Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab.

BACKGROUND: Coronavirus disease 2019 (Covid-19) disproportionately results in hospitalization or death in older patients and those with underlying conditions. Sotrovimab is a pan-sarbecovirus monoclonal antibody that was designed to prevent progression of Covid-19 in high-risk patients early in the course of disease. METHODS: In this ongoing, multicenter, double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, nonhospitalized patients with symptomatic Covid-19 (≤5 days after the onset of symptoms) and at least one risk factor for disease progression to receive a single infusion of sotrovimab at a dose of 500 mg or placebo. The primary efficacy outcome was hospitalization (for >24 hours) for any cause or death within 29 days after randomization. RESULTS: In this prespecified interim analysis, which included an intention-to-treat population of 583 patients (291 in the sotrovimab group and 292 in the placebo group), 3 patients (1%) in the sotrovimab group, as compared with 21 patients (7%) in the placebo group, had disease progression leading to hospitalization or death (relative risk reduction, 85%; 97.24% confidence interval, 44 to 96; P = 0.002). In the placebo group, 5 patients were admitted to the intensive care unit, including 1 who died by day 29. Safety was assessed in 868 patients (430 in the sotrovimab group and 438 in the placebo group). Adverse events were reported by 17% of the patients in the sotrovimab group and 19% of those in the placebo group; serious adverse events were less common with sotrovimab than with placebo (in 2% and 6% of the patients, respectively). CONCLUSIONS: Among high-risk patients with mild-to-moderate Covid-19, sotrovimab reduced the risk of disease progression. No safety signals were identified. (Funded by Vir Biotechnology and GlaxoSmithKline; COMET-ICE ClinicalTrials.gov number, NCT04545060.).

Single High Dose of Liposomal Amphotericin B in Human Immunodeficiency Virus/AIDS-Related Disseminated Histoplasmosis: A Randomized Trial.

BACKGROUND: Histoplasmosis is a major AIDS-defining illness in Latin America. Liposomal amphotericin B (L-AmB) is the drug of choice for treatment, but access is restricted due to the high drug and hospitalization costs of the conventional long regimens. METHODS: Prospective randomized multicenter open-label trial of 1- or 2-dose induction therapy with L-AmB versus control for disseminated histoplasmosis in AIDS, followed by oral itraconazole therapy. We randomized subjects to: (i) single dose 10 mg/kg of L-AmB; (ii) 10 mg/kg of L-AmB on D1, and 5 mg/kg of L-AmB on D3; (iii) 3 mg/kg of L-AmB daily for 2 weeks (control). The primary outcome was clinical response (resolution of fever and signs/symptoms attributable to histoplasmosis) at day 14. RESULTS: A total of 118 subjects were randomized, and median CD4+ counts, and clinical presentations were similar between arms. Infusion-related toxicity, kidney toxicity at multiple time-points, and frequency of anemia, hypokalemia, hypomagnesemia, and liver toxicity were similar. Day 14 clinical response was 84% for single-dose L-AmB, 69% 2-dose L-AmB, and 74% for control arm (P = .69). Overall survival on D14 was 89.0% (34/38) for single-dose L-AmB, 78.0% (29/37) for 2-dose L-AmB, and 92.1% (35/38) for control arm (P = .82). CONCLUSIONS: One day induction therapy with 10 mg/kg of L-AmB in AIDS-related histoplasmosis was safe. Although clinical response may be non-inferior to standard L-AmB therapy, a confirmatory phase III clinical trial is needed. A single induction dose would markedly reduce drug-acquisition costs (>4-fold) and markedly shorten and simplify treatment, which are key points in terms of increased access.

Invasive Aspergillosis in Patients with Acute Leukemia: Comparison Between Acute Myeloid and Acute Lymphoid Leukemia.

BACKGROUND: The epidemiology of invasive aspergillosis (IA) in patients with acute lymphoid leukemia (ALL) has not been well characterized. OBJECTIVES: To identify potential peculiarities in the natural history, treatment response and outcome of IA diagnosed in patients with ALL and AML. METHODS: This is a retrospective cohort study conducted in seven tertiary-care hospitals between 2009 and 2017 of all consecutive episodes of IA occurring in adult patients with acute leukemia. Demographic characteristics, underlying disease and recent treatment, antifungal prophylaxis, neutropenia, receipt of corticosteroids, clinical and radiological findings, mycological results, antifungal therapy, and 6-week and 12-week survival were recorded. RESULTS: We identified 77 cases of IA in 54 patients with AML and 23 patients with ALL. The majority of patients developed IA in the context of induction chemotherapy for newly diagnosed (48.0%) or relapsed (41.6%) leukemia, with no differences between ALL and AML. Lung involvement was more frequent in AML (96.3% vs. 82.6%, p = 0.06) and rhinosinusitis was more common in ALL (43.5% vs. 24.1%, p = 0.09). Galactomannan was the microbiologic documentation of IA in 76.6%, with similar patterns of positivity in AML and ALL. The 6-week survival of IA in patients with AML and ALL was 63.0% and 56.5%, respectively (p = 0.60). CONCLUSIONS: The epidemiology, clinical presentation, diagnosis and outcome of IA in ALL patients are similar to patients with AML.

The current state of Clinical Mycology in Eastern and South-Eastern Europe.

The ability of medical centers in Eastern and South-Eastern Europe to diagnose and treat fungal infections remains unknown. In order to investigate that, here we conducted a cross-sectional online survey, released at both The International Society for Human & Animal Mycology (ISHAM) and European Confederation of Medical Mycology (ECMM) websites. A total of 31 institutions responded to the questionnaire. Most centers (87.1%, n = 27) had access to Aspergillus spp. ELISA galactomannan testing as well as to Cryptococcus spp. antigen testing (83.9%, n = 26). Serological tests were mostly available for Aspergillus species (80.6%, n = 25); and most institutions reported access to mold-active antifungal drugs (83.9%; n = 26), but 5-flucytosine was available to only 29% (n = 9) of the participant centers. In conclusion, this study represents the first attempt to document the strengths and limitations of the Eastern and South-Eastern European region for diagnosing and treating fungal diseases. LAY SUMMARY: Our article is about the availability of diagnostic and treatments tools related to fungal infections in the countries of Eastern and South-Eastern region. Surveys like these are important to understand the gaps and point towards the fungal infections as a global health issue.

High rate of Clostridioides difficile colonization in patients admitted to intensive care: A prospective cohort study.

Here, we evaluated the frequency of C. difficile colonization and its impact on clinical outcomes in patients admitted to intensive care units in Brazil. From ninety-two patients screened 16 (17.3%) were colonized by C. difficile. Colonized patients had higher Simplified Acute Physiology Score III (SAPS III), however there was no association between C. difficile colonization with diarrhea or mortality. The C. difficile strains sequenced belonged to clade 1 and presented high vancomycin-resistant rates.

Candidaemia Mortality Has not Changed Over the Last 2 Decades in Brazil.

Despite advances in fungal diagnostics and antifungal therapy, mortality associated with candidaemia remains very high, particularly in developing countries. In this study, we reviewed the Brazilian literature on candidaemia over the last 20 years (1999-2019), with the aim to document if mortality rates changed over the years in Brazil. Variables studied included number of patients with candidaemia per study, age, most prevalent Candida species and use of antifungals. Selected manuscripts evaluated a median of 114 patients, the majority being men (54.4%). Median age was 45 year-old. The most prevalent species in all studies was C. albicans (37.3%), followed by C. parapsilosis (23.0%). An increase in use of echinocandins occurred in recent years, with a proportional decrease in the use of fluconazole and amphotericin B. Surprisingly, mortality of candidaemia has remained unchanged over the years in the largest Latin American country, regardless of treatment with echinocandins. Potential explanations for these findings are discussed.

Clinical mycology in Latin America and the Caribbean: A snapshot of diagnostic and therapeutic capabilities.

Despite the existence of endemic mycoses in Latin America and the Caribbean, in addition to a large population of patients at risk for invasive mycoses, the capability of medical centres to perform a proper diagnosis in mycology has not been studied in the region. Moreover, availability of antifungal drugs in the region is unknown. Here, we report the results of a survey involving 129 centres in 24 countries. Only 9% of centres would have the potential to apply for the minimum standards in mycology, as determined by the European Confederation of Medical Mycology. There is an urgent need to improve diagnostic conditions in Latin America and the Caribbean, as well as providing access to safer and more efficacious antifungal drugs.

Clinical Use of Polymyxin B.

Polymyxin B is another clinically available polymyxin that has re-emerged in clinical practice to treat infections caused by multi-drug (MDR) or extensively-drug-resistant (XDR) Gram-negative bacteria (GNB). Its chemical structure is very similar to the structure of polymyxin E (colistin). However, since the latter is administered as a prodrug, there are major pharmacokinetic differences between both polymyxins that may potentially determine different clinical and microbiological outcomes. Studies addressing clinical or microbiological outcomes in patients treated with polymyxin B for MDR or XDR GNB are reviewed in this chapter.

Severe Infusion-Related Adverse Events and Renal Failure in Patients Receiving High-Dose Intravenous Polymyxin B.

The use of very high doses of polymyxin B (PMB) against carbapenem-resistant Gram-negative bacilli has been addressed in in vitro experiments as a strategy to improve bacterial killing and suppress resistance emergence. However, the toxicities of very high doses in patients are unknown. We conducted a retrospective cohort study assessing patients receiving PMB at >3 mg/kg of body weight/day or a total dose of ≥250 mg/day. The main outcomes were severe infusion-related adverse events according to the Common Terminology Criteria for Adverse Events and the renal failure category of RIFLE criteria for acute kidney injury (AKI) during treatment. A total of 222 patients were included for analysis of infusion-related events. The mean PMB dose was 3.61 ± 0.97 mg/kg/day (median total dose/day = 268 mg). Severe infusion-related adverse events occurred in two patients, resulting in an incidence of 0.9% (95% confidence interval, 0.2 to 3.2%); one was classified as a life-threatening adverse event, and one was classified as a severe adverse event. Renal failure was analyzed in 115 patients, and 25 (21.7%) patients presented renal failure (54 [47.0%] developed any degree of AKI, categorized as risk [27.8%], injury [25.9%], and failure [46.3%]). Treatment with a vasoactive drug, concomitant treatment with nephrotoxic drugs, and baseline creatinine clearance were independent risk factors for renal failure. Neither the PMB daily dose scaled by body weight nor the total daily dose was associated with renal failure. The in-hospital mortality rate was 60% (134 patients): 26% of deaths (57 patients) occurred during treatment, and none occurred during infusion. Our data suggest that high-dose schemes have an acceptable safety profile and could be further tested in clinical trials assessing strategies to improve patient outcomes and minimize the emergence of PMB resistance.

Multicenter Prospective Cohort Study of Renal Failure in Patients Treated with Colistin versus Polymyxin B.

Nephrotoxicity is the main adverse effect of colistin and polymyxin B (PMB). It is not clear whether these two antibiotics are associated with different nephrotoxicity rates. We compared the incidences of renal failure (RF) in patients treated with colistimethate sodium (CMS) or PMB for ≥48 h. A multicenter prospective cohort study was performed that included patients aged ≥18 years. The primary outcome was renal failure (RF) according to Risk, Injury, Failure, Loss, and End-stage renal disease (RIFLE) criteria. Multivariate analysis with a Cox regression model was performed. A total of 491 patients were included: 81 in the CMS group and 410 in the PMB group. The mean daily doses in milligrams per kilogram of body weight were 4.2 ± 1.3 and 2.4 ± 0.73 of colistin base activity and PMB, respectively. The overall incidence of RF was 16.9% (83 patients): 38.3% and 12.7% in the CMS and PMB groups, respectively (P< 0.001). In multivariate analysis, CMS therapy was an independent risk factor for RF (hazard ratio, 3.35; 95% confidence interval, 2.05 to 5.48;P< 0.001) along with intensive care unit admission, higher weight, older age, and bloodstream and intraabdominal infections. CMS was also independently associated with a higher risk of RF in various subgroup analyses. The incidence of RF was higher in the CMS group regardless of the patient baseline creatinine clearance. The development of RF during therapy was not associated with 30-day mortality in multivariate analysis. CMS was associated with significantly higher rates of RF than those of PMB. Further studies are required to confirm our findings in other patient populations.

Risk factors for acute kidney injury (AKI) in patients treated with polymyxin B and influence of AKI on mortality: a multicentre prospective cohort study.

OBJECTIVES: The objectives of this study were to assess risk factors for acute kidney injury (AKI) in patients treated with polymyxin B, a last resort antibiotic against Gram-negative bacteria, with a focus on dose, and to determine the impact of AKI on mortality of these patients. METHODS: A multicentre prospective cohort study was performed including patients ≥18 years treated with intravenous polymyxin B for ≥48 h. The primary outcome was AKI defined by RIFLE criteria. Secondary outcomes were 30 day mortality and failure stage of AKI. Multivariate analysis with a Cox regression model was performed. The probability of developing AKI was determined in a logistic regression model. RESULTS: Four-hundred-and-ten patients were included. AKI occurred in 189 (46.1%) patients. Polymyxin B dose ≥150 mg/day was a risk factor for AKI: adjusted HR = 1.95, 95% CI = 1.31-2.89, P = 0.01. Higher weight and age were also independently associated with AKI. The probability of developing AKI significantly increased with doses between 150 and 199 mg/day, regardless of patient weight, with no significant increase with higher doses. Higher weight also increased the risk in patients receiving the same daily doses. AKI was barely associated with increased risk for 30 day mortality (adjusted HR = 1.35, 95% CI = 0.99-1.85, P = 0.06), while ≥150 mg/day did not increase this risk despite its association with AKI. CONCLUSIONS: Polymyxin B total dose is highly related to the risk of AKI, regardless of patient weight. Thirty-day mortality tended to be higher in patients who developed AKI. The relationship between dose, AKI and mortality must be further investigated in studies specifically designed to evaluate this latter outcome.

Comparison of nephrotoxicity associated to different lipid formulations of amphotericin B: a real-life study.

Amphotericin B (AmB) use is limited by the occurrence of kidney toxicity. Here, we evaluated the incidence and impact of nephrotoxicity in a large series of patients receiving therapy with amphotericin B deoxycholate (d-AmB), liposomal AmB (L-AmB), or AmB lipid complex (ABLC), in a clinical practice scenario. In a retrospective cohort study, patients treated with different AmB formulations between 2003 and 2012 were evaluated. Medical records and laboratory data were reviewed. Nephrotoxicity was determined according to modified RIFLE criteria. Predictors of nephrotoxicity and mortality were determined and treatment groups were compared. About 431 patients were studied (d-AmB, n = 236; L-AmB, n = 105; ABLC, n = 90). Frequency of severe nephrotoxicity (RIFLE 'Failure') was 11.5%, 2.4% and 7.2% for d-AmB, L-AmB and ABLC, respectively (P = 0.046). Use of L-AmB was found to be an independent protective factor (OR: 0.18; 95% CI: 0.03-0.64; P = 0.006) for severe nephrotoxicity, considering d-AmB as a reference. L-AmB was also a protective factor for mortality (OR: 0.56; 95% CI: 0.32-0.99; P = 0.046). In addition, in-hospital overall mortality was associated with cancer, previous dialysis, evolution to dialysis, and stay in the intensive care unit. Patients treated with ABLC showed similar frequency of severe kidney toxicity than those treated with d-AmB. L-AmB was associated with better outcomes than other formulations, including severe nephrotoxicity and overall mortality.

In vitro activity of ceftaroline against bacterial isolates causing skin and soft tissue and respiratory tract infections collected in Latin American countries, ATLAS program 2016-2020.

OBJECTIVES: Ceftaroline, a broad-spectrum cephalosporin, has activity against Gram-positive and several Gram-negative bacteria (GNB). This study aimed to evaluate the antimicrobial activity of ceftaroline and comparators against isolates causing skin and soft tissue infections (SSTIs) and respiratory tract infections (RTIs) collected in Latin America (LATAM) in 2016-2020 as part of the Antimicrobial Testing Leadership and Surveillance program (ATLAS). METHODS: Minimum inhibitory concentrations were determined using both Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. RESULTS: Ceftaroline demonstrated potent activity against methicillin-susceptible Staphylococcus aureus (CLSI/EUCAST: MIC90 0.25 mg/L; susceptibility 100%), whereas activity against methicillin-resistant S. aureus varied for SSTIs (MIC90 1 mg/L; susceptibility 92.5%) and RTIs isolates (MIC90 2 mg/L; susceptibility 72.9%) isolates. For Streptococcus pneumoniae, particularly penicillin-resistant isolates commonly causing respiratory infections, high ceftaroline activity (MIC90 0.25 mg/L; susceptibility 100%/98.4%) was noted. All isolates of ß-hemolytic streptococci were susceptible to ceftaroline (S. agalactiae: MIC90 0.03 mg/L [SSTIs]; MIC90 0.015 mg/L (RTIs); susceptibility 100%; S. pyogenes: MIC90 0.008 mg/L; susceptibility 100%). Ceftaroline was highly active against Haemophilus influenzae, including ß-lactamase positive isolates (MIC90 0.06 mg/L; susceptibility 100%/85.7%). Ceftaroline demonstrated high activity against non-ESBL-producing GNB (E. coli: MIC90 0.5 mg/L, susceptibility 91.9%; K. pneumoniae: MIC90 0.25 mg/L, susceptibility 95.1%; K. oxytoca, MIC90 0.5 mg/L; susceptibility 95.7%). CONCLUSION: Ceftaroline was active against the recent collection of bacterial pathogens commonly causing SSTIs and RTIs in LATAM. Local and regional surveillance of antimicrobial resistance patterns are crucial to understand evolving resistance and guide treatment management.

Screening with urine Histoplasma antigen test in asymptomatic patients starting TNF-alpha inhibitor therapy: a cohort study.

Background: Histoplasmosis is the second most frequent granulomatous disease in patients treated with tumor necrosis factor (TNF)-α inhibitors, second only to tuberculosis. However, there is limited information about pre-therapy screening procedures and the need for preventive treatments for patients who will start immunobiologicals. Methods: This is a cohort study that evaluated the prevalence of histoplasmosis in asymptomatic HIV-negative patients before initiation of TNF-α inhibitors by testing for Histoplasma antigen in urine samples. The patients included completed a 180-day follow-up after the initiation of the biologics to assess the onset of symptoms suggestive of histoplasmosis. Results: From January 2021 to December 2022, 54 patients who were prescribed a TNF-α inhibitor agent for treating autoimmune diseases in centers in southern Brazil were included. In the screening before therapy, the prevalence of a positive urinary Histoplasma antigen test was 14.8%. None of the 54 patients developed histoplasmosis after 6 months of immunobiological therapy, including the eight patients who tested positive. Conclusion: The prevalence of Histoplasma capsulatum infection in chronic patients may be higher than expected, but the impact of latent infection in asymptomatic patients is still uncertain, including those starting treatment with immunobiological drugs such as TNF-α inhibitors. Our study did not identify risk factors for the diagnosis of disseminated histoplasmosis in this group, including a positive result in an antigen test performed before immunobiological therapy. To date, there is no evidence to recommend routine antigen-based screening or preventive therapy for histoplasmosis before initiating a TNF-α inhibitor.

Using a urine test for fungal infection to screen people without symptoms who are about to start taking immunobiologic medications This study looked at the prevalence of histoplasmosis, a fungal infection, in asymptomatic patients who were about to start treatment with TNF-α inhibitors, which are medications used for autoimmune diseases. The researchers tested urine samples for Histoplasma antigen before the patients started the treatment and followed them for 180 days after starting the medication to see if they developed any symptoms of histoplasmosis. The study included 54 patients in southern Brazil, and they found that 14.8% of the patients tested positive for the Histoplasma antigen before starting the treatment. However, none of the patients, including those who tested positive, developed histoplasmosis during the 6-month follow-up. The researchers concluded that histoplasmosis infection may be more common in these patients than previously thought, but it's still not clear if asymptomatic patients with a positive antigen test will develop the infection when starting TNF-α inhibitor treatment. The study did not find any specific risk factors for developing histoplasmosis in this group of patients, and based on their findings, they did not recommend routine screening or preventive therapy for histoplasmosis before starting TNF-α inhibitor treatment.

Susceptibility evaluation of novel beta-lactam/beta-lactamase inhibitor combinations against carbapenem-resistant Klebsiella pneumoniae from bloodstream infections in hospitalized patients in Brazil.

Novel beta-lactams/beta-lactamase inhibitors (BIBLI) combinations are commercially available and they have been used for treating carbapenem-resistant Klebsiella pneumoniae (CRKP) infections. Continuous surveillance of susceptibility profile and resistance mechanisms identification are necessary to monitor the evolution of resistance as these agents are used. The purpose of this study was to evaluate susceptibility rates to ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam in CRKP isolates from patients with bloodstream infection screened for a randomized clinical trial in Brazil. Minimum inhibitory concentration (MIC) was determined by gradient diffusion strip method for meropenem, ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam. Carbapenemase genes were detected by multiplex qPCR. KPC-producing isolates showing resistance to any BLBLI and NDM-producing isolates showing susceptibility to any BLBLI were further submitted to whole genome sequencing. From a total of 69 CRKP isolates, 39 were positive for blaKPC, 19 for blaNDM and 11 for blaKPC and blaNDM. KPC-producing isolates demonstrated susceptibility rates above 94% for all BLBLI. Two isolates with resistance to meropenem/vaborbactam showed a Gly and Asp duplication at OmpK36 protein and truncated ompK35 genes. All NDM-producing isolates, including KPC and NDM coproducers, demonstrated susceptibility rates for ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam of 0%, 9.1 to 21.1% and 9.1 to 26.3%, respectively. Five NDM-producing isolates that presented susceptibility to BLBLI also demonstrated alterations in porins. This study demonstrated that, although high susceptibility rates to the BLBLI were found, KPC-2 isolates can also demonstrate resistance due to porin mutations. Additionally, NDM-1 isolates can demonstrate susceptibility in vitro to the BLBLI.

Population pharmacokinetics of intravenous polymyxin B in critically ill patients: implications for selection of dosage regimens.

BACKGROUND: Polymyxin 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. METHODS: Twenty-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. RESULTS: Twenty-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. CONCLUSIONS: Our 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.

Pharmacokinetics of polymyxin B in patients on continuous venovenous haemodialysis.

OBJECTIVES: To evaluate the pharmacokinetics of polymyxin B in patients on continuous venovenous haemodialysis (CVVHD) after intravenous administration of unadjusted dosage regimens. PATIENTS AND METHODS: Two 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. RESULTS: Respective 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. CONCLUSIONS: Our findings indicate that the recommended polymyxin B doses should not be reduced for patients on CVVHD.