Diego R. Falci

Population Pharmacokinetics of Intravenous Polymyxin B in Critically Ill Patients: Implications for Selection of Dosage Regimens

BACKGROUNDnPolymyxin B is a last-line therapy for multidrug-resistant gram-negative bacteria. There is a dearth of pharmacokinetic data to guide dosing in critically ill patients.nnnMETHODSnTwenty-four critically ill patients were enrolled and blood/urine samples were collected over a dosing interval at steady state. Polymyxin B concentrations were measured by liquid chromatography-tandem mass spectrometry. Population pharmacokinetic analysis and Monte Carlo simulations were conducted.nnnRESULTSnTwenty-four patients aged 21-87 years received intravenous polymyxin B (0.45-3.38 mg/kg/day). Two patients were on continuous hemodialysis, and creatinine clearance in the other patients was 10-143 mL/min. Even with very diverse demographics, the total body clearance of polymyxin B when scaled by total body weight (population mean, 0.0276 L/hour/kg) showed remarkably low interindividual variability (32.4% coefficient of variation). Polymyxin B was predominantly nonrenally cleared with median urinary recovery of 4.04%. Polymyxin B total body clearance did not show any relationship with creatinine clearance (r(2) = 0.008), APACHE II score, or age. Median unbound fraction in plasma was 0.42. Monte Carlo simulations revealed the importance of initiating therapeutic regimens with a loading dose.nnnCONCLUSIONSnOur study showed that doses of intravenous polymyxin B are best scaled by total body weight. Importantly, dosage selection of this drug should not be based on renal function.

Isolation of NDM-producing Providencia rettgeri in Brazil

Laboratório de Pesquisa em Infecção Hospitalar (LAPIH), Instituto Oswaldo Cruz-FIOCRUZ, Rio de Janeiro, RJ, Brazil; Departamento de Bioquı́mica, Instituto de Biologia Roberto Alcântara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Fundação Estadual de Produção e Pesquisa em Saúde (FEPPS IPB-LACEN-RS), Porto Alegre, RS, Brazil; Hospital Nossa Senhora da Conceição, Porto Alegre, RS, Brazil

Pharmacokinetics of polymyxin B in patients on continuous venovenous haemodialysis

OBJECTIVESnTo evaluate the pharmacokinetics of polymyxin B in patients on continuous venovenous haemodialysis (CVVHD) after intravenous administration of unadjusted dosage regimens.nnnPATIENTS AND METHODSnTwo critically ill patients had eight blood samples collected during a 12 h interval on days 8 and 10 of polymyxin B therapy. Dialysate was collected every hour during the 12 h dosing interval. Polymyxin B binding in plasma was determined by rapid equilibrium dialysis. Concentrations of polymyxin B in plasma and dialysate samples were quantified using a validated ultra-performance liquid chromatography-tandem mass spectrometry assay.nnnRESULTSnRespective maximum plasma concentrations in patients 1 and 2 were 8.62 and 4.38 mg/L; total body clearances (scaled linearly by body weight) were 0.043 and 0.027 L/h/kg, respectively, of which 12.2% and 5.62% were dialysis clearance, respectively. The corresponding volumes of distribution of polymyxin B at steady state were 0.50 and 0.34 L/kg, respectively, and protein binding in pooled plasma samples was 74.1% and 48.8%, respectively.nnnCONCLUSIONSnOur findings indicate that the recommended polymyxin B doses should not be reduced for patients on CVVHD.

Continuous Infusion of Amphotericin B Deoxycholate in the Treatment of Cryptococcal Meningoencephalitis: Analysis of Safety and Fungicidal Activity

We measured fungicidal activity of continuous infusion of amphotericin B deoxycholate plus 5flucytosine using quantitative cultures of cerebrospinal fluid (CSF) obtained from lumbar punctures of human immunodeficiency virus (HIV)-infected patients with neurocryptococcosis during 14 days of treatment. Glomerular renal function was preserved in all patients. Mycological efficacy with progressive reduction in CSF cryptococcal colony-forming units was comparable to standard 4-h infusion of amphotericin B.

Continuous infusion of amphotericin B deoxycholate: an innovative, low-cost strategy in antifungal treatment.

The combination of amphotericin B and sodium deoxycholate is the formulation most used in clinical practice. The development of new agents such as amphotericin with lipid formulations, caspofungin, voriconazole and other azolic derivatives, promoted alternatives to amphotericin B deoxycholate. However, because of the high cost of these new drugs, their use is difficult in a scenario of limited resources. A few strategies have been devised to make the use of amphotericin B deoxycholate less toxic. In this review, we seek to describe the accumulated knowledge about this molecule, with focus on its use in continuous infusion, which appears to be an alternative to reduce toxicity, while maintaining its clinical efficacy.

Progressive disseminated histoplasmosis: a systematic review on the performance of non-culture-based diagnostic tests

The diagnosis of progressive disseminated histoplasmosis is often a challenge to clinicians, especially due to the low sensitivity and long turnaround time of the classic diagnostic methods. In recent years, studies involving a variety of non-culture-based diagnostic tests have been published in the literature. We performed a systematic review by selecting studies evaluating non-culture-based diagnostic methods for progressive disseminated histoplasmosis. We searched for articles evaluating detection of antibody, antigens, as well as DNA-based diagnostic methods. A comprehensive PUBMED, Web of Science, and Cochrane Library search was performed between the years 1956 and 2016. Case reports, review articles, non-human models and series involving less than 10 patients were excluded. We found 278 articles and after initial review 18 articles were included: (12) involved antigen detection methods, (4) molecular methods, and (2) antibody detection methods. Here we demonstrate that the pursuit of new technologies is ultimately required for the early and accurate diagnosis of disseminated histoplasmosis. In particular, urinary antigen detection was the most accurate tool when compared with other diagnostic techniques.

Chronic slowly progressive monoarthritis tuberculosis of the hip without systemic symptoms mimicking osteoarthritis: a case report

The authors report and discuss the clinical and radiological features of a immunocompetent patient with chronic progressive monoarthritis tuberculosis of the hip without systemic symptoms such as fever, and weight loss presenting as caseating abscess and severe destruction of the hip joint, treated with resection arthroplasty.

Impact of polymyxin-B-associated acute kidney injury in 1-year mortality and renal function recovery

The objective of this study was to evaluate the impact of polymyxin B (PMB) -associated acute kidney injury (AKI) in 1-year mortality and renal function recovery. Patients >18 years old who survived the first 30 days after PMB therapy were followed for 1 year. The impact of AKI and renal failure (using RIFLE score) in 1-year mortality was analysed, along with other confounding variables. Variables with a P-value ≤0.2 were included in a forward stepwise Cox regression model. In the subgroup of patients who developed AKI, we evaluated renal function recovery. A total of 234 patients were included for analyses. Of these, 108 (46.1%) died, in a median time of 63 (38.3-102.5) days. The use of other nephrotoxic drugs along with PMB (P = 0.05), renal failure (P = 0.03), dialysis (P < 0.01) and re-exposure to PMB (P<0.01), were all significantly related to 1-year mortality, while male gender had a protective effect (P = 0.01). Independent factors related to death were age (adjusted hazard ratio (aHR) 1.02, 95% confidence interval (CI) 1.00-1.03, P = 0.02), re-exposure to PMB (aHR 2.69, 95% CI 1.82-3.95, P<0.01), and male gender (aHR0.6, 95% CI 0.41-0.87, P = 0.01), when controlled for renal failure (aHR 1.28, 95% CI 0.78-2.10, P = 0.34).Thirty one of 94 (33%) patients who developed AKI had renal function recovery within 1 year. Mortality rates were high in the first year after PMB use and only one-third of patients who developed AKI returned to baseline renal function. Strategies to reduce renal toxicity are urgently needed in these patients.

Polymyxin B consumption and incidence of gram-negative bacteria intrinsically resistant to polymyxins.

Polymyxins Author(s): Diego R. Falci, MD, MSc; Liliane S. Pacheco, MD; Luciana S. Puga, PharmD; Renato C. F. da Silva, MD; Anelise P. Alves, MD; Paulo R. P. Behar, MD, PhD; Alexandre P. Zavascki, MD, PhD Source: Infection Control and Hospital Epidemiology, Vol. 33, No. 5 (May 2012), pp. 536-537 Published by: The University of Chicago Press on behalf of The Society for Healthcare Epidemiology of America Stable URL: http://www.jstor.org/stable/10.1086/665308 . Accessed: 05/10/2013 15:22