week 7 - antimicrobial therapy

prophylactic therapy

• to prevent infection

• consider in individuals at increased risk of developing infection

empiric therapy

• given when infection is suspected before organism identified

• antimicrobial selection guided by patient’s presentation and history

targeted therapy

• treatment selected to target specific organism known to be causing infection

• selection guided by organism culture results and sensitivities

stepwise approach to antimicrobial therapy

• assessment

• empiric therapy

• monitoring

• targeted therapy

• follow up

components of assessment

• gather information

  • is there an infection and any infectious history

• sample collection

  • gram staining (less than 24 hours)

  • culture (24-48 hours)

  • PCR

  • antibiotic susceptibility (over 48 hours)

when to collect sample

• before antimicrobial agents

• having antimicrobial agent decreases chance of isolating organism

how to select appropriate empiric therapy

• host/patient factors

  • med hx, age, allergies, prior infection/hospitalizations, prior antimicrobial use, prior drug colonization, hx of resistance

• drug factors

  • pharmacokinetics

  • pharmacodynamics

• infection factors

pharmacokinetics

movement of drugs within the body

• absorption: route of administration

• distribution: will drug reach site of infection

• metabolism

• excretion

pharmacodynamics

the action of the drug in the body

drug spectrum of activity, MOA, combination therapy, resistance

drug factors- antimicrobial spectrum

• broad spectrum: active against large variety or organism

  • increased chance of activity against unknown

  • promote development of resistance

  • used for empiric therapy

• narrow spectrum: active against limited group of organism

  • associated with reduced development of drug resistance

  • risk of poor activity/lack of effect against unknown organism

  • used as targeted therapy

drug factors- MOA (bacteriostatic vs bactericidal)

• bacteriostatic

  • inhibits/shows bacterial growth

  • requires a functioning immune system to clear infection

  • used in less serious infections

• bactericidal

  • causes bacterial death

  • preferred in serious infections or immunocompromised hosts

drug factors- MOA (time dependent vs concentration dependent killing)

• time dependent killing

  • drug concentration must remain above minimum inhibitory concentration (MIC) for effect

  • the absolute amount above MIC does not impact activity

• concentration dependent killing

  • the peak drug concentration determines effect

  • demonstrate a post antibiotic effect where activity continues even when drug concentration is less than the MIC

drug factors- combination therapy

• synergism

  • combining different antimicrobials to produce an effect that exceeds the sum of their individual effects

• broadens spectrum

  • combining antimicrobials with different spectrum to fill gaps in coverage

• double coverage

  • combining 2 different antimicrobials with activity against the same organism of interest

    • increases likelihood od success

    • reduces development of antimicrobial resistance

drug factors- antimicrobial resistance

• the ability of certain organisms to develop a tolerance to specific antimicrobials to which they were once susceptible

• must occur naturally over time, but accelerated by the musse of overuse of antimicrobials

• risk factors for developing:

  • prior antibiotic exposure

  • underlying disease (ex. hemodialysis)

  • prior hospitalization

  • invasive procedures in healthcare settings

drug factors- mechanism of resistance

• preventing the antimicrobial from reaching its target at sufficient concentrations

  • decreased uptake

  • inactivating enzymes (ex. beta lactamases)

  • increased efflux

• modifying the target of the antimicrobial

  • altering the target

  • alternative enzymes

monitoring

• symptoms

  • can take 2-5 days to improve

• therapeutic drug monitoring

• cultures and sensitivities

• antimicrobial side effects

therapeutic drug monitoring

• measuring drug levels in blood to guide dosing to ensure efficacy and safety

• timing of blood collection is essential component

• different antimicrobials require levels to be drawn at various time points

  • trough level (lowest serum concentration)

    • = draw blood 30 minutes prior to next dose

  • peak levels (highest serum concentration)

    • = draw blood immediately after the dose has been administered

why is targeted therapy important

• minimize risk of developing antimicrobial resistance

• reduce risk of toxic side effects

antibiotics that target cell wall synthesis

• B lactams

  • penicillin

  • cephalosporins

  • monobactams

  • carbapenems

• glycopeptides

  • vancomycin

• bacitracin

bacterial cell walls

• peptidoglycan is the major component

• transpeptidation: the last step of cell wall synthesis

  • penicillin binding proteins (PBPs) form cross links in the cell wall

beta lactam classifications and common naming

beta lactam MOA

• interrupt cell wall synthesis by:

  • binding to PBPs

  • inhibiting transpeptidation

• results in:

  • improper cell wall formation → inability to withstand osmotic pressure → cell ruptures → cell death

  • bactericidal, time dependent killing

beta lactams- penicillins

beta lactams mechanism of resistance

1. bacterial cell production of beta lactamases

2. modification PBP binding site (ex, MRSA)

3. changes to porin channels

4. drug efflux pumps

beta lactamases

• produced by some bacteria

• enzymes that cleaves the beta lactam ring through hydrolysis

• inactivates beta lactam antibiotics

beta lactamase inhibitors

• some beta lactamases are paired with beta lactamase inhibitors to overcome resistance

  • inactive beta lactamases to extend spectrum of activity → MSSA, gram -ve, anaerobes

• increase risk of nausea, vomiting, and diarrhea

• ex of pairs:

  • amoxicillin- clavulanic acid (IV, PO)

  • piperacillin-tazobactam (IV)

beta lactams-cephalosporins

beta lactams- carbapenems

beta lactam allergies

• up to 10% of pts have penicillin allergy

  • less than 1% true allergy

  • many outgrow true allergy

• true penicillin allergies

  • type 1 IgE mediated: anaphylaxis, hypotension, angioedema

    • avoid all penicillins and cephalosporins with similar side chain

• cross reactivity between beta lactams

  • around 1% between penicillins and cephalosporins

  • around 0.1% between penicillins and carbapenems

severe non IgE mediated hypersensitivity reactions

• type IV non IgE mediated: stevens-johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS)

• avoid all beta lactams

vancomycin

• MOA:

  • inhibits cell wall synthesis

  • binds to the terminal end of peptidoglycan precursor → prevents polymerization → weakens the cell wall → cell death

• bactericidal, time dependent killing

vancomycin infusion reaction (flushing syndrome)

• characterized by pruritus, flushing, and erythema of the face and upper torso (NOT life threatening)

• due to rapid infusion of the drug leading to histamine release

  • related to infusion rate

• managed by slowing infusion rate

• in contrast, vancomycin allergy:

  • anaphylaxis, hypersensitivity, hives, angioedema, bronchoconstriction, can be life threatening

  • managed by stopping infusion and administering epinephrine

vancomycin monitoring

• nephrotoxicity

  • monitor for increasing serum creatinine (SCr) and decreasing urine output

• therapeutic drug monitoring

  • serum trough levels once at steady state (pre fourth dose)

  • if trough is out of range let pharmacist know for dose adjustments

fosfomycin

• MOA:

  • inactivated MurA enzyme involved in peptidoglycan synthesis → weakens cell wall → cell lysis

  • also inhibits adherence of bacteria to epithelium

  • bactericidal, concentration dependent killing

antibiotics that target the plasma membrane

• polymyxins

  • polymyxin B

  • colistin

• lipopeptide

  • daptomycin

daptomycin

• MOA:

  • binds to cell membrane leading to depolarization, efflux of potassium, and inhibition of DNA, RNA, and protein synthesis

  • bactericidal, concentration dependent killing

daptomycin monitoring

• rhabdomyolysis: rapid breakdown of skeletal muscle

  • can be life threatening

  • monitor: patient reported muscle pain, creatine kinase (CK) and dark urine

• eosinophilic pneumonia

  • monitor: eosinophils, new onset fevers and dyspnea

antibiotics that target DNA and RNA synthesis

DNA synthesis

• fluoroquinolones

  • ciprofloxacin

  • levofloxacin

  • moxifloxacin

RNA synthesis

• rifamycins

  • rifampin

fluoroquinolones

• MOA:

  • inhibits DNA synthesis by inhibiting bacterial DNA gyrase and topoisomerase IV → promotes the breakage of DNA

  • bactericidal, concentration dependent killing time

• ends in “…floxacin”

fluoroquinolones and metal cations

• bind bivalent or trivalent cations → decrease absorption

• avoid administering oral with bivalent or trivalent metal cations by 2 hours

  • this includes supplements like zinc, magnesium, iron, calcium

antibiotics that create free radicals

• metronidazole

• nitrofurantoin

metronidazole

• MOA

  • becomes reduced by anaerobic organisms → becomes cytotoxic free radical that breaks DNA, inhibits nucleic acid synthesis and results in loss of DNA integrity → cell death

  • bactericidal, concentration dependent killing

antibiotics that target metabolic pathways

• folic acid synthesis

  • sulfonamides

  • sulfones

  • trimethoprim

• mycolic acid synthesis

  • izoniazid

sulfamethoxazole/trimethoprim

• MOA:

  • the 2 work synergistically

  • inhibit folic acid synthesis which is necessary for DNA synthesis

  • bactericidal, time dependent killing

antibiotics that target ribosomes

• 30S subunit

  • aminoglycosides

  • tetracyclines

• 60S subunit

  • macrolides

  • lincosamides

  • chloramphenicol

  • oxazolidinones

linezolid (oxazolidinone)

• MOA:

  • binds to P site of 50S ribosomal unit → prevents formation of 70S complex

  • bactericidal against streptococci and bacteriostatic against staphylococci and enterococci

  • time dependent killing

macrolides

• MOA:

  • reversibly binds to 50S subunit → prevents transpeptidation → protein synthesis inhibited

  • bacteriostatic, time dependent killing

• ends in “..mycin”

clindamycin (lincosamides)

• MOA:

  • similar to macrolides; reversibly bind to 50S ribosomal subunit → inhibits transpeptidation → protein synthesis inhibited

  • bacteriostatic, time dependent killing

aminoglycosides

• MOA:

  • binds irreversibly with 30S subunit → prevents transpeptidation → protein synthesis inhibited

  • bactericidal, concentration dependent killing

aminoglycosides dosing

• extended-interval dosing: single, large dose once daily

  • more rapid bactericidal activity and less toxic

  • recommended for most infection in most patients

• traditional dosing: smaller doses given multiple times a day

  • used when can’t use extended-interval dosing and for synergy

aminoglycosides therapeutic monitoring

• troughs are used to monitor for toxicity: drawn 30 minutes prior to next dose

• peaks are used to measure efficacy: drawn 20 minutes after infusion end

• targets levels vary

tetracyclines

• MOA:

  • bind to 30S subunit → blocks attachment of tRNA to mRNA ribosome complex → protein synthesis inhibited

  • bacteriostatic, time dependent killing

are fungi eu or prokaryotic

eukaryotic

3 types of fungi

• yeast

  • single celled, budding reproduction

• mold

  • multi cellular, branching filaments

• dimorphic fungi

  • yeast at higher temps (37 degrees)

  • mold at lower temp (25)

fungal structure

• cell membrane made of ergosterol

  • azole and terbinafine target ergosterol synthesis

• cell wall of chitin and beta glucan

  • polyoxins inhibit chitin synthase

  • echinocandins inhibit beta glucans synthesis

antifungal medications

• polyenes

  • nystatin

  • amphotericin B

• echinocandins

• azoles

• terbinafine

polyenes MOA

• binds to ergosterol in the fungal membrane → form a pore through the membrane → electrolyte leakage → cell death

• resistance: rare, due to decrease or change in structure of ergosterol

• fungicidal

polyenes: nystatin

• oral suspension: swish and swallow/spit

• poorly absorbed, cannot be used for systemic infections

polyenes: amphotericin B

• lipid formulation available

  • less nephrotoxic and fewer infusion related reactions

• can reduce adverse effects by pre-treating with medications, prolonging the infusion, nad providing patient with adequate hydration

  • pre treatment includes: fluids, antipyretics, antihistamines

echinocandins

• inhibits synthesis of beta (1,3)-D-glucan (component of the cell wall) by inhibiting Beta (1,3)-D_glucan synthase

• impaired cell wall synthesis → cell rupture and death

• fungicidal (candida) or fungistatic (aspergillus)

echinocandins monitoring

• monitor for potential infusion reactions (ex. facial swelling , flushing, rash)

• monitor liver function (caspofungin requires dose adjustment in hepatic impairment)

echinocandins extra info

• IV only: if oral therapy is clinically warranted and the infection is susceptible, a switch to an alternate antifungal would be required

• poor penetration to CNS, vitreal fluid and urine

• very few drug interactions

azoles

• MOA:

  • inhibits cytochrome P450 14-alpha lanosterol demethylase → inhibits conversion of lanosterol to ergosterol → increases permeability and accumulation of toxic steroles → cell death

  • resistance: altered drug binding site

  • fungicidal or fungistatic

azoles agents

azoles extra info

• IV to oral stepdown: bioavailability is typically high and oral may be used even for deep seated infections

• many drug interactions

• renal and hepatic function must be monitored on oral/IV therapy: QTc prolongation can occur with any systemic azole

• if susceptible, use fluconazole as it has the best safety profile and excellent oral bioavailability and good penetration into CNS/vitreal fluid

terbinafine

• MOA

  • interferes with squalene epoxidase → inhibit ergosterol biosynthesis → alter cell membrane permeability and accumulation of toxic sterols → cell death

  • resistance: mutation in squalene epoxidase

  • fungicidal

viruses

• consist of DNA or RNA within a protein outer shell

• require use of host cell machinery to replicate; cannot replicate on own

• infect host cells and “re-program” to replicate and the virus

types of antivirals

• neuraminidase inhibitors

• polymerase inhibitors

neuraminidase inhibitors

• MOA:

  • it is an influenza viral enzyme that facilitates the release of new viruses

  • these drug inhibit this process- preventing the virus’ ability to spread adn replicate further

• resistance:

  • mutations in the neuraminidase enzyme prevent the antivirals from binding

polymerase inhibitors

• MOA

  • DNA polymerase is responsible for DNA synthesis

  • polymerase inhibitors incorporate into viral DNA by competing for DNA polymerase → inhibits DNA synthesis

• resistance:

  • mutations in viral DNA polymerase or thymidine kinase

narrow spectrum polymerase inhibitors

• acyclovir, valacyclovir, famciclovir

broad spectrum polymerase inhibitors

• ganciclovir, valganciclovir