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Bactericidal activity of quinolones against Streptococcus pneumoniae by time-kill methodology
JB.Infect Chemother (1999) 5:101–103 Jochimsen et al.: Stetteria hydrogenophila
© Japan Society of Chemotherapy 1999 101
NOTE Juan Carlos Rodríguez · Montserrat Ruiz Fernando García · Gloria Royo
Bactericidal activity of quinolones against Streptococcus pneumoniae by time-kill methodology
Received: June 29, 1998 / Accepted: December 3, 1998
Abstract The increase in Streptococcus pneumoniae strains resistant to the drugs traditionally used in treatment has made the search for alternative agents necessary. We studied the bactericidal activity of ciprofloxacin, ofloxacin, levofloxacin, sparfloxacin, and trovafloxacin against six penicillin-resistant Streptococcus pneumoniae strains, using time-kill methodology. Our results indicate that trovafloxacin and sparfloxacin had greater bactericidal activity than ciprofloxacin, ofloxacin, and levofloxacin against all the strains tested, since these two quinolones showed bactericidal activity against all six strains at concentrations of not more than 4 mg/l. Ciprofloxacin and levofloxacin did not have bactericidal activity, in the range of concentrations of antibiotics used, against any of the strains studied; when such activity did exist, the concentration of antibiotic used was higher. Key words Streptococcus pneumoniae · Quinolones · Bactericidal activity
Introduction The increase in Streptococcus pneumoniae antibiotic resistance has been especially noticeable in Spain,1–3 where, in addition to the already known high prevalence of Streptococcus pneumoniae strains with decreased susceptibility to penicillin, there is resistance to macrolides4 and third generation cephalosporins.5 For this reason, the appearance of new quinolones with increased activity against Grampositive cocci has given rise to great expectations regarding their therapeutic use, and these expectations need to be
J.C. Rodríguez (*) · M. Ruiz · F. García · G. Royo Laboratory of Microbiology, Hospital General Universitario de Elche, Universidad Miguel Hernández, Elche (Alicante), 03202 Elche (Alicante), Spain Tel. 134-96-6679493; Fax 134-96-6679108 e-mail: [email protected]
evaluated in depth. The objective of our study was to compare the bactericidal activity of ciprofloxacin, ofloxacin, levofloxacin, sparfloxacin, and trovafloxacin, using the timekill technique.
Materials and methods Bacteria. We used six clinical isolates of penicillin-resistant Streptococcus pneumoniae. Antibiotics. Ciprofloxacin (Bayer, Leverkusen, Germany), ofloxacin (Roussell UCLAF, Romainville, France), levofloxacin (Roussell UCLAF), sparfloxacin (RhonePoulenc Rorer, Vitry, France), and trovafloxacin (Pfizer, New York, NY, USA) were tested. The antibiotics were supplied by the manufacturers and diluted according to their instructions. Determination of minimum inhibitory concentration (MIC) and time-kill metholology. This was done as described in a previous paper.6
Results The MICs of antibiotics for the strains studied are shown in Table 1. It can be seen that sparfloxacin and trovafloxacin show an MIC90 of 0.5 mg/l, while ciprofloxacin has an MIC90 of 8 mg/l, ofloxacin an MIC90 of 4 mg/l, and levofloxacin an MIC90 of 16 mg/l for strain 1. The results (arithmetic mediaus of the six strains) obtained using the time-kill technique are shown in Table 2. Trovafloxacin and sparfloxacin had bactericidal activity against all six strains at concentrations not above 4 mg/l. Ciprofloxacin and levofloxacin did not show bactericidal activity against any of the strains studied at concentrations not exceeding 4 mg/l; when such activity was present the antibiotic concentrations were higher.
102
N. Matsuda et al.: EGF receptor and osteoblastic differentiation Table 1. MICs of antibiotics for strains studied MIC (mg/l)
Strain1 Strain 2 Strain 3 Strain 4 Strain 5 Strain 6
Ciprofloxacin
Ofloxacin
Sparfloxacin
Levofloxacin
Trovafloxacin
8 2 8 4 1 1
4 2 4 1 1 1
0.5 0.25 0.5 0.06 0.25 0.125
16 0.5 2 0.5 2 1
0.5 0.25 0.5 0.25 0.25 0.25
MIC, Minimum inhibitory concentration
Table 2. Decrease in bacterial number (log) with time Antibiotic
Concentration
1h
Ciprofloxacin
1 MIC 2 MIC 4 MIC 8 MIC 1 MIC 2 MIC 4 MIC 8 MIC 1 MIC 2 MIC 4 MIC 8 MIC 1 MIC 2 MIC 4 MIC 8 MIC 1 MIC 2 MIC 4 MIC 8 MIC
0.46 0.56 0.66 0.78 0.46 0.56 0.66 0.76 0.60 0.71 0.83 0.95 0.48 0.60 0.70 0.88 0.63 0.73 0.88 1.01
Ofloxacin
Sparfloxacin
Levofloxacin
Trovafloxacin
3h 6 0.12 6 0.12 6 0.12 6 0.16 6 0.08 6 0.08 6 0.08 6 0.08 6 0.19 6 0.22 6 0.26 6 0.27 6 0.13 6 0.12 6 0.13 6 0.21 6 0.16 6 0.16 6 0.25 6 0.32
Conclusions Studies carried out to determine bactericidal activity have produced findings in agreement with ours. Morrisey7 points out the good bactericidal activity of trovafloxacin and Visalli et al.8,9 underline the greater bactericidal activity of trovafloxacin and, to a lesser degree, of sparfloxacin in comparative studies with ciprofloxacin, clinafloxacin, and lomefloxacin, using a methodology similar to that used in our study. Klugman et al.10 emphasize that trovafloxacin is more effective than ciprofloxacin, temafloxacin, and ofloxacin in a mouse pneumonia model and in a rabbit meningitis model against both penicillin-resistant and penicillin-sensitive pneumococcus strains. On the other hand, there are discrepancies in the results regarding the activity of sparfloxacin. Dalhoff11 designed a model simulating the bronchial mucosa and evaluated the bactericidal activity of ciprofloxacin and sparfloxacin in the presence and absence of macrophages; both drugs had similar bactericidal activity despite the strains studied showing a lower MIC for sparfloxacin, and even in the absence of macrophages, ciprofloxacin had greater bactericidal activity
1.11 6 1.41 6 1.53 6 1.76 6 1.12 6 1.33 6 1.43 6 1.55 6 1.25 6 1.38 6 1.57 6 1.53 6 1.20 6 1.37 6 1.50 6 1.66 6 1.43 6 1.53 6 1.71 6 1.91 6
5h 0.14 0.29 0.28 0.30 0.16 0.36 0.36 0.40 0.11 0.07 0.22 0.58 0.41 0.35 0.33 0.31 0.33 0.38 0.40 0.51
1.56 2.03 2.28 2.43 1.48 1.88 2.13 2.28 1.58 1.85 2.45 2.62 1.66 1.88 2.18 2.43 2.00 2.15 2.50 2.70
7h 6 0.33 6 0.32 6 0.48 6 0.43 6 0.27 6 0.42 6 0.55 6 0.59 6 0.20 6 0.34 6 0.15 6 0.17 6 0.66 6 0.59 6 0.49 6 0.44 6 0.43 6 0.59 6 0.56 6 0.59
1.86 1.97 2.81 3.16 1.78 2.26 2.88 3.21 1.88 2.38 3.35 3.70 2.03 2.23 2.58 3.05 2.40 2.60 3.50 4.01
6 0.34 6 0.60 6 0.52 6 0.29 6 0.29 6 0.47 6 0.50 6 0.32 6 0.27 6 0.69 6 0.21 6 0.37 6 0.63 6 0.58 6 0.53 6 0.34 6 0.54 6 0.52 6 0.37 6 0.42
than sparfloxacin. George and Morrissey12 note that levofloxacin, ofloxacin, and ciprofloxacin show greater bactericidal activity than sparfloxacin against both penicillinresistant and penicillin-sensitive strains. Therefore, our results suggest that trovafloxacin and sparfloxacin have good antipneumococcal activity. However, we believe that these agents should be evaluated in greater detail to determine their true usefulness in the treatment of infective processes involving Streptococcus pneumoniae, and to examine the possible generation of resistance.
References 1. Lin˜ares J, Pallarés R, Pérez JL, Ayats J, Gudiol F, Villadrich PF, Martín R. Trends in antimicrobial resistance of clinical isolates of Streptococcus pneumoniae in Bellvitge Hospital, Barcelona, Spain (1979–1990). Clin Infect Dis 1992;15:99– 105. 2. Ruiz J, Ruiz Gomez J, Hernandez Carmona JL, Nun˜ez ML, Canteras M, Valdes M. Antibiotic resistance patterns of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella
B. Jochimsen et al.: Stetteria hydrogenophila
3. 4. 5.
6. 7. 8.
catarrhalis: a prospective study in Murcia, Spain, 1983–1992. Chemotherapy 1994;40:299–303. Pérez JJ, Lin˜ares J, Bosch J, López de Goicoechea MJ, Martín R. Antibiotic resistance of Streptococcus pneumoniae in childhood carriers. J Antimicrob Chemother 1987;19:278–80. Pahissa A. Los macrólidos en el tratamiento de la infección respiratoria. Enferm Infecc Microbiol Clin 1994;12:423–5. Pallarés R, Lin˜ares J, Vadillo M, Cabellos C, Manresa F, Fernández-Viladrich P. Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain. N Engl J Med 1995;333:474–80. Rodríguez JC, Ruiz de Loizaga P, Celdrán MT, Royo G. Bactericidal activity of 5 beta-lactam antibiotics against Streptococcus pneumoniae. J Infect Chemother 1997;3:146–9. Morrisey I. Bactericidal activity of trovafloxacin (CP-99, 219). J Antimicrob Chemother 1996;38:1061–6. Visalli MA, Jacobs MR, Appelbaum PC. Activity of CP 99, 219 (trovafloxacin) compared with ciprofloxacin, sparfloxacin, clin-
103
9.
10. 11. 12.
afloxacin, lomefloxacin and cefuroxime against ten penicillinsusceptible and penicillin-resistant pneumococci by time-kill methodology. J Antimicrob Chemother 1996;37:77–84. Visalli MA, Jacobs MR, Appelbaum PC. MIC and timekill study of activities of DU-6859a, ciprofloxacin, levofloxacin, sparfloxacin, cefotaxime, imipenem and vancomycin against nine penicillin-susceptible and resistant pneumococci. Antimicrob Agents Chemother 1996;40:362–6. Klugman KP, Gootz TD. In vitro and in vivo activity of trovafloxaun against Streptococcus pneumoniae. J Antimicrob Chemother 1997;Suppl B:51–5. Dalhoff A. Activities of ciprofloxacin and sparfloxacin against Streptococcus pneumoniae. Drugs 1995;49(Suppl 2):194–6. George J, Morrissey I. The bactericidal activity of levofloxacin compared with ofloxacin, D-ofloxacin, ciprofloxacin, sparfloxacin and cefotaxime against Streptococcus pneumoniae. J. Antimicrob Chemother 1997;39:719–23.
© Japan Society of Chemotherapy 1999 101
NOTE Juan Carlos Rodríguez · Montserrat Ruiz Fernando García · Gloria Royo
Bactericidal activity of quinolones against Streptococcus pneumoniae by time-kill methodology
Received: June 29, 1998 / Accepted: December 3, 1998
Abstract The increase in Streptococcus pneumoniae strains resistant to the drugs traditionally used in treatment has made the search for alternative agents necessary. We studied the bactericidal activity of ciprofloxacin, ofloxacin, levofloxacin, sparfloxacin, and trovafloxacin against six penicillin-resistant Streptococcus pneumoniae strains, using time-kill methodology. Our results indicate that trovafloxacin and sparfloxacin had greater bactericidal activity than ciprofloxacin, ofloxacin, and levofloxacin against all the strains tested, since these two quinolones showed bactericidal activity against all six strains at concentrations of not more than 4 mg/l. Ciprofloxacin and levofloxacin did not have bactericidal activity, in the range of concentrations of antibiotics used, against any of the strains studied; when such activity did exist, the concentration of antibiotic used was higher. Key words Streptococcus pneumoniae · Quinolones · Bactericidal activity
Introduction The increase in Streptococcus pneumoniae antibiotic resistance has been especially noticeable in Spain,1–3 where, in addition to the already known high prevalence of Streptococcus pneumoniae strains with decreased susceptibility to penicillin, there is resistance to macrolides4 and third generation cephalosporins.5 For this reason, the appearance of new quinolones with increased activity against Grampositive cocci has given rise to great expectations regarding their therapeutic use, and these expectations need to be
J.C. Rodríguez (*) · M. Ruiz · F. García · G. Royo Laboratory of Microbiology, Hospital General Universitario de Elche, Universidad Miguel Hernández, Elche (Alicante), 03202 Elche (Alicante), Spain Tel. 134-96-6679493; Fax 134-96-6679108 e-mail: [email protected]
evaluated in depth. The objective of our study was to compare the bactericidal activity of ciprofloxacin, ofloxacin, levofloxacin, sparfloxacin, and trovafloxacin, using the timekill technique.
Materials and methods Bacteria. We used six clinical isolates of penicillin-resistant Streptococcus pneumoniae. Antibiotics. Ciprofloxacin (Bayer, Leverkusen, Germany), ofloxacin (Roussell UCLAF, Romainville, France), levofloxacin (Roussell UCLAF), sparfloxacin (RhonePoulenc Rorer, Vitry, France), and trovafloxacin (Pfizer, New York, NY, USA) were tested. The antibiotics were supplied by the manufacturers and diluted according to their instructions. Determination of minimum inhibitory concentration (MIC) and time-kill metholology. This was done as described in a previous paper.6
Results The MICs of antibiotics for the strains studied are shown in Table 1. It can be seen that sparfloxacin and trovafloxacin show an MIC90 of 0.5 mg/l, while ciprofloxacin has an MIC90 of 8 mg/l, ofloxacin an MIC90 of 4 mg/l, and levofloxacin an MIC90 of 16 mg/l for strain 1. The results (arithmetic mediaus of the six strains) obtained using the time-kill technique are shown in Table 2. Trovafloxacin and sparfloxacin had bactericidal activity against all six strains at concentrations not above 4 mg/l. Ciprofloxacin and levofloxacin did not show bactericidal activity against any of the strains studied at concentrations not exceeding 4 mg/l; when such activity was present the antibiotic concentrations were higher.
102
N. Matsuda et al.: EGF receptor and osteoblastic differentiation Table 1. MICs of antibiotics for strains studied MIC (mg/l)
Strain1 Strain 2 Strain 3 Strain 4 Strain 5 Strain 6
Ciprofloxacin
Ofloxacin
Sparfloxacin
Levofloxacin
Trovafloxacin
8 2 8 4 1 1
4 2 4 1 1 1
0.5 0.25 0.5 0.06 0.25 0.125
16 0.5 2 0.5 2 1
0.5 0.25 0.5 0.25 0.25 0.25
MIC, Minimum inhibitory concentration
Table 2. Decrease in bacterial number (log) with time Antibiotic
Concentration
1h
Ciprofloxacin
1 MIC 2 MIC 4 MIC 8 MIC 1 MIC 2 MIC 4 MIC 8 MIC 1 MIC 2 MIC 4 MIC 8 MIC 1 MIC 2 MIC 4 MIC 8 MIC 1 MIC 2 MIC 4 MIC 8 MIC
0.46 0.56 0.66 0.78 0.46 0.56 0.66 0.76 0.60 0.71 0.83 0.95 0.48 0.60 0.70 0.88 0.63 0.73 0.88 1.01
Ofloxacin
Sparfloxacin
Levofloxacin
Trovafloxacin
3h 6 0.12 6 0.12 6 0.12 6 0.16 6 0.08 6 0.08 6 0.08 6 0.08 6 0.19 6 0.22 6 0.26 6 0.27 6 0.13 6 0.12 6 0.13 6 0.21 6 0.16 6 0.16 6 0.25 6 0.32
Conclusions Studies carried out to determine bactericidal activity have produced findings in agreement with ours. Morrisey7 points out the good bactericidal activity of trovafloxacin and Visalli et al.8,9 underline the greater bactericidal activity of trovafloxacin and, to a lesser degree, of sparfloxacin in comparative studies with ciprofloxacin, clinafloxacin, and lomefloxacin, using a methodology similar to that used in our study. Klugman et al.10 emphasize that trovafloxacin is more effective than ciprofloxacin, temafloxacin, and ofloxacin in a mouse pneumonia model and in a rabbit meningitis model against both penicillin-resistant and penicillin-sensitive pneumococcus strains. On the other hand, there are discrepancies in the results regarding the activity of sparfloxacin. Dalhoff11 designed a model simulating the bronchial mucosa and evaluated the bactericidal activity of ciprofloxacin and sparfloxacin in the presence and absence of macrophages; both drugs had similar bactericidal activity despite the strains studied showing a lower MIC for sparfloxacin, and even in the absence of macrophages, ciprofloxacin had greater bactericidal activity
1.11 6 1.41 6 1.53 6 1.76 6 1.12 6 1.33 6 1.43 6 1.55 6 1.25 6 1.38 6 1.57 6 1.53 6 1.20 6 1.37 6 1.50 6 1.66 6 1.43 6 1.53 6 1.71 6 1.91 6
5h 0.14 0.29 0.28 0.30 0.16 0.36 0.36 0.40 0.11 0.07 0.22 0.58 0.41 0.35 0.33 0.31 0.33 0.38 0.40 0.51
1.56 2.03 2.28 2.43 1.48 1.88 2.13 2.28 1.58 1.85 2.45 2.62 1.66 1.88 2.18 2.43 2.00 2.15 2.50 2.70
7h 6 0.33 6 0.32 6 0.48 6 0.43 6 0.27 6 0.42 6 0.55 6 0.59 6 0.20 6 0.34 6 0.15 6 0.17 6 0.66 6 0.59 6 0.49 6 0.44 6 0.43 6 0.59 6 0.56 6 0.59
1.86 1.97 2.81 3.16 1.78 2.26 2.88 3.21 1.88 2.38 3.35 3.70 2.03 2.23 2.58 3.05 2.40 2.60 3.50 4.01
6 0.34 6 0.60 6 0.52 6 0.29 6 0.29 6 0.47 6 0.50 6 0.32 6 0.27 6 0.69 6 0.21 6 0.37 6 0.63 6 0.58 6 0.53 6 0.34 6 0.54 6 0.52 6 0.37 6 0.42
than sparfloxacin. George and Morrissey12 note that levofloxacin, ofloxacin, and ciprofloxacin show greater bactericidal activity than sparfloxacin against both penicillinresistant and penicillin-sensitive strains. Therefore, our results suggest that trovafloxacin and sparfloxacin have good antipneumococcal activity. However, we believe that these agents should be evaluated in greater detail to determine their true usefulness in the treatment of infective processes involving Streptococcus pneumoniae, and to examine the possible generation of resistance.
References 1. Lin˜ares J, Pallarés R, Pérez JL, Ayats J, Gudiol F, Villadrich PF, Martín R. Trends in antimicrobial resistance of clinical isolates of Streptococcus pneumoniae in Bellvitge Hospital, Barcelona, Spain (1979–1990). Clin Infect Dis 1992;15:99– 105. 2. Ruiz J, Ruiz Gomez J, Hernandez Carmona JL, Nun˜ez ML, Canteras M, Valdes M. Antibiotic resistance patterns of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella
B. Jochimsen et al.: Stetteria hydrogenophila
3. 4. 5.
6. 7. 8.
catarrhalis: a prospective study in Murcia, Spain, 1983–1992. Chemotherapy 1994;40:299–303. Pérez JJ, Lin˜ares J, Bosch J, López de Goicoechea MJ, Martín R. Antibiotic resistance of Streptococcus pneumoniae in childhood carriers. J Antimicrob Chemother 1987;19:278–80. Pahissa A. Los macrólidos en el tratamiento de la infección respiratoria. Enferm Infecc Microbiol Clin 1994;12:423–5. Pallarés R, Lin˜ares J, Vadillo M, Cabellos C, Manresa F, Fernández-Viladrich P. Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain. N Engl J Med 1995;333:474–80. Rodríguez JC, Ruiz de Loizaga P, Celdrán MT, Royo G. Bactericidal activity of 5 beta-lactam antibiotics against Streptococcus pneumoniae. J Infect Chemother 1997;3:146–9. Morrisey I. Bactericidal activity of trovafloxacin (CP-99, 219). J Antimicrob Chemother 1996;38:1061–6. Visalli MA, Jacobs MR, Appelbaum PC. Activity of CP 99, 219 (trovafloxacin) compared with ciprofloxacin, sparfloxacin, clin-
103
9.
10. 11. 12.
afloxacin, lomefloxacin and cefuroxime against ten penicillinsusceptible and penicillin-resistant pneumococci by time-kill methodology. J Antimicrob Chemother 1996;37:77–84. Visalli MA, Jacobs MR, Appelbaum PC. MIC and timekill study of activities of DU-6859a, ciprofloxacin, levofloxacin, sparfloxacin, cefotaxime, imipenem and vancomycin against nine penicillin-susceptible and resistant pneumococci. Antimicrob Agents Chemother 1996;40:362–6. Klugman KP, Gootz TD. In vitro and in vivo activity of trovafloxaun against Streptococcus pneumoniae. J Antimicrob Chemother 1997;Suppl B:51–5. Dalhoff A. Activities of ciprofloxacin and sparfloxacin against Streptococcus pneumoniae. Drugs 1995;49(Suppl 2):194–6. George J, Morrissey I. The bactericidal activity of levofloxacin compared with ofloxacin, D-ofloxacin, ciprofloxacin, sparfloxacin and cefotaxime against Streptococcus pneumoniae. J. Antimicrob Chemother 1997;39:719–23.