Microbiological tests to predict treatment outcome in experimental device-related infections due to Staphylococcus aureus

Treatment outcome of experimental device-related infections cannot be predicted by the results of standard susceptibility tests such as MIC. Microorganisms involved in such infections have a slow growth rate and adhere to surfaces. Therefore, laboratory tests were developed taking into account these properties and compared with the treatment outcome in an animal model. Vancomycin, teicoplanin, ciprofloxacin and fleroxacin were tested alone, or in combination with rifampicin for their ability to cure experimental device-related infections in guinea pigs due to Staphylococcus aureus ATCC 29213. Rifampicin alone or in combination was significantly more effective than the other four drugs (P < 0·001). Combined treatment with rifampicin had a higher cure rate than rifampicin alone. Treatment success was not predicted by an antibiotic trough level exceeding the MIC at site of infection. In contrast, drug efficacy was predicted if the stationary-phase MBC was in the sensitive range, and if glass-adherent S. aureus was killed by low drug concentration

Penetration of rifampicin into the brain tissue and cerebral extracellular space of rats

Rifampicin is used to treat neurosurgical shunt infections because of its excellent in-vitro activity against staphylococci and its adequate penetration into the CSF. However, nothing is known about rifampicin concentrations in the cerebral extracellular space (CES). We measured the penetration of rifampicin into the CES of anaesthetized rats by microdialysis using low-flow and equilibrium methods. Depending on the method, rifampicin concentrations in the CES were 0·3-1% of the serum concentration or 3-8% of brain tissue concentration, respectively. These experimental data in animals suggest that the recommended dose of rifampicin in man might be inadequate for treatment of some brain infection

Preventing implant-associated infections by silver coating

Implant-associated infections (IAI) are a dreaded complication mainly caused by biofilm-forming staphylococci. Implant surfaces preventing microbial colonization would be desirable. We examined the preventive effect of a silver-coated titanium aluminium niobium (TiAlNb) alloy. The surface elicited a strong, inoculum-dependent activity against Staphylococcus (S.) epidermidis and S. aureus in an agar inhibition assay. Gamma sterilization and alcohol disinfection did not alter the effect. In a tissue cage mouse model, silver coating of TiAlNb cages prevented peri-operative infections in an inoculum-dependent manner, and led to a 100 % prevention rate after challenge with 2 x 106 CFU S. epidermidis/cage. In S. aureus infections, silver coating had only limited effect. Similarly, daptomycin or vancomycin prophylaxis alone did not prevent S. aureus infections. However, silver coating combined with daptomycin or vancomycin prophylaxis thwarted methicillin-resistant S. aureus infections in 100 % or 33%, respectively. Moreover, silver release from the surface was independent of infection and occurred rapidly after implantation. On day 2, a peak of 82 μg Ag/ml was reached in the cage fluid corresponding to almost 6 times the minimal inhibitory concentration of the staphylococci. Cytotoxicity towards leukocytes in the cage was low and temporary. Surrounding tissue did not reveal histological signs of silver toxicity. In vitro, no emergence of silver resistance was observed in several clinical strains of staphylococci upon serial subinhibitory silver exposure. In conclusion, our data demonstrate that silver-coated TiAlNb is potent for preventing IAI and thus can be considered for clinical application

Immune Reconstitution After Allogeneic Hematopoietic Stem Cell Transplantation and Association With Occurrence and Outcome of Invasive Aspergillosis

Background. Invasive aspergillosis (IA) remains a leading cause of morbidity and mortality in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). To date, no reliable immunological biomarkers for management and outcome of IA exist. Here, we investigated reconstitution of antifungal immunity in patients during the first 12 months after HSCT and correlated it with IA. Methods. Fifty-one patients were included, 9 with probable/proven IA. We determined quantitative and qualitative reconstitution of polymorphonuclear (PMN), CD4, CD8, and natural killer (NK) cells against Aspergillus fumigatus over 5 time points and compared the values to healthy donors. Results. Absolute CD4 and CD8 cell counts, antigen-specific T-cell responses, and killing capacity of PMN against A. fumigatus were significantly decreased in all patients over 12 months. In patients with probable/proven IA, reactive oxygen species (ROS) production tended to be lower compared to patients without IA, and absolute NK-cell counts remained below 200 cells/µL. Patients with well-controlled IA showed significantly higher ROS production and NK-cell counts compared to patients with poor outcome. Conclusions. This study highlights the importance of functional PMN, T-cell, and NK-cell immunity for the outcome of IA. Larger multicenter studies should address the potential use of NK-cell counts for the management of antifungal therap

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

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 μg/ml, respectively, for linezolid; 0.01, 0.08, and 2.5 μg/ml, respectively, for rifampin; and 0.16, 0.63, >20 μg/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 μg/ml, respectively, were achieved in sterile cage fluid at ≈3 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 log10 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 log10 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 implant-associated infections caused by quinolone-resistant MRSA

Rings, chains and helices: new antimicrobial silver coordination compounds with (iso-)nicotinic acid derivatives

Complexes with silver ions have great potential for applications in medicine. Appropriate bidentate ligands, binding to silver ions, are able to generate coordination polymers as well as molecular entities as a function of ligand flexibility, conformation and length. Here we present the continuation of our previous studies in this field with ligands based on oligomers of polyethylene glycol, functionalized at both ends with either nicotinic or isonicotinic acid. The structures of three ligands and nine new coordination compounds are presented. A large variety of structures are obtained as a function of counterion, solvent and ligand-to-metal ratio, such as isolated rings, offset stacked rings, parallel chains and entangled chains, and their antimicrobial properties as well as biocompatibility are assessed