Clinical presentation and immunological features of Post-Malaria Neurologic Syndrome: a case report and review of literature

BackgroundMalaria still represents a major health threat, in terms of both morbidity and mortality. Complications of malaria present a diversified clinical spectrum, with neurological involvement leading to the most serious related-conditions. The authors recently encountered a case of a 60-year old Italian man presenting with confusion, language disturbances and Parkinson-like syndrome 3 weeks after complete remission from severe Plasmodium falciparum cerebral malaria. Chemical and microbiological analysis revealed aseptic meningitis, diffuse encephalitis and abnormal immune-activation. Re-infection and recrudescence of infection were excluded. Further analysis excluded paraneoplastic and autoimmune causes of encephalitis. A diagnosis of Post-Malaria Neurological Syndrome (PMNS) was finally formulated and successfully treated with high dose of steroids.MethodsA systematic research of current literature related to PMNS was performed.Results151 cases of PMNS were included, the majority of which occurred after severe P. falciparum infections. Four main clinical pattern were identified: 37% of the cases presented as "classical" PMNS, 36% presented as delayed cerebellar ataxia (DCA), 18% resembled acute inflammatory demyelinating polyneuropathy (AIDP), and 8% presented as acute disseminated encephalomyelitis (ADEM)-like form. Differentiation between different forms was not always simple, as clinical and radiological findings frequently overlap. Overall, in almost all of the tested cases, cerebrospinal fluid was found pathological; EEG revealed nonspecific encephalopathy in 30% of classical PMNS and 67% ADEM; imaging tests were found abnormal in 92% of ADEM-like forms. Pathogenesis remains unclear. An autoimmune mechanism is the most corroborated pathogenic hypothesis. Overall, the majority of PMNS cases revert without specific treatment. In most severe forms, high dose steroids, intravenous immunoglobulins, and plasmapheresis have been shown to improve symptoms.ConclusionsPMNS is a disabling complication of malaria. The overall incidence is not known, due to frequent misdiagnosis and under-reporting. Pathogenesis is not also fully understood, but rapid response to immune-modulating treatment along with similarities to auto-immune neurological disease, strongly support a dysregulated immunological genesis of this condition. The lack of randomized controlled studies regarding therapeutic approaches is a major unmet need in this setting. A systematic collection of all the PMNS cases would be desirable, in order to increase awareness of this rare condition and to prospectively investigate the most appropriate management

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Delafloxacin for the treatment of respiratory and skin infections

Introduction: There has been a striking increase in the emergence of multidrug-resistant pathogens in recent times. Delafloxacin is a novel, broad-spectrum fluoroquinolone with antimicrobial activity against resistant Gram-positive, Gram-negative and anaerobic organisms. It has the potential to treat a variety of infections including complicated skin and skin structure infections and respiratory tract infections.Areas covered: In this review, the authors report the microbiological spectrum of activity of delafloxacin as well as its pharmacokinetic characteristics. They also report the results of recent studies investigating its safety and efficacy.Expert opinion: The profile of delafloxacin offers several advantages. Delafloxacin presents a broad spectrum of activity against pathogens involved in respiratory infections and complicated skin and skin structure infections (SSSIs), including methicillin-resistant Staphylococcus aureus. It has also shown activity against Gram-negative pathogens, such as quinolone-susceptible and -resistant strains of Escherichia coli and Klebsiella pneumoniae and quinolone-susceptible Pseudomonas aeruginosa. The availability of an oral formulation supports its use in sequential therapy. The efficacy and tolerability of delafloxacin have been demonstrated in Phase II clinical trials in comparison with moxifloxacin for respiratory infections and linezolid and vancomycin in SSSIs. Compared with other quinolones such as moxifloxacin, delafloxacin showed comparable efficacy and a lower rate of adverse effects. The results of new Phase III studies are awaited to confirm delafloxacin's future applications in the treatment of SSSI

Population Pharmacokinetic and Pharmacodynamic Analysis of Valganciclovir for Optimizing Preemptive Therapy of Cytomegalovirus Infections in Kidney Transplant Recipients

This study aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model of valganciclovir for preemptive therapy of cytomegalovirus (CMV) infection in kidney transplant patients. A population PK/PD model was developed with Monolix.This study aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model of valganciclovir for preemptive therapy of cytomegalovirus (CMV) infection in kidney transplant patients. A population PK/PD model was developed with Monolix. Ganciclovir concentrations and CMV viral loads were obtained retrospectively from kidney transplant patients receiving routine clinical care. Ten thousand Monte Carlo simulations were performed with the licensed dosages adjusted for renal function to assess the probability of attaining a viral load target of <= 290 and <= 137 IU/mL. Fifty-seven patients provided 343 ganciclovir concentrations and 328 CMV viral loads for PK/PD modeling. A one-compartment pharmacokinetic model coupled with an indirect viral turnover growth model with stimulation of viral degradation pharmacodynamic model was devised. Simulations showed that 1- and 2-log(10) reduction of CMV viral load mostly occurred between a median of 5 to 6 and 12 to 16 days, respectively. The licensed dosages achieved a probability of reaching the viral load target >= 90% at days 35 to 49 and 42 to 56 for the thresholds of <= 290 and <= 137 IU/mL, respectively. Simulations indicate that in patients with an estimated glomerular filtration rate of 10 to 24 mL/min/1.73m(2), a dose increase to 450 mg every 36 h may reduce time to optimal viral load target to days 42 and 49 from a previous time of 49 and 56 days for the thresholds of <= 290 and <= 137 IU/mL, respectively. Currently licensed dosages of valganciclovir for preemptive therapy of CMV infection may achieve a viral load reduction within the first 2 weeks, but treatment should continue for >= 35 days to ensure viral load suppression

Current and future therapies for invasive aspergillosis

Invasive fungal infections have increase worldwide and represent a threat for immunocompromised patients including HIV-infected, recipients of solid organ and stem cell transplants, and patients receiving immunosuppressive therapies. High mortality rates and difficulties in early diagnosis characterize pulmonary fungal infections. Invasive pulmonary aspergillosis has been reviewed focussing on therapeutic management. Although new compounds have become available in the past years (i.e., amphotericin B lipid formulations, last-generation azoles, and echinocandines), new diagnostic tools and careful therapeutic management are mandatory to assure an early appropriate targeted treatment that represents the key factor for a successful conservative approach in respiratory fungal infection

Determination of PCT on admission is a useful tool for the assessment of disease severity in travelers with imported Plasmodium falciparum malaria

Procalcitonin (PCT) and C-reactive protein (CRP) may be useful to predict complicated forms of malaria. A total of 30 consecutive travelers diagnosed with Plasmodium falciparum malaria over a two-year period were included in the study. Patients with complicated Plasmodium falciparum malaria showed higher levels of parasitemia (P = 0.0001), PCT (P = 0.0018), CRP (P = 0.0005), bilirubinemia (P = 0.004), and a lower platelet count (P<0.0001) compared with patients with uncomplicated forms. PCT levels above 5 ng/mL showed the highest value of specificity (0.86) and positive predictive factor (0.67) among other parameters, and equal sensitivity (0.67) was displayed by CRP levels above 150 mg/dl. None of the patients with complicated malaria showed PCT levels within normal limits (<0.5 ng/ml). Both PCT and CRP correlated with parasitemia (P<0.001) and showed areas under ROC curve of 0.83. At multivariate analysis, only PCT was associated with an increased risk of complicated malaria (OR 8.2, IC 95% 1.2\u201357.2, P = 0.03). The determination of PCT on admission showed better results compared to CRP, platelet count, and bilirubinemia and can be useful in non-endemic areas for the initial clinical assessment of disease severity in travelers with Plasmodium falciparum malaria

Might real-time pharmacokinetic/pharmacodynamic optimisation of high-dose continuous-infusion meropenem improve clinical cure in infections caused by KPC-producing Klebsiella pneumoniae?

The effect of real-time pharmacokinetic/pharmacodynamic (PK/PD) optimisation of high-dose continuous-infusion meropenem on the clinical outcome of patients receiving combination antimicrobial therapy for treatment of KPC-producing Klebsiella pneumoniae (KPC-Kp) infections was retrospectively assessed. Data for all patients with KPC-Kp-related infections who received antimicrobial combination therapy containing high-dose continuous-infusion meropenem optimised by means of therapeutic drug monitoring (TDM) were retrieved. Optimal PK/PD exposure was considered a steady-state concentration to minimum inhibitory concentration ratio (Css/MIC) of 1\u20134. Univariate binary logistic regression analysis was performed to identify independent predictors of clinical outcome. Among the 30 eligible patients, 53.3% had infections caused by meropenem-resistant KPC-Kp (MIC\u2009 65\u200916\u2009mg/L). Tigecycline and colistin were the two antimicrobials most frequently combined with meropenem. Mean doses of continuous-infusion meropenem ranged from 1.7 to 13.2\u2009g/daily. The Css/MIC ratio was 651 in 73.3% of cases and 654 in 50.0%. Clinical outcome was successful in 73.3% of cases after a median treatment length of 14.0 days. In univariate analysis, a significant correlation with successful clinical outcome was found for a Css/MIC ratio 651 (OR\u2009=\u200910.556, 95% CI 1.612\u201369.122; P\u2009=\u20090.014), a Css/MIC ratio 654 (OR\u2009=\u200912.250, 95% CI 1.268\u2013118.361; P\u2009=\u20090.030) and a Charlson co-morbidity index of 654 (OR\u2009=\u20090.158, 95% CI 0.025\u20130.999; P\u2009=\u20090.05). High-dose continuous-infusion meropenem optimised by means of real-time TDM may represent a valuable tool in improving clinical outcome when dealing with the treatment of infections caused by KPC-Kp with a meropenem MIC\u2009 64\u200964\u2009mg/L

Linezolid-resistant staphylococcal bacteraemia: A multicentre case-case-control study in Italy

The aim of this multicentre study was to analyse the characteristics of patients with bloodstream infections due to staphylococcal strains resistant to linezolid. This was a retrospective case-case-control study of patients hospitalised in three large teaching hospitals in Italy. A linezolid-resistant (LIN-R) Staphylococcus spp. group and a linezolid-susceptible (LIN-S) Staphylococcus spp. group were compared with control patients to determine the clinical features and factors associated with isolation of LIN-R strains. All LIN-R Staphylococcus spp. strains underwent molecular typing. Compared with the LIN-S group, central venous catheters were the main source of infection in the LIN-R group. The LIN-R and LIN-S groups showed a similar incidence of severe sepsis or septic shock, and both showed a higher incidence of these compared with the control group. Overall, patients in the LIN-R group had a higher 30-day mortality rate. Multivariate analysis found previous linezolid therapy, linezolid therapy >14 days, antibiotic therapy in the previous 30 days, antibiotic therapy >14 days, previous use of at least two antibiotics and hospitalisation in the previous 90 days as independent risk factors associated with isolation of a LIN-R strain. The G2576T mutation in domain V of 23S rRNA was the principal mechanism of resistance; only one strain of Staphylococcus epidermidis carried the cfr methylase gene (A2503), together with L4 insertion (71GGR72) and L3 substitution (H146Q). LIN-R strains are associated with severe impairment of clinical conditions and unfavourable patient outcomes. Reinforcement of infection control measures may have an important role in preventing these infection

Linezolid-resistant staphylococcal bacteraemia: A multicentre case-case-control study in Italy

The aim of this multicentre study was to analyse the characteristics of patients with bloodstream infections due to staphylococcal strains resistant to linezolid. This was a retrospective case-case-control study of patients hospitalised in three large teaching hospitals in Italy. A linezolid-resistant (LIN-R) Staphylococcus spp. group and a linezolid-susceptible (LIN-S) Staphylococcus spp. group were compared with control patients to determine the clinical features and factors associated with isolation of LIN-R strains. All LIN-R Staphylococcus spp. strains underwent molecular typing. Compared with the LIN-S group, central venous catheters were the main source of infection in the LIN-R group. The LIN-R and LIN-S groups showed a similar incidence of severe sepsis or septic shock, and both showed a higher incidence of these compared with the control group. Overall, patients in the LIN-R group had a higher 30-day mortality rate. Multivariate analysis found previous linezolid therapy, linezolid therapy >14 days, antibiotic therapy in the previous 30 days, antibiotic therapy >14 days, previous use of at least two antibiotics and hospitalisation in the previous 90 days as independent risk factors associated with isolation of a LIN-R strain. The G2576T mutation in domain V of 23S rRNA was the principal mechanism of resistance; only one strain of Staphylococcus epidermidis carried the cfr methylase gene (A2503), together with L4 insertion (71GGR72) and L3 substitution (H146Q). LIN-R strains are associated with severe impairment of clinical conditions and unfavourable patient outcomes. Reinforcement of infection control measures may have an important role in preventing these infection

Risk factors for ventilator associated pneumonia due to carbapenemase-producing Klebsiella pneumoniae in mechanically ventilated patients with tracheal and rectal colonization

The aim of this study was to identify the risk factors for ventilator associated pneumonia (VAP) due to Klebsiella pneumoniae carbapenemase-producing K (KPC-Kp) development in ICU patients with documented rectal and tracheal colonization