antibacterials 1

microorganisms

bacteria (gram + and -)

viruses

fungi

parasites

gram + organisms

MRSA

VRE

gram - organisms

pseudomonas

atypicals (mycoplasma, chlamydia, legionella)

antimicrobial agents

target specific microbial proteins

antimicrobial stewardship

select narrowest spectrum activity and use for shortest effective duration

2 effects of microbial resistance

increase EC50 (aka IC50) = reduce potency

reduce Emax = reduce efficacy

EC50 aka

IC50

mechanisms of antimicrobial resistance

1. reduced antimicrobial % at target

2. inactivation of microbial agent

3. alterations to bacterial target

how to reduce antimicrobial concentration at target

porins, efflux transporters

how do efflux transporters reduce antimicrobial concentration

present in bacteria, actively transport medications out, reducing drug % to ineffective

how is an antimicrobial agent inactivated

by enzymes produced by the bacterial cell that alter or destroy the microbial agent

examples of inactivating enzymes

beta-lactamase

aminoglycoside-modifiying enzymes

esterification of macrolides

how is a bacterial target altered

mutations in antimicrobial target proteins can lead to reduced affinity of the drug for the target

3 causes of altered target structure

natural mutation of target

enzyme-mediated target modification

bacterial acquisition of a resistant form of the target

when do you want to collect a biological sample

before the start of drug therapy

empiric therapy

tx initiated when there is a suspected/known infection but causative agent/susceptibility is not known

antibiogram

profile of antimicrobial sensitivity (unique to each hospital or facility)

definitive therapy

tx when testing of the biological agent confirms the exact causative organism and susceptibility

changing from empiric to definitive therapy may require what?

de-escalation (narrowing spectrum of activity) or reducing to a single agent

AUC =

area under the curve

AUC measures ____

total concentration of a drug over a period of time

MIC =

minimum inhibitory concentration

MIC measures ____

minimum serum concentration needed to inhibit microbial growth

types of antibacterial effects

concentration dependent

time dependent

concentration dependent

- Cmax is predictive of abx efficacy

- time/MIC is less relevant

- dosed intermittently

Cmax

peak drug concentration

time dependent

-time of drug % above MIC is predictive of abx efficacy

-Cmax is less relevant

- dosed more frequently

cell wall synthesis inhibitors

beta lactams

glycopeptides

lipopeptides

beta lactam antibiotics

penicillins

cephalosporins

carbapenems

monobactams

what is a common target in a bacterial cell wall structure

peptidoglycan

beta lactam MOA

bind covalently to PBP site on bacterial cell walls > inhibit peptidoglycan transpeptidation reaction( disrupts cross-linking of cell wall = inhibits cell growth = cell dies)

resistance mechanisms of beta lactams

alterations to PBP target, beta-lactamase activity

what alterations are made to the PBP target

-mutations decrease affinity of PBPs for abx

-ability to express low-affinity PBPs is acquired

beta-lactamases

enzymes that break down the antibiotic before it can elicit an effect

well-defined beta-lactamases

penicillinases

cephalosporinases

extended-spectrum beta lactamases (ESBLs)

cabapenemases

penicillin antibiotics

1. penicillin (PCN)

2. penicillinase resistant penicillins

3. aminopenicillins

4. extended spectrum penicillins

5. antipseudomonal penicillins

syphilis is treated with

penicillin G

otitis media is treated with

amoxicillin

sepsis is treated with

piperacillin/tazobactam

what penicillins cover MRSA

extended spectrum penicillins

what penicillins cover pseudomonas

antipseudomonal penicillins

adverse effects of penicillins

inj. rxn

GI issues (w oral formulation)

hypersensitivity reactions

penicillins hypersensitivity reactions

breakdown of beta-lactam ring = penicilloyl. in some cases, this can initiate an immune response = hypersensitivity reaction

subclasses of cephalosporin antibiotics

1st generation - 5th generation

clinical uses of cephalosporins

SSTI

UTI

URI

what infection can cephalosporins NOT treat

enterococcus

what cephalosporins cover MRSA

5th generation

what cephalosporins cover pseudomonas

4th generation

adverse effects of cephalosporins

(inj. rxn)

(N/D)

renal toxicity (uncommon)

hypersensitivity rxns in cephalosporins

- less frequent than those of penicillin

- cross reactivity based on b-lactam side chain

if a penicillin allergy is non-sever, can you prescribe cephalosporins?

yes

what do you do with cephalosporins and a patient with a life-threatening penicillin allergy?

skin PCN allergy testing

monobactam antibiotics

aztreonam

clinical use of monobactams

severe infections (of gram - )

spectrum of activity of monobactams

pseudomonas

adverse effects of monobactams

skin rash

hepatotoxicity

hypersensitivity reactions in monobactams

- lack of cross-reactivity with other b-lactam abx

- safe in patients with hx of penicillin anaphylaxis

carbapenem antibiotics

ertapenam

imipenem

meropenem

clinical uses of carbapenems

multidrug resistant (MDR) pathogens

ESBL producing oragnisms

what carbapenems cover pseudomonas

imipenem and meropenem

adverse effects of carbapenems

N/V

seizures (rare)

hypersensitivity reactions in carbapenems

- most patients can safely take even if they are allergic to other b-lactam abx

- those with severe allergic reactions should consider slow titration

glycopeptide antibiotics

vancomycin

glycopeptide (vanco) MOA

- binds covalently to D-ala-D-ala binding site of peptidoglycan (inhibits cross-linking of cell wall = inhibits cell growth = cell dies)

resistance mechanisms of glycopeptide abx (vanco)

alteration of D-ala-D-ala target to D--lactate or D--serine so vanco can't bind

clinical uses of glycopeptide abx (vanco)

PO - ONLY Cdiff

IV - severe infections (meningitis, endocarditis)

spectrum of activity of vanco

MRSA

adverse effects of vancomycin

ototoxicity

AKI

red man syndrome

drug monitoring of vancomycin

- serum % (trough levels) drawn at steady state

- AUC/MIC dosing

how is vancomycin removed in patients in renal failure

hemodialysis

lipopeptide antibiotics

daptomycin

lipopeptide (daptomycin) MOA

binds to inner bacterial membrane > induces polarization > loss of membrane potential = cell death

resistance mechanisms of daptomycin

poorly defined, likely impedes daptomycin binding

clinical uses of daptomycin

SSTI

bacteremia

endocarditis

when to NOT use daptomycin

respiratory infections (drug inactivated by lung surfactant)

daptomycin spectrum of activity

MRSA

VRE

adverse effects of daptomycin

myopathy, rhabdomyolysis

protein synthesis inhibitors

tetracyclines

macrolides

lincosamides

oxazolidinones

tetracycline antibiotics

tetracycline

doxycycline

monocycline

tigecycline

tetracycline MOA

bind reversibly to 30S subunit > prevent tRNA binding = inhibiting protein synthesis

resistance mechanisms of tetracyclines

reduced antimicrobial % at target

inactivate antimicrobial agent

how does bacteria reduce tetracycline % at target

- decrease influx of abx

- increased efflux

- ribosomal protection protein (displaces tetracycline from target)

how is tetracycline inactivated

destructases induce enzymatic modification of abx

clinical uses of tetracycline

URI

SSTI

zoonotic infections

spectrum of activity of tetracycline

MRSA

atypicals

adverse effects of tetracyclines

GI irritation

photosensitivity

permanent brown discoloration of teeth

when is tetracycline absorption impaired

when ingested with dairy products and antacids

what patients cannot take tetracycline

pregnant patients and kids 0-8 y/o

macrolide antibiotics

azithromycin

clarithromycin

erythromycin

fidaxomicin

macrolides and lincosamides MOA

reversibly bind to 50S subunit > conformational change that terminates protein synthesis

resistance mechanisms of macrolides

- increased efflux

- hydrolysis

- mutations fo 50S subunit, modification of ribosomal target

clinical uses of macrolides

fidaxomicin = Cdiff

all others = RTIs

macrolides spectrum of activity

atypicals

adverse effects of macrolides

cardiac toxicity

ototoxicity

tinnitus

lincosamide antibiotics

clindamycin

resistance mechanisms of lincosamide (clindamycin)

enzymatic inactivation of abx

mutations to 50S subunit

clinical uses of lincosamide (clindamycin)

inhibition of toxin production associated with necrotizing fasciitis or gas gangrene

clindamycin spectrum of activity

MRSA

adverse effects of clindamycin

diarrhea w high risk of Cdiff

skin rash

clindamycin use increases the risk of

Cdiff