Clinical predictors and microbiology of ventilator-associated pneumonia in the intensive care unit: a retrospective analysis in six Italian hospitals.

The purpose of this study was to assess the main clinical predictors and microbiological features of ventilator-associated pneumonia (VAP) in the Intensive Care Unit (ICU) environment. This work is a retrospective analysis over one year from September 2010 to September 2011. Patients' risk factors, causes of admission, comorbidities and respiratory specimens collected in six Italian ICUs were reviewed. Incidence and case fatality rate of VAP were evaluated. After stratification for VAP development, univariate and multivariate analyses were performed to assess the impact of patients' conditions on the onset of this infection. A total of 1,647 ICU patients (pts) were considered. Overall, 115 patients (6.9 %) experienced at least one episode of VAP. The incidence rate for VAP was 5.82/1,000 pts-days, with a case fatality rate of 44.3 %. Multivariate analysis showed that admission for neurological disorders (aIRR 4.12, CI 1.24-13.68, p = 0.02) and emergency referral to ICU from other hospitals (aIRR 2.11, CI 1.03-4.31, p = 0.04) were associated with higher risk of VAP, whereas a tendency to a higher risk of infection was detected for admission due to respiratory disease, cardiac disease, trauma and for having obesity or renal failure. A total of 372 microbiological isolates from respiratory specimens were collected in VAP patients. The most common species were Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa, showing high resistance rates to carbapenems. Neurological disorders and emergency referral at the admission into the ICU are significantly associated with the onset of VAP. A high incidence of multi-drug resistant Gram- species was detected in the respiratory specimens.

Successful switch to tenofovir after suboptimal response to entecavir in an immunocompromised patient with chronic hepatitis B and without genotypic hepatitis B virus resistance.

We report a case of an immunocompromised patient affected by chronic hepatitis B virus (HBV) with high basal HBV viremia (>8 log(10) IU/ml) who failed an entecavir regimen, despite the absence of primary or secondary drug resistance mutations. The patient achieved sustained virological success (serum HBV DNA <12 IU/ml) when tenofovir was added to the treatment. This case highlights the difficulty in choosing an optimal therapy in such specific conditions and supports the concept of tailoring therapy (including combination regimens) on the basis of the particular conditions of each individual patient.

Search for evidence of feline leukemia virus infection in humans with leukemias, lymphomas, or soft tissue sarcomas.

Two-hundred and thirty-nine patients, including 66 with soft tissue sarcomas and 173 with hematologic cancers, were investigated for evidence of infection with feline leukemia virus (FeLV). Included in this group were 2 patients with acute lymphocytic leukemia who had lived in the same household with leukemic cats. None of the patients demonstrated measurable levels of neutralizing antibody to FeLV or had detectable FeLV antigens in peripheral blood normal leukocytes or leukemic cells. In a smaller number of patients, there was no evidence of antibody to FOCMA or of FOCMA on tumor cells in the bone marrow.

Carbamazepine-induced syndrome of inappropriate antidiuretic hormone secretion. Reversal by concomitant phenytoin therapy.

The syndrome of inappropriate antidiuretic hormone secretion, with marked hyponatremia, was observed in an elderly women who was taking carbamazepine for trigeminal neuralgia. Subsequent studies revealed this effect to be directly related to the administration of the drug. Substantial water retention has not been previously described in patients taking normal volumes of fluid and taking standard doses of carbamazepine. Additionally, it was determined that the antidiuretic effect of carbamazepine could be blocked by phenytoin. The actions of both drugs on renal water excretion, and the interactions of the drugs were observed to be dose-related.

Two-year surveillance on fluconazole susceptibility of Candida spp isolates in a general and university hospital in Rome.

Fluconazole susceptibility was tested in 385 clinical yeast isolates (285 Candida albicans, 38 C. glabrata, 31 C. tropicalis, 31 other Candida subsp.) using the agar disk diffusion test. Yeasts were collected from specimens obtained from outpatients (69) and inpatients (intensive care unit: 79 isolates, major burn unit: 31 isolates, hematology ward: 45 isolates, gynecology ward: 67 isolates, other wards: 94 isolates). Three hundred and fifty-six (92%) yeast isolates showed to be susceptible, 18 (5%) were susceptible dose-dependent, and 10 (3%) were resistant to fluconazole. Of the resistant group, 3 isolates were C.albicans, while seven were Candida non-albicans (2 C. rugosa, 2 C. humicola, 1 C. tropicalis, 1 C. ciferrii, 1 C. glabrata). The disk-diffusion method was easy to perform and there were no difficulties in the interpretation of inhibition zone diameters. Fluconazole maintained a good activity against Candida spp despite its extensive use for the prophylaxis and treatment of fungal infections.

The influence of antineoplastic chemotherapy on antipyrine metabolism in man.

When either Doxorubicin or Mitomycin-C was administered to patients, antipyrine clearance was respectively unaltered or increased. Antipyrine was administered to patients two days prior to and one day after their first course of the chemotherapeutic drug. Antipyrine clearance increased an average of 11.2% in the 5 patients that received Doxorubicin (not significant) and 15.2% in the six patients that received Mitomycin-C (P = 0.033, students t-test). The altered clearance is likely due to a rapid induction of the mixed function oxidase system by the chemotherapy as other parameters that could influence clearance were stable throughout the study (volume of distribution, weight, creatinine clearance and liver function tests). It is unlikely that the prechemotherapy antipyrine dose accounted for this change. The administration of these two antitumor antibiotics in humans may modestly increase the mixed function oxidase activity that is responsible for the metabolism of antipyrine. These findings are in direct contrast to markedly decreased mixed-function oxidase activity observed in the rodent pretreated with the same chemotherapy.

Establishment of a near-tetraploid B-cell lymphoma line with duplication of the 8;14 translocation.

The neoplastic cells of a patient with diffuse histiocytic lymphoma were grown in three systems: Soft agar, liquid culture, and by heterotransplantation into the nude mouse. In each case, the growing cells were shown to bear the same immunoglobulin heavy and light chain type as the original neoplastic cells (IgM-lambda). In both the liquid culture and nude mouse heterotransplant tumors, karyotypic analysis revealed the presence of pseudodiploid and near-tetraploid metaphases bearing one and two copies of an 8;14 translocation, respectively. From the liquid culture separate clones of pseudodiploid and near-tetraploid cells were isolated in soft agar, and separate cell lines SK-DHL2A and SK-DHL2B were established. Studies comparing the proliferative characteristics of the two lines showed no difference in cell population doubling time or clonigenicity in soft agar. Hence, the presence of two copies of the translocated material did not confer a proliferative advantage on cells containing it. Theses lines may be valuable in future studies of cell proliferation and oncogenesis in the human immune system.

Phase-II trial of 4-demethoxydaunorubicin (DMDR) for advanced hypernephroma.

A phase-II trial of 4-demethoxydaunorubicin (4-DMDR) was performed in 21 patients with advanced renal cell carcinoma. The drug had demonstrated a broader spectrum of activity with less cardiotoxicity in preclinical evaluation than the parent compound daunorubicin. The starting dose was 12.5 mg/m2, with escalations to 15 and 17.5 mg/m2 in the absence of toxicity. Myelosuppression was the primary toxicity and cardiac toxicity was not seen in four patients who received four or more doses of DMDR. No responses were seen in 19 adequately treated patients, including 14 who had received no prior therapy.

Phase II trial of 1,2-diaminocyclohexane-(4-carboxyphthalato) platinum(II) (DACCP) in colorectal carcinoma.

In an effort to investigate the antitumor activity of new cisplatin analogues, 1,2-diaminocyclohexane-(4-carboxyphthalato) platinum (II) (DACCP) was administered in a phase II disease-oriented trial to patients with advanced colorectal carcinoma. Six patients had not received prior chemotherapy, while four had received one drug, and two had received more than one drug. Primary sites of disease were in the liver only (8 patients), liver and lung (2 patients), and intra-abdominal (2 patients). Liver radionuclide scans and CT scans were the main parameter for evaluation. The drug was administered intravenously every 4 weeks at a dose of 640 mg/m2. There were no responses in 12 adequately treated patients. One patient had stable disease for 5 months. Nausea and vomiting was milder than that seen with cisplatin. A peripheral neuropathy was seen in four patients. Fever occurred in two patients and urticaria in one patient. No patient had significant drug-induced anemia, and renal dysfunction was not observed. DACCP at this dose and schedule demonstrated no efficacy as a single agent in the treatment of colorectal carcinoma.

Phase II trial of methyl-CCNU, vincristine, 5-fluorouracil, and streptozotocin (MOF-Strep) in patients with disseminated pancreatic carcinoma.

A phase II trial of methyl-CCNU, 5-fluorouracil (5-Fu), vincristine, and streptozotocin (MOF-Strep) was conducted on 20 patients with pancreatic carcinoma. There were two partial remissions (10%) lasting 3 and 10 months. In addition, there were two minor responses. The predominant toxicity was gastrointestinal, although hematologic and renal toxicity were also seen. Since the response rate to MOF-Strep does not appear to exceed that to 5-Fu alone, the usefulness of this combination in patients with pancreatic carcinoma is limited.

Phase II trial of methylglyoxal-bis-guanylhydrazone (methyl-GAG) in patients with soft-tissue sarcomas.

A phase II study of Methylglyoxal-bis-guanylhydrazone (Methyl-GAG) was conducted on 20 previously treated patients with soft-tissue sarcomas. No major responses were seen among 18 adequately treated patients. Toxicity including severe fatigue, muscle pains, and pharyngitis was noted in most patients. Methyl-GAG does not have significant antitumor activity in previously treated patients with soft-tissue sarcomas.

Tumor localization of the metabolically trapped radiolabeled substrates 2-deoxy-D-glucose and aminocyclopentanecarboxylic acid in human melanoma heterotransplants.

Analysis of the accumulation of metabolically trapped radiolabeled substrates in normal and malignant tissues may be useful for studying biochemical processes in vivo with positron emission tomography (PET). If labeled with the short-lived, positron-emitting radionuclide carbon-11 (T1/2 = 20.4 min), the glucose analog, 2-deoxy-D-glucose (2-DG), and the synthetic amino acid, aminocyclopentanecarboxylic acid (ACPC), may be useful for studying glucose utilization and amino acid transport in vivo. This study evaluated the biodistribution of the C-14 labeled analogues of these compounds in nude mice bearing human malignant melanoma heterotransplants. The data suggest that both 2-DG and ACPC accumulate in tumor tissue within 45 min.

Etoposide (VP-16) in the treatment of advanced adenocarcinoma of the pancreas.

Twenty-six patients with advanced adenocarcinoma of the pancreas were treated with etoposide (VP-16), 100-180 mg/m2 i.v., days 1, 2, and 3, monthly. Twenty-five had bidimensionally measurable disease and one had evaluable disease only. This regimen and dosage schedule were well tolerated, with minimal toxicity including myelosuppression; a median WBC count nadir of 3,600 cells/mm3 (range 200-2,400); and a median platelet nadir of 215,000 cells/mm3 (range 15,000-405,000). However, no patients responded and only two had stable disease for 3.5 and 4 months, respectively. At this dosage and schedule, there is no role for VP-16 in the treatment of advanced pancreatic adenocarcinoma.

Evaluation of new anticancer agents against human pancreatic carcinomas in nude mice.

Heterotransplantation of human cancers in nude mice has provided an in vivo model for studying the biologic characteristics of human tumors, particularly their response to chemotherapy. In an effort to identify cytotoxic agents effective against pancreatic carcinoma, this model was used to evaluate the efficacy of three new anticancer agents--menogarol, 4'-epirubicin, and taxol--against two human transplanted pancreatic tumors. Relative area (tumor length X width) differed significantly between menogarol-treated and control groups (p = 0.034). A marked response was also observed in the tumors to 4'-epirubicin (p = 0.01). Taxol was ineffective in controlling tumor growth; by the fourth week, the size of treated tumors was similar to that of the control group (p = 0.55). No toxicity was observed in either the menogarol- or taxol-treated animals. Animals bearing the P2 tumor, and treated with 4' epirubicin displayed severe toxicity by day 18 with death by day 21 in most animals. For the second tumor, Capan-1, relative area differed significantly between the menogarol-treated and the control group (p = 0.003). In animals given 4'-epirubicin, a smaller difference was observed when comparing the relative areas (p = 0.09). Animals treated with taxol again showed no difference in the tumors when compared with controls (p = 1.0). The use of the nude mouse system has evolved so that tumor-oriented trials are now feasible with the hope of clinical applicability. This study illustrates that at least two agents--menogarol and 4'-epirubicin--may have some antitumor activity against pancreatic carcinoma in this system.

Phase II evaluation of m-AMSA (4'-(9-acridinylamino)-methanesulfon-m-anisidide) in patients with adenocarcinoma of the pancreas.

m-AMSA (4'-(9-acridinylamino)-methanesulfon-m-anisidide, a substituted acridine derivative, was administered to 27 patients with adenocarcinoma of the pancreas. The dose ranged from 90-210 mg/m2/course. The toxic effects were primarily hematologic. Twenty-four of the patients were evaluable for response. These patients received a median of 2 doses (range 1-7). The median time from diagnosis to therapy was 2 months (range 0-16). Two patients achieved an MR lasting 4 and 2 months, respectively. Two patients had stabilization for 6 and 3 months. The median survival for all patients was 3 months. Survival distribution for patients with prior chemotherapy versus no previous therapy was not significantly different (p = 0.5). This study suggests that m-AMSA has little value as a single agent in the treatment of adenocarcinoma of the pancreas.

MIFA III (mitomycin-C, 5-fluorouracil, and adriamycin) chemotherapy for advanced adenocarcinoma of the pancreas.

Twenty-nine patients with advanced adenocarcinoma of the pancreas were treated with a combination of mitomycin-C, 5-fluorouracil, and adriamycin (MIFA III). Four of these patients achieved a partial response, and two achieved a minor response. An additional seven patients had evidence of disease stabilization. The median survival period from initiation of therapy for responders was 13.5 months as compared to 7.6 months for those with stable disease and 3.2 months for nonresponders (p = 0.001). Myelosuppression was the primary toxicity. Prolongation of survival was demonstrated in responding patients who had failed prior chemotherapy. The MIFA III regimen is active, well tolerated, and warrants further investigation in previously untreated patients.

Chemotherapy of metastatic sweat gland carcinoma. A retrospective review.

Sweat gland carcinoma (SGC) is a rare malignancy of the skin. though many patients with SGC die of disseminated metastases, little is known regarding the value of systemic chemotherapy for this disease. We reviewed the records of 20 patients with metastatic SGC who were treated with chemotherapy at Memorial Hospital between 1968 and 1983. A large variety of drugs were given. Although only a few patients were treated with any given regimen, metastatic SGC appears to be poorly responsive to a wide variety of chemotherapeutic regimens. Five major responses were observed in 30 chemotherapy trials performed in 17 patients with measurable/evaluable disease. No patient responded to single agent therapy alone. In this small group of patients, SGC appears to be a relatively chemotherapy resistant tumor. Larger, group-wide or inter-group trials are needed to prospectively evaluate the use of chemotherapy in this disease. Doxorubicin and cyclophosphamide, the two drugs used most commonly in those combinations where responses were seen, appear to be reasonable choices for initial treatment of patients with metastatic disease. Our review does not provide data to support the empiric use of chemotherapy in an adjuvant setting.

Phase II evaluation of 4'-(9-acridinylamino)-methanesulfon-m-anisidide (m-AMSA) in patients with gastric adenocarcinoma.

A phase II study of m-AMSA in patients with gastric adenocarcinoma was conducted. Twenty-three patients received m-AMSA, 90-120 mg/m2, every 3 weeks. There were no major responses among 20 evaluable patients, although one patient experienced a minor response. Depression of the white blood count was the most prominent toxicity. m-AMSA has little activity in patients with gastric adenocarcinoma.

Scanning with L-(13 N) glutamate: Assessment of the response to chemotherapy of a patient with embryonal rhabdomyosarcoma.

The use of (13) N-labeled L-glutamate as an imaging agent in a patient with embryonal rhabdomyosarcoma is described. Localization of (13)N in a large, poorly defined tumor of the left pectoral region was seen, and clinically occult right axilliary metastases were also detected. A marked reduction in uptake in these areas occurred after chemotherapy, paralleling the clinical disappearance of tumor. These changes were verified on gallium scan. (13)N-labeled glutamate may be useful as an imaging agent, especially in patients with soft-tissue sarcomas.