S. aureus endocarditis: Clinical aspects and experimental approaches.

Infective endocarditis (IE) is a life-threatening disease, caused by septic vegetations and inflammatory foci on the surface of the endothelium and the valves. Due to its complex and often indecisive presentation the mortality rate is still about 30%. Most frequently bacterial microorganisms entering the bloodstream are the underlying origin of the intracardiac infection. While the disease was primarily restricted to younger patients suffering from rheumatic heart streptococci infections, new at risk categories for Staphylococcus (S.) aureus infections arose over the last years. Rising patient age, increasing drug resistance, intensive treatment conditions such as renal hemodialysis, immunosuppression and long term indwelling central venous catheters but also the application of modern cardiac device implants and valve prosthesis have led to emerging incidences of S. aureus IE in health care settings and community. The aetiologic change has impact on the pathophysiology of IE, the clinical presentation and the overall patient management. Despite intensive research on appropriate in vitro and in vivo models of IE and gained knowledge about the fundamental mechanisms in the formation of bacterial vegetations and extracardiac complications, improved understanding of relevant bacterial virulence factors and triggered host immune responses is required to help developing novel antipathogenic treatment strategies and pathogen specific diagnostic markers. In this review, we summarize and discuss the two main areas affected by the changing patient demographics and provide first, recent knowledge about the pathogenic strategies of S. aureus in the induction of IE, including available experimental models of IE used to study host-pathogen interactions and diagnostic and therapeutic targets. In a second focus we present diagnostic (imaging) regimens for patients with S. aureus IE according to current guidelines as well as treatment strategies and surgical recommendations.

Cardiac 4D phase-contrast CMR at 9.4 T using self-gated ultra-short echo time (UTE) imaging.

BACKGROUND: Time resolved 4D phase contrast (PC) cardiovascular magnetic resonance (CMR) in mice is challenging due to long scan times, small animal ECG-gating and the rapid blood flow and cardiac motion of small rodents. To overcome several of these technical challenges we implemented a retrospectively self-gated 4D PC radial ultra-short echo-time (UTE) acquisition scheme and assessed its performance in healthy mice by comparing the results with those obtained with an ECG-triggered 4D PC fast low angle shot (FLASH) sequence. METHODS: Cardiac 4D PC CMR images were acquired at 9.4 T in healthy mice using the proposed self-gated radial center-out UTE acquisition scheme (TE/TR of 0.5 ms/3.1 ms) and a standard Cartesian 4D PC imaging sequence (TE/TR of 2.1 ms/5.0 ms) with a four-point Hadamard flow encoding scheme. To validate the proposed UTE flow imaging technique, experiments on a flow phantom with variable pump rates were performed. RESULTS: The anatomical images and flow velocity maps of the proposed 4D PC UTE technique showed reduced artifacts and an improved SNR (left ventricular cavity (LV): 8.9 ± 2.5, myocardium (MC): 15.7 ± 1.9) compared to those obtained using a typical Cartesian FLASH sequence (LV: 5.6 ± 1.2, MC: 10.1 ± 1.4) that was used as a reference. With both sequences comparable flow velocities were obtained in the flow phantom as well as in the ascending aorta (UTE: 132.8 ± 18.3 cm/s, FLASH: 134.7 ± 13.4 cm/s) and pulmonary artery (UTE: 78.5 ± 15.4 cm/s, FLASH: 86.6 ± 6.2 cm/s) of the animals. Self-gated navigator signals derived from information of the oversampled k-space center were successfully extracted for all animals with a higher gating efficiency of time spent on acquiring gated data versus total measurement time (UTE: 61.8 ± 11.5%, FLASH: 48.5 ± 4.9%). CONCLUSIONS: The proposed self-gated 4D PC UTE sequence enables robust and accurate flow velocity mapping of the mouse heart in vivo at high magnetic fields. At the same time SNR, gating efficiency, flow artifacts and image quality all improved compared to the images obtained using the well-established, ECG-triggered, 4D PC FLASH sequence.

Staphylococcus aureus develops increased resistance to antibiotics by forming dynamic small colony variants during chronic osteomyelitis.

OBJECTIVES: Staphylococcus aureus osteomyelitis often develops to chronicity despite antimicrobial treatments that have been found to be susceptible in in vitro tests. The complex infection strategies of S. aureus, including host cell invasion and intracellular persistence via the formation of dynamic small colony variant (SCV) phenotypes, could be responsible for therapy-refractory infection courses. METHODS: To analyse the efficacy of antibiotics in the acute and chronic stage of bone infections, we established long-term in vitro and in vivo osteomyelitis models. Antibiotics that were tested include ß-lactams, fluoroquinolones, vancomycin, linezolid, daptomycin, fosfomycin, gentamicin, rifampicin and clindamycin. RESULTS: Cell culture infection experiments revealed that all tested antibiotics reduced bacterial numbers within infected osteoblasts when treatment was started immediately, whereas some antibiotics lost their activity against intracellular persisting bacteria. Only rifampicin almost cleared infected osteoblasts in the acute and chronic stages. Furthermore, we detected that low concentrations of gentamicin, moxifloxacin and clindamycin enhanced the formation of SCVs, and these could promote chronic infections. Next, we treated a murine osteomyelitis model in the acute and chronic stages. Only rifampicin significantly reduced the bacterial load of bones in the acute phase, whereas cefuroxime and gentamicin were less effective and gentamicin strongly induced SCV formation. During chronicity none of the antimicrobial compounds tested showed a beneficial effect on bone deformation or reduced the numbers of persisting bacteria. CONCLUSIONS: In all infection models rifampicin was most effective at reducing bacterial loads. In the chronic stage, particularly in the in vivo model, many tested compounds lost activity against persisting bacteria and some antibiotics even induced SCV formation.

Antitrypanosomal naphthylisoquinoline alkaloids and related compounds.

In view of the need to develop new drugs against human African trypanosomiasis, a series of naturally occurring naphthylisoquinoline alkaloids, axially chiral acetogenic products derived from tropical plants, have been investigated for their activity against Trypanosoma brucei brucei TC 221. Likewise compounds corresponding to the two molecular portions, the naphthalene and the isoquinoline parts were tested, as well as molecules related to the central biaryl core of the alkaloids. Among all compounds tested, the natural, genuine alkaloids themselves, in particular dioncophylline B with its biaryl system and a moderate number of free hydroxy functions, showed the highest activities. Our results demonstrate that naphthylisoquinoline alkaloids constitute an interesting novel class of antitrypanosomal compounds worth further optimization.