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Antibiotics basics for Clinical practice

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ahmed ibrahim fahmy

on 11 January 2015

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Transcript of Antibiotics basics for Clinical practice

Antibiotics

Basics
for
Clinical practice

Basic
concepts in
microbiology

Classification of bacteria
Gram +ve & Gram -ve cell walls
Determined by a technique called
gram stain

Bacteria that
retain
the primary dye are said to be
positive
while the other are said to be
negative

Atypical
bacteria
Some bacteria
lack
a
peptidoglycan
layer resulting in
no color
under the gram stain .
Example :
Mycoplasma pneumoniae
because they lack a cell wall they are
inherently resistant
to antibiotics that act on the cell wall (Ex:
beta lactams
)
Anaerobic
bacteria
Bacteria that doesn
NOT
require
oxygen
for growth
obligate
anaerobes :
Die
in the presence of oxygen
Facultative
anaerobes : can live
with
or
without
oxygen
Ex :
Bacteroides
,
Fusobacterium
,
Actinomyces
Aminoglycosides
require Oxygen dependent active transport before it inhibit the ribosome activity thus they
can NOT
work on
anaerobes
which don't utilize oxygen
When to
target
?
Around 20-30% of
CAP
are caused by
Atypical
bacteria
Clin Infect Dis. (2008) 47 (Supplement 3): S232-S236.
Antibiotics effective against Atypicals :
Azithromycin
Levofloxacin

Moxifloxacin
CAP
treatment guidelines
Outpatients
*without coexisting illnesses or recent use of antimicrobial agent
- A
macrolide
(azithromycin, clarithromycin) (strong recommendation; level I evidence)
-
Doxycycline
(weak recommendation; level III evidence)
- A
respiratory fluoroquinolone
(moxifloxacin or levofloxacin [750 mg]) (strong recommendation; level I evidence)
*Presence of
comorbidities
( chronic heart, lung, liver, or renal disease; DM , ...etc.) OR used antimicrobials within the
previous
3 months
Infectious Diseases Society of America /AmericanThoracic Society Consensus
When to target
Anaerobes
?
Anaerobes are known to be one of the causative agents of
dental
abscess .
Examples of Antibiotics with good Anaerobic coverage :
-
Amoxicillin/clavulanate

-
Clindamycin

-
Metronidazole

Penetrating Abdominal Trauma
Bowel injuries attributable to penetrating, blunt, or iatrogenic trauma that are repaired within 12 h and any other intraoperative contamination of the operative field by enteric contents should be treated with
antibiotics
for
24 hrs
or less (IDSA)
If agents with
poor
anaerobic coverage is used
add
metronidazole
OR use a
single
agent with good anaerobic coverage
-
piperacillin/tazobactam
Cetriaxone
+
Metronidazole

Cefotaxime
+
Metronidazole

-
Cefoxitin
MIC
&
MBC
MIC
is the
lowest
concentration of antibiotic that
inhibits
bacterial growth
-To provide
effective
anti-microbial therapy, the clinically obtainable antibiotic
concentration in body tissues and fluids should be
greate
r than the MIC
MBC
is the
lowest
concentration of antibiotic that
kills
99.9 percent of bacteria
MIC
breakpoints are used to determine the
susceptibility
of an
organism
to antibiotics
according to the
CDC

Staph
. bacteria are classified as

VISA
if the
MIC
for vancomycin is
4-8
µg/ml,
VRSA
if the
MIC
for vancomycin is
≥16
µg/ml.
Antibiotic

classification

Beta-Lactams
Penicillins
Cephalosporins
Carbapenems
Macrolides
Sulfonamides
Aminoglycosides
Glycopeptides
In 1945, Alexander Fleming, who discovered penicillin, warned that bacteria could become resistant to these remarkable drugs.

DECREASED DRUG ACCUMULATION IN THE BACTERIUM
ex: resistance genes in the plasmid code for inducible proteins in the bacterial membrane, which promote energy-dependent efflux of the antibiotic , and hence resistance

GENE AMPLIFICATION
treatment with antibiotics can induce an increased number of copies for pre-existing resistance genes such as antibiotic-destroying enzymes and efflux pumps.

Mechanisms of antibiotic resistance
ALTERATION OF DRUG-SENSITIVE OR DRUG-BINDING SITE
ex : The aminoglycoside-binding site on the 30S subunit of the ribosome may be altered by chromosomal mutation

PRODUCTION OF AN ENZYME THAT INACTIVATES THE DRUG
ex: Staphylococci producing β-lactamase

-When
penicillin
was first introduced it was an effective treatment for
S. aureus
infections, but resistance had already developed during the 1940s.
-This resistance was mediated by the production of a
beta-lactamase
enzyme that inactivates drugs such as penicillin, ampicillin and amoxicillin.
-Consequently,
beta-lactamase-stable
drugs (e.g.
methicillin
and
cloxacillin
) as well as beta-lactamase inhibitors (e.g.
clavulanic
acid and
sulbactam
) that could be combined with the antibacterial drugs were developed.

Gram-negative bacteria have developed several pathways to
β-lactam resistance
.
the most concerning are β-lactamases,
enzymes
that destroy the β-lactam antibiotics .
-Some β-lactamases destroy narrow spectrum drugs (only active against penicillins)
-
newer
β-lactamases (e .g .
carbapenemases
found in carbapenem-resistant Enterobacteriaceae or CRE) are active against
all
β-lactam antibiotics .

MRSA
Strains of S. aureus
resistant
to these penicillinase-stable antibacterial drugs have acquired a novel gene (
mecA
) that codes for a novel
penicillin-binding protein
; these strains are termed
m
ethicillin-
r
esistant
S
taphylococcus 
a
ureus (
MRSA
).
-The first strains of MRSA emerged during the
1960
s.
-Initially, MRSA was mainly a problem in hospital-acquired infections.
-Over the past decade,
community-acquired MRSA
has increased significantly in a number of countries.

The (
mecA
) encodes the protein
PBP2A
(
P
enicillin
b
inding
p
rotein 2A
). PBP2A has a
low affinity
for beta-lactam antibiotics such as methicillin and penicillin. This enables transpeptidase activity in the presence of beta-lactams,
preventing
them from inhibiting cell wall synthesis.
How Resistance spreads
1-by transfer of bacteria
between people
2-by transfer of resistance genes
between bacteria
(usually on plasmids)
3-by transfer of resistance genes between genetic elements
within bacteria
, on
transposons
.
transposons can jump from chromosomal DNA to plasmid DNA and back, allowing for the transfer and permanent addition of genes .
When
first-line
and then
second-line
antibiotic treatment options are
limited
by resistance or are unavailable, healthcare providers are
forced
to use antibiotics that may be
more toxic
to the patient and frequently
more expensive
and
less effective

up to
50%
of all the antibiotics prescribed for people are
not needed
or are not optimally effective as prescribed
CDC report on Antibiotic resistance
Antibiotic discovery is declining
-Common infections in
neonatal
and
intensive care
are increasingly becoming
extremely difficult
, and sometimes
impossible
, to treat.

-Antibacterial drugs used to prevent
postoperative surgical site
infections have become
less effective
or
ineffective
.

-
Cystitis
, one of the most common of all bacterial infections in women, which readily responded to oral treatment in the past, may
need
to be treated by
injected
drugs, imposing additional
costs
for patients and health systems, or become
untreatable
.

-Common
community-acquired
infections such as pneumonia, which used to be readily treatable after the introduction of penicillin, may
not respond
to available or recommended drugs in many settings, putting the lives of patients at risk

WHO report on Antibiotic resistance 2014

-
Escherichia coli
:
resistance
to third-generation
cephalosporins
, including resistance conferred by extended spectrum beta-lactamases (ESBLs), and to
fluoroquinolones
.

Antibiotics
Mechanisms of action
Classification of Penicillins
Clinicians can utilize
extended
(generally 3 to 4 hours) or continuous (24 hour) infusions to achieve prolonged time above the MIC and kill
more
bacteria.

Time-dependent (concentration-independent) killing
increasing the concentration of antibiotic to higher multiples of the MIC does not significantly increase the rate of kill The clinical efficacy of antimicrobials that have a non-significant, dose-dependent killing effect is best predicted by the percentage of
time
that blood concentrations of a drug
remain above
the MIC .
Ex :
β-lactams
,
macrolides
.

Results of randomized controlled studies and several cohorts shows that
extended infusion
PTZ
improves
patient
outcomes
, is associated with
lower
mortality rates, and
shorter length
of hospital stay.
Extended
infusion
Piperacillin-Tazobactam
: giving PTZ as an infusion over
4hrs

q8 hrs
instead of over 30 mins q 6hrs
Chant et al. : Optimal dosing of antibiotics in critically ill patients by using continuous/extended infusions: a systematic review and meta-analysis. Critical Care 2013 17:R279.
Classification
Ceftriaxone
in
Hyperbilirubinemic

neonates

FDA
states that Studies have shown that
Ceftriaxone
can
displace
bilirubin from its binding to serum albumin and
bilirubin encephalopathy
can possibly develop in
neonates (28 days of ages or less )
.
in this cases the safer alternative is
Cefotaxime
Examples
A patient in the
ICU
experienced seizures after receiving
Tienam

250 q6h
, what's the problem ?
the patient had
CrCl
=
20
ml/min ,
dose
of Imipenem should be
adjusted
to 250
q12h

1
-those with existing QT interval prolongation

2
-hypokalemia

3
-hypomagnesemia

4
-significant bradycardia

5
-bradyarrhythmias

6
-uncompensated heart failure

7
-those receiving antiarrhythmic drugs

Both the
macrolides
and the
fluoroquinolones
can cause a
prolonged QT
interval,
which can result in torsades de pointes and death.

Patients at particular risk include:
in these cases
Doxycycline
is a good alternative
Avoid
sulphonamids in patients with
glucose 6-phosphate dehydrogenase

deficiency
to prevent cases of
Hemolytic anemia
Patients taking
TMP-SMX
had higher
INR
when taken with
warfarin
(increased risk of
bleeding
)
In
older
patients (above 60 yrs old) receiving
ACEIs
or
ARBs
,
co-trimoxazole
is associated with an increased risk of
sudden death
due to
hyperkalemia
(BMJ 2014;349:g6196)
in those patients using
Norfloxacin
or
Nitrofurantoin
for
UTIs
is safer
-Giving drugs that exhibit this concentration-dependent killing by a
once-a-day
bolus infusion achieves high peak levels, favoring
rapid killing
of the infecting pathogen.

Concentration-dependent killing
-Antibiotics that show a significant increase in the rate of bacterial killing as the
concentration
of antibiotic
increases
from 4- to 64-fold the MIC of the drug for the infecting organism . Ex :
Aminoglycosides
,
Fluroquinolones


-The
best
responses occur when the concentrations
are
≥ 10
times
above
the MIC for their target organism at the site of infection
Typically seen within
5 to 10
days after initiation of therapy and manifests as a
gradual
progressive
rise
in
Scr
and
BUN
and
decrease
in
creatinine clearance
How to prevent ?
1-
limit
the
total
aminoglycoside
dose
administered

2-
Avoid
concomitant therapy with other
nephrotoxic drugs.

3-Use
High-dose

intermittent
dosing
if possible


4-
individualized
pharmacokinetic
dosing

Nephrotoxicity

EXTENDED-INTERVAL DOSING
Gentamicin
dose : 7mg/kg IV
q24h
not
suitable for patients with
CrCl
less than
60
ml/min
MULTIPLE-DAILY DOSING
2mg/kg Gentamicin as
loading
dose in case of
severe
infections (ex: sepsis)
Adjust
dose based on
CrCl

Amikacin
dose : 15mg/kg
q24h
TBW
,
IBW
,
adjusted BW
will it make a difference ?
For
underweight
patients, use
total body weight
to calculate dose.

For patients whose weight is
1-1.2 times
their ideal body weight, use
ideal body weight
.

For patients weighing
>1.2
times ideal body weight, use
adjusted body weight.
Female, 50 yrs old , 160cm ,
85
kg
use adjusted BW =
65
Kg
Exceptions
to this include some serious infections where exceptionally high antibiotic
tissue concentrations are essential (e.g.
meningitis
, infective
endocarditis
)

-
improves
patient
safety
by reducing the need for intravenous access
-IV antibiotics should be
reviewed
on a
daily basis
and, if appropriate, the patient
switched
to an oral equivalent within
24 hours
of meeting
switch criteria
.



temperature
< 37.5 °C for 24 hours

signs
and symptoms of infection are
improving

• inflammatory
markers
are
decreasing
• patient able to
tolerate
oral food and fluids
• absence of on-going or potential problem of
absorption

• oral formulation or suitable oral
alternative
is available

IV to Oral
Oral switch criteria :
Double

anaerobic

coverage

Adding metronidazole to Imipenem will it benefit the patient ?
-
Adding
Metronidazole has
never
been
shown
to
improve
clinical outcomes.
-
None
of the available treatment
guidelines
published by the Infectious Diseases Society of America (
IDSA
)
recommend
the use of
double
anaerobic coverage.
-Provide
No extra
coverage as Imipenem already has excellent anaerobic coverage
Rhinosinusitis

-More than
90 %
of rhinosinusitis is due to
viral
infections (don’t need antibiotic therapy)
-Only
2 %
of viral sinusitis may develop
secondary
bacterial infection

the recommended
duration
of antibiotic therapy ranges from
7-14
days


-
symptoms
lasting for more than
10 days
without improvement
-
high fever
(39 C or more) +
purulent
nasal discharge

When to give antibiotics ?
Amoxicillin-clavulanate
is recommended as
empiric
antimicrobial therapy
if
allergic
to penicllins :
levofloxacin
or
moxifloxacin
becomes 1st line
1- Macrolides (
Clarithromycin
,
Azithromycin
) because of high rate of
resistance
among S. pneumonia

2- (
Trimethoprim-sulfamethoxazole
) both S. pneumoniae and Haemophilus influenzae are
highly
resistant

3-Second generation cephalosporins(
Cefuroxime
) also have
high
rates of resistance

-In Managing the Patient With
ABRS
Who Has
Failed
to Respond to Empiric Treatment With
Both

First-line
and
Second-line
Agents, It Is Important to Obtain
Cultures
to Document Whether There Is Persistent Bacterial Infection and Whether Resistant Pathogens Are Present.

-An alternative management strategy is recommended if symptoms
worsen
after
48–72
hours of
initial
empiric antimicrobial therapy
Antibiotics that should NOT be used
The only
exception
todate is adding Metronidazole to treat proven
C.difficle
infections
Doxycyline
JAMA : a teachable moment
A man in his 70s with a history of rheumatoid arthritis being treated with infliximab presented to his primary care physician (PCP) with
upper respiratory tract congestion
of several days’ duration. He was diagnosed as having acute
rhinosinusitis
and treated with
cefdinir
Two days later, he developed
diarrhea
. After 24 hours of severe diarrhea,
he
discontinued
taking the antibiotic, and the following day his physician prescribed
Lomotil


Five days after the initial visit, he arrived at the
emergency department
pale, hypotensive, and reporting an “uncountable number of episodes of diarrhea.
On hospital day 2, he developed
toxic megacolon
and underwent
small bowel resection
and
near-total colectomy
.

Antibiotic exposure
is an important risk factor for the development of
CDI
JAMA Internal Medicine August 2014 Volume 174, Number 8
The patient subsequently developed
multiorgan failure
and required intubation, continuous venovenous hemofiltration (CVVH) and vasopressor support
He was aggressively treated for presumed
Clostridium difficile infection
(CDI) and was admitted in critical condition
Vancomycin (1st to be discovered)
Teicoplanin (1990s)
Telavancin (2009)
Dalbavancin(2014)
Oritavancin(2014)

Examples
Vancomycin
dosing
Dose will depend on
body weight
and
Kidney function

Vancomycin dosages of
15–20
mg/kg (based on ABW) given every
8–12
hours not to exceed 2gm per dose is required for most patients with normal renal function (CrCl ≥100 mL/min) to achieve the suggested serum concentrations when the
MIC
is
≤1
mg/L (ASHP/IDSA consensus)

critically ill
patients (sepsis, meningitis, pneumonia, or infective endocarditis) may require
loading
doses up to 25–30 mg/kg
Infusion rate
should not exceed
1gm/hr
(approx. 15 mg/min) to minimize development of “
Red Man’s Syndrome
.”
1
gm q
12
hrs is it
suitable
for all patients
?
this Dose
assume
the patient is
70 kg
with
normal
renal function
obese
patients will require
higher
doses ,
Ex :
100
kg will require
1500
mg
patients with
renal impairment
will require
less frequent
dosing , Ex : CrCl =
30 ml/min
require
q24hrs
dosing
Antibiotic

resistance

References
1-Infectious disease society of America guidelines
2-www.cdc.gov
3-Royal united hospital antibiotic guidelines
4-Antibiotic Basics for Clinicians 2nd E
5-Lippincott's Pharmacology 5th E
6-Rang & Dale's Pharmacology 7th E
7-Infectious Diseases Management Program at UCSF
Microbiology a systems approach 2nd E
Examples
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