Antibiotics Lecture 12 Flashcards
Gram Positive
Staphylococcus (CoNS, aureus, MRSA)
streptococcus (pyogenes, pneumonia, PCN-resistant)
enterococcus (faecalis, faecium, VRE)
Gram Negative
Piddly: Haemophilus, morexella, morganella, shigella, salmonella (provedencia, neisseria)
fence (pek): proteus, eschericia coli, klebsiella
SPACE: serratia, pseudomonas, acinetobacter, citrobacter, enterobacter
Atypicals
chlamydia, mycoplasma, legionella
Anaerobes
peptostreptococcus, bacteroides, clostridium
Bactericidal agent
kill bacteria
penicillins, cephalosporins
bacteriostatic agent
works but may have limitations
inhibitory to growth of susceptible microorganisms: sulfonamides
Narrow spectrum of activity
effective against a small number of microorganisms
Pen G: gram positive organisms (strep)
nafcillin: staph and strep
broad spectrum of activity
effective against a large number of microorganisms
piperacillin/ tazobactam
imipenem: gram positive, gram negative, and anaerobic organisms
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)
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
postantibiotic effect
persistent effect of an antimicrobial on bacterial growth following brief exposure of organisms to a drug
aminoglycosides and fluoroquinolones
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
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
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
Inhibitors of protein synthesis/structure
aminoglycosides: inhibits 30s ribosomes; causes misreadings of mRNA
chloramphenicol: inhibits peptidyl transferase and peptide formation
Inhibitors of protein synthesis/structure 2
erythromycin, clindamycin, lincomycin: inhibits 50s
tetracyclines: inhibits binding of aminoacyl tRNA to ribosome. 30s
streptogramins/linezolid: 23s
interference with cell membrane function
polymixin B, colistin: cationic detergent
fungal section: azole and polyene antifungals
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
Inhibitors of metabolism
isoniazid, ethambutol: inhibits lipid synthesis
sulfonamides, trimethoprim: prevents synthesis of folic acid
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
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
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
Pharmacologic considerations
route of administration, distribution, routes of elimination, drug interactions, allergies
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
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))
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.
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)
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
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)
MoR Penicillins/cephalosporins
B lactamases
PBP changes
Porin channel changes
MoR aminoglycosides
enzyme inactivation
MoR Macrolides
Methyltransferases that alter drug binding sites on 50S ribosomal subunit
MoR tetracyclines
transport systems that pump drugs out of the cell
MoR sulfonamides
Increased PABA formation
target enzyme sensitivity
MoR Fluroquinolones
target enzyme changes
drug efflux
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
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)
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)
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
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
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
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
Other factors
drug interactions: binding and compliance
microbial resistance: developed during therapy. intrinsic
lab error
viral infection
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)
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)
SPACE: Ace in the Hole and the last resort
Azetreonam (Anaphylaxis)
Colistin
