we have everything, but we cannot find the pathogen !

WE HAVE EVERYTHING,BUT WE CANNOT FIND THE PATHOGEN !

Abdullah Sayıner, MDEge Univ. Medical School

I HAVE EVERYTHINGBUT I AM NOT HAPPY

• Pathogen-directed narrower spectrum Decrease in risk of resistance development in the long term Decrease in cost of treatment• Decrease in mortality and clinical failure• Collection of epidemiologic data• Diagnosis of epidemiologically important infections (Legionella, avian flu, agents of bioterrorism etc)

• An important portion of the patients do not produce good-quality sputum.• Diagnostic yield of blood and pleural fluid cultures is low. Increase in the cost of diagnosis• Results of mikrobiologic investigations rarely change the therapeutic approach.

When / in which patientsare microbiologic examinationsuseful /Do microbiologic examinations helpin modifying treatment ?

Microbiologic investigations in TTS Groups 1/2 Microbiologic investigations in TTS Groups 1/2

At the outpatient clinic level, it is very difficult To order microbiologic examinations, For the patient to produce good-quality sputum, to overcome the breaucratic process, to follow and get the results, to re-visit the doctor.

cost/benefit ratio very high+ diagnostic yield of sputum examinations in mild pneumonia is low Clinical/syndromic approach ? Rapid tests ?

There is no clinical sign/presentation which helps identifying the etiologic agent.

The diagnostic value of five variables (age, duration of symptoms before admission, hemoptysis, lobar involvement, leukocyte count) in 441 patients:Correct diagnosis: %42 (Farr BM ve ark. Thorax 1989;44:1031)

There was no relationship between the etiologic agents and clinical presentation in 359 patients (immunosupresion in %36.3) saptanan etyolojik.(Fang GD ve ark. Medicine 1990;69:307)

Clinical/syndromic approachClinical/syndromic approach

Typical pneumonia presentation: How predictive of pneumococcal pneumonia ?Typical pneumonia presentation: How predictive of pneumococcal pneumonia ?

291 inpatients (TTS Groups 2-4)Bacteriologically confirmed 26 pneumococcal pneumonia

Typical pneumonia presentation:Sensitivity: %44, specificity: %86

(Aytemur ZA ve ark. TÜSAD 1999)

Clinical / syndromic approachClinical / syndromic approach

Clinical failureDeath

Syndromic approach 11/72 (%15) 2/72 (%3)* Rapid microbiologic tests 15/62 (%24) 8/62 (%13)Empirical treatment 27/128 (%21) 18/128 (%14)

* Significantly different from microbiologic approach (p=0.03)

(van der EErden MM ve ark. Thorax 2005;60:672)

Sputum Gram stainSputum Gram stain

144 bacteremic CAP patients Those who were able to produce good-quality sputum within the first two hours of admission, prior to the start antibiotics: 59 patients (%41)

Single morphotype < 10/high magnification field Accordance with blood culture: 6/9 (%67.7)

Single morphotype > 10/high magnification field Accordance with blood culture : 34/38 (%89.5) Yield: 40/47 (%85.1)

40/59 (%67.8)40/144 (%27.8)

(Gleckman R ve ark. J Clin Microbiol 1988;26:846)

Diagnostic value of sputum examinationsDiagnostic value of sputum examinations

Patients with bacteremic pneumococcal pneumonia (n=105)

Sputum producers (n=74, 70.5%)

Yayma(+) Kültür(+)N=33 n=46

%31 %44

%45 %62

%57 %79

%63 %86

%80 %93

Good-quality sputum (n=58, %55.2)

Prior antibiotics for less than 24 hours (n=51, 48.6%)

No prior antibiotics (n=15, %14.3)

(Musher DM ve ark. Clin Infect Dis 2004;39:165)

Sputum examinations: Use in case of failure of empirical treatmentSputum examinations: Use in case of failure of empirical treatment

(Sanyal S ve ark. Am J Respir Crit Care Med 1999;160:346)

Generally, initial microbiologic examinations have notbeen found to be helpful in treatment failures.However, the related studies did not includepatients with immunosuppression, structural lungdisease or recent hospitalization.

(Chalasani NP ve ark. Chest 1995;108:932 Ewig S ve ark. Respiration 1996;63:164 Pachon J ve ark. Am Rev Respir Dis 1990;142:369 Moine P ve ark. Chest 1994;105:1487)

Rapid tests – Pneumococcal polysaccharide antigen(Binax NOW)Rapid tests – Pneumococcal polysaccharide antigen(Binax NOW)

Sensitivity: %65.9In severe CAP (PSI IV/V): %95Bacteremic patients: %82-92No significant effect of prior antibiotic treatment(%54 - %79, p=0.261)Positivity on 3rd day of antibiotics: %83Specificity: %97-100More sensitive than Gram stain examinationThe two tests may be complimentary.

(Roson B ve ark. Clin Infect Dis 2004;38:222 Smith MD ve ark. J Clin Microbiol 2003;41:2810)

Microbiological examinations in TTS Group 3/4 patientsMicrobiological examinations in TTS Group 3/4 patients

• Sputum examination• Blood culture• Antigen tests (L pneumophila, S pneumoniae)• Intubated patients - endotracheal aspirate / BAL

Quality performance measures in sputum processingQuality performance measures in sputum processing

TTS recommendations• Patient must rinse mouth prior to producing sputum• Sputum sample must be transported to laboratory and processed within one hour• Quality of sample must be checked with microscopic criteria

Benefits of sputum examinationBenefits of sputum examination

In hospitalized patients, there is a higher chanceof infection with bacteria other than pneumococcus.

Failure to detect S.aureus or gram (-) bacilli ingood-quality specimens is strong evidence againstthe presence of these pathogens.

(Mandell LA ve ark. IDSA/ATS consensus guidelines on the management of CAP in adults. Clin Infect Dis 2007;44:S27)

Blood culturesBlood cultures

• Culture positivity low (%5-14) (but subgroups ?)• Prior antibiotic use results in 50% decrease in yield. (Metersky ML ve ark. Am J Respir Crit Care Med 2004;169:342)

• The most frequently isolated bacterium: S pneumoniae (already covered in empiric treatment) (but severe pneumonia – P.aeruginosa, EGNB ?)

• False positive results (~%5) may cause prolongation of hospital stay and lead to additional unnecessary examinations. (Houck PM ve ark. Arch Intern Med 2004;164:637; Metersky ML ve ark. Am J Respir Crit Care Med 2004;169:342).

• Presence of bacteremia does not change duration of treatment. (Ramirez J, Bordon J. Arch Intern Med 2001;161:848).

• Results of blood culture are not used to modify antibiotic treatment (and are not related to treatment success. (Yu VL ve ark. Clin Infect Dis 2003;37:230; Waterer GW ve ark. Respir Med 2001;95:78)

Do blood cultures contribute to epidemiologic data ?Do blood cultures contribute to epidemiologic data ?

• False negative results• Atypical bacteria and viruses not covered• Only a small portion of all pneumococcal infections (%17) can be diagnosed with blood cultures (Porath A ve ark. Eur J Clin Microbiol Infect Dis 1997;16:863)

• Prior antibiotic use results in 50% decrease in yield. (Metersky ML ve ark. Am J Respir Crit Care Med 2004;169:342)

Blood culturesBlood cultures

(Campbell SG ve ark. Chest 2003;123:1142)

19 Canadian hospitalsNumber of patients with blood cultures: 760Positive cultures: 43 (%5.7)

15/760(%2.0)

(Campbell SG ve ark. Chest 2003;123:1142)

Patients with positive cultures: 43 (%5.7)3/43 patients: Empirical treatment concordant23/43 patients: Changed to a broader spectrum despite

possibility for a narrower spectrum (clinical deterioration ?)

17/43 patients: No change despite possibility for a narrower spectrum

(Campbell SG ve ark. Chest 2003;123:1142)

Diagnostic yield low in CAP population as a whole.In which patients is the possibility of bacteremia higher ?Diagnostic yield low in CAP population as a whole.In which patients is the possibility of bacteremia higher ?

Retrospective analysis of the records of Medicarepatients39242 cases with pneumonia13043 cases – blood sample obtained within the first

36 hours and all data completeBacteremia in %7

(Metersky ML ve ark. Am J Respir Crit Care Med 2004;169:342)

Age, hypoxemia, pleural effusion, number of involved lobes,PSI scores not related.

(Metersky ML ve ark. Am J Respir Crit Care Med 2004;169:342)

(Metersky ML ve ark. Am J Respir Crit Care Med 2004;169:342)

Suggested approach in CAP patients

With this approach, almost 90% of all bacteremias are detectedand %38 of blood cultures avoided.In PSI groups 4 and 5 patients in whom bacteremia was missed,mortality was lower compared with other patients in thesegroups (%20 – 29).

(Metersky ML ve ark. Am J Respir Crit Care Med 2004;169:342)

Prevalence of Legionella infection in TurkeyPrevalence of Legionella infection in Turkey

• Cumhuriyet UMS – Culture and serology in inpatients Agent identified in 31/68 patients (%45.5) Serology (+) in 7 patients (Gönlügür U ve ark. Akciğer Arşivi 2001;4:143)

• Hacettepe UMS – CAP patients with atypical presentation (n=103) PCR/culture/urinary antigen (+) in 21 patients Antigen ± culture (+) in 4 patients (Pınar A ve ark. Mikrobiyoloji Bülteni 1999;33:79)

• Karadeniz TUMS and IU Istanbul MS studies Serologic tests: %0 (Özlü T ve ark. Solunum Hastalıkları 2000;11:135 Erelel M ve ark. Klimik 2000;13:46)

• Three studies investigating infectious etiologies in patients with CAP admitted to intensive care units Legionella absent / not investigated (Çelikhisar A ve ark. Toraks Dergisi 2002;3(ek:1):88 Özol D ve ark. Toraks Dergisi 2000;1:8 Kolsuz M ve ark. Tuberk Toraks 2002;50:229)

Influenza virus infectionInfluenza virus infection

Single study:

Patients with lower respiratory tract infection 3.8% (Kaygusuz S ve ark. Toraks Derneği Kongresi, 2000)

Pathogen-directed treatment /Empirical treatment Pathogen-directed treatment /Empirical treatment

Comparative studies

1 (ONE) study

Two-year, prospective study in single tertiary care center in the Netherlands(low rate of antimicrobial resistance)

(van der EErden MM ve ark. Thorax 2005;60:672)

Pathogen-directed therapy:Gram stain / antigen test / clinical presentationPathogen-directed therapy:Gram stain / antigen test / clinical presentation

(van der EErden MM ve ark. Thorax 2005;60:672)

• Agent identified in 63% of the patients receiving pathogen-directed treatment (in 82% of the patients admitted to ICU) • Monotherapy to all patients except one

(van der EErden MM ve ark. Thorax 2005;60:672)

Rapid microbiologic diagnosis: 15/62 (%24) Mortality: 2/62 (%3)Syndromic approach: 11/72 (%15)(p=0.19) 8/72 (13)(p=0.03)

(van der EErden MM ve ark. Thorax 2005;60:672)

(Mandell LA ve ark. IDSA/ATS consensus guidelines on the management of CAP in adults. Clin Infect Dis 2007;44:S27)

Clinical indications for more extensivediagnostic testingClinical indications for more extensivediagnostic testing

ConclusionsConclusions

• Blood cultures may more appropriately be ordered in selected patients. 1. Patients with severe pneumonia 2. Immunocompromised patients

Higher diagnostic yield Higher possibility of “problem” pathogens Higher chance of treatment modification

• In order for the sputum examination to be helpful, the patient must first produce a sample, this sample must be of good quality and it must be rapidly transported to the laboratory.

• Testing for urinary pneumococcal antigen is useful particularly in patients with severe pneumonia and those in whom previous antibiotic therapy failed

• We need more data: - Frequency of Legionella infections - Surveillance data on Influenza virus infections