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Antimicrobial Agents and Chemotherapy, June 2004, p. 2049-2055, Vol. 48, No. 6
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.6.2049-2055.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Antimicrobial Activities of Garenoxacin (BMS 284756) against Asia-Pacific Region Clinical Isolates from the SENTRY Program, 1999 to 2001

K. J. Christiansen,¹ J. M. Bell,^2* J. D. Turnidge,² and R. N. Jones³

Royal Perth Hospital, Perth,¹ Women's and Children's Hospital, Adelaide, Australia,² The JONES Group/JMI Laboratories, North Liberty, Iowa³

Received 7 July 2003/ Returned for modification 30 November 2003/ Accepted 22 February 2004

Top Abstract Introduction Materials and Methods Results Discussion References

 
Between 1999 and 2001, 16,731 isolates from the Asia-Pacific Region were tested in the SENTRY Program for susceptibility to six fluoroquinolones including garenoxacin. Garenoxacin was four- to eightfold less active against Enterobacteriaceae than ciprofloxacin, although both drugs inhibited similar percentages at 1 µg/ml. Garenoxacin was more active against gram-positive species than all other fluoroquinolones except gemifloxacin. For Staphylococcus aureus, oxacillin resistance was high in many participating countries (Japan, 67%; Taiwan, 60%; Hong Kong, 55%; Singapore, 52%), with corresponding high levels of ciprofloxacin resistance (57 to 99%) in oxacillin-resistant S. aureus (ORSA). Of the ciprofloxacin-resistant ORSA isolates, the garenoxacin MIC was >4 µg/ml for only 9% of them. For Streptococcus pneumoniae, penicillin nonsusceptibility and macrolide resistance were high in many countries. No relationship was seen between penicillin and garenoxacin susceptibility, with all isolates being susceptible at <2 µg/ml. There was, however, a partial correlation between ciprofloxacin and garenoxacin MICs. For ciprofloxacin-resistant isolates for which garenoxacin MICs were 0.25 to 1 µg/liter, mutations in both the ParC and GyrA regions of the quinolone resistance-determining region could be demonstrated. No mutations conferring high-level resistance were detected. Garenoxacin shows useful activity against a wide range of organisms from the Asia-Pacific region. In particular, it has good activity against S. aureus and S. pneumoniae, although there is evidence that low-level resistance is present in those organisms with ciprofloxacin resistance.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Garenoxacin is a novel des-F(6) quinolone that lacks a fluorine at the C-6 position but has fluorine incorporated through a C-8 difluoromethyl ether linkage. It has been shown to have activity against a wide range of clinical isolates (1, 7, 12, 34), and in particular, garenoxacin has been shown to have good activity against Staphylococcus aureus, both methicillin sensitive and resistant (6), and the respiratory pathogens Streptococcus pneumoniae (26), Haemophilus influenzae, and Moraxella catarrhalis (8). The activity of garenoxacin has been further assessed against strains of S. aureus with specific topoisomerase mutations (21), and more recently, it has been shown that garenoxacin has similar potency against both topoisomerase IV and gyrase (16) (dual-targeting quinolone), thus requiring mutations in both topoisomerases for resistance to occur (29). Although horizontal transfer is a major reason for the spread of ciprofloxacin-resistant strains, the role of antimicrobial selection may also play an important role. As single parC or gyrA mutations in S. aureus (31) confer resistance to ciprofloxacin, the widespread use of this antibiotic may have already selected a population of organisms requiring only one further mutation for resistance to the new fluoroquinolones to occur. Similarly, with S. pneumoniae, mutations within the quinolone resistance-determining region (QRDR) for both topoisomerases can lead to resistance for the new fluoroquinolones (18). Within the Asia-Pacific region, multidrug resistance and, specifically, fluoroquinolone resistance for both gram-positive and gram-negative organisms is relatively high (33). Rapid development of ciprofloxacin resistance in oxacillin-resistant S. aureus (ORSA) was reported in Hong Kong with 9% resistance in 1988 and 82% resistance in 1993 (27). Similar high levels of resistance have been reported for ORSA from other countries in the region, 66% for Korea (22), 97% for Taiwan (12% in oxacillin-susceptible S. aureus [OSSA]) (23), and >50% for Japan (36). Resistance to fluoroquinolones has been reported for S. pneumoniae with 13.3% (27.3% for non-penicillin-susceptible isolates) resistance to levofloxacin in a recent study in Hong Kong (15) and up to 12% resistance in Korea (22). It is therefore important to determine the comparative activities of the newer fluoroquinolones, including garenoxacin, against recent clinical isolates in the Asia-Pacific region. An earlier study presented data on respiratory pathogens in the region for 1998 to 1999 (2). This present SENTRY (Asia-Pacific Region including South Africa) study gives an updated report on comparative fluoroquinolone susceptibilities against both gram-positive and gram-negative organisms within the region and analyzes in more detail the activities of garenoxacin against S. pneumoniae and S. aureus.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Bacterial isolates. Clinically significant strains from the SENTRY surveillance program were collected by 17 hospitals from eight countries (Japan, Taiwan, Mainland China, Hong Kong, Philippines, Singapore, Australia, and South Africa) over defined intervals between 1999 and 2001. Repeat isolates from patients were excluded. Isolates were from cases of bacteremia (n = 7,793), lower respiratory infections in hospitalized patients (n = 2,124), upper respiratory tract infections (n = 2,799), wound or soft tissue infections (n = 1,069), and urinary tract infections (n = 1,223). All strains were sent to a central reference laboratory (Women's and Children's Hospital, Adelaide, Australia).

Susceptibility testing. MICs were obtained for all isolates by a broth microdilution technique (TREK Diagnostic Systems Limited, East Grinstead, United Kingdom) according to NCCLS standards (24). Isolates were tested against more than 26 antimicrobial agents, including 5 fluoroquinolones, ciprofloxacin, levofloxacin, gatifloxacin, gemifloxacin, and garenoxacin. Garenoxacin, levofloxacin, and gatifloxacin were tested against all isolates over the concentration range of 0.03 to 4 µg/ml, except that gram-positive isolates were not tested against levofloxacin in 1999. Ciprofloxacin was tested against nonfastidious pathogens over the concentration ranges of 0.25 to 2 µg/ml (1999 and 2000) and 0.015 to 2 µg/ml (2001). The ranges used for fastidious isolates were 0.015 to 2 µg/ml (1999 and 2000) and 0.03 to 4 µg/ml (2001). Gemifloxacin was tested against nonfastidious pathogens over the range of 0.03 to 4 µg/ml (1999 and 2000), and the range used for all isolates in 2001 was 0.008 to 1 µg/ml. Moxifloxacin was only tested against fastidious isolates in 2000 and 2001, over the range of 0.03 to 4 µg/ml. For S. pneumoniae MIC determination, cation-adjusted Mueller-Hinton broth containing 5% lysed horse blood was used. The same medium but without the lysed horse blood was used for M. catarrhalis, and for H. influenzae, Haemophilus test medium broth was used as the growth medium. The concen-tration of the final inoculum was 5 x 10⁵ CFU/ml. The trays were incubated for 20 to 24 h at 35°C in ambient air. MICs were defined as the lowest concentration of drug that yielded no visible growth of the test organism. Control strains were S. pneumoniae ATCC 49619, H. influenzae strains ATCC 49247 and 49766, Escherichia coli ATCC 25922, Enterococcus faecalis ATCC 29212, Pseudomonas aeruginosa ATCC 27853, and S. aureus ATCC 29213.

PCR and DNA sequencing. Primers as previously described (25) were used to amplify the QRDRs of gyrA, gyrB, parC, and parE. DNA sequencing was performed by ABI PRISM Big Dye terminator cycle sequencing (Applied Bioscience) with the ABI Prism 3700 (Applied Biosystems) automated sequencer. DNA sequences were confirmed by using products of independent PCRs to determine the sequence of each strand. DNAMAN (Lynnon BioSoft) sequence analysis software was used for alignment of DNA sequences and deduced amino acid sequences.

Active efflux. Isolates of S. pneumoniae for which ciprofloxacin MICs were >2 µg/ml were examined for active efflux. MICs of ciprofloxacin were determined by agar dilution with Mueller-Hinton agar supplemented with 5% sheep blood with or without 10 µg of reserpine per ml and an inoculum of 10⁴ CFU/spot (4, 24). Strains for which there was a fourfold or greater decrease in the ciprofloxacin MIC in the presence of reserpine were considered to be positive for reserpine-inhibited efflux.

Top Abstract Introduction Materials and Methods Results Discussion References

 
During the period 1999 to 2001, a total of 16,731 isolates were received from Australia (6,271 isolates), Hong Kong (1,587 isolates), Japan (3,106 isolates), Mainland China (357 isolates [1999 only]), Philippines (1,336 isolates), Singapore (1,052 isolates), South Africa (1,344 isolates), and Taiwan (1,678 isolates).

Table 1 shows the activities of six fluoroquinolones, including garenoxacin, against Enterobacteriaceae, nonfermenting gram-negative bacilli, enterococci, coagulase-negative staphylococci, and beta-hemolytic streptococci groups A and B. Garenoxacin was more active against gram-positive species than any other fluoroquinolone tested except gemifloxacin. All streptococcal strains were inhibited at concentrations of 1 µg/ml or less. Garenoxacin was generally less active than all other fluoroquinolones against Enterobacteriaceae. Compared to ciprofloxacin, garenoxacin was about four- to eightfold less active against Enterobacteriaceae, although similar percentages of strains were inhibited by both drugs at 1 µg/ml. Garenoxacin had activities similar to those of ciprofloxacin against Acinetobacter and Stenotrophomonas but was less active against P. aeruginosa.

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TABLE 1. Fluoroquinolone activity against Enterobacteriaceae, nonfermentative gram-negative bacilli, and gram-positive organisms from the Asia-Pacific region, 1999 to 2001a

Table 2 shows the percentage of ORSA and OSSA for each of the participating countries. Ciprofloxacin resistance in ORSA was high in all countries. Of the ORSA isolates for which the garenoxacin MIC was >4 µg/ml, most came from just two countries, Japan (80%) and Hong Kong (17%). The percentage of garenoxacin resistance for ciprofloxacin-resistant OSSA was 3.3%, with the one isolate coming from Japan.

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TABLE 2. S. aureus and S. pneumoniae susceptibility in the SENTRY Asia-Pacific region countries

S. pneumoniae susceptibilities to penicillin, erythromycin, and clindamycin for the region are shown in Table 2. The activities of the fluoroquinolones against the common pathogens causing community-acquired upper and lower respiratory tract infections are shown in Table 3. No quinolone resistance was detected in M. catarrhalis (n = 600), and the ciprofloxacin MIC was 2 µg/ml for only one (0.07%) H. influenzae isolate from Japan. Table 4 shows the distribution of MICs of garenoxacin compared with those of penicillin for S. pneumoniae. Analyzing the data with two different cutoff values for garenoxacin (0.12 and 0.25 µg/ml) and penicillin (0.06 and 1 µg/ml) will return highly significant P values with the chi-square test (P < 0.001). Therefore, elevated MICs of garenoxacin are associated with reduced susceptibility and resistance to penicillin. We hypothesize that there is possible linkage with epidemic serotypes. For ciprofloxacin-resistant strains, there was a corresponding shift in garenoxacin MICs; however, the garenoxacin MIC was not >1 µg/ml for any isolate. Mutations in topoisomerase IV and DNA gyrase were demonstrated for all ciprofloxacin-resistant isolates for which the garenoxacin MIC was 0.25 µg/ml (Table 5). No reserpine-inhibited efflux was demonstrated for these isolates.

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TABLE 3. Fluoroquinolone activity against gram-negative respiratory tract pathogens from the Asia-Pacific region, 1999 to 2001

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TABLE 4. Distribution of garenoxacin MICs for S. pneumoniae according to penicillin susceptibility

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TABLE 5. Mutations in topoisomerase IV and DNA gyrase for ciprofloxacin-resistant isolates of S. pneumoniae for which MICs of garenoxacin are elevated (0.25 to 1 µg/ml)

Top Abstract Introduction Materials and Methods Results Discussion References

 
Garenoxacin has been shown to have broad-spectrum activity in studies from other regions of the world (3, 11, 20, 36). This study provides confirmation for isolates from the Asia-Pacific region (Table 1), although the activities against Enterobacter spp., Morganella spp., P. aeruginosa, and Serratia spp. are less than those of ciprofloxacin. Good streptococcal activity is evident. The main advances of the newer fluoroquinolones, including garenoxacin, compared to the earlier agents have been against gram-positive organisms, in particular S. aureus and S. pneumoniae, with the development of resistance requiring mutations in both topoisomerase II and IV, unlike ciprofloxacin, for which changes in only one topoisomerase are necessary. For S. aureus, ciprofloxacin resistance occurs mostly in ORSA and is due to mutations in either parC or gyrA. Thus, the prevalence of ORSA and resistance to ciprofloxacin in the region is an indication of the presence of one-step mutants. The percentage of ORSA isolates was high in Japan (67%), Taiwan (60%), Hong Kong (55%), and Singapore (52%). As expected from data elsewhere in the world (10), ciprofloxacin resistance was common in these isolates (Table 2). When mutations occur in both gyrA and parC, markedly increased MICs of ciprofloxacin and a shift in MICs of moxifloxacin have been demonstrated, although not necessarily to resistant levels (30). Analysis of the Asia-Pacific data shows that of the 9% of the ORSA isolates resistant to ciprofloxacin were also resistant to 4-µg/ml garenoxacin. As garenoxacin has been shown not to be a substrate for the norA efflux pump (28), this resistance is most likely due to mutations in both topoisomerases. Interestingly, almost all of these resistant isolates came from Japan and Hong Kong. For the methicillin-susceptible S. aureus, ciprofloxacin resistance was uncommon (2%) and there was only 1 isolate that was also garenoxacin resistant, which again, came from Japan. Garenoxacin has been shown in vitro to have increased activity compared with moxifloxacin and gatifloxacin against S. aureus with mutations in both the parC and gyrA genes (28), and this was confirmed in our study for gatifloxacin. The occurrence of resistance to the newer fluoroquinolones in ORSA is disappointing and indicates that these agents may not be long-term alternatives for the treatment of ORSA infections.

For the respiratory pathogens, garenoxacin had good activity against H. influenzae and M. catarrhalis, as did all other fluoroquinolones (Table 3). These organisms do not pose any real therapeutic problem, and it is, therefore, the data for S. pneumoniae that are of interest. Within the region, penicillin nonsusceptibility is common, with rates exceeding 70% in some countries (Table 2). In addition, macrolide resistance is widespread, reaching a high of 88% in Taiwan. The clindamycin data indicate that mef efflux pump-mediated resistance (M phenotype) accounts for close to 50% of the resistance in most countries in the region, except for South Africa and China, where the erm gene pattern predominates. With these significant levels of ß-lactam and macrolide resistance, the clinical role of the fluoroquinolones assumes greater importance. Despite the previously reported study (8), penicillin and fluoroquinolone resistance in the pneumococci appears to be related (P < 0.001) (Table 4). QRDR sequencing analysis (Table 5) showed that isolates for which the MIC is 0.25 or 0.5 µg/ml had various mutations in both ParC and GyrA. Most of the 11 isolates for which the MIC was 1 µg/ml, however, had similar double mutations in ParC (Ser-79 to Phe and Lys-137 to Asn) and a single mutation in GyrA (either Ser-81 to Phe or Glu-85 to Lys). Some of these changes have been demonstrated in an in vitro resistance selection study (13) to produce low-level resistant mutants, with additional mutations in GyrA at Glu-85 and ParC at Asp-83 required to result in high-level resistance (MIC, 2 to 16 µg/ml). Eight of the 11 strains were from Hong Kong. All were of the same serotype (14) and had similar mutations as those described by Ho et al. (14), suggesting the presence of a specific clone in that area. The Australian isolates also were clonal in nature; they all came from the one center, were of the same serotype (14), and exhibited similar QRDR mutations. Similar shifts in MICs of clinafloxacin, gatifloxacin, trovafloxacin, and gemifloxacin have been demonstrated with levofloxacin-resistant isolates of S. pneumoniae (19). These changes in MIC were shown to be due to mutations in the QRDR, where small increases in MIC were associated with one-step mutations in parC, and up to 32-fold increases in MIC were associated with double mutations in parC and gyrA. It is also possible that the elevation of MICs for the fluoroquinolones is due to active efflux (9), although this is unlikely to be the sole cause of high-level resistance (5). No active efflux was demonstrated in this study for the 24 isolates for which the MIC was 0.25 µg/ml. All of these isolates had mutations in the QRDR.

In conclusion, our study shows that in the Asia-Pacific region, where fluoroquinolone resistance is well established, garenoxacin activity has been maintained against the respiratory pathogens. There were, however, strains of S. pneumoniae that had mutations in both the GyrA and ParC regions of the QRDR. Mutations conferring high-level resistance were not detected, but with the addition of only one further mutation required, resistance can be expected to emerge. For S. aureus, in particular ORSA, resistance is already present. Other studies have shown that ciprofloxacin resistance, conferred by mutations in the QRDR, is stable in an in vitro antibiotic-free environment (17) and in clonal lineages in the clinical environment over a period of years (32). It is therefore likely that staphylococcal fluoroquinolone resistance will persist in the Asia-Pacific region. Whether an agent such as garenoxacin has less potential to select for resistant mutants and therefore maintain clinical utility is unclear, but its high potency compared to its pharmacokinetics (35) suggests that this may be the case.

 
The SENTRY Antimicrobial Surveillance Program was made possible by an educational/research grant from Bristol-Myers Squibb.

Study participants and participating institutions are as follows: from Australia, Graeme Nimmo and Jacqueline Schooneveldt (Princess Alexandra Hospital, Brisbane), Irene Lim (Royal Adelaide Hospital, Adelaide), Keryn Christensen and Geoffrey Coombs (Royal Perth Hospital, Perth), and John Turnidge and Jan Bell (Women's and Children's Hospital, Adelaide); from Japan, Matsuhisa Inoue (Kitasato University Hospital, Kitasato), Shigeru Kohno and Yoichi Hirakata (Nagaski University Hospital, Nagasaki), and Yasuo Ono (Teikyo University Hospital, Tokyo); from Taiwan, Leu Hsieh-Shong (Chang Gung Memorial Hospital, Taoyuan), Hsueh Po-Ren (National Taiwan University Hospital, Taipei), and Yu Kwok-Yoon (Veterans General Hospital, Taipei); from China, Jia-Tai Li (Beijing Medical University, Beijing), First Municipal Peoples Hospital of Guangzhou, Guangzhou, and Nang-Shan Zhong (Guangzhou Medical College First Affiliated Hospital, Guangzhou); from Hong Kong, Seto Wing Hong and Raymond Leung (Queen Mary Hospital); from Philippines, Thelma Tupasi (Makati Medical Center, Manila); from Singapore, Ling Moi-Lin (Singapore General Hospital) (1998) and Timothy Barkham (Tan Tock Seng Hospital) (from 1999); from South Africa, Adrian Brink (du Buisson, Bruinette, and Partners, Johannesburg).

 
* Corresponding author. Mailing address: Microbiology and Infectious Diseases, Women's and Children's Hospital, 72 King William Rd., North Adelaide SA 5006, Australia. Phone: 61-8 8161 6359. Fax: 61-8 8161 6051. E-mail: bellj{at}mail.wch.sa.gov.au.

Top Abstract Introduction Materials and Methods Results Discussion References

 

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Antimicrobial Agents and Chemotherapy, June 2004, p. 2049-2055, Vol. 48, No. 6
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.6.2049-2055.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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