IN-DEPTH: CONDITIONS AND MANAGEMENT OF THE PERIPARTUM MARE


treated with TMP-SMX after diagnosis of placentitis via ultrasonography had a negative outcome.31,50 Furthermore, it has been demonstrated that TMP- sulfonamide drugs lose potency in the presence of purulent material and that horses treated with TMP-SMX or TMP-SDZ remained culture-positive for the infective organism after prolonged treatment.26,32,41,51 Using an ex vivo model of antibiotic activity, the authors recently confirmed that TMP-SMX was in- activated in the face of purulent uterine fluid, as was gentamicin and ceftiofur. In contrast, in the same model, penicillin and gentamicin together retained activity in purulent fluid.33,52 Ongoing work in the authors’ laboratory has further demonstrated dose- dependent activity of ciprofloxacin in purulent fluid, with bactericidal activity achieved at doses previ- ously found in equine allantoic fluid (KA Von Dollen, unpublished data).53 This dynamic is of interest for both ascending placentitis and nocardioform placentitis, which are characterized by necrotizing and mucopurulent inflammation. It is possible that a systemically administered TMP-sulfonamide reaches concentrations in uninfected allantoic fluid and fetal tissues sufficient to prevent bacterial spread, but that it is unable to inhibit bacterial growth locally in the chorioallantoic space. It may be necessary to add additional antibiotics, such as penicillin with gentamicin, or a fluoroquinolone to have an immediate bactericidal effect.


Anti-Inflammatory and Immune Modulating Therapies


Nonsteroidal anti-inflammatory (NSAID) therapy is commonly recommended for clinical cases of placen- titis. Prostaglandins are produced in response to inflammation through conversion of arachidonic acid by cyclooxygenase (COX) enzymes including COX-1 and COX-2.54 These prostaglandins, in turn, promote uterine contractility and premature delivery. Flunixin meglumine has been shown to mitigate the effects of endotoxin in mares in early gestation, abating prostaglandin production and promoting pregnancy maintenance.55 This was confirmed ex vivo in placental tissue exposed to ei- ther endotoxin or heat-killed Streptococcus zooepi- demicus organisms.20 More recently, Macpherson and colleagues56 treated mares with experimentally induced placentitis with firocoxib, a COX-2-selective NSAID, utilizing a loading dose of 0.3 mg/kg by mouth, followed by 0.1 mg/kg by mouth every 24 hours for the remainder of gestation. Mares who received firocoxib displayed decreased concentra- tions of interleukins (IL) IL-1, IL-10, TNF-, and


PGF2 in the allantoic fluid, as compared to un- treated animals. Pentoxifylline is an immune modulator with mul-


tiple potential modes of action, including decreasing the release of proinflammatory cytokines, enhancing blood flow, and diminishing bacterial adhesion.57–60 Macpherson and coworkers28,35 demonstrated that pentoxifylline crossed the fetal membranes and


144 2019  Vol. 65  AAEP PROCEEDINGS


achieved high concentrations in the fetal fluids. Subsequently, the same group included pentoxifyl- line in amultimodal treatment protocol consisting of TMP-SMX (30 mg/kg by mouth every 12 hours), pentoxifylline (8.5 mg/kg by mouth every 12 hours), and altrenogest (0.088mg/kg by mouth once daily).26 Mares with experimentally induced ascending pla- centitis that were treated with this protocol had significantly higher foaling rates compared to un- treated mares.26 However, subsequent work in the authors’ labora-


tory found that pentoxifylline did not suppress prosta- glandin production by placental tissue exposed to endotoxin or heat-killed Streptococcus zooepidemicus and did not modulate uterine arterial blood flow in pregnant pony mares treated with pentoxifylline (17 mg/kg by mouth every 24 hours).20,61 Thus, the mechanism of action for any treatment effect of pen- toxifylline is undetermined. Acetylsalicylic acid (aspirin) has also demon-


strated promising results for pregnancy support in mares. It has long been shown to inhibit platelet aggregation and increase blood flow in humans, and is used as a preventative of pregnancy-induced hy- pertension, preeclampsia, and intrauterine growth restriction.62–65 Christiansen and coworkers30 ad- ministered treatment regimens including TMP- SMX, aspirin, and altrenogest to 12 mares with experimentally induced placentitis and produced nine viable foals compared to none in the control group. A recent study found that the total arterial blood flow was significantly higher in late-term mares receiving acetylsalicylic acid compared to con- trols receiving lactulose.66 Clinically, most practitioners include a NSAID


in any treatment regimen for placentitis with the intent of suppressing prostaglandin production. Although not as well characterized as flunixin me- glumine and firocoxib in equine placentitis, ace- tylsalicylic acid has an additional potential benefit of enhancing uterine blood flow.66 In addition, while its mechanism of action has not been firmly established, disposition and efficacy of pentoxifyl- line in mares with placentitis is supported by two studies by Macpherson and coworkers26,27 and it may promote pregnancy maintenance through complementary mechanisms, such as inhibition of bacterial adherence, modification of fetal cytokine expression.57,58


Tocolytic Therapies


Betamimetics and other tocolytic agents are widely used in the treatment of preterm labor in women. In mares, limited studies have investigated the safety or efficacy of tocolytic agents. Palmer and coworkers were unable to inhibit parturition with clenbuterol, and at this time only progestins are used routinely for tocolysis in mares.67 The ratio- nale for this therapy stems from the role progestins play in inhibiting formation of myometrial gap junctions and prostaglandin secretion (the so-called


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