Antimicrobials and UTI: A clinical pharmacologist's perspective (Proceedings)

The goal of antimicrobial therapy for UTI is to resolve clinical signs of infection, eliminate bacteruria, and also avoid resistance. Increasingly, the latter is difficult to do. In order of importance, the three most important steps (in the author's opinion) to take when treating.

Confirming the need for infection

Antimicrobial therapy should be used only when reasonable evidence of infection exists. Generally, a quantitative culture yielding less than 105 CFU/ml may not need treatment, and if the risk of resistance is likely, avoiding treatment might be more prudent. Mitigating circumstances might mandate treatment (eg, immunesuppression, pyelonephritis, etc) that can lead to worsening of infection etc). In humans, the presence of bacturia is not necessarily an indication of the need for therapy. In order to avoid resistance, treatment generally is not indicated in asymptomatic bacturia except under certain conditions in which the patient is at risk, such as pregnancy, or invasive surgical procedures.Enterococcus infection in particular may be amenable to no treatment (see adjuvant therapies). Bacterial UTI occurs much less frequently in cats than in dogs, and clinical signs indicative of cystitis in cats should not be interpreted as a need for antimicrobial therapy. Cats might be cultured to detect occult infection and to rule out the presence of bacteria. Clearly, if the decision is made to treat a UTI, then therapy must be aggressive, designed to kill invading pathogens as well as emerging mutants as rapidly as possible.

Identifying the bug and matching it to the drug

The role of empirical selection in treatment of UTI should be questioned, particularly in complicated cases. That broad-spectrum, and even narrower spectrum drugs (eg, FQ) impact microflora and contribute to resistance is clear. Increasingly, scientific data supports the inappropriateness of this approach for all but the simplest of infections. An uncomplicated infection is one in which no underlying structural, neurologic, or functional abnormality can be identified. Previous antimicrobial therapy within the last 3 to 12 weeks is a clear indication for a properly collected culture (see below). E. coli is the organism targeted with empirical therapy. However, in the author's retrospective and prospective studies in dogs and cats, E .coli was the causative organism in only 50% of UTI cases. More importantly, of the E coli, and up to 50% of isolates were resistant to first choice drugs (amoxicillin-clavulanic acid, TMPS, FQs, and cephelixin; 20% resistant to cefpodoxime). In women with risk factors for infection with resistant bacteria, or in the setting of a high prevalence of TMP/SMX resistance, a FQ or nitrofurantoin is recommended for empirical treatment. In humans, the goal of treatment is eradication of infection using shorter courses of therapy (ie, 3 days) with with once-a-day dosing of a selected drug or a single dose of a particularly efficacious antibiotic. Nitrofurantoin does not share cross-resistance with more commonly prescribed antimicrobials and its use is justified from a public health perspective as a FQ-sparing agent. The need to avoid FQs is exemplified by the fact that single-dose ciprofloxacin prophylaxis increased the prevalence of ciprofloxacin-resistant faecal E. coli from 3 to 12%. After treatment with ciprofloxacin for prostatitis, 50% resulted in post-treatement faecal colonization with quinolone-resistant E. coli genetically distinct from the prostatic infection. Indeed, in humans, although FQs are effective as short-course therapy for acute cystitis, widespread empirical use is discouraged because of potential promotion of resistance. An exception is made for acute (non-obstructive) pyelonephritis, but only if culture results direct continuing therapy. The more complicated the infection or the patient, the more important is basing therapy on susceptibility data. In human patients, diagnosis of UTI in asymptomatic patients is based on at least two clean-catch midstream urine collections. The point is not to sample clean catch urines in dogs or cats, but to point out that the presence of bacturia in the absence of clinical signs is not an indication for therapy. The same organism must be present in significant (see earlier) amounts in both cultures for treatment to be recommended. A single culture is sufficient in the presence of symptoms. Urinary cultures should be the basis of antimicrobial selection in complicated infections (e.g., re-infection or relapse; history of antimicrobial use within the past 4 to 6 weeks) or if the infection represents a risk to the patient's health. Infection after recent urinary catheterization also should lead to culture collection. Quantitative urine culture should be used to discriminate harmless bacterial contaminations (e.g., from the urethra) from pathogenic organisms. In a properly collected urine sample, bacterial counts of more than 105 are indicative of infection; counts between 103 and 105 organisms are considered suspect and should lead to a second culture. Samples collected by catheterization or midstream catch techniques are more likely to yield falsely positive cultures than are samples collected by cystocentesis, particularly in females. Thus, cystocentesis is preferred. Note that if therapy is begun as culture results are pending, and the results indicate the wrong drug was selected, the microbial population that is present at the time that the results are received may not (probably does not) reflect the population that was cultured and reculture may be necessary before a new drug is begun.

Design a dosing regimen such that sufficient drug will get to the site that all CFU in the inoculum are killed.

Ideally, a drug that is renally excreted should be selected for treatment of UTIs. Urinary concentrations of such drugs often surpass serum concentrations (up to 300-fold), and as such susceptibility data should be based on urinary rather than plasma drug concentrations. Indeed, drugs that might not be useful for treatment of non-UTIs (because of failure to achieve MIC in blood or tissues) often can be used to treat UTIs (e.g., carbenicillin, nitrofurantoin). In addition, renal elimination may result in bactericidal concentrations of drugs for which only bacteriostatic concentrations can be safely achieved in serum. Many antimicrobials are characterized by a short elimination half-life. This becomes problematic when designing effective, yet convenient dosing intervals for time dependent drugs (see sister Proceedings). For renally eliminated drugs, however, plasma elimination half-life may not accurately reflect contact time of drug in the target tissue (i.e., urine). Presumably, drug eliminated in the urine will be in contact longer with the infected tissue (i.e., lower UTI) longer than other tissues, and therefore the basis for a recommendation to use drugs at a shorter interval when treating UTIs compared with other infections may not be as relevant for UTIs. 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).However, several caveats must be recognized, when basing antimicrobial selection on renal elimination and anticipation of high urine drug concentrations: 1. If the UTI is associated with infection in the blood (or in the presence of bacteremia), kidney, or prostate, then antimicrobial selection should be based on anticipated plasma (or tissue) drug concentrations and serum breakpoint MIC. Urine concentrations, albeit higher than plasma concentrations, will be helpful, but do not translate to higher concentrations in any tissue other than the urine itself. 2. Exceptions to higher concentrations will occur in the presence of decreased renal function as kidneys fail to concentrate.3. Some renally-excreted drugs present a greater risk of nephrotoxicity. This risk is even greater in the patient with renal disease.

Identify risk factors

Previous antimicrobial therapy within the past 3months profoundly impacts the likelihood of resistance in women with UTI, with the risk greater if the antibiotic of interest has been used past 3 months. Those who had taken any antibiotic were more than twice as likely to be infected with a resistant isolate; use of TMP SMX within the past 2 weeks was associated with a 16 fold greater risk of infection with a resistant isolate. Previous FQ use may result in MDR isolates (particularly E coli , resulting in susceptibility only to nitrofurantoin and aminoglycosides). Urinary catheterization is a recognized risk factor for antimicrobial resistance. Catheterization has resulted in bacturia in previous bacteria free urine, and has been associated with changes in urine microflora, as well as increased resistance. Although aseptic techniques will reduce the risk of infection, infection is not prevented. The risk of persistent UTI in cats with experimentally induced cystitis was increased with catheter placement, despite the use of a closed system of urine drainage. The risk of infection can be correlated with duration of catheter placement, with the risk being reduced in patients catheterized for less than three days. Previous antimicrobial therapy is likely to contribute to the risk of catheter-induced infection: resistance in dogs catheterized more than 5 days was strongly associated with the advent of resistant microorganisms. Catheter type influences the risk of infection, probably because of its impact on biofilm formation and bacterial swarming. However, organisms within microcosms associated with biofilm and isolated upon urine collected from the catheter – or from the catheter tip - are not necessarily causing infection, and in the presence of infection, may not be the causative organisms. The incidence of resistance in E coli collected from catheters tips is greater than that collected by cystocentesis. Which organism is actually causing infection is not clear; it is reasonable the organisms in the catheter are not necessarily causing infection and selecting antimicrobials based on these organisms generally will require drugs generally considered second or third choice. Collection of urine via cystocentesis is likely to be more representative of infecting organisms compared to the catheter or catheter tip.

Attention should be paid to the pH of the urine compared with the pKa of the chosen drug. In most situations, however, even if most of a drug is ionized (e.g., a weak base in an acidic environment), because drugs are concentrated in the urine, generally sufficient un-ionized drug is available to ensure effective concentrations. 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, Staphyloccocus, 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, poentiated sulfonamides) might be better choices.Other risk factors include structural abnormalities, metabolic disorders (eg, diabetes mellitus, hyperadreno-corticism), pyelonephritis or symptoms of a UTI that have occurred for more than 7 days.

Duration of therapy

The duration for successful treatment of uncomplicated lower UTIs might be as short as 3 to 5 days (use high doses, short intervals). Treatment may need to be longer, however, if infection occurs anywhere other than the uroepithelium. In general, a 10- to 14-day therapeutic regimen is then 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 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. Although shorter term antimicrobial therapy (ranging from single high dose to dosing for 3 days) has proved effective for female human patients with a lower UTI, caution is recommended for use of this approach for dogs and cats. Drugs that have been used successfully by humans for short-term dosing include trimethoprim/sulfonamide combinations, aminoglycosides, selected cephalosporins, and fluorinated quinolones. Both single-dose and 3-day antimicrobial treatment regimens have been studied with dogs receiving amikacin and a trimethoprim/sulfonamide combination. Therapy was not uniformly successful, suggesting that caution should be used with this treatment regimen. However, failed therapy may reflect insufficient dosing regimens. On the other hand, failed therapy may reflect increase risk of re-infection in animals compared to humans.

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. The presence of relapse should lead to a longer course of therapy, perhaps at a higher dose. A new antibiotic should be selected if infection occurs more than 10 days after cessation of therapy; as more time elapses between cessation of therapy and the presence of bacteriuria, the more likely that reinfection (rather than failed therapy) is the cause of recurrence. In the event of relapse after 6 weeks of therapy, 6 months of therapy or more may be necessary. Greater care should be taken, however, in the selection of antibiotics for longer term therapy, with special consideration to toxicity. An alternative approach might be intensive "pulse" dosing that eradicates infection, such that if and when re-infection occurs, the population of microbes is not resistant. Drugs that are used for long-term therapy for human patients include amoxicillin, cephalexin, trimethoprim/sulfonamide combination, or a fluorinated quinolone. Cultures should be repeated monthly, and, as long as significant bacteria are not present, the drug need not be changed. Should relapse occur after a drug is discontinued, the same drug or a new drug should be administered for a longer course of therapy. Long-term therapy may be particularly important for animals in which renal parenchymal damage is a risk.

Adjuvant or alternative therapies

Alternative therapies are indicated In patients for which a decision is made to not treat an infection, in patients successfully treated and avoidance of re-infection is desired, or in patients undergoing treatment of a complicated UTI. 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. In patients with pyelonephritis, an added advantage may be enhanced host defenses: Medullary hypertonicity inhibits leukocyte migration, and high ammonia concentration inactivates complement. In the presence of vesiculoureteral reflux, however, diuresis may increase the risk of acute urinary retention. Use of drugs to modify urinary pH may facilitate the antibacterial effects of urine. The presence of ionizable organic acids (hippuric and γ-hydroxybutyric acid) in an acidic pH may enhance the antibacterial activity of the urine. Antibacterial activity may be increased by ingestion of cranberry juice (if urinary pH is acidic), which contains precursors of hippuric acid. Methenamine (contraindicated in cats) releases formaldehyde at a urinary pH of 5.5 or less, which also can increase antibacterial activity of urine..Urinary acidification may be 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). The use of polysulfated glycosaminoglycans should be considered (Adequan® injectable for 4-6 weeks, with simultaneous oral glucosamine and chondroitin products until resolution) to support the bladder mucosal barriers. D-mannose. Infection of the urinary tract begins with bacterial adherence to uroepithelial cells of the urinary mucosal surface. Escherichia coli contains adhesins that bind to the glycolipid receptors.Treatment with mannose or similar molecules may block the receptors, thus reducing adherence. The severity of a UTI may be correlated with the adherence to uroepithelial cells. Several antimicrobials interfere with bacterial expression of fimbrial adhesins and thus may prevent bacterial attachment and colonization. Examples include penicillin, ampicillin, amoxicillin, and streptomycin. Probiotics which contain bifidobacterium and lactobacillus should be considered (see Paper in this Proceedings).

Pyelonephritis: Treatment for pyelonephritis may require hospitalization. Oral antibiotic therapy is acceptable for mild to moderate cases as long as oral therapy is tolerated well. Because renal dysfunction can be life threatening, antimicrobial selection should ultimately be based on culture and susceptibility data. Therapy can be initiated empirically; however, resistance among E. coli organisms should lead to selections other than amoxicillin and ampicillin. Pyelonephritis can be associated with bacteremia, particularly gram negative. Clinical signs indicative of severe, life-threatening infection should lead to parenteral antibiotic therapy with predictably effective drugs (e.g., aminoglycosides, fluorinated quinolones, extended spectrum beta-lactams, and third-generation cephalosporins). Combination therapy also should be strongly considered. The high concentration of antibiotic that facilitates treatment of the lower urinary tract (bladder and lower) may not occur in pyelonephritis; thus attention must be closely paid to using sufficiently high doses and frequent dosing. Drugs whose efficacy is dependent on a hypotonic environment (compared with the target organism) such as beta-lactams may be less effective in the face of medullary hypertonicity. As with infection lower in the tract, bacterial numbers should decrease dramatically within the first 48 hours. For uncomplicated pyelonephritis, 14 days of therapy may be sufficient. Cultures should be repeated as previously indicated during and within 1 to 2 weeks of discontinuation of therapy. Complications such as abcessation may require surgical intervention and longer term therapy.