Geographic variations in garenoxacin (BMS284756) activity tested against pathogens associated with skin and soft tissue infections: report from the SENTRY Antimicrobial Surveillance Program (2000)

Diagnostic Microbiology and Infectious Disease 43 (2002) 303–309

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Antimicrobial Susceptibility Studies

Geographic variations in garenoxacin (BMS284756) activity tested against pathogens associated with skin and soft tissue infections: report from the SENTRY Antimicrobial Surveillance Program (2000) Jeffrey T. Kirbya, Alan H. Mutnicka, Ronald N. Jonesa,b,*, Douglas J. Biedenbacha, Michael A. Pfallerc, The SENTRY Participants Group a b

The JONES Group/JMI Laboratories, North Liberty, Iowa, USA Tufts University School of Medicine, Boston, Massachusetts, USA c University of Iowa College of Medicine, Iowa City, Iowa, USA Received 15 April 2002; accepted 15 May 2002

Abstract The antimicrobial activity of garenoxacin, a des-(6)F quinolone (formally BMS284756 and T-3811), was evaluated against 2,537 skin and soft tissue infection (SSTI) isolates from the SENTRY Antimicrobial Surveillance Program. Strains isolated in 2000 from Europe, North and Latin America were tested at a central laboratory using reference broth microdilution methods. The rank order of the seven most frequent SSTI pathogens was: Staphylococcus aureus (39.9%), Pseudomonas aeruginosa (12.1%), Escherichia coli (9.7%), Enterococcus spp. (7.7%), Klebsiella spp. (5.8%), Enterobacter spp. (5.6%) and coagulase-negative staphylococci (CoNS; 4.2%). Garenoxacin exhibited a four-fold greater activity (MIC90, 0.06 ␮g/ml) compared to levofloxacin (MIC90, 0.25 ␮g/ml) against oxacillin-susceptible S. aureus; and oxacillin-resistant staphylococci were more susceptible to garenoxacin (ⱖ90.5%) at ⱕ4 ␮g/ml than ciprofloxacin or levofloxacin. Enterococcus spp. were more susceptible to garenoxacin and gatifloxacin (MIC50, 0.5 ␮g/ml) than ciprofloxacin or levofloxacin (MIC50, 2 ␮g/ml). All tested quinolones inhibited 64.7 to 69.7% of P. aeruginosa isolates, and the rank order of potency slightly favored ciprofloxacin (MIC50, ⱕ0.25 ␮g/ml). Similar susceptibility rates for the four quinolones were observed against E. coli (85.8 – 87.0%), Enterobacter spp. (90.8 –94.3%) and Klebsiella spp. (89.8 –95.2%) with the greatest levels of resistance recorded in Latin America for E. coli and Enterobacter spp. The occurrence of extended spectrum ␤-lactamase-producing isolates (predominantly K. pneumoniae) was documented in all three monitored regions (Latin America ⬎ Europe ⬎ North America). Continued development of garenoxacin as a treatment of pathogens that commonly cause SSTIs appears to be warranted. © 2002 Elsevier Science Inc. All rights reserved.

1. Introduction Skin and soft tissue infections (SSTI) occur when the structural integrity of the skin is compromised by an injury, surgical procedure, implantation of a medical device, or by an invasive skin disease such as impetigo and cellulitis. Whatever the cause, the etiologic agents of SSTI include a diverse group of pathogens which can have a wide range of antimicrobial susceptibility profiles. The problem of choosing an empiric or even a directed therapy can be compounded by the presence of a polymicrobial infection which may require several antimicrobial agents or an extended duration of therapy to resolve the infection. Nosocomial * Corresponding author. Tel.: ⫹1-319-665-3370; fax; ⫹1-319-6653371. E-mail address: [email protected] (R.N. Jones).

SSTIs are frequently associated with surgical procedures, catheterization or the debridement of wounds. Involvement of the patient’s endogenous skin flora is common during these procedures, and pathogenic species may also be introduced by healthcare workers, the hospital environment or the use of surgical equipment (Gentry, 1992). In 1999, the National Nosocomial Infections Surveillance (NNIS) Study ranked surgical site infection (SSI) as the third most common cause of all reported nosocomial infections (Mangram et al., 1999). The species isolated from suspected nosocomial infections are often less diverse, but frequently harbor more resistance mechanisms due to the selective environment, and may not respond to broad-spectrum antimicrobial therapy (Doern et al., 1999; Gales et al., 2000). Structural modifications to nalidixic acid have yielded several potent quinolones such as ciprofloxacin and ofloxacin. These fluorinated quinolones exhibit increased potency

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against Gram-positive organisms and a wider Gram-negative spectrum. Other benefits noted with these compounds were increased activity against a wide variety of clinical infections due to higher intracellular drug levels, longer serum half-lives and lower protein binding (Stein, 1996). An expanded-spectrum quinolone, garenoxacin (formerly BMS284756 or T-3811) is a novel des-fluoro(6)-quinolone differing from earlier quinolones in that it lacks a fluorine atom at the C-6 position, and has an isoindolin-5-yl substitution at the 7 position (Takahata et al., 1999). Garenoxacin has reportedly shown increased activity compared to the other quinolones against Gram-positive organisms including methicillin (oxacillin)-resistant staphylococci (MRS) and some Enterococcus spp. (Fung-Tomc et al., 2000). Broad anti-anaerobic coverage (Hoellman et al., 2001) and superior activity against fastidious organisms has also been described (Fung-Tomc et al., 2000). Garenoxacin has excellent oral bioavailability (Hayashi et al., 1997) and toxicological findings reveal a low chondrotoxicity in juvenile rats, potentially making it a suitable therapy for children and adolescents (Nagai et al., 1997). The SENTRY Antimicrobial Surveillance Program has monitored SSTIs from 1997 to 2000, and several quinolones have been tested to determine their utility against the most prevalent pathogens (Doern et al., 1999; Gales et al., 2000). Generally, ciprofloxacin and levofloxacin (ofloxacin derivative) have provided adequate spectrums of activity against common Gram-negative pathogens including Pseudomonas aeruginosa and the Enterobacteriaceae. However, they have demonstrated suboptimal activity against prominent Grampositive species particularly MRS (Gales et al., 2000). The current investigation utilizes SENTRY Program data from the 2000 study year to assess the activity of quinolones, including garenoxacin. Reference broth microdilution susceptibility results from 2,537 SSTI episodes in Europe, North and Latin America are summarized using four quinolones (ciprofloxacin, garenoxacin, gatifloxacin, and levofloxacin).

2. Materials and methods 2.1. Organisms tested During 2000, 55 participating medical centers from geographically diverse regions in North America (29 states/ provinces), Latin America (6 countries) and Europe (11 countries), each submitted 50 consecutive SSTI isolates of clinically significant strains responsible for nosocomial or community-acquired infections from hospitalized patients. The total of 2,537 isolates suitable for testing included more than 70 different bacterial species. Primary species identification was performed at each participating medical center using their routine methodologies. Upon receipt at the central laboratory, isolates were subcultured onto appropriate media and examined for purity and viability. Organism

identification was confirmed using Vitek® Automated Microbial Identification System (bioMerieux, Hazelwood, MO) as necessary. 2.2. Susceptibility test methods All strains were tested and interpreted at the monitoring laboratories using reference broth microdilution methods as described by the National Committee for Clinical Laboratory Standards (NCCLS) (NCCLS, 2000 and 2002). MICs were determined using dry-form panels rehydrated with the appropriate organism suspension broth and delivered by automated inoculators (TREK Diagnostic Systems Ltd., Westlake, OH). Inocula were prepared in cation-adjusted Mueller-Hinton broth (MHB) which was enriched with 5% lysed horse blood when testing Streptococcus spp. The final concentration in the microdilution trays was equivalent to approximately 5 ⫻ 105 CFU/ml. Quality control was performed by regularly testing the following American Type Culture Collection (ATCC) strains recommended by the NCCLS: Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 29213, P. aeruginosa ATCC 27853, Streptococcus pneumoniae ATCC 49619 and Enterococcus faecalis ATCC 29212. Antimicrobial agents were obtained from their respective manufacturers and included multiple drug classes, although only the quinolone results, which include garenoxacin, ciprofloxacin, gatifloxacin and levofloxacin, are presented in full in this report. Suspected extended spectrum ␤-lactamase (ESBL)-producing phenotypes of enteric bacilli (ceftazidime or ceftriaxone or aztreonam MIC of ⱖ2 ␮g/ml) [NCCLS 2002] were further analyzed. Phenotypic confirmation of ESBLproducing strains was accomplished using ESBL Etest® strips (AB BIODISK, Solna, Sweden). A positive result was recorded when a greater than four-fold decrease was seen in the cephalosporin or monobactam MIC in the presence of 2 ␮g/ml clavulanic acid. ESBL-producing Enterobacteriaceae and multidrug-resistant S. aureus (MDR-MRSA) were further analyzed molecularly using ribotyping (RiboPrinterTM Microbial Characterization System, Qualicon, Wilmington, DE) and then discriminated using CHEF-DR II pulsed-field gel electrophoresis (PFGE; Bio-Rad Laboratories, Hercules, CA), when necessary.

3. Results and discussion 3.1. Demographic characteristics and pathogen occurrence Among the 2,537 SSTI isolates, demographic data indicated that 38.1% of the total number of pathogens isolated were from patients with nosocomial infections, 26.0% were classified as community-acquired infections and 35.9% could not be determined based on available information.

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305

Table 1 Rank order of skin and soft tissue infection (SSTI) isolates from medical centers in North America, Latin America and Europe Rank

1 2 3 4 5 6 7 8 9 10 11 12 TOTAL a b

Organism

S. aureus P. aeruginosa E. coli Enterococcus spp. Klebsiella spp. Enterobacter spp. CoNSa Proteus spp. Streptococcus spp. Acinetobacter spp. Serratia spp. Other speciesb

Number of organisms tested (%) by region in 2000:

Total

North America

Latin America

Europe

645 (45.9) 152 (10.8) 98 (7.0) 115 (8.2) 71 (5.1) 81 (5.8) 48 (3.4) 45 (3.2) 38 (2.7) 23 (1.6) 28 (2.0) 60 (4.3) 1,404

152 (34.9) 58 (13.3) 54 (12.4) 29 (6.7) 36 (8.3) 20 (4.6) 25 (5.7) 18 (4.1) 8 (1.8) 11 (2.5) 7 (1.6) 18 (4.1) 436

216 (31.0) 97 (13.9) 94 (13.5) 51 (7.3) 40 (5.7) 40 (5.7) 34 (4.9) 31 (4.4) 19 (2.7) 21 (3.0) 15 (2.2) 39 (5.6) 697

1,013 (39.9) 307 (12.1) 246 (9.7) 195 (7.7) 147 (5.8) 141 (5.6) 107 (4.2) 94 (3.7) 65 (2.6) 55 (2.2) 50 (2.0) 117 (4.6) 2,537

CoNS ⫽ coagulase-negative staphylococci. Includes isolates from more than 21 different genera.

The cultures were taken predominately from adults (82.2%), mostly male patients (58.1%). Table 1 details the pathogens isolated from SSTIs, with the greatest number of isolates submitted by North American sites (1,404 strains) followed by Europe (697 strains) and Latin America (436 strains). The top 11 species or species groups are ranked by frequency of occurrence (ⱖ2.0% for each species overall) for combined regions. The top seven pathogens accounted for 85.0% of the total number of isolates tested and included: S. aureus (39.9%), P. aeruginosa (12.1%), E. coli (9.7%), Enterococcus spp. (7.7%), Klebsiella spp. (5.8%), Enterobacter spp. (5.6%) and coagulase-negative staphylococci (CoNS; 4.2%). The regional rank order of the top five organisms was very similar, with few exceptions. North American sites isolated Enterococcus spp. (8.2%) more often than E. coli (7.0%), and Enterobacter spp. was ranked fifth (5.8%). In Latin America, Klebsiella spp. (8.3%) were more frequent than Enterococcus spp. (6.7%). There were significant differences between the recovery of S. aureus in North America (45.9%) compared to Latin America (34.9%) and Europe (31.0%). These differences were the result of the increased isolation of Gram-negative pathogens both in Europe and in Latin America. A comparison of these data with earlier published work on the rank order of organisms causing SSTIs (1997 SENTRY data from North America), reveals a marked decrease in the percentages of ␤-hemolytic streptococci and viridans group streptococci (5.1% and 1.2%, respectively, versus 2.7% combined in 2000). An increased recovery of Klebsiella spp. was also recorded in 2000 (5.1% vs. 3.6%). 3.2. Antimicrobial susceptibility patterns Table 2 compares the in vitro activity of garenoxacin and three fluoroquinolones tested against S. aureus, CoNS and

Enterococcus spp., in each of the three geographic regions. Using a proposed susceptibility breakpoint of ⱕ4 ␮g/ml (Fung-Tomc et al., 2000), garenoxacin displayed extended coverage over comparator fluoroquinolones against oxacillin-resistant S. aureus (MRSA) (S; 90.5% vs 14.5– 44.7%), oxacillin-resistant CoNS (96.3% vs 39.5– 85.2%) and equivalent or greater activity against oxacillin-susceptible CoNS (96.0% vs 92.0 –96.0%). Moreover garenoxacin was the most potent quinolone (MIC90, 0.06 ␮g/ml) against oxacillin-susceptible S. aureus, the predominant pathogen phenotype (738 isolates) recorded in all regions. The rank order of potency using MIC90 values was garenoxacin (0.06 ␮g/ml) ⬎ gatifloxacin ⬎ levofloxacin ⬎ ciprofloxacin (0.5 ␮g/ml). Phenotypically, a total of 27.2% of S. aureus isolates were MRSA, and the rate did not vary markedly between regions, with Europe having the lowest (22%) and North America the highest rate (29%). The level of co-resistance among MRSA to ciprofloxacin and levofloxacin was high (⬎81% overall). In contrast, garenoxacin was active against ⬎90% of MRSA and against ⬎97% of all S. aureus strains, regardless of oxacillin susceptibility. Multidrug-resistant (MDR) S. aureus was defined as oxacillinresistant isolates exhibiting co-resistance to four or more of the following antimicrobial class representatives: erythromycin, clindamycin, gentamicin, tetracycline, chloramphenicol, trimethoprim/sulfamethoxazole, rifampin and ciprofloxacin. Among the MRSA strains in the monitored regions, Latin America had the highest percentage of MDR strains (89.2%) followed by Europe (70.8%) and North America (24.0%; data not shown). Among the oxacillin-susceptible CoNS, garenoxacin (MIC90, 0.06 ␮g/ml) exhibited a four-fold potency advantage compared to levofloxacin (MIC90, 0.25 ␮g/ml) and a two-fold advantage when compared to gatifloxacin (MIC90, 0.12 ␮g/ml; Table 2). Overall, garenoxacin and gatifloxacin

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Table 2 In vitro activity of garenoxacin compared to three fluoroquinolones against Gram-positive SSTI isolates from centers in North America, Latin America and Europe (2000) Organism (n)/quinolone

MIC (␮g/ml) North America

S. aureus oxacillin-resistant (275) Garenoxacin Ciprofloxacin Gatifloxacin Levofloxacin oxacillin-susceptible (738) Garenoxacin Ciprofloxacin Gatifloxacin Levofloxacin CoNS oxacillin-resistant (81) Garenoxacin Ciprofloxacin Gatifloxacin Levofloxacin oxacillin-susceptible (25) Garenoxacin Ciprofloxacin Gatifloxacin Levofloxacin Enterococcus spp. (195) Garenoxacin Ciprofloxacin Gatifloxacin Levofloxacin

Latin America

Europe

50/90%

% susc.a

50/90%

% susc.a

2/⬎4 ⬎2/⬎2 4/⬎4 ⬎4/⬎4

87.9 18.4 36.8 21.1

1/2 ⬎2/⬎2 2/4 4/⬎4

ⱕ0.03/0.06 ⱕ0.25/0.5 0.06/0.12 0.12/0.25

99.8 95.1 98.0 96.5

ⱕ0.03/ⱕ0.03 ⱕ0.25/0.5 0.06/0.12 0.12/0.25

100.0 98.3 100.0 100.0

ⱕ0.03/ⱕ0.03 ⱕ0.25/0.5 0.06/0.12 0.12/0.25

1/4 ⬎2/⬎2 2/4 4/⬎4

97.0 45.5 87.9 48.5

1/4 ⬎2/⬎2 1/4 2/⬎4

100.0 36.8 84.2 63.2

1/4 ⬎2/⬎2 2/4 4/⬎4

0.06/0.06 ⱕ0.25/ⱕ0.25 0.12/0.12 0.25/0.25

93.3 93.3 93.3 93.3

0.06/⫺ ⱕ0.25/⫺ 0.12/⫺ 0.25/⫺

100.0 100.0 100.0 100.0

ⱕ0.03/⫺ ⱕ0.25/⫺ 0.12/⫺ 0.25/⫺

0.5/⬎4 2/⬎2 1/⬎4 1/⬎4

84.3 44.3 55.7 54.8

0.25/4 1/⬎2 0.5/⬎4 1/⬎4

100.0 65.5 79.3 75.9

1/⬎4 2/⬎2 1/⬎4 2/⬎4

97.3 8.1 70.3 10.8

50/90%

2/4 ⬎2/⬎2 2/4 4/⬎4

All regions % susc.a

95.8 4.2 56.3 12.5 100.0 95.2 98.8 97.6

93.1 34.5 82.8 34.5 100.0 75.0 100.0 75.0 78.4 39.2 64.7 60.8

50/90%

% susc.a

2/4 ⬎2/⬎2 4/⬎4 ⬎4/⬎4

90.5 14.5 44.7 18.2

ⱕ0.03/0.06 ⱕ0.25/0.5 0.06/0.12 0.12/0.25

99.9 95.7 98.5 97.3

1/4 ⬎2/⬎2 1/4 4/⬎4

96.3 39.5 85.2 46.9

0.06/0.06 ⱕ0.25/ⱕ0.25 0.12/0.12 0.25/0.25

96.0 92.0 96.0 92.0

0.5/⬎4 2/⬎2 0.5/⬎4 2/⬎4

85.1 45.6 62.1 60.0

a Using proposed susceptibility breakpoint of ⱕ4 ␮g/ml (Fung-Tomc et al., 2000). All other quinolones follow NCCLS (2002) guidelines for susceptibility breakpoints. b CoNS ⫽ coagulase-negative staphylococci.

were slightly (96.0%) more active than ciprofloxacin and levofloxacin (92.0%) against oxacillin-susceptible CoNS. The potency of gatifloxacin and garenoxacin was equivalent (MIC90, 4 ␮g/ml) against oxacillin-resistant CoNS. Combined, more than 96% of all CoNS strains were inhibited by garenoxacin regardless of oxacillin susceptibility pattern, slightly superior to gatifloxacin (88%), and markedly better than both ciprofloxacin (52%) and levofloxacin (57%). The potency of garenoxacin and gatifloxacin (MIC50, 0.5 ␮g/ml) was four-fold greater than ciprofloxacin and levofloxacin (MIC50, 2 ␮g/ml) against Enterococcus spp. and the highest susceptibility rate (85.1% versus 45.6 – 62.1%) was with garenoxacin (Table 2). Among the 195 Enterococcus spp. isolates tested, 10 isolates (5.1%) from the United States (9) and the United Kingdom (1) were vancomycin-resistant (VRE). Seven of these strains exhibited the van A pattern and three the van B pattern (data not shown). All VRE strains were resistant to gatifloxacin, ciprofloxacin and levofloxacin, but garenoxacin was active against six of the strains. In general, compared to the other regions, enterococcal strains isolated from Latin America were more susceptible to the four tested quinolones.

Streptococcus spp. ranked ninth in the number of isolates recovered from SSTIs and included 47 strains of ␤-hemolytic streptococci, which were universally susceptible to the fluoroquinolones and penicillin (data not shown). An eightfold greater activity was exhibited by garenoxacin (MIC50, 0.06 ␮g/ml) compared to levofloxacin (0.5 ␮g/ml). Fig. 1 shows the MIC distribution, and the modal MICs for levofloxacin and garenoxacin against all streptococcal species. The in vitro activities of the quinolones against the four most frequently isolated Gram-negative species from SSTIs are summarized in Table 3. For the combined regions, all four quinolone compounds displayed similar susceptibility rates and activities against Enterobacteriaceae: E. coli 85.8 – 87.0%, Enterobacter spp. 90.8 –94.3%, and Klebsiella spp. 89.8 –95.2%. A noteworthy regional variation was observed for Latin American where Enterobacter spp. strains were less susceptible (65.0 –70.0%) when compared to North American (91.4 –97.5%) and European (100.0%) isolates. E. coli isolates were also less susceptible in Latin America compared to the other regions. Ciprofloxacin (MIC50, ⱕ0.25 ␮g/ml) was the most potent agent against P. aeruginosa, the second most frequently

J.T. Kirby et al. / Diagnostic Microbiology and Infectious Disease 43 (2002) 303–309

307

Fig. 1. MIC distribution of garenoxacin and levofloxacin tested against 65 strains of streptococci isolated from SSTI (SENTRY Program for the Americas and Europe, 2000).

isolated species. However, 30.3% of the isolates were nonsusceptible and no significant advantage (p ⬎ 0.05) in susceptibility rates was demonstrated for ciprofloxacin (69.7%) over the other three tested quinolone compounds (64.7– 67.1%). Latin American P. aeruginosa isolates were approximately 20% less susceptible to the quinolones compared to those submitted from North America or Europe. Among the enteric bacilli, 118 strains phenotypically had antibiograms consistent with those suspected of harboring

an ESBL. A subset of 30 isolates from this group was selected for further testing. Sixteen strains were phenotypically confirmed by Etest® methodology as having ESBL enzymes and included: E. coli (one strain), Enterobacter cloacae (three strains), Proteus mirabilis (three strains), and Klebsiella spp. (nine strains). Eleven of the screen-positive ESBL isolates were submitted by European sites, whereas Latin American and North American centers submitted only three and two strains, respectively. Molecular epidemiology

Table 3 In vitro activity of garenoxacin compared to three fluoroquinolones against Gram-negative SSTI isolates from centers in North America, Latin America and Europe (2000) Organism (n)/quinolone

MIC (␮g/ml) North America

E. coli (246) Garenoxacin Ciprofloxacin Gatifloxacin Levofloxacin Enterobacter spp. (141) Garenoxacin Ciprofloxacin Gatifloxacin Levofloxacin Klebsiella spp. (147) Garenoxacin Ciprofloxacin Gatifloxacin Levofloxacin P. aeruginosa (307) Garenoxacin Ciprofloxacin Gatifloxacin Levofloxacin

Latin America

Europe

All regions

50/90%

% susc.a

50/90%

% susc.a

50/90%

% susc.a

50/90%

% susc.a

ⱕ0.03/⬎4 ⱕ0.25/⬎2 ⱕ0.03/⬎4 ⱕ0.03/4

87.8 87.8 88.8 88.8

ⱕ0.03/⬎4 ⱕ0.25/⬎2 ⱕ0.03/⬎4 ⱕ0.03/⬎4

81.5 81.5 81.5 81.5

ⱕ0.03/⬎4 ⱕ0.25/⬎2 ⱕ0.03/4 ⱕ0.03/4

87.2 87.2 88.3 87.2

ⱕ0.03/⬎4 ⱕ0.25/⬎2 ⱕ0.03/4 ⱕ0.03/4

85.8 85.8 87.0 86.2

0.12/2 ⱕ0.25/0.5 ⱕ0.03/0.5 ⱕ0.03/0.5

91.4 96.3 97.5 97.5

0.5/⬎4 ⱕ0.25/⬎2 0.12/⬎4 0.06/⬎4

70.0 65.0 70.0 70.0

0.12/0.25 ⱕ0.25/ⱕ0.25 ⱕ0.03/0.06 ⱕ0.03/0.06

100.0 100.0 100.0 100.0

0.12/4 ⱕ0.25/0.5 ⱕ0.03/1 ⱕ0.03/1

90.8 92.9 94.3 94.3

0.12/2 ⱕ0.25/2 0.06/2 0.06/2

95.8 88.7 90.1 90.1

0.12/1 ⱕ0.25/1 0.06/1 ⱕ0.03/1

97.2 91.7 97.2 97.2

0.12/1 ⱕ0.25/0.5 ⱕ0.03/2 ⱕ0.03/1

92.5 90.0 90.0 90.0

0.12/2 ⱕ0.25/2 0.06/2 ⱕ0.03/2

95.2 89.8 91.8 91.8

2/⬎4 ⱕ0.25/⬎2 1/⬎4 0.5/⬎4

67.8 74.3 67.8 69.7

4/⬎4 0.5/⬎2 2/⬎4 2/⬎4

53.4 51.7 50.0 51.7

2/⬎4 ⱕ0.25/⬎2 1/⬎4 0.5/⬎4

68.0 73.2 69.1 72.2

2/⬎4 ⱕ0.25/⬎2 1/⬎4 0.5/⬎4

65.1 69.7 64.7 67.1

Using proposed susceptibility breakpoint of ⱕ4 ␮g/ml (Fung-Tomc et al., 2000). All other quinolones follow NCCLS (2002) guidelines for susceptibility breakpoints. a

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efforts revealed two strains of K. pneumoniae from the same North American site displaying the same ribogroup (266.7) which possessed an ESBL phenotype and antibiograms suggesting the presence of Amp C cephalosporinases (data not shown). Two hundred ninety-seven of 343 strains of E. coli and K. pneumoniae were non-ESBL phenotypes with ceftazidime MIC values of ⱕ1 ␮g/ml. Within this subset, 9% of strains were resistant to ciprofloxacin (⬎1␮g/ml), with complete cross-resistance among all quinolones tested. The isolates displaying an ESBL phenotype (ceftazidime ⱖ2 ␮g/ml) were much more resistant to ciprofloxacin (34.7%) and cross-resistance between all quinolones was once again complete. Among the Enterobacter spp. (141 strains) submitted to this study, 28 (19.9%) strains exhibited phenotypic stably derepressed Amp C ␤-lactamase expression (ceftazidime, ceftriaxone, and aztreonam resistance). 3.3. Comments Staphylococcus aureus was the predominate pathogen associated with skin and soft tissue infections tested in all three regions. In fact the total number of S. aureus isolates submitted exceeded the combined number of the subsequently ranked four pathogens. Previous SENTRY Program studies involving SSTI isolates from the United States and Canada 1997 showed a very strong correlation between the frequency and rank of the top five pathogens from North American and those from the current study region (Doern et al., 1999). This study also proposes that there is significant intra-regional concordance which may suggest a similar guide for antimicrobials be used in Latin America and Europe. Garenoxacin displayed a clear advantage over the comparator quinolones against S. aureus, CoNS, Enterococcus spp., and ␤-hemolytic streptococcus as well as equivalent coverage of enteric bacilli and P. aeruginosa. Observations of garenoxacin’s extended coverage of Grampositive pathogens, especially MRSA and equivalent spectrum against Gram-negative organisms appear to be warranted (Fung-Tomc et al., 2000). Ciprofloxacin displayed marginally increased coverage of P. aeruginosa, the second ranked SSTI pathogen in this study, when challenged by isolates submitted from North America and Europe. However this same advantage was not observed against Latin America isolates which were generally more resistant. Empiric therapies involving aminoglycosides in combination with carbapenems, cefepime, or piperacillin/tazobactam would provide increased coverage over this fluoroquinolone used alone (Jones et al., 2002). Concerns regarding vancomycin-resistant enterococci (VRE), first reported in Europe over a decade ago, (Low et al., 2001; Uttley et al., 1988) have been escalating as these strains continue to be recovered from SSTI, blood stream and urinary tract infections worldwide. Increased recovery rates of SSTI-associated VREs have been demonstrated (Low et al., 2001) and the current SENTRY Program (2000) results reveal that 6.6% of the entire population of Entero-

coccus spp. submitted exhibited a pattern of vancomycin resistance. Furthermore, an alarming percentage of these strains continue to be recovered from North American sites, e.g., 85% of VRE isolates. The increased activity of garenoxacin against Enterococcus spp. overall was not significant, and the need for additional new and potent antimicrobial agents against VRE strains continues. Overall, E. coli and Klebsiella spp. rank as the third and fifth most frequent pathogens isolated from SSTI. ESBL production has become a troublesome resistance mechanism associated with these strains. Approximately 7.3% of E. coli and 23.8% of Klebsiella spp. strains in this study exhibited antibiograms consistent with NCCLS (2002) guidelines for the screening of phenotypic ESBL-producers. Cross-resistance with other antimicrobial classes including quinolone resistance was high among confirmed ESBL producers. In fact, ciprofloxacin resistance among E. coli and Klebsiella spp. was 14.2 and 10.2%, respectively, regardless of ESBL phenotype. Information provided from geographically based surveillance studies such as the SENTRY Program have increased epidemiologic awareness of antimicrobial resistance in an effort to guide antimicrobial therapies and epidemiologic interventions based on the occurrence rates of pathogenic bacteria. Statistical data from a large number of isolates recovered from diverse geographic regions like those tested by the SENTRY Program are also powerful tools in determining emerging resistance patterns and current antimicrobial susceptibility patterns of novel candidate agents such as garenoxacin (Fung-Tomc et al., 2000; Takahata et al., 1999).

Acknowledgments The co-authors wish to thank the following persons for their assistance in the conduct of this study (2000) and their input in completing this report: D. Varnam, K. Meyer, K. Gordon, P. Rhomberg and M.L. Beach. The SENTRY Program was funded by an educational/research grant from Bristol-Myers Squibb.

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