Carbapenem versus fosfomycin tromethanol in the treatment of extended-spectrum beta-lactamase-producing Escherichia coli-related complicated lower urinary tract infection

The aim of this observational prospective study was to compare the effect of fosfomycin tromethanol (FT) and carbapenems (meropenem or imipenem cilastatin) in the treatment of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli-related complicated lower urinary tract infection (CLUTI). Inclusion criteria were: patients who were aged >18 yr with dysuria or problems with frequency or urgency in passing urine; those with >20 leukocytes/mm3 in urine microscopy and culture-proven ESBL-producing carbapenem or FT-sensitive E. coli in the urine (>10? cfu/mm3); no leukocytosis or fever; and who were treated with ft (oral 3 g sachet x 1 every other night, three times) or carbapenems between march 2005 and January 2006 in our outpatient clinic and hospital. A total of 47 CLUTI attacks in 47 patients (27 FT group, 20 carbapenem group) were observed prospectively. Clinical and microbiological success in the carbapenem and ft groups was similar (19/20 vs 21/27 and 16/20 vs 16/27 p>0.05). Drug acquisition costs were significantly lower in the FT group (p<0.001). Although it is not a randomized controlled study, these data show that ft may be a suitable, effective and cheap alternative in the treatment of ESBL-producing E. coli-related CLUTI.     

In vitro activity of ceftazidime/avibactam against clinical isolates of ESBL-producing Enterobacteriaceae in Italy

Resistance to carbapenems in Enterobacteriaceae is a serious concern for public health. Alternative treatment options involving carbapenem-sparing regimen for patients with serious infections caused by multidrug-resistant Enterobacteriaceae are urgently needed. Ceftazidime/avibactam (CZA) is a new combination of a third generation cephalosporin and a non-β-lactam β-lactamase inhibitor, in which avibactam is capable to expand the ceftazidime activity also against extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae. To date, no data exist regarding the activity of CZA against strains isolated in the Italian context, which is known as endemic for ESBL producers. The aim of this study was to evaluate the in vitro activity of CZA, in comparison to ceftazidime (CAZ), against 90 ESBL-producing Escherichia coli and Klebsiella pneumoniae isolates, collected from blood and urine samples at our Institute. Thus, avibactam has been able to restore the activity of CAZ in all cases, suggesting the potential use of CZA as a carbapenem-sparing model, especially when limited therapeutic options exist.     

Activity of Plazomicin (ACHN-490) against MDR clinical isolates of Klebsiella pneumoniae,Escherichia coli,and Enterobacter spp. from Athens,Greece

Abstract

The in vitro activity of plazomicin was evaluated against 300 multidrug resistant (MDR) (carbapenemase and/or ESBL-producing) isolates from four hospitals in Athens, an area where carbapenemase-producing organisms are endemic. Most of the isolates were also resistant to the legacy aminoglycosides with the MIC₅₀/MIC₉₀ to tobramycin, amikacin and gentamicin being 32/>32, 32/>32 and 4/>8 μg/ml, respectively. ACHN-490 retained activity (MICs?4 μg/ml) against all isolates of Klebsiella pneumoniae, Escherichia coli, and Enterobacter spp. tested with MIC₅₀ and MIC₉₀ of 1 and 2 μg/ml, respectively, irrespective of their MDR phenotype and it represents a promising alternative for the treatment of the most problematic Gram-negative pathogens.     

Inability to escalate vinorelbine dose intensity using a daily × 3 schedule with and without filgrastim in patients with metastatic breast cancer

Purpose: Vinorelbine (Navelbine) is a semisynthetic vinca alkaloid with documented activity in breast cancer. The major dose-limiting toxicity (DLT) when given weekly is myelosuppression with minimal neurologic toxicity. This phase I study attempted to define the maximally tolerated dose (MTD) and the DLT of vinorelbine on a daily ×3 schedule with and without filgrastim support. Methods: A total of 19 patients with stage IV breast cancer were enrolled in separate studies at Duke University Medical Center (DUMC) and the Dana-Farber Cancer Institute (DFCI). Eligible patients could have received up to two prior chemotherapy regimens in the metastatic setting and had to have an ANC >1500/mm², PLT >100 000 m³, creatinine <2.0 mg/dl, bilirubin <2.0 mg/dL, SGOT not more than three times normal, and performance status 0–1. Vinorelbine was administered using a daily ×3 schedule every 3 weeks. The protocols were designed to study dose escalation with and without growth factor support. At DUMC, in the initial phase of the study, the starting dose was 15 mg/m² per day and dose escalations of 5 mg/m² were planned until DLT developed and the MTD was defined. DLT was defined as granulocytopenia <500/mm³ for >7 days, grade IV thrombocytopenia, febrile neutropenia, or grade III or greater nonhematologic toxicity. In the second phase of the study, growth factor support was given with vinorelbine at the MTD. Filgrastim at a dose of 5 g/kg was started on day 4 of the 21-day cycle and was continued until the neutrophil count exceeded 10 000 cells/mm³. At DFCI, all patients received growth factor starting on day 4 and the starting dose of vinorelbine was 25 mg/m². Results: At DUMC, DLT was seen at 20 mg/m² in three of three patients and included febrile neutropenia, grade IV neutropenia >7 days, grade III neurotoxicity, and grade III vomiting. Despite the addition of filgrastim, DLT was again seen at 20 mg/m² and included grade III neurotoxicity (jaw pain, abdominal pain, constipation, ileus) and grade IV mucositis. Three patients at DFCI were treated with vinorelbine at a dose of 25 mg/m² with growth factor support, and two developed DLT including febrile neutropenia, neutropenia >7 days, and grade III stomatitis. Conclusions: Our effort to escalate the dose intensity of vinorelbine on this schedule was not successful and was complicated by hematologic and nonhematologic toxicity. A daily ×3 schedule of vinorelbine should not be pursued as an alternative treatment regimen in patients with previously treated metastatic breast cancer. Received: 27 October 1997 / Accepted: 16 April 1998     

A Comparative Study on Aztreonam,Ceftazidime and Amikacin in the Treatment of Complicated Urinary Tract Infections

Summary

In a prospective, randomized trial, aztreonam (1 g intravenously or intramuscularly, twice daily) was compared with ceftazidime (1 g intravenously or intramuscularly, twice daily) and amikacin (500 mg intravenously or intramuscularly, twice daily) in 76 patients aged 24 to 84 years (mean, 59.7 years) with complicated urinary tract infections. Initial pathogens included Escherichia coli (47.5%), Pseudomonas aeruginosa (22.5%), Klebsiella spp. (9%), Proteus spp. (7.5%) and Enterobacter spp (6%). In four patients initial urine cultures yielded more than one organism. All pathogens were sensitive to the three study drugs. Including performance of 4- to 6-week follow-up cultures, eradication of the pathogens occurred in 72% of patients treated with aztreonam, in 74% of those treated with ceftazidime and in 71% treated with amikacin (p>0.05). Clinical success was observed in 84% of patients treated with aztreonam, in 82% of those treated with ceftazidime and in 85% treated with amikacin (p>0.05). All drugs were well tolerated. It is concluded that aztreonam, ceftazidime and amikacin are equally effective and safe for the treatment of complicated urinary tract infections due to susceptible organisms.     

Intestinal Protozoa in HIV-Infected Patients: Effect of Rifaximin in Cryptosporidium parvum and Blastocystis hominis Infections

Abstract

In HIV-1 infected patients severe enteritis and chronic diarrhea are often documented as a consequence of multiple opportunistic infections. We analyzed 48 HIV-1 positive patients for the presence of intestinal pathogenic protozoa. Patients with CD4 ≥200/mm³ showed a higher prevalence of a single pathogenic protozoa than patients with CD4 ≤200/mm³, who showed the presence of multiple protozoal infections. Patients who proved positive for only a single protozoa, Cryptosporidium or Blastocystis, were also positive, by stool culture, for the presence of Proteus mirabilis (3 samples), Citrobacter freundii (3 samples), Escherichia coli (one sample) or Enterobacter cloacae (one sample). Treatment with rifaximin (600 mg, 3 times a day, for 14 days) was efficacious in resolving the clinical symptoms and clearing protozoan infections in HIV-1 infected patients with CD4 ≥200/mm³, who presented enteric and systemic symptoms due to Criptosporidium or Blastocystis associated with enteropathogenic bacteria.     

Carfilzomib monotherapy in Japanese patients with relapsed or refractory multiple myeloma: A phase 1/2 study

This multicenter, open‐label phase 1/2 study evaluated single‐agent carfilzomib in 50 heavily pretreated Japanese patients with relapsed/refractory multiple myeloma (median of five prior treatments). In phase 1, patients were dosed at three levels: 15, 20, or 20/27 mg/m². Maximum tolerated dosage was not reached at the tolerability evaluation. Patients in phase 2 were treated with 20/27 mg/m² carfilzomib. Median duration of exposure to carfilzomib in the 20/27 mg/m² group at this final analysis was 4.7 months (range: 0.3‐39.4). Overall response rate in the 20/27 mg/m² group, primary endpoint of the study, was 22.5% (n = 9) (95% confidence interval, 12.3‐37.5) with 2.5% (n = 1) stringent complete response. Median progression‐free survival and overall survival in the 20/27 mg/m² group were 5.1 months (95% CI, 2.8‐13.6) and 22.9 months (95% CI, 14.1‐not estimable), respectively. Frequently occurring grade ≥3 adverse events in the 20/27 mg/m² group included lymphopenia (72.5%), neutropenia (40.0%), and leukopenia (32.5%). Giving long‐term carfilzomib monotherapy led to long‐term overall survival for heavily pretreated multiple myeloma patients with a favorable safety profile. Carfilzomib monotherapy can be a good option for heavily pretreated multiple myeloma patients.     

Arrhenius parameter determination as a function of heating method and cellular microenvironment based on spatial cell viability analysis

Abstract

Purpose: Predictions of injury in response to photothermal therapy in vivo are frequently made using Arrhenius parameters obtained from cell monolayers exposed to laser or water bath heating. However, the impact of different heating methods and cellular microenvironments on Arrhenius predictions has not been thoroughly investigated. This study determined the influence of heating method (water bath and laser irradiation) and cellular microenvironment (cell monolayers and tissue phantoms) on Arrhenius parameters and spatial viability.

Methods: MDA-MB-231 cells seeded in monolayers and sodium alginate phantoms were heated with a water bath for 3–20?min at 46, 50, and 54?°C or laser irradiated (wavelength of 1064?nm and fluences of 40?W/cm² or 3.8?W/cm² for 0–4?min) in combination with photoabsorptive carbon nanohorns. Spatial viability was measured using digital image analysis of cells stained with calcein AM and propidium iodide and used to determine Arrhenius parameters. The influence of microenvironment and heating method on Arrhenius parameters and capability of parameters derived from more simplistic experimental conditions (e.g. water bath heating of monolayers) to predict more physiologically relevant systems (e.g. laser heating of phantoms) were assessed.

Results: Arrhenius predictions of the treated area (<1% viable) under-predicted the measured areas in photothermally treated phantoms by 23?mm² using water bath treated cell monolayer parameters, 26?mm² using water bath treated phantom parameters, 27?mm² using photothermally treated monolayer parameters, and 0.7?mm² using photothermally treated phantom parameters.

Conclusions: Heating method and cellular microenvironment influenced Arrhenius parameters, with heating method having the greater impact.     

Successful Treatment of an Aspergillus fumigatus Infection with Voriconazole Via a Nasogastric Tube

Abstract

Extended-spectrum beta-lactamase (ESBL) production by Enterobacteriaceae is an emerging problem. This 3-year prospective study was undertaken to determine the prevalence of such enzymes among the clinically significant isolates of the Enterobacteriaceae family gathered from patients, and to evaluate the different techniques for their detection as well as their clinical significance. Members of the Enterobacteriaceae family isolated from blood, inhibited by the third-generation cephalosporins with minimum inhibitory concentrations (MICs) of ≤2 μg/ml and MIC ≤8 μg/ml and isolates from other sources inhibited by MIC ≤8 μg/ml were also investigated for ESBL production by VITEK2 and E test. Their clinical significance in septicemic patients was analyzed. Out of 3,215 isolates, 1018 (31.7%) were ESBL-producers by both VITEK2 and E test. Of these, 428 (42%) were Klebsiella pneumoniae and 376 (37.0%) were Escherichia coli with overall prevalence rates of 13.3% and 11.7%, respectively. There were a total of 184 septicemic patients infected by ESBL-producing Enter-obacteriaceae out of which 134 (73%) needed modification of therapy; most (58%) of these patients were initially on third-generation cephalosporin therapy. A total of 58 (31.5%) patients were infected by ESBL-producing blood isolates which were inhibited by cefotaxime/ceftriaxone at MICs ≤8 μg/ml (within the susceptibility range). Resistance to both aminoglycosides and quinolones were significantly higher among ESBL-producing isolates compared to non-producers (P<0.05). This study highlights a high prevalence of ESBL-producing Enterobacteriaceae in a major tertiary teaching hospital in our country and demonstrates that almost a third of the ESBL-producing Enter-obacteriaceae blood isolates would have been released as susceptible by routine susceptibility testing; a finding inimical to optimal therapeutic success.     

Risk factors for coexistence of fluoroquinolone resistance and ESBL production among Enterobacteriaceae in a Greek university hospital

The purpose of this study was to identify risk factors for fluoroquinolone resistance (QR) among ESBL- producing Enterobacteriaceae causing nosocomial infections. The study was conducted in Laikon General Hospital in Athens, Greece, during the period January 2004 - January 2005. Epidemiological and clinical data were collected from the medical charts of the patients diagnosed with nosocomial infections due to an ESBL-producing Enterobacteriaceae. QR was 60% among the 84 ESBL-producing Enterobacteriaceae isolates. Infection from QR-ESBL bacteria was associated with increased hospital stay (p=0.028); QRESBL bacteria were isolated later during hospitalization than fluoroquinolone susceptible (QS)-ESBL (p=0.089); factors associated with QR were immune-deficiency (p=0.047), previous use of carbapenems (p=0.08) and fluoroquinolones (p=0.067), and admission to the Transplantation Unit (p=0.047). In addition, QR-ESBL bacteria were more likely to be resistant to co-trimoxazole (p<0.001), gentamicin (p=0.054) and tobramycin (p=0.004). Logistic regression analysis indicated that admission to the transplantation unit was an independent risk factor for infection due to a QR-ESBL isolate. Results of this study question ciprofloxacin's usefulness as a valid alternative to carbapenems in our hospital for the treatment of infections due to ESBL-producing bacteria. In addition strategies for addressing the QR-ESBL situation should focus on limiting fluoroquinolone and carbapenem consumption and emphasize on barrier precautions in patients with longer hospitalization, immunosuppression, or admission to the transplantation unit.     

Differentiation of malignant and benign lung lesions with diffusion-weighted MR imaging

Background

The aim of the study was to evaluate the role of diffusion-weighted magnetic resonance imaging in the differential diagnosis of lung lesions.

Patients and methods.

Sixty-seven patients with lung lesions (48 malignant, 19 benign) were included in this prospective study. Signal intensities (SIs) were measured in diffusion-weighted MR images that were obtained with b=0, 500 and 1000 s/mm² values. Apparent diffusion coefficient (ADC) maps were calculated by using images with b=0 and 1000 s/mm² values. The statistical significance was determined using the Student-t test.

Results

The SIs of malignant lesions were significantly higher than those of benign lesions (p<0.004 for b=0 s/mm² and p<0.000 for the other b values). Using b=500 s/mm², SI≥391 indicated a malignant lesion with a sensitivity of 95%, specificity of 73% and positive predictive value of 87%. Using b=1000 s/mm², SI≥277 indicated a malignant lesion with a sensitivity of 93%, specificity of 69% and positive predictive value of 85%. There was no significant difference between malignant and benign lesions regarding ADC values (p=0.675). There was no significant difference in SIs or ADC values between small cell carcinoma and non-small cell carcinoma. When comparing undifferentiated with well- partially differentiated cancers, SIs were higher with all b values, but the difference was statistically significant only with b=1000 s/mm² (p<0.04).

Conclusions

Diffusion-weighteted MR trace image SI is useful for the differentiation of malignant versus benign lung lesions.     

Impact of carbapenem administration on systemic endotoxemia in patients with severe sepsis and Gram-negative bacteremia

In order to investigate the effect of carbapenems on systemic endotoxemia, 20 patients with severe sepsis due to ventilator-associated pneumonia and Gram-negative bacteremia were enrolled; 10 (group A) were administered 1 g t.i.d. of imipenem/cilastatin and 10 (group B) 2 g t.i.d. of meropenem. Blood was sampled at 0 time and after 1, 2, 4, 6, 12, 24, 36, 48, 60, 72, 84 and 96 hours for detection of endotoxins (LPS), interleukin-6 (IL-6), C-reactive protein (CRP) and drug levels. LPS were determined by the QCL-1000 LAL assay, IL-6 by an enzymeimmunoassay, CRP by nephelometry and carbapenem levels by a microbiological assay. We did not find that carbapenems had any effect on the kinetics of LPS and CRP; IL-6 of group A was lower than group B at 72 and 84 hours. No correlation was observed between drug levels of any carbapenem and LPS, IL-6 or CRP. It is concluded that in septic patients with Gram-negative bacteremia administration of either imipenem or meropenem did not affect systemic endotoxemia. The above data support the safe administration of both carbapenems in patients with severe sepsis.     

Local chemotherapy of F98 rat glioblastoma with paclitaxel and carboplatin embedded in liquid crystalline cubic phases

Implanted drug carrier systems for retarded chemotherapy against gliomas are mainly based upon polymers containing nitrosoureas. The authors have developed an intracavitary carrier system of biodegradable liquid crystalline cubic phases encapsulating carboplatin and paclitaxel and studied it for release kinetics, antitumor activity, and survival prolongation. A total of 61 Fisher rats with F98 tumors were divided into six treatment groups at day 12 post-inoculation, receiving either no treatment, surgery with partial tumor resection, or partial resection with implantation of cubic phases containing either paclitaxel and carboplatin, paclitaxel alone, carboplatin alone, or no drug. Animals were killed for tumor size analysis at day 21 post-inoculation (n=28) or were included in survival studies (n=33). Additional 12 animals received a paclitaxel/carboplatin application and were killed at different time intervals (6 h, 24 h, 48 h, 5 d, 7 d, 10 d post-agent application) for in vivo diffusion studies. Animals from the paclitaxel/carboplatin group showed a significantly smaller tumor (mean 3.25 mm² ± SD 1.79 mm²) than animals from the control group (15.30 ± 5.86 mm²; P=0.0031), animals having received the empty matrix (11.62 ± 6.66 mm²; P=0.0241), and animals after tumor resection without implantation (20.87 ± 3.56 mm²; P 0.0001). There was no significant difference in survival. Carboplatin was found in brain tissue at 6 h, paclitaxel was found at up to 48 h after implantation at 3 mm distance. Biodegradable crystalline cubic phases embedding cytotoxic drugs as paclitaxel and carboplatin might play an important role in local glioblastoma treatment.     

Effects of carbapenems and their combination with amikacin on murine gut colonisation by Candida albicans

Carbapenems are broad‐spectrum antibiotics increasingly used for the treatment of severe infections. We evaluated the effects of four carbapenems given as monotherapies or in combination with amikacin on the level of gastrointestinal colonisation by Candida albicans in a previously established mouse model. Adult male Crl : CD1 (ICR) BR mice were fed chow containing C. albicans or regular chow. The mice fed with Candida chow had their gut colonised by the yeast. Both groups were subsequently given imipenem, meropenem, ertapenem, doripenem or their combination with amikacin or normal saline subcutaneously for 10 days. Stool cultures were performed immediately before, at the end and 1 week after discontinuation of treatment. Candida‐colonised mice treated with the antibiotics had higher counts of the yeast in their stools than control C. albicans‐colonised animals treated with saline. All four carbapenems and their combination with amikacin caused a significant increase in C. albicans concentration. Mice fed regular chow and treated with the study antibiotics or saline did not have any Candida in their stools. Dissemination of Candida was not detected in any animal. These data suggest that carbapenems and carbapenem plus amikacin induce substantial increases in the murine intestinal concentration of C. albicans.     

Lifestyle and nutritional determinants of bioavailable androgens and related hormones in British men

Objective: To investigate the lifestyle and nutritional determinants of serum bioavailable androgens and their related hormones in men. Methods: This study is based on a sample of 696 men with a wide range of nutrient intakes, whose diet and lifestyle characteristics were assessed with a questionnaire and serum sex hormones measured using immunoassays. Results: Men aged 70 years or older had 12% lower testosterone and 40% lower free-testosterone (FT) and androstanediol glucuronide (A-diol-g) concentrations than men who were 20–29 years of age. Conversely, sex hormone-binding globulin (SHBG) and luteinizing hormone (LH) concentrations were 90% and 49% higher in the oldest age group compared with the lowest, respectively. Men who had a body mass index (BMI) of 30+ kg/m² had 30% lower testosterone, 45% lower SHBG, 22% lower LH and 5% lower FT concentrations compared with men with a BMI of < 20 kg/m². Conversely, A-diol-g concentration was 15% higher in the highest BMI category compared with the lowest. A high waist circumference was further associated with a 12% lower testosterone and SHBG concentration, after adjusting for BMI. Compared with never-smokers, smoking 10+ cigarettes/day was associated with 15% higher testosterone, 22% higher SHBG and 17% higher LH concentrations; FT and A-diol-g were not associated with smoking. Compared with no exercise, vigorous exercise of 3+ hours/week was associated with 11% higher testosterone and 16% higher SHBG concentrations, whilst LH, FT, and A-diol-g were not associated with vigorous exercise. Dietary factors were not strongly associated with hormones, although saturated fat intake was negatively associated with SHBG (r = –0.10; p = 0.01) and alcohol intake was positively associated with A-diol-g (r = 0.11; p = 0.004). No dietary factors were associated with testosterone, FT, or LH. Conclusions: Age is the strongest determinant of serum bioavailable androgens. BMI and some lifestyle and dietary factors influence SHBG and testosterone concentrations, but have no strong association with FT, suggesting that homeostasis is effective. A-diol-g shows broadly similar associations to FT, with the exception of the effect of BMI and alcohol.     

Influence of clamping-induced ischemia and reperfusion on the response of a mouse melanoma to radiation and hyperthermia

Purpose: To study the response of a mouse melanoma to radiation and hyperthermia under acute hypoxia and reperfusion. Materials and methods: B16F1 melanoma of 100 ± 10mm³, in C57BL mouse, were locally exposed to 10 Gy gamma radiation (RT), 43°C for 30 min (HT) in a water bath, or RT followed immediately by HT, under clamping (acute hypoxia) or 1 h after reperfusion. Tumour regression, volume doubling time (VDT), growth delay (GD), apoptosis and microvascular density (MVD) were studied. Results: Under clamping, HT increased the VDT and GD to > 20 days above control and resulted in > 50% regression (PR) in all the tumours, whilst RT + HT synergistically enhanced VDT and GD. Under reperfusion, HT produced 25% PR against 16% by RT, with no increase in VDT and GD compared to RT. RT + HT significantly enhanced VDT and GD above that of RT or HT, but did not further increase PR of reperfused tumours. HT under clamping caused > 50% increase in apoptic cells over control and decreased MVD to 1/3rd of control. RT + HT further enhanced apoptotic cells to > 70% and reduced MVD to 1/6th of control. Conclusions: These results suggest that combination of radiotherapy with hyperthermia could benefit treatment of tumours with ischemia-induced acute hypoxia.     

Maternal carriage of extended-spectrum beta-lactamase-producing Escherichia coli isolates in Argentina

Abstract

The aim of this study was to determine the prevalence of vaginal Escherichia coli colonization and perianal carriage of Enterobacteriaceae resistant to third generation cephalosporins in pregnant women. Vaginal and perianal samples from 259 pregnant women were studied. Vaginal swabs were inoculated onto MacConkey agar plates and perianal swabs were inoculated onto CHROMagar extended-spectrum beta-lactamase (ESBL) plates. The minimal inhibitory concentration of the isolates was determined using the Epsilometer test method. The phenotypic detection of ESBLs was performed by the combined disc method using cefotaxime versus cefotaxime plus clavulanate. The prevalence of vaginal E. coli colonization during pregnancy was 14·3%. The resistance rate to ampicillin, gentamicin, and cefotaxime was 48·6, 10·8, and 0·8%, respectively. Enterobacteriaceae resistant to third generation cephalosporins were recovered in 7·3% of all perianal specimens. Among them, 5·4% of pregnant women were colonized with E. coli ESBL-producer strains. The present study revealed that colonization with Enterobacteriaceae resistant to third generation cephalosporins is significant in pregnancy. ESBL-producing E. coli were the most prevalent organisms. Screening strategies designed to monitor for ESBL-producing E. coli could be useful in endemic areas to prevent perinatal transmission and the introduction of multiresistant strains to the maternity ward.     

A randomized trial comparing ftorafur alone with ftorafur plus tamoxifen in postoperative adjuvant therapy for breast cancer Kinki Area Research Group for Postoperative Adjuvant Therapy for Breast Cancer

 A randomized study was performed in 35 centers in the Kinki area of Japan to determine the effectiveness of ftorafur (FT) plus tamoxifen (TAM) compared with FT monotherapy in postoperative adjuvant therapy for breast cancer. Patients were randomized by the envelope method to receive either FT 600 mg/day or FT 600 mg/day plus TAM 20 mg/day orally for 1 year, starting on day 7 after mastectomy. Between April 1982 and January 1985, 628 patients were assigned to treatment with FT alone and 626 to treatment with FT+TAM. Of these, 571 (90.9%) and 539 (86.1%) patients, respectively, met the eligibility requirements for this study. There were no significant differences in major background factors between the two groups of eligible patients. Five-year survival rates were 91.4% for FT alone and 91.1% for FT+TAM (not significantly different). Five-year disease-free survival rates showed a tendency towards a better prognosis (P=0.090) in the FT+TAM group, with observed rates of 83.0% for FT alone and 86.7% for FT+TAM. Stratified analysis showed that disease-free survival with FT+TAM is better than with FT alone for patients aged 50 years or more (P=0.048) and for patients with from one to three positive nodes (P=0.064). Received: 21 July 1994/Accepted: 21 June 1995     

Intensive combined modality therapy including low-dose TBI in high-risk ewing's sarcoma patients

Twenty-four higb-risk Ewing's sarcoma patients were treated on an intensive combined modality protocol including low-dose fractionated total body irradiation (TBI) and autologous bone marrow infusion (ABMI). Twenty patients (83%) achieved a complete clinical response to the primary and/or metastatic sites following induction therapy. The median disease-free interval was 18 months, and nine patients remain disease-free with a follow-up of 22 to 72 months. Local failure as a manifestation of initial relapse occurred in only three patients (15%), each having synchronous distant failure. Eight patients failed initially with only distant metastases, usually within 1–2 years following a complete clinical response. Two patients with a single metastasis were again rendered disease-free and remain free from second relapse with 18 and 30 months of follow-up. No other relapsed patient was able to be rendered disease-free, and most died of progressive disease within 6 to 12 months of relapse. Two patterns of granulocyte recovery following consolidative therapy (including TBI) and ABMI were recognized. Seventeen patients reached a total granulocyte count of >500 cells/mm³ within 4 weeks of ABMI (early granulocyte recovery), while 7 patients required >4 weeks from ABMI (late granulocyte recovery). The time to platelet recovery (>50,000/mm³) was different for the groups with early and late granulocyte recovery (25 days vs. 54 days, p > .001). Six of seven patients with late granulocyte recovery received local high-dose irradiation to $\text{>}\text{1}\text{2}$ pelvis prior to bone marrow storage. Patients with) late recovery did not tolerate maintenance chemotherapy. However, there was no difference in disease-free and overall survival, when comparing the groups with early and late granulocyte recovery. We conclude that these high-risk Ewing's sarcoma patients remain a poor-prognosis group in spite of intensive combined modality therapy including low-dose TBI. The control of microscopic systemic disease remains the major challenge to improving the cure rate. A new combined modality protocol with high-dose `therapeutic' TBI (800 rad/2 fractions) is being used and the protocol design is outlined.     

Comparison of the Minimum Inhibitory,Mutant Prevention and Minimum Bactericidal Concentrations of Ciprofloxacin,Levofloxacin and Garenoxacin Against Enteric Gram-negative Urinary Tract Infection Pathogens

Abstract

Acute, uncomplicated urinary tract infections (UTIs) are among the most commonly encountered bacterial infections and management has been made more complicated in the last decade due to the trend toward increasing antimicrobial resistance to ampicillin and trimethoprim/sulfamethoxazole (TMP/SMX). Fluoroquinolones are suggested as alternative antimicrobials for the treatment of UTIs in communities for which TMP/SMX resistance is ≥10%. The mutant-prevention concentration (MPC) is a novel susceptibility parameter designed to minimize the selection of first-step resistant mutants present in large, ≥10¹⁰ CFU/mL, heterogeneous bacterial populations and is a distinct measurement from minimum inhibitory concentration testing. We measured MPC results for 80 enteric Gramnegative and 20 Pseudomonas aeruginosa urinary isolates against ciprofloxacin, levofloxacin and garenoxacin. Ciprofloxacin, levofloxacin and garenoxacin MPC results for Escherichia coli, Citrobacter freundii, Enterobacter cloacae, Klebsiella pneumoniae and P. aeruginosa respectively were 0.5, 1, 1, 1 and 4 mg/L; 1, 2, 4, 2 and 16 mg/L; 1, 8, >8, 4 and ≥32 mg/L. By comparison, minimum inhibitory concentration (MIC)₉₀ results for the Enterobacteriaceae organisms ranged from ≤0.06-4 mg/L for the three drugs and 1-4 mg/L against P. aeruginosa. Similarly, MBC₉₀ results ranged from ≤0.06-4 mg/L and 2-8 mg/L respectively. For ciprofloxacin against E.coli, E. cloacae and K. pneumoniae and for levofloxacin against E.coli, C. freundii and K. pneumoniae, MPC results were below susceptible breakpoints and within clinically achievable and sustainable drug concentrations for >24 hours of the dosing interval against. For garenoxacin, urine drug concentrations are expected to be in excess of MPC results for the entire length of the dosing interval for E.coli. Application of MPCs to fluoroquinolones and management of UTIs represents a situation where high levels of in vitro activity, based on low MICs, is reflected in correspondingly low MPC values for most of the organisms tested. Incorporation of MPC strategies into current fluoroquinolone dosing in UTI represents a realistic approach for preventing the further selection of resistant organisms associated with UTIs.