Could this be lepto? Part 2

(Part 1 covered leptospirosis clinical presentations, diagnostic findings, and establishing a diagnosis; including images. Part 2 continues with treatment options.—Ed.) Treatments for leptospirosis Antibacterial therapy. Surprisingly, several studies have failed to demonstrate improved outcomes in people with leptospirosis treated with antibiotics versus those receiving a placebo; this is likely a reflection of the impact of the host immune response on the clinical manifestations and consequences of infection.20 Despite a dearth of hard evidence, antibiotics are recommended by the World Health Organization (WHO). From the veterinary perspective, expert opinion supports empirical administration of an appropriate antibiotic in a canine patient with a reasonable index of suspicion for leptospirosis.1,21 Antibiotics should not be withheld until infection is confirmed, as a delay may impact patient outcome and increases the risk of infection for those handling the animal. Various antibiotics have some efficacy against leptospires, but penicillins and doxycycline remain the initial drugs of choice. A dog drinking standing water should be considered high risk for leptospirosis if living in an endemic area. Courtesy Dr. Audrey Cook The 2010 ACVIM Consensus Statement recommends using doxycycline at 5 mg/kg PO or IV every 12 hours for two weeks.2Doxycycline is available for injection (as doxycycline hyclate, 100 mg/ml); this should be diluted to 1mg/ml and administered via IV over 30 minutes. If doxycycline is not available or cannot be tolerated, ampicillin (20 mg/kg IV every six hours; dose interval should be increased in severely azotemic animals) may be used initially, and the patient switched to doxycycline as soon as possible. The 2016 European Consensus Statement is similar, and both emphasize the need for a full two weeks of doxycycline to eliminate the carrier state.2,21 However, a recent study suggests this approach does not predictably eliminate the carrier state, and additional intervention may be needed (see below: Follow up).22 In my practice, we routinely start leptospirosis suspects on ampicillin/sulbactam at 30 mg/kg IV. This is less expensive than injectable doxycycline and provides better coverage for possible pyelonephritis, which is often an appropriate differential diagnosis. Patients are switched to doxycycline as soon as the urine culture is negative, unless another cause of acute kidney injury (AKI) has been established. Unfortunately, in susceptible individuals, doxycycline can cause an increase in liver enzymes similar to that seen in dogs with leptospirosis. If liver enzymes increase after the initiation of doxycyclinem, and the timing suggests a drug reaction, minocycline should be considered as an alternative. Fluid therapy. Creating an effective fluid plan can be complicated, as some patients are profoundly polyuric whilst others are oliguric or anuric. Rapid fluid resuscitation and rehydration using a balanced and buffered crystalloid, such as lactated Ringer’s solution or Normosol-R, is indicated for all patients in the initial stages, as it is imperative to ensure adequate renal perfusion. As a general rule, I try to restore euvolemia within six hours to prevent further tubular injury. Having said that, iatrogenic fluid overload should be avoided as this impacts the lungs, gastrointestinal tract, and brain. It also causes interstitial edema within the renal tissues, which can exacerbate azotemia and precipitate oligiuria. An indwelling urinary catheter should be placed at admission if possible; this reduces environmental contamination and exposure of staff to infectious urine, and lets the clinician reliably determine urine output. The catheter should be placed using sterile technique, and cleaned routinely to reduce the risk of nosocomial infection. If the patient is producing adequate amounts of urine (i.e., >2 ml/kg/hr), the catheter can be removed after the first 36 hours (by which time antibiotics will prevent the excretion of live leptospires). In markedly polyuric patients, the catheter should be maintained for longer, as information about urine output can guide decisions about fluid needs. A detailed discussion of fluid therapy is beyond the scope of this article, but the importance of a carefully tailored fluid plan cannot be understated. In a polyuric patient, the fluid rate should be adjusted every few hours to compensate for excessive obligatory losses. In the anuric, but volume-replete patient, the fluid provided should allow for insensible losses across the airway; these are approximately 1 ml/kg/hr of water. Evidence of volume overload such as serous nasal discharge (Figure 1), increased respiratory rate, gelatinous subcutaneous tissues, etc., requires all fluids are discontinued. Figure 1. A dog with serous nasal discharge is usually a sign of volume overload; fluid therapy should be discontinued immediately. Courtesy Dr. Audrey Cook Electrolytes should be checked at least every 12 hours so that adjustments can be made. Care must be taken to avoid iatrogenic hyperchloremia as this has been shown to negatively impact glomerular filtration rate. Potassium supplementation is usually needed in polyuric patients. Adjunctive therapies. Oliguria/anuria in a volume-replete patient should be addressed using furosemide +/- mannitol. I personally reach for furosemide, as recent evidence suggests mannitol has minimal effect on urine output in healthy dogs, and this drug has been associated with renal ischemia in people.23 In human patients given furosemide for anuric renal failure, the dose is routinely escalated based on serum creatinine concentrations as the drug must be actively secreted by the proximal convoluted tubules before reaching its site of action in the loop of Henle.24 Similar guidelines are not available for companion animals, but it is certainly appropriate to start with an initial bolus of at least 4 mg/kg IV. Dogs with non-responsive oliguria/anuria should be referred to a facility offering continuous renal replacement therapy or hemodialysis. Peritoneal dialysis is an option in dogs with life-threating hyperkalemia, but it has significant technical limitations/challenges and substantial risks. Figure 2. Dog with an esophageal feeding tube. This device allows for effective nutritional therapy and oral hydration and may allow a recovering patient to be discharged sooner. Courtesy Dr. Audrey Cook Results of a study evaluating the impact of diltiazem on outcome in a small cohort of dogs with leptospirosis indicated a positive effect, with a more rapid reduction in serum creatinine in treated dogs compared to controls.25 Additional supportive care may include anti-emetics (such as maropitant or ondansetron), acid suppressant agents (such as pantoprazole), gastric mucosal barriers agents (such as sucralfate), and pain relief (such as opioids). Nutritional support should be provided early in the course of the disease. Capromorelin should be introduced as soon as possible to support voluntary intake. If this is inadequate, a feeding tube (nasoesophageal or esophageal) should be placed (Figure 2). The latter will require anesthesia, but will permit the owner to continue supported feeding and maintain hydration at home. If possible, dogs with leptospirosis should be referred to a 24-hour care facility. Alternatively, the patient may be transferred to an emergency clinic for out-of-hours care and then returned to the day clinic for further care. It is not appropriate for these dogs to be left unattended during the night hours because fluid therapy cannot be appropriately provided or monitored. Prognosis For dogs without respiratory issues, the prognosis (if treated promptly and appropriately) is good, with reported survival rates of 80 percent. A patient that presents with oliguria or anuria should be given a more guarded prognosis. Outcomes in regions in which pulmonary involvement is commonly noted are worse; 32 out of 99 dogs died or were euthanized as a result of this complication in a recent retrospective study from Germany.26 Hepatic involvement also carries a more negative prognosis (Figure 3). Renal function usually improves quickly in polyuric patients, and continued improvement is expected over the next few months. Some dogs have persistent renal compromise following acute leptospirosis and should be managed appropriately. Figure 3. Icteric sclera may be noted in dogs with leptospirosis. Courtesy Dr. Audrey Cook Follow up A recent study looked at urine polymerase chain reaction (PCR) results for 32 dogs following antibiotic therapy for AKI attributable to leptospirosis.22 More than 50 percent were still PCR-positive despite several days of apparently appropriate antibiotic use, and 38 percent of dogs were still positive on urine PCR after up to 18 days of doxycycline. Two of the dogs with persistent leptospiuria were subsequently diagnosed with chronic kidney disease (CKD). The authors of this study recommended routine follow-up PCR testing and retreatment if necessary. Public health issues Every dog with unexplained AKI should be regarded as a potential leptospirosis case. All body fluids should be handled with care, and contact with urine should be minimized. Gloves and face shields are appropriate for personal protection. As a general guideline, urine is likely to be contagious until 24-36 hours following the start of antibiotics. In a recent study of veterinary personnel and pet owners, infection appeared to be uncommon despite exposure to body fluids from affected dogs.27 All staff members and pet owners should be informed of the risk of zoonotic transmission and instructed to seek medical care if they become unwell. Leptospires are susceptible to UV irradiation, desiccation, and common disinfectants (bleach, iodine-based, hydrogen peroxide, quaternary ammonium solutions). Infected dogs do not need to be kept in an isolation ward, but they should be gurneyed rather than walked around the hospital and urinate in a restricted area. Routine laundering will kill organisms in bedding. Current recommendations include the prophylactic treatment (doxycycline 5 mg/kg by mouth every 12 hours for 14 days) of any other dogs in the household.2 Vaccination Current vaccines appear to be effective for the serovars listed. Cross immunity appears modest at best, and it is appropriate to think of vaccinial protection as serovar-specific.28 Although leptospirosis vaccines have been anecdotally associated with anaphylactoid reactions, recent data suggests these vaccines are not more likely than other routine ones to cause problems.29Annual vaccination or biannual should be recommended to all owners if the dog is judged to be at risk (Figure 4). Defining risk can be challenging, but geographic locations and immediate environmental circumstances should be considered. Spring vaccination is wise, as this coincides with reemergence of the disease as the weather warms. Although recurrent leptospirosis following treatment and recovery has not been reported, it is probably prudent to vaccinate dogs because post-infection immunity may not cover all serovars. Chronic kidney disease and leptospirosis Although acute renal injury secondary to leptospirosis is known to cause CKD, most dogs with CKD are not tested for leptospirosis. The current International Renal Interest Society guidelines for managing CKD recommend investigating and treating any underlying conditions, but do not specifically refer to leptospirosis.30 However, a recent study indicated dogs with CKD were more likely to be urine PCR positive for leptospirosis than healthy controls (75 percent vs. 21 percent).31 This suggests subclinical infection should be considered in dogs diagnosed with CKD so treatment can be provided. The impact on longevity for treated dogs has not been established, but intervention reduces environmental contamination and the risk to human and canine family members. Audrey Cook, BVM&S, MRCVS, MSc Vet Ed, Dip ACVIM (SAIM), Dip ECVIM (CA), Dip ABVP (feline practice) is professor of Small Animal Internal Medicine at Texas A&M University. She is chief of the Internal Medicine Section, and currently divides her time between the Internal Medicine Service and the Interventional Radiology and Endoscopy Service. References Abela-Ridder B, Sikkema R, Hartskeerl RA. Estimating the burden of human leptospirosis. Int J Antimicrob Ag. 2010;36:S5-S7. Sykes JE, Hartmann K, Lunn KF, et al. 2010 ACVIM small animal consensus statement on leptospirosis: diagnosis, epidemiology, treatment, and prevention. J Vet Intern Med 2011;25:1-13. White AM, Zambrana-Torrelio C, Allen T, et al. Hotspots of canine leptospirosis in the United States of America. Vet J.2017;222:29-35. Murillo A, Goris M, Ahmed A, Cuenca R, Pastor J. Leptospirosis in cats: Current literature review to guide diagnosis and management. J Fel Med Surg. 2020;22(3):216-228. Dorsch R, Ojeda J, Salgado M, et al. Cats shedding pathogenic Leptospira spp.—An underestimated zoonotic risk? PloS One. 2020;15(10):e0239991. Costa F, Wunder Jr EA, De Oliveira D, Bisht V, Rodrigues G, Reis MG, Ko AI, Begon M, Childs JE. Patterns in Leptospira shedding in Norway rats (Rattus norvegicus) from Brazilian slum communities at high risk of disease transmission. PLoS Neglect Trop D. 2015;9(6):e0003819. Ward MP, Guptill LF, Wu CC. Evaluation of environmental risk factors for leptospirosis in dogs: 36 cases (1997–2002). J Am Vet Med Assoc. 2004 Jul 1;225(1):72-77. Goldstein RE, Lin RC, Langston CE, et al. Influence of infecting serogroup on clinical features of leptospirosis in dogs. J Vet Int Med. 2006;20(3):489-494. Langston CE, Heuter KJ. Leptospirosis: A re-emerging zoonotic disease. Vet Clin N Am-Small. 2003;33(4):791-807. Tangeman LE, Littman MP. Clinicopathologic and atypical features of naturally occurring leptospirosis in dogs: 51 cases (2000–2010). J Am Vet Med Assoc. 2013;243(9):1316-1322. Barthélemy A, Magnin M, Pouzot‐Nevoret C, Bonnet‐Garin JM, Hugonnard M, Goy‐Thollot I. Hemorrhagic, hemostatic, and thromboelastometric disorders in 35 dogs with a clinical diagnosis of leptospirosis: a prospective study. J Vet Intern Med.2017;31(1):69-80. Kohn B, Steinicke K, Arndt G, Gruber AD, et al. Pulmonary abnormalities in dogs with leptospirosis. J Vet Intern Med. 2010;24(6):1277-1282. Reagan KL, Sykes JE. Diagnosis of canine leptospirosis. Vet Clin N Am-Small. 2019;49(4):719-731. Martin LER, Wiggans KT, Wennogle SA, et al. Vaccine associated Leptospira antibodies in client-owned dogs. J Vet Int Med. 2014;28(3):789-792. Fraune CK, Schweighauser A, Francey T. Evaluation of the diagnostic value of serologic microagglutination testing and a polymerase chain reaction assay for diagnosis of acute leptospirosis in dogs in a referral center. J Am Vet Med Assoc. 2013;242(10):1373-1380. Lizer J, Velineni S, Weber A, et al. Evaluation of 3 serological tests for early detection of leptospira‐specific antibodies in experimentally infected dogs. J Vet Int Med. 2018;32:201-207. Curtis KM, Foster PC, Smith PSet al. Performance of a recombinant LipL32 based rapid in-clinic ELISA (SNAP® Lepto) for the detection of antibodies against Leptospira in dogs. International Journal of Applied Research in Veterinary Medicine. 2015;13(3). Midence JN, Leutenegger CM, Chandler AM, et al. Effects of recent Leptospira vaccination on whole blood teal‐time PCR testing in healthy client‐owned dogs. J Vet Intern Med. 2012;26(1)149-152. Harkin KR, Roshto YM, Sullivan JT. Clinical application of a polymerase chain reaction assay for diagnosis of leptospirosis in dogs. J Am Vet Med Assoc. 2003;222:1224-1229.

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Could this be lepto? Part 2

Treatment modalities and prognosis for leptospirosis

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