The Use of Antibiotics in Broodmares With Post-service Endometritis
a Knowledge Summary by
Elizabeth Barter BVSc, MRCVS 1*
Annalisa Barrelet BVetMed, MSc, CertESM, MRCVS 1
1Rossdales and Partners, Beaufort Cottage Laboratories, High Street Newmarket, Suffolk CB8 8JS
*Corresponding Author (ebarter@bigpond.net.au)
Vol 3, Issue 1 (2017)
Published: 19 Jan 2018
Reviewed by: Polly Compston (BSc (Hons), BVM&S, MSc) and Adam Swallow (BVSc, AFHEA, MRCVS)
Next Review date: 20 Mar 2019
DOI: 10.18849/VE.V3I1.132
There is currently a lack of evidence to suggest that antibiotics delivered into the uterus post-service improves pregnancy rates. The evidence does support that post-service treatment with or without antibiotics improves pregnancy rates in mares with endometritis compared to no treatment (pregnancy rates between 40-90% compared to 0-56% respectively). The studies further identify the need to recognise mares at risk of post-service endometritis to target appropriate therapy.
Question
In broodmares with post-service endometritis after natural cover, is antibiotic intervention superior to other routine therapies without antibiotic intervention in increasing pregnancy rates?
Clinical scenario
It is well recognised that endometritis decreases pregnancy rates (Le Blanc and Cause 2009). However, there is no clear definition of post-service endometritis (Le Blanc and Cause 2009). When mares are presented post-service, and suspected to have endometritis a decision is required by the clinician to use or not use antibiotics in combination with other routine therapies such as uterine flushing and ecbolic agents. It is often unknown when the clinician is making an assessment if the endometritis is infectious or sterile in origin and mares are currently recommended to be treated with antibiotics regardless of cause (Morel 2003; Blanchard et.al., 2000). The use of antibiotics should be evidence-based to minimise the risk of microbial resistance and opportunist fungal infections (Assad et.al. 2015).
The evidence
Seven publications were identified in the literature searches. These comprised 2 descriptive studies, 1 observational study, 2 randomised non-blinded controlled trials and 2 non-randomised non-blinded controlled trials. Included publications were of level 3 (randomised control trials) or level 4 (lower quality controlled trial) (OCEBM Levels of Evidence Working Group). The outcomes studied varied between the studies including pregnancy rates at 15 days (Pycock and Newcombe 1996; Gores-Lindholm et.al. 2013; Sharma et.al. 2011), 45 days (El-Roos 2004), 60 days (Noseir 2002; Taha 2007), or unknown (Pascoe 1990). Further, there was no standard population treated, antibiotic prescribed or method of administration between the studies.
In the three studies with no case selection any treatment was seen to benefit pregnancy rates over no treatment at all (Pycock and Newcombe 1996; Pascoe 1990; El-Roos 2004). This is similar to mares with a previous history of endometritis with a significantly higher pregnancy rate in mares treated with antibiotics and ecbolic agents compared to no treatment at all (Noseir 2002; Taha 2007). In the two studies which compared mares with and without signs of endometritis and treatment with antibiotics, higher pregnancy rates were achieved in mares that were not treated and had no signs of endometritis (Sharma et al., 2011; Gores-Lindholm et.al., 2013). The findings support the need for case selection in treating mares with post-service induced endometritis.
Summary of the evidence
Population: | 574 Thoroughbreds, 647 hunters (crossbreds) and 46 pony types with ages ranging from 3-22 years and mixed reproductive status (maiden, barren, post-parturient) |
Sample size: | n = 1267 |
Intervention details: | Mares were assigned in rotation to one of four treatment groups.
Group 1: no treatment (n=322) Group 2: intrauterine antibiotic treatment within 72 hours of mating (1200mg procaine penicillin combined with 1500mg dihydrostreptomycin and 900mgs framycetin made to a volume of 12 mls or neomycin (1g) polymyxin B (40,000 iu) and furaltadone (600mg) with crystalline benzylpenicillin (3g). (n=317) Group 3: oxytocin (25 iu) administered by IV injection within 72 hours of mating (n=316) Group 4: oxytocin (25 iu) administered IV followed 30mins later by intrauterine antibiotics as described for group 2 within 72 hours after mating (n=314) |
Study design: | Prospective non-blinded, non-randomised controlled- trial |
Outcome Studied: | Ultrasound pregnancy detection on day 13, 14, or 15 post ovulation and repeat examination between 27-30 days after ovulation. Early embryonic death rate determined by the presence of a vesicle at first scan and absence at second scan |
Main Findings (relevant to PICO question): |
|
Limitations: |
|
Population: | Unknown population of foaling mares bred on foal heat, short cycled and bred at 18 days or bred after 30 days |
Sample size: | n = 1090 |
Intervention details: | Mares were treated post ovulation with plasma and intrauterine antibiotic (n=420 composed of foal heat n=240; short cycled n=100; and bred after 30 days n=80), intrauterine antibiotic alone (n= 450 composed of foal heat n=240; short cycled n=100; and bred after 30 days n=110) or control no treatment (n= 220 composed of foal heat n=120; short cycled n=50; and bred after 30 days n=50). (Antibiotic used was 6 million IU procaine penicillin and 4gm neomycin sulphate) |
Study design: | Observational study |
Outcome Studied: | Conception rate (unknown determination) |
Main Findings (relevant to PICO question): |
|
Limitations: |
|
Population: | Arabian maiden mares ranging from 4 to 8 years with a diagnosis of persistent mating induced endometritis. Mares were determined to have persistent mating induced endometritis if they met one of 3 criteria:
|
Sample size: | n = 42 |
Intervention details: | Mares 6 hours after breeding received a uterine lavage with antibiotics (n=36). 8 hours after breeding mares were divided into 3 groups (n=12 in each group) and received either prostaglandin (250ug cloprostenol SC), or oxytocin (20 I.U IM), or no treatment. Control mares (n=6) received no treatment. Uterine lavage was performed with 500ml N-saline containing 4 million IU of crystalline penicillin and 4g streptomycin sulphate. |
Study design: | Prospective, randomised, non-blinded controlled trial |
Outcome Studied: | Pregnancy rate after 2 months of treatment |
Main Findings (relevant to PICO question): |
|
Limitations: |
|
Population: | Mares aged 4-24 years majority thoroughbred (3 standard bred and 1 quarter horse) |
Sample size: | n = 154 |
Intervention details: | Mares were client owned and divided into groups based on endometrial swab and culture results obtained pre-breeding.
Group 1 (n=44): repeat breeders that had clinical findings suggestive of mucus over-secretion with no evidence of bacterial infection from culture of uterine lavage fluids. Mares were treated with N-acetylcysteine (NAC) 24-36 hours prior to cover followed by oxytocin (20 iu IM) 4-8 hours after infusion Group 2 (n=85): control group of reproductively normal mares presented on their first cycle showing no evidence of infection or inflammation on swab and cytology and intra-uterine fluid <5mm Group 3 (n=25): mares that had previous positive uterine cultures treated with lavage and antibiotics on previous cycle and no evidence of mucus over-secretion, intrauterine fluid >1cm Mares within these groups were additionally treated with intrauterine antibiotics (1g ceftiofur) dependent on previous history and farm management preferences. |
Study design: | Descriptive study |
Outcome Studied: | First cycle pregnancy rate between 13 and 15 days |
Main Findings (relevant to PICO question): |
|
Limitations: |
|
Population: | Thoroughbred mares aged 10-15 years with a history of recurrent and persistent endometritis |
Sample size: | n = 36 |
Intervention details: | Mares were assigned into 4 treatment groups post-mating (9 horses in each)
Group 1: untreated control Group 2: intrauterine infusion of antibiotics (1200mg procaine penicillin with 1500 mg dihydrostreptomycin, and 1500mg gentamicin made up to 20mls) Group 3: single intravenous injection 4-12 hours post-mating of oxytocin (20iu) Group 4: intrauterine infusion of antibiotics and subsequently injected with oxytocin intravenously 30mins later |
Study design: | Prospective, non-blinded, non-randomised, controlled trial |
Outcome Studied: | Pregnancy rates at 60 days post mating either by palpation or rectal ultrasound |
Main Findings (relevant to PICO question): |
There was no significant difference in pregnancy rates between mares receiving intrauterine antibiotics alone (57.3%)or oxytocin administration alone (52.5%). There was, however, a significantly higher pregnancy rate between mares receiving antibiotics combined with oxytocin (67.8%) compared to other treatment groups. There was a significantly higher pregnancy rate in all treatment groups compared to the control (22.5%). |
Limitations: |
|
Population: | Native bred mares both barren and lactating |
Sample size: | n = 115 (60 barren and 55 lactating) |
Intervention details: | Post-breeding mares were randomly assigned into 9 treatment groups. Group 1: no treatment (control) (n=13, 7 barren, 6 lactating) Group 2: intrauterine infusion of 120mls of homologues plasma (n=15, 7 barren, 8 lactating) Group 3: intrauterine infusion of leukocyte enriched plasma (n=14, 7 barren, 7 lactating) Group 4: intrauterine infusion of antibiotics (5x106 IU procaine penicillin and 2g streptomycin sulphate) (n=11, 6 barren, 5 lactating) Group 5: intrauterine infusion of plasma and antibiotics (n=12, 6 barren, 6 lactating) Group 6: intrauterine infusion of antibiotics and leukocyte enriched homologous plasma (n=13, 7 barren, 6 lactating) Group 7: intravenous injection with oxytocin at 0, 12, and 16 hours post breeding (n=11, 6 barren, 5 lactating) Group 8: intrauterine infusion with homologous plasma and intravenous oxytocin given at breeding. (n=12, 6 barren, 6 lactating) Group 9: intrauterine infusion of leukocyte enriched homologous plasma and intravenous oxytocin given at breeding (n=14, 8 barren, 6 lactating). Breeding and treatment was repeated every 48 hours until ovulation was detected |
Study design: | Prospective, non-blinded, randomised controlled trial |
Outcome Studied: | Pregnancy confirmed by ultrasound at 45 days |
Main Findings (relevant to PICO question): |
Higher pregnancy rates were achieved with the combination of leukocyte enriched plasma and oxytocin (72%), compared to leukocyte enriched plasma and antibiotics (61%) |
Limitations: |
|
Population: | Thoroughbred mares in India aged from 3 years to greater than 18 years |
Sample size: | N = 253 mares, (n= 1976 oestrous cycles) |
Intervention details: | Untreated oestrous cycles (n=1619) (control) with treated oestrous cycles (n=357) receiving either:
|
Study design: | Descriptive study |
Outcome Studied: | Day 16 and day 39 pregnancy rates |
Main Findings (relevant to PICO question): |
Significantly higher (p<0.05) day 39 pregnancy rates and foaling rates observed in untreated oestrous cycles (46.39%) than treated cycles (40.62%). No difference in pregnancy rates between treated oestrous cycle and untreated oestrous cycle at day 16 of pregnancy (46% and 51% respectively)
The incidence of uterine therapies increased with increasing age |
Limitations: |
|
Appraisal, application and reflection
Post-service endometritis is a common condition and can be challenging for the clinician to diagnose and treat. Current treatment options for endometritis include intrauterine antibiotics, lavages (LRS or antibiotic infused), other uterine infusions such as mucolytics (NAC, EDTA), immune modulation treatments (plasma), and ecbolic agents (oxytocin and / or prostaglandin). The purpose of this Knowledge Summary was to evaluate the evidence comparing the use of intrauterine antibiotics in the treatment of endometritis to other routine therapies.
The diagnosis of post-service endometritis can be challenging for the clinician and varied between the studies. 4/7 studies compared treatments in mares affected by endometritis whilst the remaining studies compared treatment in all mares. Two studies gave descriptions of how they diagnosed endometritis. Sharma et.al., (2011) and Noseir (2002) treated mares with endometritis with no definition stated. Taha (2007) defined persistent mating induced endometritis as a history of repeat breeding of more than 3 natural services without a pregnancy, intrauterine fluid one to two days after breeding, or endometrial cytology showing >5% PMN’s. Gores-Lindholm et.al., (2013) diagnosed endometritis based on previous cycle uterine lavage fluid with a positive culture, repeat breeding of at least 2 cycles or 2 unsuccessful embryo transfer attempts. The lack of a consistent definition of endometritis makes comparison of treatment options challenging.
The use of controls that did not receive antibiotics was highly variable amongst the studies. The most consistent comparisons used between the studies were either no treatment or ecbolic agents alone. 6/7 studies compared no treatment as a control (Pycock and Newcombe 1996; Pascoe 1990; Taha 2007; Gores-Lindholm et.al. 2013; Noseir 2002; Sharma et.al 2011), while 4/7 studies compared oxytocin at intervals ranging from 1-72 hours post mating [(Pycock and Newcombe 1996) 72 hours post mating, (Noseir 2002) 4-12 hours post mating, (El-Roos 2004) 1, 12, 16 hours post mating, (Sharma et.al. 2011) unspecified time/s]. Taya (2007) was the only study to evaluate the use of prostaglandin as an ecbolic agent. Consistently it was observed that treatment of mares with endometritis improved pregnancy rates over no treatment at all (Pycock and Newcombe 1996; Pascoe 1990; Taha 2007; Gores-Lindholm et.al. 2013; Noseir 2002; Sharma et.al 2011). Ecbolic agents and antibiotics had similar improvement to pregnancy rates when used alone (Pycocok and Newcombe 1996; Noseir 2002). The combined effect of antibiotics and ecbolic agents were seen to act in synergy and further improve pregnancy rates (Pycock and Newcombe 1996; Taya 2007; Noseir 2002).
Intrauterine antibiotics have been postulated to not only aid in the treatment of potential pathogens but also by cervical dilation enhancing fluid removal (Pycock and Newcombe 1996). The combination of oxytocin to stimulate uterine evacuation and manual dilation of the cervix has been similarly treated with the use of plasma and uterine lavages (Sharma et.al. 2011; Gores-Lindholm 2013; El-Roos 2004). Gores-Lindholm (2013) demonstrated no significant difference in pregnancy rates for mares previously treated for endometritis with lavage and oxytocin (50%) compared to lavage, oxytocin and antibiotics (62%). Similarly, Sharma et.al (2011) showed no difference in day 16 pregnancy rates in mares treated with uterine lavage and oxytocin (52%) and intra-uterine antibiotics and oxytocin (45%). While the type, volume of antibiotic and method of antibiotic installation varied between the studies, all involved uterine placement which would have led to cervical dilation.
Supporting the use of antibiotics are culture and sensitivity studies. Common bacterial isolates in endometritis include beta-haemolytic streptococcus, corynebacterium spp, and Escherichia coli (Assad et.al 2015). In all studies, the choice of antibiotic was empirical and not determined by culture and sensitivity results. Four of the studies used a combination of procaine penicillin with streptomycin, gentamicin, framomycin, and or neomycin (Pycock and Newcombe 1996; Pascoe 1990; Taha 2007; Noseir 2002) whilst one study used ceftiofur alone (Gores-Lindholm 2013). Two studies did not comment on the antibiotic used (Sharma et.al., 2011 ; El-Roos 2004), and no studies commented on the use of systemic antibiotics. Whilst the types of bacteria isolated are likely to vary geographically, Assad et.al., (2015) showed all isolates were sensitive to gentamicin and ceftriazone (100%) followed by tetracycline and chloramphenicol (92.8%). There was widespread resistance against streptomycin (92.8%) and penicillin (50%) which were commonly used in the studies. Sensitivity patterns varied based on which bacteria were isolated, with streptococcus spp having maximum sensitivity to gentamycin and tetracycline antibiotics (100%) and moderate sensitivity to penicillin (71.4%), while E. coli isolates were 100% resistant to ampicillin and streptomycin. Indiscriminate use of antibiotics has shown to increase the risk of fungal and resistant bacterial species (Assad et.al. 2015). Further use of diagnostics to identify the bacterial isolate(s) involved, and antibiotic sensitivity, may aid in the reduction of restricted antibiotics such as tetracyclines and chloramphenicol.
The outcome achieved varied between the studies, with different days of gestation considered. Majority of the studies examined for pregnancy at 13-16 days (Sharma et. al 2011; Gores-Lindholm et.al 2013; Pycock and Newcombe 1996), whilst two studies examined only later at 45 days (El-Roos 2004), and 60 days (Taha 2007). 2/7 studies (Pycock and Newcombe 1996; Sharma et. al. 2011) commented on embryonic loss with uterine treatments by comparing pregnancy rates at 12-16 days to 28 days. There was no significant difference in embryonic loss in either study, however Pycock and Newcombe (1996) noted a higher embryonic loss when antibiotics were installed via a syringe compared to a catheter system. Early embryonic loss is estimated to be between 2.6% to 24% due to progesterone deficiency or failure of maternal recognition (Vanderwall 2008). Such that the later scanning dates in the studies by El-Roos (2004) and Taya (2007) may have had a higher negative pregnancy rate from early embryonic loss rather than failure to conceive.
Post-service endometritis is a multifactorial disease and can be challenging to manage. Currently the collective data supports the combined use of intrauterine treatments and ecbolic agents to increase pregnancy rates in mares with a history and or signs of endometritis. It is unclear if similar pregnancy results may be obtained with cervical dilation methods that do not include antibiotics in combination with ecbolic agents alone. Further, this summary identifies the need for ongoing research into defining which mares have endometritis in order to determine those that may benefit from treatment. Additional diagnostics such as culture and cytology of endometrial samples post-service could be utilised by clinicians to justify antibiotic usage. Currently clinicians should use intrauterine antibiotics judiciously as they are unlikely to improve pregnancy rates and may be detrimental to fertility in mares with no history or signs of endometritis.
Glossary
EDTA - Ethylenediaminetetraacetic acid
LRS - Lactate Ringer’s solution
NAC - N-acetylcysteine
PMN - Polymorphonuclear Cell
Methodology Section
Search Strategy | |
Databases searched and dates covered: | Search terms were applied in PubMed Central accessed on NCBI website (1910-2017), CAB abstracts database accessed on OVID platform (1973-2017) |
Search terms: | CAB Abs
PubMed
|
Dates searches performed: | March 2017 |
Exclusion / Inclusion Criteria | |
Exclusion: | Non-English language, narrative or non-systematic review articles, unpublished data, pharmacokinetic, in vitro or in vivo experimental studies, artificial insemination protocols. |
Inclusion: | Any reported use of antibiotics used in post-service treatment from natural coverings. |
Search Outcome | |||||||
Database |
Number of results |
Excluded – non-English language publication |
Excluded – non-systematic review article, conference proceeding or letter |
Excluded – artificial chilled or frozen insemination |
Excluded – pre-service treatment not post service |
Excluded – did not answer PICO question |
Total relevant papers |
CAB Abstracts |
53 | 3 | 15 | 6 | 2 | 20 | 7 |
NCBI PubMed |
25 | 1 | 5 | 2 | 0 | 15 | 2 |
Total relevant papers when duplicates removed |
7 |
The authors declare no conflicts of interest.
Intellectual Property Rights
Authors of Knowledge Summaries submitted to RCVS Knowledge for publication will retain copyright in their work, and will be required to grant to RCVS Knowledge a non-exclusive licence of the rights of copyright in the materials including but not limited to the right to publish, re-publish, transmit, sell, distribute and otherwise use the materials in all languages and all media throughout the world, and to licence or permit others to do so.
Disclaimer
Knowledge Summaries are a peer-reviewed article type which aims to answer a clinical question based on the best available current evidence. It does not override the responsibility of the practitioner. Informed decisions should be made by considering such factors as individual clinical expertise and judgement along with patient’s circumstances and owners’ values. Knowledge Summaries are a resource to help inform and any opinions expressed within the Knowledge Summaries are the author's own and do not necessarily reflect the view of the RCVS Knowledge.