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ANTIBIOTIC THERAPY STATE OF THE ART bronchitis

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					ANTIBIOTIC THERAPY:
     STATE OF THE ART



    Iwan Darmansjah, MD
PUKO, Clinical Trial Center, FKUI
    What is “the State of Art”?
   Establish diagnosis (history, PD, auxilary aid needs)
   Decide on AB or non-AB therapy.
   Empiric treatment first.
    – Culture needed before using AB?
    – Attack most common pathogen and its sensitivity pattern by
      educated guess.
    – Narrowest spectrum possible.
    – Anticipate response time, in order to decide whether to
      change the AB, previously used by educated guess.
    – Evaluate progress.
   Pathogen-specific therapy - when culture is ready.
   Apply AB with high AUC/MIC or Cmax/MIC ratio.
    “Points to Consider” Doc. (FDA) (Nov.26,
    1996 http://www.fda.gov/cder/guidance/ptc.htm)



   Indication, Claim and Use of ABs has been
    confusing.
   C.T. data are not very specific and labeling of an AB
    is equally unclear.
   Equivalence and superiority claims, and even
    unrestricted effectiveness claims have been granted.
   A new doc.”Specific Points to Consider” is being
    introduced to rectify “Clinical development and
    labeling of anti-infective drug products”, (see:
    respiratory tract drugs). 24-25 new Specific Infections
    have so far been included.
              What is the State of Art?
                Points to Consider
   Community vs Hospital acquired.
    – Use different approaches in AB selection.
    – Resistant or non-resistant case?
   Use Evidence-based Guidelines.
    – How strong was that evidence?
      RCT(s); open trial, expert opinion, etc?
   Recognize different settings between
    origin of guideline and local condition(s).
   Eradicate MO completely with first encounter to minimize
    resistance!
AB Therapeutic Standards

   Selection of AB
                           Use of
   Dosing Regimens
                            trustworthy
   Adverse Reactions
                            Guidance
   Costs                   documents.
        DIAGNOSIS
                                              * CLINICAL ONLY
FALSE   CORRECT      INSECURE                        OR
                                           WITH DIAGNOSTIC AIDS


            *        FALSE
                                      THROUGH SCIENTIFIC OR
                  ASSUMPTION          “SCIENTIFIC” ARGUMENT
                       +
                  IMAGINATION
   DOCTOR :                        * DRUG INDUSTRY FACILITATING
   • PRIDE                              “SCIENTIFIC” IMAGINATION
   • PROFIT                         * PATIENT’S PRESSURE
   • IGNORANCE
            *     DEFENSIVE
                   THERAPY
                                     MORE DRUGS USED
                                     THAN NEEDED

            *          IRRATIONALITY
                             +
                  SIDE EFFECTS INCREASED
PRINSIP UMUM PENGGUNAAN AB
DIDASARKAN RASIO            MANFAAT
                             RISIKO
   TEMPAT INFEKSI
   SPEKTRUM AB ( INDIKASI)
   SIFAT FARMAKOKINETIK AB, dll
   EFEKTIVITAS KLINIS/ HASIL UJI KLINIS
   PENGALAMAN KLINIS
   KEAMANAN AB and “MASKING EFFECT”
   POTENSI TIMBULNYA RESISTENSI
   BIAYA OBAT
    STRATEGI PEMILIHAN AB
   AB dgn SPEKTRUM SESEMPIT MUNGKIN BILA
       KUMAN PENYEBAB PEKA,
       KECUALI BILA KUMAN PENYEBAB ??
   PENISILIN G SEBAIKNYA TIDAK DIGANTI dgn
    AMPISILIN.
   SEBAIKNYA: AB TUNGGAL dgn DOSIS CUKUP.
   PILIHLAH AB yg DIANJURKAN.
   PRINSIP “HEMAT”.
   AB yg BAIK UNTUK INFEKSI BERAT TDK
    SELALU BAIK UNTUK yg RINGAN.
     Mis. : FLUOROQUINOLONE
           AMINOGLIKOSIDA
           SEFALOSPORIN G 3
           LINKOMISIN
KAPAN MENGGUNAKAN AB PADA KEADAAN DEMAM ?

INDIKASI PASTI         INDIKASI SAMAR     TDK ADA INDIKASI

INFILTRAT              INFLUENZA          MALARIA
ABSES                  CAMPAK             HEPATITIS VIRUS
ERISIPELAS
TONSILITIS AKUT LAK.   VARISELA           MONONUKLEOSIS
PNEUMONIA              PENY. VIRUS LAIN   PAROTITIS EPIDEMIKA
OTITIS MEDIA AKUTA     (KOMPLIKASI?)      HERPES ZOSTER
U T I AKUT
LIMFADENITIS BAKT.     BRONCHITIS         HODGKIN
MENINGITIS             KOLESISTITIS       SLE
TBC AKTIF              APENDISITIS        DEMAM OBAT
LEPTOSPIROSIS
TIFOID                 PROFILAKSIS
SEPSIS, etc.           FUO
              What is FUO?

   Illness > 3 weeks

   Documented fever > 38.30 C

   Negative diagnostic evaluation during
    1 week in hospital.
     PERLUKAH DIBUAT ANTIBIOGRAM ?

   MUNGKINKAH AB DIPAKAI
      TANPA DIBUAT ANTIBIOGRAM ?

             “EDUCATED GUESS”


   BERDASAR TEMPAT INFEKSI
          -KULIT, Tr. URINARIUS, MULUT/GIGI
                                    ATAS
          -JALAN PERNAFASAN
                                    BAWAH
          -ABDOMEN – DSB
   PILIHAN DIDASARKAN PENYEBAB PALING SERING
   POLA RESISTENSI (SETEMPAT)
KAPAN DIPERLUKAN KULTUR ?

•   INFEKSI SALURAN KEMIH KRONIS
•   DUGAAN DEMAM TIFOID.
•   “FEVER OF UNKNOWN ORIGIN “.
•   SEPSIS.
•   PENYAKIT INFEKSI YG KRONIS DAN
    BERAT.

      KULTUR PERLU DILAKUKAN
        SEBELUM DIBERI AB
“ There is no such UNIVERSAL
antibiotic good for all infections
                “

 “The newest antibiotic is not
necessarily the better antibiotic
               “
 What new ABs are NOT for :
Fluoroquinolones : - skin and oral infections
                   - upper resp. tr. Infections (not first)
                   - lower resp. tr. inf. (after culture)

Azithromycin      : - common urinary tr. inf.
                    - serious inf.

Cephalosporins (oral) : serious infections

Amox-clavulanic acid :
    - simple inf. / community acquired
    - non-beta-lactamase producers
    Narrow Spectrum Abs should be chosen
       when indicated by MO involved:

   PENICILIN G
   PENICILIN V
   ERYTHROMYCIN
   SPIRAMYCIN
   LINCOMYCIN/ CLINDAMYCIN
   ROXITHROMYCIN
   CLARITHROMYCIN +
   AZITHROMYCIN +
           BENEFIT- RISK of
       PENICILLIN G INJECTION
Assume :

1960’s : All doctors in Indonesia inject PP for every
         case of fever with/without infection.

Then…. 20.000 X 10 pat./day=200.000 injections/day.
In 1 year : 300 (days) X 200.000 inj.= 60.000.000 inj
         1 Anaphylactic Shock per 50.000 pat.
Then…. There will be: 60.000.000/50.000 =
              1200 A.S. annually

Assume : 10 % fatality rate : then...120 Deaths
                                         annually
      BENEFIT- RISK of
 PENICILLIN G INJECTION (2)
Assume :

Now : with Evidence-based therapy

Estimated…. 20.000 X 1 pat./week= 20.000 injections/wk.
In 1 year :     50 X 20.000= 1.000.000 injections.
Then …. 20 A.S. annually with ca. 2 fatal cases/year.

THIS IS MORE ACCEPTABLE !!
    KEGAGALAN PENGOBATAN
•    Demam bukan karena infeksi kuman
     (Virus atau sebab lain)
•    Kuman membentuk PENISILINASE
     (PENISILIN G           KLOKSASILIN
      AMOKSISILIN         + KLAVULANAT)
•    Salah tafsir kuman penyebab
•    Terdapat nanah (perlu disalir)
•    Superinfeksi
•    Timbul Drug Fever:
            - Sulfa / Kotrimoksazol
            - Penisilin/ Ampisilin
            - Sefalosporin
 AB Cyt. P-450 Related Interactions
      (clinically significant)
Inhibits Cyt.P-450:   Anticoagulants oral -- hypoprothromb.>
                      Carbamazepine toxicity -- >
 Erythromycins
                      Cisapride --Ventric. Arrhytmia
 Fluconazole         Digoxin bl.levels -- >>
                      Dilantin bl.levels -- <
 Itraconazole        Terfenadine -- Ventric. Arrhytmia
                      Theophylline bl.levels -- >
 Ketoconazole        Valproate bl.levels -- >



Induces Cyt. P-450:   Anticoagulants -- hypothrombinaeia <
                      Chloramphenicol levels -- <
 Rifampicin          Contraceptives levels -- <
                      Corticoster. levels -- <
                      Cyclosporine levels -- <
        Typhoid Management
   Chloramphenicol 10 days (oral gives
    higher blood levels than IV !!).
   Cipro or Oflox for 8-10 days.
   Amp and cotrimox are less effective.
   Ceftriaxone or cefotaxime when IV is
    needed.
   Gentamicin is contraindicated.
   Bed-care is more important than diet.
      S. typhi antibiogram (Case:4yrs)
                           (µg/mL)

Cfz   <2   Amp   <2   Sx       > 256   Chl       <8
                               R
Cfx   <2   Pip   <8   Cf        <8     Cfm      <8

Crm    4   Tic   <8   Fd        < 32   Amo/Cl   < 8/4

Caz   <2   Gm    <1   Tob       <4     Nxn      <4

Cax   <4   Ak    <2   Ti/Cla    < 16   Imp      <4

                      Tr/Sx    < 2/38 Cip       <1
             M. tuberculosis

   Resistant cases should be treated with
    the usual agents PLUS:

    Cipro or Oflox or Amik or Doxyc (less
    data)
    Respiratory Tract Infections
            (FDA “Points to Consider” doc.)
   The terms of URTI and LRTI are being
    refined by more specific infections:

 5. Community-acquired pneumonia
 6. Nosocomial pneumonia
 7. Acute bacterial exacerbations of chronic bronchitis
 8. Secondary bacterial infections of acute bronchitis
 9. Acute otitis media
10. Acute sinusitis
11. Streptococcal pharyngitis
    (More will be produced in response to industry’s application of claims)
    Community acquired pneumonia (1):
         (FDA “Points to Consider” doc.)
Differentiation of CAP acc. to Label Claim:

   Atypical pneumonia
   Viral peumonia
   Acute bacterial pneumonia
   Aspiration pneumonia
   Ventilator-associated pneumonia
   Pneumonia in an immunocompromised
    and/or neutropenic host.
    Community acquired pneumonia (2):
          (FDA “Points to Consider” doc.)

Differentiation made for bacterial
 pneumonia:
   Pediatric patients:
          –   no sputum for culture
          –   infants 3-24 mo higher baseline value for fever
          –   WBC count >15000 usually assoc. with severe inf.
          –   Radiographic findings different, etc

   Geriatric patients: ……………..
        New Pediatric Studies
    will change current State of the Art
   Pediatric studies are rare, although FDA
    recommended since 1970s.
   There will be more Pediatric Clinical
    Trials in the future to support claim.
   FDAMA (1993) and the Pediatric
    Exclusivity Right Act (1997) will make
    the above an incentive for the industry.
    Community acquired pneumonia (3):
           (FDA “Points to Consider” doc.)

Therapeutic principles:
 common bacterial pneumonias:
          – 5 -10 days AB therapy

   pneumonia due to M.pneumoniae,
    Chlamydia pneumoniae:
       • outpatient (recomm.): 10 -14 days AB therapy
       • inpatient: 14 - 21 days
   Legionnaires’ dis.: 14 - 21 days (hosp.)
      Susceptibility of S.pneumoniae to commonly used
      ABs, stratified by susceptibility to penicillin

                             Susceptibility to indicated agent,
                             per penicillin MIC category
       Agent
                      < 0.1 µg/mL        0.1-1.0 µg/mL        > 2 µg/mL

Amoxicillin ……..      +++                 +++                     +
                                                                          +++ : > 90%
Doxycycline           +++                  +                      +/-
Ery, Clari, Azi-      +++                   +                     +/-
                                                                          ++ : > 75%
Clindamycin           +++                 ++                       +
TMP-SMZ …….           ++                    _                      _
                                                                           + : > 50%
Cefuroxime            +++                   +                      _
Cefotaxime            +++                 +++                      +
                                                                           +/- : > 40%
Levo, Grepa, Trova-   +++                 +++                     +++
Imipenem              +++                 +++                       _
                                                                            - : < 40%
Vancomycin …..        +++                 +++                     +++
Empirical Selection* of AB in CAP
             (IDSA 2000)            (1)
 Not requiring hospitalization:
     - erythromycin, clarithromycin,
     azithromycin, doxycyclin, levoflox,
     moxiflox, or gatiflox.
    Alternate options:
     - amox-clav, cefuroxime, cefpodoxime,
         cefprocil
    (What about penicillin G??)
        * Selection based on multiple variables.
Empirical Selection* of AB in CAP
                   (IDSA 2000)           (2)
   Hospitalized patients:
    - cefotaxime or ceftriaxone + ery, clari, or azithro; or
    - levoflox, gatiflox, moxiflox, trovaflox.
   In ICUs:
    - cefotaxime, ceftriaxone, ampi-sulbact, or piperac-
      tazobact + macrolide or fluoroquinolone.
Special considerations:
    - Ps aeruginosa,
    - Clindamycin to substitute for beta-lactam allergy,
    - Aspiration: beta-lactam/beta-lactam inhibitor +
                  metronidazole or clindamycin.
           Organ Specific Infections
        according to evidence: (Bartlett: 2000)
   Acute otitis media: Amox; Alt: Cotrim, amox-clav, ery+SMA, cefurox,
    cefacl, tetra, ceftriax (Parent.)
   Chronic OM: Otic drops (Neo-Polymyx-hydrocort); Chloram.
   Malignant OE: Cipro; Alt: Tobra-ticar, piperacil, mezlocil,
    cefoper,ceftazid, aztreon, cefepime, imipenem, cipro.
   Ac.diffuse OE: Neo-Polymix drops; Chloram or boric / acetic acid
    drops.
   Otomycosis: Boric or acetic acid drops, cresylate actic acid drops.
   Acute mastoiditis: Amox; Cefotaxime or ceftriaxone.
   Chronic mastoiditis: None; surgery

   Sinusitis acute: Amox; cefurox, amoxi-clav, levo,moxi,gati, clari,
    azithro, cefpodox, cefpro, cefdinir, loracarbef, doxyc.
   Sinusitis chronic: Penic, amox; amox-vlav, clinda.
           Organ Specific Infections
        according to evidence: (Bartlett: 2000)
   Pharyngitis (Strep. Pyogenes): Penic oral 10 days; Benzathine
    penicillin.
   Peritons or tonsillar abcess (Strep pyogenes): Penicillin G;
    clinda.
   Membraneous pharyngitis (C.diphteria): Penic or
    erythromycin.
   Epiglottitis: Cefotax, ceftizox, ceftriax, cefurox.
   Parotitis (S.aureus): Penicillin resistant penic.
   Dental: Penicillin, clinda.
   Aphtous stomatitis: Topical corticosteroid.; oral corticosteroid
    (few days)
   Skin and Soft Tissue -
       AB Selection
MO: Strep. pyogenes, S.aureus. (mostly streptococcal)
Impetigo, erysipelas, cellulitis:
    - Penicillins, erythromycins.
Severe form: necrotizing fasciitis or myositis,
    empyema (prompt surgery!).
        - Dicloxacillin (flucloxacillin), clindamycin  penicillin

    .
     Urinary Tract Infections

Symptomatic UTI may be seen as:
A. Cystitis / pyelonephritis:
  with fever + leucocytosis + neutrophils shift to the left.


B. Irritative symptoms only:
  Urinalysis: WBC < 10 / field.
  No culture needed.
  Water treatment, but No AB treatment is needed.
      UTI Antibiotic Therapy
           (IDSA recommendations)
Uncomplicated bacterial cystitis (3 days):
      - Cotrimoxazole or TMP
     - Oflox, Cipro, other quinolone
     - Beta-lactams inferior
     - Nitrofurantoin (7 days)

Pyelonephritis:
 Oral: - Fluoroquinolone
      - Cotrimoxazole if sensitive.
 Parenteral (hospitalized): - Fluoroquinolone, Amik + ampi,
      -Ceftriaxone/cefotaxime + Amik, Ampi-sulbactam + Amik.
       Anaerobic Infections

   Metronidazole (best)
   Chloramphenicol
   Imipenem / meropenem
   Betalactam/betalactam-inhibitor combin.
   Clindamycin
   Antistaph. penicillins
   Cefoxitin
                   Diarrhea
   Common diarrhea needs no AB.
   Oralit is best when diarrhea is profuse;
    should take by small sips.
   Food: no chilli, hot sauce, milk, fatty food
   AB may be needed when assoc. with
    cramps, fever, and foul stools:
    Cipro or oflox (1-3 days), cotrimoxazole.
             Tinea Corporis

Diagnosis is often missed.

   Griseofulvin 500 mg/day for 3 weeks;
    boil underwear for one hour on day 10-11.

   Topical agents disappointing.
 What is the Bottomline of



“Art” in Antibiotic Therapy ?
      Antibiotics, a unique
          drug group
   Widely used through misuse.
   Life-saving when appropriately used.
   Kill when wrongly applied.
   Destructive when overused.
   Personal and wide social impact.
   And yet … the least recognized!
Collective Leadership Needed

   Prescribing Specialists must change and
    become role models;
    you are being followed by others!
   Start Campaigning: A large-scale initiative is
    being organized in the US and the World,
    called: “A Public Health Action Plan to
    Combat Antimicrobial Resistance” (June 00).
   URL: http://www.cde.gov/drugresistance/actionplan
             Special Issues (1)
   Are FDA/IDSA guidelines fully applicable in
    Indonesia, in the face of lack of trusted data
    (lab/resist. and epidem.) and different needs?
   The RCT is still the gold standard, but not
    enough to assess what treatment is best in
    each individual case.
   CTs are biased in many ways, - and full of
    caveats.
   It excludes patients with non-susceptible MO,
    seriously ill patients and the very old. Making
    empiric therapy not always applicable.
             Special Issues (2)
   Long-term outcome studies are rare - costly.
   Comparative drugs used in CTs are often
    biased.
   AB equivalence studies use weak design and
    analytical methods (small N, not using a “two-
    tailed 95% CI between the difference of
    outcomes”).
   The clinical activity of an AB in treating similar
    infections in other body sites are seldom
    revealed.
                Special Issues (3)
   Total AB consumption is low, but skewed.
   Should we stop using penicillin G injections?
   Should we always use the newest AB?
   But, should the Health Department still advocate
    the use of TMP/SMZ in upper respiratory tract
    infections in the light of its low efficacy and safety
    profile, except for its low cost?
   Lastly, AB cost is soaring, and becoming a
    luxury! (The latest: linezolid costs ca. Rp 400.000 / tab)

				
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