Luces y sombras de la infección por citomegalovirus en el trasplante de órgano sólido / Lights and shadows of cytomegalovirus infection in solid organ transplantation

La infección por citomegalovirus (CMV) aparece en el 30–80% de los pacientes sometidos a trasplante de órgano sólido (TOS). Su incidencia y la presencia de enfermedad sintomática varían dependiendo del tipo de trasplante, de la presencia de factores de riesgo asociados, de la intensidad de inmunosupresión y de las estrategias de prevención. El impacto que el CMV tiene en el TOS no sólo viene dado por sus efectos directos produciendo una enfermedad por CMV, sino también por sus múltiples efectos indirectos dado su papel inmunomodulador y de inmunoactivación debido a la latencia viral. Las 2 estrategias de profilaxis (profilaxis universal y terapia anticipada) son igualmente útiles, presentan ventajas e inconvenientes y quedan dudas por resolver en cuanto a las poblaciones que la deben recibir y el período que se debe administrar. Es necesario tanto para el diagnóstico y pronóstico como para la evaluación de la respuesta terapéutica que los pacientes con TOS sean monitorizados virológicamente para detectar la infección por CMV. Las nuevas técnicas de PCR real time han supuesto numerosas ventajas, pero hay problemas de estandarización y es preciso obtener valores de referencia comunes. Disponemos de antivirales anti-CMV específicos, pero temas como el papel del valganciclovir frente al ganciclovir, la aparición de resistencias y la duración óptima del tratamiento son objeto de debate. La terapia complementaria con inhibidores mTOR o el ensayo de vacunas frente a CMV son aspectos terapéuticos alternativos sobre los que no hay datos concluyentes (AU)

Cytomegalovirus (CMV) develops in 30-80% of patients undergoing solid organ transplantation (SOT). The incidence and presence of symptomatic disease varies depending on the type of transplant, the presence of associated risk factors, the intensity of immunosuppression, and the prevention strategies used. The impact of CMV on SOT is due not only to the effects of CMV disease per se, but also to its multiple indirect effects resulting from its immunomodulatory role and immunoactivation caused by viral latency. The two prophylactic strategies used (universal prophylaxis and preemptive therapy) are equally useful. Both strategies have advantages and disadvantages, and uncertainties remain on the populations that should receive prophylaxis and for how long. Viral monitoring to detect CMV infection is important for diagnosis, prognosis and evaluation of treatment response. The new real-time polymerase chain reaction techniques have provided numerous advantages but standardization remains an issue and common reference values are required. Specific anti-CMV drugs are available but issues such as the role of valganciclovir versus ganciclovir, the development of resistances and optimal treatment length are still being debated. Complementary therapy with mTOR inhibitors and vaccine strategies against CMV are alternatives for which conclusive data are lacking (AU)

[Lights and shadows of cytomegalovirus infection in solid organ transplantation]. / Luces y sombras de la infección por citomegalovirus en el trasplante de órgano sólido.

Cytomegalovirus (CMV) develops in 30-80% of patients undergoing solid organ transplantation (SOT). The incidence and presence of symptomatic disease varies depending on the type of transplant, the presence of associated risk factors, the intensity of immunosuppression, and the prevention strategies used. The impact of CMV on SOT is due not only to the effects of CMV disease per se, but also to its multiple indirect effects resulting from its immunomodulatory role and immunoactivation caused by viral latency. The two prophylactic strategies used (universal prophylaxis and preemptive therapy) are equally useful. Both strategies have advantages and disadvantages, and uncertainties remain on the populations that should receive prophylaxis and for how long. Viral monitoring to detect CMV infection is important for diagnosis, prognosis and evaluation of treatment response. The new real-time polymerase chain reaction techniques have provided numerous advantages but standardization remains an issue and common reference values are required. Specific anti-CMV drugs are available but issues such as the role of valganciclovir versus ganciclovir, the development of resistances and optimal treatment length are still being debated. Complementary therapy with mTOR inhibitors and vaccine strategies against CMV are alternatives for which conclusive data are lacking.

Data mining validation of fluconazole breakpoints established by the European Committee on Antimicrobial Susceptibility Testing.

European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints classify Candida strains with a fluconazole MIC < or = 2 mg/liter as susceptible, those with a fluconazole MIC of 4 mg/liter as representing intermediate susceptibility, and those with a fluconazole MIC > 4 mg/liter as resistant. Machine learning models are supported by complex statistical analyses assessing whether the results have statistical relevance. The aim of this work was to use supervised classification algorithms to analyze the clinical data used to produce EUCAST fluconazole breakpoints. Five supervised classifiers (J48, Correlation and Regression Trees [CART], OneR, Naïve Bayes, and Simple Logistic) were used to analyze two cohorts of patients with oropharyngeal candidosis and candidemia. The target variable was the outcome of the infections, and the predictor variables consisted of values for the MIC or the proportion between the dose administered and the MIC of the isolate (dose/MIC). Statistical power was assessed by determining values for sensitivity and specificity, the false-positive rate, the area under the receiver operating characteristic (ROC) curve, and the Matthews correlation coefficient (MCC). CART obtained the best statistical power for a MIC > 4 mg/liter for detecting failures (sensitivity, 87%; false-positive rate, 8%; area under the ROC curve, 0.89; MCC index, 0.80). For dose/MIC determinations, the target was >75, with a sensitivity of 91%, a false-positive rate of 10%, an area under the ROC curve of 0.90, and an MCC index of 0.80. Other classifiers gave similar breakpoints with lower statistical power. EUCAST fluconazole breakpoints have been validated by means of machine learning methods. These computer tools must be incorporated in the process for developing breakpoints to avoid researcher bias, thus enhancing the statistical power of the model.

Correlation of the MIC and dose/MIC ratio of fluconazole to the therapeutic response of patients with mucosal candidiasis and candidemia.

We report on the correlation of the outcomes for two cohorts of patients who had been treated for candidemia (126 episodes) or oropharyngeal candidiasis (110 episodes) with various doses of fluconazole and the MIC of fluconazole obtained by using the EUCAST standard for fermentative yeasts. Of 145 episodes caused by an isolate with a fluconazole MIC < or =2 mg/liter, 93.7% (136 of 145) responded to fluconazole treatment. The response for those infected with a strain with a MIC of 4 mg/liter was 66% but reached 100% when the dose was greater than 100 mg/day, whereas the response for those infected with strains with MICs > or =8 mg/liter was only 12%. Hence, a MIC of 2 mg/liter or 4 mg/liter was able to predict successful treatment. A cure rate of 93.9% (140 of 149) was achieved when the dose/MIC ratio was > or =100 but fell to 14.6% (16 of 109) when the ratio was less. The dose/MIC required to achieve a response rate of 50% (the 50% effective concentration) was 43.7 for the cohort of patients with oropharyngeal candidiasis. Classification and regression analysis indicated that a dose/MIC of 35.5 was the threshold for the prediction of cure or failure. However, an increase in exposure above this threshold further increased the probability of cure, and all patients were cured when the dose/MIC exceeded 100. Monte Carlo simulations showed a probability of target attainment of 99% at MICs < or =2 mg/liter and a pharmacodynamic target of a dose/MIC ratio of 100, which was equivalent to an unbound fraction of the fluconazole area under the curve versus the MIC of 79.

Arabidopsis thaliana expresses two functional isoforms of Arvp, a protein involved in the regulation of cellular lipid homeostasis.

Arv1p is involved in the regulation of cellular lipid homeostasis in the yeast Saccharomyces cerevisiae. Here, we report the characterization of the two Arabidopsis thaliana ARV genes and the encoded proteins, AtArv1p and AtArv2p. The functional identity of AtArv1p and AtArv2p was demonstrated by complementation of the thermosensitive phenotype of the arv1Delta yeast mutant strain YJN1756. Both A. thaliana proteins contain the bipartite Arv1 homology domain (AHD), which consists of an NH(2)-terminal cysteine-rich subdomain with a putative zinc-binding motif followed by a C-terminal subdomain of 33 amino acids. Removal of the cysteine-rich subdomain has no effect on Arvp activity, whereas the presence of the C-terminal subdomain of the AHD is critical for Arvp function. Localization experiments of AtArv1p and AtArv2p tagged with green fluorescent protein (GFP) and expressed in onion epidermal cells demonstrated that both proteins are exclusively targeted to the endoplasmic reticulum. Analysis of beta-glucuronidase (GUS) activity in transgenic A. thaliana plants carrying chimeric ARV1::GUS and ARV2::GUS genes showed that ARV gene promoters direct largely overlapping patterns of expression that are restricted to tissues in which cells are actively dividing or expanding. The results of this study support the notion that plants, yeast and mammals share common molecular mechanisms regulating intracellular lipid homeostasis.

Antibiotic-lock therapy for long-term intravascular catheter-related bacteraemia: results of an open, non-comparative study.

BACKGROUND: Infection is one of the main problems associated with long-term central venous catheters. This study assesses the effectiveness of antibiotic-lock therapy (ALT) for treating catheter-related bacteraemia (CRB). METHODS: CRB was defined as quantitative blood culture counts through any catheter lumen 5-fold greater than concurrent peripheral blood culture, and qualitative blood culture positive for the same microorganism in all samples. Systemic treatment and ALT were started simultaneously using vancomycin (2000 mg/L) for Gram-positive organisms, and ciprofloxacin or amikacin (2000 mg/L) for Gram-negative bacilli. Heparin was added to ALT. Effectiveness was assessed by clinical and microbiological criteria. Cure was defined as negative blood cultures at both sites without catheter removal at 1 month after the completion of therapy. RESULTS: A total of 115 episodes of CRB in 98 patients were analysed. Catheters were used for chemotherapy (50 episodes), haemodialysis (37), total parenteral nutrition (24) and combined chemotherapy and nutrition (4). Median time from catheter placement to CRB onset was 105 days (IQ range 26-210). Aetiologies included Gram-positive organisms [56 coagulase-negative staphylococci (CoNS), 20 Staphylococcus aureus and 5 other organisms] in 81 episodes (70%), Gram-negative bacilli (11 Escherichia coli, 5 Pseudomonas aeruginosa and 10 other organisms) in 26 (23%) and polymicrobial in 8 (7%). A total of 94 episodes were cured (82%). There were 21 therapeutic failures: 9 S. aureus (1 related death), 9 CoNS, 1 P. aeruginosa, 1 Proteus vulgaris and 1 polymicrobial. Median catheter follow-up in therapeutic success was 168 days (range 7-2740). CONCLUSIONS: ALT combined with systemic antibiotics seems to be effective for treating CRB, especially in Gram-negative and CoNS episodes. S. aureus CRB had an elevated rate of therapeutic failure.

Influence of penicillin resistance on outcome in adult patients with invasive pneumococcal pneumonia: is penicillin useful against intermediately resistant strains?

OBJECTIVES: To compare outcome between patients with pneumonia due to penicillin-susceptible S. pneumoniae and patients with pneumonia due to penicillin intermediately resistant strains and to study the outcome of patients with pneumococcal pneumonia caused by strains with MICs of 0.12-1 mg/L treated empirically during the first 48 h with beta-lactam antibiotics. MATERIALS AND METHODS: We studied 247 adult patients with invasive pneumococcal pneumonia occurring from 1997 to 2001. The following data were recorded from each patient: socio-demographic characteristics, underlying diseases, clinical presentation, initial severity of pneumonia, initial and subsequent antimicrobial therapy, in-hospital complications, hospital mortality and length of hospital stay. Multivariate analysis was done to identify variables associated with the development of pneumonia caused by a non-susceptible strain. RESULTS: The overall presence of penicillin non-susceptibility was 26.7%; no strain had an MIC >2 mg/L. Overall mortality was 23.5% in patients with pneumonia caused by intermediately resistant pneumococci and 12.7% in those with pneumonia caused by susceptible strains (P=0.075). Mortality during the first 7 days of admission, considered to be pneumonia-related deaths (13.7% versus 9.9%; P=0.448) was similar in both groups. The multivariate analysis showed that serotype 14 (OR, 140.18; 95% CI, 16.95-1159.20), serotype 19 (OR, 7.53; 95% CI, 1.98-28.7), haematological malignancy or splenectomy (OR, 4.46; 95% CI, 1.5-13.23) and HIV infection (OR, 4.54; 95% CI, 1.54-13.44) were the only independent factors associated with pneumonia caused by penicillin intermediately resistant pneumococci. In patients with strains having MICs of 0.1-1 mg/L, overall mortality was similar in the group of penicillin-treated patients (22.2%) to those treated with broad-spectrum beta-lactams (23.5%). CONCLUSIONS: There is a non-significant trend to higher mortality in patients with pneumococcal pneumonia caused by intermediately resistant strains; however, they do not have a poorer outcome when they are treated with amoxicillin.

Invasive pneumococcal disease in patients infected with HIV: still a threat in the era of highly active antiretroviral therapy.

We studied all human immunodeficiency virus (HIV)-infected patients with invasive pneumococcal disease who received their diagnosis during 1996-2002 to investigate the incidence of this disease in the highly active antiretroviral therapy era and to study the influence of CD4 lymphocyte count on the clinical presentation and outcome of disease. The overall incidence of invasive pneumococcal disease was 11.3 cases per 100,000 person-years in adult patients without known HIV infection and 677 cases per 100,000 person-years in HIV-infected patients. This incidence remained stable over the study period. Clinical presentation, severity of illness, and number of recurrent episodes were similar in patients with CD4+ cell counts of >200 or < or =200 cells/ microL. Patients receiving trimethoprim-sulfamethoxazole (TMP-SMZ) were more likely to present with TMP-SMZ-resistant pneumococci than were those who were not receiving this agent (76.7% vs. 43.6%; P=.007). The mortality rate was high (21%).

Efficacy of ampicillin combined with ceftriaxone and gentamicin in the treatment of experimental endocarditis due to Enterococcus faecalis with no high-level resistance to aminoglycosides.

OBJECTIVE: This study tests the usefulness of ceftriaxone combined with ampicillin as an alternative to ampicillin plus gentamicin for the treatment of experimental endocarditis due to Enterococcus faecalis without high-level resistance to aminoglycosides. It also determines whether adding ceftriaxone to ampicillin and gentamicin increases the effectiveness against experimental enterococcal endocarditis resulting from E. faecalis. METHODS: Animals with catheter-induced endocarditis were infected intravenously with 108 cfu of the EF91 strain of E. faecalis and were treated for 3 days with ampicillin 2 g every 4 h administered as 'human-like' (H-L) pharmacokinetics, plus gentamicin 1 mg/kg every 8 h H-L, or ceftriaxone 2 g every 12 h H-L alone or combined with gentamicin 6 mg/kg every 24 h administered subcutaneously. RESULTS: The results of therapy for experimental endocarditis resulting from EF91 showed that the combination of ampicillin plus ceftriaxone was as effective as ampicillin plus gentamicin. The triple combination did not improve on the overall efficacies of the two-drug combinations. CONCLUSIONS: Because of its lower nephrotoxicity, ampicillin plus ceftriaxone may be a useful alternative therapy for E. faecalis endocarditis in selected patients.

Efficacy of ceftriaxone and gentamicin given once a day by using human-like pharmacokinetics in treatment of experimental staphylococcal endocarditis.

We compared the efficacy of ceftriaxone combined with gentamicin, both given once a day, with that of cloxacillin given every 4 h plus gentamicin given once a day or in three daily doses (t.i.d.) for the treatment of experimental methicillin-susceptible staphylococcal endocarditis. The antibiotics were administered by using human-like (H-L) pharmacokinetics that simulated the profiles of these drugs in human serum. Animals with catheter-induced endocarditis were infected intravenously with 10(5) CFU of Staphylococcus aureus S5 (MICs and minimal bactericidal concentrations of cloxacillin, ceftriaxone, and gentamicin, 0.5 and 2 microg/ml, 4 and 8 microg/ml, and 0.5 and 1 microg/ml, respectively). The animals were then treated for 24 h with cloxacillin at a dose of 2 g that simulated H-L pharmacokinetics (H-L 2 g) every 4 h alone or combined with gentamicin (administered at doses of H-L 1 mg/kg of body weight every 8 h or H-L 4.5 mg/kg every 24 h) or with ceftriaxone at H-L 2 g every 24 h alone or combined with gentamicin (administered at doses of H-L 1 mg/kg every 8 h or H-L 4.5 mg/kg every 24 h). The results of therapy for experimental endocarditis due to the S5 strain showed that (i) cloxacillin alone is more effective than ceftriaxone alone in reducing the bacterial load (P < 0.01), (ii) the combination of cloxacillin or ceftriaxone with gentamicin is more effective than each of these drugs alone (P < 0.01), and (iii) Ceftriaxone H-L plus gentamicin H-L 4.5 mg/kg, both administered every 24 h, showed efficacy similar to that of the "gold standard," cloxacillin H-L plus gentamicin H-L 1 mg/kg t.i.d. (P > 0.05). An increase in the interval of administration of gentamicin to once daily resulted in a reduction in the numbers of bacteria in the vegetations equivalent to that achieved with the recommended regimen of cloxacillin plus gentamicin t.i.d. in the treatment of experimental endocarditis due to methicillin-susceptible S. aureus. Ceftriaxone plus gentamicin, both administered once a day, may be useful for home-based therapy for selected cases of staphylococcal endocarditis.