Efficacy of Ceftaroline Fosamil against Escherichia coli and Klebsiella pneumoniae strains in a rabbit meningitis model.

In this study, the efficacy of ceftaroline fosamil was compared with that of cefepime in an experimental rabbit meningitis model against two Gram-negative strains (Escherichia coli QK-9 and Klebsiella pneumoniae 1173687). The penetration of ceftaroline into inflamed and uninflamed meninges was also investigated. Both regimens were bactericidal, but ceftaroline fosamil was significantly superior to cefepime against K. pneumoniae and E. coli in this experimental rabbit meningitis model (P < 0.0007 against K. pneumoniae and P < 0.0016 against E. coli). The penetration of ceftaroline was approximately 15% into inflamed meninges and approximately 3% into uninflamed meninges.

Efficacy of ceftaroline fosamil against penicillin-sensitive and -resistant streptococcus pneumoniae in an experimental rabbit meningitis model.

Ceftaroline is a new cephalosporin with bactericidal activity against resistant Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae, as well as common Gram-negative organisms. This study tested the prodrug, ceftaroline fosamil, against a penicillin-sensitive and a penicillin-resistant strain of S. pneumoniae in an experimental rabbit meningitis model. The penetration of ceftaroline into inflamed meninges was approximately 14%. Ceftaroline fosamil was slightly superior to ceftriaxone against the penicillin-sensitive strain and significantly superior to the combination of ceftriaxone and vancomycin against the penicillin-resistant strain.

Evaluation of ceftobiprole activity against a variety of gram-negative pathogens, including Escherichia coli, Haemophilus influenzae (ß-lactamase positive and ß-lactamase negative), and Klebsiella pneumoniae, in a rabbit meningitis model.

Ceftobiprole medocaril, a new cephalosporin, is highly active against a broad spectrum of Gram-positive and Gram-negative clinical pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant pneumococci. In this study, we tested ceftobiprole against various Gram-negative pathogens in a rabbit meningitis model and determined its penetration into the cerebrospinal fluid (CSF). In this animal model, ceftobiprole produced an antibacterial activity similar to that of cefepime against an Escherichia coli strain, a Klebsiella pneumoniae strain, and a ß-lactamase-negative Haemophilus influenzae strain. Against a ß-lactamase-positive H. influenzae strain, ceftobiprole was significantly superior. The penetration of ceftobiprole through inflamed meninges reached about 16% of serum levels compared to about 2% of serum levels through uninflamed meninges.

Combination of daptomycin plus ceftriaxone is more active than vancomycin plus ceftriaxone in experimental meningitis after addition of dexamethasone.

We examined the cerebrospinal fluid penetration of daptomycin after the addition of dexamethasone and its bactericidal efficacy with and without ceftriaxone in an experimental rabbit model of pneumococcal meningitis. The combination of daptomycin with ceftriaxone was the most efficacious regimen for pneumococcal meningitis. The previous addition of dexamethasone affected the antibacterial activity of daptomycin only marginally, either as monotherapy or combined with ceftriaxone, although the penetration of daptomycin into inflamed meninges was significantly reduced from 6 to 2%. Daptomycin with ceftriaxone might be a potential candidate for the empirical therapy of bacterial meningitis, although the activity of this regimen against Listeria monocytogenes remains to be demonstrated.

Sub-inhibitory concentrations of vancomycin prevent quinolone-resistance in a penicillin-resistant isolate of Streptococcus pneumoniae.

BACKGROUND: The continuous spread of penicillin-resistant pneumococci represents a permanent threat in the treatment of pneumococcal infections, especially when strains show additional resistance to quinolones. The main objective of this study was to determine a treatment modality impeding the emergence of quinolone resistance. RESULTS: Exposure of a penicillin-resistant pneumococcus to increasing concentrations of trovafloxacin or ciprofloxacin selected for mutants resistant to these drugs. In the presence of sub-inhibitory concentrations of vancomycin, development of trovafloxacin-resistance and high-level ciprofloxacin-resistance were prevented. CONCLUSIONS: Considering the risk of quinolone-resistance in pneumococci, the observation might be of clinical importance.

New therapies for pneumococcal meningitis.

The treatment of pneumococcal meningitis remains a major challenge, as reflected by the continued high morbidity and case fatality of the disease. The worldwide increase of penicillin-resistant pneumococci and more recently cephalosporin- and vancomycin-tolerant pneumococci has jeopardised the efficacy of standard treatments based on extended spectrum cephalosporins alone or in combination with vancomycin. This review provides a summary of newly developed antibiotics tested in the rabbit meningitis model. In particular, newer beta-lactam monotherapies (cefepime, meropenem, ertapenem), recently developed quinolones (garenoxacin, gemifloxacin, gatifloxacin, moxifloxacin) and a lipopeptide antibiotic (daptomycin) are discussed. A special emphasis is placed on the potential role of combination treatments with some of the new compounds, which are of interest based on the background of increasing resistance problems due to their often synergistic activity in the rabbit model of pneumococcal meningitis.

Inhibition of HSV-1 and vaccinia virus replication by cephalosporin derivatives.

Derivatives of beta-lactam antibiotics of the cephalosporin type at 0.02-1 mM concentrations interfered with in vitro replication of two DNA-containing viruses, herpes simplex I and vaccinia, but showed no effects on two RNA-viruses, lymphocytic choriomeningitis virus and vesicular stomatitis virus, or on cell viability. The exact structure of the active compounds remains unknown, but opening of the beta-lactam ring appears to be a prerequisite for their formation. Whereas cephalosporin derivatives were most active, no active products were obtained from penicillins and monobactams. The potential of these unexpected antiviral effects of widely used beta-lactam antibiotics remains subject of further study.

Reactive macrophage activation syndrome: a simple screening strategy and its potential in early treatment initiation.

QUESTIONS UNDER STUDY: starting treatment of reactive macrophage activation syndromes as early as possible (rMAS, haemophagocytic lymphohistiocytosis), e.g., with intravenous immunoglobulins (IVIG), seems to be essential for optimal outcome. However, there is no diagnostic gold standard which reliably indicates need for early treatment. We used a simple screening strategy consisting of serum ferritin measurements and/or morphological assessment of haemophagocytosis and compared the studied patient population with published series. METHODS: Retrospective analysis of clinical and laboratory data of 57 patients experiencing 60 episodes of rMAS. RESULTS: Screening by serum ferritin measurements and/or morphological assessment of haemophagocytosis of patients presenting with a systemic inflammatory response syndrome (SIRS) indicates that rMAS might be considerably more frequent than stated in the literature. Serum ferritin exceeded >10,000 microg/L in 91% rMAS episodes. Although the patient population studied was otherwise similar in most aspects to the published rMAS series, the fact that 40% of patients fulfilled the criteria for Still's disease (SD) as the disorder underlying rMAS is remarkable and questions the distinct nature of the two diseases. IVIG responders and non-responders did not differ regarding their initial characteristics with exception to the timepoint of IVIG administration, confirming the importance of early treatment initiation. Malignancy-associated rMAS however, has a poor prognosis and seems to be refractory to manipulation with IVIG in most instances, even when responding initially. CONCLUSIONS: rMAS has to be considered in patients with a SIRS- or SD-like clinical presentation. Hyperferritinaemia >or=10,000 microg/l seems to be a good marker for defining patients with or at risk for developing rMAS and should be completed with a morphological assessment of haemophagocytosis. The perception of acute SD and rMAS as two distinct entities has to be questioned at least in a subgroup of patients.

[28-year-old patient with iron deficiency anemia]. / 28-jährige Patientin mit Eisenmangelanämie.

We report the case of a 28-years-old woman with Turner's syndrome and iron deficiency anaemia. The faecal occult blood test was intermittently positive whereas earlier upper and lower endoscopy revealed no source of bleeding. Capsule endoscopy showed multiple vascular malformations on the jejunum and ileum. Our case report emphasizes the importance of capsule endoscopy in the localising occult bleedings in the small bowel. We discuss the different diagnostic modalities and possible treatments.

[A 58-year-old soldier with a history of weight loss and exercise intolerance. Giant cell arteritis]. / 58-jähriger Berufssoldat mit Gewichtsverlust und reduzierter Leistungsfähigkeit. Riesenzellarteriitis.

We report the case of a 58-years-old soldier with a history of movement related neck pain, weight loss and exercise intolerance. Blood tests presented signs of an inflammatory syndrome. The CT-scan showed extended thickening of the aortic wall characteristic for aortitis. The diagnosis of giant cell arteritis could be histologically confirmed by biopsy of the temporal arteries. Our case report emphasizes the importance of the various imaging modalities. We discuss the different forms of disease evolution and the treatment regimen.

[Working under pressure]. / Arbeiten unter erschwerten Bedingungen. Betreuung von Patienten im Regionalgefängnis Bern und der Bewachungs- station des Inselspitals Bern--Dokumentation und Literaturübersicht.

From medical view the main problems of investigation and convicts are in particular in the range of the drugs and alcohol illnesses to see transferable diseases (HIV, hepatitis B - C and tuberculosis) and psychological illnesses. These complex diseases require a close meshed and intensive support of each individual patient and represent actually the main problem during an arrest. The development of the health service could address the new requirements making possible cost-conscious acting in handling with resources in the health service. In the canton Berne 957197 inhabitants live on a total area of 5959 km2. The police and military management operates the regional and district prisons as well as the transportation service for prisoners in the canton Berne for prisoners. The canton Berne has altogether 327 places. Since May 1971 persons from the regional and district prison and the penal institutions needing hospitalisation can be accepted. In the University hospital Berne on a specially equipped guard station and be cared for their medical problems. The prisoners profit in such a way from the entire range of the university facilities.

Daptomycin produces an enhanced bactericidal activity compared to ceftriaxone, measured by [3H]choline release in the cerebrospinal fluid, in experimental meningitis due to a penicillin-resistant pneumococcal strain without lysing its cell wall.

Daptomycin monotherapy was superior to ceftriaxone monotherapy and was highly efficacious in experimental pneumococcal meningitis, sterilizing the cerebrospinal fluid (CSF) of three of three rabbits after 4 to 6 h. With daptomycin therapy only a negligible release of [(3)H]choline as marker of cell wall lysis was detectable in the CSF, peaking around 250 cpm/min after 4 h, compared to a peak of around 2,400 cpm/min after 4 to 6 h for the ceftriaxone-treated rabbits.

[Eosinophilia, diarrhea and asthma in a young woman]. / Eosinophilie, Diarrhoe und Asthma bei einer jungen Frau.

We present the case of a young woman that was diagnosed with Churg-Strauss syndrome. The classical as well as the atypical symptoms, signs and findings are discussed in the context of clinically relevant differential diagnoses. The diagnostic criteria and the relevant aspects of pathogenesis, clinical course and treatment are reviewed. In addition, the similarities and differences with respect to the other idiopathic interstitial eosinophilic pneumopathies are described.

[Rare cause of right heart failure: two cases]. / Seltene Ursache einer Rechtsherzinsuffizienz: zwei Fälle.

HISTORY AND ADMISSION FINDINGS: Two asylum seekers (patient A, 30 year old man from Mongolia; patient B, 18 year old woman from the Sudan) were referred to our outpatient clinic because of acute and chronic deterioration of their general condition and shortness of breath. Both patients presented with a clear clinical picture of systemic venous hypertension and moderate pulmonary congestion. Patient B had a paradoxical pulse compatible to cardiac tamponade. INVESTIGATIONS: In patient A, the chest radiogram revealed a markedly enlarged cardiac silhouette and an infiltrate in the upper left lobe of the lung. The echocardiogram confirmed a pericardial effusion causing a cardiac tamponade. A therapeutic and diagnostic pericardiocentesis was performed immediately. In patient B, the chest radiogram revealed a thickened and calcified pericardium and a left-sided pleural effusion. The pleural fluid revealed a lymphocyte-predominant exudate. In both patients the tuberculin skin test was positive. DIAGNOSIS, TREATMENT AND COURSE: In both patients we initiated an antituberculous therapy (four-drug therapy with isoniazid, rifampin, pyrazinamide and ethambutol; in patient A in addition corticosteroids). In patient A the PCR for Mycobacterium tuberculosis complex from pericardial fluid was positive. In patient B we started the antibiotic treatment despite negative microbiological studies because of the high degree of suspicion in a person at high risk. Due to the impaired ventricular filling, patient B required additional pericardectomy. After completion of treatment, both patients have been doing well. CONCLUSION: Despite a clear reduction in the incidence of tuberculous pericarditis in Europe this multifaceted condition should still be of concern in patients at high risk as e. g. immigrants from areas with a high tuberculosis prevalence. Early diagnosis and adequate treatment are required for prevention of severe complications and disabling constrictive pericarditis.

Cellular and molecular aspects of drugs of the future: meropenem.

Meropenem, first synthesized in the late eighties, has become one of the most important beta-lactam antibiotics of the carbapenem subclass used for the treatment of a variety of life-threatening infections. Due to its unique chemical structure, meropenem is not inactivated by the kidney dehydropeptidase I and the majority of microbial beta-lactamases. Its antimicrobial activity is based on its high affinity for the majority of cell wall-synthesizing enzymes, the so-called penicillin-binding proteins, of Gram-positive and -negative bacteria. However, bacteria have evolved several approaches to resist meropenem: (i) by reducing the affinity of the penicillin-binding proteins for the antibiotics, (ii) by decreasing the permeability of the outer membrane of Gram-negative bacteria, (iii) by using efflux pumps, and (iv) by activating zinc-dependent carbapenemases. Meropenem has a low toxicity profile and, in contrast to imipenem, no central nervous system toxicity.

Triggering of pneumococcal autolysis by lysozyme.

Lysozyme had no effect on the rate of multiplication of growing cultures of Streptococcus pneumoniae, but it greatly reduced the lag period that precedes autolysis of these bacteria in stationary phase. Several experiments were done to understand the mechanism of this effect. Lysozyme had no hydrolytic activity on intact cell walls, and cell walls of pneumococci grown with or without lysozyme had identical composition and susceptibility to the pneumococcal autolysin. The acceleration of stationary-phase autolysis by lysozyme involved triggering of the pneumococcal autolytic enzyme since lysozyme had no detectable effect on nonautolysing (LytA-) mutants and heat-inactivated lysozyme completely lacking enzymatic activity was as effective as the nondenatured enzyme in facilitating stationary-phase autolysis. The role of lysozyme in host defense against pneumococcal infection remains elusive.

Haemophilus influenzae infections among hospitalized adult patients.

BACKGROUND: Relatively few data are available about Haemophilus influenzae (Hi) infection among adults. MATERIALS AND METHODS: We studied all adult patients with Hi infection hospitalized between 1988 and 1997 at the University Hospital of Berne. Data were abstracted retrospectively from clinical charts and microbiology records using a standardized questionnaire. RESULTS: 12 invasive and 19 noninvasive Hi infections were observed during the study period. The main clinical manifestations were pneumonia (38.7%), bronchitis (29.0%) and meningitis (12.9%). Most patients (71.8%) had an underlying condition. Lethality was high (22.6%), especially in pneumonia patients (50%). The frequency of meningitis caused by Hi serotype b (Hib) seemed to decrease after 1990 when conjugated vaccines against Hib were introduced. CONCLUSION: Hi remains an important cause of lower respiratory and invasive disease associated with high lethality among polymorbid adult patients. The frequency of Hib infections may also decrease in adults due to herd immunity induced by universal vaccination of children.

Vancomycin acts synergistically with gentamicin against penicillin-resistant pneumococci by increasing the intracellular penetration of gentamicin.

Vancomycin and gentamicin act synergistically against penicillin-resistant pneumococci in vitro and in experimental rabbit meningitis. The aim of the present study was to investigate the underlying mechanism of this synergism. The intracellular concentration of gentamicin was measured by using the following experimental setting. Bacterial cultures were incubated with either gentamicin alone or gentamicin plus vancomycin for a short period (15 min). The gentamicin concentration was determined before and after grinding of the cultures by using the COBAS INTEGRA fluorescence polarization system (Roche). The grinding efficacies ranged between 44 and 54%, as determined by viable cell counts. In the combination regimen the intracellular concentration of gentamicin increased to 186% compared to that achieved with gentamicin monotherapy. These data suggest that the synergy observed in vivo and in vitro is based on an increased intracellular penetration of the aminoglycoside, probably due to the effect of vancomycin on the permeability of the cell wall.

Synergy between trovafloxacin and ceftriaxone against penicillin-resistant pneumococci in the rabbit meningitis model and in vitro.

The bactericidal activities of monotherapy with trovafloxacin (-0.37 +/- 0.15 Delta log(10) CFU/ml. h), vancomycin (-0.32 +/- 0.12 Delta log(10) CFU/ml. h), and ceftriaxone (-0.36 +/- 0.19 Delta log(10) CFU/ml. h) for the treatment of experimental meningitis in rabbits due to a clinical penicillin-resistant pneumococcal strain (MIC, 4 mg/liter) were similar. The combination of ceftriaxone with trovafloxacin considerably improved the killing rates (-0.67 +/- 0.16 Delta log(10) CFU/ml. h) and was slightly superior to ceftriaxone with vancomycin (killing rate, -0.53 +/- 0. 22 Delta log(10) CFU/ml. h), the regimen most commonly used in clinical practice. In vitro, synergy was demonstrated between ceftriaxone and trovafloxacin by the checkerboard method (fractional inhibitory concentration index, 0.5) and by time-killing assays over 8 h.