Journal of Antimicrobial Chemotherapy Advance Access published September 26, 2005

Journal of Antimicrobial Chemotherapy Advance Access published September 26, 2005 Journal of Antimicrobial Chemotherapy doi:10.1093/jac/dki348 Compa...
Author: Augustus Waters
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Journal of Antimicrobial Chemotherapy Advance Access published September 26, 2005

Journal of Antimicrobial Chemotherapy doi:10.1093/jac/dki348

Comparative in vitro antimicrobial activity of a novel quinolone, garenoxacin, against aerobic and anaerobic microbial isolates recovered from general, vascular, cardiothoracic and otolaryngologic surgical patients Charles E. Edmiston, Jr1*, Candace J. Krepel1, Karen S. Kehl2, Gary R. Seabrook1, Lewis B. Somberg3, G. Hossein Almassi4, Timothy L. Smith5, Todd A. Loehrl5, Kellie R. Brown1, Brian D. Lewis1 and Jonathan B. Towne1 1

Division of Vascular Surgery, Medical College of Wisconsin, Milwaukee, WI, USA; 2Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA; 3Division of Trauma & Critical Care Surgery, Medical College of Wisconsin, Milwaukee, WI, USA; 4Division of Cardiothoracic Surgery, Medical College of Wisconsin, Milwaukee, WI, USA; 5Department of Otolaryngology & Communication Sciences, Medical College of Wisconsin, Milwaukee, WI, USA Received 6 June 2005; returned 1 July 2005; revised 13 August 2005; accepted 5 September 2005

Objectives: The aim of the study was to analyse the susceptibility of unique and non-duplicate aerobic and anaerobic isolates from surgical patients to a novel des-F(6)-quinolone (garenoxacin) and other selected antimicrobial agents. Methods: Eleven hundred and eighty-five aerobic and anaerobic isolates from general, vascular, cardiothoracic and otolaryngologic surgical patients were tested for susceptibility to garenoxacin and seven other antibiotics (ciprofloxacin, moxifloxacin, levofloxacin, piperacillin/tazobactam, imipenem, clindamycin and metronidazole) using the referenced microbroth and agar-dilution method. Results: Garenoxacin exhibited greater antimicrobial activity than comparator quinolones such as ciprofloxacin, levofloxacin and other antimicrobials when tested against selected Gram-positive organisms. The in vitro aerobic and anaerobic activity of garenoxacin was similar to that of moxifloxacin. All fluoroquinolones tested were effective against most Gram-negative facultative anaerobes including Escherichia coli. Garenoxacin and moxifloxacin demonstrated similar in vitro antimicrobial activity against selected anaerobic Gram-positive and Gram-negative anaerobic bacteria such as members of the Bacteroides fragilis group. Overall, the in vitro activity of the advanced spectrum quinolones against anaerobic surgical isolates compared favourably with selected comparator agents, metronidazole, imipenem and piperacillin/ tazobactam. Conclusions: These findings suggest that 82.4% of aerobic surgical isolates were susceptible to a concentration of garenoxacin £1.0 mg/L, whereas 84.5% of the anaerobic isolates were susceptible to a garenoxacin concentration £1.0 mg/L. Garenoxacin may be a valuable surgical anti-infective for treatment of serious head and neck, soft tissue, intra-abdominal and diabetic foot infections. Keywords: surgical infections, MICs, in vitro susceptibility

Introduction Since the introduction of ciprofloxacin in the late 1980s, the fluoroquinolones have been viewed as a potent group of

anti-infectives for serious Gram-negative infections. However, prior to the development of trovafloxacin the fluoroquinolones were considered as having limited utility as monotherapy for surgical infections. Serious intra-abdominal infections resulting from

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*Correspondence address. Division of Vascular Surgery, 9200 West Wisconsin Avenue, Milwaukee, WI 5326, USA. Tel: +1-414-805-5739; Fax: +1-414-454-0152; E-mail: [email protected] .............................................................................................................................................................................................................................................................................................................................................................................................................................

Page 1 of 7  The Author 2005. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected]

Edmiston et al. surgical complications or perforation of the gastrointestinal tract often involve multiple bacterial strains, including Gram-negative aerobic and facultative bacilli, anaerobic bacilli and Gram-positive cocci.1–3 Effective monotherapy for potentially serious abdominal and deep tissue infections requires an agent that exhibits broadspectrum activity against both aerobic and anaerobic bacteria, demonstrating adequate distribution into targeted tissues.4,5 To achieve broad-spectrum coverage against polymicrobial bacterial infections, multidrug regimens have commonly been used. The fluoroquinolones represent a potent group of anti-infectives for serious Gram-negative infections.6 These agents exhibit a broadspectrum of activity and a favourable pharmacokinetic profile that make them attractive for use in a variety of bacterial infections.6–8 However, despite their demonstrated efficacy in the treatment of serious bacterial infections such as complicated intra-abdominal and diabetic foot infections, their use has been limited by adverse events or lack of adequate anaerobic coverage.3,6,7,9 Garenoxacin is a novel des-F-(6)-quinolone that is being investigated for a variety of bacterial infections, including intraabdominal and diabetic foot infections. While historically, quinolone activity against selected staphylococcal isolates has been poor, it has been suggested that garenoxacin may exhibit good to excellent in vitro activity against a broad spectrum of clinically important bacteria including selected strains of methicillinresistant Staphylococcus aureus (MRSA) as well as Gram-positive/ Gram-negative aerobes and anaerobic microorganisms.10–14 In addition to its broad-spectrum bactericidal properties, the pharmacokinetic and safety profile of garenoxacin may make it an appropriate monotherapeutic option for serious polymicrobial surgical infections and other treatment-resistant infections.15 This comparative in vitro study was conducted to determine the antimicrobial activity of garenoxacin against aerobic and anaerobic microbial isolates recovered in culture from selected surgical tissues and device-related infections. This study was approved by the institutional IRB.

Materials and methods Eleven-hundred and eighty-five unique and non-duplicate aerobic (531) and anaerobic (654) microbial isolates were obtained over a 3 year period (1999–2002) from five surgical services: trauma, general, vascular, cardiothoracic and otolaryngology. The microbial isolates representative of multiple loci of infection were recovered from intra-operative cultures, including intra-abdominal, skin and skin structure, pulmonary abscess, rhinosinusitis or biomedical device-related infections (catheter-related blood stream infections, ventilator-associated pneumonia and explanted prosthetic devices). NCCLS-recommended reference broth and agar dilution methods were used for respective aerobic and anaerobic susceptibility testing.16,17 Microbroth and agar dilution plates were prepared the day of testing and incubated at 35 C for 24 h (aerobes) and 48 h (anaerobes), respectively. Gram-positive and Gram-negative aerobic/facultative isolates were tested in Mueller–Hinton broth. Anaerobic strains were tested on brucella blood agar plates supplemented with 5 mg haemin, 1 mg vitamin K1 per mL and 5% lysed sheep blood. The agar-dilution plates were inoculated (105 cfu/spot) using a 32-prong Steers replicator device. Antimicrobial standard powders were reconstituted according to instructions obtained from the manufacturers, serially diluted, and added to appropriate media for testing: garenoxacin (Bristol-Myers Squibb, Princeton, NJ, USA); ciprofloxacin and moxifloxacin (Bayer Corporation, West Haven, CT, USA); levofloxacin (Ortho-McNeil Pharmaceuticals, Raritan, NJ, USA); imipenem

(Merck and Company, Rahway, NJ, USA); piperacillin/tazobactam (Wyeth-Ayerst, St Davids, PA, USA); clindamycin (PharmaciaUpJohn, Kalamazoo, MI, USA); and metronidazole (SCS, Chicago, IL, USA). The MIC was defined as the lowest concentration of antimicrobial agent that yielded no growth compared with control plates as per NCCLS endpoint interpretation.16,17 Control strains included S. aureus ATCC 29213, Enterococcus faecalis ATCC 29212, Escherichia coli ATCC 25922, Bacteroides fragilis ATCC 25285, Bacteroides thetaiotaomicron ATCC 29741 and Eubacterium lentum ATCC 4305.

Results The susceptibilities of the 531 aerobic and facultative surgical isolates, listed by species, are shown in Table 1. The results are expressed as the range and MIC at which 50 and 90% of the strains were inhibited (MIC50 and MIC90, respectively) by the selected antimicrobial agents. The in vitro activity of garenoxacin against methicillin-susceptible S. aureus was found to be in the MIC range of £0.03–0.12 mg/L, while activity against methicillin-resistant, quinolone susceptible/resistant strains was characterized as good to poor (MIC range quinolone susceptible £0.03–1.0; quinolone resistant 0.25–>8.0 mg/L, respectively). Garenoxacin activity against methicillin-resistant, quinolone-resistant S. aureus and methicillinresistant Staphylococcus epidermidis was similar to ciprofloxacin, levofloxacin and moxifloxacin. Garenoxacin exhibited the lowest range (£0.03–0.25) and MIC90 (0.06) compared with the other test quinolones, including moxifloxacin (MIC range 0.12–0.5; MIC90 0.25) against penicillin non-susceptible Streptococcus pneumoniae. Enterococcal activity for both garenoxacin and moxifloxacin were similar for all test isolates, Enterococcus avium, Enterococcus faecium and E. faecalis. Garenoxacin demonstrated the lowest MIC50 and MIC90 values for the Streptococcus milleri group (Streptococcus anginosus, Streptococcus constellatus and Streptococcus intermedius) compared with the five comparator compounds. Overall, garenoxacin exhibited in vitro activity against staphylococci and streptococci that was comparable to piperacillin/tazobactam and imipenem. The Gram-negative in vitro activity of garenoxacin was similar to the activity of ciprofloxacin, moxifloxacin and levofloxacin (Table 1). The activity of garenoxacin against strains of E. coli from intra-abdominal locus was similar to ciprofloxacin, levofloxacin and moxifloxacin (– one dilution). However, the MIC90 values for garenoxacin and moxifloxacin against Klebsiella pneumoniae were three dilutions higher than the MIC90 for ciprofloxacin and levofloxacin (1.0 versus 0.12 mg/L). Five of seven strains of Stenotrophomonas maltophilia exhibited a susceptibility to garenoxacin of £1.0 mg/L. The anti-pseudomonal (Pseudomonas aeruginosa) activity (MIC90) of the extended spectrum quinolones (garenoxacin and moxifloxacin: MIC90 > 8.0 mg/L) was less than that observed for ciprofloxacin (MIC90 = 8.0). Overall, garenoxacin demonstrated similar in vitro activity to piperacillin/tazobactam and imipenem against selected Gram-negative surgical isolates, including E. coli and K. pneumoniae. However, the quinolones and imipenem were more active against Enterobacter aerogenes and Enterobacter cloacae (MIC90 0.25–1.0 mg/L and 0.25 mg/L, respectively) compared with piperacillin/tazobactam (MIC90 > 128.0 mg/L). Overall, garenoxacin demonstrated similar in vitro activity against anaerobic bacteria compared with moxifloxacin, with the exception of selected strains including Bacteroides vulgatus and

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In vitro activity of garenoxacin in surgical patients Table 1. Comparative ranges, MIC50s and MIC90s for garenoxacin tested against 531 Gram-positive and Gram-negative aerobic-facultative isolates from surgical patients Organism (no. of isolates) and agent

Range (mg/L)

MIC50 (mg/L)

MIC90 (mg/L)

Methicillin-susceptible Staphylococcus aureus (25) garenoxacin £0.03–0.12 0.06 0.12 ciprofloxacin 0.5–2.0 0.5 2.0 moxifloxacin £0.03–0.5 0.25 0.25 levofloxacin 0.25–1.0 0.5 1.0 piperacillin/tazobactam £0.12–16.0 1.0 4.0 imipenem 0.06–0.25 0.06 0.25 Methicillin-resistant quinolone-susceptible Staphylococcus aureus (20) garenoxacin £0.03–1.0 0.12 0.5 ciprofloxacin 0.5–2.0 0.5 1.0 moxifloxacin 0.12–0.5 0.12 0.25 levofloxacin 0.25–2.0 0.25 1.0 piperacillin/tazobactam 8.0–>128.0 8.0 128.0 imipenem 4.0–>16.0 4.0 8.0 Methicillin-resistant quinolone-resistant Staphylococcus aureus (20) garenoxacin 0.25–>8.0 1.0 4.0 ciprofloxacin 4.0–>8.0 >8.0 >8.0 moxifloxacin 0.25–>8.0 2.0 >8.0 levofloxacin 8.0–>8.0 >8.0 >8.0 piperacillin/tazobactam 2–>128.0 32.0 >128.0 imipenem 0.5–>16.0 4.0 >16.0 Methicillin-resistant Staphylococcus epidermidis (20) garenoxacin 0.12–>8.0 1.0 8.0 ciprofloxacin 0.25–>8.0 >8.0 >8.0 moxifloxacin 0.25–>8.0 2.0 >8.0 levofloxacin 0.5–>8.0 >8.0 >8.0 piperacillin/tazobactam 0.5–>128.0 4.0 >128.0 imipenem 0.25–>16.0 2.0 >16.0 Penicillin-non-susceptible Streptococcus pneumoniae (21) garenoxacin £0.03–0.25 0.03 0.06 ciprofloxacin 0.25–>8.0 1.0 4.0 moxifloxacin 0.12–0.5 0.12 0.25 levofloxacin 0.25–8.0 1.0 4.0 piperacillin/tazobactam 2.0–32.0 4.0 16.0 imipenem 0.12–4.0 0.5 2.0 Enterococcus avium (16) garenoxacin 0.25–1.0 0.5 1.0 ciprofloxacin 0.5–8.0 1.0 2.0 moxifloxacin 0.12–1.0 1.0 2.0 levofloxacin 0.5–>16.0 2.0 4.0 piperacillin/tazobactam 2–64 4.0 8.0 imipenem 1.0–8.0 2.0 4.0 Enterococcus faecium (18) garenoxacin 0.12–>8 4.0 >8.0 ciprofloxacin 1.0–>8.0 >8.0 >8.0 moxifloxacin 0.25–>8.0 2.0 >8.0 levofloxacin 0.5–>8.0 >8.0 >8.0 piperacillin/tazobactam 2.0–>128.0 64.0 >128.0 imipenem 0.5–>16.0 8.0 >16 Enterococcus faecalis (52) garenoxacin 0.06–8.0 0.5 1.0 ciprofloxacin 2.0–>8.0 >8.0 >8.0 moxifloxacin 0.12–>8 1.0 4.0

Table 1. (continued) Organism (no. of isolates) and agent

Range (mg/L)

levofloxacin 4.0–>8.0 piperacillin/tazobactam 2.0–64.0 imipenem 0.5–>16.0 Streptococcus anginosus (23) garenoxacin £0.03–0.12 ciprofloxacin 0.25–4.0 moxifloxacin £0.03–0.25 levofloxacin 0.5–8.0 piperacillin/tazobactam £0.12–0.5 imipenem 0.03–0.5 Streptococcus constellatus (27) garenoxacin £0.03–1.0 ciprofloxacin 0.12–2.0 moxifloxacin £0.03–0.25 levofloxacin £0.12–4.0 piperacillin/tazobactam £0.12–1.0 imipenem 0.03–0.5 Streptococcus intermedius (39) garenoxacin £0.03–0.5 ciprofloxacin 0.03–4.0 moxifloxacin 0.06–1.0 levofloxacin 0.12–2.0 piperacillin/tazobactam 0.12–2.0 imipenem 0.03–0.25 Citrobacter freundii (15) garenoxacin £0.03–4.0 ciprofloxacin £0.03–8.0 moxifloxacin 0.03–4.0 levofloxacin 128 imipenem 128.0 imipenem £0.03–1.0 Enterobacter cloacae (18) garenoxacin £0.03–1.0 ciprofloxacin £0.03–0.5 moxifloxacin 0.03–1.0 levofloxacin 0.06–0.5 piperacillin/tazobactam 1.0–>128.0 imipenem £0.03–2.0 Escherichia coli (55) garenoxacin £0.03–0.25 ciprofloxacin £0.03–0.12

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MIC50 (mg/L) >8.0 2.0 2.0

MIC90 (mg/L) >8.0 16.0 8.0

0.03 1.0 0.03 2.0 0.12 0.12

0.12 4.0 0.25 8.0 0.25 0.12

0.03 0.5 0.06 0.5 0.12 0.25

0.12 2.0 0.25 2.0 0.5 0.25

0.03 1.0 0.25 0.5 0.12 0.12

0.12 1.0 0.5 2.0 0.5 0.25

0.25 0.06 0.25 0.03 4.0 0.12

2.0 0.5 1.0 0.5 >128 0.5

0.12 0.06 0.12 0.12 4.0 0.12

0.50 0.25 0.50 0.25 >128 0.25

0.25 0.06 0.25 0.12 4.0 0.12

1.0 0.25 0.5 0.5 >128.0 0.25

0.03 £0.03

0.06 0.03

Edmiston et al. Table 1. (continued) Organism (no. of isolates) and agent

Range (mg/L)

moxifloxacin £0.03–0.25 levofloxacin £0.03–0.12 piperacillin/tazobactam 0.12–>128.0 imipenem £0.03–0.5 Klebsiella oxytoca (16) garenoxacin £0.03–0.25 ciprofloxacin £0.03–0.12 moxifloxacin £0.03–0.25 levofloxacin £0.03–0.12 piperacillin/tazobactam 0.25–128.0 imipenem £0.03–1.0 Klebsiella pneumoniae (35) garenoxacin 0.06–2.0 ciprofloxacin £0.03–1.0 moxifloxacin 0.06–2.0 levofloxacin £0.03–1.0 piperacillin/tazobactam 0.12–64.0 imipenem £0.03–1.0 Morganella morganii (8)a garenoxacin 0.25–1.0 ciprofloxacin 0.06–0.5 moxifloxacin 0.25–2.0 levofloxacin 0.03–0.5 piperacillin/tazobactam 0.25–16.0 imipenem 0.06–4.0 Proteus mirabilis (18) garenoxacin 0.12–1.0 ciprofloxacin 0.03–0.5 moxifloxacin 0.12–1.0 levofloxacin 0.03–0.5 piperacillin/tazobactam 0.5–128.0 imipenem £0.03–0.5 Pseudomonas aeruginosa (55) garenoxacin 1–>8.0 ciprofloxacin 0.25–>8.0 moxifloxacin 2–>8 levofloxacin 0.5–>8.0 piperacillin/tazobactam 0.5–>128.0 imipenem 0.25–>16.0 Pseudomonas fluorescens (6)a garenoxacin 1.0–>8.0 ciprofloxacin 0.12–4.0 moxifloxacin 0.5–>8.0 levofloxacin 0.25->8.0 piperacillin/tazobactam 1.0–64.0 imipenem 0.25–8.0 Stenotrophomonas maltophilia garenoxacin ciprofloxacin moxifloxacin levofloxacin piperacillin/tazobactam mipenem a

(7)a 0.5–>8.0 1.0–>8.0 0.5–>8.0 2.0–>8.0 32–>128.0 4–>16.0

Fewer than 10 isolates, reported as range only.

MIC50 (mg/L)

MIC90 (mg/L)

0.03 £0.03 0.5 0.12

0.12 0.03 4.0 0.25

0.06 0.03 0.12 0.03 0.5 0.25

0.25 0.12 0.25 0.12 4.0 0.50

0.25 0.06 0.25 0.06 1.0 0.12

1.0 0.12 1.0 0.12 8.0 0.5

Fusobacterium mortiferum (Table 2). Against the B. fragilis group isolates, both garenoxacin and moxifloxacin demonstrated good to excellent in vitro activity, which was comparable to metronidazole, piperacillin/tazobactam and imipenem. MIC90 values for garenoxacin and moxifloxacin were within a similar range for both clostridial (MIC90 range 1.0–4.0 mg/L) and eubacterial isolates (MIC90 range 0.25–0.5 mg/L). While most clinical isolates of Fusobacterium nucleatum and F. mortiferum were susceptible to the extended-spectrum quinolones, Fusobacterium varium and Fusobacterium russii, however exhibited higher (non-therapeutic) MIC values (MIC > 8.0 mg/L for both garenoxacin and moxifloxacin, respectively) compared with metronidazole (MIC 1.0 mg/L), piperacillin/tazobactam (MIC 4.0–8.0 mg/L) and imipenem (MIC 1.0–2.0 mg/L). Garenoxacin and moxifloxacin demonstrated similar in vitro activity against Porphyromonas (MIC90 1.0 mg/L) and Prevotella (pigmented and non-pigmented: MIC90 1.0–2.0 mg/L) surgical isolates. Overall, garenoxacin demonstrated in vitro activity against a broad range of anaerobic bacteria, especially those strains most often associated with polymicrobial infections in surgical patients, such as B. fragilis, Clostridium perfringens and the peptostreptococci species.

Discussion

0.5 0.06 0.5 0.06 0.5 0.12 4.0 0.5 4.0 1.0 4.0 0.5

1.0 0.12 1.0 0.12 2.0 0.25 >8.0 8.0 >8.0 8.0 64.0 >16.0

Infections that involve the diabetic limb, abdominal/pelvic vaults and head/neck often comprise a mixed microbial flora. Common microbial populations associated with intra-abdominal infections include enterococci, Klebsiella species, Bacteroides species, Enterobacter species, staphylococci, E. coli and P. aeruginosa.1–3 In the case of head/neck infection, many of the bacterial isolates express potent b-lactamase activity requiring use of a b-lactam/ inhibitor combination for effective treatment.18 While agents such as ciprofloxacin, levofloxacin and gatifloxacin have been used in the treatment of severe polymicrobial infections, such as diabetic foot infections, they must be used in combination with an antianaerobic drug for optimal antimicrobial coverage. In addition, many surgical infections occur in sites where there is significant disruption of tissue plains and vascular supply.3,4 The quinolones have been used successfully in a broad range of surgical infections, especially in regions of poor vascular perfusion, such as in diabetic foot, intra-abdominal abscesses or the obstructed biliary tree.3,5,7 The present in vitro data suggest that garenoxacin would be an effective agent for the treatment of infection in surgical patients involving either a mono or polymicrobial flora, such as those organisms associated with biomedical device-associated infection, intra-abdominal infection, soft tissue or diabetic foot infections, pulmonary abscess, nosocomial pneumonia (ventilator-associated pneumonia), or selected head and neck infections. In the present study, garenoxacin demonstrated good to excellent in vitro activity against a broad group of Gram-positive organisms. This in vitro activity encompassed many of the strains that are commonly responsible for difficult to treat healthcare-associated infections. For example, garenoxacin was active against penicillin non-susceptible S. pneumoniae, with an MIC90 four times lower than that of moxifloxacin and 66 times lower than that of levofloxacin and ciprofloxacin. While garenoxacin was active against selected strains of MRSA, including quinolone-susceptible and resistant S. aureus (MIC90 = 0.5 and 4.0 mg/L, respectively), a cautionary note is indicated since the quinolones have, in general, demonstrated limited or poor clinical utility against these serious

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In vitro activity of garenoxacin in surgical patients Table 2. Comparative ranges, MIC50s and MIC90s for garenoxacin tested against 654 Gram-positive and Gram-negative anaerobic isolates from surgical patients Organism (no. of isolates) and agent Actinomyces spp. (10)a garenoxacin clindamycin imipenem moxifloxacin metronidazole piperacillin/tazobactam Bacteroides caccae (12) garenoxacin clindamycin imipenem moxifloxacin metronidazole piperacillin/tazobactam Bacteroides distasonis (30) garenoxacin clindamycin imipenem moxifloxacin metronidazole piperacillin/tazobactam Bacteroides fragilis (135) garenoxacin clindamycin imipenem moxifloxacin metronidazole piperacillin/tazobactam Bacteroides gracilis (12) garenoxacin clindamycin imipenem moxifloxacin metronidazole piperacillin/tazobactam Bacteroides ovatus (10) garenoxacin clindamycin imipenem moxifloxacin metronidazole piperacillin/tazobactam Bacteroides stercoris (10) garenoxacin clindamycin imipenem moxifloxacin metronidazole piperacillin/tazobactam Bacteroides thetaiotaomicron garenoxacin clindamycin imipenem

Range (mg/L)

MIC50 (mg/L)

MIC90 (mg/L)

0.12–2 £0.06–32 £0.03–0.5 0.25–4.0 2–16.0 32.0 £0.03–4.0 0.06–0.25 0.03–0.25 £0.06–0.12

0.03 0.06 0.03 0.06 0.12 0.06

0.12 0.5 0.5 0.25 0.25 0.12

£0.03–4.0 0.03–>32.0 0.12–0.5 0.12–4.0 0.06–1.0 0.5–>128.0

0.5 0.12 0.25 0.5 0.5 8.0

1.0 4.0 0.5 2.0 1.0 32.0

£0.03–4.0 0.25–>32.0 0.03–>16.0 0.12–>8.0 0.12–2.0 £0.06–128

0.12 2.0 0.25 0.5 0.5 2.0

0.5 4.0 2.0 1.0 1.0 8.0

£0.03–2.0 0.06–16.0 0.06–0.5 0.12–4.0 0.06–0.25 £0.06–0.12

0.06 0.5 0.25 0.25 0.12 £0.06

0.5 2.0 0.5 1.0 0.25 £0.06

0.25–1.0 1.0–>32 0.12–1.0 0.5–>8.0 0.12–8.0 0.06–16.0

0.5 2.0 0.5 2.0 2.0 4.0

£0.03–1.0 0.03–4.0 0.06–0.25 0.12–2.0 0.25–4.0 0.5–128.0 (80) 0.5–>8 0.25–>32 0.06–2.0

0.06 0.25 0.12 0.25 1.0 4.0 0.5 4.0 0.12

1.0 >32.0 1.0 2.0 4.0 16.0 0.5 1.0 0.25 1.0 2.0 8.0 2.0 >32 0.5

Table 2. (continued) Organism (no. of isolates) and agent

Range (mg/L)

moxifloxacin 1.0–>8.0 metronidazole 0.25–4.0 piperacillin/tazobactam 1.0–64.0 Bacteroides uniformis (60) garenoxacin 0.12–>8 clindamycin 0.5–>32.0 imipenem 0.06–>8 moxifloxacin 0.25–>8 metronidazole 0.12–2.0 piperacillin/tazobactam 1.0–128.0 Bacteroides vulgatus (30) garenoxacin 0.12–1.0 clindamycin 0.03–>32.0 imipenem 0.12–1.0 moxifloxacin 0.25–>8.0 metronidazole 0.25–4.0 piperacillin/tazobactam 2.0–128.0 Bacteroides species (15)b garenoxacin 0.12–>8.0 clindamycin £0.03–>32.0 imipenem 0.06–8.0 moxifloxacin 0.25->8.0 metronidazole 0.06–2.0 piperacillin/tazobactam 0.12–>128.0 Bilophilia wadsworthii (5) garenoxacin 0.12–2.0 clindamycin 0.06–16.0 imipenem 0.12–4.0 moxifloxacin 0.25–2.0 metronidazole 0.03–2.0 piperacillin/tazobactam 0.5–32.0 Clostridium clostridiiforme (10) garenoxacin 0.06–2.0 clindamycin 0.03–0.5 imipenem 0.12–4.0 moxifloxacin 0.25–4.0 metronidazole 0.06–1.0 piperacillin/tazobactam 0.5–128.0 Clostridium perfringens (25) garenoxacin 0.12–4.0 clindamycin 0.03–>32.0 imipenem 0.03–0.50 moxifloxacin 0.25–>8.0 metronidazole 0.25–4.0 piperacillin/tazobactam 0.06–0.5 Clostridium species (37)c garenoxacin 0.12–4.0 clindamycin 0.03–16.0 imipenem 0.06–8.0 moxifloxacin 0.25–4.0 metronidazole 0.12–4.0 piperacillin/tazobactam £0.06–32.0 Eubacterium aerofaciens (5) garenoxacin 0.03–0.25 clindamycin 0.06–4.0

Page 5 of 7

MIC50 (mg/L)

MIC90 (mg/L)

2.0 1.0 16.0

2.0 2.0 32.0

2.0 4.0 0.5 0.5 0.5 16.0

>8.0 16.0 2.0 >8.0 1.0 64.0

0.25 0.5 0.5 0.5 1.0 16.0

1.0 2.0 1.0 4.0 2.0 64.0

0.5 2.0 0.25 1.0 1.0 2.0

2.0 >32.0 1.0 4.0 2.0 16.0

0.5 0.25 0.5 1.0 0.25 4.0

1.0 0.5 2.0 2.0 0.5 16.0

0.5 4.0 0.25 1.0 2.0 0.12 0.25 4.0 0.5 0.5 2.0 4.0

2.0 8.0 0.25 4.0 4.0 0.25 2.0 16.0 4.0 2.0 4.0 32.0

Edmiston et al. Table 2. (continued) Organism (no. of isolates) and agent

Table 2. (continued) Range (mg/L)

imipenem 0.03–0.5 moxifloxacin 0.03–0.5 metronidazole 0.06–4.0 piperacillin/tazobactam 0.12–4.0 Eubacterium lentum (20) garenoxacin £0.03–0.5 clindamycin 0.12–8.0 imipenem 0.03–2 moxifloxacin 0.03–1.0 metronidazole 0.06–4.0 piperacillin/tazobactam 0.25–32.0 Fusobacterium mortiferum (10) garenoxacin £0.03–0.5 clindamycin 0.03–0.5 imipenem 0.03–2.0 moxifloxacin 0.5–1.0 metronidazole £0.03–0.5 piperacillin/tazobactam 0.12–2.0 Fusobacterium nucleatum (10) garenoxacin 0.12–1.0 clindamycin 0.06–0.5 imipenem £0.03–0.12 moxifloxacin 0.25–1.0 metronidazole £0.03–0.25 piperacillin/tazobactam £0.06–1.0 Fusobacterium spp. (10)d garenoxacin 0.12–>8.0 clindamycin 0.06–>32.0 imipenem £0.03–2.0 moxifloxacin 0.12–>8.0 metronidazole £0.03–2.0 piperacillin/tazobactam 0.12–32.0 Gemella morbillorum (15) garenoxacin £0.03–1.0 clindamycin 0.03–0.5 imipenem £0.03–0.12 moxifloxacin 0.06–0.5 metronidazole £0.03–1.0 piperacillin/tazobactam 0.06–2.0 Peptostreptococcus anaerobius (10) garenoxacin £0.03–0.50 clindamycin 0.06–16.0 imipenem 0.03–0.5 moxifloxacin 0.06–2.0 metronidazole 0.50–8.0 piperacillin/tazobactam 0.03–8.0 Peptostreptococcus magnus (25) garenoxacin £0.03–1.0 clindamycin 0.06–8.0 imipenem £0.03–0.5 moxifloxacin 0.06–1.0 metronidazole 0.25–2.0 piperacillin/tazobactam 0.12–8.0 Peptostreptococcus micros (20) garenoxacin £0.03–0.5 clindamycin 0.06–2.0

MIC50 (mg/L)

MIC90 (mg/L)

0.12 0.25 0.12 0.25 0.5 1.0

0.25 2.0 0.5 0.5 4.0 8.0

0.12 0.12 0.25 0.5 0.06 0.5

0.25 0.5 0.5 1.0 0.25 2.0

1.0 0.12 0.03 0.25 0.25 0.06

1.0 0.25 0.12 0.5 0.25 0.25

1.0 2.0 0.50 1.0 0.25 0.5

>8.0 32.0 2.0 >8.0 1.0 8.0

0.12 0.06 0.03 0.25 0.12 0.06

0.25 0.12 0.12 0.5 0.5 0.25

0.25 0.25 0.06 0.50 2.0 0.06

0.50 2.0 0.12 1.0 4.0 0.50

0.50 0.25 0.12 0.25 2.0 0.12

0.50 4.0 0.12 1.0 2.0 0.5

0.06 0.12

0.25 0.5

Organism (no. of isolates) and agent

Range (mg/L)

imipenem £0.03–0.25 moxifloxacin 0.03–1.0 metronidazole 0.12–2.0 piperacillin/tazobactam 0.06–2.0 Peptostreptococcus species (8)e garenoxacin 0.03–1.0 clindamycin 0.06–4.0 imipenem £0.03–0.5 moxifloxacin 0.12–1.0 metronidazole £0.03–4.0 piperacillin/tazobactam 0.06–1.0 Porphyromonas species (10)f garenoxacin £0.03–1.0 clindamycin £0.03–4.0 imipenem £0.03–0.5 moxifloxacin 0.06–2.0 metronidazole 0.06–16.0 piperacillin/tazobactam 0.12–4.0 Prevotella species (30)g garenoxacin 0.12–1.0 clindamycin £0.03–0.12 imipenem £0.03–0.25 moxifloxacin 0.25–2.0 metronidazole 0.12–8.0 piperacillin/tazobactam 0.06–2.0

MIC50 (mg/L)

MIC90 (mg/L)

0.06 0.12 0.5 0.12

0.12 0.5 1.0 0.25

0.5 0.06 0.12 1.0 1.0 0.12

1.0 0.12 0.25 1.0 4.0 0.25

0.5 0.03 0.06 1.0 0.5 0.12

1.0 0.03 0.25 2.0 4.0 0.25

a

Actinomyces species: A. viscosus (4), A. odontolyticus (4), A. naeslundii (2). Bacteroides species: B. eggerthii (6), B. merdae (5), B. splanchnicus (4). c Clostridium species: C. bifermentans (2), C. butyricum (1), C. cadaveris (3), C. difficile (4), C. hastiforme (1), C. histolyticum (2), C. innocuum (7), C. ramosum (7), C. sporogenes (1), C. subterminale (6), C. tertium (2), C. tyrobutyricum (1). d Fusobacterium species: F. varium (3), F. necrophorum (5), F. russii (2). e Peptostreptococcus species: P. prevotii (4), P. asaccharolyticus (4). f Porphyromonas species: P. asaccharolytica (5), P. gingivalis (5). g Prevotella species: P. buccae (5), P. denticola (5), P. intermedia (5), P. disiens (5), P. bivia (5), P. melaninogenicus (5). b

infections. While garenoxacin demonstrated the lowest MIC50 (1.0 mg/L) and MIC90 (8.0 mg/L) values against methicillinresistant S. epidermidis compared with other quinolone comparators, infections (especially those involving biomedical devices) are often recalcitrant to a wide range of anti-infectives including quinolones. All of the comparator quinolones, as well as imipenem and piperacillin/tazobactam, exhibited good to excellent activity against Gram-negative and facultative surgical microbial isolates. Although garenoxacin demonstrated in vitro activity against most of these organisms, the MIC90 values observed for ciprofloxacin and levofloxacin indicated that these agents exhibited greater in vitro activity against many Gram-negative isolates, including E. coli, K. pneumoniae and Proteus mirabilis. None of the antibiotics tested was highly active against the Pseudomonas species, with the exception of piperacillin/tazobactam. Garenoxacin, imipenem and piperacillin/tazobactam demonstrated good to excellent activity against most Gram-positive and Gram-negative anaerobic bacteria. Approx. 90% of B. fragilis

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In vitro activity of garenoxacin in surgical patients group surgical isolates were inhibited by a garenoxacin concentration £1.0 mg/L. A recent study has also noted that garenoxacin exhibited excellent in vitro activity against members of the B. fragilis group.12 However, other investigators have suggested that the MIC90 range of garenoxacin for all members of the B. fragilis group was between 4.0 and 32.0 mg/L.19,20 Resistance of anaerobic bacteria to trovafloxacin and other quinolones has been suggested to be due to mutations in the gyrase (gyrA) and topoisomerase IV (parC) genes with or without involvement of an efflux pump.21 The clinical impact of these findings is currently unknown. In healthy subjects, once-daily dosing with garenoxacin results in plasma trough levels of >1.0 mg/L at a dose of 400 mg.15 A recent study using a microdialysis technique for in situ analysis of subcutaneous tissue concentrations of moxifloxacin in patients with soft tissue infection found that tissue concentrations mimicked plasma levels.22 While published microdialysis garenoxacin data in patients are currently lacking, the present in vitro susceptibility findings (MIC90 values £1.0 mg/L for 82.4% and 84.5% of aerobic and anaerobic surgical isolates, respectively) indicate that if tissue levels of garenoxacin are found to mimic published plasma values then that would suggest a possible therapeutic utility in the treatment of selected surgical infections. Such broad-spectrum activity, if validated in clinical trials would make garenoxacin an appropriate choice for the treatment of severe mono or polymicrobial surgical infections.

Acknowledgements This study was supported in part by a grant from Bristol Myers Squibb Company.

Transparency declarations None of the indicated authors have any proprietary interests in the manufacturer of garenoxacin or the other compounds mentioned in this manuscript.

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