Regarding resistance

Antibiotic selection, however, must also take into account the continued evolution of antimicrobial resistance among uropathogens. While amoxicillin and ampicillin were once standard therapy for uncomplicated UTIs, E. coli resistance rates in North America to those agents and to other beta-lactams is now approaching 50%.7,8

As the clinical utility of the beta-lactams declined, trimethoprim/sulfamethoxazole (TMP/SMX) emerged about 30 years ago as a first-line treatment. However, uropathogen resistance to TMP/SMX has also increased over the last decade worldwide. Rates of E. coli resistance to TMP/SMX are now approximately 25% in some geographic areas of the United States and Canada and are even higher (29%-45%) in parts of Europe, Latin America, and Israel.9-11

Studies showing correlations between increased prevalence of E. coli resistance to TMP/SMX and higher rates of clinical and bacteriological failure demonstrate that resistance is not just a laboratory phenomenon.11-13 As such, it has again become necessary to re-evaluate first-line empiric therapies for UTIs and CBP. Therefore, fluoroquinolones have emerged as a valuable option for management of these infections. Several drugs within this class have indications for both UTI and CBP treatment, although in North America, ciprofloxacin and levofloxacin are used most widely.


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Levofloxacin and ciprofloxacin both offer broad-spectrum coverage against common uropathogens, achieve high concentrations in target tissues and fluids, have generally been associated with low levels of resistance (<1%-11%), and have resulted in high levels of bacteriological eradication and clinical cure when used to treat community-acquired and nosocomial UTIs as well as CBP, even in patients with uropathogens resistant to TMP/SMX.5,12 In addition, these fluoroquinolones do not significantly alter the normal fecal and vaginal flora, are available in formulations that require conveniently infrequent dosing, and are safe and well tolerated.2,5

Theoretically, levofloxacin may have better activity against gram-positive pathogens, a higher urinary excretion rate vs. ciprofloxacin, superior prostatic-tissue penetration, and an approved once-daily dosing regimen for all indications.14-16

Experts weigh in

Recommendations from expert reviewers and the European Association of Urology (EAU) support the fluoroquinolones as first-line treatment for complicated UTIs, recurrent UTIs, and CBP.14-17 According to the EAU and evidence-based guidelines from the Infectious Diseases Society of America (IDSA), fluoroquinolones also represent the treatment of choice for mild-to-moderate acute pyelonephritis unless the organism has known susceptibility to TMP/SMX.17-18 The Sanford Guide to Antimicrobial Therapy also recommends fluoroquinolone therapy for uncomplicated UTI unless TMP/SMX resistance is <20%.19

However, while uropathogen susceptibility to fluoroquinolones generally remains high, pockets of resistance are beginning to appear. The problem seems to be greatest outside North America — a multicenter study in Canada and 16 European countries reported the resistance rate to ciprofloxacin at 36% in Portugal and 20% in Spain.20 (Among study participants, women from Spain and Portugal also had the lowest mean symptom score.20) The most common pathogen identified in that study, which looked at urine specimens from women with uncomplicated, community-acquired UTIs, was E. coli

To forestall resistance emergence and preserve the efficacy of the fluoroquinolones for the treatment of more serious urinary and other infections, it may be best to avoid using these agents routinely for empiric management of uncomplicated UTIs. Such a fluoroquinolone-sparing strategy is reflected in the IDSA guidelines that recommend using a three-day course of fluoroquinolones as an alternative to TMP/SMX only in areas in which the E. coli TMP/SMX resistance rate exceeds 10%-20%.

Nitrofurantoin may be another option to consider for uncomplicated UTIs. Despite 50 years of use, it continues to offer potent activity against E. coli and S. saprophyticus.20 However, IDSA guidelines note that it must be given for seven days and should be studied against current standard therapies.18 Nitrofurantoin is not an option for the treatment of complicated UTIs or pyelonephritis because it has limited penetration into renal tissue and does not achieve bactericidal concentrations in blood.

Looking toward the future

As we now know, early anticipation that the availability of antibiotic medication would virtually eliminate UTI occurrence proved to be overly optimistic. Still, today’s clinicians have in their armamentarium agents that are highly effective against the urinary infections that continue to plague patients. Notably, the fluoroquinolones can be administered empirically by virtue of their demonstrated high efficacy rates across the spectrum of UTI and CBP uropathogens. The ideal agent for treating these infections is one that combines high efficacy with minimal risk of bacterial resistance as well as factors such as good tolerability and a convenient dosing regimen, both of which are likely to contribute to patient adherence.

A progressive pattern of emerging bacterial resistance throughout the history of antimicrobial treatment of UTIs has most recently brought fluoroquinolones to the forefront of management for these infections. However, the identification of areas of uropathogen resistance to fluoroquinolones is generating concern in some quarters. Given that the next generation of UTI-specific antibiotics has not been identified, and considering the high frequency of UTIs, judicious use of fluoroquinolones for these infections will be critical for minimizing bacterial resistance to this valuable class of antibiotics.

Dr. Nickel is Professor of Urology at Queen’s University, Kingston, Ontario, Canada.

References

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