Rosario López

Effect of discontinuing prophylaxis with norfloxacin in patients with hematologic malignancies and severe neutropenia a matched case-control study of the effect on infectious morbidity

The use of fluorinated quinolones for prophylaxis of infections in neutropenic cancer patients has led to a reduction of infections with gram-negative enteric bacilli, but there is concern about the emergence of antibiotic-resistant enterobacterial infections and a rise of gram-positive bacteremias. Due to these concerns, in mid-1995 the use of prophylactic norfloxacin was discontinued in our unit. In order to evaluate the impact of this measure on the infectious morbidity in our unit, 91 severe neutropenic episodes in 58 patients with hematologic malignancies who did not receive norfloxacin prophylaxis (NO group) were closely matched to 91 episodes in 60 patients who received norfloxacin prophylaxis (NORFLO group). There were no differences in the incidence of febrile neutropenia, fever of unknown origin or bacteremia during the first febrile episode. There was a trend for a higher rate of coagulase-negative staphylococcal bacteremia in the NORFLO group (5 vs. 11 cases in the NO and NORFLO groups, respectively, p = NS). Enterobacterial bloodstream infections were more frequent in the NO group (13 vs. 2 cases, respectively, p = 0.01), especially Escherichia coli (9 vs. 1 case, respectively, p = 0.01). Twelve of 13 enterobacterial isolates in the NO group were sensitive to the fluoroquinolones vs. 0/2 in the NORFLO group (p = 0.07). We conclude that the abrupt discontinuation of norfloxacin prophylaxis in our ward led to a rapid increase in the rate of fluoroquinolone-susceptible enterobacterial infections, with a scarce impact on infectious morbidity. This suggests that the selection of resistant flora in an inpatient ward by prophylactic antimicrobials may be reversible following the discontinuation of the prophylactic agent(s).

Exuberant granulation tissue associated with chronic graft-versus-host disease after transplantation of peripheral blood progenitor cells

Angiomatous lesions appearing in chronic graft versus host disease (cGVHD) has been reported previously. We report a case of a patient in whom cutaneous exuberant granulation tissue developed in the course of a cGVHD after allo-peripheral blood progenitor cells transplantation.

Infection by Listeria monocytogenes in the early period post‐bone marrow transplantation

To the Editor: Listeria monocytogenes has been reported to cause bacteremia and meningitis in immunosuppressed patients (1-3), although it has only rarely been described as a long-term complication in bone marrow transplant (BMT) patients (4). The occurrence of this infection in this patient population is not surprising since the microorganism is a well-known infective agent in patients with cell-mediated immunodeficiencies (1-3), and BMT is known to produce long-lasting abnormalities of the immune system ( 5 ) . We describe an unusual form of presentation of an infection by Listeria monocytogenes in the immediate post-BMT phase. A 28-year-old male with chronic myelogenous leukemia in chronic phase was submitted to an unrelated-donor allogeneic B MT on February 1993 after conditioning with cyclophosphamide and total body irradiation. Norfloxacin, acyclovir and oral nystatin were given as antimicrobial prophylaxis, and he was managed in a laminar-air flow isolation room receiving sterilized food. Fever of unknown origin with negative blood cultures first appeared on day + 6 of the procedure, and iniipenem was empirically started; amikacin was added 72 hours later for persistent fever, and by d + 12 the fever had disappeared, although both antibiotics were maintained. On d + 18 he again developed fever, accompanied by drowsiness, headache and vomiting; physical examination revealed no signs of meningism nor other focal neurologic signs. The WBC was 0.2 x 10’//1. Two blood cultures were positive for L . monocytogenes, but lumbar puncture was not performed because of severe thrombocytopenia. A computerized tomography head scan was normal. Therapy with ampicillin 2 g q6 h iv was added to previous empirical therapy with amikacin and imipenem. Blood cultures and clinical symptoms attributable to this infection resolved within 2 d, although he remained feverish for 15 d. Septicemia and meningoencephalitis are the most common manifestations of nonperinatal listeriosis (2). Listeria infections are common in patients with cell-mediated immunodeficiencies (1 -3). Long et al. (4) described 3 patients who developed Listeria meningitis after BMT, 1 of whom had undergone an autologous BMT (ABMT) 90 months earlier, an interval after which immune function has usually recovered following ABMT (5 ) ; however, the patient was an insulin-dependent diabetic, which is a risk factor for infections (2). The present case is remarkable in that L. monocytogenes bacteriemia developed during the early (aplastic) period post-BMT, a period in which bacteremias by gram-positive cocci, gram-negative bacilli and fungal infections (usually Candidu sp. and Aspergillus sp.) clearly predominate (6,7). Since a lumbar puncture was not performed prior to initiating high-dose ampicillin, we did not establish whether or not meningitis was present, although the patient’s symptoms suggested this possibility. We have not found any previous reports of Listeriu infection complicating the immediate postBMT phase. Early diagnosis of this infection and prompt institution of adequate treatment is warranted in order to ensure a favorable outcome (1, 3).

Theoretical study of ester enolate-imine condensation route to ?-lactams

The condensation reaction of the enolate of methyl acetate with formaldimine to afford a β‐lactam was studied using the MP2‐FC/6‐31+G* level of theory taking into account the electrostatic effect of the solvent by means of a self‐consistent reaction field continuum model. The reaction is a stepwise process with three main steps: the formation of the C3(SINGLE BOND)C4 bond, the closure of the β‐lactam ring, and the elimination of the methoxide ion. The formation of the C3(SINGLE BOND)C4 bond is rate determining and according to our calculations is not a reversible step. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 1826–1833, 1998

Pharmacogenetic analysis in the treatment of Hodgkin lymphoma

Abstract About 15–20% of patients with Hodgkin lymphoma (HL) treated with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy ± radiotherapy still die following relapse or progressive disease. The outcome might be influenced by gene polymorphisms influencing chemotherapy metabolism. We studied 126 patients with HL treated with the ABVD regimen. We analyzed glutathione S-transferases (GSTT1, GSTM1 and GSTP1), cytochromes P450 (CYP3A4 and CYP2D6), UGT1A1 and BLMH gene polymorphisms and their association with clinical and outcome variables. Patients with a GSTM1 genotype associated with extensive or ultrahigh activity had a probability of 93.8% to achieve a complete response, while the remainder of the patients had a probability of 82.3% (p = 0.04). This variable maintained its statistical significance in multivariate analysis (hazard ratio 3.7, 95% confidence interval 1–13, p = 0.05). Patients with an extensive or ultrahigh GSTM1 genotype had better prognostic factors than those with poor or intermediate genotypes (hemoglobin level, p = 0.003; serum albumin, p = 0.05; and International Prognostic Score, p = 0.038). Thus, in the treatment of HL, clinical determinants might be more relevant than the pharmacogenetic parameters analyzed to date.

Clinical usefulness of bronchoalveolar lavage in haematologic patients with suspected pulmonary infection

To the Editor: We read with great interest the report by von Eiff et al. (1) published in the May 1995 issue of your journal regarding the clinical usefulness of bronchoscopic procedures in the study of pulmonary infiltrates in patients with haematologic malignancies. We would like to briefly describe the results of 30 consecutive bronchoscopies (BC) with bronchoalveolar lavage (BAL) performed in 25 haematologic patients at our institution over a 1-year period. The male:female ratio was 5: 1, with ages from 21 to 71 yr, and their initial diagnoses were acute leukaemia (n = 13), chronic myelogenous leukaemia (n = 2), lymphoma (n = 5), chronic lymphocytic leukaemia, multiple myeloma, aplastic anaemia, idiopathic myelofibrosis and Evan’s Syndrome (1 case each). All BC were performed for clinical and radiographic evidence of pulmonary infection except in 4 patients who had a normal chest X-ray but signs and symptoms of lung infection. Twenty patients had recently received cytotoxic therapy; 8 of these were undergoing stem cell transplantation [ peripheral blood stem cell or bone marrow transplantation (BMT)] following conditioning with chemotherapy alone (n = 2) or chemotherapy and total body irradiation (n = 6). Fifteen (50%) patients were severely neutropenic (neutrophils < 0.5 x 109/1) when the BC was performed, and 13 had severe thrombocytopenia (platelet count <20 x lo9)) and received a pooled platelet transfusion just before the procedure. Before BC, 24 (77%) patients received empiric antimicrobial therapy which included a broad-spectrum betalactam antibiotic plus an aminoglycoside in all and empiric amphotericin-B in 11 cases. The median time elapsed from the onset of the pulmonary infection to the BC was 3 (range 0-16) days. In transplanted patients BC was performed in the early posttransplant phase (first 60 d). Three BC were performed through an endotracheal tube. No serious complications occurred during the procedure. All BAL samples were stained and cultured for fungi, viruses, aerobic and anaerobic bacteria, parasites and Mycobacteria. A specific aetiologic infectious agent was isolated in 13 (43 %) cases (Table 1). A bacterial pathogen was found in 3 (23 %) of these patients, one soon after BMT, initial empiric therapy was correct in 2 cases while specific therapy was started in the 3rd. In 2 (1 5 %) patients Aspergillus spp. was isolated, and high-dose antifungal therapy was started in both. P. carinii pneumonia (PCP) was diagnosed in 4 (31%) patients, one shortly after BMT, and specific therapy with high-dose trimethoprim-sulphamethoxazole was started in 2 patients. Legionella pneumophila and Mycobacterium tuberculosis were identified in one case each, but both patients were already receiving adequate empiric treatment. In another case the BAL was negative but an open lung biopsy was diagnostic for M . tuberculosis infection. In all cases, a positive diagnosis following BAL allowed the withdrawal of many antimicrobials given empirically, thus reducing the risk of later superinfection by resistant organisms and many potential drug toxicities. Three patients, 2 with PCP and one with a negative BAL died from the pulmonary infection; postmortem examinations were not performed. An open lung biopsy was performed in only one patient with a negative BC, but also failed to help with diagnosis.

Ab initio study of the reaction of CHO+ with H2O and NH3

An MP4(full,SDTQ)/6‐311++G(d,p)//MP2(full)/6‐311++G(d,p) ab initio study was performed of the reactions of formyl and isoformyl cations with H2O and NH3, which play an important role in flame and interstellar chemistries. Two different confluent channels were located leading to CO+H3O+/NH  4+ . The first one corresponds to the approach of the neutral molecule to the carbon atom of the cations. The second one leads to the direct proton transfer from the cations to the neutrals. At 900 K the separate products CO+H3O+/NH  4+ are the most stable species along the Gibbs energy profiles for the processes. For the reaction with H2O the reaction channel leading to HC(OH)  2+ (protonated formic acid) is disfavored with respect to the two CO+H3O+ channels in agreement with the experimental evidence that H3O+ is the major ion observed in hydrocarbon flames. According to our calculations, NH  4+ +H2O are considerably more stable in Gibbs energy than NH3+H3O+;NH  4+ will predominate in the reaction zone when ammonia is added to CH4+Ar diffusion flame, as experimentally observed. At 100 K the most stable structures are the intermediate complexes CO…HOH  2+ /HNH  3+ . Particularly the CO…HOH  2+ complex has a lifetime large enough to be detected and, therefore, could play a certain role in interstellar chemistry. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 1432–1443, 1999

Capnocytophaga Bacteremia in Neutropenic Patients: Report of Two Cases

Dr. Salut Brunet, Departament d’Hematologia, Hospital de la Santa Creu i Sant Pau, Av. Sant Antoni Maria Claret, 167, E08025 Barcelona (Spain) Recently, several cases of blood-borne infections by Capnocytophaga species have been reported in immuno-compromised patients [1-5]. Although these microorganisms are an infrequent cause of bacteremia in neutropenic patients, we have recently observed two such infections, which occurred in our department within a short time period. The first patient was a 63-year-old male with acute nonlympho-blastic leukemia, diagnosed in October 1991, who entered complete remission after appropriate induction chemotherapy. The patient’s condition was complicated by invasive pulmonary aspergillosis (IPA) successfully treated with itraconazole. His leukemia relapsed in February 1993, and salvage chemotherapy was delivered, using a protocol which includes intermediate-dose cytarabine, intermediate-dose methotrexate, vindesine, mitoxantrone and cyclophosphamide [6]. This treatment was further complicated by severe oral mucositis (grade IV according to the WHO classification), diarrhea (grade II) and severe vomiting (grade III). During the period of severe neutropenia (absolute neutrophil count < 0.5 × 109/1), which lasted 21 days, three blood cultures drawn from a peripheral vein (n = 1) and a central venous catheter (n = 2) during an initial febrile episode were positive for Escherichia coli and Capnocytophaga sp. Empirical antibiotic treatment with meropenem was instituted, with rapid clinical improvement and no further positive blood cultures. Fever later reappeared due to reactivation of the IPA, which again resolved with oral itraconazole and recovery of the neutrophil count. In vitro susceptibility testing showed that Capnocytophaga was sensitive to penicillin, cephalosporins, imipenem, meropenem, fluo-roquinolones, chloramphenicol and tetracyclines whereas it was resistant to aminoglycosides, vancomycin and trimethoprim-sulfameth-oxazole. The second patient was a 61-year-old female who suffered from advanced-stage low-grade nonHodgkin’s lymphoma since 1980, and had received outpatient treatment with combination chemotherapy and involved-field

An ab initio study of the reaction of CH2F+ with acetylene

Abstract An ab initio study of the σ attack of CH 2 F + on acetylene at the MP4(SDTQ)-FC/6-31G ∗∗ //MP2-FC/6-31G ∗∗ +ZPVE (MP2) level was performed. According to our results there are one reaction channel leading to C 3 H 3 + +HF and three reaction channels rendering C 3 H 2 F + +H 2 . The statistical production of C 3 H 3 + obtained through these σ channels, that require a practically collinear collision of the reactants, and the π channel previously reported allows to explain the relatively low yield of C 3 H 3 + experimentally observed.