Bertrand Gachot

Treatment with Piperacillin-Tazobactam and False-Positive Aspergillus Galactomannan Antigen Test Results for Patients with Hematological Malignancies

We report the occurrence of a high rate of false-positive test results during the surveillance of hematology patients for galactomannan (GM) antigenemia. Among 218 patients surveyed from June 2002 through June 2003, 42 (19.3%) had > or =1 serum sample positive for GM (optical density index, >1.5). Of these patients, 38 had no additional evidence of invasive aspergillosis, and, therefore, their test results were considered to be false-positives. Case-control analysis showed that treatment with piperacillin-tazobactam was the only risk factor significantly associated with receiving false-positive test results. When tested for GM antigen, 3 of 4 piperacillin-tazobactam batches had positive results. Physicians should be aware of the possible interference of treatment with piperacillin-tazobactam when interpreting the results of the GM assay.

Prognostic factors for neutropenic patients in an intensive care unit : Respective roles of underlying malignancies and acute organ failures

The admission of neutropenic patients to an intensive care unit (ICU) is still controversial, especially if mechanical ventilation is required. To avoid useless stays in ICU, the evaluation of the respective role of the underlying malignancy and acute organ failures might be useful for better definition of the categories of patients who could benefit from aggressive ICU support. For this purpose, we carried out a retrospective study of the charts of 107 consecutive neutropenic patients admitted to an ICU in a comprehensive cancer centre over a four-year period. The following characteristics were recorded within 24 h of admission: patient data, characteristics of neutropenia and the underlying malignancy, the type and number of organ system failures (OSFs) and simplified acute physiological scores (SAPS and SAPS II). The impact of each variable on outcome in the ICU was studied by univariate and multivariate (logistic regression) analysis. 59 patients died in the ICU (mortality rate: 55%). Patients with a haematological malignancy (n = 57, 53%) were more likely to experience respiratory failure, an underlying malignancy deemed rapidly fatal, and to have longer lasting neutropenia than patients with a solid tumour (n = 50, 47%). However, the mortality rate did not differ in the two groups (haematological malignancy 61% versus solid tumour 48%, p = 0.16). Respiratory and cardiovascular organ failure (p < 0.001 for both) correlated with mortality in the ICU. In the multiple logistic regression model, only the number of organ system failures and respiratory failure remained predictive of ICU mortality. In conclusion, the characteristics of the underlying malignancy are not relevant when deciding whether or not neutropenic patients should be admitted to an ICU. The main risk factors for death in an ICU are the number of organ failures on admission, and among them the presence of respiratory failure.

Epidemiology and Outcome of Fungemia in a Cancer Cohort of the Infectious Diseases Group (IDG) of the European Organization for Research and Treatment of Cancer (EORTC 65031)

BACKGROUND Anti-cancer treatment and the cancer population have evolved since the last European Organisation for Research and Treatment of Cancer (EORTC) fungemia survey, and there are few recent large epidemiological studies. METHODS This was a prospective cohort study including 145 030 admissions of patients with cancer from 13 EORTC centers. Incidence, clinical characteristics, and outcome of fungemia were analyzed. RESULTS Fungemia occurred in 333 (0.23%; 95% confidence interval [CI], .21-.26) patients, ranging from 0.15% in patients with solid tumors to 1.55% in hematopoietic stem cell transplantation recipients. In 297 evaluable patients age ranged from 17 to 88 years (median 56 years), 144 (48%) patients were female, 165 (56%) had solid tumors, and 140 (47%) had hematological malignancies. Fungemia including polymicrobial infection was due to: Candida spp. in 267 (90%), C. albicans in 128 (48%), and other Candida spp. in 145 (54%) patients. Favorable overall response was achieved in 113 (46.5%) patients by week 2. After 4 weeks, the survival rate was 64% (95% CI, 59%-70%) and was not significantly different between Candida spp. Multivariable logistic regression identified baseline septic shock (odds ratio [OR] 3.04, 95% CI, 1.22-7.58) and tachypnoea as poor prognostic factors (OR 2.95, 95% CI, 1.66-5.24), while antifungal prophylaxis prior to fungemia (OR 0.20, 95% CI, .06-.62) and remission of underlying cancer (OR, 0.18; 95% CI, .06-.50) were protective. CONCLUSIONS Fungemia, mostly due to Candida spp., was rare in cancer patients from EORTC centers but was associated with substantial mortality. Antifungal prophylaxis and remission of cancer predicted better survival.

Liver abscess after radiofrequency ablation of tumors in patients with a biliary tract procedure.

AIM The rate of liver abscesses after radiofrequency ablation (RFA) of liver tumors is probably high in patients with a biliary tract drainage procedure connecting the biliary duct system to the upper gastrointestinal tract. And yet, to date this rate, the time of onset of these abscesses, and the prior status of the bile ducts have never been reported in the literature. METHODS Among 574 patients treated with RFA over 8 years, only 11 patients (with 13 sessions of RFA, 2 patients undergoing two different RFA sessions) presented with an enterobiliary anastomosis or biliary stenting at the time of RFA. This is a retrospective study of patients who were verified prospectively. RESULTS Among the 9 patients in whom a biliary tract procedure preceded RFA, 4 developed a liver abscess at the site of RFA, which emerged between 13 and 62 days after RFA. It occurred in spite of different types of short-term antibiotic prophylaxis. Pathogenic bacteria were typical of the digestive flora. Abscesses were cured after percutaneous drainage. No abscess occurred among the 4 patients in whom a biliary tract diversion was performed synchronously with RFA. CONCLUSION When RFA is performed in a patient with a preexisting biliary diversion, the risk of developing a liver abscess is high. Currently, we are unable to recommend any kind of preventive antibiotherapy. A preexisting biliary diversion is not an absolute contraindication for RFA, but the risk of developing a liver abscess is close to 40-50%. When RFA is performed synchronously with a biliary diversion, the risk of a liver abscess seems to disappear.

A retrospective series of gut aspergillosis in haematology patients

Gut invasive aspergillosis is an extremely rare infection in immunocompromised patients. The goal of this retrospective multicentre study is to report on cases of gut aspergillosis in haematology patients, including clinical presentation, risk factors, and outcome. Twenty-one patients from nine centres were identified. Eight had isolated gut aspergillosis, with no evidence of other infected sites, and 13 had disseminated aspergillosis. Thirteen patients had acute leukaemia. Nine were allogeneic stem cell transplant recipients. Clinical symptoms and imaging were poorly specific. The galactomannan antigenaemia test result was positive in 16/25 (64%) patients, including in four of the eight cases of isolated gut aspergillosis. Five of 21 patients had a dietary regimen rich in spices, suggesting that, in these cases, food could have been the source of gut colonization, and then of a primary gut Aspergillus lesion. The diagnosis was made post-mortem in six patients. The mortality rate in the remaining patients at 12 weeks was 7/15 (47%). Gut aspergillosis is probably misdiagnosed and underestimated in haematology patients, owing to the poor specificity of symptoms and imaging. Patients with a persistently positive galactomannan antigenaemia finding that is unexplained by respiratory lesions should be suspected of having gut aspergillosis in the presence of abdominal symptoms, and be quickly investigated. In the absence of severe abdominal complications leading to surgery and resection of the lesions, the optimal treatment is not yet defined.

Elaboration of a consensual definition of de-escalation allowing a ranking of β-lactams

Empirical broad spectrum antimicrobial therapy prescribed in life-threatening situations should be de-escalated to mitigate the risk of resistance emergence. Definitions of de-escalation (DE) vary among studies, thereby biasing their results. The aim of this study was to provide a consensus definition of DE and to establish a ranking of β-lactam according to both their spectra and their ecological consequences. Twenty-eight experts from intensive care, infectious disease and clinical microbiology were consulted using the Delphi method (four successive questionnaires) from July to November 2013. More than 70% of similar answers to a question were necessary to reach a consensus. According to our consensus definition, DE purpose was to reduce both the spectrum of antimicrobial therapy and the selective pressure on microbiota. DE included switching from combination to monotherapy. A six-rank consensual classification of β-lactams allowing gradation of DE was established. The group was unable to differentiate ecological consequences of molecules included in group 4, i.e. piperacillin/tazobactam, ticarcillin/clavulanic acid, fourth-generation cephalosporin and antipseudomonal third-generation cephalosporin. Furthermore, no consensus was reached on the delay within which DE should be performed and on whether or not the shortening of antibiotic therapy duration should be included in DE definition. This study provides a consensual ranking of β-lactams according to their global ecological consequences that may be helpful in future studies on DE. However, this work also underlines the difficulties of reaching a consensus on the relative ecological impact of each individual drug and on the timing of DE.

Successful Rescue in a Patient with High Dose Methotrexate-Induced Nephrotoxicity and Acute Renal Failure

We describe the case of a 35-year old male who developed acute renal failure following high dose methotrexate therapy for Burkitts non Hodgkin lymphoma. Serum methotrexate levels reached 37 micromol/l, and remained higher than 1 micromol/l for more than a week. Folinic acid rescue was intensified to 200-400 mg intravenously every 4 hours. As methotrexate binds markedly to proteins, plasma exchange was initially chosen, 4 sessions being performed from day 2 to day 4. The methotrexate pharmacokinetic profile was not significantly modified during plasma exchange, and serum drug level was 3 micromol/l. Continuous veno-venous hemodiafiltration was therefore performed from day 5 to day 10. This procedure also seemed ineffective, with evidence of low ultrafiltrate clearance. No extrarenal toxicity was observed in our patient. Thus, conventional extrarenal procedures appear to have a limited role in the setting of overexposure to methotrexate. The use of very high doses of folinic acid in our case probably played a major role in the eventual favorable outcome.

The strategy of antibiotic use in critically ill neutropenic patients

Suspicion of sepsis in neutropenic patients requires immediate antimicrobial treatment. The initial regimen in critically ill patients should cover both Gram-positive and Gram-negative pathogens, including Pseudomonas aeruginosa. However, the risk of selecting multidrug-resistant pathogens should be considered when using broad-spectrum antibiotics for a prolonged period of time. The choice of the first-line empirical drugs should take into account the underlying malignancy, local bacterial ecology, clinical presentation and severity of acute illness. This review provides an up-to-date guide that will assist physicians in choosing the best strategy regarding the use of antibiotics in neutropenic patients, with a special focus on critically ill patients, based on the above-mentioned considerations and on the most recent international guidelines and literature.

Discontinuation of empirical antibiotic therapy in neutropenic acute myeloid leukaemia patients with fever of unknown origin: is it ethical?

Based on recommendations of the ECIL-4, we prospectively evaluated discontinuation of empirical antibiotic therapy in high-risk neutropenic acute myeloid leukaemia patients with fever of unknown origin. Seven patients (median neutropenia duration 30 days) were included. Four of them remained afebrile but quickly recovered from neutropenia. The other three had rapid recurrent fever. Two of these three patients had bacteraemia with susceptible strains and one of them was transferred to the ICU for septic shock. Median duration of sparing of antibiotics for the seven patients was 3 days (2-4). Because of these limited results the study was stopped.

Factors influencing posaconazole plasmatic concentrations in patients presenting with acute myeloid leukemia

PURPOSE The effectiveness of posaconazole (PSZ) prophylaxis on invasive fungal infections, in patients presenting with acute myeloid leukemia (AML), seems to be correlated to its blood plasma concentration. Our goal was to identify the risk factors for underdosing. PATIENTS AND METHODS We retrospectively reviewed the records of patients treated for AML treated with PSZ, during a 2-year period. Assays<500ng/mL were considered as under dosed. RESULTS Fifty-nine assays (43 patients) were performed during induction (n=22) or consolidation (n=37) chemotherapy. PSZ treatment was initiated within a median of 3 days before neutropenia with a first assay performed at 8 days (3-28). The median PSZ blood plasma concentration was 375ng/mL (<200-1900). Forty-one (69%) treatment were maintained until the end of neutropenia. One patient presented with candidemia, 9 with possible invasive aspergillosis, without any significant association with underdosing. The univariate analysis showed that co-administration of proton pump inhibitors (PPIs) (P=0.01) and cause of hospitalization (induction chemotherapy vs consolidation, P=0.008) were associated with underdosing, contrary to feeding difficulties (P=0.07) and digestive disorders (P=0.5). The multivariate analysis confirmed the impact of PPI use (P=0.01) and the cause of hospitalization (P=0.003). CONCLUSION This study highlights the major impact of PPI administration on PSZ blood plasma levels and stresses the risk of non-effective prophylaxis during induction treatment of AML.