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ABSSSI and CABP: Maximizing the Anti‐Infective Arsenal to Optimize Patient Outcomes
1. Zyvox [package insert]. New York, NY: Pharmacia & Upjohn Company; 2013. 2. Moran GJ et al. J Emerg Med. 2013;44(6):e397‐e412. 3. FDA Drug Safety Alert. 3/16/07. Available at: www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm085249.htm.
Disadvantages• Potential for myotoxicity1 and eosinophilic pneumonia
• Development of treatment‐emergent resistance3
601. Moran GJ et al. J Emerg Med. 2013;44(6):e397‐e412. 2. Stryjewski ME et al. ClinInfect Dis. 2008;46:S368‐S377.3. Bayer AS et al. Ann NY Acad Sci. 2013;1277:139‐158.
BSI, blood‐stream infection
ABSSSI and CABP: Maximizing the Anti‐Infective Arsenal to Optimize Patient Outcomes
Advantages• Activity against major gram‐positive pathogens1
• Available as IV or PO1
– Oral: qd dosing; 6 d was noninferior to linezolid Q 12 h for 10 d1
– IV: qd dosing for 6 d was noninferior to linezolid Q 12 h for 10 d2
• No cfr resistance reported
Disadvantages• Toxicity for extended therapy unknown
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1. Prokocimer P et al. JAMA. 2013;309(6):559‐569. 2. Fang E et al. Presented at the European Congress of Clinical Microbiology and Infectious Diseases: Berlin; 4/28/13. Poster LB 2964. Available at: http://triusrx.com/pdfs/LB_2964_Efficacy_and_Safety_Results_from_the_ESTABLISH‐2_ABSSSI_Study_Comparing_IV_and_Oral_Tedizolid_Phosphate_and_Linezolid.pdf
The BIG Question Now
Which serious staphylococcal infections will these new compounds “take on”?
• HAP/VAP
• Prosthetic joint infections
• Bloodstream infections (± IE)
• Less commonly considered problems– Meningitis1
– Endophthalmitis2
– Gastroenteritis3
691. Kim JH et al. Rev Infect Dis. 1989;11(5):698‐706. 2. Durand ML. Clin Microbiol Infect. 2013;19(3):227‐234. 3. Boyce JM et al. J Clin Microbiol. 2005;43(12):5992‐5995.
IE, infectious endocarditis
ABSSSI and CABP: Maximizing the Anti‐Infective Arsenal to Optimize Patient Outcomes
– ≈50,000 deaths/y, especially elderly and patients with comorbidities1,5
– #1 cause of mortality due to infection in US6
• Annual incidence7
– General population: 1‐12 cases/1,000
– ≥65 y/o: 25‐44 cases/1,000
• Annual prevalence: >4 million cases3
– ≈1.1 million admissions/y, 40% 1‐y mortality4,5
– ≈80% treated as outpatients8
• Annual cost of treatment >$17 billion3
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1. File TM Jr. Lancet. 2003;362(9400):1991‐2001. 2. File TM Jr et al. JAMA. 2005;294(21):2760‐2763. 3. File TM Jr et al. Postgrad Med. 2010;122(2):130‐141. 4. Kaplan V et al. Arch Intern Med. 2003;163(3):317‐323. 5. CDC/National Center for Health Statistics. April 5, 2013. http://www.cdc.gov/nchs/fastats/pneumonia.htm. 6. Klevens RM et al. Public Health Rep. 2007 ;122(2):160‐166. 7. Ochoa‐Gondar O et al. BMC Public Health. 2008;8:222. 8. Gaydos CA. Infect Dis Clin North Am. 2013;27(1):46‐69.
ARS
CAP
HCAP
HAP/VAP
1. Yap V et al. Infect Dis Clin North Am. 2013;27(2):1‐18. 2.Craven DE. Curr Opin Infect Dis. 2006;19(2):153‐160.
Are Present CAP and HCAP Definitions the Best Way to Define Risk of MDR Infection?1
75
ABSSSI and CABP: Maximizing the Anti‐Infective Arsenal to Optimize Patient Outcomes
2005 Guidelines for Nosocomial Pneumonia: HCAP Etiology
• Risk factors for MDR pathogens causing HCAP1
– Hospitalized ≥2 d in preceding 90 d
– Nursing home/extended care facility residence
– Home infusion therapy (including antibiotics)
– Chronic dialysis within 30 d
– Home wound care
– Family member with MDR pathogen
• Treat for MDR pathogens1
– But this is an overgeneralization; updated guidelines are under development
• Designation of HCAP—poor predictor of resistant pathogens2
• Current definition needs further modification so adequate coverage can consistently be provided while avoiding excessive antibiotic use2
761. ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388‐416. 2. Yap V et al. Infect Dis Clin North Am. 2013;27(2):1‐18.
Which Scoring Tool Best Predicts Clinical Response, Long‐term Outcomes?
• PSI• CURB‐65• CRB‐65• SMART COP• SCAP
“In regards to the best scoring tool to predict clinical response and long term outcomes, Pneumonia Severity Index (PSI) is probably a more accurate score to predict a wide range of clinical outcomes.”
791. Johnstone J et al. Infect Dis Clin North Am. 2013;27(1):71‐86. 2. Asadi L et al. Clin Infect Dis. 2012;55(3):371‐380. 3. Jha A et al. N Engl J Med. 2012;366(17):1606‐1615.
CMS 2014 CAP Quality Measures for Inpatients
• Empiric antimicrobials according to guidelines― Exceptions: pathogen-directed therapy,
clinical trials, diagnostic uncertainty
• CAP mortality
• 30-d readmission rate for pneumonia*
*Complements Core Measures as part of the Hospital Readmissions Reduction Program—hospitals with higherthan expected 30-d readmission rates for AMI, heart failure, and pneumonia will incur penalties against their total Medicare payments beginning in FFY 2013.
aIf aged <65 y with no risk factors for drug‐resistant Pneumococcus.
1. JC, CMS. http://www.jointcommission.org/specifications_manual_for_national_hospital_inpatient_quality_measures.aspx. Good through 12/31/2013. 2. File TM Jr et al. Clin Infect Dis. 2011;53(suppl 1):S15‐S22, by permission of Oxford University Press.
CABP: New Antimicrobials
• Tigecycline IV– Glycylcycline (derivative of minocycline): broad spectrum including
S pneumoniae, atypicals1
– Approved for ABSSSI, CABP, intra‐abdominal infections2
• CABP: comparable to levofloxacin1
• HAP/VAP: comparable to imipenem for HAP; inferior for VAP3,4
– Listed as option for CABP admitted to general ward • 100 mg initially, then 50 mg Q 12h2
What is the Benefit of CAPBiomarkers in Patient Management?
861. Upadhyay S, et al. Infect Dis Clin North Am. 2013;27(1):19‐31. 2. Christ‐Crain M et al. Am J Respir Crit Care Med. 2006;174:84‐93. 3. Schuetz P et al. JAMA. 2009;302:1059‐1066. 4. Bouadma L et al. Lancet. 2010;375:463‐474.
Biomarker procalcitonin (PCT) guides reduction in hospital antibiotic treatment of CAP without increasing mortality risk1
Trials of PCT to Guide Therapy Duration in CAP Hospital Patients1
Study LocationDuration PCT, d
Duration Control, d
Mortality PCT
Mortality Control
Christ‐Crain M et al2 1 ED 5 (median) 12 (median) 10% 10%
Schuetz P et al3 6 EDs 7 (median) 10 (median) 5.2% 5.6%
Bouadma L et al4 7 ICUs 5.5 (mean) 10.5 (mean) 16.9% 19%
PCT for Antimicrobial Stewardship When Treating RTIs
PCT value <.01 µg/L <.025 µg/L ≥0.25 µg/L >0.5 µg/L
Bacterial infection?
Very unlikely Unlikely Likely Very likely
Antibiotic recommendation
Strongly discouraged
Discouraged EncouragedStrongly
encouraged
F/UReassess and recheck PCT after 6‐24h if no clinical improvement
Recheck PCT every 2‐3 d to consider early stop antibiotic therapy
When to overrule
Consider antibiotic if patient is clinically unstable or at high risk for adverse outcomes (PSI IV‐V) or has strong evidence for bacterial pathogen
87RTI, respiratory tract infectionSchuetz P et al. Curr Opin Infect Dis. 2013;26:159‐167.
ABSSSI and CABP: Maximizing the Anti‐Infective Arsenal to Optimize Patient Outcomes
– Potential for more rapid diagnosis, greater sensitivity
– Allows for pathogen‐directed therapy
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1. Gaydos CA. Infect Dis Clin North Am. 2013;27(1):49‐69. 2. Bartlett JG. Clin Infect Dis. 2011;52(suppl 4):S296‐S304. 3. Falguera M et al. Thorax. 2010;65:101‐106. 4. Christ‐Crain M et al. Crit Care. 2010;14:203. 5. Schuetz P et al. Curr Opin Infect Dis. 2013;26:159‐167. 6. Xiao D et al. Diagn Microbiol Infect Dis. 2012;73(4):301‐307.
PCR, polymerase chain reaction; MALDI‐TOF, matrix‐assisted laser desorption/ionization Time of Flight mass spectrometry
Enriched PCR Detection of CAP Pathogens
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Among the 38 patients who had complete sampling (conventional + molecular assays), a microbial etiology was determined for 89%
Reprinted from Johansson N et al. Etiology of community‐acquired pneumonia: increased microbiological yield with new diagnostic measures. Clin Infect Dis. 2010;50(2):202‐209 by permission of Oxford University Press.
ARS
ABSSSI and CABP: Maximizing the Anti‐Infective Arsenal to Optimize Patient Outcomes
• Reviewed evidence– Multiple studies; but different designs– Considered “collateral damage”– Immunomodulatory effects of macrolides– Fluoroquinolone PK and resistance
• Conclusion– Neither of the two first‐line regimens has been proved to have clear‐cut
clinical superiority
• “Therapeutic decision making should be individualized, taking into account additional patient information such as the presence of drug allergies, local resistance patterns, patient comorbidities, and risk factors for the presence of resistant S pneumoniae”
93Ruhe J et al. Infect Dis Clin North Am. 2013;27(1):115‐132.
How Important is MRSA as a Cause of CAP?1
“MRSA clearly is an important pathogen in CAP. While currently causing a relatively low percentage of CAP cases, the disproportionate frequency of otherwise healthy young people with this infection drives concern and therefore empiric antibiotic therapy.”1
• EMERGEncy ID Net study (2006‐2007)2
– N=595 CAP patients, pathogen identified in 17%
– S pneumoniae: 9.6%; MRSA, 2.4%; MSSA: 1.5%;K pneumoniae: 0.7%; H influenzae: 0.3%
• Clinical features suggesting increased risk of CA‐MRSA pneumonia1
– Cavitary pneumonia ‒ Lung necrosis
– Neutropenia ‒ Hemoptysis
941. Wunderink RG. Infect Dis Clin North Am. 2013;27(1):177‐188. 2. Moran G et al. Clin Infect Dis. 2012;54:1126‐1133.
ABSSSI and CABP: Maximizing the Anti‐Infective Arsenal to Optimize Patient Outcomes
Greater impact of MRSA on clinical and economic outcomes
Filice GA et al. Infect Control Hosp Epidemiol. 2010;31:365‐373.
aBased on medical records, accounting systems, and interviews between January 1, 2004 and June 30, 2006bPatients with S aureus infection within the Minneapolis Veterans Affairs hospital and associated clinicscWithin 6 mo of onsetdMedian 6‐mo inpatient unadjusted costs in 2006 US dollars
Attributable Costs of Resistance*
Outcomes Patients with ARI (n=188)
Length of stay (LOS) 6.4 ± 12.7 d
Deatha 6.5%
Medical costs (mean ± SE)b,c $18,588–$29,069
Total hospital costsb,d $3.4–$5.4 million
Total societal costsb,e $10.7–$15.0 million
105Roberts RR et al. Clin Infect Dis. 2009;49:1175‐1184.
ARI, antibiotic‐resistant infection*Additional clinical or economic costs of ARI relative to the costs without ARI, based on analysis of medical records for a sample of 1,391 high‐risk adult patients at an urban teaching hospital in 2000 (without ARI, n=1203)aAdjusted attributable mortality. Absolute mortality 18.1% with ARI vs 3.0% without ARI; adjusted OR = 2.16bEconomic costs were reported in 2008 US dollarscVariable costs for a base case patient, including medications and blood productsdIncluding labor, benefits, supplies, equipment used, and allocated administrative and support costs for employees and space occupiedeCosts of mortality, lost productivity
ABSSSI and CABP: Maximizing the Anti‐Infective Arsenal to Optimize Patient Outcomes
• Restrictions common in academic centers, not community hospitals1,2
• Lack of strong scientific evidence to support improved outcomes1,3
• Lack of a full‐time ID consult service2
– Role of pharmacist, physician, ID fellow unclear and varies1
• Limited use of local guidelines1
• Limited use of CPOE and CDSS1
• Program funding inconsistent1
• Administrative support and data analysis inconsistent1
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CPOE, computerized provider order entry; CDSS, clinical decision support system
1. Barlam TF et al. Infect Control Hosp Epidemiol. 2006;27:695‐703. 2. Weston A et al. Presented at IDWeek 2012. October 19, 2012; San Diego, CA. Poster 717. Available at: https://idsa.confex.com/idsa/2012/webprogram/Paper34170.html. 3. Chung GW et al.Virulence. 2013;4(2):151‐157.
Antibiotic Use Evaluation = Antimicrobial Stewardship
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Assess patient Make diagnosis Select treatment plan
• Are antibiotics needed?• What are my options?• Formulary restrictions?• Will it work?
Implement plan Reassess patient Modify plan
• Risk stratification (severity, risk factors for MDROs)• Guidelines (local or national)• Spectrum of activity and local antibiogram• Nonscientific inputs: peer opinion, marketing
• Are antibiotics still needed?• Can I streamline therapy?• Specific microbiology• Convenience and cost
1. MacDougal C et al. Clin Microbiol Rev. 2005;18(4):638‐656. 2. File TM Jr et al. Clin Infect Dis. 2011;53(suppl 1)S15‐S22.
MDROs, multi‐drug resistant organisms
ABSSSI and CABP: Maximizing the Anti‐Infective Arsenal to Optimize Patient Outcomes
- Labor intensive- Recommendations optional- Potential for inappropriate exposure
Advantages1,3
- Initial orders funneled through experts- Can be facilitated through computer
surveillance- Immediate educational opportunities- Control of antimicrobial use
Disadvantages1,3
- Delays therapy for critically ill patients- Requires trained personnel- Loss of prescriber autonomy- Potential for prescriber to circumvent- Potential for inappropriate exposure
1. Dellit TH et al. Clin Infect Dis. 2007;44(2):159‐177. 2. Chung GW et al. Virulence. 2013;4(2):151‐157. 3. Reed EE et al. Virulence. 2013;4(2):158‐162. 111
ABSSSI and CABP: Maximizing the Anti‐Infective Arsenal to Optimize Patient Outcomes
•ASP should facilitate development of evidenced‐based guidelines
•Must be tailored to local practice and epidemiologyGuidelines
•Opportunity for screening information as it becomes available
•Can develop alerts, reports, and decision support pathways
Computer Surveillance
OutcomesMeasurement
•Determines the impact of new policies
•Opportunities for research and publication
Dellit TH et al. Clin Infect Dis. 2007;44(2):159‐177. 112
ARS
ASP Improves Clinical Outcomes
1141. Fishman N. Am J Med. 2006;119(suppl 1):S53‐S61. 2. Ohl CA et al. Clin Infect Dis.2011;53(1):S23‐S28. By permission of the Oxford University Press.
University of Pennsylvania Hospital observational study, clinical outcomes with a comprehensive stewardship program compared with usual practice.1,2
90 91
51
32
55
31
9
0
20
40
60
80
100
AppropriateAntimicrobial
ClinicalCure
TreatmentFailure
AntibioticResistance
Patients, %
ASP Usual practice
ABSSSI and CABP: Maximizing the Anti‐Infective Arsenal to Optimize Patient Outcomes
CA‐MRSA leads to significantly greater rates of hospitalization, failure of initial therapy, and infection recurrence in patients with cSSSI vs those with CA‐MSSA (2003‒2005)
P <.001
P <.001
P <.015
Davis SL et al. J Clin Microbiol. 2007;45(6):1705‐1711.
Parenteral antibiotic use in >10% (by 2009) of adult cases within first 24 h of admission to ≈100 US hospitals, based on chart review of 22,382 admissions for cSSSI between 1/1/00 and 6/30/09.
Vancomycin used as initial therapy in 58% of cSSSI cases in 2009
Berger A et al. Infect Dis Clin Pract. 2013;21(3):159‐167.
[p159, 160 Table 2, p161 Table 3]
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ABSSSI and CABP: Maximizing the Anti‐Infective Arsenal to Optimize Patient Outcomes
• Additional therapy results– 85% of cellulitis inpatients received MRSA coverage
• ≈50% of 66 cases discharged on TMP/SMX
• Highest rate of failure, 12.1% (8/66)
• 5/8 (63%) cases of cellulitis failure discharged on TMP/SMX
• Conclusions– Substantial healthcare resources used to treat SSTI
– Some diagnostic testing poorly defined, expensive, unnecessary
– Many patients received inappropriate broad antibiotic coverage, including gram‐negative and anaerobic coverage
– Duration of hospitalization for treatment appeared excessive, and many patients could have received part of therapy at home
124Jenkins TC et al. Clin Infect Dis. 2010;51(8):895‐903.
ARS
Impact of ASP on Inpatient Treatment of ABSSSI
• Objective
Observe impact of ASP on ABSSSI treatment and outcomes since ASP implemented 2/2012– Appropriateness of antibiotic therapy
– LOS
– 30‐d readmission rate
• Historic controlTreatment outcomes of ABSSSI (ICD9 codes 681‐682.9) at Summa Health System in 2011– Mean LOS: 6.2 d
– 30‐d readmission rate: 6.2%
126Pasquale TR et al. Presented at: IDWeek 2012. October 19, 2012; San Diego, CA. Poster 744. Available at: https://idsa.confex.com/idsa/2012/webprogram/Session4786.html.
76%
26%
8%3% 2%
ABSSSI Subtypes (N=62)
Cellulitis Major or deep abscess Surgical site infection Diabetic wound Decubitus ulcer
ABSSSI and CABP: Maximizing the Anti‐Infective Arsenal to Optimize Patient Outcomes
Impact of ASP on Inpatient Treatment of ABSSSI (continued)
24%
37%44%
7% 11%
ASP Intervention Types (N=85)
Antibiotic regimen change De‐escalation Dose change ID consult Other
Outcomes2012(N=62)
2011 (N=1149)
LOS, mean (d) 4.4 6.2
30‐d All‐Cause Readmission
6.5% 16.71%
30‐d ABSSSI Readmission
3.33% 6.27%
127Pasquale TR et al. Presented at: IDWeek 2012. October 19, 2012; San Diego, CA. Poster 744. Available at: https://idsa.confex.com/idsa/2012/webprogram/Session4786.html.