diagnosis, treatment and prevention of hospital acquired pneumonia michael zgoda, md asst....

Diagnosis, Treatment and Prevention of Hospital Acquired Pneumonia

Michael Zgoda, MDAsst. Professor, Division of Pulmonary,

Critical Care and Sleep Medicine

Director, Interventional Pulmonology

University of Kentucky, Lexington, KY

A Case Study

Day 1

A 76-year-old white male is sent to the local hospital from a long-term care (LTC) facility for evaluation of a pneumonic process

Past medical history reveals multiple admissions, with a history of diabetes, hypertension, and foot ulcer

The patient was discharged 10 days ago following a cholecystectomy.

The patient is admitted for pneumonia. Necessary blood work, cultures, and labs are performed. Ceftriaxone and azithromycin IV are started.

Chest X-Ray

A Case Study

Day 3

The patient is still febrile and has developed a cough (mucoid). He is uncomfortable and very restless. Staff notes that he is somewhat disoriented to time and place. The patient has no history of dementia

Follow-up information sent from the LTC facility shows that the patient has been on oral dicloxacillin, for previous infections, with poor results

Current laboratory test values denote increased white blood cell count and Gram-positive cocci

Days 5 to 7

The patient’s therapy was reviewed by the attending physician: – Therapy was changed on day 3 by adding levofloxacin– At present the patient is worsening and requires intubation and mechanical

ventilation – Several hours later he continues to spike temperatures at 102 degrees and

becomes hypotensive despite 6 liters of lactated ringers IVF. – Pressors are started and the patient is then transferred to a tertiary care

hospital

A Case Study

A Case Study

Day 7

Culture results from referring hospital reveal:– Species of bacteria; S aureus– Strain of bacteria; MRSA

The patient is treated with appropriate antibiotics upon arrival to tertiary care hospital and the pneumonia resolves. He has a prolonged ICU stay of 28 days at which point the family decides to withdraw care because profound malnutrition and subsequent ICU associated complications from his underlying diabetes including a NSTEMI, pseudomonas sinusitis, and Pseudomembranous colitis with associated diarrhea and a stage 3 sacral ulcer requiring debridement.

Haddadin AS et al. Postgrad Med J. 2002;78:385-392.Diekema DJ et al. Clin Infect Dis. 2001;32(suppl 2):S114-S132. Deresinski S. Clin Infect Dis. 2005;40:562-573.Zetola N et al. Lancet Infect Dis. 2005;5:275-286.

Nosocomial Infections and Resistance

2 million nosocomial infections per year in US hospitals

60% involve antibiotic-resistant bacteria– Staphylococcus aureus is the most common overall bacterial cause of

infection involving bloodstream, respiratory tract, and skin/soft tissue, according to the SENTRY Antimicrobial Surveillance Program

– Strains of S aureus that have acquired resistance to β-lactam antibiotics, most commonly through inheritance of the mecA resistance gene, are known as methicillin-resistant S aureus (MRSA)

– MRSA accounts for 29% to 35% of all clinical isolates of S aureus in US and European hospitals

Estimated excess costs related to antibiotic resistance approach $30 billion per year in US hospitals

The MRSA Story

Infections due to gram-positive cocci, eg, S aureus, particularly MRSA, are:

–Rapidly emerging in the United States

–More common in certain patient populations• Diabetes mellitus

• Head trauma

• Intensive-care unit (ICU)

50% of ICU infections (US) caused by S aureus are MRSA

ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416.

Progression of Methicillin Resistance: S aureus Among Intensive Care Unit (ICU)

Patients

CDC. Available at: http://www.cdc.gov/ncidod/hip/ARESIST/ICU_RESTrend1995-2004.pdf.Accessed August 30, 2005.Lowy FD. J Clin Invest. 2003;111:1265-1273.

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Definitions


Health care-associated pneumonia (HCAP)

– Includes HAP and VAP

– Pneumonia in patients • Hospitalized for 2 days in an

acute care facility within 90 days of infection

• Residing in a nursing home or long-term care (LTC) facility

• Attending a hospital or hemodialysis clinic

• Receiving immunosuppressive therapy or wound care within 30 days of infection

Hospital-acquiredpneumonia (HAP) – Pneumonia occurring

48 hours post-hospital admission

Ventilator-associated pneumonia (VAP)– Pneumonia occurring

48-72 hours post-intubation

How Do Pathogens Find the Patient?


Sources of infections

– Healthcare devices– Environment (air, water, equipment,

fomites)

– Staff-patient/patient-patient transfer of microorganisms

Host- and treatment-related colonization factors

– Severity of underlying disease– Prior surgery

– Exposure to antibiotics– Other medications– Exposure to invasive respiratory

devices and equipment

Routes of bacterial entry into the lower respiratory tract

– Aspiration of oropharyngeal pathogens

– Leakage around endotracheal tube cuff

Embolization of infected biofilm in the endotracheal tube to distal airways may play a role

NNIS. Am J Infect Control. 1999;27:520-532. Fridkin SK et al. Infect Dis Clin North Am. 1997;11:479-496.

Pn

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%)

1718

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54 4

18 18

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S aureus Pseudomonas aeruginosa

Enterobacter spp Klebsiella pneumoniae

Candida albicans

Escherichia coli Haemophilus influenzae

All HAP*

VAP†

*January 1992-May 1999. †1990-1995.

Most Common Isolates: All ICU HAP vs VAP

Risk Factors for Multidrug-Resistant (MDR)Pathogens Causing HAP, HCAP, and VAP


Antimicrobial therapy in preceding 90 days

Current hospitalization of 5 days

High frequency of community or hospital-unit antibiotic resistance

Presence of risk factors for HCAP – Hospitalization for 2 days in preceding 90 days– Residence in a nursing home or LTC facility– Home infusion therapy (including antibiotics)– Chronic dialysis within 30 days– Home wound care– Family member with MDR pathogen

Immunosuppressive disease and/or therapy

HAP, VAP, and HCAP Mortality

Crude mortality rate for HAP may be as high as 30% to 70%

– However, many critically ill patients with HAP do not die of pneumonia, but rather of their underlying disease

Mortality attributable to HAP estimated at 33% to 50%

Increased mortality rates were associated with

– Bacteremia

– P aeruginosa or Acinetobacter spp

– Medical, not surgical, illness

– Ineffective antibiotic therapy

ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416.Heyland DK et al. Am J Respir Crit Care Med. 1999;159:1249-1256.

Improving Outcomes

Prevention

Decreasing resistance

Improving our antibiotic selections

Craven DE et al. Infect Dis Clin North Am. 2004;18:939-962.Singh N et al. Am J Respir Crit Care Med. 2000;162:505-511.Lodise TP et al. Cin Infect Dis. 2003;36:1418-1423.Kollef MH et al. Chest. 1999;115:462-474.

Benefits of Early, Appropriate Therapy

Cumulative evidence from multiple studies has demonstrated that early, appropriate therapy is associated with:

Shorter duration of antibiotic therapy

– Short-course therapy is only an option when the right antibiotic is used from the start

Decreased length of ICU or hospital stay

Lower total cost

Decreased mortality

– Appropriate antimicrobial therapy reduces infection-related and all-cause mortality

Adapted from Kollef MH et al. Chest. 1999;115:462-474.ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416.

“…selection of initial appropriate antibiotic therapy (ie, getting the antibiotic treatment right the first time) is an important aspect of care for hospitalized patients with serious infections.”

– ATS/IDSA Guidelines

A Study by Kollef and Colleagues Evaluating the Impact of Inadequate Antimicrobial Therapy on Mortality

Inadequate antimicrobial treatment(n=169)

Adequate antimicrobial treatment(n=486)

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All-Cause Mortality Infection-Related Mortality

24

42*

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Importance of Initial, Appropriate Antibiotic Therapy

ATS=American Thoracic Society; IDSA=Infectious Diseases Society of America.

Initial Empiric Therapy in Patients Without Risk Factors for MDR Pathogens

Adapted from ATS/IDSA. Am J Respir Crit Care Med. 2005;171:401. Table 3.

Potential Pathogens Recommended Antibiotic

Streptococcus pneumoniae*H influenzaeMethicillin-sensitive S aureus (MSSA)

Antibiotic-sensitive, enteric, gram-negative bacilli E coli K pneumoniae (ESBL-) Enterobacter spp Proteus spp Serratia marcescens

Ceftriaxone/AzithromycinorLevofloxacin, moxifloxacin, or ciprofloxacin†

orAmpicillin/sulbactamorErtapenem

ESBL=extended-spectrum β-lactamase producer.*The frequency of penicillin-resistant S pneumoniae and MDR S pneumoniae is increasing.†Levofloxacin or moxifloxacin are preferred to ciprofloxacin and the role of other new quinolones, such as gatifloxacin, has not been established.

Initial Empiric Therapy for Late-Onset Disease, Risk

Factors, or MDR Pathogens

Initial, Broad-Spectrum,

plus¶

Linezolid 600 mg q12h orVancomycin 15 mg/kg q12h§

Antipseudomonal cephalosporinorAntipseudomonal carbepenemor-Lactam/-lactamase inhibitorplusAntipseudomonal fluoroquinolone‡

orAminoglycoside‡

MDR pathogens*P aeruginosaK pneumoniae (ESBL+)†

Acinetobacter spp†

Non-MDR, gram-negative bacilli Legionella pneumophila†

MDR, gram-positive cocciMRSA

Combination Antibiotic TherapyPotential Pathogens

*Including pathogens from slide 19, (S pneumoniae, H influenzae, MSSA, E coli, K pneumoniae (ESBL-), Enterobacter spp, Proteus spp, S marcescens.†If an ESBL+ strain K pneumoniae or MDR Acinetobacter spp is suspected, a carbepenem is suggested as initial therapy.‡If L pneumophila is suspected, the combination antibiotic regimen should include a macrolide or a fluoroquinolone rather than an aminoglycoside.¶If MRSA is suspected or there is a high incidence locally.§Trough levels for vancomycin should be 15 µg/mL to 20 µg/mL.

Adapted from ATS/IDSA. Am J Respir Crit Care Med. 2005;171:402. Tables 4 and 5.

Inpatient Antibiogram of SOMC

Escherichia coli 572 49 53 NI 91 98 97 94 100 81 NI 97 NI 61 97 85 95 76 NIStaphylococcus aureus 513 2 24 30 24 NT 24 90 NT 32 24 NT 1 NT NT 95 NT 94 100Staphylococcus aureus (MRSA) 389 0 0 0 0 NT 0 94 0 NI 0 NT 0 NT NT 90 NT 98 100Enterococcus faecalis 322 98 98 7 NI NI NI NT NT 42 0 97 1 NT NT 31 68 95Staphylococcus - Coag Negative 312 56 63 35 60 NI 60 NI NI 52 58 NT 47 NI NI 87 NI 61 100Pseudomonas aeruginosa 211 0 0 NI 0 75 14 76 83 59 NI 0 NI 87 92 17 90 5 NIKlebsiella pneumoniae 172 0 76 NI 85 93 93 93 100 92 NI 74 NI 82 90 NT 93 90 NIProteus mirabilis 148 48 87 NI 91 99 98 82 98 43 NI 4 NI 75 100 0 81 49 NIStaphylococcus aureus (MSSA) 124 10 100 77 100 NT 100 100 100 97 100 NT 10 NT NT 100 NT 100 100Streptococcus, Group B 101 100 100 62 100 NI 100 NT NT 98 79 100 100 NT NT 0 NT NT 100Streptococcus, viridans 69 95 95 47 95 NT 98 NT NT 88 43 80 97 NT NT 71 NT 59 100Streptococcus pneumoniae 60 69 69 56 69 NT 98 NI NT 98 68 NT 66 NT NT 85 NI 94 100Enterobacter cloacae 47 0 12 NI 4 80 65 70 100 72 NI 63 NI 65 68 NT 68 76 NIHaemophilus influenzae 45 80 100 93 45 NT 97 NT NT 100 2 NT 75 NT NT 100 NT 82 NIEnterococcus faecium 38 13 13 0 NI NI NI NT NT 0 0 45 0 NT NT 37 NT 7 2Acineotbacter anitratus 35 2 79 NI 0 28 8 20 94 20 NI 0 NI 11 85 NT 25 22 NISerratia marcescens 35 5 7 NI 0 97 91 88 100 91 NI 0 NI 80 71 NT 58 94 NIEnterobacter aerogenes 32 3 9 NI 12 93 84 90 100 93 NI 61 NI 77 84 NT 90 87 NICitrobacter freundii 28 10 57 NI 14 89 85 82 100 82 NI 100 NI 80 89 NT 85 82 NIStentrophomonas maltophilia 24 0 0 NI 0 26 0 8 0 65 NI NI NT 21 16 12 95 NIAlcaligenes species 14 0 10 NI 7 14 14 28 64 50 NI 0 NI 71 78 NT 28 85 NIProvidencia stuartii 13 0 0 NI 15 92 92 30 100 0 NI 0 NI 40 84 NT 7 38 NIMorganella morganii 11 0 0 NI 9 72 72 72 100 54 NI NI NI 100 100 NT 90 72 NI

Green - Antibiotic of choice for most infections due to this organismBlue - Combination of both antibiotics is recommended

SOMC Annual AntibiogramInpatients

July 1, 2004 - June 30, 2005

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Special thanks to Timothy R. Cassity, Ph. D.

Outpatient Antibiogram SOMC (2004-2005)

Acineotbacter anitratus 26 15 90 NI 0 50 23 38 100 42 NI 0 NI 21 64 NT 38 46 NIAlcaligenes species 10 0 0 NI 0 20 20 30 90 30 NI 20 NI 90 90 NT 40 60 NICitrobacter diversus 18 0 100 NI 100 94 100 100 100 100 NI 100 NI 100 100 NT 100 94 NIEnterococcus faecium 37 10 10 2 NI NI NI NT NT 0 0 52 0 NT NT 29 NT 13 5Haemophilus parahaemolyticus 26 92 100 76 92 NT 100 NT NT 100 19 NT 92 NT NT 92 NT 96 NIHaemophilus parainfluenzae 12 91 100 100 83 NT 100 NT NT 100 8 NT 91 NT NT 100 NT 91 NIMoraxella catarrhalis 17 70 100 100 88 NT 100 NT NT 100 17 NT 17 NT NT 100 NT 82 NIStaphylococcus saprophyticus 70 87 88 41 85 NT 82 NT NT 100 43 NT 84 NT NT 87 NT 92 100Sterptococcus, Group A 19 100 100 73 100 NT 100 NT NT 100 100 NT 100 NT NT 73 NT 10 100Staphylococcus - Coag Negative 259 54 61 31 59 NI 82 NI NI 50 55 NT 47 NI NI 83 NI 58 100Citrobacter freundii 54 11 66 NI 14 81 75 85 100 84 NI 100 NI 50 85 NT 92 77 NIEnterobacter aerogenes 82 1 23 NI 9 82 85 96 98 97 NI 65 NI 69 80 NT 96 97 NIEnterobacter cloacae 70 31 4 NI 10 81 75 87 98 81 NI 66 NI 80 80 NT 87 81 NIMorganella morganii 54 9 44 NI 18 74 92 59 96 46 NI NI NI 92 92 NI 79 70 NIProteus mirabilis 419 60 88 NI 93 99 99 86 99 53 NI 2 NI 69 99 0 86 57 NIProvidencia stuartii 33 6 33 NI 18 87 93 33 100 9 NI 3 NI NT 78 NT 27 45 NIStentrophomonas maltophilia 14 0 0 NI 0 7 0 28 0 46 NI 0 NI 21 21 0 28 71 NIStreptococcus, Group B 591 99 100 61 100 NI 100 NT NT 99 80 99 100 NT NT 0 NT NT 100Streptococcus, viridans 122 96 96 50 99 NT 99 NT NT 87 53 86 97 NT NT 61 NT 45 100Enterococcus faecalis 532 98 98 10 NI NI NI NT NT 52 0 98 0 NT NT 24 NT 70 97Escherichia coli 2856 55 66 NI 95 99 99 96 100 88 NI 98 NI 71 99 86 96 81 NIHaemophilus influenzae 62 77 100 90 64 NT 100 NT NT 100 6 NT 69 NT NT 98 NT 90 NIKlebsiella pneumoniae 492 0 74 NI 89 96 97 96 100 97 NI 77 NI 87 95 NT 96 95 NIPseudomonas aeruginosa 282 0 0 NI 0 83 24 80 87 59 NI 2 NI 73 92 27 90 3 NIStaphylococcus aureus 160 9 48 20 48 NT 38 89 NT 46 48 NT 9 NT NT 92 NT 92 100

SOMC Annual Antibiogram

July 1, 2004 - June 30, 2005Outpatients

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Nursing Home Patients Antibiogram SOMC

Acineotbacter anitratus 11 0 80 NI 0 9 0 0 100 9 NI 0 NI 12 36 NT 0 18 NIEnterococcus faecium 25 8 8 4 NI NI NI NT NT 0 0 60 0 NT NT 28 NT 16 0Staphylococcus - Coag Negative 22 13 22 18 22 NI 18 NI NI 13 13 NT 13 NI NI 72 NI 31 100Enterobacter aerogenes 11 0 0 NI 9 81 81 81 100 90 NI 66 NI 72 NT NT 81 81 NIEnterobacter cloacae 14 0 0 NI 0 50 28 71 100 35 NI 80 NI 35 35 NT 71 50 NIMorganella morganii 14 7 66 NI 28 85 100 28 100 21 NI NI NI 100 100 NT 57 64 NIProteus mirabilis 197 41 78 NI 92 99 98 76 100 25 NI 2 NI 50 98 0 76 31 NIProvidencia stuartii 20 0 33 NI 5 95 90 20 100 0 NI 5 NI NT 75 NT 20 25 NIStreptococcus, Group B 19 100 100 75 100 NI 100 NT NT 100 90 100 100 NT NT 0 NT NT 100Enterococcus faecalis 104 96 97 7 NI NI NI NT NT 25 0 96 0 NT NT 43 NT 64 97Escherichia coli 283 30 30 NI 92 99 100 85 100 46 NI 95 NI 16 98 80 86 46 NIHaemophilus influenzae 10 70 100 80 50 NT 100 NT NT 100 0 NT 70 NT NT 100 NT 90 NIKlebsiella pneumoniae 60 0 33 NI 80 90 90 90 100 88 NI 62 NI NT 96 NT 88 80 NIPseudomonas aeruginosa 77 0 0 NI 0 67 6 67 80 37 NI 0 NI 57 83 7 83 0 NISerratia marcescens 15 0 0 NI 0 93 93 100 100 93 NI NT NI 13 13 NT 13 100 NIStaphylococcus aureus 96 6 19 4 17 NT 17 91 NT 12 17 NT 0 NT NT 86 NT 90 100

SOMC Annual AntibiogramNursing Home Patients

July 1, 2004 - June 30, 2005

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Ford CW et al. Curr Drug Targets Infect Disord. 2001;1:181-199.

Oxazolidinone: Birth of a New Antimicrobial Agent Class

1987: First report of oxazolidinone family of molecules at the 27th ICAAC meeting. Early studies illustrated:

– Potent activity against Gram-positive organisms, including S aureus (MSSA and MRSA), Staphylococcus epidermidis, Streptococcus pneumoniae, and enterococci; modest activity against a few fastidious Gram-negative bacteria was noted

– Equally effective when administered orally

– Novel inhibition of protein synthesis

1995: 25 presentations at the 35th ICAAC meeting, including the first phase I study results

2000: FDA approval based on 9 trials in more than 4000 patients

Conte JE Jr et al. Antimicrob Agents Chemother. 2002;46:1475-1480.Adapted from French G. Int J Clin Pract. 2001;55:59-63.Meka VG et al. Clin Infect Dis. 2004;39:1010-1015.

A Small Molecule With Good Penetration Into Lung and Skin Tissue

O

C 3HH

CN

O

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N

F

O N

H

Linezolid Characteristics

Available in oral and intravenous formulations– Oral formulation has 100% bioavailability

Has activity against most clinically important Gram-positive pathogens Resistance remains uncommon

– Linezolid inhibits bacterial protein synthesis through a mechanism of action different from that of the other antibacterial agents; therefore, cross-resistance between linezolid and other classes of antibiotics is unlikely

Pharmacokinetics in healthy volunteers and in vitro activity do not necessarily imply a correlation with clinical effectiveness.

Adapted from Conte JE Jr et al. Antimicrob Agents Chemother. 2002;46:1475-1480.

Time After Last Dose (h)

Co

nc

en

tra

tio

n (

µg

/L)

Epithelial lining fluid

Plasma

MIC90 S aureus

MIC90 Enterococcus spp

MIC90 S pneumoniae

Lung Penetration Concentration vs MIC90 of Linezolid Against Gram-Positive Organisms

5 doses of linezolid 600 mg q12h were administered orally to 25 healthy volunteers

Plasma and pulmonary epithelial lining fluid (ELF) linezolid concentrations exceeded MIC90 for staphylococci and streptococci through the dosing interval

MIC90=minimum concentration needed to inhibit 90% of organisms.

Pharmacokinetic Characteristics of Linezolid in Adults

Parameter Effect

Oral bioavailability 100%

Ingestion of food No dose adjustment

Volume of distribution Total body water, 40 L to 50 L

Dosage formulations IV, tablets, oral suspension (PO)

Distribution Readily distributes into well-perfused tissues

Protein binding 31%, independent of drug concentration

Linezolid Pharmacokinetics in VAP

16 critical-care patients with late-onset VAP (≥5 days on the ventilator)

Pharmacokinetic profile was evaluated after 2 days of linezolid (600 mg q12h IV) therapy. ELF samples were collected by mini-BAL brush

Boselli E et al. Crit Care Med. 2005;33:1520-1533.

Peak Trough

Plasma (mg/L) 17.7±4 2.4±1.2

ELF (mg/L) 14.4±5.6 2.6±1.7

Steady State Concentrations in 16 VAP Patients

First Prospective Comparison of Linezolid vs Vancomycin for Empiric Treatment of Nosocomial

Pneumonia (NP)C

linic

al C

ure

(%

)

86/161 19/41 18/31

A randomized, double-blind, multicenter, multinational, comparator-controlled trial to compare the safety and efficacy of linezolid versus vancomycin for NP

Linezolid 600 mg q12h IV Vancomycin 1 g q12h IV

Safety and efficacy of linezolid versus vancomycin were compared in 402 patients with NP, including VAP; 398 patients received at least 1 dose of study medication. Patients were treated for 7 to 21 days, with optional aztreonam 1 g to 2 g q8h. Clinical cure rates were assessed 12 to 28 days after end of therapy.

Rubinstein E et al. Clin Infect Dis. 2001;32:402-412.Data on file. Pfizer Inc.

53 5255

46

5850

74/142 31/56 10/200

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60

70

Intent-to-treat (ITT) S aureus NP MRSA NP

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50

60

70

ITT S aureus NP MRSA NP

Second Prospective Comparison of Linezolid vs Vancomycin for Empiric Treatment of NP

Clin

ical

Cu

re (

%)

128/245 40/95 12/41

A randomized, double-blind, multicenter, multinational, comparator-controlled trial to compare the safety and efficacy of linezolid versus vancomycin for NP.


The safety and efficacy of linezolid IV versus vancomycin IV were compared in 623 patients with NP, including VAP. Patients were treated for 7 to 21 days, with optional aztreonam 1 g to 2 g q8h. Clinical cure rates were assessed 15 to 21 days after end of therapy.

Wunderink RG et al. Clin Ther. 2003;25:980-992.Data on file. Pfizer Inc.

53 52 4942

60

29

18/3040/81135/256

Linezolid Demonstrates Excellent Efficacy in a Retrospective Analysis of Two Prospective

Clinical TrialsC

linic

al C

ure

(%

)

221/417 70/136 36/61

A retrospective analysis of the combined results from the 2 prospective, identical design trials in 1019 patients with NP including ventilator-associated

pneumonia (VAP)


Linezolid was equally effective in the ITT and S aureus NP populations (P=NS).The outcome difference in the MRSA NP subgroup is provided as a descriptive measure only. No further inference should be drawn due to the retrospective nature of the analysis (P<.01).

53 52 52

43

59

0

10

20

30

40

50

60

70


36

Wunderink RG et al. Chest. 2003;124:1789-1797.Data on file. Pfizer Inc.

202/387 59/136 22/62

Linezolid Demonstrates Excellent Efficacy in a Retrospective Analysis of Two Prospective

Clinical TrialsA retrospective analysis of 544 patients with VAP from the two prospective,

identical design trials in 1019 patients with NP.

0

10

20

30

40

50

60

70

80


Clin

ica

l Cur

e (%

)


103/227 76/207 43/88 32/91 23/37 7/33

Linezolid was equally effective in the ITT and S aureus NP populations (P=NS).The outcome difference in the MRSA NP subgroup is provided as a descriptive measure only. No further inference should be drawn due to the retrospective nature of the analysis (P<.01).

Kollef MH et al. Intens Care Med. 2004;30:388-394.

Wunderink RG et al. Chest. 2003;124:1789-1797.Data on file. Pfizer Inc.

4537

49

35

62

21

Key Points About Vancomycin Recommendations

The new ATS/IDSA guidelines recommend dosing vancomycin by body weight (mg/kg) and adjusted for renal impairment

– Monitor and adjust trough levels to maintain 15 μg/mL to 20 μg/mL

Clinical trials report 40% or greater failure rate for MRSA pneumonia with vancomycin at standard dosing (1 g q12h)

No prospective clinical trials have shown the value of dosing vancomycin to achieve a trough level at 15 μg/mL or more

Combination therapy with vancomycin + rifampin, or vancomycin + aminoglycosides has not been proven effective in randomized controlled trials

ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416.Craven DE, et al. Infect Dis Clin North Am. 2004;18:939-962.

Key Points About Linezolid in Treating MRSA HAP

linezolid is now recommended as empiric therapy, on a par with vancomycin, for late-onset HAP or for patients with risk factors for MRSA

Clinical setting where linezolid may be preferred:

– Patients at risk for, or already with, renal insufficiency• In these patients, physicians may have a stronger tendency to prescribe

less adequate doses of vancomycin

– Patients at increased risk of nephrotoxicity or on concomitant nephrotoxic drugs

ATS/IDSA. Am J Crit Care Med. 2005;171:388-416.Craven DE et al. Infect Dis Clin North Am. 2004;18:939-962.

Linezolid formulations are indicated for the treatment of infections caused by susceptible strains of the designated microorganisms:

Pneumonia Nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and

-resistant strains), or Streptococcus pneumoniae (including multi-drug resistant strains [MDRSP*]). Combination therapy may be clinically indicated if the documented or presumptive pathogens include gram-negative organisms

Community-acquired pneumonia caused by Streptococcus pneumoniae (penicillin-susceptible strains only), including cases with concurrent bacteremia or S aureus (methicillin-susceptible strains only)

Indication

*MDRSP refers to isolates resistant to 2 or more of the following antibiotics: penicillin, second-generation cephalosporins, macrolides, tetracycline, and trimethoprim/sulfamethoxazole.

Skin infection Complicated skin and skin structure infections, including diabetic foot infections

without concomitant osteomyelitis, caused by S aureus (methicillin-susceptible and -resistant strains), S pyogenes, or S agalactiae. linezolid has not been studied in the treatment of decubitus ulcers. Combination therapy may be clinically indicated if the documented or presumptive pathogens include gram-negative organisms

Uncomplicated skin and skin structure infections caused by S aureus (methicillin-susceptible only) or S pyogenes

Vancomycin-resistant Enterococcus Vancomycin-resistant E faecium infections including cases with concurrent bacteremia

Indication

Important Safety Considerations Contraindications

Linezolid is contraindicated in patients who have known hypersensitivity to linezolid or any of the other product components

Warnings

Pseudomembranous colitis Pseudomembranous colitis has been reported with nearly all antibacterial agents,

including linezolid, and may range in severity from mild to life-threatening. It is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of any antibacterial agent

Important Safety Considerations Warnings

Myelosuppression Myelosuppression (including anemia, leukopenia, pancytopenia, and

thrombocytopenia) has been reported in patients receiving linezolid

In cases where the outcome is known, when linezolid was discontinued, the affected hematologic parameters have risen toward pretreatment levels

Complete blood counts should be monitored weekly in patients who receive linezolid, particularly in those who receive linezolid for longer than 2 weeks, those with preexisting myelosuppression, those receiving concomitant drugs that produce bone marrow suppression, or those with a chronic infection who have received previous or concomitant antibiotic therapy

Discontinuation of therapy with linezolid should be considered in patients who develop or have worsening myelosuppression

Important Safety Considerations Precautions

Lactic acidosis Lactic acidosis has been reported with the use of linezolid. In reported cases, patients

experienced repeated episodes of nausea and vomiting. Patients who develop recurrent nausea or vomiting, unexplained acidosis, or a low bicarbonate level while receiving linezolid should receive immediate medical evaluation

Serotonin syndrome (linezolid + serotonergic agent) Spontaneous reports of serotonin syndrome associated with co-administration of

linezolid and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been reported

Patients who are treated with linezolid and concomitant serotonergic agents should be closely observed for signs and symptoms of serotonin syndrome (eg, cognitive dysfunction, hyperpyrexia, hyperreflexia, incoordination)

If any signs or symptoms occur, physicians should consider discontinuation of either one or both agents (linezolid or concomitant serotonergic agents)


Peripheral/optic neuropathy Peripheral and optic neuropathy have been reported in patients treated with linezolid,

primarily those patients treated for longer than the maximum recommended duration of 28 days

In cases of optic neuropathy that progressed to loss of vision, patients were treated for extended periods beyond the maximum recommended duration

Visual blurring has been reported in some patients treated with linezolid for less than 28 days

If patients experience symptoms of visual impairment, such as changes in visual acuity, changes in color vision, blurred vision, or visual field defect, prompt ophthalmic evaluation is recommended

Visual function should be monitored in all patients taking linezolid for extended periods (≥3 months) and in all patients reporting new visual symptoms regardless of length of therapy with linezolid

If peripheral or optic neuropathy occurs, the continued use of linezolid in these patients should be weighed against the potential risks


Drug interactions Linezolid is a reversible nonselective inhibitor of monoamine oxidase. Therefore,

linezolid has the potential for interaction with adrenergic and serotonergic agents

A reversible enhancement of the pressor response with either pseudoephedrine HCl or phenylpropanolamine HCl was observed when linezolid was administered to healthy normotensive subjects. Patients should inform their physician if they are taking medications containing pseudoephedrine HCl or phenylpropanolamine HCl, such as cold remedies and decongestants

A significant pressor response has been seen in normal adult subjects receiving linezolid and tyramine doses of more than 100 mg. Advise patients to avoid large quantities of foods or beverages with high tyramine content while taking linezolid

Important Safety Considerations Adverse Events

The most common adverse events include:

Incidence (%) of Adverse Events Reported in ≥2% of Adult Patients in Comparator-Controlled Clinical Trials with linezolid

Eventlinezolid(n=2046)

All Comparators*(n=2001)

Diarrhea 8.3 6.3

Headache 6.5 5.5

Nausea 6.2 4.6

Vomiting 3.7 2.0

Insomnia 2.5 1.7

Constipation 2.2 2.1

Rash 2.0 2.2

Dizziness 2.0 1.9

Fever 1.6 2.1

*Comparators included cefpodoxime proxetil 200 mg PO q12h; ceftriaxone 1 g IV q12h; clarithromycin 250 mg PO q12h; dicloxacillin 500 mg PO q6h; oxacillin 2 g IV q6h; vancomvcin 1 g IV q12h.

DosingSpecial Populations

Renal insufficiency The pharmacokinetics of the parent drug, linezolid, are not altered in patients with any

degree of renal insufficiency Both linezolid and its metabolites are eliminated by dialysis. Approximately 30% of

dose was eliminated during a 3-hour dialysis; therefore, linezolid should be administered after hemodialysis

Two primary metabolites may accumulate in patients with renal insufficiency; in the absence of information on the clinical significance of metabolite accumulation, use of linezolid in patients with renal insufficiency should be weighed against the risks of metabolite accumulation

Because similar plasma concentrations of linezolid are achieved regardless of renal function, no dose adjustment is recommended for patients with renal insufficiency

Hepatic Insufficiency No adjustment recommended for mild-to-moderate hepatic insufficiency

– Pharmacokinetics in severe hepatic insufficiency have not been evaluated

Questions?

Opening Day April 7th

Summary

The progressive emergence of gram-positive organisms as dominant isolates in nosocomial infections has become a primary health care concern

As demonstrated, a multitude of risk factors exist for the development of MRSA, including previous hospitalization, longer length of stay before infection, previous surgery, enteral feedings, and previous use of antibiotics

Linezolid is an effective treatment for NP due to MRSA

Jones RN. Clin Infect Dis. 1999;29:495-502.Graffunder EM et al. J Antimicrob Chemother. 2002;49:999-1005.

diagnosis, treatment and prevention of hospital acquired pneumonia michael zgoda, md asst....

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