Acute uncomplicated cystitis

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Authors

Hiroshi Hayami (Blood Purification Center, Kagoshima University Hospital, Kagoshima, Japan)

Shingo Yamamoto (Department of Urology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan)

Executive summary

Epidemiology and pathogenesis

1. Acute uncomplicated cystitis (AUC) frequently occurs in young sexually active as well as postmenopausal, women without relevant structural or functional abnormalities within the urinary tract (LE: 2b).

2. Escherichia coli is the predominant pathogen isolated most frequently (approximately 75%) during episodes of AUC, followed by Staphylococcus saprophyticus (LE: 2a). Occasionally, other pathogens, such as Enterococcus faecalis, Klebsiella pneumoniae, and Proteus mirabilis,are involved (LE: 2a).

Diagnosis

1. Diagnosis of AUC can be made with a high probability based on a history of urinary irritative symptoms, absence of fever, and physical examination findings in women who have no risk factors for complication with a urinary tract infection(UTI) (LE: 2a, GR: B).

2. A urine dipstick test is useful for diagnosis of AUC. Microscopy of urine sediment is recommended,not only to secure the diagnostic accuracy, but also to distinguish between coccus- and coli-forms(LE: 2a, GR: B).

3. A urine culture is recommended prior to treatment for patients with a high risk for drug resistance (LE: 4, GR: B) in order to avoid an inappropriate choice of antimicrobials.

4. A colony count of ≥ 103 colony-forming units (cfu)/mL of uropathogensis required for microbiologic diagnosis in patients presenting with symptoms of AUC (LE: 2, GR: B).

Treatment

1. The standard antimicrobial drugs for treatment of AUC are fosfomycin trometamol (LE: 1a, GR: A), nitrofurantoin macrocrystals (LE: 1a, GR: A), trimethoprim-sulfamethoxazole (TMP/SMX) (LE: 2a, GR: B), and β-lactams, including cephalexin, cefaclor,and amoxicillin/clavulanate (LE: 1a, GR: A).

2. If Gram-positive cocci are present amoxicillin/ clavulanate could be recommended, because the drug is active against enterococci and staphylococci(LE: 1a, GR: A).

3. Fluoroquinolones should be considered only as alternative choice in young sexually active women with S. saprophyticus (LE: 3, GR: B), but not as the first choice for treatment of AUC (LE: 1a, GR: A).

4. Third generation oral cephalosporins, including cefdinir, cefcapene-pivoxil, and cefpodoxime-proxetil, are alternative choices when other recommended agents cannot be used, but should not be prescribed if cocci are present (LE: 1a, GR: A).

5. Amoxicillin or ampicillin should not be prescribed for empirical treatment because of high prevalence of antimicrobial resistance to these agents worldwide (LE: 2a, GR: B).

6. It should be noted that in some Asian countries the resistance of E. coli against TMP/SMX, β-lactams, and fluoroquinolones might be above 20%, a recommended threshold for empiric therapy.

Pregnant women with asymptomatic bacteriuria / AUC

1. Pregnant women with AUC or asymptomatic bacteriuria should be treated with the standard regimen of antimicrobials (LE: 1b, GR: A).

2. Fluoroquinolones, tetracycline, and TMP/SMX should be avoided because of their associated toxicity in newborns (LE: 1b, GR: A).  

Introduction

Acute uncomplicated cystitis (AUC) accounts for the greatest number of urinary tract infections (UTIs), particularly among young sexually active[1] and postmenopausal women, and should be treated with an effective antimicrobial agent. Recently,the emergence of antimicrobial resistant bacteria has made empiric antibiotic therapy increasingly more difficult for treatment of AUC and several reports have indicated increased isolation of fluoroquinolone-resistant or ESBL-producing gram-negative bacilli in patients with AUC throughout the world[2][3][4][5]. Therefore, it is important for physicians to be aware of regional resistance ratios before initiating empiric antimicrobial therapy for treatment of AUC.

AUC is a frequently encountered problem in primary care, and its condition is diagnosed and treated by all types of physicians, including urologists and gynecologists, as well as other medical and health care providers. Therefore, appropriate guidelines for diagnosis and treatment of AUC should be provided and constantly renewed based on reviews of epidemiological, pharmacological and clinical investigations.

Definition

Acute cystitis, frequently occurs in adult women, is considered to be uncomplicated if it is sporadic and a community-acquired episode in otherwise healthy individuals if the patient is not pregnant or elderly, there has been no recent instrumentation or antimicrobial treatment, and there are no known structural and functional abnormalities of the genitourinary tracts[6][7](LE: 2b).

Characterization (Etiology/Epidemiology)

AUC is of significant importance in the community due to its high prevalence, particularly among young sexually active and postmenopausal women. A previous cohort study showed that the incidence of AUC accounts for 0.5-0.7 per individuals per year among young women[1], while more than half of all women experience at least one UTI in their lifetime[8].

The microbial etiology of AUC is regarded to be well established and reasonably consistent. Escherichia coli is the predominant pathogen isolated most frequently (approximately 75%) in episodes of AUC, followed by Staphylococcus saprophyticus (5-15%), mainly in young sexually active women[9][10][11](LE: 2a). Occasionally, other pathogens such as Enterococcus faecalis, Klebsiella pneumoniae, and Proteus mirabilis are involved[3][4][12](LE: 2a). In a recent study conducted in Japan, E. coli was detected in 77.8% of 387 AUC cases, followed by S. saprophyticus in 5.2% (Fig. 1)[13].

Figure 1. Pathogens isolated from 364 patients with acute uncomplicated cystitis in Japan from 2009 to 2010[13]

The fecal-perineal-urethral hypothesis is widely recognized to explain the cause of increasing UTIs, in which uropathogenic organisms reside in individual rectal flora and serve as a reservoir for UTIs[14][15](LE: 2a).

Risk factors

The most important risk factors for AUC in young women are a history of previous episodes of cystitis and frequent or recent sexual activity[16]. Physiological changes associated with menopause, such as decreased vaginal glycogen and increased pH, are also considered to be risk factors for developing a UTI. Another study reported that insulin-treated diabetes and a lifetime history of UTI are risk factors for AUC among postmenopausal women, whereas AUC was not found to be associated with sexual activity, urinary incontinence, parity, postcoital urination, vaginal dryness, consumption of cranberry juice, vaginal bacterial flora,orpostvoid residual bladder volume[17].

Diagnosis

Symptoms (physical examination)

The signs of AUC are generally urinary irritative symptoms, such as dysuria, frequency, micturition pain, and urgency, and not associated with signs or symptoms of upper UTIs, such as fever, chills, or flank pain[18]. When a woman previously affected by cystitis has symptoms suggesting recurrence, there is an 84% chance that an infection is present[19].

Laboratory tests (radiological investigation, Others)

A diagnosis of AUC can be made with high probability based on a history of urinary symptoms and physical examination findings in women who have no risk factors for complication with a UTI[20](LE: 2a, GR: B).

A urine dipstick test, microscopy of urine sediment, and a counting chamber are reasonable tools to urinalysis for diagnosis of AUC[21][22](LE: 2a, GR: B). Of those, a microscopy of the urine sediment with or without Gram-stainis recommended,not only to securethe diagnostic accuracy, but also to distinguish between coccus- and coli-forms. Flow cytometry may take the place of microscopic examination, because the system discriminating between Gram-positive and negative bacteria is now under development and would be available in the near future.

A urine culture testing is recommended prior to treatment for patients at high risk for drug resistance in order to avoid an inappropriate choice of antimicrobials. Also, that is warranted to identify unusual or resistant organisms in patients whose symptoms either do not abate or recur within 2 to 4 weeks after the completion of treatment[18](LE: 4, GR: B).

A colony count of ≥103cfu/mLof uropathogensis considered to represent the compromised threshold for microbiological diagnosis in patients presenting with symptoms of AUC[23](LE: 2b, GR: B).

Treatment (medication/surgery/alternative/prevention)

Overview of treatments for AUC

Antibiotic therapy is recommended for women with AUC because clinical success was found to be significantly more likely as compared to those treated with a placebo[24](LE: 1a, GR: A). Since the resistance patterns of pathogens causing AUC vary considerably between regions and countries, it is difficult to recommend a specific treatment that is universally acceptable for all areas. To appropriately select an antimicrobial agent, it is important for physicianto understand the susceptibility profile of the causative bacteria, particularly the local antimicrobial susceptibility of E. coli, because of resistance to antibiotics in the pathogens of AUC is increasing worldwide[2][3][4][5].

In general, fosfomycin trometamol, nitrofurantoin macrocrystals, trimethoprim-sulfamethoxazole (TMP/SMX), and β-lactams, including cefaclor, cephalexin, and amoxicillin/ clavulanate,are considered to be the drugs offirst choice in Asian countries. In addition, pivmecillinammay be a good candidate for treatment of AUC, though this agent is unavailable in most of Asia. Third generation oral cephalosporins and fluoroquinolones should be considered only as alternatives when other recommended agents cannot be used, but not as the first choice for treatment of AUC. Amoxicillin or ampicillin should not be prescribed for empirical treatment because of high prevalence of antimicrobial resistance to these agents worldwide. In principle, the prescribing physician should always try to distinguish between the coccus- and coli-form of the uropathogen causing AUC based on microscopic findings.

Table 1 shows the recommended antimicrobial agents and duration of treatment for AUC. For reference, Table 2 shows antimicrobials presently available for treatment of AUC in Asian countries.

AUC Table 1.png


AUC Table 2.png

Antimicrobilas for treatment of AUC

Fosfomycin trometamol (3 g, single dose)[25](LE: 1a, GR: A) is an appropriate choice for therapy due to minimal resistance and propensity for collateral damage[26](LE: 2b). However, it is less effective than TMP/SMX or fluoroquinolones, and not reliably effective against S. saprophyticus[13][27](LE: 3). Fosfomycin trometamol is not available in some countries, though fosfomycin calcium may be available. A previous study reported that a regimen of fosfomycin calcium (1 g three times daily for 2 days) showed excellent microbiological eradication rates as well as clinical efficacy rates at 5-9 days and 4-6 weeks after drug administration in patients with AUC[28](LE: 2a, GR: B).

Nitrofurantoin macrocrystals at 100 mg twice daily for 5 days has efficacy comparable to 3 days of TMP/SMX[29](LE: 1a, GR: A). Although nitrofurantoin is considerably less active than TMP/SMX or fluoroquinolones toward aerobic Gram-negative rods other than E. coli, it may assume a more important role if fluoroquinolone-resistance continues to spread or if short-term nitrofurantoin therapy is efficacious[18](LE: 4, GR: B). Nitrofurantoin is the standard, though not available in some countries.

The Infectious Diseases Society of America (IDSA) guidelines recommend TMP/SMX at 160/800 mg twice daily for 3 days as the first choice for empirical treatment when the resistance rate among uropathogens that cause AUC is <20% in the community[30](LE: 1a, GR: A). However, the emergence of TMP/SMX-resistant uropathogens has led to a shift in the prescribing pattern of fluoroquinolones[31](LE: 2a, GR: B). Several studies have shown that TMP/SMX resistance has indeed increased in many countries[32](LE: 2a, GR: B).

Beta-lactams, including cephalexin, cefaclor, and amoxicillin/clavulanate are appropriate choices for therapy when other recommended agents cannot be used[30](LE: 1a, GR: A). Single-dose therapy with β-lactams was found to be significantly less effective than longer duration therapy in terms of the eradication rate[27]. On the other hand, 3-day therapy with β-lactams may show excellent eradication rates, similar to those obtained with 3-day therapy with TMP/SMX or fluoroquinolones, though most studies have shown that β-lactams are inferior to TMP/SMX and fluoroquinolones in terms of the bacterial recurrence rate[30][33](LE: 1a, GR: A). For these reasons, prolonged (7-day) therapy using β-lactams is recommended for empirical therapy[32](LE: 2a, GR: B).

Aminopenicillins in combination with a β-lactamase inhibitor such as amoxicillin/clavulanate is not highly effective as short-term therapy as compared to fluoroquinolones, though may be used in selected cases[34](LE: 1b, GR: A). If Gram-positive cocci are present amoxicillin/clavulanate could be recommended, because the drug is active against enterococci and staphylococci (LE: 1a, GR: A). Furthermore, aminopenicillins (amoxicillin or ampicillin) are no more useful for empirical treatment, because of the high prevalence ofE. coli resistance against these antimicrobial agents worldwide[3][13][12][32](LE: 2a, GR: B).

Fluoroquinolones are currently accepted as the standard agents for short-term (3 days) therapy[30] [33][35][36][37](LE: 1b, GR: A). Current opinion is that low-dose fluoroquinolones should no longer be used because of the potential for emergence of resistance[32][38](LE: 2a, GR: B).In this regard, 500-mg levofloxacin tablets are recommended as a once-daily administration for treatment of infections[39](LE: 2a, GR: B). Although a high-dose fluoroquinolone regimen may still be effective for treatment of AUC caused by a resistant pathogen and despite fluoroquinolones are presently recommended in several guidelines and reviews for treatment of AUC as the most popular alternative antimicrobials [30][40][41], it should be noted, that the rates of fluoroquinolone-resistant E. coli are much higher in some Asian than in European countries[42][43][44][45][46]. Thus it is important to consider strategies for better use of fluoroquinolones in Asia. Fluoroquinolones have a propensity for collateral damage and should be reserved for more important infections than AUC, and should be considered only as alternatives but not as the first choice for treatment of AUC[30](LE: 1a, GR: A).

S. saprophyticusis uniquely associated with uncomplicated UTIs in humans. A UTI caused by S. saprophyticusis associated with recent sexual intercourse, and occurs more often during the late summer and fall[47]. According to the detection rate of pathogens by menopausal status, AUC caused by S. saprophyticusis significantly more common in premenopausal women[13](LE: 3). In addition, S. saprophyticus strains were found have a high susceptibility to fluoroquinolones as compared to other β-lactams and FOM[13](LE: 3). Thus, fluoroquinolones are an alternative choice in young sexually active women with S. saprophyticus as 2nd most frequent pathogen[13](LE: 3, GR: B).

Third generation oral cephalosporins, including cefdinir, cefcapene-pivoxil, and cefpodoxime-proxetil,given as 5-7-day regimens are alternative choices for therapy when other recommended agents cannot be used[30](LE: 1a, GR: A), but should not be prescribed if cocci are present. It has been reported that cefpodoxime-proxetil may beuseful as short-term therapy in selected cases[48](LE: 1b, GR: A)

Consideration of antimicrobial resistance

The global increase in antibiotic resistance and regionally different antibiogram results make it difficult to choose the most appropriate antimicrobial agent for empirical treatment of a UTI. In addition, adverse effects including negative ecological effects and selection of resistance must be carefully considered. Recent reports have indicated increased isolation of fluoroquinolone-resistant or ESBL-producing Gram-negative bacilli in patients with AUC in Asian countries[13][49][50](LE: 3). Striking evidence has also been presented in regard to the increase in E. coli strains resistant to fluoroquinolones, which may reflect overuse of quinolones[46](LE: 3) and prior exposure to them[51](LE: 3) for treatment of community-acquired UTIs. Production of ESBL byE. coli largely contributes toresistance to third- and fourth-generation cephalosporins. Abuse of several different classes of antibiotics in the same patient may cause the resultant mutants to be resistant to structurally and functionally diverse antimicrobials[52]. It should be noted that in many Asian countries the resistance of E. coli against TMP/SMX, β-lactams, and fluoroquinolones might be above 20%, a recommended threshold for empiric therapy[42][43][44][49](LE: 3).

Pregnant women with asymptomatic bacteriuria / AUC (unusual andspecial cases)

Risk/ Epidemiology/ Etiology

Asymptomatic bacteriuria occurs in 2-10% of pregnancies and 30% of women with asymptomatic bacteriuria develop pyelonephritis during pregnancy[53]. Early detection of asymptomatic bacteriuria in pregnant patients is important, as bacteriuria is an established risk factor for serious complications including acute pyelonephritis, preterm delivery, and low birth weight. Antibiotic treatment is effective for reducing the risk of pyelonephritis during pregnancy[53](LE: 1a, GR: A). Organisms causing bacteriuria are similar in both pregnant and non-pregnant women, with E. coli being the most common pathogen associated with both symptomatic and asymptomatic bacteriuria, representing 70-80% of isolates.

Selection of antimicrobilas for treatment of asymptomatic bacteriuria / AUC during pregnancy

Acute cystitis should be effectively treated and asymptomatic bacteriuria detected during pregnancy should also be eradicated with antimicrobial therapy[53](LE: 1a, GR: A). According to the available susceptibility patterns of uropathogens in AUC, fosfomycin trometamol, nitrofurantoin macrocrystals, and β-lactams including cephalexin and amoxicillin/clavulanate are considered to be the drugs of first choice[54][55](Table 3). The safety of fosfomycin calcium taken during pregnancy has not been established, while fluoroquinolones, tetracycline, and TMP/SMX should be avoided because of their associated toxicity in newborns[55](LE: 1b, GR: A).

AUC Table 3.png

Duration of therapy / AUC during pregnancy

There is no clear consensus in presented reports regarding antimicrobial choice or duration of therapy for uncomplicated UTIs and asymptomatic bacteriuria during pregnancy. A single dose regimen for asymptomatic bacteriuria or AUC in pregnant women was been reported to result in a lower incidence of adverse effects,as well as newborn and maternal adverse outcomes as compared to longer periods of antimicrobial therapy[56][57]. However, a single-dose regimen with nitrofurantoin or β-lactams was found to be less efficient than a 7-day regimen. Therefore, nitrofurantoin or β-lactams should be administeredfor 5 or more days[56]. On the other hand,a comparison of single-dose fosfomycin trometamol with 7-day amoxicillin clavulanate treatment for asymptomatic bacteriuria during pregnancy showed no differences between the two treatments regarding cure and recurrence[58](LE: 1b, GR: A). Pregnant women with asymptomatic bacteriuria should be treated using the standard regimen of antimicrobials until more data become available testing 7-day compared with three- or five-day regimens[57](LE: 1b, GR: A). Consequently, it is recommended that those patients with AUC or asymptomatic bacteriuria should be treated by a single dose of fosfomycin trometamol, or a 5- to 7-day treatment of nitrofurantoin or β-lactams.

Treatment algorithm

Figure 2 presents an algorithm for clinical management of AUC.

Figure 2. Algorithm for clinical management of acute uncomplicated cystitis

Abbreviations

AUC: acute uncomplicated cystitis, CFU: colony-forming units, EAU: European Association of Urology, ESBL: extended-spectrum β-lactamase, IDSA:Infectious Diseases Society of America, RCT:randomized controlled trial, TMP/SMX: trimethoprim-sulfamethoxazole, UTI: urinary tract infection

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