In vivo efficacy of trovafloxacin (CP-99,219), a new quinolone with extended activities against gram-positive pathogens, Streptococcus pneumoniae, and Bacteroides fragilis

The pharmacodynamic and pharmacokinetic properties of trovafloxacin were studied in a standardized murine model of established subcutaneous abscesses. Daily dosing regimens of 37.5 to 300 mg/kg every 8 h (q8h) or every 24 h (q24h) were started 3 days after inoculation with mixtures containing either Bacteroides fragilis-Escherichia coli-autoclaved cecal contents (ACC) or B. fragilis-vancomycin-resistant Enterococcus faecium (VREF)-ACC. Treatment was continued for 3 or 5 days. The efficacy of treatment was determined by the decrease in abscess bacterial counts and abscess weights, as well as by the reduction in inflammation (biodistribution of 99m Tc-HYNIC immunoglobulin G) compared to saline-treated controls. Trovafloxacin showed a significant dose-response effect on the bacterial counts, weight, and inflammation of B. fragilis-E. coli abscesses after 3 and/or 5 days of treatment. A maximum 3.4 and 3.1 log 10 reduction in CFU/abscess in the respective B. fragilis and E. coli bacterial counts was attained after 5 days of treatment with daily doses of 300 mg/kg. The peak serum concentration was more predictive for effect than the area under the concentration-time curve. The C max was the pharmacodynamic index most predictive for success, and the efficacy of the q24h regimens was significantly better than the q8h regimens. The antibiotic was ineffective against the VREF in mixed infection with B. fragilis, while the killing of the anaerobe in the same combination was significantly less than in the E. coli combination (P < 0.05). We conclude that this is a useful model for studying the activity of antimicrobials for the treatment of small (<1-cm), undrainable, mixed-infection abscesses. In addition, we have shown for the first time that a decrease in bacterial numbers also leads to a reduction in both abscess weight and inflammation.

Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 91%

In Vivo Efficacy of Trovafloxacin against Bacteroides fragilis in Mixed Infection with either Escherichia coli or a Vancomycin-Resistant Strain of Enterococcus faecium in an Established-Abscess Murine Model

Stearne

Gyssens

Goessens

et al. 2001

“…Based on previously published studies, mice were administered subcutaneous (to the flank skin) or oral (via gavage) therapeutic doses of vancomycin (110 mg/kg administered subcutaneously twice daily) (30, 31) (Novaplus; Hospira, Inc., Lake Forest, IL), daptomycin (50 mg/kg administered subcutaneously daily) (32, 33) (Cubicin; Cubist Pharmaceuticals, Inc., Lexington, MA), linezolid (60 mg/kg administered subcutaneously and orally twice daily) (34) (Zyvox; Pfizer, Inc., New York, NY), clindamycin (100 mg/kg administered orally three times a day) (35,36) (Cleocin phosphate; Pfizer, Inc.), doxycycline (100 mg/kg orally twice daily) (33), and TMP-SMX (320/ 1,600 mg/kg administered orally twice daily) (37,38). Linezolid was used at the same dose for subcutaneous and oral administration because of equivalent bioavailability when given via either route (39).…”

Section: Methodsmentioning

confidence: 99%

In Vivo Bioluminescence Imaging To Evaluate Systemic and Topical Antibiotics against Community-Acquired Methicillin-Resistant Staphylococcus aureus-Infected Skin Wounds in Mice

Guo

Ramos

Cho

et al. 2013

c Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) frequently causes skin and soft tissue infections, including impetigo, cellulitis, folliculitis, and infected wounds and ulcers. Uncomplicated CA-MRSA skin infections are typically managed in an outpatient setting with oral and topical antibiotics and/or incision and drainage, whereas complicated skin infections often require hospitalization, intravenous antibiotics, and sometimes surgery. The aim of this study was to develop a mouse model of CA-MRSA wound infection to compare the efficacy of commonly used systemic and topical antibiotics. A bioluminescent USA300 CA-MRSA strain was inoculated into full-thickness scalpel wounds on the backs of mice and digital photography/image analysis and in vivo bioluminescence imaging were used to measure wound healing and the bacterial burden. Subcutaneous vancomycin, daptomycin, and linezolid similarly reduced the lesion sizes and bacterial burden. Oral linezolid, clindamycin, and doxycycline all decreased the lesion sizes and bacterial burden. Oral trimethoprim-sulfamethoxazole decreased the bacterial burden but did not decrease the lesion size. Topical mupirocin and retapamulin ointments both reduced the bacterial burden. However, the petrolatum vehicle ointment for retapamulin, but not the polyethylene glycol vehicle ointment for mupirocin, promoted wound healing and initially increased the bacterial burden. Finally, in type 2 diabetic mice, subcutaneous linezolid and daptomycin had the most rapid therapeutic effect compared with vancomycin. Taken together, this mouse model of CA-MRSA wound infection, which utilizes in vivo bioluminescence imaging to monitor the bacterial burden, represents an alternative method to evaluate the preclinical in vivo efficacy of systemic and topical antimicrobial agents. C ommunity-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) skin and soft tissue infections (SSTIs), such as impetigo, folliculitis, cellulitis, and infected wounds and ulcers, have been increasing for more than a decade and are creating a serious public health concern (1, 2). In particular, outpatient and emergency room visits for SSTIs have been estimated to result in 11.6 to 14.2 million ambulatory care visits per year in the United States (3, 4). In 2004 and 2008, CA-MRSA was identified as the most common cause (59%) of all SSTIs presenting to emergency rooms across the United States (5, 6). In these and other studies, the USA300 clone has been isolated in up to 90% of all CA-MRSA SSTIs in the United States (5-8). USA300 causes severe and necrotic SSTIs and often causes infections in otherwise healthy individuals without any known risk factors for infection (1, 2, 9).Uncomplicated CA-MRSA SSTIs, such as impetigo, infected abrasions, and folliculitis/furunculosis can be managed in an outpatient setting with oral antibiotics and/or incision and drainage (10-12). Typical oral antibiotic regimens used for CA-MRSA infections include trimethoprim-sulfamethoxazole (TMP/SMX), a tetracycline...

“…As discussed above, the fluoroquinolone class of antibiotics appears to have better activity against stationary-phase antibiotics than does the beta-lactam class. Trovafloxacin, the agent used in the present studies, is a drug of this class that has a greater spectrum of activity against gram-positive and anaerobic bacteria than the earlier fluoroquinolone drugs (8).…”

Section: Discussionmentioning

confidence: 99%

Effect of Zinc-Reversible Growth-Inhibitory Activity in Human Empyema Fluid on Antibiotic Microbicidal Activity

Sohnle

Hahn

2000

Abscess fluid supernatants have zinc-reversible microbial growth-inhibitory activity that is mediated by calprotectin, a zinc-binding protein. Because it inhibits microbial growth, this activity might interfere with killing by antibiotics that require their target organisms to be proliferating. In the present study, we cultured bacteria in human empyema fluid and used zinc to overcome the growth-inhibitory effect of calprotectin. We then compared the effect of zinc on killing by the beta-lactams ampicillin and cefazolin with that of the fluoroquinolone trovafloxacin, since the latter may be better able to kill nonproliferating organisms. In empyema fluid diluted 1:5 in normal saline, addition of zinc (30 M) increased growth of two strains of Staphyloccocus aureus and two strains of Escherichia coli but did not affect the MICs or MBCs of the three antibiotics in Mueller-Hinton broth. For one strain of S. aureus, no effect of zinc was found on killing by either ampicillin or cefazolin. However, with the other strain of S. aureus and both strains of E. coli, significant enhancement of killing by both drugs was observed with zinc addition. On the other hand, no effect on the killing of any of the organisms was observed for trovafloxacin when zinc was added. These results suggest that the zinc-reversible growth-inhibitory activity of abscess fluid may interfere with the microbicidal activity of antibiotics requiring proliferating target organisms, although antibiotics better able to kill nonproliferating organisms may be less affected by this phenomenon.