Antibiotics Lecture 12 Flashcards Preview

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1

Gram Positive

Staphylococcus (CoNS, aureus, MRSA)

streptococcus (pyogenes, pneumonia, PCN-resistant)

enterococcus (faecalis, faecium, VRE)

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Gram Negative

Piddly: Haemophilus, morexella, morganella, shigella, salmonella (provedencia, neisseria)

fence (pek): proteus, eschericia coli, klebsiella

SPACE: serratia, pseudomonas, acinetobacter, citrobacter, enterobacter

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Atypicals

chlamydia, mycoplasma, legionella

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Anaerobes

peptostreptococcus, bacteroides, clostridium

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Bactericidal agent

kill bacteria

penicillins, cephalosporins

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bacteriostatic agent

works but may have limitations

inhibitory to growth of susceptible microorganisms: sulfonamides

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Narrow spectrum of activity

effective against a small number of microorganisms

Pen G: gram positive organisms (strep)

nafcillin: staph and strep

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broad spectrum of activity

effective against a large number of microorganisms

piperacillin/ tazobactam

imipenem: gram positive, gram negative, and anaerobic organisms

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Synergy

enhancement of action of one drug by another

trimethoprim/sulfamethoxazole: sequential inhibition of folic acid synthesis

penicillin/aminoglycoside: increased penetration of aminoglycoside as penicillin breaks down cell wall (enterococcus)

different site for mechanism of action (psedomonas)

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antagonism

decreased action of one drug by another

bacteriostatic/bactericidal: most cidal agents require active cell division or acitve protein synthesis for expression of their bactericidal activity.

many static agents inhibit these "active" processes

may be more in vitro than in vivo

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postantibiotic effect

persistent effect of an antimicrobial on bacterial growth following brief exposure of organisms to a drug

aminoglycosides and fluoroquinolones

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pharmacodynamics: concentration and time dependent killing

concentration dependent killing: killing dependent on peak concentration. Optimal kill occurs when conc exceeds 10x MIC. Quinolones, aminoglycosides

time dependent killing: Killing is dependent on amount of time the concentration stays above the MIC (40-50%). B-lactam antibiotics

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Mechanism of action of antimicrobial agents

inhibitors of cell wall synthesis

inhibitors of protein synthesis or structure

interferes with cell membrane function

interferes with DNA/RNA syntehsis

inhibitors of metabolism

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Inhibitors of cell wall synthesis

Penicillins/cephalosporins/carbapenems/aztreonam: prevents cross linking of peptidoglycan strands by inhibiting transpeptidases

vancomycin: inhibits peptidoglycan synthetase and polymerization of linear peptide

bacitracin

cycloserine

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Inhibitors of protein synthesis/structure

aminoglycosides: inhibits 30s ribosomes; causes misreadings of mRNA

chloramphenicol: inhibits peptidyl transferase and peptide formation

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Inhibitors of protein synthesis/structure 2

erythromycin, clindamycin, lincomycin: inhibits 50s

tetracyclines: inhibits binding of aminoacyl tRNA to ribosome. 30s

streptogramins/linezolid: 23s

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interference with cell membrane function

polymixin B, colistin: cationic detergent

fungal section: azole and polyene antifungals

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interference with DNA/RNA synthesis

rifampin: inhibits DNA dependent RNA polymerase

fluoroquinolones: intereres with super coiling of DNA by action of DNA gyrase topoisomerase II

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Inhibitors of metabolism

isoniazid, ethambutol: inhibits lipid synthesis

sulfonamides, trimethoprim: prevents synthesis of folic acid

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confirm presence of infection

antimicrobial stwardship

fever

signs and symptoms: physical findings (cackles, SOB, erythema, dysuria), leukocytosis/left shift, pain, blood

predisposing factors: disruption of natural barriers, immunosuppressive state, age

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basic steps in therapy

determine the site of infection

determine the causative organisms: which antimicrobial agents are effective against it (them)

select a drug based on: sensitivity of the microorganism, physiochemical properties, toxicities of the drug, patient characteristics

follow patient for clinical response

alter therapy as necessary

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Starting empiric ABX coverage

site of infection difficult to culture: cellulitis, pneumonia, brain abscesses, middle ear infection

serious or life-threatening infections: timing to collect cultures

empiric therapy: culture site before starting antibiotics. Gram stains very informative for selection of empiric antibiotic

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Pharmacologic considerations

route of administration, distribution, routes of elimination, drug interactions, allergies

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routes of administration

oral candidates: mild to moderate infections

intravenous candidates: moderate to severe infections. patient unable to take oral agents. afebrile for 2-3 days consider change to oral

intramuscular: IV access is not obtainable. Short term solution

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distribution

consider site of infection and distribution of agent to that site

urine concentration, bone penetration, lung tissue penetration, skin and osft tissue concentration, meningitis (penetration into CNS when meninges are inflamed vs uninflammed (ceftriaxone vs unasyn))

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route of elimination

renal vs hepatic: dose reduction for renal insufficiency. Recommendation for dialysis patient. Many drugs are eliminated through the renal system.

urinary tract infection: renal excretion is desired. High concentration of drugs are eliminated unchanged.

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drug interactions

concurrent medication interferes with antibiotic: antacids with quinolones and tetracycle

antibiotic interferes with concurrent agent: bactrim or erythromycin with warfarin. Ciprofloxacin with theophylline, and linezolid with selective serotonin reuptake inhibitor (SSRIs)

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microbial resistance

certain organisms inherit resistance patterns from environmental exposure to ABX

resistance may be natural or may result from mutation, adaptation, or gene transfer

multiple resistance-plasmids

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mechanisms of resistance

increased drug inactivating enzyme activity (b-lactamases)

alter cell wall/ membrane permeability: alteration of the porin channel

altered binding site/ receptor of drug

drug efflux

increase endogenous metabolite: sulfonamides (bacteria may synthesize PABA to antagonize drug)

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MoR Penicillins/cephalosporins

B lactamases

PBP changes

Porin channel changes

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MoR aminoglycosides

enzyme inactivation

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MoR Macrolides

Methyltransferases that alter drug binding sites on 50S ribosomal subunit

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MoR tetracyclines

transport systems that pump drugs out of the cell

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MoR sulfonamides

Increased PABA formation

target enzyme sensitivity

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MoR Fluroquinolones

target enzyme changes

drug efflux

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Combination therapy Pros and cons

advantages: treatment of mixed bacterial infections. treatment of severe infections when organism is unknown. Enhancement of antibacterial activity (synergy: endocarditis tx; pseudomonas spp)

disadvantage: added risk of toxicity

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Adverse effects

allergic reactions

dose related toxicities: imipenem: seizures, amphotericin: nephrotoxicitiy, cefazolin: neutropenia (dose and duration)

idiosyncratic reactions: aplastic anemia: chloramphenicol

alteration of normal flora (superinfection)

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Cost

the least expensive agent that will treat the patient's infection should be used

de escalation from broad spectrum to narrow

side effect profile

required monitoring of therapy: vancomycin peak/trough, very expensive (CBC, SCR/BUN, trough levels)

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delays in beginning therapy

initiate therapy as soon as possible

first dose in ER (mixed research 2, 4, 6, 8 hours)

balance overuse vs timely administration

important to culture suspected sites before beginning antibiotics

check gram stain and results of cultures for verification of appropriate antibiotics

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inadequate drug or drug levels

patient not culture before initiating therapy

meningitis: inadequate penetration of drug into the CNS

pneumonia: aminoglycosides concentration of 8-10 mcg/ml necessary to penetrate the lung (40% of blood conc reaches lung)


balance high enough peak with low enough trough

call pharmacy to dose and monitor

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host defenses inadequate

immunocomrpomised host: cancer patients or HIV/AIDS patients

success dependent on achieving a level of antibacterial activity: sufficient to tip the balance in favor of the host. dWhile preventing toxicities, resistance and superinfection

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abscess

antibiotic therapy, in most cases, is not adequate

drainage of involved area necessary to resolve infection

antibiotic cleans up the remaining infection and/or cellulitis

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Other factors

drug interactions: binding and compliance

microbial resistance: developed during therapy. intrinsic

lab error

viral infection

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superinfection

alterations in normal flora results in removal of inhibitory influences in the body

usually due to broad spectrum antibiotics

enterobacteriaceae (PEK, SE)

candida spp.

clostridium difiicile (pseudomembranous colitis)

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SPACE bug coverage: Box and one coverage

cell wall inhib: PCN (piperacillin, ticarcillin), Ceph (cetazadime, cefepime), Carbapenem (imipenem, meropenem), Monobactam

DNA gyrase: FQN (ciprofloxacin, levofloxacin)

30S: aminoglycosides (gentamicin, tobramycin, amikacin)

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SPACE: Ace in the Hole and the last resort

Azetreonam (Anaphylaxis)

Colistin