Efficacy of ceftaroline and rifampin, alone or combined, in a rat model of methicillin-resistant Staphylococcus epidermidis osteomyelitis without implant.

IMPORTANCE: Methicillin-resistant Staphylococcus epidermidis (MRSE) contributes to a high percentage of orthopedic infections, and their treatment represents a huge challenge. The present study aimed to evaluate the efficacy of ceftaroline alone or combined with rifampin in a rat MRSE osteomyelitis model and the bone penetration of ceftaroline. A ceftaroline monotherapy showed a significant bacterial reduction in infected bones after a 7-day period of treatment. The combination ceftaroline plus rifampin leveraged rifampin's bactericidal activity, shortening the duration of positive culture in infected animals. These results suggest that ceftaroline and rifampin combination therapy could represent a valuable therapeutic option for human MRSE osteomyelitis and deserves further preclinical and clinical evaluation.

Activity of Different Antistaphylococcal Therapies, Alone or Combined, in a Rat Model of Methicillin-Resistant Staphylococcus epidermidis Osteitis without Implant.

We developed a rat model of methicillin-resistant Staphylococcus epidermidis (MRSE) osteitis without implant to compare the efficacy of vancomycin, linezolid, daptomycin, ceftaroline, and rifampin either alone or in association with rifampin. A clinical strain of MRSE was inoculated into the proximal tibia. Following a 1-week infection period, rats received either no treatment or 3, 7, or 14 days of human-equivalent antibiotic regimen. Quantitative bone cultures were performed throughout the 14-day period. The mean ± SD quantity of staphylococci in the bone after a 1-week infection period was 4.5 ± 1.0 log10 CFU/g bone, with this bacterial load remaining stable after 3 weeks of infection (4.9 ± 1.4 log10 CFU/g bone). Vancomycin monotherapy was the most slowly bactericidal treatment, whereas ceftaroline monotherapy was the most rapidly bactericidal treatment. The addition of rifampin significantly increased the bacterial reduction for vancomycin, linezolid, and daptomycin. All tibias were sterilized after 2 weeks of treatment except for animals receiving vancomycin or daptomycin alone (66.6% and 50% of sterilization, respectively). These results show that ceftaroline and linezolid alone remain good options in the treatment of MRSE osteitis without implant. The combination with rifampin increases the antibiotic effect of vancomycin and daptomycin lines.

Efficacy of Bacteriophages in a Staphylococcus aureus Nondiabetic or Diabetic Foot Infection Murine Model.

This study investigated the in vivo efficacy of three bacteriophages combined compared with linezolid in two mouse models (nondiabetic and diabetic) of Staphylococcus aureus foot infection. In both models, a single injection of bacteriophages in the hindpaw showed significant antibacterial efficacy. Linezolid was as effective as bacteriophages in nondiabetic animals but ineffective in diabetic animals. These findings further support preclinical and clinical studies for the development of phage therapy.

Factors associated with mucoid transition of Pseudomonas aeruginosa in cystic fibrosis patients.

Although the mucoid form of Pseudomonas aeruginosa (Pa) is largely responsible for the progression of lung disease in cystic fibrosis (CF), the relationship between factors relating daily-care regimes to mucoidy acquisition are as yet poorly investigated. Fifty-two CF patients registered at the CF centre of Dijon, France, were retrospectively evaluated from the date of Pa colonization either to the first positive sputum culture for mucoid Pa (n = 26) or to the last culture in which the Pa remained non-mucoid (n = 26). All clinical, pathological and therapeutic events were recorded. The association between the parameters collected and mucoid transition of Pa was assessed in a Cox model with time-dependant covariables. The mean follow-up was 4.7 + or - 4.3 years. Three independent parameters were associated with the higher risk of mucoid transition of Pa: persistence of Pa in sputum (OR 7.89; p <0.01), use of inhaled bronchodilators (OR 3.40; p = 0.04), and the use of inhaled colimycin (OR 4.04; p = 0.02). Isolation of Staphylococcus aureus, Haemophilus influenzae or Streptococcus pneumoniae in sputum was associated with a lower risk (OR 0.24; p < 0.01). Mucoid transition of Pa was associated with variables that reflected the severity of both lung disease and Pa colonization. Although they do not lead to prophylactic measures, these results corroborate the need to avoid Pa persistence.

[Mutation window for the "pneumococcus-fluoroquinolone" couple. Contribution of experimental models]. / La fenêtre de mutation pour le couple "pneumocoque-fluoroquinolone". Apport des modèles expérimentaux.

Low-level resistance to fluoroquinolones (in vitro susceptible but with topoisomerase mutation, parC) is currently rare among pneumococci in France. However, this resistance is more frequently observed in previously exposed patients and therapeutic failure has been reported. These issues were investigated by using a humanized model of experimental pneumonia induced by pneumococci exhibiting this low-level resistance profile. The results are as follows: 1) when the pneumonia is due to a wild type pneumococcus, humanized ciprofloxacin treatment is not effective because of resistant mutants with parC mutation; moreover, levoflaxin treatment is less bactericidal than gatiflo- or moxifloxacin (-4 vs -6 log CFU/g); 2) when an efflux strain is used, levo-treatment is not efficient but there are no mutants, a gatiflo-treatment is combined when mutants appear and moxiflo-treatment is effective; 3) when the pneumonia is induced with susceptible parC strains, treatment with either levo, or gati, or moxifloxacin is completely ineffective because resistant mutants appear (acquisition of another gyrA mutation). Measure of the mutation prevention concentration (MPC) allows anticipating these results since the mutation window can be determined. These results stress the necessity to identify patients with such pneumococcal strains in order to avoid therapeutic failure and the emergence of fluoroquinolone resistant mutants.

In-vivo impact of the MexXY efflux system on aminoglycoside efficacy in an experimental model of Pseudomonas aeruginosa pneumonia treated with tobramycin.

Aminoglycosides are of major importance in treating Pseudomonas aeruginosa pneumonia (PAP). However, their efficacy may be compromised by low-level resistance caused by the inducible MexXY multidrug efflux pump. In the present study, the impact of the MexXY efflux pump was investigated in vivo in an experimental model of PAP in rabbits treated with intravenous tobramycin. Three strains were used to induce PAP in rabbits: PAO1 (wild-type strain; MIC 1 mg/L), mutant 11B (mexX::Tn501; no expression of MexXY; MIC 0.5 mg/L) and mutant MutGR1 (MexZ null; constitutive expression of MexXY; MIC 2 mg/L). Five hours after inoculation, treatment with tobramycin (10 mg/kg) was implemented (peak serum concentration 30 mg/L). The animals were killed humanely 48 h after inoculation, and the residual pulmonary bacterial concentration was determined. Selection of bacteria expressing MexXY was determined by plating lung homogenates on agar plates containing antibiotic. Mean bacterial counts (log(10) CFU/g) for treated vs. untreated rabbits were 6.26 and 8.13 (p < 0.0001), 6.00 and 8.38 (p < 0.001), and 7.25 and 8.79 (p 0.04) for PAO1, 11B and MutGR1, respectively, with an overall mortality rate of 0% vs. 8.9% (p < 0.01). MexXY-overexpressing bacteria were recovered from three (21%) treated rabbits. The C(max)/MIC ratio was the parameter that was best associated with tobramycin efficacy. The bacteria overexpressing MexXY, recovered from lung, occurred with a C(max)/MIC window of 19-26. It was concluded that the experimental PAP model highlights poor tobramycin bacteriological efficacy in vivo, contrasting with survival gain, and that the contribution of the MexXY system to this low level of tobramycin efficacy is modest. Finally, this model appears to be suitable for the investigation of new anti-pseudomonal therapeutic strategies.