Antimicrobial activity evaluations of gatifloxacin, a new fluoroquinolone

ORIGINAL ARTICLE

Antimicrobial activity evaluations of gatifloxacin, a new fluoroquinolone: contemporary pathogen results from a global antimicrobial resistance surveillance program (SENTRY, 1997) Clin Microbiol Inzct 1999; 5: 540-546

Ronald N.Jones, Matthew A . I: Croco, Michael A . l$aller, Mondell L. Beach, Kari C. Kugler and the SENTRY Antimicrobial Surveillance Program Participants (The Americas) University of Iowa College of Medicine, Department of Pathology, Medical Microbiology Division, Iowa City, IA, USA Objective: To investigate the in vitro potency and spectrum of activity of gatifloxacin and five comparator fluoroquinolones tested against over 23 000 clinical isolates from diverse geographic and clinical sources i n the Americas.

Methods:Gram-negative, Gram-positive and fastidious bacterial isolates were tested against gatifloxacin, ciprofloxacin, levofloxacin, ofloxacin, sparfloxacin and trovafloxacin using broth microdilution methods recommended by the National Committee for Clinical Laboratory Standards (NCCLS).

Results: Gatifloxacin demonstrated a potency and spectrum very similar to those of other new fluoroquinolones such as levofloxacin, sparfloxacin, and trovafloxacin. Gatifloxacin was particularly active against the Enterobacteriaceae (94.8% susceptible at S2 mg/L), Acinetobacter spp. (77.2%), Stenotrophomonas rnaltophilia (75.1%), Streptococcus pneurnoniae (99.8%), other Streptococcus spp. (198.9%), and various Staphytococcus spp. (79.2-100.0%). Trovafloxacin was the most similar comparison drug overall. Conclusions: These results indicate a potential therapeutic role for gatifloxacin that would widen the potency or spectrum of fluoroquinolones, particularly against Gram-positive species, when considering its favorable bioavailability. Key words: Gatifloxacin, SENTRY, fluoroquinolone, activity

[8-111. The limitations of ciprofloxacin and ofloxacin (dosing frequency and spectrum) have led to the development of gatifloxacin, trovafloxacin, sitafloxacin (DU-6859), levofloxacin, and sparfloxacin, each of which can be administered once daily to treat a wider variety of infections [l-6,9-111. These infections would include those caused by penicillin-resistant Streptococcus spp., multiresistant enterococci, oxacanresistant Staphylococcus spp., and some anaerobes [8]. The continuing problem of microbial resistance to marketed antimicrobial agents has prompted many within government, industry and the academic community to propose the initiation of comprehensive programs aimed at curbing the emerging resistances [12]. To address this problem, the SENTRY Antimicrobial Surveillance Program was initiated in early 1997 [13]. During the first year over 35 000 strains were isolated fiom 72 medical centers worldwide, of which 23 000 isolates from Canada, the USA, and Latin America were processed at the University of Iowa College of Medicine (Iowa City, Iowa, USA). The scope of the study encompassed ciprofloxacin, gatifloxacin, levofloxacin, ofloxacin, sparfloxacin and trova-

INTRODUCTION

Gatifloxacin (AM-1155 or CG5501) is a new 8methoxy fluoroquinolone with demonstrated antibacterial activity against a broad range of Gram-positive or -negative organisms, anaerobes and many fastidious species [1-6]. As a group, the fluoroquinolones inhibit various topoisomerases [7], which prevents bacterial replication at the DNA level. Ciprofloxacin, the first used broad-spectrum fluoroquinolone, remains the leader among the avdable agents as measured by usage, but the newer fluoroquinolones with expanded Grampositive potencies may prove to be valuable in the treatment of some currently refractory pathogens

Correspondingauthor and reprint requests: Ronald N. Jones, Medical Microbiology Division, C606 GH, Department of Pathology, University of Iowa College of Medicine, Iowa City, IA 52242, USA Tel: +319 356 2990 Fax: +319 356 4916 E-mail: ronald-jonesQuiowa.edu Revised version accepted 10 March1999 540

541

J o n e s e t at: G a t i f l o x a c i n i n v i t r o a c t i v i t y

floxacin, tested against isolates categorized by site of infection. The results of these in vitro trials using reference dilution methods [14,15] are reported here.

ichia coli ATCC 25922, Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212, Pseudomonas aeruginosa ATCC 27853, H . influenzae ATCC 49247, and Streptococcus pneumoniae ATCC 49619.

MATERIALS AND METHODS

Gatifloxacin was kindly provided by BristoI-Myers Squibb (Princeton, NJ, USA). All other antimicrobials were supplied by their respective manufacturers. Gatifloxacin and five other fluoroquinolones were evaluated in various study phases using a collection of over 23 000 clinical isolates. The isolates were taken fiom the 1997 SENTRY Program, which included strains from 48 medical centers in Canada, the USA and Latin America (six countries) [13]. This surveillance program monitors consecutive isolates in a prevalence study design using local clinical isolates from: the bloodstream (20 isolates/monthx 12 months per center); communityacquired respiratory tract infections caused by Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis; pneumonia in hospitalized patients; skin and soft tissue infections; and urinary tract infections. Approximately equal numbers of strains were contributed by each participant, and differences in the endemic resistance patterns of fluoroquinolones have been observed, with rates greater in Latin America> USAXanada (data on file). The six compounds were tested using broth microdilution methods recommended by the National Committee for Clinical Laboratory Standards (NCCLS) [14,15]. The fluoroquinolones were tested over the following log2 dilution schedules: gatifloxacin at 50.03-4 mg/L, ciprofloxacin at 50.06-2 mg/L, levofloxacin at 50.5-4 mg/L, ofloxacin at 50.03-4 mg/L, sparfloxacin at 50.25-2 mg/L and trovafloxacin at 10.03-4 mg/L. All non-fastidious organisms were inoculated into cation-adjusted Mueller-Hinton broth and then incubated for 16-20 h at 35OC in ambient air. The streptococci were inoculated into cation-adjusted Mueller-Hinton broth supplemented with 3-5% lysed horse blood, and then incubated for 24 h at 35°C in ambient air. H . influenzae and H. parainfluenzae were tested in Haemophilus Test Medium (HTM) incubated for 24 h at 35°C in ambient air. Two types of panels were utilized for this investigation. Frozen panels, stored at -7O"C, were manufactured by PML Microbiologics (Wilsonville, OR, USA). Dade Microscan (Sacramento, CA, USA) dry-form panels were also utilized in determining organism MICs. The MIC panels were interpreted manually and results validated using the appropriate American Type Culture Collection (ATCC) quality control strains in accordance with NCCLS documents [15]. These strains included Escher-

Gatifloxacin activity against Enterobacteriaceae

Table 1 lists the comparative activities of six fluoroquinolones tested against over 5000 strains of Enterobacteriaceae. Many of these strains had emerging problematic resistances to other antimicrobial agents. Among the Citrobacter spp. and Enterobacter spp., only 74.5-79.6% of strains were susceptible to 'thirdgeneration' cephalosporins (data not shown). Resistant strains were phenotypically consistent with producing Bush-Jacoby-Mederios group 1 stably derepressed plactamases. Similarly, some Escherichia coli (3.0%) and Klebsiella spp. (5.9%) strains had elevated ceftazidime MICs ( 2 2 mg/L), representing the production of extended-spectrum p-lactamases (ESBLs) (see footnotes to Table 1). Generally, ciprofloxacin was most active (see MIC5o values). Gatifloxacin and trovafloxacin had a median MIC50 of 0.06 mg/L and a median MICW of 1 rng/L. At breakpoint concentrations published in NCCLS documents or justified by pharmacodynamic criteria, the rank order of spectrum was as follows: levofloxacin (96.1%) > gatifloxacin (94.8% at 5 2 mg/L) > ofloxacin (94.5%)> ciprofloxacin (94.4%)> trovafloxacin (91.5% at 11 mg/L) > sparfloxacin (91.1%). The most resistant isolates were the Serratia spp. (225 strains) that had MIC90 results of 1-4 mg/L for trovafloxacin and sparfloxacin, and only inhibited 78.2% and 80.9%, respectively, of strains at 1 mg/L. All other tested fluoroquinolones inhibited 89.8-94.2% of the Serratia spp. isolates at recognized susceptible concentrations. Also, Morganella morganii (59 strains) was less susceptible to the newer fluoroquinolones such as trovafloxacin (MIC9,,, > 4 mg/L) and sparfloxacin > 2 mg/L) when compared to older compounds in the class (ciprofloxacin MICw, 2 mg/L). Gatifloxacin activity against non-fermentative Gram-negative bacilli

In Table 2, three species groups of non-fermentative Gram-negative bacilli are listed with MIC results for the six fluoroquinolones. Against the Acinetobacter spp. strains, trovafloxacin was most active (MICw, 0.06 mg/L) among the agents with on-scale results, but, most importantly, the overall spectra of the six compounds did not significantly differ (72.8-78.1% susceptible). The Pseudomonas aeruginosa isolates varied widely in their susceptibility to the fluoroquinolones,

542

Clinical M i c r o b i o l o g y a n d Infection, Volume 5 N u m b e r 9, September 1999

Table 1 Antimicrobid activity of gatifloxacin and five comparison fluoroquinolones tested against 5034 Enterobacteriaceae strains (SENTRY Antimicrobial Surveillance Program, 1997) ~~

MIC (mg/L) 50%

90%

Range

% inhbited (breakpomt)

Gatifloxacin Ciprofloxacin Levofloxacin Ofloxacin Spadoxacin Trovafloxacin

0.06 0.03 10.5 0.12 10.25 0.06

1 0.5 1 2 2 2

50.03 to >4 50.016 to >2 10.5 to >4 10.03 to 2 4 10.25 to >2 10.03 to >4

92.6 (52) 92.0 (11) 93.8 (12) 92.6 (52) 86.4 (11) 87.0 (11)

Enterobacter spp. (647)b

Gatifloxacin Ciprofloxacin Levofloxacin Ofloxacin Spdoxacin Trovailoxacin

0.06 0.03 10.5 0.12 50.25 0.06

1 0.5 10.5 1 1 1

10.03 to >4 10.016 to >2 10.5 to >4 10.03 to >4 10.25 to 22 10.03 to >4

95.2 (12) 93.0 (51) 94.9 (12) 93.0 (12) 91.3 (11) 91.5 (11)

Escherichia coli (2527)'

Gatifloxacin Ciprofloxacin Levofloxacin Ofloxacin Spdoxacin Trovafloxacin

10.03 10.016 50.5 0.06 10.25 50.03

0.06 0.06 10.5 0.12 50.25 0.12

10.03 to >4 50.016 to >2 10.5 to >4 10.03 to >4 50.25 to >2 10.03 to >4

97.9 (12) 97.5 (51) 97.9 (12) 97.6 (12) 97.7 (11) 97.4 (51)

Mebsiella spp. (1089)d

Gatifloxacin Ciprofloxacin Levofloxacin Ofloxacin Spdoxacin Trodoxacin

0.12 0.03 10.5 0.12 10.25 0.12

0.5 0.25 10.5 1 0.5 1

10.03 to >4 50.016 to >2 10.5 to >4 10.03 to >4 10.25 to >2 10.03 to >4

96.9 (12) 95.6 (11) 97.1 (12) 94.9 (12) 95.0 (11) 93.8 (51)

Motgunella morganii (59)


0.12 10.016 10.5 0.06 50.25 0.25

4 2 2 4 >2 >4

10.03 to >4 10.016 to >2 10.5 to >4 10.03 to >4 10.25 to >2 0.03 to >4

89.8 (12) 89.8 (11) 91.5 (12) 89.8 (12) 88.1 (51) 88.1 (11)

Pantoea qglomerans (38)


0.06 0.03 10.5 0.12 50.25 0.06

0.12 0.25 50.5 0.25 0.5 0.5

10.03-4 10.16-2 10.5-4 0.06-4 10.25-2 50.03-4

97.2 (12) 97.2 (11) 97.4 (12) 97.4 (12) 94.7 (11) 97.4 (11)

I? mirabilis (242)


0.25 0.03 50.5 0.12 10.25 0.25

1 0.25 10.5 1 2 1

0.06 to >4 10.016 to >2 10.5 to >4 10.03 to >4 10.25 to >2 10.03 to >4

94.2 (12) 96.3 (11) 97.9 (12) 95.0 (12) 88.4 (11) 90.1 (11)

Salmonella spp. (45)

Gatdoxacin Ciprofloxacin Levofloxacin Ofloxacin Spdoxacin Trovafloxacin

0.06 10.016 10.5 0.12 10.25 50.03

0.12 0.06 50.5 0.12 10.25 0.12

10.06-0.25 50.016 to >2 10.5 0.06-1 10.25 to >2 10.03-4.5

100.0 (12) 97.7 (11) 100.0 (12) 100.0 (12) 97.8 (11) 100.0 (11)

Serrafia spp. (225)

Gatifloxacin Ciprofloxacin Levofloxacin Ofloxacin Sparfloxacin Trovafloxacin

0.5 0.12 10.5 0.25 0.5 0.5

4 1 2 2 2 4

10.03 to >4 10.016 to >2 50.5 to >4 0.06 to >4 10.25 to >2 10.03 to >4

89.8 (12) 90.7 (11) 94.2 (12) 90.2 (12) 80.9 (11) 78.2 (11)

Organum (no. tested)

Antimicrobialagent

Citrobmferspp. (162)a

Stably derepressed Bush group 1 isolates (ceftazidime MIC 2 16 mg/L)=20.4% of tested strains. bStably derepressed Bush group 1 isolates (ceftazidime MIC 216 mg/L)=25.5% of tested strains. 'ESBL-phenotypes (ceftazidime MIC at 2 2 mg/L)=3.0% of tested strains. dESBL-phenotypes (ceftizidime MIC at 1 2 mg/L)=5.9% of tested strains. ESBL, extended-spectrum p-lactamase.

J o n e s et al: G a t i f l o x a c i n i n v i t r o a c t i v i t y

543

Table 2 Antimicrobial activity of gatifloxacin and five comparator quinolones tested against the three most prevalent nonfermentative Gram-negative bacilli (1536 strains) isolated in the SENTRY Antimicrobial Surveillance Program, 1997 MIC (mg/L) Organism (no. tested) Acinetobncfer spp. (224)

Pseudomonas aenrginosa (1135)"

Sfenotrophomonas maltophilia (177)

Antimicrobial agent

50%

90%

Gatifloxacin Ciprofloxacin Levofloxacin Ofloxacin Sparfloxacin Trovdoxacin

0.12 0.25 50.5 0.25 10.25 0.06

>4


1 0.25 10.5 1 1 1


1 2 1 2 0.5 1

>2 >4 >4

>2 >4 >4

22 24 >4 >2 >4 4

>2 4 >4 2 4

Range

% inhibited (breakpoint)

10.03-4 50.016 to >2 50.5 to >4 50.03 to >4 50.25 to >2 10.03 to >4

77.2 (52) 72.8 (51) 76.3 (52) 75.4 (12) 77.2 (11) 78.1 (11)

50.03 to >4 50.016 to >2 50.5 to 2 4 50.03 to >4 50.25 to >2 50.03 to 2 4

68.5 (52) 79.8 ( 5 1 ) 74.4 (52) 66.6 ( 5 2 ) 60.2 (51) 65.9 (51)

50.03 to >4 0.03 to >2 50.5 to >4 50.03 to >4 50.25 to >2 50.03 to >4

75.1 (52) 20.9 (51) 78.0 (52) 56.5 (52) 76.8 (51) 70.6 (51)

"Greater than 90% coverage only noted for amikacin (93.8%). meropenem (92.2%). tobramycin (91.0%),and piperacdhdtazobactam (90.7%).

with ciprofloxacin remaining most active (79.8%) and sparfloxacin having the narrowest spectrum of activity (60.2%). Among the other tested agents, levofloxacin was approximately two-fold more potent than gatifloxacin, trovafloxacin, and ofloxacin. Strains of Stenotrophomonas maltophilia were only marginally susceptible to some of the tested fluoroquinolones. Ciprofloxacin and ofloxacin demonstrated the least activity (MICso 2 mg/L) and the poorest susceptibility rates of 20.9% and 56.5%, respectively. Gatifloxacin (75.1%), spadoxacin (76.8%) and levofloxacin (78.0%) showed potential therapeutic promise. To place the above results in perspective, other tested antimicrobial agents exhibiting the greatest activity against the most prevalent species in this group, Pseudomonas aeruginosa, were amikacin (93.8% susceptible), meropenem (92.2%), tobramycin (91.0%), and piperacillin/tazobactam (90.7%) (data not shown).

MICs 50.25 mg/L. Moraxella catarrhalis was also very susceptible to the fluoroquinolones, regardless that 90% of strains produced a detectable P-lactamase (data not shown). Pneumococci were often resistant to penicillin (60.3% susceptible at 50.06 mg/L), and many of these strains were also resistant to macrolides (erythromycin susceptibility at 86.7%). Gatifloxacin, sparfloxacin and trovafloxacin (MIC90, 0.5 mg/L) were equally active and generally four-fold more potent than ciprofloxacin or levofloxacin versus Streptococcus pneumoniae. At published or proposed interpretive breakpoint concentrations [15-171, gatifloxacin ( 5 2 mg/L), levofloxacin ( 5 2 mg/L), sparfloxacin (10.5 mg/L) and trovafloxacin ( 5 1 mg/L) were very active (98.4-99.896 susceptible). High-level resistance to these agents has been secondary to multiple mutations in topoisomerase genes (gyrA, parC) [7] and has usually produced complete cross-resistance among the fluoroquinolones tested here.

Gatifloxacin activity against fastidious organisms

Table 3 summarizes the in vitro results for nearly 4000 strains of H . infuenzae, H. parainfuenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. Among the H. infuenzae, strains, 36.2% were ampicillin/amoxyciUin resistant by virtue of P-lactamase production. However, gatifloxacin and the other tested fluoroquinolones were all very active (MIC90s 10.5 mg/L). The highest recorded H . infuenzae MIC for a fluoroquinolone was 1 mg/L for levofloxacin, and all other compounds had

Gatifloxacin activity against Gram-positive organisms

The MIC testing results for non-pneumococcal streptococci, Staphylococcus spp. and enterococci are shown in Table 4. Only four fluoroquinolones were routinely assessed against these species in the SENTRY Program, and the rank order of spectrum and potency for the P-hemolpc and viridans group streptococci was: (MIC90, gatifloxacin = spadoxacin = trovafloxacin 0.5 mg/L; 98.3-99.7% susceptible) > ciprofloxacin

544

Clinical M i c r o b i o l o g y a n d Infection, Volume 5 N u m b e r 9, September 1999

Table 3 Antimicrobial activity of gatifloxacin compared to five or six other orally administered antimicrobial agents tested against 3738 strains of Huemophilus species, Moraxellu cuturrhulis and Streptococruspneumoniue (SENTRY Antimicrobial Surveillance Program, 1997) MIC (mg/L) Organism (no. tested)

Antimicrobial agent

50%

90%

H . inyuenzae (1403)

Amoxycillin Gatifloxacin Ciprofloxacin Levofloxacin Spadoxacin Trovafloxacin

1 10.03 50.016 50.5 50.12 50.03

10.03 10.016 10.5 10.12 10.03

Amoxycikn Gatifloxacin Ciprofloxacin Levofloxacin Sparfloxacin Trovafloxacin

0.5 10.03 50.015 10.5 50.12 0.06

Mormella catanltalis (605)

Amoxycihn Gatifloxacin Ciprofloxacin Levofloxacin Sparfloxacin Trovafloxacin

Streptoroms pneumoniae (1717)

PeniciUln Erythromycin Gatifloxacin Ciprofloxacin Levofloxacin Sparfloxacin Trovafloxacin

H. parainzuenzae (13)

% inhibited"

Range

(breakpoint)

50.06 to >8 50.0?-0.25 50.01&-0.25 50.5-1 10.12-0.25 50.03-0.25

63.8 (12) 100.0 (12) 100.0 (11) 100.0 (12) 100.0 (51) 100.0 (11)

0.12 0.03 50.5 10.12 0.25

0.25 to >8 10.034.5 10.15-1 10.5-2 50.12-1 50.03-1

84.6 (12) 100.0 (52) 100.0 (11) 100.0 (12) 100.0 (51) 100.0 (51)

4 50.03 0.03 50.5 10.12 10.03

8 10.03 0.03 10.5 50.12 50.03

10.06 to >8 10.03-1 10.016-1 50.5-2 50.1245 50.03-0.5

8.9 (10.12) 100.0 (12) 100.0 (51) 100.0 (52) 100.0 (8

28

50.008 to >I6 10.25 to >32 0.06 to >4 50.016 to >2 50.5 to >4 50.12 to > I 10.03->4

60.3 (50.06) 86.7 (S0.25) 99.8 (11)

- WYb 99.2 (12) 98.4 (50.5) 99.8 (11)

"Concentrationin parentheses indicates criteria applied. MIC breakpoint for susceptibihty was that of the NCCLS [I51 when available. bNA, not applicable. Penicillin results used to predict the clinical utility of many oral cephalosporins. No criteria have been published for ciprofloxacin.

(MIC90, 1 to >2 mg/L). Gatifloxacin (MIC90, 4 mg/L) was routinely more active than comparison drugs against the coagulase-negative staphylococci, while trovafloxacin (MIc90,2mg/L) was most active against the Staphylococcus aureus strains. Approximately twothirds of Enterococcus faecalis strains were susceptible to gatifloxacin, sparfloxacin and trovafloxacin, but only 48.9% were inhibited by 51 mg/L of ciprofloxacin. Enterococcus faecium strains (often multiresistant, including glycopeptide resistances) were less susceptible (8.3-17.5%) to all tested fluoroquinolones. CONCLUSIONS

Using a geographically diverse sample of clinical isolates collected in 1997 f?om the Americas, gatifloxacin activity and spectrum were compared to those of other broad-spectrum fluoroquinolones. As noted in earlier investigations 11-61, gatifloxacindemonstrated a potency and spectrum very similar to those of levofloxacin [9], sparfloxacin [16], and trovafloxacin [18]. Gatifloxacin

was particularly active against the Enterobacteriaceae (94.8% susceptible at 5 2 mg/L), Acinetobacter spp. (77.2%), Stenotrophomonas maltophilia (75.1%), Streptococcus pneumoniae (99.8%). other Streptococcus spp. (298.9%), and various Staphylococcus spp. (79.2100.0%). The most prevalent enterococcus, Ertterococcus faeculis, was also susceptible to gatifloxacin (MIC50, 0.5 mg/L). Trovafloxacin was the most sirmlar comparison drug overall [17,18]. These results indicate a potential therapeutic role for gatifloxacin that would widen the spectrum or potency of fluoroquinolones against several Gram-positive species, especially associated with its favorable bioavailability [ll], which includes a C , of 3.35 mg/L, elimination half-life of 7-8 h and a 24-h AUC of 32.4 mg.h/L following a single 400-mg oral dose. We anxiously await the results of the clinical trials and the assessment of safety. Acknowledgments

The co-authors express their gratitude for the contributions of K.L. Meyer, M.E. Erwin, K. Mills,

Enterococcus faecalis (763)

79.7 100.0 78.5 68.2 18.9 70.0 64.3 54.4 58.0

71.1 100.0 70.9 66.4 14.1 60.0 57.1 50.0 55.3

4 0.12 >4 >4 >4 >4 >4 >4 >4

>4 4 >4 >4 1 0.25

90.1 77.5 79.2 76.5 72.0 94.7 100.0

98.3 99.7

98.3 99.7 83.7 70.4 79.2 68.0 56.0 94.7 100.0

2

0.5 0.5

>2 >2 >2 >2 >2

1

>2

S0.25 22

>2 S0.25 >2

22 22

>2 >2 >2

0.5 0.5

50.0 54.2

64.5 16.0 70.0 64.3

82.3 61.5

100.0 63.3

56.4 40.0 84.2

61.6 79.2

76.4

99.7

98.3

MIGo % I t mg/L

1 >2 1 0.5 1

10.25 10.25

10.25 10.25 S0.25

10.25 10.25 >2

0.25 10.25

0.25

0.25

MICso

Sparfloxacin

2 2

2 r2 >2 1

0.25 0.5

0.5 0.25

0.5 22 0.12

0.5 0.25

0.5

0.5

2

MICso

MIC9o

Ciprofloxacin

36.8 40.3

8.3 30.0 50.0

48.9

59.9

100.0 62.5 92.3

55.3 28.0 84.2

73.7 59.7 79.2

42.5 96.2

% 1 1 mg/L

'Included in the viridans group were: Streptococcus anginosus (four strains), Streptococcus bovis (eight strains), Streptococcus intermediw (two strains), Streptococcus milleri (six strains), Streptococcus mitis (29 strains), Streptococcus mutans (two strains), Streptococcus oralis (three strains), Streptococcus salivarius (five strains), Streptococcus sanguis (16 strains), Streptococcus spp. (10 strains), and Streptococcus viridans group (96 strains). bIncluded in P-hemolytic group were: Streptococcus group A (118 strains), Streptococcus group B (210 strains), Streptotoas group C (12 strains), Streptococcus group F (five strains), Streptococcus group G (41 strains), and Streptococrus P-hemolytic not specified (12 strains). 'Includes all coagulase-negative staphylococci (CNS) tested &om significant clinical infections. dOnly species with 10 or more isolates were listed in the table.

Enterococci, all strains (1121)d

Enterococus spp. (114)

Enterococcus, group D (14)

Enterococcus gallinarum (10)

Enterococcus faecium (206)

>4

0.5 >4 1 0.25 1 1

67.2 17.5 70.0 57.1 53.5 56.8

0.25 4

0.12 0.12

CNS, all strains (1121)'

Staphylococrus spp, (128) Staphylococcus warnerii (13)

1

0.12

88.4

0.25 4

0.25 0.12

Staphylococcus saprophyticus (10)

Staphylococcus hominis (19)

>4 >4 >4 >4 >4

0.12 0.12 10.03

100.0 85.9 92.3

4 1

Staphylococcus haemolyticus (25)

0.5 >4 1 0.5 2

0.12 1 S0.03

93.3 60.0 100.0

4

2

0.12 0.25 2 0.12

Staphylococcus capitis (24)

Staphylococcus epidermidis (282)

0.06 0.12 0.12

81.2 87.5 79.2

4 4

0.12 0.12

CNS, non-speciated (601)

Staphylococcus aureus (3100)

0.25 0.25

98.9 99.7

0.5 0.5

0.5

% I 1 mg/L %12mg/L

Trovafloxacin M I G O MICw

0.5

%12mg/L

P-Hemolym streptococci (398)b

MICso

Viridans group streptococci (181)'

Organism (no. tested)

Gatdoxacin

Table 4 Antimicrobial activity of gatifloxacin compared to three other fluoroquinolones tested by reference methods (NCCLS, 1997) against streptococci, staphylococci, and enterococci (5921 strains from the SENTRY Antimicrobial Surveillance Program, 1997)

ul

u1 P

546

Clinical M i c r o b i o l o g y and Infection, Volume 5 N u m b e r 9, September 1999

T. Barrett, L. Schomberg and R. Gupta to this study and manuscript. The study was made possible by the SENTRY Antimicrobial Surveillance Program research grant fiom Bristol-Myers Squibb and the generous contributions of comparison compounds by various pharmaceutical manufacturers. References 1. Bauernfeind A. Comparison of the antibacterial activities of the quinolones BAY 12-8039, gatifloxacin (AM-1155), trovafloxacin, clinafloxacin, levofloxacin, and ciprofloxacin. J Antimicrob Chemother 1997; 40: 639-51. 2. Hosaka M, Yasue T, Fukuda H, Tomizawa H, Aayama H, Hirai K. In vitro and in vivo antibacterial activities of AM-1155, a new 6-fluoro-8-methoxy quinolone. Antimicrob Agents Chemother 1992; 36: 2108-17. 3. Hosaka M, Kinoshita S, Toyama A, Itsuki M, Nishino T. Antibacterial properties of AM-1155, a new 8-methoxyquinolone.J Antimicrob Chemother 1995; 36: 293-301. 4. Tanaka M, Tetsuro M, Kobayashi I, Uchino U, Kumazawa J. Emergence of in vitro resistance to fluoroquinolonesin Neissm'a gonorrhoeue isolated in Japan. Antimicrob Agents Chemother 1995; 39: 2367-70. 5. Wakabayashi E, Mitsuhashi S. In vitro antibacterial activity of AM-1 155, a novel 6-fluoro-8-methoxy quinolone. Antimicrob Agents Chemother 1994; 38: 594-601. 6. Wise R, Brenwald P, Andres JM, Bowell I. The activity of the methylpiperazinyl fluoroquinolone CG5501: a comparison with other fluoroquinolones. J Antimicrob Chemother 1997; 39: 447-52. 7. Hopper DC. Bacterial topoisomerases, anti-topoisomerases, and anti-topoisomerase resistance. Clin Infect Dis 1998; 27(suppl 1): s54-63. 8. Cormican MG, Jones RN. Emerging resistance to antimicrobial agents in Gram-positive bacteria. Drugs 1996; 5l(suppll): 6 1 2 . 9 Davis R,Bryson HM. Levofloxacin: a review of its antibacterial activity, pharmacokinetics and therapeutic efficacy. Drugs 1994; 47: 677-700.

10. Visdi MA, Jacobs MR, Appelbaum PC. MIC and time-kill 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 3624. 11. Nakashima M, Uematsu T, Kosuge K, et al. Single- and multiple-dose pharmacokinetics of AM-1155, a new 6-fluoro8-methoxy quinolone in humans. Antimicrob Agents Chemother 1995; 3 9 2635-40. 12. Jones RN. The emergent needs for basic research, education, and surveillance of antimicrobial resistance. Problems facing the report from the American Society for Microbiology Task Force on Antibiotic Resistance. Diagn Microbiol Infect Dis 1996; 25: 153-61. 13. Pfaller MA, Jones RN, Doern GV, Kugler K, The SENTRY Participants Group. Bacterial pathogens isolated from patients with bloodstream infection: Frequencies of occurrence and antimicrobial susceptibility patterns from the SENTRY Antimicrobial Surveillance Program (United States and Canada, 1997). Antimicrob Agents Chemother 1998; 42: 1762-70. 14. National Committee for Clinical Laboratory Standards (NCCLS). Methods for dilution antimicrobial susceptibilitytests for bacteria that grow aerobically: approved standard M7-A4, 4th edn. Wayne, PA NCCLS, 1997. 15. National Committee for Clinical Laboratory Standards (NCCLS). Performance standards for antimicrobial susceptibility testing, 8th information supplement, M10048. Wayne, PA NCCLS, 1998. 16. Jones RN, Ballow CH, SchentagJ, Johnson DM, Deinhart JA, the SPAR Study Group. In vitro evaluation of spadoxacin activity and spectrum against 24,940 pathogens isolated in the United States and Canada, the final analysis. Diagn Microbiol Infect Dis 1998; 31: 313-25. 17. Jones RN, Pfaller MA, Doern GV. Comparative antimicrobial activity of trovafloxacin tested against 3,049 Shepfococnrs pneumoniae isolates from the 1997-98 respiratory infection season. Diagn Microbiol Infect Dis 1998; 3 2 119-26. 18. Briggs-Gooding BB, Jones RN. In vitro antimicrobial activity of CP-99,219, a novel azabicyclonaphthyridone. Antimicrob Agents Chemother 1993; 37: 349-53.