antimicrobials Flashcards
complications of antibiotic therapy
1) hypersensitivity
2) Direct toxicity
3) superinfection
beta lactam abx
PCN, cephalosporins, carbapenems, monobactams
beta-lactamases
bacterial enzymes: penicillinases, cephalosporinases that hydrolyze beta lactam ring
PCNs MOA
inhibit last step in PGN synthesis via PBP binding
PBPs = inactivate bacterial enzymes
autolysin production
PCNs are inactive against
mycoplasma
protozoa
fungi
viruses
organisms without PGN cell walls
PCN G use
syphillis strep pneumococci gram positives, some gram negatives - NOT STAPH
most anaerobes - not bacteroides
DOC for syphillis and rheumatic fever prophylaxis
PCN G benzathine
PCN G vs V, which is more stable? oral?
PCN V more acid stable and oral
DOC for strep throat
PCN V
antistaphylococcal PCNs
b-lactamase resistant methicillin nafcillin oxacillin dicloxacillin
1st line tx for staphylococci endocarditis in pt w/o artificial heart valves
antistaphylococcal PCNs methicillin nafcillin oxacillin dicloxacillin
extended spectrum pcn
ampicillin
amoxicillin
which PCN has higher oral bioavailability
amoxicillin
extended spec PCN use
OM, strep throat, PNA, skin infections, UTI, URI
prophylaxis for dental or respiratory tract procedures
amoxicillin
combination tx for enterococci and listerial infections
ampicillin + aminoglycoside
prophylactic tx for dog, cat and human bites
amoxicillin + clauvinic acid
antipseudomonal PCN
carbenicillin
ticarcillin
piperacillin
antipseudomonal PCN use
gram neg and gram pos
PSEUDOMONAS
injectable tx of gram -
antipseudomonal PCNs: carbenicillin, ticarcillin, piperacillin
PCN AE***
GI distrubance: diarrhea
PCN + aminoglycoside
synergistic effect: PCN facilitate movement of aminoglycosides into cell wall
- DONT place in same infusion fluid
empiric tx for infective endocarditis
PCN + aminoglycoside
PCN resistance mechanisms (4)
1) inactivation by b-lactamase
2) modified PBP target
3) impaired penetration of drug to target PBP
4) inc efflux
PCN distribution
therapeutic levels everywhere EXCEPT prostate and eye
also - poor CNS penetration
PCN excretion
kidney - be careful in kidney failure
exception: nafcillin = excreted in bile
nafcillin excretion
bile
oxacillin excretion
renal and biliary excretion
dicloxacillin excretion
renal and biliary excretion
PCN hypersensitivity AE
penicilioc acid = major antigenic determinant
which PCN cause maculopapular rash
ampicillin
amoxicillin
beta lactamase inhibitors (3)
clavulanic acid
sulbactam
tazobactam
cephalosporins 1st-3rd generation
gram +
cephalosporins 4th generation
gram + and gram -
cephalosporins 5th generation
only one activate against MRSA. works against gram + and -; not effective against pseudomonas
1st generation cephalosproin drugs
cefazolin
cephalexin
can substitute PCN G
resistance to staph penicillinase
DOC for surgical prophylaxis**
cefazolin: 1st generation cephalosporin
2nd generation cephalosporin drugs
cefaclor
cefoxitin
cefotetan
cefamandaole
2nd generation cephalosporin use
gram negative - greater against h.flu, enterobac
sinusitis, otitis, lower resp tract infections
DOC prophylaxis and therapy of abdominal and pelvic cavity infections
cefotetan
cefoxitin
3rd generation cephalosporin drugs
ceftriaxone cefoperazone cefotaxime ceftazidime cefixime
3rd generation cephalosporin use
gram negative cocci
h flu, neisseria, enterobacter - pseudomonas
less active against gram pos
which 3rd generations are useful for pneumococci
ceftriaxone
cefotaxime
DOC for gonorrhea
ceftriaxone
DOC for meningitis d/t ampicillin-resistant h.flu
ceftriaxone
DOC prophylaxis of meningitis of exposed individuals
ceftriaxone
which 3rd generation cephalosporin can help tx lyme’s (but is not DOC)
ceftriaxone
4th generation cephalosporin
cefipime - parenteral admin only
cefipime use
wide spectrum - only use as empiric therapy and you’re not sure
gram + like 1st generation and gram - of 3rd generation = enterbac, hemophilus, neisseria, e.coli, pneumococci, proteus, pseudo
UTIs, complicated intra-abdominal infections, febrile neutropenia
5th generation cephalosporin
ceftaroline
5th generation cephalosproin use
ONLY FOR MRSA - reserved drug - similar to 3rd generation
parenteral only
drug tx for skin/soft tissue infection due to MRSA (esp with gram - coinfection)
ceftaroline
which cephalosporins are not given parenterally
cephalexin
cefaclor
cefixime
which generatoin cephalosporin reaches adequeate levels in CSF
3rd generation - useful for meningitis
elimination of cephalosporins
kidneys
which cephalosporins are excreted in bile
ceftriaxone
cefoperazone
cephalosporins AE
allergic reaction pain at infection site (IM) thrombophlebitis (IV) superinfection: c. diff kernicterus: pregnant
If pt has allergy to PCN, what should you remember about cephalosporin use
cross sensitivity with cephalosporin CAN occur
only okay if the PCN allergic reaction was very mild - but don’t risk it
which cephalosporins can cause hypoprothrombinemia and disulfiram like reactions?
cefamandole
cefoperazone
cefotetan
all contain methyl-thiotetrazole group
if woman is pregnant and has meningitis, is ceftriaxone safe?
YES - risk outweighs benefit
- even with possible kernicterus risk
- but if pregnant mother has OM, choose ampicillin or another Abx
2 carbapenems
imipenem
meropenem
carbapenem use
empiric therapy - multiple infections - resists b-lactamases
very broad spectrum: pencillinase producing gram positive and negative, aerobes, anaerobes, pseudomonas
not active against carbapenemase producing organisms
not active against MRSA
DOC for enterobacter infections
carbapenems
DOC for extended spec B-lactamase producing gram negatives
carbapenems
Imipenem danger
can form nephrotoxic metabolite - combine with cilastatin prevents metabolism and toxicity = increased bioavailability
not needed for meropenem- not metabolized by same enzyme
carbapenem AE
n/v/d high imipenem = seizures allergic reaction (with PCN cross reactive)
Monobactam drug
aztreonam
monobactam use
AEROBIC gram - rods only
(includes pseudomonas)
not active against gram positive or anaerobes
UTIs (for pt who’s infection hasn’t been tx properly with 1 or 2nd line)
lower resp tract infections
septicemia…
monobactam PK
IV, IM, inhalation for CF)
can penetrate CSF when inflamed (not normally)
monobactam excretion
urine
best route of administration in CF patients
inhalation
monobactam AE
IV: phlebitis/thrombophlebitis
skin rashes, inc serum aminotransferases
GI upset
little cross hypersensitivty with other b-lactam abx
vancomycin
bactericidal
bacterial glycoprotein
ONLY gram +: multi-drug resistant organisms
gram - organisms are resistant
vancomycin MOA
binds @ D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide
- therefor inhibits bacterial cell wall synthesis and polymerization (NOT cross linking** like PCN)
development of vancomycin resistance
modified D-ala-D-ala binding site
plasmid mediated changes in drug permeability
enterococcal endocarditis tx
vancomycin + aminoglycoside
empirical infective endocarditis tx
aminoglycoside + vancomysin
tx gram + in pt severely allergic to b-lactams
vancomycin
tx b-lactam resistance gram + organisms (MRSA)
vancomycin
staphylococcal enterocolitis tx
vancomycin orally
antibiotic associated pseumembranous colitis tx
vancomycin orally
when is vancymycin used orally
for GI infections
vancomycin PK
SLOW IV infusion - if too quick –> red man syndrome
vancomycin excretion
kidneys
red man syndrome
fast vancomycin administration = massive histamine release - flushing to face and upper torso
vancomycin AE
fever/chills/phlebitis
red neck syndrome
otoxocitiy and nephrotoxicity with drug accumulation
daptomycin for PNA treatment
NO EFFECT: can’t reach cell membranes passing through surfactant
daptomycin
bactericidal
Gram positive organisms - MRSA, enterococci
inactive against gram negative
daptomycin MOA
binds cell membrane via calcium dependent insertion of lipid tail = K+ leaks out - depolarization = cell death
useful for multidrug resistant bacteria
daptomycin clinical app
severe infections with MRSA or VRE
tx complicated skin/structure infections d/t s. aureus
daptomycin administration
IV
if accumulate - renal insufficiency
daptomycin AE
inc creatine phosphokinases (MYOPATHY)- discontinue coadministration of statins
will c/o muscle pains
which Abx should not be used with statins
daptomycin
macrolides
Bacitracin MOA
interferes in late stage cell wall synthesis = effective against gram positive
bacitracin unique mechanism
NO cross resistance
Bacitracin AE
nephrotoxicity - mainly topical
Fosfomycin MOA
inhibits cytoplasmic enzyme enolpyruvate transferase in early stage cell wall synthesis (compare to bacitracin - late stage)
Gram + and Gram -
tx of uncomplicated lower UTI (not DOC)
fosfomycin
tetracycline
protein synthesis inhibitior
glycylcylines
protein synthesis inhibitior
aminoglycosides
protein synthesis inhibitior
macrolides
protein synthesis inhibitior
chloramphenicol
protein synthesis inhibitior
clindamycin
protein synthesis inhibitior
streptogramins
protein synthesis inhibitior
linezolid
protein synthesis inhibitior
mupirocin
protein synthesis inhibitior
bacterial vs mammalian ribosome
bacterial - 70s
mammaliam - 80s
bacteriostatic
tetracyclines (3)
doxycycline
minocycline
tetracycline
tetracycline use
broad spectrum
bacteriostatic - (don’t want to use with PCN - b/c only attacks actively dividing cells)
aerobic and anaerobic gram + and -
tetracycline MOA
binds 30S subunit = no attachment of aminoacyl tRNA
entry via passive diffusion/energy dependent transport
drug concentrated intracellularly
tetracycline resistance
WIDESPREAD
1) imparied influx/inc efflux by active protein pump
2) proteins produced that interfere with ribosome binding
3) enzymatic inactivation
tetracycline clinical app
severe acne and rosacea
empiric therapy for CAP
respiratory tract, sinuses, middle ear, UT, intestinal infections
syphillis
severe acne and rosacea tx
tetracycline
syphillis tx for pt allergic to PCN
tetracyclines
empiric therapy for community acquired PNA
tetracycline
DOC for chlamydia
tetracycline
DOC for mycoplasma pneumoniae
tetracycline
DOC for lyme disease
tetracycline
DOC for cholera
tetracycline
DOC for anthrax prophylaxis
tetracycline
DOC for ricketssia: RMSF, typhus
tetracycline
Tetracycline combo tx for
h. pylori malaria prophylaxis and tx plague tularemia brucellosis
tetracycline PK
variable oral absorption - dec by divalent/trivalent cations
which tetracycline is preferred for parenteral admin, STDs, prostatitis
doxycycline
which tetracycline reaches high concentrations in all secretions - spec for tx of meningitis
minocycline - eradicate meningococcal carrrier
tetracycline excretion
urine - except doxy in bile
doxycycline excretion
bile
tetracycline and pregnancy
TERATOGENIC
category D
tetracycline AE
discoloration/hypoplasia of teeth
stunting growth (avoid in pregnant female and kids under 8)
photosensitization
hepatotoxicity
exacerbate renal dysfunction
glycylcyclines
tigecycline
broad spec against multidrug resistant: gram pos, some gram neg and anaerobics
Glycylcyclines clinical app
complicated skin, soft tisue and intraabd infections
glycylcyclines AE
Black box warning = inc mortality risk - FDA recommend alternative antimicrobial use
similar AE as tetracyclines
contraindicated in pregnancy and children under 8
glycylcyclines PK
IV only
biliary and fecal elimination
Only protein synthesis inhibitor that is bactericidal
aminoglycoside
amikacin
aminoglycoside
gentamicin
aminoglycoside
tobramycin
aminoglycoside
streptomycin
aminoglycoside
neomycin
aminoglycoside
aminoglycosides MOA
passive diffuse across Gram - membranes
active transp (O2 dependent) across cytoplasmic membrane = AEROBIC GRAM NEG only
bind 30s = mRNA misreading, inhibits translocation
serious toxicities - replaced by other abx
aminoglycosides resistance
1) plasmid associated syntehsis of enzymes that modify/inactivate drug
2) decreased accumulation of drug
3) 30s receptor protein may be deleted
aminoglycoside clinical pp
in combo
empiric therapy of speticemia, nocosomial respiratory tract infections, complicated UTIs, endocarditis
DOC for empiric therapy of infective endocarditis
PCN/vancomycin + aminoglycoside
DOC for plague/Y. pestis
streptomycin
Aminoglycoisdes admin
parenteral admin only
1x daily
high levels accum in renal cortex and inner ear
except neomycin = dopical
aminoglycoside excretion
urine
dec dose in renal insufficiency
aminoglycoside AE
time and concentration dep
ototoxicity
nephrotoxicity - contraindicated in MG
NM blockade
pregnancy - category D
aminoglycosides PD
postAb effect + concentration dependent killing - ONCE DAILY DOSING
doesn’t matter if concentration falls below MIC - already gets greatest killing at peak
time dependent drugs
PCN
cephalosporins
concentration dep: aminoglycosides
Oral neomycin
adjunt for hepatic encephalopathy tx
Alt tx options for hepatic encephalopathy
lactulose
oral vanco
oral metro
rifaximin
Lactulose
nonasorbable disaccharide
lactulose MOA
degraded by intestinal bacteria –> lactic acid + other organic acids
gut becomes acidic
NH3 –> NH4 - trapped in colon = dec ammonia concentrations
osmotically active laxative
prebiotic (supresses urase producing organisms)
erthryomycin
macrolide
clarithromycin
macrolide
azithromycin
macrolide
telithromycin
macrolide
macrolides function
tx gram positive infection
bacteriostatic - bactericidal at high concentrations
macrolides MOA
reversible binding to 23S rRNA of 50S = stops translocation
similar binding site to that of clindamycin and chloramphenicol
macrolides resistance
1) dec membrane permeability or active efflux
2) production of esterase - hydrolyzing drugs
3) modification of ribosomal bidning site**
cross resistance b/c erythrromcyin, azithromycin, clarithromycin - partially with clindamycin and streptogramins
macrolides with broader spectrum
azithromycin
clarithromycin
telithromycin
DOC mycoplasma pneumoniae
macrolides - erythromycin AND tetracycline
If pregnant female - go for erythromycin
DOC pertussis
macrolides - erythromycin
macrolide clinical app
empiric therapy of CAP with b-lactam if an inpatient
upper respiratory tract, soft tissue infections
substitute for PCN allergy
which macrolides have long t 1/2
clarithromycin
azithromycin
telithromycin
- better oral absorption = longer half life
(compared to erythromycin)
which macrolides have greater tissue penetration
azithromycin
telithromycin
macrolides AE
GI irritation = activate motilin!!!**
hepatic abnormalities: erythromycin, azithromycin
QT prolongation - only contraindicated in people with CAD, prolonged QT
which macrloides inhibit CYP P450
erythromycin
clarithromycin
telithromycin
macrolides contraindications
statins
telithromycin = lots of toxicity, dont use if minor. can cause fatal hepatotoxicity, exacerbations of MG, visual disturbances
tetracyclines contraindicated with
beta lactams
TC: static
lactam: cidal
CAP empirical tx
macrolide (bacteriostatic) + b lactam (bactericidal)
macrolides = coverage for atypicals beta-lactams = good coverage over s. pneumoniae
GOOD coverage for most likely agents
chloramphenicol
protein synthesis inhibitor
chloramphenicol use
broad spec: aerobic and anaerobic - gram + and negative
TOXICITY limits use only to life threatening infections with no alternatives.
active against many VREs.
topical tx of eye infections
bacteriostatic
chloramphenicol MOA
reversible binding to 50S ribosomal subunit = inhibits peptidyltransferase
chloramphenicol toxicity
can also inhibit protein synthesis in mitochondrial ribosomes = BM toxicity
**aplastic anemia can occur
chloramphenicol resistance
presence of factor that codes for chloramphenicol acetyltransferase
changes in membrane permeability
chloramphenicol PK
inhibits hepatic oxidases: 3A4, 2C9
chloramphenicol AE
BM depression = dose related reversible depression
gray baby syndrome = cyanosis - restricted in newborns
clindamycin
MOA same as macrolides - binding 50s
bacteriostatic
GRAM POS ANAEROBIC - and bacteroides and gram + aerobes
“anaeroboic infections above diaphragm”
anaerobic infections below diaphgragm
metronidazole
clindamycin resistance
1) mutated ribosomal receptor site
2) modified receptor
3) enzymatic inactivation
most gram - aerobes and enterococci are
intrinsically resistant with macrolides and chloramphenicol
clindamycin use
anaerobic infections: bacteroides, abscesses, abd infections
complicated skin and soft tissue infections: strep, staph, some MRSA
clindamycin + primaquine
PCP tx alternative
clindamycin + pyrimethamine
toxoplasmosis of brain tx alternative
prophylaxis of endocarditis in valvular pt allergic PCN
clindamycin (s. viridans is covered)
- normally PCN or IV ampicillin
clindamycin AE
fatal c. diff superinfection
quinupristin
streptogramin
dalfopristin
streptogramin
streptogramins
give both together - synergistic effect is bactericidal, alone is bacteristatic
streptogramin MOA
bind 50s
resistance is uncommon = needs two different mutations b/c of both drugs used
streptogramin use
gram pos cocci and multi drug resistant bacteria
RESTRICTED USE: drug resistant staph or VRE
streptogramin PK
CYP3A4 inhibitor
Linezolid
bacteriostatic - cidal for strep and clostridium perfringes
- good for multi drug resistant bacteria
linezolid MOA
inhibits formation of 70s initation complex
**UNIQUE SITE to 23S on 50S subunit - thats why it works on drug resistant drugs
linezolid resistance
dec binding to drug site
no cross resistance with other drug class
**could occur very rapidly with a single course of tx
linezolid use
advantage: ORAL - 100% bioavailable
most gram positive, some activity against m. tuberculosis
linezolid PK
weak reversible inhibitor of MAO - lots of interactions; serotonin syndrome
oral!!! 100% bioavailability
linezolid AE
long term:
reversible myelosuppression
optic/peripheral neuropathy
lactic acidosis
linezolid contraindications
reversible MAOI = interaction with adrenergic and serotinergic drugs
–> serotonin syndrome (ex used in clicker: amitrytiline)
fidaxomicin
narrow spectrum macrocyclic Abx = ORPHAN DRUG
active against gram + aerobes and anerobes - esp CLOSTRIDIA
not active against gram -
fidaxomicin MOA
bind RNA polymerase: inhibits bacterial protein synthesis
Fidaxomicin use
C. diff
**advantage: prevents reoccurence!!!
despite high price, saves money in long run that using vanco or metronidazole
fidaxomicin PK
systemic absorption = negligible
fecal concentration = high
mupirocin
topic and nasal tx of MRSA
monoxycarbolic acid class of abx
gram + cocci (MRSI and most strep - not enterococci)
only topical agent against MRSA
mupirocin
mupirocin MOA
binds bacterial isoleucyl transfer RNA synthetase = inhibit protein synthesis
mupirocin use
nasal MRSA
impetigo, secondary skin infection via s. aureus or s. pyogenes
HIGH rate of resistance
drugs that affect nucleic acid synthesis
fluoroquinolones
sulfonamides
trimethoprim
nalidixic acid/quinolone
1st generation fluroquinolones
ciprofloxacin
2nd generation fluroquinolones
levofloxacin
3rd generation fluroquinolones
synergistic with beta lactams
gemifloxacin
4th generation fluroquinolones
moxifloxacin
4th generation fluroquinolones
fluoroquinoles MOA
broad spec
enters bacterium via porins = inhibits DNA replication vai topoisomeriase II (DNA gyrase) and IV interference
fluorquinolones resistance
chromosomal mutations: encode subunits of DNA gyrase and topo IV
regulate expression of efflux pumps
cross resistance b/w drugs
Lower generations of fluoroquinolones
gram -
higher generation of fluoroquinolones
gram +
which generation fluoroquinlones is good against s. pneumoniae
3rd = levofloxacin
first line traveller’s diarrhea
ciprofloxacin
alternative ceftriaxone and rifampin for meningitis prophylaxis
2nd gen fluoroquinolone = ciprofloxacin
suspect CAP in admitted pt
fluroquinolones: 3rd and 4th generation
reserved for aggressive tx: when 1st lines failed, comorbidities
fluoroquinolones PK
iron, zinc, calcium interfere with absorption = don’t give with antacids or milk
adjust doses in renal dysfunction
fluoroquinolones AE
photosensitivity (like with tetracyclines)
- ** Black box warning: CT problems = rupture of tendons - contraindicated in pregnant, nursing, under 18
- stop if c/o tendon pain
peripheral neuropathy
QT prolongation: moxifloxacin, gemifloxacin, levofloxacin
risk of superinfections: c.diff, candida, streptococci
which fluoroquinolones can cause QT prolongation
moxifloxacin, gemifloxacin, levofloxacin
what drug can cause tendon ruptures
fluoroquinolones - black blox warning
fluoroquinolones interactions
inc toxicity with theophyllin, NSAIDs, corticosteroids
3rd/4th gen can inc levels of warfarin, caffeine, cyclosporine
sulfonamides
sulfamethoxazole
sulfadiazine
sulfasalazine
tx chlamydia in pregnant female
azithromycin
sulfonamides use
bacteriostatic against gram + and negative
sulfonamides MOA
inhibit bacterial folic acid synthesis
PABA analog - comp inhibitor of dihydropteroate synthase. inc p-aminobenzoic acid (accumulates)
sulfonamide resistance
plasmid transfer/mutations:
- alterated dihydropteroate synthase
- dec cellular permeability
- enhanced PABA
- dec intracellualr drug accum
sulfonamide clincial app
topical agents = ocular/burns
oral: UTIs
sulfasalazine: oral - UC, enteritis, IBD
sulfonamide PK
can accumulate in renal failure
acetylated in liver = kidney damage
sulfonamides AE
crystaluria: nephrotoxic
HS rxn
hematopoeitic disturb = G6PD def
kernicterus (contraindic in babies <2 mo)
sulfonamides interaction
inc plasma levels with:
warfarin
phenytoin
MTX
sulfonamide contraindication
babies < 2 mo
drugs that compete with bilirubin for binding sites on albumin
trimethoprim
bacteriostatic against gram + and negative
trimethoprim MOA
inhibitor of bacterial dihydrofolate reducatse = inhibits purine, pyrimidine, aa synthesis
accumulate dihydrofolic acid
no THF made
trimethoprim use
UTI
bacterial prostatitis, vaginitis
trimethoprim excretion
kidney
trimethoprim AE
antifolate - COMPLETELY CONTRAINDICATED IN PREGNANCY
cotrimoxazole
TMP-MTX combination
bactericidal
cotrimoxazole MOA
synergistic - inhib THF synthesis
DOC for uncomplicated UTIs
cotrimoxazole*******
DOC for PCP
cotrimoxazole
DOC for cardiosis
cotrimoxazole
toxoplasmosis tx alternative
cotrimoxazole
h. flu and m.catarrhalis URI, OM, sinus infections tx
cotrimoxazole
cotrimoxazole AE
dermatological
hemolytic anemia in G6PD**
AIDS pt = higher incidence of all the AE - specifically dermatological (rashes)
CONTRAINDICATED IN PREGNANCY (1st trim)
metronidazole
antimicrobial
amebicide
antiprotozoal
active against anaerobic bacteria: bacteroides, clostridium
bactericidal
metronidazole MOA
anaerobic vital for optimal activity
= reductive bioactivity of nitro group by ferredoxin. forms cytotoxic productions that interfere with nucleic acid synthesis
metronidazole clincial app
c. diff anerobic/mix intra abd vaginitis brain abscess h. pylori
DOC c. diff
metronidazole
metronidazole elimination
hepatic
metronidazole AE
leukopenia, ataxia
opp fungal infection
peripheral neuropathy with prolonged use
disulfiram like effect with alcohol (anything with azole group)
not advised in 1st trimester
nitrofurantoin
urinary antiseptic: bacteriostatic and cidal
gram pos and gram - activity
nitrofurantoin MOA
reduction by bacteria in urine = metabolites damage bacterial DNA
nitrofurantoin AE
anorexia, n/v
neuropathies, hemolytic anemia in G6PD
nitrofurantoin contraindication
renal insufficiency
pregnant 38-42 weeks (at term) – used regularly in other stages of pregnancy
infants : b/c of possible G6PD deficiency
1st line of UTI in pregnant female (NOT AT TERM)
nitrofurantoin
PCNs resistance
via PBP mutations