Efficacy of a Novel Rifamycin Derivative, ABI-0043, against
            <i>Staphylococcus aureus</i>
            in an Experimental Model of Foreign-Body Infection

Since levofloxacin at high doses was more active than levofloxacin at conventional doses and was the best therapy alone in a rat model of staphylococcal foreign-body infection, in this study we tested how these differences affect the activities of their respective combinations with rifampin in vitro and in vivo. In vitro studies were performed in the log and stationary phases. By using this model, rifampin at 25 mg/kg of body weight/12 h, levofloxacin at 100 mg/kg/day, levofloxacin at 100 mg/kg/day plus rifampin, levofloxacin at 50 mg/kg/day, levofloxacin at 50 mg/kg/day plus rifampin, or a control treatment was administered for 7 days; and therapy with for levofloxacin at 100 mg/kg/day alone and rifampin alone was prolonged to 14 days. We screened for the appearance of resistant strains. Killing curves in the log phase showed a clear antagonism with levofloxacin at concentrations >2؋ MIC and rifampin and tended to occur in the stationary phase. At the end of 7 days of therapy, levofloxacin at 100 mg/kg/day was the best treatment and decreased the bacterial counts from tissue cage fluid (P < 0.05 compared with the results for groups except those receiving rifampin alone). At the end of 14 days of therapy with levofloxacin at 100 mg/kg/day, levofloxacin at 100 mg/kg/day plus rifampin, and the control treatment, the bacterial counts on the coverslips were 2.24 (P < 0.05 compared with the results with the combined therapy), 3.36, and 5.4 log CFU/ml, respectively. No rifampin or levofloxacin resistance was detected in any group except that receiving rifampin alone. In conclusion, high-dose levofloxacin was the best treatment and no resistant strains appeared; the addition of rifampin showed an antagonistic effect. The efficacy of the rifampin-levofloxacin combination is not significantly improved by the dosage of levofloxacin.Orthopedic prosthetic infections are difficult to treat because of the presence of bacterial biofilms. The definitive therapy for such infections requires a combination of surgical and medical approaches and the use of selected antibiotics active against the microorganisms involved (11, 40, 48).On the basis of previous experimental and clinical studies, rifampin plays a main role in the treatment of staphylococcal foreign-body infections (4,45,47,49), while fluoroquinolones are considered the best drugs for use in combination with rifampin (14,15,46). Recent work recommended the use of a combination of high doses of levofloxacin (750 to 1,000 mg/ day) plus rifampin for the treatment of staphylococcal prosthetic infections (48), even though the information available from this setting is limited (3, 34, 39).The rat model of staphylococcal tissue cage infection is a well-standardized model of chronic foreign-body infection that has provided relevant information in this regard (8,9,32,44). Using this model, we previously reported that high-dose levofloxacin (equivalent to 750 to 1,000 mg/day) was more active than the conventional levofloxacin dose (500 mg/day) and that it was the best therapy for u...

Section: Vol 52 2008 Effect Of Rifampin On High-dose Levofloxacin 3683supporting

confidence: 73%

Antagonistic Effect of Rifampin on the Efficacy of High-Dose Levofloxacin in Staphylococcal Experimental Foreign-Body Infection

Murillo¹,

Pachón²,

Euba³

et al. 2008

“…This effect could result from the fact that cell wall synthesis is reduced in SCVs (40). In contrast, daptomycin, aminoglycosides, fluoroquinolones, oritavancin, and, to a lesser extent, rifampin have been shown to remain bactericidal against extracellular slow-growing bacteria (11,33,37,54).…”

Section: Discussionmentioning

confidence: 94%

Pharmacodynamic Evaluation of the Activity of Antibiotics against Hemin- and Menadione-Dependent Small-Colony Variants of Staphylococcus aureus in Models of Extracellular (Broth) and Intracellular (THP-1 Monocytes) Infections

Garcia

Lemaire

Kahl

et al. 2012

Staphylococcus aureus small-colony variants (SCVs) persist intracellularly, which may contribute to persistence/recurrence of infections and antibiotic failure. We have studied the intracellular fate of menD and hemB mutants (corresponding to menadione-and hemin-dependent SCVs, respectively) of the COL methicillin-resistant S. aureus (MRSA) strain and the antibiotic pharmacodynamic profile against extracellular (broth) and intracellular (human THP-1 monocytes) bacteria. Compared to the parental strain, SCVs showed slower extracellular growth (restored upon medium supplementation with menadione or hemin), reduced phagocytosis, and, for the menD SCV, lower intracellular counts at 24 h postinfection. Against extracellular bacteria, daptomycin, gentamicin, rifampin, moxifloxacin, and oritavancin showed similar profiles of activity against all strains, with a static effect obtained at concentrations close to their MICs and complete eradication as maximal effect. In contrast, vancomycin was not bactericidal against SCVs. Against intracellular bacteria, concentration-effect curves fitted sigmoidal regressions for vancomycin, daptomycin, gentamicin, and rifampin (with maximal effects lower than a 2-log decrease in CFU) but biphasic regressions (with a maximal effect greater than a 3-log decrease in CFU) for moxifloxacin and oritavancin, suggesting a dual mode of action against intracellular bacteria. For all antibiotics, these curves were indistinguishable between the strains investigated, except for the menD mutant, which systematically showed a lower amplitude of the concentration-effect response, with markedly reduced minimal efficacy (due to slower growth) but no change in maximal efficacy. The data therefore show that the maximal efficacies of antibiotics are similar against normal-phenotype and menadione-and hemin-dependent strains despite their different intracellular fates, with oritavancin, and to some extent moxifloxacin, being the most effective.

“…The rifampin dose of 12.5 mg/kg was chosen as described previously (31,34). The peak levels in tissue fluid were equal to or less than the maximal concentrations reached in humans (1), and the rifampin concentration in cage fluid was greater than the MIC during 12 h after administration.…”

Section: Discussionmentioning

confidence: 99%

“…The test The mean values of C max and AUC 0-24 in cage fluid after administration of a single intraperitoneal dose were used. Pharmacokinetic data for rifampin and levofloxacin were described previously (22,31). organism was inhibited by linezolid at 2.5 g/ml.…”

Section: Discussionmentioning

confidence: 99%

Linezolid Alone or Combined with Rifampin against Methicillin-Resistant Staphylococcus aureus in Experimental Foreign-Body Infection

Baldoni

Haschke

Rajacic

et al. 2009

Self Cite

108

We investigated the activity of linezolid, alone and in combination with rifampin (rifampicin), against a methicillin-resistant Staphylococcus aureus (MRSA) strain in vitro and in a guinea pig model of foreign-body infection. The MIC, minimal bactericidal concentration (MBC) in logarithmic phase, and MBC in stationary growth phase were 2.5, >20, and >20 g/ml, respectively, for linezolid; 0.01, 0.08, and 2.5 g/ml, respectively, for rifampin; and 0.16, 0.63, >20 g/ml, respectively, for levofloxacin. In time-kill studies, bacterial regrowth and the development of rifampin resistance were observed after 24 h with rifampin alone at 1؋ or 4؋ the MIC and were prevented by the addition of linezolid. After the administration of single intraperitoneal doses of 25, 50, and 75 mg/kg of body weight, linezolid peak concentrations of 6.8, 12.7, and 18.1 g/ml, respectively, were achieved in sterile cage fluid at Ϸ3 h. The linezolid concentration remained above the MIC of the test organism for 12 h with all doses. Antimicrobial treatments of animals with cage implant infections were given twice daily for 4 days. Linezolid alone at 25, 50, and 75 mg/kg reduced the planktonic bacteria in cage fluid during treatment by 1.2 to 1.7 log 10 CFU/ml; only linezolid at 75 mg/kg prevented bacterial regrowth 5 days after the end of treatment. Linezolid used in combination with rifampin (12.5 mg/kg) was more effective than linezolid used as monotherapy, reducing the planktonic bacteria by >3 log 10 CFU (P < 0.05). Efficacy in the eradication of cage-associated infection was achieved only when linezolid was combined with rifampin, with cure rates being between 50% and 60%, whereas the levofloxacin-rifampin combination demonstrated the highest cure rate (91%) against the strain tested. The linezolid-rifampin combination is a treatment option for implantassociated infections caused by quinolone-resistant MRSA.