Optimizing Empiric Antibiotic Therapy for Improved Patient Outcome: Focus on UTI

At a symposium held May 25, 2003, during the American Academy of Physician Assistants Conference, three experts discussed the best ways to treat urinary tract infections with antibiotics, in light of current trends in antimicrobial resistance among urinary tract pathogens.

This program was supported by an unrestricted educational grant from Bayer Pharmaceuticals Corporation.

Antimicrobial Resistance in Urinary Tract Infections—An Emerging Problem

Richard Colgan, MD, Assistant Professor and Medical Director, Department of Family Medicine, University of Maryland School of Medicine, Baltimore, presented an overview of antimicrobial resistance in urinary tract infections (UTIs).

He began by describing the difference between an uncomplicated and a complicated UTI. “Uncomplicated UTIs,” he explained, “occur in premenopausal, sexually active, non-pregnant women who have had no medical instruments placed in the genitourinary tract, no past antibiotic treatment, and no history of genitourinary tract abnormalities.”

“Complicated UTIs involve anatomic, metabolic, or functional abnormalities of the genitourinary system,” he continued. Any UTI in a man, a person with diabetes or who is over 65, or a person with a kidney stone, urethral stent or catheter, is considered complicated.

Over 50% of women will have a UTI in their lifetime, making this the most common bacterial infection in women. There are 30 to 50 million cases per year in the U.S.

“I think we tend to minimize bladder infections because you don’t die from them,” Dr. Colgan said. “I look at bladder infections as being a quick win—you can quickly make the diagnosis with just a history, a physical, and a dipstick urine analysis, and you can quickly make your patients feel better.”

Citing research from Foxman, he noted that the average patient with a bladder infection has symptoms for six days and misses one or more days of work (Am J Public Health. 1985;75: 1306).

Most commonly, infections are caused by E. coli, followed by Entero-coccus and Klebsiella. While 6% of conference attendees named ampicillin as their drug of choice for treating uncomplicated UTIs, Dr. Colgan urged attendees to avoid this drug because the resistance rate of E. coli to ampicillin is more than 30%. Resistance of E. coli to trimethoprim-sulfamethoxazole (TMP/SMX) is also on the rise, and now is about 18% and as high as 30% to 40% in some areas.

Resistance to ciprofloxacin has held steady at about 3%, which is most likely also true of other drugs in the fluoroquinolone class.

Because resistance varies regionally, Dr. Colgan noted, “what really matters is what’s happening in the town where you practice.” He urged attendees to get in touch with the microbiology office at their local hospital and ask for an antibiogram card. Resistance rates also vary between university hospitals and smaller hospitals in the same area, and between community-acquired and hospital-acquired infections.

So far, researchers have identified certain risk factors for multi-drug resistant UTI: having a urinary catheter, being over 65, past antibiotic use, and being male, Dr. Colgan noted. The most common pattern for multi-drug resistance in acute uncomplicated UTIs is resistance to ampicillin, cephalosporin, and TMP/SMX.

Risk factors for resistance to TMP/SMX include recent hospitalization, diabetes, use of any antibiotic, use of TMP/SMX, Asian or Hispanic ethnicity, travel, and secondary antibiotic exposure, for example through interfamily spread or daycare attendance.

There’s also a clear correlation between laboratory studies of local antibiotic resistance and the effectiveness of these antibiotics in treating UTIs among individuals in the United States, with people who have TMP/SMX-resistant bacterial infections responding less well to the drug than those without resistance. The same difference is true when treating pyelonephritis. One study found that while the drug cured 92% of non-resistant cases of pyelonephritis, it achieved clinical cure in only 35% of women with resistant strains of the bacteria (JAMA. 2000;283:1583-1590).

Fluoroquinolones are strongly recommended for treating this type of infection, he added. “One of their real hallmarks is that they do an excellent job of getting into the end-organ tissue.”

In terms of cost, Dr. Colgan noted, “it’s been said that the most expensive antibiotic is the one that doesn’t work.” One study found that a seven-day course of ciprofloxacin for pyelonephritis was more effective and less expensive than a 14-day course of TMP/SMX, with the cost of $615 per cure for ciprofloxacin and $770 for TMP/SMX (JAMA.2000; 283:1583-1590).

For complicated UTIs, Dr. Colgan recommended doing a urine culture before beginning antimicrobial therapy, and using the most potent drug, which would be a fluoroquinolone, empirically. Finally, he added, a urine culture should be performed as a test of cure.

He recommended contacting a specialist when a diagnosis is not certain, when a patient doesn’t respond as expected to treatment, and when a structural abnormality is present or suspected; for example, if it appears that a patient might have a stone.

“Antimicrobial resistance in UTIs will continue to grow, including E. coli resistance to some of the less active fluoroquinolones,” Dr. Colgan concluded. “Continued surveillance of resistance patterns and clinical outcomes is essential.”

David R. Coleman, MPAS, PA-C, of Cheyenne Urological, P.C. and the Wyoming Research Foundation, discussed UTI incidence, socioeconomic factors, guidelines and classification of UTIs, and guidelines on treatment.

Urinary tract infections strike infants of both sexes at about the same rate, Mr. Coleman noted, while in preschool they begin to affect girls more frequently, with 4.5% getting the infections compared to 0.5% of boys. Incidence drops among school-age children, and is equal in both sexes. But during the reproductive years, 50% of women will develop UTIs, compared to less than 1% of men. After age 65, the incidence of UTIs is 20% among women and 10% among men.

Women have a higher rate of UTIs because of their anatomy: a shorter urethra located near the anus, and a warm, moist genital area. Bacteria responsible for UTIs tend to first colonize the entrance to the vagina and then are introduced into the bladder by the massaging of intercourse. While pregnant women don’t face a higher rate of UTIs, Mr. Coleman noted, they are at a greater risk—about 20% to 30%—of having bacteriuria progress to pyelonephritis.

Infectious Diseases Society of America (IDSA) guidelines classify UTI into six types: acute uncomplicated UTI of the lower tract in women, acute pyelonephritis, complicated UTI and UTI in men, asymptomatic bacteriuria, recurrent UTI, and UTI in children.

UTI in males, Mr. Coleman noted, seems to occur mainly among uncircumcised men, men who have sex with women who have UTIs or bacterial
colonization, and men who have anal intercourse.

Consequences of UTIs can be serious among children. Seventeen percent will develop renal scarring, and 10% to 20% will become hypertensive, and each subsequent UTI increases these risks. “So you need to do thorough evaluations with them, such as voiding cystourethrograms and renal ultrasounds,” he added.

Most uncomplicated UTIs, Mr. Coleman said, are seen among young women, and the incidence of these infections increases sharply during adolescence when sexual activity begins.

Sexual intercourse is by far the biggest risk factor for uncomplicated UTIs, he added. Others include delayed urination after coitus, history of UTIs, and use of diaphragm and/or spermicide.

For complicated UTIs, known risk factors and comorbidities include obstruction of the urinary tract, diabetes, an indwelling foreign body, such as a catheter, stroke and other neurologic dysfunction, and being a nursing home patient. Conditions that can lead to urinary stasis, such as prostate enlargement and subsequent urinary retention, cystocele, and bladder diverticulitis, also boost UTI risk.

Mr. Coleman noted that dysuria and frequency usually, but don’t always, signal a UTI. For women, overactive bladder can be responsible. When older men complain of urinary frequency, it may be due to urinary retention caused by prostate enlargement, which itself can also increase the risk of infection. He urged the audience to also consider such differential diagnoses when seeing a patient with these symptoms.

Microscopic examination of urine usually contains white blood cells, and red blood cells may frequently appear, he said. While the presence of red blood cells is not unusual, another test should be performed after treatment to ensure that they are no longer present. “If they haven’t left, you have a whole new beast you need to hunt down,” he said. This continued evaluation is particularly important if a patient is a smoker, because smokers have a nine times greater risk of bladder and kidney cancer compared to non-smokers.

According to IDSA guidelines, UTIs should be treated with trimethoprim-sulfamethoxazole, unless there is high resistance to the drug locally. Then another drug should be considered, such as a fluoroquinolone (Table 1).

For pyelonephritis, fluoroquinolones are considered the first-line treatment. The fluoroquinolone ciprofloxacin is now available in a once-a-day formulation. Mr. Coleman noted that this drug is “comparable in terms of urine concentrations, MIC levels, clinical response, and cure rates” to the standard twice-a-day formulation, and the cost is lower.

As far as special populations, Mr. Coleman noted, any UTI in a diabetic person should be considered complicated. Tight glucose control can improve the outcome of treatment. Diabetic individuals also face a higher risk with intravenous pyelograms (IVP), especially if they are on metformin. This is because in patients taking metformin intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis. And it’s important to perform a fungal culture in these patients, as fungal infections are common.

Pregnant women are the only patients in whom asymptomatic bacteriuria is treated, because of their high risk of developing pyelonephritis, Mr. Coleman reiterated. And, he added, resolution of the infection should be documented. Fluoroquinolones, he noted, are not recommended for pregnant women.

Among elderly patients, he said, there can be many reasons for bacterial colonization of the urinary tract, such as incomplete voiding, catheter use, and neurogenic bladder. While elderly patients need only be treated when they are symptomatic, they may have none of the symptoms that typically signal a UTI, such as dysuria, urgency, frequency, or fever. In some instances, a change in mental status can signal a UTI that needs treatment.

“The most effective treatment will be guided by culture sensitivity or broad spectrum empiric therapy,” Mr. Coleman summarized. “If you’re doing empiric therapy, then you really need to know the resistance rates in your area so you can better judge which antibiotic to use.”

Michael E. Gould, PA-C, of The Urology Center, PC, New Haven, Connecticut, presented three case studies along with questions for the audience.

The first is a 21-year-old woman with dysuria for three days, along with suprapubic pressure and low lumbar pain, but no fever, chills or flank pain. She is taking oral contraceptives and had no known drug allergies, and had her last menstrual period a week ago. A physical exam revealed no acute tenderness, no costovertebral angle (CVA) tenderness, and apparent general good health.

First, Mr. Gould asked attendees if they would perform a dipstick analysis, dipstick plus microscopic urine analysis (UA), urine culture, dipstick or microscopic UA and urine culture, or no urine tests before treatment. The result: a tie between dipstick and microscope UA and both tests with culture. If the patient was well known to the clinician, Mr. Gross said, no tests might be needed, or a dipstick might be enough. If this was the first time the clinician had seen the patient, he added, a culture would be a good idea as well. “Really get a baseline for what they have for the bacteria and the resistance,” he said.

A UA in this case revealed nitrates and 2+ leukocyte esterase, he continued. Should treatment be TMP/SMX, ampicillin, nitrofurantoin, cephalosporin, or oral fluoroquinolone? The lead answer was TMP/SMX, followed by oral fluoroquinolines and nitrofurantoin. “All are good answers,” Mr. Gould said, “depending on local resistance, length of treatment and so on.”

Patient #2 is an 81-year-old female nursing home patient with an indwelling catheter. She has no symptoms, but has a history of Alzheimer’s and high blood pressure. She is taking donepezil and verapamil. A physical exam finds no fever.

First, Mr. Gould asked, should urine from the Foley bag be examined microscopically; should urine be cultured from the Foley catheter port; should broad spectrum antibiotic treatment be initiated; should all three be performed; or should the patient simply be observed? Most attendees chose “observation,” which Mr. Gould said would be the right choice given that the woman has no other symptoms.

Two weeks later, he continued, the woman becomes lethargic and her appetite worsens. She is disoriented and has not eaten for two days, but does not have a fever. An exam finds slight dehydration, while her chest is clear.

For lab tests, a urinalysis found many white and red blood cells, while other tests are fairly normal and show normal renal function.

What is the next step here, Mr. Gould asked: urine culture from Foley catheter port, blood culture, starting broad antibiotic coverage, all three or none of the above? Most responders said all three. Dr. Colgan agreed that this would be the right approach. “We’re seeing now an elderly person who is dwindling. She has a change in her mental status.” This, he explained, could be an early sign of sepsis.

The third case is a 47-year-old woman who arrives at the emergency room at 10 p.m. complaining of back pain and fever. She has had frequency, urgency, dysuria and left flank pain for four days, and has had shaking, chills, nausea and vomiting for two days. The woman is not taking any medications and has about one or two UTIs every year. She passed two small calcium oxalate stones five and seven years ago.

Physical exam reveals a fever of 101.7 and a pulse of 90. She has a distended and tympanitic abdomen and hypoactive bowel sounds, left-sided CVA tenderness, suprapubic tenderness, and no masses. Her vaginal exam is normal.

Labs reveal a urine pH of 6.5, which means stone formation may be likely. She has a white blood cell count of 20 to 50, with too many red blood cells to count, and 10 to 20 bacteria. She has a white blood count with a left shift and a hemoglobin of 11.9, but creatine is normal.

Would the next step be broad-spectrum antibiotic coverage such as IV fluoroquinolines, antibiotics and renal ultrasound, antibiotics and an IVP, antibiotics and spiral CT, or observation? Answers were mixed. “I think it really depends on what your suspicion is for what you think the diagnosis might be,” Mr. Gould said. Some might think she has pyelonephritis, while others think she might have a stone.

While “you can’t go wrong with an IVP,” he added, “it’s clear that broad-spectrum antibiotics should also be started. A spiral CT might also be a good choice for imaging, while an ultrasound would probably not be sufficient to identify problems.”

Dr. Colgan noted that the local urologist might prefer an IVP or a spiral CT. Another possibility, Mr. Gould noted, would be to do a CT scan with an IVP portion.

At 2 a.m., imaging identifies a 1-centimeter stone in the left ureteropelvic junction (UPJ). Would the next step be: IV broad spectrum antibiotic coverage, a stat urology consult, both of the above, antibiotics and a urology consult at 9 a.m., or observation?

Most people chose the antibiotics and the stat consult, which Mr. Gould said would be the best choice. Quick intervention, either a percutaneous nephroscopy tube or stent placement, would be necessary. “Something in order to drain the kidney to make sure that the sepsis does not continue,” he said. “Left untreated, this could be deadly,” he added.