Sequential treatment of cytomegalovirus infection or disease with a short course of intravenous ganciclovir followed by oral valganciclovir: efficacy, safety, and pharmacokinetics.

Oral (p.o.) or intravenous (IV) ganciclovir (GCV) has been the first-line agent for prevention and treatment of cytomegalovirus (CMV) infection and disease in solid organ transplantation (SOT). The introduction of p.o. valganciclovir, with higher bioavailability than p.o. GCV, has proven to be a suitable approach toward outpatient p.o. therapy for CMV infection/disease. The present single-arm, exploratory pilot trial performed with 21 patients investigates the efficacy and safety of a short therapeutic course (21 days) based on an initial IV treatment with GCV (5 mg/kg twice daily, for 5 days) followed by p.o. valganciclovir (900 mg twice daily, for 16 days) for CMV infection/disease in SOT patients. In all cases, doses were adjusted for renal function. Moreover, the study allowed comparison of exposure to GCV after p.o. valganciclovir with respect to IV GCV in the same patients. Response to treatment was monitored until day 180. Viral load eradication was achieved in 66.7% of patients, on day 21. Although not statistically significant, a trend was seen toward increased persistence of viral load on day 21 for patients with donor positive/recipient negative CMV serostatus or receiving either anti-rejection therapy or polyclonal anti-thymocyte globulin. CMV clinical infection recurred in 14.3% of patients, with higher recurrence rates in patients with risk factors for persistence of viremia. Exposures to GCV after using IV GCV or p.o. valganciclovir showed comparable values (P=0.054). This short course, combining initial IV GCV and subsequent p.o. valganciclovir, may provide effective exposure and therapeutic response in the treatment of CMV infection in SOT patients with adequate drug exposure and with the additional potential benefit of shortening the length of hospital stay, which may result in cost reduction and improved patient comfort.

Risk factors for invasive aspergillosis in solid-organ transplant recipients: a case-control study.

BACKGROUND: To facilitate the design of strategies for prevention of invasive aspergillosis in solid-organ transplant recipients, this study investigates whether the development of early-onset and late-onset aspergillosis are related to different risk factors, thereby distinguishing 2 risk populations for this serious complication. METHODS: A retrospective case-control study was performed, including 156 cases of proven or probable invasive aspergillosis in patients recruited from 11 Spanish centers since the start of the centers' transplantation programs. RESULTS: Among all patients, 57% had early-onset IA (i.e., occurred during the first 3 months after transplantation). Risk factor analysis in this group identified as significantly associated risk factors a more complicated postoperative period, repeated bacterial infections or cytomegalovirus disease, and renal failure or the need for dialysis. Among patients with late-onset infections (i.e., occurred > 3 months after transplantation), who comprised 43% of cases, the patients at risk were older, were in an overimmunosuppressed state because of chronic transplant rejection or allograft dysfunction, and had posttransplantation renal failure. CONCLUSIONS: Risk factors in patients with early-onset cases and patients with late-onset cases of posttransplantation invasive aspergillosis are not the same, a fact that could have implications for the preventive approaches used for this infection.

Four days of penicillin therapy for meningococcal meningitis.

Fifty consecutive patients with meningococcal meningitis aged 7 to 75 years (mean, 29 years) were treated with intravenous penicillin G sodium (2 to 3 X 10(5) U/kg/d) for four days. Two of the patients (both teenagers) died of fulminant infection during the first 36 hours of therapy and one elderly woman developed aspiration pneumonia requiring penicillin therapy to be prolonged beyond four days. The remaining 47 patients recovered from the infection. On the fourth day, fever, mild meningeal signs, and moderate elevations of cerebrospinal fluid cell counts and protein contents persisted in some patients; nevertheless, all patients were cured without relapse. The results of our study suggest that meningococcal meningitis may be successfully treated with a four-day course of intravenous penicillin G.

Clindamycin vs penicillin for anaerobic lung infections. High rate of penicillin failures associated with penicillin-resistant Bacteroides melaninogenicus.

Thirty-seven adult patients with anaerobic lung infections (27 lung abscesses and 10 necrotizing pneumonias) were submitted to transthoracic needle-aspiration and/or bronchoscopic specimen brush cultures before therapy and thereafter in all cases considered to be failures. Patients were randomly assigned to receive either clindamycin, 600 mg intravenously every 6 hours, or penicillin G, 2 million U every 4 hours for no less than 8 days, until clinical and radiological improvement became apparent. Treatment was continued orally with clindamycin, 300 mg every 6 hours, or penicillin V, 750 mg every 6 hours, until completing a minimum of 4 weeks. Ten of the 47 anaerobes initially isolated from the lung (nine Bacteroides melaninogenicus and one Bacteroides capillosus) were resistant to penicillin, but none were resistant to clindamycin. Five of the nine patients harboring these penicillin-resistant Bacteroides received penicillin, and all failed to respond to therapy. Overall, eight of the 18 patients in the penicillin group and one of 19 in the clindamycin group failed to respond to therapy. These drugs were equally well tolerated in both groups. The presence of penicillin-resistant Bacteroides is a frequent cause of penicillin failure in patients with anaerobic lung infections. In this setting, clindamycin appears to be the current therapy of choice for initial treatment.

Steroids do not enhance the risk of developing tuberculosis or other AIDS-related diseases in HIV-infected patients treated for Pneumocystis carinii pneumonia.

OBJECTIVE: To evaluate the risk of developing tuberculosis or other AIDS-related diseases (ARD) in HIV-infected patients treated with corticosteroids as adjunctive therapy for Pneumocystis carinii pneumonia (PCP). DESIGN: Retrospective study. SETTING: Infectious Disease Service of a 1000-bed university teaching hospital in Barcelona, Spain. PATIENTS: HIV-infected patients diagnosed with PCP from 1985 to 1992. Patients were classified into two groups: steroid (group A) and non-steroid (group B) adjunctive therapy. Baseline characteristics, antibiotherapy, dose and duration of steroidal treatment were analysed. Endpoints were either the development of tuberculosis or other ARD or death. RESULTS: From the 129 patients included in this study 72 were in group A and 57 in group B. No differences between groups were observed in baseline characteristics or mean follow-up period (15 versus 14 months, respectively). The mean total dose of steroids was 420 mg (range, 160-1260 mg) methylprednisolone or its equivalent in dexamethasone, with a mean treatment duration of 12 days (range, 4-33 days). No differences were found in the occurrence of tuberculosis or other endpoints in the first 6 months of follow-up. In addition, the cumulative rate of developing tuberculosis was 7% in group A and 12% in group B at 12 months of follow-up, and 13 versus 12% at 24 months (P = 0.622, Mantel-Cox): 4 versus 4% at 12 months and 27 versus 24% at 24 months (P = 0.873) for non-tuberculosis mycobacterial infection, and 40 versus 42% at 12 months, and 88 versus 66% at 24 months (P = 0.330) for non-mycobacterial ARD. The cumulative survival rate was 79 versus 71% and 46 versus 34% at 12 and 24 months, respectively (P = 0.526). CONCLUSIONS: Our data suggest that the use of corticosteroids during PCP in HIV-infected patients at the doses and for the duration used in our patients did not enhance the risk of developing or relapsing tuberculosis or other ARD.

Characteristics and antibiotic therapy of adult meningitis due to penicillin-resistant pneumococci.

Of 66 episodes of pneumococcal meningitis seen in Bellvitge Hospital, Barcelona, Spain (January 1981 to June 1987), 15 (23 percent) were due to penicillin-resistant pneumococci [minimal inhibitory concentrations (MICs) of 0.1 to 4 micrograms/ml]. Fifty percent of these strains were also resistant to chloramphenicol. Most were sporadic community-acquired cases. Clinical characteristics were similar in both penicillin-resistant and penicillin-sensitive cases. Those cases with MICs of greater than 1 microgram/ml did not show a response to penicillin therapy. Of nine patients treated with cefotaxime (200 to 350 mg/kg per day) with penicillin G MICs of 0.1 to 4 micrograms/ml and cefotaxime MICs of less than or equal to 0.03 to 1 microgram/ml, seven recovered, one experienced a relapse after 14 days of therapy and the infection was cured with intravenous vancomycin, and one patient died with sterile cerebrospinal fluid. Thus, adults with meningitis due to penicillin-resistant pneumococci may be adequately treated with high doses (around 300 mg/kg per day) of intravenous cefotaxime if MICs of penicillin G are less than or equal to 4 micrograms/ml. Cases with higher resistance may require another antibiotic such as vancomycin.

Clinical presentation and outcome of tuberculosis in kidney, liver, and heart transplant recipients in Spain. Spanish Transplantation Infection Study Group, GESITRA.

BACKGROUND: Tuberculosis is unusual in transplant recipients. The incidence, clinical manifestations, and optimal treatment of this disease in this population has not been adequately defined. The present study was undertaken to assess the incidence, clinical features, and response to therapy of Mycobacterium tuberculosis infection in solid-organ transplant recipients. METHODS: We evaluated retrospectively the incidence, clinical characteristics, diagnostic procedures, antituberculous treatment, clinical course, and factors influencing mortality in 51 solid-organ transplant recipients who developed tuberculosis after transplantation. We also reviewed the world literature on tuberculosis in solid-organ transplantation. RESULTS: The overall incidence of tuberculosis was 0.8%. The localization was pulmonary in 63% of the cases, disseminated in 25%, and extrapulmonary in 12%. Tuberculosis developed from 15 days to 13 years after surgery (mean, 23 months). In one third of the cases, diagnosis was not suspected initially, and in three cases, diagnosis was made at necropsy. Fever was the most frequent symptom, followed by constitutional symptoms, cough, respiratory insufficiency, and pleuritic pain. Fifteen patients (33%) developed hepatotoxicity during treatment; hepatotoxicity was severe in seven cases. Hepatotoxicity was higher in patients receiving four or more antituberculous drugs (50%) than in patients receiving three drugs (21%; P=0.03). Serum levels of cyclosporine decreased in the 26 patients under the simultaneous use of rifampin. Nine of them (35%) developed acute rejection, and five (56%) died, in comparison with 3 of 17 patients (18%) who did not develop rejection after the use of cyclosporine and rifampin (P=0.03). Although microbiological response was favorable in 94% of the 35 patients who completed 6 or more months of treatment, 16 other patients (31%) died before diagnosis or in the course of treatment. None of the patients treated for more than 9 months died as a consequence of tuberculosis, whereas the mortality rate was 33% among those treated for 6 to 9 months (P=0.03). Use of antilymphocyte antibodies or high doses of steroids for acute rejection before tuberculosis was associated with a higher mortality rate. CONCLUSIONS: M tuberculosis causes serious and potentially life-threatening disease in solid-organ transplant recipients. Treatment with at least three drugs during 9 months or more, avoiding the use of rifampin, appears to be appropriate.

B-lymphocytes and co-stimulatory molecules in Mycobacterium tuberculosis infection.

SETTING: The immunological mechanisms that lead to the control of Mycobacterium tuberculosis infection are not well known. OBJECTIVE: To study the role of lymphocyte subsets and co-stimulatory molecules in M. tuberculosis infection. DESIGN: In 35 patients with pulmonary tuberculosis (PTB) and their contacts, 29 persons with tuberculin skin test conversion (TSTC) and 20 healthy individuals with negative tuberculin skin test (NTST), we studied T-lymphocyte subsets (CD3, CD4, CD8, alphabetaTCR and gammadeltaTCR), B-cells, monocytes and co-stimulatory molecules CD28 and CD86 in peripheral blood. The results were analysed at univariate and multivariate level through discriminant analysis. RESULTS: At univariate level, compared with TSTC and NTST, PTB patients presented a decrease in CD4+ T-cells (P = 0.002), and B-cells (P = 0.02 and 0.001, respectively). With regard to NTST subjects, PTB patients also showed a decrease in the percentage of CD86+ monocytes (P = 0.02) and an increase in the percentage of CD86+ B-lymphocytes (P = 0.02). At multivariate level, CD4+ T-lymphocytes showed statistical differences between PTB and TSTC subjects (P = 0.001). B-lymphocytes were discriminant between PTB and NTST (P < 0.001) and between TSTC and NTST individuals (P = 0.01). CONCLUSION: The number of total CD4+ T-cells is the best discriminant parameter for distinguishing between disease and infection, whereas the B-cell count is the best between healthy and infected individuals.

Characteristic cutaneous lesions in patients with brucellosis.

Among 436 cases of brucellosis included in a 12-year prospective protocol, we identified 27 patients (6%) with cutaneous lesions (13 men and 14 women; mean age, 35.1 +/- 16.5 years). Twenty-one patients had positive blood cultures for Brucella melitensis. A disseminated violet-erythematous, papulonodular eruption (20 cases) and erythema nodosum-like lesions (three cases) were the most frequent eruptions observed, appearing during the initial episode of the disease or in relapse. Histologic findings were a dermal inflammatory infiltrate of lymphocytes and histiocytes in a perivascular and periadnexal arrangement, with a focally granulomatous appearance, and occasional extension to subcutaneous fat. Skin cultures were positive for B melitensis in two of four cases. Our results suggest that there are characteristic clinical and histologic cutaneous findings in patients with brucellosis and that hematogenous spread of the microorganism can be the most important pathogenic mechanism of these lesions.

[Cytomegalovirus disease in patients with acquired immunodeficiency syndrome. Report of 63 cases]. / Enfermedad por citomegalovirus en pacientes afectados del síndrome de inmunodeficiencia adquirida. A propósito de 63 episodios.

BACKGROUND: The aim of the present was to study the clinical and therapeutic characteristics of patients with the human immunodeficiency virus (HIV) with disease by the cytomegalovirus (DCMV) observed between 1984-1990. Some concrete aspects such as viremia by the cytomegalovirus (CMV) without focal disease or the profitability of cultures of different samples as predictors of DCMV were analyzed. METHODS: The clinical records of the patients diagnosed with DCMV as well as cultures of blood, saliva, and urine CMV of the global collective of patients with HIV were retrospectively studied. RESULTS: Sixty-three episodes of DCMV were collected in 41 patients corresponding to 29 episodes of retinitis by CMV (46%), 8 with digestive involvement (13%), 7 with lung involvement (11%), 18 with fever without focality and viremia by CMV 9 (29%) and 1 of encephalitis by CMV (1.5%). Eighty percent of the patients had been previously diagnosed of AIDS. The mean of CD4 lymphocytes was 43 cells/mm3 and the estimated probability of survival at 12 month was 18%. In 89% of the episodes of retinitis and 87% with digestive involvement improvement was achieved with treatment. Retinitis developed a posteriori in 38% of the patients with viremia without focality. During the period studied, 105/244 (43%) of the patients with the HIV showed some sample positive for CMV. Sixty-four percent of the patients with positive cultures in urine and/or saliva did not present DCMV after prolonged follow up. CONCLUSIONS: Cytomegalovirus disease is produced in advanced phases of infection by the human immunodeficiency virus. Response to treatment was good in cases of retinitis, digestive involvement and symptomatic viremia without focality. The symptomatic viremia by cytomegalovirus constitutes a predictor of localized disease. Positivity of urine and saliva cultures has slight predictive value for cytomegalovirus disease in patients with the human immunodeficiency virus.

[Ocular toxoplasmosis in patients with acquired immunodeficiency syndrome]. / Toxoplasmosis ocular en pacientes con síndrome de inmunodeficiencia adquirida.

Ocular toxoplasmosis is an uncommonly reported complication in patients with acquired immunodeficiency syndrome. Three patients with human immunodeficiency virus (HIV) infection and ocular toxoplasmosis are reported. In two of them, cerebral toxoplasmosis was associated. Ocular involvement presented as exudative chorioretinitis, bilateral in 2 cases and unilateral in 1. The diagnosis was made on the basis of ocular disease associated with lesions consistent with toxoplasmosis of central nervous system (CNS) and response to antitoxoplasma treatment in one case, and ocular disease with rising antitoxoplasma serologic titers in the remaining two. Initial therapy included pyrimethamine plus sulfadiazine in 2 cases and pyrimethamine plus clindamycin in 1. The 2 patients treated with sulfadiazine showed hypersensitivity features, and clindamycin had to be substituted. The response to therapy was favorable, although one patient died few days after the development of CNS lesions. When chorioretinitis develops in a patient with HIV infection, ocular toxoplasmosis should be considered. As CNS involvement is commonly associated and relapse after the withdrawal of therapy is likely, these patients should be treated as those with isolated toxoplasma encephalitis.

[Cerebral tuberculoma. Report of 8 cases]. / Tuberculoma cerebral. A propósito de ocho casos.

A series of eight patients with cerebral tuberculoma seen between 1980 and 1990 is reported. Headache was the leading clinical finding, followed by focal neurological findings and seizures. Papilledema was the most uniform examination finding associated with intracranial hypertension. Five patients had another localization of tuberculosis: three had tuberculous meningitis, one had tuberculous pericarditis and only one had associated active pulmonary involvement. Cerebrospinal fluid was investigated in seven patients. In three patients data of tuberculous meningitis were found, with positive culture in Löwenstein medium. Two patients had the acquired immunodeficiency syndrome. All patients received medical treatment with good response, except in one who developed paradoxical expansion of the lesions after two months of therapy.

[Analysis of 500 liver transplantations at Bellvitge Hospital, Spain]. / Análisis de 500 trasplantes hepáticos en el Hospital de Bellvitge.

BACKGROUND: We present the experience of the liver transplantation program at the Hospital of Bellvitge with 500 transplantations performed during 15 years, to describe changes in liver transplantation observed throughout the time and to analyze the long term results. PATIENTS AND METHOD: Five groups each one including 100 consecutive transplantations are studied. RESULTS: The main indications were hepatocellular carcinoma (23%), alcoholic cirrhosis (22.8%), and post-hepatitis C cirrhosis (18.8%). Sixty-five retransplantations were performed in 59 patients (13%), being the more frequent indications arterial thrombosis (13 patients) and primary nonfunction of graft (10 patients). In 10 patients a hepatorenal transplantation was performed. In group I, the most frequent donor cause of death was cranial traumatism (80%), while in group V it was the vascular pathology (52%). There were other significative differences between these groups of patients (I vs V): patients with stage 2 or 3 from UNOS status (45 vs 19%), blood use (29.6 [26] vs 4.6 [5.3] PRBC), ICU stay (13 [13] vs 7.4 [11] days), hospital stay (40 [52] vs 23.7 [17] days), rejection rate (46 vs 20%) and primary graft nonfunction (9 vs 3%). However, the infection rates (48 vs 54.5%) and biliary tract complications (26 vs 20%) have not shown statistically significant differences. Actuarial one and 5-year survival are 83 and 70% respectively. CONCLUSIONS: An important and progressive improvement of liver transplantation results has been observed. However, de novo tumours, hepatitis C virus recurrence and chronic rejection can limit long term results.