RESUMO
Consolidated data from pharmacokinetic and pharmacodynamic studies support the administration of ß-lactam antibiotics in prolonged infusion (i.e., extended or continuous) to optimize therapeutic efficacy by increasing the probability of attaining maximal bactericidal activity. This is the longest possible time during which the free drug concentrations are approximately four-fold the minimum inhibitory concentration between dosing intervals. In the context of antimicrobial stewardship strategies, achieving aggressive pharmacokinetic and pharmacodynamic targets is an important tool in the management of multi-drug resistant (MDR) bacterial infections and in the attainment of mutant preventing concentrations. However, prolonged infusion remains an unexploited resource. Novel ß-lactam/ß-lactamase inhibitor (ßL/ßLI) combinations (ceftolozane-tazobactam, ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-cilastatin-relebactam) have been released in recent years to face the emerging challenge of MDR Gram-negative bacteria. Pre-clinical and real-life evidence has confirmed the promising role of prolonged infusion of these molecules in specific settings and clinical populations. In this narrative review we have summarized available pharmacological and clinical data, future perspectives, and current limitations of prolonged infusion of the novel protected ß-lactams, their application in hospital settings and in the context of outpatient parenteral antimicrobial therapy.
Assuntos
Antibacterianos , Infecções por Bactérias Gram-Negativas , Humanos , Antibacterianos/uso terapêutico , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Inibidores de beta-Lactamases/uso terapêutico , Combinação de Medicamentos , Monobactamas/farmacologia , Monobactamas/uso terapêutico , Farmacorresistência Bacteriana Múltipla , Testes de Sensibilidade MicrobianaRESUMO
BACKGROUND: Tuberculous meningitis (TBM) is an important disease leading to morbidity, disability and mortality that primarily affects children and immune-depressed patients. Specific neuromarkers predicting outcomes, severity and inflammatory response are still lacking. In recent years an increasing number of evidences show a possible role for infective agents in developing neurodegenerative diseases. METHODS: We retrospectively included 13 HIV-negative patients presenting with TBM and we compared them with two control groups: one of patients with a confirmed diagnosis of AD, and one of those with syphilis where lumbar punctures excluded central nervous system involvement. Lumbar punctures were performed for clinical reasons and CSF biomarkers were routinely available: we analyzed blood brain barrier permeability (CSF to serum albumin ratio, "CSAR"), intrathecal IgG synthesis, (CSF to serum IgG ratio), inflammation (neopterin), amyloid deposition (Aß1-42), neuronal damage (T-tau, P-tau, 14.3.3) and astrocytosis (S-100 ß). RESULTS: TBM patients were 83 % male and 67 % Caucasian with a median age of 51 years (24.5-63.5 IQR). Apart from altered CSAR (median value 18.4, 17.1-30.9 IQR), neopterin (14.3 ng/ml, 9.7-18.8) and IgG ratios (15.4, 7.9-24.9), patients showed very low levels of Aß1-42 in their CSF (348.5 pg/mL,125-532.2), even lower compared to AD and controls [603 pg/mL (IQR 528-797) and 978 (IQR 789-1178)]. Protein 14.3.3 tested altered in 38.5 % cases. T-tau, P-tau and S100Beta were in the range of normality. Altered low level of Aß1-42 correlated over time with classical TBM findings and altered neuromarkers. CONCLUSIONS: CSF Biomarkers from patients with TBM were compatible with inflammation, blood brain barrier damage and impairment in amyloid-beta metabolism. Amyloid-beta could be tested as a prognostic markers, backing the routine use of available neuromarkers. To our knowledge this is the first case showing such low levels of Aß1-42 in TBM; its accumulation, drove by neuroinflammation related to infections, can be central in understanding neurodegenerative diseases.
Assuntos
Doença de Alzheimer , Tuberculose Meníngea , Peptídeos beta-Amiloides , Biomarcadores , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos , Estudos Retrospectivos , Proteínas tauRESUMO
We measured severe acute respiratory syndrome coronavirus 2 spike protein subunits S1/S2 antibodies by using capillary electrophoresis and a chemiluminescence immunoassay for 5,444 active healthcare workers in Italy. Seroprevalence was 6.9% and higher among participants having contact with patients. Seroconversion was not observed in 37/213 previously infected participants.
Assuntos
COVID-19/epidemiologia , Pessoal de Saúde , SARS-CoV-2 , Humanos , Itália/epidemiologiaRESUMO
BACKGROUND: Antiviral and immune-modulating properties of low-molecular-weight heparin (LMWH) against Coronaviridae have been reported by in vitro studies, but no in vivo evidence is yet available. We sought to know whether the timing of prophylactic doses of LMWH during the course of COVID-19 may affect the time to SARS-CoV-2 nasal-oropharyngeal swab negativization. METHODS: Retrospective monocentric cross-sectional study on patients requiring sub-intensive ward admission due to first SARS-CoV-2 infection and undergoing early (EH; within 7 days from COVID-19 signs and symptoms onset) versus delayed prophylactic LMWH (DH; after 7 days). SARS-CoV-2 RNA was measured by reverse transcription real-time PCR according to scheduled time points: first swab after 2 weeks from COVID-19 onset, then at 1-week intervals until negativity. RESULTS: Time to SARS-CoV-2 swab negativity was shorter in EH (38 patients) compared with DH (55 patients): 22 versus 37 days (P=0.004). The number of confirmative negative swabs in EH was significantly higher compared with DH at week 2 (21.1% versus 3.6%; P=0.017) and 4 (60.0% versus 19.6%; P<0.001). At univariate, EH differed from DH for several disease severity and clinical management parameters. Nevertheless, after accounting for the differences, Cox regression showed early LMWH administration (hazard ratio [HR] 2.91 [1.51, 5.63]; P=0.002) and higher lymphocytes nadir (HR 1.04 [1.01, 1.08]; P=0.020) as predictors of shorter time to swab negativity. CONCLUSIONS: This potential antiviral and/or immune-modulating activity of LMWH needs further in vivo confirmations by randomized controlled trials.
Assuntos
Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Heparina de Baixo Peso Molecular/uso terapêutico , Mucosa Nasal/virologia , SARS-CoV-2/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , COVID-19/diagnóstico , Estudos Transversais , Feminino , Humanos , Imunomodulação/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , RNA Viral/genética , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
OBJECTIVE: The current study aimed to investigate whether cerebrospinal fluid (CSF) Epstein-Barr virus (EBV) or cytomegalovirus (CMV) DNA was associated with viral, inflammatory and neuronal damage biomarkers in people living with HIV (PLWH). DESIGN: A cross-sectional diagnostic study on CSF fluid samples in patients undergoing lumbar punctures for clinical reasons, to better understand the role of EBV and CMV in the CNS on HIV RNA replication, blood-brain-barrier (BBB) damage and biomarkers of neuronal damage/inflammation. METHODS: EBV, CMV DNA and HIV RNA were measured on CSF, through real time (RT)-PCR, from PLWHs undergoing lumbar punctures for clinical reasons (excluding oncho-haematological comorbidities). Immune-enzymatic assays evaluated blood-brain barrier inflammation and damage. Patients were stratified according to plasma HIV RNA levels in viremic (≥50 copies/ml) and aviremic (<50 copies/ml). RESULTS: We included 297 participants. Among 167 viremic patients CSF EBV and CMV DNA were detectable in 42 (25.1%) and 10 (6.3%) participants; among 130 aviremic individuals CSF EBV and CMV DNA were detectable in 12 (9.2%) and 0 (0%) participants, respectively. In viremic group detectable CSF EBV DNA was associated with CSF pleocytosis (Pâ<â0.001), higher CSF HIV RNA (Pâ<â0.001) and neopterin levels (Pâ=â0.002). In aviremic participants detectable EBV DNA was associated with pleocytosis (Pâ=â0.056), higher neopterin (Pâ=â0.027) and immune globulins (Pâ=â0.016) in the CSF; CSF escape was more common in those with detectable EBV DNA (50 vs. 21.2%, Pâ=â0.036). CONCLUSION: EBV DNA was frequently detected in the CSF of viremic and fewer aviremic patients on antiretroviral treatment. In PLWH without clinical evidence of encephalitis CSF EBV DNA was associated with higher biomarkers levels of neuronal damage/inflammation. The role of EBV reactivation in HIV-associated central nervous system disorders warrants further studies.
Assuntos
DNA Viral , Infecções por HIV , Herpesvirus Humano 4 , Adulto , Líquido Cefalorraquidiano , Estudos Transversais , DNA Viral/líquido cefalorraquidiano , Feminino , Infecções por HIV/líquido cefalorraquidiano , Infecções por HIV/complicações , Herpesvirus Humano 4/isolamento & purificação , Humanos , Leucócitos Mononucleares , Masculino , Pessoa de Meia-Idade , RNA , Carga ViralRESUMO
BACKGROUND: Central nervous system (CNS) may be infected by several agents, resulting in different presentations and outcomes. Analysis of cerebrospinal fluid (CSF) markers could be helpful to differentiate specific conditions and setting an appropriate therapy. METHODS: Patients presenting with signs and symptoms were enrolled if, before receiving a diagnostic lumbar puncture, signed a written informed consent. We analyzed CSF indexes of blood-brain barrier permeability (CSF to serum albumin ratio or CSAR), inflammation (CSF to serum IgG ratio, neopterin), amyloid deposition (1-42 ß-amyloid), neuronal damage (Total tau (T-tau), Phosphorylated tau (P-tau), and 14.3.3 protein) and astrocyte damage (S-100ß). RESULTS: Two hundred and eighty-one patients were included: they were mainly affected by herpesvirus encephalitis, enterovirus meningoencephalitis, bacterial meningitis (Neisseria meningitidis and Streptococcus pneumoniae), and infection by other etiological agents or unknown pathogen. Their CSF features were compared with HIV-negative patients and native HIV-positive individuals without CNS involvement. 14.3.3 protein was found in bacterial and HSV infections while T-tau and neopterin were abnormally high in the herpesvirus group. P-tau, instead, was elevated in enterovirus meningitis. S-100ß was found to be high in patients with HSV-1 and HSV-2 infections but not in those with Varicella Zoster Virus (VZV). Thirty-day mortality was unexpectedly low (2.7%): patients who died had higher levels of T-tau and, significantly, lower levels of Aß1-42. CONCLUSION: This work demonstrates that CSF biomarkers of neuronal damage or inflammation may vary during CNS infections according to different causative agents. The prognostic value of these biomarkers needs to be assessed in prospective studies.
Assuntos
Infecções do Sistema Nervoso Central/líquido cefalorraquidiano , Proteínas 14-3-3/líquido cefalorraquidiano , Adulto , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Infecções do Sistema Nervoso Central/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neopterina/líquido cefalorraquidiano , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidiano , Análise de Sobrevida , Proteínas tau/líquido cefalorraquidianoRESUMO
The landscape of central nervous system HIV infection is rapidly changing, leading to the recognition of a new constellation of overlapping syndromes and to a better insight for the elder ones. Among these, progressive multifocal leukoencephalopathy (PML) still poses several diagnostic and therapeutic challenges; nevertheless, recent developments in understanding PML in patients with multiple sclerosis may have benefitted HIV-positive patients suffering from PML too. We describe a peculiar case of PML-immune reconstitution inflammatory syndrome (IRIS) presenting a punctate pattern with "milky way" appearance on magnetic resonance imaging. Despite the fact that brain imaging and histopathology remain the mainstays for extricating through the expanding galaxy of HIV-related central nervous system dysimmune syndromes and although punctate pattern has been already well acknowledged as a suggestive finding of PML among patients on natalizumab, this radiological presentation is still poorly recognised in AIDS-related PML cases, leading to possible life-threatening diagnostic delays. This is also the first report about intravenous immunoglobulin treatment in AIDS-related PML-IRIS; the favourable clinical and radiological outcome of our case and the preliminary administrations of intravenous immunoglobulins in natalizumab-associated PML-IRIS from literature support probable benefits also among HIV-positive patients.
Assuntos
Infecções por HIV/complicações , Síndrome Inflamatória da Reconstituição Imune/patologia , Leucoencefalopatia Multifocal Progressiva/patologia , Adulto , Encéfalo/patologia , Infecções por HIV/tratamento farmacológico , Humanos , Síndrome Inflamatória da Reconstituição Imune/tratamento farmacológico , Imunoglobulinas Intravenosas/uso terapêutico , Leucoencefalopatia Multifocal Progressiva/tratamento farmacológico , MasculinoRESUMO
A case of progressive multifocal leukoencephalopathy (PML) is described in an HIV-negative patient with mixed connective-tissue disease (MCTD) on a minimally immunosuppressive treatment with hydroxychloroquine. The patient presented with right-sided weakness, episodes of disorientation and loss of short-term memory and of vision in her right eye. PML was diagnosed by JCV DNA on cerebrospinal fluid and radiological criteria. She was treated with off-label maraviroc and mirtazapine but died two months after hospital admission, despite a surprising decrease in the viral load of cerebrospinal fluid three weeks after starting therapy. Prompt diagnosis and antiviral treatment of PML even in low-risk patients are warranted. Future studies are required to define the therapeutic role of maraviroc (MVC) and mirtazapine in this setting.
Assuntos
Antagonistas dos Receptores CCR5/administração & dosagem , Leucoencefalopatia Multifocal Progressiva/tratamento farmacológico , Maraviroc/administração & dosagem , Mirtazapina/administração & dosagem , Quimioterapia Combinada , Feminino , Soronegatividade para HIV , Humanos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: HIV late presenters are at high risk of cytomegalovirus (CMV) reactivation and end-organ disease. CMV viraemia has been associated with poor survival but the effect of anti-CMV treatment has not been studied in this setting. METHODS: HIV-positive patients were included in a retrospective study if presenting with <350 CD4+ T-cells/µl and starting an antiretroviral treatment within 3 months of the diagnosis. Primary end point was 5-year survival according to the presence of CMV viraemia, CMV end-organ disease and anti-CMV treatment. RESULTS: 302 patients were included. 157 patients (52%) presented CMV viraemia (CMV-V) and 44 (14.6%) CMV end-organ disease (CMV-EOD). 5-year mortality was higher in CMV-EOD and CMV-V patients than in CMV-negative patients (11.4 versus 9.6 versus 0%; P=0.002). In patients with CMV-V, 5-year mortality was numerically higher in untreated patients (12.9% versus 6.9%; P=0.257) without reaching statistical significance. At univariate analysis the diagnosis of serious opportunistic infections (cryptococcosis, progressive multifocal leukoencephalopathy, lymphoma; P=0.001) and the absence of a negative CMV DNA in the follow-up (P<0.001) were associated with poor outcome. At multivariate analysis HCV coinfection (P=0.016; aOR 6.98, 95% CI 1.50, 32.59), the absence of a negative CMV DNA in the follow-up (P<0.001; aOR 19.40, 95% CI 3.70, 101.64) and marginally the absence of anti-CMV treatment (P=0.052; aOR 4.944, 95% CI 0.99, 24.73) were independent predictors of poor outcome. CONCLUSIONS: CMV reactivation in HIV-positive patients with poor immunity is associated with worse prognosis: the pre-emptive use of anti-CMV therapy was associated with a better outcome in patients with CMV-V.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Antivirais/uso terapêutico , Infecções por Citomegalovirus/tratamento farmacológico , Citomegalovirus/efeitos dos fármacos , DNA Viral/genética , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Infecções Oportunistas Relacionadas com a AIDS/imunologia , Infecções Oportunistas Relacionadas com a AIDS/mortalidade , Infecções Oportunistas Relacionadas com a AIDS/virologia , Adulto , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/virologia , Citomegalovirus/genética , Citomegalovirus/metabolismo , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/mortalidade , Infecções por Citomegalovirus/virologia , DNA Viral/antagonistas & inibidores , DNA Viral/metabolismo , Feminino , Infecções por HIV/imunologia , Infecções por HIV/mortalidade , Infecções por HIV/virologia , HIV-1/genética , HIV-1/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Análise de Sobrevida , Fatores de Tempo , Ativação Viral/efeitos dos fármacosRESUMO
The majority of neurologically symptomatic cerebrospinal fluid HIV-1 escape cases are connected with resistance-associated mutations and potentially explained by low cerebrospinal fluid antiretroviral concentrations. However, there are still significant knowledge gaps regarding the physiopathology and long-term management of neurosymptomatic viral escape. We report a case of Parkinson-like syndrome following cerebrospinal fluid HIV-1 escape in a 40-year-old female patient with an history of persistent low-level plasma viremia under treatment. No resistance-associated mutations, high viral diversity (env deep sequencing), adequate pharmacokinetics, atypical CD3-CD14-CD4+CD5-CD2-/+CD7-/+ lymphocytes, low-level Epstein-Barr virus replication, and white matter autoimmune reactivity were observed in the cerebrospinal fluid. Antiretroviral regimen modification led to rapid clinical and radiological improvements. This case may increase the current uncertain knowledge on the origin of cerebrospinal fluid HIV-1 and illustrates the consequences of uncontrolled compartmental viral replication; it also highlights the relevance and persistence of immune activation and the possibility of various detrimental mechanisms underlying neurosymptomatic viral escape.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por Vírus Epstein-Barr/virologia , Infecções por HIV/virologia , Doença de Parkinson/virologia , RNA Viral/genética , Paralisia Supranuclear Progressiva/virologia , Viremia/virologia , Adulto , Terapia Antirretroviral de Alta Atividade , Substituição de Medicamentos , Infecções por Vírus Epstein-Barr/líquido cefalorraquidiano , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Feminino , Infecções por HIV/líquido cefalorraquidiano , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , HIV-1/genética , HIV-1/crescimento & desenvolvimento , HIV-1/patogenicidade , Herpesvirus Humano 4/efeitos dos fármacos , Herpesvirus Humano 4/crescimento & desenvolvimento , Herpesvirus Humano 4/patogenicidade , Humanos , Doença de Parkinson/líquido cefalorraquidiano , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Paralisia Supranuclear Progressiva/líquido cefalorraquidiano , Paralisia Supranuclear Progressiva/complicações , Paralisia Supranuclear Progressiva/tratamento farmacológico , Viremia/líquido cefalorraquidiano , Viremia/complicações , Viremia/tratamento farmacológico , Replicação Viral/efeitos dos fármacosRESUMO
Intravesical Bacillus Calmette-Guérin (BCG) immunotherapy decreases the progression risk of non-muscle-invasive bladder cancer, but potentially yields a broad spectrum of side effects. We report the case of a 73-year-old man affected by miliary pulmonary BCG infection, whose microbiological diagnosis was probably hindered by empiric fluoroquinolones, focusing on imaging and clinical work-up.
Assuntos
Vacina BCG/efeitos adversos , Imunoterapia/efeitos adversos , Mycobacterium bovis/patogenicidade , Tuberculose Miliar/etiologia , Tuberculose Pulmonar/etiologia , Idoso , Antituberculosos/uso terapêutico , Líquido da Lavagem Broncoalveolar/microbiologia , Carcinoma de Células de Transição/terapia , Diagnóstico Tardio , Febre de Causa Desconhecida/microbiologia , Humanos , Masculino , Mycobacterium bovis/isolamento & purificação , Ofloxacino/uso terapêutico , Escarro/microbiologia , Tuberculose Miliar/diagnóstico , Tuberculose Miliar/tratamento farmacológico , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/diagnóstico por imagem , Tuberculose Pulmonar/tratamento farmacológico , Neoplasias da Bexiga Urinária/terapiaRESUMO
BACKGROUND: Lymphoproliferative disorders are frequently diagnosed in HIV-positive patients and severe infections may occur during antineoplastic treatments: the incidence and impact of such events are not well-characterized. OBJECTIVE: To describe the occurrence and mortality of incident infections in HIV-positive individuals treated for lymphoproliferative disorders. METHODS: A retrospective study in HIV-positive adults with lymphoproliferative disorders (2000- 2012) who were hospitalised to receive antineoplastic chemotherapy; antimicrobial prophylaxis with alternate day co-trimoxazole (800/160 mg) was administered to all individuals. RESULTS: 103 patients were included: mostly males (81, 78.6%), Caucasians (101, 98.1%), with a median age of 43 years (39-51). Fifty-eight (56.3%) patients had non-Hodgkin's lymphoma (NHL), thirty-two (29.1%) had Hodgkin's lymphoma (HL) and ten patients (9.7%) had Burkitt's lymphoma (BL). Five year survival was 63.1%: the best survival rates were reported in HL (78.1%), followed by NHL (58.6%) and BL (50%). Forty-four patients (42.7%) developed 82 infections during follow up: identified causative agents were bacteria (35, 42.7%), viruses (28, 34.1%), mycobacteria (7, 8.5%), protozoa (7, 8.5%) and fungi (5, 6.1%). Cytomegalovirus infections (n=17, including 5 endorgan diseases) emerged 53 days after the diagnosis: multivariate analysis showed CD4+ cell count <100/uL as the only independently associated factor (p<0.001, aOR=23.5). Two factors were associated with mortality risk: an IPI/IPS-score of >2 (p=0.004, aOR=6.55) and the presence of CMV disease (p=0.032, aOR=2.73). CONCLUSION: HIV positive patients receiving treatment for lymphoproliferative disorders suffer from a high incidence of infections and associated mortality risk. Tailored prophylactic strategies need to be considered in this setting.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/epidemiologia , Infecções Oportunistas Relacionadas com a AIDS/mortalidade , Antineoplásicos/uso terapêutico , Infecções por HIV/complicações , Transtornos Linfoproliferativos/complicações , Transtornos Linfoproliferativos/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/etiologia , Adulto , Animais , Bactérias/classificação , Bactérias/isolamento & purificação , Feminino , Fungos/classificação , Fungos/isolamento & purificação , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Parasitos/classificação , Parasitos/isolamento & purificação , Estudos Retrospectivos , Análise de Sobrevida , Vírus/classificação , Vírus/isolamento & purificaçãoRESUMO
During June 9-September 30, 2015, five cases of louseborne relapsing fever were identified in Turin, Italy. All 5 cases were in young refugees from Somalia, 2 of whom had lived in Italy since 2011. Our report seems to confirm the possibility of local transmission of louse-borne relapsing fever.
Assuntos
População Negra , Borrelia , Refugiados , Febre Recorrente/epidemiologia , Febre Recorrente/microbiologia , Borrelia/classificação , Borrelia/genética , Borrelia/isolamento & purificação , Humanos , Itália/epidemiologia , RNA Ribossômico 16S/genética , Febre Recorrente/diagnóstico , Febre Recorrente/transmissãoRESUMO
Cytomegalovirus (CMV) central nervous system involvement is uncommon and hardly diagnosed because it can mimic many different conditions. We here present a case of an HIV-positive patient with neurological signs and symptoms (headache, asthenia, confusion, hallucinations, ataxia) with concurrent opportunistic diseases (neurotoxoplasmosis, disseminated Kaposi's sarcoma, disseminated CMV infection). CMV CNS involvement was not initially considered given the observed multiple comorbidities: antiviral treatment duration was probably not adequate given the end-organ disease. Concomitantly, plasma CMV DNA was undetectable while cerebrospinal fluid viral load was 31,340 copies/ml. Ganciclovir treatment followed by oral valganciclovir maintenance was associated with the slow disappearance of symptoms, the improvement of MRI images and the persistent undetectability of CMV DNA. The case here reported highlights the challenges of diagnosing CMV encephalitis in HIV-positive patients (with several cerebral comorbidities), the incomplete knowledge of the appropriate treatment for such a disease and the possibility of CMV replication in the cerebrospinal fluid despite undetectable plasma CMV DNA.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS , Infecções por Citomegalovirus/virologia , Citomegalovirus , Encefalite Viral/virologia , Adulto , Citomegalovirus/genética , Infecções por Citomegalovirus/diagnóstico , DNA Viral , Encefalite Viral/diagnóstico , Humanos , Imageamento por Ressonância Magnética , Masculino , Carga ViralRESUMO
INTRODUCTION: Low level HIV-1 CSF replication (CsfLLV) is often found even in patients with controlled plasma viraemia. The clinical consequences of such finding are uncertain; however, both symptomatic neurological disturbances and neurocognitive disorders may arise in the context of CSF-escape. Two reports suggested that low level replication in the CSF may be associated with increased CSF neopterine although the impact on other markers of neuroinflammation/damage is currently unknown. MATERIALS AND METHODS: Patients with neurocognitive disorders, new neurological symptoms or followed in longitudinal studies were included provided that they were on HAART, with last available viral load below 20 copies/mL and without central nervous system (CNS)-involving infections/neoplasms. After brain Magnetic Resonance (MR) CSF HIV RNA (CAP/CTM HIV-1 v2.0) and biomarkers [total tau (t-tau), phosphorylated tau (p-tau), 1-42 Beta amyloid (Beta42), neopterine and S100beta] were measured through validated methods. Data are presented as medians (IQR); non-parametric tests are used for all analysis. RESULTS: 70 patients [66.7% male, median age 47.8 years (40-56), median BMI 22.2 kg/m2 (20-24)] were enrolled. Current and nadir CD4+ cell count were 379 (219-656) and 116 cell/mm3 (46-225); HIV RNA was undetectable since 19.7 months (9-53). CSF HIV RNA was undetectable in 24 (34.3%), below 20 copies/mL in 26 (37.1%), above 20 copies/mL in 25 patients [35.7%, median 69 copies/mL (41-134]). Median (IQR) CSF biomarkers values were as follows: t-tau 109 pg/mL (<75-161), p-tau 31.6 pg/mL (23.4-35.4), Beta42 818 pg/mL (623-973), neopterine 0.58 ng/mL (0.45-0.87) and S100beta 149 pg/mL (110-186). Patients with CsfLLV did not show significant differences as for demographic, therapeutic, virological, radiological variables. t-tau (134 vs 92.6, p=0.05) and Beta42 (953 vs 675, p=0.007) were higher in patients with CsfLLV. Neopterine levels were directly associated with p-tau (rho=0.42, p=0.01), with CSF HIV RNA (rho=0.24, p=0.06). and inversely with current CD4 cell count (rho=-0.29, p=03). CONCLUSIONS: In patients with controlled HIV viraemia (below 20 copies/mL), CSF total tau, Beta42 and neopterine were higher in patients with detectable HIV RNA. Prospective and adequately powered studies are warranted for evaluating the clinical significance of compartmental viral replication and immune activation.
RESUMO
AIM: To investigate the pharmacokinetics of voriconazole when administered to HIV-positive patients receiving treatment with atazanavir-containing therapies according to CYP2C19 genotype. MATERIALS & METHODS: We describe four HIV-positive patients with pulmonary aspergillosis treated with voriconazole and atazanavir-based regimens (with or without ritonavir). They were managed by assessing their CYP2C19 genotype (CYP2C19*2, rs4244285, G>A, real-time PCR) and therapeutic drug monitoring (HPLC-based validation methods). RESULTS & CONCLUSION: Voriconazole exposure was variable but Ctrough levels were above 1000 ng/ml in all patients; one CYP2C19 intermediate metabolizer required lower doses of voriconazole (50 mg twice daily) to obtain satisfactory drug concentrations. Atazanavir and ritonavir plasma levels were moderately reduced (area under the curve: -23 and -26%, respectively); raltegravir exposure seemed increased by voriconazole administration (area under the curve: 2.5-fold higher) in a single subject. Coadministration of atazanavir and voriconazole may be feasible in selected HIV-positive patients; therapeutic drug monitoring and CYP2C19 genotyping may optimize exposure of both drugs.
Assuntos
Citocromo P-450 CYP2C19/genética , Oligopeptídeos/administração & dosagem , Aspergilose Pulmonar/tratamento farmacológico , Piridinas/administração & dosagem , Voriconazol/administração & dosagem , Adulto , Idoso , Sulfato de Atazanavir , Interações Medicamentosas/genética , Feminino , Genótipo , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/patologia , Infecções por HIV/virologia , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/farmacocinética , Aspergilose Pulmonar/complicações , Aspergilose Pulmonar/patologia , Aspergilose Pulmonar/virologia , Piridinas/farmacocinética , Ritonavir/administração & dosagem , Ritonavir/sangue , Voriconazol/farmacocinéticaRESUMO
OBJECTIVES: To analyse the determinants of raltegravir CSF penetration, including the pharmacogenetics of drug transporters located at the blood-brain barrier or blood-CSF barrier. METHODS: Plasma and CSF raltegravir concentrations were determined by a validated HPLC coupled with mass spectrometry method in adults on raltegravir-based combination antiretroviral therapy undergoing a lumbar puncture. Single nucleotide polymorphisms in the genes encoding drugs transporters (ABCB1 3435, SLCO1A2, ABCC2 and SLC22A6) and the gene encoding hepatocyte nuclear factor 4 α (HNF4α) were determined by real-time PCR. RESULTS: In 41 patients (73.2% male, 95.1% Caucasians), the median raltegravir plasma and CSF concentrations were 165 ng/mL (83-552) and 31 ng/mL (21-56), respectively. CSF-to-plasma ratios (CPRs) ranged from 0.005 to 1.33 (median 0.20, IQR 0.04-0.36). Raltegravir trough CSF concentrations (n = 35) correlated with raltegravir plasma levels (ρ = 0.395, P = 0.019); CPRs were higher in patients with blood-brain barrier damage (0.47 versus 0.18, P = 0.02). HNF4α 613 CG genotype carriers had lower trough CSF concentrations (20 versus 37 ng/mL, P = 0.03) and CPRs (0.12 versus 0.27, P = 0.02). Following multivariate linear regression analysis, the CSF-to-serum albumin ratio was the only independent predictor of raltegravir penetration into the CSF. CONCLUSIONS: Raltegravir penetration into the CSF shows a large interpatient variability, although CSF concentrations were above the wild-type IC50 in all patients (and above IC95 in 28.6%). In this cohort, blood-brain barrier permeability is the only independent predictor of raltegravir CPR. The impact of single nucleotide polymorphisms in selected genes on raltegravir penetration warrants further studies.
Assuntos
Fármacos Anti-HIV/farmacocinética , Barreira Hematoencefálica , Líquido Cefalorraquidiano/química , Infecções por HIV/tratamento farmacológico , Proteínas de Membrana Transportadoras/genética , Farmacogenética , Pirrolidinonas/farmacocinética , Adulto , Fármacos Anti-HIV/administração & dosagem , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 2 Associada à Farmacorresistência Múltipla , Plasma/química , Polimorfismo de Nucleotídeo Único , Pirrolidinonas/administração & dosagem , Raltegravir PotássicoAssuntos
Antivirais/uso terapêutico , Infecções por HIV/complicações , Hepatite C/tratamento farmacológico , Interferon-alfa/uso terapêutico , Adulto , Feminino , Humanos , Interferon alfa-2 , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis , Proteínas Recombinantes , Resultado do Tratamento , Adulto JovemRESUMO
This study reports the results of a one-day point prevalence study of infections performed in 2001 (SPIR01) and 2002 (SPIR02) in a Regional network of ICUs in Piedmont, Italy. The study aims were to illustrate the overall proportion of infected patients and the rate of ICU-acquired infections. Mortality rate was evaluated three weeks after the study days. Resistance pattern of Staphylococcus aureus, coagulase negative Staphylococci and Pseudomonas aeruginosa were recorded. The primary end-point of the study was to document the prevalence and associated risk factors of the ICU-acquired infections, and the impact of infections on mortality. The prevalence of ICU-acquired infection was 30% in SPIR01, and 38.3% in SPIR02. The rate of methicillin-resistance was high among isolates of Staphylococcus aureus and coagulase-negative Staphylococci. The prevalence of ICU-acquired infections was lower than that reported in the EPIC study. In our experience, this Regional survey stimulated further research and collaboration to improve the prophylaxis, diagnosis and treatment of ICU-acquired infections.
Assuntos
Infecção Hospitalar/epidemiologia , Unidades de Terapia Intensiva/estatística & dados numéricos , Infecção Hospitalar/microbiologia , Farmacorresistência Bacteriana , Infecções por Bactérias Gram-Positivas/epidemiologia , Infecções por Bactérias Gram-Positivas/microbiologia , Cocos Gram-Positivos/efeitos dos fármacos , Cocos Gram-Positivos/isolamento & purificação , Humanos , Itália/epidemiologia , Prevalência , Infecções por Pseudomonas/epidemiologia , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/isolamento & purificação , Fatores de RiscoRESUMO
The paper describes a case report of a young female with invasive aspergillosis diagnosed after brief treatment with high-dose steroids for autoimmune thrombocytopenia. Early diagnosis of invasive aspergillosis was made with cultures of tracheoaspirates and bronchoalveolar lavage and was confirmed with a transbronchial biopsy. After initial ineffective treatment with liposomal amphotericin B and dissemination from pulmonary to central nervous system involvement, treatment was switched to a combination of voriconazole and caspofungin. After marked clinical and radiological improvement, treatment was switched to the orally administered formulation of voriconazole until the complete disappearance of central nervous system lesion was observed. In the discussion section we underscore the most significant data of the host susceptibility, diagnosis of invasive aspergillosis, complications and treatment. This case ably demonstrates the efficacy of new antifungal agents, even when administered orally, and underscores the variability of host susceptibility to atypical and often unexpected invasive fungal infections.