Clavulanic acid and amoxicillin

Recommended drugs for uncomplicated UTI include amoxicillin, cephalosporins, and trimethoprim-sulfonamide. 3,6 Although patients with an uncomplicated UTI are often successfully treated empirically, repeated treatment without culture and susceptibility results may lead to incorrect choice of antimicrobial, unnecessary adverse effects, and potential selection of resistant bacteria.

Antibiotics should never be selected empirically for complicated UTI without culture susceptibility results (see Culture & Sensitivity ).

Management of pyelonephritis, prostatitis, and relapsing or recurrent UTI is often unsuccessful without therapy guided by culture and susceptibility results.

However, therapy should be instituted while culture and susceptibility results are being awaited. Rational initial drug choices for complicated UTI include amoxicillin, fluoroquinolones, or trimethoprim-sulfonamide.

To best use antibiotic urine data, an important consideration is whether a drug is time- or concentration-dependent. Time-dependent drugs include beta-lactams, cephalosporins, sulfa drugs, tetracyclines, and chloramphenicol. These drug classes are most effective when the tissue concentration exceeds the isolate’s MIC for 50% to 75% of the dosing interval.

10 However, few clinical trials have evaluated this suggestion. Product inserts and pharmacology texts often contain the drug elimination curves, which are helpful in choosing the dosage and frequency that ensure these criteria are met.

The plasma drug elimination curve and renal drug elimination rate can be used as surrogates to predict the urine drug concentration curve.

Less is known about urine drug concentration and clinical efficacy, but several authors have stated that urine, not plasma, drug concentration is important in ensuring successful eradication of bacteria (see Urine Drug Concentration & Clinical Efficacy ).

Antimicrobial drugs must achieve an adequate urine concentration, which must be maintained for a sufficient time for a drug to be effective in treating UTI. 16 It has been suggested that clinical efficacy is observed when the urine drug concentration is maintained at a concentration 4-fold higher than the isolate’s MIC throughout the time between doses.

Experimental studies in rats have shown that the time for which the plasma drug concentration exceeds the isolate’s MIC correlates to the magnitude of bacterial colony count reduction; the longer the time for which the drug concentration remained above the MIC, the lower the urine colony counts.

12 Successful eradication of bacteria within the renal parenchyma or urinary bladder wall is correlated to the plasma, not urine, drug concentration. When prescribing time-dependent antibiotics, shortening the interval between drug administration is the most effective method to allow the tissue/urine drug concentration to exceed the MIC for the majority of the dosing interval. Drug elimination follows first-order kinetics, where 50% of the drug is lost in 1 half-life.

In contrast, doubling the dose would only add 1 half-life to the dosing interval.

To add 2 half-lives to the dosing interval, the initial dose would have to be increased 4-fold. The peak serum drug concentration achieved by this approach may exceed the window of safety, producing adverse drug effects.

For example, amoxicillin could be administered to dogs at a dosage of 10 to 20 mg/kg q12h; however, to maintain higher drug concentrations, the same dose could be administered q8h.

One method to ensure that the tissue or plasma drug concentration consistently exceeds the MIC is to deliver the antibiotic as a continuous IV infusion.

This may be particularly useful in critically ill animals, such as those with urosepsis or those that have an impaired immune response.

The efficacy of concentration-dependent antibiotics is best predicted by the C max and the isolate’s MIC.

Such drugs as fluoroquinolones and aminoglycosides are most effective when the C max is at least 8- to 10-fold higher than the MIC.

13 These drugs are typically administered every 24 hours.

Another method to evaluate the activity of these antibiotics is comparing the drug concentration area under the curve (AUC) to the MIC. This AUC/MIC ratio has been investigated for some antibiotics, and although some authors generally recommend an AUC/MIC greater than 125 to 250, studies have shown some drugs to be effective with an AUC/MIC of 40.

The dosage of these antibiotics is typically chosen to create a high peak urine concentration, well above the isolate’s MIC. Once-daily administration is acceptable for most concentration-dependent drugs, and this frequency may help increase owner compliance in administering medications.

However, it may not be consistent with antibiotic stewardship to prescribe a fluoroquinolone antibiotic for an uncomplicated lower UTI when drugs belonging to the penicillin or cephalosporin class would also be effective. The ideal duration of antibiotic therapy for uncomplicated and complicated UTI is unknown. Many textbooks recommend 10 to 14 days for uncomplicated UTI and 4 to 8 weeks for complicated UTI; however, these guidelines are not evidence-based, and much shorter

durations

3 The recommendations mostly reflect expert consensus because well-designed clinical trials to determine optimal antibiotic duration are lacking in veterinary medicine. For uncomplicated UTI, this group recommended 7 or fewer days of antibiotic therapy; humans are typically treated for 3 to 7 days.

For complicated UTI, the group recommended antibiotic therapy for up to 4 weeks; humans are typically treated for 1 to 2 weeks, although 3 weeks may be indicated in some instances. Recently, 2 studies evaluated short duration versus long duration of antibiotics for uncomplicated UTI in dogs (3 days of trimethoprim-sulfamethoxazole versus 10 days of cephalexin and 3 days of enrofloxacin versus 14 days of amoxicillin-clavulanic acid). 17,18 Both studies demonstrated that the short duration of antibiotic administration was noninferior to the longer duration in bacterial cure rates.

However, because both studies compared short duration of one drug with long duration of another, their design precludes determination of optimal treatment time for the

drugs

A systematic literature review conducted in 2015 to determine the optimal therapy for UTI in veterinary medicine found insufficient evidence available for analysis. 19 Currently, evidence-based guidelines for the duration of UTI in small animals do not exist, and further studies evaluating a single drug in both short

and

Patients with a simple, uncomplicated UTI may not require rigorous monitoring.

However, patients with complicated, relapsing, or recurrent infections should be monitored very closely. The following protocol is recommended to monitor response to therapy in patients with relapsing, recurrent, or refractory UTI.

Recheck urine culture 5 to 7 days into antibiotic therapy.

This confirms that the prescribed dose and frequency of the drug were successful in treating the organism isolated. This culture also may reveal an additional isolate that could not be identified in the initial culture. Any bacterial growth observed at this time suggests treatment failure.

Reconsider the choice of antibiotic, dose, and administration frequency. Recheck urine culture 3 days before discontinuing antibiotic therapy.

This is an optional step, but it confirms that, when therapy was discontinued, the patient still had a negative culture. Positive bacterial growth at this stage suggests a refractory infection or newly inoculated organism.

Investigate patients for any nidus of infection (eg, urolithiasis, anatomic abnormality, local neoplasia). Alter treatment and institute

new

intended

Recheck urine culture 7 days after discontinuing antibiotic therapy. Positive growth should prompt investigation for causes of relapse or reinfection. Complicated, relapsing, recurrent, and refractory UTI may be challenging to cure. However, understanding drug PK/PD and potential alterations in the animal’s metabolism/excretion of the drug can help increase the likelihood of successful treatment. Guidelines for appropriate antibiotic dosing for animals with kidney disease have not been established; therefore, a working knowledge of pharmacology and the prescribed drug’s PK/PD profile is needed to help create a successful antibiotic prescription with the smallest risk for adverse effects. When possible, in patients with kidney disease, avoid drugs that have a narrow margin of safety and undergo significant renal elimination (eg, fluoroquinolones in cats, aminoglycosides) and then choose alternative drugs (based on susceptibility results) that undergo hepatic elimination or those with a wide margin of safety. The International Society for Companion Animal Infectious Diseases (ISCAID) Antimicrobial Working Group Guidelines for Treatment of Urinary Tract Infections are available at iscaid.org/wp-content/uploads/2013/10/Urinary- guidelines.pdf .

The lack of data and the limitations in well-designed studies prevent complete evidence-based guidelines from being described for treatment of urinary tract infection (UTI). This article presents an approachable and logical process for treating UTI; however, it too lacks clinical validation. The usefulness of urine drug concentrations has been debated, but several textbooks and peer-reviewed manuscripts suggest that these concentrations can play a role in creating a valid antimicrobial drug prescription. In addition, while the clinical success of drug

therapy

This article focuses on relevant topics in drug pharmacokinetics/pharmacodynamics, urine susceptibility testing, and educated drug therapy, and numerous holes in our understanding prevent these topics from being without question or debate. However, I hope this article helps increase the understanding of drug pharmacology, where it pertains to UTI, to the best of our understanding.

Uropathogenic E coli promote a paracellular urothelial barrier defect characterized by altered tight junction integrity, epithelial cell sloughing and cytokine release.

Antimicrobial use guidelines for treatment of urinary tract disease in dogs and cats: Antimicrobial guidelines working group of the international society for companion animal infectious diseases. Antimicrobial susceptibility patterns in urinary tract infections in dogs (2010-2013).

Vet Clin North Am Small Anim Pract 2006; 36(5):1003-1047-vi.

Effects of processing delay, temperature, and transport tube type on results of quantitative bacterial culture of canine urine. UTIs in small animal patients: Part 2: Diagnosis, treatment, and complications. Therapeutic strategies involving antimicrobial treatment of the canine urinary tract.

The pharmacokinetic-pharmacodynamic approach to a rational dosage regimen for antibiotics.

Efficacy and tolerability of once-daily cephalexin in canine superficial pyoderma: An open controlled study. Correlation between pharmacokinetic/pharmacodynamic parameters and efficacy for antibiotics in the treatment of urinary tract infection.

Pharmacokinetic and pharmacodynamic issues in the treatment of bacterial infectious diseases.

Eur J Clin Microbiol Infect Dis 2004; 23(4):271-288.

Mutant-prevention concentration and mechanism of resistance in clinical isolates and enrofloxacin/marbofloxacin-selected mutants of Escherichia coli of canine origin.

Clinical pharmacology of the fluoroquinolones: Studies in human dynamic/kinetic models.

Appropriate antibiotic treatment of

genitourinary

Evaluation of the efficacy and safety of high dose short duration enrofloxacin treatment regimen for uncomplicated urinary tract infections in dogs.

Effect of antibiotic treatment in canine and feline urinary tract infections: A systematic review. What are the best practices for antibiotic use in feline upper respiratory tract disease?

Diagnosis and treatment can be simplified by assessing whether the disease is in the acute or chronic state. The following article is the first in a three-part series

summarizing

with

Feline upper respiratory tract disease (URTD) can present with clinical signs that include serous or mucopurulent nasal discharge, sneezing, epistaxis and conjunctivitis.

The most common infectious causes of acute URTD in cats are feline herpesvirus 1 (FHV-1) or feline calicivirus (FCV), which can often be complicated by secondary bacterial infections caused by a variety of organisms.

It is these secondary bacterial pathogens that are often the focus of treatment in cats with URTD. A thorough patient history should be obtained with particular attention paid to vaccination status; exposure to other cats; recent shelter, veterinary clinic or kennel exposure; recent environmental stressors; and contact with foreign bodies (such as house plants or grasses).

Thoracic auscultation is performed to determine the presence of concurrent lower airway disease, and screening for feline leukemia and feline immunodeficiency viruses is recommended, given their detrimental impact on feline immunity.

The diagnosis and treatment of URTD in cats can be further simplified by categorizing the disease

into

While nasal cytology and bacterial cultures are often performed, they are not recommended by the guideline authors because the results are difficult to interpret due to the presence of commensal organisms or false negative results.

The use of polymerase chain reaction (PCR) assays for Mycoplasma species, Chlamydia species, FHV-1 and FCV can also prove problematic because the diseases can be isolated from both healthy and diseased cats.

Furthermore, recent vaccination can confound interpretation. In cats with acute URTD, the working group recommends no antimicrobial treatment be initiated during a 10-day observation period, unless the patient is exhibiting fever, lethargy or anorexia along with mucopurulent nasal discharge. If antimicrobial therapy is indicated, the working group recommends empirical administration of doxycycline (5 mg/kg orally every 12 hours, or 10 mg/kg orally every 24 hours) for seven to 10 days. Doxycycline is recommended because of its broad spectrum of activity against common feline nasal pathogens and because it is well-tolerated by cats. To counteract the potential for esophageal stricture, tablets and capsules should be given coated with a lubricating substance, followed by water; administered in a pill treat, along with at least 2 ml of a liquid; or followed by a small amount of food.