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112 Cards in this Set
- Front
- Back
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Folate Antagonists
types |
Sulfonamides
Inhibitor of synthesis Trimethoprim and pyrimethamine Inhibitors of folate reduction |
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Sulfonamides
moA |
Competitive inhibitor of dihydropteroate synthase which prevents PABA incorporation into folic acid (anti-folate)
Folate synthesis is essential for bacterial growth Humans can use reduced folate obtained in diet |
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Sulfonamides
common indications |
Current common indication is enterobacteria in urinary tract and nocardia
Broad spectrum, but resistance severely limits actual clinical spectrum |
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Sulfonamide Adverse Effects
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Hypersensitivity
*****Kernicterus in newborns Sulfonamide displacement of bilirubin from albumin is cause ****Highest risk of acute hemolysis in patients with genetic deficiency in RBC glucose-6-phosphate dehydrogenase African-Americans and those of Mediterranean origin *****Crystal formation in urine Minimize with adequate hydration and alkalization of urine |
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Sulfonamides
named and specific indications |
Urinary tract infections
Sulfisoxazole (Gantrisin) Ophthalmic and topical infectious Sulfacetamide (Bleph-10, Klaron) Topical infections – burns Silver sulfadiazine (Silvadene) |
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Trimethoprim (Primsol)
moA |
Pyrimethamine (Daraprim)also
Inhibition of dihydrofolate reductase (can't reduce folate=antagonist)we use also but BAct more sensitive spectrum of action like sulfonamides |
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Pyrimethamine
adverse reactions |
also Trimethoprim
Similar to sulfonamides Skin rashes in AIDS patients(especially trimeth)***** Folic acid deficiency (long-term use) Avoid use in patients with Blood dyscrasias Hepatic damage Renal impairment |
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Trimethoprim-sulfamethoxazole (Bactrim, Cotrim, Septra, Sulfatrim)
indications DOC |
(folic acid antagonistish)
primary-Urinary tract infections Prostatitis Chronic bronchitis caused by sensitive pathogens Drug of choice********* for prophylaxis of recurrent urinary tract infections and Pneumocystis carinii infections |
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Pyrimethamine – sulfadoxine (Fansidar
indications |
Malaria prevention and treatment
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Trimethoprim & Pyrimethamine Combinations
Adverse reactions |
trimeth with sulfamethox
pyrimeth w sulfadoxine Increased risk of rashes Increased risk of blood problems Increased risk of nausea, vomiting and diarrhea Increased risk of drug interactions with other drugs Higher adverse reactions noted in HIV patients |
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Nitrofurans
named moa |
Nitrofurantoin
Reactive nitro group damages nucleic acids Superoxides Other toxic oxygen compounds Selectively toxic High biotransformation potential Low serum levels (we have good scavenge) |
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Nitrofurantoin
Adverse effects |
Nausea, vomiting
Hypersensitivity Pulmonary reactions *****Acute pneumonia (probably allergic)(increased o2 for ros) Interstitial fibrosis Peripheral neuropathy (esp. With renal impairment) Hemolytic anemia-esp-g6pd |
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Nitrofurans
indications |
Urinary tract infections
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Fluoroquinolone Agents
moA |
Enters bacterium through a water-filled protein channel (porin)
Inhibits topoisomerase II (DNA gyrase) and IV. Inhibition of DNA gyrase blocks transcription and duplication Inhibition of topoisomerase IV disrupts separation of DNA during cell division |
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Fluoroquinolone Agents
Res. soA |
Resistance
Less sensitive topoisomerase enzymes Decreased permeability (porin change) Spectrum of action Bactericidal with concentration-dependent killing Gram-negative rods of urinary and gastrointestinal tract Some gram-positive |
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Fluoroquinolone Agents
p-kinetics special considerations |
Distribution in most body fluids and tissues
Chelates with some metals (don't take with min. suppl. milk metals) Primary elimination by tubular secretion Blocked by probenecid(increases t1/2)but not good in UTI |
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Fluoroquinolone Adverse Effects
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Nausea, vomiting and diarrhea
*****Photosensitivity Hepatoxicity for trovafloxacin Nephrotoxicity ******Central nervous system effects dizziness, depression, psychosis, hallucinations ******Cartilage effects (“lones hurt connections to bones”) Avoid use in pregnancy and children under 18 Ruptured tendons have been reported in adults (rare) |
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Fluoroquinolone
generation trends |
Four generations
First gen is gram negative Second to fourth generation (increased spectrum) Increased gram negative activity Increased gram positive activity Increase atypical organisms activity Fourth generation has anaerobic coverage |
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Fluoroquinolone
1st gen named indications |
Nalidixic acid (g -)
Used for uncomplicated urinary tract infections |
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Fluoroquinolone
2nd gen named indications |
Norfloxacin (Noroxin)
Ciprofloxacin (Cipro) Levofloxacin (3rd gen) (Levaquin) Expanded spectrum of action to include some gram positive organisms |
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Fluoroquinolone
3rd gen named indications |
Levofloxacin (2nd also) (Levaquin)
Gatifloxacin (Tequin) Expanded gram positive and negative bacteria |
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Ciprofloxacin Indications
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2nd gen flouroquin
Respiratory tract infections Anthrax Gonorrhea Urinary tract infections Gastrointestinal infections |
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Fluoroquinolone
4th gen named indications |
Trovafloxacin (Trovan)
Expanded gram positive and anaerobic activity |
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Methenamine
moA |
In acid pH of 5.5 or less in urine, converted to formaldehyde which is toxic to most bacteria.
Orally active, often combined with urine acidifier mandelic acid |
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Methenamine
soA |
(formaldehyde guy)
Chronic suppressive therapy of recurrent urinary tract infections by susceptible bacteria Proteus bacteria alkalize urine and disrupt mechanism |
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Methenamine
SEs |
Systemic effects are limited as little conversion outside of urine
Elevated ammonia levels make this contraindicated in hepatic dysfunction patients Mandelic acid form contraindicated in renal dysfunction patients to avoid acid crystallization May not be used with sulfonamides which reacts with formaldehyde |
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Three Steps in Cell Wall Synthesis
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Precursor** (UDP-acetylmuramyl-pentapeptide) synthesized.
Formation of sugar-pentapeptide, its transport out of membrane and subsequent addition and polymerization to linear*** peptidoglycan strands. Cross-linking**** of adjacent peptidoglycan (murein) strands by a transpeptidase reaction . |
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Vancomycin
moA |
inhibits step 2 of CW synthesis-
Binds to D-alanyl-D-alanine terminal of the peptidoglycan pentapeptide side chain and prevents transglycosidation – thus stopping the growth of the linear***** peptidoglycan component of the CELL WALL. EARLY d-ALA, to D-lac = resistance |
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Vancomycin
soA |
Gram-positive spectrum of action
Drug-resistant gram-positive organisms Methicillin-resistant Staphylococcus aureus (MRSA) Methicillin-resistant Staphylococci epidermidis (MRSE) Penicillin-resistant pneumococci Clostridium difficile(oral route with poor absorption good) Second line drug due to high toxicity potential |
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Vancomycin Toxicity
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Ototoxicity***** (especially with other ototoxicity drugs)
Tinnitus High frequency hearing loss Balance problems Fever and chills Red man” syndrome, aka flushing Histamine-induced rash of the head and upper thorax Most common in presence of anesthetic ***(HoTN,b-constrict) Nephrotoxicity (especially with other nephrotoxic drugs) Thrombophlebitis called--Gorillacillin” but only guy left for some S. aureus and C. difficile |
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Bacitracin
moA soA everything |
Mechanism of action
Binds to lipid pyrophosphate carrier to inhibit cell wall synthesis**(step 2) topical only severe nephro toxic if oral Prevents dephosphorylation of the lipid carrier Resistance is rare, but is possible Gram-positive cocci, few gram-negatives and clostridium difficile |
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-lactam Antibiotics
moA |
Mechanism of action
Binds to penicillin-binding proteins (PBPs) PBPs can vary between organisms Specific PBP binding blocks the transpeptidase crosslinking**** of cell wall components (step 3** of cell wall synthesis) Activates autolytic enzymes (murein hydrolase) Results in weakened cell wall, aberrant morphological form, cell lysis and death Beta-lactam ring conveys activity R-group substitutions determine pharmacokinetics |
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b-lactam Antibiotics
resistance mechanisms |
Inactivation (opening) of required -lactam ring by---
Penicillinase, cephalosporinase, -lactamase********* Acquired via plasmids or transposons Natural via chromosomal (inducible) genes Decreased permeability Altered PBPs |
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penicillins
p-kinetics considerations |
Absorption
Variable, acid stability is problem******* Distribution Body water distribution - uneven Crosses blood brain barrier when inflammation is present Elimination Renal 10% filtration, 90% tubular secretion (secretion blocked with probenecid******) Biotransformation or biliary Nafcillin, ampicillin and piperacillin |
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Natural Penicillins
named soA DOC for |
Penicillin G
Unstable in acid Intramuscular and intravenous route of administration Penicillin V Acid stable--Oral Gram-positive spectrum of action Streptococci Meningococci Gram-positive bacilli Spirochetes *******Drug of choice for prophylaxis of syphilis************** |
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Anti-staphylococcal Penicillins
consideration named soA |
(Penicillinase-resistant)**
Very narrow Gram-positive Agent Staphylococcal infections Agents Methicillin (not available in US) Nafcillin (Nallpen) (iv only) Oxacillin (oral and iv forms) Dicloxacillin (oral forms) |
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Anti-staphylococcal Penicillins
p-kin considerations |
Elimination – Unique to class
Combination of hepatic and renal mechanisms Rarely requires dosage adjustment in renal failure Require dose adjustment in hepatic failure (naf,oxa, (also ampicillin piperacillin from other classes) |
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Aminopenicillins
named |
Ampicillin (Omnipen, Principen, oral and injectable forms)
Amoxicillin (Amoxil, Trimox, generics, oral forms) |
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Ampicillin soA
DOC for |
amoxicillin also
Extended/broad spectrum of action (HELPS) Similar to Penicillin G Haemophilus influenzae Escherichia coli Listeria monocytogenes Proteus mirabilis Salmonella Drugs of choice for preventing *******endocarditis with surgical (simple surgical) or dental procedures Ampicillin reaches therapeutic levels in cerebrospinal fluid in meningitis making it an effective treatment of sensitive bacterial meningitis. Ampicillin sometimes produces a serious rash in sensitive patients. |
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Antipseudopenicillins
named soA |
Ticarcillin (Ticar, injectable preps)
Piperacillin (Pipracil, injectable preps) Indanyl Carbenicillin (Pyopen) Pseudomonas*** Enterobacter Klebsiella |
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Penicillins & Aminoglycosides
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Aminoglycosides are bacteriocidal protein synthesis inhibitors
Penicillins are synergistic with aminoglycosides Penicillins enhance permeability of aminoglycosides Do not mix together, acid penicillin will inactivate the basic aminoglycoside (acid base neatralization) |
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B-Lactamase Inhibitors
named |
Suicide inhibitors
Clavulanate Ticarcillin-clavulanic acid (Timentin™) Amoxicillin-clavulanic acid (Augmentin™) Sulbactam Ampicillin-sulbactam (Unasyn) (injectable) Tazobactam Piperacillin-tazobactam (Zosyn) (injectable) |
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Penicillin Toxicity
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****Nonallergic rashes and eruptions
40% to 100% incidence with Epstein-Barr viral infections ***Neurotoxicity, penicillin are neural irritants Peripheral pain Seizures and convulsions *Hematological toxicity (Vitamin K deficiency) Causes coagulation disorders in newborns Most common in extended spectrum agents *Acute interstitial nephritis Especially methicillin, but possible with all agents *Cation toxicity Sodium and potassium salts accumulation |
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penicillin allergy
mechanism and types of reactions |
(10%)
Penicillin and breakdown products interact with proteins** and act as haptens** Skin rashes of all types, including dermolysis Stevens-Johnson syndrome Acute anaphylactic reactions Fever Serum sickness (especially after one week or more of therapy) Nephrotoxicity (especially with methicillin) Neutropenia with nafcillin |
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syphyllis in preg Tx with allergy to penicillin
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There is NO acceptable alternative for penicillin for the treatment of penicillin-sensitive syphilis in pregnant women allergic to penicillin
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penicillin Allergic cross-reactions
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Allergic cross-reactions is significant (~6%)
Patients with Type I reaction should avoid all beta lactams EXCEPT aztreonam Patients with only history of rashes are up to 90% likely to not react to another penicillin |
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Cephalosporins
generation trends |
Four generations
Moving from first to third generation Increase activity against gram-negatives Decrease activity against gram-positives Increased resistance to -lactamases Increased distribution to body tissues and fluids, especially during inflammation |
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cephalosporins
p-kinetics trends |
Parenteral (IM) route most common
Distribution follows generations Protein binding follows generations Urinary excretion still major elimination route Most require dosage adjustment in renal failure |
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1st Generation Cephalosporins Indications
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Antimicrobial chemoprophylaxis
Urinary tract infections When penicillins and other less expensive drugs fail PEcK Proteus mirabilis E. Coli |
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1st Generation Cephalosporins
named |
all with an i as second to last letter
Cefazolin Cephalothin Cephalexin (PO prep) Cefadroxil |
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2nd Generation Cephalosporin Indications
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(incr g-,dec g+, incr distr(deeper),incr b-lactamse resistance)
Community-acquired infections Intraabdominal infections Gynecologic pelvic infections Skin and soft tissue infections Otitis media and sinusitis HEN PEcKS Haemophilus influenzae Enterobacter aerogens Neisseria Proteus mirabilis E. Coli Klebsiella pneumoniae Serratia marcescens |
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Second Generation Cephalosporins
named |
not with i 2nd to last, e as last letter(except META FUROX) or cofepime(the fourth gen)
Cefaclor Cefotetan Cefuroxime Cefoxitin Cefmetazole |
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3rd Generation Cephalosporin Indications
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like 2nd gen add
******Meningitis due to gram-negative Penicillin-resistant gonorrhea and syphilis Gram-negative bacteria resistant to less expensive agents When more toxic agents are not tolerated |
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3rd Generation Cephalosporins
named |
all end with an e (and not cefepime the fourth gen)
Cefoperazone Ceftazidme Ceftizoxime Ceftriaxone Cefixime |
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4th Generation Cephalosporins
named indications |
Cefepime(Maxipime)
Indications are similar to third generation agents More resistant to beta-lactamases that 3rd generation agents More gram positive activity than 3rd generation agent good meningitis |
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Cephalosporins Toxicity
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Similar to those of penicillins
Anaphylactic reactions are relatively rare Patients with anaphylactic reactions to penicillins should NOT receive cephalosporins Allergic cross-reactions between cephalosporins and penicillins (plus the alcohol rx to some) |
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cephalosporin
Agents producing a dangerous interaction with alcohol (disulfiram-like reaction) |
Cefotetan
Cefoperazone Cefamandole Disulfiram inhibits the second step of alcohol oxidation, resulting in a buildup of toxic acetaldehyde. |
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Penicillin – Cephalosporins Reactivity
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Complete cross-reactivity within class should be assumed
Cross-reactivity between penicillins and cephalosporins in incomplete A patient presenting with an anaphylaxis to any beta-lactam should not be given another beta-lactam |
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Carbapenems
named moA |
(Synthetic beta-lactam)Binds PBP-2 = very broad soA (everyones got it)
Imipenem with cilastatin (Primaxin) Meropenem (Merrem) |
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Imipenem with cilastatin
moA SEs DOC for |
Broadest spectrum of action with low susceptibility to beta-lactamases
Parenterally (IM, IV) administered but inactivated by renal dehydropeptidase-1 Coadministration of cilastatin prevents inactivation (stops rapid elimination) ****High cross reactivity in penicillin- or cephalosporin-sensitive patients ******Relatively high incidence (~1%) of seizures especially with Old age head trauma previous seizure or cerebrovascular accidents renal failure *********Drug of choice for treating Enterobacter |
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Meropenem
who is he whats his deal |
Carbapenems (snth b-lact pbp-2)
an attempt to do better than imipenem Similar to imipenem Not biotransformed by dehydropeptidase Not as likely to produce seizures |
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Monobactams
named |
Aztreonam (Azactam)
a funky b-lactam (ase -R) |
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Aztreonam
soA |
a monobactam
Gram-negative spectrum of activity Resistant to beta-lactamases Low cross reactivity noted in patients sensitive to either penicillins or cephalosporins Preferred agent for penicillin-sensitive patients and those who cannot tolerate aminoglycosides or have renal insufficiency. he is good in shotgun Tx him for g-, and so vancomycin for g+ to cover all |
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Polymyxin
moA |
Mechanism of action is membrane disruption
Hydrophilic and hydrophobic components incorporate into membrane and forms pores Aerobic gram-negative spectrum of action Agents Polymyxin B Colistin (polymyxin E, Coly-Mycin) ( only topical...in triple abio ointments) |
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Polymyxin
SEs |
Resistance is rare (so far)
Pharmacokinetics Topical applications Adverse effects High toxicity limits use Nephrotoxicity (even topical) Neurotoxicity |
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Daptomycin (Cubicin)
moA |
New Agent
Unique mechanism of Action A lipoprotein, daptomycin binds membranes of gram positive bacteria Causes rapid depolarization leading to cell death No known mechanism of resistance No evidence of cross-resistance with other antimicrobials. |
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Daptomycin
soA p-kin |
Spectrum of action
Gram positive Recommended for treatment of infections that do not respond to other antimicrobials (toxic w/high DIs) Pharmacokinetics Intravenous only Extensive protein binding***diplaces others |
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Daptomycin Toxicity
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Hypersensitivity
Gastrointestinal distress Superinfections Myopathy (watch statins) Peripheral neuropathy(it DPs tissues) |
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Daptomycin Drug-Drug Interactions
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HMG CoA Reductase inhibitors
Increased risk of myopathy Warfarin Protein displacement can increase warfarin toxicity Tobramycin May decrease tobramycin(an AG)blood levels and increase relative toxicity |
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30S Inhibitors
classes |
Aminoglycosides
Tetracyclines |
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50S Inhibitors
classes or drugs |
Chloramphenicol
Macrolides (erythromycins) Clindamycin Streptogramin Linezolid |
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Protein Synthesis Inhibitors
drug selection based on |
Within a class there is often little difference in clinical response
Drug selection is often based on Tolerance to drug toxicity Ease of administration Cost |
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Aminoglycosides
structural characteristics chemistry |
Hydrophilic, polycationic amine-containing carbohydrates
Aminoglycoside structure binds to anionic sites in Outer anionic bacterial membrane Essential for antibacterial action Anionic phospholipids of mammalian renal proximal tubular cells Responsible for renal toxicity Hydrophilic character impairs transport across bacterial membrane plus they are huge |
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Aminoglycosides
named |
(GNATS)
Streptomycin Neomycin Gentamicin Tobramycin Amikacin |
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Streptomycin
indications |
an AGs
Tuberculosis, plague and tularemia |
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Neomycin
indic. |
an AGs
Bowel sterilization and skin infections |
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Amikacin
indicat. |
(an AGs)
Serious infections of Escherichia coli, Enterobacter, klebsiella, proteus, pseudomonas, and serratia |
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Aminoglycoside
moA |
Phase 1 - entry
+ charged AG enters bact through - pores Disrupted by low pH and metal ions In an aerobic event****, the internalized AG changes the perm of the membrane (Disrupted by low oxygen) Subsequent AG entry is facilitated by the permeability change As initial entry is via pores, prior use of cell wall synthesis inhibitors (penicillins) increases overall permeability to AG and is a synergistic action Phase 2 - inhibition of protein synthesis Bind various sites on bacterial 30S****ribosomal subunits Inhibits initiation of protein synth Induces errors in t-lation of mRNA (miscoded peptide chain) Inhibit translocation Concentration-dependent action Post-antibiotic effect Likely the effect of long-lasting disruption of ribosomal structure Resumption of protein synthesis probably requires new ribosomal synthesis Permits once-daily dosing |
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Aminoglycoside
soA Resistance |
Resistance
Increased degradation of aminoglycosides** Alterations in ribosomal proteins Altered permeability(use peni) Spectrum of action Aerobic gram-negative |
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Aminoglycosides
p-kinetic |
Poor oral absorption (thus can clean GI)
Distribution Extracellular fluid Plasma drug levels correlate with clinical responses, both good and bad Concentrated in bone, *renal cortical and endo- and peri-lymph of the ear Primary elimination is in urine unchanged Biotransformation enzymes are intracellular and aminoglycosides rarely penetrate into cells |
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Aminoglycoside
renal effects explained some prevention |
Low margin of safety
Nephrotoxicity Related to intracellular binding to phospholipids of lysosomes, disrupting their structure Generally reversible Dose and time related Once daily dosing important to minimize this toxicity Reduced incidence with verapamil or calcium administration Calcium decreases antibiotic activity Additive nephrotoxicity with other nephrotoxic drugs |
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Aminoglycoside
Adverse effects |
Low margin of safety
***Nephrotoxicity Hypersensitivity ***Ototoxicity (all are capable of both forms) Cochlear & Vestibular toxicity *****Neuromuscular paralysis Treat with calcium gluconate or neostigmine |
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Aminoglycosides
BBW |
Nephrotoxicity
Ototoxicity Neuromuscular blockade and side note FDA Pregnancy Category D |
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Aminoglycosides
Drug interactions |
Penicillins may enhance permeability for aminoglycosides enhancing activity
Inactivated by acids Avoid coadministration with other nephrotoxic or ototoxic drugs |
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Tetracyclines
moA |
Organic bases, unstable in solution
Mechanism of action Inhibition of protein synthesis Binds to 30S******** ribosome subunit Inhibits amino acid-tRNA complex binding to the Acceptor site on the 50S subunit. Selective toxicity related to specific energy-dependent transport and accumulation systems found in bacteria |
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Tetracyclines
short acting long acting named |
Short acting (half life of about 8 hrs)
Tetracycline(Achromycin V, Sumycin) Oxytetracycline ((Urobiotic-250) Long-lasting (>12 hrs) Doxycycline (Doryx, Periostat, Vibramycin) Minocycline (Minocin, Minocin IV, Vectrin) |
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Tetracyclines
p-kinetic considerations |
Oral absorption-Impaired by food and metal ions
Except doxycycline and minocycline which is improved with food (EH circ =long t1/2, can dec w/cholestyramine to get rid) (still use short act. if Hx of sensitivity) Distribution Distributed in body tissues and fluids according to lipid solubility (and protein binding) Short acting are poorest in lipid solubility and protein binding Longer acting are best in lipid solubility and protein binding Penetrate blood brain barrier(good) and placental barrier |
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Tetracyclines
soA |
Broad spectrum of action
Primary use is for infections of Mycoplasma pneumonia, Chlamydia, rickettsia and vibrios Secondary drug for syphilis and some sensitive respiratory system pathogens. Sometimes used for prophylaxis of chronic bronchitis and treatment of acne. Component of triple therapy for H. pyl. |
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Tetracyclines
toxicities |
Hypersensitivities are rare
Gastrointestinal disturbances Reduce by taking with food ****Teeth and bone accumulat Avoid use during pregnancy and in children under 8 **Photosensitivity(burn) Vestibular toxicity Especially with minocycline and doxycycline Nephrotoxicity Degraded or outdated tetracyclines Synergistic with other nephrotoxic drugs or situations *****Hepatotoxicity Fatal hepatotoxicity has been noted in pregnant/high doses and esp if w/ pyeloneph *****Pseudotumor cerebri -Benign intracranial hypertension associated with headache and blurred vision Superinfections |
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Tetracycline Contraindications
|
Renally impaired patients
Doxycycline can be used Accumulation of tetracyclines may aggravate azotemia Pregnant or breast-feeding women Children under eight years of age |
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Tetracyclines Indications
not tested |
“VACUUM The BedRoom
Vibrio choleras Acne Chlamydia Ureaplasma Urealyticum Mycoplasma pneumoniae Tularemia Helicobacter pylori Borrelia burgdorferi (lyme disease) Rickettsia |
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Chloramphenicol
moA |
Binds to 50S****ribosomal subunit to prevent peptide bond formation
Broad spectrum of action Toxicity limits use to severe infections that have not responded to safer drugs Resistance by increased degradation |
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Chloramphenicol
p-kinetics considerations |
good oral-Iv only if puking
Inactivation by conjugation before excretion (poorly dev in neo) Alternative biotransformation pathways are noted in neonates and young children but are inadequate to handle normal dosing regimens |
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Chloramphenicol (Chloromycetin)
adverse rxs |
Low safety index
Inhibits mitochondrial protein synthesis in human cells Gastrointestinal distress and superinfections Bone marrow depression Dose related anemia Reversible Daily dose > 4 g or plasma levels > 25 µg/cc ******Idiosyncratic aplastic anemia (not dose related) Onset may be delayed months*********** after therapy is stopped Usually fatal Most common with oral or ocular administration “Gray baby syndrome” Poorly developed conjugation processes allows blood levels to increase Potentially fatal Abdominal distension, vomiting, cyanosis, irregular respiration, hypothermia, vasomotor collapse ***Neurological problems Optic and peripheral neuritis, confusion, delirium Most common in **cystic fibrosis*********** patients |
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Chloramphenicol
BBWs |
Black Box Warning
Appropriate use Hospitalize patients and monitor for hematological toxicity Blood dyscrasias (appropriate = meningitis Haemophilus influenzae, Neisseria meningitidis, Streptococcus pneumoniae ) |
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Concentration-Dependent Killing?
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Some agents demonstrate higher “kill” rates at higher drug levels
Fluoroquinolones Aminoglycosides Drugs can be administered in boluses or “once daily” at high doses to optimize kill and minimize toxicity ( can get 10-20* the kill expected) like dose response effect |
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Concentration-Independent Killing
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Some agents do not exhibit the concentration-dependent killing effect
Beta-lactams Macrolides Clindamycin Preferred delivery of drug may be continuous infusion rather than intermittent dosing to optimize therapy |
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Post-Antibiotic Effect (PAE)
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Suppression of microbial growth persists long after drug has fallen below effective levels
Aminoglycosides Fluoroquinolones Suggestive of mechanism of action involving some irreversible process or a stable drug-mechanism complex |
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Macrolides
moA soA |
or Erythromycins
Mechanism of action Bind irreversibly to 50S ribosomal subunit Inhibits translocation, and blocks acceptor site. Broad spectrum of action Relatively few primary indications Mycoplasma pneumoniae Corynebacterium diphtheria Legionnaires’ disease |
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Macrolides
named |
Erythromycin
Erythromycin base (E-Mycin, Ery-Tab, Eryc) Erythromycin estolate (Ilosone) Erythromycin ethylsuccinate (E.E.S., EryPed) Erythromycin lactobionate (Erythrocin IV ) Erythromycin stearate (Erythrocin) Clarithromycin (Biaxin) Short acting Azithromycin (Zithromax) Long-acting |
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Macrolides
p-kin considerations |
Orally absorbed but limited acid stability
Erythromycin stearates and estolate and clarithromycin have better absorption and achieve higher blood levels Food interferes with absorption elim through bile good EH circ (espec azithrolong act |
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Macrolides
Adverse effects |
or Erythromycins
-Gastrointestinal upset -Ototoxicity High dose effect -**Cholestatic hepatitis Most likely when therapy > 10 days or repeated courses Fever, enlarged and tender liver, hyperbilirubinemia, dark urine, eosinophilia, elevated serum bilirubin and transaminase levels -Cytochrome P450 induction -*****PROLONGED QT INTERVAL |
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Macrolides
DIs** |
******Never co-administer with cisapride (Propulsid used for gastroesophageal reflux disease) or other drugs noted to prolong ******QT interval*****
Prolongation of the QT interval Cardiac arrhythmias Ventricular tachycardia Ventricular fibrillation Torsades de pointes ******Sudden cardiac death Associated with concurrent use of erythromycins and drugs that inhibit CYP3A4**** Calcium channel blockers Antifungals (azoles) Typical Antidepressants |
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Erythromycin
indic. |
(Macrolide)
Upper respiratory infections Pneumonemia Sexually Transmitted Diseases Gram-positive cocci in patients sensitive to penicillins Mycoplasma Legionella Chlamydia Neisseria |
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Clindamycin
moA soA |
(Cleocin)
Mechanism of action Binds irreversibly to the 50S****** ribosomal subunit and blocks peptide bond formation Similar action to chloramphenicol but with little mitochondrial penetration**(good) Most gram-positive and many anaerobic gram-negative Highly active against staphylococci and streptococci |
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Clindamycin
adverse RXs |
(Cleocin)
Hypersensitivity Gastrointestinal upset ******Pseudomembranous colitis (Black Box Warning) Must distinguish drug-induced from C. difficile Limits use to patients that can not tolerate other drugs May require colectomy if severe Hepatic and bone marrow suppression |
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Clindamycin
BBW |
Pseudomembranous colitis (Black Box Warning)
Must distinguish drug-induced from C. difficile Limits use to patients that can not tolerate other drugs Limits use to patients that can not tolerate other drugs May require colectomy if severe |
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Quinupristin-Dalfopristin
Mechanism of action |
(Synercid)
Binds to separate sites on 50S********* ribosomal subunit (TWISTING OF RIBOSOME) Synergistic action with long post-antibiotic effect Constricts exit channel Blocks normal function of ribosome tRNA synthetase activity is inhibited Decreases free tRNA in cell. |
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Quinupristin-Dalfopristin
adv Rx |
Pain at site of infusion
Joint and muscle pain ********Hepatotoxicity in 1% of patients Hypobilirubinemia in up to 25% of patients Interacts with drugs at the CYP3A4 level |
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Quinupristin-Dalfopristin
BBW |
Vancomycin-resistant streptococcus faecium (Black Box Warning)
BBW is indication I guess because we need to save the drug for this indications- Complicated skin and skin-structure infections Nosocomial pneumonia |
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Linezolid
Mechanism of action soA |
(Zyvox)
Mechanism of action Binds to the 50S subunit and blocks the formation of a functional tRNA-ribosome-mRNA complex Essentially disrupts formation of stable 70S ribosome Spectrum of action Gram positive infections, vancomycin-resistant enterococcal infections |
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Linezolid
adv RXs |
(Zyvox)
Diarrhea, nausea and vomiting Reversible thrombocytopenia with prolonged use Oral suspension contains *****phenylalanine***** and should not be given to phenylketonurics ******Inhibition of monoamine oxidase *****Hypertension in combination with sympathetics(incl tyramine scene)***** |
