Thomas Valentin

Posaconazole plasma concentrations and invasive mould infections in patients with haematological malignancies

Posaconazole (PCZ) is a triazole antifungal agent that has broad activity against pathogenic fungi and is increasingly used for prophylaxis and treatment of invasive mould infections (IMIs). PCZ is only available as an oral formulation, with varying absorption from the gastrointestinal tract. However, reports correlating PCZ plasma concentrations (PPCs) with breakthrough IMIs are rare. In this study, PPCs were analysed in a prospective, observational, single-centre study and the correlation of PPCs with breakthrough IMIs in patients with haematological malignancies was evaluated. Risk factors associated with low PPCs were further evaluated. A total of 109 PPCs were measured in 34 cases receiving PCZ prophylaxis (n=31) or treatment (n=3). Levels below the target of 0.5 μg/mL were detected in 24 (71%) of the 34 cases; in 15 (63%) of these 24 cases concentrations were found to be <0.20 μg/mL. Three patients receiving PCZ prophylaxis met the criteria of breakthrough infection. Notably, prior to development of IMI, PPCs were below the target in all three individuals. Associated risk factors for insufficient PPCs varied from previous reports. In conclusion, these data demonstrate that therapeutic drug monitoring of PCZ is mandatory in all patients with haematological malignancies as low PPCs are common and may be associated with development of IMIs.

Diagnostic accuracy of soluble urokinase plasminogen activator receptor (suPAR) for prediction of bacteremia in patients with systemic inflammatory response syndrome.

OBJECTIVES Soluble urokinase plasminogen activator receptor (suPAR) serum concentrations have recently been described to reflect the severity status of systemic inflammation. In this study, the diagnostic accuracy of suPAR, C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6) to predict bacteremia in patients with systemic inflammatory response syndrome (SIRS) was compared. METHODS A total of 132 patients with SIRS were included. In 55 patients blood cultures had resulted positive (study group 1, Gram positive bacteria: Staphylococcus aureus and Streptococcus spp., n=15; study group 2, Gram-negative bacteria, n=40) and 77 patients had negative blood culture results (control group, n=77). Simultaneously with blood cultures suPAR, CRP, PCT, IL-6 and white blood count (WBC) were determined. RESULTS SuPAR values were significantly higher in study group 1 (median 8.11; IQR 5.78-15.53; p=0.006) and study group 2 (median 9.62; IQR 6.52-11.74; p<0.001) when compared with the control group (median 5.65; IQR 4.30-7.83). ROC curve analysis revealed an AUC of 0.726 for suPAR in differentiating SIRS patients with bacteremia from those without. The biomarkers PCT and IL-6 showed comparable results. Regarding combinations of biomarkers multiplying suPAR, PCT and IL-6 was most promising and resulted in an AUC value of 0.804. Initial suPAR serum concentrations were significantly higher (p=0.028) in patients who died within 28 days than in those who survived. No significant difference was seen for PCT, IL-6 and CRP. CONCLUSION In conclusion, suPAR, IL-6 and PCT may contribute to predicting bacteremia in SIRS patients.

European Organization for the Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) host factors and invasive fungal infections in patients with haematological malignancies

OBJECTIVES Fulfilment of host factors defined by the revised European Organization for the Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria is required for establishing the diagnosis of possible or probable invasive fungal infection (IFI). This case-control study evaluates EORTC/MSG host factors among patients with haematological malignancies. METHODS Fifty-eight patients with haematological malignancies who developed probable (n = 38) or proven (n = 20) IFI over a 5 year period were retrospectively evaluated regarding EORTC/MSG host factors. Results were compared with those obtained from patients with haematological malignancies who did not develop IFI (116 patients who received systemic antifungal prophylaxis or empirical therapy and 116 patients who did not; all data collected in 2010). RESULTS Fourteen patients had invasive yeast infection and 44 patients had invasive mould infection (IMI). Prolonged neutropenia (35/58, 60% versus 29/116, 25%), prolonged systemic corticosteroid (cut-off 21 days: 13/58, 22% versus 6/116, 5%; cut-off 14 days: 18/58, 31% versus 9/116, 8%) and T cell suppressive therapy (35/44, 80% versus 69/116, 59%) were significantly associated with development of IFI/IMI in our cohort. Previous allogeneic stem cell transplantation (SCT; >6 months prior to episode) was not significantly associated with development of IMI (8/44, 18% versus 22/116, 19%), while recent SCT (<6 months prior to episode) was (11/44, 25% versus 12/116, 10%). CONCLUSIONS We conclude that host factors according to revised EORTC/MSG criteria were significantly associated with the development of IFI/IMI in our patients. Previous allogeneic SCT was not a predisposing host factor for the development of IMI. Concerning prolonged corticosteroid treatment, a cut-off of 14 days seems preferable to the proposed cut-off.

Role of Klebsiella oxytoca in Antibiotic-Associated Diarrhea

BACKGROUND Klebsiella oxytoca was recently shown to be the causative agent of antibiotic-associated hemorrhagic colitis. Because it is unclear whether K. oxytoca also causes nonhemorrhagic antibiotic-associated diarrhea, our study investigated a possible association between K. oxytoca and that disorder. METHODS A total of 371 consecutive patients were recruited into 4 study groups: (1) group A+D+ (patients who received antibiotics and experienced diarrhea; n = 107), (2) group A+D- (patients who received antibiotics but did not experience diarrhea; np93), (3) group A-D+ (patients who experienced acute-onset diarrhea but did not receive antibiotics; n = 60), and (4) group A-D- (patients without diarrhea who did not receive antibiotics; n = 111). Stool samples were plated on MacConkey agar and K. oxytoca was identified using a standard test kit. Clostridium difficile was detected by a toxin A/B antigen test. K. oxytoca strains were tested for cytotoxicity with use of cell-culture assays. RESULTS In 15 of 371 stool samples, K. oxytoca strains were isolated during the study period. There was no significant difference in the distribution of K. oxytoca among the 4 study groups. Six of the 15 strains were found to be toxin producing. Three of the toxin-producing strains caused antibiotic-associated hemorrhagic colitis. No case of nonhemorrhagic antibiotic-associated diarrhea due to toxin-producing K. oxytoca was detected. CONCLUSION K. oxytoca is not the causative agent of nonhemorrhagic antibiotic-associated diarrhea. This is in contrast to the distinct clinical entity of antibiotic-associated hemorrhagic colitis. Testing for K. oxytoca is therefore only warranted for patients who experience bloody diarrhea during antibiotic therapy.

Potential Factors for Inadequate Voriconazole Plasma Concentrations in Intensive Care Unit Patients and Patients with Hematological Malignancies

ABSTRACT Voriconazole plasma concentrations (VPCs) vary widely, and concentrations outside the therapeutic range are associated with either worse outcome in invasive aspergillosis (IA) or increased toxicity. The primary goal of this cohort study conducted in a real-life setting was to identify potential factors associated with inadequate VPCs in ICU patients and patients with hematological malignancies. Within a period of 12 months, trough VPCs were obtained and analyzed with high-performance liquid chromatography, and the adequate range was defined as 1.5 to 5.5 mg/liter. VPCs of <1.5 mg/liter were defined as low, whereas VPCs of >5.5 mg/liter were defined as potentially toxic. A total of 221 trough VPCs were obtained in 61 patients receiving voriconazole, and 124/221 VPCs (56%) were found to be low. Multivariate analysis revealed that low VPCs were significantly associated with clinical failure of voriconazole, prophylactic use, younger age, underlying hematological malignancy, concomitant proton pump inhibitor (PPI) (pantoprazole was used in 88% of the patients), and absence of side effects. Low VPCs remained an independent predictor of clinical failure of voriconazole. The defined adequate range was reached in 79/221 (36%) VPCs. In 18 samples (8%), potentially toxic levels were measured. Multivariate analysis revealed higher body mass index (BMI), absence of hematological malignancy, therapeutic application, and diarrhea as factors associated with potentially toxic VPCs. Neurotoxic adverse events occurred in six patients and were mostly associated with VPCs in the upper quartile of our defined adequate range. In conclusion, potential factors like younger age, prophylaxis, underlying hematological malignancy, BMI, and concomitant PPI should be considered within the algorithm of voriconazole treatment.

Rifaximin intake leads to emergence of rifampin-resistant staphylococci

OBJECTIVES Rifaximin is a poorly absorbed non-systemic antimicrobial agent used in various gastrointestinal disorders. Rifampin is pivotal for the treatment of staphylococcal foreign body infections and resistance develops rapidly during monotherapy. The close structural relation of rifaximin to rifampin may lead to cross-resistance. The aim of our study was to determine whether rifampin-resistance emerges in human skin staphylococci during or after oral intake of rifaximin. METHODS Rifampin resistance of skin staphylococci in healthy volunteers during and after intake of rifaximin was determined by E-Test. RESULTS Seven out of eleven volunteers developed rifampin-resistant staphylococci after intake of rifaximin. A total of eleven rifampin-resistant and three rifampin-intermediate staphylococcal isolates were found. Before or during intake no resistant isolate was detected. Shortly after discontinuation the rifampin-resistant strains were primarily isolated from the perianal skin, a few weeks later they were found more frequently on the skin of the hands and lower arms. CONCLUSION Our data show that rifampin-resistant staphylococci emerge after intake of rifaximin. Since rifampin resistance is associated with treatment failure in staphylococcal foreign body infections, we conclude that rifaximin should be avoided in patients at risk for these infections.

Impact of galactomannan testing on the prevalence of invasive aspergillosis in patients with hematological malignancies

Galactomannan (GM) is a polysaccharide component of the cell wall of Aspergillus spp. and is released into the hosts circulation by growing hyphae. GM testing of patients with hematological malignancies has been rarely considered in recent epidemiologic studies of invasive mould infections (IMIs). The aim of the investigation was to analyze the impact of GM testing on the reported prevalence of IMI by comparing detection rates of IMI before and after the introduction of this diagnostic procedure. Prevalence of IMI was assessed by conducting a prospective single-centre study over seven months in 2010. Results obtained were then compared to those obtained with a representative collection of patients assessed by the same investigators at the same institution over seven months in 2007, i.e., prior to the introduction of GM testing. We found that, in general, detection rates of invasive aspergillosis (IA) and invasive mould infections increased significantly after the introduction of GM analysis. This study may therefore indicate that GM testing has a significant impact on the reported prevalence of IMI. Broad usage of such testing in patients with hematological malignancies may be able to produce a realistic picture of IMI rates when current diagnostic criteria are applied.

Contaminated Handwashing Sinks as the Source of a Clonal Outbreak of KPC-2-Producing Klebsiella oxytoca on a Hematology Ward

ABSTRACT We investigated sinks as possible sources of a prolonged Klebsiella pneumonia carbapenemase (KPC)-producing Klebsiella oxytoca outbreak. Seven carbapenem-resistant K. oxytoca isolates were identified in sink drains in 4 patient rooms and in the medication room. Investigations for resistance genes and genetic relatedness of patient and environmental isolates revealed that all the isolates harbored the blaKPC-2 and blaTEM-1 genes and were genetically indistinguishable. We describe here a clonal outbreak caused by KPC-2-producing K. oxytoca, and handwashing sinks were a possible reservoir.

Soluble urokinase plasminogen activator receptor predicts mortality in patients with systemic inflammatory response syndrome

The soluble urokinase plasminogen activator receptor (suPAR) reflects inflammation. However, the prognostic value of suPAR measurements, particularly at the very early onset of systemic inflammatory response syndrome (SIRS), is less well defined.

Disseminated Geosmithia argillacea infection in a patient with gastrointestinal GvHD

Fungal infections remain a major complication after haematopoietic SCT. Patients with GvHD are especially at risk for pulmonary fungal infections. Prophylactic regimens for patients with GvHD include posaconazole and voriconazole, and have demonstrated ability to prevent invasive fungal infections in a majority of patients undergoing allo-SCT for haematological malignancies. However, zygomycetes, Fusarium spp., and other rare moulds may cause major problems due to their resistance to these commonly used antifungal agents. We report on a 52-year-old Caucasian male with a bcrabl positive Pro-B ALL, who was treated according to the risk adapted German Multicenter Protocol GMALL 07/ 2003 (http://www.kompetenznetz-leukaemie.de/content/ aerzte/studien/studienregister) and underwent allo-SCT with reduced intensity conditioning in January 2010. A grade II acute GvHD of the skin was successfully treated with corticosteroids. In October, the patient was readmitted because of severe diarrhea. Endoscopic examination of the gastrointestinal tract, including multiple biopsies was performed, revealing late onset gastrointestinal acute GvHD grade III. Because of diarrhea and subtherapeutical posaconazole serum levels of 0.24mg/L, the antifungal prophylaxis was changed to i.v. voriconazole 200mg twice daily. High-dose corticosteroid treatment with methylprednisone 2mg/kg per day was initiated, and mycophenolate mofetil dose was increased to 1.5mg/kg twice daily. Initially, the patient responded well to the treatment, but after 10 days, watery diarrhea reoccurred. Thus, infliximab (10mg/kg once weekly, two doses) was commenced as third line GvHD therapy. A few days later, the C-reactive protein markedly increased and the patient developed respiratory symptoms, together with an incomplete hemiparesis caused by a stroke. Concurrently, the serum galactomannan index (Bio-Rad Laboratories, Marnes-laCoquette, France) increased from 0.36 to 4.44 OD (normal range o0.5 OD) within a week, and increased up to 420 OD in the following days. A computed tomography scan of the lungs revealed a new infiltrate with a halo sign (Figure 1a). Broncho-alveolar lavage (BAL) was performed the next day, and the patient was empirically switched to liposomal amphotericin B (5mg/kg per day) and caspofungin (70mg per day). Gram stain obtained from BAL revealed fungal hyphae, and cultures from lavage fluid grew a mould (Figure 2a), microscopically resembling Penicillium or Paecilomyces (Figure 2b). The BAL galactomannan was 420 OD. Bacterial cultures, Pneumocystis jirovecii microscopy, PCR for CMV and mycobacteria were all negative. The mould was identified as Geosmithia argillacea by sequencing of rDNA ITS and b-tubulin gene (GenBank accession number HQ686279 and HQ686280, respectively). Thermotolerance tests showed that G. argillacea is highly thermotolerant with active growth up to 50 1C on Sabourauds and malt extract agar. Susceptibility testing revealed a high in vitro minimum inhibition concentration against voriconazole (432mg/L) and fluconazole (4256mg/L), but lower minimum inhibition concentrations to amphotericin B (1.0mg/L), posaconazole (0.25mg/L), itraconazole (0.5mg/L) and echinocandins (0.004–0.032mg/L). After 7 days of caspofungin and liposomal amphotericin B, the C-reactive protein decreased significantly and a follow-up computed tomography scan revealed the occurrence of a second lesion, whereas the halo sign of the primary infiltrate had resolved (Figure 1b). However, later in the course, the patient deteriorated and the C-reactive protein increased again. Aside from adaptations of the empiric antibacterial treatment, i.v. itraconazole 200mg twice daily was added. Despite triple antifungal therapy,