Introduction
The previous discussion focused on resistance of E. coli, with a focus on uropathogens of dogs and cats. This second part will focus on virulence and the pathophysiology of urinary tract infections (UTI), and how this might influence therapeutic decision making. Because multidrug resistance is so difficult to treat, this session will focus on how to avoid MDR, including empirical treatment of UTI. It will finish with a discussion of how to treat MDR.
Virulence refers to the ability of an organism to cause disease, whereas resistance refers to the ability of the organism to avoid harm, although clinically we tend to use the term in reference to avoidance of harm caused by antimicrobials. Although enteric E. coli are generally nonpathogenic, the presence of virulence factors in some strains allows classification of E. coli into 6 groups capable of causing enteric disease, 5 of which occur in the gastrointestinal tract (e.g., OH157:H7). The 6th is extraintestinal E. coli (ExPEC) which includes UPEC (uropathogenic). Resistance and virulence are often mutually exclusive although recently, virulent and resistant isolates have emerged. The ExPEC appear to easily colonize the gastrointestinal tract, potentially displacing commensals, and eventually emerging as infectious organisms in other body tissues, particularly in the urinary tract. These factors are of concern not only to the small animal clinician, but increasingly are contributing to a potential public health concern. UPEC are ExPEC that acquire virulence factors necessary for survival of the organism outside of the gastrointestinal tract. In humans, E. coli is associated with 90% of UTI in otherwise healthy persons. It is also responsible for approximately 50% of nosocomial UTI. Emerging statistics indicate the same is true in dogs. The pathophysiology of human and canine UTI associated with E. coli is quite similar. Isolates causing UTI are from the gastrointestinal tract. Ascending infection up the urethra to the bladder may be further complicated by infection in the ureter and kidney if the isolate contains the necessary virulence factors. Once in the bladder, several virulence factors facilitate survival in the bladder. Initial release of cytotoxic materials destroy uroepithelial cells, facilitating penetration, but also providing nutrients for the microbes. Critical to successful infection is the ability of E. coli to adhere to the uroepithelium, thus protecting the microbe from bulk urine flow, among the most important defenses of the bladder. Once the E. coli has adhered to the uroepithelium, the production of biofilm will protect it from damage by host cells and antimicrobials. Biofilm communities are complex and sophisticated. Biofilm will potentially protect microbes such that they become senescent, and thus less susceptible to antimicrobial therapy. Such cells may remain under the uroepithelial cells until they are exfoliated, only to become active again such that infection continues. Studies have demonstrated transfer of virulent and/or resistant E. coli between animals and humans, a fact which was documented as early as 1975. Evidence that pets and owners share E. coli is increasing as has been demonstrated in studies within family members, including pets. However, what is not clear is if zoonoses or reverse zoonoses predominated.
Subclinical bacteriuria is the presence of bacteria in the urine as determined by positive bacterial culture, in the absence of clinical and cytological evidence of UTI; in humans, asymptomatic bacteriuria (ABU) includes the presence of white blood cells. In humans, in most circumstances, ABU is not an indication for systemic antimicrobial therapy. Treatment may not be necessary in animals that have no clinical signs of UTI despite evidence of UTI based on examination of urine sediment. In our studies, up to 20% of canine uropathogens were associated with no clinical signs.
Treatment of Urinary Tract Infections
Virulence and Adjuvant Therapy
Diuresis has been advocated in the treatment of UTIs in humans. Advantages include rapid dilution of bacteria, removal of infected urine, and subsequent rapid reduction of bacterial counts. Mannose has been suggested as a preventative or adjunct to therapy; blockade of mannose receptors may preclude E. coli from adhering to uroepithelial cells. However, the data supporting this approach are not clear. In contrast, limited data do exist for cranberry juice extracts which contain proanthocyanidins that block adherence to receptors. Use of drugs to modify urinary pH may facilitate the antibacterial effects of urine. Antibacterial activity may be increased by ingestion of cranberry juice (if urinary pH is acidic), which contains precursors of hippuric acid. Methenamine releases formaldehyde at a urinary pH of 5.5 or less, which also can increase antibacterial activity of urine. In human patients, urinary acidification is very difficult to achieve and can result in dissolution of crystals. Urinary acidification is recommended rarely and only with concomitant use of organic acids (or methenamine). Local urinary analgesics, such as phenazopyridine, are rarely indicated for the management of urinary tract infections. Dysuria is most likely to respond to appropriate antimicrobial therapy. Drugs or nutraceutical products that enhance polysulfated glycosaminoglycan synthesis (e.g., ADEQUAN, pentosan polysulfate, glucosamine, chondroitin sulfate) might be considered for patients with complicated UTI. Such materials may cover or help repair the uroepithelium, thus decreasing bacterial adherence. Probiotics might also be considered for their ability to potentially replace emerging resistant populations in the gastrointestinal tract with "good" bacteria. Note that many probiotics are characterized by poor quality; accordingly, attention should be made to stick with a brand-name product. Doses should be in terms of billions in order to assure colonization of the gastrointestinal tract. In general, target organisms should include lactobacilli, Bifidobacterium, enterococci, streptococci and others.
Antimicrobial Therapy
The 1st treatment of a UTI may be the most important if chronic infection is to be avoided.
The most important considerations for selection of an antimicrobial are, in order of priority:
1. Confirm the need to treat.
2. Identify the target in order to match the drug to bug. ISCAID recommends a 1st tier antimicrobial.
3. Ensure drug distributes to the site of infection.
4. Adjust the dose to ensure concentrations that will kill all infecting colonies.
The approach to treatment may begin by determining whether the infection is simple or uncomplicated because this may determine the need for culture and susceptibility testing. This latter consideration requires that host (such as inflammation) and microbial factors (such as biofilm) be taken into account. The International Society for Companion Animal Infectious Diseases (ISCAID) has provided *guidelines for the treatment of UTI and many of these tenets are included in this discussion. Simple uncomplicated UTI is a sporadic bacterial infection of the bladder in an otherwise healthy individual with normal urinary tract anatomy and function. A UTI is considered complicated if it occurs in the presence of an anatomic or functional abnormality or a comorbidity that predisposes the patient to persistent infection, recurrent infection, or treatment failure. Concurrent disease complicating UTI might include prostatitis, urinary calculi, a neurogenic bladder, pregnancy, diabetes mellitus, or immunocompromising disorders (humans). The minimum database for evaluation of suspected UTI should include complete urinalysis, including urine specific gravity, urine glucose level determination, and examination of the sediment for crystalluria is considered. Underlying causes of infection must be identified and treated if possible. Clinically significant infection implies the presence of a clinical abnormality and is characterized by dysuria, pollakiuria, and/or increased urgency of urination along with the presence of bacteria in urine. None of these signs is considered pathognomonic for infection. Further, the committee did not confirm the need to treat covert bacteriuria/subclinical bacteriuria present in the absence of clinical signs.
Empirical Antimicrobial Selection
Antibiograms might be consulted for empirical selection of an antimicrobial. Objective data regarding the prevalence of resistance that indicates a need to change initial therapy are lacking. If baseline resistance rates to a given drug from non-biased sample collection exceed 10%, the drug chosen for initial therapy should be changed to another of the recommended initial choices. Ideally, empirical therapy will begin with 1st tier antimicrobial drugs. In the presence of an alkaline pH, weakly basic antibiotics might be considered (aminoglycosides, fluorinated quinolones). Because urease producers may alkalinize the urine, drugs including such organisms (e.g., Proteus, Staphylococcus, and some Klebsiella species) should be selected. In the presence of an acidic urinary pH (perhaps caused by E. coli), weakly acid drugs (e.g., penicillins, cephalosporins, potentiated sulfonamides) might be better empirical selections.
1st Tier:
Beta-Lactams
The beta-lactams remain excellent first-choice drugs. Not only is resistance, should it emerge, likely to be reflect beta-lactamases and thus be limited to single drug resistance, beta lactams also impair pili of E. coli more so than other drugs. Amoxicillin or amoxicillin clavulanic acid are recommended for first choice for empirical therapy. In general, cephalexin is a poor choice. Generic Augmentin® (human Clavamox®) is now available. However, the ratio of clavulanic acid to amoxicillin varies among the human tablets and solution, but not the small animal versions. The 400-mg human capsule has the same ratio as the veterinary ratio. The variability reflects an attempt to minimize vomiting. However, it is not clear if the ratio also impacts efficacy, although a ratio as high as 8:1 is available in the generic human product. There is no reason to believe that a similar ratio would be ineffective in dogs, although it is not clear if dogs will absorb the drug the same as in humans. An alternative approach is to dose an animal with Clavamox® but add to the regimen a dose of amoxicillin that will bring the total dose up to a target of 25 mg/kg BID to TID.
Potentiated Sulfonamides
Only 9% of E. coli pathogens of dogs were resistant to TMPS, probably reflecting its potential to cause allergies. Use for 5 days or less can minimize the emergence of side effects although allergies can emerge if the patient is dosed again in the future.
2nd Tier:
Fluorinated Quinolones (FQ)
Assume that an isolate resistant to one FQ is resistant to all. If resistance emerges to FQ, it will be multidrug resistance. Thus, the fluoroquinolones are preferably reserved as second-tier drugs with use based on culture and susceptibility; use at the highest dose is preferred. As concentration-dependent drugs, doses of FQs should be designed to reach at least 10x the MIC of the infecting bug at the site of infection. Ciprofloxacin oral bioavailability in dogs is 40 to 60% and in cats 0–20%. A recent study demonstrated that 3 days of enrofloxacin at 18–20 mg/kg once daily was just as effective as 14–25 mg/kg BID amoxicillin clavulanic acid for 14 days in treating uncomplicated UTI in dogs (J Vet Intern Med. 2012). Although ciprofloxacin is more potent toward gram-negative organisms, the dose should nonetheless be increased two fold compared to enrofloxacin, and 3-fold for Gram positive because of reduced oral bioavailability. Oral ciprofloxacin should not be used in cats. For other fluoroquinolones in cats, marbofloxacin and apparently orbifloxacin are among the safest in regards to retinal degeneration. Resistance to one veterinary FQ should be considered as evidence of resistance to any FQ and an alternative drug should be chosen. The use of 3rd-generation cephalosporins for empirical treatment of UTI should be avoided: although their spectrum is typical of 1st generation, ESBL-associated resistance will target other 3rd-generation cephalosporins which have broader (3rd tier) gram-negative susceptibility patterns.
Nitrofurantoin
Many MDR isolates are susceptible to nitrofurantoin. However, its use is associated with gastrointestinal upset and peripheral neuropathies which have been anecdotally reported in dogs. Other side effects occur in humans. An advantage to nitrofurantoin is its minimal effect on the normal gut flora. As such, selection pressure for antimicrobial resistance is reduced compared to other antimicrobials.
3rd Tier
By the time the 3rd tier of drugs has been reached, it is critical to remove the underlying cause of infection. It is this group in particular for which the risks of treatment need to be weighed against the risk of non-treatment; strong consideration should be given to not treat asymptomatic patients.
Aminoglycosides
Caution is recommended when intervals shorter than 24 hours are used for aminoglycosides. Contact between drug and microbe in the urinary tract can be facilitated by administration of a drug immediately after micturition or before an anticipated micturition-free period (e.g., at night). The nephrotoxicity associated with aminoglycosides is exposure dependent, meaning it can be avoided if the kidneys are granted a drug-exposure-free period during which they can excrete drug which has accumulated. Accordingly, aminoglycosides are dosed once daily. Maintaining hydration (to the extent of providing sodium-containing fluids at the time of dosing in at-risk patients) and dosing in the morning (perhaps the evening in cats) may reduce toxicity, as will avoiding other nephroactive drugs (e.g., NSAIDs). N-acetylcysteine may help decrease the risk or extent of damage.
Fosfomycin Tromethamine (Monurol®)
Fosfomycin, a phosphonic acid which contains a carbon-phosphorus bond, is a natural antibiotic produced by Streptomyces fradiae. Its in vitro spectrum is broad, with potential efficacy toward isolates expressing MDR, including E. coli and gram-positive isolates. Approved for human use in the USA, its indication is as a one-time (or up to 3 days) treatment of E. coli UTI in humans. Although its mechanism of action is similar to the beta-lactams, unlike the beta-lactams fosfomycin is not susceptible to destruction by any class of beta-lactamases. As a cell wall inhibitor, fosfomycin is bactericidal when present at the site of infection at therapeutic concentrations. Other attributes of fosfomycin that support its use for treatment of E. coli UTI include renal excretion, synergistic interaction with several other classes of antimicrobials and preparation as a 3-g sachet (granules) which is mixed with water to orally deliver approximately 40 mg/kg (in humans). We anticipate that a week of treatment with Monurol® at 75 mg/kg (40 mg/kg fosfomycin) BID will cost approximately $ 8–12/kg for 1 week of therapy. Alternative therapies are based generally on injectable drugs (aminoglycosides, carbapenems) and thus hospitalization, and for aminoglycosides, intensive monitoring. Side effects of fosfomycin appear to be limited to diarrhea. We have demonstrated the efficacy of fosfomycin toward MDR E. coli.
Duration of Therapy
The duration for successful treatment of uncomplicated lower UTIs might be as short as 3 to 5 days. Such an approach is more likely to be successful if high doses and appropriate intervals are chosen. Treatment may need to be longer, however, if infection occurs anywhere other than the uroepithelium. In general, a 10- to 14-day therapeutic regimen has been recommended for the first episode of therapy. The "test for cure" can be based on a second culture 3 to 5 days into therapy. Cure should be anticipated only if the organism count at that time is less than 100 per milliliter of urine. Urine culture a second time just before discontinuation of therapy has been recommended, particularly if antimicrobial prophylaxis is to be implemented. However, increasingly, evidence is emerging that in uncomplicated cases, 3 to 5 days of therapy may be most appropriate. Drugs that have been used successfully by humans for short-term dosing include trimethoprim/sulfonamide combinations, aminoglycosides, selected cephalosporins, and fluorinated quinolones. Limited information is available regarding duration of therapy in dogs. However, Westropp et al. (J Vet Intern Med. 2012) have demonstrated that 3 days of dosing of enrofloxacin at 18–20 mg/kg/day for 3 days was not inferior to 13 to 25 mg/kg amoxicillin BID for 14 days in dogs with uncomplicated UTI. For infections that reflect a relapse, the duration of therapy should be at least 2 weeks; however, for human patients suffering from a relapse, a higher cure rate occurred with a 6-week course of therapy. For animals, a duration of 4 to 6 weeks is recommended. Because relapse is likely to occur shortly after antimicrobial therapy is discontinued, cultures should be collected 7 to 10 days after cessation of therapy. In the event of relapse after 6 weeks of therapy, 6 months of therapy or more may be necessary. However, if the patient is asymptomatic, strong consideration should be given to no treatment unless mitigating circumstances indicate the need for therapy. Unless the underlying cause of infection can be removed, however, it is likely that resistance will emerge.
Prophylaxis
Long-term prophylaxis can be implemented for patients at risk for recurrence. Prophylaxis (by definition) can occur only after the infection has been eradicated. The use of low doses of antimicrobials in the presence of bacteriuria is likely to lead to the generation of resistant organisms and is contraindicated. Thus, prophylactic antimicrobial therapy of UTIs is indicated for reinfection but not relapse (the latter suggests that the organism was never completely eradicated). The antimicrobial chosen for long-term prophylaxis should be both safe and inexpensive. Trimethoprim/sulfonamide combinations (monitor for immune-mediated reactions) and fluoroquinolones are examples. The dose generally can be reduced to 30% to 50% of the full dose. Despite this low dose, therapeutic concentrations of drugs are likely to be achieved in urine; in addition, subtherapeutic concentrations of drugs often are sufficiently inhibitory to prevent infection of the uroepithelium. The drug should be administered at night to maximize contact of the drug with the urinary tract. Intermittent urine cultures (monthly) are indicated to detect breakthrough infections in animals receiving long-term antimicrobial prophylaxis. Negative cultures for 6 to 9 months or more may indicate that prophylaxis is no longer necessary.