Community-Acquired Pneumonia (CAP)

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1 Community-Acquired Pneumonia (CAP) Infectious Diseases Advisory Board 14/01/ Woluwé St Lambert Colloquium Longartsen - 11/02/2000 Dr Yvan Valcke

2 Belgian guidelines on the initial diagnostic and therapeutic approach of CAP in the immunocompetent patient Update of the CAP consensus text of the IDAB 2000

3 Working group CAP of IDAB 2000 Herman Goossens (UIA) Paul Jordens Willy Peetermans (KUL) Yves Sibille (UCL-MontGodinne) Yvan Valcke (AZ-St Niklaas) Johan Van Eldere Yves Van Laethem (CHU St Pierre, Bxl) Walter Vincken

4 BELGIAN CAP - GUIDELINES AIMS Providing recommendations for empirical antimicrobial drug use in CAP patients, in terms of: Clinical and bacteriological efficacy Prevention of resistance selection

5 Belgian situation = different, in terms of : 1. Epidemiology : - incidence of CAP pathogens - resistance patterns 2. Availability of anti-microbial drugs

6 CAP - Classification SUBGROUPS 1. Outpatient, < 60 yr, no comorbidity 2. Outpatient, > 60 yr and/or comorbidity 3. CAP requiring hospitalization 4. CAP requiring ICU-hospitalization

7 BELGIAN CAP - GUIDELINES Premises (1) 1. No demonstrated need for systematic coverage of atypicals in subgroups 1, 2 and 3 atypicals in subgroups 1, 2 and 3 should be covered only when suspected on clinical or epidemiological grounds 2. In Belgium, presently available macrolides, azalides and quinolones offer inadequate coverage of S. pneumoniae

8 BELGIAN CAP - GUIDELINES Premises (2) 3. High β lactam dosages are preferred :! resistance selection adequate time > MIC for Peni I Peni R S. pneumoniae 4. First generation cephalosporins (also cefaclor) are less active than amoxicillin or cefuroxime against Peni I / R S. pneumoniae

9 BELGIAN CAP - GUIDELINES Premises (3) 5. Parenteral 3 rd generation cephalosporins are a first choice only in subgroup 4 especially when : - previous b-lactam treatment (within last 15 days?) - previously hospitalized patients - proven/potential simultaneous CNS spread 6. DD atypical versus bacterial CAP : only reliable in subgroup 1

10 CAP 2000 DISCUSSION TOPICS 1. Epidemiological evolution 2. New antimicrobials (FQ) 3. Dosage regimens and Drug recommendations

11 CAP 2000 DISCUSSION TOPICS 1. Epidemiological evolution 2. New antimicrobials (FQ) 3. Dosage regimens and Drug recommendations

12 Evolution of S. pneumoniae resistance in Belgium penig tetra erythro peni full R

13 Evolution of S. pneumoniae resistance in Belgium penig tetra erythro peni full R 25 percentage year Referentielabo pneumokokken

14 Antimicrobial resistance patterns of pathogens causing CAP S. pneumoniae : tetracycline resistance : 28 % erythromycin resistance : 31 %» complete cross-resistance between all macrolides (including miocamycin) in 90% of erythromycin-resistant strains Surveillance Pneumokokkeninfecties België, 1998 Verhaegen et al. Tijd. v. Geneesk. 98, 54, 1539

15 Antimicrobial resistance patterns of pathogens causing CAP penicillin-resistant S. pneumoniae : resistance not due to b-lactamase production but linked to altered Penicillin Binding Proteins pneumococci with reduced penicillinsusceptibility have also reduced susceptibility to other b-lactams

16 Antimicrobial resistance patterns of pathogens causing CAP S. pneumoniae : reduced penicillin susceptibility : 14.2 %» intermediate resistance (Peni-I) : 11.2 %» high-level resistance (Peni-R) : 3.0 % Surveillance Pneumokokkeninfecties België, 1998

17 Antimicrobial resistance patterns of pathogens causing CAP H. influenzae : production of b-lactamase Belgium 94-95, non-capsulate strains : 16,8 % Delmée et al, Acta Clin Belg 96, 51, 237 Higher rates have been found in type b encapsulated strains Doern et al 86 and 89, Jorgensen et al 90, Powell et al 92 Belgium 88-89, type b capsulate strains : 10% (versus 17.4 % in non-capsulated strains) Kayser et al Eur J Clin Microbiol Infect Dis 90, 9, 810

18 Antimicrobial resistance patterns of pathogens causing CAP Very high resistance rates for all macrolides make macrolides contra-indicated if S. pneumoniae possible cause of CAP S. pneumoniae increasingly penicillin-resistant but (increased dosages of) b-lactams still first choice for S. pneumoniae CAP Production of b-lactamase in H. influenzae stable around 17%

19 CAP 2000 DISCUSSION TOPICS 1. Epidemiological evolution 2. New antimicrobials (FQ) 3. Dosage regimens and Drug recommandations

20 FQ: CLASSIFICATION Paul Erhlich Society for Chemotherapy Int J Antimicrob Ag 1998;10: Leading article : Classification of Fluoroquinolones

21 GROUP I CLASSIFICATION Oral Limited to UTI Norfloxacin GROUP II GROUP III GROUP IV Broad Systemic use Improved vs. Gram-pos. atypicals Improved vs. Gram-pos. atypicals anaerobes Ciprofloxacin Ofloxacin Pefloxacin Levofloxacin Sparfloxacin Grepafloxacin Gatifloxacin Trovafloxacin Moxifloxacin Clinafloxacin

22 FQ: Antibacterial activity MIC90 (mcg/ml) Organism OFL GRP LFX TFX S. pneumoniae / /0.25 H. influenzae Bla + en - M. catarrhalis Bla + en / / / /0.06 Adis drug evaluation 1997 and 1998

23 FQ: Antibacterial activity MIC90 (mcg/ml) Organism OFL GRP LFX TFX Myc. pneumoniae Chl. pneumoniae Leg. pneumophila Adis drug evaluation 1997 and 1998

24 FQ: CAUTIONS (1) Commercial benefits = flu-like syndroms, URTI, AECB Massive use = resistance among respiratory pathogens among commensal gut-flora Guidelines are needed When FQ are indicated : use correct (= high) dosages use correct lenghth of treatment

25 FQ: CAUTIONS (2) Unexpected toxicity in PMS: tema : hemolytic-uremic syndrome trova : severe hepatitis grepa : dose related QTc-prolongation withdrawn

26 Unexpected and severe FQ-toxicities 1992: The temafloxacin syndrome: hemolytic uraemic anemia discoloured urine, fever jaundice, nausea, vomiting abdominal pain coagulopathy hepatic and renal dysfunction 0.056% incidence 2 deaths withdrawn in June : The trovafloxacin syndrome: serious hepatic events laboratory abnormallities ALT, bilirubin, encephalopathies necrotic inflammation % incidence 5 transplants 6 deaths (multifactorial) withdrawn in June 1999

27 FQ: CAUTIONS (3) From ofloxacin to levofloxacin... H 3 C N Ofloxacin is a racemic mixture F N O O C N O CH 3 O - - O N H CH 3 Levofloxacin is the pure (-) S isomer * The active form of ofloxacin is the (-) S isomer * Eur. pat. 206,283 to Daiichi, 1987

28 FQ: CAUTIONS (3) Levofloxacin : - to be considered as ameliorated ofloxacin - unlimited use : resistance!! - limited to Ig-E mediated beta-lactam allergy (BID) - documented resistance among S. peumoniae!!

29 CAP 2000 DISCUSSION TOPICS 1. Epidemiological evolution 2. New antimicrobials (FQ) 3. Dosage regimens and Drug recomendations

30 CAP Guidelines DOSAGE REGIMENS Higher dosages of oral beta-lactams : time > MIC % for peni-i and -R resistance selection No demonstrated benefit from IV mega-doses

31 1. Outpatient, < 60 yr, no comorbidity ATYPICAL M. pneumoniae C. pneumoniae Virus (Legionella) versus BACTERIAL S. pneumoniae H. influenzae (rare) Neo-macrolide/azalide PO Doxycycline PO Amoxicilline 0.5-1g q8h PO Cefuroxime-axetil 0.5g q8 PO FQ (IgE-beta-lactam allergy)

32 2. Outpatient, > 60 yr and/or comorbidity First choice: (amoxi/clav 500/125 mg + amoxi 500) q8h PO or amoxi/clav 875/125 mg q8h PO +/- neo-macrolide or azalide PO Alternative: cefuroxime - axetil 500 mg q8h PO FQ (IgE-beta-lactam allergy) +/- neo-macrolide or azalide PO

33 First choice: 3. Hospitalized CAP amoxi/clav 1g q6h IV or cefuroxime 0.75 g q8h IV +/- neo-macrolide or azalide PO or IV Alternative: FQ (IgE-beta-lactam allergy) sequential to oral: when afebrile for h, declining inflammatory parameters, and O2 Sat > 95 %

34 First choice : 4. ICU - hospitalized CAP cefotaxime 2g q8h IV with (clarithromycin 0.5g q12h IV or FQ IV) OR ceftriaxone 2g q24h IV with (clarithromycin 0.5g q12h IV or FQ IV) +/- aminoglycoside OD IV

35 Alternative : 4. ICU - hospitalized CAP amoxi/clav 1g q6h IV with (clarithromycin 0.5g q12h IV or FQ IV) OR cefuroxime 1.5 g q8h IV with (clarithromycin 0.5g q12h IV or FQ IV) +/- aminoglycoside OD IV

36 CAP with PENICILLIN- RESISTANT S. PNEUMONIAE in subgroup 3 and 4 Peni - I (MIC : mg/l) Peni - R (MIC : > 1 mg/l) Peni G (HD) or Amoxi (HD) Ceph - S / I (MIC < 1 mg/l) Cefotax / Ceftria Ceph - R (MIC: > 1 mg/l) Carbapenem or Glycopeptide

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