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An

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ahmed ibrahim fahmy

on 15 October 2015

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Transcript of An

Antibiotics in
Clinical Practice

Introduction
Antibiotic Resistance
Antibiotic Stewardship
Antibiotic classification
Lippincott’s pharmacology 5th ed

Determined by a technique called
Gram staining
*gram-
positive
bacteria :
blue
or
purple
*gram-
negative
bacteria :
pink

Gram +ve & gram -ve bacteria:
Microbiology a systems approach 2nd ed

All mycoplasmas lack a cell wall and, therefore, all are inherently
resistant
to
beta-lactam
antibiotics (e.g., penicillin).

Mycoplasmas are bacteria that naturally
lack
a cell wall.
the mycoplasma cell membrane is stabilized by sterols and is resistant to lysis.
Ex:
Mycoplasma pneumoniae

Mycoplasma

In order to enter a cell,
aminoglycosides
require an energy-dependent
phase using
oxygen
or nitrate, Because anaerobes do not utilize oxygen or nitrate, aminoglycosides
cannot
enter anaerobic cells to inhibit ribosomal activity
Are bacteria that does not require oxygen for growth.
-
Obligate
anaerobe : die in the presence of oxygen
-
Facultative
anaerobes : can grow with
or
without oxygen
Anaerobic Bacteria
Narrow-spectrum antibiotics
Administration of broad-spectrum antibiotics can drastically

alter
the nature of the normal bacterial flora and precipitate a
super-infection
of an organism such as
Clostridium difficile
, the growth of which is normally kept in check by the presence of other microorganisms
Broad-spectrum antibiotics
-affect a wide variety of microbial species
-agents acting only on a limited group of microorganisms

chloramphenicol
is
bacteriostatic
against gram-negative rods and is
bactericidal
against other organisms, such as S. pneumoniae.

Bactericidal
Bactericidal drugs
kill
bacteria at drug serum levels achievable in the patient
(Ex:
Beta-lactams
)
Bacteriostatic
Bacteriostatic drugs
stop
the growth and replication of bacteria thus limiting the spread of infection until the body’s immune system eliminates the pathogen. (Ex :
macrolides
)
-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

Minimum inhibitory concentration (MIC)
-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


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
.

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 .

-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.

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
.
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

-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
.

Countries that notified at least one case of
e
xtensively
d
rug-
r
esistant
TB
(
XDR-TB
) by the end of 2012 (WHO)

Antibiotic resistance is a global threat
Antibiotic discovery is declining
-skin and skin structure infections caused by S. aureus and Streptococcus pyogenes

-Community-Acquired Bacterial Pneumonia
-Skin & Skin Structure Infections
-HAP
-skin and skin structure infections 
-Complicated Intra-abdominal Infection
-Complicated UTI
-complicated skin and skin structure infections
-complicated intra-abdominal infections and(CAP).
Antibiotics approved in the last 10 years (from 2004 to 2014)
Antibiotic Guidelines
Duration of therapy:
minimum
of
5
days, should be
afebril
e for
48-72
hours,
longer duration
of therapy may be needed if initial therapy was not active against the
identified
pathogen or if it was
complicated
by extrapulmonary infections

For
all
suspected CAP patients, in light of better outcomes with the earliest possible interventions the Infectious Diseases Society of America (IDSA) recommends
initial empiric
antimicrobial therapy until
laboratory results
can be obtained to guide more specific therapy

Community acquired pneumonia(CAP)

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

Recent therapy
or a
repeated
course of therapy with beta-lactams, macrolides, or
fluoroquinolones are
risk factors
for pneumococcal
resistance
to the same class of antibiotic. Thus, an antimicrobial agent from an
alternative
class is preferred for a patient who has
recently
received one of these agents.

Health care professionals should
reserve
Tygacil for use in situations when
alternative
treatments are
not
suitable. (FDA 2013)
is one of the recommended beta-lactam antibiotics for CAP in immunocompetent,
non-ICU patients
-account for approximately
15%
of all CAP cases
-mainly caused by
Mycoplasma
pneumoniae,
Legionella
species, and
Chlamydia
pneumoniae.

Atypical pneumonia
3
D
s =
1.
Stop
antibiotics if there is no evidence of infection
2. Switch
IV to Oral

3.
Change
antibiotics – ideally to a narrower spectrum – or broader if required
4. Continue and
review
again after a further 24 hours
5.
Outpatient Parenteral
Antibiotic Therapy (OPAT)

There is no single template for a program to optimize antibiotic prescribing in hospitals.
How to Rationalize Antibiotic use
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
.


1-Written hospital
guidelines
2-
Educationa
l efforts aimed at changing prescribing practices of physicians
3-
Restriction
of hospital formulary through pharmacy and therapeutics Committee
4-Requirement of
consultation
with infectious diseases subspecialists for certain antimicrobial choices
5-Antimicrobial susceptibility
reporting

Methods to implement antibiotic control or restriction policy

All clinicians should perform a
review
of antibiotics
48 hours
after antibiotics are initiated to answer these key questions:

-Does this patient have an
infection
that will respond to antibiotics?
-If so, is the patient on the
right
antibiotic(s), dose, and route of administration?
-Can a more
targeted
antibiotic be used to treat the infection (
de-escalate
)?
-How
long
should the patient receive the antibiotic(s)?

As soon as the
causative
pathogen has been identified,
de-escalation
should be performed
by selecting the most appropriate antimicrobial agent that covers the pathogen

Because patients with
severe sepsis
or
septic shock
have little margin for error in the choice of therapy, the initial selection of antimicrobial therapy should be
broad enough
to cover all likely pathogens

obtain
appropriate cultures
before
anti-microbial therapy is initiated if such cultures
do not cause significant
delay
(> 45 minutes) in the start of antimicrobial(s) Administration

in situations where therapy might be
unnecessarily
duplicative including simultaneous use of
multiple
agents with
overlapping
spectra e.g. anaerobic activity, atypical activity,
Gram-negative activity
and resistant Gram-positive activity.

Resources

1
- Lippincott's Pharmacology 5th edition
2
- Rang & dale’s pharmacology 7th edition
3
- Infectious Diseases Society of America latest guidelines
4
- Centers for Disease Control and Prevention recommendation on use of antibiotics
5
- Royal United Hospital antibiotic guidelines

Streptococcal Pharyngitis
-the clinical features alone do not reliably discriminate between bacterial and viral Pharyngitis except when overt
viral
features like
rhinorrhea
,
cough
,
oral ulcers
, and/or
hoarseness
are present
- 1st line =
Amoxicillin
OR other
penicillins

-if
allergic
= 1st generation cephalosporin (
cefadroxil
OR
cephalexin
)
-if allergic to
both
=
Clindamycin
OR
Clarithromycin
OR
azithromycin

-around
80 %
of cases of Pharyngitis
won’t
need antibiotic therapy
(
Viral
in origin)
- Antimicrobials that should
not
be used :
1-
Tetracyclines
: high prevalence of
resistant
strains.
2-
trimethoprim-sulfamethoxazole
(Septrin) do
not
eradicate group A streptococcus(GAS)
3-
Ciprofloxacin
have
limited
activity against GAS
4-
levofloxacin
(Tavanic) and
moxifloxacin
(Avalox):
expensive
and have an
unnecessarily
broad spectrum of activity and are therefore not recommended for routine treatment of bacterial pharyngitis

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

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


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

Asymptomatic bacteriuria

-Treatment of asymptomatic bacteriuria
neither
decreases the
frequency
of Symptomatic infection
nor
prevents
further
episodes of asymptomatic bacteriuria.

Acute Uncomplicated Cystitis

-
Amoxicillin
(Amoxil™ ) or
ampicillin
should
not
be used for empirical treatment given the relatively
poor
efficacy, and the very high prevalence of antimicrobial
resistance
to these agents worldwide

Acute Pyelonephritis

-
Beta-lactams
(Amoxicillin , Cephalexin)
-
trimethoprim sulfamethoxazole
(Septrin DS)


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.
Antibiotics that may be released soon in the market
Tedizolid
(by end of 2014)
-infections caused by certain
Gram-positive
bacteria, including those caused by (MRSA).

Delafloxacin
(phase3)
-treatment of
a
cute
b
acterial
s
kin and
s
kin
s
tructure
i
nfections (
ABSSSI
) caused by
Gram-positive
(including MRSA) and
Gram-negative
bacteria
-uncomplicated
gonorrhea
.

Solithromycin
(phase3)
-
CAP

-uncomplicated
gonorrhea
Eravacycline
(phase3)
-complicated
intra-abdominal infections
(cIAI)
-complicated
urinary tract infections
(cUTI)

Plazomicin
(phase3)
-
MDR
Enterobacteriaceae

Ex :
Actinomyces
(caustive agent for many dental infections )
-The
best
responses occur when the concentrations
are
≥ 10
times
above
the MIC for their target organism at the site of infection
-once daily dosage
can't
be used in
Renal insufficiency
(CrCL<
30
ml/min)
Amikacin Dosing
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
).
Mechanisms summary
transposons can jump from chromosomal DNA to plasmid DNA and back, allowing for the transfer and permanent addition of genes .
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
-Dosing
intervals
of aminoglycosides will also depend on
CrCl
Resistant
to
isoniazid
and
rifampin
, plus any
fluoroquinolone
and at least one of three injectable second-line drugs (i.e.,
amikacin
,
kanamycin
, or
capreomycin
)
penumoccoal vaccine
Tigecycline
(
2005
)
Doripenem
(
2007
)
Telavancin
(
2008
)
Ceftaroline
(
2010
)
Dalbavancin
(
2014
)
Pneumococcal conjugate vaccine (PCV13) is recommended for
all
children

younger
than
5
years old and for
adults
with certain
risk factors
. (CDC)
A new version of the pneumococcal conjugate vaccine (PCV13) introduced in
2010
-
protects
against infections with the most
resistant
pneumococcus strains
-
reduced
antibiotic
resistance
by blocking the
transmission
of resistant S. pneumoniae strains.

Risk factors :
1
-Immunocompromised persons
2
-Persons with functional or anatomic asplenia
3
-Cochlear implants
4
-CSF leaks

-
symptoms
lasting for more than
10 days
without improvement
-
high fever
(39 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
-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.

Antibiotics that shouldn’t be used :
-An alternative management strategy is recommended if symptoms
worsen
after
48–72
hours of
initial
empiric antimicrobial therapy
-
Asymptomatic
means presence of bacteria in the urine culture but with
no
apparent symptoms on the patient (
frequency
,
urgency
,
dysuria
, or
suprapubic
pain in women)
-
Pyuria
accompanying
asymptomatic
bacteriuria is
not
an indication for
antimicrobial
treatment
-
Pregnant
women should be screened for bacteriuria by
urine culture
at least once in early pregnancy, and they should be
treated
if the results are positive
-
Screening
for and
treatment
of asymptomatic bacteriuria before
transurethral
resection of the prostate is
recommended
and

other urologic procedures for which
mucosal bleeding
is anticipated

-
Nitrofurantoin
(Uvamin )(100 mg twice daily for 5 days) is an appropriate choice for therapy due to
minimal
resistance and propensity for collateral damage and efficacy
-
trimethoprim-sulfamethoxazole
(Septrin DS) (twice-daily for 3 days) is an appropriate choice for therapy, given its
efficacy
as assessed in numerous clinical trials
Antibiotics that should not be used as 1st line :
-
ofloxacin
(Tarvid™),
ciprofloxacin
(Ciprobay™), and
levofloxacin
(tavanic™), are highly efficacious in 3-day regimens but have a propensity for collateral damage and should be
reserved
for important uses other than acute cystitis and thus should be considered alternative antimicrobials for acute cystitis
-In patients suspected of having pyelonephritis, a
urine culture
and
susceptibility test
should always be
performed
, and initial empirical therapy should be tailored appropriately on the basis of the infecting uropathogen
-
Ciprofloxacin
(500 mg twice daily) for 7 days, is an appropriate choice for therapy in patients not requiring hospitalization
-
levofloxacin
(750 mg for 5 days), is an appropriate choice for therapy in patients not requiring hospitalization
Antibiotics that should not be used as 1st line :
both are
less
effective and will require
longer
duration of therapy (14days) thus should not be used as 1st line treatment
Monitoring antibiotic prescribing and resistance patterns with regular reporting of information on antibiotic use and resistance to doctor , nurses and relevant staff
Tracking & Reporting :
The five Antimicrobial Prescribing Decision options are:

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 :
Antibiotic “Time outs.”
Double coverage
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:
Tigecycline
Ceftaroline (2010)
Dose = 600 mg IV q12h
in these cases
Doxycycline
is a good alternative
Ceftazidime + Levofloxacin + Amikacin
Ceftazidime + levofloxacin
right
D
ose
right
D
uration
right
D
rug
Full transcript