Pharmacodynamics of Ceftolozane Combined with Tazobactam against Enterobacteriaceae in a Neutropenic Mouse Thigh Model.

Ceftolozane is a new broad-spectrum cephalosporin and is combined with tazobactam to broaden the activity of ceftolozane against strains producing extended-spectrum beta-lactamases (ESBLs). We determined the pharmacodynamics (PD) of the combination in the neutropenic mouse thigh model to determine the optimal exposure of tazobactam. Treatment of CD-1 neutropenic mice was started 2 h after infection with ceftolozane every 2 h (q2h) alone or in combination with tazobactam at different dosing frequencies for 24 h, and the number of CFU in the thighs was determined before and after treatment. The maximum effect model was fit to the dose-response and the pharmacokinetic/PD index (PDI)-response to determine the PDI values for ceftolozane alone and ceftolozane in combination with tazobactam resulting in a static effect and a 1-log kill. The effect of tazobactam was dependent on the percentage of time that the free drug concentration remained above the concentration threshold (percent [Formula: see text]), whereby dosing q2h was more efficacious than dosing every 8 h (q8h), reducing the tazobactam daily dose by a factor 6.9 to 59.0 (n = 3 strains) to obtain a static effect. Using R2 as an indicator of the best fit of the percent [Formula: see text]-response relationships, the concentration threshold best correlating with the response varied from 0.5 to 2 mg/liter, depending on the strain. A similar result was obtained when the q2h and q8h regimens were analyzed. For all isolates tested, the mean [Formula: see text] for 0.5 mg/liter tazobactam was 28.2% (range, 17.5 to 45.8%) and 44.4% (range, 26.6 to 54.7%) for a static effect and a 1-log kill, respectively, at ceftolozane exposures that produced a ceftolozane concentration of 4 mg/liter (a concentration greater than the MIC) for 33.9 to 63.3% of a 24-h period under steady-state pharmacokinetic conditions. The main PDI that correlated with the effect of tazobactam was the [Formula: see text] achieved with a CT of 0.5 mg/liter tazobactam.

Plasma and epithelial lining fluid pharmacokinetics of ceftolozane and tazobactam alone and in combination in mice.

Ceftolozane is a new cephalosporin with activity against Gram-negative and Gram-positive microorganisms. However, the compound is susceptible to degradation by extended-spectrum beta-lactamases (ESBLs). Tazobactam is an ESBL inhibitor and is combined with ceftolozane to broaden its activity. Surprisingly, although tazobactam has been available for over 20 years, few if any reliable data exist on the tazobactam pharmacokinetic (PK) properties in mice. To evaluate the PK and pharmacodynamic (PD) relationships in mice, the PK properties of tazobactam and ceftolozane were extensively investigated. Thigh-infected neutropenic CD-1 mice were injected intraperitoneally with a single 0.1-ml dose containing ceftolozane, tazobactam, or both compounds. Ceftolozane was applied in 2-fold-increasing doses of 4 mg/kg of body weight to 64 mg/kg alone or in combination. Tazobactam was combined in reverse doses (thus, 64/4 mg/kg, 32/8 mg/kg, etc.) (n = 2 per time point). In separate validation experiments, ceftolozane-tazobactam was given alone or in combination at 32/8 mg/kg and 8/32 mg/kg (n = 4 per time point). Plasma samples (one per mouse) and bronchoalveolar lavage samples were collected at up to 12 time points until 6 h after administration. There were no significant differences in the ceftolozane and tazobactam PK alone versus combined, indicating no PK interaction. The PKs were linear and dose proportional for both compounds and showed a good penetration in the epithelial lining fluid. The estimated mean (standard deviation) half-life of ceftolozane was 0.287 h (0.031 h), and that of tazobactam was 0.176 h (0.026), and the V was 0.43 liter/kg and 1.14 liter/kg, respectively. The estimates of tazobactam parameters can also be used to (re)interpret PD data.

Efficient and stable adeno-associated virus-mediated transduction in the skeletal muscle of adult immunocompetent mice.

Recombinant adeno-associated virus (rAAV) vectors were evaluated for gene transfer into the skeletal muscle of adult immunocompetent mice. A study using a vector encoding nuclear localized beta-galactosidase (rAAV-nls-lacZ) examined: (i) the efficiency and duration of transgene expression; (ii) the status of the AAV genome in the transduced fibers; and (iii) the possibility of improving gene transfer by inducing muscle regeneration. In the absence of regeneration, the injection of 1.7 x 10(7) particles in the quadriceps resulted in gene transfer to 10-70% of myofibers. Histological analysis indicated that the vector was able to reach myofiber nuclei distant from the injection point. Cellular infiltrates were absent at early time points but became conspicuous in the vicinity of some positive fibers at 4-8 weeks and subsided by 26 weeks. Southern analysis indicated that one to three copies of the vector genome were present per cell genome equivalent. They were associated with high-molecular-weight DNA in the form of tandem oligomers or interlocked circles. Gene transfer was not facilitated in the regenerating muscle. Rather, an early inflammatory response resulted in the elimination of most positive fibers after 8 weeks. The presence of regenerated fibers with beta-galactosidase-positive nuclei suggested that myoblasts had been transduced and were able to fuse to form new fibers. Gene transfer in the absence of immune reactions against the transgene product was studied by injecting mice with a rAAV carrying the murine erythropoietin (mEpo) cDNA. Dose-dependent elevation in the hematocrit was measured for over 200 days and corresponded to 5- to 20-fold increases in plasma Epo levels. We conclude that AAV vectors efficiently and stably transduce post-mitotic muscle fibers and myoblasts in vivo.

Early-phase pharmacokinetics of doxorubicin in non-Hodgkin lymphoma patients. Dose-dependent and time-dependent pharmacokinetic parameters.

The early-phase (20 min) pharmacokinetics of doxorubicin was studied in 18 patients suffering from non-Hodgkin lymphoma and receiving various schedules and/or dosages of the drug. This pharmacokinetics was time-dependent in most patients over a 2-week interval: repeating similar doses in patients leads to a decrease of the drug exposure due to a decrease of the half-life and/or to a decrease of the extrapolation to 0 time (intercept parameter). The pharmacokinetics was generally time-independent within a 6-h interval in most patients. During this time interval, the kinetics was not linear: increasing the dose by large proportions does not lead to a proportional increase of drug exposure. This time- and dose-dependence of doxorubicin pharmacokinetics makes it very difficult to monitor the treatments according to the individual pharmacokinetic patterns of patients.

The strategy of treatment of Hodgkin's disease.

The treatment of Hodgkin's disease necessitates, in most cases, an association of radiotherapy for the macroscopic tumoral masses and chemotherapy for the cells generalized in the organism. Whenever a systematic chemotherapy is associated with radiotherapy, a precise staging topography with laparotomy is useless. The current therapeutic trials should seek methods to lighten these treatments by determining the best equilibrium between the two principal methods and by specifying the ventual place of immunotherapy. The present possibility of curing more than three-fourths of Hodgkin's patients incites us to look for means of reducing the treatment and its inconveniences for the curable forms, and search for more active or tolerable treatments for the uncurable forms.

BCG in the immunotherapy of non-Hodgkin's malignant lymphomas: preliminary results of a controlled trial.

Thirty-three patients exhibiting non-Hodgkin's malignant lymphoma with one or more criteria of poor prognosis and in whom complete remission had been induced by an association of chemo + radio + chemotherapy were randomized to either receive BCG or no further treatment. The present results indicate that BCG may be useful to maintain remission in about one-third of the patients, but these results are not yet significant.

Malignant lymphoplasmacytoid lymphomas. Clinical and evolutive data.

A series of 31 cases of malignant lymphoplasmacytoid lymphomas (excluding Waldenström disease) is analyzed. Two-thirds of the patients initially had localizations elsewhere than in the lymph nodes and presented clinical stage I or II. The median survival is around 4 years and is particularly favorable for stage I and II patients who have received an association of radiotherapy and systematic chemotherapy; the estimated "cure rate" for these patients is around 80%.

[Attitudes of physicians and medical students towards cancer and cancer patients]. / Attitudes des médecins et des étudiants en médecine vis-à-vis des cancers et des cancéreux.

We used the Cancer Attitude Survey (Haley-Blanchard) to investigate attitudes of general practitioners, oncologists in a cancer center, and medical students (during the second part of medical studies (DCEM), at the beginning and the end of a clinical course, and at the last examination ("Cliniques")) towards cancer and cancer patients. This CAS is designed to determine mainly attitudes on inner resources of patients to cope with cancer, value of early diagnosis, aggressive treatments and preparation for, and acceptance of death. There are significant differences between different groups, and for younger students between the beginning and the end of a clinical course in a cancer hospital. There are also differences between French and American doctors. In comparison with American, French mainly underestimate the inner resources of cancer patients while their attitudes are similar for early diagnosis and aggressive treatment. Such a survey is able to give objective data on present attitudes and also to examine how they change with time.

[Cancer information of the general practitioner]. / L'information cancérologique de l'omnipraticien

Inquiries among more than 1 000 general practitioners in the South-West area of France permitted us to precise their needs and wishes about information in the cancer field. The aim of these data is to adapt in a better way the teaching for students and graduates on the base of a close collaboration between general practitioners and cancer specialists.

[Anticancerous chemotherapy and the general practitioner]. / Chimiothérapie anticancéreuse et omnipraticiens

The evolution of anti-cancer chemotherapy has led to long duration treatments, which preferentially are given at home, with the participation of the general practitionner (G.P.). The indications and general supervision of these belong to the oncologist, so thus necessitates a coordinated effort between the many physicians. A postal inquiry has permitted the collection of the opinions of 169 G.P. (more than half of the consulted physicians) from the southwest of France, in the region depending on the Fondation Bergonié. Thus it was possible to establish the importance of this type of treatment for the majority of the G.P., the details of problems of practical application, and the value attached to the relationships with the oncologist, which need further development.

[Prognosis of lymphosarcomas. Multivariate analysis in a series of 334 patients]. / Pronostic des lymphosarcomes. Etude multivariée dans une série de 334 malades.

In this retrospective study, we analysed prognostic factors of 334 previously untreated patients with non Hodgkin's malignant lymphoma. The importance of the different prognostic variables was first studied with survival curves. Next, using a "segmentation" method and a logistic regression analysis, we studied the factors influencing the complete remission rate which is the most important prognostic factor. For the "low-grade" lymphosarcomas, with the segmentation method, we obtained five patients groups for which the complete remission rates varied between 7 and 95.5 per cent according to clinical staging, age and mediastinal involvement. For the "high-grade" lymphosarcomas, we obtained four patients groups in which the complete remission rates varied between 8.7 and 84.7 per cent according to mediastinal and sub-diaphragmatic involvement and clinical staging. Lastly, the Cox model was used in order to determine the best variable combination capable of predicting the survival of patients with clinical stages I or II. These variables were pathological grading, complete initial remission, clinical staging and BCG immunotherapy. With scores deduced from the Cox model, we were able to determine three prognostic groups for which the survivals at 3 years were very significantly different (7 to 89%).

[Xeroradiographic and thermographic contributions to the diagnosis and prognosis of operable breast cancer]. / Apport de la xéroradiographie et de la thermographie au diagnostic et au bilan des cancers du sein opérables.

The methods of paraclinical investigation of breast cancer, advantageously assisted by cytology, do not compete with the biopsy. A clinico-pathologic examination is necessary, prior to any treatment, to ascertain the presence of a cancer and to determine its degree of malignancy. These methods mainly aim at:--discovering the tumor as early as possible,--determining its various morphologic and dynamic aspects, especially its growth rate,--guiding the biopsy and combining this surgical act with coherent therapeutic tactics. The xeroradiographic plate has all the qualities of an excellent detecting device, but in order to replace the mammography on film in daily practice the technical aspects need to be improved. Thermography gives an original and valuable point of view concerning breast tumors. We feel it is one of the most reliable prognostic elements.

[Anticancer chemotherapy: practical management and medical coordination (author's transl)]. / Chimiothérapie anti-cancéreuse: conduite pratique et coordination médicale.

The authors have studied the conditions of application of a protocol of palliative chemotherapy in breast cancers for the first 100 patients undergoing this protocol. The overall management of the treatment has been satisfactory. The medical team from the cancer center has directed the treatments; however, their participation, although substantial has been limited. The participation of other doctors, especially general practitioners, has been important and of good quality. The coordination between the various doctors has been almost always satisfactory. The authors stress the positive aspects of this study: the protocol has been respected in the majority of the cases; the duties have been well distributed among the various participating doctors; good medical cooperation leaves only a few minor details which could be improved. These results encourage the continuation of an approach whereby the general practitioner participates fully with the oncologic team in patient management and cancer control.

[Induction chemotherapy in high risk breast cancer. Results of a prospective therapeutic study (author's transl)]. / La chimiothérapie d'induction dans les cancers du sein à haut risque. Résultats d'une étude thérapeutique prospective.

The action of an induction chemotherapy was studied in 54 patients with extensive localized tumour. An association of doxorubicin (adriamycin), vincristine and methotrexate were used in five days courses every three weeks. Three to four courses were applied before radiotherapy (minimum of two months of treatment). This chemotherapy gave very good immediate objective responses (87% of the cases), especially for breast tumors which follow an acute course. No adverse effects on the later sequences of the treatment program were observed. The follow up period is too short to establish long term efficacy. Nevertheless, it now seems of value to apply the chemotherapy from the onset of the disease: on one hand it represents a preparatory factor which is probably useful in reinforcing the action of loco-regional treatment; on the other hand it represents the first treatment for these high risk breast cancers, whose prognosis is mainly determined by metastasis.

[Development of a knowledge-based system for aiding therapeutic decision in breast cancer]. / Développement d'un système à base de connaissances pour l'aide à la décision thérapeutique dans les cancers du sein.

The SENEX project has been initiated at the fondation Bergonié in 1985 and is intended for providing physicians in general hospitals with knowledge based systems for the management of cancer treatment protocols. The design and building of a knowledge-based system for the management of breast cancer protocols (SENEX) was the first goal of this project. SENEX has been developed using a commercially available development tool (Personal Consultant Plus, Texas-instruments) derived from EMYCIN. It runs on IBM and compatible microcomputers. The knowledge base embeds the formal knowledge contained in the breast cancer protocols currently in use at the fondation Bergonié, and some judgmental knowledge acquired form breast cancer experts. Production rules and frames allowed us to adequately represent and structure this knowledge and the problem solving processes related to the management of breast cancer. A preliminary informal evaluation of the system has shown that it performs at the expert-level in giving advice for patients included in formal protocols. Its use and acceptability are good. However, we have to add judgmental knowledge into the knowledge base and to interface the system with a temporal data base management system to improve the overall performances of SENEX. Moreover the effectiveness of the system remains to be demonstrated before one can anticipate is routine use in clinical practice.

[Metastatic cancer of the prostate: phase II study of spirogermanium (NSC 192965)]. / Cancer de la prostate métastatique: étude de phase II du spirogermanium (NSC 192965).

A phase II study of spirogermanium was conducted in a series of 15 patients with metastatic prostatic carcinoma. All the patients have previously received multiple hormonal therapies. The drug was administered at the dose of 200 mg/m2 by a continuous infusion for five days, and 120 mg/m2, three times a week subsequently. The side effects were mainly neurological toxicity and phlebitis at the injection points which were dose and schedule dependent. Only one partial response for two months was noted in this series. Thus, spirogermanium seems to have a limited value in patients with prostatic cancer.

[Significance of chemotherapy complementary to radiotherapy in stages I and II in Hodgkin's disease]. / Intérêt d'une chimiothérapie complémentaire de la radiothérapie dans les stades I et II de la maladie de Hodgkin

In a series of 118 cases of Hodgkin's disease in stage I and II successively treated by irradiation alone or by chemotherapy followed by irradiation or by chemotherapy + irradiation + chemotherapy, a retrospective analysis brings out the share of classical radiotherapy in the cures associated with chemotherapy, which in providing a remission rate of the order of 90 p. 100 renders superfluous the maintenance of a long course of chemotherapy and of negligible interest the performance of an exploratory laparotomy.

[Non-Hodgkin's malignant lymphomas. Clinico-pathological data and course in 370 patients (author's transl)]. / Lymphomes malins non hodgkiniens. Caractères anatomocliniques et évolutifs dans une série de 370 malades.

Three hundred and seventy non-Hodgkin's malignant lymphomas were seen at the Fondation Bergoniéé between 1965 and 1978 and classified according to the Kiel classification. Pretherapeutic data and evolution allow to recognize three distinct pathologic groups: 1) a first type of lymphosarcoma, so-called "low grade malignancy", is observed only in adults and old patients; the disease is often disseminated, the evolution is slow and the prognosis favorable; 2) a second type, so-called "lymphoblastosarcoma", is only one observed in young patients, the evolution is fast with frequent leukemic transformation and this group is thus very close to acute lymphoid leukemia; 3) a third type, so-called "immunoblastosarcoma", is observed only in old patients; the evolution is fast but without major spread; for these two latter groups, the prognosis is unfavorable. This highly significant and clearcut distinction may be a help for scheduling treatment according to each group of patients.

[Prognostical factors of breast neoplasms without metastasis. Synthesis by a multifactoral analysis]. / Facteurs pronostiques des cancers du sein sans métastase. Essai de synthèse par une analyse multifactorielle.

Multifactorial analysis by dichotomous split was applied to a consecutive series of 541 female breast cancer patients without detectable metastasis at onset of treatment. These patients were entirely treated in the same institution (Fondation Bergonié), in the years 1960-1974. This multifactorial analysis sets a hierarchical order among the different prognostic factors and defines groups of patients homogeneous for metastatic risks. The significant prognostic factors in these series are : number of malignant axillary nodes; location and size of tumour; state of adjacent skin; relations with thoracic wall; pre or post-menopausal status; inflammatory signs; thermographic and mammographic data.

Radiation dose profile in 125I brachytherapy: an 8-year review.

The use of episcleral plaques containing radioactive 125I seeds for brachytherapy treatment of selected retinoblastoma cases of patients is being done in Riyadh, Saudi Arabia since 1994. There are about three to four patients per year. A total of 31 patients were treated with a tumour dose in the range of 40-60 Gy using 8 seeds of 125I each from 1994 to 2002. This study determines the trend of occupational doses received by surgeons, anaesthesiologists and nurses and the dose rate profile around the eyes. Only 3% of the 275 persons monitored for Hp(10) have measurable doses with a weighted average of 4 microSv and 7% of the 175 persons monitored for Hp(0.07) have measurable doses with a weighted average of 0.3 mSv. The dose rate is maximum (110 microSv h(-1)) at the point of contact with the eye plaque and reduces to approximately 40% on the side of the other eye.