Adult Haematology Patients Research Articles

Parameters influencing the pharmacokinetics/pharmacodynamics of piperacillin/tazobactam in patients with febrile neutropenia and haematological malignancy: a prospective study.

To assess population pharmacokinetics (PK) and pharmacodynamics (PD) of both piperacillin and tazobactam in neutropenia patients and examine dosage requirements related to the MIC distribution for Gram-negative bacteria involved in bloodstream infections (BSIs). We conducted a prospective study including adult haematological malignancy patients with febrile neutropenia receiving piperacillin/tazobactam as short (30 min) or prolonged (4 h) intravenous infusions. Concentration data were analysed using a population approach. Dosing simulations with the final model investigated factors influencing the PK/PD of piperacillin/tazobactam quantified by fT>MIC or PTA for piperacillin and tazobactam, respectively. In parallel, the local MIC distribution of β-lactams was documented for Gram-negative bacteria involved in BSIs. Over 10 months, 31 patients were enrolled, with 11 (35.5%) short and 20 (64.5%) prolonged infusion regimens. A one-compartment model adequately described the data for both drugs. Prolonged infusion, increased serum alkaline phosphatase (ALP) values and renal function impairment were associated with increased piperacillin fT>MIC. For patients with normal or augmented renal CL, dosing regimens q8h or q6h with 30 min of infusion were insufficient to achieve acceptable PTA for piperacillin/tazobactam at the median MIC value of 8 mg/L. Prolonged infusion of large doses was associated with the best PTA for both piperacillin and tazobactam. In a population of haematological malignancy patients with neutropenia, renal function and ALP influenced the PK of piperacillin/tazobactam. Prolonged intravenous infusion would optimize the PK of piperacillin/tazobactam, especially in the case of augmented renal CL and/or low-range bacterial susceptibility.

PB2033 IMMUNOGLOBULIN REPLACEMENT THERAPY IN ADULT HEMATOLOGICAL PATIENTS: EFFECT ON THE INCIDENCE OF INFECTIOUS COMPLICATIONS

Background:The problem of infectious complications in hematology is determined by their high frequency, severity and difficulty of diagnosis. The clinical effect of immunoglobulin replacement therapy in relation to the risk of infectious complications in adult hematological patients currently needs to be assessed and revised.Aims:The aim of this prospective study was to evaluate the independent effect of immunoglobulin replacement therapy on the risk of developing infectious complications in hematological patients.Methods:The study included 34 adult patients receiving chemotherapy for hematological disease. Intervention groups (immunoglobulin replacement therapy) and the control group were matched by clinical and demographic characteristics. The primary outcome in the analysis was taken as the infection‐free period in the 180‐days survival analysis performed by Kaplan‐Meier with log‐rank test, Cox regression and Cox regression.Results:The average age of patients was 57.8 years, with sex distribution: 19 female and 15 male. Hematological diseases were distributed as follows: chronic lymphocytic leukemia ‐ 18, multiple myeloma ‐ 8, acute myeloid leukemia ‐ 2, acute lymphocytic leukemia ‐ 4, myelodysplastic syndrome ‐ 2. Among the included ‐ 15 patients had profound hypogammaglobulinemia (less than 4 g/l). Statistically significant association of immunoglobulin replacement therapy and reduction of the risk of infectious episodes was shown in a 180‐days period (log‐rank test, p = 0.037), Fig 1. The average duration of the period without infectious complications in the replacement group was 164 days (95% CI 147‐180 days), while in the control group it was 148 days (95% CI 124‐171 days). No additional confounding factors, which could cause the differences in the groups were found in the regression analysis (p = 0.035). The number needed to treat (NNT) was 3 patients (p = 0.018).Summary/Conclusion:The obtained data show that the use of immunoglobulin replacement therapy is independently associated with a longer period of infection‐free survival in adult hematological patients, what substantially improves the quality of life of such patients. The clinical effect may be assessed within 6 months from the start of immunoglobulin replacement therapy.image

MMP-10 and TIMP-1 as indicators of severe sepsis in adult hematological patients with febrile neutropenia

Commonly used indicators of sepsis are nonspecific and insufficient for predicting the course of febrile neutropenia (FN) in hematological patients. We analyzed data from 91 adult FN patients who received intensive chemotherapy for acute myeloid leukemia or autologous stem cell transplantation. Compared to patients with non-severe sepsis, patients with severe sepsis had significantly higher serum levels of tissue inhibitor of metalloproteinases-1 on the day of first occurrence of fever (day 0: 172 vs. 112 µg/L, p= .002) and for the two following days (day 1: 219 vs. 128 µg/L, p< .001; day 2: 443 vs. 128 µg/L, p= .001), and significantly higher serum levels of matrix metalloproteinase-10 on day 1 (1975 vs. 876 ng/L, p= .001) and day 2 (2020 vs. 841 ng/L, p< .001). We conclude that the measurement of these biomarkers may be useful in predicting the severity of sepsis in FN patients.

Isavuconazole Prophylaxis in Patients With Hematologic Malignancies and Hematopoietic Cell Transplant Recipients.

Isavuconazole (ISA) is an attractive candidate for primary mold-active prophylaxis in high-risk patients with hematologic malignancies or hematopoietic cell transplant (HCT) recipients. However, data supporting the use of ISA for primary prophylaxis in these patients are lacking. We conducted a retrospective review of breakthrough invasive fungal infections (bIFIs) among adult hematologic malignancy patients and HCT recipients who received ≥7 days of ISA primary prophylaxis between 1 September 2016 and 30 September 2018. The incidence of bIFIs in patients receiving ISA was compared to those receiving posaconazole (POS) and voriconazole (VOR) during the same time period. One hundred forty-five patients received 197 courses of ISA prophylaxis. Twelve bIFIs (Aspergillus fumigatus [5], Aspergillus species [2], Mucorales [2], Fusarium species [2], and Candida glabrata [1]) occurred, representing 8.3% of patients and 6.1% of courses, after a median duration of 14 days of ISA prophylaxis. All bIFIs occurred during periods of neutropenia. Seven patients (58.3%) died within 42 days of onset of bIFI. In addition, bIFIs complicated 10.2% of ISA, 4.1% of POS, and 1.1% of VOR courses among patients with de novo or relapsed/refractory acute myeloid leukemia during the study period, with invasive pulmonary aspergillosis (IPA) complicating 6.8% of ISA, 1.3% of POS, and zero VOR courses. Although ISA has been approved for treatment of invasive Aspergillus and mucormycosis, we observed an increased rate of bIFI, notably IPA, using ISA for primary prophylaxis. These results support the need for further study to determine the role of ISA as primary prophylaxis.

Discontinuation of antimicrobial therapy in adult neutropenic haematology patients: A prospective cohort

ObjectivesAntibiotics for febrile neutropenia (FN) in acute myeloid leukaemia (AML) patients undergoing intensive chemotherapy are usually maintained until neutropenia resolution, because of the risk of uncontrolled sepsis in this vulnerable population. This leads to unnecessarily prolonged antimicrobial therapy. MethodsBased on ECIL-4 recommendations, we modified our management strategy and discontinued antibiotics after a pre-established duration in patients treated for a first episode of FN between August 2014 and October 2017. ResultsAntibiotics were stopped during 62 FN episodes, and maintained in the control group (n = 13). Median age of patients was 54 years. A total of 39 (63%) patients received induction and 23 (37%) consolidation chemotherapy; 36 (58%) patients had fever of unknown origin. Median neutropenia length was 26 days (IQR 24–30). Antibiotics were started at day 9 (IQR 5–13). Most patients received piperacillin-tazobactam (56%) or cefepime (32%). Antimicrobial therapy was longer in the control group than in the policy compliant group, 10 (IQR 7–16) vs. 19 days (IQR 15–23), P = 0.0001. After antibiotics discontinuation, 20% patients experienced fever recurrence, within 5.5 days (IQR 3–7.5). None of these febrile episodes were severe and 80% patients remained afebrile, with neutrophil recovery occurring within 5 days (IQR 2–8.5). Overall, 287 antibiotics days were spared; this represents 49% of all days with antibiotics. No patient had died at day 30 from intervention; six died during late follow-up, two from graft-versus-host disease and four from relapsed or refractory leukaemia. ConclusionsDiscontinuing antibiotics in neutropenic AML patients treated for a first episode of FN is safe, and results in significant antibiotic sparing.

Defining standards of CARE for invasive fungal diseases in adult haematology patients: antifungal prophylaxis versus treatment.

Despite the availability of four different classes of antifungal agents, invasive fungal infections, in particular mould diseases, continue to have a high crude mortality rate in adult haematology patients, especially when diagnosed late. Early diagnosis, resulting in prompt and adequate antifungal intervention, is of great importance when trying to improve the overall outcome of these infections, but depends on the availability of rapid and sensitive diagnostic tools. The medical community has developed and continues to evaluate a continuum of antifungal strategies (starting with prophylaxis followed by empirical therapy and more recently a diagnostic-driven or pre-emptive approach) to better tackle these life-threatening diseases. While the empirical approach seems to have lost some of its popularity, the jury is still out about the pros and cons of universal antifungal prophylaxis in at-risk adult haematology patients compared with an approach that uses radiological and mycological diagnostic methods with good to excellent negative predictive values (also erroneously called pre-emptive), trying to exclude the presence of an invasive fungal disease. Whilst awaiting the results of comparative clinical studies, believers and non-believers around the globe continue to argue about the advantages and shortcomings of both strategies. The debate presented here provides a rationale for both prophylaxis for 'high-risk' haematology patients as well as for a more targeted approach based on the appropriate use of mycological, radiological, immunological (and genetic) methods for the diagnosis of invasive fungal diseases.

A Phase I/2 Study of Ixazomib for Chronic Graft-Versus-Host Disease (cGVHD) Prophylaxis after Allogeneic Transplantation (alloHCT).

Background Chronic GVHD (cGVHD) causes significant morbidity and mortality after alloHCT. Oral proteasome inhibitor, ixazomib (Ixa) regulates dendritic cell maturation, decreases proinflammatory cytokines and modulates GVHD in murine model. The efficacy of Ixa in preventing cGVHD is unknown. Methods We report here a phase 1/2 trial (NCT02250300) evaluating safety and efficacy of Ixa for cGVHD prophylaxis. Adult hematologic malignancy patients (pts) status post a peripheral blood (PB) alloHCT with tacrolimus/methotrexate-based GVHD prophylaxis and no grade 3-4 aGVHD or steroid-refractory aGVHD were eligible. Recipients of matched related donor (MRD) and matched unrelated donor (MUD) alloHCT were enrolled in 2 independent cohorts. In vivo and ex vivo T-cell depletion was not permitted. Oral Ixa was started days 60-90 post-HCT for 4 weekly doses. Primary outcome was cumulative incidence (CI) of cGVHD at 1-yr by NIH criteria. The cGVHD was graded by an Independent Review Panel (IRP). Results No dose-limiting toxicities were seen in phase I and recommended phase II dose was 4 mg. 25 MRD and 26 MUD alloHCT pts were enrolled. The IRP assessed CI of cGVHD at 1-yr was 31% and 37% in MRD and MUD cohorts, respectively. The respective figures for moderate-severe cGVHD were 22% and 28%. 1-yr non-relapse mortality and relapse in MRD and MUD cohorts were 0% and 4% and 20% and 35%, respectively. 1-yr PFS of 80% and 64% and 1-year OS of 92% and 88% were seen in MRD and MUD cohorts, respectively. Serum B-cell activating factor (BAFF) levels before and after Ixa exposure increased significantly in pts who did not develop cGVHD (median, 2459 vs. 6969 pg/mL, p=.001), and in those without moderate/severe cGVHD (median, 2989 vs. 6438 pg/mL, p=.002). Treg counts before and after Ixa (median, 34 vs. 34.5/µL) for the overall cohort were similar. Conclusion Ixa is feasible, safe and potentially effective for cGVHD prophylaxis after PB alloHCT. BAFF level after Ixa may serve as a biomarker for later development of cGVHD.

Feasibility and safety of targeting the anterior superior iliac spine to perform a bone marrow procedure: a prospective, clinical study

AimsThe bone marrow procedure (BMP) has been performed worldwide for years. Nonetheless, no generally accepted standards or guidelines for the performance of the BMP exist. Recent studies suggested that the...

Pharmacokinetics of extended dose intervals of micafungin in haematology patients: optimizing antifungal prophylaxis.

Extended dosing intervals for micafungin could overcome the need for hospitalization for antifungal prophylaxis. This multicentre, open-label, randomized trial compared the pharmacokinetics of 300 mg of micafungin given twice weekly with 100 mg once daily as antifungal prophylaxis in adult haematology patients at risk of developing invasive fungal disease. Secondary objectives were assessment of adequate exposure with an alternative dosing regimen of micafungin (700 mg once weekly) through Monte Carlo simulations and assessment of safety in this patient population. Twenty adult patients were randomized to receive either 300 mg of micafungin twice weekly or 100 mg once daily for 8 days. Blood samples were drawn daily and pharmacokinetic curves were determined on days 4/5 and 8. Monte Carlo simulations were performed for both investigated regimens as well as a frequently proposed alternative regimen (700 mg once weekly). The predicted median AUC0-168h (IQR) for a typical patient on the investigated regimens of 100 mg once daily and 300 mg twice weekly and the hypothetical regimen of 700 mg once weekly were 690 (583-829), 596 (485-717) and 704 (585-833) mg·h/L, respectively. We observed comparable exposure with 300 mg of micafungin twice weekly and 100 mg of micafungin once daily. We provide the pharmacokinetic proof for an extended dosing regimen, which now needs to be tested in a clinical trial with hard endpoints.

European guidelines for primary antifungal prophylaxis in adult haematology patients: summary of the updated recommendations from the European Conference on Infections in Leukaemia.

The European Conference on Infections in Leukaemia (ECIL) updated its guidelines on antifungal prophylaxis for adults using the grading system of IDSA. The guidelines were extended to provide recommendations for other haematological diseases besides AML and recipients of an allogeneic haematopoietic stem cell transplantation (HSCT). Posaconazole remains the drug of choice when the incidence of invasive mould diseases exceeds 8%. For patients undergoing remission-induction chemotherapy for AML and myelodysplastic syndrome (MDS), fluconazole can still offer an alternative provided it forms part of an integrated care strategy that includes screening with biomarkers and imaging. Similarly, aerosolized liposomal amphotericin B combined with fluconazole can be considered for patients at high risk of invasive mould diseases but other formulations of the polyene are discouraged. Fluconazole is still recommended as primary prophylaxis for patients at low risk of invasive mould diseases during the pre-engraftment phase of allogeneic HSCT whereas only a moderate recommendation could be made for itraconazole, posaconazole and voriconazole for patients at high risk. Posaconazole is strongly recommended for preventing invasive mould disease post-engraftment but only when graft-versus-host disease (GvHD) was accompanied by other risk factors such as its severity, use of an alternative donor or when unresponsive to standard corticosteroid therapy. The need for primary prophylaxis for other patient groups was less clear and should be defined by the estimated risk of invasive fungal disease (IFD).

A cohort study assessing the impact of small volume blood tubes on diagnostic test quality and iatrogenic blood loss in a cohort of adult haematology patients.

To estimate the reduction in blood volume loss and impact on diagnostic test quality associated with introduction of small volume blood tubes in a cohort of haematology inpatients compared to a historical comparator group. Prospective cohort study of haematology inpatients admitted to a tertiary referral hospital in Adelaide. Small volume blood tubes were used in an intervention cohort admitted between 2012 and 2013 and compared to a control cohort admitted between 2009 and 2010 where standard volume blood tubes had been used. The diagnostic test quality, specimen integrity and total reduction in blood loss associated with small volume blood tubes were estimated. Small volume blood tubes demonstrated acceptable collinearity on commonly assayed haematological and biochemical parameters. Small volume tubes were associated with a 42% reduction in blood volume loss equating to a saving of 8.5 mL per patient per day or 180 mL of blood loss over a 3-week admission. Small volume blood tubes were associated with a slight but significantly increased rate of fibrin contamination of ethylenediaminetetraacetic acid samples (0.2-0.5% of specimens). Small volume blood tubes are associated with a substantial reduction in total blood volume collected per day in haematology inpatients. They have similar diagnostic validity and sample integrity to that of standard volume containers.

Moderate correlation between systemic IL‐6 responses and CRP with trough concentrations of voriconazole

AimsVoriconazole (VCZ) exhibits wide intrapatient pharmacokinetic variability, which is disadvantageous because of its narrow therapeutic range. A considerable part of this variation remains unexplainable, despite extensive knowledge of this drug. It is hypothesized that inflammation has an impact on VCZ pharmacokinetics. In the present study, we investigated the correlation between VCZ trough concentrations and various cytokines.MethodsA prospective single‐centre analysis was performed in adult haematology patients receiving VCZ for possible, probable or proven invasive fungal disease. A linear mixed model was built to explore the contribution of each of the seven pro‐ and anti‐inflammatory cytokines to VCZ trough levels. The Akaike information criterion (AIC) was used to determine the model that fitted the best.ResultsTwenty‐two patients, with a total of 143 combined samples of VCZ trough levels and cytokines, were included. A significant correlation (P < 0.005) was found between VCZ trough concentrations and interleukin (IL) 6, IL‐8 and C‐reactive protein (CRP). IL‐6 showed the lowest AIC, although differences with the other mediators were marginal.ConclusionVCZ trough concentrations correlate with IL‐6, IL‐8 and CRP levels but only moderately explain the variability in VCZ pharmacokinetics. Future prospective studies should be undertaken to confirm these findings, and incorporate the data obtained into pharmacokinetic models, to refine the predictive behaviour.

Administration of taurolidine-citrate lock solution for prevention of central venous catheter infection in adult neutropenic haematological patients: a randomised, double-blinded, placebo-controlled trial (TAURCAT)

BackgroundCatheter-related bloodstream infection (CRBSI) is one of the most frequent complications in patients with cancer who have central venous catheters (CVCs) implanted and is associated with substantial morbidity and mortality. Taurolidine is a non-antibiotic agent with broad-spectrum antimicrobial activity, which has been used as a lock solution to prevent CRBSI in some settings. However, little is known about its usefulness in high-risk adult neutropenic patients with cancer. This prospective randomised clinical trial aims to test the hypothesis that taurolidine-citrate lock solution is more effective than placebo for preventing catheter infection in neutropenic haematological patients.MethodsThis study is a prospective, multicentre, randomised, double-blinded, parallel, superiority, placebo-controlled trial. Patients with haematological cancer who are expected to develop prolonged neutropenia (> 7 days) and who have a non-tunnelled CVC implanted will be randomised to receive prophylactic taurolidine-citrate-heparin solution using a lock technique (study group) or heparin alone (placebo group). The primary endpoint will be bacterial colonisation of the CVC hubs. The secondary endpoints will be the incidence of CRBSI, CVC removal, adverse events, and 30-day case-fatality rate.DiscussionThe lock technique is a preventive strategy that inhibits bacterial colonisation in the catheter hubs, which is the initial step of endoluminal catheter colonisation and the development of infection. Taurolidine is a nontoxic agent that does not develop antibiotic resistance because it acts as an antiseptic rather than an antibiotic. Taurolidine has shown controversial results in the few trials conducted in cancer patients. These studies have important limitations due to the lack of data on adult and/or high-risk neutropenic patients, the type of catheters studied (tunnelled or ports), and the lack of information regarding the intervention (e.g. dwelling of the solution, time, and periodicity of the lock technique). If our hypothesis is proven, the study could provide important solid evidence on the potential usefulness of this preventive procedure in a population at high risk of CRBSI, in whom this complication may significantly impair patient outcome.Trial registrationISRCTN, ISRCTN47102251. Registered on 9 September 2015.

Changes in the microbiological epidemiology of febrile neutropenia in autologous stem cell transplant recipients

Background: The aim of the study was to explore the incidence, microbiological etiology and outcome of febrile neutropenia among adult hematological patients following autologous stem cell transplantation (ASCT).Methods: The study population consisted of patients who received ASCT between 1 December 2006 and 30 November 2012. The epidemiology was compared to a retrospective series covering eleven previous years at the same institution. Non-Hodgkin lymphoma (NHL) patients, who had been identified as a risk group in the retrospective study, received ciprofloxacin prophylaxis from January 2008.Results: Altogether, 142 out of 178 of the included patients (80%) developed febrile neutropenia. The blood cultures were positive in 24 cases (17%). Of all bacteremia’s, 88% were caused by Gram-positive and 12% by Gram-negative bacteria. The number of Gram-negative bacteremia were significantly lower in the prospective study compared to the retrospective study (3/142, 2.1% vs. 23/265, 8.7%, p = .01). Pseudomonas aeruginosa was prevalent in the retrospective series but not discovered in the present series. Enterococcus faecium was found more frequently in the prospective study (6/142, 4.2 vs. 2/265, 0.8%, p = .02). The infectious mortality among patients with febrile neutropenia was 4/142 (2.8%) in the present series and 9/265 (3.4%) in those who received ASCT in 1996–2006.Conclusion: Most patients who received ASCT developed febrile neutropenia and a minority had bacteraemia. In comparison to the earlier time period, the incidence of Gram-negative bacteraemias decreased, probably due to ciprofloxacin prophylaxis in NHL patients, but simultaneously the incidence of Enterococcus bacteraemias increased. Infectious mortality during febrile neutropenia was low in both series.

The evolving landscape of new diagnostic tests for invasive aspergillosis in hematology patients: strengths and weaknesses.

The diagnosis of invasive aspergillosis in hematologic patients is a complex composite of clinical preconditions and features, imaging findings, biomarker combinations from appropriate clinical samples and microbiological and/or histological findings. Recent developments in the evolving landscape of diagnostic tests for invasive aspergillosis in adult hematology patients are highlighted. Novel approaches and tools are currently under development. Focusing optimized diagnostic performance, in particular the combination of biomarkers from appropriate clinical samples, improved diagnostic performance distinctly.

Evaluation of a multiplex panel for the diagnosis of acute infectious diarrhea in immunocompromised hematologic patients.

IntroductionDiarrhea is a frequent complication in hematologic patients, being an infectious cause frequently suspected. Rapid and accurate detection of gastrointestinal pathogens is vital in immunocompromised hosts. The aim of this study was to compare routine diagnostic methods versus a multiplex polymerase chain reaction (PCR) assay for the diagnosis of infectious diarrhea in immunocompromised hematologic patients.Material and methodsWe conducted a prospective observational study from March 2015 to January 2016 to compare conventional methods for the diagnosis of infectious diarrhea with FIlmArray GI Panel (BioFire-bioMérieux, France). Samples from adult immunocompromised hematologic patients with acute diarrhea were collected. In cases with discordant results, a second multiplex assay was performed (Allplex, Seegene, Korea). The result was considered positive or negative when the same result was obtained by at least two of the methods.ResultsA total of 95 samples were obtained from 95 patients (median age of 52 years (46–64)). Sixty-one (64%) episodes were hospital-acquired and 34 (36%) were community-acquired diarrhea. Twenty-five (26%) patients had a positive microbiological result, being Clostridium difficile the most frequent pathogen, followed by Campylobacter spp and norovirus. The concordance between FilmArray methods was good (k = 0.79). The FilmArray GI panel showed a sensitivity of 95%, a specificity of 100% for positive results. The time required to obtain results was markedly reduced with the use of multiplex PCR methods.ConclusionsMultiplex molecular panels provide a rapid and sensitive tool for the diagnosis of infectious diarrhea, thereby allowing more timely clinical decisions in immunocompromised hematologic patients.

Vancomycin dose optimisation comparing a pharmacokinetic/pharmacodynamic model versus the pharmacokinetic model

ObjectivesTo compare vancomycin dosage adjustment by evaluating trough concentrations (Ctrough) of vancomycin and its pharmacokinetic/pharmacodynamic (PK/PD) correlation (AUC/MIC ≥400).MethodsA retrospective study of 52 adult haematological patients and 29 ICU patients...

Voriconazole treatment in adults and children with hematological diseases: can it be used without measurement of plasma concentration?

Indication and timing of trough plasma-voriconazole (VCZ)-concentration (t-PVC) measurement during VCZ treatment is a debated issue. Patterns of t-PVC were prospectively evaluated in pediatric (50 courses) and adult (95 courses) hematologic patients. Efficacy patterns were defined: adequate, t-PVC always ≥1 mcg/ml; borderline, at least one t-PVC measurement <1 mcg/ml but median value of the measurements ≥1 mcg/ml; inadequate, median value of the measurements <1 mcg/ml. Toxicity patterns were defined: favorable, t-PVC always ≤5 mcg/ml; borderline, one or more t-PVC measurements >5 mcg/ml but median value of the measurements ≤5 mcg/ml; unfavorable, median value of the measurements >5 mcg/ml. In children and adults the mean t-PVCs were higher during intravenous treatments. The t-PVC efficacy pattern was adequate, borderline and inadequate in 48%, 12%, and 40% of courses, respectively, in children, and in 66.3%, 16.8%, and 16.8% of courses, respectively, in adults. Adequate efficacy pattern was more frequent in children with body weight above the median (≥25kg) (OR 4.8; P = .011) and in adults with active hematological disease receiving intravenous therapy (OR 3.93; P = .006). Favorable toxicity pattern was more frequent in children receiving VCZ daily dosage below the median (<14mg/kg) (OR 4.18; P = .027) and in adults with body weight below the median (<68kg) (OR 0.22; P = .004). T-PVC measurement is generally needed, however, a non t-PVC guided approach may be considered in heavier adults receiving intravenous VCZ. The risk of supratherapeutic levels does not seem an absolute indication for t-PVC monitoring.

Plasma concentrations of atovaquone given to immunocompromised patients to prevent Pneumocystis jirovecii.

Atovaquone is one of the alternatives to trimethoprim/sulfamethoxazole for prophylaxis of Pneumocystis jirovecii pneumonia (PCP) in immunocompromised patients. In volunteers, there was wide inter-individual variability in atovaquone bioavailability. The aim of this study was to assess the plasma concentrations of atovaquone in immunocompromised patients under PCP prophylaxis. Adult haematology or HIV-positive patients receiving atovaquone (750 mg oral suspension twice a day) for PCP prophylaxis were included. Plasma concentrations were assessed using UV-HPLC, around 12 h after the evening dose (Cmin) and 1-5 h after the morning dose (Cmax). A total of 82 measurements were performed in 33 patients. This included 19 HSCT recipients, 7 haematology non-transplant patients and 7 HIV-positive patients. The median Cmin (IQR) was 11.3 μg/mL (6.2-27.8) and the median Cmax was 13.4 μg/mL (6.0-28.3). The Cmin and Cmax of atovaquone were not different between HIV-negative and HIV-positive patients, or between HSCT and non-HSCT patients. Atovaquone concentrations were not influenced by the co-administration of valaciclovir (n = 20) or ciclosporin (n = 11), by gut graft-versus-host disease (n = 7) or by the intake of atovaquone with food. Nineteen of the 33 (58%) patients had Cmin <15 μg/mL, a threshold associated with a low rate of clinical response in PCP treatment. Atovaquone is poorly absorbed in more than half of immunocompromised patients and its bioavailability varies between individuals. These unpredictable variations raise the question of therapeutic drug monitoring, in order to identify patients with low concentrations and those who could benefit from regimen adaptation or from alternatives.

Implementation of a Central Line-associated Bloodstream Infection (CLABSI) Prevention Bundle for Adult Hematologic Malignancy and Bone Marrow Transplant Patients

Implementation of a Central Line-associated Bloodstream Infection (CLABSI) Prevention Bundle for Adult Hematologic Malignancy and Bone Marrow Transplant Patients