David Helfgott

Emergence of carbapenem-resistant Enterobacteriaceae as causes of bloodstream infections in patients with hematologic malignancies

Abstract Carbapenem-resistant Enterobacteriaceae (CRE) are increasingly prevalent pathogens. However, little is known about their emergence in patients with hematologic malignancies. We identified 18 patients with hematologic malignancies over 3.5 years who developed bloodstream infections (BSIs) caused by CRE. Fourteen BSIs were caused by Klebsiella pneumoniae, three by Enterobacter cloacae, and one was polymicrobial. Initial empirical antimicrobial therapy was active in two patients (11%), and a median of 55 h elapsed between culture collection and receipt of an active agent. Ten patients (56%) died, including nine (69%) of 13 neutropenic patients, with a median of 4 days from culture collection until death. CRE isolates were analyzed for carbapenemase production, β-lactamase genes and outer membrane porin deletions and characterized by multilocus sequence typing and pulsed-field gel electrophoresis (PFGE). Carbapenem resistance mechanisms included Klebsiella pneumoniae carbapenemase production and CTX-M-15 production with an absent outer membrane porin protein. No isolate had ≥95% homology on PFGE, indicating a heterogeneous, non-outbreak population of isolates. CRE BSIs are emerging in patients with hematologic malignancies and are associated with ineffective initial empirical therapy, long delays in administration of active antimicrobials and high mortality rates. New diagnostic, therapeutic and preventive strategies for CRE infections in this vulnerable population are needed.

Phase 1b Study of New Posaconazole Tablet for Prevention of Invasive Fungal Infections in High-Risk Patients with Neutropenia

ABSTRACT Posaconazole tablets, a new oral formulation of posaconazole, can be effective when given as antifungal prophylaxis to neutropenic patients at high risk for invasive fungal infection (e.g., those with acute myelogenous leukemia or myelodysplastic syndrome). Such effectiveness might be specifically important to patients with poor oral intake because of nausea, vomiting, or chemotherapy-associated mucositis. This was a prospective, global study in high-risk patients to characterize the pharmacokinetics and safety profile of posaconazole tablets and to identify the dose of posaconazole tablets that would provide exposure within a predefined range of exposures (steady-state average concentration [area under the concentration-time curve/24 h] of ≥500 ng/ml and ≤2,500 ng/ml in >90% of patients). The study evaluated two sequential dosing cohorts: 200 mg posaconazole once daily (n = 20) and 300 mg posaconazole once daily (n = 34) (both cohorts had a twice-daily loading dose on day 1) taken without regard to food intake during the neutropenic period for ≤28 days. The exposure target was reached (day 8) in 15 of 19 (79%) pharmacokinetic-evaluable patients taking 200 mg posaconazole once daily and in 31 of 32 (97%) patients taking 300 mg posaconazole once daily; 300 mg posaconazole once daily achieved the desired exposure target. Posaconazole tablets were generally well tolerated in high-risk neutropenic patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01777763.)

Phase 3 pharmacokinetics and safety study of a posaconazole tablet formulation in patients at risk for invasive fungal disease

BACKGROUND Antifungal prophylaxis with a new oral tablet formulation of posaconazole may be beneficial to patients at high risk for invasive fungal disease. A two-part (Phase 1B/3) study evaluated posaconazole tablet pharmacokinetics (PK) and safety. METHODS Patients with neutropenia following chemotherapy for haematological malignancy or recipients of allogeneic HSCT receiving prophylaxis or treatment for graft-versus-host disease received 300 mg posaconazole (as tablets) once daily (twice daily on day 1) for up to 28 days without regard to food intake. Weekly trough PK sampling was performed during therapy, and a subset of patients had sampling on days 1 and 8. Cmin-evaluable subjects received ≥6 days of dosing, and were compliant with specified sampling timepoints. Steady-state PK parameters, safety, clinical failure and survival to day 65 were assessed. ClinicalTrials.gov, NCT01777763; EU Clinical Trials Register, EUDRA-CT 2008-006684-36. RESULTS Two hundred and ten patients received 300 mg posaconazole (as tablets) once daily. Among Cmin-evaluable subjects (n = 186), steady-state mean Cmin was 1720 ng/mL (range = 210-9140). Steady-state Cmin was ≥700 ng/mL in 90% of subjects with 5% (10 of 186) <500 ng/mL and 5% (10 of 186) 500-700 ng/mL. Six (3%) patients had steady-state Cmin ≥3750 ng/mL. One patient (<1%) had an invasive fungal infection. The most common treatment-related adverse events were nausea (11%) and diarrhoea (8%). There was no increase in adverse event frequency with higher posaconazole exposure. CONCLUSIONS In patients at high risk for invasive fungal disease, 300 mg posaconazole (as tablets) once daily was well tolerated and demonstrated a safety profile similar to that reported for posaconazole oral suspension: most patients (99%) achieved steady-state pCavg exposures >500 ng/mL and only one patient (<1%) had a pCavg <500 ng/mL.

Pharmacokinetics of different dosing strategies of oral posaconazole in patients with compromised gastrointestinal function and who are at high risk for invasive fungal infection.

ABSTRACT The aim of this study was to assess different dosing strategies that may result in increased posaconazole bioavailability in patients with compromised gastrointestinal function and at high risk for invasive fungal infections. Patients undergoing chemotherapy and at risk for compromised gastrointestinal function received open-label posaconazole at 200 mg three times daily (TID) on days 1 to 8. Patients were randomized to one of three open-label dosing regimens of posaconazole on days 9 to 15: 200 mg TID, 400 mg twice daily (BID), or 400 mg TID. The plasma concentrations of interest on days 8 and 15 were 500 and 700 ng/ml, respectively; day 2 plasma concentrations of 250 and 350 ng/ml were chosen as levels that might result in steady-state concentrations of >500 and >700 ng/ml, respectively. A total of 75 patients enrolled; 52/75 (69%) completed the study, and 49/75 were included in the pharmacokinetic analyses. Mean plasma concentrations were 230, 346, and 637 ng/ml on days 2, 3, and 8, respectively. The day 15 values were 660, 930, and 671 ng/ml for 200 mg TID, 400 mg BID, and 400 mg TID, respectively. In 12 patients with a day 8 posaconazole concentration of <250 ng/ml, an overall benefit of the higher two doses was not apparent, suggesting that a subset of patients has low steady-state plasma concentrations. A change in dosing regimen on day 9 did not lead to higher exposures in these “poor absorbers” on day 15. Poor absorption may be enhanced with a high-fat meal, a nutritional supplement, or acidification.

Interferon‐β2/Interleukin‐6 in Plasma and Body Fluids during Acute Bacterial Infection

The interferon-&/interleukin-6 (IFN-&/IL-6) gene is inducible in many cell types, such as fibroblasts, monocytes /macrophages, endothelial cells, and keratinocytes,’ by an array of exogenous and endogenous stimuli that include bacterial lipopolysaccharide (LPS),’ interleukin-1 (IL-1); and tumor necrosis factor (TNF),’ each of which appears to be involved in the host response to bacterial infection. In addition, IFNp2/IL-6 directly enhances the expression of many of the hepatic acute phase plasma proteins in vitro. Therefore, we became interested in determining if IFN-D2/IL-6 could be found in the plasma and body fluids involved in acute bacterial infection. Cerebrospinal fluid, joint fluid, and plasma samples from patients with or without acute bacterial infection were obtained at The New York Hospital. Sample aliquots were tested for IFN-f12/IL-6 activity using a bioassay that takes advantage of the ability of IFN-P2/IL-6 to enhance the production of an acute phase plasma protein, a,-antichymotrypsin (ACT), in the human hepatoma cell line Hep3B clone 2.5 We demonstrated a linear relationship between the human rIFN-&/IL-6 concentration and the density of the ACT autoradiographic signal, as well as the absence of any LPS, IL-1, or TNF effect on this assay.5 Also, each experimental pair included the test sample and the test sample preincubated with anti-rIFN-P2/IL-6 antibody to ensure that the enhancement of ACT in the assay was attributable to IFN-P2/IL-6 alone. We detected high levels (greater than 5 0 0 ng/mL) of IFN-PJIL-6 in the body fluids of patients with acute bacterial infections. Cerebrospinal fluid (CSF) from four patients with acute bacterial meningitis (Streptococcus pneumoniae, Staphylococcus aureus, two cases of Listeria rnonocytogenes) all contained high levels of IFN-0, /IL6, ranging from 70 to greater than 5 0 0 ng/mL. Two of these patients with concomitant bacteremia (S. aureus, L. monocytogenes) had about tenfold lower concentrations of IFN-&/IL-6 in their plasma as compared to the CSF. Three additional patients with bacteremia alone (Neisseria meningitidis, Pseudomonas aeruginosa, Escherichia coU) had significant plasma levels of IFN-&/ILd (ranging from 2.5 to 70 ng/mL), as

Septic Shock Caused by Klebsiella pneumoniae Carbapenemase-Producing Enterobacter gergoviae in a Neutropenic Patient with Leukemia

ABSTRACT We present the first reported infection caused by Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacter gergoviae. The patient had leukemia and neutropenia and died of septic shock from KPC-producing E. gergoviae bacteremia. The emergence of KPCs in additional species of Enterobacteriaceae is alarming and may disproportionately affect patients with hematologic malignancies.