Urinary Tract Infections (Uncomplicated) in Women - Treatment

Acute Uncomplicated Cystitis in Pre-menopausal, Non-pregnant Women

Treatment

               There seems to be no long-term adverse effects with respect to renal function or increased mortality associated with acute uncomplicated cystitis, even in women who experience frequent recurrences, and in the non-pregnant population. Untreated cystitis rarely progresses to symptomatic upper tract infection. Thus, the significance of lower tract infection in non-pregnant women seems to be limited to the morbidity of symptoms caused by the infection, which can lead to substantial disruption of the lives of affected individuals. In fact, most lower UTIs (50-70%) clear spontaneously if untreated, although symptoms may persist for several months. Knowledge of the antimicrobial susceptibility profile of uropathogens causing uncomplicated UTIs in the community should guide therapeutic decisions. The resistance pattern of E. coli strains causing an uncomplicated UTI, however, may vary considerably between regions and countries. Short courses of antimicrobials are highly effective in the treatment of acute uncomplicated cystitis in pre-menopausal women (Table 1). Short-course regimens are desirable because of the improved compliance that they promote, their lower cost, and lower frequency of adverse reactions. However, in assessing the potential cost advantages of short-course regimens, it is necessary to consider the potential added expense associated with treatment failures or recurrences arising from short-course therapy. It is also important to consider the potential psychological aspects of single-dose therapy; as symptoms may not subside for 2 or 3 days, the patient may have misgivings during this time about the ‘insufficient’ treatment provided to her. Such a scenario may result in unnecessary visits or calls to the physician.

The following antimicrobial agents can be used for treatment of uncomplicated cystitis: trimethoprim (TMP), trimethoprim-sulfamethoxazole (TMP-SMX), fluoroquinolones (ciprofloxacin, enoxacin, fleroxacin, gatifloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin), ß-lactams (amoxicillin, ampicillin-like compounds, cefadroxil, cefuroxime axetil, cefpodoxime proxetil, ceftibuten, pivmecillinam, ritipenem axetil), fosfomycin trometamol, and nitrofurantoin (see Table right below).

Table. Recommended Antimicrobial Regimens for the Treatment of Acute Uncomplicated Bacterial Cystitis in Adult Premenopausal, Non-pregnant Women

Substance	Dosage	Duration
Cefpodoxime	100 mg bid	3 days
Ciprofloxacin*	250 mg bid	3 days
CiproXR*	500 mg od	3 days
Fosfomycin trometamol	3000 mg SD	1 day
Levofloxacin*	250 mg od	3 days
Nitrofurantoin	50-100 mg tid,	5-7 days
	100 mg SR bid
Norfloxacin*	400 mg bid	3 days
Ofloxacin*	200 mg bid	3 days
Pivmecillinam	200 mg bid	7 days
Trimethoprim (TMP)*	200 mg bid	5-7 days
TMP-SMX*	160/800 mg bid	3 days

*Resistance rates of E.coli vary considerably within countries. These substances are only recommended for empirical therapy when the resistance rate of E. coli is < (10%-)20%.

CiproXR = ciprofloxacin sustained release; SMX = sulphamethoxazole; od = once daily; bid = twice daily; qid = four times daily; SD = single dose; SR = sustained release

               The following conclusions about antimicrobial therapy can be made:

Treatment Duration: In otherwise healthy, adult, non-pregnant women with acute uncomplicated cystitis, single-dose therapy (with some exceptions) is significantly less effective in eradicating initial bacteriuria than are longer durations of treatment with antimicrobials tested in this manner, such as TMP-SMX, TMP, norfloxacin, ciprofloxacin, fleroxacin, and as a group ß-lactams. However, TMP-SMX, TMP, norfloxacin, ciprofloxacin, and fleroxacin given for 3 days are as effective as the same antimicrobials used over longer durations. Longer treatment usually shows a higher rate of adverse events.

Trimethoprim, Co-trimoxazole: A 3-day regimen with TMP-SMX can be considered to be the standard therapy. TMP alone was equivalent to TMP-SMX with regard to eradication and adverse effects. Considering possible rare, but serious, adverse effects caused by sulphonamides, TMP alone may be considered the preferred drug over TMP-SMX. TMP or TMP-SMX can be recommended as first-line drugs for empirical therapy, but only in communities with rates of uropathogen resistance to TMP < 10-20% because there is a close correlation between susceptibility and the eradication of E. coli on the one hand and resistance and persistence of the uropathogen on the other. The risk of emerging resistant uropathogens in the case of recurrence was also much higher when using TMP as a first-line drug than when using pivmecillinam or ciprofloxacin, which had the lowest risk of the drugs investigated.

Fluoroquinolones: The fluoroquinolones (ciprofloxacin, fleroxacin, norfloxacin and ofloxacin) are equivalent to TMP-SMX when given as a 3-day regimen. Pefloxacin and rufloxacin, each as single-day therapies, are interesting options and may be equivalent to TMP-SMX in the eradication of bacteriuria and its recurrence. Questions remain as to the possibility of a higher incidence of adverse effects with these agents than with other recommended therapies. A 3-day regimen with levofloxacin, 250 mg once daily, was similarly effective to a 3-day regimen of ofloxacin 200 mg twice daily, but with levofloxacin there was a trend to lesser adverse events. A 3-day course with CiproXR (500 mg) once daily was equivalent inregard to efficacy and safety as a course of conventional ciprofloxacin (250 mg twice daily).

              Fluoroquinolones are more expensive than TMP and TMP-SMX, and are thus not recommended as first-line drugs for empirical therapy except in communities with rates of uropathogen resistance to TMP > 10-20%. In some countries, however, the resistance of E. coli to fluoroquinolones has already increased to more than 10%. In this situation, alternative oral drugs should be considered for empirical therapy. Treatment with any of these agents should result in more than 90% eradication of the bacteriuria.

ß-lactam Antibiotics: In general, ß-lactams as a group are less effective than the aforementioned drugs. First- and second-generation oral cephalosporines are not recommended as first-line antimicrobials for a 3-day treatment of uncomplicated UTI. However, among third-generation oral cephalosporins, a 3-day course with cefpodoxime-proxetil (200 mg twice daily) was as safe and effective as that of TMP-SMX. One exception might be pivmecillinam. 7 days of pivmecillinam, 200 mg twice daily, was equivalent to 3 days of norfloxacin, 400 mg twice daily. With pivmecillinam, however, the rate of vaginal candidiasis was significantly lower than with norfloxacin. Pivmecillinam also shows low resistance rates for E. coli and other Enterobacteriaceae, without cross-resistance to other antimicrobials used for the treatment of UTI.

Fosfomycin: Single dose fosfomycin trometamol (3 g) therapy has shown good results regarding bacteriological eradication. Considering that fosfomycin trometamol has been extensively used in several European countries for single-dose therapy of uncomplicated UTI since 1988, the resistance rate for E. coli remained very low without cross-resistance to other antimicrobials used for the treatment of UTI.

Nitrofurantoin: Nitrofurantoin (50-100 mg four times daily, or sustained release formulation 100 mg twice daily) cannot be considered a suitable drug for short-term therapy (up to 3 days) of acute uncomplicated cystitis. A course of 5-7 days is recommended if nitrofurantoin is used for this indication. Despite the clinical use of nitrofurantoin for many years, the resistance rate for E. coli and S. saprophyticus is still low throughout Europe, although in some areas a two-fold increase in nitrofurantoin resistance has already been observed for E. coli within the last 10 years. Nitrofurantoin is, however, not active against P. mirabilis and Klebsiella spp., the second and third most frequently isolated Gram-negative uropathogens. There is also some concern about the safety of nitrofurantoin, especially the acute and chronic pulmonary syndromes, which are common in the elderly. These severe adverse events, however, were not observed when nitrofurantoin was used for long-term and low-dose prophylaxis for recurrent UTIs in girls and women.

Other Treatment Modalities: Urinary analgesics, such as phenazopyridine, 200 mg three times daily, can be administered to patients who have experienced severe dysuria for 1 or 2 days. Women with cystitis, including those with severe dysuria and urgency, usually show resolution or marked improvement of symptoms within 2-3 days of initiating therapy. This should be explained to the patient. Thus, the need for, and duration of, analgesic therapy in women with UTIs must be individualized. Although it is generally recommended that patients with UTIs increase their fluid intake to promote micturition and the elimination of uropathogens, it remains unclear as to whether this is beneficial or detrimental to patients with UTI.

Post-treatment Follow-up

               Urinalysis (e.g using a dipstick method) is sufficient for routine follow-up. Routine post-treatment cultures in asymptomatic patients may not be indicated because the benefit of detecting and treating asymptomatic bacteriuria in healthy women has been demonstrated only in pregnancy and prior to urological instrumentation or surgery. In women whose symptoms do not resolve by the end of treatment and in those whose symptoms resolve but recur within 2 weeks, urine culture and antimicrobial susceptibility testing should be performed. For therapy in this situation, one should assume that the infecting organism is not susceptible to the agent originally used and retreatment with a 7-day regimen using another agent should be considered.

Acute Uncomplicated Pyelonephritis in Non-pregnant, Pre-menopausal Women

Treatment

           The following aspects should be considered for treatment (see Table right below):

Table 2. Oral Treatment Options of Acute Uncomplicated Pyelonephritis in Adult Pre-menopausal Non-pregnant Women.

Substance	Dosage	Duration
Ciprofloxacin	500 mg bid	7 days
CiproXR	1000 mg od	7-10 days
Cefpodoxime*	200 mg bid	10 days
Gatifloxacin	400 mg od	10 days
Levofloxacin	250 mg od	10 days
Lomefloxacin	400 mg od	10 days
TMP-SMX	160/800 mg bid	14 days

*Cefpodoxime proxetil.

TMP = trimethoprim; SMX = sulphamethoxazole; bid = twice daily; od = once daily

1. TMP-SMX is preferred over ampicillin.

2. Two weeks of therapy with TMP-SMX for acute uncomplicated pyelonephritis appears to be adequate for the majority of women.

3. In communities in which the resistance rate of E. coli to TMP is > 10%, a fluoroquinolone should be recommended as the drug of choice for empirical therapy. It was demonstrated that a 7-day regimen of ciprofloxacin, 500 mg twice daily, showed a significantly higher rate of bacterial eradication and a lower rate of adverse effects when compared with a 14-day therapy using TMP-SMX, 960 mg twice daily. The following fluoroquinolones are also comparable to conventional ciprofloxacin 500 mg twice daily: ciprofloxacin extended release formulation (1000 mg once daily), gatifloxacin (400 mg once daily), levofloxacin (250 mg twice daily), and lomefloxacin (400 mg once daily).

4. A 10-day therapy with cefpodoxime proxetil 200 mg twice daily is probably equivalent with ciprofloxacin 500 mg twice daily.

5. In areas with a rate of E. coli resistance to fluoroquinolones > 10% and in situations in which fluoroquinolones are contraindicated (e.g. pregnancy, lactating women, adolescence), an aminopenicillin plus a beta-lactamase inhibitor, or a group three oral cephalosporin is recommended, either for initial use, or if a patient has to be switched to an oral regimen.

               Therefore in mild and moderate cases an oral fluoroquinolone could be used for 7 days as first-line therapy. In situations where a fluoroquinolone is not indicated, a group three oral cephalosporin, e.g. cefpodoxime proxetil, may be an alternative for empirical therapy. More severe cases of acute uncomplicated pyelonephritis should be admitted to hospital and, if the patient cannot take oral medication, treated parenterally with a fluoroquinolone, an aminopenicillin plus a beta-lactamase inhibitor, a group three cephalosporin, or an aminoglycoside. With improvement, the patient can be switched to an oral regimen using one of the above-mentioned antibacterials (if active against the infecting organism) to complete the 1-2 weeks’ course of therapy.

               Although approximately 12% of patients hospitalized with acute uncomplicated pyelonephritis have bacteraemia, it is common practice to obtain blood cultures only if the patient appears ill enough to warrant hospitalization. There is no evidence that bacteraemia has prognostic significance or warrants longer therapy in an otherwise healthy individual with pyelonephritis.

Post-treatment Follow-up

               Routine post-treatment cultures in an asymptomatic patient may not be indicated; routine urinalysis using a dipstick method is sufficient. In women whose pyelonephritis symptoms do not improve within 3 days, or that resolve and then recur within 2 weeks, a repeat urine culture, antimicrobial susceptibility testing and an appropriate investigation, such as renal ultrasound or scan, should be performed. In the patient with no urological abnormality, it should be assumed that the infecting organism is not susceptible to the agent originally used and retreatment with a 2-week regimen using another agent should be considered. For those patients who relapse with the same pathogen as the initially infecting strain, a 6-week regimen is usually curative. An overview of the clinical management of acute pyelonephritis is shown in Figure 1.

Figure 1. Clinical Management of Acute Pyelonephritis

Recurrent (uncomplicated) UTIs in Women

            With respect to antibiotic prophylaxis, it is not known which antibiotic schedule is best or the optimal duration of prophylaxis, the incidence of adverse events, or the recurrence of infections after stopped prophylaxis or treatment compliance.

Prophylactic Antimicrobial Regimens

               One effective approach for the management of recurrent uncomplicated UTI is the prevention of infection through the use of long-term, prophylactic antimicrobials taken on a regular basis at bedtime or postcoital. Generally, the number of patients with microbiological recurrent UTIs decreased by eightfold as compared to the period of time before prophylaxis and compared to placebo by fivefold. The UTI episodes per patient-year is reduced in general by 95% during antimicrobial prophylaxis as compared to the period of time before prophylaxis. The duration of prophylactic therapy usually extends between 6 months or 1 year. Prophylaxis does not appear to modify the natural history of a recurrent UTI. When discontinued, even after extended periods, approximately 60% of women will become re-infected within 3-4 months.

               The recommendations for antimicrobial regimens for the prevention (prophylaxis) of recurrent uncomplicated UTI in pre-menopausal women are listed in Table 3. Trimethoprim, co-trimoxazole or nitrofurantoin can still be considered as the standard regimen. Fosfomycin trometamol (FT), 3g every 10 days for 6 months can be considered as an alternative. An alternative prophylactic approach is post-intercourse prophylaxis for women in whom episodes of infection are associated with sexual intercourse. Generally, for this approach, the same antimicrobials can be used in the same doses as though recommended for continuous prophylaxis. A patient-initiated treatment may also be suitable for management in well-informed, young women, in whom the rate of recurrent episodes is not too common. This is, however, strictly speaking, not prophylaxis but early treatment.

Table 3. Recommendations for Antimicrobial Prophylaxis of Recurrent Uncomplicated UTI in Women

Agent1	Dose
Standard regimen:
• Nitrofurantoin	50 mg/day
• Nitrofurantoin macrocrystals	100 mg/day
• Trimethoprim-sulphamethoxazole	40/200 mg/day or three times weekly
• Trimethoprim	100 mg/day
• Fosfomycin trometamil	3 g/10 day
‘Breakthrough’ infections:
• Ciprofloxacin	125 mg/day
• Norfloxacin	200-400 mg/day
• Pefloxacin	800 mg/week
During pregnancy:
• Cephalexin	125 mg/day
• Cefaclor	250 mg/day

¹ Taken at bedtime.

UTIs in Post-menopausal Women

            In post-menopausal women with recurrent UTIs, therapy with oral or intravaginal oestriol reduced significantly the rate of recurrence. For other patients, an antimicrobial prophylactic regimen should be recommended in addition to hormonal treatment. In the case of an acute UTI, the antimicrobial treatment policy is similar to that in pre-menopausal women. Short-term therapy in post-menopausal women is not, however, as well documented as in younger women.