principles of infectious disease therapeutics Flashcards
antimicrobial PKPD that is important in combatting superbugs
- clinical: focus on the patient
- translational: turning bench research into clinical guidance –> stewardship
- interdisciplinary: pharmacy, medicine, science, pharm sci
- global: bridge collaboration
- trainee focused
interdisciplinary aspect of ID
- pharmaceutics
- pharmacometrics
- drug delivery and design
- drug discovery and development
- bacterial
- chemotherapy
- gene therapy
- ID
most common organism of infection is…
the one that lives in that area
most common eye infection
staph aureus
most common gastritis infection (stomach)
helicobacter pylori
most common food poisoning infection (intestines)
Escherichia coli
most common urinary tract infection
E. coli
most common skin infection
Staph aureus
most common community acquired pneumonia infection (lungs)
Strep pneumoniae
most common ear infection
strep penumoniae
most common bacterial meningitis infection (brain)
strep penumoniae
infectious and parasitic disease is the number __ cause of death globally
2
post-antibiotic world
when superbugs do not respond to the last line antibiotic defense
polymyxin mono therapy vs combination therapy for all-cause mortality endpoint
for invasive CRE (carbapenem resistant enterobacterales) infections
- combination therapy (second antibiotic causes damage in outer membrane)
for other infections
- no evidence to support combination > monotherapy
- lots of trial issues
ID triad
- host
- drug
- bacteria
ID patient considerations
- host
- infection site and severity
- MICs
- treatment regimens
vancomycin route of administration
IV ONLY!!!
if staph aureus, which antibiotics can you NEVER USE alone even if S? why?
- ciprofloxacin
- rifampin
***will develop resistance within 24 hours!! (very susceptible to resistance)
(can use in combo therapy tho (?) (only rifampin?))
what is the target vanco AUC 24 hr from the guidelines?
400 mg*hr/L
what is the equation to adjust vanco dosing?
D target = D observed (AUC 24 target / AUC 24 obser)
aka
D target AUC 24 target
————- = ————————
D observed AUC 24 observed
antibiogram selection considerations
- cost
- dosage form (IV vs PO)
- is failure okay or would it be lethal?
- may become resistance once administer it
what number on an antibiogram is safe for susceptibility?
80
on an exam, highest wins
does susceptible mean it will be sucessful?
no
the primary mechanism of resistance is…
the primary mechanism of action of the antibiotic being used
mechanism of action for ciprofloxacin –> mechanism of resistance for ciprofloxacin
MoA: fluoroquinolone -> DNA synthesis inhibitor
MoR: mutational event in the DNA replication process
mechanism of action for linezolid –> mechanism of resistance for linezolid
MoA: oxazolodonones –> protein synthesis inhibitor
MoR: ribosomal protection (tet protein) –> allows for no inhibition and protein synthesis to continue
mechanism of action for vancomycin –> mechanism of resistance for vancomycin
MoA: glycopeptide –> cell wall agent (blocks peptidoglycan synthesis)
MoR: decrease cell wall permeability to vanco –> prevents peptidoglycan synthesis)
mechanism of resistance for beta lactamase bacteria enzyme
the beta lactamase enzyme will open the ring of the beta lactam antibiotics, thus inactivating them –> enzymatic inactivation mechanism of resistance
the beta lactamase inhibitor drugs will act as bet lactam decoys and trick the beta lactamase enzymes to break them down instead, thus saving the beta lactam ring and the action of the antibiotics
bacteriocidal
99% killing, CFU below 10^4
bacteriostatic
inhibitory, CFU above
HEM PEK SPACE are all…
gram negative aerobes
which HEM PEK SPACE are cocci?
H,M
Haemophilus influenzae
Moraxella catarrhalis
*the rest are bacilli
HEM PEK SPACE
H: Haemophilus influenzae
E: Enterobactericiae (group)
M: Moraxella catarrhalis
P: Proteus sp.
E: E. coli
K: Klebsiella sp.
S: Serratia
P: Pseudomonas aeruginosa
A: Acinetobacter
C: Citrobacter
E: Enterobacter sp.
what is methicillin?
the first penicillin that caused bacterial resistance, pulled from market for AEs –> use to determine if we can use penicillins or not
clindamycin is used for
above diaphragm anaerobes
metronidazole is used for
below diaphragm anaerobes
staph is
aerobe
gram positive
clusters
strep pneumoniae is
aerobe
gram positive
pairs
GAS and GBS are
aerobe
gram positive
chains
e coli is
aerobe
gram negative
bacilli
pseudomonas aeruginosa is
aerobe
gram negative
bacilli
staph aureus is
aerobe
gram positive
clusters
coagulase positive
staph epidermidis is
aerobe
gram positive
cluster
coagulase negative
what is coagulase?
bacterial enzyme that coagulates blood/plasma that is produced by infectious staph
is strep pneumoniae typical or atypical bacteria?
typical
penicillin MoA
beta lactams –> cell wall active
bind to transpeptidase enzymes (penicillin binding proteins) in the bacterial cell and disrupt cell wall formation
penicillins are bacterio…
cidial
penicillins are bacterio…
cidia
pencillin spectrum
gram positive aerobes
MSSA
some gram negative aerobes
some pseudomonas
cephalosporins MoA
beta lactams –> cell wall active
bind to transpeptidase enzymes in bacterial cell wall and disrupt cell wall formation (same as penicillins bc all beta lactams)
cephalosporins are bacterio…
cidal
cephalosporin spectrum
gram positive aerobes
MSSA
gram negative aerobes
some pseudomonas
which cephalosporins cover pseudomonas?
ceftazidime (3rd)
cefepime (4th)
which penicillins cover pseudomonas?
piperacillin
piperacillin/tazobactam
ticarcillin
ticarcillin/clavanute
which cephalosporins cover MRSA?
ceftaroline (5th)
which cephalosporin covers both MRSA and pseudomonas?
none
carbapenems MoA
beta lactams –> cell wall active agents
carbapenems spectrum
MOST BROAD SPECTRUM SINGLE AGENT!!
gram positive aerobes
MSSA
gram negative aerobes
pseudomonas (NOT ertapenem)
gram negative anaerobes
monobactams MoA
beta lactam –> cell wall active agent
monobactams spectrum
gram negative aerobes
pseudomonas
aminoglycoside MoA
protein synthesis inhibiting agents
bind to 30S ribosomal subunit and inhibit bacterial protein synthesis
aminoglycosides are bacterio….
cidal
aminoglycoside spectrum
some gram positive aerobes
some MSSA
some MRSA
gram negative aerobes
pseudomonas
aminoglycoside rank of activity against pseudomonas
- amikacin
- tobramycin
- gentamicin
which amino glycoside covered gram positive aerobes including MSSA and MRSA and infective endocarditis
gentamicin + cell wall active agent
aminoglycoside AEs
- nephrotoxicity
- ototoxicity (hearing/balance)
- enhanced neuromuscular blockade
which antibiotics cause nephrotoxicity?
- aminoglycosides
- polymyxins
- vancomycin (glycopeptide – cell wall active)
(- piperacillin/tazobactam (Zosyn))
tetracyclines MoA
protein synthesis inhibiting agent
reversibly bind the 30S ribosomal subunit and inhibit bacterial protein synthesis
tetracyclines are bacterio…
STATIC!
tetracycline counseling
do not take with di and trivalent cations aka milk, antacids, sucralfate –> dec oral absorption
worse with tetracycline than doxycycline
tetracycline AEs
- GI intolerance
- phototoxicity (skin or eyes become sensitive to light)
- fanconi syndrome (dec kidney reabsorption)
tetracycline spectrum
gram positive aerobes
MSSA
MRSA
gram negative aerobes
atypicals
macrolides MoA
protein synthesis inhibitor
reversibly binds to 50S ribosomal subunit and inhibits bacteria protein synthesis
macrolides are bacterio…
STATIC
macrolide AEs
- GI intolerance (EVEN WITH IV erythromycin)
- IV erythromycin: phlebitis (inflammation that causes blood clot)
macrolide spectrum
gram positive aerobes
MSSA
gram negative aerobes
atypical
lincosamides MoA
protein synthesis inhibiting agent
reversibly bind 50S ribosomal subunit and inhibit bacteria protein synthesis
lincosamides are bacterio…
STATIC
lincosamide AEs
- GI
- pseudomembranous colitis (inflammation in colon (large intestine) bc overgrowth of C diff)
lincosamide spectrum
gram positive aerobes
MSSA
MRSA
gram negative anaerobes
**excellent bone penetration
fluoroquinolone MoA
DNA synthesis inhibitors –> antimetabolite and other
inhibit DNA gyrase which causes breakage of bacterial DNA –> therefore inhibits DNA
fluoroquinolones are bacterio…
cidal
fluoroquinolone counseling
do not take with di and trivalent cations (milk, antacids, sucralfate) bc dec oral absorption
DDI!!!
which two antibiotic classes can you not take with milk, antacids, sucralfate? why?
tetracyclines (doxycycline, tetracycline)
fluoroquinolones (ciprofloxacin, levofloxacin)
dec oral absorption
fluoroquinolone AEs
- GI
- HA
- seizures
- dizzy
- QTc prolongation
NOT for children < 18 or pregnant
fluoroquinolone spectrum
gram positive aerobes
MSSA
gram negative aerobes
some pseudomonas
atypicals
which fluoroquinolones cover pseudomonas?
ciprofloxacin
levofloxacin
glycopeptide MoA
cell wall active agent
bind to D-alanyl-D-alanine terminal residue in the growing peptidoglycan chain –> prevents further cell wall formation
glycopeptides are bacterio…
cidal
glycopeptide AEs
- nephrotoxicity
- ototoxicity
- Red Man’s Syndrome (allergic reaction to vanco often after IV infusion, rash on face, neck, torso)
- neutropenia
- rash
what is the drug of choice for MRSA?
glycopeptides (vanco)!
glycopeptide spectrum
gram positive aerobes
MSSA
MRSA
c. diff
lipopeptide MoA
cell membrane active agent
irreversibly binds to bacterial cell membrane and a calcium-dependent molecule insertion occurs –> rapidly depolarize cell membrane –> potassium efflux, ruins ion-concentration gradient –> cell death
lipopeptide AE and monitoring
skeletal myopathy (loss of muscle mass)
therefore….all patients monitor for
- muscle pain/weakness, especially in distal extremities
- CPK (creatinine phosphokinase) levels weekly
if elevated CPK levels…
- monitor more frequently
- discontinue treatment for unexplained myopathy s/s + CPK > 1000 (5x ULN)
- discontinue treatment for CPK > 10x ULN
lipopeptide spectrum
gram positive aerobes
MSSA
MRSA
lipopeptide CI
NOT INDICATED FOR PNEUMONIA!!
- low pulmonary penetration
- microbiological activity inhibited by surfactant
which antibiotics cover pseudomonas aeruginosa?
beta lactams
- piperacillin
- ticarcillin
- ceftazidime
- cefepime
- imipenem
- meropenem
- doripenem
(NOT ertapenem)
protein synthesis inhibitors
- gentamicin
- tobramycin
DNA synthesis inhibitors
- ciprofloxacin
- levofloxacin
which antibiotics cover MRSA/MRSE?
beta lactams
- ceftarolin
additional cell wall active agents
- vancomycin
cell membrane active agents
- daptomycin
protein synthesis inhibitors
- gentamicin + cell wall active
- tetracycline
- doxycycline
- clindamycin
- linezolid
DNA synthesis inhibitor
- TMP/SMX
measures/indicies of drug action
Cmax : MIC
%T > MIC
AUC : MIC
which drugs are time dependent minimal/moderate persistent effects?
penicillins
cephalosporins
carbapenems
macrolides
oxazolidiones
which drugs are concentration dependent prolonged persistent effects?
aminoglycosides
fluoroquinolones
which drugs are time dependent prolonged persistent effects?
vancomycin (glycopeptide)
tetracycline (tetracyclines)
azithromycin (macrolide)
are aminoglycosides hydrophilic or lipophilic?
hydrophilic
therefore…
renal CL
tissue distribution limited to extracellular space
antibiotics without renal dose adjustment
NOCk a TAD on the DECk MM Lunch
nafcillin
oxacillin
ceftriaxone
tigecycline!!!
azithromycin
doxycycline
dalfopristin/quinupristin
erythromycin
clindamycin
metronidazole
moxifloxacin
linezolid
what is the biggest factor controlling PD?
bacteria species!
what is the second biggest factor for controlling PD?
MIC
which drugs may be S but develop rapid resistance once used –> therefore should be avoided?
rifampin
ciprofloxacin (flourorquinolones)
clindamycin
which organisms may appear S at first, but due to inducible AmpC develop rapid resistance –> may need to use less desireable antibiotics?
SPACE-M
Serratia
Pseudomonas aeruginosa
Acinetobacter
Citrobacter
Enterobacter
Moraxella catarrhalis
fluoroquinolone optimal target dosing
AUC:MIC ratio between 125 and 250
vancomycin optimal target dosing
AUC:MIC ratio above 400 mg*hr/L
AUC:MIC is dependent on what factors?
dose 24 (daily dose pt recieves)
patient specific CL
bacterial specific MIC
most purulent SSTIs are caused by
staph aureus
most are MSSA
signs of systemic infection
fever
leukocytosis
(note that these could also be signs of other causes)
which drugs are not reliable for MRSA empirically?
clindamycin
levofloxacin
empiric treatment
assume most common situation bc have no labs, start broad bc don’t want to miss anything
for empiric s. aureus, assume
MRSA
defined treatment
once you know organism only target it
for defined s. aureus
if MSSA –> deescalate therapy!
goal vanco trough for SSTIs
10-15 mcg/mL
how is vanco generally doses?
multiple times per day, also monitoring
iv vancomycin AEs
nephrotoxicity
infusion AEs
VRE risk (vanco resistant enterococci)
daptomycin, ceftaroline, dalbavancin, oritavancin are generally dosed
every 12 hours, once a day, or once a week –> longer, therefore hospitals may want to use
how do you Dx SIRS?
systemic inflammatory response syndrome
NEED 2 OR MORE:
temp < 36 Celsius or >38 Celsius
> 24 breaths/min (tachypnea)
> 90 bpm (tachycardia)
WBC < 4000 or > 12000 cells/uL
risk factors for non-purulent SSTI
**anything that could allow bacteria to invade deeper tissues
- dry skin
- fragile skin
- obesity
- previous skin trauma
- previous cellulitis
- edema from venous insufficiency
- tinea pedis (athlete’s foot)
non purulent SSTI cellulitis most caused by
streptococcus (usually group B)
duration of purulent SSTI treatment
5-10 days after I and D
not reliable for oral streptococcus non purulent SSTI?
doxycycline
SMX/TMP
duration of mild cellulitis?
5 days
duration of mod-severe cellulitis?
10-14 days, maybe longer
what cultures do we need to do in non purulent SSTI?
blood!!
necrotizing fascilitis caused by
monomicrobial:
strep pyogenes (GAS) (flesh eating)
s aureus
clostridium
which cultures do you need for necrotizing facilitis?
blood
deep tissues
take them from surgery
duration of necrotizing facilitis treatment
until..
no longer need debridement
patient clinically improved
afebrile for 48-72 hours
which patients do you need bacteriocidal activity in?
CNS infections
immunocompromised
sepsis
what inc risk of resistance
previous use of antibiotics long term
hospital exposure
pervious documented resistance
linezolid serious AEs
- serotonin syndrome
- thrombocytopenia
reasons to assume MRSA in DFI
Hx MRSA infection or colonization
high local prevalence
sereve infection
DFI often caused by
gram positive aerobes: strep, staph, MRSA
gram negative aerobes: pseudomonas
anaerobes
polymicrobial
reason to assume pseudomonas?
- warm climate
- frequent water exposure
- high prevalence
