Acute Pneumonia

“The most widespread and fatal of all acute diseases, pneumonia is now Captain of the Men of Death.”

The Principals and Practice of Medicine

Sir William Oscar, 1901

Principles and Practice of Infectious Diseases

Principals and Practice of Infectious Diseases

Diagnosis of CAP

• Chest radiograph is the most important diagnostic tool

• Clinical presentation is not diagnostic of an etiology

• Yield of pathogens from Gram stain of expectorated sputum from patients with CAP is only 30%–40%.

Diagnosis Chest Radiograph

Gram Stain’s Role in CAP Diagnosis

CAP Treatment Issues

• Causative pathogen frequently not found

– Treatment predominantly empiric

– Pneumococcal and atypical coverage important

• Increasing antibiotic resistance

– Clinical significance in question

• Use double-coverage for pneumococci?

• If outcomes are similar, which agent do we choose?

CAP: Changing Presentation

• Aging of the population

• Increased number of nursing home beds

• Increased number of AIDS cases

• Increased number of organs transplanted

Clin Infect Dis 2000;31:347-82Ramirez et al. IDSA 2000Clin Infect Dis 2000;31:347-82Ramirez et al. IDSA 2000

16%

6%

1%

10%

7%20%

40%S. pneumoniae

H. influenzae

Legionella spp.

M. pneumoniae

C. pneumoniae

M. catarrhalis

Others

AtypicalAtypicalPathogens:Pathogens:

23%23%

AtypicalAtypicalPathogens:Pathogens:

23%23%

Key Bacterial Pathogens in CAP

• Up to 60% of cases have an unknown etiology• Up to 15% with ≥ 2 etiologies

The reported age-related mortality per 100,000 US population from pneumonia and influenza in individuals >15 yr, 1982-1990

0

200

400

600

800

1000

1200

15-24 25-34 35-44 45-54 55-64 65-74 75-84 85+

AGE

Deatth rates per 100,000

19901982

ASCAP Guidelines for Outpatient Treatment of CAP

• Otherwise healthy patients (all ages)–First-line

• Azithromycin PO

–Alternative first-line• Moxifloxacin PO (preferred) or levofloxacin PO

or clarithromycin PO or gatifloxacin PO

The ASCAP 2002 Consensus Panel. Hosp Med Consensus Rep. 2002:1-32; Emerman CL, Bosker G. In: Bosker G, ed. Textbook of Adult and Pediatric Emergency Medicine. 2nd ed. Atlanta, Ga: American Health Consultants. 2002:375-395.

Indications for Hospitalization

• Pulse >140, SBP <90 mm Hg, and/or respiratory rate >30/min

• Altered mental status

• Hypoxemia (PO <60 mm Hg)

• Suppurative complication

• Metabolic abnormality

ASCAP Guidelines for Inpatient Treatment of CAP

• Hospitalized, non-ICU– First-line

• Ceftriaxone PLUS azithromycin IV– Alternative first-line

• Moxifloxacin or levofloxacin IV or gatifloxacin

• ICU Patients– First-line

• Ceftriaxone IV PLUS levofloxacin IV (±) aminoglycoside or ceftriaxone IV PLUS azithromycin IV (±) an antipseudomonal agent

– Alternative first-line• Ciprofloxacin IV PLUS an aminoglycoside IV PLUS azithromycin

IV The ASCAP 2002 Consensus Panel. Hosp Med Consensus Rep. 2002:1-32; Emerman CL, Bosker G. In: Bosker G, ed. Textbook of Adult and Pediatric Emergency Medicine. 2nd ed. Atlanta, Ga: American Health Consultants. 2002:375-395.

ASCAP Guidelines for Inpatient Treatment of CAP – Special Considerations

• Nursing home acquired– First-line

• Ceftriaxone IV PLUS azithromycin IV – Alternative first-line

• Ceftriaxone PLUS doxycycline or moxifloxacin or levofloxacin IV or gatifloxacin

• Severe, bacteremic CAP with documented Streptococcus pneumoniae*– First-line

• Ceftriaxone PLUS moxifloxacin or ceftriaxone IV PLUS levofloxacin IV

– Alternative first-line• Vancomycin† PLUS azithromycin IV

* Showing high-level or complete resistence to macrolides, cephalosporins and/or penicillin.

† If S. pneumoniae demonstrates complete resistance to extended-spectrum quinolones (very rare), third generation cephalosporins and macrolides, then vancomycin may be required as part of initial therapy, although this would be necessary only in rare circumstances.

The ASCAP 2002 Consensus Panel. Hosp Med Consensus Rep. 2002:1-32; Emerman CL, Bosker G. In: Bosker G, ed. Textbook of Adult and Pediatric Emergency Medicine. 2nd ed. Atlanta, Ga: American Health Consultants. 2002:375-395.

Infections caused by S. pneumoniae, USA 1997

Otitis media 7,000,000

Pneumonia 500,000

Bacteremia 50,000

Meningitis 3,000

Death 40,000

Mortality rate (30-40%) for bacteremic cases

Worldwide Prevalence Rates for Penicillin Resistant S.pneumoniae

Unknown

< 5%

5-10%

10-25%

> 25% Doern CID 1998; Felmingham JAC 1996 and 2000.Zhanel Low and Hoban AAC 1999.

0

5

10

15

20

25

30

35

40

1979-87 1988-89 1990-91 1992-93 1994-95 1997-98 1999-00

Per

cen

t

Resistant (MICs >2)

Intermediate (MICs 0.12-1)

5589 487 524 799 1527 1601 1531 1940 35 15 17 19 30 34 33 45

2001-02

1980’s 1990’s

Penicillin Resistance with S pneumoniae in the United States

Antimicrob Agents and Chemother 2001;45:1721 and submitted

S. pneumoniae Resistance Rates Selected Agents, 1999-2000*

* n=1,531 isolates; 33 U.S. medical centers, winter (1999-2000)

Antimicrobial % Resistance

Macrolides 25.9

Clindamycin 8.8

Tetracycline 16.4

Chloramphenicol 8.6

TMP/SMX 30.3

Fluoroquinolones 1.2

Antimicrob Agents and Chemother 2001;45:1721

Clin Infect Dis 2002;34:330

• PBP alterations - not -lactamaseproduction - mediate penicillin resistance in pneumococcusthus - lactamase inhibitors do not enhance activity of -lactam agents against penicillin-resistant pneumococci

PRSP-Mechanism

Drug-Resistant S. pneumoniae

• Age > 65 years or < 5 years

• Exposure to a child in a day care center

• Multiple medical comorbidities

• Alcoholism

• Recent use of antibiotics

• Immunosuppression

• Recent hospitalization

MIC Interpretive Criteria for S. pneumoniae Susceptibility to Ceftriaxone Effective

January 1, 2002

Meningeal Breakpoints Nonmeningeal Breakpoints

Sensitive 0.5 g/mL 1 g/mL

Intermediate 1 g/mL 2 g/mL

Resistant 2 g/mL 4 g/mL

For cerebrospinal fluid isolates, report only meningitis interpretations.For all other isolates, report interpretations for both meningitis and nonmeningitis.

NCCLS. 2002. M100.

Mortality of Hospitalized Patients With Invasive Pneumococcal Disease

Years N Mortality Reference

Austrian & Gold

Kings County Brooklyn Hospital

1952-62 1130 13%Annals Int Med

1964

Fine

Meta-analysis of 127 cohorts 1966-95 4432 12% JAMA 1996

Feikin

Population-based, active surveillance

1995-97 5837 12%Am J Public

Health 2000

Mortality Due to Pneumococcal Pneumonia / Sepsis

Location YearPatients with

DRSP (%)

Mortality (%)

P StudyPen-S Pen-NS

Ohio 1991-94 39/499 (8) 19 21 NS Plouffe, JAMA 1996

Israel 1987-92 67/293 (23) 11 16 NS Rahav, Medicine 1997

Barcelona 1984-93 145/504 (29) 24 38 NS Pallares, NEJM 1995

South Africa‡ 1993-94 35/108 (32) 16 24 NS Friedland PIDJ 1995

Atlanta 1994 44/192 (23) 11 23 NS Metlay, CID 2000

Barcelona 1996-9849/101-Pen (49)

12/101-Mac (12)

6

14*

16

7†

NS

NSEwig, AJRCCM 1999

N. America 1995-97 741/4193 (18) 11% 14 NS Feikin AJPH 2000

* Mac-S; † Mac-NS‡ Children Bishai, JAC 2001

New NCCLS Breakpoints for Streptococcus pneumoniae

Overall Rates of Resistance (I + R)

Drug Old Breakpoints New Breakpoints

Amoxicillin 24.2% 6.3%

Amoxicillin/clavulanate 24.2% 6.3%

Ceftriaxone/cefotaxime 24.0% 4.0%

Cefuroxime 29.1% 27.3%

Antimicrob Agents Chemother 2001;45:1721-29NCCLS, M100 document January 2002

Antibiotic Activity Against H. influenzae

MIC90 (g/m )LGati Cipro Trova Azithro Clari

. H influenzae-Lac t (-) 1002isolates-Lac t (+) 485isolates

<0.03

<0.03

<0.015

<0.015

<0.03

<0.03

2.0

2.0

16.0

16.0

H. influenzaeIncreasing -Lactamase Production

0%

5%

10%

15%

20%

25%

30%

35%

1970 1984 1988 1992 1996

Slide28

Atypical Pneumonia

• AP encompasses pneumonias due to Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella spp*

• Prospective studies have failed to identify the cause of 40% to 60% of CAP cases‡

• Today, AP implies–An often benign course (ambulatory)*–Gradual onset§

–Systemic complaints often greater than respiratory complaints§

• AP often a “mixed” infection*

**File TM Jr, et al. File TM Jr, et al. Infect Dis Clin North Am. Infect Dis Clin North Am. 1998;12:572,570,579.1998;12:572,570,579. ††Reimann HO.Reimann HO. JAMA JAMA. 1938;111:2377,2384. . 1938;111:2377,2384. ‡‡Bartlett JG, et al. Bartlett JG, et al. Clin Infect DisClin Infect Dis. 1998;26:813.. 1998;26:813.§§Levison ME. Levison ME. Harrison’s Principles of Internal Medicine. Harrison’s Principles of Internal Medicine. McGraw-Hill; 1998:1439.McGraw-Hill; 1998:1439.

Pharmacokinetics and Pharmacodynamic Parameters

Con

cen

trat

ion

Time (hours)

MIC

0

Peak/MIC

AUC/MIC

Time > MIC

AUC/MIC90 Ratio of Major FQ for S. pneumoniae

Dose Cmax AUC MIC AUC/MICLevoTrovaCiproGati

500mg200mg500mg400mg

5.12.12.44.0

47.926.711.651.0

2.00.252.00.5

24.0106.6

5.8102.0

FQ Prescription per Capita and Frequency of Pneumococci with Reduced

Susceptibility to FQs in Canada According to Patient’s Age (Bars)

Treatment for 7 to 14 days

2 days

2 days

Newly HospitalizedCAP Patients(18 years)

Gatifloxacin IV400 mg QD

n=141

Gatifloxacin PO400 mg QD

Ceftriaxone IV 1 or 2 g (32%) QD ± Erythromycin IV

0.5 or 1 g (39%) q6hn=142

Clarithromycin PO500 mg BID

Fogarty C et al. J Respir Dis. 1999;20(suppl 11):S60-S69.

Please see IMPORTANT SAFETY INFORMATION slides. Please see full Prescribing Information.

Gatifloxacin vs Ceftriaxone ± Macrolide in Hospitalized CAP Patients

Gatifloxacin vs Ceftriaxone ± Macrolide* in CAP: Clinical and Bacteriologic Response

*Macrolides were erythromycin IV and clarithromycin PO step-down.†No. cured/total of clinically evaluable patients; ‡No. eradicated/total of microbiologically evaluable patients.NSD=not statistically differentFogarty C et al. J Respir Dis. 1999;20(suppl 11):S60-S69.

Gatifloxacin efficacy rates in CAP from clinical trials used as a basis for approval—up to 90%

Please see IMPORTANT SAFETY INFORMATION slides. Please see full Prescribing Information.

97 97

9092

Gatifloxacin Ceftriaxone ± erythromycin/clarithromycin

Clinical Cure† Microbiologic Eradication‡0

70

80

90

100

96/99 96/106 69/71 73/79

Pat

ien

ts w

ith

Cu

re

or

Era

dic

atio

n (

%)

NSD NSD

*Macrolides were erythromycin IV and clarithromycin PO step-down; †ATS severity scores; ‡No. cured/total of clinically evaluable patients.NSD=not statistically differentNiederman MS et al. Am Rev Respir Dis. 1993;148:1418-1426; Fogarty C et al. J Respir Dis. 1999; 20(suppl 11):S60-S69.

Gatifloxacin efficacy rates in CAP from clinical trials used as a basis for approval—up to 90%

Please see IMPORTANT SAFETY INFORMATION slides. Please see full Prescribing Information.

Gatifloxacin vs Ceftriaxone ± Macrolide* in CAP: Clinical Response by Pneumonia Severity†

Gatifloxacin Ceftriaxone ± erythromycin/clarithromycin

NSD NSD NSD

All Patients Mild/Moderate CAP‡

Pat

ien

ts w

ith

C

ure

(%

)

Severe CAP ‡0

70

80

90

100 97

91

100

9296

90

96/99 96/106 28/28 24/26 68/71 72/80

Role of FQ in Treatment of CAP

• To limit the emergence of FQ-resistant strains, To limit the emergence of FQ-resistant strains, the new FQ should be limited to adults:the new FQ should be limited to adults:

• For whom one of the above regimens has already failed,

• Who are allergic to alternative agents,

OR• Who have documented infection with highly drug-

resistant pneumococci (MIC ≥4 µg/ml)

Pneumococcal Vaccine

• Older than 2 years with:• functional or anatomic asplenia**• immunocompromise or immunosuppression**• HIV infection**• malignancy**• chronic renal failure, HD, nephrotic syndrome**• chronic cardiovascular or pulmonary illness**• Alaskan natives, American Indians

• Revaccination• if >65 years, consider revaccination in 5 yr**

CDC Recommendations: Who Should Receive Influenza Vaccine?

• Persons at increased risk (age 6 mos)

• Hospital and outpatient employees

• Nursing home employees with patient contact

• Home health care providers working with high-risk persons

• Household members of high-risk persons

• Persons desiring to avoid influenza infection

MMWR. 1999;48:5-7.

Guidelines for CAP

Guideline Inpatient Outpatient

IDSA -lactam + macrolide or

Fluoroquinolone

Macrolide or

Doxycycline or

Fluoroquinolone

ATS IV azithromycin or

-lactam + macrolide or

Fluoroquinolone

Macrolide or doxy

-lactam + macrolide

Fluoroquinolone

CDC -lactam + macrolide or

Fluoroquinolone

-lactam or macrolide or doxycycline

(reserve quinolones)

Clin Infect Dis 2000;31:347-82Am J Resp Crit Care Med 2001;163:1730-54Arch Int Med 2000;160:1399-1408

I prefer to decide my prescription strategies for CAP on the basis of severity of the patient’s condition, the presence of comorbidities, and the epidemiologic pattern in each geographical area.

J. Rello - Chest (May 98)

Acknowledgements

• Dr Naiel Nassar MD FACP

Assistant professor of Medicine

UTSW Dallas