clinical year in review 2007: respiratory tract infections

1

Clinical Year In Review 2007: Respiratory Tract Infections

Michael S. Niederman, M.D.

Chairman, Department of Medicine

Winthrop-University Hospital

Mineola, NY

Professor of Medicine

Vice-Chairman, Department of Medicine

SUNY at Stony Brook

2

Community –Acquired Pneumonia Topics

• Epidemiology and Prediction of Outcome– Risk Factors– Prognostic Scoring

• Serum Markers to Predict Outcome• Bacteriologic Considerations

– MRSA– Pneumococcal Resistance

• Therapy– Antibiotic Use and strategies to reduce usage

• Prevention– Pneumococcal Vaccination

3

CAP Topics

• Epidemiology and Prediction of Outcome– Risk Factors– Prognostic Scoring

• Serum Markers to Predict Outcome• Bacteriologic Considerations

– MRSA– Pneumococcal Resistance

• Therapy– Antibiotic Use and strategies to reduce usage

• Prevention– Pneumococcal Vaccination

4

COPD Is NOT a Comorbid Factor in The PSI

• Retrospective, observational study– 744 CAP patients, 215 with

COPD• COPD with higher PSI than non-

COPD (105 vs. 87, p=0.05) ) and more ICU admit (25% vs. 18%,p=0.04)– BUT even after adjusting for

severity of illness, COPD patients had a higher 30 and 90 day mortality (HR= 1.32,1.34)

• More P. aeruginosa with COPD (not bronchiectasis): 5.6% vs. 1.3% (p=0.001)

• Restropo MI, et al. Eur Resp J 2006, in press.

5

A European Comparison of PSI and CURB-65

• Apply both tools to 1100 outpatients and 676 inpatients at 1 hospital

• 30 day mortality for CURB-65 of:1,2,3,4,5: 0%, 1.1%, 7.6%, 21%, 41.9%,60%– 29.2% of admitted patients with

score of 0,1, 2 had comorbid illness• CURB-65 correlated (P<0.05) with:

mortality, need for mechanical ventilation, hospital admission, LOS

• CRB-65 equally effective (without measure of BUN) for mortality, MV, admission.

• CURB-65, CRB-65, PSI all with similar ROC for Mortality

• Capelastegui A, et al. Eur Resp J 2006; 27: 151-157

8

When is the ICU Used in CAP?

• National database in UK of 172 ICU’s with 17,869 CAP cases (5.9% of all ICU admits)

• 59% admitted within first 2 days, 21.5% days 2-7, 19.5% > 7 days.

• 54.6% mechanically ventilated on admission to ICU

• Mortality rate in ICU 34.9%, 49.4% in hospital– 46.3% mortality if admit in first 2

days– 50.4% if admit day 2-7, 57.6% if

after day 7 ( p<0.001)

• Woodhead et al. Critical Care 2006; 10: S1

0

10

20

30

40

50

60

Day0-2

Day2-7

> Day7

% Mortality

p<0.001

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A New Rule for ICU Admission• A study using one derivation cohort

and two validation cohorts found that a rule identifying patients with:– one of two major criteria (arterial

pH < 7.30 or systolic blood pressure < 90 mm Hg )

– OR 2 of 6 minor criteria (confusion, BUN > 30 mg/dL, respiratory rate > 30/minute, multilobar infiltrates, PaO2/FiO2 < 250 mm Hg, and age of at least 80 )

– Up to 92% sensitive with a score of 10 or more for identifying those with severe CAP, and was more accurate than other rules such as the PSI, modified ATS criteria and CURB-65.

– Espana PP, et al. Am J Respir Crit Care Med 2006; 174: 1249-1256.

10

Criteria for Severe CAP: New IDSA/ATS Guidelines

• Thrombocytopenia– Muliticenter study of 822 patients with

severe CAP – 3 categories according to platelet count:

>150x10(9)/L, 51-149x10(9)/L, and < 50x10(9)/L

– ICU mortality rates were 30.8% ,44.1% and 70.7% , respectively (p<0.0001). • Brogly et al: Infection 2007 e pub.

• Hyponatremia– On admit: 28% of 342 CAP patients with

hyponatremia ( < 136 mEq/L). 4.1% < 130 mEq/L.• Hyponatremia on admit with higher

HR, WBC, PSI class– Had increased mortality and

increased length of stay • 10.5% developed in hospital,

unrelated to severity of illness on admit.

• Nair, Niederman, et al: Am J 2007; 27:184-190.

Mandell LA et al. Clin Infect Dis 2007;44 Suppl 2:S27-72

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Combining Data from The PSI and CURB-65: Getting the Best of Both Worlds

• PSI was developed to define LOW RISK patients, and often UNDERESTIMATES need for hospital or ICU– Young, no comorbid illness, clinical variable below a

dichotomous variable cutoff– BUT may also OVERESTIMATE need for expensive

resources by emphasis on age and comorbitity and NOT severity features

• CURB-65 good for avoiding overlooking severe illness, BUT may be limited in elderly and those with comorbidity

• Suggest: Draw from BOTH. Either can define low risk (PSI of I-III, CURB-65 of 0-1). IF use PSI, add vital sign and severity evaluation; if use CURB-65, add assessment of comorbid illness and its stability. Add social factors to both.

• Niederman MS, et al. Eur Resp J 2006;27: 9-11.

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CAP Topics

• Epidemiology and Prediction of Outcome– Risk Factors– Prognostic Scoring

• Serum Markers to Predict Outcome• Bacteriologic Considerations

– MRSA– Pneumococcal Resistance

• Therapy– Antibiotic Use and strategies to reduce usage

• Prevention– Pneumococcal Vaccination

13

Serial PCT To Guide Duration of CAP Therapy

• Prospective, randomized trial of 302 patients with radiographic CAP : PCT guided vs. standard rx

• PCT by commercial assay (Kryptor)• PCT-guided Rx: <0.1 strongly

discouraged, <0.25 discouraged, > 0.25 encouraged, > 0.5 mcg/L strongly encouraged– No PCT data available to

doctors of control patients• Measure PCT on admit, 6-24 hours

(if withheld), day 4,6,8.• PCT with 55% shorter duration rx. • Christ-Crain M, et al: Am J Respir

Crit Care Med 2006; IN PRESS

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CAP Topics

• Epidemiology and Prediction of Outcome– Risk Factors– Prognostic Scoring

• Serum Markers to Predict Outcome• Bacteriologic Considerations

– MRSA– Pneumococcal Resistance

• Therapy– Antibiotic Use and strategies to reduce usage

• Prevention– Pneumococcal Vaccination

16

Clinical Implications of CA-MRSA CAP

• Incidence is unknown• Is a distinct illness

– Severe, necrotizing– USA 300 strain– PVL toxin leads to necrotizing infection

• Optimal therapy uncertain– After influenza or viral illness– ? Use antibiotics that inhibit protein synthesis (add

clindamycin to vancomycin or use linezolid alone) to counteract toxin production

• Micek et al. : Chest 2005; 128:2732

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Clinical Implications of CA-MRSA CAP

• 4 Cases of PVL –producing MRSA: – 3 post –influenza CAP – 1 VAP (post pancreatitis). Nasal

colonization on ICU admit• All with positive respiratory

secretions, 3 with + BC’s– All initially inappropriate Rx, then

vancomycin• 3 failures (2 persistent

bacteremia after 48 h vancomycin)

– RX: 2 linezolid (and rifampin), 1 clindamycin added and all recovered

• Micek et al. : Chest 2005; 128:2732

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Macrolide Resistance in Bacteremic Pneumococcal Infection

• 1696 pneumococcal bacteremias; 3.5% (60) were failures of outpatient macrolide rx (macrolide therapy and BC positive on therapy or w/i 2 days of completion)– 32 clarithromycin, 22 azithromcyin, 3 e-

mycin, 3 mixed macrolides– 60% had pneumonia– 15% mortality for macrolide failures vs. 18%

for all others (NS) – 64% of macrolide failures were resistant

• Failures with susceptible vs. resistant more often: > age 65 (p=0.01), underlying heart disease (p=0.03), nursing home (p=0.008)

• Failure more if MIC =1mg/L vs. < 0.25 mg/L– Failures with both erm and mef

• Limitations: – No denominator of how many successfully

treated without failure– No mortality impact: is it relevant? – Daneman et al. Clin Infect Dis 2006; 65:432-

438 Macrolide resistance more common with macrolide failure than with other drug failure , or no prior therapy

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CAP Topics

• Epidemiology and Prediction of Outcome– Risk Factors– Prognostic Scoring

• Serum Markers to Predict Outcome• Bacteriologic Considerations

– MRSA– Pneumococcal Resistance

• Therapy– Antibiotic Use and strategies to reduce usage

• Prevention– Pneumococcal Vaccination

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CAPRIE: Select Demographics & Co-Morbidities Elderly Hospitalized CAP

Moxifloxacin

(n=195)

% Patients

Levofloxacin

(n=199)

% Patients

Total

(n=394)

%Age

Mean (yr)

(min-max)

77.9

(65-95)

77.4

(65-98)

77.6

(65-98)

Cardiac Disorders

CAD

CHF

SV Arrhythmias

Ischemic Disorders

71.8

37.9

32.8

24.1

21.0

76.4

36.2

36.2

24.6

23.1

74.1

37.2

34.5

24.4

22.0

Diabetes 26.7 31.7 29.2

COPD 63.6 62.3 62.9

Anzueto A et al. Clin Infect Dis. 2006 Jan 1;42(1):73-81. Morganroth J et al. Chest. 2005 Nov;128(5):3398-406..

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Efficacy Population

97.9

90.0

86

88

90

92

94

96

98

100

Moxifloxacin Levofloxacin

*Cli

nic

al r

eso

luti

on

or

imp

rove

men

t (%

Pat

ien

ts)

*

* 95% Confidence Interval = (1.7%, 14.1%)

n=141 n=140

CAPRIE: Efficacy Recovery on Day 3 - 5 in a 7-14 Day Study Elderly Hospitalized CAP

Anzueto A et al. Clin Infect Dis. 2006 Jan 1;42(1):73-81. Morganroth J et al. Chest. 2005 Nov;128(5):3398-406.

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Oral Quinolone Therapy of Nursing Home Pneumonia

• Cluster-randomized trial of 680 patients > age 65 at 20 nursing homes in Canada with radiographic pneumonia– 10 with usual care, 10 with Clinical pathway

• Clinical pathway: oral rx with levofloxacin 500 mg qD, oxygen saturuation monitor, rehydration, close nursing observation– 247/664 with (+) CXR– Fewer hospitalizations (10% vs. 22%, p= 0.001), fewer hospital days (0.79 vs. 1.74,

p=0.004), similar mortality and functional status• Cost saving of $1016 per resident

• Loeb M, et al. JAMA 2006; 2503-10.

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How Low Can We Go?? Short, short therapy for CAP

• Randomized, double-blind study of 3 vs. 8 days of amoxicillin for mild-moderate CAP in Netherlands hospital

• All with PSI < 110, had to improve with IV amoxicillin by day 3 and then to oral (n=63) or placebo ( n=56) for 5 days.

• All with radiographic CAP. EXCLUDE: pregnant, HIV, asplenia, effective rx > 24 hours, other active infection, HCAP, severe hypoxemia, ICU, empyema, aspiration, atypical CAP, Gram negative or Staph infection

• 46 of 186 could not be randomized, 38 because of failure to improve by day 3

• 41% in both groups PSI III and IV. No PSI V. Both groups comparable at days 10 and 28 for clinical cure, bacteriologic and radiologic success Moussaoui R, et al. BMJ 2006; 332 : 1355

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Topics In New ATS/IDSA Guidelines

• The admission decision• The value of diagnostic testing (blood cultures,

sputum culture, antigen testing)• Risk factors for specific pathogens • Recommended empiric antibiotic therapy• The role of adjunctive and supportive therapies• Quality improvement and performance measures• The value of prevention efforts: smoking cessation,

vaccination – Mandell LA et al. Clin Infect Dis 2007;44 Suppl

2:S27-72

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Community-acquired PneumoniaEmpiric Therapy – ATS/IDSA 2007

Inpatient – general ward

• Respiratory fluoroquinolone (levofloxacin, moxifloxacin)» OR

• β-lactam PLUS macrolide/doxycycline– (preferred agents include: cefotaxime, ceftriaxone, amp/sulbactam;

consider ertapenem in selected patients) – Cefepime, imipenem, meropenem, piperacillin/tazobactam only if

pseudomonal risks present

(For carefully selected patients without risk factors for DRSP or GNR, monotherapy with azithromycin can be considered)

Consider ‘Other pathogens’ based on epidemiology

Mandell LA et al. Clin Infect Dis 2007;44 Suppl 2:S27-72

37

Therapy for Severe CAP: ATS /IDSA 2007 Regimens

• No pseudomonal risk factors–Selected β-lactam (cefotaxime, ceftriaxone, ampicillin/sulbactam)PLUS

•IV macrolideOR•IV quinolone

• Pseudomonal risk factors present

– Selected β-lactam (cefepime,piperacillin/ tazobactam, imipenem, meropenem)PLUSCiprofloxacin or high dose levofloxacin (750 mg)

– Selected β-lactam PLUS aminoglycosidePLUS• IV macrolide OR• IV antipneumococcal quinolone

(levofloxacin 750 mg or moxifloxacin)

Mandell LA et al. Clin Infect Dis 2007;44 Suppl 2:S27-72

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Compliance with SCAP Guideline Therapy Improves Outcomes

• 199 SCAP patients with >24 h intubation

• IDSA compliant therapy in 60%, but 22% got monotherapy

• Non-compliant therapy with longer duration of MV (mean of 3 days)– Omitted all patients who died

(not able to measure mortality impact)

• Shorr AF, et al. Chest 2006; 130:93-100.

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CAP Topics

• Epidemiology and Prediction of Outcome– Risk Factors– Prognostic Scoring

• Serum Markers to Predict Outcome• Bacteriologic Considerations

– MRSA– Pneumococcal Resistance

• Therapy– Antibiotic Use and strategies to reduce usage

• Prevention– Pneumococcal Vaccination

41

Benefits of Prior Pneumococcal Vaccination

• 62,918 hospitalized CAP patients 1999-2003. – 7390 prior vaccination in lifetime

(12%)– 14,585 unvaccinated (23%)– 40,943 with unknown vaccine status

• 7.6% died of all causes. Vaccinated with OR mortality of 0.29 vs. non-vaccinated and 0.56 vs. unknown status

• Benefit of vaccine applied to all PORT scores (ex Class I)

• Vaccination reduced risk of : respiratory failure, ARDS, tracheostomy, renal failure, sepsis, cardiac arrest

• Vaccination reduced LOS (5.5 vs. 6.5 days, p<0.001)

• Fisman DN , et al. Clin Infect Dis 2006; 42: 1093-1101.

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Nosocomial Pneumonia Topics

• Pathogenesis/Prognosis

• Epidemiology and Risk Factors

• Diagnosis

• Bacteriology

• Therapy

• Prevention

43

Nosocomial Pneumonia Topics

• Pathogenesis/Prognosis

• Epidemiology and Risk Factors

• Diagnosis

• Bacteriology

• Therapy

• Prevention

47

Serial CRP in VAP: Prognosis after Diagnosis and Patterns of Resolution

• Daily CRP, Temp, WBC in 47 microbiologically confirmed VAP while on rx.

• Fast and slow patterns with no mortality. 75% mortality with non-response, 78% mortality with bi-phasic.

• Day 0=day of dx. Ratio is level compared to Day 0.

• If day 4 CRP > 0.6 initial level, prognosis poor.

• Appropriate vs. inapp rx mortality : 18.4% vs. 66.7% (p=0.025). CRP decreased with app rx, not with inapp. (p<0.001)

• Povoa P , et al. Eur Resp J 2005; 25:804-812.

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Nosocomial Pneumonia Topics

• Pathogenesis/Prognosis

• Epidemiology and Risk Factors

• Diagnosis

• Bacteriology

• Therapy

• Prevention

63

Diagnostic Methods and Focused Antibiotic Therapy

• 740 patients, suspected VAP after 4 days ICU

• BAL (quantitative cultures) or EA (non-quantitative cult)– Initial rx with meropenem and

cipro vs. meropenem– Try to exclude if Pseudomonas or

MRSA (14% high risk organisms)

• 74% targeted therapy in both groups (discontinuation or modification based on cultures)– Positive cults:76% EA; 79% BAL– Negative cults:73% EA; 67% BAL

• Heyland et al.: NEJM 2006; 355: 2619-2630.

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Nosocomial Pneumonia Topics

• Pathogenesis/Prognosis

• Epidemiology and Risk Factors

• Diagnosis

• Bacteriology

• Therapy

• Prevention

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De-Escalation: A Multi-center Experience

• 398 VAP patients , 20 sites• De-escalation is EITHER OR BOTH:

fewer drugs, narrower spectrum– Carbapenem>cefepime>

piperacillin/taz, > quinolone– 22.1% de-escalate, 15.3% escalate– 36.3% (highest) de-escalation with

carbapenem– 57 with P. aeruginosa: 13 de-

escalate, 14 escalate– 26.8% vs. 6.5% de-escalate if

identify pathogen – 27.1% vs. 16.6% de-escalate with

app rx ( p=0.01) • Kollef MH, Morrow LE, Niederman MS,

et al. Chest 2006; 129:1210-1218

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De-Escalation: A Multi-center Experience

• Kollef MH, Morrow LE, Niederman MS, et al. Chest 2006; 129:1210-1218

De-escalation Reduces Mortality,Escalation Increases Mortality

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A “Holistic” Approach to MRSA VAP

• Uncontrolled study of 21 patients with nosocomial pneumonia (18 VAP) with MRSA

• 7 days of linezolid + rifampin and aerosol vancomycin and local disinfection

• Culture 2,3,4,7 days after rx and at 2 months

• 16 multilobar pneumonia, 4 bacteremia

• All evaluable patients (14) clinically cured, no MRSA re-colonization or re-infection in next 2 months

• Wenisch C, et al. Infection 2006; 34:148-154

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Nosocomial Pneumonia Topics

• Pathogenesis/Prognosis

• Epidemiology and Risk Factors

• Diagnosis

• Bacteriology

• Therapy

• Prevention

78

Ventilator Bundle to Prevent VAP In A Trauma ICU

• Use of a ventilator bundle alone did NOT decrease VAP until the addition of real-time feedback to the ICU.

• Bundle began in 2002 based on CDC Guidelines

• HOB elevation, PUD prophylaxis, ET tube suction, hand washing, out of bed, oral care, protected suction catheter, new NG irrigant daily, chlorhexidine bath 2x/week, glucose control

• Drop in VAP rate reduced total costs

• Cocanour CS, et al. J Trauma 2006; 61:122-130.

Are all these interventionsnecessary for success??

82

Is Head of Bed Elevation a Feasible and Effective Strategy for VAP Prevention?

• Prospective randomized, multicenter trial of semi-recumbent with target of 45o vs. standard care

• 109 supine, 112 semi-recumbent

• Avg elevation 10 vs. 30 degrees for the two groups, with 85% not achieving target of 45 degrees

• No difference in VAP rates, mortality, duration MV, ICU LOS– 5-7 deviations per day with

semi-recumbent

• May need to re-test with SSD endotracheal tube

• Van Nieuwenhoven CA, et al. Crit Care Med 2006; 34:396-402