FEVER IN THE ICU Infectious Diseases in Clinical Practice February - - PDF document

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FEVER IN THE ICU

Infectious Diseases in Clinical Practice February 2015 Jennifer Babik, MD, PhD Division of Infectious Diseases University of California, San Francisco

Disclosures

• None

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Outline

• 1. Approach to the DDx of fever in the ICU
• 2. Clinical presentation, diagnosis, and

management of common ICU infections

• Catheter-related bloodstream infection
• Catheter-associated UTI
• Ventilator-associated PNA
• Clostridium difficile
• 3. Common non-infectious causes of fever

Fever in the ICU: Epidemiology

• Fever occurs in 26-70% of patients
• Infectious vs non-infectious?
• 35-55% are thought to be infectious
• So, at least 50% of febrile episodes are non-infectious!
• Etiologies depended on type of ICU (MICU vs SICU vs NICU)
• Most common infections: PNA, bloodstream, abdominal infections
• Most common non-infectious etiologies: post-op fever, central fever

Niven et al, J Intensive Care Med 2012, 27:290.

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Framework for Building the DDx

1.

Is this a complication of the underlying reason for admission?

• Untreated, relapsed, or metastatic focus of infection
• Post-surgical infection (surgical site infection, intra-abdominal abscess)

2.

Is this a separate nosocomial process?

• Hospital-acquired PNA (VAP, aspiration)
• CA-UTI
• Catheter-Related Bloodstream Infection (CRBSI)
• Clostridium difficile

3.

Is this non-infectious?

• Drug fever
• Central fever

DDx: Head-to-Toe Approach

• Nosocomial meningitis

(post-NSG) CNS

• Nosocomial Sinusitis
• Hospital-acquired URI

HEENT

• Hospital-acquired PNA
• Empyema
• ARDS

Pulmonary

• Endocarditis
• Pericarditis

Cardiac

• C. Difficile
• CA-UTI
• Abdominal abscess
• Peritonitis
• Acalculous cholecystitis
• Pancreatitis

GI/GU

• Osteomyelitis
• Septic arthritis
• Gout

MSK

• Cellulitis at line sites
• Infected decub ulcer
• Surgical site infection

Skin

• CRBSI
• Candidemia

Bloodstream

• Drug Fever
• Central fever
• DVT/PE
• Malignancy
• Rheumatologic
• Post-op fever
• Transfusion reaction
• Transplant rejection
• Adrenal insufficiency

Other non- infectious etiologies

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Bedside Evaluation

Questions to Ask

• Any change in secretions or

respiratory status?

• Any diarrhea?

Exam Elements to Include

• Careful neuro exam
• Sinus exam for nasal

discharge or tenderness

• Back and joint exam
• Skin exam:
• Line sites
• Decubitus ulcers
• Rashes
• Remove bandages

Case #1

A 55 year old man with CHF and ESRD on HD is admitted to the ICU with decompensated heart failure. He is slowly improving but then spikes a fever to 39 associated with rigors but no other symptoms. He is found to be bacteremic with Klebsiella pneumoniae from both hemodialysis line and peripheral blood cultures.

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Do You Need to Change the Line?

1.

Yes

2.

No

3.

I need more information

What Information Would Be Most Helpful?

1.

Abdominal CT scan

2.

Talk to micro and get the differential time to positivity

3.

Examine the line exit site for inflammation

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For Uncomplicated Klebsiella HD-line Infection, IDSA Recommends:

1.

Line removal

2.

Option for line retention or guidewire exchange

CRBSI: Diagnosis

Mermel et al, Clin Infect Dis 2009, 49:1. Safdar and Maki, Crit Care Med 2002, 30:2632. Liñares, Clin Infect Dis 2007, 44:827. Bouza et al, Clin Infect Dis 2007, 44:820. Bouza et al, Clin Microbiol Infect 2013, 19: E129. Safdar et al, Ann Intern Med 2005, 142:251.

Techni hnique Cha haracteristics Clinical Findings Inflammation at the exit site is extremely insensitive (<3%)

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CRBSI: Diagnosis

Mermel et al, Clin Infect Dis 2009, 49:1. Safdar and Maki, Crit Care Med 2002, 30:2632. Liñares, Clin Infect Dis 2007, 44:827. Bouza et al, Clin Infect Dis 2007, 44:820. Bouza et al, Clin Microbiol Infect 2013, 19: E129. Safdar et al, Ann Intern Med 2005, 142:251.

Techni hnique Cha haracteristics Clinical Findings Inflammation at the exit site is extremely insensitive (<3%) Catheter Tip Culture

• CRBSI = (+) peripheral bcx and > 15 CFU/plate from catheter tip
• 79% sensitive, 92% specific
• But >80% of catheters are removed unnecessarily

CRBSI: Diagnosis

Mermel et al, Clin Infect Dis 2009, 49:1. Safdar and Maki, Crit Care Med 2002, 30:2632. Liñares, Clin Infect Dis 2007, 44:827. Bouza et al, Clin Infect Dis 2007, 44:820. Bouza et al, Clin Microbiol Infect 2013, 19: E129. Safdar et al, Ann Intern Med 2005, 142:251.

Techni hnique Cha haracteristics Clinical Findings Inflammation at the exit site is extremely insensitive (<3%) Catheter Tip Culture

• CRBSI = (+) peripheral bcx and > 15 CFU/plate from catheter tip
• 79% sensitive, 92% specific
• But >80% of catheters are removed unnecessarily

Differential Time to Positivity

• CRBSI = central line bcx turns (+) ≥ 2 hrs before peripheral bcx
• 85-95% sensitive, 83-90% specific
• Allows for diagnosis without removing the line

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CRBSI: Diagnosis

Mermel et al, Clin Infect Dis 2009, 49:1. Safdar and Maki, Crit Care Med 2002, 30:2632. Liñares, Clin Infect Dis 2007, 44:827. Bouza et al, Clin Infect Dis 2007, 44:820. Bouza et al, Clin Microbiol Infect 2013, 19: E129. Safdar et al, Ann Intern Med 2005, 142:251.

Techni hnique Cha haracteristics Clinical Findings Inflammation at the exit site is extremely insensitive (<3%) Catheter Tip Culture

• CRBSI = (+) peripheral bcx and > 15 CFU/plate from catheter tip
• 79% sensitive, 92% specific
• But >80% of catheters are removed unnecessarily

Differential Time to Positivity

• CRBSI = central line bcx turns (+) ≥ 2 hrs before peripheral bcx
• 85-95% sensitive, 83-90% specific
• Allows for diagnosis without removing the line

Quantitative Blood Cultures

• CRBSI = cfu from central line bcx is ≥ 3x cfu from peripheral bcx
• Most sensitive and specific but not routinely available

DTTP: Possible Scenarios

Line (+) and peripheral (+)

DTTP ≥ 2 hrs CRBSI DTTP < 2 hrs Look for another source

Line (+) and peripheral (−)

Possibili1es ¡

• Contaminant ¡
• Line ¡coloniza1on ¡ ¡
• Bacteremia ¡from ¡other ¡source ¡

with ¡1/2 ¡posi1ve ¡cultures ¡

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What about for Candida?

• DTTP cut-off of 2 hours is 85% sensitive, 82% specific
• The special case of C. glabrata:
• It is the most slow growing Candida with median TTP of 37h (other

species 17-29h)

• Using 2hr cut-off DTTP: sensitivity 77%, specificity 50%
• Optimal DTTP cut-off was 6 hours à sensitivity 63%, specificity 75%

Park et al, J Clin Microbiol 2014, 52:2566.

When to Remove the Line

• Severe sepsis
• Persistent bacteremia (>72h
• f appropriate ABx)
• Septic thrombophlebitis
• Exit site or tunnel infection/

abscess

• Evidence of metastatic

infection: endocarditis,

• steomyelitis
• Virulent organisms
• Staphylococcus aureus
• Pseudomonas
• Candida
• Difficult to eradicate (must r/o

contamination)

• Micrococcus
• Bacillus
• Propionobacteria

Mermel et al, Clin Infect Dis 2009, 49:1

Certain Organisms Complicated Infections

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Line Management for Other Organisms

Organism PICC/Short-term CVC Tunneled Cath/Port HD Catheter Coag-negative staphylococci Remove or retain Remove or retain Retain or guidewire exchange Enterococcus Remove Remove or retain Retain or guidewire exchange* Other GNRs (not Pseudomonas) Remove Remove or retain Retain or guidewire exchange*

Mermel et al, Clin Infect Dis 2009, 49:1

*Assuming uncomplicated infections. Consider removal on a case-by-case basis.

Line Salvage

• General principles
• Studied primarily in long-term catheters
• Treat with antibiotic lock therapy PLUS systemic antibiotics for 7-14 days
• Get surveillance blood cultures 1 week after stopping ABx
• Antibiotic Lock Therapy
• Goal is to fill the catheter with supra-therapeutic ABx concentrations to

kill intra-luminal bacteria and penetrate biofilms

• Success rate for line salvage is ~75% (depends on organism)
• Cannot use if signs of exit site/tunnel infection (extra-luminal infection)
• Give systemic ABx through the line?
• Good in theory but no data
• It is recommended in IDSA guidelines if ABx lock is not an option

Mermel et al, Clin Infect Dis 2009, 49:1

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Line Management: Take-Home Points

• Differential time to positivity (line positive ≥ 2 hours before

peripheral) allows for diagnosis of CRBSI without line removal

• All lines should be removed for:
• Any complicated infection
• Staph aureus, Pseudomonas, or Candida
• Difficult to eradicate organisms
• Line management for other organisms depends on line type

(lower barrier to remove line for short term catheter > long- term catheter > HD catheter) A 65 y/o M is admitted with a stroke. 4 days into his hospitalization he spikes a fever to 39, starts coughing, drops his SaO2 to the low 90s on RA, and becomes altered. He is pan-cultured and started on vancomycin and pip/tazo. He improves, and work-up reveals:

• CXR with a new LLL infiltrate
• Blood cultures and sputum culture negative at 48h
• UA (from his catheter) shows 30 WBC, Urine cx >100K VRE

Case #2

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What Would You Do with His Vanco?

• 1. Stop vancomycin
• 2. Change vancomycin to linezolid
• 3. Change vancomycin to daptomycin
• Asymptomatic Bacteriuria (ASB) =
• Isolation of bacteria from a urine sample (see criteria below) AND
• No symptoms or signs related to UTI
• Criteria for ASB:

Asymptomatic Bacteriuria

Nicolle et al, Clin Infect Dis 2005, 40:643.

Wome men Me Men Cathe heterized p patient nts (me men o n or w wome men) n) ≥105 bacteria on 2 separate voided specimens ≥105 bacteria form a single voided specimen ≥102 bacteria from a single specimen

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ASB is Common

Pregnant Women 2-10% Post-menopausal Women 3-9% Diabetic patients 9-27% Elderly patients 4-19% Long term care patients 15-50% Spinal cord patients 23-89% HD patients 28% Short term catheter (<30d) 9-23% Long term catheter (>30d) 100%

Nicolle et al, Clin Infect Dis 2005, 40:643.

Bacteriuria in the Hospital is Usually ASB

In hospitalized patients with a positive urine culture (with or without a catheter)

Leis et al, Clin Infect Dis 2014, 58:980.

~90% of cultures are ASB

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• Why not to treat?
• Treatment does not ê the risk of symptomatic UTI or later ASB
• Overtreatment is associated with adverse effects and development of

resistant organisms

• This has been studied by RCT in many different populations

ASB Usually Does Not Require Treatment

Nicolle et al, Clin Infect Dis 2005, 40:643.

• Pregnant women
• ê risk of pyelo, premature delivery, low weight infants
• Patients undergoing GU procedures with mucosal bleeding
• ê rate of post-procedure bacteremia and sepsis
• Immunosuppressed/transplant patients?
• Little data, not addressed in most guidelines
• Many treat ASB in renal transplant patients in the first 3 months
• We also treat in neutropenic pts b/c of the risk of invasive disease

Exceptions: Who With ASB Should Be Treated?

Nicolle et al, Clin Infect Dis 2005, 40:643.

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The Heart of the Problem

• It’s Hard to Ignore a Positive Culture
• Proof of concept study:
• At Mount Sinai, ~90% of their inpatient urine cultures (after admission)

were considered ASB, and almost 50% were treated with ABx

• They stopped reporting the positive urine cultures on these patients

(non-catheterized subgroup)

• The percentage of ASB that was treated dropped from 48% to 12%
• There were no untreated UTIs and no patients developed sepsis

Leis et al, Clin Infect Dis 2014, 58:980.

The Million Dollar Question

How do I distinguish between ASB and UTI?

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Does the UA Help?

• Pyuria is very common in patients with ASB
• 30-75% of pts with short-term indwelling catheters (<30d)
• 50-100% of pts with long-term indwelling catheters (>30d)
• PPV only 32-36% for catheterized patients!
• The absence of pyuria suggests an alternative diagnosis
• Bottom line: YES, if it is negative
• The presence of pyuria is not helpful
• But the absence of pyuria suggests an alternative diagnosis

Nicolle et al, Clin Infect Dis 2005, 40:643. Tambyah et al, Arch Intern Med 2000, 160:678.

• Microbiology of ASB:
• GNRs:
• E. coli (most common organism isolated from women wth ASB)
• Klebsiella
• Indwelling devices: Proteus, Pseudomonas, Providencia, Morganella
• GPCs:
• Enterococcus (55% ASB, 45% UTI)
• Group B Strep
• Coag negative Staph
• Bottom line: NO, the same bugs cause both ASB and UTI

Does the Organism Help?

Nicolle et al, Clin Infect Dis 2005, 40:643. Lin et al, Arch Int Med 2012, 172:33.

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What if I Can’t Assess Symptoms?

• 2 main scenarios where is it difficult to determine if “classic” UTI

symptoms are present:

1.

The patient has a catheter (CA-UTI)

2.

The patient is altered or otherwise unable to communicate

Nicolle et al, Clin Infect Dis 2005, 40:643.

What if I Can’t Assess Symptoms?

How to define UTI in these patients (CA-UTI, AMS)?

Nicolle et al, Clin Infect Dis 2005, 40:643.

(1) Symptoms or signs c/w UTI

• New or worsening fever, rigors, AMS,

malaise and no other clear cause

• Flank pain, CVAT, pelvic discomfort
• Acute hematuria
• Spinal cord injury: ñspasticity,

autonomic dysreflexia, sense of unease

(2) No other source of infection (i.e.,

diagnosis of exclusion)

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Alternate Diagnosis Likely? (Signs/ sx of other illness present) Yes Do not order U/A, urine cx No Send U/A, urine cx U/A, urine cx (-) Do not treat for UTI U/A (-), urine cx (+) Asymptomatic bacteriuria U/A (+), urine cx (+) Treat for UTI (If no alternate dx identified)

Slide courtesy of Catherine Liu.

U/A (+), urine cx (-)

How to Interpret Urine Studies in a Patient Who is Altered or Has a Catheter

Do not treat for UTI

• Antibiotics
• Empiric choices: Ceftriaxone, ertapenem, pip/tazo
• Duration:
• 7 days if there is prompt resolution of symptoms
• 10-14 days if response is delayed
• Catheter change?
• Yes, if the catheter has been in for >2 weeks, change it
• This has been associated with:
• ê CA-UTI at 28d
• ê time to resolution of sx

CA-UTI: Treatment

Hooton et al, Clin Infect Dis 2010, 50:625.

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• Candiduria is very common in patients with catheters
• Candiduria is usually asymptomatic
• In general, don’t treat!
• Change the foley: can eliminate candiduria in 20-40%
• Exceptions: Same as for ASB
• Pregnancy
• Patients undergoing urologic procedures
• Neutropenia, Renal transplant <3 mo
• Symptomatic candiduria (uncommon)
• Look for same symptoms as bacterial UTI
• Treat

Candiduria: Who Needs Treatment?

Pappas et al, Clin Infect Dis 2009, 48:503.

• Fluconazole is the drug of choice
• Excellent urine levels
• 10-fold higher than in serum
• Can get concentrations in the urine that are higher than the MIC for
• rganisms that are intermediate or resistant (like C glabrata)

Candida UTI: Treatment Options

Fisher et al, Clin Infect Dis 2011, 52:S457.

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• Try fluconazole and re-check Ucx (if not systemically ill)
• Other options all have poor efficacy or side effect profile:
• Flucytosine, conventional amphotericin B, ampho bladder washes
• Other azoles? à Vori, posa, itra have poor urinary penetration
• Echinocandins? à Poor urinary penetration, but can use if

suspect systemic disease

Fluconazole-Resistant Candida UTI

Fisher et al, Clin Infect Dis 2011, 52:S457.

ASB vs. UTI: Take-Home Points

• Pyuria ≠ UTI, but the absence of pyuria points to an alternative source
• ASB and asymptomatic candiduria do not require Rx except for:
• Pregnancy
• Urologic procedures
• Neutropenia, renal transplant <3 mo
• UTI diagnosis in a patient with a catheter or who cannot report sx requires:
• Signs and symptoms compatible with UTI
• No other source for infection (i.e., diagnosis of exclusion)
• CA-UTI can be treated with 7 days of antibiotics if symptoms resolve quickly
• Fluconazole is the drug of choice for C. albicans (and often non-albicans)

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Case #3

85 y/o man is admitted with fever and respiratory failure to the ICU and treated with vanc/pip-tazo. He initially responds but then 5 days into therapy he began spiking high fevers up to 39˚C daily. His respiratory status is unchanged. He is escalated to vanc/meropenem with no change in his fever or respiratory status after another 5 days. Extensive work-up for

• ther sources of infection is negative.

What is Your Next Step?

• 1. Change vanco to linezolid
• 2. Add tobramycin
• 3. Stop antibiotics

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Drug Fever

• 3-4 % of all drug reactions
• Multiple mechanisms:
• Altered Thermoregulatory Mechanisms (eg amphetamine)
• Drug Administration (eg amphotericin)
• Pharmacologic Effects (eg Jarisch-Herxheimer Reaction)
• Idiosyncratic Reactions (eg malignant hyperthermia)
• Immune-Mediated/Hypersensitivity Reactions (eg most ABx)

Drugs Associated with Drug Fever

Patel, et al. Pharmacotherapy 2010; 30(1):57-69.

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Clinical

• May appear well and be unaware of fevers (but not

necessarily)

• No typical fever pattern
• Pulse-temperature dissociation (11%)
• Expected pulse = [(last digit in F -1 ) x 10] +100
• Rash (5-10%)
• Eosinophilia (~20%)
• Labor. Drug Intell Clin Pharm 1986; 20:413-20. Mackowiak, Ann Int Med 1987; 106:728-33.

Mackowiak, et al. Ann Int Med 1987; 106:728-33. Foster, et al. Med Clin North Am 1966;42:523-39

Class of Offending Agent Episodes Lag Time Mean Median SD N

• -------------------Days--------------------

Cardiac 36 44.7 10 131.1 Antimicrobial 44 7.8 6 8.4 Antineoplastic 11 6 0.5 12.3 CNS 24 18.5 16 15.4 Other 20 18.8 7 34.1

• But with re-challenge, fever can occur within hours

Timeline of Fever Onset

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Fever Characteristics

• Fever is high
• Usually defervesce within

1-2 days of stopping drug

Mackowiak, et al, Ann Intern Med 1987, 106:728.

38.5 39 39.5 40 40.5 41 41.5 0.5 1 1.5 2 Temp (˚C) Days to defervescence

Treatment

• Discontinue all potentially causative meds, together or sequentially
• In cases where benefit > risk in continuing, can try to pre-treat:
• Corticosteroids
• Antihistamines
• But watch for signs/sx of progression of hypersensitivity
• Rechallenge will usually cause recurrence of fever within a few

hours, confirming the diagnosis

• If fever was accompanied by severe adverse effects, avoid rechallenge
• Important to document suspected drug fever in the allergy section with as

much detail of associated symptoms as possible

Patel, et al, Pharmacotherapy 2010, 30:57.

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Cross-Reactivity of Antibiotics?

— Change to another class if possible (i.e. Beta-lactam to

fluoroquinolone)

— No studies exist which address drug fever cross reactivity

specifically – focus is on all symptoms of hypersensitivity

Joint Task Force on Practice Parameters. Ann Allergy Asthma Immunol 1999; 83:665-700.

Drug Fever: Take Home Points

• Always consider it in the ddx for fever in the hospital
• Look for eosinophils, temp-pulse dissociation, rash although

remember these are present in <20% of cases

• Consider stopping the ABx or swtiching classes if you really

suspect it

• Remember to document drug fever as an allergy!

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VTE and Fever

• Seen in 5-15% of

patients presenting with PE/DVT

• Characteristics:
• Usually <38.9
• Peaks on day of PE
• Gradually subsides

within 1 week

10 20 30 Di Distribution o n of F Fever a and nd P PE ( (Pio Piope ped) )

Stein et al, Chest 2000, 117:39. Nucifora et al, Circulation 2007, 115:e173. Barba et al, J Thromb Thrombolysis 2011, 32:288.

# patients

Central Fever

• Accounts for ~50% of fever in the NICU
• Seen in patients with brain tumors, SAH,

intraventricular hemorrhage

• Associated with vasospasm
• Appears within 72 hours of admission,

persists for longer than infectious causes

• f fever
• No difference in height of fever

Hocker et al, JAMA Neurol 2013, 70:1499.

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Can ARDS Itself Cause Fever?

• The fibroproliferative phase of ARDS can

cause fever and leukocytosis that is indistinguishable from infection

• Open lung biopsy in 7/9 patients with late

ARDS and fever à fibroproliferative phase

• f DAD with no evidence of infection
• So…probably, but would look very hard

elsewhere and this is a diagnosis of exclusion

Meduri et al, Chest 1991, 100:943.

Case #4

65 y/o man with HCV cirrhosis is intubated for severe influenza A leading to ARDS. He had been slowly improving but then over the last 2 days has starting having fevers to 38.4 with new production of thick secretions. He has trouble following commands when sedation is lifted. Blood and urine cultures are negative. CXR is unchanged. Head CT shows pansinusitis.

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Your Next Diagnostic Step is:

• 1. Sinus puncture
• 2. Lumbar puncture
• 3. Mini-BAL or endotracheal aspirate

Pneumonia in the ICU

• Hospital-Acquired PNA (HAP) = PNA acquired after 48 hours

in the hospital and not incubating at the time of admission

• Ventilator-Associated PNA (VAP) = PNA acquired after 48

hours of intubation (subset of HAP)

• Microbiology is similar
• GPCs: S. aureus, particularly MRSA
• GNRs: P. aeruginosa, E. coli, Klebsiella pneumoniae, Acinetobacter

IDSA/ATS Guidelines, Am J Resp Crit Care Med 2005.

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VAP: Diagnosis

• Use to prompt testing, empiric Rx
• New or progressive CXR infiltrate

+ 2/3 clinical criteria:

• F > 38˚C
• é or ê WBC
• Purulent secretions
• 69% sensitive, 75% specific
• ARDS: consider PNA with ≥ 1

clinical criteria b/c may not see CXR change

• Obtain lower respiratory tract

culture before ABx

• Quantitative cultures preferred
• BAL and mini-BAL both are ~80%

sensitive and specific

• Endotracheal aspirate (quantitative)

~75% sensitive and specific

• Blood cultures positive in <25%
• Thoracentesis if an effusion is

large or the patient is toxic

IDSA/ATS Guidelines, Am J Resp Crit Care Med 2005. Klompas, JAMA 2007, 297:1583.

Microbiologic Diagnosis Clinical Criteria

VAP/HAP: Empiric ABx (IDSA Guidelines)

Options:

• Ceftriaxone
• Fluoroquinolone
• Ertapenem
• Amp/sulbactam

Risk Factors for MDR Pathogens Present?

• HCAP
• HAP/VAP with ≥ 5 days in the hospital
• Immunosuppression
• Abx in last 90 days
• High frequency of ABx resistance in a specific unit

No Yes

Linezolid or Vancomycin + Anti-pseudomonal beta-lactam + Anti-pseudomonal FQ or AG

IDSA/ATS Guidelines, Am J Resp Crit Care Med 2005.

*Use local resistance patterns for guidance

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• RTC of 400 patients with VAP randomized to 8 vs. 15 days of ABx
• 8-day group had:
• No difference in mortality, recurrent infections, length of ICU stay
• More ABx-free days (9 vs 13%)
• Less MDR organisms if had recurrent infections (42 vs 65%)
• But…higher pulmonary reinfection rate (41 vs 25%) if had a glucose

nonfermenter (Pseudomonas, Acinetobacter, or Stenotrophomonas)

• Bottom line:
• Pseudomonas, Acinetobacter, Stenotrophomonas: 14 (or 15) days
• MRSA: 7-21 days depending on extent of infection (IDSA MRSA guidelines)
• 7 (or 8) days for everyone else

Duration of ABx in VAP

Chastre et al, JAMA 2003, 290:2588.

Linezolid vs. Vancomycin for MRSA PNA?

• Historical perspective:
• Post-hoc analysis of RCT subgroups showed that linezolid had é

clinical cure and ê mortality compared to vanc

• Vancomycin was not dose optimized and so ?due to low vanco levels
• Proposed MOA: linezolid could be inhibiting toxin production
• RCT of linezolid (IV) vs vancomcyin in 448 patients with

MRSA HAP/VAP/HCAP

• Vanco dose-optimized by unblinded pharmacist
• Treated for 7-14 days (up to 21 days if bacteremia)
• Primary outcome: Clinical cure

Wunderink et al, Clin Infect Dis 2012; 54: 621.

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Linezolid vs. Vancomycin: Outcomes

57.6%& 15.7%& 46.6%& 17.0%& 0.0%& 10.0%& 20.0%& 30.0%& 40.0%& 50.0%& 60.0%& 70.0%& Clinical&Cure& Mortality& Vancomycin& Linezolid&

p=.042& p=NS&

Wunderink et al, Clin Infect Dis 2012; 54: 621.

Linezolid vs. Vancomycin: Conclusions

• Compared to vancomycin, linezolid has a modest benefit in

clinical response but no effect on mortality

• Limitations:
• Were the vanco patients sicker?
• Compared to linezolid group: ñ ventilation, concurrent MRSA bacteremia,

kidney disease, and diabetes

• Did not evaluate length of ICU stay, length of hospitalization,

mechanical ventilation

Wunderink et al, Clin Infect Dis 2012; 54: 621.

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HAP/VAP: Take Home Points

• Think about risk factors for MDR pathogens and use that to

guide empiric therapy

• Diagnosis is based on a combination of clinical and

microbiologic paramters

• Duration of therapy = 7 (or 8) days with the exception of the

glucose nonfermenters +/- MRSA

• Consider linezolid for MRSA if not responding to vancomycin

Nosocomial Sinusitis

• Epidemiology:
• Radiographic sinusitis in 25-75% of ICU pts
• But etiology of nosocomial fever in ~5%
• Radiographic sinusitis ≠ infectious sinusitis
• Micro: Pseudomonas, S. aureus, can be polymicrobial
• Clinical: classic signs/sx of sinusitis often absent
• Dx: CT, aspirate by ENT to confirm dx and guide ABx therapy
• Treatment duration: 7 days

O’Grady et al, Crit Care Med 2008, 35:1330. George et al, Clin Infect Dis 1998, 27:463. Talmor et al, Clin Infect Dis 1997, 25:1441. Borman et al, JAMA 1992, 164:412. Stein and Kaplan, Curr Opin Infect Dis 2005, 18:147.

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Case #5

A 65 y/o woman is admitted to the ICU for sepsis due to cholangitis with retained stone. She gradually improves after ERCP and pip/tazo. On her 4th day in the ICU she develops a new fever, leukocytosis to 16, and diarrhea. She is found to have C.

• difficile. Creatinine is baseline and blood pressure is stable.

What Would You Start?

• PO metronidazole
• PO vancomycin
• PO vancomycin + IV metronidazole
• Fidaxomicin

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Case #5 continued

She is started on PO vancomycin 125mg qid. Fever and leukocytosis resolve but she has not yet had improvement of her diarrhea after 4 days of treatment.

What Would You Do With Her ABx?

1.

No change

2.

Add IV metronidazole

3.

Switch to fidaxomicin

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IDSA Guidelines for Cdiff Treatment

Mild to moderate

• WBC <15
• Cr <1.5x baseline

Severe

• WBC ≥ 15
• Cr ≥ 1.5x baseline

Severe + Complications

• Hypotension
• Ileus
• Toxic megacolon

Metronidazole 500mg PO tid x 10-14d Vancomycin 125mg PO qid x 10-14d

Vanco 500mg PO qid + Metronidazole 500mg IV q8 +/- Vanco 500mg PR qid (ileus)

Cohen et al, Infect Control Hosp Epi 2010, 31:431.

When Should My Patient Get Better?

Al-Nassir et al, Clin Infect Dis 2008, 47:56. Cornely et al, Lancet Infect Dis 2012, 12:281.

• Resolution of diarrhea takes ~5-7 days (longer for PO metronidazole)
• Symptoms can be prolonged 1-2 days with concomitant ABx
• Failure rate only 5-15% so most will get better eventually

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The Benefit of Adding IV Metronidazole?

• Part of the IDSA guidelines (C-III) for severe, complicated disease
• To ensure drug levels in the colon in the case of ileus (when PO vanc may

not transit to the colon)

• No clinical data for the combination (with or without ileus)
• Anecdotally, some patients get better after addition of IV

metronidazole, but this has not been studied systematically

• Concordance with IDSA guidelines for C difficile results in:
• ê mortality (5% vs 22%)
• ê infection recurrence (14% vs 36%)

Cohen et al, Infect Control Hosp Epi 2010, 31:431. Brown et al, Am J Med 2014, 127:865.

Fidaxomicin

• General points:
• First-in class macrocyclic antibiotic with minimal absorption from GI tract
• Treatment dose: 200mg PO bid x 10 days
• Efficacy:
• Equivalent to vancomycin for cure rate in initial episode (~85-90%) and

may have slight advantage if patient is on concomitant ABx

• Lower recurrence rate than PO vanco (15% vs 25%)
• Issues:
• Not as much experience with fulminant disease
• No data for switching from vanco to fidaxomicin in case of failure
• $$$$ ($2600 for a treatment course vs ~$15 for compounded PO vanc)

Louie et al, NEJM 2011. Cornely et al, Lancet ID 2012. Mullane et al, CID 2011. Cornely et al, CID 2012.

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Rectal Swabs for C. difficile

• C. difficile can occasionally present without diarrhea

(especially very early in disease or with severe disease complicated by ileus)

• Rectal swabs for C. difficile PCR testing:
• Sensitivity 96-100%
• Specificity 100%
• Studies done on patients having diarrhea, so unclear if test

characteristics would be different in patients without diarrhea

Shakir et al, Am J Gastroenterol 2012, 107:1445. Kundrapu et al, Clin Infect Dis 2012, 11:1527.

• C. difficile: Take-Home Points
• The IDSA guidelines recommend PO vancomycin for WBC ≥

15 and Cr ≥ 1.5x baseline

• Resolution of diarrhea takes ~5-7 days (longer for PO

metronidazole and if on concomitant ABx)

• The main benefit of fidaxomicin is in its lower risk of

recurrence (rather than initial treatment efficacy)

• Rectal swabs for C. difficile may be useful in patients

presenting without diarrhea

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Thank you!

• Questions?