Dr.T.V.

Rao MD

Dr.T.V.Rao MD 1
 Antibiotics Advanced Medicine

 The discovery of potent

and safe antimicrobial
agents is arguably the
single greatest health care
advance in history. The
availability of these
agents rapidly reduced
the morbidity and
mortality associated with
a host of formerly fatal
diseases.
Dr.T.V.Rao MD 2
Microbes follow the Darwin's
Theory
 The widespread use of

antibiotics has been
associated with what we
now know to be the
predictable emergence of
resistance.
 Early confidence that
infections would eventually
be conquered has given way
to a greater appreciation of
the genetic flexibility of
common human pathogens

Dr.T.V.Rao MD 3
 ESKAPE AND CDC


According to the latest
data from the Centers
for Disease Control
and Prevention
(CDC), the six
ESKAPE bacteria are
responsible for two
thirds of all health
care-associated
infections (HAIs)
Dr.T.V.Rao MD 4
 ESKAPE
Pathogens of Highest Concern


 The most serious, life-
threatening infections are
caused by a group of drug-
resistant bacteria that the
 Infectious Diseases Society
of America (IDSA) has
labeled the "ESKAPE"
pathogens, because they
effectively escape the effects
of antibacterial drugs

Dr.T.V.Rao MD 5
 ESKAPE - Bacteria
 ESKAPE bacteria—


Enterococcus faecium,
Staphylococcus aureus,
Klebsiella species,
Acinetobacter baumannii,
Pseudomonas aeruginosa,
and
Enterobacter species—are
among the biggest threat of
infectious diseases
physicians face today,

Dr.T.V.Rao MD 6
Bad Bugs, No Drugs: No
New Drugs


 Enterococcus faecium(E), Staphylococcus aureus(S),
Klebsiella pneumoniae(K), Acinetobacter
baumannii(A), Pseudomonas aeruginosa(P), and
Enterobacter spp. (also E. coli) (E)
 The late-stage clinical development pipeline remains
unacceptably lean
 Some important molecules for problematic pathogens
such as MRSA and E. faecium
 Few novel prospects for other ESKAPE pathogens,
especially multidrug-resistant gram-negative bacilli, such
as A. baumannii and P. aeruginosa)
Dr.T.V.Rao MD 7
 Why ESKAPE ARE THREAT
 The ESKAPE pathogens


(Enterococcus faecium,
Staphylococcus aureus,
Klebsiella pneumoniae,
Acinetobacter baumannii,
Pseudomonas aeruginosa, and
Enterobacter species) are
responsible for a substantial
percentage of nosocomial
infections in the modern
hospital and represent the vast
majority of isolates whose
resistance to antimicrobial
agents presents serious
therapeutic dilemmas for
physician
Dr.T.V.Rao MD 8
 Why ESKAPE Microbes are a
Global Concern


 The ESKAPE MICROBES
are extraordinarily
important, not only because
they cause the lion’s share of
nosocomial infections but
also because they represent
paradigms of pathogenesis,
transmission, and resistance.

Dr.T.V.Rao MD 9
Dr.T.V.Rao MD 10
 ESKAPE Bacteria are Major
Nosocomial Agents


 According to the latest
data from the Centers for
Disease Control and
Prevention (CDC), the six
ESKAPE bacteria are
responsible for two thirds of
all health care-
associated infections
(HAIs).

Dr.T.V.Rao MD 11
 Enterococcus species

for one out of eight HAIs in
 Enterococci were responsible
2006-2007. A 2004 study found about two thirds of E.
faecium bloodstream infections were resistant to
vancomycin, one of the most commonly used antibiotics
to treat enterococcal infections. Some physicians are
treating vancomycin-resistant E. faecium with the new
antibiotics linezolid, daptomycin, and tigecycline, but
these drugs have not been studied extensively for use
against these infections. Furthermore, many patients
cannot tolerate them.

Dr.T.V.Rao MD 12
 Enterococcus faecium
(and faecalis)


With the advent of vancomycin-resistant E.
faecium, which are intrinsically resistant to
ampicillin and carbapenems, in the mid-1990s we
encountered virtually untreatable organisms
–However, enterococci have relatively low
virulence, and treatment is not always required in
mixed infections, unless also in blood;
IV catheter infections may clear if the catheter is
removed.
Dr.T.V.Rao MD 13
 Newer Drugs Active Against VRE
(and MRSA)


 Synercid (synergistic combination of two streptogramins)
Bactericidal
 –Active against E. faecium but not E. faecalis
 –Side-effect of total-body tenderness
 –Rarely used
 •Linezolid (oxazolidinone)
 –Bacteriostatic Both po and IV
 –Occasional thrombocytopenia, esp. after 14 days (need to
check plt counts at least weekly)
 –Emergence of resistant isolates
 –Increasingly important for MRSA
Dr.T.V.Rao MD 14
Newer Drugs Active Against VRE
(and MRSA)


Daptomycin (lipopeptide)

–Rapidly bactericidal (important for bacteremia's)
 –IV only
 –Binds to surfactant, so not effective in pneumonia
 –Occasional elevations of creatine phosphokinase (CPK) and
associated muscle aches; seems not to be a serious problem
 –Increasingly important for MRSA
 •Tigecycline (glycylcycline; derivative of minocycline)
 –Bacteriostatic
 –IV only
 –Active not only against Staph, Strep, and Enterococcus, but
also against Enterobacteriaceae

Dr.T.V.Rao MD 15
 Staphylococcus aureus


The prominent name among the ESKAPE
bacteria, methicillin-resistant Staphylococcus
aureus (MRSA) outbreaks have been reported
among otherwise-healthy athletes, military
recruits, school children, and others. MRSA
caused an estimated 94,000 invasive infections—
more than 19,000 of them fatal—in 2005,
according to a recent study by CDC. MRSA is a
serious and growing threat in hospitals and
other health care facilities,
Dr.T.V.Rao MD 16
 MRSA
MRSA has drawn


more attention from
the pharmaceutical
industry than any of
the other ESKAPE
bugs. Several new
drugs are effective
against these
infections.
Dr.T.V.Rao MD 17
 Problems with MRSA in
Treatments


 60-65% of SA are MR (both ICU and non-ICU) (DMC 2009) (for
presumptive treatment, must assume MR)
 Vancomycin MIC –MICs have been generally rising
 For vanco MIC >1 µg/ml, efficacy reduced, and even higher MICs
may be selected (hVISA)
 Therefore, for MIC >1 (>50%), we use daptomycin (esp. for
bacteremia) (but not for pneumonia, in which case we use linezolid)
 Other alternatives to vancomycin
 TMP/SMX: IV/po; cidal; ~90% are S
 –Clindamycin: IV/po; not reliably cidal; must check D-test; ~50%
Sensitive
 •We are losing vancomycin, but we have alternatives

Dr.T.V.Rao MD 18
 Klebsiella species

bacteria cause
These gram-negative
infections in the urinary, biliary, and
gastrointestinal tracts, and in trauma
wounds. Klebsiella species and their
gram-negative cousin E. coli together
accounted for 18 percent of all HAIs in
2006-2007, and a growing proportion of
these two carry resistance to a remarkable
spectrum of antibiotics.
Dr.T.V.Rao MD 19
 Problems with
Enterobacteriaceae


ESBL –Klebsiella pneumonia and E. coli
(~8-10%)
–>90% Sensitive to carbapenems,
Cefotetan/cefoxitin, tigecycline
KPC ß-lactamases (~1-3% Kleb
pneumonia Resistant to carbapenems,
as well as other ß-lactams)
Dr.T.V.Rao MD 20
 KPC’s


Might appear susceptible to imipenem or meropenem,
but with borderline MICs Usually ertapenem-resistant
–Modified Hodge test to confirm
•Usually susceptible only to colistin, tigecycline, select
aminoglycosides, and possibly TMP/SMX
•Easily spread in hospitals (often requires cohorting of
staff and patients to control)

Dr.T.V.Rao MD 21
 Acinetobacter baumannii
 Traditionally infects


patients in ICU and Burn
Units
 •Now being seen in
general hospital
population and nursing
homes
 •Antimicrobial
resistance is a major
concern

Dr.T.V.Rao MD 22
 Acinetobacter baumannii:


 Drug resistance is a major
problem in Acinetobacter
infections, which are
responsible for about 3 percent
of all HAIs,. Soldiers are
returning from Iraq and
Afghanistan with cases of
highly resistant Acinetobacter
wound infections. Strains have
emerged that are resistant to all
but the most toxic new
generation of Antibiotics

Dr.T.V.Rao MD 23
 Pseudomonas aeruginosa
 The most commonly

encountered multiresistant
gram-negative pathogen
 Relatively low pathogenicity:
mainly a problem in ICUs Burn
Unit Patents from long-term
care facilities Additional risk
factors:
Immunocompromised,
debilitated, prior
hospitalizations, prior
antibiotic therapy,
trauma outdoors with
exposure to water/soil

Dr.T.V.Rao MD 24
 Pseudomonas aeruginosa:
Pseudomonas is a


particular problem for
patients on respirators and
those with cystic fibrosis.
Eight percent of all HAIs are
caused by P. aeruginosa, and
one quarter of these are
resistant to carbapenems, a
class of antibiotics
commonly used for these
infections. There are no new
drugs in development for
these highly resistant
infections.

Dr.T.V.Rao MD 25
 Enterobacter species:


 One in 20 HAIs is caused by
this group of bacteria. Like
Klebsiella, E. coli, and the other
gram-negatives, Enterobacter
species have developed broad-
spectrum resistance to multiple
classes of antibiotics. One drug,
tigecycline, might work against
these infections. There is no
new antibiotics in the pipeline.

Dr.T.V.Rao MD 26
 The Challenge:
Global Antibiotic Resistance


Clinical and media reports have documented the
rapid rise of antibiotic-resistant and MDR
bacterial infections, now a major global public
health concern. Most hospital-acquired
infections are resistant to at least one drug, and
the incidence of multi-drug resistance is rising.
The inability to rapidly get these infections under
control results in nearly 100,000 deaths every year
in the United States, many more in Developing
World
Dr.T.V.Rao MD 27
Dr.T.V.Rao MD 28
 Antimicrobial Stewardship.


 Antimicrobial stewardship is a key component of a
multifaceted approach to preventing emergence of
antimicrobial resistance. Good antimicrobial
stewardship involves selecting an appropriate drug and
optimizing its dose and duration to cure an infection
while minimizing toxicity and conditions for selection
of resistant bacterial strains. Studies conducted over the
years indicate that antibiotic use is unnecessary or
inappropriate in as many as 50% of cases.

Dr.T.V.Rao MD 29
 Other Aspects of Antimicrobial
Stewardship


 The appropriate use of antimicrobials is an essential part
of patient safety.
 The frequency of inappropriate antimicrobial use is often
used as a surrogate marker for the avoidable impact on
antimicrobial resistance.
 The combination of antimicrobial stewardship and
comprehensive infection control has been shown to limit
the emergence and transmission of antimicrobial resistant
bacteria.

Dr.T.V.Rao MD 30
 ANTIMICROBIAL
STEWARDSHIP GUIDELINES
 Current efforts to thwart the

siege of MDROs and to address
the lack of development of
antimicrobial agents center on
antimicrobial stewardship. In
2007, The Infectious Diseases
Society of America (IDSA)
published guidelines in
conjunction with the Society for
Healthcare Epidemiology of
America to outline
antimicrobial stewardship
practices.

Dr.T.V.Rao MD 31
 Developing Antibiotic Stewardship -
Committee Membership and Leadership


 Medical Staff- Active participation is critical to success
Includes Chief Medical Officer support, ID , Hospitalists,
Intensivists, Pulmonary, ED, Community MDs and others as
willing
 Pharmacy- Coordinates the efforts of the team, guideline
development, education and tracking reports
 Infection Prevention & Control- Prevention Strategies, hand
hygiene, precautions, medical staff-nursing laison
 Microbiology- Data trends, special testing expertise
 Quality & Organizational Development- Performance
Improvement guidance; meeting guidance
Dr.T.V.Rao MD 32
 Core Members of the Antimicrobial
Stewardship Team


 Infectious disease physician (Director or Co-director)
Clinical pharmacist with infectious disease training (Co-
director or core member)
 Other members of the team
 – Microbiologist
 – Information system specialist
 – Infection control professional
 – Hospital epidemiologist

Dr.T.V.Rao MD 33
 Goals of Committee


 Assist providers in appropriate use of
antimicrobial therapy with improved patient
outcomes
 Slow the development of antimicrobial resistance
 Develop evidence- based appropriate use
guidelines
 Educate providers and staff regarding guidelines
 Track resistance patterns and report back to medical and
hospital staff
Dr.T.V.Rao MD 34
 Need to Develop Antibiotic
Stewardship in Developing Nations


 Antimicrobial stewardship is one method many
institutions are implementing to achieve this balance.
Antimicrobial stewardship encompasses a wide range of
services aimed at improving patient outcomes and
minimizing the untoward effects of antimicrobial agents
including side effects as well as induction of resistance.
These programs have been shown to decrease both the
development of resistance as well as expenditures on
antimicrobial agents.

Dr.T.V.Rao MD 35
 Antimicrobial Stewardship:
Plan the programme to the Needs of your
Hospital on ……


 Restriction of the
oximinocephalosporins
 – VRE
 – C. difficile
 – ESBLs
 – AmpC hyperproduction
 • Use vancomycin according to
HICPAC
 guidelines
 – VRE
 – VISA
 – VRSA

Dr.T.V.Rao MD 36
 Should Plan Matter on
Judicious Use of Antibiotics

 Fluoroquinolones – judicious
use
 – Elimination of ciprofloxacin
 • Association with MRSA
 • Association with C. difficile
 • Cost benefit with a single
fluoroquinoloneformulary
 • Carbapenems – restriction
 – Metallo-beta-lactamases
 – Other carbapenemases (KPC
1 – 3, OXA)

Dr.T.V.Rao MD 37
 Why Participate in
Stewardship?
 The primary goal of
stewardship is to…Optimize


clinical outcomes while
minimizing unintended
consequences of
antimicrobial use, including
toxicity, the selection of
pathogenic organisms, and
emergence of resistance.
 Secondary goals…Reduce
healthcare costs without
adversely impacting quality
of care.

Dr.T.V.Rao MD 38
 Modifying Empiric Therapy


 “Empiric therapy”: treatment prescribed before culture data and
other testing results are available
 In most cases, empiric therapy should be narrowed at day 3-4 or
earlier
 –If cultures are negative, try to narrow regimen
 –If cultures are positive, usually can focus regimen
 Often, empiric antibiotics are continued due to inertia, complicated
clinical picture
 Need automated reminders at day 3-4 for regimens including
multiple antibiotics –aggressive efforts to decrease number and
duration of antibiotics
 Success might be stopping one agent out of 3, or limiting durations to
7 days instead of 14

Dr.T.V.Rao MD 39
 Supplemental Elements to a
Stewardship Program


 Education –e.g., Antibiotic
rounds in the ICU
 Guidelines and clinical
pathways
 Antimicrobial cycling
 Antimicrobial order forms or
computer order entry
 Combination therapy
 Streamlining and de-escalation
of therapy
 Dose optimization
 •Parenteral to oral
conversion
Dr.T.V.Rao MD 40
 Alliance for the Prudent Use of
Antibiotics
The Alliance for the Prudent Use of Antibiotics


(APUA) is a nonprofit organization founded in 1981
by Dr. Stuart B. Levy, Professor of Medicine at
Tufts University and headquartered in Boston,
Massachusetts APUA’s mission is to strengthen
society’s defenses against infectious disease by
promoting appropriate access and use to
antimicrobial agents (antibiotics, antivirals,
antimalarial etc.) and controlling antimicrobial
resistance on a worldwide basis.

Dr.T.V.Rao MD 41
Become a Member of Alliance for the
Prudent Use of Antibiotics (APUA)
www.apua.org


 An international
organization dedicated to
curbing antibiotic
resistance
 Chapters exist currently
in several Asian countries:
Australia, China, India,
Nepal, Pakistan,
Philippines, South Korea,
Taiwan, Vietnam

Dr.T.V.Rao MD 42
 Research on Newer Antibiotics is a
Priority


 "The difficulty in identifying
novel antimicrobial agents
with reliable activity against
these pathogens argues for
an augmentation of research
in the basic and population
science of resistance, as well
as careful studies to identify
optimal strategies for
infection control and
antimicrobial use.

Dr.T.V.Rao MD 43
Infectious Diseases Society of America supports
Issues on antibiotic use


 IDSA support
strengthening current
approaches to antimicrobial
resistance, to protect
effectiveness of the drugs
currently available. We must
maximize hospital infection-
control practices, to limit the
spread of resistance

Dr.T.V.Rao MD 44
 References


 No ESKAPE! New Drugs Against MRSA, Other
Superbugs Still Lacking IDA
 Clinical Impact of Resistance and Control of Antibiotic Usage
Stephen A. Lerner, M.D. Professor of Medicine Division of Infectious
Diseases Wayne State University School of Medicine Detroit,
Michigan, USA

Dr.T.V.Rao MD 45


Programme Created by Dr.T.V.Rao
MD for ‘ e ‘ learning resources for
Medical and Paramedical Students in
the Developing World
 Email
 doctortvrao@gmail.com

Dr.T.V.Rao MD 46