addressing antibiotic resistance

Addressing Antibiotic Resistance

Kalpana Gupta, MD, MPH

Management of uncomplicated urinary tract infections (UTIs) has traditionally been based on 2 important principles: the spectrum of organisms causing acute UT1 is highly predictable (Escherichk coli accounts for 75% to 90% and Staphylococcus saprophyticus accounts for 5% to 15% of isolates), and the susceptibility patterns of these organisms have also been relatively predictable. As a result, empiric therapy with short-course trimethoprim-sulfamethoxazole (TMP-SMX) has been a standard management approach for uncomplicated cystitis.

However, antibiotic resistance is now becoming a major factor not only in nosocomial complicated UTIs, but also in uncomplicated community-acquired UTIs. Resistance to TMP-SMX now approaches 18% to 22% in some regions of the United States, and nearly 1 in 3 bacterial strains causing cystitis or pyelonephritis demonstrate resistance to amoxicillin. Fortunately, resistance to other agents, such as nitrofurantoin and the fluoroquinolones, has remained low, at approximately 2%. Preliminary data suggest that the increase in TMP-SMX resistance is associated with poorer bacteriologic and clinical outcomes when TMP-SMX is used for therapy. As a result, these trends have necessitated a change in the management approach to community- acquired UTI. The use of TMP-SMX as a first-line agent for empiric therapy of uncomplicated cystitis is only appropriate in areas where TMP-SMX resistance prevalence is < 10 % to 20%. In areas where resistance to TMP-SMX exceeds this rate, alternative agents need to be considered.

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anagement of uncomplicated urinary tract infections (UTIs) has traditionally been based on 2 important principles. First, the spectrum of organisms causing acute UT1 is highly predictable,

with Escherichia coli accounting for 75% to 90% of isolates, Staphylo- coccus saprophyticus accounting for 5% to 15% of isolates, and other organisms accounting for 5% to 10% of isolates. Second, the susceptibility patterns of these organisms have also been relatively predictable. Based on these principles, empiric therapy with short-course trimethoprim-sulfamethoxazole (TMP-SMX) has been a standard management approach for uncomplicated cystitis.“2 In addition, these principles have guided initial therapeutic choices while awaiting urine culture and susceptibility results for uncomplicated pyelonephritis and complicated UTIs.

However, antibiotic resistance, which has traditionally been a problem only in nosocomial complicated UTIs, is now also becoming a major factor in uncomplicated community-acquired UTIs. Resistance among cystitis isolates to ampicillin and cephalothin has increased from approximately 20% to 30% to 40% within the last decade.3Y8 Resistance to TMP-SMX, the current drug of choice in the United States for empiric therapy of uncomplicated UT1 in women, now approaches 18% to 22% in some regions of the United States.5’8 Fortunately, resistance to other agents, such as nitrofurantoin and the fluoroquinolones, has remained low.4,5,8 These trends have necessitated a change in the management approach to community-acquired UTI. Specifically, the use of TMP-SMX as a first-line agent for empiric therapy of uncomplicated cystitis is recommended only in areas where TMP-SMX resistance prevalence is < 10% to 20%.2 In areas where resistance to TMP-SMX exceeds this rate, alternative agents need to be considered. In addition to geographic variation in the prevalence of resistance, consideration of individual patient risk factors for resistance needs to be incorporated into the management strategy for uncomplicated UTI. An understanding of the trends in resistance in uncomplicated UT1 is essential for successfully managing UT1 in an era of evolving antibiotic resistance.

Acute Uncomplicated Cystitis

Several studies have examined the resistance profiles of uropathogens causing community-acquired UTI. A multicenter trial of fluoroquinolones versus TMP-SMX for therapy of acute uncomplicated cystitis that was conducted in the early 1990s reported a TMP-SMX resistance rate of 7%

100 DM, February 2003

30 0” g 25

j 20

0 Ciprofloxacin

n Nitrofurantoin

A TMP-SMX

X Ampicillin

0 Cephalothin

1992 1993 1994 Year

1995 1996

FIG 1. Prevalence of resistance among Escherichio co/i causing uncomplicated cystitis in women.

TMP-SMX = trimethoprim- sulfamethoxazole. (Adapted from JAMA.4)

among E cob isolates.’ Resistance to the fluoroquinolones studied, ofloxacin and ciprofloxacin, was 0%. A population-based survey of urine isolates from outpatient women with acute uncomplicated cystitis also found that the prevalence of TMP-SMX resistance among E coli was relatively low during the early 1990s (9% in 1992) but showed a significantly increasing trend over time, reaching 18% by 1996.4 Resis- tance to the p-lactams studied, ampicillin and cephalothin, was already high in 1992 at approximately 20% to 30% and increased to 28% to 34% by 1996. Resistance to nitrofurantoin and ciprofloxacin was < 1% in each study year (Figure 1). Larger, nationwide laboratory surveys have demonstrated the same rates of resistance among UT1 isolates collected from 1998 through 2000 (Table 1).5s

Another important trend in in vitro resistance profiles among community-acquired uropathogens is that of multidrug resistance. A recent nationwide survey of UT1 isolates collected from January 1 through September 30, 2000 from various patient groups found that 7% of E coli isolates were resistant to ~3 of the drugs tested.8 The most common phenotype of the multidrug-resistant E coli was resistance to ampicillin, cephalothin, and TMP-SMX. This survey included isolates from both upper and lower urinary tract sources, inpatients and outpatients, as well as men and women of all age groups. Thus, the prevalence of multidrug resistance among uncomplicated cystitis isolates is still unknown. Strat- ified analyses did reveal that isolates from patients with complicated UTIs


TABLE 1. Urinary Tract Infection Isolates: 1999 National Outpatient Data

Antimicrobial

% Susceptible

Escherichia coli StaphyrocoCcus sapfophyticus

Ampicillin 60.6 29.3 Ceftazidime 99.1 No data Ceftriaxone 99.7 74.5 Ciprofloxacin 97.4 99.1 Levofloxacin 97 98.2 Ofloxacin 97 100 TMP-SMX 81.7 93.9

TMP-SMX = trimethoprim-sulfamethoxazole. Adapted from The Surveillance Network (T.SNTM) Databases-MRL.

(patients who were male, >65 years, or inpatients) were more likely to be multidrug resistant. The prevalence of multidrug-resistant isolates also varied geographically (see below).

Geographic Variation Because there is no systematic surveillance system for monitoring

susceptibility profiles of community-acquired UT1 isolates, few data are available to practitioners regarding resistance rates in their specific practice area. Most studies assess resistance rates from 1 institution or report national averages. There are now commercial organizations that attempt to collect susceptibility data from laboratories throughout the United States. In addition to culture and susceptibility data, information on such factors as sex, age, culture source (urine versus blood), and patient location (inpatient versus outpatient) is also collected, allowing for better epidemiologically defined studies. Two recent studies have been published based on such data from The Surveillance Network (TSN; MRL, Hemdon, VA) Database-USA, a national surveillance system that collects antimicrobial susceptibility results from clinical microbiology laboratories distributed in 9 geographic regions of the United States.“’ One of the studies examined data specifically from community-acquired UT1 isolates from females 15 to 50 years of age and >50 years. In this study, significant geographic variation in TMP-SMX resistance among E coli isolates was reported, with rates as high as 22% in the western and southern regions of the United States and as low as 10% in the northeast. There was no significant geographic variation in rates of resistance to nitrofurantoin or the fluoroquinolones studied. However, there was a difference by age group. Women >50 years tended to have higher resistance rates to both of these classes of drugs, mainly because of an


increased percentage of non-E coli organisms in this age group. In the study of multidrug resistance that was mentioned earlier, rates of multidrug-resistant E coli were higher in the Pacific and West South Central US Bureau of Census regions of the United States.’

Thus, these studies verify that there is significant variation in resistance rates by geographic location within the United States. However, there are still limitations inherent in laboratory-based surveillance studies. Many practitioners do not obtain a urine culture before treating episodes of truly uncomplicated cystitis. Thus, data from these episodes is not included in a laboratory-based analysis. Urine cultures may be more likely to be collected from cystitis episodes that are associated with some complicat- ing factor, thus potentially skewing the susceptibility results in these studies. In addition, although these studies provide important regional information, there still is little information available for individual practice areas; that is, the regions encompass many small areas where resistance rates may be higher or lower than the regional average.

Risk Factors for Resistance In addition to the resistance prevalence in the local community, specific

host factors likely influence whether a given individual will have a TMP-SMX-resistant UTI. There are few data available regarding this issue. One of the best studies to date is that by Wright et al.” They conducted a case-control study of patients arriving at an emergency room with cystitis symptoms. All patients had urine cultures performed. Potential factors contributing to resistance were ascertained from chart review on each patient and were compared between women with a TMP-SMX-resistant uropathogen (cases) and women with a TMP-SMX- susceptible infection (controls). Age, history of UTI, the presence of diabetes, cancer, chronic neurologic or urologic disorder, residence in a long-term care facility, recent hospitalization, and recent antimicrobial use were some of the factors considered. Four variables were significantly and independently associated with risk of having a TMP-SMX-resistant UT1 in the multivariate analysis: diabetes, recent hospitalization, current use of any antibiotic, and current or recent use of TMP-SMX (Table 2). Women who were using TMP-SMX at the time of presentation or who had used it in the past 3 months had a 5-fold increased risk of having a TMP-SMX-resistant uropathogen. More surprising was the fact that use of any antimicrobial within the past 3 months was associated with a 4.5-fold increased risk of having a TMP-SMX-resistant organism. Dia- betes was not an independent risk factor for antibiotic resistance after


TABLE 2. Risk Factors for TrimethoprimSulfamethoxazole (TMP-SMX) Resistance*

Independent Factors Odds Ratio (95% Cl)

Diabetes 3.1 (1.2-8.4) Recent hospitalization 2.5 (1.1-5.7) Current use of antimicrobials 4.5 (2.0-10.2) Current/recent use of TMP-SMX 5.1(2.2-11.5)

Cl = confidence interval. *Of 448 emergency department patients with Escherichia co/i UTI, 67 (15%) had TMP-SMX- resistant strains. Adapted from J Gen Intern Med.lO

recent hospitalization was excluded. Thus, it may be that hospitalization is a mechanism by which diabetic patients acquire resistant organisms. Another smaller study conducted in the United Kingdom also found that use of trimethoprim in the previous 6 months was associated with an increased risk of having a UT1 with a trimethoprim-resistant organism and that diabetes was not independently associated with resistance.”

In summary, it is likely that current or recent use of TMP-SMX or recent use of other antimicrobials increases the risk that a patient with acute cystitis has an organism resistant to TMP-SMX. However, the contribution of additional factors, such as comorbid diseases, travel to areas with high rates of TMP-SMX resistance, and exposure to family members who are on antibiotics or children in daycare, all need further study.12-14

Acute Uncomplicated Pyelonephritis

Susceptibility Patierns Management of pyelonephritis should always include urine culture and

susceptibility testing. However, therapy is usually chosen and initiated before this information is available. An understanding of susceptibility patterns in community-acquired pyelonephritis is therefore essential, especially in settings where the patient will be treated as an outpatient. Compilation of data from 3 studies reveals that the trends in resistance among cystitis strains are also being seen among strains from episodes of acute uncomplicated pyelonephritis (Table 3).3,15,‘6 In the 198Os, susceptibility of community-acquired pyelonephritis isolates approached 75% for ampicillin and 100% for TMP-SMX.3,15 Susceptibility rates for fluoroquinolones were not reported in this study. By the mid-1990s, susceptibility of community-acquired pyelonephritis isolates decreased to approximately 50% for ampicillin and 70% to 82% for TMP-SMX. On the other hand, susceptibility of these isolates to the fluoroquinolones was


TABLE 3. Antimicrobial In Vitro Resistance: Pyelonephritis

Antimicrobial Year of Study/% Susceptible

198~1987* 1995* 199~1997+ Ampicillin 72 57 TMP-SMX 100 70 Fluoroquinolones NA 98

NA = not available; TMP-SMX = trimethoprim-sulfamethoxazole. *Data from infect Dis C/in North Am.3 +Data from JAMA.16

NA 82

>99

excellent (>98%) during this time period. The study by Talan et a1,16 which included pyelonephritis isolates from 1994 to 1997, found that <l% of 255 isolates were resistant to ciprofloxacin as compared with an 18% resistance rate to TMP-SMX. As seen with cystitis isolates, the rate of TMP-SMX resistance among E coli strains ranged consid- erably by geographic region, with only 7% resistance among isolates from study sites in the eastern United States as compared with 32% resistance among isolates from study sites in the western United States.

Aside from current resistance profiles of pyelonephritis isolates, thisstudy also provides data with important therapeutic implications for uncomplicated pyelonephritis in women. The main aim was to compare the efficacy of ciprofloxacin 500 mg twice a day for 7 days versus TMP-SMX 160/800 mg twice a day for 14 days for outpatient oral therapy of acute uncomplicated pyelonephritis in women. Patients randomized to ciprofloxacin were eligible to receive 1 dose of intravenous ciprofloxacin, and patients randomized to TMP-SMX were eligible to receive 1 dose of intravenous ceftriaxone if deemed necessary by the treating physician. Patients were continued on their study drug even if the infecting organism was resistant to the drug unless they had a clinical failure. In an intent-to-treat analysis, patients randomized to 7 days of ciprofloxacin had better bacteriologic and clinical cure rates than patients in the TMP-SMX treatment group, at least in the early follow-up period of 4 to 11 days after therapy. In a safety and cost analysis, adverse drug events were not significantly different between the 2 treatment groups. However, the mean cost of treatment was lower in the ciprofloxacin group by $155 as compared with the TMP-SMX group. This study also provided important information regarding the clinical implications of in vitro resistance in treatment of pyelonephritis (see below).


TABLE 4. Success Rates with Use of Trimethoprim&dfamethoxazole (TMP-SMX) for Treatment of TMP-SMX-Resistant Urinary Tract Infections (UTls)

Study Population

Outpatient women (n = 17) Outpatient women, 18-93 yr of age (n = 9) Healthy premenopausal women (n = 20)

Success Rates in TMPSMX-resistant UTls Treated with TMPSMX n (%)

Bacterial Eradication Clinical Cure

7/14 (50) NA 5/10 (50) 6/10 (60)

64/151(42) 81/151(54)

NA = not available.

Implications of TrimethoprimSulfamethoxazole Resistance

Acute Uncomplicated Cystitis With increasing evidence for significant in vitro changes in TMP-SMX

resistance among community-acquired cystitis isolates, a major research area of interest has been understanding the clinical and bacteriologic ramifications of this resistance. Because it is known that most antimicrobials used to treat UTIs achieve urinary concentrations in excess of serum concentrations (on which National Committee for Clinical Laboratory Standards susceptibility breakpoints for most drugs are based), it is reasonable to expect that not all cases of in vitro resistance will translate into therapeutic failure. Until recently, there has been relatively little study of this issue. However, data from a few older studies as well as a recent trial specifically designed to address this issue suggest that laboratory-defined resistance does have a significant impact on microbi- ological and clinical outcomes (Table 4).

In a treatment trial comparing a high-dose, single-sachet formulation of arnoxicillin-clavulanate versus 7-day therapy with TMP-SMX for treatment of acute uncomplicated cystitis, 12% of 135 women randomized to TMP-SMX had a TMP-SMX-resistant uropathogen.‘7 Bacterial eradication at day 14 was achieved in 50% of women (7 of 14) with a TMP-SMX-resistant uropathogen as compared with 86% of all women (106 of 123) treated with TMP-SMX. Clinical cure rates in the resistant group were not reported. In another treatment trial, McCarty et al9 found a 50% bacterial eradication rate and 60% clinical cure rate among 10 women with a TMP-SMX-resistant uropathogen who had been randomized to receive TMP-SMX. All of the women with clinical failure also had bacteriologic failure. Definitive conclusions cannot be drawn from either of these studies because of the small sample sizes and the fact that they were not designed to specifically address this issue.


More recently, we and others have used modeling to estimate the outcomes and costs associated with in vitro resistance.18’19 In a simple mathematical model, we estimated that a 10% TMP-SMX resistance prevalence would result in a clinical cure rate of 92% and bacteriologic cure rate of 89%. At a resistance prevalence of 20%, the estimated cure rates would be 88% and 84%, respectively. Using a decision tree model, Le and Miller found that the cost of empirical treatment of uncomplicated cystitis with TMP-SMX increased only slightly with increasing rates of TMP-SMX resistance among E co& with mean costs of $92, $99, $106, and $113 with TMP-SMX resistance rates of O%, lo%, 20% and 30%, respectively.’ 9 They calculated the mean cost of treatment with a fluoroquinolone at $107 and concluded that only at a TMP-SMX resistance prevalence of 22% does it become less expensive to use a fluoroquinolone rather than TMP-SMX for empiric UT1 therapy.

Although these models are interesting and potentially useful for clinicians trying to determine when to use an alternative agent for acute cystitis, they are both based on very limited data regarding actual outcomes in the setting of in vitro resistance. Fortunately, the results of a trial specifically designed to address this issue recently became available.20 This study was conducted in Israel, where the prevalence of TMP-SMX resistance among community-acquired uropathogens is estimated at 30% to 40%. Healthy women with acute cystitis symptoms had a urine culture performed and were treated with TMP-SMX 160/800 mg twice daily for 5 days. The overall TMP-SMX resistance rate was 29%. Bacteriologic cure was achieved in 86% of women with a susceptible uropathogen as compared with 42% of women with a resistant uropathogen. The corresponding clinical cure rates were 88% and 54%, respectively. The authors conclude that TMP-SMX should not be used in a setting of such high resistance.

It does appear, based on older treatment trials, modeling systems, and this most recent study, that the clinical failure rate in the setting of TMP-SMX resistance is significant. The correlation between in vitro resistance and clinical failure is not 100% but is probably in the range of 40% to 50%. Bacterial failure is even more closely correlated with in vitro resistance, occurring in 50% to 58% of cases. Thus, the Infectious Diseases Society of America guidelines are quite reasonable in recom- mending an alternative agent for therapy of uncomplicated cystitis when the TMP-SMX resistance prevalence is about 20%.2 If the threshold for clinical failure is low because of other patient factors, then the use of a fluoroquinolone could be considered even at the level of 10% TMP-SMX resistance. DM, February 2003 107

Acute Uncomplicated Pyelonephritis From the Talan study, l6 it is also clear that in vitro resistance correlates

highly with clinical and bacteriologic outcomes in pyelonephritis. In the TMP-SMX treatment arm, the bacteriologic cure rate at 4 to 11 days after therapy was 96% among the 76 women with a TMP-SMX-susceptible uropathogen versus 50% among the 14 women with a TMP-SMX- resistant uropathogen (P CO.001). The clinical cure rates in the TMP- SMX-treated group were 92% in women with a TMP-SMX-susceptible uropathogen compared with 35% in women with a TMP-SMX-resistant uropathogen (P CO.001). Interestingly, the use of an initial dose of intravenous ceftriaxone resulted in improved bacteriologic outcomes in the setting of TMP-SMX resistance. Among women with a TMP-SMX- resistant uropathogen, 5 of 5 who received an initial intravenous dose of ceftriaxone had achieved bacteriologic cure compared with the 2 of 9 patients with a resistant uropathogen who received only oral TMP-SMX. The clinical cure rates were also better when ceftriaxone was given, although the sample size was too small to reach statistical significance. Thus, this study clearly demonstrates lower bacteriologic and clinical efficacy among patients with pyelonephritis treated with TMP-SMX in the setting of a TMP-SMX-resistant uropathogen.

Conclusions Antimicrobial resistance rates among bacteria causing community-acquired cystitis and pyelonephritis are increasing. The resistance rates for TMP-SMX exceed 20% in some regions of the United States, and nearly 1 in 3 bacterial strains causing cystitis or pyelonephritis demonstrate resistance to amoxicillin. However, resistance to the fluoroquinolones and nitrofurantoin remains low, at approximately 2%. Studies demonstrate that the increase in TMP-SMX resistance does correlate with poorer bacteriologic and clinical outcomes when TMP-SMX is used for therapy. Thus, the empiric use of TMP-SMX for acute uncomplicated cystitis is recommended only in those regions where E coli resistance to TMP-SMX is <20%. If E coli resistance to TMP-SMX is >20%, the empiric use of fluoroquinolones, including ciprofloxacin, gatifloxacin, and levofloxacin, is recommended for equal efficacy in a 3-day regimen. Alternatively, nitrofurantoin may be used in a 7-day regimen or fosfomycin may be considered as a single-dose regimen. A fluoroquinolone is also the recommended drug for outpatient oral therapy of acute uncomplicated pyelonephritis unless the infecting pathogen is known to be susceptible to TMP-SMX. Further research on which factors best predict resistance and


continued surveillance of resistance rates in the community are needed to enable clinicians to choose appropriate empiric therapy for uncomplicated UT1 in this era of evolving resistance.

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20. Raz R, Chazan B, Kennes Y, et al. Empiric use of trimethoprim-sulfamethoxazole (TMP-SMX) in the treatment of women with uncomplicated urinary tract infections, in a geographical area with a high prevalence of TMP-SMX-resistant uropathogens. Clin Infect Dis 2002;34: 1165-l 169.

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addressing antibiotic resistance

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