Potency and spectrum of garenoxacin tested against an international collection of skin and soft tissue infection pathogens: report from the SENTRY antimicrobial surveillance program (1999–2004)

Diagnostic Microbiology and Infectious Disease 58 (2007) 19 – 26 www.elsevier.com/locate/diagmicrobio

Potency and spectrum of garenoxacin tested against an international collection of skin and soft tissue infection pathogens: report from the SENTRY antimicrobial surveillance program (1999–2004) Thomas R. Fritschea,4, Helio S. Sadera, Ronald N. Jonesa,b a

b

JMI Laboratories, North Liberty, IA 52317, USA Tufts University School of Medicine, Boston, MA 02111, USA Received 8 December 2006; accepted 8 December 2006

Abstract The spectrum and potency of garenoxacin, a novel des-F(6)-quinolone, against a large international collection (11 723 strains) of Grampositive and Gram-negative bacterial pathogens that cause skin and soft tissue infections (SSTIs) were evaluated for the years 1999 to 2004. Consecutive nonduplicate bacterial isolates were collected from patients with documented community-acquired or nosocomial SSTI in N 70 medical centers participating in the SENTRY Antimicrobial Surveillance Program in North America (37.4%), Europe (26.7%), Latin America (16.7%), and the Asia-Pacific region (19.2%). All isolates were tested using the reference broth microdilution methods against garenoxacin, ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, and representative comparator agents used for the empiric or directed therapy for SSTI. Ranking pathogens producing SSTI during these years included Staphylococcus aureus (42.8%), Pseudomonas aeruginosa (11.1%), Escherichia coli (9.0%), Enterococcus spp. (7.3%), Klebsiella spp. (4.8%), Enterobacter spp. (4.7%), h-hemolytic streptococci (4.3%), coagulase-negative staphylococci (4.0%), Proteus mirabilis (2.5%), and Acinetobacter spp. (2.1%). Garenoxacin was the most potent agent tested against S. aureus and was at least 2-fold more active than gatifloxacin (MIC50, 0.06 mg/L) and 8-fold more active than levofloxacin (MIC50, 0.25 mg/L). Furthermore, garenoxacin was 2- to 8-fold more potent than the fluoroquinolones against h-hemolytic and viridans group streptococci, as well as up to 4-fold more active against enterococci. Garenoxacin was largely comparable with the comparator fluoroquinolones against E. coli, Klebsiella spp., and Acinetobacter spp., but it is less active than these agents against P. aeruginosa. In summary, garenoxacin was documented to be the most potent quinolone when tested against key Gram-positive pathogens (S. aureus, h-hemolytic streptococci, viridans group streptococci, and enterococci) and was similar in activity to these agents against other species (Enterobacteriaceae and Acinetobacter spp.). These in vitro data suggest that garenoxacin warrants further clinical studies in SSTI, especially against staphylococci and streptococcal pathogens. D 2007 Elsevier Inc. All rights reserved. Keywords: Garenoxacin; Skin and soft tissue infections; Fluoroquinolones

1. Introduction Options for successful antimicrobial treatment of skin and soft tissue infections (SSTIs) are complicated by patient-specific risk factors (age, severity of disease, underlying comorbidities, and allergies), spectrum of pathogens responsible (Gram-positive cocci, Gram-negative bacilli, fungi, parasites, viruses), organism-specific resistances (innate or acquired), pharmacokinetic/pharmacodynamic parameters of the drugs being used, and the anatomic site being targeted (Eron et al., 2003; Stevens et al., 2005). Of 4 Corresponding author. Tel.: +1-319-665-3370; fax: +1-319-655-3371. E-mail address: [email protected] (T.R. Fritsche). 0732-8893/$ – see front matter D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.diagmicrobio.2006.12.009

all the characteristics that may result in clinical failure, selection for or acquisition of resistance among the offending pathogen(s) to existing antimicrobial agents is known to occur rapidly and spread globally, resulting in rising health care costs (Jones, 2003; Lee et al., 2005). With these changes, there is a critical need to modify, and add to, our antimicrobial therapeutic armamentarium. Among the new agents currently undergoing phase III clinical trials is garenoxacin (formerly T-3811ME or BMS284756), a novel des-F(6)-quinolone that has a structure lacking the C6-position fluorine but having a unique difluoromethoxy substitution at position C8. These alterations are known to favorably influence potency against

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both DNA gyrase and topoisomerase IV at achievable serum concentrations after garenoxacin 400-mg doses by oral or intravenous routes. Garenoxacin has been found to be highly active in vitro against important Gram-positive and Gram-negative pathogens, including staphylococci, streptococci (Streptococcus pneumoniae, viridans group species, and h-hemolytic streptococci), Enterobacteriaceae, Acinetobacter spp., and certain other Gram-negative nonfermentative bacilli, Haemophilus influenzae, Moraxella catarrhalis, atypical respiratory tract pathogens (mycoplasmas, Chlamydia pneumoniae, and Legionella spp.), and many enterococci and anaerobes, especially Gram-positive species (Donati et al., 2002; Fung-Tomc et al., 2000; Gordon et al., 2002; Hecht and Osmolski, 2003; Higa et al., 2005; Liebetrau et al., 2003; Pereyre et al., 2004; Roblin et al., 2003). These features are complimented by the high probability of favorable target attainment (AUC/MIC) that would be expected to predict successful bacterial eradication and minimization of mutational events (low mutant prevention concentration) among indicated species (Andes and Craig, 2003; Andrews et al., 2003; Lister, 2003). These elements of spectrum and potency favor garenoxacin applications for 1) community-acquired respiratory tract infections (RTIs) (hospitalized or ambulatory patients), 2) SSTI (uncomplicated or complicated with mixed flora), and 3) selected community-acquired intra-abdominal or acute pelvic infection indications. A number of recent clinical trials have validated these indications by demonstrating equivalency of garenoxacin against standard-of-care regimens when used to treat SSTI, upper and lower RTIs, and acute pelvic infections (Ariza et al., 2005; Free et al., 2005; Krievins et al., 2005; Lopez Sisniega et al., 2005; Tellier et al., 2005). As garenoxacin moves through the clinical development pathway leading to United States Food and Drug Administration approval, surveillance to detect emerging antimicrobial resistance becomes necessary to further characterize the spectrum and potency of this agent against contemporary SSTI pathogens. In this study, in vitro testing results from the SENTRY Antimicrobial Surveillance Program were summarized from 1999 to 2004, assessing a large international collection of isolates. A total of 11 723 isolates were analyzed from results generated by reference (National Committee for Clinical Laboratory Standards [NCCLS], currently the Clinical and Laboratory Standards Institute [CLSI]) methods, comparing activity of garenoxacin with that of other quinolone agents and members of other representative antimicrobial classes used in the empiric or directed therapy for SSTI (CLSI, 2006a; CLSI, 2006b).

2. Materials and methods 2.1. Bacterial isolates tested Nonduplicate consecutive clinical isolates (11 723 total) were submitted from more than 70 medical centers annually,

in North America (z 30 sites in the United States and Canada, 37.4% of isolates), South America (10 nations, 16.7%), Asia-Pacific region (9 nations plus South Africa, 19.2%), and Europe (z 30 sites, 26.7%), as part of global surveillance programs for the years 1999 to 2004. Isolates originated from patients with documented SSTI and were of either nosocomial or community-acquired origin. The distributions of species, isolate counts, and rankings are found in Table 1. All isolates were submitted in a prevalence mode format and were not enriched with resistant isolates. Species identifications were performed by the submitting laboratories with confirmation performed by the central laboratory monitors (JMI Laboratories, North Liberty, IA; Women’s and Children’s Hospital, Adelaide, Australia) using established biochemical algorithms, including use of the Vitek Microbial Identification System (bioMerieux, Hazelwood, MO). 2.2. Antimicrobial susceptibility testing All isolates were tested by the reference broth microdilution method of the CLSI in Mueller–Hinton broth (with the addition of 2–5% lysed horse blood for testing of fastidious species) against a variety of antimicrobial agents representing the most common classes and examples of drugs used in the treatment of the indicated pathogen (CLSI, 2006a). Validated dry-form microdilution panels and broth reagents were purchased from TREK Diagnostics (Cleveland, OH). Garenoxacin standard powder was provided by Bristol-Meyers Squibb (New York, NY); other agents were acquired from their respective manufacturers or purchased from Sigma Chemical (St. Louis, MO). Interpretation of quantitative MIC results was in accordance with CLSI criteria (CLSI, 2006b); breakpoints used for garenoxacin (V 0.012/ 0.25/ z 0.5 Ag/mL for S/I/R for Gram-positive isolates and V 1/2/ z 4 Ag/mL for Gram-negative isolates) are for comparison purposes only (Andes and Craig, 2003). Enterobacteriaceae with elevated MIC values (z 2 mg/L) for Table 1 Distribution of 11 723 bacterial pathogens isolated from SSTIs monitored in the SENTRY Antimicrobial Surveillance Program (1999–2004) Rank

Pathogen

No. (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

S. aureus P. aeruginosa E. coli Enterococci Klebsiella spp. Enterobacter spp. h-Hemolytic streptococci CoNS P. mirabilis Acinetobacter spp. Serratia spp. Indole-positive proteae Citrobacter spp. Viridans group streptococci Stenotrophomonas maltophilia Other species

5015 1302 1057 859 564 550 510 474 298 246 189 177 126 83 75 198

(42.8) (11.1) (9.0) (7.3) (4.8) (4.7) (4.3) (4.0) (2.5) (2.1) (1.6) (1.5) (1.1) (0.7) (0.6) (1.9)

T.R. Fritsche et al. / Diagnostic Microbiology and Infectious Disease 58 (2007) 19 – 26

ceftazidime and/or ceftriaxone were considered as extendedspectrum h-lactamase (ESBL)–producing phenotypes according to CLSI criteria (CLSI, 2006b). ESBL confirmation was performed using the disk approximation method, incorporating testing with and without clavulanic acid. Quality control isolates used included Escherichia coli ATCC 25922 and 35218, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus ATCC 29213, S. pneumoniae ATCC 49619, and Enterococcus faecalis ATCC 29212 (CLSI, 2006b). 3. Results 3.1. Demographic characteristics and pathogen prevalence Among the 11 723 SSTI bacterial pathogens submitted during the years 1999 to 2004 for which demographic data were available (54.7% of the total), 42.0% of isolates were recovered from patients with nosocomial infections and 58.0% were community-acquired organisms. The collection was predominantly from adults (z 18 years, 84.2%) and mostly from male patients (56.6%). Most of the isolates originated from North America (37.4%) and Europe (26.7%), with lesser numbers submitted from medical centers in Latin America (16.7%) and the Asia-Pacific region (19.2%). The top 10 ranked pathogens included 92.8% of recovered isolates, and the top 15 included 98.1% (Table 1). Although S. aureus was by far the most commonly isolated pathogen (42.8%), Gram-positive species together constituted 59.1%. Among the Gram-negative species, P. aeruginosa (11.1%) and E. coli (9.0%) were most prevalent followed by other Enterobacteriaceae (4.2%) and Acinetobacter spp. (2.1%).

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3.2. Antimicrobial susceptibility testing results Among a large population of S. aureus, including 33.1% oxacillin (methicillin)-resistant strains, garenoxacin was at least 2-fold more potent than the other quinolone agents tested (MIC50 and MIC90, V 0.03 and 2 Ag/mL; Tables 2 and 3) and displayed near-identical activity (71.3% susceptibility) at a tentative breakpoint of V 0.12 Ag/mL. When examining the oxacillin-resistant subset separately, S. aureus were largely resistant to the quinolones (51.9–80.1%). Again, garenoxacin retained the most activity with MIC50 and MIC90 values (1 and 4 Ag/mL, respectively) each being 2-fold lower than those of the other quinolones (Table 4). Garenoxacin was equally active, or superior to, the other quinolones against coagulase-negative staphylococci (CoNS) (MIC50 and MIC90, 0.12 and 4 Ag/mL, respectively; 53.6% inhibited at V 0.12 Ag/mL). Only moxifloxacin demonstrated enhanced potency (MIC90, 2-fold lower) against the coagulase-negative staphylococcal collection, including the oxacillin-resistant strains (MIC50, 2-fold lower; Tables 3 and 4). All staphylococci were susceptible to linezolid (MIC90, 2 Ag/mL) and vancomycin (MIC90, 1–2 Ag/mL), and N99% of isolates were susceptible to quinupristin/dalfopristin (MIC90, 0.5 Ag/mL). The potency of garenoxacin and moxifloxacin (MIC50, 0.25 Ag/mL) was 2-fold greater than that of gatifloxacin and 4-fold greater than either ciprofloxacin or levofloxacin against Enterococcus spp. (Tables 2 and 3). Among the quinolones, ciprofloxacin displayed the lowest susceptibility rate (52.2%) and garenoxacin the lowest resistance rate (30.5%), although the breakpoint criteria used for ciprofloxacin (V 1 Ag/mL) are intended for isolates recovered from the urinary tract only. The most active agents tested

Table 2 Cumulative MIC frequency distributions for garenoxacin and levofloxacin tested against SSTI pathogens (SENTRY Program, 1999–2004) Organism (no. tested)

Agent

Cumulative % inhibited at MIC (Ag/mL) V 0.03

0.06

0.12

0.25

0.5

1

S. aureus (5015)

GAR LEV GAR LEV GAR LEV GAR LEV GAR LEV GAR LEV GAR LEV GAR LEV GAR LEV GAR LEV

68.1 0.1 29.3 0.0 0.7 0.0 13.9 0.0 51.5 69.4 1.6 38.5 3.6 52.4 0.3 32.2 0.0 0.2 21.5 4.1

70.7 5.8 47.5 0.8 2.0 0.1 69.6 0.2 70.4 72.8 18.6 72.9 34.2 72.4 1.3 67.8 0.2 0.5 30.9 20.3

71.3 48.8 53.6 22.1 13.9 0.3 98.8 0.2 73.1 73.7 65.8 76.1 67.8 76.9 10.1 77.5 0.5 1.7 37.0 30.5

72.5 69.1 55.1 51.3 50.3 0.9 100.0 8.8 76.3 77.1 74.8 80.5 76.0 82.7 49.7 78.9 1.6 19.7 41.1 39.8

76.0 71.1 58.9 53.3 59.0 9.5

86.8 71.4 73.6 54.1 61.1 52.7

92.6 72.5 86.9 61.5 69.5 61.1

97.1 83.2 94.7 77.4 85.9 63.0

81.9 78.0 78.9 80.1 84.0 82.5 86.7 70.8 80.5 9.8 53.5 41.9 41.5

98.7 78.8 80.2 83.7 87.1 84.4 88.9 78.2 87.2 41.5 63.0 45.1 42.7

100.0 79.7 80.4 86.5 88.3 86.5 90.9 79.2 91.6 60.5 71.0 46.7 45.9

80.6 84.6 88.7 92.0 88.7 92.9 80.9 93.3 69.8 75.3 56.1 58.9

CoNS (474) Enterococcus spp. (859) h-Hemolytic streptococcus (510) E. coli (1057) Klebsiella spp. (564) Enterobacter spp. (550) P. mirabilis (298) P. aeruginosa (1302) Acinetobacter spp. (246)

GAR = garenoxacin; LEV = levofloxacin.

2

4

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Table 3 Antimicrobial activity of garenoxacin and selected comparison agents tested against the top 4 ranked Gram-positive pathogens causing SSTI in the SENTRY Program (1999–2004)a Organism (rank, no. tested)/ antimicrobial agent S. aureus (1, 5015) Garenoxacin Ciprofloxacin Gatifloxacin Levofloxacin Moxifloxacin Oxacillin Erythromycin Clindamycin Gentamicin Linezolid Quinupristin/ dalfopristin Tetracycline Trimethoprim/ sulfamethoxazole Vancomycin Enterococci (4, 859) Garenoxacin Ciprofloxacin Gatifloxacin Levofloxacin Moxifloxacin Ampicillin Chloramphenicol Gentamicin (high level) Linezolid Teicoplanin Vancomycin

MIC (Ag/mL)

% by categoryb

50%

Susceptible Resistant

90%

71.3c 70.3 71.7 71.4 70.3 66.9 58.1 78.2 86.3 100.0 99.8

27.5 28.8 26.6 27.5 20.1 33.1 41.2 21.6 13.2 –d 0.1

N8 1

84.5 95.1

15.1 4.9

1

100.0

0.0

61.1c 52.2 64.1 61.1 – 85.9 83.6 69.8

30.5 40.4 33.9 37.0 – 14.1 14.2 30.2

99.5 93.1 91.6

0.2 5.8 7.8

V 0.03 V 0.25 0.06 0.25 0.06 0.5 0.5 0.12 V2 2 V 0.25

2 N2 4 N4 4 N8 N8 N8 N8 2 0.5

V4 V 0.5 1

0.25 1 0.5 1 0.25 V2 8 V 500 2 V2 1

N4 N2 N4 N4 N4 N 16 N 16 N 1000 2 V2 4

b-Hemolytic streptococci (7, 510) e Garenoxacin 0.06 Ciprofloxacin 0.5 Gatifloxacin 0.25 Levofloxacin 0.5 Moxifloxacin 0.12 Cefepime V 0.12 Ceftriaxone V 0.25 Clindamycin V 0.06 Erythromycin V 0.06 Linezolid 1 Meropenem V 0.06 Penicillin V 0.016 Vancomycin 0.5

0.12 1 0.25 1 0.25 V 0.12 V 0.25 V 0.06 2 1 V 0.06 0.06 0.5

98.8c – 100.0 100.0 – 99.8 100.0 94.1 85.1 100.0 100.0 100.0 100.0

0.0 – 0.0 0.0 – – – 5.7 14.7 – – – –

CoNS (8, 474) Garenoxacin Ciprofloxacin Gatifloxacin Levofloxacin Moxifloxacin Oxacillin Erythromycin Clindamycin Gentamicin Linezolid Quinupristin/dalfopristin

4 N2 4 N4 2 N8 N8 N8 N8 2 0.5

53.6c 54.2 55.5 54.1 62.7 24.3 42.2 70.3 65.4 100.0 99.8

44.9 43.2 32.9 38.5 23.5 75.7 57.6 29.1 27.8 – 0.0

0.12 0.25 0.25 0.25 0.12 2 N8 0.12 V2 1 V 0.25

Table 3 (continued) Organism (rank, no. tested)/ antimicrobial agent

MIC (Ag/mL)

% by categoryb

50%

Susceptible Resistant

CoNS (8, 474) Tetracycline Trimethoprim/ sulfamethoxazole Vancomycin

90%

V4 V 0.5 1

N8 N2

81.4 76.7

17.5 23.3

2

100.0

0.0

a

Includes 6858 isolates or 98.8% of tested Gram-positive SSTI pathogens. b Susceptibility breakpoint criteria of the CLSI (2006a, 2006b). c Garenoxacin breakpoints used ( V 0.12/0.25/0.5 Ag/mL for S/I/R) are for comparison purposes only (Andes and Craig, 2003). d – = no interpretive criteria. e Includes streptococci from groups A (242 strains), B (168), C (18), F (6), and G (68); h-hemolytic streptococci (not otherwise identified, 7); and Streptococcus equisimilis (1).

against enterococci included linezolid (99.5% susceptible), teicoplanin (93.1%), and vancomycin (91.6%). Vancomycin-resistant enterococci (VRE) (7.8% of isolates) were also largely resistant to quinolones (N 85%, data not shown). All quinolone MIC50 values among the vancomycin-resistant strains were N4 Ag/mL compared with 0.25 to 1 Ag/mL for vancomycin-susceptible strains. Table 4 Antimicrobial activity of garenoxacin and other quinolone agents tested against oxacillin-susceptible and oxacillin-resistant subsets of staphylococci causing SSTI (SENTRY Program, 1999–2004) Organism (rank, no. tested)/ antimicrobial agent

MIC (Ag/mL)

% by categorya

50%

Susceptible

S. aureus Oxacillin susceptible (3356) Garenoxacin V 0.03 Ciprofloxacin 0.25 Gatifloxacin 0.06 Levofloxacin 0.12 Moxifloxacin V 0.03 Oxacillin resistant (1659) Garenoxacin 1 Ciprofloxacin N4 Gatifloxacin 2 Levofloxacin 4 Moxifloxacin 2 CoNS Oxacillin susceptible (115) Garenoxacin 0.03 Ciprofloxacin V 0.25 Gatifloxacin 0.12 Levofloxacin 0.25 Moxifloxacin 0.06 Oxacillin resistant (359) Garenoxacin 1 Ciprofloxacin N2 Gatifloxacin 1 Levofloxacin 2 Moxifloxacin 0.5

90%

0.03 0.5 0.12 0.25 0.06 4 N4 N4 N4 N4

0.12 0.5 0.25 0.5 0.25 4 N2 4 N4 4

Resistant

96.4 95.6 96.7 96.2 95.6

3.3 3.5 3.0 3.4 3.1

20.6 19.1 21.1 20.8 23.1

76.6 80.1 79.9 76.6 51.9

92.2 92.2 93.0 90.7 90.7

7.8 7.0 4.3 7.2 1.9

41.2 42.1 43.5 42.0 52.7

56.8 54.9 42.1 48.8 31.3

a Susceptibility breakpoint criteria of the CLSI (2006b); garenoxacin breakpoints used ( V 0.12/0.25/0.5 Ag/mL for S/I/R) are for comparison purposes only.

T.R. Fritsche et al. / Diagnostic Microbiology and Infectious Disease 58 (2007) 19 – 26 Table 5 Antimicrobial activity of garenoxacin and selected comparison agents tested against the top 5 ranked Gram-negative pathogens causing SSTI in the SENTRY Program (1999–2004)a MIC (Ag/mL)

% by categoryb

50%

90%

Susceptible

Resistant

2 V 0.25 1 0.5 2 4 4 V2 1 8 0.5

N4 N2 N4 N4 N4 N 16 N 16 N8 N8 N 64 N 16

41.5c 72.5 69.3 71.0 –d 80.0 79.0 78.0 81.2 83.6 83.0

39.5 24.3 25.8 24.7 – 11.4 17.4 18.0 12.4 16.4 16.4

E. coli (3, 1057) Garenoxacin Ciprofloxacin Gatifloxacin Levofloxacin Moxifloxacin Amoxicillin/clavulanate Cefepime Cefoxitin Ceftazidime Ceftriaxone Gentamicin Imipenem Piperacillin/tazobactam Trimethoprim/ sulfamethoxazole

V 0.03 V 0.25 V 0.03 V 0.03 0.06 8 V 0.12 4 V1 V 0.25 V2 V 0.5 2 V 0.5

N4 N2 N4 N4 N4 N 16 1 16 2 0.5 N8 V 0.5 8 N2

78.8c 80.1 80.8 80.4 – 73.7 94.4 88.3 93.2 91.3 86.1 100.0 93.3 73.7

20.3 19.8 14.2 15.4 – 10.1 4.9 6.3 4.4 (11.5)e 6.8 (11.1)e 12.8 0.0 3.3 26.3

Klebsiella spp. (5, 564) Garenoxacin Ciprofloxacin Gatifloxacin Levofloxacin Moxifloxacin Amoxicillin/clavulanate Cefepime Cefoxitin Ceftazidime Ceftriaxone Gentamicin Imipenem Piperacillin/tazobactam Trimethoprim/ sulfamethoxazole

0.12 V 0.25 0.06 0.06 0.12 4 V 0.12 4 V1 V 0.25 V2 V 0.5 2 V 0.5

N4 N2 4 4 N4 N 16 8 16 N 16 N 32 N8 V 0.5 N 64 N2

83.7c 86.9 89.4 88.3 – 72.0 90.2 84.9 83.5 79.8 81.0 100.0 82.3 86.2

13.5 11.3 7.3 8.0 – 11.0 7.8 8.9 13.3 (25.0)e 13.1 (23.6)e 16.9 0.0 12.9 13.8

N4 2 2 2 N4 N 16 4 N 32 N 16 N 32 8

84.4c 89.6 91.3 90.9 – 3.8 97.3 2.9 73.6 77.1 88.9

13.5 8.9 6.2 7.1 – 94.4 2.0 94.7 22.2 14.2 10.2

Organism (rank, no. tested)/ antimicrobial agent P. aeruginosa (2, 1302) Garenoxacin Ciprofloxacin Gatifloxacin Levofloxacin Moxifloxacin Cefepime Ceftazidime Gentamicin Imipenem Piperacillin/tazobactam Tobramycin

Enterobacter spp. (6, 550) Garenoxacin 0.12 Ciprofloxacin V 0.25 Gatifloxacin 0.06 Levofloxacin V 0.03 Moxifloxacin 0.12 Amoxicillin/clavulanate N 16 Cefepime V 0.12 Cefoxitin N 32 Ceftazidime V1 Ceftriaxone V 0.25 Gentamicin V2

23

Table 5 (continued) Organism (rank, no. tested)/ antimicrobial agent

MIC (Ag/mL)

% by categoryb

50%

Susceptible

Resistant

90%

Enterobacter spp. (6, 550) Imipenem V 0.5 Piperacillin/tazobactam 2 Trimethoprim/ V 0.5 sulfamethoxazole

1 64 N2

99.1 78.7 89.5

0.2 9.6 10.5

P. mirabilis (9, 298) Garenoxacin Ciprofloxacin Gatifloxacin Levofloxacin Moxifloxacin Amoxicillin/clavulanate Cefepime Cefoxitin Ceftazidime Ceftriaxone Gentamicin Imipenem Piperacillin/tazobactam Trimethoprim/ sulfamethoxazole

N4 2 4 2 N4 8 V 0.12 4 V1 V 0.25 N8 2 1 N2

78.2c 85.9 86.6 91.6 – 90.3 95.6 98.0 99.3 95.3 85.9 99.7 99.7 79.9

20.8 9.1 8.7 6.7 – 3.4 3.7 0.7 0.3 (4.0)e 4.0 (5.7)e 12.1 0.0 0.0 20.1

45.1 41.1 46.3 45.9 – 45.5 41.9 39.8 80.5 40.7 99.2

53.3 58.1 37.8 41.1 – 32.1 50.8 56.5 16.3 48.0 0.8

0.5 V 0.25 0.12 0.06 0.25 V2 V 0.12 4 V1 V 0.25 V2 1 V 0.5 V 0.5

Acinetobacter spp. (10, 246) Garenoxacin 4 Ciprofloxacin N2 Gatifloxacin 4 Levofloxacin 4 Moxifloxacin 4 Cefepime 16 Ceftazidime N 16 Gentamicin N8 Imipenem V 0.5 Piperacillin/tazobactam 64 Polymyxin B V1

N4 N2 N4 N4 N4 N 16 N 16 N8 N8 N 64 V1

a

Includes 3453 isolates or 73.3% of tested Gram-negative SSTI pathogens. b Susceptibility breakpoint criteria of the CLSI (2006b). c Garenoxacin breakpoints used ( V 1/2/4 Ag/mL for S/I/R) are for comparison purposes only. d – = no interpretive criteria. e Percentages in parentheses are the proportion of ESBL phenotypes using CLSI (2006b) criteria.

h-Hemolytic streptococci were uniformly susceptible ( N 98%) to all agents tested, with the exceptions of erythromycin (85.1%) and clindamycin (94.1%, Tables 2 and 3). Although h-lactam agents were the most active of those tested by weight (penicillin, ceftriaxone, meropenem, and cefepime; MIC90 values, V 0.25 Ag/mL), garenoxacin exhibited 2- to 8-fold greater potency (MIC50 and MIC90, 0.06 and 0.12 Ag/mL, respectively) than the other quinolones (gatifloxacin/moxifloxacin and ciprofloxacin/levofloxacin, respectively) against these species. This agent also displayed 2- to 8-fold greater potency than the tested fluoroquinolones against viridans group streptococci (data not shown, only 0.7% of all SSTI isolates). P. aeruginosa recovered from SSTI were generally less susceptible to all quinolones (41.5% to 72.5% susceptible)

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at published or tentative breakpoints, with ciprofloxacin and levofloxacin being the most potent (MIC50 values, V 0.25 and 0.5 Ag/mL, respectively) and garenoxacin and moxifloxacin the least (MIC50, 2 Ag/mL; Tables 2 and 5). Those agents providing the broadest coverage of P. aeruginosa isolates included piperacillin/tazobactam (83.6% susceptible) N tobramycin (83.0%) N imipenem (81.2%) N cefepime (79.0%). Among the E. coli recovered from SSTI, all quinolones tested were equally active, with 78.8% (garenoxacin) to 80.8% (gatifloxacin) of isolates being susceptible at tested breakpoint concentrations (Table 5). Imipenem (100% susceptible) and the group consisting of cefepime, ceftazidime, ceftriaxone, and piperacillin/tazobactam (94.4–91.3%) provided the broadest coverage. Up to 11.5% of E. coli displayed an ESBL phenotype, and of this group, 64 isolates (52.9%) were confirmed using the clavulanate inhibition assay (CLSI, 2006a; CLSI, 2006b). Susceptibilities to quinolone agents were markedly decreased among the confirmed ESBL isolates (23.4–26.6%) with only imipenem retaining broad activity at V 4 Ag/mL (100% susceptibility). Other members of the Enterobacteriaceae (Klebsiella spp., Enterobacter spp., and Proteus mirabilis) had quinolone susceptibility rates of 78.2% to 91.6% with levofloxacin and gatifloxacin being most active (MIC50 results, V 0.03 to 0.12 Ag/mL; and MIC90 results, 2–4 Ag/mL). Up to 25% of Klebsiella spp. also displayed an ESBL phenotype, of which 97 isolates (68.6%) were confirmed as positive. Quinolones displayed greater activity against ESBL-confirmed Klebsiella spp. (52.6–68.0% susceptible) than against ESBL-confirmed E. coli. Acinetobacter spp. isolates exhibited similar decreased potencies (all MIC50 and MIC90 values, z 4 Ag/mL) and susceptibility rates (41.1% to 46.3%; garenoxacin, 45.1%) to quinolones, but these agents were more active than b3rd or 4th-generationQ cephalosporins, piperacillin/tazobactam, and gentamicin (Tables 2 and 5). Only imipenem and polymyxin B had susceptibility rates at z 80.0%. 4. Discussion Infections of skin and soft tissues are among the most common of community-acquired infections, usually requiring therapeutic interventions consisting of local wound management, surgical incision and debridement, and treatment with an orally active antimicrobic, usually penicillin, cephalosporin, macrolide, or fluoroquinolone (Eron et al., 2003; Fung et al., 2003; Stevens et al., 2005). The rapid spread of methicillin-resistant S. aureus (MRSA) SSTI in the community is especially worrisome, given the clonal nature of the responsible strains, unique genetic virulence markers (Panton–Valentine leukocidin and staphylococcal chromosomal cassette mec type IVa), and lack of established risk factors, including occurrence in otherwise healthy children (Buck et al., 2005; Kowalski et al., 2005; Mongkolrattanothai and Daum, 2005). Although these

strains produce primarily local cutaneous infections, they are known to rarely progress to serious invasive disease, including bacteremia and necrotizing pneumonia, the latter of which has been near uniformly fatal (Frazee et al., 2005). In hospitalized patients, SSTI are known to produce significant morbidity and mortality, resulting in increased costs due to required intensive management and extended hospital stays (Eron et al., 2003; Lee et al., 2005). Recent surveillance network publications have documented changes occurring in SSTI pathogen prevalence and in emerging resistances among Gram-positive and Gramnegative pathogens. Although S. aureus in all studies continues to be the primary pathogen (31–55%, depending upon the region), other species vary considerably in their prevalence depending again upon the geographic region sampled and nosocomial versus community acquisition, among other factors. Enterococcus spp., P. aeruginosa, or E. coli invariably are found as the other ranking pathogens with E. coli being more prominent in Latin America and P. aeruginosa in Europe and North America (Andrade et al., 2003; Fluit et al., 2001; Fritsche et al., 2005; Kirby et al., 2002; Sader et al., 2002). A third tier of SSTI pathogens requiring therapeutic coverage consists of h-hemolytic streptococci, CoNS, and other Enterobacteriaceae (Fritsche et al., 2005; Kirby et al., 2002; Rennie et al., 2003). Empiric therapy for these infections remains complicated, given the diversity of pathogens responsible, severity of infection, patient risk factors, and inherent or acquired resistance profiles of each pathogen group. Outpatient therapy has traditionally been reliant upon orally administered antistaphylococcal penicillins, amoxicillin/clavulanate, cephalosporins, macrolides/clindamycin, and tetracyclines. Depending upon case severity, complicated SSTI may require parenteral therapy (either outpatient or in-patient) using agents such as b3rd- or 4th-generationQ cephalosporins (excluding MRSA infections), vancomycin or teicoplanin, daptomycin, linezolid, fluoroquinolones, and/or carbapenems with or without additional anaerobic coverage (Eron et al., 2003; Stevens et al., 2005). The emergence of methicillin resistance in S. aureus, macrolide resistance in streptococci, vancomycin resistance in enterococci, ESBL and AmpC production in Enterobacteriaceae, carbapenem resistance in nonfermentative Gram-negative bacilli, and fluoroquinolone resistance in both Gram-positive and Gramnegative bacteria have made treatment decisions particularly difficult (Jones, 2003; Nathwani, 2005). The role of fluoroquinolones in the setting of SSTI has primarily been as an alternative agent as recognized by various professional guidelines and is usually reserved for those patients who cannot tolerate h-lactam agents or clindamycin. As a class, the fluoroquinolones are generally very active against target pathogens and are well tolerated. Concerns over emergence of resistance through chromosomal mutations occurring in the quinolone resistance determining region are also credible, although the introduction of the newer C8 methoxy fluoroquinolones with improved activity

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against staphylococci has been a positive development (Ince et al., 2002). More recently, the novel des-F(6)quinolone garenoxacin has been shown to provide even greater enhanced activity against staphylococci and streptococci (Streptococcus pyogenes and S. pneumoniae), including strains with reduced susceptibility to ciprofloxacin due to alterations in parC and gyrA (Schmitz et al., 2002a; Schmitz et al., 2002b; Schmitz et al., 2002c). In these studies, garenoxacin was shown to exhibit 2- to 4-fold greater activity than that of moxifloxacin and 4- to 8-fold greater activity than that of gatifloxacin against ciprofloxacin-resistant S. aureus, including heterovancomycin-intermediate S. aureus; also, garenoxacin was not a substrate for efflux pump activity via NorA (Schmitz et al., 2002a). These characteristics of garenoxacin are attractive considering the inherent limitations of older fluoroquinolones in the treatment of staphylococcal infections, especially those resistant to oxacillin. As demonstrated here, garenoxacin was superior in potency to the tested fluoroquinolones against S. aureus, CoNS, streptococci (h-hemolytic and viridans group streptococci), and enterococci, and was generally comparable with these other agents against E. coli, Klebsiella spp., and Acinetobacter spp. However, against P. aeruginosa (the second ranking pathogen in this study), ciprofloxacin was at least 2- to 4-fold more active than the other quinolones. With the exception of P. aeruginosa, the improvements demonstrated by garenoxacin in spectrum and activity over those of other quinolones may be of clinical importance, especially in those patients where a fluoroquinolone agent is indicated. None of the fluoroquinolone agents studied here provided enhanced coverage of VRE or ESBL-producing E. coli and Klebsiella spp. ESBL producers are increasingly prevalent among isolates producing SSTI and other infections in many parts of the world, and in some regions, such as Latin America, these changes have been dramatic (Sader et al., 2002). In this study, up to 11.5% of E. coli and 25.0% of Klebsiella spp. were screen-positive isolates for ESBL production, an increase over that of a prior surveillance study of 36% and 5%, respectively (CLSI, 2006b; Kirby et al., 2002). Cross-resistance between fluoroquinolones and other antimicrobial classes is known to occur commonly among confirmed ESBL-producing isolates, a worrisome development, especially in those geographic regions (Latin America and Europe) where such isolates are exceedingly common or increasing in occurrence (Goossens, 2005; Jones, 2003; Sader et al., 2002). Coupled with the recognized activity of garenoxacin against anaerobic species, the potency documented here against the most prevalent SSTI aerobic and facultative anaerobic pathogens and the recent success of the agent in a phase III clinical trial demonstrating comparability with standard of care for complicated SSTI indicates that this investigative des-F(6)quinolone could be applied to mixed SSTI (complicated or uncomplicated), either as monotherapy or combined therapy (Krievins et al., 2005).

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Caution will need to be exercised in patients with known risk factors or when in hospital environments where P. aeruginosa may be endemic and less susceptible to garenoxacin when used alone. Because a variety of newer agents move through clinical development and into the marketplace, ongoing surveillance activities, such as those described here, will be helpful in identifying the agent’s particular strengths and limitations, and in tracking changes in resistance profiles as each new antimicrobial gains acceptance in clinical practice. Acknowledgments The authors express their gratitude to the following individuals who have assisted in the preparation of this report: D. Biedenbach, P. Rhomberg, and N. O’MaraMorrissey. This study was funded in part by an educational/research grant from Schering-Plough Research Institute (Kenilworth, NJ). References Andes D, Craig WA (2003) Pharmacodynamics of the new des-f(6)quinolone garenoxacin in a murine thigh infection model. Antimicrob Agents Chemother 47:3935 – 3941. Andrade SS, Jones RN, Gales AC, Sader HS (2003) Increasing prevalence of antimicrobial resistance among Pseudomonas aeruginosa isolates in Latin American medical centres: 5 year report of the SENTRY Antimicrobial Surveillance Program (1997–2001). J Antimicrob Chemother 52:140 – 141. Andrews J, Honeybourne D, Jevons G, Boyce M, Wise R, Bello A, Gajjar D (2003) Concentrations of garenoxacin in plasma, bronchial mucosa, alveolar macrophages and epithelial lining fluid following a single oral 600 mg dose in healthy adult subjects. J Antimicrob Chemother 51:727 – 730. Ariza H, Jasovich A, Fuentes C, Waskin H (2005) Sequential IV to PO garenoxacin vs. IV ampicillin/sulbactam to amoxicillin/clavulanate to treat serious acute pelvic infection. 45th ICAAC, Washington, DC (Abstr. L-2236). Buck JM, Como-Sabetti K, Harriman KH, Danila RN, Boxrud DJ, Glennen A, Lynfield R (2005) Community-associated methicillin-resistant Staphylococcus aureus, Minnesota, 2000–2003. Emerg Infect Dis 11:1532 – 1538. Clinical and Laboratory Standards Institute (2006a) Approved Standard M7-A7: Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically. (7th ed.). Wayne, PA7 NCCLS. Clinical and Laboratory Standards Institute (2006b) Performance Standards for Antimicrobial Susceptibility Testing, 16th Informational Supplement M100-S16. Wayne, PA7 NCCLS. Donati M, Pollini GM, Sparacino M, Fortugno MT, Laghi E, Cevenini R (2002) Comparative in vitro activity of garenoxacin against Chlamydia spp.. J Antimicrob Chemother 50:407 – 410. Eron LJ, Lipsky BA, Low DE, Nathwani D, Tice AD, Volturo GA (2003) Managing skin and soft tissue infections: expert panel recommendations on key decision points. J Antimicrob Chemother 52(Suppl 1):i3 – i17. Fluit AC, Schmitz FJ, Verhoef J (2001) Frequency of isolation of pathogens from bloodstream, nosocomial pneumonia, skin and soft tissue, and urinary tract infections occurring in European patients. Eur J Clin Microbiol Infect Dis 20:188 – 191. Frazee BW, Salz TO, Lambert L, Perdreau-Remington F (2005) Fatal community-associated methicillin-resistant Staphylococcus aureus pneumonia in an immunocompetent young adult. Ann Emerg Med 46:401 – 404.

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