In vitro and in vivo activities of piperacillin-tazobactam and meropenem at different inoculum sizes of ESBL-producing Klebsiella pneumoniae.

The inoculum effect is a laboratory phenomenon in which the minimal inhibitory concentration (MIC) of an antibiotic is increased when a large number of organisms are exposed. Due to the emergence of extended-spectrum ß-lactamase-producing Klebsiella pneumoniae (ESBL-Kpn) infections, the inoculum effect of ESBL-Kpn on ß-lactams was studied in vitro and in vivo using an experimental model of pneumonia. The in vitro inoculum effect of 45 clinical ESBL-Kpn isolates on ß-lactams was evaluated at standard (10(5) CFU/mL) and high (10(7) CFU/mL) organism concentrations. The MIC50 of piperacillin-tazobactam, cefotaxime and cefepime was increased eight-fold or more and that of meropenem was increased two-fold. The in vivo inoculum effect was evaluated in an ESBL-Kpn pneumonia mouse model treated with bacteriostatic effect-adjusted doses of piperacillin-tazobactam (1000 mg/kg four times daily, %T>MIC; 32.60%) or meropenem (100 mg/kg twice daily, %T>MIC; 28.65%) at low/standard (10(4) CFU/mouse) and high (10(6) CFU/mouse) inocula. In mice administered a low inoculum, no mice died after treatment with piperacillin-tazobactam or meropenem, whereas all the control mice died. In contrast, in the high inoculum model, all mice in the piperacillin-tazobactam-treated group died, whereas all meropenem-treated mice survived and had a decreased bacterial load in the lungs and no invasion into the blood. In conclusion, meropenem was more resistant to the inoculum effect of ESBL-Kpn than piperacillin-tazobactam both in vitro and in vivo. In the management of severe pneumonia caused by ESBL-Kpn, carbapenems may be the drugs of choice to achieve a successful outcome.

Permanent catheterization of the carotid artery induces kidney infection and inflammation in the rat.

Catheterization of the carotid artery and the jugular vein is one of the most commonly applied techniques used to gain intravascular access in pharmacology studies on rodents. We catheterized 10 rats by conventional clean techniques, 10 rats by aseptic techniques and 10 rats by conventional clean techniques using a heparin-coated catheter rather than an ordinary non-coated polyvinyl chloride catheter. In all groups, approximately 80% of the rats developed kidney infection and 10-30% of the rats were septicaemic. Clinical chemistry did not indicate severe kidney damage, but serum haptoglobin and body temperature rises indicated an inflammatory response in rats independent of the surgical method. Heparin coating did not seem to improve the usability of the catheter. It is concluded that this commonly used method for catheterization has an impact on animals that may very well render them unsuitable for the purpose, e.g. pharmacological research, and therefore an alternative method would be preferable.

[Efficacy of combination with granisetron and methylprednisolone for nausea, vomiting and appetite loss in remission induction chemotherapy of acute myeloid leukemia--a randomized comparative trial between granisetron alone and granisetron plus methylprednisolone].

The prevention of nausea, vomiting and appetite loss induced by remission induction chemotherapy for acute myeloid leukemia was compared by randomization between granisetron alone and combination with granisetron plus methylprednisolone. Granisetron was administered at 40 micrograms/kg during chemotherapy, and methylprednisolone was administered concomitantly at 125 mg/body for 3 days or more in the combination group. The single and combination groups comprised 14 and 13 patients, respectively, and there was no significant difference between the background of both groups. To evaluate the effect they were scored according to 4 grades, and evaluated every 24 hours from the start of chemotherapy to 5 days after its completion. The complete inhibition rate of vomiting was as high as 71.4% and 92.3% in the single and combination groups, respectively, showing no significant difference. The grade of vomiting was mild in both groups. Nausea was noted in 71.4% and 46.2%, respectively, and the inhibitory effect tended to be higher in the combination group. Appetite loss developed in 92.9% and 41.7%, respectively, and the prevention effect was clearly higher in the combination group. The prevention effects on nausea 7, 8 and 10 days after the start of chemotherapy, on appetite loss 2-10 days after it, and 2-5 days after its completion, were higher in the combination group. Granisetron revealed an excellent inhibitory effect on vomiting induced by remission induction chemotherapy for acute myeloid leukemia, but combination with granisetron and methylprednisolone was considered useful for nausea in the latter half of the treatment period and for appetite loss during the whole period.

[Epstein-Barr virus associated Richter's syndrome accompanied by interstitial pneumonia].

A 65-year-old man who had an 8-year history of chronic lymphocytic leukemia was admitted to our hospital on February 19, 1998 because of high fever, dry cough, and weight loss. Laboratory data on admission included serum lactate dehydrogenase at 980 IU/l, CRP at 21.8 mg/dl, and soluble interleukin-2 receptor at 7,280 U/ml. The results of serological tests for Epstein-Barr virus (EBV) antibodies were as follows: EBV capsid antigen IgG 1:2560, EBV early antigen IgG 1:640, and EBV nuclear antigens 1:20. Computed tomography revealed diffuse interstitial pneumonia in both lungs, hepatosplenomegaly with multiple nodules, and enlarged intra-abdominal lymph nodes. In addition, Gallium-67 scintigraphy demonstrated abnormal accumulations. Although the patient initially responded well to combination chemotherapy, he eventually deteriorated and died on November 2, 1988, despite salvage chemotherapy. Postmortem needle biopsy specimens from the liver and spleen revealed diffuse proliferation of polymorphic large lymphoma cells. The lymphoma cells were positive for L-26, latent membrane protein 1, and EBV nuclear antigen, but negative for UCHL-1 and CD3, 5, 10, and 30. In situ hybridization procedures disclosed the presence of EBV-encoded small RNA in lymphoma cells. These findings suggested the possibility of association with EBV infection in some cases of Richter's syndrome.

[Photostimulation that induces flattening of photopic electroretinograms--first report. An apparatus for slope photostimulation].

PURPOSE: We developed a new photostimulation system for electroretinograms (ERGs). This apparatus is capable of varying the transients during stimulus on and off (up-slope and down-slope times, respectively) as well as the stimulus and background intensities. We applied this system to evaluate the photopic ERG in human eyes. CASES AND METHODS: Seven normal volunteers and a 43-year-old patient with pre-proliferative diabetic retinopathy served as test subjects. We recorded ERGs with relatively long intervals of up-slope and down-slope times for photostimulation. RESULTS: As the up-slope and down-slope times were increased, the amplitude was reduced and the peak latency was prolonged for both the on and off responses. When the normal subjects' retinas were stimulated with a 341-msec up-slope time and a 34.1-msec down-slope time, the ERG waves showed complete flattening in both on and off responses. The ERGs of a patient with pre-proliferative diabetic retinopathy showed much longer peak latency than that of the normal volunteers as the up-slope time was prolonged. When the patient's retina was stimulated for a prolonged up-slope time, the average of the amplitude of ERG waves was similar to that of the normal volunteers. CONCLUSION: These results suggest that this new type of photostimulation might potentially uncover some novel aspect of clinical ERGs and might be useful for testing retinal functions of patients with diabetic retinopathy.

Eosinophilia associated with adult T-cell leukemia: role of interleukin 5 and granulocyte-macrophage colony-stimulating factor.

To clarify the mechanism of eosinophilia in adult T-cell leukemia (ATL), we studied three ATL patients having marked eosinophilia. Eosinophil-predominant colony-stimulating activity was detected in the serum of one patient and in the conditioned media (CM) from cultured ATL cells from two patients. Soluble interleukin 5 (IL-5), but no interleukin 3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF), was detected in sera from all patients. On the other hand, GM-CSF was produced in vitro by ATL cells from all cases, whereas detectable IL-3 and IL-5 was produced by cells from only one, suggesting that in the other two cases, the serum IL-5 was produced by the normal reacting lymphocytes. The fact that no patient showed marked neutrophilia supports the possibility that IL-5 may have a leading role in the development of eosinophilia, with GM-CSF produced by ATL cells playing a complementary role.

[Lymphoma associated hemophagocytic syndrome with plasmacytosis in the bone marrow and hypergammaglobulinemia].

A 72-year-old woman was admitted to our hospital because of fever, anemia and thrombocytopenia in March 1997. Laboratory findings showed elevated serum LDH levels and polyclonal gammopathy. Bone marrow aspiration samples revealed hemophagocytosis and plasmacytosis. Although serum interleukin-6 was elevated, serum interferon-lambda and tumor necrosis factor-alpha were below detectable limits. Magnetic resonance images disclosed a tumor in the patient's pelvic cavity. The tumor was resected and diagnosed as non-Hodgkin's lymphoma. The patient was treated with combination chemotherapy and has remained in complete remission. Also, histiocyte and plasma cell counts in the bone marrow fell significantly and the serum interleukin-6 level returned to the normal range. We reasoned that lymphoma cells may have induced plasmacytosis in the bone marrow and polyclonal gammopathy accompanied by hemophagocytic syndrome.

Hemolytic uremic syndrome following autologous peripheral blood stem cell transplantation in a patient with malignant lymphoma.

Hemolytic uremic syndrome (HUS) has been reported in patients receiving bone marrow transplantation. However, only a few cases of HUS following autologous peripheral blood stem cell transplantation (PBSCT) have been reported. We present a case of HUS developing after autologous PBSCT in a 40-year-old man with non-Hodgkin's lymphoma. It appears that the chemotherapeutic agents administered during the conditioning regimen for PBSCT may have played an important role in the development of HUS in our patient. In the present case, the combination therapy of vincristine, methylprednisolone, and ticlopidine hydrochloride was effective.

Evaluation of left ventricular wall motion and function in patients with previous myocardial infarction by three-dimensional 99mTc-HSAD multigated cardiac pool imaging.

To evaluate left ventricular (LV) wall motion stereoscopically from all directions and to calculate the LV volume by three-dimensional (3D) imaging. 99mTc-DTPA human serum albumin-multigated cardiac pool-single photon emission computed tomography (99mTc-MUGA-SPECT) was performed. A new data processing program was developed with the Application Visualization System-Medical Viewer (AVS-MV) based on images obtained from 99mTc-MUGA-SPECT. In patients with previous myocardial infarction, LV function and LV wall motion were evaluated by 3D-99mTc-MUGA imaging. The LV end-diastolic volume (LVEDV) and end-systolic volume (LVESV) were obtained from 3D-99mTc-MUGA images by the surface rendering method, and the left ventricular ejection fraction (LVEF) was calculated at thresholds of 35% (T1), 40% (T2), 45% (T3), and 50% (T4). There was a strong correlation between the LV volume calculated by 3D-99mTc-MUGA imaging at a threshold of 40% and that determined by contrast left ventriculography (LVEDV: 194.7 +/- 36.0 ml vs. 198.7 +/- 39.1 ml, r = 0.791, p < 0.001; LVESV: 91.6 +/- 44.5 ml vs. 93.3 +/- 41.3 ml, r = 0.953, p < 0.001), respectively. When compared with the LVEF data obtained by left ventriculography, significant correlations were found for 3D images reconstructed at each threshold (T1: r = 0.966; T2: r = 0.962; T3: r = 0.958; and T4: r = 0.955). In addition, when LV wall motion obtained by 3D-99mTc-MUGA imaging (LAT and LAO views) was compared with the results obtained by left ventriculography (RAO and LAO views), there was good agreement. 3D-99mTc-MUGA imaging was superior in allowing evaluation of LV wall motion in all directions and in assessment of LV function, since data acquisition and image reconstruction could be done within a short time with the three-detector imaging system and AVS-MV. This method appears to be very useful for the observation of both LV wall motion and LV function in patients with ischemic heart disease, because it is a noninvasive examination.

[Acute lymphoblastic leukemia with marked morphologic abnormalities after chemotherapy for gastric cancer].

A 76-year-old man was admitted to our hospital in February, 1994 because of fever and general fatigue. The patient had received radical gastrectomy for gastric cancer in August, 1987 and was subsequently treated with adjuvant chemotherapy using UFT for 25 months. On admission, the leukocyte count was 57,700/microliters with 74% blasts. Bone marrow aspiration revealed proliferation of blasts with marked giant cells and polynucleolar cells. The diagnosis of T-lineage of acute lymphoblastic leukemia (ALL) was then made by analysis of surface markers and T-cell receptor rearrangement. Although combination chemotherapy was initially effective, blasts rapidly reappeared in the peripheral blood, and the patient died of pneumonia in August, 1994. In the presented case, blasts showed marked morphologic abnormalities. It is well known that most cases of therapy-related leukemia deviate from the myeloid lineage, and rarely from the lymphoid lineage. In addition, morphologic abnormalities are rare in de novo ALL. Since such abnormalities were demonstrated in our patient, and UFT was administered for a long period, it is possible that this leukemia occurred as a second malignancy related to UFT treatment.

[Combined clinical effect of amikacin and cefoxitin in patients with severe infections complicated by hematological diseases].

A clinical investigation was made on the concurrent use of amikacin (AMK) and cefoxitin (CFX) against complicated infections with hematological disorders. The results obtained were summarized as follows: Eleven patients were treated with AMK and CFX. Clinical responses were excellent in 2 (18%), good in 4 (36%), fair in 1 (9%), and poor in 4 (36%), with an efficacy rate of 64%. No significant side effects requiring cessation of the treatment were observed.

[Clinical evaluation of a combination therapy using cefmenoxime and cefsulodin on infections complicated by hematological disorders. Tohkai Research Group on Infections in Hematopoietic Disorders].

Infected patients with hematological disorders were treated with the combination of cefmenoxime (CMX) and cefsulodin (CFS). This therapy was done on 74 patients, of whom 38 (51%) had acute myelocytic leukemia, 14 (19%) malignant lymphoma, 7 (9%) acute lymphocytic leukemia, 5 aplastic anemia, 4 adult T cell leukemia, 4 chronic myelocytic leukemia, 1 multiple myeloma and 1 histiocytic medullary reticulosis. Complicated infections included 5 cases of septicemia, 41 cases of suspected septicemia, 19 cases of respiratory tract infection, 2 with anal abscess, 1 with urinary tract infection and others. The obtained results were as follows: Clinical effectiveness of the combination therapy was excellent in 17 cases (23.0%), good in 24 (32.4%) and poor in 33 (44.6%). Total clinical efficacy rate was 55.4%. Clinical efficacy rate was 40% against septicemias, 51.2% against suspected septicemias and 57.9% against respiratory tract infections. Causative pathogens were isolated in only 21 cases (28.4%): Gram-positive bacteria in 9 cases, Gram-negative bacteria in 11 and fungus in 1. About half of the Gram-negative bacteria belonged to Pseudomonas sp. The efficacy rate of this combination therapy against Gram-negative bacterial infections was 72.7% but the rate against Gram-positive bacterial infections were only 33.3%. Only in 1 case, this combination therapy was discontinued because of drug eruption. Abnormal laboratory findings were observed in 5 cases: Elevation of BUN in 3, GOT and GPT in 1 and prolongation of activated partial thromboplastin time in 1. In conclusion, this combination therapy of CMX and CFS is useful and safe against infections complicated by hematological disorders.

[Clinical investigation of cefotiam in combination with aminoglycoside or (and) penicillin against complicated infections with hematopoietic disorders].

Clinical investigation of combination use of cefotiam (CTM), aminoglycoside, or (and) penicillin against complicated infections with hematopoietic disorders was performed, and the results were as follows. Fifty-one patients were administered CTM in combination with aminoglycoside or (and) penicillin. The clinical response was excellent 19.6%, good 27.4%, fair 21.6%, and poor 31.4% showing efficacy rate of 47.1%. The combined therapy of CTM and aminoglycoside was clinical effective in 70% of 10 patients with complicated sepsis. Therefore, combination use of CTM and aminoglycoside is considered to be the first choice for the treatment of complicated sepsis with hematopoietic disorders. The clinical effectiveness of CTM was not influenced by the number of mature neutrophil at the first phase of CTM treatment, but was influenced at the end phase of CTM treatment. Gram-negative bacilli were dominantly isolated from the patients. Pseudomonas sp. was isolated from 70% of the patients with sepsis. No remarkable side effects were observed in this investigation.

Ultrastructures of leuco-adsorption on monolayers infected with influenza virus.

Leuco-adsorption occurring in influenza virus infected-cell cultures was studied morphologically to clarify the mechanisms of adsorption of leukocytes. Among the various types of chicken leukocytes studied, such as lymphocytes, monocytes, granulocytes, and thrombocytes, all were found to adhere to the virus-infected cells. The adsorption seems to occur through at least two processes, one is mediated by microvilli (microvillus-attachment), and the other is direct adherence of both cells (cell-to-cell-attachment). In the former, the leukocytes are bound to the microvilli protruding from the infected MDCK cells and in the latter both cell membranes attach directly. In the cell-to-cell-attachment, there was an electron-lucent gap of about 12 nm in width in the intermembranous space of the junctional regions. This region was similar morphologically to the gap junction. As a result of leucoadsorption no cytolytic effects occurred in the MDCK cells under the experimental conditions.

[Clinical experience with cefoxitin in infections associated with hematopoietic disorders].

Ten inpatients at the Second Department of Internal Medicine, Mie University Hospital, developed infections in the course of treatment for hematopoietic disorders and were administered cefoxitin (CFX). Patients suffered from the following infections: pharyngitis, 2; bronchitis, 2; pneumonia, 2; sepsis, 2; bacteremia, 1; suspected cases of bacteremia, 2; and fever of unknown origin, 1. The number of infections totaled 12 as 1 patient with pharyngitis also developed sepsis and 1 patient with pneumonia developed bacteremia. Duration for the administration of CFX ranged between 5 and 18 days with a total dosage of between 30 and 108 g. Of the 10 patients treated with CFX, 9 were treated concomitantly with micronomicin (MCR), doxycycline (DOXY), or sulbenicillin (SBPC), some were treated concomitantly with only 1 of the drugs and some were treated concomitantly with 2 of the drugs. The following clinical results were obtained: Following treatment, 4 patients were considered "excellent", 5, "good", and 3, "poor". Clinical efficacy rate was 75%. Four strains of Gram-positive cocci (1 strain of S. aureus, 2 strains of S. epidermidis and 1 strain of Streptococcus sp.) and 3 strains of Gram-negative rods (2 strains of P. aeruginosa and 1 strain of E. cloacae) were found in the clinical specimens of the 10 patients. These results differed somewhat from reported data that Gram-negative rods such as E. coli, Klebsiella sp., Pseudomonas sp., Serratia sp., are dominant. No serious side effects requiring cessation of treatment were observed. Elevations in the levels of S-GOT, S-GPT, serum alkaline phosphatase, blood urea nitrogen, etc. were observed.(ABSTRACT TRUNCATED AT 250 WORDS)