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DIAGN MICROBIOLINFECTDIS 1990;13:333-336

NOTES

In vitro Activity of Tosufloxacin Against Bacterial Enteric Pathogens Ellen J. Glick, John Segreti, Larry J. Goodman, and Gordon M. Trenholme

The in vitro activity of tosufloxacin (A-61827), a new quinolone antibiotic, was compared with that of four other quinolones against 162 bacterial enteric pathogens. Susceptibility testing was performed by using an agar dilution method. The minimal inhibitory concentration (MIC) was defined as the lowest concentration of antibiotic without visible growth. Tosufloxacin was the most active agent against Campylobacter

jejuni and C. coli, and ciprofloxacin was the most active agent against Salmonella, Shigella, and Vibrio. The frequency of spontaneous point mutational resistance to tosufloxacin for three C. jejuni ranged from 1.2 x 10-9 to 5.1 x 10 -13. No significant differences in mutational frequency were seen among the quinolones.

Several fluoroquinolones have been shown to have good activity against common bacterial enteric pathogens (Goodman et al., 1984; Fliegelman et al., 1985; Goosens et al., 1985). Tosufloxacin (A-61827, T-3262) has in vitro activity against a number of Gram-positive and -negative organisms comparable to that of the older quinolones (Fernandes et al., 1988; Fujimaki et al., 1988; Takahata et al., 1988; Barry and Jones, 1989). Furthermore, it has demonstrated greater potency than other fluoroquinolones against certain Gram-positive organisms and anaerobes (Espinoza et al., 1988; Fernandes et al., 1988; Barry and Jones, 1989). However, there are few data on the in vitro activity of tosufloxacin against Campylobacter jejuni, C. coli, Vibrio, Shigella, Yersinia, Aeromonas, and Plesiomonas. We evaluated the activity of tosufloxacin against 162 bacterial enteric pathogens and compared it to four other quinolones. The activity of tosufloxacin was also compared to that of erythromycin against C. jejuni and C. coli.

MATERIALS A N D METHODS

From the Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois. Address reprint requests to: John Segreti, M.D., Rush-Presbyterian-St. Luke's Medical Center, 1653West Congress Parkway, Chicago, IL 60612. ReceivedJanuary 15, 1990; revised and accepted February 10, 1990. © 1990Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/90/$3.50

Antimicrobial Activity Susceptibility testing was performed with MuellerHinton agar and standard agar dilution methods, except for C. jejuni and C. coli, for which Wilken-Chalgren agar was used (Fliegelman et al., 1985). Organisms were prepared by transferring three to five colonies from an overnight culture of the organism into tryptic soy broth. Turbidity was adjusted to a 0.5 McFarland turbidity standard with sterile saline. For C. jejuni and C. coli, three to five colonies from a 24-hr growth were placed in Wilken-Chalgren broth, adjusted to 0.5 McFafland, and inoculated onto agar. Incubation temperature for all organisms was 35°C, except for C. jejuni and C. coli, which were incubated at 42°C. Plates were inoculated with a multipoint replicator (Cathra, St. Paul, MN) assigned to deliver exactly 0.001 ml per spot to the surface of antibiotic impregnated agar. Inocula contained - 104 CFU of organisms per spot. Plates were inoculated from the lowest to the highest concentration of antibiotic. All organisms except C. jejuni and C. coli were incubated in ambient air. Campylobacterjejuni and C. coli plates were placed in a microaerobic atmosphere by utilizing the poly bag technique (Fliegelman et al., 1985). These plates were read at 24 and 48 hr. Control plates without antibiotics were inoculated before and after each antibiotic series. The appropriate control organisms were included in each

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TABLE 1.

E.J. Glick et al.

In vitro Susceptibility of 162 Bacterial Enteric P a t h o g e n s to Five Q u i n o l o n e s MIC (~,g/ml) (No. of Isolates)

Antimicrobial Agent

Campylobacter jejuni

34

Tosufloxacin Erythromycin Temafloxacin Lomefloxacin Norfloxacin Ciprofloxacin

Campylobacter coli

31

Salmonella

Organism

50%

90%

0.015-0.125 0.25-2.0 0.03-0.25 0.03-0.25 0.25-2.0 0.25-0.5

0.03 1.0 0.06 0.06 0.5 0.25

0.06 2.0 0.125 0.125 1.0 0.5

Tosufloxacin Erythromycin Temafloxacin Lomefloxacin Norfloxacin Ciprofloxacin

0.015-0.06 0.25->8.0 0. 015-0.125 0.03-0.5 0.25-2.0 0.015-0.25

0.03 1.0 0.015 0.25 0.5 0.06

0.06 > 8.0 0.125 0.25 1.0 0.25

20

Tosufloxacin Temafloxacin Lomefloxacin Norfloxacin Ciprofloxacin

4 0.008-0.06 0.015-0.5 0.03-2.0 0.06-1.0 4 0.008-0.015

0.015 0.06 0.125 0.125 4 0.008

0.03 0.125 0.50 0.25 4 0.008

25

Tosufloxacin Temafloxacin Lomefloxacin Norfloxacin Ciprofloxacin

40.008-0.06 4 0.008-0.06 40.008-0.06 40.008-0.03 40.008-0.015

0.015 0.015 0.06 0.015 40.008

0.03 0.03 0.06 0.03 40.008

Yersinia enterocolitica

13

Tosufloxacin Temafloxacin Lomefloxacin Norfloxacin Ciprofloxacin

40.008-0.03 40.008-0.25 0.015-0.25 40.008-0.125 40.008-0.015

0.008 0.015 0.03 0.06 40.008

0.03 0.06 0.25 0.125 0.015

Vibrio

15

Tosufloxacin Temafloxacin Lomefloxacin Norfloxacin Ciprofloxacin

40.008-0.125 4 0.008-0.25 4 0.008-0.25 40.008-0.125 40.008-0.015

0.125 0.25 0.125 0.03 4 0.008

0.125 0.25 0.125 0.03 40.008

Aeromonas hydrophila

18

Tosufloxacin Temafloxacin Lomefloxacin Norfloxacin Ciprofloxacin

40.008-0.125 4 0.008-0.25 0.015-0.25 0.015-1.0 40.008-0.06

0.015 0.06 0.015 0.015 40.008

0.06 0.25 0.125 0.125 0.06

Plesiomonas shigelloides

6

Tosufloxacin Temafloxacin Lomefloxacin Norfloxacin Ciprofloxacin

40.008 40.008-0.03 40.008-0.03 40.008-0.06 4 0.008

40.008 0.015 0.015 0.015 4 0.008

spp.

Shingella spp.

spp.

series of antibiotic plates. Minimal inhibitory concentrations (MICs) were defined as the lowest concentration of antibiotic with no visible g r o w t h .

Bacterial Strains A total of 162 isolates were tested. Except for the C. coli isolate, all were of h u m a n origin from our

Range

clinical microbiology laboratory at Rush-Presbyterian-St. L u k e ' s Medical Center. H i p p u r a t e h y d r o l ysis was d o n e as described previously (Harvey, 1980). All C. jejuni were h i p p u r a t e positive, a n d all C. coli were hippurate negative. Organisms were stored at - 7 0 ° C a n d were subcultured at least twice on appropriate m e d i a before susceptibility testing.

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Notes

TABLE 2.

Mutational Frequency of Three Campylobacter jejuni to Five Quinolones

Drug Tosufloxacin Temafloxacin Lomefloxacin Norfloxacin Ciprofloxacin

Mean Mutational Frequency 3.2 3.6 1.4 2.0 1.0

x x x x x

10-11 10-11 10-11 10-11 10 -12

DISCUSSION Tosufloxacin had been shown previously to have good in vitro activity against Salmonella and Shigella (Fernandes et al., 1988; Fujimaki et al., 1988; Barry and Jones, 1989). The data presented in this paper demonstrate similar activity for isolates from the Chicago area and, in addition, show the drug's excellent in vitro activity against C. jejuni, C. coli, Yersinia enterocolitica, Aeromonas hydrophila, and P. shi-

gelloides.

Antimicrobial Agents C o m p o u n d s used in the study were obtained from the following sources: Tosufloxacin, temafloxacin, and erythromycin were obtained from Abbott Laboratories (North Chicago, IL); ciprofloxacin was from Miles Pharmaceuticals (West Haven, CT); norfloxacin was from Merck, Sharpe, and Dohme (Rahway, NJ); and lomefloxacin was from Searle Pharmaceuticals (Skokie, IL).

Mutational Frequency The frequency of spontaneous, single-step resistance to tosufloxacin and the three other quinolones for three isolates of C. jejuni was determined by planting/> 1013 CFU onto Wilken-Chalgren agar that contained concentrations of quinolone eight times the MIC for the isolate. The number of resistant mutants was assessed after 48 hr of incubation at 42°C.

RESULTS Table 1 shows the comparative in vitro activity of tosufloxacin and other agents against bacterial enteric pathogens, expressed as the 50% MIC (MICs0), 90% MIC (MIC90), and the range. Overall, tosufloxacin was the most active agent tested against C. jejuni and C. coli. Temafloxacin, lomefloxacin, and ciprofloxacin were only slightly less active. All of the quinolones except for norfloxacin were at least four times more active than erythromycin against C. jejuni. Although many C. coli isolates were resistant to erythromycin, they were all susceptible to the quinolones tested. Tosufloxacin and ciprofloxacin were the most active agents against Pleisomonas shigelloides, but all of the quinolones had excellent activity against this organism. Ciprofloxacin was also the most active agent against Salmonella, Shigella, and Vibrio, but the other quinolones had excellent activity as well. The frequency of spontaneous point mutational resistance to tosufloxacin for the three isolates of C. jejuni was very low (mean = 3.2 x 1011) and comparable to that seen with other quinolones (Table 2).

In vivo studies of the older fluoroquinolones, such as ciprofloxacin and norfloxacin, have shown that these agents are effective in the prophylaxis of travelers' diarrhea, the treatment of travelers' diarrhea, acute diarrhea in adult nontravelers, and eradication of the chronic Salmonella carriage state (Ericsson et al., 1987; Pichler et al., 1987; Keusch, 1989; Lolekha and Patanacharoen, 1988; Tigaud et al., 1988; Goodman et al., 1990). Several quinolones are effective for the treatment of typhoid fever in adults due to susceptible Salmonella isolates (Ramirez et al., 1985; Hajji et al., 1988). Stool concentrations are typically high, which may also contribute to the efficacy of these agents against bacterial enteric pathogens. The development of Clostridium difficile colitis with fluoroquinolone therapy has been a rare complication (Arcieri et al., 1987). Although clinical data pertaining to the incidence of C. difficile colitis associated with tosufloxacin is not yet available, in vitro studies have shown the MICg0s of tosufloxacin against C. difficile to be 3.13-4.0 ~g/ml (Fernandes et al., 1988; Fujimaki et al., 1988). It would be of additional interest to evaluate the in vivo activity of tosufloxacin against this pathogen. Although there is a paucity of in vitro data with tosufloxacin, pharmacokinetic studies performed in mice have demonstrated peak serum concentrations equivalent to ciprofloxacin, with the half-life of tosufloxacin three times longer than the half-life of ciprofloxacin following oral administration of the drug (Fernandes et al., 1988). Also in a recent clinical study of superficial skin infections, 17 patients had levels of tosufloxacin monitored after doses of 150 mg. Three of these subjects had nondetectable drug levels (

In vitro activity of tosufloxacin against bacterial enteric pathogens.

The in vitro activity of tosufloxacin (A-61827), a new quinolone antibiotic, was compared with that of four other quinolones against 162 bacterial ent...
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