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Complex Pneumonia Case

Marc H. Scheetz, Pharm.D., MSc, BCPS AQ-ID Associate Professor

Midwestern University Downers Grove, Illinois

Infectious Diseases Pharmacist Northwestern Memorial Hospital

Chicago, Illinois

Learning Objectives

At the conclusion of this session, given a patient case, the participant should be able to

1. Correctly answer case-based questions about appropriate treatment and monitoring of a complex patient with multiple conditions, including healthcare-associated pneumonia, acute renal insufficiency, sepsis, COPD and dehydration.

2. Interpret clinical data, including lab, physical examination and vital signs.

3. Determine and prioritize pneumonia-related treatment goals.

4. Explain relevant Joint Commission pneumonia-related core measures.

5. Discuss economic and safety issues in patients receiving treatment for pneumonia.

Format: Today’s session will be a highly interactive discussion of the attached case studies.

Premise: Participants in this course are pharmacists who practice in clinical acute care settings. You are responsible for evaluating and monitoring the patient’s therapy. You are responsible for providing comprehensive patient management and education.

______________________________________________________________________________________________ ©2015 American Society of Health-System Pharmacists, Inc. All rights reserved.

1

CASE Date: June 2015 Initials AB

DOB/Age 74 yo

Sex F

Race/Ethnicity African American

Source Patient and medical records

CC/HPI (including sx analysis for CC): “I can’t breathe!” AB with a PMH of COPD presented to the emergency department (ED) several hours ago complaining of SOB. Ten days prior to today’s admission, she presented to your ED with hypoxia and dehydration. She was found to have H3N2 influenza and was treated with intravenous fluids and oseltamivir 75 mg orally every 12 hours. She returned to her baseline state of health and was discharged home 3 days ago with a prescription for an additional 3 days of oseltamivir. On the day of discharge the patient displayed the following vital signs. BP= 137/97 mm Hg Pulse= 64 bpm, regular R=16 T=98.2°F (oral) Yesterday at home, she noted increased production of thick, yellow sputum, used her albuterol inhaler five times, and had “chills and sweats” so she came to the ED this morning. Vitals signs on presentation were : BP= 105/65 mmHg, T= 101.4°F. Her O2 saturation was 88% on room air, so she was placed on 4 liters/min of O2 via nasal cannula. Her O2 saturation improved to 92% with this intervention. The ED physician ordered the following labs: CBC with differential, CMP, ABG, Blood cultures, Sputum cultures, and a CXR.

Past Medical History (major illnesses and surgeries) HTN x 30 years Dyslipidemia x 23 years Chronic Obstructive Pulmonary Disease (x 5 years) Osteoarthritis (knees, uses walker) Obesity (BMI = 30 kg/m2) Osteopenia


2

Objective Data (observations/vital signs/physical examination/labs) Physical Exam General: Obese, moderate respiratory distress HEENT: Pursed lips with exhalation. Normocephalic. Pupils equally reactive to light and accommodation. No lymphadenopathy. Neck supple. Lungs: Tachypneic, increased respiratory effort, prolonged expirations with end-expiratory wheezing, decreased air movement, inspiratory crackles at the left lower lung base. CV: Tachycardia, regular rhythm, no murmurs/rubs/gallops, no jugular venous distension > 10 cm, warm extremities with < 2 second capillary refill. Abd: normal active bowel sounds, no abdominal tenderness to palpation, no distension Ext: No lower extremity edema. Neuro/Psych: A + O x 3, lethargic but arousable Vital Signs BP= 105/65 mm Hg Pulse= 92 bpm R=24 T=101.4°F (oral) Height = 5’ 5” Weight = 180 lb BMI = 30 kg/m2 ECG = sinus tachycardia Laboratory Tests (measured today) ABG (room air): pH=7.32 / PaCO2=60 / PaO2= 67 / O2 sat=87% CBC with Differential: WBC = 16 X 109/L (85% neutrophils), Hgb = 13.1 g/dL, Platelets = 365K Na = 139 mEq/L K = 4.5 mEq/L Cl = 99 mEq/L CO3 = 27 mmol/L BUN = 37 mg/dL Cr = 1.2 mg/dL Glucose = 107 mg/dL AST = 22 units/L ALT = 44 units/L Blood culture: pending


3

Respiratory culture: pending Urinary Legionella antigen: negative Radiology: CXR: Hyperexpanded lungs, mild cardiomegaly. Consolidation in left lower lobe concerning for pneumonia.


4

Presentation Questions (* not in PowerPoint presentation) Dehydration

1. AB progressively deteriorates and is transferred to the medical intensive care unit for maintenance of hemodynamic stability and intubation. Which of the following is an appropriate initial fluid regimen?

a. Furosemide 20 mg intravenously b. Normal Saline at 125 mL/hr over 24 hours c. Normal Saline 1000 mL infused over 30 minutes d. Albumin 25 g (100 mL of 25% solution) infused over 24 hours

Healthcare-Associated Pneumonia and Sepsis

2. If AB is ventilated on the first day that she presents to your medical facility, which of the following would represent her pneumonia diagnosis?

a. Community Acquired Pneumonia (CAP) b. Health Care Associated Pneumonia (HCAP) c. Ventilator Associated Pneumonia (VAP) d. Nursing Home Acquired Pneumonia (NHAP)

COPD

3. Which of the following risk factors predisposes AB to pneumonia with Gram-positive and Gram-negative multidrug-resistant pathogens?

a. Five year history of COPD b. Status as a retired nurse c. Post influenza infection d. Recent hospitalization

Healthcare-Associated Pneumonia and Sepsis

4. In addition to fluid status correction and vasopressor initiation, which of the following is the next most important intervention to help AB regain hemodynamic stability?

a. Recombinant human activated protein C (drotrecogin alfa) b. Broad-spectrum antibacterial coverage c. Hydrocortisone d. Intravenous immune globulin

5. Which of the following is a guideline-approved, empiric drug regimen to provide coverage for

Gram-negative organisms in AB? e. Doripenem 1 g intravenously every 8 hours f. Moxifloxacin 400 mg intravenously once daily + gentamicin 500 mg intravenously once

daily g. Piperacillin-tazobactam 4.5 g intravenously every 6 hours + gentamicin 500 mg

intravenously once daily h. Tigecycline 100 mg intravenously as a loading dose followed by 50 mg intravenously

every 12 hours + moxifloxacin 400 mg intravenously once daily


5

A blood culture that was drawn upon transfer to the MICU is now showing Gram-positive cocci. Also, a bronchoscopic alveolar lavage (BAL) is performed and an initial report indicates that many Gram-positive cocci are visualized. The following fluid analysis is provided for the BAL fluid. Fluid Specimen BAL Fluid Turbidity 4+ Fluid Color Red Fluid WBC 100 /UL Fluid RBCs 32500 /UL Fluid Segmented Neutrophils 74% Fluid Lymphocytes 6% Fluid Monocytes 9% Fluid Macrophages 8% Fluid Other Cells 3%

6. Which of the following would be an appropriate regimen for AB given the Gram-positive cocci identified in the BAL fluid?

a. Vancomycin 1.5 g intravenously every 24 hours b. Daptomycin 650 mg intravenously every 24 hours c. Ceftaroline 600 mg intravenously every 12 hours d. Oxacillin 2 g intravenously every 6 hours

7. If vancomycin therapy is initiated, which of the following strategies is guideline supported to

improve efficacy? a. Obtain a peak concentration after the first dose to ensure adequate exposure b. Obtain a serum trough concentration immediately before the second dose c. Obtain a trough concentration immediately before the fifth dose at steady state. d. Obtain a minimum of 3 randomly timed concentrations at steady state to calculate the

area under the concentration curve It is now two days later, and AB is now hemodynamically stable in the MICU. Only norepinepherine remains for vasopressor therapy and it is being infused at a rate of 5 mcg/minute. The culture and susceptibility results return for the blood culture and BAL. The following is reported to you: BLOOD CULTURE: STAPHYLOCOCCUS AUREUS GROWTH AT 48 HOURS

Susceptibility Results Tested Interpretation Result (mg/L) CLINDAMYCIN Susceptible <=0.25 ERYTHROMYCIN Susceptible <=0.25 OXACILLIN Susceptible 0.5 GENTAMICIN Susceptible <=0.5 RIFAMPIN Susceptible <=0.5 TETRACYCLINE Susceptible <=1 TRIMETHOPRIM/SULFAMETHOXAZOLE Susceptible <=0.5/9.5 VANCOMYCIN Susceptible 1

BAL


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RESPIRATORY CULT/GRAM ST: STAPHYLOCOCCUS AUREUS: 90,000 COL/ML Susceptibility Results

Tested Interpretation Result (mg/L) CLINDAMYCIN Susceptible <=0.25

ERYTHROMYCIN Susceptible <=0.25 OXACILLIN Susceptible <=0.5 GENTAMICIN Susceptible <=0.5 LINEZOLID Susceptible 2 RIFAMPIN Susceptible <=0.5 TETRACYCLINE Susceptible <=1 TRIMETHOPRIM/SULFAMETHOXAZOLE Susceptible <=0.5/9.5 VANCOMYCIN Susceptible 1

8. Given the above susceptibilities, which of the following would be most appropriate for AB?

a. Vancomycin 1.5 g intravenously every 24 hours b. Linezolid 600 mg every 24 hours c. Ceftaroline 600 mg intravenously every 12 hours d. Oxacillin 2 g intravenously every 6 hours

9. Which of the following total durations of therapy would be most appropriate for AB if she has a

favorable response to treatment? a. 3-5 days b. 7-21 days c. 21-28 days d. 42-56 days

10. After AB stabilizes, which of the following would be the most appropriate blood glucose target

to balance safety and efficacy? a. <110 mg/dL b. <140 mg/dL c. <180 mg/dL d. <250 mg/dL

Acute Renal failure

11. AB is diagnosed with a type-1 mediated allergy to cephalosporin agents by the allergy service. Which of the following treatments for the MSSA infection would be best for AB given her development of renal failure and her newly diagnosed beta-lactam allergy?

a. Oxacillin; there is insignificant cross reactivity between cephalosporins and penicillins b. Vancomycin; mortality data favor vancomycin for treatment of MSSA c. Linezolid; several trials found reduced rates of nephrotoxicity with linezolid when

compared with vancomycin d. Daptomycin; daptomycin is the drug of choice in patients with bloodstream infections in

whom vancomycin is not an option.


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12. Due to her acute renal failure and hemodynamic instability, AB is initiated on continuous veno-venous hemofiltration at an ultrafiltration rate of 4 liters per hour. Which of the following antimicrobial drug regimens is appropriate for AB given this rate of extracorporeal clearance?

a. Vancomycin 1500 mg intravenously every 24 hours b. Linezolid 600 mg intravenously every 72 hours c. Ceftazidime 1000 mg every 48 hours d. Moxifloxacin 400 mg every 72 hours


8

References / Resources COPD/Dehydration Relative to pneumonia, the interested reader should be familiar with the sepsis guidelines: Dellinger RP, Levy MM, Rhodes A et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013; 41:580-637. Available at: http://www.sccm.org/Documents/SSC-Guidelines.pdf HCAP American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005; 171:388-416. http://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/PDF_Library/HAP.pdf Also CAP guidelines are very helpful. Mandell LA, Wunderink RG, Anzueto A et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007; 44(suppl 2):S27-72. Available at: http://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/PDF_Library/CAP%20in%20Adults.pdf Rybak M, Lomaestro B, Rotschafer JC et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm. 2009; 66:82-98. http://www.ajhp.org/content/66/1/82.full Liu C, Bayer A, Cosgrove SE et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011; 52:1-38. Available at: http://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/PDF_Library/MRSA.pdf Kollef MH, Morrow LE, Baughman RP et al. Health care-associated pneumonia (HCAP): a critical appraisal to improve identification, management, and outcomes--proceedings of the HCAP Summit. Clin Infect Dis. 2008; 46(suppl 4):S296-334. Sepsis Dellinger RP, Levy MM, Rhodes A et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013; 41:580-637. Available at: http://www.sccm.org/Documents/SSC-Guidelines.pdf Kidney Injury Bellomo R, Ronco C, Kellum JA et al. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004; 8(4):R204-12. Available at: http://ccforum.com/content/8/4/R204. Scheetz MH, Scarsi KK, Ghossein C et al. Adjustment of antimicrobial dosages for continuous venovenous hemofiltration based on patient-specific information. Clin Infect Dis. 2006; 42:436-7.


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http://www.sccm.org/Documents/SSC-Guidelines.pdf

http://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/PDF_Library/HAP.pdf

http://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/PDF_Library/CAP%20in%20Adults.pdf

http://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/PDF_Library/CAP%20in%20Adults.pdf

http://www.ajhp.org/content/66/1/82.full

http://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/PDF_Library/MRSA.pdf

http://www.sccm.org/Documents/SSC-Guidelines.pdf

http://ccforum.com/content/8/4/R204

The Joint Commission The Joint Commission. Specifications Manual for National Hospital Inpatient Quality Measures. Available at: http://www.jointcommission.org/specifications_manual_for_national_hospital_inpatient_quality_measures.aspx.


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http://www.jointcommission.org/specifications_manual_for_national_hospital_inpatient_quality_measures.aspx

http://www.jointcommission.org/specifications_manual_for_national_hospital_inpatient_quality_measures.aspx

Marc H. Scheetz, Pharm.D., M.S., BCPS (AQ‐ID)Associate Professor of Pharmacy Practice Midwestern University Chicago College of Pharmacy Downers Grove, IllinoisInfectious Diseases Pharmacist Northwestern Memorial Hospital Chicago, Illinois

Complex Pneumonia CaseDisclosures

• I have been on the Advisory board for Cepheid and Trius with proceeds donated to Midwestern University.

• The views offered in the presentation are not necessarily the views of Midwestern University or Northwestern Memorial Hospital.

Learning Objectives• Correctly answer case‐based questions about appropriate treatment and

monitoring of a complex patient with multiple conditions, including healthcare‐associated pneumonia, acute renal insufficiency, sepsis, COPD and dehydration.

• Interpret clinical data, including lab, physical examination and vital signs.

• Determine and prioritize pneumonia‐related treatment goals.

• Explain relevant Joint Commission pneumonia‐related core measures.

• Discuss economic and safety issues in patients receiving treatment for pneumonia.

CC/HPI (including sx analysis for CC):

“I can’t breathe!”

AB with a PMH of COPD presented to the Emergency Room several hours ago complaining of SOB. Ten days prior to today’s admission, she presented to your ED with hypoxia and dehydration. She was found to have H3N2 influenza A and was treated with intravenous fluids and oseltamivir 75mg orally every 12 hours. She returned to her baseline state of health and was discharged home 3 days ago with a prescription for an additional three days of oseltamivir.

InitialsAB

Age74yo

SexF

Race/EthnicityAA

Source Patient and medical records

The Case: Please let me introduce you to AB

The CaseOn the day of discharge the patient displayed the following vital signs.

BP= 137/97 mmHg Pulse= 64, regular R=16 bpm T=98.2°F (oral)

Yesterday at home, she noted increased production of thick, yellow sputum, used her albuterol inhaler five times, and had “chills and sweats” so she came to the ER this morning.

Vitals signs on presentation were : BP= 105/65 mmHg Pulse=95, regular R=28 bpm T= 101.4°F (oral)

Her O2 saturation was 88% on room air, so she was placed on 4 liters/min of O2 via nasal cannula. Her O2 saturations improved to 92% with this intervention.

The ED physician ordered the following labs: CBC with differential, comprehensive metabolic panel (CMP), ABG, Blood cultures, Sputum cultures, and a CXR.

The Case

Past Medical History (major illnesses and surgeries)

•HTN x 30 years

•Dyslipidemia x 23 years

• Chronic Obstructive Pulmonary Disease (x 5 years)

•Osteoarthritis (knees, uses walker)

•Obesity (BMI = 30 kg/m2)

•Osteopenia


11

The Case The Case

The CasePhysical Exam

General: Obese, moderate respiratory distress

HEENT: Pursed lips with exhalation. Normocephalic. Pupils equally reactive to light and accommodation. No lymphadenopathy. Neck supple.

Lungs: Tachypneic, increased respiratory effort, prolonged expirations with end‐expiratory wheezing, decreased air movement, inspiratory crackles at the left lower lung base.

CV: Tachycardia, regular rhythm, no murmurs/rubs/gallops, no jugular venous distension > 10 cm, warm extremities with < 2 second capillary refill.

Abd: normal active bowel sounds, no abdominal tenderness to palpation, no distension

Ext: No lower extremity edema.

Neuro/Psych: A + O x 3, lethargic but arousable

The CaseVital SignsBP= 105/65 mmHg Pulse= 95 bpm R=28 T=101.4°F (oral)Height = 5’ 5” Weight = 180 lb BMI = 30 kg/m2

EKG = sinus tachycardia

Laboratory Tests (measured today) ABG (room air): pH=7.32 / PaCO2=60 / PaO2= 67/ O2 sat=87%CBC with Differential: WBC = 16 x109 (85% Neutrophils), Hgb = 13.1, Platelet = 365K

Na = 139 mEq/L K = 4.5 mEq/L Cl = 99 mEq/L CO3 = 27 mmol/LBUN = 37 mg/dL Cr = 1.2 mg/dL Glucose = 107 mg/dLAST = 22 units/L ALT = 44 units/L

Blood culture: pendingRespiratory culture: pending Urinary Legionella antigen: negative

Radiology:CXR: Hyperexpanded lungs, mild cardiomegaly. Consolidation in left lower lobe concerning for

pneumonia.

Question 1:AB progressively deteriorates and is transferred to the medical intensive care unit for maintenance of hemodynamic stability and intubation. Which of the following is an appropriate initial fluid regimen?

A. Furosemide 20 mg intravenously

B. Normal Saline at 125 mL/hr over 24 hours

C. Normal Saline 1000 mL infused over 30 minutes

D. Albumin 25 grams (100 mL of 25% solution) infused over 24 hours

Surviving Sepsis, Volume Repletion

• Correction of the patient to euvolemia is paramount

• A shift toward crystalloid therapy in recent guidelines (grade 1B)

• Another key factor is the bolus amount… which is suggested at 30 mL/kg (grade 1C).

Dellinger RP et al. Crit Care Med. 2013; 41:580-637. URL in handout.

Brunkhorst FM et al. N Engl J Med. 2008 Jan 10; 358(2):125-39.

Perner A et al. N Engl J Med. 2012 Jul 12; 367(2):124-34.

Myburgh JA. N Engl J Med. 2012 Nov 15; 367(20):1901-11.

+Low Cost

+Equal Outcomes

‐Excess Volume

‐High Cost

‐Kidney Insulting

+Low Volumes cr

ystalloid

colloid


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Goals of Initial Resuscitation

“Protocolized, quantitative resuscitation of patients with sepsis‐ induced tissue hypoperfusion (defined in this document as hypotension persisting after initial fluid challenge or blood lactate concentration ≥ 4 mmol/L).”

Goals during the first 6 hr of resuscitation (Grade 1C):– Central venous pressure 8–12 mm Hg

– Mean arterial pressure (MAP) ≥ 65 mm Hg

– Urine output ≥ 0.5 mL/kg/hr

– Central venous (superior vena cava) or mixed venous oxygen saturation 70% or 65%, respectively.


Question 2:If AB is ventilated on the first day that she presents to your medical facility, which of the following would represent her pneumonia diagnosis?

A. Community Acquired Pneumonia (CAP)

B. Health Care Associated Pneumonia (HCAP)

C. Ventilator Associated Pneumonia (VAP)

D. Nursing Home Acquired Pneumonia (NHAP)

First, HCAP

• Any patient who …

– Was hospitalized in an acute care hospital for two or more days within 90 days of the infection

– Resided in a nursing home or long‐term care facility

– Received recent intravenous antibiotic therapy, chemotherapy, or wound care within the past 30 days of the infection

– Attended a hospital or hemodialysis clinicAmerican Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of

adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005; 171:388-416.

HAP, CAP, HCAP, VAP, … different letters… different treatments

Pathogens may vary on the basis of pneumonia classification

HAP: Hospital acquired pneumonia‐ a pneumonia that occurs 48 hours or more after admission, which was not incubating at the time of admission

VAP: pneumonia that arises more than 48–72 hours after endotracheal intubation

CAP: Now a pneumonia diagnosis of exclusion

American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J

Respir Crit Care Med. 2005; 171:388-416.

HAP, VAP, HCAP guideline revisions in progress, many participating

• American College of Chest Physicians • American College of Emergency Physicians • American Thoracic Society • European Society of Clinical Microbiology and • Infectious Diseases• European Society of Intensive Care Medicine • Infectious Diseases Society of America

Society of Critical Care Medicine … and many more international groups.

Question 3:Which of the following risk factors predisposes AB to pneumonia with Gram‐positive and Gram‐negative multidrug‐resistant pathogens?

A. Five year history of COPD

B. Status as a retired nurse

C. Post influenza infection

D. Recent hospitalization


13

• Risk factors for MDRO include:

– HCAP designation

– Antimicrobial therapy in last 90 days

– Current hospitalization of 5 days or more

– High frequency of antibiotic resistance in the community or in the specific hospital unit

– Home infusion therapy (including antibiotics)

– Family member with multidrug‐resistant pathogen

– Immunosuppressive disease and/or therapy

American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital‐acquired, ventilator‐associated, and healthcare‐associated pneumonia. Am J Respir Crit Care

Med. 2005; 171:388‐416.

Multidrug‐Resistant Organism (MDRO)

HCAP Criteria… one more time

• Was hospitalized in an acute care hospital for two or more days within 90 days of the infection

• Resided in a nursing home or long‐term care facility

• Received recent intravenous antibiotic therapy, chemotherapy, or wound care within the past 30 days of the current infection

• Attended a hospital or hemodialysis clinicAmerican Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;

171:388-416.

“CAP” before 2005, is now “HCAP”… the trade‐off

HCAP: Overtreatment?

Fewer missed cases?

Higher individual resistance?

CAP: Undertreatment?

More missed cases?

Lower individual resistance?

Enteric Gram negativesNon‐fermentersMRSA/MSSAS.pneumoniae

Weird/Strange/Unusual

S.pneumoniaeH.influenzae

VirusesAtypicals

Weird/Strange/Unusual

HAP HCAP CAP

Incidence of Pathogens, Overlap

• What is known:

– Different pathogens exist in HCAP vs. CAP

– Studies document inconsistent incidence rates

—e.g., the incidence of both MRSA and P. aeruginosarange from several percent to upwards of 25% for each in HCAP1

1. Brito V, Niederman M. Curr Opin Infect Dis. 2009, 22: 316-25.

ControversyThe experts can agree… on disagreeing

0%

10%

20%

30%

40%

50%

60%

70%IDSA, n=744

HCAP Summit, n=10

Kollef MH et al. Clin Infect Dis. 2008; 46(suppl 4):S296-334.

“Clinical and microbiological features of HCAP are more similar to HAP and VAP than CAP”


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Question 4:In addition to fluid status correction and vasopressor initiation, which of the following is the next most important intervention to help AB regain hemodynamic stability?

A. Recombinant human activated protein C (drotrecogin alfa)

B. Broad‐spectrum antibacterial coverage

C. Hydrocortisone

D. Intravenous immune globulin

Scarsi K, et al. Antimicrob Agents Chemother. 2006; 50:3355‐60.

-10%0%

10%

20%

30%

40%

50%

60%

<24 24-48h 48-72h 72-96h >96h

Scarsi et al. Percent Mortality for Gram-negative BSI

0%

10%

20%

30%

40%

50%

60%

<24 24-72h 72-120h >120h

Kang et al. Percent Mortality for P.aeruginosa BSI

Kang C, et al. Clin Infect Dis. 2003; 37:745‐51.

Time to Active Therapy

0

10

20

30

40

50

60

70

80

1 2 3 4 5 6

Percent Survival

Hour

Average survival if active therapy was started within hour “x” of shock

Kumar A, Roberts D, Wood KE et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006; 34(6):1589-96.

Even more important in Septic Shock Oversight is in place

… for CAP… not HCAP

PN‐3a: Blood cultures within 24 hours of hospital arrival

PN‐3b: Blood cultures prior to antibiotic

PN‐6(a)(b): Antibiotic treatment selection

•make sure your empiric/formulary choices are “approved”!

The Joint Commission Specifications Manual for National Hospital Inpatient Quality Measures. http://www.jointcommission.org/specifications_manual_for_national_hospital_inpatient_quality_measures.aspx

(accessed 2013 April 28).

To Start Dosing CAP Patients Correctly

Modified from:http://en.wikipedia.org/wiki/File:Unclesamwantyou.jpg#filelinks

β‐lactam (IV or IM) + Macrolide (IV or PO)

Or

Anti‐pneumococcal Quinolone monotherapy (IV or PO)

Or

β‐lactam (IV or IM) + Doxycycline (IV or PO)

Or

Tigecycline monotherapy (IV)

Acceptable drugs

β‐lactam = Ceftriaxone, Cefotaxime, Ampicillin/Sulbactam, Ertapenem, Ceftaroline

Macrolide = Erythromycin, Clarithromycin, Azithromycin

Anti‐pneumococcal Quinolones = Levofloxacin, Moxifloxacin, Gemifloxacin

The Joint Commission Specifications Manual for National Hospital Inpatient Quality Measures. http://www.jointcommission.org/specifications_manual_for_national_hospital_inpatient_quality_measures.aspx

(accessed 2013 Mar 28).

National Hospital Inpatient Quality Measures… one example for CAP, Non‐ICU

Drotrecogin alfa?

Most recent guidelines update:

PROWESS SHOCK trial reporting on 1,696 patients (2011): No benefit of rhAPC in patients with septic shock • Mortality 26.4% for recombinant human

activated protein C (rhAPC) vs. 24.2% placebo• Relative risk of 1.09 and a p‐value of 0.31 • Drug withdrawn from the market.

Dellinger RP et al. Surviving Sepsis Campaign…. Crit Care Med. 2013; 41:580-637. URL in handout.


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Other Therapies?1

• IV Immune Globulin= One large RCT in adults and 1 large RCT in infants showed no benefit (2B)

• Hydrocortisone 200 mg should only be considered if fluid resuscitation and vasopressors do not restore hemodynamic stability (2C)

—French RCT2: benefit in patients with vasopressor unresponsive shock

—CORTICUS 3: enrolled patients with vasopressor responsive shock, no benefit.

—The use of ACTH is no longer recommended due to a lack of ability to predict resolution of shock (2B)

1. Dellinger RP et al. Crit Care Med. 2013; 41:580-637. URL in handout.

2. Annane D, Sebille V. JAMA 2002: 288: 862-71.

3. Sprung CL, et al. N Engl J Med. 2008 Jan 10;358(2):111-24.

Question 5:Which of the following is a guideline‐approved, empiric drug regimen to cover Gram‐negative organisms in AB?

A. Doripenem 1 g IV every 8 hrB. Moxifloxacin 400 mg IV once

daily + Gentamicin 500 mg IV once daily

C. Piperacillin‐tazobactam 4.5 g IV every 6 hr + Gentamicin 500 mg IV once daily

D. Tigecycline 100 mg IV as a loading dose followed by 50 mg IV every 12 hr + Moxifloxacin 400 mg IV once daily

All PneumoniasRisk factor for MDRO or late onset (i.e.

≥5days)

Broad SpectrumPseudomonal and MRSA Coverage

Limited Spectrum

Coverage BUT

No Pseudomonal

or MRSA Coverage

American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J

Respir Crit Care Med. 2005; 171:388-416.

Therapy Pathways

• Risk factors for MDRO include:

– HCAP designation

– Antimicrobial therapy in last 90 days

– Current hospitalization of 5 days or more

– High frequency of antibiotic resistance in the community or in the specific hospital unit

– Home infusion therapy (including antibiotics)

– Family member with multidrug‐resistant pathogen

– Immunosuppressive disease and/or therapy

American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;

171:388-416.

Revisiting MDRO, AB in Mind

A

B

C

Guideline Approved Choices

No MDRO risk

Ceftriaxoneor

Levofloxacin, moxifloxacin, or ciprofloxacin

or

Ampicillin/sulbactamor

Ertapenem

MDRO riskAntipseudomonal cephalosporin

(cefepime, ceftazidime)or

Antipseudomonal carbapenem(imipenem or meropenem)

or

β‐Lactam/‐lactamase inhibitor (piperacillin–tazobactam)

plus

Antipseudomonal fluoroquinolone (ciprofloxacin or levofloxacin)

or

Aminoglycoside (amikacin, gentamicin, or tobramycin)

plus

Vancomycin or linezolid

American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;

171:388-416.

No Doripenem

FDA statement on recently terminated clinical trial with Doribax (doripenem). January 5, 2012. http://www.fda.gov/Drugs/DrugSafety/ucm285883.htm.

VAP Clinical Cure Rates and All‐Cause 28‐Day Mortality Rate, Doripenem vs. Imipenem

Doripenem 1g every 8 hr, 4hr infusion

Imipenem 1g every 8 hr, 1hr

infusionDifference 95% CI

Clinical Cure RatesMicrobiological

Intent‐to‐Treat (MITT) 45.6% 56.8% ‐11.2% ‐26.3 to 3.8Microbiologically

Evaluable 49.1% 66.1% ‐17% ‐34.7 to 0.8

All Cause 28‐day Mortality Rate (MITT) 21.5% 14.8% 6.7% ‐5.0 to 18.5

Stopped early! “Healthcare professionals should be aware that Doribax is not approved to treat any type of pneumonia, nor is it approved for doses greater than 500 mg every eight hours.”


16

Question 6

A blood culture that was drawn upon transfer of AB to the MICU is now showing Gram positive cocci. Also, a Bronchoscopic Alveolar Lavage (BAL) is performed and an initial report indicates that many Gram positive cocci are visualized. The following fluid analysis is provided for the BAL fluid.

Fluid Specimen BALTurbidity 4+ Color Red WBC 100 /µL RBCs 32500 /µL Segmented Neutrophils 74 % Lymphocytes 6 % Monocytes 9 % Macrophages 8 % Other Cells 3 %

Question 6: cont.Which of the following would be an appropriate regimen for AB given the Gram positive cocci isolated from the BAL above?

A. Vancomycin 1.5 g intravenously every 24 hours

B. Daptomycin 650 mg intravenously every 24 hours

C. Ceftaroline 600 mg intravenously every 12 hours

D. Oxacillin 2 g intravenously every 6 hours

MRSA Pneumonia Coverage

American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005; 171:388-416.

• Pre‐2012

– Post‐hoc analyses of RCTs

– Observational Studies

– Meta‐analyses

• 2012 and beyond

– RCT!

A

B

C

MDRO riskAntipseudomonal cephalosporin

(cefepime, ceftazidime)or

Antipseudomonal carbepenem (imipenem or meropenem)

or

B‐Lactam/‐lactamase inhibitor (piperacillin–tazobactam)

plus

Antipseudomonal fluoroquinolone (ciprofloxacin or levofloxacin)

or

Aminoglycoside (amikacin, gentamicin, or tobramycin)

plus

Vancomycin or linezolid

• The original studies, Wunderink et al.1,2

– Combination of 2 prospective studies with identical methodologies. al.3

1. Rubinstein E, Cammarata S, Oliphant T et al. Clin Infect Dis. 2001 Feb 1;32(3):402-12. 2. Wunderink RG, Cammarata SK, Oliphant TH et al. Clin Ther. 2003 Mar;25(3):980-92.

3. Wunderink RG, Rello J, Cammarata SK et al. Chest. 2003 Nov;124(5):1789-97.

* Chi square or Fishers Exact performed as appropriate post hoc by M.Scheetz

Linezolid Efficacy, n (%)

Vancomycin Efficacy, n (%)

Reported

p value My calcs*

Study 1

Microbiologic

Efficacy 15/23 (65.2) 7/9 (77.8) NS 0.68Study 2

Microbiologic

Efficacy 12/19 (63.2) 10/23 (43.5) NS 0.2Combination

from Above

(Microbiologic

Efficacy) 27/42 (64.3) 17/32 (53.1) 0.33Study 3

(Clinical

Efficacy) 36/61 (59) 22/62 (35.5) 0.009 0.009

Quick Summary of Pre‐2012…other observational studies support and refute

Linezolid vs. Vancomycin The long anticipated RCT

• Study took 5.5 yr; 1,255 patients randomized to find 448 patients with MRSA infections

• After exclusions, which ranged between 20‐25% of the patients, 172 linezolid patients were compared to 176 vancomycin patients (Per Protocol analysis)

• Arguments about the baseline differences between the groups will be endless… but they were reasonably well matched.

• Most surrogate endpoints (e.g. clinical cure, microbiologic eradication) favored linezolid at pre‐planned analysis times (e.g. end of study, end of therapy)

• Kaplan‐Meier mortality curves were super‐imposable (see supplementary materials online) and not different at 60 days… raising the question of the validity of the surrogate endpoints

Wunderink R et al. Clin Infect Dis. 2012; 54(5):621-9.

http://clinicaltrials.gov/ct2/show/NCT00084266?term=linezolid+vancomycin&rank=9 (accessed 2012 April 18).

Question 7:If vancomycin therapy is initiated, which of the following strategies for serum concentration monitoring is guideline‐supported to improve efficacy?

A. Obtain a peak concentration after the first dose to ensure adequate exposure

B. Obtain a serum trough concentration immediately before the second dose

C. Obtain a trough concentration immediately before the fifth dose at steady state.

D. Obtain a minimum of 3 randomly timed concentrations at steady state to calculate the area under the concentration curve


17

Variable Recommendation Level of Evidence and

Grade of Recommendation

Recommended TDM ParametersOptimal monitoring parameter

Trough serum vancomycin concentrations are the most accurate and practical method for monitoring efficacy.

IIB

Timing of monitoring Troughs should be obtained just prior to the next dose at steady‐state conditions (just before the fifth dose).

IIB

Optimal trough concentration(see also Optimal troughconcentration—complicatedinfections)

Minimum serum vancomycin trough concentrations should always be maintained above 10 mg/L to avoid development of resistance. For a pathogen with an MIC of 1 mg/L, the minimum trough concentration would have to be at least 15 mg/L to generate the target AUC:MIC of 400.

IIIB

Rybak M, Lomaestro B, Rotschaffer J et al. Am J Health-Syst Pharm. 2009; 66:82-98.

?

Can there really be any ID pharmacy talk without a vanco monitoring slide?

Vancomycin Guidelines, continue

Variable RecommendationLevel of Evidence and

Grade of Recommendation

Optimal trough concentration—complicated infections (bacteremia,endocarditis, osteomyelitis, meningitis, and hospital‐acquired pneumonia caused by Staphylococcus aureus)

Vancomycin serum trough concentrations of 15–20 mg/L are recommended to improve penetration, increase the probability of obtaining optimal target serum concentrations, and improve clinical outcomes.

IIIB

Criteria for monitoring Trough monitoring is recommended for patients receiving aggressive dosing (i.e., to achieve sustained trough levels of 15–20 mg/L) and all patients at high risk of nephrotoxicity (e.g., patients receiving concurrent nephrotoxins).

Monitoring is also recommended for patients with unstable (i.e., deteriorating or significantly improving) renal function and those receiving prolonged courses of therapy (more than three to five days).

IIIB

IIB

Rybak M, Lomaestro B, Rotschaffer J et al. Am J Health-Syst Pharm. 2009; 66:82-98.

Question 8

It is now two days later, and AB is now hemodynamically stable in the MICU. Only norepinepherine remains for vasopressor therapy, and it is being infused at a rate of 5 mcg/minute. The culture and susceptibility results return for the blood culture and BAL.

The following is reported to you:

Question 8, cont.

http://phil.cdc.gov/phil/details.asp , CDC/ Matthew J. Arduino, DRPH.

BLOOD CULTURE: STAPHYLOCOCCUS AUREUS GROWTH AT 48 HOURS Susceptibility Results

Tested Interpretation MIC Result (mg/L)

CLINDAMYCIN Susceptible <=0.25

ERYTHROMYCIN Susceptible <=0.25

OXACILLIN Susceptible 0.5

GENTAMICIN Susceptible <=0.5

RIFAMPIN Susceptible <=0.5

TETRACYCLINE Susceptible <=1

TRIMETHOPRIM/SULFAMETHOXAZOLE

Susceptible <=.5/9.5

VANCOMYCIN Susceptible 1

Tested InterpretationMIC Result(mg/L)

CLINDAMYCIN Susceptible <=0.25 ERYTHROMYCIN Susceptible <=0.25OXACILLIN Susceptible <=0.5GENTAMICIN Susceptible <=0.5 LINEZOLID Susceptible 2 RIFAMPIN Susceptible <=0.5 TETRACYCLINE Susceptible <=1

TRIMETHOPRIM/SULFAMETHOXAZOLE Susceptible <=.5/9.5

VANCOMYCIN Susceptible 1

RESPIRATORY CULT/GRAM ST: STAPHYLOCOCCUS AUREUS: 90,000 COL/ML

http://phil.cdc.gov/phil/details.asp , CDC/ Matthew J. Arduino, DRPH

Question 8: cont.Given the above susceptibilities, which of the following would be most appropriate for AB?

A. Vancomycin 1.5 g intravenously every 24 hours

B. Linezolid 600 mg every 24 hours

C. Ceftaroline 600 mg intravenously every 12 hours

D. Oxacillin 2 g intravenously every 6 hours

The Options

• Vancomycin is inferior to anti‐staphylococcal penicillins for treatment of MSSA.1

• Ceftaroline has been studied in limited fashion for MSSA pneumonia– MSSA subset analyses from clinical trials are insufficient to

recommend use

– Focus I : Ceftaroline clinical cure 8/10 (80%) vs. ceftriaxone clinical cure 9/13 (69%) 3, p=0.66 (my calcs)

– Focus II: Ceftaroline clinical cure 10/15 (67%) vs. ceftriaxone clinical cure 8/15 (53%) 4, p=0.46 (my calcs)

1. Kim S, Kim K, Kim H et al. Antimicrob Agents Chemother. 2008; 52:192-7.

2. File T, Low D, Eckburg P et al. J Antimicrob Chemother. 2011; 66 Suppl 3:iii19-32.

3. Low D, File T, Eckburg P et al. J Antimicrob Chemother. 2011; 66 Suppl 3:iii33-44.


18

Copyright © American College of Chest Physicians. All rights reserved. Date of download: 3/28/2013

From: Linezolid vs Glycopeptide Antibiotics for the Treatment of Suspected Methicillin-Resistant Staphylococcus aureus Nosocomial Pneumonia: A Meta-analysis of Randomized Controlled Trials

A, Forest plot for clinical success in subjects with culture-positive MRSA pneumonia. B, Forest plot for clinical success in subjects without culture-positive MRSA pneumonia. aAlso includes the data from Rubinstein et al 2001. MRSA = methicillin-resistant Staphylococcus aureus.

Figure Legend:

Walkey AJ et al. Chest. 2011; 139(5):1148-55.

Question 9:Which of the following total durations of therapy would be most appropriate for AB if she has a favorable response to treatment?

A. Total of 3‐5 days

B. Total of 7‐21 days

C. Total of 21‐28 days

D. Total of 42‐56 days

Duration… one of the toughest questions to answer

• I am not aware of a RCT that compares treatment duration for HCAP MSSA pneumonia… nor will one likely be conducted for a while.

– A large trial randomizing 633 VAP patients to 8 vs. 15 days of treatment has been performed.1

—MSSA equally represented in the 8‐day and 15‐day groups 13.6% vs. 11.7% of total, respectively

—Death from all causes did not differ significantly

– For all patients, 37/197 (19%) vs. 35/204 (17%), respectively

– For MRSA patients, 6/21 (29%) vs. 5/21 (24%), respectively

– For “other bacteria” patients, 16/112 (14%) vs. 11/120 (9%), respectively

– MRSA guidelines suggest therapy durations of 7‐21 days.2

1. Chastre J, Wolff M, Fagon J et al. JAMA. 2003. 19; 290:2588-98.

2. Liu C, Bayer A, Cosgrove S et al. Clin Infect Dis. 2011; 52:e18-55.

Question 10:After AB stabilizes, which of the following would be the most appropriate blood glucose target to balance safety and efficacy?

A. <110 mg/dL

B. <140 mg/dL

C. <180 mg/dL

D. <250 mg/dL

Conflicting Data

• Several randomized trials have assessed the target bloodsugars

• The initial study found benefits from highly restrictive protocols (i.e. goal=~80‐110 mg/dL) in terms of mortality and decreased LOS when performed in a research setting althoughincreased toxicity has become apparent in clinical settings (1A)– Clinical applicability is questionable especially given that severe hypoglycemia

is a concern

– Several recent trials stopped early for unacceptable adverse event rates

• Thus, expert opinion in the guidelines recommends targeting <180 mg/dL instead of <110 mg/dL


The NICE‐SUGAR Study Investigators. Intensive versus Conventional Glucose Control in Critically Ill Patients

– n=3054 intensive control and n=3050 to conventional control

The NICE-SUGAR Study Investigators. Intensive versus Conventional Glucose Control in Critically Ill Patients. N Engl J Med 2009; 360:1283-97.

0

5

10

15

20

25

30

28 day mortality 90 day mortality Severe hypoglycemia

Percentage of Patients

Target 81‐108mg/dL

Target </=180

*p=0.02, OR= 1.14 (95%CI 1.02 to 1.28)

*p<0.001, OR= 14.7 (95%CI 9.0 to 25.9)

The Study that led to 1A recommendations

Enlarged slide at back of handout.

______________________________________________________________________________________________©2015 American Society of Health-System Pharmacists, Inc. All rights reserved.

19

Question 11:AB is diagnosed with a type‐1 mediated allergy to cephalosporin agents by the allergy service. Which of the following treatments for the MSSA infection would be best for AB given her development of renal failure and her newly diagnosed beta‐lactam allergy.

A. Oxacillin; there is insignificant cross reactivity between cephalosporins and penicillins

B. Vancomycin; mortality data favor vancomycin for treatment of MSSA

C. Linezolid; several trials found reduced rates of nephrotoxicity with linezolid when compared with vancomycin

D. Daptomycin; daptomycin is the drug of choice in patients with bloodstream infections in whom vancomycin is not an option

The Choices

• Oxacillin should not be given to patients experiencing hives to cephalosporins, cross reactivity going this way is ~25%1

• Vancomycin is inferior to anti‐staphylococcal penicillins for treatment of MSSA.2 Less is known re: comparing vancomycin to linezolid.

• Daptomycin is inactivated by surfactant.3

• Several studies are now focusing on vancomycin nephrotoxicity with higher trough goals.

1. Romano A, Gaeta F, Valluzzi RL et al. J Allergy Clin Immunol. 2010 Nov; 126(5):994-9.

2. Kim S, Kim K, Kim H et al. Antimicrob Agents Chemother. 2008 January; 52(1): 192-7.

3. Silverman J, Mortin L, Vanpraagh A et al. J Infect Dis. 2005 Jun 15; 191(12):2149-52.

Vancomycin Nephrotoxicity

Bosch K, McLaughlin M, Esterly JS et al. International Journal of Antimicrobial Agents. 2014; (43):297-9.

Risk‐adjusted (controlled for contrast use and sex) probability of serum creatinine (SCr) increase of 0.5 mg/dL stratified by drug category. P = 0.02 for vancomycin 2 g versus linezolid and vancomycin 1 g categories.

Graph generated by M. Scheetz

Study Data (purple=prospective, blue=retrospective)

0%

5%

10%

15%

20%

25%

30%

35%

40%

Trough<15mg/L Trough 15‐20mg/L Trough>20mg/L

18%22%

37%

16%13%

27%

Wunderink R et al. Clinical Infectious Diseases 2012; 54(5):62-9.

Kullar R, Davis S, Levine D et al. Clin Infect Dis. 2011 Apr 15; 52(8):975-81.

Wunderink R et al. Clinical Infectious Diseases 2012; 54(5):621-9.

Kullar R, Davis S, Levine D et al. Clin Infect Dis. 2011 Apr 15; 52(8):975-81.

Vancomycin Renal Toxicity by Trough

Question 12:Due to her acute renal failure and hemodynamic instability, AB is initiated on continuous veno‐venous hemofiltration (CVVH) at an ultrafiltration rate of 4 liters per hour. Which of the following antimicrobial regimens is appropriate for AB given this rate of extracorporeal clearance?

A. Vancomycin 1.5 g intravenously given every 24 hrs

B. Linezolid 600 mg intravenously given every 72 hrs

C. Ceftazidime 1 g given every 48 hrs

D. Moxifloxacin 400 mg given every 72 hrs

CVVH can mimic normal physiology for renal drug clearance

Hemofiltration

or Hemodialysis

Blood

(Amount cleared by filter based on flow rate and filter pore size)

drug

Proteindrug

Proteindrug

Protein

drug Protein

drug

drug

drug

Clearance= ultrafiltrate flow rate * efficiency


20

Calculating Drug Doses and Schedules

• One can approximate CVVH doses

– …if the renal portion of drug clearance is explained by freely filtered GFR elimination (i.e., no secretion or reabsorption)

• Every 1L/hr=16.7 mL/min ~~renal clearance

• e.g., (4L/hr) x (1 hr/60 min) x (1000mL/L)= 66.7 mL/min equivalent renal clearance


21

Copyright © American College of Chest Physicians. All rights reserved. Date of download: 3/28/2013

From: Linezolid vs Glycopeptide Antibiotics for the Treatment of Suspected Methicillin-Resistant Staphylococcus aureus Nosocomial Pneumonia: A Meta-analysis of Randomized Controlled Trials

A, Forest plot for clinical success in subjects with culture-positive MRSA pneumonia. B, Forest plot for clinical success in subjects without culture-positive MRSA pneumonia. aAlso includes the data from Rubinstein et al 2001. MRSA = methicillin-resistant Staphylococcus aureus.

Figure Legend:

Walkey AJ et al. Chest. 2011; 139(5):1148-55.


22