Dr. Sayed Fathy , PhD, Livestock Technical Manager
Intervet Middle East, Ltd.
Date 29/02/2012

Positioning statement - Give the new life a clear start
Uterine infections cause decreased fertility in cattle:
● disruption of ovarian function
● interference during fertilization process
● impaired embryonic development and greater embryonic losses
A healthy uterus gives the cow a better chance to conceive and maintain pregnancy to term.
Metricure® is a tailor made intrauterine antibiotic formulation developed especially to meet the requirements of endometritis therapy in cows.
Treatment with Metricure brings improved fertility giving the treated cows higher chances to conceive and carry pregnancy to term.
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New clinical classification of uterine infections
Sheldon et al., Theriogenology 65 (2006) 1516–1530
Definition
Puerperal metritis acute systemic illness due to infection of the uterus with bacteria, usually within 10 days after parturition
Clinical signs fetid red-brown watery uterine discharge and, usually, pyrexia; in severe cases, reduced milk yield, dullness, inappetance or anorexia, elevated heart rate, and apparent dehydration
Clinical endometritis infection of the uterus within 21 days or more post partum , not accompanied by systemic signs presence of purulent (>50% pus) or mucopurulent (approx. 50% pus, 50% mucus) uterine exudate. No signs of clinical illness.
Subclinical endometritis endometrial inflammation of the uterus usually determined by cytology vagina
, in the absence of purulent material in the presence of >18% neutrophils in uterine cytology samples collected 20 –33 days post partum or
>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
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General considerations in the treatment of uterine infections
• Type of uterine condition and morphology
Metritis in early pp.
Inflammation process involves practically all layers of uterine wall
Endometritis in later pp. period
Inflammation process usually involves only endometrium
The blood-endometrium barrier is not yet orphologically/functionally restored
The blood/endometrium barrier function is restored
- It is necessary to reach with AIF and
AINFL to all layers
Antibiotics administered parenterally will cross the
B/E barrier and reach endometrium and uterine lumen
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Antibiotics given parenterally have very limited chance to cross the barrier and reach endometrium &lumen

Main directions in the treatment of uterine infections
Puerperal metritis
- elimination of bacterial contamination
- improvement of uterine tonicity
- improvement of the function of endometrial defence
Antibiotics: iu,
E.coli (+), no irritation
Optional: PGF*
Antibiotics: i.m, E.coli (+), pass B/E barrier
NSAIDs
IV therapy
- limitation of the damage caused by the bacterial toxins and inflammatory process
* Data from recent studies support the idea that exogenous PGF
2 a may have a direct effects on uterine immune defences : effects that are independent of luteal function and progesterone concentrations. (Lewis 2004)
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Main directions in the treatment of uterine infections = endometritis
Clinical/Subclinical endometritis
- elimination of bacterial contamination
- elimination of immunosuppressive influence of progesterone
- fast return of reproductive function
Prostaglandins if CL present
Antibiotics: iu,
A.pyogenes (+) anaerobes (+), penetration, no irritation
Metricure
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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
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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
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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)
No negative effect on endometrial defence mechanisms
No irritation to endometrium
No withdrawal time for milk
Easy to administer, hygienic packaging
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20 ml injector with uterus pipette each syringe contains 500 mg cephapirin

Bacterial dynamics in (endo)metritis
Bacteria Acute Subacute
A. pyogenes
Gram neg. anaerobes
E. coli
Peptostreptococci remaining
33-83%
49-67%
67-85%
60-80%
23-52%
Bacteriology in uteri infected or non-infected with A. pyogenes
33-85%
17-70%
0-17%
<5%
7-39%
60
40
20
0
100
80
Bact spp
Fusobact
E. coli
A. pyo + A. pyo -
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Bacteriological efficacy of Metricure
Values of MIC
90 of cephapirin (mcg/ml) for the major pathogens involved in clinical endometritis in cattle
Bacteria MIC
90 in mcg/ml
0.12 – 0.25
0.25
A. pyogenes
Black pigmented
G(-) anaerobes
F. necrophorum
Streptococcus spp.
Staphylococcus spp.
0.12
0.12
0.25
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Levels of cephapirin in endometrium
100
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
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Concentrations of cephapirin in endometrium and plasma at 4, 8, 24 and 72 hours after administration of Metricure
Hours after administration of Metricure 4h
Concentration of cephapirin in endometrium (mcg/g)
9.62
(>38MIC )
Concentration of cephapirin in plasma
(mcg/g)
0.06
8h
23.08
(>92 MIC )
0.02
24h
4.9
(>19 MIC)
< 0.01
72h
0.8
(>3MIC)
< 0.01
MIC
90
= 0.25 mcg/ml
Detection limit – 0.01mcg/ml
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High concentrations in endometrium – from features to benefits
High concentrations of active are reached and maintained for at least 2 4h in endometrium
Bacteria are eliminated not only from the uterine lumen but also from endometrial crypts
High cure rate and limited chance for relapses ( no surviving “hidden” bacteria )
Higher pregnancy rates and reduced days open = improved profitability of the herd
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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
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Selective efficacy against A.pyogenes – from features to benefits
Effective elimination of
A.pyogenes
contamination
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Fast return of treated cows to full reproductive potential
Higher pregnancy rates and reduced days open = improved profitability of the herd

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:
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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
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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)
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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
Intrauterine antibiotic
(e.g. Metricure)
Presence of CL on the ovary
PGF
2 a i.m. (e.g. Estrumate; 2ml)
72h later – intrauterine antibiotic
(e.g. Metricure)
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