Le Infezioni in Medicina

ISSN 1124-9390 LE INFEZIONI IN MEDICINA

Position paper on uncomplicated cystitis and single dose antibiotic therapy with prulifloxacin

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Vol. 24 - Supplemento 1 - 2016 LE INFEZIONI IN MEDICINA Rivista trimestrale di eziologia, epidemiologia, diagnostica, clinica e terapia delle patologie infettive

Volume 24 - Suppl. n. 1 - 2016 O Sommario

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Registrazione Trib. di Milano n. 506 Introduction 3 del 6/9/2007 Silvano Esposito

Direzione e Redazione Dipartimento di Medicina e Chirurgia Università degli Studi di Salerno Position paper 5 Via Allende, Baronissi, Salerno - Italy Tel. 0039 (089) 672420 on uncomplicated cystitis e-mail: [email protected] www.infezmed.it and single dose antibiotic therapy with prulifloxacin Direttore responsabile P.E. Zoncada Carlo Tascini, Rossella Nappi, Luigi Cormio, Massimo Lazzeri, Gabriele Alberto Saracino, Chiara Benedetto

www.infezmed.it LE INFEZIONI IN MEDICINA A quarterly journal covering the etiological, epidemiological, diagnostic, clinical and therapeutic aspects of infectious diseases

Editor in chief Esposito S. Editorial assistant Noviello S. Esposito I.

Associate editors Dos Santos V.M. (Brasília, Brazil) Ece G. (Izmir, Turkey) HIV/AIDS Filice G. (Pavia, Italy) Andreoni M. Galli L. (Milan, Italy) Cauda R. Garau J. (Barcelona, Spain) Giacometti A. (Ancona, Italy) Viral hepatitis Gaeta G. B. Giamarellou H. (Athens, Greece) Taliani G. Gould I. (Aberdeen, UK) Gollapudi S. (Los Angeles, USA) Fungal infections Grossi P. (Varese, Italy) Viale P. Gyssens I. (Nijmegen, The Netherlands) Viscoli C. Heisig P. (Hamburg, Germany) Karamanou M. (Athens, Greece) Bacterial infections Kazama I. (Sendai Miyagi, Japan) Bassetti M. Lakatos B. (Budapest, Hungary) De Rosa F.G. Lari R. (Teheran, Iran) Emerging infectious diseases Lipsky B.A. (Seattle, USA) Ippolito G. Lye D. (Singapore) Marinis A. (Piraeus, Greece) Tropical diseases Marvaso A. (Naples, Italy) Castelli F. Menichetti F. (Pisa, Italy) Meletis G. (Thessaloniki, Greece) History of infectious diseases Milkovich G. (Richmond, USA) Contini C. Novelli A. (Florence, Italy) Papadopoulos A. (Athens, Greece) Paparizos V. (Athens, Greece) Editorial board Parvizi J. (Philadelphia, USA) Angarano G. (Bari, Italy) Pea F. (Udine, Italy) Anyfantakis D. (Chania, Crete, Greece) Reitan J.F. (Crown Point, USA) Atalay M.A. (Kayseri, Turkey) Sanduzzi A. (Naples, Italia) Biçer S. (Istanbul, Turkey) Scaglione F. (Milan, Italy) Bonnet E. (Tolouse, France) Scotto G. (Foggia, Italy) Boccazzi A. (Milan, Italy) Segreti J. (Chicago, USA) Bouza E. (Madrid, Spain) Sganga G. (Rome, Italy) Bouza J.M.E. (Valladolid, Spain) Soriano A. (Barcelona, Spain) Camporese A. (Pordenone, Italy) Stefani S. (Catania, Italy) Concia E. (Verona, Italy) Coppola N. (Naples, Italy) Tambic A.A. (Zagreb, Croatia) Dal Tuba (Ankara, Turkey) Ünal S. (Ankara, Turkey) de Araújo F.J.A. (Goiânia, Brazil) Vullo V. (Rome, Italy) d’Arminio Monforte A. (Milan, Italy) Yalcin A.D. (Antalya, Turkey) Di Perri G. (Turin, Italy) Yalcin N. (Antalya, Turkey) Le Infezioni in Medicina, Suppl. n. 1, 3-4, 2016 3

Introduction

Silvano Esposito Department of Infectious Diseases, University of Salerno, Italy

rinary tract infection (UTI) is character- vey (NHANES-III), the incidence for UTI Uized by the presence of >105 microor- is 13,320 per 100,000 adult women per year. ganisms per milliliter of urine with pus cells [4] Among young healthy women with cys- and red blood cells [1] titis, the infection recurs in 25% of women The term uncomplicated urinary tract infec- within 6 months after the first episode. tion refers to the invasion of a structurally Women are especially susceptible to cysti- and functionally normal urinary tract by a tis for reasons that are poorly understood. nonresident infectious organism while com- One factor may be that a woman’s urethra is plicated UTI refers to the occurrence of in- short, allowing bacteria quick access to the fection in patients with an abnormal struc- bladder. Also, a woman’s urethral opening tural or functional urinary tract, or both. is near sources of bacteria from the anus and UTI is differentiated from asymptomatic vagina. bacterial colonization by the presence of an Uncomplicated cystitis in the women are inflammatory response, and the associated commonly caused by Gram negative or- signs and symptoms that result from bacte- ganisms like Escherichia coli, Klebsiella, rial invasion. Proteus, Pseudomonas, Enterobacter and Acute uncomplicated bacterial cystitis is also less commonly by gram positive or- common in general practice and among sex- ganisms like Staphylococcus saprophyticus ually active young women, the incidence of [5]. Co-trimoxazole, β-lactams, aminoglyco- symptomatic urinary tract infection (UTI) is sides, and fluroquinolones are the groups high. Risk factors include recent sexual in- of antimicrobials commonly prescribed for tercourse, recent spermicide use, and a his- treatment of UTI [6]. tory of urinary tract infection [2]. Short duration treatment leads to better pa- Most episodes of cystitis are generally con- tient compliance, less adverse effects and sidered to be uncomplicated in otherwise cost reduction. healthy non pregnant adult women as not Acute uncomplicated bacterial cystitis are associated with an underlying condition common in general practice and because that increases the risk of infection or of fail- of their high frequent occurrence they do ing therapy (such as obstruction, anatom- represent a cause of particular concern. ic abnormality, urologic dysfunction, or a This supplement includes a position paper multiply-resistant uropathogen). giving a multidisciplinary approach to the It has been estimated that at least one-third management of the same diseases that can of all women in the United States are diag- be frequently observed in the everyday nosed with a UTI by the time they reach 24 medical practice by different specialists (in- years of age [3]. According to the Nation- fectious diseases specialist , urologist, gyne- al Health and Nutrition Examination Sur- cologist). 4 S. Esposito

n REFERENCES tract infections: transmission and risk factors, incidence, and costs. Infect. Dis. Clin. North Am. 17, [1] Nicolle L.E. Epidemiology of urinary tract 227-241, 2003. infections. Clin. Microbiol. Newsl 24, 135–140, [5] Lawrenson R.A., Logie J.W. Antibiotic fail- 2002. ure in the treatment of urinary tract infections in [2] Hooton T.M., Scholes D., Hughes J.P., et al. A young women. J. Antimicrob. Chemother. 48, 6, 895- prospective study of risk factors for symptomatic 901, 2001. urinary tract infection in young women. N. Engl. [6] Trienekens T.A.M., London N.H.HJ., Houben J. Med. 335, 7, 468, 1996. A.W. Double-blind comparison of 3-day versus [3] Patton J.P., Nash D.B., Abrutyn E. Urinary tract 7-day treatment with norfloxacin in symptomat- infection: economic considerations. Med. Clin. ic urinary tract infections. The Inter-Nordic Uri- North Am. 75, 495–513, 1991. nary Tract Infection Study Group. Scand. J. Infect. [4] Foxman B., Brown P. Epidemiology of urinary Dis. 20, 6, 619-624, 1988. Le Infezioni in Medicina, Suppl. n. 1, 5-16, 2016 5

Position paper on uncomplicated cystitis and single dose antibiotic therapy with prulifloxacin

Carlo Tascini1, Rossella Nappi2, Luigi Cormio3, Massimo Lazzeri4, Gabriele Alberto Saracino5, Chiara Benedetto6 1U.O. Infectious Diseases, Nuovo Santa Chiara Hospital, Pisa, Italy; 2Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause, IRCCS S. Matteo Foundation, Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Italy; 3Department of Urology and Renal Transplantation, University of Foggia, Italy; 4Department of Urology, Istituto Clinico Humanitas IRCCS, Clinical and Research Hospital, Rozzano, Milan, Italy; 5UOC Urology I, bari University, Policlinico di Bari, Italy; 6Obstetrics & Gynaecology I, Department of Surgical Sciences, University of Torino, Italy

Summary Episodes of acute cystitis occurring occasionally in healthy have a supply of antimicrobial agents available at home. pre-menopausal, non-pregnant women, with no history sug- Therefore a single dose antibiotic therapy for UC may be useful gestive of an abnormal urinary tract, are generally classified in order to reduce the antibiotic pressure and to reduce the pre- as uncomplicated cystitis. scription of diagnostic examinations. A woman who is treated Uncomplicated cystitis (UC) is diagnosed by the clinical point successfully with single dose therapy is unlikely to have a uri- of view according to the following symptoms: patients with nary tract abnormality. The practical consequence of this is dysuria, pollakiuria, stranguria, without fever and without that only those women who are single-dose failures warrant flank pain. UC with blood in the urine is possible. Blood is not urinary tract investigation. Furthermore, a single dose of an a criterion used to classify an UTIs as complicated. antimicrobial drug is associated with fewer side effects. Urine cultures and/or dip stick results are not necessary for Among drugs used to treat UC, single dose fluoroquilones the diagnosis of UC. The most frequent pathogen of UC is was as effective as other drugs used in single dose. Pruli- E. coli, followed by S. saprophyticus and other enterobacte- floxacin was approved in Italy for single dose therapy for ria. In UC MDR microrganisms are rare. Fluoroquinolones UC. Prulifloxacin efficacy in UC may be due, beside its are the most frequently used drugs, followed by fosfomycin, broad-spectrum antimicrobial activity, to its long post-an- cotrimoxazole and nitrofurantoin. tibiotic effect. For many investigators traditional dosage regimes for UC Prulifloxacin, in single dose, may have less adverse effect are eccessive. Ideally a patient should be treated with the than prolonged treatment and this is also true with other flu- shortest course of the safest and less expensive drug that will oroquinolones. Furthermore, due to lack of activity towards eradicate the offending organism. anaerobes, prulifloxacin may respect the fecal microbioma Many women with cystitis will stop their prescribed treat- and reduce the risk of C. difficile colitis. ment when their symptoms are resolved. This is often after In conclusion UC might be treated with a single dose of a the first few doses and explains why these women often potent fluoroquinolone such as prulifloxacin. n INTRODUCTION women, with no history suggestive of an abnormal urinary tract, renal insufficiency Definition and clinical diagnosis or co-morbidities, are generally classified as ncomplicated cystitis (UC): Episodes uncomplicated, whereas all others are classi- Uof acute cystitis occurring occasionally fied as complicated (simple cystitis might be in healthy pre-menopausal, non-pregnant a synonymous with uncomplicated cystitis). Because definition of UC is not clear to the Indirizzo per la corrispondenza different physicians who care for it; includ- Carlo Tascini ing general practitioners, gynecologists, e-mail: [email protected] urologists and infectious disease specialists, 6 C. Tascini, et al.

a survey was performed by a marketing Complicated agency. A survey performed in Italy on gen- - abnormal urinary tract: bladder-urethra eral practitioners (GP) (160) and gynecology stones, vesico-ureteric reflux, obstruc- specialists (Gy) (80) about uncomplicated tion, paraplegia, atonic bladder, indwell- cystitis (UC) has given different results about ing catheter, chronic prostatitis; diagnosis, antibiotic treatment and length of - Impaired host defense such as neutrope- treatment. Many physicians (25% of GP and nia, diabetes mellitus, immune-suppres- 33% of Gy) believe that urinalysis and/or sive therapy; urine culture, differently from guidelines, - Impaired renal function; are necessary for the diagnosis of UC. - Virulent microrganisms: urease-produc- Only 15% of the participating doctors being Proteus spp, metastatic staphylococ- lieve that sporadic cystitis is an UC; in fact cal infections; recurrence (caused by the same microorgan- - All males [1]. ism) or relapsing cystitis (caused by a different microorganism) is complicated cystitis Uncomplicated cystitis is diagnosed from (at least three episodes in one year or at least the clinical point of view; patient with two episodes in the last 6 months). For 15% dysuria, pollakiuria, stranguria. UC with of GP and 8% of Gy, hematuria excludes UC. blood in urine is possible. Blood is not a cri- Instead from the definition of UC, this con- terion used to classify UTIs as complicated. dition may have hematuria. Absence of fe- Instead clinical manifestations suggestive ver is a major criteria for defining UC: only of pyelonephritis include fever (tempera- 12% of GP and 7% of Gy, correctly define ture >37,5°C), chills, flank pain, costo-verte- UC based on the absence of fever. Although bral-angle tenderness, and nausea or vomit- many physicians believe that drugs to treat ing. Dysuria is also common with urethritis UC have to be effective, rapidly bactericidal, or vaginitis, but cystitis is more likely when have few adverse effects and easily accept- symptoms include frequency, urgency, or ed by patients. Only 5% of GP and 3% of Gy hematuria, when the onset of symptoms is know that a single dose of antibiotic might sudden or severe, and when vaginal irrita- be effective in the treatment of UC [Mencac- tion and discharge are not present [2, 3]. ci F, Personal comunication]. Acute UC is a benign condition, with fre- In order to better define the possibility of quent early resolution of symptoms and treating UC with a single dose of antibiotic, only rare cases of progression to pyelone- a consensus among 6 Italian experts (1 ID phritis [1]. However, cystitis is associated C.T, 2 Gy, R.N, C. B, 3 urologists, L. C., M. with considerable morbidity, and antimicro- L., A. S.) was agreed to write a position pa- bial drugs are routinely prescribed in order per on definition, diagnosis and single dose to reach a rapid resolution of symptoms [1]. treatment of UC. The choice of therapy has become more dif- From a management point of view it has ficult as antimicrobial resistance among the been found extremely valuable to consider uropathogenic strains of E. coli have in- UTI as uncomplicated or complicated: creased worldwide. Recent large international studies of the in vitro susceptibility Uncomplicated of E. coli strains that cause uncomplicated - normal urinary tract, urinary tract infection [4, 5] have revealed - normal renal function, rates of resistance to amoxicillin and tri- - no co-morbidities, methoprim–sulfamethoxazole of 20% or - no pregnancy, higher. These rates of resistance are com- - no menopause. mon worldwide. Rates of resistance to other Position paper on uncomplicated cystitis and single dose antibiotic therapy with prulifloxacin 7

agents used for UC such as fluoroquinolo- Did you have recent urinary tract infections? nes, oral cephalosporins, and amoxicillin– Did you have recent urological procedure? clavulanate are generally lower than 10%, If the answers to the questions are all no; UC but resistance to the fluoroquinolones is in- diagnosis is highly probable. creasing worldwide [6, 7]. Beside the increase of antimicrobial resis- Epidemiology of UC tance, the “ecological adverse effects” of the E. coli is the predominant pathogen, while antibiotics used in UC have been claimed, in sexually active women S. saprophyticus especially for a prolonged course of fluoro- may cause as many as 25% of episodes of quinolones. In fact these drugs used for a bacterial cystitis in the spring and summer long period may cause changes in microbio- months. Proteus mirabilis is also encountered ma and may select resistant strains as well. in general practice and should always raise Therefore shortened duration of antibiotic the question of underlying urinary tract cal- therapy for UC has been proposed in order culi. A single bacterial species is responsible to reduce the “ecological adverse effect” [8]. for 95% of all episodes of UC [1]. Local antimicrobial susceptibility patterns of E. coli in particular should be consid- n DIAGNOSIS ered in empirical antimicrobial selection for UC. Since the resistance patterns of E. Clinical diagnosis coli strains causing UC varies consider- Because the diagnosis of UC is almost al- ably between regions and countries, a spe- ways done based on a clinical point of view cific treatment recommendation may not which could be done also by phone, there be universally suitable for all regions or are several key questions that may help to countries. Resistance rates for all antimi- carry out this diagnosis: crobials were higher in US medical centers than in Canadian medical centers and were Key question for clinical diagnosis of UC. usually higher in Portugal and Spain than Patients with UC should have the following other European countries [4]. In general, characteristics. resistance rates >20% were reported in all Adult women with acute onset and at least 1 of regions for ampicillin, and in many coun- the following symptoms: tries and regions for trimethoprim/sulfa- dysuria, methoxazole. Fluoroquinolone resistance frequency, rates were still <10% in most parts of North urgency, America and Europe, but there was a clear gross hematuria. trend for increasing resistance compared with previous years [5, 9]. Questions useful for the clinical diagnosis: In the ECO-Sens study performed in 5 coun- Are you in menopause? tries in Europe in the year 2007-2008, study- Have you uncontrolled diabetes? ing UC, the authors have found different Have you fever? levels of resistance according to the country Have you flank pain? of isolation. MDR were more frequent in Are you pregnant? Greece and Portugal, however MDR were Are you immune depressed? extremely low in UK, Sweden and Austria. Have you voiding abnormalities? The resistance rate, in the previous men- Have you a new sex partner? tioned countries, in E. coli was 2-8,9% for Have you a sexually transmitted disease? amoxicillin-clavulanate, 0,5-7,6% for cipro- Have you vaginal symptoms? floxacin, 21-34% for ampicillin, 21,2-31,3% 8 C. Tascini, et al.

for sulfamethoxazole. So this study confirms Many women with cystitis will stop their that, also in countries with a high incidence prescribed treatment when their symptoms of MDR, fluoroquinolone resistance in UC are resolved. This is often after the first few is still under 10%, It is true that from the doses and it explains why these women of- first ECO-SENS of 1999-2000 the mean rate ten have a supply of antimicrobial agents of fluoroquinolone resistance is increased available at home. from 1,1% to 3,9% by the second. Instead re- Furthermore, the compliance of patients sistance to sulfamethoxazole is higher than with drugs administered many times during 20%, the threshold of dangerous resistance the day might be low. The regimens for UC [4, 10]. Resistance rate of urinary pathogens should be as simple as possible. There is a to fosfomycin is still low in the community strong ecological argument that a patient but is increasing among nosocomial patho- should be treated with the possible shortest gens [11]. regimen in order to discourage the development of bacterial resistance. Therefore it is suggested that there is no benefit in extend- n DIFFERENTIAL DIAGNOSIS ing treatment of bacterial cystitis beyond 3 days [18]. Asymptomatic bacteriuria Amoxicillin remains the drug of choice for Asymptomatic bacteriuria, defined as the treating Enterococcus faecalis. There is some presence of bacteria in the urine of an in- concern about the role of beta-lactams as a dividual without signs or symptoms of a group for UC. The results are inferior, clini- urinary tract infection [12], is thought to be cal response slower, relapse rate higher, and present in 3%-5% of young healthy women the side effects more troublesome [1]. and is more common in patients with dia- Trimethoprim-sulfamethoxazole (160/800 betes and elderly persons [13]. In the major- mg [1 double- strength tablet] twice-daily ity of cases, even if it is not recommended, for 3 days) is an appropriate choice for ther- asymptomatic bacteriuria is treated with apy, given its efficacy if local resistance rates poor results and occasionally can allow the do not exceed 20%. The threshold of 20% as development of a selection of multidrug-re- the resistance prevalence at which the agent sistant bacteria [14]. Recently Cai et al. have is no longer recommended for empirical demonstrated that asymptomatic bacteri- treatment of acute UC [19]. uria treatment is associated with a higher Fosfomycin trometamol (3 g in a single occurrence of antibiotic-resistant bacteria, dose or two-days regimen), where it is indicating that asymptomatic bacteriuria available is an appropriate choice for ther- treatment is potentially dangerous [15-17]. apy due to minimal resistance and propen- Asymptomatic bacteriuria shows indica- sity for collateral damage, but it appears to tions to be treated only during pregnancy. have inferior efficacy compared with fluoroquinolones [20]. Furthermore fosfomycin UC Antibiotic Therapy should be reserved for important uses in For many investigators, traditional dos- countries where nosocomial outbreaks of age regimens for UC are eccessive. Ideally carbapenem-resistant Klebsiella pneumoni- a patient should be treated with the short- ae (KPC) are ongoing, because many KPC est course of the safest and less expensive isolated from UTI are still susceptible to drug that will eradicate the causative organ- fosfomycin. Therefore the use of fosfomy- ism. The adverse effect of the drug chosen cin for UC should be considered also for should be weighed against the severity of “collateral damage” as selection of resis- the illness. tance in most important nosocomial patho- Position paper on uncomplicated cystitis and single dose antibiotic therapy with prulifloxacin 9

gens. This concept should be applied to have shown that prulifloxacin has very po- fosfomycin more than to fluoroquinolones tent in vitro antimicrobial activity against [21, 22]. Fosfomycin has also a high rate of Gram-negative pathogens and more potent emergence of resistance when used alone than levofloxacin[ 25]. The prulifloxacin against Enterobacteria [23]. Fosfomycin is MICs and minimum bactericidal concen- active against bacteria in the planktonic trations tend to be equal or even lower phase in urine but not against bacteria that compared with ciprofloxacin, while they adhere to the epithelial cells or are includ- are generally lower compared with levo- ed inside these cells and therefore relapses floxacin, for most Gram-negative patho- might be more frequent [23]. gens, including P. aeruginosa. The mutant Nitrofurantoin remains a valuable drug, al- prevention concentration of prulifloxacin though it is ineffective against Proteus mi- has also been shown to be lower in com- rabilis. Unfortunately the manufacturers in parison with other relevant fluoroquino- the past have promoted this drug for use in lones for both E. coli and P. aeruginosa [26, a dose of 100 mg every 6 h for five days, 27]. This ability to prevent the generation which frequently causes nausea or vomit- of resistant strains might be very useful ing. Repeated studies over the past decades in case of single dose treatment of UC. have shown the same efficacy and minimal Regarding specifically the urinary tract side effects with 50 mg 8-hourly for five pathogens studied, prulifloxacin had more days. A macrocrystalline formulation of potent activity than levofloxacin against nitrofurantoin is associated with fewer gas- the uro-pathogens and more potent activ- trointestinal side effects, and a dose of 100 ity than ciprofloxacin against P. mirabilis mg every 12 hours is currently recommend- and S. saprophyticus. Fluoroquinolones are ed [1]. more effective than amoxicillin/clavula- Fluoroquinolones are the most studied anti- nate and cotrimoxazole [1]. biotic for UC. Ciprofloxacin 250 mg b.i.d for 3 days was as effective as ciprofloxacin giv- Single dose therapy en for 7 days, using the same regimen [1]. The single dose strategy might be accepted In order to understand differences among more favorably by patients, might have less fluoroquinolones used in UTI, not only adverse events (e.g. rashes, gastrointestinal UC, prulifloxacin was tested in comparison symptoms, vaginal candidiasis), it may re- with ciprofloxacin 500 mg every 12 h. Mi- duce the cost of treatment and might reduce crobiological eradication was achieved in antibiotic pressure and therefore the collat- 97% of patients treated with prulifloxacin eral damage on isolation of MDR microor- and ciprofloxacin, but at the early follow- ganisms. up, the rate of patients showing successful A woman that is treated successfully with treatment was 90.8% in the prulifloxacin single dose therapy is unlikely to have a group, and 77.8% in the ciprofloxacin group urinary tract abnormality [28]. The practical (p=0.008). Clinical success rates at 5-7 days consequence of this is that only those wom- (98,1% vs 98,2%) and at 30 days (97,1% vs en who are single-dose failures warrant a 96,3%) after prulifloxacin or ciprofloxacin prolonged antibiotic therapy and/or uri- therapy were similar [24]. nary tract investigation [29]. Among the fluoroquinolones, pruliflox- The patients should be instructed to return acin and levofloxacin have a very broad only if the symptoms failed to be resolved spectrum of antimicrobial activity, which or they recurred shortly after finishing treat- covers both Gram-positive and Gram-neg- ment and in this case urine culture could be ative, including P. aeruginosa. Prior studies useful [30]. 10 C. Tascini, et al.

Table 1 - Pharmacokynetic parameters of ulifloxacin infection that involves all mucosa layers, after administration of a sigle dose of 600 mg of prulifloxacin. therefore the drugs of choice have to pene- trate the deeper layers of bladder. This may C max t max t 1/2 be the reason why fosfomycin may be less 1,6 µg/ml 1 h 10,7 h effective than quinolones in the treatment of UC. In case of failure of eradication of the Prulifloxacin 600 mg/day single dose was microorganism from the bladder, the epi- compared with pefloxacin 800 mg/day sin- thelial layer may be further damaged and gle dose in 239 women with UC [31]. The mi- subsequent relapse or recurrence might oc- crobiological eradication was similar in both cur [34]. treatment arms (97% vs 96%). The clinical Early clinical and microbiological efficacy of efficacy rate was also similar with only 7,8% different classes of antimicrobial in UC, in and 15,7% failure in the prulifloxacin and pe- single dose or in multiple dose regimens are floxacin-treated patients respectively, these listed in table 2. In table 2 are listed the drugs results were confirmed after 30 days[ 31]. used for single dose therapy. Prulifloxacin with its long half-life (10,7 hours), favorable C max 1,6 mg/L (Tab. 1) Antimicrobial stewardship and long post-antibiotic effect, including a Although principles of appropriate use potent anti-gram negative activity might be of antibiotics have been encouraged since the right solution for a single tablet thera- the introduction of antimicrobials, now py for UC. Furthermore prulifloxacin is not they are more urgent than ever. The an- active against anaerobes and it might have timicrobial stewardship programs (ASP) less impact on fecal microbioma thus being have been designed to improve antibiotic useful in reducing the incidence of C. difficile prescription and they have proven highly colitis and selection of MDR gram-negative. successful in improving antibiotic use, al- In English literature, so far, there are no cas- though their impact has been difficult to es of C. difficile associated to prulifloxacin measure [35]. Effective ASP might have an use [32]. impact on antibiotic selection and duration Fluoroquinolones are the most frequently in UTI [36]. used drugs to treat UC [33]. Therefore in ASPs are necessary, not only in the hospital, this class of antibiotic; a drug with the above but also in the community, in fact MDR mi- mentioned characteristics such as pruliflox- croorganism are no longer limited to health acin may be very useful. UC is a bladder care settings [37].

Table 2 - Early efficacy of different treatment for UC. Drug Dose Mean age of women Early clinical Early microbiological included in the studies efficacy % efficacy Cotrimoxazole 160/800 mg b.i.d 32 (18-58) 91 (86-100) 91 (85-100) for 3-7days Nitrofurantoin 100 mg b.i.d.for 5-7days 35 (16-89) 92 (87-95) 87 (82-92) Fosfomycin 3 g sigle dose 38 (15-92) 91 (83-95) 83 (78-98) Fluoroquinolone Variable (3-7 days) 35 (18-89) 90 (81-98) 91 (78-96) Fluoroquinolone Ciprofloxacin 500 mg 18-65 91 91 single dose Prulifloxacina 600 mg 25-47 92 97 Pefloxacina 800 mg 25-47 84 92 Beta-lactams Variable (3 days) 30 (18-59) 86 (79-98) 81 (74-98) Position paper on uncomplicated cystitis and single dose antibiotic therapy with prulifloxacin 11

One of the most common infections encoun- activity, which covers both Gram-positive tered in emergency departments (ED) and and Gram-negative aerobes, including E. coli. in the community is urinary tract infections Prulifloxacin was approved for single dose (UTIs). therapy for UC in Italy, due to its long half- These common infections are managed in life and long post-antibiotic effect. Because both in- and outpatient settings, and ED it has no activity against anaerobes, its effect practitioners and general practitioner (GP) on fecal microbioma might be less import- are involved with establishing empiric and ant with respect to other fluoroquinolone. definitive treatment. In conclusion UC might be treated with a Antimicrobial over-prescribing in the ED single dose of an effective fluoroquinolone and community determines “collateral dam- such as prulifloxacin. age” also in the community. Therefore, ED Patients may better accept the use of a sin- and general practitioners are important tar- gle dose therapy that may have less adverse gets for ASP initiatives in order to produce effects, less impact on gut microbioma and beneficial effects in the community. also it might be less expensive. In an antimi- Asymptomatic bacteriuria (ASB) does not crobial stewardship program of the commu- require antibiotic treatment [38]. UTI diag- nity, a single dose therapy for UC may have nosis based on a urinalysis (UA) or dipstick a positive ecological impact. alone in the absence of symptoms leads to overuse of antibiotics [39]. UC might be an- Acknowledgments other field of application of ASP in ED and There is no conflict of interest for each of the community. authors. In fact UC does not need microbiology and In the past 2 years, C.T. has been paid for the diagnosis is only based on clinical judg- lectures on behalf of Astellas, Angelini, Gil- ment. In the past pharmaceutical companies ead, Pfizer, Novartis and Merck. have pushed for longer therapy in order to avoid failure but with more incidence of adverse effects and selection of resistance. Pru- n REFERENCES lifloxacin might be an important agent to use for ASP in the community. From our perspec- [1] Gupta K., Hooton T.M., Naber K.G., et al. In- tive, it is useful that a pharmaceutical compa- ternational clinical practice guidelines for the ny support a shorter treatment for UTI. treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Panel conclusion infectious diseases society of America and the european society for microbiology and infectious Episodes of acute cystitis occurring oc- diseases. Clin. Infect. Dis. 52, e103-e120, 2011. casionally in healthy pre-menopausal, [2] Grigoryan L., Trautner B.W., Gupta K. Diagno- non-pregnant women, with no history sug- sis and management of urinary tract infections in gestive of an abnormal urinary tract, are the outpatient setting: a review. JAMA 312, 1677- generally classified as UC. The diagnosis 1684, 2014. of UC is clinical. Laboratory examination is [3] Warren J.W., Abrutyn E., Hebel J.R., Johnson not necessary. If the patient’s problems are J.R., Schaeffer A.J., Stamm W.E. Guidelines for an- not resolved by a single tablet therapy, fur- timicrobial treatment of uncomplicated acute bac- ther investigation will be necessary, includ- terial cystitis and acute pyelonephritis in women. ing urinalysis, urine culture and study of Infectious Diseases Society of America (IDSA). the urinary tract. Clin. Infect. Dis. 29, 745-758, 1999. Among the fluoroquinolones, prulifloxacin [4] Kahlmeter G. An international survey of the has a very broad spectrum of antimicrobial antimicrobial susceptibility of pathogen from 12 C. Tascini, et al.

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