Journal Club Lee V. Herold, DVM, DACVECC DoveLewis Annual Conference Speaker Notes

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decisions with evidence rather than tradition. Despite the lack of good research evidence to back many of our clinical decisions, the veterinary scientific literature continues to expand yearly.

1 Journal Club Lee V. Herold, DVM, DACVECC DoveLewis Annual Conference Speaker Notes Evidence based medicine defined as the integration of best research with clinical expertise mandates that we guide our clinical decisions with evidence rather than tradition. Despite the lack of good research evidence to back many of our clinical decisions, the veterinary scientific literature continues to expand yearly. The infrastructure to help veterinarians sift through the literature and apply it to clinical practice is much less developed compared to the resources available to our human physician counterparts. Though the infrastructure is not present the burden of applying current evidence to clinical decision making in veterinary medicine remains a priority for clinical veterinarians. I present several recent articles in the veterinary literature that have direct clinical applications either to guide our therapeutic decisions, or allow us to better interpret diagnostic tests. This is by no means a comprehensive look at the past several years in the veterinary literature but hopefully will present articles and information that may be helpful to the practicing veterinarian. Urinary Tract Disease in Dogs Urinary tract infections occur in approximately 14% of dogs and cats. Urinary tract infections present with characteristic clinical signs of hematuria, pollakiuria, dysuria, and pelvic pain. Bacteriuria without lower urinary tract signs has been reported in a subset of dogs with predisposing diseases or conditions. Dogs with diabetes mellitus (DM), hyperadrenocorticism, and dogs undergoing therapy with immunosuppressive medications are some of the patients in which asymptomatic bacteriuria is reported. In these patients that have illness, treatment for asymptomatic bacteriuria is considered important either because the urinary tract infection even in the absence of clinical signs can contribute to dysregulation of disease (as in DM), or because the patient will be unable to mount an adequate immune response due to inherent or exogenous immunosuppression. However the prevalence asymptomatic bacteriuria in the absence of predisposing or immunosuppressive disease- i.e. in the healthy patient is not well documented in veterinary medicine. The natural course of asymptomatic bacteriuria has not been well characterized. In veterinary medicine bacteriuria is often considered an indication for antibiotic treatment even in the absence of clinical signs in healthy patients. Asymptomatic bacteriuria in healthy women is better characterized. The definition of asymptomatic bacteriuria includes 10 5 CFU/ml growth of an uropathogen in 2 consecutive midstream urine samples in human females. In healthy human women asymptomatic bacteriuria is not an indication for antibiotic treatment. With increasing concerns over antibiotic resistance and appropriate antibiotic use- do we in veterinary medicine need to re-evaluate the standard practice of antibiotic treatment of asymptomatic bacteriuria in dogs? Additionally even when patients are clinical for urinary tract infection- are alternative antibiotic protocols that might minimize development of antibiotic resistance more appropriate than traditional approaches. The initial two articles presented give data regarding of the prevalence of asymptomatic bacteriuria in healthy canine populations and the article by Wan et.al. evaluates the natural course of asymptomatic bacteriuria over a 3 month follow-up.(1)(2) The articles by Westropp et. al. and Daniels et. al. provides supportive evidence for a different approach to treating uncomplicated lower urinary tract infections. (3)(4)

2 McGhie J, Stayt J, Hosgood GL. Prevalence of bacteriuria in dogs without clinical signs of urinary tract infection presenting for elective surgical procedures. Aust Vet J Jan;92(1-2):33-7. This prospective observational study enrolled 140 client owned dogs presenting for elective surgical procedures (soft tissue and orthopedic) with the goal of determining the frequency of bacteriuria in patients without urinary tract clinical signs. Patients with neurologic disease, previous history of urinary tract disease, or predisposing diseases contributing to bacteriuria (DM, cushings), and those underoing immunosuppressive treatment were excluded from enrollment. A secondary goal was to determine the agreement between microscopic UA evaluation of pyuria/bacteria and urine culture results. Dogs had urine samples collected via cystocentesis prior to anesthesia or just after anesthetic induction for UA and urine culture. A positive UA was defined as the presence of pyuria (>5 WBC/hpf), or the presence of bacteria or motile debris on an unstained wet mount. Positive urine culture was defined as > 10 5 CFU/ml of growth of a single uropathogen. Urinanalysis results identified 19/140 (13.6%) positive samples. Only 2 of these samples were culture positive. Urine culture identified 3/140 (2.1%) positive samples. Two of the three culture positive samples were positive on urinalysis. One of the three culture positive samples had no pyuria or bacteriuria (ie. UA negative). All samples with positive cultures grew E.coli. Conclusions from this study are that the prevalence of assymptomatic bacteriuria is low (2.1% if using culture criterion). The agreement between culture and UA results is poor. Urinalysis only had a 66.7% specificity and 50.6% sensitivity to predict positive culture (true bacteriuria) in this patient population. What this study was not able to discern due to the low number of positive cultures is whether there was a difference in the prevalence of bacteriuria between ortho and soft tissue procedures. There was no followup to determine the natural course of bacteriuria in these patients. For example where those patients with culture positive more likely to develop clinical signs of lower urinary tract infection or surgical site infection? Wan S, Hartman FA, Jooss MK, Viviano KR. Prevalence and clinical outcome of subclinical bacteriuria in female dogs. J Amer Vet Med Assoc July 1; 245: Wan et.al. prospectively evaluated the prevalence of asymptomatic bacteriuria in a population of healthy female dogs. In addition they followed dogs with asymptomatic bacteriuria for 3 months to determine the natural course of bacteriuria- i.e. whether they went on to develop clinical signs. 101 healthy female dogs were screened with midstream free catch UA, urine culture, and mini-chem screen. A positive culture result from the initial screen was defined as >10 5 CFU/ml of one organism. Those dogs that were positive on initial free catch screen were returned 7-14 days later for cystocentesis UA, urine culture, full chemistry, and lateral abdominal radiograph. If the dog cultured positive on the cystocentesis sample they were considered to have subclinical bacteriuria. Those patients with subclinical bacteriuria were evaluated 3 months later with physical exam and cystocentesis urine culture. The prevalence of subclinical bacteriuria in this healthy female dog population was low = 9/101 (8.9%). There was no difference in the prevalence of asymptomatic bacteriuria between different age groups. The agreement between UA results and culture results were low. No animals with asymptomatic bacteriuria went on to develop clinical signs in the 3 month follow-up period.

3 Take Home Points: Taken together these two articles support that asymptomatic bacteriuria in healthy canines exists. The prevalence is low ( %). Urinalysis is a poor screening test for asymptomatic bacteriuria. Even culture positive asymptomatic bacteriuria may not require antibiotic treatment. Westropp JL, Sykes JE, Irom S, et.al. Evaluation of the efficacy and safety of high dose short duration enrofloxacin treatment regimen for uncomplicated urinary tract infections in dogs. J Vet Intern Med 2012; 26: This prospective, multi-center, randomized, controlled and blinded clinical trial sought to compare the efficacy between treatment of uncomplicated lower urinary tract infection in dogs with either 1. Conventional 14 day course of amoxicillin clavulanate or 2. Three day course of 20mg/kg of enrofloxacin (High Dose Short Duration Fluoroquinolone- HDSD) The authors hypothesized that HDSD enrofloxacin would be non-inferior to conventional 2 week clavamox course. 68 adult dogs with uncomplicated UTI were enrolled. 35 in the HDSD enrofloxacin group and 33 in the clavamox group. The patients had repeat urine culture at 10days (7 days after completion of HDSD enro) and 21 days (7 days after completion of clavamox). Endpoints of evaluation were clinical and microbiologic cure rates. Owners also were asked to record adverse events. Results of the study supported that HDSD enrofloxacin was non-inferior to conventional clavamox treatment- i.e. there was no statistical significance between clinical and microbiologic cure rates between the two treatment groups. HDSD enrofloxacin may result in greater compliance, is non-inferior to 14d clavamox and can be considered for treatment of uncomplicated urinary tract infections in dogs. It is not certain based on this study if HDSD enrofloxacin will result in lower bacterial resistance rates. Daniels JB, Tracy G, Irom SJ, Lakritz J. Flouroquinolone levels in healthy dog urine following a 20mg/kg oral dose of enrofloxacin exceed mutant prevention concentration targets against E.coli isolated from canine urinary tract infections. J vet pharmacology and therapeutics 2013: 37: Development of fluoroquinolone resistance in E.coli occurs via acquisition of exogenous DNA (plasmids) with resistance genes or more importantly by selection of naturally occurring E.coli mutants containing resistance genes. Typically clinical resistance results from the accumulation of more than one resistance mutation within a single bacterium. This has resulted in the concept of Mutant Prevention Concentration (MPC) of antibiotics, in which antibiotic concentrations are high enough to kill those bacteria with one resistance mutation so they don t go one to accumulate multiple mutations that would confer clinical resistance. MPC of ciprofloxacin was determined for E.coli. This study evaluated the 24 hour concentration of ciprofloxacin and enrofloxacin in healthy dogs after a single dose of 20mg/kg of enrofloxacin. The area under the concentration curve:mutant prevention concentration (AUC/MPC) ratio was determined. The results in this study indicated that the AUC/MPC if ciprofloxacin in healthy dogs after single dose enrofloxacin exceeded target AUC/MPC s for E.coli by fold. The high dose enrofloxacin may reduce resistance development for E.coli in urinary tract infections.

4 Take Home Points: High dose short duration enrofloxacin is equally efficacious (non-inferior) compared to standard dose/duration amoxi/clav in uncomplicated UTIs in dogs. This HDSD enrofloxacin is unlikely to select for resistant E.coli in the urinary bladder Seizures Dogs with seizures die at a younger age than the general population of dogs. In a 12 year followup of dogs with seizures by Berendt et.al.- the median age of death in dogs with seizures was 7 years compared with the general population of dogs who had a median age at death of 10 years. (5) Acceptable seizure control as assessed by owners was varied. In addition acceptable seizure control assessed by clients did not necessarily correlate with the professional (veterinarian s) assessment of adequate seizure control. Despite the varied assessments of acceptable seizure control, the study identified that generally owners were able to tolerate monthly seizures, or even weekly seizures for a short time. Owners were less tolerant of status epilepticus, cluster seizures, or anti-convulsant side effects. Clearly controlling cluster seizures and status epilepticus combined client education and support by veterinary staff can have positive implications in increasing the lifespan of dogs with epilepsy. In patients already undergoing anti-convulsant therapy, there are several options traditionally used to control cluster seizures at home or stop an episode of status epilepticus. These options include Rectal diazepam administration Administering an extra dose of the patient s regular of phenobarbital Administering a several day course of the oral benzodiazepine- clorazepate to stop a cluster cycle. Each of these traditional methods has positives and negatives. Rectal diazepam has been demonstrated to be efficacious in stopping cluster cycles. Whereas there are commercially available rectal diazepam suppositories for use in humans these are rarely used in veterinary medicine probably for cost reasons. In veterinary medicine rectal diazepam is typically given by administering the injectable drug intra-rectally with a red rubber or other catheter and a syringe. This method of diazepam administration has some limitations. It requires dispensing large volumes of a scheduled injectable drug to clients where there may be safety or controlled drug abuse/diversion concerns. In addition injectable diazepam is light sensitive and binds to plastic. Therefore if the diazepam for rectal administration is dispensed in single dose plastic syringes- the stability of the drug becomes questionable if it needs to sit on a shelf for any length of time. Administering an extra dose of phenobarbital or short course clorazepate can stop a cycle of clusters but is less optimal to stop an episode of status epilepticus because it relies on the patient being able to take oral medications. It would be unsafe to have a client try to administer an oral medication in the midst of a status seizure. The following article by Peters et. al. provides rational evidence for another at home treatment option for status and/or clusters. (6) Peters RK, Schubert T, Clemmons R, Vickroy T. Levetiracetam Rectal Administration in Healthy Dogs. J Vet Intern Med 2014; 28: Levetiracetam is a newer anti-convulsant increasingly used as an adjunct to manage chronic seizures in dogs due to limited adverse effect profile and perceived clinically efficacy. Widespread use of levetiracetam was previously limited by high cost but generic formulations have improved this. Levetiracetam is commercially available as oral formulations and an

5 injectable formulation. The injectable formulation is used IV to stop clusters or status seizures. This study evaluated serum concentrations of rectally administered levetiracetam in 6 healthy dogs to assess whether rectal administration achieved target serum levels which might control seizures. Side effects and tolerability were assessed. Results in 6 healthy dogs administered 40mg/kg of levetiracetam rectally by way of a teat cannula support that serum levetiracetam reached target serum concentrations within 15 minutes of administration, and through 9 hours of measurement. The side effects were minimal with mild ataxia observed between minutes after drug administration. A limitation of this study is the patient population of a small number of healthy animals, who were not on anticonvulsants. Additionally, the target range of 5-40ug/ml for a therapeutic concentration was extrapolated from humans and it is not known what the therapeutic target in dogs is. It should be noted that the volume of levetiracetum to administer rectally is larger than that with diazepam which may be a factor for owners administering this to dogs (especially large dogs) at home. For example the volume of levetiracetam to administer is 8ml for 20kg dog, 20ml for a 100kg dog. Take Home Points: The efficacy of levetiracetam to stop seizures in clinical patients still needs to be examined but given the importance of seizure control to the overall life expectancy of dogs with seizures; this article provides rational pharmacokinetic support for using rectal levetiracetum as an adjunct to managing cluster seizures in the home environment. Analgesia The efficacy of the local anesthetic technique of inferior temporal-palpebral (ITP) injection for motor and sensory analgesia of the globe has been well established. (7)(8) Inferior temporalpalpebral injection uses a 22 gauge, 1.5 inch needle to inject local anesthetic into the orbital fascia and retrobulbar space for analgesia. Enucleation procedures are common surgeries in emergency medicine indicated for globe proptosis, or rupture secondary to trauma or penetrating corneal foreign objects. There is no question that systemic and local analgesia techniques are the standard of care for managing ocular pain associated with enucleations. Whereas ITP injection is efficacious, the technique may be daunting for clinicians who are not familiar with the technique or who use the technique rarely. The next article offers an alternative to ITP injection for use in patients undergoing enucleations. (9) Ploog CL, et.al. Use of lidocaine-bupivacaine infused absorbable gelatin hemostatic sponges versus lidocaine-bupivacaine retrobulbar injections for post-operative analgesia following eye enucleations in dogs. J Am Vet Med Assoc 2014; 244: dogs undergoing enucleation were randomized into two intervention groups. One group was administered ITP injection of lidocaine/bupivacaine for analgesia prior to enucleation. The second group received placement of gelfoam infused with bupivacaine + lidocaine into the orbit post enucleation. Both groups had the same anesthesia protocol- premed hydro + midazolam, propofol induction, isoflurane anesthesia. Both groups were evaluated by blinded pain scorers post op. There were no differences in pain scores between treatment groups. One dog in the gel foam group required rescue analgesia. Take Home Point: Gel foam infused with bupivacaine/lidocaine can be effective as a local analgesic technique in patients undergoing enucleation.

6 References: 1. McGhie J a, Stayt J, Hosgood GL. Prevalence of bacteriuria in dogs without clinical signs of urinary tract infection presenting for elective surgical procedures. Aust Vet J Jan;92(1-2): Wan S, Hartmann FA, Jooss MK, Viviano KR. Prevalence and clinical outcome of subclinical bacteriuria in female dogs. J Am Vet Med Assoc 2014;245: Westropp JL, Sykes JE, Irom S, Daniels JB, Smith a, Keil D, et al. Evaluation of the efficacy and safety of high dose short duration enrofloxacin treatment regimen for uncomplicated urinary tract infections in dogs. J Vet Intern Med. 2012;26(3): Tracy G, Irom SJ. Fluoroquinolone levels in healthy dog urine following a 20-mg / kg oral dose of enrofloxacin exceed mutant prevention concentration targets against Escherichia coli isolated from canine urinary tract infections. J Vet Pharmacol Therap 2013; 37: Berendt M, Gredal H, Ersboll AK, Alving J. Premature death, risk factors and life patterns in dogs with epilepsy. J Vet Intern Med 2007;21: Peters RK, Schubert T, Clemmons R, Vickroy T. Levetiracetam rectal administration in healthy dogs. J Vet Intern Med 2014;28(2): Accola PJ, Bentley E, Smith LJ, Forrest LJ, Baumel C a, Murphy CJ. Development of a retrobulbar injection technique for ocular surgery and analgesia in dogs. J Am Vet Med Assoc Jul 15;229(2): Myrna KE, Bentley E, Smith LJ. Effectiveness of injection of local anesthetic into into the retrobulbar space for postoperative analgesia following eye enucleation in dogs. J Vet Med Assoc 2010;237: Ploog CL, Swinger RL, Spade J, Quandt KM, Mitchell MA. Use of lidocaine-bupivicaine infused absorbable gelatin hemostatic sponges versus lidocain-bupivicaine retrobulbar injections for post operative analgesia following eye enucleation in dogs. J Am Vet Med Assoc 2014;244:57 59.

ANTIBIOTIC USE GUIDELINES FOR URINARY TRACT AND RESPIRATORY DISEASE

ANTIBIOTIC USE GUIDELINES FOR URINARY TRACT AND RESPIRATORY DISEASE Jane Sykes, BVSc(Hons), PhD, DACVIM (SAIM) School of Veterinary Medicine Dept. of Medicine & Epidemiology University of California Davis,