Community-Acquired Pneumonia (CAP) Infectious Diseases Advisory Board 14/01/2000 - Woluwé St Lambert Colloquium Longartsen - 11/02/2000 Dr Yvan Valcke
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
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
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
Belgian situation = different, in terms of : 1. Epidemiology : - incidence of CAP pathogens - resistance patterns 2. Availability of anti-microbial drugs
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
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
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
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
CAP 2000 DISCUSSION TOPICS 1. Epidemiological evolution 2. New antimicrobials (FQ) 3. Dosage regimens and Drug recommendations
CAP 2000 DISCUSSION TOPICS 1. Epidemiological evolution 2. New antimicrobials (FQ) 3. Dosage regimens and Drug recommendations
Evolution of S. pneumoniae resistance in Belgium 35 30 25 20 15 10 5 0 85 86 87 88 89 90 91 92 93 94 95 96 97 98 penig tetra erythro peni full R
Evolution of S. pneumoniae resistance in Belgium 35 30 penig tetra erythro peni full R 25 percentage 20 15 10 5 0 85 86 87 88 89 90 91 92 93 94 95 96 97 98 year Referentielabo pneumokokken
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
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
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
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
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%
CAP 2000 DISCUSSION TOPICS 1. Epidemiological evolution 2. New antimicrobials (FQ) 3. Dosage regimens and Drug recommandations
FQ: CLASSIFICATION Paul Erhlich Society for Chemotherapy Int J Antimicrob Ag 1998;10:255-257 Leading article : Classification of Fluoroquinolones
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
FQ: Antibacterial activity MIC90 (mcg/ml) Organism OFL GRP LFX TFX S. pneumoniae 2 0.25/0.5 1 0.125/0.25 H. influenzae Bla + en - M. catarrhalis Bla + en - 0.05 0.008/0.015 0.03 0.015/0.03 0.12 0.0125/0.025 0.12 0.003/0.06 Adis drug evaluation 1997 and 1998
FQ: Antibacterial activity MIC90 (mcg/ml) Organism OFL GRP LFX TFX Myc. pneumoniae 1 0.25 0.5 0.25 Chl. pneumoniae 2 0.12 0.12 0.12 Leg. pneumophila 0.03 0.06 0.015 0.015 Adis drug evaluation 1997 and 1998
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
FQ: CAUTIONS (2) Unexpected toxicity in PMS: tema : hemolytic-uremic syndrome trova : severe hepatitis grepa : dose related QTc-prolongation withdrawn
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 1992 1999: The trovafloxacin syndrome: serious hepatic events laboratory abnormallities ALT, bilirubin, encephalopathies necrotic inflammation 0.0056% incidence 5 transplants 6 deaths (multifactorial) withdrawn in June 1999
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
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!!
CAP 2000 DISCUSSION TOPICS 1. Epidemiological evolution 2. New antimicrobials (FQ) 3. Dosage regimens and Drug recomendations
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
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)
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
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 24-48 h, declining inflammatory parameters, and O2 Sat > 95 %
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
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
CAP with PENICILLIN- RESISTANT S. PNEUMONIAE in subgroup 3 and 4 Peni - I (MIC : 0.1-1 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