Pathophysiology,diagnosis and treatment of neonatal sepsis

Sepsis is a major cause of death in neonatal foals and, in recent years, significant progress in the understanding of the underlying pathophysiology has been made. To achieve a successful outcome, early diagnosis and treatment focusing on supporting vital functions and neutralising the effects of the causative organisms are essential. The pharmacokinetics of many drugs differ in neonatal foals and more information for appropriate dosing of antimicrobial and anti‐inflammatory drugs for neonatal foals is now available to guide clinicians in choosing the best dosages. Prevention remains difficult and focuses on early recognition while prophylactic use of antimicrobials is discouraged.     

Bacterial isolates from blood and their susceptibility patterns in critically ill foals: 543 cases (1991-1998)

OBJECTIVE: To assess microorganisms isolated from blood specimens obtained from critically ill neonatal foals and to evaluate their antimicrobial susceptibility patterns. DESIGN: Retrospective study. ANIMALS: 543 neonatal foals. PROCEDURE: Medical records of foals that were < 1 month old and were admitted to a referral neonatal intensive care unit were reviewed for results of bacteriologic culture of blood and antimicrobial susceptibility patterns. RESULTS: At least 1 microorganism was isolated from 155 of 543 (28.5%) foals. Escherichia coli was the most commonly isolated bacterium. A single gram-positive organism was detected in 49 foals. Although 90% of the E coli isolates were susceptible to amikacin, some gram-negative and gram-positive organisms had resistance against multiple antimicrobials. CONCLUSIONS AND CLINICAL RELEVANCE: Gram-negative bacteria remain the most common isolates from blood of neonatal foals; however, gram-positive organisms were also found, and with greater prevalence than reported elsewhere. Susceptibility patterns may vary, and resistance to multiple antimicrobials may develop. This is especially true for organisms such as Enterobacter spp and Enterococcus spp. Prudent empirical treatment for neonatal sepsis should include broad-spectrum antimicrobials.     

Diseases in neonatal foals. Part 1: The 30 day incidence of disease and the effect of prophylactic antimicrobial drug treatment during the first three days post partum

Reasons for performing study: Neonatal diseases have been grouped and analysed but up‐to‐date statistically significant information about the incidence and prevalence of diseases in foals is limited. Since the 1950s it has been a common management practice to administer a 3 day course of antimicrobial drugs to neonatal foals. This was shown to significantly reduce the incidence of infections (Platt 1977). Since then management practices have improved and it is widely believed that prophylactic antimicrobial drugs are no longer necessary in foal rearing. Objectives: To determine the 30 day incidences or prevalences (depending on case definition) of various diseases and conditions in the neonatal foal and ascertain the influence of a prophylactic 3 day treatment on the frequency of infections. Methods: The population consisted of Thoroughbred foals born on stud farms in the Newmarket (UK) area in 2005 (n = 1031). Depending on the stud farm's practice in the use of prophylactic antimicrobial drugs, 2 groups of newborn foals (treated and untreated) were identified and followed for 30 days. Results: The 30 day incidences of infectious diseases under study were between 0.2% (osteomyelitis) and 5.85% (systemic disease with diarrhoea). The overall incidence for ‘total infectious diseases’ was 8.27%. The most commonly observed noninfectious condition was limb deformities (12.11% of all foals). There was no significant difference in the incidence of infectious diseases between the 2 groups. Conclusion: Infectious diseases are still an important problem in neonatal foals requiring further investigation as to which factors other than antimicrobial prophylaxis are relevant for disease prevention. Potential relevance: The results provide an up‐to‐date overview about the frequencies of various neonatal foal diseases. They do not support the traditional prophylactic use of antimicrobials to prevent infectious diseases in healthy newborn foals. However, it should be noted that this study was not a randomised controlled trial and therefore does not provide the strongest possible evidence for this conclusion.     

Blood culture isolates and antimicrobial sensitivities from 427 critically ill neonatal foals

OBJECTIVE: To assist correct decision-making about antimicrobial treatment of equine neonates with septicaemia. DESIGN: Retrospective study of microbial blood culture results obtained from foals less than 7 days of age. METHODS: Microbial blood culture results from foals less than 7 days of age admitted to an intensive care unit between July 1999 and December 2004 were reviewed. Antimicrobial sensitivity was assessed by the Kirby Bauer disc diffusion method. Antimicrobials were defined as an effective first-line choice antimicrobial if greater than 70% of isolates were susceptible. Multiple drug resistance (MDR) was defined as resistance to at least three antimicrobials in different chemical classes or with different mechanisms of resistance. RESULTS: Of the 427 Thoroughbred foals included in the study, a positive blood culture was obtained in 110 foals and 124 microorganisms were isolated. Gram-positive isolates, predominantly Streptococcus/Enterococcus spp, were obtained in 41% of foals. Gram-negative isolates were predominantly of the Enterobacteriaceae family, in particular Escherichia coli. The overall antimicrobial sensitivity of the isolates was low. The Gram-positive organisms had unpredictable sensitivity patterns. MDR was recorded in 32% of isolates. In total, 81% of foals were discharged from hospital and 74.5% of foals with a positive blood culture were discharged. CONCLUSION: With the increasing prevalence of Gram-positive microorganisms and their unpredictable sensitivity patterns, blood cultures remain important in the diagnosis and treatment of equine neonatal septicaemia.     

Bacteremia in equine neonatal diarrhea: a retrospective study (1990-2007)

Background: Bacteremia in sick foals is associated with survival, but the association of bacteremia and diarrhea is not reported.
Hypothesis: Neonatal foals with diarrhea will commonly be bacteremic.
Animals: One hundred and thirty-three neonatal foals.
Methods: Records of all foals <30 days of age presenting with diarrhea between January 1990 and September 2007 were reviewed.
Results: Sixty-six of 133 foals (50%) were bacteremic at admission, with 75 isolates from the 66 samples. The blood culture from a further 18 foals (13.5%) grew coryneform bacteria. Nine foals (6.8%) had 2 or more organisms grown on blood culture. One foal had 5 different organisms, interpreted as contamination. Forty-eight foals (36%) had no growth on admission blood cultures. No cultures isolated fungal organisms. Excluding coryneform bacteria, 43 isolates (57%) were Gram-negative organisms and 32 isolates (43%) were Gram-positive organisms. The most common isolate was Enterococcus spp. (22 isolates, 29%), followed by Pantoea agglomerans (13 isolates, 17%). IgG concentration at admission was not associated with blood culture status. Blood culture status was not associated with survival to hospital discharge.
Conclusions and Clinical Importance: Bacteremia is common in neonatal foals with diarrhea. Decisions regarding antimicrobial selection should be made with these differences in mind.     

Pharmacokinetics of butorphanol and evaluation of physiologic and behavioral effects after intravenous and intramuscular administration to neonatal foals

Background: Despite frequent clinical use, information about the pharmacokinetics (PK), clinical effects, and safety of butorphanol in foals is not available. Objectives: The purpose of this study was to determine the PK of butorphanol in neonatal foals after IV and IM administration; to determine whether administration of butorphanol results in physiologic or behavioral changes in neonatal foals; and to describe adverse effects associated with its use in neonatal foals. Animals: Six healthy mixed breed pony foals between 3 and 12 days of age were used. Methods: In a 3‐way crossover design, foals received butorphanol (IV and IM, at 0.05 mg/kg) and IV saline (control group). Butorphanol concentrations were determined by high‐performance liquid chromatography and analyzed using a noncompartmental PK model. Physiologic data were obtained at specified intervals after drug administration. Pedometers were used to evaluate locomotor activity. Behavioral data were obtained using a 2‐hour real‐time video recording. Results: The terminal half‐life of butorphanol was 2.1 hours and C₀ was 33.2 ± 12.1 ng/mL after IV injection. For IM injection, C_max and T_max were 20.1 ± 3.5 ng/mL and 5.9 ± 2.1 minutes, respectively. Bioavailability was 66.1 ± 11.9%. There were minimal effects on vital signs. Foals that received butorphanol spent significantly more time nursing than control foals and appeared sedated. Conclusions and Clinical Importance: The disposition of butorphanol in neonatal foals differs from that in adult horses. The main behavioral effects after butorphanol administration to neonatal foals were sedation and increased feeding behavior.     

Concentrations of amino acids in the plasma of neonatal foals with septicemia

Concentrations of amino acids in the plasma of 13 neonatal foals with septicemia were compared with the concentrations of amino acids in the plasma of 13 age-matched neonatal foals without septicemia. Analysis of the results revealed significantly lower concentrations of arginine, citrulline, isoleucine, proline, threonine, and valine in the plasma of foals with septicemia. The ratio of the plasma concentrations of the branched chain amino acids (isoleucine, leucine, and valine) to the aromatic amino acids (phenylalanine and tyrosine), was also significantly lower in the foals with septicemia. In addition, the concentrations of alanine, glycine, and phenylalanine were significantly higher in the plasma of foals with septicemia. Therefore, neonatal foals with septicemia had significant differences in the concentrations of several amino acids in their plasma, compared with concentrations from healthy foals. These differences were compatible with protein calorie inadequacy and may be related to an alteration in the intake, production, use, or clearance of amino acids from the plasma pool in sepsis.     

Effect of omeprazole paste on intragastric pH in clinically normal neonatal foals

OBJECTIVE: To evaluate the efficacy of omeprazole paste, a commonly used antiulcer drug, on intragastric pH in clinically normal neonatal foals. ANIMALS: 6 clinically normal foals between 5 and 14 days of age. PROCEDURE: Intragastric pH was recorded in each foal by use of a disposable antimony pH electrode with internal reference. Values for intragastric pH were recorded every 4 seconds by use of an ambulatory pH monitor. There were two 24-hour recordings of intragastric pH for each foal, with 24 hours between recordings. Foals were not administered any drugs during the first recording. Foals were administered omeprazole paste (4 mg/kg, PO) 1 hour after the start of the second recording. Mean pH was calculated for each hour of each 24-hour recording session. Hourly mean values were compared between the first and second 24-hour recordings. RESULTS: Complete data were obtained from 4 of 6 foals during the first 24-hour recording and 6 of 6 foals during the second 24-hour recording. Foals had significantly higher mean hourly intragastric pH for hours 2 to 22 following omeprazole administration, compared with corresponding hourly pH values in foals during the first recording. CONCLUSION AND CLINICAL RELEVANCE: Omeprazole paste can effectively increase intragastric pH in clinically normal neonatal foals within 2 hours after oral administration of the first dose and can be administered to neonatal foals at the rate of 4 mg/kg, PO, every 24 hours.     

Antimicrobial therapy in neonatal foals

There are several differences in treatment of neonatal foals with antimicrobials, compared to mature horses. Firstly, the dose of many antimicrobials is different in the foal. For orally administered drugs, this may also affect their efficacy, due to different enteral absorption. Secondly, neonatal foals are not yet hindgut fermentors and this allows antimicrobials with a high propensity to cause colitis in mature horses to be used. Thirdly, toxicities are different and some antimicrobials used in mature horses, such as enrofloxacin, are not suitable for use in foals. Foal-specific information is therefore needed for their safe and effective treatment with antimicrobials.     

Cochet-Bonnet aesthesiometer-determined corneal sensitivity in neonatal foals and adult horses

Corneal touch threshold (CTT) was measured in sick neonatal foals, healthy foals, and healthy adult horses with a Cochet-Bonnet aesthesiometer. The mean overall CTT for the adult horses, sick foals, and healthy foals was 4.82 +/- 0.87 cm, 3.21 +/- 0.24 cm, and 5.01 +/- 0.61 cm, respectively. The central cornea of adult horses was more sensitive than the limbal cornea. Corneal sensitivity was significantly reduced in sick neonatal foals compared to adults. The mean Schirmer I tear test values were significantly lower in foals than adults, and were 14.2 +/- 1.0 mm, 12.8 +/- 2.4 mm, and 18.3 +/- 2.1 mm wetting in sick neonatal foals, normal neonatal foals, and adult horses, respectively. Reduced corneal sensation and lower tear production may be associated with ulcerative keratitis and slow corneal healing in some foals.     

Rhodococcus equi foal pneumonia: Update on epidemiology,immunity, treatment and prevention

Pneumonia in foals caused by the bacterium Rhodococcus equi has a worldwide distribution and is a common cause of disease and death for foals. The purpose of this narrative review was to summarise recent developments pertaining to the epidemiology, immune responses, treatment, and prevention of rhodococcal pneumonia of foals. Screening tests have been used to implement earlier detection and treatment of foals with presumed subclinical R. equi pneumonia to reduce mortality and severity of disease. Unfortunately, this practice has been linked to the emergence of antimicrobial-resistant R. equi in North America. Correlates of protective immunity for R. equi infections of foals remain elusive, but recent evidence indicates that innate immune responses are important both for mediating killing and orchestrating adaptive immune responses. A macrolide antimicrobial in combination with rifampin remains the recommended treatment for foals with R. equi pneumonia. Great need exists to identify which antimicrobial combination is most effective for treating foals with R. equi pneumonia and to limit emergence of antimicrobial-resistant strains. In the absence of an effective vaccine against R. equi, passive immunisation remains the only commercially available method for effectively reducing the incidence of R. equi pneumonia. Because passive immunisation is expensive, labour-intensive and carries risks for foals, great need exists to develop alternative approaches for passive and active immunisation.     

Risk factors for Clostridium piliforme infection in foals

OBJECTIVE: To determine risk factors for Clostridium piliforme infection in neonatal foals on a Thoroughbred breeding farm in California. DESIGN: Case-control and retrospective cohort studies. ANIMALS: 322 neonatal Thoroughbred foals either born on the study farm or born elsewhere but traveled to the farm with their dam during the 1998, 1999, and 2000 breeding seasons. PROCEDURE: Mare and foal records from 1998, 1999, and 2000 were examined, using case-control design methods to determine variables associated with increased risk of C. piliforme infection in foals. Important risk factors identified in the case-control study were then reevaluated by use of a retrospective cohort design, using data from all neonatal foals present on the farm during the 3-year study period. RESULTS: Foals born between March 13 and April 13 were 7.2 times as likely to develop C. piliforme infection as were those born at any other time of the foaling season. Foals of nonresident (visiting) mares were 3.4 times as likely to develop disease as were foals born to mares that were permanent residents of the study farm. Foals of mares < 6 years of age were 2.9 times as likely to develop disease as were foals born to older mares. CONCLUSIONS AND CLINICAL RELEVANCE: Results of this research can be used to better understand the epidemiologic factors of C. piliforme infection in horses. High-risk foals can be closely monitored to aid in early diagnosis and treatment, resulting in the best possible clinical outcome for affected individuals.     

Use of pressor therapy in 34 hypotensive critically ill neonatal foals

Background Arginine vasopressin (AVP) is used in human medicine in the management of vasodilatory shock and cardiac arrest, but it is not widely used in equine neonatal intensive care because of concerns about potential side effects and suboptimal efficacy. This retrospective study reports the clinical use of AVP and norepinephrine (NE) in foals with refractory hypotension. Objectives To report the cardiovascular responses and fluid balance in critically ill, hypotensive foals receiving either NE or AVP. Design The medical records of neonatal foals (<7 days of age) from 2000 to 2007 admitted to the Marion duPont Scott Equine Medical Center were reviewed. Results The use of exogenous AVP infusion was associated with a significant increase in mean arterial pressure (MAP) and urinary output, and a significant decrease in heart rate. NE administration was also associated with a significant increase in MAP. Conclusions The findings of this first report of the clinical treatment of foals with refractory hypotension support the use of AVP and NE.     

Endotoxin release after antimicrobial treatment in sick foals is mediated by antimicrobial class

The objective of this study was to determine whether treatment with antimicrobials leads to increased serum endotoxin concentrations in sick foals and to further determine whether an effect of class of antimicrobial on endotoxin release occurs in sick foals in vivo. This was a prospective, observational study at a university equine hospital. Twenty-four foals aged 12 hours to 12 days admitted to the hospital in 2004 and 2005 were used. Blood was collected from all foals at time 0 (admission) and at 30 minutes, 8 hours, 12 hours, and 24 hours after treatment with an antimicrobial. The choice of antimicrobial was determined by the clinician caring for the foal, and any other treatment, as deemed necessary for appropriate care of the foal, was employed. For each serum sample, the endotoxin concentration was determined using the limulus amebocyte lysate assay. Those foals that received a beta-lactam alone, more specifically the cephalosporin ceftiofur, showed a significant increase in endotoxin concentration 12 hours after antibiotic administration (P = .005). An increase in serum endotoxin concentration was not seen in the first 24 hours after antimicrobial administration when foals were treated with a combination of beta-lactam and aminoglycoside antimicrobials. In conclusion, a significant increase in endotoxin concentration as a consequence of ceftiofur administration occurs in sick foals. Administration of a combination of a beta-lactam antimicrobial and an aminoglycoside did not result in a significant increase in endotoxin release. Consideration of these findings should be made when choosing antimicrobial therapy for the sick foal.     

Pharmacokinetics of an orally administered methylcellulose formulation of gallium maltolate in neonatal foals

Chaffin, M. K., Fajt, V., Martens, R. J., Arnold, C. E., Cohen, N. D., O’Conor, M., Taylor, R. J., Bernstein, L. R. Pharmacokinetics of an orally administered methylcellulose formulation of gallium maltolate in neonatal foals. J. vet. Pharmacol. Therap. doi: 10.1111/j.1365‐2885.2009.01150.x. Gallium is a trivalent semi‐metal with anti‐microbial effects because of its incorporation into crucial iron‐dependent reproductive enzyme systems. Gallium maltolate (GaM) provides significant gallium bioavailability to people and mice following oral administration and to neonatal foals following intragastric administration. To study the prophylactic and therapeutic effects of GaM against Rhodococcus equi pneumonia in foals, we developed a methylcellulose formulation of GaM (GaM‐MCF) for oral administration to neonatal foals. Normal neonatal foals were studied. Six foals received 20 mg/kg and another six foals received 40 mg/kg of GaM‐MCF orally. Serial serum samples were collected and serum gallium concentrations were determined using inductively coupled plasma mass spectroscopy. Gallium was rapidly absorbed (T_max of 4 h), and a mean C_max of 0.90 or 1.8 μg/mL was achieved in foals receiving 20 or 40 mg/kg respectively. Marked variability existed in C_max among foals: only half of the foals receiving 20 mg/kg attained serum concentrations of >0.7 μg/mL, a level suggested to be therapeutic against R. equi by previous studies. Mean elimination half‐life was 32.8 or 32.4 h for foals receiving 20 or 40 mg/kg respectively. The results of this study suggest that at least 30 mg/kg orally every 24 h should be considered in future pharmacodynamic and efficacy studies.     

Hematuria associated with cystic hematomas in three neonatal foals

Cystic hematomas were diagnosed in 3 neonatal foals. In all 3 foals, cystic hematomas resulted from umbilical trauma or thrombocytopenia. Findings in these foals suggest that cystic hematoma should be included in the differential diagnosis of hematuria in neonatal foals. Management of cystic hematomas includes both medical and surgical options.     

Antimicrobial-induced endotoxin and cytokine activity in an in vitro model of septicemia in foals

OBJECTIVE: To determine which antimicrobials that are used to treat neonatal foals with septicemia attributable to Escherichia coli will minimize endotoxin release from bacteria and subsequent activity of inflammatory mediators while maintaining bactericidal efficacy. SAMPLE POPULATION: Blood samples from 10 healthy foals. PROCEDURE: Escherichia coli isolates A and B were isolated from 2 septicemic foals, and minimal inhibitory concentrations (MIC) were determined for 9 antimicrobials. Five of these antimicrobials were tested in vitro at 2 and 20 times their respective MIC. Whole blood or mononuclear cells grown in tissue-culture media were incubated with 105 colony-forming units of E. coli and each antimicrobial or saline (0.9% NaCl) solution. After 6 hours, number of viable bacteria remaining was determined, and supernatant was tested for endotoxin and tumor necrosis activity. RESULTS: Testing in whole blood was compromised by bactericidal effects of the blood itself. In mononuclear cell suspensions, each antimicrobial significantly reduced the number of viable bacteria to low or undetectable amounts. Antimicrobials did not differ significantly in efficacy of bacterial killing. Amikacin used alone or in combination with ampicillin resulted in significantly less endotoxin activity than did ampicillin, imipenem, or ceftiofur alone. There was a correlation between TNF-alpha and endotoxin activity. CONCLUSIONS AND CLINICAL RELEVANCE: Aminoglycosides appear less likely to induce endotoxemia and TNF-alpha synthesis during bactericidal treatment of E. coli septicemia, compared with beta-lactam antimicrobials. Use of ampicillin, imipenem, or ceftiofur in the treatment of septicemic neonatal foals should be accompanied by appropriate treatment for endotoxemia.     

A review of equine sepsis

Sepsis is defined as an exaggerated, systemic inflammatory response to infection and is a common condition in horses. Systemic inflammatory response syndrome (SIRS) associated with bacterial infection is a hallmark of sepsis. Sepsis in neonatal foals is a common sequela of failure of passive transfer and, in addition to development of SIRS, may be characterised by bacteraemia, pneumonia, enterocolitis, omphalophlebitis, meningoencephalitis or arthritis. Sepsis in mature horses is most commonly observed secondary to gastrointestinal lesions that result in disrupted mucosa and bacterial translocation into circulation (endotoxaemia). Pleuropneumonia and metritis may also cause sepsis in mature horses. Diagnosis of sepsis is based on SIRS criteria as well as suspected or confirmed infection. Due to the relatively low sensitivity of microbial culture and the subjectivity of sepsis scoring, many sepsis biomarkers are being studied for their usefulness in diagnosis and prognostication of sepsis in horses. Treatment of sepsis requires an intensive care approach that includes antimicrobial drug administration, fluid resuscitation and pressure support, and treatment for inflammation, endotoxaemia and coagulopathy. Early recognition of sepsis and prompt antimicrobial drug treatment are critical for a successful outcome. Multiple organ dysfunction syndrome may occur in severe cases of sepsis, with common manifestations including laminitis and coagulopathies. Although prognosis for septic mature horses depends highly on the primary disease process, the overall survival rate in septic neonatal foals ranges from 26 to 86%, with most studies indicating a survival rate of 45–60%.     

Gastrointestinal diseases of foals

Few foals escape gastrointestinal disease during the first weeks of life. Diarrhea is an extremely common problem; fortunately, however, it is usually mild and self-limiting. When it is not, the underlying cause is often an infectious agent, such as rotavirus or Salmonella spp. Our understanding of many of the infectious agents causing neonatal diarrhea is far from complete. Gastric and duodenal ulcers are a less common disease of neonatal foals. There has been an apparent increase in the incidence of ulcer disease in foals during the past few years. The most effective way of decreasing serious gastrointestinal disease in foals is through the use of good management practices. Environmental and dietary stress must be minimized, and good hygienic practices should be followed. Unfortunately, the needs of the neonate are often ignored, while attention is focused on the mare during the breeding season.