Urinary tract infections (UTIs) are a frequent occurrence in small animal veterinary practice, with studies indicating that up to 27% of dogs may develop such an infection at some point in their lives. While most UTIs are effectively managed with standard drug regimens, infections involving the kidneys (pyelonephritis) or prostate (prostatitis) can present significant treatment challenges. Furthermore, managing antibiotic therapy in patients with kidney disease is complicated by reduced drug clearance. A thorough understanding of drug pharmacokinetics (PK) and pharmacodynamics (PD) is crucial for determining the most effective antibiotic treatment. Successful antimicrobial therapy hinges on the appropriate selection of an antibiotic, along with the correct dosage, frequency, and duration of administration.
Clinical Signs of UTI
Pets experiencing a UTI may exhibit several symptoms, including:
- Dysuria: Difficulty or pain during urination.
- Hematuria: Blood in the urine.
- Pollakiuria: Increased frequency of urination.
- Stranguria: Straining or difficulty in passing urine.
Pathophysiology of UTIs
The vast majority of UTIs are caused by pathogenic bacteria, though fungal or viral infections are rare possibilities. Typically, bacterial infections of the lower urinary tract arise from bacteria ascending from the external genitalia and urethra. Less frequently, bacteria can travel through the bloodstream and colonize the urinary tract.
The body possesses several innate defense mechanisms to prevent UTIs. Regular and complete bladder voiding, combined with the urine’s inherent properties—such as high osmolality and antimicrobial solutes—creates an environment hostile to microbes. Anatomic barriers and mucosal defenses further impede the adherence of virulent bacteria to the urothelium.
When pathogenic bacteria are present, they can increase the permeability of the urothelium, allowing inflammatory solutes and cytokine secretion into the subepithelium. This leads to inflammation and pain, manifesting as the clinical signs mentioned above. Eradicating the infectious organism allows the urothelium to regain its normal permeability and integrity.
Classification of UTIs
Urinary tract infections can be categorized in several ways:
- Uncomplicated UTI: This refers to a sporadic bacterial cystitis in a healthy patient with normal urinary tract anatomy and function.
- Complicated UTI: This type occurs in patients with functional or anatomical abnormalities of the urinary tract, or those with risk factors for persistent or recurrent infections, treatment failure, or both. Such risk factors include immunosuppression (due to disease or medication), diabetes mellitus, hyperadrenocorticism, kidney disease, prostatitis, pregnancy, urinary incontinence, and altered neurogenic bladder function.
- Recurrent UTI: This classification necessitates further investigation to determine if the infection is a reinfection, relapse, or refractory.
- Reinfection is defined as the return of a UTI caused by a different organism within six months of discontinuing antibiotic therapy.
- Relapsing UTI occurs when the same organism is cultured again within six months of discontinuing antibiotic therapy. This suggests an underlying condition that allows for recolonization or prevents complete eradication of the infection, warranting additional diagnostics.
- Refractory UTI is identified when a positive urine culture is obtained during appropriate antibiotic therapy, based on in vitro susceptibility testing. Potential causes include decreased renal drug elimination leading to lower urine drug concentrations, inappropriate dosage or schedule, low drug bioavailability (due to compounding or gastrointestinal disease), or poor owner compliance. In some instances, drugs may demonstrate in vitro efficacy but fail to produce the same effect in vivo for unknown reasons.
Diagnostics and Data for Antibiotic Selection
Pharmacokinetics (PK) and Pharmacodynamics (PD)
PK describes the movement of a drug through the body, encompassing absorption, distribution, metabolism, and excretion. PD refers to the drug’s effect on the body, including its impact on microorganisms in the case of antibiotics. Understanding the interplay between PK and PD is essential for predicting the success of antibiotic therapy.
Abnormalities in PK can arise from issues with absorption (e.g., severe gastrointestinal disease), metabolism (e.g., liver dysfunction), altered protein binding (e.g., uremia, hypoproteinemia), and diminished excretion (e.g., liver or kidney failure). The PD of an antibiotic is typically assessed clinically through in vitro culture and susceptibility testing.
Urine Culture and Sensitivity Testing
Ideally, a urine sample collected via cystocentesis from any patient suspected of having a UTI should be submitted for aerobic culture and antibiotic susceptibility testing. Urine culture is considered the gold standard for diagnosing UTIs.
Two primary methods are used for determining antibiotic susceptibility: disk diffusion and serial dilution. Disk diffusion testing is generally considered less reliable as it does not provide the Minimum Inhibitory Concentration (MIC) of the antibiotic. Antimicrobial dilution methods, which do provide the MIC, are preferred.
In antimicrobial dilution, varying concentrations of an antibiotic are added to a liquid medium inoculated with the bacterial isolate. The MIC is the lowest concentration of the antibiotic that inhibits visible bacterial growth. This MIC value is then used to categorize the isolate as susceptible, intermediate, or resistant.
False-negative results can occasionally occur due to improper urine storage or slow organism growth (e.g., Corynebacterium species). Quantitative urine cultures should be processed immediately after collection, as bacterial colony counts can decrease significantly after 24 hours of refrigeration. If immediate processing is not possible, a urine transport tube is recommended to help prevent false-negative or underestimated colony counts.
CLSI Classification
The Clinical Laboratory Standards Institute (CLSI) establishes classifications for isolates (susceptible, intermediate, or resistant) based on drug PK and PD data. Several factors influence these breakpoint classifications. For an isolate to be classified as susceptible, the peak drug concentration (Cmax) achieved with a standard dose and route of administration must be higher than the isolate’s MIC. The Cmax is not always based on urine drug concentration. Some antibiotics have established CLSI breakpoints for UTIs in specific bacterial species, while others are based on infections in different organ systems or are extrapolated from human medicine.
Even when a specific breakpoint for UTIs has not been determined, drugs may still be effective against intermediate organisms if the drug concentration in the urine is significantly higher than in plasma. When using urine culture and susceptibility results to guide therapy for pyelonephritis, plasma breakpoints should be used rather than urine breakpoints.
All these factors should be considered when selecting the most appropriate antibiotic, dosage, and frequency of administration.
Urine Drug Concentration
Many antibiotics are primarily excreted in the urine, achieving concentrations substantially higher than those in plasma. Evaluating the urine drug concentration relative to the isolate’s MIC is crucial for determining the likelihood of eradicating the organism. Table 2 (in the original article) provides observed urine concentrations of various antibiotics at specified dosages in healthy animals.
Research into urine antibiotic concentrations in veterinary patients with kidney disease is still limited. A reduced glomerular filtration rate (GFR) can decrease drug excretion into the urine, leading to lower urine concentrations. Additionally, in polyuric patients, further dilution of filtered antibiotics can reduce urine drug concentrations. Decreased renal excretion due to diminished GFR can result in plasma drug concentrations exceeding normal levels, potentially causing adverse effects, particularly for drugs with significant renal elimination. Drugs eliminated primarily by the liver may experience minimal alteration in excretion. However, the accumulation of uremic toxins and hypoproteinemia common in kidney disease can affect drug protein binding and alter PK/PD.
Antibiotics for Prostatitis
The protein binding and lipid solubility of an antibiotic influence its volume of distribution. Highly lipophilic drugs can readily cross cell membranes and penetrate tissues. These drugs are most effective for treating prostatitis, where the blood-prostate barrier can hinder the passage of many water-soluble antibiotics, such as beta-lactams.
In the early stages of prostatitis, the blood-prostate barrier may be compromised, allowing water-soluble antibiotics to reach the infection site. However, once the initial inflammation subsides (typically after 1-2 weeks, based on clinical experience), this barrier can re-establish, preventing antibiotics from achieving effective tissue concentrations within the prostate and hindering bacterial cure.
Lipophilic drugs that achieve effective concentrations in the prostate include fluoroquinolones, sulfonamides, and macrolides. However, the choice of antibiotic should always be guided by urine culture and susceptibility results.
Antibiotic Selection by UTI Classification
Empiric Antibiotic Selection
The increasing prevalence of antimicrobial resistance and multidrug resistance makes empiric antibiotic selection increasingly challenging, especially in patients with a history of previous antibiotic therapy.
Uncomplicated UTI
For uncomplicated UTIs, recommended antibiotics include amoxicillin, cephalosporins, and trimethoprim-sulfonamide. While patients with uncomplicated UTIs are often successfully treated empirically, repeated treatment without culture and susceptibility results risks selecting the wrong antimicrobial, leading to unnecessary adverse effects and potentially fostering the development of resistant bacteria.
Complicated & Recurrent UTI
Antibiotics should never be selected empirically for complicated UTIs without culture and susceptibility results. Management of pyelonephritis, prostatitis, and relapsing or recurrent UTIs is often unsuccessful without therapy guided by culture and susceptibility data. However, initiating empirical therapy is sometimes necessary while awaiting culture results. Rational initial choices for complicated UTIs include amoxicillin, fluoroquinolones, or trimethoprim-sulfonamide.
Antibiotic Selection Based on Urine Drug Concentration
When utilizing antibiotic urine data, it is important to consider whether a drug is time-dependent or concentration-dependent.
Time-Dependent Drugs
Time-dependent antibiotics, such as beta-lactams, cephalosporins, sulfa drugs, tetracyclines, and chloramphenicol, are most effective when the drug concentration at the site of infection exceeds the isolate’s MIC for 50% to 75% of the dosing interval. However, clinical trials validating this specific threshold are limited.
Drug elimination curves, often found in product inserts and pharmacology texts, can assist in choosing dosages and frequencies that meet these criteria. The plasma drug elimination curve and renal drug elimination rate can serve as proxies for predicting the urine drug concentration curve.
While less is understood about the direct correlation between urine drug concentration and clinical efficacy, several sources suggest that urine, rather than plasma, drug concentration is significant for successful bacterial eradication.
Urine Drug Concentration and Clinical Efficacy
For an antibiotic to be effective in treating a UTI, it must achieve an adequate urine concentration and maintain it for a sufficient duration. Some research suggests that clinical efficacy is observed when the urine drug concentration remains at least four times the isolate’s MIC throughout the interval between doses.
Experimental studies in rats have indicated that the duration for which plasma drug concentration exceeds the MIC correlates with the degree of bacterial colony count reduction; longer periods above the MIC led to lower urine colony counts. Successful eradication of bacteria within the renal parenchyma or bladder wall appears to be correlated with plasma, not urine, drug concentration.
When prescribing time-dependent antibiotics, shortening the dosing interval is the most effective strategy to ensure that tissue/urine drug concentrations exceed the MIC for a larger portion of the dosing interval. Drug elimination typically follows first-order kinetics, where 50% of the drug is eliminated in one half-life. Doubling the dose only adds approximately one half-life to the dosing interval. To add two half-lives, the initial dose would need to be quadrupled, potentially exceeding the safety window and causing adverse effects. For instance, amoxicillin can be given to dogs at 10-20 mg/kg every 12 hours, but to maintain higher concentrations, the same dose could be administered every 8 hours.
Delivering the antibiotic as a continuous IV infusion can ensure that tissue or plasma drug concentrations consistently exceed the MIC. This method may be particularly beneficial for critically ill animals, such as those with urosepsis or compromised immune systems.
Concentration-Dependent Antibiotics
The efficacy of concentration-dependent antibiotics is best predicted by the Cmax and the isolate’s MIC. Drugs like fluoroquinolones and aminoglycosides are most effective when the Cmax is at least 8- to 10-fold higher than the MIC. These drugs are typically administered once daily, which can improve owner compliance. However, prescribing a fluoroquinolone for an uncomplicated lower UTI when equally effective penicillin or cephalosporin options exist may not align with antibiotic stewardship principles.
Another way to evaluate the activity of these antibiotics is by comparing the area under the drug concentration-time curve (AUC) to the MIC (AUC/MIC ratio). While some sources suggest an AUC/MIC ratio greater than 125-250, studies have shown effectiveness with ratios as low as 40 for certain drugs. Dosing for these antibiotics usually aims to achieve a high peak urine concentration well above the isolate’s MIC.
Duration of Therapy
The optimal duration of antibiotic therapy for uncomplicated and complicated UTIs remains unknown. Many veterinary textbooks recommend 10-14 days for uncomplicated UTIs and 4-8 weeks for complicated UTIs, but these are not evidence-based guidelines. Human medicine often utilizes much shorter treatment durations.
In 2011, the International Society for Companion Animal Infectious Diseases (ISCAID) published recommendations for antimicrobial therapy in UTIs, largely based on expert consensus due to a lack of robust clinical trials in veterinary medicine. For uncomplicated UTIs, they recommended seven or fewer days of antibiotic therapy, aligning with typical human treatment of 3-7 days. For complicated UTIs, they recommended up to four weeks of therapy, compared to the 1-2 weeks (sometimes 3) common in human medicine.
More recently, two studies evaluated short-duration versus long-duration antibiotic therapy for uncomplicated UTIs in dogs, finding that shorter durations were non-inferior to longer durations in achieving bacterial cure rates. However, these studies compared different drugs for short and long durations, precluding definitive conclusions about optimal treatment times for specific drugs. A 2015 systematic literature review found insufficient evidence to determine optimal UTI therapy in veterinary medicine. Currently, evidence-based guidelines for UTI duration in small animals are lacking, and further studies comparing single drugs at both short and long durations are needed.
Monitoring Response to Therapy
While simple, uncomplicated UTIs may not require intensive monitoring, patients with complicated, relapsing, or recurrent infections warrant close observation. The following protocol is recommended for monitoring therapy response in these cases:
- Recheck urine culture 5 to 7 days into antibiotic therapy. This confirms the effectiveness of the prescribed dose and frequency. It may also identify additional organisms missed in the initial culture. Any bacterial growth at this stage suggests treatment failure, necessitating a reevaluation of the antibiotic choice, dose, and administration frequency.
- Recheck urine culture 3 days before discontinuing antibiotic therapy. This optional step verifies a negative culture at the end of treatment. Positive growth indicates a refractory infection or a new inoculation. Investigate potential sources of infection, such as urolithiasis, anatomical abnormalities, or local neoplasia. Adjust treatment and initiate new therapy for the intended duration.
- Recheck urine culture 7 days after discontinuing antibiotic therapy. Positive growth should prompt an investigation into the causes of relapse or reinfection.
Curing complicated, relapsing, recurrent, and refractory UTIs can be challenging. However, a solid understanding of drug PK/PD and potential alterations in the animal’s drug metabolism and excretion can significantly improve the chances of successful treatment.
Summary
Established guidelines for appropriate antibiotic dosing in animals with kidney disease are lacking. Therefore, a working knowledge of pharmacology and the PK/PD profile of the prescribed drug is essential for creating effective antibiotic prescriptions with minimal risk of adverse effects.
Whenever possible, in patients with kidney disease, clinicians should avoid drugs with a narrow safety margin and significant renal elimination (e.g., fluoroquinolones in cats, aminoglycosides). Instead, alternative drugs (based on susceptibility results) that undergo hepatic elimination or possess a wide safety margin should be chosen.
Learn More
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.
Author’s Note
The absence of comprehensive data and limitations in well-designed studies prevent the establishment of complete evidence-based guidelines for treating UTIs. This article presents a logical and accessible approach to UTI treatment, though it too lacks extensive clinical validation. The clinical utility of urine drug concentrations remains a subject of debate, yet numerous textbooks and peer-reviewed articles suggest their potential role in formulating valid antimicrobial prescriptions. While the clinical success of drug therapy cannot be solely predicted by urine drug concentration, in the absence of individual patient drug therapeutic monitoring, GFR testing, and urine drug bactericidal assessment data, concrete facts to guide therapy are scarce. This article aims to illuminate relevant aspects of drug pharmacokinetics/pharmacodynamics, urine susceptibility testing, and informed drug therapy, acknowledging that gaps in our understanding lead to ongoing questions and debates. Hopefully, this discussion enhances the understanding of drug pharmacology as it pertains to UTIs, to the best of our current knowledge.
—JD Foster, VMD, DACVIM
