chronic bronchitis is estimated to affect between 3.7% and 6.8% of the population in europe ( ball and make 1998 ) , and prevalence increases with age ( mcguire et al 2001 ) .
patients with chronic bronchitis are predisposed to recurrent attacks of bronchial inflammation  termed acute exacerbations of chronic bronchitis ( aecb)characterized by increased cough , worsening dyspnea , and changes in sputum purulence and volume ( anthonisen et al 1987 ) .
infectious agents are estimated to account for around 80% of these episodes , with the remaining 20% attributed to noninfectious causes such as inadequate medical treatment , congestive heart failure , pulmonary embolism , etc ( sethi 2000 ) .
patients with recurrent exacerbations are exposed to frequent courses of antimicrobials with a possible selection of antimicrobial resistance among common bacterial pathogens .
antibacterial therapy for aecb is aimed at relieving symptoms , preventing loss of pulmonary function that may lead to hospitalization , speeding recovery , and prolonging the time to the next exacerbation .
fluoroquinolones are widely used antibiotics for the treatment of aecb due to their excellent pharmacokinetic / dynamic properties , high antimicrobial activity , and low incidence of side - effects ( blasi et al 2003 ) .
we will review the available data on prulifloxacin efficacy and tolerability in the treatment of aecb.the review is based on a pubmed literature search , using as keyword  prulifloxacin 
, for original articles and reviews published in english from january 1990 to april 2006 .
thirty - five articles were retrieved , 15 articles on urinary tract infections or strictly preclinical studies were discarded , and 20 papers were analysed .
prulifloxacin ( 6-fluoro-1-methyl-7-[4-[(5-methyl-2-oxo-1 , 3-dioxol-4-yl)methyl]-1-piperazinyl]-4-oxo-1h , 4h-[1 , 3]thiazeto[3 , 2-a]quinoline-3-carboxylic acid ) , the prodrug of ulifloxacin , is a broad - spectrum oral fluoroquinolone antibacterial agent .
prulifloxacin is absorbed mainly from the upper small intestine and then metabolized to ulifloxacin in the liver by an -esterase ( paraoxonase ) ( first pass or presystemic metabolism ) ( tougou et al 1998 ) .
table 1 shows pharmacokinetic characteristics of prulifloxacin ( picollo et al 2003 ; matera 2006).ulifloxacin concentrations in serum and lung have been recently evaluated ( concia et al 2005 ) . in this open label study 27
a single dose of prulifloxacin 600 mg was administered and concentrations evaluated at 2 , 4 , 6 , 12 , or 24 hours preoperatively .
ulifloxacin concentrations in plasma and lung tissue were determined by reversed - phase high - performance liquid chromatography .
the results reported show lung tissue levels higher than plasma levels , however values appear to be widely dispersed . at time 2 , 4 , 6 , 12 , and 24-hour the values ranges ( lung tissue after correction for blood contamination )
the mean lung / plasma concentration ratio was 6.9  0.6 ( standard error ) reflecting the wide dispersion of concentration values .
good intracellular penetration in macrophages and human polimorphonuclear cells has been reported ( ozaki et al 1996 ) .
ulifloxacin strengthens the phagocytic and microbicidal activities of the peritoneal macrophages against klebsiella pneumoniae ( tullio et al 2000 ) . when intracellularly concentrated , ulifloxacin can kill the bacteria directly or make them more susceptible to the phagocyte bactericidal effect ( tullio et al 1999 )
moreover , ulifloxacin seems to modulate human polymorphonuclear ( pmn ) s in vitro synthesis of proinflammatory cytokines such as interleukin ( il)-8 , il 1 , and tumor necrosis factor- ( tnf ) ( reato et al 2004 ) . in healthy volunteers co - administration of theophylline and prulifloxacin
induces an increase of 15% theophylline area under the curve ( auc ) and t and a 15% reduction of clearance ( fattore et al 1998 ) .
likewise the other fluoroquinolones , cation - containing antacid , and iron preparations reduce absorption of prulifloxacin , these drugs should be administered 3 hours before or 2 hours after prulifloxacin ( keam et al 2004 ; prats et al 2006 ) .
in healthy volunteers co - administration of theophylline and prulifloxacin induces an increase of 15% theophylline area under the curve ( auc ) and t and a 15% reduction of clearance ( fattore et al 1998 ) .
likewise the other fluoroquinolones , cation - containing antacid , and iron preparations reduce absorption of prulifloxacin , these drugs should be administered 3 hours before or 2 hours after prulifloxacin ( keam et al 2004 ; prats et al 2006 ) .
ulifloxacin , the active metabolite of prulifloxacin , shows a wide spectrum of activity against gram - positive and gram - negative bacteria . in this review
we will address the activity against the main respiratory pathogen involved in exacerbations of chronic bronchitis .
as stated in a recent paper by roveta and colleagues ( 2005 ) , due to the absence of a defined breakpoint for prulifloxacin / ulifloxacin all the data are referred to ciprofloxacin breakpoint .
the activity against streptococcus pneumoniae seems to vary considerably between studies . in three of these studies
the ulifloxacin activity against s. pneumoniae resulted in fairly low minimum inhibitory concentration ( mic ) values ranging from 0.12 to > 4 g / ml , with a mic required to inhibit the growth of 90% of organisms ( mic90 ) value of > 4 g / ml ( ozaki et al 1991 ; yoshida and mitsuhashi 1993 ; prats et al 2002 ) . in their study , prats and colleagues showed a mic50 of ulifloxacin of 1 g / ml against the penicillin - susceptible strains and 2 g / ml for those presenting moderate and high resistance ; the mic90 was 4 g / ml for the penicillin - sensitive and intermediate strains and 2 g / ml for the highly resistant strains ( prats et al 2002 ) .
another study , performed on 36 italian strains , showed a better activity with mic values ranging from 0.015 to 2 g / ml and a mic90 value of 1 g / ml ( montanari et al 2001 ) .
ulifloxacin in vitro activity against strains of methicillin - susceptible staphylococcus aureus is fairly good with a reported mic90 value of < 0.5 g / ml ( montanari et al 2001 ; prats et al 2002 ) .
roveta and colleagues ( 2005 ) performed a susceptibility study on 300 clinical isolates . using ciprofloxacin breakpoint ,
72% of the strains were susceptible and prulifloxacin resulted in the most powerful available antipseudomonal fluoroquinolone with mic values ranging from 0.015 to 128 g / ml and a mic90 of 16 g / ml . in this study time 
kill tests at 4 mic confirmed the pronounced bactericidal potency of the drug against p. aeruginosa . amongst the members of the fluoroquinolone class assessed ,
prulifloxacin produced the lowest mutant prevention concentration ( mpc ) values ( 4 g / ml ) .
ulifloxacin activity against enterobacteriaceae is one of the best among fluoroquinolones , with mic90 values ranging from 0.015 to 0.25 g / ml .
haemophilus influenzae and moraxella catarrhalis are both highly susceptible to ulifloxacin with a mic90 always lower than 0.12 g / ml . no data are reported in the literature on the activity against mycoplasma pneumoniae and chlamydophila pneumoniae , though keam and perry ( 2004 ) report unpublished data on a limited activity of ulifloxacin against c. pneumoniae .
one study has been published on the activity of prulifloxacin in aecb indication ( grassi et al 2002 ) .
this double - blind , double - dummy , randomized study compared prulifloxacin 600 mg once daily with ciprofloxacin 500 mg twice daily for 10 days .
a total of 235 patients ( 117 prulifloxacin and 118 ciprofloxacin ) with anthonisen i and ii exacerbations of chronic bronchitis were enrolled ( anthonisen et al 1987 ) .
the clinical response at the end of treatment was assessed as : ( i ) cure ( resolution of all baseline symptoms ) , ( ii ) improvement ( decrease in intensity of all symptoms ) , and ( iii ) failure ( no decrease in the intensity of at least one symptom detected at baseline ) .
the primary parameter for the evaluation of efficacy was the clinical outcome . clinical cure or improvement
ninety - four patients ( 50 in prulifloxacin and 44 in ciprofloxacin group ) had a microbiological evaluation on sputum culture .
the bacteriologic response was based on the result of the sputum culture at the end of treatment as compared with baseline and was assessed as follows : ( i ) eradication ( the pathogen observed at baseline was not found at endpoint ) ; ( ii ) presumed eradication ( absence of sputum sample because the patient was clinically improved ) ; ( iii ) persistence ( presence of causative organism at the end of therapy ) ; ( iv ) superinfection ( a new organism at the end of therapy , regardless of whether the original pathogen was present ) . eradication and presumed eradication
one or more drug - related adverse events were reported by 15.4% ( 18/117 ) and 12.7% ( 15/118 ) patients in prulifloxacin and ciprofloxacin group , respectively .
the most common treatment - related adverse event in both treatment groups was gastric pain , reported by 10/117 ( 8.5% ) and 8/118 ( 6.8% ) patients in prulifloxacin and ciprofloxacin group , respectively .
one unpublished study comparing prulifloxacin with amoxicillin - clavulanate is reported in three reviews ( keam and perry 2004 ; cazzola et al 2006 ; prats et al 2006 ) , and another unpublished dose - finding study by cazzola and colleagues ( cazzola et al 2006 ) .
these two studies will not be described in the present review as they are not published .
limited data are reported in the literature on tolerability of prulifloxacin in the treatment of respiratory infections . in the grassi and colleagues ( 2002 ) study the pattern and incidence ( around 10%15% ) of adverse reaction were similar in prulifloxacin and ciprofloxacin treated patients , and mainly related to gastrointestinal disturbances . in their review , prats and colleagues ( 2006 ) report on some data on file concerning phototoxicity .
they describe a cross - over study on healthy volunteers that showed comparable effects with that of ciprofloxacin .
two studies address the potential cardiotoxicity of prulifloxacin ( lacroix et al 2003 ; akita et al 2004 ) .
both these studies show negligible effects on cardiac depolarization / repolarization cycle in vitro and in vivo indicating a very low probability of qc interval prolongation .
isolation of bacteria from sputum samples and the distal airways using a protected specimen brush ( fagon et al 1990 ; soler et al 1998 ) has identified haemophilus influenzae , streptococcus pneumoniae , and moraxella catarrhalis as the predominant respiratory pathogens in patients with aecb , with h.influenzae being identified most frequently ( in 30%70% of all episodes ) .
other bacteria identified in bronchial samples include the atypical pathogens chlamydophila ( chlamydia ) pneumoniae and mycoplasma pneumoniae , which have been implicated either as the sole causative agent or as co - pathogens in approximately 5%15% of acute exacerbations ( blasi et al 1993 ; mogulkoc et al 1999 ) .
the nature of the causative pathogen tends to vary according to the severity of the underlying chronic bronchitis and the degree of lung function impairment .
official or unofficial guidelines for the classification and antibacterial treatment of aecb and/or exacerbations of copd are available in a number of countries .
the treatment choice usually depends on a number of factors , including suspected or confirmed aetiology , clinical features and history , and local patterns of antibacterial resistance .
two additional criteria for antibacterial selection should be taken into account , the ability of the antibacterial to penetrate bronchial tissue and mucus , and low ecological risk ( ie , a low propensity to induce resistance ) . across the guidelines
, patients with chronic bronchitis or copd presenting with symptoms of an acute exacerbation are usually stratified into three groups .
the first group of patients presents with 2 anthonisen criteria , but generally have only mild to moderate impairment of lung function ( forced expiratory volume in one second [ fev1 ] > 50% of the predicted value ) , no comorbidities and <3 exacerbations / year .
a second group of patients is characterized by the presence of additional risk factors for treatment failure , which include moderate to severe lung function impairment ( fev1 > 35%<50% of the predicted value ) and/or significant comorbidity ( eg , cardiac disease , diabetes , hepatic / renal insufficiency ) and/or frequent exacerbations ( 4/year ) .
patients considered at the highest risk for treatment failure are included in the third group and often demonstrate very severe impairment of lung function ( fev1 < 35% of the predicted value ) and/or multiple risk factors ( including significant comorbidity , chronic corticosteroid therapy ) and frequent exacerbations ( 4/year ) .
this kind of patient stratification is also related to the bacterial flora associated with the exacerbations .
thus , in patients with mild to moderate chronic bronchitis , h. influenzae and s. pneumoniae are the most commonly isolated bacteria during aecb , while staphylococcus aureus and gram - negative bacteria , including pseudomonas aeruginosa and enterobacteriaceae species , are predominantly isolated from patients with a severe degree of airflow obstruction ( fev1 < 35% of the predicted value ) ( eller et al 1998 ; miravitlles et al 1999 ) . notwithstanding the paucity of published clinical data , the antimicrobial spectrum and the results of grassi and colleagues ( 2002 ) study
seem to indicate the possible role of prulifloxacin in the treatment of exacerbations of outpatients with moderate to severe copd , which are generally caused by gram - negative bacteria ( mainly haemophilus influenzae ) , enterobacteriaceae , and pseudomonas spp .
prulifloxacin is a new fluoroquinolone with indications in the treatment of urinary tract infection and acute exacerbations of chronic bronchitis .
the antibacterial spectrum is similar to that of ciprofloxacin with clear advantages in terms of antipseudomonal in vitro activity .
only few data on pharmacokinetic and pharmacodynamic characteristics , including bronchial and lung tissues , have been published .
the available data indicate a fairly good penetration into the lung tissue with high intracellular concentrations in phagocytes and pmns , with an interesting  immunomodulatory  activity .
the only published aecb treatment study shows a clinical and microbiological activity comparable with ciprofloxacin .
more data are clearly required to better evaluate the role of this new fluoroquinolone in the panorama of antibiotics .
 exacerbations of chronic bronchitis ( aecb ) are a major cause of morbidity and mortality in patients with chronic obstructive pulmonary disease ( copd ) , and their impact on public health is increasing . 
 the new fluoroquinolones have an excellent spectrum providing cover for the most important respiratory pathogens , including atypical and  typical  pathogens . 
 not surprisingly , different guidelines have inserted these agents among the drugs of choice in the empirical therapy of aecb . 
 the pharmacokinetic and dynamic properties of the new fluoroquinolones have a significant impact on their clinical and bacteriological efficacy . 
 they cause a concentration - dependent killing with a sustained post - antibiotic effect . 
 this review discusses the most recent data on the new fluoroquinolone prulifloxacin and critically analyses its activity and safety in the management of aecb . 
Introduction
Pharmacokinetic and pharmacodynamic features
Drug interactions
Microbiology
Clinical study
Safety and tolerability
Positioning of prulifloxacin in the treatment of AECB
Conclusions