Ch. 10 Therapy of Urinary Tract Disorders PDF

CHAPTER 10 THERAPY OF URINARY TRACT DISORDERS LEARNING OBJECTIVES FROM THE PATHOPHYSIOLOGY, PREDICT WHO GETS WHAT AND WHEN FROM A URINALYSIS, PREDICT THE MOST LIKELY BACTERIAL PATHOGENS PLAN INITIAL THERAPY OF SPORADIC BACTERIAL CYSTITIS OR RECURRENT BACTERIAL CYSTITIS...

CHAPTER 10 THERAPY OF URINARY TRACT DISORDERS LEARNING OBJECTIVES FROM THE PATHOPHYSIOLOGY, PREDICT WHO GETS WHAT AND WHEN FROM A URINALYSIS, PREDICT THE MOST LIKELY BACTERIAL PATHOGENS PLAN INITIAL THERAPY OF SPORADIC BACTERIAL CYSTITIS OR RECURRENT BACTERIAL CYSTITIS DETERMINE THE LIKELY CAUSES OF THERAPEUTIC FAILURES AND FORMULATE A NEW PLAN PLAN THERAPY OF PROSTATITIS IN MALE DOGS DEVELOP A TREATMENT PLAN FOR PATIENTS ACCORDING TO THE STAGE OF RENAL FAILURE. DEVELOP A TREATMENT PLAN FOR DOGS WITH URINARY INCONTINENCE BACTERIAL URINARY TRACT INFECTIONS Bacterial urinary tract infections are the most common cause of urinary tract disease in dogs. Approximately 14% of all dogs will acquire a bacterial urinary tract infection (UTI) during their lifetime and many dogs presented to a veterinarian for other problems will have a concurrent bacterial UTI.1-3 Studies of feline lower urinary tract disease suggest that the prevalence of bacterial UTI is less than 5% in cats presenting with an initial episode of signs related to urinary tract disease (“blocked” cats).2,3 The incidence of UTI is much higher in older cats, as they may be more susceptible to bacterial UTI because of diminished host defenses secondary to aging or concomitant disease (diabetes mellitus, renal failure, and hyperthyroidism).4 Bacterial UTIs in ruminants are associated with catheterization or parturition in females and as both a cause and consequence of urolithiasis in males.5-7 In horses, UTIs are uncommon and typically associated with bladder paralysis, urolithiasis or urethral damage.8 Colonization of any part of the urinary tract with bacteria increases susceptibility to infection in other parts of the urinary tract and body. Consequences of UTI can include infertility, urinary incontinence, discospondylitis, pyelonephritis, and renal failure.9 Septicemia can occur as a consequence of UTI in immunosuppressed patients. In intact males, the UTI frequently extends to the prostate gland or other accessory sex glands. Due to the blood-prostate barrier, it is difficult to eradicate bacteria from the prostate gland, potentially resulting in reinfection of the 328 urinary tract following appropriate treatment, systemic bacteremia, infection of other parts of the reproductive tract, or local infection within the prostate and eventual abscess formation. In dogs, infection of the urine with urease producing bacteria (Staphylococcus pseudintermedius and Proteus mirabilis) is associated with the formation of struvite uroliths. Corynebacterium urealyticum, also a rapid urea-splitting organism, is associated with alkaline urine and struvite and calcium phosphate precipitation, which can result in bladder wall encrustations.10 PATHOGENESIS The establishment of bacterial UTI primarily depends on the interaction between host defenses and virulence factors of the bacteria. Studies in cats and dogs have shown that when the host defenses are altered by catheterization, surgery or other diseases of the urinary tract (idiopathic cystitis, urolithiasis, polyps, neoplasia, etc.), the incidence of bacterial UTI is high.11,12 Abnormalities of host defenses are thought to be the most important factor in the pathogenesis of UTI and the persistence of complicated UTI. Defense mechanisms of the host can be found in all areas of the urinary tract including the urethra, bladder, ureters, kidneys and urine itself. Normal bacterial flora of the distal urethra is thought to compete with invading uropathogenic bacteria through bacterial interference. In the normal urethra, the resident flora may consume essential nutrients, interfere with bacterial adhesion to the uroepithelium or secrete bacteriocins, thus preventing the uropathogen from colonizing the urethra. In addition, the surface of the urethra has intrinsic properties that prevent bacterial colonization. Scanning electron microscopy of the urethra in female dogs reveals that the uroepithelium of the distal urethra and vagina has surface microvilli that allows for the attachment of resident bacteria. In contrast, the surface of the proximal urethra and bladder has microplicae. These folds flatten when the lumen of the urethra is distended during the act of micturition, thus making it difficult for bacteria to adhere. Such structural differences between epithelia may be associated with resistance to bacterial colonization. Another host defense of the urethra involves secretory IgA, which prevents bacterial adherence and colonization. Intrinsic properties of the urethra such as urethral peristalsis and a functional high-pressure zone in the mid-urethra also act to prevent bacterial colonization. Micturition is an important defense against bacterial colonization of the lower urinary tract. Frequent voiding of adequate amounts of urine removes ascending bacteria that gain access to the urethra. In addition, the flattening of urethral folds may dislodge adherent bacteria during voiding. The production of fresh urine dilutes bacterial counts in urine and complete voiding empties the bladder of bacteria. The pH extremes and osmolarity of urine inhibit bacterial growth and salts, urea and organic acids in urine reduce bacterial survival. Urine lactoferrin 329 scavenges essential iron from bacteria. Soluble and cell associated factors in the bladder, such as Tamm-Horsfall protein, glycosaminoglycans, secretory IgA and uromucoid act to block bacterial adherence. If bacteria successfully attach to the uroepithelium, additional host defense mechanisms are triggered. The uroepithelium normally has a very slow turnover rate. But in response to intracellular invasion, bladder cells exfoliate in an apoptosis-like mechanism to clear the bacteria through the urine flow. Intracellular invasion also triggers neutrophil infiltration of the uroepithelium and the bladder lumen and the presence of pyuria is a hallmark of UTI. Diseases of the urinary tract such as bladder atony, urolithiasis and prolonged urine retention predispose to infection because of the presence of residual urine. Urine dilution as well as an impaired immune response contribute to the development of UTI in dogs receiving corticosteroids. In addition, excessive amounts of glucose in the urine inhibit phagocytosis and may predispose to bacterial colonization of the uroepithelium. Dogs and cats with concurrent diseases such as diabetes mellitus and/or hyperadrenocorticism or who are receiving immunosuppressive drugs (eg, oclacitinib or cyclosporine) are at increased risk for urinary tract infection and may have asymptomatic bacteriuria.13-16 Anatomical abnormalities of the lower urinary tract (such as vulvar abnormalities), urethrostomies, as well as indwelling catheters and cystotomy tubes are risk factors for ascending bacterial infections. The anatomy and function of the ureters provide a mechanism of defense against bacterial invasion of the kidneys. The distal ureter courses through the bladder wall at an angle that forms a one-way flap, thus preventing vesicoureteral reflux. Peristalsis of the ureters promotes unidirectional flow of urine from the kidneys to the bladder and is an important defense against the migration of bacteria that are able to ascend the ureters independent of vesicoureteral reflux. Renal defenses are primarily local and systemic immune responses. The renal cortex is much less susceptible to infection than is the medulla, possibly due to increased blood flow in the cortex. Several factors, including decreased blood flow, high ammonia concentrations and increased osmolality, interfere with local immune responses in the medulla, increasing susceptibility to infection. Pyelonephritis is infection and inflammation of the upper urinary tract system, including the kidneys and ureters. It usually occurs as extension of a lower UTI and is suspected when there is a history of recurring lower UTI and/or clinical signs of infection. Chronic pyelonephritis can be very difficult to treat and may lead to irreversible kidney damage and renal failure. Long-term antimicrobial therapy is usually required.9 In addition to a disruption of the normal host defenses, certain bacterial virulence factors enhance colonization of the urinary epithelium and allow the development of UTI. Bacterial adhesion to the uroepithelium is thought to be the most important virulence factor of uropathogenic organisms. E. coli and Proteus mirabilis both have specific fimbriae that enhance bacterial adherence to the epithelial surface of the urinary tract. E. coli, Proteus spp., 330 Staphylococcus spp. and Pseudomonas spp., carry resistance plasmids which confer bacterial resistance to one or more antimicrobials, enhancing their pathogenicity. Other virulence factors include capsules that surround bacteria that limit phagocytosis, antibody coating, and opsonization. In addition, E. coli produces factors such as hemolysin and aerobactin that promote bacterial growth. Analysis of E. coli virulence factors suggests that some canine isolates cause both cystitis and diarrhea, and that these strains may be infectious for humans.17- 19 UROPATHOGENS The most frequently isolated bacteria causing UTI in dogs, cats, horses and cattle are E. coli.20 In dogs and cats, Staphylococcus pseudintermedius, Proteus spp., Streptococcus spp., and Klebsiella spp. are reported less frequently, and enterococci and Pseudomonas aeruginosa tend to be isolated from recurrent or complicated UTIs. Streptococci and enterococci follow E. coli in prevalence in UTI in horses, while Corynebacterium renale follows in cattle.7,21 Canine Uropathogens from the WCVM DIAGNOSIS Diagnosis of UTI is based on the presence of clinical signs of lower urinary tract disease and urinalysis, ideally with confirmation by bacterial culture and therapy guided by susceptibility results. Clinical signs of bacterial UTI can include dysuria, hematuria, pollakiuria, and stranguria. However, many dogs and cats will not show overt clinical signs of UTI. 331 URINALYSIS When possible, cystocentesis is the best method of collecting urine for examination. Free catch or catheterized samples must be interpreted in light of possible contamination. Urine sediment should always be evaluated for bacteria and white and red blood cells. Urine dipsticks are unreliable for evaluating white blood cells. Rod-shaped bacteria may not be visible when their concentration is ≤ 10,000/ml and cocci may not be visible when their concentration is ≤ 100,000/ml. Dogs with E. coli infections are more likely to have dilute urine (urine specific gravity MIC for treatment of UTI may explain the poor efficacy results of beta-lactam antibiotics in treatment of UTI as they have probably not been dosed frequently enough. So while the label dose of amoxicillin for dogs and cats is sufficient, the label frequency of every 12 hours may be less effective than dosing every 8 hours. Obviously, this impacts on client compliance with increased daily dosing. Highly protein bound beta-lactams, such as cefovecin and ceftiofur, overcome this limitation, as the protein- bound drug acts as a depot to provide 14 days of therapy after a single injection. As their bacterial killing effect is concentration-dependent, fluoroquinolones and aminoglycosides efficacy correlates best to AUC:MIC ratios, and in the murine model, gentamicin and fluoroquinolone treatment results in significantly lower bacterial counts than the beta-lactam antimicrobials, indicating that rapid bacterial kill is important in the treatment of UTI. Therefore, client compliance during therapy for UTI is imperative. This makes single daily dose administration (e.g., fluoroquinolones, cefpodoxime) or long acting injectables (e.g., cefovecin, ceftiofur) attractive, and is the basis for much of the first line use of fluoroquinolones and third generation cephalosporins. For dogs, antimicrobials should be administered just before bedtime or confining the dog, to maintain high urine concentrations in the bladder for the longest possible time. ANTIMICROBIAL TREATMENT CHOICES AMOXICILLIN/AMPICILLIN Amoxicillin and ampicillin are bactericidal and relatively nontoxic with a spectrum of antibacterial activity greater than penicillin G. They are easily administered orally to dogs and cats. Injectable ampicillin products are available for large animals. Initially, they have excellent activity against staphylococci, streptococci, enterococci, and Proteus spp., and may achieve high enough urinary concentrations to be effective against E. coli and Klebsiella spp. Pseudomonas spp. and Enterobacter spp. are resistant. Absorption of ampicillin is affected by food, so therapeutic success may be easier to achieve with amoxicillin. Injectable amoxicillin trihydrate (Polyflex®) is approved for use in cattle and swine and can be administered to small ruminants. As penicillins, amoxicillin and ampicillin are weak acids with a low volume of distribution, so do not achieve therapeutic concentrations in prostatic fluid. 334 AMOXICILLIN/CLAVULANIC ACID Amoxicillin/clavulanic acid (Clavamox®, Clavaseptin®) is used orally in small animals. It has an increased spectrum of activity against Gram-negative bacteria due to the presence of the “suicide” drug, clavulanic acid. Clavulanic acid irreversibly binds to beta-lactamases, allowing the amoxicillin fraction to interact with the bacterial pathogen. This combination usually has excellent bactericidal activity against beta-lactamase-producing staphylococci, E. coli and Klebsiella spp. Pseudomonas spp. and Enterobacter spp. remain resistant. However, clavulanic acid undergoes some hepatic metabolism and excretion, so the antimicrobial activity in urine may be due primarily to the high concentrations of amoxicillin achieved in urine. It is not clear that amoxicillin/clavulanic acid is more efficacious for sporadic UTIs than amoxicillin and most treatment guidelines suggest amoxicillin as first line therapy of UTIs in dogs and cats.22,23 CEPHALOSPORINS Cephalexin is a first generation cephalosporin available in human and veterinary formulations (Vetolexin®, Cephaseptin®). Cefadroxil (Cefa Tabs®) is available as a veterinary product for dogs and cats. Like the penicillins, they are bactericidal, acidic drugs with a low volume of distribution and are relatively nontoxic. Vomiting and gastrointestinal disturbances may occur in dogs and cats treated with cephalosporins. Cephalosporins have greater stability to beta- lactamases than penicillins, so have greater activity against staphylococci and Gram-negative bacteria. They have excellent activity against staphylococci, streptococci, E. coli, Proteus spp. and Klebsiella spp. Pseudomonas spp., enterococci and Enterobacter spp. are resistant. Use of cephalosporins (and fluoroquinolones) predisposes patients to enterococcal infections, including vancomycin-resistant clones. Cefovecin (Convenia®) is a third generation cephalosporin approved for the treatment of UTI in dogs due to E. coli and Proteus spp. Due to a high degree of protein binding, after SC dosing therapeutic concentrations are achieved for 14 days, making this an attractive treatment choice for fractious animals. It is not approved for cats for UTI, but it is used extralabel for this. Cefpodoxime (Simplicef®) is an oral third generation cephalosporin approved for use in dogs for skin infections (wounds and abscesses) but is used extralabel for the treatment of canine UTI. Cefpodoxime has a relatively long half-life in dogs due to a high degree of protein binding, so it is dosed once daily. Ceftiofur (Excenel®) is a third generation injectable cephalosporin approved for treatment of canine UTI caused by E. coli and Proteus spp. It is approved for treatment of respiratory tract infections in horses, cattle, sheep, goats and swine. Like cefovecin and cefpodoxime, it is highly protein bound and slowly eliminated. After injection, ceftiofur is rapidly metabolized to 335 desfuroylceftiofur. Desfuroylceftiofur has equivalent activity to ceftiofur against E. coli but is half as potent as ceftiofur against staphylococci and has variable activity against Proteus spp. If the microbiology service utilizes ceftiofur when performing susceptibility testing, a false expectation of therapeutic efficacy may result. Pseudomonas spp., enterococci, and Enterobacter spp. are resistant to ceftiofur and desfuroylceftiofur. Ceftiofur is associated with a duration and dose-related thrombocytopenia and anemia in dogs that would not be expected with the recommended dosage regimen. FLUOROQUINOLONES Enrofloxacin (Baytril®), orbifloxacin (Orbax®), marbofloxacin (Zenequin®) and pradofloxacin (Veraflox®) are all fluoroquinolones used for treatment of UTIs. Pradofloxacin is approved for use in dogs and cats in Europe and Canada, but only in cats in the United States due to a small incidence of thrombocytopenias occurring in treated dogs. Large animal injectable fluoroquinolone formulations are available for the treatment of respiratory tract infections in food animals; however, extralabel drug use in the US is strictly prohibited. Ciprofloxacin is the most commonly used human fluoroquinolone and may be less expensive than approved veterinary products to use in very large dogs, but pharmacokinetics differences in oral absorption in other veterinary species may result in inefficacy. The fluoroquinolones are bactericidal, amphoteric drugs; they possess acidic and basic properties, but they are very lipid soluble at physiological pH (pH 6.0-8.0), so have very high tissue distribution. Ciprofloxacin has the greatest antimicrobial activity of all the fluoroquinolones against Pseudomonas spp. All fluoroquinolone drugs usually have excellent activity against staphylococci and Gram-negative bacteria but may have variable activity against streptococci and enterococci. The therapeutic advantage of these drugs is their Gram-negative antimicrobial activity and high degree of lipid solubility. The use of fluoroquinolones should be reserved for UTIs that involve Gram-negative bacteria, especially Pseudomonas spp., UPECs (uropathogenic E coli) that are potentially intracellular in location, and for UTIs in intact male dogs because of excellent penetration into the prostate gland and activity in abscesses. As they are concentration-dependent killers with a long post-antibiotic-effect (PAE), the fluoroquinolones are efficacious with once daily, high-dose therapy for a short time period. The newest fluoroquinolone for dogs and cats, pradofloxacin, requires two genetic mutations for resistance, so MIC values for Enterobacteriaceae are lower than for other fluoroquinolones and it is hoped that pradofloxacin will be less selective for antimicrobial resistance. The fluoroquinolones should be avoided for chronic, low-dose therapy, as this encourages the development of bacterial resistance that is often multi-drug. Cases that involve Pseudomonas spp. and UPEC should be carefully investigated for underlying pathology and corrected if at all possible. Once Pseudomonas spp. and E. coli become resistant to the fluoroquinolones, there are no other patient and client-convenient therapeutic options. 336 AMINOGLYCOSIDES Gentamicin (Gentocin®) and the other aminoglycosides are basic drugs, but they are very large polar (water soluble) drugs, so have a low volume of distribution and will not penetrate the blood-prostate barrier. They are not absorbed orally, so must be given by subcutaneous, intramuscular or intravenous injection. The aminoglycosides have a similar spectrum of activity to the fluoroquinolones, but their use for UTIs is limited because of the necessity of parenteral injections and potential for nephrotoxicity and ototoxicity. Enterococci are inherently resistant to the aminoglycosides. Like the fluoroquinolones, the aminoglycosides are concentration- dependent, bactericidal killers with a long PAE, so once daily therapy of short duration is efficacious and minimizes the risk of nephrotoxicity. They can be considered for in-hospital or outpatient treatment of UTI due to fluoroquinolone-resistant pathogens; but again, the importance of identifying and correcting underlying pathology must be emphasized. NITROFURANTOIN Nitrofurantoin was approved for treatment of UTI in dogs, cats and horses in Canada but the veterinary product is no longer marketed. It is available as tablets, capsules and a pediatric suspension for humans. It is only used for treatment of UTI in humans, as it has a very low volume of distribution and therapeutic concentrations are only attained in urine. It is considered a carcinogen, so it is banned for use in food producing animals, but its use in small animals is increasing with increasing rates of antimicrobial resistance to veterinary antimicrobials.24,25 Nitrofurantoin is used for infections caused by E. coli, enterococci, staphylococci (including MRSP), Klebsiella spp. and Enterobacter spp. Proteus spp and Pseudomonas spp. are resistant. It is increasingly indicated for treatment of UTI caused by multidrug-resistant bacteria, which are otherwise difficult to treat using conventional veterinary antimicrobial agents. The pharmacokinetics and adverse effect profile of nitrofurantoin have not been well investigated in dogs, cats, or horses, and the need for multiple daily dosing makes it inconvenient for clients. Nitrofurantoin is associated with nausea and vomiting in both dogs and cats. TETRACYCLINES Tetracyclines are bacteriostatic, amphoteric drugs with a high volume of distribution. Tetracyclines are broad-spectrum antimicrobials, but because of plasmid-mediated resistance, variable susceptibility occurs in staphylococci, enterococci, Enterobacter spp., E. coli, Klebsiella spp., and Proteus spp. Pseudomonas spp. are resistant. Doxycycline is a very lipid soluble tetracycline that is better tolerated in cats and will achieve therapeutic concentrations in urine and the prostate, so it may be useful for some UTIs. Doxycycline may also be effective in the 337 treatment of methicillin-resistant staphylococcal UTI. If capsules or tablets are administered, it is critical to follow the dose with fluids afterwards to insure passage into the stomach. If capsules lodge in the esophagus, severe local necrosis with subsequent esophageal stricture can occur. CHLORAMPHENICOL Chloramphenicol (Chlor®-1000, Chlor®Palm 250) has a high volume of distribution and is capable of achieving high tissue concentrations, including in the prostate of male dogs. It is active against a wide range of Gram-positive and many Gram-negative bacteria, against which it is usually bacteriostatic. Chloramphenicol is typically active against Enterococcus spp., staphylococci, streptococci, E. coli, Klebsiella spp., and Proteus spp. Pseudomonas spp. are resistant. North American isolates of methicillin-resistant Staphylococcus aureus and Staphylococcus pseudintermedius are typically susceptible, but resistance may emerge with use. Well known for causing idiosyncratic (non-dose dependent) anemia in humans and dose- dependent bone marrow suppression in animals, its use in both human and veterinary medicine is increasing due to antimicrobial resistance rates. It is banned for use in food animals. FOSFOMYCIN Fosfomycin (Monurol®) is a bactericidal, broad spectrum antibiotic approved as a first line treatment for UTI in women. It comes as a 3 gram oral sachet and administered as a single dose to deliver 40 mg/kg BW. It is structurally unrelated to other classes of antimicrobials, and it is highly active against many MDR strains of bacteria including uropathogenic E coli and methicillin resistant Staphylococcus pseudintermedius. It has a low degree of protein binding and has time-dependent killing action and a long post antibiotic effect. It interferes with bacterial cell wall synthesis but in a different manner than beta-lactam antibiotics. Its use in veterinary medicine should be reserved for documented resistance to other antimicrobials. POTENTIATED SULFONAMIDES Trimethoprim/sulfonamides (TMP/sulfas) are combinations of two very different drugs that act synergistically on different steps in the bacterial folic acid pathway. Trimethoprim is a bacteriostatic, basic drug that has a high volume of distribution and a short elimination half-life, while the sulfonamides are bacteriostatic, acidic drugs with a medium volume of distribution and long half-lives (ranging from 6 to over 24 hours). These drugs are formulated in a 1:5 ratio of TMP to sulfa, however the optimal bactericidal concentration is a ratio of 1:20 TMP:sulfa. Microbiology services utilize the 1:20 ratio in susceptibility testing, however the widely varying pharmacokinetic properties of this drug combination make it difficult to determine a 338 therapeutic regimen with that achieves the 1:20 ratio at the infection site. Although the combination does penetrate the blood:prostate barrier, the sulfa drugs are ineffective in purulent material because of the freely available PABA from lysed phagocytes. The combination of TMP/sulfa is synergistic and bactericidal against staphylococci, streptococci, E. coli and Proteus spp. Activity against Klebsiella spp. is variable and Pseudomonas spp. are resistant. Although enterococci may appear susceptible to TMP/sulfas in vitro, they escape the antifolate activity of the drug combination in vivo by incorporating preformed exogenous folates, so they should not be considered for treatment even if reported as susceptible. While frequently recommended as a second treatment after amoxicillin for canine UTI, TMP/sulfas are associated with a number of adverse effects, and chronic low-dose therapy may result in bone marrow suppression and keratoconjuctivitis sicca. DOSAGE REGIMENS Currently, the duration of therapy for UTI is controversial. While animals are routinely treated with antimicrobial drugs for 10-14 days, shorter duration antimicrobial regimens are routinely prescribed in human patients, including single dose fluoroquinolone therapy. A clinical comparison of three days of therapy with a once-daily high dose of enrofloxacin with two weeks of twice daily amoxicillin/clavulanic acid showed equivalence in the treatment of simple UTI in dogs.26 However, further studies are needed to determine the optimal dosage regimens for different classes of antimicrobials and it is inappropriate to use fluoroquinolones as first line therapy for sporadic UTI. If initial treatment fails, simply prescribing a different antimicrobial is not recommended. Instead, the underlying cause of the failure needs to be determined and addressed (eg, antimicrobial resistance, poor client compliance). 339  Antimicrobial Drug Dosage Typical Antimicrobial Activity Mean Urine Concentration (μg/ml) amoxicillin 11 mg/kg q 8 hr PO Staph, Strep, Enterococci, Proteus 201 ampicillin 25 mg/kg q 8 hr PO Staph, Strep, Enterococci, Proteus 309 amoxicillin/clavulanic acid 12.5 mg/kg q 8 hr PO Staph, Strep, Enterococci, Proteus 201 cephalexin 30 mg/kg q 8 hr PO Staph, Strep, Proteus, E coli, Klebsiella 500 cefovecin 8 mg/kg q 14 d SC Proteus, E coli Not available ceftiofur 2.0 mg/kg q 24 hr SQ E coli, Proteus 8 enrofloxacin, 5-10 mg/kg q 24 hr PO Staph, some Strep, E coli, Proteus, Klebsiella, 200 (enro) ciprofloxacin, Pseudomonas, Enterobacter pradofloxacin, orbifloxacin, marbofloxacin fosfomycin 40 mg/kg q 12 hr Staph, Step, Enterococci, E coli, Proteus, Klebsiella Not available gentamicin 4-6 mg/kg q 24 hr SQ Staph, some Strep, E coli, Proteus, Klebsiella, 107 Pseudomonas, Enterobacter nitrofurantoin 5 mg/kg q 8 hr PO Staph, some Strep, some Enterococci, E coli, Klebsiella, 100 Enterobacter tetracycline 20 mg/kg q 8 hr PO Strep, some activity against Staph and E coli at high urine 300 doxycycline 5 mg/kg q 12 hr PO concentrations 50 chloramphenicol 25-50 mg/kg q 6-8 hr Staph, some Strep, Enterococci, E coli, Proteus, Klebsiella trimethoprim/sulfa 15 mg/kg q 12 hr PO Strep, Staph, E coli, Proteus, some Klebsiella 55/246 Dosage, Typical Antimicrobial Activity and Mean Urinary Concentrations of Antimicrobials Commonly Used to Treat Urinary Tract Infections in Dogs and Cats 340 TREATMENT OF RECURRENT BACTERIAL CYSTITIS Recurrent bacterial cystitis is due to a persistent underlying abnormality in the urinary tract or host defenses that results in 3 or more episodes of UTI in the preceding 12 months or 2 or more in the preceding 6 months.22 A relapse occurs when the original infection is not cleared despite therapy. Reinfection occurs when the patient is infected with a new bacterial species or strain after successful therapy (documented by a negative urine culture post-treatment). A superinfection occurs when a different bacterial species or strain colonizes the urinary tract while the patient is still on antimicrobial therapy for the original infection. Subclinical bacteriuria is the presence of bacteria in urine confirmed by bacterial culture but without clinical evidence of lower urinary tract disease. In addition to antimicrobial resistance, other differentials for recurrent bacterial cystitis include immunocompromising states, urolithiasis, encrusting cystitis, bladder polyps, bladder neoplasia, micturition abnormalities, pyelonephritis and chronic prostatitis (intact males). In addition, conditions that damage the uroepithelium such as neoplasia, catheterization, surgery or cystitis caused by cyclophosphamide or idiopathic causes can predispose to the development of complicated UTI. Other causes of recurrent bacterial cystitis include anatomic defects (ectopic ureters, urachal diverticula), interference of normal micturition (urinary obstruction, damaged nervous innervation causing bladder atony) or changes in urine concentration or composition (glucosuria). Urine culture (preferably collected by cystocentesis) and susceptibility testing should be done for all recurrent bacterial cystitis cases. Additional diagnostics to consider include abdominal radiographs (with contrast studies), abdominal ultrasound, complete blood count and serum chemistries, and cystoscopy with biopsy or exploratory laparotomy. Although not automatically warranted, patients with recurrent bacterial cystitis may require longer courses of therapy and underlying pathology must be addressed. Chronic complicated cases of UTI, including pyelonephritis and prostatitis, may require antimicrobial treatment for 4 to 6 weeks, with the risk of selecting for antimicrobial resistance. A follow up urine culture should be performed after 4 to 7 days of therapy to determine efficacy. If the same or a different pathogen is observed, then an alternative therapy should be chosen, and the culture repeated again after 4 to 7 days. Urine should also be cultured 7 to 10 days after completing antimicrobial therapy to determine if the UTI is cured or has recurred. TREATMENT FAILURE Treatment failures may be due to poor owner compliance, inappropriate choice of antimicrobials, inappropriate dose or duration of treatment, antimicrobial resistance, 341 superinfection or an underlying predisposing cause (e.g., urolithiasis, neoplasia, urachal diverticula). If treatment for sporadic or recurrent UTI fails, a thorough evaluation should be carried out to determine and when possible, address the cause of failure. When faced with a therapeutic failure, the practitioner needs to consider if the UTI is due to a relapse or a reinfection. REINFECTIONS Reinfections are attributed to re-inoculation of the urinary tract from gastrointestinal flora in a host with deficiencies in their immune defense mechanisms. The deficiencies can be intrinsic to the patient (e.g., diabetes mellitus, hyperadrenocorticism) or iatrogenic (eg, corticosteroid or chemotherapy administration). In dogs, reinfections are often due to a different strain or species of bacteria. Since reinfections are associated with an underlying cause, identification and management of relevant risk factors and concurrent disease(s) is critical for successful therapy. However, it is not always possible to identify or manage an underlying cause, and previous recommendations were to keep patients (animals and humans) on daily, low dose antimicrobial therapy to prevent reinfections. This is no longer recommended as continuous antimicrobial therapy is unlikely to result in elimination of infection and significantly contributes to antimicrobial resistance, treatment costs and adverse effects of antimicrobials.22 So the focus needs to be on correcting the predisposing causes of UTI, not treating asymptomatic (subclinical) bacteriuria, and treating each episode of symptomatic UTI appropriately. RELAPSING URINARY TRACT INFECTION Relapses are often suspected when the same species of pathogen is repeatedly cultured, especially if the susceptibility pattern is the same. But advanced molecular studies are required to prove that the bacterial species present is identical to that previously isolated, and this testing is not available clinically. Relapses can be due to pathology that prevents eradication of the bacteria with appropriate antimicrobial therapy (eg, urolithiasis, pyelonephritis). Relapses can also be due to infection by uropathogens with enhanced intrinsic virulence that occur with what should be effective antimicrobial therapy. Bacterial virulence factors enhance colonization of the urinary epithelium and the development of UTI. Strains of uropathogenic E. coli (UPEC) have a number of virulence mechanisms that enable them to invade, survive and multiply within the uroepithelium. These bacteria are responsible for >90% of cases of UTI and are often found amongst the fecal flora of the same host. 342 Upon entry into host uroepithelium, UPEC can both multiply and emerge from the host cells or remain latent in membrane bound vesicles. The multiplying UPEC form intracellular bacterial communities free within the cytoplasm and can move into neighboring cells without entering the urine. Urine may then culture negative for the pathogen for a time, even though the infection is not actually cleared. The exfoliation of infected uroepithelium and the influx of neutrophils are normal defense mechanisms which work to the advantage of UPECs. Bladder cell exfoliation leaves underlying tissue exposed and susceptible to bacteria within the urine. The shedding of infected host cells into the urine facilitates the spread of UPEC in the environment. The influx of neutrophils compromises the integrity of the uroepithelium and may allow UPEC to penetrate deeper tissues.27 Other virulence factors of UPEC include capsules that surround bacteria that limit phagocytosis, antibody coating, and opsonization and the formation of biofilms. In addition, E. coli produce factors such as hemolysin and aerobactin that promote bacterial growth. These virulence mechanisms allow UPEC to persist within the uroepithelium in the face of antimicrobial therapy that effectively kills bacteria in the urine.28 Other uropathogens may have similar strategies to UPEC in establishing tissue reservoirs and persistent infection. The sequestration of UPEC within the bladder uroepithelium presents a great therapeutic challenge in human and veterinary patients. For relapsing or persisting UTI, it is important to ensure that adequate antimicrobial concentrations are achieved in the urine and bladder tissues to clear the infection. The antimicrobial choice, dosage regimen, the susceptibility pattern and client compliance should 343 be reviewed. The goal of treatment needs to be reviewed as “clinical cure” may not always result in “microbiological cure”.22 This C&S is from a 14 yr old FS Jack Russell Terrier. The recurring E coli isolates show susceptibility to all the treatment choices yet keep recurring after treatment with amoxicillin/clavulanic acid. Consider UPEC if the same isolate is cultured after discontinuing appropriate first line therapy and there is no evidence of antimicrobial resistance as a cause of treatment failure. SUBCLINICAL BACTERIURIA Subclinical bacteriuria is not uncommon, with rates of up to 12% in otherwise healthy dogs and as high as 30% in dogs with co-morbidities such as diabetes, chronic kidney disease or who are being treated with immunosuppressive drugs.29,30 Despite fears of secondary complications, there is little evidence that subclinical bacteriuria increases risk of clinical UTI or other infectious complications in dogs or cats. In human medicine, it is standard practice to not treat asymptomatic bacteriuria, even in compromised patients (such as patients with diabetes or hyperadrenocorticism). Treatment may eliminate the bacteriuria in the short term, but recolonization is common, and it is associated with increasing antimicrobial resistance. Therefore, if the patient shows no clinical signs of lower urinary tract disease and there is no pyuria, it is reasonable to not treat with antimicrobials or at least use a short duration (eg, 5 days) of therapy.22 Even isolation of a multi-drug resistant bacterial species should not affect the treatment decision. In patients that are unable to show clinical signs of UTI (eg, a patient with a spinal cord injury, immunosuppressed patients), the veterinarian must make a clinical judgement on whether to treat or not. 344 PYELONEPHRITIS Pyelonephritis is bacterial infection of the renal parenchyma and usually is due to infection from the bladder or less commonly, from bacteremia. Enterobacteriaceae, predominantly E coli, cause most cases of pyelonephritis.31 Even in cattle, E coli is more common than Corynebacterium renale. 6,7 Pyelonephritis can be acute or chronic. It may cause vague systemic clinical signs (anorexia, fever, back pain, pain on abdomen on palpation, GI upset, polyuria- polydipsia) or be clinically silent. Diagnosis is usually based on history, clinical signs, positive urine culture and supportive ultrasonography and/or excretory urogram. Ideally, infection would be confirmed by pyelocentesis or renal biopsy, but both are invasive and rarely done. When diagnosed, aggressive antimicrobial treatment is warranted, and serum concentrations are better determinants of efficacy than urine concentrations. Initial therapy while waiting for C&S results should be with drugs known to have activity against E coli and adequate tissue penetration. This means that fluoroquinolones are a reasonable first choice for cases of pyelonephritis. Oral antimicrobial therapy can be considered for small animal or equine patients that are clinically well with normal appetite. In ruminants and for all animals that are dehydrated, inappetent or lethargic, antimicrobials should be administered parenterally. Duration of treatment, based on human recommendations, should be from 10-14 days with re- evaluation.22 Positive cultures post-treatment need to be evaluated in light of clinical results. If the animal shows clinical cure, then consider that subclinical bacteriuria is present and that it does not necessarily need treatment. Poor clinical response and re-isolation of the same bacterial species may indicate persistence due to pharmacokinetic limitations of the chosen antimicrobial, antimicrobial resistance, urolithiasis, anatomic defects or immune deficiency. ANTIMICROBIAL RESISTANCE IN UROPATHOGENS Acquired resistance to antimicrobials by uropathogens is of great concern in human and veterinary medicine. The prevalence of multi-drug resistance (MDR) in uropathogens is increasing, particularly in canine and feline infections. Extended-spectrum beta-lactamase (ESBL) genes are increasingly identified in E. coli isolates from companion animals.32 Increases in the occurrence of fluoroquinolone-resistant E. coli in dogs have been widely reported.33,34 As the mechanism of resistance to fluoroquinolones frequently involves efflux pumps, multi-drug resistance occurs. Fluoroquinolone resistance is also increasing in other uropathogens, including enterococci, Proteus mirabilis and Staphylococcus pseudintermedius isolates. Enterococci isolated from canine and feline UTIs have been associated with several different resistant phenotypes, with the majority exhibiting resistance to three or more antimicrobials.35 There is increasing evidence that animals are an important reservoir of antimicrobial-resistant bacteria causing infections in humans.36 345 This C&S is from an 8 yr FS Labrador RetrieverX with recurring bacterial cystitis. The MRSP infection has limited treatment choices, and it is likely that the dog’s commensal flora is also MRSP. The use of “last resort” human antimicrobials in veterinary patients with resistant infections is controversial. Vancomycin, imipenem-cilastatin, meropenem, fosfomycin, quinupristin- dalfopristin and tigecycline should not be used routinely in the treatment of UTI in animals. Non-antimicrobial control of infection should be considered whenever feasible. Custom-made vaccines, cranberry juice/extract, probiotics and adherence/colonization inhibitors, and establishment of asymptomatic bacteriuria may be useful in preserving the efficacy of antimicrobials.37,38 In people, dietary supplements may help to prevent but not treat UTIs. When choosing cranberry-based treatments, be aware of the variability in quality and potency of these “nutraceutical” products and choose an extract that has a higher concentration of proanthocyanidins, the antioxidants thought to be responsible for antibacterial effects. FUNGAL URINARY TRACT INFECTIONS Although uncommon, most fungal UTI in dogs and cats are caused by Candida sp. (yeast).39,40 Finding Candida organisms in the urine may indicate sample contamination; however, finding yeast in two serial urine samples collected by cystocentesis is consistent with infection and warrants culture and definitive identification. Treatment includes eliminating potential predisposing factors (eg, excessive endogenous or exogenous corticosteroids, urinary catheters) and administering antifungal drugs with or without urinary alkalinization. Fluconazole is the antifungal drug of choice for the treatment of candidal cystitis. The dose in cats is 50 mg/cat, PO, q 12-24 hr, and in dogs is 2.5-5.0 mg/kg/day, PO, divided BID. The duration of treatment needed to eliminate infection is unknown but may be as short as 7 days. 346 THERAPY OF BACTERIAL PROSTATITIS Bacterial prostatitis is a common prostate disease in sexually intact male dogs and rarely in intact male cats.41 It can develop as an acutely fulminating systemic disorder, or most commonly, as a chronic problem associated with recurrent UTI. Care should be taken when rectally palpating an acutely infected prostate, as septicemia/endotoxemia can occur. Most, if not all sexually intact male dogs with UTI will also have bacterial prostatitis. The prostate gland is uniquely different from the rest of the urinary tract due to the acidity of the prostate glands, leading to a decreasing pH gradient from the blood through the tissue to the acinar glands. The distribution of antimicrobials in the prostatic tissue as well as in the prostatic secretions is completely dependent on the local pH (6.4) and the pKa of the drugs. For alkaline drugs, a high degree of ionic trapping leads to high antimicrobial concentrations in the tissue and secretions, while the acidic drugs such as the β-lactam antimicrobials do not reach concentrations equivalent to plasma concentrations. The choice of antimicrobial for treatment should be based on culture and susceptibility results, and on the ability of the drug to penetrate the blood- prostate barrier. Ideal antimicrobials should be very lipid-soluble, basic, and not highly protein- bound.22 Fluoroquinolones are the best empirical choice for E. coli infections, while chloramphenicol, doxycycline, or TMP/sulfas can be considered with supportive C&S results. Fosfomycin is used to treat resistant bacterial prostatitis in men.42 Antimicrobial therapy may need to be continued for up to 2 months, which increases selection pressure for antimicrobial resistance. Chronic bacterial prostatitis may be difficult to "cure". Neutering the dog may increase the likelihood of successful therapy and prevent recurrence.43 THERAPY OF SEMINAL VESICULITIS Bacterial infection of the seminal vesicles is common in bulls. The most common organisms isolated are Trueperella pyogenes, B. abortus, Mycoplasma, Ureaplasma, Chlamydia and Histophilus somni. It commonly occurs in young bulls housed together and fed high energy rations. Treatment should be based on culture and susceptibility results and drugs with the appropriate volume of distribution are needed. The pH of seminal vesicular fluid is 7.3-7.5 and bulbourethral gland secretion has a pH of 8.0-8.2. While tulathromycin, tilmicosin, erythromycin and florfenicol appear to be logical therapy choices, because of the pathology the prognosis for affected bulls is only fair to poor.44 347 TEST YOUR KNOWLEDGE 1. What are some reasons for a negative culture despite seeing bacteria on the Gram stain? 2. Why can amoxicillin be used as an empirical treatment choice for UTI in dogs and cats, but not for superficial bacterial folliculitis? 3. Why is cefovecin approved for UTI in dogs but not cats? 4. What are some predisposing causes to UTIs in cats, dogs, horses and ruminants? 5. Explain the pathophysiology of UPEC. 6. Which antimicrobials are most suitable for treatment of prostatitis and pyelonephritis? 7. Why should we avoid treating subclinical bacteriuria? 348 THERAPY OF RENAL FAILURE Acute kidney disease (AKD) in veterinary patients is usually precipitated by a toxin or drug or a severe metabolic derangement. If otherwise young and healthy, most of these patients will recover with supportive therapy. Common Causes of Acute Renal Failure Ischemia Infarction Toxins Ethylene glycol Heavy metals Organic compounds Grapes or raisins (dogs) Hemoglobin or myoglobin Lily plant (cats) Melamine Infectious Diseases Pyelonephritis Leptospirosis Hypercalcemia Calciferol-containing rodenticides Human dermatologic preparations containing vitamin D analogues Hyperviscosity Hyperglobulinemia Polycythemia Sepsis Acute pancreatitis Drugs DRUGS ASSOCIATED WITH NEPHROTOXICITY Drug Cause of Renal Toxicity Nonsteroidal Anti-inflammatory Acute interstitial nephritis, altered intraglomerular hemodynamics, Drugs chronic interstitial nephritis, glomerulonephritis Antidepressants/mood stabilizers Amitriptyline (Elavil*), doxepin (Zonalon), fluoxetine (Prozac) 349 Antihistamines Diphenhydramine (Benadryl), Rhabdomyolysis doxylamine (Unisom) Antimicrobials Acyclovir (Zovirax) Acute interstitial nephritis, crystal nephropathy Aminoglycosides Tubular cell toxicity Amphotericin B (Fungizone) Tubular cell toxicity Tetracyclines Acute interstitial nephritis Sulfonamides Acute interstitial nephritis, crystal nephropathy Vancomycin (Vancocin) Acute interstitial nephritis Cyclosporine (Atopica) Altered intraglomerular hemodynamics, chronic interstitial nephritis, thrombotic microangiopathy Angiotensin-converting enzyme Altered intraglomerular hemodynamics inhibitors Chemotherapeutics Cisplatin (Platinol) Chronic interstitial nephritis, tubular cell toxicity Methotrexate Crystal nephropathy Diuretics (loop, thiazides) Acute interstitial nephritis, altered intraglomerular hemodynamics Lansoprazole (Prevacid), omeprazole Acute interstitial nephritis (Prilosec), pantoprazole (Protonix) Gold therapy Glomerulonephritis Phenytoin (Dilantin) Acute interstitial nephritis Ranitidine (Zantac) Acute interstitial nephritis 350 Chronic kidney disease (CKD) is characterized by variably progressive and irreversible intrarenal lesions and loss of renal functions. A variety of interventions (diet and drugs) can slow the progression of the renal disease, improve the quality of life for the patient, and/or extend the duration of life. The International Renal Interest Society (IRIS) staging of the degree of renal failure helps to direct therapy. Creatinine 440 mmol/L (cats) Stage Creatinine >440 mmol/L (dogs) Severe Azotemia 4 Intensify efforts to provide nutrition Intensify fluid therapy Renal transplantation Say goodbye IRIS CKD staging is based currently on fasting blood creatinine concentrations, but sub-staging using symmetric dimethylarginine (SDMA), proteinuria and blood pressure may be helpful in refining the treatment plan. IRIS also provides a grading system for Acute Kidney Injury (AKI) and treatment recommendations for CKD in dogs and cats. Treatments for CKD may target slowing the progression of CKD and increasing the life span of the animal or reducing the clinical signs of CKD and improve the quality of life of the animal. 352 TREATMENT OF DEHYDRATION Fluid balance in patients with renal failure is initially maintained by compensatory polydipsia (PD). If water consumption is insufficient to compensate for polyuria (PU), dehydration will result. Cats and some dogs with CKD fail to consume sufficient water to prevent chronic or recurrent dehydration. Dehydration and volume depletion exacerbate renal hypoperfusion and prerenal azotemia. In addition to prerenal azotemia, dehydration may cause hyperphosphatemia, hyperkalemia, and metabolic acidosis. Clinical signs of dehydration include decreased appetite, lethargy, and constipation. In some patients, prerenal azotemia may precipitate a uremic crisis. Further, if dehydration and decreased renal blood flow persist, additional ischemic renal damage occurs. Intravenous fluid therapy is used in hospitalized patients, while long-term subcutaneous (SC) fluid therapy can be administered at home by the owner to dogs and cats in stages 3 and 4 of chronic kidney disease.45 SC fluid therapy improves appetite and activity and reduces constipation. The decision to recommend administration of SC fluids is made on a case-by-case basis. While many cats with CKD benefit from SC fluids, fewer dogs require fluid therapy. While fluid therapy is relatively inexpensive, it does require time and may be stressful to the owner and the pet. As well, SC fluids may cause hypokalemia, hypertension and fluid overload. Normal saline or lactated Ringer's solutions are commonly used for SC fluid therapy. They are well tolerated by most cats and dogs and are reasonable choices for most patients. However, chronic administration of lactated Ringer's solution or normal saline as the principal maintenance fluid source may cause hypernatremia because they fail to provide sufficient electrolyte-free water. A typical cat or small dog gets 75 to 150 ml of fluids daily or as needed. Chronic SC fluid therapy will overload some patients, particularly when volumes in excess of those recommended are used. Monitor fluid therapy by repeatedly assessing hydration status, clinical signs, hematocrit, total serum protein concentrations, blood pressure, and serum urea nitrogen, creatinine, phosphorus, potassium, total CO2, sodium and chloride concentrations. 353 THERAPY OF HYPERTENSION Hypertension has become a well-recognized complication of CKD in both cats and dogs. The most profound clinical effect of hypertension in cats is hypertensive retinopathy with retinal detachment, hemorrhage and blindness. Cats with such severe ocular manifestations reflect only a tiny percentage of cats with CKD and hypertension.46 Hypertension-related CNS disorders (e.g., seizures, loss of balanced, abrupt changes in personality, obtundation) have been observed in small animals. Hypertension shortens survival times in dogs with CKD and may similarly affect survival times in cats. ANGIOTENSIN-CONVERTING ENZYME INHIBITORS While originally developed for the treatment of heart failure in small animals, angiotensin-converting enzyme inhibitors (ACE-Is) may be beneficial in the management of dogs and cats in CKD. Mechanism of Action: Angiotensin II decreases renal blood flow and increases glomerular capillary pressure. It increases pre- and post-glomerular vascular resistance, but it primarily vasoconstricts the efferent, and not the afferent, arteriole. Angiotensin II decreases sodium and water excretion indirectly via aldosterone but also by direct intrarenal effects, which are important in the animal’s adaptation to low sodium intake and long-term control of renal function, body fluid volumes, and arterial pressure. Bradykinin, which is increased by ACE-I treatment, induces vasodilation by stimulating the production of arachidonic acid derivatives, nitric oxide, and endothelium derived hyperpolarizing factor in the vascular endothelium. In the kidney, bradykinin induces natriuresis. So angiotensin converting enzyme controls the balance between angiotensin II induced vasoconstriction and salt retention and bradykinin induced vasodilation and natriuresis. Renal disease that damages nephrons progresses to CKD as a consequence of the functional adaptations of the remaining nephrons. These include glomerular hyperperfusion and hypertension controlled by angiotensin II, which initially enhances nephron filtration capacity and compensates for the decrease in glomerular filtration rate (GFR), but ends up being detrimental in the long-term and causes further nephron loss. Regardless of the original etiology of the renal disease, glomerulosclerosis and interstitial fibrosis are pathologic findings in end-stage renal failure. Angiotensin II increases concentrations of transforming growth factor-β (TGF-β), a powerful fibrogenic cytokine, which stimulates excessive production and deposition of extracellular matrix (ECM) (e.g. fibronectin, laminin, collagens). 354 The ACEIs lower glomerular pressure by decreasing systemic blood pressure and locally inhibiting angiotensin II. In CKD patients, the ACEIs may decrease proteinuria caused by changes in glomerular membrane permeability and selectivity from mechanical injury induced by glomerular hypertension. Decreasing proteinuria potentially slows the progression of renal failure. The ACEIs also tend to increase appetite and body weight in CKD patients, which is the most noticeable benefit of ACE-Is to clients. 355 Adverse Effects: Unfortunately, ACE-Is may cause acute renal failure, especially in dogs and cats that already have decreased renal perfusion (eg, dehydration from diuretics or GI losses, severe congestive heart failure). In these patients, angiotensin II maintains glomerular filtration by constricting the efferent arteriole, so blocking angiotensin II may dramatically decrease GFR. Affected patients often improve simply by discontinuing the ACE-I while the precipitating factors are corrected. ACE-I therapy may cause hyperkalemia. Decreasing angiotensin II causes a decrease in aldosterone production, which controls urine excretion of potassium and sodium reabsorption. Clinically, the risk of hyperkalemia is minimal in dogs and cats. Drug Interactions: Patients receiving diuretics may be more sensitive to the hypotensive effects of ACE-Is. Potentially, blocking prostaglandins will reduce the anti-hypertensive effects of the ACEI, as well as increase the risk of acute renal damage. Simultaneous administration of ACE-Is and NSAIDs or Coxibs to dogs and cats should be done carefully, but the concurrent use of benazepril and robenacoxib did not cause adverse effects in healthy dogs.47 Clinical Use: Enalapril (Enacard®), imidapril (Prilium®) and benazepril (Fortekor®) are approved for heart disease in dogs and can be used in the treatment of CKD to reduce proteinuria.48-50 Benazepril is approved “as an aid in the management of chronic renal insufficiency associated with proteinuria in cats” (in Canada but not in the US). Enalapril seems to be less effective than benazepril in reducing hypertension in cats. In many cats, benazepril does reduce proteinuria, improves appetite and extends survival. Check renal function one week after starting an ACE-I to make sure that GFR has not been significantly reduced. ANGIOTENSIN RECEPTOR BLOCKERS Telmisartan (Semintra®) is an angiotensin receptor blocker (ARB) approved for the reduction of proteinuria associated with chronic kidney disease in cats. It is available in a 4 mg/ml oral solution and dosed once daily at 1 mg/kg. Telmisartan acts directly on the AT1 receptor to displace angiotensin II from its binding site and preventing receptor activation. This inhibits the pressor response of the RAAS, resulting in a dose- dependent decrease in mean arterial pressure and subsequent reduction in proteinuria. As telmisartan is selective for the AT1 receptor, it does not interfere with the beneficial activation of the AT2 receptor that results in vasodilation, natriuresis and inhibition of inappropriate cell growth. The receptor binding is characterized by high affinity and slow disassociation, allowing for once daily administration. There is some evidence that it is more effective in reducing proteinuria in cats than benazepril.51 It can be 356 used to control hypertension in cats.52,53 Telmisartan can be used for proteinuria and hypertension in dogs as well.54 In cats, telmisartan is rapidly absorbed after oral administration and is not affected by food. It has a high degree of lipophilicity. It is hepatically metabolized by glucuronide conjugation and eliminated primarily in the feces. The elimination half-life is approximately 8 hrs. Telmisartan is well tolerated in cats; mild gastrointestinal signs may be seen. It can be administered concurrently with amlodipine. CALCIUM CHANNEL BLOCKER Amlodipine besylate (Amodip® - veterinary, Norvasc® - human), a long-acting dihydropyridine calcium channel blocker (CCB), is used for feline hypertension. It decreases systemic arterial blood pressure in hypertensive cats with or without chronic renal failure. Amlodipine currently appears to be the drug of choice for managing hypertension in cats.55 It has been shown to be effective in clinical trials in reducing blood pressure.56,57 Amlodipine may be co-administered with an ACE-I or ARB. Cats are usually started on 0.125 mg amlodipine PO once daily and the dose may be doubled if necessary. TREATMENT OF METABOLIC ACIDOSIS Metabolic acidosis promotes severe catabolism of endogenous proteins, exacerbates azotemia regardless of diet, promotes wasting (degradation of protein), inhibits protein synthesis, causes a negative nitrogen balance and enhances hypokalemia.45 Therapy for acidosis is rarely indicated except for patients with very advanced CKD. Alkalinizing agents (potassium citrate or sodium bicarbonate) should be administered when necessary to correct metabolic acidosis. Because even mildly reduced plasma bicarbonate concentrations may promote some of the adverse effects of chronic metabolic acidosis, oral alkalinisation therapy is probably indicated when serum bicarbonate concentration ≤ 17 meq/L (total CO2 concentrations of 18 meq/L or below). The patient's response to alkalinisation therapy should be determined by measuring blood bicarbonate or serum (plasma) total CO2 concentrations 10 to 14 days after initiating therapy. Ideally, blood should be collected just prior to administration of the drug. Dosage of alkalinizing agents should be adjusted so that blood bicarbonate (or serum total CO2) concentrations are maintained between 18 and 24 meq/L. 357 THERAPY OF HYPOKALEMIA Polyuria results in increased K+ loss in urine. Dietary acidification causes metabolic acidosis that shifts K+ out of cells into the extracellular compartment (including serum), giving falsely elevated/normal serum K+ values. Potassium replacement therapy should be considered for cats with hypokalemia, even without clinical signs of hypokalemia.45 Oral administration is the safest route of administration for potassium replacement therapy. Potassium gluconate is the potassium salt of choice for replacement therapy. Potassium may be administered orally as potassium gluconate in a palatable powder form (Tumil-K®), potassium gluconate elixir (Kaon Elixir ®), or potassium citrate solution (Polycitra-K ®). Depending on the size of the cat and severity of hypokalemia, potassium gluconate is given initially at a dose of 2 to 6 mEq per cat per day. Potassium dosage should thereafter be adjusted based on the clinical response of the patient and serum potassium determinations performed during the initial phase of therapy. THERAPY OF UREMIC GASTRITIS Dogs and cats with uremic gastritis may show only signs of partial anorexia, or nausea rather than outright vomiting. H2 receptor antagonists are safe and effective in reducing gastric acid production. Famotidine (Pepcid AC®) (0.5 mg/kg PO q 24-48h) or ranitidine (Zantac®) (2-3 mg/kg q12 h PO) may be considered once the serum creatinine is > 2.5 mg/dl (220 µmol/L) whether patients seem nauseous or not. Maropitant (Cerenia®) can be used to control nausea and vomiting. Azodyl™ is a probiotic nutritional supplement for dogs and cats in renal failure that contains a mixture of three beneficial bacteria: Enterococcus thermophilus, Lactobacilus acidophilus, and Bifidobacterium longum, combined with a prebiotic (psyllium husk). Azodyl's bacteria metabolize uremic toxins. TREATMENT OF CALCIUM AND PHOSPHORUS IMBALANCES Most dogs and cats with CRD benefit from therapy that maintains calcium and phosphorus balances. The goals of treatment are: 358  to maintain serum concentrations of calcium and phosphorus as close to normal as possible to prevent or suppress excessive secretion of parathyroid hormone (PTH) to prevent or ameliorate renal osteodystrophy to prevent or reverse extraskeletal mineralization to limit progressive kidney dysfunction Calcium and phosphate balance in patients with CKD may be improved by limiting phosphate intake and providing adequate quantities of dietary calcium and metabolically active forms of vitamin D. There appears to be a consensus of opinion that phosphate retention and hyperparathyroidism is a major cause for progression in CKD in many species.58,59 Dietary phosphate restriction is an important and effective first step toward normalizing phosphate balance because it may normalize serum phosphate concentrations in mild to moderate CKD, and it reduces the quantity of phosphate that must be bound by intestinal phosphate binding agents if their use becomes necessary. Serum phosphate concentrations should be determined after the patient has been consuming the phosphate-restricted diet for about 2 to 4 weeks. Collect samples after a 12-hour fast to avoid postprandial effects. Phosphate binding agents should be used in conjunction with dietary phosphate restriction when dietary therapy alone fails to reduce serum phosphate concentrations to within the normal range. Intestinal phosphate binding agents render ingested phosphate and the phosphate contained in saliva, bile, and intestinal juices unabsorbable so they need to be given with meals. These drugs are best administered with or mixed into the food, or just prior to each meal. Currently available phosphate binding agents include aluminum-based and calcium-based compounds. Aluminum-containing intestinal phosphate binding agents include aluminum hydroxide, aluminum carbonate, and aluminum oxide. Epakitin™ is a highly palatable and safe phosphate binder approved for dogs and cats. It is made of chitosan (crab and shrimp shell extract). The combined use of Epakitin and a low-phosphorus diet is recommended from the onset of CKD signs.60 Calcium salts such as calcium acetate, calcium carbonate, or calcium citrate may be highly effective as phosphate binding agents. Calcium-based phosphate-binding agents reduce the risk of aluminum toxicity seen with aluminum-based phosphate-binding agents. Calcium-based products may promote clinically significant hypercalcemia; therefore, you must carefully monitor serum 359 calcium concentrations when using these drugs. Calcium acetate is the most effective calcium- based phosphate-binding agent as well as the agent least likely to induce hypercalcemia because it releases the least amount of calcium compared to the amount of phosphate it binds. It is particularly important that calcium-based phosphate-binding agents be administered with meals both to enhance the effectiveness of phosphate binding and to minimize absorption of calcium and the risk of hypercalcemia. Calcium-based phosphorus binding agents are not to be used for patients receiving calcitriol therapy because they substantially increase the risk of hypercalcemia. The dose of phosphate binding agents should be individualized so that serum phosphate concentrations are normalized. 100 mg/kg/day divided into two or three doses is an appropriate starting dose for aluminum or calcium based phosphate-binding agents. The effect of therapy should be monitored by serial evaluation of serum phosphate concentrations at about 10 to 14 day intervals. The dose should be increased until serum phosphate concentrations are reduced to or near normal. The dose of calcium-based phosphate binding agents should be decreased if serum calcium concentrations exceed normal limits; additional aluminum-based agents should be used in these patients if hyperphosphatemia persists. Thereafter, serum calcium and phosphate concentrations should be monitored every 4 to 6 weeks or as needed. Calcitriol (Rocaltrol®, Calcijexis®) or 1,25-dihydroxycholecalciferol (abbreviated 1,25-(OH)2D3) is the active form of vitamin D found in the body. It increases the absorption of calcium and phosphate from the gastrointestinal tract and kidneys and inhibits release of calcitonin. Calcitriol use is controversial in renal failure patients as some clinicians feel that it is more necessary than others do.61 Advocates of calcitriol recommend starting it at 2.5-3.5 ng/kg/day in early renal insufficiency when serum creatinine (SC) is 177-265 µmol/L (2-3 mg/dl), urine specific gravity is compatible with CKD as the cause of azotemia and serum phosphorus is 3 mg/dl) and serum phosphorous