Outbreak of carbapenem-resistant Acinetobacter baumannii in the intensive care unit: a multi-level strategic management approach.

An outbreak of carbapenem-resistant Acinetobacter baumannii (CRAb) occurred in an interdisciplinary intensive care unit, affecting 10 patients. Within hours of recognition of the spread of CRAb an intervention team was instituted for collection of available data, decision-making, communication and monitoring of all interventions performed, including cohorting, temporary stop of admissions, staff education, and enforcement of infection control measures. An area was defined for cohortation of patients colonized with CRAb, with a separate nursing team and a second set of mobile equipment. New transmissions were no longer observed after only four days into the institution of enhanced infection control measures.

A collaborative hit-to-lead investigation leveraging medicinal chemistry expertise with high throughput library design, synthesis and purification capabilities.

High throughput screening (HTS) campaigns, where laboratory automation is used to expose biological targets to large numbers of materials from corporate compound collections, have become commonplace within the lead generation phase of pharmaceutical discovery. Advances in genomics and related fields have afforded a wealth of targets such that screening facilities at larger organizations routinely execute over 100 hit-finding campaigns per year. Often, 10(5) or 10(6) molecules will be tested within a campaign/cycle to locate a large number of actives requiring follow-up investigation. Due to resource constraints at every organization, traditional chemistry methods for validating hits and developing structure activity relationships (SAR) become untenable when challenged with hundreds of hits in multiple chemical families per target. To compound the issue, comparison and prioritization of hits versus multiple screens, or physical chemical property criteria, is made more complex by the informatics issues associated with handling large data sets. This article describes a collaborative research project designed to simultaneously leverage the medicinal chemistry and drug development expertise of the Novartis Institutes for Biomedical Research Inc. (NIBRI) and ArQule Inc.'s high throughput library design, synthesis and purification capabilities. The work processes developed by the team to efficiently design, prepare, purify, assess and prioritize multiple chemical classes that were identified during high throughput screening, cheminformatics and molecular modeling activities will be detailed.

Peptide deformylase inhibitors as antibacterial agents: identification of VRC3375, a proline-3-alkylsuccinyl hydroxamate derivative, by using an integrated combinatorial and medicinal chemistry approach.

Peptide deformylase (PDF), a metallohydrolase essential for bacterial growth, is an attractive target for use in the discovery of novel antibiotics. Focused chelator-based chemical libraries were constructed and screened for inhibition of enzymatic activity, inhibition of Staphylococcus aureus growth, and cytotoxicity. Positive compounds were selected based on the results of all three assays. VRC3375 [N-hydroxy-3-R-butyl-3-(2-S-(tert-butoxycarbonyl)-pyrrolidin-1-ylcarbonyl)propionamide] was identified as having the most favorable properties through an integrated combinatorial and medicinal chemistry effort. This compound is a potent PDF inhibitor with a K(i) of 0.24 nM against the Escherichia coli Ni(2+) enzyme, possesses activity against gram-positive and gram-negative bacterial pathogens, and has a low cytotoxicity. Mechanistic experiments demonstrate that the compound inhibits bacterial growth through PDF inhibition. Pharmacokinetic studies of this drug in mice indicate that VRC3375 is orally bioavailable and rapidly distributed among various tissues. VRC3375 has in vivo activity against S. aureus in a murine septicemia model, with 50% effective doses of 32, 17, and 21 mg/kg of body weight after dosing by intravenous (i.v.), subcutaneous (s.c.), and oral (p.o.) administration, respectively. In murine single-dose toxicity studies, no adverse effects were observed after dosing with more than 400 mg of VRC3375 per kg by i.v., p.o., or s.c. administration. The in vivo efficacy and low toxicity of VRC3375 suggest the potential for developing this class of compounds to be used in future antibacterial drugs.

Alpha-substituted hydroxamic acids as novel bacterial deformylase inhibitor-based antibacterial agents.

We report the synthesis and biological activity of analogues of VRC3375 (N-hydroxy-3-R-butyl-3-[(2-S-(tert-butoxycarbonyl)-pyrrolidin-1-ylcarbonyl]propionamide), an orally active peptide deformylase inhibitor. This study explores the structure-activity relationship of various chelator groups, alpha substituents, P(2)' and P(3)' substituents in order to achieve optimal antibacterial activity with minimal toxicity liability.

[Acute pancreatitis caused by atrial fibrillation?]. / Vorhofflimmern als mögliche Ursache für eine akute Pankreatitis?

HISTORY: We report three male patients who had atrial fibrillation with a rapid and irregular ventricular rate, aged 60, 69 and 70 years, respectively, in whom development of acute pancreatitis occurred simultaneously with other ischaemic events. INVESTIGATIONS: One of these patients simultaneously suffered from a transient ischaemic attack (TIA), another developed a stroke and an infarction of the spleen, while the third one had a splenic infarction and an embolism in the region of the mesenteric arteries. Two patients had paroxysmal atrial fibrillation, while the third suffered from ischemic cardiomyopathy with chronic atrial fibrillation. DIAGNOSIS AND TREATMENT: Oedematous pancreatitis occurred in one patient while, in the two others, the diagnosis of severe necrotizing pancreatitis was made. CONCLUSION: Atrial fibrillation is the most common sustained arrhythmia encountered in clinical practice and a recognized risk factor for the development of peripheral embolism, which often takes the form of an ischaemic stroke. It is a major cause of stroke, especially in the elderly. Because of the simultaneous occurrence of thromboembolic events in all three patients, an ischaemic cause for the acute pancreatitis can be assumed with a high degree of probability. This is one of the first reports of acute ischaemic pancreatitis probably caused by microembolization secondary to atrial fibrillation. Because of the relatively frequent occurrence of atrial fibrillation, this factor deserves increased attention in the differential diagnosis of supposedly idiopathic pancreatitis.

Design and synthesis of potent and selective inhibitors of integrin VLA-4.

The synthesis and identification of a novel series of inhibitors of integrin VLA-4 are described. Their in vitro activity and selectivity against closely related integrins are also presented.

[Fibrinolytic therapy of deep vein thrombosis]. / Lysetherapie bei tiefen Beinvenenthrombosen.

BACKGROUND: The most important complications of deep vein thrombosis are pulmonary embolism and postthrombotic syndrome. While the medicine of lethal pulmonary embolism is reduced to less than 2% by conventional anticoagulation, fibrinolytic therapy aims at a reduction of the greater than 50% incidence of postthrombotic syndrome. The optimal therapeutic regimen concerning risks and effect has not been established yet. RESULTS: A review of 26 studies involving ultrahigh-dose streptokinase (UHSK), urokinase (UK), and tissue-type plasminogen activator (rt-PA) shows the highest success rate for UHSK (45% complete and 40% parital patency), whereas there are lower rates for UK (25% and 40%) and low-dose locoregionally applied rt-PA (22% and 44%). The studies were not directly comparative, however. Published data concerning complications range from 1.7% mortality for UHSK to 0.9% for UK and 0.0% for rt-PA. Success criteria, however, are varying and not well defined. The influence of fibrinolytic therapy on the incidence of postthrombotic syndrome has not been established prospectively, but a reduction by 40 to 50% can be assumed. Calf vein thromboses are not indication for lytic therapy. In patients with iliacal vein thromboses there is an increased risk of pulmonary embolism using UHSK. CONCLUSIONS: UHSK can be regarded the standard concerning success rate in deep vein thromboses. DATA involving locoregional therapy with rt-PA are inconsistent and worse, but bleeding complications might be less frequent. Large prospective studies evaluating the impact on incidence and severity of the postthrombotic syndromes, which involve a controlled application of compression therapy are needed.

Structural and conformational requirements for high-affinity binding to the SH2 domain of Grb2(1).

Following earlier work on cystine-bridged peptides, cyclic phosphopeptides containing nonreducible mimics of cystine were synthesized that show high affinity and specificity toward the Src homology (SH2) domain of the growth factor receptor-binding protein (Grb2). Replacement of the cystine in the cyclic heptapeptide cyclo(CYVNVPC) by D-alpha-acetylthialysine or D-alpha-lysine gave cyclo(YVNVP(D-alpha-acetyl-thiaK)) (22) and cyclo(YVNVP(D-alpha-acetyl-K)) (30), which showed improved binding 10-fold relative to that of the control peptide KPFYVNVEF (1). NMR spectroscopy and molecular modeling experiments indicate that a beta-turn conformation centered around YVNV is essential for high-affinity binding. X-ray structure analyses show that the linear peptide 1 and the cyclic compound 21 adopt a similar binding mode with a beta-turn conformation. Our data confirm the unique structural requirements of the ligand binding site of the SH2 domain of Grb2. Moreover, the potency of our cyclic lactams can be explained by the stabilization of the beta-turn conformation by three intramolecular hydrogen bonds (one mediated by an H2O molecule). These stable and easily accessible cyclic peptides can serve as templates for the evaluation of phosphotyrosine surrogates and further chemical elaboration.

Hypersensitivity reactions to parenteral lipid solutions.

In cancer patients, hypersensitivity reactions to adjunctive medications are easily mistaken for cytostatic toxicities. We report on three patients with systemic reactions (flush, dyspnea, tachycardia, hypotension, back pain) to a lipid emulsion containing long chain fatty acids (LCT). Reexposure to LCT and exposure to MCT (medium chain fatty acids) solutions of slightly different composition--no soybean lecithin used as an emulsifier--were well tolerated. These data suggest that traces of soybean proteins are the allergenic agents. Therefore, hypersensitivity to concomitant medications, including parenteral nutrition, has to be considered in oncologic patients demonstrating severe systemic reactions to intravenous therapy.

Myocardial infarction as a complication of dobutamine stress echocardiography.

Only few cases of myocardial infarction complicating dobutamine stress echocardiography have been reported. We observed a 42-year-old woman in whom acute inferior wall infarction developed 10 minutes after discontinuation of dobutamine stress echocardiography with up to 20 micrograms/kg/min dobutamine. The right coronary artery, which had had a 50% stenosis in the prior angiography, showed proximal complete occlusion on the immediately performed recatheterization. Thrombolysis in myocardial infarction study flow grade 3 was rapidly accomplished by intracoronary thrombolysis with recombinant tissue type plasminogen activator. For recurrent unstable angina, the patient received coronary bypass grafting on the same day. The case shows that myocardial infarction not preceded by regional wall motion abnormalities is a possible complication of dobutamine stress echocardiography. Post-test monitoring even after negative tests is recommended.

Technetium-99m-HMPAO brain SPECT in patients with syndrome X.

Ninety-five patients with syndrome X were studied by brain single-photon emission computed tomographic examination; 72 (76%) had pathologic findings suggestive of cerebral perfusion abnormalities. These findings support the hypothesis of a vascular disorder not confined to cardiac vessels.

[Upper gastrointestinal bleeding as the first manifestation of a nonseminomatous testicular carcinoma]. / Obere gastrointestinale Blutung als Erstmanifestation eines nicht-seminomatösen Hodenkarzinoms.

HISTORY AND CLINICAL FINDINGS: For one week a 23-year-old man had been suffering from nausea and upper abdominal pain, followed by several bouts of haematemesis. On admission the haemoglobin level was 7.8 g/dl. INVESTIGATION: Endoscopy revealed a bleeding vessel stump at the posterior gastric wall: adrenaline was injected around it. A chest radiogram showed numerous round foci in the lung, while physical examination found gynaecomastia and changes in the left testis suspicious of tumour. beta-HCG (human chorionic gonadotrophin) activity was 230,000 U/l. TREATMENT AND COURSE: Histological examination of the immediately resected testis showed a necrotic non-seminomatous germ cell tumor (pT1N2M1). Repeat gastroscopy because of renewed tarry stools and haematemesis revealed bleeding from an area of polypoid mucosa. At laparotomy the lesion was excised. Histologically it was a submucosal metastasis of the testicular carcinoma. Chemotherapy resulted in normalisation of the beta-HCG-level. Subsequently retroperitoneal lymphadenectomy and bilateral thoracotomy with resection of residual tumour tissue were performed: no active tumour was found histologically. There has been no sign of tumour recurrence after 56 months. CONCLUSION: Upper gastrointestinal bleeding from a haematogenous metastasis is a very rare initial manifestation of a testicular carcinoma. But a malignant tumour should be thought of in a young patient with unexplained haematemesis.

[Congenitally corrected transposition of the great vessels in adulthood. The value of noninvasive study methods]. / Kongenital korrigierte Transposition der grossen Arterien im Erwachsenenalter. Wert nicht-invasiver Untersuchungsmethoden.

A 57-year-old man with a cough and increasing exertional dyspnoea for the past 6 weeks was found on examination to have a loud systolic murmur and cardiomegaly with pulmonary congestion. Echocardiography revealed congenitally corrected transposition of the great arteries (cTGA: atrioventricular and ventriculoarterial discordance): a morphologically right ventricle with a tricuspid valve on the left, a morphologically left ventricle with bicuspid a-v valve on the right, the aorta arising ventrally from the left-sided (morphologically right) ventricle. The tricuspid valve showed an Ebstein-like anomaly with obvious regurgitation. Transoesophageal and contrast echocardiography defined valvar anatomy, attachment of the great arteries and cardiac chambers to the venous and arterial circulations, as well as absence of a left to right shunt. Angiography revealed a coronary anatomy typical for cTGA. The exertional dyspnoea responded to diuretics and low doses of ACE inhibitor. Follow-up monitoring of the valvar regurgitation and appropriate endocarditis prophylaxis were recommended. As the haemodynamics in cTGA is normal, in the absence of additional anomalies, it is a congenital cardiac defect which can, though rarely, present first in adulthood. Life expectancy depends on the nature of any additional defects and the degree of commonly associated tricuspid valve regurgitation. As this case demonstrates, echocardiography can largely define the anomalies.