1 Division of Vascular Surgery, Medical College of Wisconsin, Milwaukee, WI, USA; 2 Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA; 3 Division of Trauma & Critical Care Surgery, Medical College of Wisconsin, Milwaukee, WI, USA; 4 Division of Cardiothoracic Surgery, Medical College of Wisconsin, Milwaukee, WI, USA; 5 Department 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
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Abstract |
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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
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Introduction |
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Garenoxacin is a novel des-F-(6)-quinolone that is being investigated for a variety of bacterial infections, including intra-abdominal 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 methicillin-resistant Staphylococcus aureus (MRSA) as well as Gram-positive/Gram-negative aerobes and anaerobic microorganisms.1014 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.
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Materials and methods |
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Results |
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Overall, garenoxacin demonstrated similar in vitro activity against anaerobic bacteria compared with moxifloxacin, with the exception of selected strains including Bacteroides vulgatus and 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 1.04.0 mg/L) and eubacterial isolates (MIC90 range 0.250.5 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 4.08.0 mg/L) and imipenem (MIC 1.02.0 mg/L). Garenoxacin and moxifloxacin demonstrated similar in vitro activity against Porphyromonas (MIC90 1.0 mg/L) and Prevotella (pigmented and non-pigmented: MIC90 1.02.0 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.
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Discussion |
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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 infections. While garenoxacin demonstrated the lowest MIC50 (1.0 mg/L) and MIC90 (8.0 mg/L) values against methicillin-resistant 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 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.
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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Acknowledgements |
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