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Prulifloxacin: a brief review of its potential in the treatment of acute exacerbation of chronic bronchitis.

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
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 infl ammation-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 prulifl oxacin effi cacy and tolerability in the treatment of AECB.The review is based on a PUBMED literature search, using as keyword "prulifl oxacin", for original articles and reviews published in English from January 1990 to April 2006. Thirty-fi ve articles were retrieved, 15 articles on urinary tract infections or strictly preclinical studies were discarded, and 20 papers were analysed.
Good intracellular penetration in macrophages and human polimorphonuclear cells has been reported (Ozaki et al 1996). Ulifl oxacin strengthens the phagocytic and microbicidal activities of the peritoneal macrophages against Klebsiella pneumoniae (Tullio et al 2000). When intracellularly concentrated, ulifl oxacin can kill the bacteria directly or make them more susceptible to the phagocyte bactericidal effect (Tullio et al 1999). Moreover, ulifl oxacin seems to modulate human polymorphonuclear (PMN)'s in vitro synthesis of proinfl ammatory cytokines such as interleukin (IL)-8, IL 1β, and tumor necrosis factor-α (TNFα) (Reato et al 2004).

Drug interactions
In healthy volunteers co-administration of theophylline and prulifl oxacin induces an increase of 15% theophylline area under the curve (AUC) and T ½ and a 15% reduction of clearance (Fattore et al 1998). Likewise the other fl uoroquinolones, cation-containing antacid, and iron preparations reduce absorption of prulifl oxacin, these drugs should be administered 3 hours before or 2 hours after prulifl oxacin (Keam et al 2004;Prats et al 2006).

Microbiology
Ulifl oxacin, the active metabolite of prulifl oxacin, 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 defi ned breakpoint for prulifl oxacin/ulifl oxacin all the data are referred to ciprofl oxacin breakpoint. This clearly hampers the clinical interpretation of the susceptibility data.
The activity against Streptococcus pneumoniae seems to vary considerably between studies. In three of these studies the ulifl oxacin activity against S. pneumoniae resulted in fairly low minimum inhibitory concentration (MIC) values ranging from 0.12 to >4 μg/ml, with a MIC required to inhibit the growth of 90% of organisms (MIC 90 ) value of >4 μg/ml (Ozaki et al 1991;Yoshida and Mitsuhashi 1993;Prats et al 2002).
In their study, Prats and colleagues showed a MIC 50 of ulifl oxacin of 1 μg/ml against the penicillin-susceptible strains and 2 μg/ml for those presenting moderate and high resistance; the MIC 90 was 4 μg/ml for the penicillin-sensitive and intermediate strains and 2 μg/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 μg/ml and a MIC 90 value of 1 μg/ml (Montanari et al 2001).
Ulifl oxacin in vitro activity against strains of methicillin-susceptible Staphylococcus aureus is fairly good with a reported MIC 90 value of <0.5 μg/ml (Montanari et al 2001;Prats et al 2002). No activity was demonstrated against methicillin-resistant strains.
The spectrum of activity mainly addresses Gram negative bacteria, including Pseudomonas aeruginosa. Roveta and colleagues (2005) performed a susceptibility study on 300 clinical isolates. Using ciprofl oxacin breakpoint, 72% of the strains were susceptible and prulifl oxacin resulted in the most powerful available antipseudomonal fl uoroquinolone with MIC values ranging from 0.015 to 128 μg/ml and a MIC 90 of 16 μg/ml.

Prulifl oxacin and AECB
In this study time-kill tests at 4× MIC confi rmed the pronounced bactericidal potency of the drug against P. aeruginosa. Amongst the members of the fl uoroquinolone class assessed, prulifl oxacin produced the lowest mutant prevention concentration (MPC) values (ഛ4 μg/ml).
Ulifl oxacin activity against Enterobacteriaceae is one of the best among fl uoroquinolones, with MIC 90 values ranging from 0.015 to 0.25 μg/ml .
Haemophilus infl uenzae and Moraxella catarrhalis are both highly susceptible to ulifl oxacin with a MIC 90 always lower than 0.12 μg/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 ulifl oxacin against C. pneumoniae.

Clinical study
One study has been published on the activity of prulifl oxacin in AECB indication (Grassi et al 2002). This double-blind, double-dummy, randomized study compared prulifl oxacin 600 mg once daily with ciprofl oxacin 500 mg twice daily for 10 days. The study was performed in 18 French and 7 Italian centers. A total of 235 patients (117 prulifl oxacin and 118 ciprofl oxacin) 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 effi cacy was the clinical outcome. Clinical cure or improvement were considered as therapeutic success.
Ninety-four patients (50 in prulifl oxacin and 44 in ciprofl oxacin 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 were considered a microbiological success.
One unpublished study comparing prulifl oxacin with amoxicillin-clavulanate is reported in three reviews (Keam and Perry 2004;Cazzola et al 2006;Prats et al 2006), and another unpublished dose-fi nding 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.

Safety and tolerability
Limited data are reported in the literature on tolerability of prulifl oxacin 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 prulifl oxacin and ciprofl oxacin treated patients, and mainly related to gastrointestinal disturbances. In their review, Prats and colleagues (2006) report on some data on fi le concerning phototoxicity. They describe a cross-over study on healthy volunteers that showed comparable effects with that of ciprofl oxacin. Two studies address the potential cardiotoxicity of prulifl oxacin (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.

Positioning of prulifl oxacin in the treatment of AECB
Isolation of bacteria from sputum samples and the distal airways using a protected specimen brush (Fagon et al 1990;Soler et al 1998) has identifi ed Haemophilus infl uenzae, Streptococcus pneumoniae, and Moraxella catarrhalis as the predominant respiratory pathogens in patients with AECB, with H.infl uenzae being identifi ed most frequently (in 30%-70% of all episodes) . Other bacteria identifi ed 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. Offi cial or unoffi cial guidelines for the classifi cation 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 confi rmed aetiology, clinical features and history, and local patterns of antibacterial resistance. Other relevant factors include the tolerability, convenience, and cost of treatment. 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 stratifi ed into three groups. The fi rst group of patients presents with ജ2 Anthonisen criteria, but generally have only mild to moderate impairment of lung function (forced expiratory volume in one second [FEV 1 ] >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 (FEV 1 >35%-<50% of the predicted value) and/or signifi cant comorbidity (eg, cardiac disease, diabetes, hepatic/renal insuffi ciency) and/or frequent exacerbations (ജ4/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 (FEV 1 <35% of the predicted value) and/or multiple risk factors (including signifi cant comorbidity, chronic corticosteroid therapy) and frequent exacerbations (≥4/year). This kind of patient stratifi cation is also related to the bacterial fl ora associated with the exacerbations.
Thus, in patients with mild to moderate chronic bronchitis, H. infl uenzae 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 airfl ow obstruction (FEV 1 <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 prulifl oxacin in the treatment of exacerbations of outpatients with moderate to severe COPD, which are generally caused by Gram-negative bacteria (mainly Haemophilus infl uenzae), Enterobacteriaceae, and Pseudomonas spp.

Conclusions
Prulifl oxacin is a new fl uoroquinolone with indications in the treatment of urinary tract infection and acute exacerbations of chronic bronchitis. The antibacterial spectrum is similar to that of ciprofl oxacin 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 ciprofl oxacin.
More data are clearly required to better evaluate the role of this new fl uoroquinolone in the panorama of antibiotics.