Prulifloxacin in the treatment of acute exacerbations of COPD in

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     1Unitof Pulmonary Rehabilitation,
       IRCCS San Raffaele, Velletri,
                 Rome, Italy
      2Unit of Respiratory Medicine,

     Department of Internal Medicine,
     University of Rome “Tor Vergata”,
                 Rome, Italy



Prulifloxacin in the treatment of
acute exacerbations of COPD in
        cigarette smokers
Gianluca Biscione1, Girolmina Crigna1,
   Franco Pasqua1, Mario Cazzola2
 Bacterial isolates and cigarette smoking in patients with
    COPD: results from an Italian multicentre survey
            No         H.         S.             S. aureus    M.            No         Smoking
            patients   influenzae pneumoniae                  catarrhalis   isolates   index*
South       193        36,6%      22,3%          7,3%         6,7%          17,1%      648,9


North       83         15,7%      15,7%          25,3%        6,0%          12,0%      653,6


Totals      276        30,4%      20,3%          12,7%        6,5%          15,6%      650,4


Smoking                827,1      599,1          691,2        541,9%        445,6%
index
   >800                  48.8%       26,8%        40,0%          11,2%         20,9%
   <400                  21.4%       46,4%        20,0%          55,6%         51,1%
Pulmonary
function
  FEV1                 56.6%      65,7%          55,1%        69,1%         70,1%
  FVC                  68.8%      74,8%          63,0%        80,5%         77,8%

*Number of cigarettes smoked daily x years of smoking
                                                             Cazzola et al, Clin Ther 1990;12:105-17
Cigarette smoking and Haemophilus
               influenzae
There is an association between heavy
 cigarette smoking and LRTI.
Heavy smokers are particularly
 susceptible to LRTI caused by H.
 influenzae.
The effect on respiratory function of
 both cigarette smoking and H.
 influenzae infection appeared to be
 cumulative.
                         Cazzola et al, Clin Ther 1990;12:105-17
Tobacco or pure nicotine stimulate the growth
 of H. influenzae in vitro in nutritionally poor
             bacteriological media
    tobacco                             nicotine




                          Roberts e Cole, J Clin Pathol 1979;32:728-31
Germs isolated in sputum during exacerbations of
    COPD according to impairment in FEV1




                             Miravitlles et al, Chest 1999;116:40-6
Factors independently associated with isolation
  of the most common potentially pathogenic
               microorganisms




                             Miravitlles et al, Chest 1999;116:40-6
    Degree of functional impairment,
  smoking habit and empiric treatments

 Low FEV1 and active tobacco smoking are
  data that should be considered when
  establishing an empiric antibiotic treatment
  for exacerbated COPD.
 The influence that new empiric treatments,
  which are used according to the degree of
  functional impairment and the smoking habit,
  may have on improving the condition of the
  patient is a subject worthy of further
  investigation.
                           Cazzola et al, J Chemother 1991;3:245-9
                             Miravitlles et al, Chest 1999;116:40-6
                      Prulifloxacin


                                                             CH3
                O
                               N
        O                                                        S

                O                      N                 N
                         CH3


                                        F                          COOH

                                                         O



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

       Prulifloxacin is the prodrug of ulifloxacin
   A comparison of the MICs of ulifloxacin and
      other fluoroquinolones for respiratory
    pathogens isolated in 1998 to 2000 in Italy

Organism           Ulifloxacin      Ciprofloxacin            Levofloxacin
                 (prulifloxacin)
H. influenzae       ≤0,015                 0,03                     0,06

M. catarrhalis        0,06                 0,12                     0,12

K. pneumoniae         0,12                 0,25                       1

S. pneumoniae          1                     1                        1

P. aeruginosa          1                     1                        2

S. aureus             0,5                   0,5                     0,25

                                                 Montanari et al. AA&C 2001;45:3616-22
                             Prats et al. Eur J Clin Microbiol Infect Dis 2002;21:328-334
Penetration of prulifloxacin (600 mg) into lung
 tissue after oral administration to subjects
 undergoing lobectomy or pneumonectomy
   Concentrazione




                     tempo




                        Concia et al. Clin Pharmacokinet 2005;44:1287-94
   The efficacy of an antibiotic to
    treat lower respiratory tract
   infections can depend on the
  levels reached by the drug and
the retention times in the different
    pulmonary sites of infection


                  Cazzola et al, Am J Respir Med 2002
          Aim of the study
 These   features suggest that
  prulifloxacin should be considered an
  appropriate antibiotic for the
  treatment of AECOPD in smokers.
 In order to confirm this hypothesis, we
  treated a group of smokers that came
  to our observation because of an
  AECOPD with this fluoroquinolone.
                 Patients
 Sixty-one eligible adult smokers suffering
  from COPD, hospitalized or outpatients, of
  both sexes, with symptoms and signs
  compatible with the usual diagnosis criteria
  for acute exacerbation (e.g., increased
  cough, dyspnea, increased sputum volume,
  and increased sputum purulence) and a
  positive culture of a pre-therapy sputum
  specimen with a respiratory pathogen.
              Methods
Clinical evaluation and bacteriological
 examination of sputum before therapy
 and at 3–5 (post therapy) and 10–14
 (late post therapy) days after the
 completion of treatment.
Oral prulifloxacin 600mg once daily for
 10 days and a short course of oral
 prednisolone 25 mg/die.
Clinical (symptomatic) response
           assessment
 cure: an elimination of signs and symptoms
  and no recurrence at the follow-up visits;
 improvement: a significant, but incomplete,
  resolution of signs or symptoms;
 relapse: worsening of signs and symptoms
  following an initial improvement;
 failure: no improvement.

   Patients were designated as unappreciable if they could
   not be assigned to a category and were disqualified for
                      efficacy analysis.
  Bacteriological response assessment
At post- therapy visit
• eradication: pathogen eliminated;
• persistence: culture positive for original pathogen;
• colonization: culture positive for a new pathogen without
   the signs of infection;
• superinfection: culture positive for a new pathogen
   during therapy (required symptomatic response)
At late post therapy visit
• eradication: pathogen eliminated;
• relapse: recurrence of the same pathogen with or
   without the development of resistance (required a
   positive follow-up culture preceded by at least one
   negative culture);
• colonization: culture positive for a new pathogen without
   the signs of infection;
• eradication with reinfection: culture positive for a new
   pathogen after treatment (required symptomatic
   response of failure or relapse).
    No follow-up sputum specimen
         produced for culture
• presumed microbiological persistence: no follow-up
  culture obtained with asymptomatic response of
  relapse or failure;
• presumptive eradication: implied absence of
  appropriate material for culture, or culture not
  clinically indicated (required symptomatic response
  of cure or improvement);
• indeterminate: could not be evaluated
  (bacteriological response could not be defined or
  categorized), or new antibiotic started for a
  condition other than the study indication before
  appropriate material for culture was obtained, or no
  pathogen isolated from the pre-therapy culture.
Most common bacterial species isolated
in sputum of 61 smokers suffering from
               AECOPD
Clinical response rates
Bacteriological responses by
          organism
                Conclusion
The results of our study show that 10 day
 treatment with 600mg prulifloxacin od was
 effective and well tolerated in the treatment of
 AECOPD in adult smokers.
Prulifloxacin was extremely active against the
 main pathogen of clinical relevance in
 smokers, H. influenzae, and it was also active
 against S. pneumoniae, S. aureus, and M.
 catarrhalis.
Thus, prulifloxacin 600mg od can be
 considered a first choice treatment for
 AECOPD in smokers.