PNEUMONIE by FU84Hzk

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									                PNEUMONIE
     Gemeenskapsverworwe Pneumonie
      Community-acquired pneumonia
                 (CAP)

Ref: Harrison‟s Principles of Internal Medicine. 14th Edition. Vol.2 P1437 -P1445
                                        1995
             DEFINISIE:

„n Infeksie van die longparenchiem.
  Verskeie bakteriele spesies,
  mikoplasma, chlamidia, ricketsia,
  virusse, fungi of parasiete kan
  pneumonie veroorsaak.
Pneumonie is nie „n enkele siekte nie maar „n
  groep van spesifieke infeksies, elk met „n
  spesifieke epidemiologie, patogenese,
  kliniese beeld en verloop.
      EPIDEMIOLOGIE -
Omstandighede wat leidrade gee
tov die etiologie van pneumonie
•   Leef omstandighede
•   Beroep
•   Reisgeskiedenis
•   Diere blootstelling
•   Kontakte met ander siek mense
•   Geneesheer se kennis van die epidemiese
    kurwe van “gemeenskaps goggas”
         VEROORSAKENDE
            PATOGENE
•   Mycoplasma pneumoniae
•   Streptococcus pneumoniae
•   Haemophilus influenzae
•   Chlamydia pneumoniae
•   Legionella pneumophila
•   Orale anaerobe
•   Moraxella catarrhalis
              VEROORSAKENDE
                 PATOGENE
•   Staphylococcus aureus
•   Nocardia spp
•   Virusse*
•   Fungi#
•   Mycobacterium tuberculosis
•   Chlamydia psittaci

* Influenza virus, cytomegalovirus,respiratory syncytial virus, measles
    virus and varicella-zoster virus


# Histoplasma, Coccidioides, and Blastomyces spp
           Community-acquired respiratory
                 tract pathogens
                                        Prevalence in infection (%)

                           S. pneumoniae        H. influenzae        M. catarrhalis
Acute otitis media (AOM)        42                     38                   17

Acute sinusitis                 42                     29                   22

Community-acquired
pneumonia (CAP)                20–75                 3–10                    –

Acute exacerbations
of chronic bronchitis           15                     32                   13



                                       Hoberman et al. Pediatr Infect Dis J 1996; 15:955–962
                                             Bartlett & Mundy. NEJM 1995; 333:1618–1624
                                                    Zeckel et al. Clin Ther 1992; 14:214–228
KLINIESE MANIFESTASIES

• CAP kan presenteer as een van 2 sindrome:

  – “ Tipiese” pneumonie

  – “ Atipiese ” pneumonie
      “ TIPIESE “ PNEUMONIE
• Sx en Tx:
  –   Skielike aankoms koors
  –   hoes purulente sputum
  –   pleuritiese borskaspyn
  –   tekens van konsolidasie
• Causative organisms:( most common)
  – S. pneumoniae
  – H. influenza
    “ ATIPIESE PNEUMONIE
• Sx en Tx:
  – Stadige aanvang
  – non produktiese hoes
  – Prominente ekstra pulmonale simptome
    (hoofpyn, mialgie, moegheid, naarheid,
    braking, seer keel)
  – abnormaliteite op X-fotos
• Organismes (mees algemeen)
  – Mycoplasma pneumoniae
  – Chlamydia pneumoniae
  – Legionella pneumophila
           INVESTIGATIONS

• X - fotos
  – bevestig die teenwoordigheid en posisie van
    infiltrate.
  – Selfs normaal by:
     • geen inflammatoriese respons (bv. agranulositose)
     • vrooe staduim van „n infiltratiewe proses. (bv.
       Pneumocystis pneumonie)
           Spesiale ondersoeke
• Sputum
  – Die hoeksteen van die evaluasie. Ongelukkig
    meestal gekontamineer deur patogene
    kolonisasie en orofaringeale organismes.
• Serologiese studies
  – Van waarde by sekere etiologiese tipes
    pneumonie
          Spesiale ondesoeke

• Indringende Prosedures
  – Transtracheale aspirasie:
     • nie algemeen hedendaags
  – Perkutane transtorakale longpunksie
  – Veseloptiese brongoskopie
     • Veilig en goed verdra
     • Goue standaard indringende prosedure.
              Behandeling

• Aanvanklikse terapie meestal empiries op
  grond van:
• situasie waar infeksie opgedoen is
• kliniese beeld
• X-foto bevindinge
• Gevolge van sputum MKS.
• Huidige partrone van gevoeligheid van
  moontlike organismes vir antibiotika.
                TREATMENT
• Empirical Outpatient therapy for CAP
  – “Typical” pneumonia
     •   amoxicillin/clavulanate
     •   2nd generation cephalosporins
     •   doxycycline
     •    older fluoroquinolones
  – “Atypical” pneumonia
     • beta-lactam & macrolide combination
     • doxycycline
              TREATMENT
• Empirical Inpatient therapy for CAP
  – “Typical” pneumonia/moderately ill
     • 2nd /3rd generation cephalosporins
     • ampicillin/sulbactam
     • metronidazole
  – “Atypical” pneumonia - moderately ill
     • beta-lactam & macrolide combination
   Behandeling - CAP - ernstig
        gehospitaliseerd
• Intraveneuse beta laktam met
• met makrolied
• of nuwere generasie kinoloon
  (verbeterde effektiwiteit teen
  pneumokok).
• Pneumonie - klinies
• Weerstandigheid internasionaal
• Farmakologie van antiobiotika
• Oordeelkundige voorkryfmetodiek.
S. pneumoniae: prevalence of penicillin-
 non-susceptible strains – 1992 to 1999
 Prevalence of pen-non-
   susceptible strains
 (MIC 0.12 µg/ml; %)




                                        Felmingham et al. J Chemother 1999; 11:5–21
                          Alexander Project 1998/1999 – GlaxoSmithKline, data on file
                                Alexander Project 1997 (www.alexander-network.com)
S. pneumoniae: prevalence of macrolide-
     resistant strains – 1992 to 1999
   Prevalence of macrolide
          resistance
 (erythro MIC 1 µg/ml; %)




                                           Felmingham et al. J Chemother 1999; 11:5–21
                             Alexander Project 1998/1999 – GlaxoSmithKline, data on file
                                   Alexander Project 1997 (www.alexander-network.com)
H. influenzae: prevalence of -lactamase
    producing strains – 1992 to 1999
 Prevalence of -lactamase-
         producing
     H. influenzae (%)




                                            Felmingham et al. J Chemother 1999; 11:5–21
                              Alexander Project 1998/1999 – GlaxoSmithKline, data on file
                                    Alexander Project 1997 (www.alexander-network.com)
M. catarrhalis: prevalence of -lactamase
    producing strains – 1992 to 1998
 Prevalence of -lactamase-
        producing
     M. catarrhalis (%)




                                      Felmingham et al. J Chemother 1999; 11:5–21
                              Alexander Project 1998 – GlaxoSmithKline, data on file
                               Alexander Project 1997 (www.alexander-network.com)
   The clonal spread of S. pneumoniae 23F

                                              Finland
                                          France
                                         BM4200
                                                 Germany 1994
                                          1978 ?
      Cleveland                         Spain
                                                                     South Korea
Tennessee
Mexico                                                                   Taiwan
                                                                      Hong Kong
                                                                         Philippines
                                                                  Thailand
            Colombia                                                   Malaysia
                                                                  Singapore
                       Brazil



               Chile                               South Africa
                              Uruguay
                       Argentina
               The Alexander Project –
              data from across the globe
• Longitudinal, multi-country surveillance since 1992
• Clinical isolates of community-acquired lower respiratory tract
  infections (RTIs)
• 1999 worldwide collection
   – 8676 isolates
   – 77 centers
   – 23 countries
• 1999 European collection
   – 3662 isolates
   – 25 centers
   – 13 countries
• MIC data for 23 antibacterials, including amoxicillin, penicillin,
                              Slide no                         24
  cefuroxime, erythromycin and amoxicillin/clavulanate
      S. pneumoniae: prevalence of penicillin-
     intermediate and -resistant strains – 1999
                                                                                    Russia
                                                                                  5.0% 2.0%

                                                                                  Poland
   UK                                                                          5.0% 17.2%
5.9% 7.8%
                                                                                   Czech Rep
  Belgium                                                                          1.0% 2.0%
5.8% 12.6%
                                                                                    Slovakia
Switzerland                                                                       15.5% 15.5%
3.2% 11.2%
                                                                                 Germany
                                                                                0.8% 3.9%
   Portugal
 12.9% 9.9%
                                                                                  Greece
            Spain           France      Italy
                                                                               19.4% 29.0%
         9.9% 37.4%      17.2% 45.3% 6.9% 5.9%

   Penicillin intermediate (defined as penicillin MIC 0.121 µg/ml)
   Penicillin resistant (defined as penicillin MIC 2 µg/ml)
                                        Alexander Project data 1999 – GlaxoSmithKline, data on file
    Patterns of antibacterial activity

Pattern                    Pharmacodynamic
                                correlate
Time-dependent killing       Time above MIC
and minimal to moderate         (T>MIC)
persistent effects
Time-dependent killing        AUC/MIC ratio
and prolonged persistent
effects
Concentration-dependent       AUC/MIC ratio
killing and prolonged              or
persistent effects            Peak/MIC ratio
 Pharmacokinetic/pharmacodynamic
parameters correlating with efficacy in
   murine thigh and lung infections
  Time Above MIC     AUC/MIC or Peak/MIC
  Penicillins        Aminoglycosides
  Cephalosporins     Fluoroquinolones
  Carbapenems        Azithromycin
  Monobactams        Tetracyclines
  Macrolides         Vancomycin
  Clindamycin        Ketolides
  Oxazolidinones     Streptogramins
                                      Time above MIC
 Correlation of serum pharmacokinetics with
                    MIC (susceptibility) of an organism
                                  8
    Antibacterial concentration



                                  6
                                                 Drug A
                                                                          X
              (µg/ml)




                                        Drug B                      Time above MIC
                                  4


                                  2
                                          B A

                                  0
                                                             Time
                                           Dosing interval

Drug A present at concentration of 2 µg/ml for 50% of dosing interval
                                of 2 µg/ml for 30% of dosing interval 28
Drug B present at concentration Slide no
                                24-hour AUC/MIC
Correlation of serum pharmacokinetics with
                  MIC (susceptibility) of an organism
  Antibacterial concentration



                                    Area under the curve
                                          over MIC
            (µg/ml)




                                                    Time

       24-hour AUC/MIC is correlated with outcome of infection,
       the magnitude required for success and MIC at which this
       occurs becomes the PD breakpoint
                                 Slide no                         29
         Cefaclor                  20–40 mg/kg/day (bid or tid)
                                   250–500 mg tid or 500 mg ext rel bid

    64                   Pen R: MIC90= >64 µg/ml
                          Pen I: MIC90= 64 µg/ml


Conc.
(µg/ml)             H. infl and M. cat: MIC90= 16 µg/ml

   10
                                                                 Peak 13 µg/ml


                          Pen S: MIC90= 2 µg/ml
    1

                          PK/PD bkpt. 0.5 µg/ml
   0.1
          0                     12 hr                                          24
                     Adapted from Craig et al. Pediatr Infect Dis J 1996; 15:944–948
                and Jacobs et al. Antimicrob Agents Chemother 1999; 43:1901–1908
         Cefuroxime                             30 mg/kg/day (bid)
                                                500 mg bid

Conc.
(µg/ml)
   10                                                  Peak 5.1 µg/ml
                              Pen R: MIC90= 8 µg/ml

                              Pen I: MIC90= 4 µg/ml

    1                                      H. infl and M. cat: MIC90= 2 µg/ml
              PK/PD bkpt. 1 µg/ml



   0.1                      Pen S: MIC90= 0.12 µg/ml
          0                        12 hr                                          24


                        Adapted from Craig et al. Pediatr Infect Dis J 1996; 15:944–948
                   and Jacobs et al. Antimicrob Agents Chemother 1999; 43:1901–1908
         Amoxicillin (S. pneumoniae)
         Amox/clavulanate (H. influenzae; M. catarrhalis)
         45 mg/kg/day (bid); 500 mg tid; 875 mg bid
Conc.
(µg/ml)                                                       Peak 12 µg/ml
   10


                                      Pen R: MIC90= 4 µg/ml
                                      PK/PD bkpt. 2 µg/ml

    1
              Pen I: MIC90= 1 µg/ml                        H. infl: MIC90= 1 µg/ml
                                   M. cat: MIC90= 0.25 µg/ml


   0.1                             Pen S: MIC90= 0.03 µg/ml

          0                              12 hr                                           24
                               Adapted from Craig et al. Pediatr Infect Dis J 1996; 15:944–948
                          and Jacobs et al. Antimicrob Agents Chemother 1999; 43:1901–1908
         Amoxicillin (S. pneumoniae)
         Amox/clavulanate (H. influenzae; M. catarrhalis)
         90 mg/kg/day (bid); 1000 mg tid; 1750 mg bid
Conc.
(µg/ml)
   10

                                      PK/PD bkpt. 4 µg/ml

                                      Pen R: MIC90= 4 µg/ml
    1
              Pen I: MIC90= 1 µg/ml                        H. infl: MIC90= 1 µg/ml
                                   M. cat: MIC90= 0.25 µg/ml


   0.1                             Pen S: MIC90= 0.03 µg/ml

          0                              12 hr                                           24
                               Adapted from Craig et al. Pediatr Infect Dis J 1996; 15:944–948
                          and Jacobs et al. Antimicrob Agents Chemother 1999; 43:1901–1908
         Clarithromycin                     15 mg/kg/day (bid)
                                            250–500 mg bid

                    Macrolide R: MIC90= >32.0 µg/ml
Conc.
(µg/ml)                  H. infl: MIC90= 16 µg/ml
   10
                                                   Peak 2.5 µg/ml
                                                   (parent + metabolite)


    1
                         M. cat: MIC90= 0.5 µg/ml
                         PK/PD bkpt. 0.25 µg/ml

   0.1               Macrolide S: MIC90= 0.06 µg/ml
          0                    12 hr                                         24
                     Adapted from Schito et al. J Chemother 1997; 9(suppl 3):18–28
                and Jacobs et al. Antimicrob Agents Chemother 1999; 43:1901–1908
      Azithromycin                     10 mg/kg day 1; 5 mg/kg d 2–5
                                       500 mg day 1; 250 mg d 2–5
       32
                 Macrolide R: MIC90= >32 µg/ml; AUC:MIC ratio <0.1
       16

        8                   AUC = 3 mg.l/hr
Serum
conc. 4
(µg/ml) 2       Haemophilus: MIC90= 1 µg/ml; AUC:MIC ratio = 3
        1
                Peak conc. = 0.2–0.4 µg/ml
      0.5

     0.25
                             PK/PD bkpt. 0.12 µg/ml
     0.12
                            M. cat: MIC90= 0.12 µg/ml
     0.06
                Macrolide S: MIC90= 0.06 µg/ml; AUC:MIC ratio = 50
            0                         12 hr                                    24


                       Adapted from Drusano et al. J Chemother 1997; 9(suppl 3):38–44
       Ciprofloxacin                       500–750 mg bid

       32

       16
                         24-h AUC = 23–40 mg.l/hr
                         Protein binding 30%
        8
Serum 4                                                 Peak conc. = 2.4–4.3 µg/ml
conc.
(µg/ml) 2
                   S. pneumoniae: MIC90 = 2 µg/ml; AUC:MIC ratio = 12–20
        1
                               PK/PD bkpt. 1 µg/ml
      0.5

     0.25

     0.12

     0.06
                Haemophilus/Moraxella: MIC90 <0.06 µg/ml; AUC:MIC ratio >1000
            0                                12 hr                                     24

                             Adapted from Drusano et al. J Chemother 1997; 9(suppl 3):38–44
                                                              and Craig. Clin Infect Dis 1999
       Levofloxacin                        500 mg qd

       32

       16
                         24-h AUC = 47.5 mg.l/hr
        8
                         Protein binding 31%
                                                              Peak conc. = 5.1 µg/ml
Serum 4
conc.                                  PK/PD bkpt. 2 µg/ml
(µg/ml) 2
        1
                       S. pneumoniae: MIC90 = 1 µg/ml; AUC:MIC ratio = 47
      0.5

     0.25

     0.12

     0.06
                Haemophilus/Moraxella: MIC90 <0.06 µg/ml; AUC:MIC ratio >1000
            0                                12 hr                                     24

                             Adapted from Drusano et al. J Chemother 1997; 9(suppl 3):38–44
                                                              and Craig. Clin Infect Dis 1999
                                  Duration of symptoms in 139
% of patients with symptom              rhinovirus colds

                             70
                                                                                          fever
                             60

                             50
                                                                                       sore throat

                             40                                                          cough
                             30                                                      nasal discharge
                             20

                             10

                             0
                                  1   2   3   4   5   6   7   8   9 10 11 12 13 14
                                                  Day of illness


                                                                             Gwaltney. JAMA 1967; 202:158
              Acute sinusitis

• Antibacterial treatment should be limited to
  patients with:
  – prolonged nonspecific upper respiratory signs and
    symptoms (i.e. rhinorrhea and cough) without
    improvement for at least 10 days
  – worsening of symptoms (i.e. fever  39ºC, facial
    swelling, facial pain, maxillary tooth pain) after
    5–7days
        Relative rank order of predicted
         efficacy in adults with ABRS
Predicted efficacy   Agents

>90%                 amoxicillin/clavulanate
                     gatifloxacin, levofloxacin, moxifloxacin

80%–90%              amoxicillin, cefpodoxime, cefixime, cefuroxime
                     TMP/SMX
                     doxycycline

70%–80%              clindamycin
                     cefprozil
                     azithromycin, clarithromycin, erythromycin

50%–60%              cefaclor, loracarbef

46.6%                placebo (i.e. predicted rate of spontaneous
                     resolution)

								
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