmid-encoded beta lactamases?
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yeah. including enzymes active against ceftazidime and cefotaxime (3rd gen)
-but generally do not inhibit chromosomal beta-lactamases (induced in g- bacilli by 2nd and 3rd gen ceph) |
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what is the only oral prep beta lactamase inhibitor combo?
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amoxicillin and clavulanic acid
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What does vancomycin do?
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binds tightly to alanine-alanine end of peptidoglycan pentapeptide
-inhibits transglycosylase --prevents building block bound to phospholipid carrier from binding to growing peptidylglycan chain *binds to ala-ala and prevents NAG and NAM from going into the cell wall |
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so vancomycin is bactericidal, yeah?
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yes, but it's not a beta lactam.
-it's for oral use only to treat GI infections like colitis and enterocolitis -otherwise it's given parenterally. |
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is vancomycin good for gram+ or gram-?
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gram positives only.
-use limited to SERIOUS infections (MRSA drug of choice, enterococci, clostidium difficile alt choice) |
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what is the DOC for pseudomembranous colitis?
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metronidazole. vancomycin is the alternative.
this is from an overgrowth of clostridium difficile. |
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adverse effects of vancomycin?
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-ototoxiticity
-nephrotoxicity -EXTREME FLUSHING with RAPID INFUSION (red man or red neck syndrome, histamine release though not allergic (direct toxic effect on mast cells)) |
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What are the drug interactions of vancomycin?
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synergistic effects with aminoglycosides
--increased antimicrobial effects (enhances uptake of aminoglycosides) |
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What type of bacteria is bacitracin good for?
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gram positives. once again, it's bactericidal, but not a beta lactam.
topical only (bc very nephrotoxic) |
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what is the MoA of bacitracin?
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interferes with REGENERATION of membrane phospholipid carrier (bactoprenol)
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