Peripheral inactivation of gentamicin

Peripheral inactivation of aminoglycosides is defined as a reversible process related to the specific physico-chemical conditions prevailing in abscesses. Conditions of reduced pH and pO2, such as are found frequently within abscesses, may reduce strongly the antibacterial effect of aminoglycosides, possibly by their interfering action on aminoglycoside transport into the bacteria. In addition, binding factors in purulent exudates, such as leukocyte chromatin exposed to any aminoglycoside after cell lysis, may bind a significant proportion of the total antibiotic, leading to an equivalent decrease of the concentration of the free, biologically active drug. In contrast, intact phagocytes, which do not bind aminoglycosides on their chromatin because of drug exclusion from the viable cells, protect ingested bacteria from being killed by large amounts of antibiotics. The role played by the different inactivating factors has yet to be defined in a clinical context, by analysis of experimental abscesses as an extension of the present in-vitro data. L'inactivation périphérique des aminosides est définie comme un processus reversible lié aux conditions physico-chimiques locales des sites infectés. L'abaissement du pH et de la pO2 fréquemment décrit au niveau des abcès, peut réduire fortement l'activité antibactérienne des aminosides, en réduisant l'accumulation intracellulaire de ces antibiotiques par les bactéries. D'autre part, on observe un effet de captation des aminosides par des constituants du matériel purulent, en particulier par la chromatine des neutrophiles lysés. Cette captation diminue la concentration d'antibiotique libre qui seule est biologiquement active. Par contraste avec les neutrophiles lysés, les neutrophiles vivants ne captent pas les aminosides au niveau de leur chromatine et protègent les bacténes qu'ils ont phagocytés de l'effet bactéricide des aminosides. Ces effets semblent être dûs à l'absence de pénétration des aminosides a l'intérieur des neutrophiles vivants. L'importance clinique de ces différents facteurs inactivant les amino-sides n'est pan encore établie, en l'absence de données expérimentales obtenues chez l'anima

Gentamicin Inactivation in Purulent Exudates: Role of Cell Lysis

Factors contributing to the binding and reversible inactivation of gentamicin by purulent exudates were studied in a simplified in vitro model consisting of purified human polymorphonuclear leukocytes (PMNLs). Whereas intact PMNLs (106-108/ml) bound almost no [14C]gentamicin, freeze-thawed PMNLs showed extensive [14C]gentamicin binding, expressed as antibiotic cosedimenting with particulate material from the lysed PMNLs. Antibiotic binding could be related to the concentration of lysed PMNLs and to the amount of [14C]gentamicin added. Binding of [14C]gentamicin by lysed PMNLs was highly sensitive to DNase I but was unaffected by RNase, Triton X-100, or protease. Purified chromatin or DNA from either purulent exudates or lysed PMNLs reproduced the [14C]gentamicin-binding pattern obtained with crude PMNL lysate. These results show that gentamicin inactivation in purulent exudates can be correlated with binding of the antibiotic to lysed PMNLs; PMNL chromatin DNA is identified as one of the major binding factor

Concentrations of azithromycin in tonsillar and/or adenoid tissue from paediatric patients

Azithromycin levels in tonsillar and/or adenoid tissue were determined in children (1.6-7.5 years old) who were scheduled for surgical removal of their tonsils and/or adenoids. The children received azithromycin oral suspension lOmg/kg once daily for 3 days. Tissue samples were obtained during surgery 1 (n = 4), 2 (n = 5), 4 (n = 6), or 8 (n = 5) days after the last dose of azithromycin. Serum samples were also obtained from four children in each of these groups at the time of surgery. Mean tissue concentrations of azithromycin were 10.33 ± 3.01, 7.21 ± 4.04, 9.30 ± 3.74 and 1.49 ± 0.48 mg/kg, respectively, 1, 2, 4 and 8 days after the last dose. At the corresponding times, serum concentrations were markedly lower: 47.25 ± 19 19, 14.00 ± 8.45, 8.00 ± 2.16 and <4 μg/L, respectively. The mean tissue:serum concentration ratios were, 227 ± 54, 547 ± 184 and 956 ± 355, respectively, 1, 2 and 4 days after treatment. No adverse events attributable to azithromycin were observed in any of the 23 children who had received at least one dose of azithromycin. The study shows that levels of azithromycin in tonsillar and adenoid tissue were consistently higher than in serum and remained elevated up to 8 days after the end of dosing, supporting the use of a short-course (3-day), once-daily regimen of azithromycin in the treatment of upper respiratory tract infection

Perioperative Antibiotic Prophylaxis of Wound and Foreign Body Infections: Microbial Factors Affecting Efficacy

Numerous microbial factors are responsible for perioperative infections and influence the efficacy of antibiotic prophylaxis. These factors include the staphylococcal carrier state, bacterial adherence to a number of host proteins, the production of glycocalyx by sessile bacteria, and shifts in antibiotic resistance. A full understanding of the mechanisms involved will lead to further reductions in the number of postoperative infections. Unfortunately, the microbial factors affecting prophylaxis cannot be evaluated separately under clinical conditions; they are easier to study under circumstances whose bacteriologic features are well defined and in which the presence of foreign materials (e.g., sutures) greatly potentiates pathogenic mechanisms. Such circumstances exist, for example, in infections developing after "clean” surgery and in experimental models. Since even clean wounds are found to be contaminated when sampled carefully, the control of infection is more a quantitative than a qualitative problem. The critical period for the development of infection is short: an antibiotic course not exceeding 24 hours seems effective in preventing infectio

Host-Bacteria Interactions in Foreign Body Infections

Persistent staphylococcal infections are a major medical problem, especially when they occur on implanted materials or intravascular catheters. This review describes some of the recently discovered molecular mechanisms of Staphylococcus aureus attachment to host proteins coating biomedical implants. These interactions involve specific surface proteins, called bacterial adhesins, that recognize specific domains of host proteins deposited on indwelling devices, such as fibronectin, fibrinogen, or fibrin. Elucidation of molecular mechanisms of S aureus adhesion to the different host proteins may lead to the development of specific inhibitors blocking attachment of S aureus, which may decrease the risk of bacterial colonization of indwelling device

Prevalence of isolates with reduced glycopeptide susceptibility in orthopedic device-related infections due to methicillin-resistant Staphylococcus aureus

We evaluated, by an improved susceptibility testing method, the prevalence and significance of low-level glycopeptide resistance in methicillin-resistant Staphylococcus aureus (MRSA) isolates, which belonged to a previously described, retrospective cohort of patients treated for orthopedic device-related infections (ODRI) at the Geneva University Hospital between 2000 and 2008. Fifty-seven individual or multiple isolates were retrieved from 41 ODRI patients for glycopeptide susceptibility and clonality studies, including 20 patients with prosthetic joint (PJ) and 21 with osteosynthesis (OS) MRSA infections. Low-level glycopeptide resistance was detected by elevated teicoplanin or/and vancomycin minimum inhibitory concentrations (MICs ≥4mg/L), as determined by a previously validated combination of macrodilution and agar dilution assays of improved sensitivity. MRSA isolates with elevated teicoplanin MICs were detected in 20/41 (49%) ODRI patients at the onset or during the course of glycopeptide therapy, namely, in 10 of 20 patients with PJ and 10 of 21 patients with OS infections. Only one isolate developed a concomitant increase in vancomycin MIC during therapy. 13/20 (65%) glycopeptide-intermediate S. aureus (GISA)-infected patients, including 7/10 (70%) with PJ and 6/10 (60%) with OS, experienced treatment failure. In contrast, therapy failed in only 5/21 (24%) ODRI patients with non-GISA isolates (p = 0.012), including 2/10 (20%) with PJ and 3/11 (27%) with OS infections. The emergence of low-level teicoplanin resistance could not be explained by teicoplanin administration, since only four patients received teicoplanin. The evaluation of low-level teicoplanin resistance may improve the detection of GISA isolates. Further studies are warranted to evaluate the impact of low-level teicoplanin resistance on the outcome of glycopeptide therap

Qualification and Start of Production of the Ultrasonic Welding Machines for the LHC Interconnections

The Large Hadron Collider (LHC) is presently under installation at CERN, Geneva. The approximately 4000 superconducting corrector magnets required by the machine are powered through copper-stabilized Nb-Ti busbars. To interconnect the magnets along the machine, about 50 000 joints between superconducting cables rated at 600 A have to be performed in-situ during the interconnection activities. An ultrasonic welding technique has been developed and optimised by CERN which led to the development of a dedicated machine which was qualified during the assembly of the STRING II, a 110-m chain of cryomagnets assembled as a prototype of the LHC. The realization of the â series â interconnections together with the procurement of the tooling based on functional specifications have been contracted to a consortium of firms. Qualification tests and acceptance criteria in terms of electrical contact resistance, mechanical resistance, reliability and reproducibility have been defined by CERN. This paper presents the tests and some results of the qualification process relevant to the industrialized tooling provided by the contractor. Results of pre-series junctions done in the LHC tunnel are presented together with the perspective for the continuation of the work