Title:
URL Source: blob://pdf/6771acee-e3c8-4797-a8e6-aa8722fa63ed
Markdown Content:
INTRODUCTION TO ANTIBIOTICS &
BETA -LACTAM AND OTHER CELL
WALL/MEMBRANE -ACTIVE ANTIBIOTICS
> PHAR 6030
# Introduction and Terminology
Pharmacokinetics
Movement
Elimination
Pharmacodynamics
Three things needed for an antibiotic to be effective
Antibiotic must bind to a target site of the bacterium
Abx must occupy sufficient no. of binding sites
Abx must remain at the sites long enough
I
2
5
Pharmacokinetics = this is the move to and elimination of a drug. The drug
administered needs to get from site that it is administered to the site that it
needs to work, also called the site of activity. We can administer medications
many di ff erent ways. Not all can be injected or given orally. A drug taken
through oral/GI tract needs to be able to get to a site to work. There are di ffi cult
places for antibiotics to get to, for example not all can penetrate the CNS, or
the meninges. Another example of a hard place for antibiotics to get to is inside
an abscess. The abscess needs to be incised and drained before antibiotics
can be e ff ective. The site of infection will also determine how to treat.
Elimination of antibiotics can happen either via metabolism in liver or in kidney,
or drugs can be excreted unchanged into urine.
Pharmacodynamics correlates drug concentration to a clinical or pharmacological e ff ect. Three things
needed for antibiotics to be e ff ective - First, it needs to be able to bind to a target site on bacteria.
Second, it must occupy a su ffi cient number of binding sites to be e ff ective and this relates to
concentration as if concentration is not high enough then you wont occupy enough sites to be e ff ective.
Third, antibiotics must remain at sites long enough to inhibit bacterial metabolism, including growth. ANTIBIOTIC CLASSIFICATION
Based on mechanisms :
Cell wall synthesis inhibitors
Penicillins , cephalosporins , imidazole antifungal
Cell membrane disruptors
Detergents and polyene antifungals
Protein synthesis inhibitors
Tetracyclines , aminoglycosides
DNA synthesis inhibitors
Rifamycins , TMP, acyclovir
Folic acid metabolism
Bacteria have to have a cell wall for these
antibiotic to be e ff ective. These are not e ff ective
to viruses due to them lacking cell wall.
Wont test from this
slide speci fi cally
We classify antibiotics on mechanism of action. Beta-lactams
and other cell wall antibiotics will be included in this lecture.
This lecture will go in depth on cell wall synthesis inhibitors,
including penicillins, cephalosporins, imidazole anti-fungals. Treatment of infection requires
## consideration of many factors
Constantly juggling the bacteria, drug, and host
Drug has to reach the site of infection
Once the antibiotic gets to the site, it has to be active
against the bug
Bactericidal vs bacteriostatic drugs
When treating an infection there are many factors including bacterial characteristics,
antibiotic characteristics, and host characteristics such as comorbidities and
medications. Some antibiotics can increase and decrease dose of some medication.
Also need to take into account abscesses and bone infections as these are di ffi cult to
get to. Once they get to site they need to be active against the organism.
There are also bactericidal and bacteriostatic antibiotics. Bactericidal means to kill the
bacteria. Bacteriostatic means inhibiting the growth.
Chemotherapy for cancer > weak immune system > want to attack infection ASAP > -cidal is the choice ANTIBIOTIC RESISTANCE
4 general mechanisms
Target modification
Efflux
Immunity and bypass
Enzyme -catalyzed destruction
Acquired resistance through mutation or horizontal
gene transfer
Antibiotics exert selective pressure
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2942819/
2 separate mechanisms = action in how it works, and the mechanism of
resistance the organism employs to be resistant to the antibiotic.
There are 4 general mechanisms employed by bacteria to resist
antibiotics. These are NOT speci fi c to beta lactams, these are just general
mechanisms that bacteria can use to become resistant to antibiotics.
Target modi fi cation
Can change the binding sites to gain resistance
Effl ux, meaning pumping out
Some bacteria can pump or get rid of the antibiotic that entered
them
Immunity and bypass
Enzyme-catalyzed destruction
Some bacteria produce beta lactamases, so beta lactam
antibiotics can be rendered useless by these enzymes.
There are inhibitors of these enzymes that can be given with
antibiotic to aid in killing the bacteria.
If antibiotics are given too often then they can exert selective pressure and
this is why many organisms in a hospital setting have become resistant.
MOA how does the Abx kill or stop the
growth of pathogenic organisms
Mechanisms that the organisms use to be
resistant to Abx
Mechanisms of Resistance
From 1 resistant bacteria to the next one
Survival of the fi ttest
Overuse of Abx can promote R against it ANTIBIOTIC RESISTANCE
When clearly indicated
Do not select the most broad spectrum medication
Choose antibiotic most likely to be effective given the
specific infection
Be aware of the spread of resistant strains
Dont use the newest antibiotics unless clearly necessary
Clinically : Add natural antimicrobials that will support
destruction of pathogenic bacteria and immune
support to increase success of treatment.
Unless indicated.
Broad spectrum = covers many organisms. Also possible the patient may have multiple pathogens. If septic then may need broad spectrum, but
in general you would never do this and always try to be as speci fi c as possible. You usually have to pick an antibiotic to work for pneumonia from
imaging and symptoms but cannot tell what organism is causing it, unless in blood and can fi nd out from blood culture. But with UTI you can fi nd
out the organism then be more speci fi c. Need to aware of what is becoming resistant also and NEVER use the newest antibiotic unless reason to
do. When you get sensitivity test back from culture it will have dollar signs next to the antibiotic, so keep cost e ff ectiveness in mind.
Also take into account the patients tolerance to pill size and such. CLINICALLY we
would add antimicrobials that will support destruction of pathogenic bacteria and
immune support to increase success of treatment.
Clinical improvement means symptoms are becoming better. Pharmacological
improvement means the culture is improving as organisms is being destroyed. Ex: strep rapid test > we know what it is! >
dont need broad spectrum
But when we want to empirically tx after we
send to lab to test for specimens
Must know the microbio of inf to empirically
tx someone; and know the infectious
process and the pt pop
Ex: bacterial overgrowth = ex:
vaginal candidiasis
When you get your culture
and sensitivity back you
can change the drug to the
most appropriate for the inf,
cost of drug, mechanism of
delivery (liquid, capsule,
etc) and pts ability to
tolerate that ANTIBIOTIC SELECTION
Empirical treatment (educated guess)
Determine most likely infectious agent
Determine how to make a definitive dx
Definitive - tailored to the organism
Select/change based on c/s
Use narrow spectrum, low toxicity to complete therapy
Administration of antibiotics AFTER all necessary
cultures are obtained
Culture can take 24-48 hours and you dont
wont want the patient to go on su ff ering so you
start them on an antibiotic. You have to know -
infection as diagnosis, age, co-morbidities,
and then determine what organism might
cause this in the person. Then you have to
consider the antibiotic that can aid the patient.
Then you say what can I do for a de fi nitive
diagnosis to determine this organism and
some of the time the answer is not always
straight forward. For example, you might not
know what is causing pneumonia. Sputum
culture may not yield enough microorganisms
to determine so you will need to treat
empirically. Empirical treatment would mean
educated guess. De fi nitive would be made
from tests and can be tailored to the organism
found. De fi nitive will allow you to determine a
narrow spectrum antibiotic. Never treat
partially. Always ask if they have self
administered antibiotics previously, if they have
then ask them to stop and then get culture and
then treat. You ask to stop administering so the
organism can grow on culture. Never partially
treat in clinic and then collect culture, partially
treating will mess with culture.
Ex: pneumonia seen on chest
x-ray but we wont know the
etiological agent ; cant really get
a specimen from the lungs :(( so
clinical ddx but use chest x-ray
and CBC and maybe CBGs(?)
tx emperically
Can get a UA for UTI and
sensitivity tx emperically
results in 1-2d tx for Abx if
bacterial inf or switch Abx etc
Ex: if e.coli we know now!
Also, should be a realist and ask the pt if they have taken any medications yet often could be an
old Rx (friend or family) and may self tx an infection not all Abx cover everything
Partial Tx if a pt has been on an Abx for a couple days 1-3D or so cultures can be SKEWED!!
Tell them to stop Abx, wait 2D or so, then draw again :/ MECHANISMS (CIDAL v. STATIC)
Bactericidal kills microbes
Bacteriostatic prevents microbial growth
Does not kill the existing microbes
Must use -cidal for
Immune suppressed
Endocarditis
Meningitis
Pseudomonas in CF
Watch for toxin producers
May release more toxin when using -cidal drugs
May add corticosteroids to reduce inflammation
Just stops them from growing.
Never want to leave any
organisms when a patient has
these conditions. Need to take
care of it and kill them, so one
would use bactericidal when it
comes to immune suppressed,
endocarditis, meningitis,
pseudomonas in CF and more.
Gram negative bacteria will release endotoxins. Neg-N-eNdo.
When treating gram Negative one will usually add steroid to
treat the in fl ammation caused by the release of endotoxins. Immune suppressed people (always!)
> Ask they die the toxins release
> Yes, low dose for short term without
> impacting the immune system!
# SENSITIVITY TESTING
Disk diffusion and agar or
broth dilution
Clear zone show sensitivity to a
given drug
Minimal inhibitory
concentration (MIC)
Lowest concentration that
prevents growth
Minimal bactericidal
concentration (MBC)
Lowest dose that kills 99.9% of the
infectious organisms
Two things will be reported with Sensitivity Testing -
Minimal inhibitory concentration (MIC), which is 1.
the lowest concentration that prevents growth
Minimal bacterial concentration (MBC), which is 2.
the lowest dose that kills 99.9% of the infectious
organisms.
Most of the ti me thing are reported with the MIC. OTHER CONSIDERATIONS
Access of antibiotic to site of infections
Transport across membranes
Transport out of fluids
Decrease in integrity of membranes during
inflammation
Plasma binding of drug and other kinetic
considerations
Dosing schedules
Pulse -intermittent or continuous
If a patient is outpatient taking an oral antibiotic, we say they are taking QID or TID means
either 4 or 3 times a day. This implies pulse-intermittent dosing.
If we need to dose continuous through the night we will say Q 8 hours which means dose
every 8 hours. Most of the time it will be BID, TID, or QID and if in hospital then they will do
continuous or every so many hours.
Normally if a pt is hospitalized or an
spec med or IV med hourly is
important!! Not Q12H
Nurses come in at hourly times
At home, orally BID 2xd pulse
intermittent
BID is di ff from Q12H
Some drugs and some meds and esp
IV it would be Q__hours PATIENT CONSIDERATIONS
Renal functions
Liver functions
Age of patient, genetics, allergy (?)
Route of administration
Host defense mechanisms
Location of infection -abscess, prosthetic device
For some medications renal dysfunction
needs to be taken into consideration. Liver
function is the same way.
Can they swallow etc.
Always ask for an allergy to medication, but also need to know what happened when taking said medication.
True allergies are di ff erent from side e ff ects. Side e ff ects are not allergies. But if patient said they immediately
vomited after taking the medication and then broke out in hives the second time then this would be a true
allergy.
When patients take antibiotics and the bacteria starts to die a patient can develop a rash due to toxins
released. It can be macular, maculopapular, so non palpable or palpable, but a mild rash with mild or no
itching might be from toxin release. But in urticarial rash with mucosal swelling will be an from allergy
reaction.
Endotoxins are heat stable toxins that are released from gram negative bacteria being lysing by the antibiotic.
Exotoxins are released from bacteriophage without destruction. Strep for example produces exotoxins.
Exotoxins are more usually more potent than endotoxins, but not always the case.
2 most common things to be concerned about!!
Hx of allergic rxn is not always reliable often a pt would
say theyre allergic to __ or __ ask them what happens
when they take that medication!!!!
CAN AHVE LIFE OR DEATH CONSEQUENCES IF THEY GET
A SERIOUS INF
common to get a GI side e ff ect with Abx - like augmentin
Toxins being released lead to a rxn maculopaule? Non-raised rash, non-itching, this is NOT an allergic rxn COMBINATION THERAPY
Consider interactions
May potentiate activity, toxicity
Different mechanisms
Additive or synergistic effects
Necessary for mixed infections
Unknown organism
Prevention of resistance
Some antibiotics used together will potentiate the
activity of each other. This can be additive or
synergistic. Additive means doubling the
eff ectiveness, and synergistic means multi fold
greater e ff ectiveness. Sometimes using two
together can cause toxicity or decrease
eff ectiveness.
Combination therapy is useful in mixed infections,
meaning high probability of more than one
infectious agent. So if someone has a bowel
obstruction, rupture, or diverticulum rupture then
they may have mixed infection.
If we do not know the organism and they are ill
then we will need to cover many classes of
bacteria so we would do combination therapy. An
example will be a newborn with sepsis and
possible meningitis.
Would also use combination therapy to prevent
resistance from developing.
Endotoxins heat-stable and released from
cell walls when the organism is lysed
Exotoxins heat-labile; more potent;
released by bacteria but not from cell wall
when theyre lysed
Sometimes the drugs we use can interact with others some interactions
potentiate activity of the other drug and lead to toxic levels or lead to a
decr activity and ine ff ectiveness
Additive double e ffi cacy
Synergistic e ff ect much more than double?
Multiple organisms
If we dont know the organism
Prevent resistance to 1
Start with 4 drug regimen for TB meds we use for TB the organism
become R quickly PROPHYLAXIS
30 -50% of antibiotics
Sometimes may be effective
STDs, UTIs, endocarditis, surgery
Destroys some normal defenses of host
Increases risk of fungal infections
30-50% of antibiotics have the potential to be prophylactic. Specialists like
urologist elect to use prophylactic antibiotics to prevent UTI. This will be done
by giving a low dose of antibiotic before infection is present. Can also be
used in STDs, endocarditis and for surgery. It is also normal to give antibiotic
before patient goes to surgery to prevent another infection. Unfortunately it
can disrupt the normal fl ora and can increase fungal infections such as
vaginal candidiasis.
> Prevents recurrent infections/infs
# SUPER INFECTIONS
New infections appearing during treatment
Due to death of normal protective flora
Competition for nutrients
Broader spectrum more likely to produce
Resistant bacteria
Fungal infections
The broader the spectrum to
kill the more likely it is to
make a super infection due
to killing all of the fl ora in
general.
> Can cause the emergence of R/resistant bacteria
# HERB -DRUG INTERACTIONS
>
Typically, ginseng potentiates antibiotic effects
>
Immune herbs may have synergistic effects
>
Always check interactions when prescribing a new
drug or herb! CI IN PREGNANCY (NPLEX)
Aminoglycosides
Tetracyclines
Chloramphenicol
Quinolones
Caution sulfamethoxazole (cleft palate in rats)
Caution trimethoprim ( folate antagonist)
Caution clarithromycin (animal studies show harm
yet category C) Category A means there is no harm at all in pregnant individuals.
Category B means there are no controlled studies, and there are no
demonstrated risk in animal studies or in women after the fact. Pre natal
vitamins, acetaminophen, and amoxicillin are all category B.
Category C means there are adverse e ff ects in animal studies but no human
fetal harm has been documented and so the bene fi t of the drug may outweigh
the risk.
Category D drugs have been know to cause human fetal harm.
Wont test speci fi cally
on the categories.
May be required to know by NPLEX II ?
Use without concern
(In the 1st term of pregnancy)
Depending on what the condition is and how serious it is. Use with great caution.
^ Amoxicillin, acetaminophen, folate??? Microbiology Review
Gram + cocci: staph aureus, strep pyogenes
Gram cocci
M.cat: OM, sinusitis
H. flu: OM, epiglottis, meningitis, pneumonia
N. gonorrhea and N. meningitidis (diplococci)
Gram + bacilli
Bacillus: anthrax, spore -forming, aerobic
Clostridium: C. diff, botulism,tetanus , spore -forming,
anaerobic
Listeria: sepsis/meningitis neonates and elderly
Corneybacteria : diptheria
Many gram negative cocci produce the beta
lacatamases that inhibit beta lactam antibiotic.
Gram + cocci include staph aureus, strep pyogenes and
enterococci. Stap and strep can cause pneumonia and
others. Enterococci can cause skin and soft tissue infections
and pharyngitis.
Gram - cocci include M. cat, which causes OM and sinusitis,
H. Flu that causes OM, epiglottis, meningitis, and
pneumonia. Also include N. Gonorrhea and N meningitidis.
HIB vax will prevent H fl uEnterobacter
gram - rod
Bacillus (rod)
Entero from GI tract
Enterococci
gram + coccus EZs/enzymes created by bacteria that inactivate the beta-lactam Abx
M. Cat
H. Flu
Otitis media Microbiology Review continued
Gram bacilli
E. coli: UTI, neonatal meningitis, diarrhea
Salmonella, Shigella, Campylobacter
Enterobacter: UTI, diarrhea
Klebsiella: UTI, pneumonia, sepsis/meningitis
Serratia: UTI (complicated)
Legionella: pneumonia
Proteus: UTI (complicated)
H. pylori
Vibrio: cholera
Pseudomonas and Bacteroides
> Atypical
> bloody diarrhea
> E. coli cause uncomplicated UTIs.
## Beta -Lactam Compounds
## Introduction
Penicillins , cephalosporins , monobactams ,
carbapenems , Beta -lactamase inhibitors
Four -membered lactam ring
Mechanism of action
Generally bactericidal
Sometimes you can give a beta lactam compound with a beta
lactamase inhibitor and it will make the bacteria sensitive to the
antibiotic.
The beta lactam compounds have a four member lactam ring.
The mechanism of action for beta lactams include interference
with the Trans-peptidation that occurs during bacterial wall
synthesis. Beta lactams interfere with this adding on of
proteins that creates the bacterial cell wall. So beta lactams
interferes with bacterial cell wall production. Generally beta
lactam compounds are bactericidal due to interference of trans-
peptidation.
> Used with Abx to thwart the
> ___ review
## Classification: 3 Groups of Penicillins
First group: Penicillins
Examples: PenG , PenVK
Bacteria most susceptible
Bacteria resistant
2nd group: Antistaphylococcal penicillins
Examples
Bacteria susceptible
Bacteria resistant
Also resistant strains include staph, which are gram positive, however
staph are resistant due to production of beta lactamases.
Second group of penicillins include the anti-staph penicillins, an example
is nafcillin. The bacteria that are susceptible are strep and staph that are
beta lactamase producers. Gram negative organisms, both cocci and
bacilli, enterococci and anaerobes are resistant.
First groups of penicillins is penicillin. Examples include PenG, and
PenVK. PenG is injectable (Gee that hurts) and PenVK is taken
orally.
Bacteria that are most susceptible are gram positive organisms
that do NOT produce beta lactamases. Bacteria that are resistant
to these are gram negative rod bacilli, such as E. coli. Penicillin is a
horrible choice to treat a UTI because most of them are caused by
gram negative bacilli. Gram negative bacteria are surrounded by a
LPS layer, so the antibiotic cannot get into the binding site and this
is why many gram negative are mostly resistant to Penicillin.
Natural not synthetic or semi-
IM oral
Gram + organisms that do NOT prod beta-lactamases
To PenG and PenVK
gam - rods (e.coli)
Staph that ARE resistant!
LPS + _peptidoglycan_ layer
di ffi cult to penetrate so gam - are
very R Penicillinace-resistant
NAFCILLIN
Staph and strep that PROD beta-
lactamases
NAFCILLIN cannot be broken down by the beta-
Gram - cocci and bacilli
Anaerobes
Enterococci Three Groups continued
3rd group: Extended -spectrum penicillins
Aminopenicillins (amoxicillin and ampicillin)
Anti -pseudomonal PCNs (carbenicillin, ticarcillin,
piperacillin)
Spectrum of activity for 3 rd group
Same as penicillin, better against gm cocci
Relatively susceptible to hydrolysis by b -lactamases
The third group are extended spectrum penicillins and they include the two groups. The fi rst
group include aminopenicillins that include amoxicillin and ampicillin. Extended spectrum
penicillins include a second group, known as anti-pseudomonas PCNs and this group includes
carbenicillin, ticarcillin and piperacillin.
Spectrum of activity for the extended spectrum penicillins is same as penicillin group 1 and is
better against gram negative cocci like H fl u and M cat and those cause OM and sinusitis. Use
amoxicillin quite often for ear infections. The fi rst choice in ear infection is amoxicillin. But if have
recurrent then wont treat with same antibiotic.
^ these are NOW considered the 4th group
Eff ective against pseudomonas
OXACLLIN
DICLOXACILLIN
CLOXACILLIN
all these ^ are other drugs that are anti
staphylococcal ampicillin? In 2nd gen
H. fl u
M.cat
Amoxicillin is an extended
expectrum penicillin would be
a great choice
If we have an org prod beta-
lactamases that is causing OM
ex the org may be
somewhat R to it..
monitor pt and make sure
theyre getting better
Mechanism of Action (MOA)
Cell wall of bacteria (rigid outer layer prevents lysis)
Structure: peptidoglycan (thicker in gm + organisms)
PBP: penicillin -binding protein
Penicillin binding protein (PBP) is the target of these antibiotics
PBP facilitates cross -linking to give bacterial wall rigidity
MOA of beta -lactam antibiotics
Only kills bacteria when they are synthesizing cell wall
Beta lactams
PBP helps the bacteria to facilitate cross
linking to give bacterial wall its rigidity. If you
can target the cross linking and decrease
rigidity then you can lyse the bacteria.
Antibiotics bind the PBP and stop
peptidoglycan synthesis and the cell dies.
Only kills bacteria when they are
synthesizing cell wall.
> For beta-lactam Abx
> IF THE BATCERIA ARE NOT GROWING
> AND MAKING A CELL WALL THEN THESE
> ABX WILL NOT WORK
> Bind to PBP 1.
> Stop __ 2.
> __ 3.
## BETA -LACTAM RESISTANCE: Four
## General Mechanisms
Inactivation by b -lactamase
Modification of PBPs
Alter porins to impair abx penetration to PBPs
Antibiotic efflux
Penicillins wont kill invasive organisms in host cells
Ineffective with invasive infections
Most common mechanism of resistance to beta lactam
antibiotics is the fi rst bullet - inactivation by b-lactamase.
Many b-lactamases, classi fi ed as class A, B and C.
Another mechanism includes modi fi cation of PBPs. So some
bacteria can change the binding sites so the antibiotic cannot
bind.
There can also be alteration of porins where the antibiotics
penetrate to get into the PBPs.
Some bacteria produce e fl ux mechanisms where they can
pump out the antibiotic.
Invasive infections occur in tissue that are not
usually infected and this includes sepsis,
meningitis, encephalitis etc.
Most common mechanism to gain resistance
Org can modify the binding proteins
Changing the locks on your door
^ get to the PBP
Pump out Abx
Wont kill host cell ALSO !
Tissues that are not normal infected
CSF, meningitis, sepsis infections, all invasive infections where we would NOT use the beta-lactam Abx for B-Lactamase Production
Organisms resistant to penicillin, but sensitive to
cephalosporins
Produce b -lactamases with narrow substrate specificity (only PCN)
Organisms in this category
Organisms with extended spectrum b -lactamases
resistant to penicillins and cephalosporins
Organisms that produce b-lactamases with narrow substrate
speci fi city like in those that can only make b-lactamases against
penicillin for example: staph aureus, H fl u, and E. coli. These will
produce b-lactamases that will render them resistant to b-lactams
but will remain susceptible to cephalosporins.
Organisms with extended spectrum b-lactamases
are resistant to penicillins and cephalosporins,
which include pseudomonas and enterobacter.
penicillin
Those inf like OM or UTI if caused by either
of the 3 orgs then there could be a problem
with beta-lactamases but maybe NOT
cephalosporins if these are R to penicillins Mechanisms of Resistance cont
>
Modification of PBPs: organisms
MRSA, pneumococci, enterococci
>
Impaired penetration to target PBPs: only gram
>
Efflux pump: gram organisms do this PENICILLINS
Excretion
Mostly through kidney
Rapid
Administration
Depends on stability of drug to gastric acid and by severity of
infection
Oral preparations
Penicillin V, amoxicillin, amoxicillin + clavulanic acid
Amoxicillin is almost completely absorbed
Distribution
Distribute well through the body
Penetration into bone or CSF are insufficient unless inflamed
Excretion of beta lactams is
through the kidney except nafcillin.
Nafcillin goes through hepatic
excretion. Rapid excretion in both
so given more frequently.
Through GI tract.
K
> Expect for NAFCILLIN (biliary excretion)
> If something is destroyed by gastric acid we would not give them an oral Abx
# Penicillins cont
Uses
Pen G (injectable): strep pharyngitis, syphilis
Pen V (oral): minor gm+ infections, needs QID dosing
Renal excretion
Tubular secretion
Glomerular filtration
Must decrease dose by a quarter to a third if Cr
clearance is 10 ml/min or less
Pen V needs to be given
4 times a day because it
is rapidly processed
90% of secretion is through tubular secretion and 10%
is glomerular fi ltration into bowmans capsule.
If someone has kidney dsyfunction in which creatinine
clearance is 10 ml/min or less then you need to
decrease the dose by 1/4 or 1/3. 4xd Compliance can be an issue
May miss a dose
PCT secreted WHOLE
Must decr the pts dose by 1/4 or 1/3 if
creatinine clearance is 10mL or < Penicillinase Resistant Antibiotics
Oxacillin , cloxacillin , dicloxacillin
Oral
Nafcillin
Not as active as Pen G
Usually injected
Binds plasma proteins
May be used in meningitis (penetration into CSF)
Nafcillin can be given IV or IM. Binds plasma
proteins and may be used with meningitis due
to being able to penetrate into CSF. Not used
for empiric treatment of anything. Can be given
orally for some intestinal infections and will go
straight into the infected intestine.
All orall
2 other drugs
methicillin
fl ucloxacillin
All are also in this 2nd gen
Supplemental NPLEX blueprint ! Ampicillin / Amoxicillin
Broader spectrum
Pneumococci
Shigellosis
Amoxicillin
Adult dose: 250 -500 mg TID
Children: dose 20 -40mg/kg/day divided TID
Common uses
Not active against gram neg aerobes in hospital
acquired infections
Beta -lactamase sensitive
Not useful for most staphyloccal infections
Often prescribed with a B -lactamase inhibitor
Common uses = OM, UTI, sinusitis, community
acquired lower resp tract infection.
Ampicillin is injected and
amoxicillin is oral.
Base dose on weight in
kids. Then divide the dose
by three x day. Then need
to know either chewable,
suspension etc.
# l
3nd gen
Doesnt mean you could use 275mg they dont OFFER this as tabs/caps
need an oral dose when deciding what to give a pt what do
they weigh?! How severe is the inf? What IS the inf?
250-500 pick either 250 or 500 or within the range !
Higher or lower dose?
Research and see the dosage and use knowledge about the individual
Based on KG of weight!
Not lbs or age
pick dose
Convert lbs to kilos
Then convert mg to
mL etc? OM, sinusitis, CAP/community acquired pneumonia (amoxicillin)
NOT for klebsiella, enterobacter, __, __
- but not active against gram - aerobes in hospitals
Just extended spectrum penicillins
We are inhibiting the inhibition
breakdown of beta-lactamases
Speci fi c inhibitors made for amoxicillin and penicillin? Beta Lactamase Inhibitors
Inhibitors of many but not all bacterial lactamases and
can protect hydrolyzable penicillins from inactivation by
these enzymes
Most active against class a beta lactamases
Produced by staph, H.flu , N. gonorhheae , Salmonella
and Shigella
Not good against class C beta lactamases
Produced by enterococci, Klebsiella, Pseudomonas
Do inhibit beta lactamases of B. fragilis and M. cat
Available only in fixed combinations with specific
penicillins
Clavulanic acid used with amoxicillin
Sulfbactam used with ampicillin
Can use beta lactamase inhibitor
with the amino penicillin against
these organisms.
Clavulanic acid used with amoxicillin can be
used against M cat so OM, sinusitis and GI tract
infection with bacterioides. These inhibitors are
off ered in a fi xed combination dosage - it is also
called Augmentem and comes in chewable, oral,
tablet and suspension form.
Ampicillin is injectable and is used with
sulfbactam. It is called unison. Dont
need to know dosage of inhibitor.
> And SPEC inhibitors
> Trade name = unison
> Both cause OM and
> sinusitis clinically
> the pt would not get
> better if they were R
> to Abx
> Prod beta-lactamases that
> can cause it to be R
> against amoxicillin ?
# PENICILLINS ADVERSE REACTIONS
Hypersensitivity (allergic reaction)
Ranges from maculopapular rash to angioedema and
anaphylaxis
Cross -allergic reactions occur among Beta -lactams
*** A hx of PCN allergy is NOT always reliable
Diarrhea: mild to colitis
Interstitial nephritis
Neurotoxicity (esp. in renal dz )
Hematologic toxicities
Vaginal candidiasis
Skin rashes in setting of viral illness and amox . or amp.
Hematological - hemolytic anemia,
eosinophilia, vasculitis, and nafcillin
can lead to neutropenia.
Augmentum, the combo of clavulanic acid
with amoxicillin can cause diarrhea.
If someone REALLY has an
allergy to ex: amoxicillin then
they have an allergy to
ampicillin and PenG etc d/t
cross-allergic reactions
ALWAYS ASK FOR WHAT SX
DEVELOP WHEN THEY TAKE
IT BECAUSE THEY MIGHT
NOT BE ALLERGIC TO THE
ENTIRE CLASS A common/usual SE ^ SIGNIFICANT!!
Generally not permanent
hematologic toxicities
OM + viral URI/cold can be seen (esp in kids) results in a mild rash CEPHALOSPORIN CLASSIFICATION
More stable to beta lactamases
First Generation
Examples: cephalexin and cefadroxil
Activity: gm+ cocci
Bacteria resistant: MRSA, pseudomonas,
Enterobacter, B.fragilis
Dosage: cephalexin 250 -500 mg QID
Excretion
Clinical uses: UTI, cellulitis, staph or strep
Excreted through the kidneys.
Similar dosage to amoxicillin
but QID instead of TID.
B. Fragilis is a gram - anaerobic
rod found as normal fl ora in the
colon. Can cause abscesses in
the GI or GU tract and can cause
endocarditis and osteomyelitis.
These are resistant to fi rst
generation of cephalosporins.
Not used for invasive infections. Ke fl ex
Gram - anaerobic rod
Same as AMOXIL
If cellulitis is MRSA it may not work
Stable means the Abx will NOT be broken down by the
beta-lactamase EZ wont be inhibited
If sensitive could be ine ff ective and torn up but
not the case
Not used for serious systemic/
invasive infections ex: meningitis,
osteomyelitis, absences
^ B. Fragilis resistant to 1st
gen!!
if you have endocarditis
serious systemic inf
Second Generation
# Cephalosporins
Examples
Cefaclor
Cefuroxime
Cefprozil
Activity: same as first gen., extended gm - coverage
Bacteria resistant
Dosage of cefaclor: 250 -500 mg p.o. TID
Clinical uses: OM, sinusitis, community acquired
pneumonia
Not for meningitis
H. Flu and Klebsiella are sensitive.
Pseudomonas and enterococci are resistant.
TID instead of QID
Or sepsis
H
> To the 2nd gen
> Invasive inf and we do not have good penetration
# Third Generation Cephalosporins
Examples: cefotaxime, ceftazidime,
ceftriaxone, cefixime, cefdinir
Activity: more gm - coverage, some cross BBB
Bacteria resistant: Enterobacter, Serratia, S.
aureus
Dosage ceftriaxone
Adults 1 gm IV q day (2 gm IV q 12 hours in
meningitis)
Children 50 mg/kg/d
> Cefotaxime, ceftazidime,
> ceftriaxone are given IV or
> IM. Ce fi xime and cefdinir is
> given orally.
> Covers H Flu, Neisseria, and some cross BBB
> like ceftriaxone so can be used for encephalitis.
> / BID ROCEFIN trade name
> ROCEFIN trade name
# Third Generation Clinical Uses
Gonococcal infection (may need 2 abx )
Meningitis NOT caused by Listeria
Empirical tx of serious infections with pneumococci
resistant to penicillins
Empirical tx of febrile, neutropenic patients
Ceftazidime often in combination with other abx
May need 2 ABX because
of possible resistance
Neutropenic like in those
on chemotherapy with
leukemia
> Neonates and elderly pts?
> In hospital
> Develop fever
> Dont know the inf (could be opportunistic)
> Use combo of ABX
> Ceftazidime !
# Fourth Generation Cephalosporins
Cefepime - IV only
Dosage: .5 -2 gm q 12 hours
Bacteria highly active against
Bacteria it has good activity against
> Good activity against
> pseudomonas, enterobacter, staph
> aureus and strep pneumo.
> Highly active against H fl u
> and Neisseria.
# Adverse Effects of Cephalosporins
Hypersensitivity reactions
Many with a pcn allergy tolerate cephalosporins
Cross allergincity with pcn very low (<1%)
Cross allerginicity is most common if using fi rst group
of PCN or amino penicillin like ampicillin or amoxicillin
with fi rst generation of cephalosporin. So fi rst gen
cephalosporin should not be used in someone with an
anaphylactic reaction to Pen V, VK or amoxicillin.
Could be a mild rash to anaphylaxis
Penicillin
More common with the 1st group
penicillins and aminopenicillins and early
generation cephalosporins
clinical correlation
Anaphylaxis with ANY penicillin =
do NOT use 1st or 2nd gen
cephalosporins Other Beta -Lactam Drugs
Monobactams
Aztreonam (IV or IM)
Uses in those with penicillin anaphylaxis
Carbapenems
Resistant to hydrolysis by most -lactamases
Broad spectrum of activity
> some of the uses include pneumonia, meningitis, even
> sepsis causes by susceptible gram negative bacteria
# CARBAPENEMS
Imipenem
## Wide spectrum
## IV administration
## Administered with cilastatin (inhibits
## dipeptidase in renal tubule)
## Adverse effects: N/V/D, rashes
## Resistant orgs: MRSA and C. difficile
Covers many gram - rods including pseudomonas,
gram + including anaerobes. Given by IV and given
with cilastatin. Given with cilastatin to inhibit
dipeptidase in the renal tubule.
Excreted through kidneys so in
those with renal impairment
can lead to seizures.
Cilastatin inhibits dipeptidase, which
would inactivate imipenem if left alone.
Can precipitate in renal tubules
Inactivated in kidneys when not given with cilia statin CARBAPENEMS
Doripenem /Doribax IV
Complicated intra -abdominal infections
caused by E.coli , Klebsiella , Pseudomonas,
Bacteroides , Strep, peptostreptococcus
Complicated pyelonephritis (per last
quarter)
Decreases serum concentration of valproic
acid
May precipitate seizures
Increasing serum concentration can lead to
toxicity and decreasing serum concentration can
lead to decrease in e ff ectiveness. Both are bad. Usually multifactorial intra-
abdominal inf could be
caused by many di ff orgs
Can decr the serum concentration of Valproic acid / depacote a seizure med
Could cause seizures
Doripenem can decrease the
serum concentration of
valproic acid which can
precipitate to seizures VANCOMYCIN
Effective against many Gram positive
MRSA and MRSE
No beta -lactam ring
Resistance in enterococci by modification of binding
site
Glycopeptide antibiotic
Clinical uses
Usually given IV
Oral vancomycin for C. difficile (try metronidazole first)
Dosage: .125 -.25 gm po q 6 hours for C. diff
IV for MRSA sepsis, endocarditis, and with ceftriaxone for
meningitis
> Goes directly to work at the gut for C.di ff
> Alt med if metronidazole does not work
> When not tx c/dif give IV
> Given emperically until know the org is in the CSF
# VANCOMYCIN
Adverse reactions in 10% of cases
Most are relatively minor
Ototoxicity and nephrotoxicity is uncommon
Red man syndrome
Phlebitis at site of injection
Renal excretion
Vancomycin fl ushing syndrome = infusion
related fl ushing from histamine release.
90% by glomerular fi ltration.
Ototoxicity can a ff ect
Hearing
Balance
Or both
Name change Related to the IV infusion
Histamine release
Flush / turn red
Vs tubular secretion BACITRACIN
Active against gram -positive microorganisms
Highly nephrotoxic when administered systemically
and is only used topically
Suppression of mixed bacterial flora in surface lesions
of the skin, in wounds, or on mucous membranes Never ingest
> Not for serious, deep skin infections!
# Bibliography
>
Beauduy CE, Winston LG. Beta -Lactam & Other Cell
Wall - & Membrane -Active Antibiotics, Chapter 43 . In:
Katzung BG, Vanderah TW. eds. Basic & Clinical
Pharmacology, 15e. McGraw Hill; 2021. Accessed
September 29, 2022. https://accessmedicine -
mhmedical -
com.scnmlib.idm.oclc.org/content.aspx?bookid=298
8§ionid=250601638