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					           Metricure®
Dr. Sayed Fathy , PhD, Livestock Technical Manager
             Intervet Middle East, Ltd.

                                                     Date 29/02/2012
Positioning statement - Give the new life a clear start

                                       Metricure® is a tailor made
 Uterine infections cause
 decreased fertility in cattle:        intrauterine antibiotic formulation
 ● disruption of ovarian function      developed especially to meet the
                                       requirements of endometritis
 ● interference during fertilization
                                       therapy in cows.
 process
 ● impaired embryonic                  Treatment with Metricure brings
 development and greater               improved fertility giving the
 embryonic losses                      treated cows higher chances to
 A healthy uterus gives the            conceive and carry pregnancy to
 cow a                                 term.
 better chance to conceive and
 maintain pregnancy to term.




                                       2
New clinical classification of uterine infections
Sheldon et al., Theriogenology 65 (2006) 1516–1530
Definition                                        Clinical signs

                           Puerperal metritis
acute systemic illness due to infection           fetid red-brown watery uterine discharge and,
of the uterus with bacteria, usually              usually, pyrexia; in severe cases, reduced milk
within 10 days after parturition                  yield, dullness, inappetance or anorexia, elevated
                                                  heart rate, and apparent dehydration

                          Clinical endometritis
infection of the uterus within 21 days            presence of purulent       (>50% pus) or
or more post partum, not                          mucopurulent               (approx. 50% pus, 50% mucus)
accompanied by systemic signs                     uterine exudate.           No signs of clinical illness.

                         Subclinical endometritis
endometrial inflammation of the uterus            presence of >18% neutrophils in uterine cytology
usually determined by cytology, in the            samples collected 20–33 days post partum
absence of purulent material in the                                  or
vagina                                            >10% neutrophils at 34–47 days post partum
                                                  Usually the main symptom is repeat breeding

                                Pyometra
accumulation of purulent or mucopurulent material within the uterine lumen and distension of the uterus, in
the presence of an active CL
                                                       3
General considerations in the treatment of uterine
infections
 • Type of uterine condition and morphology

  Metritis in early pp.                         Endometritis in later pp. period
  Inflammation process involves                 Inflammation process usually
  practically all layers of uterine wall        involves only endometrium

  The blood-endometrium barrier is              The blood/endometrium barrier
  not yet orphologically/functionally           function is restored
  restored


- It is necessary to    Antibiotics administered         Antibiotics given
reach with AIF and      parenterally will cross the      parenterally have very
AINFL to all layers     B/E barrier and reach            limited chance to cross
                        endometrium and uterine          the barrier and reach
                        lumen                            endometrium &lumen

                                           4
Main directions in the treatment of uterine infections

 Puerperal metritis
     - elimination of bacterial
       contamination
                                                Antibiotics: iu,
                                                E.coli (+), no
                                                irritation
     - improvement of uterine tonicity
                                                                        Optional: PGF*
     - improvement of the function
       of endometrial defence                      Antibiotics:
                                                   i.m, E.coli (+),
                                                   pass B/E
                                                   barrier
     - limitation of the damage caused                         NSAIDs
      by the bacterial toxins and                                       IV therapy
      inflammatory process

 * Data from recent studies support the idea that exogenous PGF2a may have a direct effects
 on uterine immune defences: effects that are independent of luteal function and progesterone
 concentrations. (Lewis 2004)

                                               5
Main directions in the treatment of uterine infections =
                     endometritis
Clinical/Subclinical endometritis

   - elimination of bacterial
     contamination
                                                              Prostaglandins
                                                              if CL present
   - elimination of immunosuppressive
    influence of progesterone
                                                Antibiotics: iu,
                                                A.pyogenes (+)
                                                anaerobes (+),
   - fast return of reproductive function       penetration, no
                                                irritation
                                                          Metricure




                                            6
Requirements for anti-infective preparations used
        in the treatment of endometritis
  low MIC’s for relevant pathogens, also in anaerobic environment

  effective concentration in endometrium

  resistance to penicillinases

  activity in presence of cellular debris

  active at pH 7

  no interference with normal uterine defence

  should be well tolerated and not caustic

  short or no withdrawal period for milk




                                       7
Antibiotics – activity at present
Penicillins
              – susceptible to penicillinase, increasing resistance of Bacteroides spp.
Tetracyclines
              – no inhibition of activity in uterine environment, some increase in bacterial
    resistance noted
Aminoglycosides
              – broad spectrum of activity, reduced activity in anaerobic environment, resistance
    of A.pyogenes and G(-) often found
Macrolides & lincosamides
                        - mainly effective against G(+) bacteria, suitable mainly for the treatment
    of infections with clear prevalence of G(+) bacteria
Cephalosporines
              – active against G(+) (including penicillinase+), very efficient against A.pyogenes
    and other G(-) anaerobes. Maintained activity in the presence of pus and in anaerobic
    conditions
                                                    8
Why Metricure?
 Appropriate antibacterial spectrum = proven high
    activity against A. pyogenes, F. necrophorum
    and other G(-) anaerobes

 Maintained activity in anaerobic conditions

 Ability to reach sufficient levels in endometrium and
    uterine lumen (proven with biopsy studies)
                                                         20 ml injector with uterus pipette
 No negative effect on endometrial defence               each syringe contains 500 mg cephapirin
    mechanisms

 No irritation to endometrium

 No withdrawal time for milk

 Easy to administer, hygienic packaging
                                            9
Bacterial dynamics in (endo)metritis
  Bacteria                                               Acute   Subacute


  A. pyogenes                                           33-83%    33-85%
  Gram neg. anaerobes                                   49-67%    17-70%
  E. coli                                               67-85%     0-17%
  Peptostreptococci                                     60-80%       <5%
  remaining                                             23-52%     7-39%

Bacteriology in uteri infected or non-infected with A. pyogenes

    100
                              Bact spp
                              Fusobact
    80                        E. coli


    60




    40




    20




     0
             A. pyo +                   A. pyo -
                                                   10
Bacteriological efficacy of Metricure

Values of MIC90 of cephapirin (mcg/ml) for the major pathogens involved in clinical
endometritis in cattle

          Bacteria                              MIC90 in mcg/ml


          A. pyogenes                               0.12 – 0.25

          Black pigmented                               0.25
          G(-) anaerobes

          F. necrophorum                                0.12

          Streptococcus spp.                            0.12

          Staphylococcus spp.                           0.25



                                               11
Levels of cephapirin in endometrium



                          100
          % of biopsies




                          80
                          60
                          40
                          20
                           0
                                0.10 mcg/g               0.25 mcg/g
                                       concentration above

  What really counts is that the effective concentrations of cephapirin
  were shown in endometrium through biopsy – the active not only is
  present in the uterine lumen but well inside the endometrium



                                                    12
 Concentrations of cephapirin in endometrium and plasma at 4, 8, 24 and 72 hours after
 administration of Metricure


Hours after administration of Metricure       4h             8h           24h        72h



Concentration of cephapirin in             9.62              23.08       4.9         0.8
endometrium (mcg/g)                       (>38MIC)        (>92 MIC)   (>19 MIC)   (>3MIC)



Concentration of cephapirin in plasma     0.06            0.02        < 0.01      < 0.01
(mcg/g)



MIC90 = 0.25 mcg/ml
Detection limit – 0.01mcg/ml




                                                     13
High concentrations in endometrium –
from features to benefits


                                           Bacteria are eliminated not
                                           only from the uterine lumen but
                                           also from endometrial crypts

  High concentrations of active are        High cure rate and limited
  reached and maintained for at
  least 24h in endometrium                 chance for relapses (no
                                           surviving “hidden” bacteria)

                                           Higher pregnancy rates and
                                           reduced days open = improved
                                           profitability of the herd



                                      14
Why does fast elimination of A.pyogenes brings
 such important benefits?
   Effect of elimination of contamination with A.pyogenes on
   subsequent fertility of dairy cows




                                      15
Selective efficacy against A.pyogenes –
from features to benefits




 Effective elimination of         Fast return of treated cows to full
 A.pyogenes contamination         reproductive potential



                                  Higher pregnancy rates and
                                  reduced days open = improved
                                  profitability of the herd




                             16
Efficacy of Metricure –
results of the independent field trials
Scott McDougall. Effect of intrauterine antibiotic treatment on reproductive performance of dairy cows
following periparturient disease.


 Results:




                                                              17
Efficacy of Metricure –
results of the independent field trials
Kanismanickam et al. The effect of a single administration of cephapirin or
cloprostenol on the reproductive performance of dairy cows with subclinical
endometritis. Theriogenology 63 (2005) 818-830




                                                18
The basic direction for the use of Metricure in
the treatment of uterine disorders in cattle

Metricure has been specially developed for treatment of clinical and
  subclinical endometritis in later post partum period.

Its features match exactly the needs:
   - bacteriological activity focusing on A.pyogenes
   - excellent penetration into endometrium
   - zero withdrawal time for milk
   - proven prompt return to fertility


Metricure should not be used to treat acute puerperal metritis (product
  focusing on E.coli should be selected)



                                          19
Proposed decision tree for the treatment of
endometritis in cows
  Day > 21 pp - Check for size consistence and contents of the uterus
  and presence of vaginal/cervical discharge/add lab methods if in
  doubt

     Endometritis confirmed



  No CL on the ovary               Presence of CL on the ovary



                                         PGF2a i.m. (e.g. Estrumate; 2ml)
  Intrauterine antibiotic                72h later – intrauterine antibiotic
                                         (e.g. Metricure)
  (e.g. Metricure)

                                    20
21
     Thank
      you
22

				
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