Intravenous fosfomycin for the treatment of nosocomial infections caused by carbapenem-resistant Klebsiella pneumoniae in critically ill patients: a prospective evaluation.

Intensive care unit (ICU)-acquired infections as a result of multidrug-resistant Gram-negative pathogens remain a serious problem in critically ill patients. Adult ICU patients who received intravenous fosfomycin were prospectively examined to assess its safety and effectiveness as an adjunct to the antimicrobial therapy of life-threatening infections caused by carbapenem-resistant Klebsiella pneumoniae. Fosfomycin was administered intravenously in 11 patients for treatment of hospital-acquired infections caused by carbapenem-resistant K. pneumoniae. Fosfomycin (2-4 g every 6 h) was administered in combination with other antibiotics. The mean +/- SD duration of treatment was 14 +/- 5.6 days. All patients had good bacteriological and clinical outcome of infection. All-cause hospital mortality was two out of 11 (18.2%) patients. No patient experienced adverse events related to the administration of fosfomycin. Intravenous fosfomycin may be a beneficial and safe adjunctive treatment in the management of life-threatening ICU-acquired infections caused by carbapenem-resistant K. pneumoniae.

Liver and brain mucormycosis in a diabetic patient type II successfully treated with liposomial amphotericin B.

A case of liver and brain mucormycosis in a 73-y-old diabetic patient is described. The patient presented with fever and a moderate, tender hepatomegaly and a C/T scan examination of the abdomen and brain showed multiple hepatic and cerebral nodular lesions. The largest of the liver lesions was aspirated and broad hyphae of mucor were demonstrated in the purulent material obtained. The patient was treated successfully (for 40 d) with intravenous liposomal amphotericin B and then with itraconazole for 3 months. To our knowledge, this is the first case of a diabetic patient with both liver and brain mucormycosis who has been treated successfully.

Rapid extraction of fungal DNA from clinical samples for PCR amplification.

A hexadecyltrimethylammonium bromide (CTAB) method for isolating fungal DNA from clinical samples, suitable for PCR amplification is described. Yeast and filamentous fungi DNA from clinical samples was amplified with primers complementary to the genes coding for rRNA, amplifying a 105 bp fragment and internal transcribed spacer primers amplifying fragments between 242 and 622 bp. The level of sensitivity was 10 +/- 5 yeast and 28 Aspergillus fumigatus CFU ml-1 of biological fluid.

Dissociation of ACTH, beta-endorphin and cortisol in graded sepsis.

The function of the hypothalamic-pituitary-adrenal axis as related to the degree of severity of a septic process was assessed by measuring plasma levels of beta-endorphin, ACTH and cortisol. Sixty-one cases of postoperative patients treated at the intensive care unit were classified into four groups according to the severity of infection: Group 1 (control) included patients who did not show any sign of infection, group 2 patients with sepsis, group 3 patients with septic syndrome and group 4 patients with septic shock. Compared to G1 patients' ACTH values (4.16+/-2.6pg/ml), a statistically significant increase in ACTH values in various stages of septicemia (p < 0.005) with a noticeable difference also between G3 (7.11 +/-3.7pg/ml) and G4 (11.5+/-6.6pg/ml) (p<0.05) was found. Differences were also observed in beta-endorphin (with a level of significance between the several groups of p = 0.0001). Also, beta-endorphin values in G4 (40.6+/-30.3 pg/ml) differed significantly from each of G1 (17.5 +/-6.6 pg/ml), G2 (21.1+/-11.3 pg/ml) and G3 (23.5+/-12 pg/ ml) (p<0.05). A progressive hypercortisolemia was obvious, with values of G4 (37.2+/-15.6 microg/dl) differing significantly from those of G1 (18+/-4.6microg/dl) and G2 (24-/+8.4microg/dl) (p<0.05) and of G3 (28.5+/-12.3 microg/dl) from that of G1 (p < 0.05). Interestingly, a dissociation of ACTH, beta-endorphin and cortisol was observed, in that the increased values of beta-endorphin and cortisol, detected in the G3 were not associated with a parallel increase in ACTH. These findings might be interpreted in the sense of an impairment of the stress stimulation of the hypothalamic pituitary adrenal axis. Provided that such a situation can be lethal, our results further confirm the idea that a low-dose, steroid replacement might be beneficial to critical illness.

Comparative in vitro and in vivo efficacy of roxithromycin and erythromycin against a strain of methicillin-susceptible Staphylococcus epidermidis.

The in vitro and in vivo efficacy of roxithromycin was compared with that of erythromycin, against a methicillin-susceptible strain of Staphylococcus epidermidis. We performed standard in vitro testing (MIC, MBC, and time-kill kinetics) for roxithromycin, erythromycin, and rifampin. Both macrolides were bacteriostatic in vitro. There was no significant difference in microbial survival between erythromycin and roxithromycin groups in the time-kill kinetics (p = 0.3). For the in vivo experiments, using the rabbit experimental endocarditis model, roxithromycin was found to be inferior to erythromycin in decreasing the microbial burden of the endocardial vegetations (p < 0.05). Rifampin was highly effective, both in vitro and in vivo. In conclusion, the efficacy of roxithromycin was poor and inferior to erythromycin against a strain of methicillin-susceptible S. epidermidis.

Pancreatic tuberculosis in non-immunocompromised patients: reports of two cases, and a literature review.

We present two cases of biopsy proven tuberculosis of the pancreas in non-immunocompromised patients diagnosed and treated in our unit within the last 14 years. The first case presented with abdominal pain and fever, and the second with iron deficiency anaemia and severe weight loss. In both cases abdominal ultrasound and computed tomography suggested a pancreatic carcinoma. There was no pulmonary or intestinal tuberculosis. The tuberculin skin test was positive. Upon exploratory laparotomy the macroscopic appearance of the pancreas was that of an inoperable pancreatic carcinoma. Following the histological diagnosis of pancreatic tuberculosis, both patients were successfully treated with triple antituberculous therapy for 6 months. Isolated pancreatic tuberculosis is an extremely rare disease with only 41 cases in non-immunocompromised patients reported worldwide (1966-1997). It is a curable disease and should be considered in the differential diagnosis of a pancreatic mass or abscess shown on ultrasound or computed tomography, especially in developing countries, where tuberculosis is common.

Efficacy of deoxycholate amphotericin B and unilamellar liposomal amphotericin B in prophylaxis of experimental Aspergillus fumigatus endocarditis.

OBJECTIVE: To evaluate and compare in vivo the protective efficacy of unilamellar liposomal amphotericin B (L-AmB) with that of deoxycholate amphotericin B (D-AmB) in experimental endocarditis. MATERIAL AND METHODS: In the rabbit model of experimental Aspergillus fumigatus endocarditis, two doses of each antifungal agent (1.5 mg/kg each) were administered intravenously at 4 hours and at 30 minutes before challenge with an inoculum of A. fumigatus. Three days later, the animals were sacrificed, and the aortic vegetations were analyzed. RESULTS: All 19 animals that did not receive chemoprophylaxis acquired endocarditis. In contrast, endocarditis developed in 2 of 10 animals pretreated with D-AmB (P < 0.01) and 3 of 8 animals pretreated with L-AmB (P < 0.01). Both D-AmB and L-AmB prevented the development of endocarditis due to A. fumigatus and decreased the concentration of fungi in the aortic vegetations by more than 1 log10. CONCLUSION: In the rabbit experimental model of Aspergillus endocarditis, D-AmB and L-AmB were equally effective in reducing the incidence of the infection and the tissue burden of fungi.

Codon 12 ras mutations in patients with myelodysplastic syndrome: incidence and prognostic value.

To determine the prevalence of activated rasoncogenes (N-ras, Harvey-ras Kirsten-ras), DNA derived from peripheral blood of 51 patients with myelodysplastic syndrome (MDS) was investigated. The method was based on the polymerase chain reaction (PCR) technique to amplify DNA, followed by restriction fragment length polymorphism (RFLP) analysis. Among the French-American-British (FAB) subtypes, N-ras mutations were found in two patients with refractory anemia with excess of blasts (RAEB), in one patient with refractory anemia with excess of blasts in transformation (RAEB-t), and in two patients with chronic myelomonocytic leukemia (CMML). MDS patients with a mutation at codon 12 of the N-ras gene showed shorter survival duration than other MDS patients of the same FAB subtypes, although these findings proved to be not statistically significant (P > 0.1). Interestingly, all but one patient with N-ras mutation developed acute myelogenous leukemia (AML). In conclusion, the presence of mutation at codon 12 of the N-ras gene might serve as a negative prognostic factor at diagnosis of MDS.

Tuberculous esophagitis. Report of a case and review of modern approaches to diagnosis and treatment.

We describe a patient with tuberculous esophagitis who was referred to us with low-grade fever, but no esophageal symptoms. The diagnosis was established in biopsies obtained from a deep midesophageal ulcer seen on endoscopy. Investigation of the patient failed to identify any extra-esophageal tuberculous foci, but a computed tomography scan revealed mediastinal lymphadenopathy without lung involvement. Primary infection of the esophagus by tuberculosis is questioned, and widespread use of computed tomography may show it to be a fiction.

delta-Aminolaevulinic acid dehydratase as an index of lead toxicity. Time for a reappraisal?

delta-Aminolaevulinic acid dehydratase activity is traditionally accepted as the most sensitive measurable biological index of lead toxicity. We have measured delta-aminolaevulinic acid dehydratase activity and blood lead concentration in 47 healthy controls (A), 42 iron deficient patients (B) and 38 occupationally exposed to lead subjects (C). Blood lead levels [mean (SD)] did not differ between groups A and B [0.51 (0.21) and 0.43 (0.19) mumol L-1, respectively] while those of group C [2.28 (0.56) mumol L-1 were significantly higher (P < 0.001) as compared to the controls. delta-Aminolaevulinic acid dehydratase activity [mean (SD)] was significantly increased [3599 (1909) mumol L-1 h-1] in group B and decreased in group C [1052 (532) mumol L-1 h-1] as compared to the controls [2034 (446) mumol L-1 h-1] (P < 0.001). There was a significantly negative correlation of logarithm of delta-aminolaevulinic acid dehydratase with lead in both groups B (P < 0.05) and C (P < 0.001) but not in group A (P = 0.1). delta-Aminolaevulinic acid dehydratase activity had a high specificity (100%) but a low sensitivity (37%) as an index of toxic lead exposure. According to our data the value of delta-aminolaevulinic acid dehydratase measurement in the diagnosis of lead intoxication is doubtful in cases with low blood lead levels, while in the presence of iron deficiency its reliability is further reduced, since low blood lead levels may be falsely predicted. delta-Aminolaevulinic acid dehydratase activity should be restricted only to monitoring cases with moderate or severe lead poisoning.

Antiphospholipid syndrome: clinical and therapeutic aspects.

The purpose of the present study was to evaluate patients with the antiphospholipid syndrome with particular attention to their initial clinical features, final diagnoses and the course of thrombotic events in association with therapy. The methodology applied was the following: retrospective analysis of 30 patient files (20 female, 10 male) with antiphospholipid syndrome (APS). Four types of therapy were evaluated for their efficacy to prevent thrombotic recurrences, aspirin 100 mg daily plus low-dose prednisone 10-15 mg daily, warfarin (with international normalized ratio 2 to 2.6), immunotherapy alone and no therapy. None of the patients was followed-up during pregnancy. The probability of thrombosis-free survival was estimated according to Kaplan-Meier method, while the statistical significance was tested by the log rank test. There were 21 patients with primary APS and 9 with secondary, 8 of whom had SLE and one patient who had primary Sjögren's syndrome. The age at onset and the disease duration did not differ between men and women, while patients with secondary APS had a longer disease duration than patients with primary APS, a finding indicating that SLE patients develop, for unknown reasons, APS a long time after the initiation of their disease. Twenty patients experienced recurrent thrombotic events (a total of 46 recurrences) of which 43 (93%) were identical to the first event. Thus, in the majority of the cases arterial were followed by arterial and venous by venous thrombotic events: a finding suggesting a tissue-related factor for initiation of thromboses.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of myelodysplastic syndromes with human granulocytic-macrophage colony stimulating factor (GM-CSF) or GM-CSF combined with low-dose cytosine arabinoside.

In a phase II study, 21 patients with MDS (RAEB, RAEBt, CMML and RA and RAS with severe cytopenia) were randomized to be treated with 3 courses of GM-CSF (3 micrograms/kg/day s.c.) alone (11 patients) or in combination with AraC (20 mg/m2/d s.c.) (10 patients) for 14-d periods, interrupted by 14-d rest periods. Eight patients discontinued the treatment. In the GM-CSF group a marked increase in WBC and neutrophil counts during each course of treatment administration were seen in most patients. Platelet counts decreased in 14 of 24 courses of treatment in the GM-CSF plus AraC group but in none of the GM-CSF group. Although the changes in the circulating blood cells were transient and the counts tended to return to the pretreatment levels during the rest periods, some more durable effects were seen. In 3/6 patients of the GM-CSF group who completed the designed treatment, both WBC and neutrophils remained elevated above the pretreatment levels throughout the 3-month period of treatment, while in one of them thrombocytopenia improved considerably. In the GM-CSF plus AraC group, 4 out of the 7 patients who completed the treatment showed an improvement of neutropenia as well as anaemia. In these 4 patients the BM percentage of blasts was also decreased. In conclusion, the results of this study indicate that GM-CSF given intermittently improves leukopenia in some patients with MDS. In addition, the administration of GM-CSF seems to prevent granulocytopenia of concurrent AraC treatment and may be of benefit in the treatment of these diseases.

Paraplegia in a pregnant thalassemic woman due to extramedullary hematopoiesis: successful management with transfusions.

The investigation and treatment of a pregnant thalassemic woman who developed severe paraplegia is presented. Magnetic resonance imaging showed a paravertebral mass infiltrating the epidural space, resulting from extramedullary hematopoiesis (marrow heterotopia). The patient was treated successfully with repeated blood transfusions and made a complete recovery. The literature (36 cases) is reviewed and the magnetic resonance imaging features of spinal extramedullary hematopoiesis are presented. The efficacy of transfusions in the management of spinal cord compression due to marrow heterotopia in thalassemic patients is discussed.

Globin chain synthesis in myelodysplastic syndromes.

Globin chain synthesis was studied in the reticulocytes of 30 patients with various myelodysplastic syndromes (MDS) to determine the alpha:beta globin chain synthetic ratio and its probable prognostic value. The mean (SD) value of the total alpha:beta ratio was 0.82 (0.45) ranging from 0.05 to 1.73. The same ratio in 10 normal controls was 1.01 (0.04). This difference was significant. Furthermore, the alpha:beta ratios were lower than normal in 14 patients (alpha-thalassaemia-like) (group I), almost within normal limits in 11 (group II), and higher than normal in five (beta-thalassaemia-like) (group III). In each group almost all the FAB subtypes were represented. The addition of exogenous haem in several of the test samples resulted in a slight to pronounced increase in the alpha:beta ratios, particularly in group I. In 92% of the high risk cases (refractory anaemia with excess blasts (RAEB), chronic myelomonocytic leukaemia (CMML] or 87.5% of patients who finally developed acute non-lyphoid leukaemia (ANLL) low or normal alpha:beta ratios were found. No significant correlation was noticed between alpha:beta ratios and various haematological variables or survival. It is concluded that in MDS the alpha:beta ratio varied enormously across the entire population of patients, as well as within each FAB subtype, thereby restricting its prognostic value. Although haem deficiency may be implicated in some cases of MDS, why this should be remains unclear.

[Effect of starvation and phenobarbital on the activity of liver uroporphyrinogen synthetase]. / Effet du jeûne et du phénobarbital sur l'activité de l'uroporphyrinogène synthétase hépatique.

Liver uroporphyrinogen synthetase activity was measured in 45 mice, divided in three groups. The mice of the 1st group served as controls, those of the 2nd starved for 24 hours, while those of the 3rd were injected intraperitoneally with phenobarbital. The enzymic activity was found significantly (p less than 0.001) lower in the animals of the 2nd group (17.49 +/- 2.25 nmol/g/h) and higher in those of the 3rd (25.82 +/- 3.73 nmol/g/h) as compared to the controls (20.89 +/- 2.11 nmol/g/h). If these effects also exist in the human it could be suggested that starvation may be doubly harmful for the patients with acute intermittent porphyria by aggravating both their enzymic disorders. On the contrary, in the case of phenobarbital its undesired effect on porphyria may be moderated by a simultaneous induction of the uroporphyrinogen synthetase.

Effect of isoniazid, a haem inhibitor, on globin chain synthesis in reticulocytes from non-thalassaemic and beta thalassaemic subjects.

The effect of isonicotinic acid hydrazide (INH), a potent haem inhibitor, on globin chain synthesis was studied in reticulocytes from the following groups of patients: four non-thalassaemic patients (group i); five beta thalassaemia heterozygotes (group ii); three Hb S/beta thalassaemia heterozygotes (group iii); and two additional patients--one with homozygous beta thalassaemia and the other with thalassaemia intermedia (group iv). This was done to determine whether haem inhibitors depress alpha globin chain synthesis. The progressive increase of INH concentration (10-40 mmol l-1) in reticulocytes from a beta thalassaemia heterozygote resulted in a remarkable decrease of the alpha and beta chain synthesis, ranging from 80% to 97% and from 74% to 96% of control values, respectively, and in a gradual drop of alpha:beta ratio from 1.87 to 1.38. Furthermore, in the samples incubated with 40 mmol l-1 INH, a pronounced inhibition of globin chain synthesis 77 (19%) for alpha chain and 67 (27%) for beta or beta S chain) and a substantial drop of the alpha:beta or beta S ratio in samples with INH (median 1.16) compared with that in samples without INH (median 1.70) were observed. The inhibitory effect of INH was significantly or completely corrected by adding exogenous haem. It is suggested that haem inhibition and the resulting preferential diminution of alpha chain synthesis could provide a new approach to the treatment of homozygous beta thalassaemia with an excess of detrimental free alpha chain in erythroid cells.

Atypical location of extramedullary hematopoietic masses in thalassemia.

A case of beta-thalassemia with multiple foci of extramedullary hematopoiesis (EH) is reported. EH masses were demonstrated in the presacral and the costovertebral space. EH foci were also encountered in the spleen.

Monoclonal gammopathy in chronic myeloproliferative disorders.

The incidence of monoclonal gammopathy in 61 patients with chronic myeloproliferative disorders (CMPD) was studied. The distribution of patients among the CMPD subgroups was: chronic myelocytic leukemia, 24 patients; myelofibrosis, 11; polycythemia vera, 15; essential thrombocythemia, 7; unclassified MPD, 4 patients. Monoclonal gammopathy was found in 5 patients (8.2%). Two of these patients (1 IgA/k and 1 IgM/k) had myelofibrosis and 3 (2 IgG/k and 1 IgG/lambda) polycythemia vera. The presence of monoclonal gammopathy indicates an involvement of the lymphoplasmatic system in CMPD.

Estimation of glycated fetal hemoglobin in normal cord blood by isoelectric focusing. Correlation with maternal glycated hemoglobin and birth weight.

Glycated fractions of hemoglobin F and A (F1, A1c) were measured simultaneously in cord and maternal blood, respectively, in 109 normal women at delivery using an isoelectric focusing, method in polyacrylamide gel plates. Cord blood hemoglobin F1 values (mean +/- SD) were 5.92 +/- 1.09% and maternal blood hemoglobin A1c values were 6.51 +/- 0.92%. The difference was statistically highly significant (p less than 0.001) and their values were also significantly correlated (p less than 0.001). Moreover, both values were also well correlated with those of maternal blood glucose (p less than 0.01), actual birth weight (p less than 0.01) and birth weight ratio (p less than 0.01). It is concluded that hemoglobin F1 can be successfully separated and measured by isoelectric focusing. However HbF1 estimation seems to have no obvious advantages against the maternal HbA1c measurement as an index of fetal exposure to glucose during the last weeks of pregnancy.