Treatment options for acute uncomplicated cystitis in adults. Kurt G. Naber*

Transcription

1 Journal of Antimicrobial Chemotherapy (2000) 46, Suppl. S1, Treatment options for acute uncomplicated cystitis in adults JAC Kurt G. Naber* Urological Clinic, Hospital St Elisabeth, Straubing, Teaching Hospital of the Technical University of Munich, Germany Urinary tract infection (UTI) is classified as uncomplicated if it occurs in a patient with a structurally and functionally normal urinary tract. Acute uncomplicated cystitis is observed chiefly in women. It needs, however, to be differentiated depending on whether it occurs in premenopausal, postmenopausal or pregnant women. Only a small number of year old, otherwise healthy men suffer acute uncomplicated cystitis. In premenopausal, non-pregnant women, single-dose antimicrobial therapy is generally less effective than the same antibiotic used for longer duration. However, most antimicrobial agents given for 3 days are as effective as those given for longer duration, and adverse events tend to be found more often with longer treatment. Trimethoprim (or co-trimoxazole) can be recommended as first-line empirical therapy only in communities with resistance rates of uropathogens to trimethoprim of < 10 20%. Otherwise fluoroquinolones are recommended. Alternatives are fosfomycin trometamol or β-lactams, such as second- or third-generation oral cephalosprins or pivmecillinam, especially when fluoroquinolones are contraindicated or a high proportion (>10%) of Escherichia coli strains in the community are already resistant to fluoroquinolones, as in Spain, for example. Recurrent UTIs are common among young, healthy women even though they generally have anatomically and physiologically normal urinary tracts. The following prophylactic antimicrobial regimens are recommended: (i) the use of long-term, low-dose prophylactic antimicrobials taken at bedtime; (ii) post-coital prophylaxis for women in whom episodes of infection are associated with sexual intercourse. Other prophylactic methods are not as yet as effective as antimicrobial prophylaxis. Introduction For optimal management of urinary tract infections (UTIs), it is necessary to classify them according to the status of the patient (symptomatic or asymptomatic), the status of the urinary tract (uncomplicated or complicated), the pattern of infection (isolated, recurrent or unresolved) and the site of infection (cystitis, pyelonephritis or prostatitis). A UTI is classified as uncomplicated if it occurs in a patient with a structurally and functionally normal urinary tract. A UTI is classified as complicated if there are functional or anatomical abnormalities within the urinary tract or underlying diseases that predispose to UTI, such as diabetes mellitus or AIDS. Acute uncomplicated cystitis is observed chiefly in women. It needs, however, to be differentiated depending on whether it occurs in premenopausal, postmenopausal or pregnant women. Recurrent cystitis is common in young, healthy women, even though they generally have anatomically and physiologically normal urinary tracts. Whether UTI in pregnancy should be classified as uncomplicated or complicated remains debatable. Although data dealing specifically with UTIs in healthy postmenopausal women without genitourinary abnormalities are limited, it is likely that most UTIs in this group of women are uncomplicated. Data on uncomplicated UTI in healthy adult men are also sparse and much less is known about optimal diagnosis and therapy. Aetiological spectrum Escherichia coli is the causative pathogen in c.70 95% of cases and Staphylococcus saprophyticus in between 5% and 20% of cases. Occasionally, other Enterobacteriaceae, such as Proteus mirabilis and Klebsiella spp., or *Corresponding author. Tel: ; Fax: ; naberk@klinikum-straubing.de 2000 The British Society for Antimicrobial Chemotherapy 23

2 K. G. Naber enterococci are isolated from patients with UTIs. In as many as 10 15% of symptomatic patients, there are low levels of bacteriuria ( cfu/ml), which cannot be detected with routine culture methods, which use 1 L of urine per agar plate. 1 Treatment options There seem to be no long-term adverse effects with respect to renal function or increased mortality associated with acute uncomplicated cystitis in non-pregnant women, even in those with frequent recurrences. 1 Untreated cystitis rarely progresses to symptomatic upper UTI. Thus, the significance of uncomplicated lower UTI in non-pregnant women is limited to the morbidity produced by the symptoms of UTI, although these may substantially disrupt the lives of affected individuals. In fact, 50 70% of lower UTIs clear spontaneously if untreated, although symptoms may persist for several months. 1 Knowledge of the antimicrobial susceptibility profile of uropathogens causing uncomplicated UTIs in the community should guide therapeutic decisions, although the trend away from routinely culturing samples from patients with uncomplicated cystitis may lead to the lack of such data. The resistance pattern of E. coli strains causing uncomplicated UTI, however, varies considerably between regions and countries, so no general recommendations are suitable. Acute uncomplicated cystitis in premenopausal, non-pregnant women Short courses of antimicrobial agents are highly effective in the treatment of acute uncomplicated cystitis in premenopausal women. 2 Short-course regimens are desirable because they improve compliance, cost less and lead to a lower frequency of adverse reactions. However, in assessing the potential cost advantages of short-course regimens, one must also consider the potential added expense associated with treatment failure or recurrence arising from short-course therapy. One must also consider the potential psychological aspects of single-dose therapy: symptoms may not subside for 2 or 3 days, during which time the patient may doubt the efficacy of the treatment and so visit her physician again unnecessarily. A wide variety of drugs, doses, schedules and durations have been used to treat these common bacterial infections. Only a few of these regimens have been compared directly in adequately designed studies. In order to develop evidence-based guidelines for antimicrobial therapy of uncomplicated acute bacterial cystitis and pyelonephritis in women, a committee of the Infectious Diseases Society of America (IDSA) reviewed systematically the literature published in English up to The recommendations were classified by the strength and quality of the evidence. These guidelines were reviewed by a number of infectious disease specialists and urologists worldwide and were endorsed by the American Urological Association (AUA) and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID). Of the several thousand titles and abstracts screened, only 75 studies met the inclusion criteria and only 32 were double-blinded. The following antimicrobial agents were considered: trimethoprim, co-trimoxazole, trimethoprim sulphadiazine, quinolones (ciprofloxacin, fleroxacin, lomefloxacin, norfloxacin, ofloxacin, pefloxacin, pipemidic acid and rufloxacin), nitrofurantoin, β-lactams (amoxycillin, ampicillin-like compounds, cefadroxil, pivmecillinam and ritipenem axetil) and fosfomycin trometamol. The guidelines 3 came to the following seven conclusions: (i) In otherwise healthy, non-pregnant adult women with acute uncomplicated cystitis, single-dose therapy is generally less effective than the same antibiotic used for longer. However, trimethoprim, co-trimoxazole and quinolones given for 3 days are as effective as treatment of longer duration. Longer duration of treatment usually causes higher rates of adverse events. (ii) Co-trimoxazole was the drug most frequently studied (30 studies). A 3 day regimen of co-trimoxazole, therefore, can be considered standard therapy. Trimethoprim alone was equivalent to co-trimoxazole in eradication and adverse effects. Considering the possible rare, but serious, adverse effects caused by sulphonamides, trimethoprim alone may be considered the preferred drug. However, trimethoprim (or co-trimoxazole) can be recommended as first-line empirical therapy only in communities where 10 20% of uropathogens are resistant to trimethoprim, because there is a close correlation between susceptibility and eradication of E. coli. 4 The risk of resistant uropathogens emerging and causing recurrences was also much higher when using trimethoprim as the first-line drug than with pivmecillinam and, especially, ciprofloxacin. 5 (iii) The fluoroquinolones (ciprofloxacin, fleroxacin, norfloxacin and ofloxacin) are of similar efficacy to co-trimoxazole when given as a 3 day regimen. Pefloxacin and rufloxacin, given as 1 day therapies, are options and may be equivalent to co-trimoxazole in eradication of bacteriuria and prevention of recurrences; questions remain as to the possibility of a higher incidence of adverse effects than with other recommended therapies. Fluoroquinolones are more expensive than trimethoprim and co-trimoxazole and are thus not recommended as first-line drugs for empirical therapy, except in communities with rates of resistance to trimethoprim of 10 20% among uropathogens causing uncomplicated UTIs. With any of these agents, one should expect eradication of the bacteriuria in 90% of cases. 24

3 Treatment of acute uncomplicated cystitis (iv) β-lactams as a group are less effective than the abovementioned drugs. For second- or third-generation oral cephalosporins or aminopenicillins combined with a β-lactamase inhibitor, no large enough comparative studies of 3 day trimethoprim, co-trimoxazole or one of the above-mentioned fluoroquinolones were available for analysis. The only study of adequate size that assessed a β-lactam antimicrobial for 3 days compared with a longer duration was of pivmecillinam; 6 3 days of therapy was equivalent to 7 days of therapy in initial eradication of bacteriuria, although the shorter duration of treatment was associated with an increased incidence of recurrence. (v) Nitrofurantoin cannot, at present, be considered suitable for short-term therapy of acute uncomplicated cystitis. Further studies are needed. (vi) Fosfomycin trometamol used as single-dose therapy may be an alternative. However, published trials are still needed to demonstrate equivalence with standard agents, e.g. trimethoprim, co-trimoxazole or one of the fluoroquinolones administered for 3 days. (vii) Although no controlled trials have been undertaken, cystitis caused by S. saprophyticus may respond better to longer duration of therapy, e.g. 7 days. Urinary analgesics, such as phenazopyridine 200 mg tds, can be administered for 1 or 2 days to patients with severe dysuria. Women with cystitis, including those with severe dysuria and urgency, usually have resolution or marked improvement of symptoms within 2 3 days of initiating therapy. 1 This probable course of events should be explained to the patient. The need for and duration of analgesic therapy for women with UTI must be individualized. Although it is generally recommended that patients with UTI increase their fluid intake to promote micturition and elimination of uropathogens, it remains unclear whether this is beneficial or detrimental. 1 Urinalysis including a dipstick method is sufficient as routine. 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 before 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, a urine culture and antimicrobial susceptibility testing must 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 of agent should be considered. 1 Prevention of recurrent uncomplicated cystitis One effective approach for the management of recurrent uncomplicated UTIs is to prevent infection by using longterm, low-dose prophylactic antimicrobials taken at bedtime. 7 A summary of different regimens is given in the Table. Generally, the occurrence of infection is decreased by 95% by the use of prophylaxis. The initial duration of prophylactic therapy is usually 6 months or 1 year. However, with co-trimoxazole, continuous prophylaxis for as long as 2 years 8 or 5 years 9 has remained efficacious. Prophylaxis does not modify the natural history of recurrent UTI. When discontinued, even after extended periods, approximately 60% of women will have another infection within 3 4 months. An alternative prophylactic approach is post-coital prophylaxis for women in whom episodes of infection are associated with sexual intercourse Alternative methods, such as acidification of urine, cranberry juice, 13 extract from the dried leaves of Arctostaphylos uva-ursi and vaginal application of lactobacilli 14,15 show variable effects. It has been claimed that immunostimulating extracts of E. coli reduce the frequency of recurrent infection 16 and even decrease the degree of bacteriuria in paraplegic patients. 17 These reports are difficult to explain in view of what is known about the immune response to UTI. 18 Water diuresis may be effective in some women with uncomplicated UTI, but its use often delays more effective management with antimicrobial drugs. The evidence is also too weak to recommend that women change their personal hygiene and menstrual practices or void after intercourse. 18 Acute uncomplicated cystitis during pregnancy UTIs are common during pregnancy. There is a debate about whether these infections can be classified as uncomplicated even in the absence of other risk factors. Most symptomatic UTIs in pregnant women represent acute cystitis as in their non-pregnant counterparts. Short-term therapy, Agent Table. Antimicrobial regimens of documented prophylactic efficacy for prevention of acute uncomplicated urinary infection in women (adapted from reference 28) Dose (mg/day) Standard regimens a co-trimoxazole 240 or three times weekly trimethoprim 100 nitrofurantoin 50 nitrofurantoin macrocrystals 100 Others cephalexin 125 or 250 norfloxacin 200 ciprofloxacin 125 a Taken at bedtime. 25

4 K. G. Naber however, is not established yet as suitable for non-pregnant women. Second- and third-generation oral cephalosporins, pivmecillinam or fosfomycin trometamol might be candidates for short-term therapy. Some smaller studies and expert opinion support this approach. 19 Otherwise, conventional courses of therapy with amoxycillin, cephalexin or nitrofurantoin are recommended. Quinolones, tetracyclines, trimethoprim (in the first trimester) and sulphonamides (in the last trimester) should not be used during pregnancy. Follow-up urine cultures should be obtained after therapy to demonstrate eradication of bacteriuria. There is no advantage in general in using long-term prophylaxis except for recurrent infections (as in non-pregnant women). Low-dose cephalexin ( mg) or nitrofurantoin (50 mg) taken at night up to and including the puerperium are recommended for prophylaxis if indicated. Post-coital prophylaxis 20,21 may be an alternative approach. Acute uncomplicated cystitis in postmenopausal women The vagina normally contains only low numbers of Gramnegative enteric bacilli because of competition from the resident microbial flora. Lactobacilli account for the low vaginal ph. They tend to be less abundant in postmenopausal women and after antimicrobial therapy. Oestrogens are presumed to protect against recurrent UTIs in postmenopausal women because they enhance the growth of lactobacilli and decrease vaginal ph. 22 Gramnegative enteric bacilli do not normally colonize the vagina in postmenopausal women, unless these women are prone to recurrent UTIs. 23 In postmenopausal women with recurrent UTIs, therapy with intravaginal oestriol 22 reduces the rate of recurrences significantly. For the remaining patients an antimicrobial prophylactic regimen (see Table) should be recommended. In cases of acute cystitis, antimicrobial treatment is similar to that in premenopausal women. Short-term therapy in postmenopausal women is, however, not as well documented as in younger women. Raz et al. 24 found that for postmenopausal women (mean age 65 years) with uncomplicated UTI, ofloxacin 200 mg od for 3 days was significantly more effective in both short- and long-term follow-up than a 7 day course of cephalexin 500 mg qds, even though all uropathogens were susceptible to the two agents. Acute uncomplicated cystitis in young men It has been conventional to consider all UTIs in men as complicated because most of them occur in newborns, infants or the elderly and are associated with urological abnormalities, bladder outlet obstruction or instrumentation. 18 UTIs in otherwise healthy adult men between the ages of 15 and 50 years are very uncommon. In Norway, a rate of six to eight cases of UTI/year/ men aged years was reported. 25 The large difference in prevalence between men and women is thought to be caused by a variety of factors, including the greater distance between the anus (the usual source of uropathogens) and the urethral meatus, the drier environment surrounding the male urethra, the greater length of the male urethra and the antibacterial activity of prostatic fluid. It has become clear, however, that a small number of year old men suffer acute uncomplicated UTIs. The reasons for such infections are not always clear, but risk factors include intercourse with an infected partner, anal intercourse and lack of circumcision. 26 The aetiological agents causing uncomplicated UTI in men are similar to those in women. Krieger et al. 27 noted that 37 (92.5%) of 40 uncomplicated UTIs in men were caused by E. coli. Symptoms of uncomplicated UTI in men are similar to those in women. Dysuria is common to UTI and urethritis. Urethritis must be ruled out in sexually active men by means of a Gram s stain of a urethral swab or examination of a first-voided urine wet mount to look for urethral leucocytosis. A urethral Gram s stain demonstrating leucocytes and a predominance of Gram-negative rods suggests E. coli urethritis, which may precede or accompany UTI. As a result of the infrequency with which UTIs occur in this group of men, there are no data from controlled treatment studies. Empirical use of the agents discussed previously for uncomplicated cystitis or pyelonephritis in women is recommended. Nitrofurantoin should probably not be used in men, since it does not achieve reliable tissue concentrations and would be ineffective for occult prostatitis or pyelonephritis. For acute uncomplicated pyelonephritis, the use of a fluoroquinolone as initial empirical oral treatment is recommended. Although it is possible that short-course treatment is effective in men with uncomplicated cystitis, there are no studies to support this practice. It is recommended, therefore, that such men receive a 7 day regimen, because the likelihood of an occult complicating factor is greater in men than in women, and because longer treatment may reduce the likelihood of persistent prostatic infection. The value of a urological evaluation in a man who has had a single uncomplicated UTI has not been determined. Urological evaluation should certainly be done routinely in adolescents and men with pyelonephritis, recurrent infections, or whenever a complicating factor is present. References 1. Hooton, T. M. & Stamm, W. C. (1997). Diagnosis and treatment of uncomplicated urinary tract infection. Infectious Disease Clinics of North America 11, Naber, K. G. (1999). Short-term therapy of acute uncomplicated cystitis. Current Opinion in Urology 9,

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