Antibiotic treatment of acute uncomplicated cystitis based on rapid urine test and local epidemiology: lessons from a primary care series

The emergence of multidrug resistant Enterobacteriaceae in the community reinforces the need to reduce antibiotic prescription, particularly for molecules at high risk of ecological effect such as broad spectrum beta-lactams and quinolones. Given its benign nature, acute uncomplicated cystitis (AUC) is an ideal target of action. Rapid urine test (RUT) for detection of nitrites and leucocytes have a high negative predictive value, so that some guidelines on AUC recommend their systematic use, such as the French [1], the Scottish [2] and that of the European Association of Urology [3]. Of note, diagnostic procedures are not addressed by the current IDSA and ESCMID guidelines [1, 4]. To spare beta-lactams and quinolones, it is now recommended worldwide to treat AUC with nitrofurantoin, trimethoprim-sulfamethoxazole (TMP-SMX), fosfomycin or pivmecillinam, depending on local community resistance prevalence [1, 4]. Unfortunately, as underlined by the IDSA and ESCMID guidelines, local epidemiological data on AUC lack, and surveillance networks mix complicated and uncomplicated urinary tract infection (UTI) [5]. In France, fosfomycin is the only drug recommended first line for AUC; because of its poor efficacy against Staphylococcus saprophyticus, it is suggested, but with a low level of evidence, that patients under 30 years (at higher risk of S. saprophyticus infection) and with negative nitrite detection should be treated with nitrofurantoin or quinolones.

Thus, the current study was performed to evaluate the current epidemiology of AUC, the contribution of RUT in a primary care practice, and to compare different treatment strategies.

Three main messages can be learnt from this series performed at the GP’s office in a strict “real-life” clinical setting: (a) the rate of antibiotic resistance remains extremely low in this specific population of female patients with non recurrent AUC, so that fluoroquinolones, fosfomycin, nitrofurantoin, TMP-SMX, and to a lesser extent pivmecillinam, offer excellent bacterial coverage; (b) the bacterial thresholds retained in the guidelines for biological diagnosis derive from specific studies mainly on inpatients, and might not fit daily care reality; (c) rapid urine test can reduce inappropriate antibiotic prescriptions by 10%, but cannot accurately suspect S. saprophyticus infections. From these results, we suggest that RUT and recent epidemiology data offer prescribers the rare opportunity both to optimize and to reduce antibiotic prescription, hence lowering risk of adverse ecological effects.

Optimal probabilistic antibiotic prescription requires recent and detailed epidemiological data. In this series, very few levels of resistance were observed (only 3% of resistance to fluoroquinolone and 1% of resistance to third generation cephalosporin for E. coli). Resistance rates in our series are very similar to recent international studies specifically devoted to AUC [1, 4, 26–31]. This can probably be explained by the fact that women with non recurrent AUC are otherwise healthy subjects, uncommonly exposed to antibiotics and thus to any ecological adverse effect on their gut flora. Indeed only a quarter of our patients had received antibiotics during the previous six months, a rate twice lower than that of the general population of 18–65 years old [32]. Our results markedly differ from those of French and international surveillance networks that reported during the same period resistance for outpatient urinary E. coli isolates up to 14% for fluoroquinolones and up to 5% for third generation cephalosporin. These latter networks are biased, because they include patient cohorts visiting urologists, or patients with recurrent or complicated UTI that have higher antibiotic pretreatments hence are at higher risk of multidrug resistance [1, 6–10, 33–35]. Hence global epidemiology data UTI should not be used to guide antibiotic choice for AUC.

The second prerequisite for improving the accuracy of antibiotic prescription is using reliable diagnosis methods. As for AUC diagnosis can rely on symptoms, RUT, or urine analysis. Numerous studies have proposed scores based on clinical symptoms and RUT, all of them using urine analysis as the gold standard. In these studies the pretest likelihood of infection increased RUT performance [4, 12–22]. In our study, since all patients were young females without comorbidities, consulting for symptoms suggesting AUC, it was assumed that the probability of AUC exceeded 80% when RUT detected nitrites or leukocytes [1, 4, 12]. Using the standard bacterial thresholds retained in French guidelines (≥10³ CFU/mL for Enterobacteriaceae or S. saprophyticus, and ≥10⁵ CFU/mL for other pathogens), 148 (43%) patients did not have the biological criteria for diagnosis of AUC [1, 4]. A high rate of AUC differential diagnosis (e.g., vaginitis or urethritis) is most unlikely, and we suspect that standard thresholds do not fit reality. Indeed, standard thresholds have been determined from morning concentrated urines [6–10], whereas in our study as in daily life, urine was mostly collected during daytime so that significant thresholds were certainly lower. This explanation is supported by the high rate of significant leukocyturia (82% of our patients) while no visible growth was uncommon (only 9.5% of patients). Using reduced thresholds for all pathogens, 247 urine analyses (71%) would have been positive, which is more consistent with other studies. This debate on diagnosis thresholds is crucial for evaluating RUT performances for diagnosis of AUC. As a fact, depending on the diagnosis thresholds used, the negative predictive value of RUT lowered from 92% to 84%. But, more meaningful for the prescriber than the negative predictive value of RUT, may be evaluation of the impact of RUT-based strategies on the appropriateness of decision-making regarding antibiotic prescription: if GPs had prescribed antibiotics only in patients with leukocyte or nitrite positive RUT, antibiotic prescription would have been reduced by 10% and the appropriateness of the decision improved, regardless of diagnosis thresholds used. Of those patients with biologically confirmed AUC, only three to six out of 347 patients would not have been treated with antibiotics, but, according to data from the literature, up to three patients might have been cured spontaneously, or all six patients could have consulted later with minimal risk of progression to pyelonephritis [1, 11]. RUT however cannot help in identifying the causative pathogen. Contrary to French guideline suggestions, RUT demonstrated low ability to discriminate between Enterobacteriaceae and Gram positive pathogens, since patients were more likely to have a Gram positive infection when nitrite detection was positive than negative. Even taking into account the subgroup of patients below 30 years old, in which prevalence of S. saprophyticus is higher, Gram positive only represented 15% of patients. Thus, we recommend that the diagnosis thresholds retained in urine analysis be tempered, and that RUT be used to limit inappropriate antibiotic prescriptions, not to anticipate microbiological diagnosis.

As a consequence of the low resistance rates, bacterial coverage rate was high for all antibiotics evaluated, with only a slight superiority for nitrofurantoin or fluoroquinolones. Bacterial coverage rate can only be cautiously considered as an indirect, and probably underestimated evaluation of the cure rate of antibiotic treatment for AUC, because of spontaneous cure in up to 40% of untreated patients, and because of high antibiotic urine concentrations that may lead to cure despite in vitro resistance [6, 8–11]. However, bacterial coverage rate might be accurate for comparing antibiotic regimen such as nitrofurantoin and fosfomycin which demonstrated similar clinical and microbiological efficacy on susceptible strains in previous studies [23–25]. In our study, both molecules exhibited high (≥95%) and similar rates of bacterial coverage. Pivmecillinam had the lowest rate of bacterial coverage, estimated by in vitro susceptibility data, because Gram positive are considered naturally resistant. Nevertheless, several clinical studies have demonstrated up to 93% clinical cure rate in S. saprophyticus AUC because of high pivmecillnam concentration in urine [26–31]. If pivmecillinam had been considered active in vivo on S. saprophyticus infections, the estimated success rates of pivmecillinam treatments would have reached 81% in our series.

Since all simulated antibiotic strategies appeared highly effective, priority should be given to the risk of adverse effects, including ecological damage. Among the for antibiotics currently recommended the 2010 IDSA and ESCMID guidelines, we consider that fosfomycin has the best benefit-risk balance, at the individual and collective levels; pivmecillinam though well tolerated requires a heavier regimen (bid for 3–5 days) for potentially a lower efficacy; TMP-SMX causes early and sustained ecological damage as well as rare but serious toxicity [36]; nitrofurantoïn is proposed first-line by many countries, because of good coverage rate and low ecological pressure. Because severe adverse effects such as allergic pneumonia or hepatitis and neuropathy have rarely been described even after a very short course, we suggest it should be used second-line [1, 33].

In conclusion despite worldwide increase in the prevalence of resistance for complicated UTI, patients with AUC still exhibit extremely low resistance rates. Systematic use of rapid urine test could reduce, the amount of antibiotics prescribed by 10%. Whenever required, antibiotics should be chosen exclusively from molecules that have minimal adverse effects including collateral damages.

Bacyst study group: Philippe André, Alain Barbot, Nicole Bénard, Danièle Bouillon, Pascal Boulet, Thomas Bourez, Laurence Brenet, Jean-Michel Bunel, Martine Courtier, François De Golmard, Marc Durand, Pierre Fainsilber, Rodolphe Hautot, Jean-Loup Hermil, Pascal Julienne, Marie-Catherine Lagaude, Karine Larese, Laurent Laval, Rrené Le, Janick, Lefebvre, Laure Lefebvre, Serge Lejeal, Jérome Longueville, Jean-Pierre Mineo, Philippe Nguyen-than, Xavier Odoux, Marc-Henri Othman, Roseline Peluchon, Marc Salaun, Sébastien Taupin, Jean-Paul Thueux, Françoise Valla, Jean Van Elslande.