multi-drug resistant pathogens helmut albrecht, md division of infectious diseases
TRANSCRIPT
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Multi-drug resistant pathogensMulti-drug resistant pathogens
Helmut Albrecht, MD
Division of Infectious Diseases
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DisclosuresDisclosures
• Grant/Research Support–MSD, J&J, VIIF, Gilead (no payment to me)
• Consultant–France Foundation (non profit project with Duke), VIIF, Gilead (no honoraria)
• Speaker’s Bureau–(no honoraria)
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AgendaAgenda
• State of the union
• The players (Resistant pathogens)
• What to do about them
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AntibioticsAntibiotics• “Deaths in the US declined by 220 per 100,000 with the
introduction of sulfonamides and penicillin. This far outweighs any other medical advance in the past century.”
Armstrong et al. JAMA 1999;6:61ff
• From 1983 to 2010, FDA approval of new antibiotics has continuously declined, from 4 per year in the early 1980s to less than 1 antibiotic per year now
• The last class of drugs with a novel mechanism of action against GN bacteria goes back 40 years. A review of drugs currently in trials revealed no such new drugs.
• For the US, antibiotic resistance is responsible for nearly 100,000 deaths caused by hospital-acquired infections per year at an estimated annual cost of $23 billion.
Roberts et al CID 2009;49:1175ff
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Why do we see more resistance?Why do we see more resistance?• Sicker inpatient population• Patients chronically ill• Larger immunocompromised population• More instrumentation/new procedures• Presence of devices• Increasing resistance in community• Emerging pathogens• Complacency regarding antibiotics• Increased use of (empiric) broad-spectrum antibiotics• Ineffective infection control and compliance• Crowding of patients in confined areas• Decreasing nurse/patient ratio
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Why do we see more resistance?Why do we see more resistance?• Sicker inpatient population• Patients chronically ill• Larger immunocompromised population• More instrumentation/new procedures• Presence of devices• Increasing resistance in community• Emerging pathogens (Superbugs!)• Complacency regarding antibiotics• Increased use of (empiric) broad-spectrum antibiotics• Ineffective infection control and compliance• Crowding of patients in confined areas• Decreasing nurse/patient ratio
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My patient is really ill…My patient is really ill…
What is the price of prescribing a little more than needed if I do not want to think that hard?
• Healthcare dollars (irrelevant, if title true)
• C. difficile (potentially deadly)
• Side effects (potentially deadly)
• Resistance (relevant?)
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27.4
38.4
17.8
30.7
20.2
34.4
0
5
10
15
20
25
30
35
40
45
Kang et al Micek et al Leibovici et al
Appropriate Therapy
Inappropriate Therapy
Getting It RightGetting It RightBloodstream InfectionsBloodstream Infections
% Mortality
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14.8
44.237.5
91.2
15.6
37.1
0
10
20
30
40
50
60
70
80
90
100
Clec'h et al Luna et al Rello et al
Appropriate Therapy
Inappropriate Therapy
Getting It RightGetting It RightVentilator-associated PneumoniaVentilator-associated Pneumonia
% Mortality
It is a lot more difficult to get it right if the bacteria are multi-drug resistant
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Scope of the problemScope of the problem
• Nosocomial infections > 8 million excess hospital days
• Approximately 80,000 deaths
• >75% resistant to at least one drug class
• > 50% of inpatients receive antibiotics
• 30-50% of these receive them inappropriately
• Cost of res. pathogens 100 million - 30 billion US$/year
Phelps Med Care 1989
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NEW SUPERBUGSNEW SUPERBUGS
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Adapted from Livermore and Woodford, Trends in Microbiol, 2006.
The Gram Negative Cell Wall
Porin channels
Efflux system
PBPs
B-lactamases
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Bush classification of Bush classification of ββ-lactamases in GN bacteria-lactamases in GN bacteria
Functional Group
Major Subgroups
Attributes Known types in 2000
1 AllChromosal >>> plasmid, SPICE-A bacteria, all β-lactams except carbapenem, not inhibited by beta-lactamase inhibitors
51
2 2-bPlasmid >>> chromosomal, broad-spectrum β-lactamases (TEM, SHV), usually inhibited by β-lactamase inhibitors
16
2 2-bePlasmid >>> chromosomal, ESBLs, variably inhibited by β-lactamase inhibitors 119
3 3-a,b,cMetallo β-lactamases, ESBLs including carbapenems (not monobactams)
not inhibited by β-lactamase inhibitors24
4 AllMixed group (incl. B. fragilis)
Inhibited by β-lactamase inhibitors 9
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Substrate ProfileSubstrate Profile
• Penicillinase
• Cephalosporinase
• Broad spectrum
• Extended broad spectrum
• Carbapenemase
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Substrate ProfileSubstrate Profile
• Penicillinase
• Cephalosporinase
• Broad spectrum
• Extended broad spectrum
• Carbapenemase
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19 Months ESBL Klebsiella pneumoniae Outbreak 19 Months ESBL Klebsiella pneumoniae Outbreak
New York Hospital Medical Center of QueensNew York Hospital Medical Center of Queens
• 432 ceftazidime-resistant Klebsiella pneumoniae
• 155 patients colonized (61%) or infected (39%)
• 53% crude mortality rate
• Not detected for 12 months!
Meyer et al. Ann. Int. Med. 119: 353-358 1993
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Substrate ProfileSubstrate Profile
• Penicillinase
• Cephalosporinase
• Broad spectrum
• Extended broad spectrum
• Carbapenemase
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Is Klebsiella bad?Is Klebsiella bad?
It depends!
Most Klebsiella infections are easy to deal with, but some are worse than others
Because the host is bad?!
Because the bug is bad?!
Because the drugs are bad?!
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Susceptibility Profile of KPC-Producing K. pneumoniaeAntimicrobial Interpretation Antimicrobial Interpretation
Amikacin I Chloramphenicol R
Amox/clav R Ciprofloxacin R
Ampicillin R Ertapenem R
Aztreonam R Gentamicin R
Cefazolin R Imipenem R
Cefpodoxime R Meropenem R
Cefotaxime R Pipercillin/Tazo R
Cetotetan R Tobramycin R
Cefoxitin R Trimeth/Sulfa R
Ceftazidime R Polymyxin B MIC >4g/ml
Ceftriaxone R Colistin MIC >4g/ml
Cefepime R Tigecycline S
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Drugs with Most Reliable Activity Against Drugs with Most Reliable Activity Against
ESBL-producing Enterobacteriaceae ESBL-producing Enterobacteriaceae
Drugs with Most Reliable Activity Against Drugs with Most Reliable Activity Against
ESBL-producing Enterobacteriaceae ESBL-producing Enterobacteriaceae
• CarbapenemsCarbapenems
• (Cephamycins)(Cephamycins)
• (Fluoroquinolones)(Fluoroquinolones)
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Carbapenem Resistance: Mechanisms
Enterobacteriaceae Cephalosporinase + porin loss
Carbapenemase
P. aeruginosa Porin loss
Up-regulated efflux
Carbapenemase
Acinetobacter spp. Cephalosporinase + porin loss
Carbapenemase
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Carbapenemases
Classification Enzyme Most Common Bacteria
Class A KPC, SME, IMI, NMC, GES
Enterobacteriaceae(rare reports in P. aeruginosa)
Class B
(metallo--lactamse)
IMP, VIM, GIM, SPM
NDM
P. aeruginosa
Enterobacteriacea
Acinetobacter spp.
Class D OXA Acinetobacter spp.
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Carbapenemases in the U.S.Enzyme Bacteria
KPC, NDM Enterobacteriaceae
Metallo--lactamase P. aeruginosa
OXA Acinetobacter spp.
SME Serratia marcesens
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Klebsiella Pneumoniae Carbapenemase KPC is a class A -lactamase
Confers resistance to all -lactams including extended-spectrum cephalosporins and carbapenems
Occurs in Enterobacteriaceae Most commonly in Klebsiella pneumoniae Also reported in: K. oxytoca, Citrobacter freundii,
Enterobacter spp., Escherichia coli, Salmonella spp., Serratia spp.,
Also reported in Pseudomonas aeruginosa (Columbia, thankfully we are talking the country, not us!)
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Susceptibility Profile of KPC-Producing K. pneumoniaeAntimicrobial Interpretation Antimicrobial Interpretation
Amikacin I Chloramphenicol R
Amox/clav R Ciprofloxacin R
Ampicillin R Ertapenem R
Aztreonam R Gentamicin R
Cefazolin R Imipenem R
Cefpodoxime R Meropenem R
Cefotaxime R Pipercillin/Tazo R
Cetotetan R Tobramycin R
Cefoxitin R Trimeth/Sulfa R
Ceftazidime R Polymyxin B MIC >4g/ml
Ceftriaxone R Colistin MIC >4g/ml
Cefepime R Tigecycline S
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KPC Enzymes Located on plasmids; conjugative and
nonconjugative
blaKPC is usually flanked by transposon sequences
blaKPC reported on plasmids with: Normal spectrum -lactamases Extended spectrum -lactamases Aminoglycoside resistance
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Geographical Distribution of KPC-Producers
Frequent Occurrence
Sporadic Isolate(s)
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KPC Outside of United States France (Nass et al. 2005. AAC 49:4423-4424)
Singapore (report from survey)
Puerto Rico (ICAAC 2007)
Columbia (Villegas et al. 2006. AAC 50:2880-2882 & ICAAC 07)
Brazil (ICAAC 2007)
Israel (Navon-Venezia et al. 2006. AAC 50:3098-3101)
China (Wei Z, et al. 2007. AAC 51: 763-765)
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Inter-Institutional & Inter-State Spread of KPC-Producing K. pneumoniae
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Carbapenemase – Producing Enteric GNR; U.K.
< 10% susceptible to usual Rx>40% resistant to tigecycline, >90% susceptible to colistin
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NDM1 Carbapenemase First described from India 2008
Novel resistance mechanism
Gene compatible with multiple types of plasmids- greatly enhances global spread
Already in California, Illinois and Mass.
Some strains sensitive to only polymyxins (highly neuro and nephro-toxic) or Tigecycline
No new drugs close to release
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Phenotypic Tests for Carbapenemase Activity
Modified Hodge Test
100% sensitivity in detecting KPC; also positive when other carbapenemases are present
100% specificity
Procedure described by Lee et al. CMI, 7, 88-102. 2001.
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New transmission mechanisms
NDM-1: 77 cases in 13 European countries 60% from England Travel to India (including medical tourism)
ESBLs Travellers diarrhea Foodborne outbreak Adoption
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25% of E. coli ESBL (3% Europe, 79 % India, 50% Egypt, 22% Thailand)
Antibiotic use not predictive except for ciprofloxacin
5/21 persistently colonized
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156 pts affected
35% of kitchen surfaces colonized
6 of 44 (14%) of food workers fecal carriers
2 y.o. from China
Adopted
Secondary transmission in family
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Modified Hodge Test
Lawn of E. coli ATCC 25922 1:10 dilution of a 0.5 McFarland suspension
Imipenem disk
Test isolates
Described by Lee et al. CMI, 7, 88-102. 2001.
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Which is more dangerous?Which is more dangerous?
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Resistance in gram-positive organismsResistance in gram-positive organisms
1990 1997 2000
PRSP 4% 30-50% 48%
VTSP < 0.2% 3.6-5.1%
MRSA 20-25% 25-50%
GISA 0 <0.1 <0.1
VRE <0.1 15 21
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Evolution of E. faecium Evolution of E. faecium resistanceresistance
MIC90 of E. faecium
1968 1969-88 1989-90
Penicillin 8 64 512
Ampicillin 2 32 128
% VRE 0 0 61%
Grayson et al, AAC
1.Community acquired (ca-) MRSA strains generally CANNOT be distinguished from hospital acquired strains by the presence of:1.MEC-A gene 2.SCC pattern 3.Panton-Valentine leukocidin
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Why is this different?Why is this different?
Outbreaks in new populations
Different disease spectrum (boils, CAP)
Spider bite history
Specific clones
SCCmec type IV
Panton-Valentine Leukocidin (PVL)
Susceptible to many antibiotics
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Populations with ca-MRSAPopulations with ca-MRSA
• Children
• Inmates
• Military recruits
• Native populations
• MSM
• HIV+ patients
• Religious communities
• Football teams
• Wrestlers
• Gymnasts
• Fencing teams
• IDU
• Homeless
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Disease Syndrome
Skin/soft tissue (non-Trauma)
Abscess
Cellulitis
Folliculitis
Other/Unknown
Wound (Traumatic)
Urinary Tract Infection
Sinusitis
Bacteremia
Pneumonia
Osteomyelitis
Septic arthritis
Bursitis
No. (%)
1, 266 (77%)
751 (59%)
528 (42%)
88 ( 7%)
212 (17%)
157 (10%)
64 ( 4%)
61 ( 4%)
43 ( 3%)
31 ( 2%)
21 ( 2%)
15 ( 1%)
19 ( 1%)
Clinically Relevant CA-MRSA DiseaseClinically Relevant CA-MRSA Disease (GA/MD/MN n=1,674, 78%) (GA/MD/MN n=1,674, 78%)
Fridkin et al. NEJM, 2005
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MRSA skin infection: differential MRSA skin infection: differential diagnosisdiagnosis
Common misdiagnosis: “spider bite”, complete with history of having been bitten!
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Range of the brown recluseRange of the brown recluse
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déjà vudéjà vu
Prevalence of PCN resistant Staph aureus
0
20
40
60
80
100
1940 1950 1960 1970 1980
HospitalCommunity
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Phage type 80/81: PCN-R clone of SANeonatal outbreaks in Australia in 50’sBecame pandemic in adults/children
in hospitals/communitiesHighly transmissible and virulentCarried leukocidin
Robinson et alPhage type 80/81 carried PVLMLST 30Current SWP clone of CA-MRSA
descendant – acquired SCC IV
déjà vu IIdéjà vu II
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Okuma et al. J Clin Micro 2002
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Distribution of Virulence and Resistance DeterminantsDistribution of Virulence and Resistance DeterminantsCA-MRSA CA-MRSA
(France, Switzerland, USA, Oceania)(France, Switzerland, USA, Oceania)
Gene/Gene Product Total n=117 (%)
SCCmec IV
PVL
lukE-lukD (leukocidin)
γ-hemolysin
γ -hemolysin variant
enterotoxin a
enterotoxin b
enterotoxin c
enterotoxin h
enterotoxin k
117 (100%)
117 (100%)
116 (99%)
13 (11%)
100 (85%)
23 (20)
9 (8%)
20 (17%)
29 (25%)
24 (21%)Vandenesch et al. EID Aug 2003
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PVL associated with severe PVL associated with severe diseasedisease
Necrotizing pneumonias
Septic syndrome
Empyema
Most CA-MRSA strains PVL +
Causal role in severe disease presentations is not
proven
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Centers for Disease Control CampaignCenters for Disease Control Campaign
12 steps to prevent antimicrobial resistance 12 steps to prevent antimicrobial resistance Prevent Infection• Vaccinate• Remove catheters
Diagnose and Treat Effectively• Target the pathogen• Access the experts
Use Antimicrobials Wisely• Practice antimicrobial control• Use local data• Treat infection, not colonization• Know when to say no to vancomycin• Stop treatment when infection is cured or unlikely
Prevent transmission• Isolate the pathogen• Brake the chain of contagion
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How To Prevent ResistanceHow To Prevent Resistance
Adequate infection control
Appropriate use of antibiotics
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Strategies for Managing Outbreaks of ResistanceStrategies for Managing Outbreaks of Resistance
Lack of associationof resistance with aplasmid mechanism
Plasmid-mediatedmechanism
Ahmad M et al. Clin Infect Dis 1999;29:352-355
Amenable to strictinfection control procedures
Necessitates antibioticrestriction before
significant reduction in resistance occurs
Favors clonal oroligoclonal epidemiology
Polyclonalepidemiology
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Optimal Use of Antimicrobial: Optimal Use of Antimicrobial: It’s Role in Preventing ResistanceIt’s Role in Preventing Resistance
Will optimal use, including control of antibiotic use, prevent or slow the emergence of resistance?
“It is unlikely that the resistance problem will rapidly wane, simply by being more prudent in our use of antimicrobial agents; on the other hand, it is certain that if we do not cut back on the use of these agents, the resistance problem will worsen.”
Williams Science 1998;279:1153
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What to do to slow antibiotic resistanceWhat to do to slow antibiotic resistance
Aggressively attack misuseAggressively attack misuse
• Animal feeds and “treatment” of inanimate objects
• Upper respiratory tract infection• Colds • Sinusitis • Pharyngitis • Bronchitis - acute
• Fever without evidence of bacterial infections • ICUs • Children • Chronic care facilities
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Appropriate Use of AntibioticsAppropriate Use of Antibiotics
The appropriate empiric treatment for the patient with
Sneezococcus congestii
Coughobacillus snifficile
is Tylenol, decongestants and antitussives not antibiotics
If the patient is really sick and may have pneumonia with
Tyrannococcus rex or other superbugs
you may want to consider Bumfacillin or Gorillamycin
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SHEA and IDSA SHEA and IDSA Recommendation for HospitalsRecommendation for Hospitals
• Implementation of a system for periodic monitoring of antimicrobial resistance in community and nosocomial isolates
• Implementation of a system for periodic monitoring of antibiotic use according to hospital location and/or prescribing service
• Monitoring of relationship between antibiotic use and resistance,
assignment of responsibility through practice guidelines or other
institutional policies
• Application of contact isolation precautions in patients known or
suspected to be colonized or infected with epidemiologically
important microorganisms
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Can we win the global battle?Can we win the global battle?
• Keep on developing new antibiotics
• Surprise your opponent (combination, rotation)
• Use the optimal dose of the right antibiotic for the appropriate duration of therapy
• Know as much about antibiotics as your ID folksalternatively call them to help you
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Double coverage?Double coverage?
• Reasonable data for some gram-positives
• No good data for gram-negatives
• May still be reasonable to cover 2 organisms and
in specific situations
• Double coverage across the board will result in
increased financial burden, resistance, drug-
associated morbidity, and potentially antagonism
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=
=
Synergy vs. antagonism
1 + 1 = 3 vs. 1 + 1 = 0
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Can we win the global battle?Can we win the global battle?
• Keep on developing new antibiotics
• Surprise your opponent (combination, rotation)
• Use the optimal dose of the right antibiotic for the appropriate duration of therapy
• Know as much about antibiotics as your ID folks, alternatively call them to help you
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Know Antibiotic Principles! Know Antibiotic Principles! Drug levels and activity
• Volume of distribution (Obesity, third spacing)
• Compartments
• Protein binding
Time vs. concentration-dependant killing
• >MIC > 50% DI vs. Cmax/MIC >8-10
• Aminoglycosides and quinolones
Combining drugs
• Synergy vs. antagonism
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You have homefield advantage – use itYou have homefield advantage – use it
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Empiric TherapyEmpiric Therapy
Empiric therapy is not an educated guess but asophisticated decision based on intimate knowledge of
• The bug• The host• The local environment• All available options
• Antimicrobials• Principles of antimicrobial therapy• Supportive and critical care
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Take homeTake home
• Empiric therapy is overrated
• Diagnostic effort is underrated
• Consider going narrow (may be diagnostic)
• Your empiric therapy will save some, not save some (if you do not get it right), or in some cases kill someone