Abstract

The in vitro activity of gatifloxacin was determined for 873 isolates from various infections during 1997–1998 in Japan. Gatifloxacin was active against streptococci, Escherichia coli, Klebsiella pneumoniae, Moraxella catarrhalis, Haemophilus influenzae and Neisseria gonorrhoeae, with MIC90s of ≤0.39 mg/L. The activity was two- to 32-fold greater than that of ciprofloxacin and levofloxacin against Gram-positive bacteria, and comparable to that against Gram-negative bacteria. Gatifloxacin was more active than the other quinolones against quinolone-resistant staphylococci, Enterococcus faecalis, E. coli and Enterobacter cloacae. It also had good activity against penicillin- or macrolide-resistant Streptococcus pneumoniae and ampicillin-resistant H. influenzae.

Introduction

The increasing prevalence of antimicrobial resistance, for example methicillin resistance in Staphylococcus aureus, penicillin resistance in Streptococcus pneumoniae, vancomycin resistance in enterococci and ampicillin resistance in Haemophilus influenzae, has become a serious problem.13 Quinolones are active against Gram-positive and -negative bacteria and have been used in the treatment of various infections, but resistance to these agents has been demonstrated in many bacterial species.4

Gatifloxacin, a new 8-methoxyquinolone, has a broad spectrum of activity with expanded potency against Gram-positive cocci.58 In this study, we examined the in vitro activity of gatifloxacin against recent clinical pathogens isolated from patients with respiratory tract, urinary tract or surgical infections in Japan, and compared it with that of other quinolones and structurally unrelated antimicrobial agents.

Materials and methods

Antibacterial agents

Gatifloxacin, levofloxacin, ciprofloxacin and sparfloxacin were synthesized at Kyorin Pharmaceutical Co., Ltd (Tokyo, Japan). Oxacillin, penicillin G, ampicillin, cefaclor and minocycline were purchased from Sigma Chemical Co. (St Louis, MO, USA), and clarithromycin was obtained from Dainabot Co., Ltd (Tokyo, Japan).

Bacterial strains

All 873 clinical strains used in this study were isolated from patients with respiratory tract, urinary tract or surgical infections during 1997–1998 in Japan.

Susceptibility testing

MICs were determined by a two-fold agar dilution method with Mueller–Hinton medium (Difco, Detroit, MI, USA) and an inoculum of approximately 1 × 104 cfu/spot as recommended by the Japan Society of Chemotherapy.9 This medium was supplemented with 5% defibrinated horse blood for streptococci, Enterococcus faecalis and Moraxella catarrhalis, and with 5% Fildes extract (Oxoid, Basingstoke, UK) for H. influenzae. Chocolate agar was used for Neisseria gonorrhoeae. H. influenzae and N. gonorrhoeae were incubated in a CO2 incubator. For the detection of methicillin-resistant staphylococci, oxacillin was used with salt agar (2% NaCl) incubated at 32°C. β-Lactamase production was assessed using nitrocefin-impregnated sticks (Oxoid).

Results and discussion

The Table shows the in vitro activities of gatifloxacin against recent isolates from respiratory (A), urinary tract (B) and surgical (C) infections.

The MIC90s of gatifloxacin for methicillin-susceptible staphylococci were 0.20 mg/L for respiratory tract pathogens, 1.56–25 mg/L for urinary tract pathogens and 0.10–1.56 mg/L for surgical pathogens. The activity against methicillin-resistant S. aureus was lower than that against methicillin-susceptible S. aureus (MSSA). Gatifloxacin inhibited all isolates of S. pneumoniae and Streptococcus pyogenes at 0.78 mg/L. The MIC90 for uropathogenic E. faecalis was 25 mg/L (none of the E. faecalis strains were resistant to vancomycin). Gatifloxacin was two- to 32-fold more active than levofloxacin and ciprofloxacin and its activity against Gram-positive cocci was comparable to that of sparfloxacin.

The activity of gatifloxacin against Enterobacteriaceae was comparable to that of the other quinolones. All isolates of Escherichia coli and Klebsiella pneumoniae from respiratory tract infections were inhibited at 0.78 mg/L of gatifloxacin. The MIC90s for Pseudomonas aeruginosa were 3.13 mg/L for respiratory and surgical pathogens and 100 mg/L for uropathogens. H. influenzae and M. catarrhalis were highly susceptible to gatifloxacin, with MIC90s of 0.025 and 0.05 mg/L, respectively. The activity of gatifloxacin was two- to four-fold higher than that of levofloxacin and ciprofloxacin against N. gonorrhoeae. Gatifloxacin activity was roughly comparable to that of the other quinolones against Gram-negative organisms.

In this study, gatifloxacin showed potent in vitro antibacterial activity against the majority of recent Japanese clinical isolates of MSSA, streptococci, E. coli, K. pneumoniae, M. catarrhalis, H. influenzae and N. gonorrhoeae. In particular, all isolates of H. influenzae, S. pneumoniae and M. catarrhalis, major causative pathogens of respiratory infections, were susceptible to≤0.39 mg/L of gatifloxacin.

We determined the MIC of gatifloxacin for recent clinical isolates from various clinical fields separately. Compared with the respiratory or surgical pathogens, most of the isolates from urinary tract infections were less susceptible to quinolones. This decline in the susceptibility of urinary isolates could be associated with the selection of resistant mutants caused by exposure to the drug.

Highly quinolone-resistant strains were observed in staphylococci, E. faecalis, the Enterobacteriaceae and P. aeruginosa. Gatifloxacin was more potent than the other quinolones against these resistant strains, except for P. aeruginosa, while it showed comparable activity against quinolone-susceptible Gram-positive and/or -negative strains. The finding that quinolone-resistant strains showed incomplete cross-resistance to gatifloxacin suggests a difference in the mode of action between gatifloxacin and other quinolones. Fukuda et al.7 have reported that gatifloxacin is more potent than other quinolones against quinolone-resistant S. aureus possessing mutations in grlA and gyrA, encoding the quinolone target enzymes topoisomerase IV and DNA gyrase, respectively, and overproducing NorA protein, which functions as an efflux pump. The findings obtained in this study with clinical isolates are consistent with the results of Fukuda et al.7

Of 42 S. pneumoniae strains, eight (19%) were resistant to penicillin G (MIC≥0.78 mg/L), six (14%) to clarithromycin (MIC≥1.56 mg/L) and 29 (69%) to minocycline (MIC≥1.56 mg/L). Gatifloxacin showed good activity against S. pneumoniae strains resistant to these drugs; it also showed good activity against seven strains of ampicillin-resistant H. influenzae (MIC of ampicillin≥1.56 mg/L, one of which was β-lactamase positive) with MICs of 0.0125–0.25 mg/L.

The maximum serum concentration of gatifloxacin is 1.71 mg/L and its elimination half-life is 7–8 h, with a mean peak urinary concentration of 240 mg/L after a single oral administration of 200 mg in humans.10 The in vitro antibacterial activity of gatifloxacin described in this study, together with its favourable pharmacokinetic profile, indicate that gatifloxacin may be useful in the treatment of infections caused by various pathogens, including drug-resistant strains.

Table. Antibacterial activity of gatifloxacin against recent clinical isolates in Japan

  MIC (mg/L) 
Organism (no. of strains) Drug range 50% 90% 
aCoagulase-negative staphylococci: S. epidermidis (21), S. saprophyticus (4), S. warneri (2), S. simulans (1), S. haemolyticus (1), S. lugdunensis (1). 
A. Respiratory infections     
Methicillin-susceptible gatifloxacin 0.025–3.13 0.10 0.20 
Staphylococcus aureus (30) levofloxacin 0.10–6.25 0.20 0.39 
(oxacillin≤2 mg/L) ciprofloxacin 0.10–12.5 0.39 0.78 
 sparfloxacin 0.025–12.5 0.05 0.10 
Methicillin-resistant gatifloxacin 0.05–100 3.13 6.25 
Staphylococcus aureus (33) levofloxacin 0.10–>100 6.25 25 
(oxacillin >2 mg/L) ciprofloxacin 0.20–>100 25 100 
 sparfloxacin 0.025–100 6.25 12.5 
 gatifloxacin 0.10–0.39 0.39 0.39 
 levofloxacin 0.39–1.56 0.78 1.56 
 ciprofloxacin 0.78–3.13 1.56 1.56 
Streptococcus pneumoniae (42) sparfloxacin 0.10–0.78 0.39 0.39 
 ampicillin ≤0.0063–6.25 0.05 3.13 
 cefaclor 0.025–>100 0.78 50 
 clarithromycin ≤0.0063–>100 0.025 100 
 minocycline ≤0.0063–25 6.25 12.5 
 gatifloxacin 0.0125–0.78 0.0125 0.10 
Escherichia coli (39) levofloxacin 0.0125–0.78 0.025 0.20 
 ciprofloxacin ≤0.0063–0.78 0.0125 0.10 
 sparfloxacin ≤0.0063–0.78 0.0125 0.10 
 gatifloxacin 0.0125–0.78 0.05 0.05 
Klebsiella pneumoniae (35) levofloxacin 0.025–0.78 0.05 0.10 
 ciprofloxacin ≤0.0063–0.39 0.025 0.05 
 sparfloxacin ≤0.0063–0.39 0.05 0.05 
 gatifloxacin 0.10–50 0.78 3.13 
Pseudomonas aeruginosa (50) levofloxacin 0.10–100 0.78 3.13 
 ciprofloxacin 0.05–25 0.20 1.56 
 sparfloxacin 0.10–100 0.78 3.13 
 gatifloxacin ≤0.0063–0.05 0.025 0.05 
Moraxella catarrhalis (21) levofloxacin 0.0125–0.05 0.05 0.05 
(20 β-lactamase producers) ciprofloxacin ≤0.0063–0.05 0.025 0.05 
 sparfloxacin ≤0.0063–0.025 0.0125 0.025 
 gatifloxacin ≤0.0063–0.10 0.0125 0.025 
 levofloxacin 0.0125–0.20 0.025 0.025 
Haemophilus influenzae (27) ciprofloxacin ≤0.0063–0.39 0.0125 0.025 
 sparfloxacin ≤0.0063–0.20 0.0125 0.05 
 ampicillin 0.20–6.25 0.39 1.56 
B. Urinary tract infections     
Methicillin-susceptible gatifloxacin 0.05–25 0.10 1.56 
Staphylococcus aureus (22) levofloxacin 0.10–100 0.20 6.25 
(oxacillin≤2 mg/L) ciprofloxacin 0.20–>100 0.39 12.5 
 sparfloxacin 0.025–100 0.05 3.13 
Methicillin-resistant gatifloxacin 1.56–25 6.25 25 
Staphylococcus aureus (18) levofloxacin 3.13–50 25 50 
(oxacillin >2 mg/L) ciprofloxacin 12.5–>100 100 >100 
 sparfloxacin 3.13–25 12.5 25 
Methicillin-susceptible CNSa (30) gatifloxacin 0.05–50 0.39 25 
(oxacillin≤2 mg/L) levofloxacin 0.05–>100 0.39 50 
 ciprofloxacin 0.05–50 3.13 50 
 sparfloxacin 0.05–100 3.13 50 
Methicillin-resistant gatifloxacin 0.10–50 1.56 50 
Staphylococcus epidermidis (17) levofloxacin 0.10–>100 6.25 >100 
(oxacillin >2 mg/L) ciprofloxacin 0.20–100 25 50 
 sparfloxacin 0.025–100 6.25 100 
 gatifloxacin 0.20–50 0.78 25 
Enterococcus faecalis (75) levofloxacin 0.78–>100 3.13 50 
 ciprofloxacin 0.39–>100 3.13 100 
 sparfloxacin 0.20–100 0.78 100 
 gatifloxacin 0.0125–12.5 0.025 0.20 
Escherichia coli (40) levofloxacin 0.0125–25 0.025 0.39 
 ciprofloxacin ≤0.0063–50 0.0125 0.20 
 sparfloxacin ≤0.0063–50 0.0125 0.20 
 gatifloxacin ≤0.0063–25 0.20 12.5 
Enterobacter cloacae (29) levofloxacin 0.0125–50 0.20 50 
 ciprofloxacin ≤0.0063–100 0.05 100 
 sparfloxacin 0.0125–100 0.20 100 
 gatifloxacin 0.025–25 0.78 12.5 
Serratia marcescens (40) levofloxacin 0.0125–25 0.78 12.5 
 ciprofloxacin 0.0125–25 0.39 12.5 
 sparfloxacin 0.025–25 1.56 12.5 
 gatifloxacin 0.20–>100 1.56 100 
Pseudomonas aeruginosa (49) levofloxacin 0.10–>100 1.56 >100 
 ciprofloxacin 0.05–>100 0.39 100 
 sparfloxacin 0.20–>100 1.56 >100 
 gatifloxacin ≤0.0063–1.56 0.10 0.39 
Neisseria gonorrhoeae (42) levofloxacin ≤0.0063–6.25 0.39 0.78 
 ciprofloxacin ≤0.0063–6.25 0.20 1.56 
 sparfloxacin ≤0.0063–6.25 0.10 0.78 
C. Surgical infections     
Methicillin-susceptible gatifloxacin 0.05–1.56 0.10 0.10 
Staphylococcus aureus (47) levofloxacin 0.10–3.13 0.20 0.39 
(oxacillin≤2 mg/L) ciprofloxacin 0.20–6.25 0.39 0.78 
 sparfloxacin 0.0125–3.13 0.05 0.10 
Methicillin-resistant gatifloxacin 0.10, 0.10, 6.25   
 Staphylococcus aureus (3) levofloxacin 0.20, 0.20, 12.5  
 (oxacillin >2 mg/L) ciprofloxacin 0.10, 0.39, >100  
 sparfloxacin 0.05, 0.05, 6.25   
Methicillin-susceptible gatifloxacin 0.05–50 0.10 1.56 
Staphylococcus epidermidis (38) levofloxacin 0.10–>100 0.20 12.5 
(oxacillin≤2 mg/L) ciprofloxacin 0.10–100 0.20 50 
 sparfloxacin 0.05–100 0.10 6.25 
Methicillin-resistant gatifloxacin 0.0125–1.56 0.20 1.56 
Staphylococcus epidermidis (12) levofloxacin 0.025–12.5 0.78 6.25 
(oxacillin > 2 mg/L) ciprofloxacin 0.0125–50 1.56 50 
 sparfloxacin ≤0.0063–6.25 0.20 3.13 
 gatifloxacin 0.10–0.78 0.20 0.39 
Streptococcus pyogenes (34) levofloxacin 0.39–3.13 0.39 1.56 
 ciprofloxacin 0.20–3.13 0.39 3.13 
 sparfloxacin 0.10–1.56 0.39 0.78 
 gatifloxacin ≤0.0063–6.25 0.025 0.10 
Escherichia coli (50) levofloxacin ≤0.0063–25 0.05 0.20 
 ciprofloxacin ≤0.0063–50 0.0125 0.10 
 sparfloxacin ≤0.0063–25 0.0125 0.10 
 gatifloxacin 0.10–>100 0.78 3.13 
Pseudomonas aeruginosa (50) levofloxacin 0.10–>100 0.78 6.25 
 ciprofloxacin 0.025–100 0.20 0.78 
 sparfloxacin 0.20–>100 0.78 3.13 
  MIC (mg/L) 
Organism (no. of strains) Drug range 50% 90% 
aCoagulase-negative staphylococci: S. epidermidis (21), S. saprophyticus (4), S. warneri (2), S. simulans (1), S. haemolyticus (1), S. lugdunensis (1). 
A. Respiratory infections     
Methicillin-susceptible gatifloxacin 0.025–3.13 0.10 0.20 
Staphylococcus aureus (30) levofloxacin 0.10–6.25 0.20 0.39 
(oxacillin≤2 mg/L) ciprofloxacin 0.10–12.5 0.39 0.78 
 sparfloxacin 0.025–12.5 0.05 0.10 
Methicillin-resistant gatifloxacin 0.05–100 3.13 6.25 
Staphylococcus aureus (33) levofloxacin 0.10–>100 6.25 25 
(oxacillin >2 mg/L) ciprofloxacin 0.20–>100 25 100 
 sparfloxacin 0.025–100 6.25 12.5 
 gatifloxacin 0.10–0.39 0.39 0.39 
 levofloxacin 0.39–1.56 0.78 1.56 
 ciprofloxacin 0.78–3.13 1.56 1.56 
Streptococcus pneumoniae (42) sparfloxacin 0.10–0.78 0.39 0.39 
 ampicillin ≤0.0063–6.25 0.05 3.13 
 cefaclor 0.025–>100 0.78 50 
 clarithromycin ≤0.0063–>100 0.025 100 
 minocycline ≤0.0063–25 6.25 12.5 
 gatifloxacin 0.0125–0.78 0.0125 0.10 
Escherichia coli (39) levofloxacin 0.0125–0.78 0.025 0.20 
 ciprofloxacin ≤0.0063–0.78 0.0125 0.10 
 sparfloxacin ≤0.0063–0.78 0.0125 0.10 
 gatifloxacin 0.0125–0.78 0.05 0.05 
Klebsiella pneumoniae (35) levofloxacin 0.025–0.78 0.05 0.10 
 ciprofloxacin ≤0.0063–0.39 0.025 0.05 
 sparfloxacin ≤0.0063–0.39 0.05 0.05 
 gatifloxacin 0.10–50 0.78 3.13 
Pseudomonas aeruginosa (50) levofloxacin 0.10–100 0.78 3.13 
 ciprofloxacin 0.05–25 0.20 1.56 
 sparfloxacin 0.10–100 0.78 3.13 
 gatifloxacin ≤0.0063–0.05 0.025 0.05 
Moraxella catarrhalis (21) levofloxacin 0.0125–0.05 0.05 0.05 
(20 β-lactamase producers) ciprofloxacin ≤0.0063–0.05 0.025 0.05 
 sparfloxacin ≤0.0063–0.025 0.0125 0.025 
 gatifloxacin ≤0.0063–0.10 0.0125 0.025 
 levofloxacin 0.0125–0.20 0.025 0.025 
Haemophilus influenzae (27) ciprofloxacin ≤0.0063–0.39 0.0125 0.025 
 sparfloxacin ≤0.0063–0.20 0.0125 0.05 
 ampicillin 0.20–6.25 0.39 1.56 
B. Urinary tract infections     
Methicillin-susceptible gatifloxacin 0.05–25 0.10 1.56 
Staphylococcus aureus (22) levofloxacin 0.10–100 0.20 6.25 
(oxacillin≤2 mg/L) ciprofloxacin 0.20–>100 0.39 12.5 
 sparfloxacin 0.025–100 0.05 3.13 
Methicillin-resistant gatifloxacin 1.56–25 6.25 25 
Staphylococcus aureus (18) levofloxacin 3.13–50 25 50 
(oxacillin >2 mg/L) ciprofloxacin 12.5–>100 100 >100 
 sparfloxacin 3.13–25 12.5 25 
Methicillin-susceptible CNSa (30) gatifloxacin 0.05–50 0.39 25 
(oxacillin≤2 mg/L) levofloxacin 0.05–>100 0.39 50 
 ciprofloxacin 0.05–50 3.13 50 
 sparfloxacin 0.05–100 3.13 50 
Methicillin-resistant gatifloxacin 0.10–50 1.56 50 
Staphylococcus epidermidis (17) levofloxacin 0.10–>100 6.25 >100 
(oxacillin >2 mg/L) ciprofloxacin 0.20–100 25 50 
 sparfloxacin 0.025–100 6.25 100 
 gatifloxacin 0.20–50 0.78 25 
Enterococcus faecalis (75) levofloxacin 0.78–>100 3.13 50 
 ciprofloxacin 0.39–>100 3.13 100 
 sparfloxacin 0.20–100 0.78 100 
 gatifloxacin 0.0125–12.5 0.025 0.20 
Escherichia coli (40) levofloxacin 0.0125–25 0.025 0.39 
 ciprofloxacin ≤0.0063–50 0.0125 0.20 
 sparfloxacin ≤0.0063–50 0.0125 0.20 
 gatifloxacin ≤0.0063–25 0.20 12.5 
Enterobacter cloacae (29) levofloxacin 0.0125–50 0.20 50 
 ciprofloxacin ≤0.0063–100 0.05 100 
 sparfloxacin 0.0125–100 0.20 100 
 gatifloxacin 0.025–25 0.78 12.5 
Serratia marcescens (40) levofloxacin 0.0125–25 0.78 12.5 
 ciprofloxacin 0.0125–25 0.39 12.5 
 sparfloxacin 0.025–25 1.56 12.5 
 gatifloxacin 0.20–>100 1.56 100 
Pseudomonas aeruginosa (49) levofloxacin 0.10–>100 1.56 >100 
 ciprofloxacin 0.05–>100 0.39 100 
 sparfloxacin 0.20–>100 1.56 >100 
 gatifloxacin ≤0.0063–1.56 0.10 0.39 
Neisseria gonorrhoeae (42) levofloxacin ≤0.0063–6.25 0.39 0.78 
 ciprofloxacin ≤0.0063–6.25 0.20 1.56 
 sparfloxacin ≤0.0063–6.25 0.10 0.78 
C. Surgical infections     
Methicillin-susceptible gatifloxacin 0.05–1.56 0.10 0.10 
Staphylococcus aureus (47) levofloxacin 0.10–3.13 0.20 0.39 
(oxacillin≤2 mg/L) ciprofloxacin 0.20–6.25 0.39 0.78 
 sparfloxacin 0.0125–3.13 0.05 0.10 
Methicillin-resistant gatifloxacin 0.10, 0.10, 6.25   
 Staphylococcus aureus (3) levofloxacin 0.20, 0.20, 12.5  
 (oxacillin >2 mg/L) ciprofloxacin 0.10, 0.39, >100  
 sparfloxacin 0.05, 0.05, 6.25   
Methicillin-susceptible gatifloxacin 0.05–50 0.10 1.56 
Staphylococcus epidermidis (38) levofloxacin 0.10–>100 0.20 12.5 
(oxacillin≤2 mg/L) ciprofloxacin 0.10–100 0.20 50 
 sparfloxacin 0.05–100 0.10 6.25 
Methicillin-resistant gatifloxacin 0.0125–1.56 0.20 1.56 
Staphylococcus epidermidis (12) levofloxacin 0.025–12.5 0.78 6.25 
(oxacillin > 2 mg/L) ciprofloxacin 0.0125–50 1.56 50 
 sparfloxacin ≤0.0063–6.25 0.20 3.13 
 gatifloxacin 0.10–0.78 0.20 0.39 
Streptococcus pyogenes (34) levofloxacin 0.39–3.13 0.39 1.56 
 ciprofloxacin 0.20–3.13 0.39 3.13 
 sparfloxacin 0.10–1.56 0.39 0.78 
 gatifloxacin ≤0.0063–6.25 0.025 0.10 
Escherichia coli (50) levofloxacin ≤0.0063–25 0.05 0.20 
 ciprofloxacin ≤0.0063–50 0.0125 0.10 
 sparfloxacin ≤0.0063–25 0.0125 0.10 
 gatifloxacin 0.10–>100 0.78 3.13 
Pseudomonas aeruginosa (50) levofloxacin 0.10–>100 0.78 6.25 
 ciprofloxacin 0.025–100 0.20 0.78 
 sparfloxacin 0.20–>100 0.78 3.13 
*
Corresponding author. Tel: +81-280-562201; Fax: +81-280-571293; E-mail: fvbb0984@mb.infoweb.ne.jp

The authors would like to thank Hideyuki Fukuda and Yasuo Oomori for their critical review of the manuscript.

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