therapeutic strategies for gram negative multi drug
TRANSCRIPT
Therapeutic Strategies for Gram Negative Multidrug resistant Bacterial Infections
Debra A. Goff, Pharm.D., FCCPDebra A. Goff, Pharm.D., FCCP
Clinical Associate ProfessorInfectious Diseases Specialist
The Ohio State University Medical CenterColumbus, Ohio
Therapeutic Strategies for Gram Negative Multi-drug resistant Bacterial Infections
Debra A. Goff, Pharm.D., FCCPDebra A. Goff, Pharm.D., FCCP
Clinical Associate ProfessorInfectious Diseases Specialist
The Ohio State University Medical CenterColumbus, Ohio
Columbus, Ohio USAColumbus, Ohio USA
The Ohio State University Medical Center
• James Cancer Centerbone marrow transplants & oncology
• Ross Heart HospitalHeart and lung transplants, cardiac
• The Ohio State University Hospitalsolid organ transplant, General MedicineSurgery, SICU, MICU, NICU, Burn unit
The Ohio State University Medical Center
165 bedsbone marrow transplants & oncology
130 beds
The Ohio State University Hospital 850 bedssolid organ transplant, General MedicineSurgery, SICU, MICU, NICU, Burn unit
The Ohio State University Football StadiumCapacity up to 105,000 people
Imagine the stadiums filled with people
The Ohio State University Football StadiumCapacity up to 105,000 people
Imagine the stadiums filled with people
Impact of Antibacterial Resistance• Each year an estimated 1.7 million patients in
U.S. hospitals acquire an infection resulting in 100,000 deaths1
• This results in an additional $6.5 billion in health care expenditures
• On October 1, 2008, Centers for Medicare • On October 1, 2008, Centers for Medicare Services in USA hospital-acquired conditions deemed preventable
- catheter-associated urinary infections- vascular catheter- mediastinitis after coronary artery bypass graft
(CABG) surgery- surgical site infections
1. Klevens et al. Public Health Rep. 2007;122(2):160-166. 2. Stone et al. 100,000 people
Impact of Antibacterial ResistanceEach year an estimated 1.7 million patients in U.S. hospitals acquire an infection resulting in
1
This results in an additional $6.5 billion in health care expenditures 2
On October 1, 2008, Centers for Medicare On October 1, 2008, Centers for Medicare Services in USA limited reimbursement for
acquired conditions deemed preventableassociated urinary infections
vascular catheter-associated infectionsmediastinitis after coronary artery bypass graft
surgical site infections
166. 2. Stone et al. Am J Inf Control. 2005;33(9);542-547.
ESCAPE PathogensESCAPE Pathogens•• ESKAPE: Describes the most critical drug resistant pathogens:ESKAPE: Describes the most critical drug resistant pathogens:
–– E = E = Enterococcus faeciumEnterococcus faecium–– S = S = Staphylococcus aureusStaphylococcus aureus–– C = C = Clostridium difficile Clostridium difficile –– C = C = Clostridium difficile Clostridium difficile
A = A = Acinetobacter baumanniiAcinetobacter baumannii–– P = P = Pseudomonas aeruginosaPseudomonas aeruginosa–– E = E = EnterobacteriaceaeEnterobacteriaceae ((E. coli E. coli infection more numerous than infection more numerous than
KlebsiellaKlebsiella and and EnterobacterEnterobacter combined)combined)
ESCAPE PathogensESCAPE PathogensESKAPE: Describes the most critical drug resistant pathogens:ESKAPE: Describes the most critical drug resistant pathogens:
infection more numerous than infection more numerous than combined)combined)
Peterson, LR. Clin Inf Dis. 2009;49;992.
Surrogate for Serious Infections Caused by Multidrug-Resistant (MDR) Gram
Year
2003-2004
Colistin Use at OSUMC
2003-2004
2007-2008
2008-2009
Colistin is only prescribed for MDR organisms when there are no other options.
Surrogate for Serious Infections Caused by Resistant (MDR) Gram-Negative Bacilli
Cost
$2,375
Colistin Use at OSUMC
$2,375
$23,309
$48,324
Colistin is only prescribed for MDR organisms when there are no other
Multidrug resistant gram negative organismsBAD BUGS We NEED DRUGS
Antibiotics are unique in that they become LESS effective the more they are used
Antibiotics are unlike any other drugs in that use of antibiotics in one patient can compromise efficacy in another.another.
Resistant microorganisms can be spread to patients who have never received an antibiotic.
You can’t “catch cancer” from the patient next to you.
You CAN catch Acinetobacter or many other drugresistant microorganisms!
Acute MI STEMI alert“Minutes mean muscle”
Multidrug resistant gram negative organismsBAD BUGS We NEED DRUGS
Antibiotics are unique in that they become LESS effective the more they are used
Antibiotics are unlike any other drugs in that use of antibiotics in one patient can compromise efficacy in
Resistant microorganisms can be spread to patients who have never
You can’t “catch cancer” from the patient next to you.
You CAN catch Acinetobacter or many other drug-resistant microorganisms!
Hospital and Societal Costs of Antimicrobial
All patients
n (%) 1391
APACHE III score 42.1
Duration of stay(days) 10.2
HAI (n) 260HAI (n) 260
Cost per day (US$) 1651
Total cost (US$) 19,267
Death [n (%)] 70
Mean values shown in table.HAI: health care–acquired infection1. Roberts RR et al. Clin Infect Dis. 2009 vol49(8) p1175-84.
Hospital and Societal Costs of Antimicrobial-Resistant Infections1
Patients with ARI Patients without ARI
188 (13.5) 1203 (86.5)
54.8 40.1
24.2 8.0
135 125135 125
2098 1581
58,029 13,210
34 (18.1) 36 (3.0)
Hospital and Societal Costs of Antimicrobial
organism Mean cost (USD) per patientsN=1391
E VRE $66,416
S MRSA $46,236
Roberts et al Clin Inf Dis 2009;49:1175-84.
A Acinetobacterresistant to amikacin or imipenem
$97,444
E Klebsiella or Ecoliresistant to quinolones or 3GC
$26,549
Multiple ARIs $157,835
Hospital and Societal Costs of Antimicrobial-Resistant Infections
Mean cost (USD) per patientsN=1391
Mean cost (USD) per patients
Health-care acquired
$66,416 $73,481
$46,236 $60,984
$97,444 $111,062
$26,549 $39,403
$157,835
Hospital and Societal Costs of Antimicrobial-Resistant Infections
Roberts RR et al.
Hospital and Societal Costs of Resistant Infections
Roberts RR et al.Clin Inf Dis.2009;49:1175-84.
Hospital and Societal Costs of Antimicrobial-Resistant Infections
Roberts et al Clin Inf Dis 2009;49:1175-84.
Hospital and Societal Costs of Resistant Infections
Hospital and Societal Costs of Antimicrobial-Resistant Infections
• The attributable medical and societal costs of ARIs are considerable.
• The lowest estimate using sensitivity analysis resulted in a cost of $13.35 million in 2008 dollars in this patient cohort.
Roberts RR et al.
$13.35 million in 2008 dollars in this patient cohort.• This detailed analysis of the cost of antibiotic resistance in a single
large teaching hospital gives an indication of the magnitude of the burden imposed by resistance.
• Efforts must be increased to control antibiotic resistance.
Hospital and Societal Costs of Resistant Infections
The attributable medical and societal costs of ARIs are
The lowest estimate using sensitivity analysis resulted in a cost of dollars in this patient cohort.
Roberts RR et al. Clin Infect Dis. 2009; 49:1175-84.
dollars in this patient cohort.This detailed analysis of the cost of antibiotic resistance in a single large teaching hospital gives an indication of the magnitude of the
increased to control antibiotic resistance.
Strategy #1Antimicrobial Stewardship TeamStrategy #1Antimicrobial Stewardship Team
ClinicalPharmacist
ID Physician
Infection
InformationSystem
Specialist
HospitalEpidemiologist
InfectionControl
ProfessionalPatient
1. Dellit TH et al. Clin Infect Dis 2007;44(2):159-77. 2. Drew RH. J Manag Care Pharm. 2009;15(2 Suppl):S18
Optimal Team Members (A
Antimicrobial Stewardship TeamAntimicrobial Stewardship Team
ID Physician
Clinical “ASP: there’s no such
InformationSystem
Specialist
Clinical Microbiologist
. 2009;15(2 Suppl):S18-23.
Optimal Team Members (A-III)1
“ASP: there’s no such thing as too much”Dr Pagani Bolzano Italy
OSU Antimicrobial Stewardship Program
ASP is a corporate commitment!
OSU Antimicrobial Stewardship Program
Are Guidelines Focused and Easy to Follow?Are Guidelines Focused and Easy to Follow?
Strategy #2 Develop Specific Antibiograms
Consensus Guideline from Clinical and Laboratory Standards Institute (CLSI)
• Monitoring of drug resistance at the local level is crucial to support clinical decision making.
• Algorithms for handling repeat isolates- patient-based- patient-based- episode-based- resistance phenotype-based
• Combination Antibiogramsuseful in ICU with high gram-negative resistance
Hindler JF et al. Kuper KM et al.
Strategy #2 Develop Specific Antibiograms
Consensus Guideline from Clinical and Laboratory Standards Institute (CLSI)
Monitoring of drug resistance at the local level is crucial to support clinical decision making.Algorithms for handling repeat isolates
basedCombination Antibiograms
negative resistance
Hindler JF et al. Clin Infect Dis. 2007; 44:867-73.Kuper KM et al. Pharmacotherapy. 2009; 29:1326-43.
Do MD’s Use Hospital Antibiograms?Online survey of 545 residents at a University Teaching Hospital
1%3%
64%
always frequently occasionally
Do MD’s Use Hospital Antibiograms?Online survey of 545 residents at a University Teaching Hospital
32%
•How data is communicated to the medical staff is critical
occasionally never
Mermel et al. Clin Inf Dis. 2008:46;1789.
is critical
Antibiograms• Should be produced annually• ICU specific is necessary in era of escalating
resistance• ED specific skin/skin structure antibiogram • ED specific skin/skin structure antibiogram
Developed in response to escalating prevalence of CA
• Combination AntibiogramsUseful in ICU with high gram-negative resistance
• Use this data to guide/change prescribingIt’s based on evidence/data from your own hospital
CA-MRSA = community-acquired methicillin
AntibiogramsShould be produced annuallyICU specific is necessary in era of escalating
ED specific skin/skin structure antibiogram ED specific skin/skin structure antibiogram Developed in response to escalating prevalence of CA-MRSA
Combination Antibiogramsnegative resistance
Use this data to guide/change prescribingIt’s based on evidence/data from your own hospital
acquired methicillin-resistant Staph. aureus
Example: Hospital
K. pneumoniae(954) 91 95
E. cloacae(287) 79 95
Pip/tazo Cefepime
(287) 79 95E. coli(1971) 96 99P. aeruginosa(1039) 87 70A. bauma nnii(121) 91 80
Example: Hospital-wide Antibiogram
99 88 92
95 92 91
Imipenem Cipro Tobramycin
95 92 91
99 89 98
81 70 89
100 70 85
Example:ICU Antibiogram First isolates only
K. pneumoniae(32) 66 71E. cloacae 77 77
Pip/tazo Cefepime
E. cloacae(13) 77 77E. coli(16) 94 94P. aerug inosa(37) 81 59A. bauma nnii(21) 86 14
Example:ICU Antibiogram First isolates only
100 63 63
92 77 69
Imipenem Cipro Tobramycin
92 77 69
94 89 94
70 78 95
86 52 19
Targeted Empiric Coverage
Ertapenem
Ampicillin/sulbactam
Piperacillin/tazobactam
Imipenem
Empiric coverage
Anaerobes
Gram-positives
Non-Pseudomonas gram-negatives
Targeted Empiric Coverage
Resistant ESBL’s Pseudomonas aeruginosa
ASP initiative in the Management of complicated intraExample: Surgical ICU and Hospital Antibiogram
Organism Ampicillin/sulbactam
SICU
E. coli 42%
E. coli 0%E. coli ESBL-producing
0%
K. pneumoniae 75%
K. pneumoniae ESBL-producing
0%
Anaerobes +
Enterococcus +
Neither ampicillin-sulbactam nor ertapenem covers
ASP initiative in the Management of complicated intra-abdominal InfectionExample: Surgical ICU and Hospital Antibiogram
Ampicillin/sulbactam
Ertapenem
hospital SICUhospital
45% 100%
0% 100%0% 100%
78% 100%
0% 100%
+ +
+ -
sulbactam nor ertapenem covers P. aeruginosa
Antibiotic By Site of InfectionComputer order entry
Antibiotic By Site of InfectionComputer order entry
Strategy # 3 Evaluate the impact of your recommendationsErtapenem: No Effect on Imipenem Susuceptibility to Gram
Years after Formulary AdditionCarbapenem Use and P. aeruginosa
25
30
35
40
DD
D/1
000P
D
0
5
10
15
20
2002 2003 2004
DD
D/1
000P
D
imipenem ertapenem
Goff D, Mangino J. 2008 J. Infection 57(2);123
Strategy # 3 Evaluate the impact of your recommendationsErtapenem: No Effect on Imipenem Susuceptibility to Gram-Negative Pathogens 5
Years after Formulary AdditionP. aeruginosa Susceptibility
60
70
80
90
100
Imip
enem
su
scep
tib
le P
. ae
rug
ino
sa
2005 2006 20070
10
20
30
40
50
60
Imip
enem
su
scep
tib
le P
. ae
rug
ino
sa
ertapenem imipenem % susceptible
57(2);123-127
Consensus Guideline from Clinical and Laboratory Standards Institute: Antibiograms
• Monitoring of drug resistance at the local level is crucial to support clinical decision making.
• Algorithms for handling repeat isolates- patient-based- episode-based- resistance phenotype
Hindler JF et al. Kuper KM et al.
Consensus Guideline from Clinical and Laboratory Standards Institute: Antibiograms
Monitoring of drug resistance at the local level is crucial to support clinical decision
Algorithms for handling repeat isolates
resistance phenotype-basedHindler JF et al. Clin Infect Dis. 2007; 44:867-73.Kuper KM et al. Pharmacotherapy. 2009; 29:1326-43.
Examples of How Different Methods Yield Different % Susceptibility
Hindler JF et al.
Examples of How Different Methods Yield Different % Susceptibility
Hindler JF et al. Clin Infect Dis. 2007; 44:867-73.
Combination Antibiogram:SICU
P. aeruginosa. (116) 84% 67%
Pip/tazo Cefepime
Empiric antibiotics: pip/tazo + amikacin
P. aerug inosa(19 ) 0 9
For all pip/tazo resistant P. aeruginosa what is the most effective 2
pip/tazo R
17/19 pip/tazo resistant isolates are covered (susceptible) by amikacinThe additional of empiric amikacin benefits only 14.6% (17/116) of all patients.
Combination Antibiogram:SICU
69% 65% 89%
Imipenem Cipro Amikacin
Empiric antibiotics: pip/tazo + amikacin
39 33 89
For all pip/tazo resistant P. aeruginosa what is the most effective 2nd agent?
17/19 pip/tazo resistant isolates are covered (susceptible) by amikacinThe additional of empiric amikacin benefits only 14.6% (17/116) of all patients.
Utilize current data to support change in therapy
• CLSI (EUCAST in Europe) will be adjusting the MIC break points for susceptibility of P. aeruginosa tazobactam.
• Currently an MIC of 64 mg/L is considered susceptible. This will be considered resistant based on published PK/PD data.PK/PD data.
• Evaluate your own hospital isolates to determine what % have MIC=64 mg/L.
• When evaluating patients, if the MIC is 64 mg/L, recommend alternative therapy.
CLSI = Clinical and Laboratory Standards Institute MIC = minimum inhibitory concentration
Utilize current data to support change in therapy
will be adjusting the MIC break points P. aeruginosa to piperacillin-
Currently an MIC of 64 mg/L is considered susceptible. This will be considered resistant based on published
Evaluate your own hospital isolates to determine what %
When evaluating patients, if the MIC is 64 mg/L, recommend alternative therapy.
CLSI = Clinical and Laboratory Standards Institute MIC = minimum inhibitory concentration
Who is Your Audience?
ID MDsResidents and Fellows
Emergency room MDs
Critical Care
Who is Your Audience?RNs
Pharmacists in your department!
Residents and Fellows
Surgeons
Hospitalists
Strategy #4 Take old drugs and maximize the PK/PD
Implement Continuous/Extended Infusion pip/tazo
• Why do this?Have knowledge of the literature
• How do I do this?• How do I do this?Talk with the IV room pharmacists, discuss logistics and work load, discuss infusion pump-related issues
• Think about who might object to the idea?The person who is inconvenienced most is the RNNeed to worry about drug incompatibilityTies up the line
Take old drugs and maximize the PK/PD
Implement Continuous/Extended Infusion pip/tazo
Have knowledge of the literature
Talk with the IV room pharmacists, discuss logistics and work related issues
Think about who might object to the idea?The person who is inconvenienced most is the RNNeed to worry about drug incompatibility
Pharmacodynamic Dose Optimization
• Extended infusionpip/tazo, Purpose: optimize current antimicrobialsMaximize dosing to treat resistant or high MIC organisms
• Efficacy of pip/tazo extended infusionreduced mortality compared with intermittent infusion in patients with P. aeruginosascores ≥17
APACHE II = Acute Physiological and Chronic Health EvaluationLodise TP Jr et al. Clin Infect Dis.
Pharmacodynamic Dose Optimization
optimize current antimicrobialsMaximize dosing to treat resistant or high MIC
Efficacy of pip/tazo extended infusionreduced mortality compared with intermittent infusion in
P. aeruginosa infection and APACHE II
Acute Physiological and Chronic Health Evaluation-IIClin Infect Dis. 2007; 44:357-63.
Extended-Infusion Dosing StrategySlide used at OSUMC to Educate RNs
Lodise TP Jr et al. Clin Infect Dis. 2007; 44:357-
Infusion Dosing StrategySlide used at OSUMC to Educate RNs
-63.
Strategy #5Checklist of Interventions to Decrease Healthcare
C. difficileBundled approach: antimicrobial use, infection control, and proper environmental cleaning
Strategy #5Checklist of Interventions to Decrease Healthcare-Associated
Infectionantimicrobial use, infection control, and proper environmental cleaning
antibiotic
Infection control
housekeeping
Checklist of Interventions to Decrease HCA
Bundled approach: antimicrobial use, infection control, and proper environmental cleaning
Abbett SK et al. Infect Control Hosp Epidemiol.Owens RC Jr et al. Clin Infect Dis.
Checklist of Interventions to Decrease HCA-C. difficile Infection
antimicrobial use, infection control, and proper environmental cleaning
antibiotic
Infect Control Hosp Epidemiol. 2009; 30:1062-9.Clin Infect Dis. 2006; 42(Suppl 4):S173-81.
Infection control
housekeeping
Hospital-wide impact of a standardized order set for the management of bacteremic severe sepsis
Order sets were derived from the Surviving Sepsis Campaign
A retrospective before after study design of 400 patients
Patients had have a diagnosis of severe sepsis & + blood culture
Patients in the after group receivedmore IV fluids in the 1more likely to receive appropriate initial antibioticslower in
Order sets improved the management of severe sepsis and improved survival.
Ref: Thiel Crit Care Med 2009;37:819
wide impact of a standardized order set for the management of bacteremic severe sepsis
Order sets were derived from the Surviving Sepsis Campaign
A retrospective before after study design of 400 patients
Patients had have a diagnosis of severe sepsis & + blood culture
Patients in the after group receivedmore IV fluids in the 1st 12 hours after hypotensionmore likely to receive appropriate initial antibioticslower in-house mortality (55% vs 39.5%, p<0.01)
Order sets improved the management of severe sepsis and improved survival.
Ref: Thiel Crit Care Med 2009;37:819-824.
Strategy #6 New diagnostic testsMultiplex PCR detection enhancement of bacteremia and fungemia
• Objective: test a multiplex RTsimultaneous detection of multiple organisms in bloodstream infections
• Methods: Prospective observational study of
200 patients at risk of BSI with signs of SIRS.
Louie R. et al 2008 CCM :36(5);1487-1492.Tsalik E et al 2010 JCM 48(1); 26-33.
Strategy #6 New diagnostic testsMultiplex PCR detection enhancement of bacteremia and fungemia
: test a multiplex RT-PCR method for simultaneous detection of multiple organisms in
: Prospective observational study of
200 patients at risk of BSI with signs of SIRS.
Organisms detected by multiplex PCR
Louie R. et al CCM 2008:36(5);1487
Organisms detected by multiplex PCR
Louie R. et al CCM 2008:36(5);1487-1492.
Results
Louie R. et al CCM 2008:36(5);1487-1492.
Results
PCR detected bacteria/fungi in 45 cases vs 37 by blood culture.
PCR detected mecA in all 3 culture confirmed MRSAconfirmed MRSA
PCR did not detect E. faecalis in 5 BC confirmed cases
7 samples could be tested simultaneously in 6.54 hours
Conclusion• Despite limitations of both blood culture and
RT multiplex PCR methods1.PCR could be an adjunct to BC2. PCR can facilitate early detection2. PCR can facilitate early detection3. Early detection can facilitate
based treatment decisions
Louie R. et al 2008 CCM 36(5);1487-1492.Tsalik E et al 2010 JCM 48(1); 26-33.
ConclusionDespite limitations of both blood culture and RT multiplex PCR methods
PCR could be an adjunct to BC2. PCR can facilitate early detection2. PCR can facilitate early detection3. Early detection can facilitate evidence-
based treatment decisions
Use of procalcitonin to reduce patients exposure to antibiotics in ICU (PRORATA trial)
A randomized multicenter effectiveness trial to assess the benefit of procalcitonin to help MDstart,continue, or stop antibiotics for patients in ICUwith suspected bacterial infections
Ref; Bouadma et al Lancet 2010;375:463
Use of procalcitonin to reduce patients exposure to antibiotics in ICU (PRORATA trial)
start,continue, or stop antibiotics for patients in ICU
Results: Procalcitonin guided antibiotic treatmentLowers antibiotic exposure by 2.7 days and is Non-inferior to standard care with respect to
outcomes.
Ref; Bouadma et al Lancet 2010;375:463-474
Here's how it works. 1. The hospital workers squirt sanitizer gel or wash with soap
Strategy # 7 New technology
1. The hospital workers squirt sanitizer gel or wash with soap before passing their hands under a wall-mounted sensor.
2. A wireless signal from a badge the worker is wearing activates a green light on the handwashing sensor.
3. When the worker approaches the patient's bedside, a monitor detects the status of the badge. Clean hands get a green light.
4. If the person has not washed, or if too much time has passed since washing up, the badge will vibrate as a reminder to wash
their hands again.
The hospital workers squirt sanitizer gel or wash with soap The hospital workers squirt sanitizer gel or wash with soap mounted sensor.
A wireless signal from a badge the worker is wearing activates
When the worker approaches the patient's bedside, a monitor detects the status of the badge. Clean hands get a green light.If the person has not washed, or if too much time has passed since washing up, the badge will vibrate as a reminder to wash
Infectious Disease resources for the iPhone
50 million users
Leading handheld platform Leading handheld platform for medical personnel
Over 100,000 apps
Ref: Oehler et al CID 2010;50:9
Infectious Disease resources for the iPhone
Outbreaks near me app
Swine flu tracker map app
In 2008 Apple created a medical community
OSU is developing aSTAB-IT app for internaluse