Risk of infections during interferon-based treatment in patients with chronic HCV infection and advanced hepatic fibrosis.

BACKGROUND & AIMS Pegylated interferon-based treatment is still the backbone of current hepatitis C therapy and is associated with bone marrow suppression and an increased risk of infections. The aim of this retrospective cohort study was to assess the risk of infections during interferon-based treatment among patients with chronic HCV infection and advanced hepatic fibrosis and its relation to treatment-induced neutropenia. METHODS This cohort study included all consecutive patients with chronic HCV infection and biopsy-proven bridging fibrosis or cirrhosis (Ishak 4-6) who started treatment between 1990 and 2003 in five large hepatology units in Europe and Canada. Neutrophil counts between 500/μL-749/μL and below 500/μL were considered as moderate and severe neutropenia, respectively. RESULTS This study included 723 interferon-based treatments, administered to 490 patients. In total, 113 infections were reported during 88 (12%) treatments, of which 24 (21%) were considered severe. Only one patient was found to have moderate neutropenia and three patients were found to have severe neutropenia at the visit before the infection. Three hundred and twelve (99.7%) visits with moderate neutropenia and 44 (93.6%) visits with severe neutropenia were not followed by an infection. Multivariable analysis showed that cirrhosis (OR 2.85, 95%CI 1.38-5.90, p=0.005) and severe neutropenia at the previous visit (OR 5.42, 95%CI 1.34-22.0, p=0.018) were associated with the occurrence of infection, while moderate neutropenia was not. Among a subgroup of patients treated with PegIFN, severe neutropenia was not significantly associated (OR 1.63, 95%CI 0.19-14.2, p=0.660). CONCLUSIONS In this large cohort of patients with bridging fibrosis and cirrhosis, infections during interferon-based therapy were generally mild. Severe interferon-induced neutropenia rarely occurred, but was associated with on-treatment infection. Moderate neutropenia was not associated with infection, suggesting that current dose reduction guidelines might be too strict.

Prophylactic antibiotics or G(M)-CSF for the prevention of infections and improvement of survival in cancer patients receiving myelotoxic chemotherapy.

BACKGROUND Febrile neutropenia (FN) and other infectious complications are some of the most serious treatment-related toxicities of chemotherapy for cancer, with a mortality rate of 2% to 21%. The two main types of prophylactic regimens are granulocyte (macrophage) colony-stimulating factors (G(M)-CSF) and antibiotics, frequently quinolones or cotrimoxazole. Current guidelines recommend the use of colony-stimulating factors when the risk of febrile neutropenia is above 20%, but they do not mention the use of antibiotics. However, both regimens have been shown to reduce the incidence of infections. Since no systematic review has compared the two regimens, a systematic review was undertaken. OBJECTIVES To compare the efficacy and safety of G(M)-CSF compared to antibiotics in cancer patients receiving myelotoxic chemotherapy. SEARCH METHODS We searched The Cochrane Library, MEDLINE, EMBASE, databases of ongoing trials, and conference proceedings of the American Society of Clinical Oncology and the American Society of Hematology (1980 to December 2015). We planned to include both full-text and abstract publications. Two review authors independently screened search results. SELECTION CRITERIA We included randomised controlled trials (RCTs) comparing prophylaxis with G(M)-CSF versus antibiotics for the prevention of infection in cancer patients of all ages receiving chemotherapy. All study arms had to receive identical chemotherapy regimes and other supportive care. We included full-text, abstracts, and unpublished data if sufficient information on study design, participant characteristics, interventions and outcomes was available. We excluded cross-over trials, quasi-randomised trials and post-hoc retrospective trials. DATA COLLECTION AND ANALYSIS Two review authors independently screened the results of the search strategies, extracted data, assessed risk of bias, and analysed data according to standard Cochrane methods. We did final interpretation together with an experienced clinician. MAIN RESULTS In this updated review, we included no new randomised controlled trials. We included two trials in the review, one with 40 breast cancer patients receiving high-dose chemotherapy and G-CSF compared to antibiotics, a second one evaluating 155 patients with small-cell lung cancer receiving GM-CSF or antibiotics.We judge the overall risk of bias as high in the G-CSF trial, as neither patients nor physicians were blinded and not all included patients were analysed as randomised (7 out of 40 patients). We considered the overall risk of bias in the GM-CSF to be moderate, because of the risk of performance bias (neither patients nor personnel were blinded), but low risk of selection and attrition bias.For the trial comparing G-CSF to antibiotics, all cause mortality was not reported. There was no evidence of a difference for infection-related mortality, with zero events in each arm. Microbiologically or clinically documented infections, severe infections, quality of life, and adverse events were not reported. There was no evidence of a difference in frequency of febrile neutropenia (risk ratio (RR) 1.22; 95% confidence interval (CI) 0.53 to 2.84). The quality of the evidence for the two reported outcomes, infection-related mortality and frequency of febrile neutropenia, was very low, due to the low number of patients evaluated (high imprecision) and the high risk of bias.There was no evidence of a difference in terms of median survival time in the trial comparing GM-CSF and antibiotics. Two-year survival times were 6% (0 to 12%) in both arms (high imprecision, low quality of evidence). There were four toxic deaths in the GM-CSF arm and three in the antibiotics arm (3.8%), without evidence of a difference (RR 1.32; 95% CI 0.30 to 5.69; P = 0.71; low quality of evidence). There were 28% grade III or IV infections in the GM-CSF arm and 18% in the antibiotics arm, without any evidence of a difference (RR 1.55; 95% CI 0.86 to 2.80; P = 0.15, low quality of evidence). There were 5 episodes out of 360 cycles of grade IV infections in the GM-CSF arm and 3 episodes out of 334 cycles in the cotrimoxazole arm (0.8%), with no evidence of a difference (RR 1.55; 95% CI 0.37 to 6.42; P = 0.55; low quality of evidence). There was no significant difference between the two arms for non-haematological toxicities like diarrhoea, stomatitis, infections, neurologic, respiratory, or cardiac adverse events. Grade III and IV thrombopenia occurred significantly more frequently in the GM-CSF arm (60.8%) compared to the antibiotics arm (28.9%); (RR 2.10; 95% CI 1.41 to 3.12; P = 0.0002; low quality of evidence). Neither infection-related mortality, incidence of febrile neutropenia, nor quality of life were reported in this trial. AUTHORS' CONCLUSIONS As we only found two small trials with 195 patients altogether, no conclusion for clinical practice is possible. More trials are necessary to assess the benefits and harms of G(M)-CSF compared to antibiotics for infection prevention in cancer patients receiving chemotherapy.

Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial

BACKGROUND Postoperative hemithoracic radiotherapy has been used to treat malignant pleural mesothelioma, but it has not been assessed in a randomised trial. We assessed high-dose hemithoracic radiotherapy after neoadjuvant chemotherapy and extrapleural pneumonectomy in patients with malignant pleural mesothelioma. METHODS We did this phase 2 trial in two parts at 14 hospitals in Switzerland, Belgium, and Germany. We enrolled patients with pathologically confirmed malignant pleural mesothelioma; resectable TNM stages T1-3 N0-2, M0; WHO performance status 0-1; age 18-70 years. In part 1, patients were given three cycles of neoadjuvant chemotherapy (cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 given every 3 weeks) and extrapleural pneumonectomy; the primary endpoint was complete macroscopic resection (R0-1). In part 2, participants with complete macroscopic resection were randomly assigned (1:1) to receive high-dose radiotherapy or not. The target volume for radiotherapy encompassed the entire hemithorax, the thoracotomy channel, and mediastinal nodal stations if affected by the disease or violated surgically. A boost was given to areas at high risk for locoregional relapse. The allocation was stratified by centre, histology (sarcomatoid vs epithelioid or mixed), mediastinal lymph node involvement (N0-1 vs N2), and T stage (T1-2 vs T3). The primary endpoint of part 1 was the proportion of patients achieving complete macroscopic resection (R0 and R1). The primary endpoint in part 2 was locoregional relapse-free survival, analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00334594. FINDINGS We enrolled patients between Dec 7, 2005, and Oct 17, 2012. Overall, we analysed 151 patients receiving neoadjuvant chemotherapy, of whom 113 (75%) had extrapleural pneumonectomy. Median follow-up was 54·2 months (IQR 32-66). 52 (34%) of 151 patients achieved an objective response. The most common grade 3 or 4 toxic effects were neutropenia (21 [14%] of 151 patients), anaemia (11 [7%]), and nausea or vomiting (eight [5%]). 113 patients had extrapleural pneumonectomy, with complete macroscopic resection achieved in 96 (64%) of 151 patients. We enrolled 54 patients in part 2; 27 in each group. The main reasons for exclusion were patient refusal (n=20) and ineligibility (n=10). 25 of 27 patients completed radiotherapy. Median total radiotherapy dose was 55·9 Gy (IQR 46·8-56·0). Median locoregional relapse-free survival from surgery, was 7·6 months (95% CI 4·5-10·7) in the no radiotherapy group and 9·4 months (6·5-11·9) in the radiotherapy group. The most common grade 3 or higher toxic effects related to radiotherapy were nausea or vomiting (three [11%] of 27 patients), oesophagitis (two [7%]), and pneumonitis (two [7%]). One patient died of pneumonitis. We recorded no toxic effects data for the control group. INTERPRETATION Our findings do not support the routine use of hemithoracic radiotherapy for malignant pleural mesothelioma after neoadjuvant chemotherapy and extrapleural pneumonectomy. FUNDING Swiss Group for Clinical Cancer Research, Swiss State Secretariat for Education, Research and Innovation, Eli Lilly.

Regulation of Neutrophil Serine Proteases by Intracellular Serpins

Neutrophil granules contain serine proteases that are central components of the antimicrobial weapons of the innate immune system. Neutrophil proteases also contribute to the amplification and resolution of inflammatory responses through defined proteolytic cleavage of mediators, cell surface receptors, and extracellular matrix proteins. In the blood and at mucosal surfaces, neutrophil serine proteases are regulated by serpins found in plasma and by non-serpin secreted inhibitors. Distinct mechanisms leading to neutrophil cell death have been described for the granule serine proteases, neutrophil elastase, cathepsin G, and proteinase-3. Granule leakage in neutrophils triggers death pathways mediated by cathepsin G and proteinase-3, and both proteases are tightly regulated by their inhibitor SERPINB1 in a cell intrinsic manner. Although stored in the same types of granules, neutrophil elastase does not significantly contribute to cell death following intracellular release from granules into the cytoplasm. However, heterozygous mutations in ELANE, the gene encoding elastase, are the cause of severe congenital neutropenia, a life-threatening condition characterized by the death of neutrophils at an early precursor stage in the bone marrow. This chapter focuses on recent work exploring the biology of clade B intracellular serpins that inhibit neutrophil serine proteases and their functions in neutrophil homeostasis and serine protease control at sites of inflammation.

Telomerase Inhibitor Imetelstat in Patients with Essential Thrombocythemia.

BACKGROUND Imetelstat, a 13-mer oligonucleotide that is covalently modified with lipid extensions, competitively inhibits telomerase enzymatic activity. It has been shown to inhibit megakaryocytic proliferation in vitro in cells obtained from patients with essential thrombocythemia. In this phase 2 study, we investigated whether imetelstat could elicit hematologic and molecular responses in patients with essential thrombocythemia who had not had a response to or who had had unacceptable side effects from prior therapies. METHODS A total of 18 patients in two sequential cohorts received an initial dose of 7.5 or 9.4 mg of imetelstat per kilogram of body weight intravenously once a week until attainment of a platelet count of approximately 250,000 to 300,000 per cubic millimeter. The primary end point was the best hematologic response. RESULTS Imetelstat induced hematologic responses in all 18 patients, and 16 patients (89%) had a complete hematologic response. At the time of the primary analysis, 10 patients were still receiving treatment, with a median follow-up of 17 months (range, 7 to 32 [ongoing]). Molecular responses were seen in 7 of 8 patients who were positive for the JAK2 V617F mutation (88%; 95% confidence interval, 47 to 100). CALR and MPL mutant allele burdens were also reduced by 15 to 66%. The most common adverse events during treatment were mild to moderate in severity; neutropenia of grade 3 or higher occurred in 4 of the 18 patients (22%) and anemia, headache, and syncope of grade 3 or higher each occurred in 2 patients (11%). All the patients had at least one abnormal liver-function value; all persistent elevations were grade 1 or 2 in severity. CONCLUSIONS Rapid and durable hematologic and molecular responses were observed in patients with essential thrombocythemia who received imetelstat. (Funded by Geron; ClinicalTrials.gov number, NCT01243073.).

Bloodstream infection in paediatric cancer centres--leukaemia and relapsed malignancies are independent risk factors.

UNLABELLED In a prospective multicentre study of bloodstream infection (BSI) from November 01, 2007 to July 31, 2010, seven paediatric cancer centres (PCC) from Germany and one from Switzerland included 770 paediatric cancer patients (58% males; median age 8.3 years, interquartile range (IQR) 3.8-14.8 years) comprising 153,193 individual days of surveillance (in- and outpatient days during intensive treatment). Broviac catheters were used in 63% of all patients and Ports in 20%. One hundred forty-two patients (18%; 95% CI 16 to 21%) experienced at least one BSI (179 BSIs in total; bacteraemia 70%, bacterial sepsis 27%, candidaemia 2%). In 57%, the BSI occurred in inpatients, in 79% after conventional chemotherapy. Only 56 % of the patients showed neutropenia at BSI onset. Eventually, patients with acute lymphoblastic leukaemia (ALL) or acute myeloblastic leukaemia (AML), relapsed malignancy and patients with a Broviac faced an increased risk of BSI in the multivariate analysis. Relapsed malignancy (16%) was an independent risk factor for all BSI and for Gram-positive BSI. CONCLUSION This study confirms relapsed malignancy as an independent risk factor for BSIs in paediatric cancer patients. On a unit level, data on BSIs in this high-risk population derived from prospective surveillance are not only mandatory to decide on empiric antimicrobial treatment but also beneficial in planning and evaluating preventive bundles. WHAT IS KNOWN • Paediatric cancer patients face an increased risk of nosocomial bloodstream infections (BSIs). • In most cases, these BSIs are associated with the use of a long-term central venous catheter (Broviac, Port), severe and prolonged immunosuppression (e.g. neutropenia) and other chemotherapy-induced alterations of host defence mechanisms (e.g. mucositis). What is New: • This study is the first multicentre study confirming relapsed malignancy as an independent risk factor for BSIs in paediatric cancer patients. • It describes the epidemiology of nosocomial BSI in paediatric cancer patients mainly outside the stem cell transplantation setting during conventional intensive therapy and argues for prospective surveillance programmes to target and evaluate preventive bundle interventions.

Long-term central venous catheter-related candidemia: A new approach towards diagnosis and management

A case-series analysis of approximately 811 cancer patients who developed Candidemia between 1989 and 1998 and seen at M. D. Anderson Cancer Center, was studied to assess the impact and timing of central venous catheter (CVC) removal on the outcome of fungal bloodstream infections in cancer patients with primary catheter-related Candidemia as well as secondary infections. ^ This study explored the diagnosis and the management of vascular catheter-associated fungemia in patients with cancer. The microbiologic and clinical factors were determined to predict catheter-related Candidemia. Those factors included, in addition to basic demographics, the underlying malignancy, chemotherapy, neutropenia, and other salient data. Statistical analyses included univariate and multivariate logistic regression to determine the outcome of Candidemia in relation to the timing of catheter removal, type of species, and to identify predictors of catheter-related infections. ^ The conclusions of the study aim at enhancing our mastery of issues involving CVC removal and potentially will have an impact on the management of nosocomial bloodstream infections related to timing of CVC removal and the optimal duration of treatment of catheter-related Candidemia. ^

Clinical and economic outcomes of serious postoperative infections following resection of common respiratory and gastrointestinal solid tumors

Unlike infections occurring during periods of chemotherapy-induced neutropenia, postoperative infections in patients with solid malignancy remain largely understudied. The purpose of this population-based study was to evaluate the clinical and economic burden, as well as the relationship of hospital surgical volume and outcomes associated with serious postoperative infection (SPI) – i.e., bacteremia/sepsis, pneumonia, and wound infection – following resection of common solid tumors.^ From the Texas Discharge Data Research File, we identified all Texas residents who underwent resection of cancer of the lung, esophagus, stomach, pancreas, colon, or rectum between 2002 and 2006. From their billing records, we identified ICD-9 codes indicating SPI and also subsequent SPI-related readmissions occurring within 30 days of surgery. Random-effects logistic regression was used to calculate the impact of SPI on mortality, as well as the association between surgical volume and SPI, adjusting for case-mix, hospital characteristics, and clustering of multiple surgical admissions within the same patient and patients within the same hospital. Excess bed days and costs were calculated by subtracting values for patients without infections from those with infections computed using multilevel mixed-effects generalized linear model by fitting a gamma distribution to the data using log link.^ Serious postoperative infection occurred following 9.4% of the 37,582 eligible tumor resections and was independently associated with an 11-fold increase in the odds of in-hospital mortality (95% Confidence Interval [95% CI], 6.7-18.5, P < 0.001). Patients with SPI required 6.3 additional hospital days (95% CI, 6.1 - 6.5) at an incremental cost of $16,396 (95% CI, $15,927–$16,875). There was a significant trend toward lower overall rates of SPI with higher surgical volume (P=0.037). ^ Due to the substantial morbidity, mortality, and excess costs associated with SPI following solid tumor resections and given that, under current reimbursement practices, most of this heavy burden is borne by acute care providers, it is imperative for hospitals to identify more effective prophylactic measures, so that these potentially preventable infections and their associated expenditures can be averted. Additional volume-outcomes research is also needed to identify infection prevention processes that can be transferred from higher- to lower-volume providers.^

Impacto clínico de la pancitopenia en pacientes hospitalizados

Objetivo: Determinar etiología, manifestaciones clínicas, morbimortalidad y recursos diagnósticos y terapéuticos utilizados en pacientes internados con pancitopenia. Material y métodos: Estudio protocolizado, descriptivo y observacional de 14 meses. Criterios de inclusión: pacientes internados con pancitopenia definida por hemoglobina (Hb) <12 g/dL; plaquetas <150.000/ mL y leucocitos <3.800/mL. Los datos fueron analizados con Epi Info 6.04. Resultados: Se diagnosticaron 54 casos de pancitopenia. Prevalencia: 22/1.000 egresos. Edad media: 48,72 años (DS±20,64); 29,63% fueron > 65 años y 53,70% hombres. Permanencia media: 17,13 días (DS±13,22) vs 7,25 días (DS±5,4) del Servicio (p<0.0001). Charlson medio: 7,16 (DS±2,96) y APACHEII medio: 12 (DS±5,04). El 83,33% (45/54, IC95%70,71-92,08) de las pancitopenias fueron secundarias a compromiso medular, 22 casos (40,74%; IC95%27,57-54,97) postquimioterapia (15 en neoplasias oncohematológicas y 7 en sólidas), 11 (20,37%; IC95%10,63-33,53) por mieloptisis y 4 casos (7,41%; IC95%2,06-17,89) por megaloblastosis. El 16,66% (9/54; IC95%7,92- 29,29) fue secundaria a hiperesplenismo y el 16,66% asociadas a infecciones (3 casos por SIDA). Se realizó estudio de médula ósea en 19 casos (35,18%). El 96,29% (IC95%87,25-99,55) presentó comórbidas. El síndrome de respuesta inflamatoria sistémica (85,19%), síndrome anémico (77,8%) y púrpura (50%) fueron las manifestaciones clínicas más frecuentes. Presentó sepsis el 81,48% (IC95%68,57-90,75) y el 29,63% (IC95%17,98-46,31) hemorragias. El 81,48% tuvo infecciones; el 50% de origen nosocomial y el 65,91% clínicamente documentadas. El 34,09% (IC95%20,49-49,92) tuvo aislamiento microbiológico, con hemocultivos positivos en 29,55%. El 51,85% (IC95%37,84-65,66) desarrolló neutropenia febril (75% postquimioterapia). El 64,81% recibió hemoderivados y factores estimulantes de colonias (G-CSF) el 46,34% (IC95%32,62-60,39). La mortalidad fue mayor a la media global del Servicio (16,66 vs 8,65%)(p=0.07).- Conclusiones: Las pancitopenias en pacientes hospitalizados se caracterizaron por ser secundarias a compromiso medular, hiperesplenismo e infecciones, asociarse a permanencia prolongada, altos índices de comorbilidad, complicaciones infecciosas, y mayor mortalidad que la media global del Servicio.

Bacteriemias por Pseudomonas Aeruginosa : análisis comparativo

Objetivos: Analizar características clínicas y morbimortalidad de las bacteriemias por Pseudomonas aeruginosa comparadas con Klebsiella spp en pacientes hospitalizados en un Servicio de Clínica Médica de adultos. Material y métodos: Estudio protocolizado, descriptivo, observacional de 15 años de duración. Criterio de inclusión: 2 o más hemocultivos positivos para el germen. Los datos fueron procesados en EPI Info 6.04. El criterio de significación se estableció para un error alfa menor del 5%. Resultados: Se detectaron en el período de estudio 282 bacteriemias por bacilos gram negativos de las cuales 19 fueron por Pseudomonas aeruginosa (6.7%) y 76 por Klebsiella (26.9%). No se encontraron diferencias significativas entre ambas en cuanto a edad media [53.9 años (DS±17.9 ) vs 58.7 años (DS±15.2)], sexo (femenino: 26.3 vs 38.2%) ni complicaciones (77.8 vs 77.3%). La presencia de neutropenia (52.6 vs 9.2%)(p<0.0001), comorbilidad mayor (94.7 vs 68.4%)(p<0.05), neoplasias (47.4 vs 22.4%)(p<0.05), uso de corticoides (21.1 vs 3.9%)(p<0.05), e inmunosupresores (31.6 vs 7.9%)(p<0.01), trombocitopenia (77.7 vs 49.3%) (p<0.05) y leucopenia (52.6 vs 21.3%)(p<0.01) fueron más frecuentes en las bacteriemias por P. aeruginosa. Resultó más frecuente la hipoalbuminemia (88.5 vs 37.5%)(p<0.001) en las bacteriemias por Klebsiella spp. No se encontraron diferencias significativas en cuanto a puerta de entrada conocida (78.9 vs 77.6%), anemia (84.2 vs 71.2%), complicaciones infecciosas (84.2 vs 73.7%), descompensación de comórbidas (55.6 vs 51.3%) y encefalopatía (36.8 vs 57.9%)(pNS). La mortalidad precoz (dentro de los 7 días) fue significativamente mayor en el grupo de las bacteriemias por P.aeruginosa (57.1 vs 12%) (p<0.01), sin diferencias en la mortalidad global (36.8 vs 32.9%) (pNS). Conclusiones: Las bacteriemias por P.aeruginosa comparadas con las producidas por Klebsiella spp. se asociaron significativamente a mayor frecuencia de neoplasias, leucopenia, trombocitopenia y neutropenia, comorbilidad mayor, uso de corticoides e inmunosupresores, y a mortalidad precoz.

The crucial role of polymorphonuclear leukocytes in resistance to Salmonella dublin infections in genetically susceptible and resistant mice

Macrophages are considered to be the mediators of resistance to extra-intestinal Salmonella infections. Nevertheless, the initial cellular response to Salmonella infections consists primarily of polymorphonuclear leukocytes (PMN). To determine whether PMN serve an important function for the infected host, we made mice neutropenic with the rat mAb to RB6–8C5 and infected them i.v. with ≈103 Salmonella dublin or an isogenic derivative that lacks the virulence plasmid (LD842). We infected BALB/c mice, which have a point mutation in the macrophage-expressed gene Nramp1 that makes them susceptible to Salmonella, and BALB/c.D2 congenic mice, which have the wild-type Nramp1 gene that makes them resistant to Salmonella. Both mouse strains were resistant to LD842, and neutropenia made only the BALB/c strain susceptible to this infection. Neutropenic congenic mice, however, were susceptible only to wild-type S. dublin (plasmid+). These results show a complex interplay between plasmid-virulence genes in Salmonella, host macrophages, and PMN. Mice with normal macrophages need PMN to defend against nontyphoid Salmonella that carry a virulence plasmid but not against Salmonella without virulence plasmids. Mice with a mutant Nramp1 gene need PMN to defend against all Salmonella, even those that lack virulence plasmids. These results, plus the evidence that PMN kill Salmonella efficiently in vitro, suggest that Salmonella have adapted to grow inside macrophages where they are relatively sheltered from PMN. The adaptations that allow Salmonella to survive in macrophages do not protect them from PMN.

Continuous infusion of ticarcillin-clavulanate for home treatment of serious infections: clinical efficacy, safety, pharmacokinetics and pharmacodynamics

Continuous infusion (CI) ticarcillin-clavulanate is a potential therapeutic improvement over conventional intermittent dosing because the major pharmacodynamic (PD) predictor of efficacy of beta-lactams is the time that free drug levels exceed the MIC. This study incorporated a 6-year retrospective arm evaluating efficacy and safety of CI ticarcillin-clavulanate in the home treatment of serious infections and a prospective arm additionally evaluating pharmacokinetics (PK) and PD. In the prospective arm, steady-state serum ticarcillin and clavulanate levels and MIC testing of significant pathogens were performed. One hundred and twelve patients (median age, 56 years) were treated with a CI dose of 9.3-12.4 g/day and mean CI duration of 18.0 days. Infections treated included osteomyelitis (50 patients), septic arthritis (6), cellulitis (17), pulmonary infections (12), febrile neutropenia (7), vascular infections (7), intra-abdominal infections (2), and Gram-negative endocarditis (2); 91/112 (81%) of patients were cured, 14 (13%) had partial response and 7 (6%) failed therapy. Nine patients had PICC line complications and five patients had drug adverse events. Eighteen patients had prospective PK/PD assessment although only four patients had sufficient data for a full PK/PD evaluation (both serum steady-state drug levels and ticarcillin and clavulanate MICs from a bacteriological isolate), as this was difficult to obtain in home-based patients, particularly as serum clavulanate levels were found to deteriorate rapidly on storage. Three of four patients with matched PK/PD assessment had free drug levels exceeding the MIC of the pathogen. Home Cl of ticarcillin-clavulanate is a safe, effective, convenient and practical therapy and is a therapeutic advance over traditional intermittent dosing when used in the home setting. (c) 2005 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Multi-centre Phase II trial of the polyamine synthesis inhibitor SAM486A (CGP48664) in patients with metastatic melanoma

Purpose: To determine the activity and tolerability of SAM496A, an inhibitor of S-adenosylmethionine decarboxylase (SAMDC), in patients with metastatic melanoma who had not received prior chemotherapy. Selected patients were offered participation in two sub-studies examining early changes in tumor metabolism with FDG-PET and changes in tumor polyamine content. Patients and methods: Fifteen patients with measurable metastatic melanoma, normal cardiac function, and no known CNS metastases were eligible and received SAM486A by 1-hour IV infusion daily for 5 days every 3 weeks. Response was assessed by SWOG criteria. Results: No patient had a confirmed partial response. Fatigue/lethargy, myalgia and neutropenia were the main toxicities but no febrile neutropenia or grade 4 non-hematological toxicity occurred. Five patients had PET scans pre-treatment and on days 8-12 of cycle 1. No patient had reduction of tumor metabolism. Serial biopsy in one patient showed alterations in polyamines consistent with SAMDC inhibition. Conclusions: Using the present dose and schedule of administration, SAM486A does not have significant therapeutic potential in patients with metastatic melanoma.