Equine neonatal sepsis: treatment (Proceedings)

Treatment of failure of passive transfer (fpt)

     A. If the foal is less than 12 hours, it can be given 1-3 liters of high quality (sp gr > 1.090) colostrum. (Frozen colostrum should be thawed in warm water, rather than the microwave. Ideally colostrum should be < 12 months old). Serum or plasma is too low in IgG to be of benefit given orally. Bovine colostrum can be given, but it is not nearly as good as equine colostrum.

     B. Intravenous IgG- concentrated serum products have a higher risk of anaphylaxis because they are made from multiple donors. After plasma or serum administration, IgG concentration should be rechecked 12-24 hours later. More should be administered if IgG is < 400 mg/dl. Most foals will receive 1-2 L of plasma; however, large foals with an IgG concentration <200 mg/dl will usually require 3L. As a foal's blood volume is ~ 10% of body weight, and whole blood is 2/3 plasma, the plasma volume of a 45 kg (100lb) foal is: 4.5 liters x 0.666 = 3 liters. Therefore a maximum of 1 liter of plasma should be given to a 40-60 kg foal per day. If necessary, the second liter can be administered the following day. Septic foals can consume or leak IgG and IgG should be reassessed every few days. Septic foals often benefit from additional plasma transfusions.

Sepsis therapy

Should begin as soon as disease is suspected; don't wait until disease is confirmed!

          1. Broad-spectrum antimicrobials. Intravenous penicillin and an aminoglycoside (gentamicin or amikacin) are commonly given. Treatment should be long-term (at least 10 days) to prevent localization. Localized infection should be treated for at least 21 days to prevent recrudescence.

          2. Plasma, if there is failure of passive transfer. Most clinicians believe that intravenous plasma therapy is a valuable treatment even for septicemic foals that have adequate IgG concentration.

          3. Fluid therapy. Intravenous isotonic fluids with added glucose. 3-5% at shock rates or 5-10% dextrose at maintenance rates. Immediately revives some comatose, septicemic foals. Intravenous balanced electrolyte solutions are often bloused at periodic intervals. If IV fluids are required > 24 hrs then a maintenance fluid (or mix of 5% glucose and a balanced isotonic replacement fluid) should be given. Replacement fluids are high in sodium and foals are designed to live on a low sodium milk diet. There kidneys have difficulty excreting the excess sodium, so hypernatremia can become an issue. Maintenance fluids have lower sodium and higher potassium concentrations.

          4. Good nursing care – nutritional support (enteral or parenteral)

          5. Monitor – cardinal signs, PCV, TP, electrolyte levels, blood glucose and presence of glycosuria must be regularly checked and foal checked regularly for development of any localizing signs.

Antibiotic régimes

Injectable

     A. Intravenous penicillin and an aminoglycoside (gentamicin or amikacin). High dose ceftiofur can be added to further increase the spectrum.

     B. Intravenous penicillin and a effective 3rd generation cephalosporin (cefotaxime or ceftriaxone) would be an excellent choice, but very expensive

     C. Procaine penicillin G and gentamicin ± ceftiofur

     D. Ceftiofur and gentamicin

     E. Ceftiofur alone

Oral antibiotics (usually after iv or im therapy)

          • Cefpodoxime

          • Azithromycin

          • Clarithromycin

          • Doxycycline

          • Trimethoprim-sulfonamide

Antibiotic Spectrum

Although chloramphenicol, ceftiofur, tetracyclines and trimethoprim-sulfonamide combinations are considered "broad spectrum", they may only effectively treat 50-70% of organisms that infect neonatal foals. As the majority of etiologic agents responsible for neonatal bacteremia are aggressive Gram negative organisms, therefore it is advisable that an antibiotic with high efficacy against gram negative organisms is selected. Cefpodoxime is an excellent choice.

Antibiotic Penetration

Many antibiotics do not reach high concentrations in synovial fluid, bone, abscesses or the CNS. High blood levels create a gradient that is advantageous to tissue penetration. Local therapy: nebulization, intraarticular injections and regional limb perfusion can assist in obtaining concentrations above MIC in localized areas.

Antibiotic Dosing Interval

Effective antibiotic dosing intervals for antibiotics depends on whether the antibiotic is time or concentration dependent.

Concentration dependent antibiotics (aminoglycosides and fluoroquinolones).

Efficacy is directly related to the peak concentration in plasma. The peak plasma concentration is more important than the amount of time that plasma antibiotic concentration exceeds bacterial minimum inhibitory concentration (MIC). An additional effect of concentration dependent antibiotics is their post antibiotic effect that prevents bacterial growth despite serum and tissue concentrations below MIC. Plasma antibiotic concentrations greater than 10 times MIC reportedly maximizes post antibiotic effect, however plasma concentrations 4-8 times MIC may be sufficient. Often it is sufficient to give the drug once per day.

Time dependent antibiotics (macrolides, penicillins,cephalosporins, etc)

Efficacy of depends on the length of time that plasma concentrations exceed the MIC of pathogens. Steady high concentrations are required and often the drug must be given multiple times per day.

Aminoglycosides

(gentamicin, amikacin) are bactericidal and kill bacteria by inhibiting the 30s ribosomal subunit which prevents bacterial protein synthesis. Their spectrum is mainly against aerobic Gram negative bacteria and Staphylococcus sp. Aminoglycosides are ineffective against anaerobes because they are transported into bacteria through an oxygen-dependent process. The bioavailability of intramuscular gentamicin is approximately 100% and plasma concentration time curves are similar except that peak plasma concentration is less than with intravenous administration. Intramuscular administration of gentamicin is a feasible alternative if intravenous administration is not possible.

Once daily dosing of aminoglycosides (gentamicin 6.6 mg/kg, IV, q 24 h; amikacin 21 mg/kg, IV, q 24 h) minimizes renal toxicity of these antibiotics. Renal proximal tubular cells actively take up aminoglycosides by endocytosis. Renal toxicity is more dependent on the duration of antibiotic exposure rather than the magnitude of plasma concentration. Administration of calcium (20 mg/kg, IV, q 12 h) attenuates gentamicin induced acute renal failure. Horses fed alfalfa diets had a lesser degree of gentamicin induced nephrotoxicosis than horses fed only oats. This protective effect is apparently associated with the larger concentration of dietary calcium in legumes such as alfalfa. A dehydrated septic foal may be more susceptible to aminoglycoside toxicity than a healthy foal. Serum aminoglycoside peak and trough concentrations can be measured at Auburn University Clinical Pharmacology Laboratory. Dr. Dawn Boothe is extremely helpful. Aminoglycoside clearance is also an excellent diagnostic tool for assessing renal function.

Enrofloxacin

The use of enrofloxacin in foals is generally contraindicated because of the potential for articular cartilage degeneration. Fluoroquinolones are bactericidal antibiotics that inhibit DNA gyrase, an enzyme needed for the supercoiling of bacterial DNA. Fluoroquinolones have activity against most Gram negative bacteria and lower, but usually therapeutically useful activity against many Gram positive aerobes. They are ineffective against anaerobes. Reported doses of enrofloxacin in adult horses are: 5.5 mg/kg, IV, q 24 h; 7.5 mg/kg, PO, q 24 h; 4.0 mg/kg, PO, q 12 h. After multiple intragastric doses in adult horses, concentrations of enrofloxacin in synovial fluid, urine, and endometrium exceeded serum concentration. However, peritoneal fluid and cerebrospinal fluid concentrations were lower than serum concentration.

Administration of enrofloxacin (10 mg/kg, PO, q 24 h for eight days) to 2-week-old foals resulted in lameness in 3 of 4 foals, primarily affecting the tibiotarsal joints. Gross lesions in joints included cartilage erosions and roughening in weight bearing joints. However, another study reported that synovial concentrations of enrofloxacin that would be expected after oral administration at 5 mg/kg did not suppress chondrocyte metabolism in vitro.

New macrolides

Azithromycin and clarithromycin are bacteristatic macrolide antibiotics that bind to the 50s ribosomal subunit and inhibit bacterial protein synthesis. These antibiotics have substantial activity against Gram-positive aerobes and some Gram negatives. They have little activity against anaerobes, Gram-negative enterics, and pseudomonads. Interest in these antibiotics arose because 13% of Rhodococcus equi isolates were found to be resistant to erythromycin and progressive development of resistance during treatment with erythromycin and rifampin has been reported.

Compared to erythromycin, both azithromycin and clarithromycin have increased tissue concentrations and achieve higher concentrations in phagocytic cells. Intracellular concentrations of azithromycin may exceed plasma by more than 80 times. Azithromycin concentrations in bronchoalveolar lavage fluid and pulmonary macrophages considerably exceed MIC90 of R. equi isolates from foals with pneumonia. The persistence of high azithromycin concentrations for 48 hours following dosing indicates that after 5 daily doses at 5 mg/kg, PO, q 24 h, administration of the same dose every 48 hours should be adequate. In foals, clarithromycin (7.5 mg/kg, PO, q 12 h) is predicted to maintain serum concentrations above MIC90 of R. equi for the entire 12 hour dosing interval. It is suggested that rifampin (5 mg/kg, PO, q 12 h) should be combined with whatever macrolide is used in the treatment of R. equi infections. Steve Giguère recently discussed results of a small retrospective study looking at outcome and side effects in 72 foals with R. equi pneumonia treated with rifampin in combination with azithromycin, clarithromycin or erythromycin.12 In vitro susceptibilies found clarithromycin > azithromycin> erythromycin. Of 76 foals treated, 46 survived (18 died in the initial 36 hours). Although the numbers of foals in each treatment group were small clarithromycin out performed the other drugs. Clarithromycin was 14 times more successful than erythromycin, and 10 times more successful than azithromycin. The foals treated with clarithromycin had a decreased number of days of hospitalization, fewer days of fever, and had greater evidence of radiographic improvement on reevaluation.

Unfortunately macrolides are not recommended as sole antibiotic agents in neonates due to their relatively low efficacy against many Gram negative organisms.

New oral 3rd generation cephalosporin – "Cefpodoxime proxetil is an orally administered third generation cephalosporin approved for use in humans. Pharmacokinetics have recently been determined in neonates, weanlings and adult horses by N. Carrillo et al. Concentrations of cefpodoxime in synovial and peritoneal fluids were similar to that of concurrent serum concentrations. Urine concentrations were 12 to 72 times higher than concurrent serum concentrations. The drug could not be detected in CSF. No adverse reactions were noted in foals whereas mild colic developed in 2 adult horses. MIC90 of cefpodoxime against Salmonella enterica, Escherichia coli, Pasteurella spp., Klebsiella spp., and β-hemolytic streptococci was 0.38, 1.0, 0.16, 0.19, and 0.09 μg/ml, respectively. Dosing schedules for β-lactam antimicrobials should maintain serum concentrations above the MIC of a given pathogen for at least 50% of the dosing interval to achieve therapeutic efficacy. Oral cefpodoxime administered to 7- to 14-day-old foals at a dose of 10 mg/kg every 12 h resulted in serum concentrations above the MIC90 of Klebsiella spp., Pasteurella spp. and β-hemolytic streptococci for more than 50% of the dosing interval. The same dose given at 8-h intervals would be required for therapy of S. enterica infections. Administration at 8-h intervals would also result in serum concentrations above the MIC of 75% of E. coli isolates for approximately 50% of the dosing interval. Further studies are required to determine the efficacy and safety of these dosages in a clinical setting."

Supportive care

     1. Keep warm, well padded, and dry

     2. Protect sinking fetlocks from abrasion, but avoid heavy bandages which tend to promote tendon laxity. Glue or strap on heel extension shoes if toe lifts off ground.

     3. Restrict exercise if carpal/tarsal bones unossified, splint if necessary.

     4. Keep in sternal rather than lateral recumbency (if recumbent) to prevent progressive atelectasis.

     5. Hydration and Nutrition – Foals not sucking will require feeding by stomach tube with milk/milk replacer. Mares should be milked out and foal fed at least 10% body weight daily in small feeds, starting at 400 mls for T/B foals, (less for small or premature foals) at least every 2 hours. The caloric requirements of sick foals may be as high as 100-150 k cal/kg/day (20-25% bw/day milk). This is not easily achieved and the recommended minimum maintenance dose is 50-60 kcal/kg/day or 10% bw/day milk. Monitor blood glucose and supply by IV infusion if necessary (slow, continuous drip rather than bolus (which results in dramatic hyperglycemia). Hypoglycemia can be corrected with IV 5% dextrose. The recommended infusion rate is 5-10 ml/kg/hr (which is 200-500 ml/hr/TB foal) during periods of hypoglycemia. This is much more physiologic than bolus glucose. Maintenance fluid rate is 80ml/kg/day, with additions for % dehydration and ongoing losses (ie diarrhea). Marked dehydration and hypovolemic shock can be treated at shock rates of 60 to 90 mls/kg/hr for ONE hour. Care must be taken with additives such as KCl, glucose, calcium or magnesium when shock rates are given, as a day's volume of fluid is given in one hour. For shock rates glucose should be supplemented at 2-3%. (Add 40-60 mls of 50% dextrose to each 1 liter bag). After dehydration has been corrected, most foals can be maintained in adequate energy and fluid balance with oral feeding unless diarrhea or ileus develops.

     6. Depending on serum electrolyte concentrations, maintenance electrolyte solutions can be supplemented with potassium 20-40 mEq/l; 10 mls of 23% calcium gluconate/liter, 2 mls MgSO4/ liter.

     7. If oral feeding can not be tolerated: severe diarrhea, premature gut, reflux, bloat etc, partial parenteral nutrition is required. Energy is supplied by hypertonic solutions (usually 50% dextrose, 10% amino acid solutions, and 10% lipid emulsions), which are calculated according to requirements, then diluted with electrolyte solutions to make up the required volume.

          • Dextrose (3.4 kcal/g) is introduced at a rate of 10g/kg/day and slowly increased to 12g/kg/day, then 15g/kg/day (remember a 50% solution contains 50g mEq/L).

          • Proteins (4 kcal/g) are started at 1g/kg/day and may be increased to 3g/kg/day.

          • Lipid emulsions (10 kcal/g) are started at 1g/kg/day and may be increased to 2 or 3 g/kg/day.

     8. Supply O2 (5-10 l/min through nasal tube) if hypoxic or dyspneic (if, however, a shunt of 50% or more exists, increasing the inspired oxygen concentration will not improve arterial oxygenation). Ventilation is indicated when arterial CO2 levels are substantially elevated.

Septic arthritis treatment:

Long term treatment is required. Many of these procedures are used in combination and repeatedly.

     1. Systemic Antibiotics – are invariably indicated in foals where septic arthritis/osteomyelitis is assumed to develop subsequent to hematogenous spread of bacteria (whereas in adult horses it is more likely to be the result of a penetrating injury or iatrogenically secondarily to joint injection); prolonged treatment (2-4 weeks) is recommended as reoccurrence is common.

     2. Joint Lavage – is beneficial both in removing damaging lysosomal enzymes and physically removing fibrin clots and joint debris which may harbor bacteria beyond the reach of antibiotics. Lavage may be achieved through 18g needles, catheters, arthroscopic equipment or larger incisions and drains, depending on the magnitude of debris to be removed and the persistence of the problem. Incisions left to drain must be covered by frequently changed sterile bandages.

     3. Intraarticular Antibiotics – may cause chemical irritation, but this pales in significance given the marked inflammatory response evoked by infection itself. Very high levels are achieved for a short period and assists in eliminating infection. Intraarticular antibiotics should never be regarded as a substitute for adequate systemic antibiotics. Amikacin 125-250 mg per joint, but do not exceed the systemic dose.

     4. Bone Curettage – is likely to be required to eliminate osteomyelitis either of the epiphysis or physis. Curetting epiphyseal lesions may destroy considerable articular cartilage, and physeal curettage may interfere with long bone growth.

     5. Regional perfusion – 250 mg of Amikacin in 20cc saline or 1 g cefotaxime in 20 cc saline. Tourniquet above and below joint. Inject antibiotic solution and leave tourniquet in place for 20 minutes.