Pharmacokinetics/pharmacodynamics and therapeutic drug monitoring of ceftazidime/avibactam administered by continuous infusion in patients with MDR Gram-negative bacterial infections.

BACKGROUND: Therapeutic drug monitoring (TDM) of ß-lactams in critically ill patients has been correlated with better clinical outcomes. Evidence on TDM of newer ß-lactams such as ceftazidime/avibactam administered by continuous infusion (CI) is very limited. OBJECTIVES: To describe our experience with TDM of ceftazidime/avibactam and pharmacokinetic/pharmacodynamic (PK/PD) target attainment in patients with MDR bacterial infections. Clinical outcomes of ceftazidime/avibactam administered by CI were also assessed. METHODS: Patients treated with ceftazidime/avibactam administered by CI and undergoing TDM of ceftazidime plasma concentrations were included. Blood samples were obtained as part of the TDM program. The PK/PD therapeutic target of ceftazidime/avibactam was defined as 100%fT > 4 × MIC of the causative pathogen, and 100%fT > 10 × MIC was considered overexposure. Dose changes were made according to the TDM results. RESULTS: Thirty-one patients were included. Ceftazidime/avibactam total daily doses ranged from 1 g/0.25 g to 6 g/1.5 g. Twenty-six patients (83.9%) achieved a 100%fT > 4 × MIC, 15 (48.4%) of which were overexposed (100%fT > 10 × MIC). Dose reduction was suggested in 16/28 (57.1%) patients and dose maintenance in 12/28 (42.9%). Overall clinical cure was observed in 21 (67.7%) patients, and 18 of these (85.7%) achieved a 100%fT > 4 × MIC. CONCLUSIONS: Administering ceftazidime/avibactam by CI enabled the desired PK/PD target to be achieved in a large proportion of patients, even at lower doses than those recommended for a 2 h extended infusion. We suggest that the use of CI with TDM may be a useful tool for reducing initial doses, which could help to reduce antimicrobial-related adverse effects and treatment costs.

Macrolide resistance in Mycoplasma genitalium in Catalonia, Spain: a 1 year prospective study.

BACKGROUND: Mycoplasma genitalium is an emergent cause of sexually transmitted disease (STD). The first-line treatment is azithromycin, but macrolide resistance is increasing due to mutations in the 23S rRNA gene. OBJECTIVES: To determine the rates of M. genitalium infection and macrolide resistance in an area adjacent to Barcelona. METHODS: This 1 year prospective study was performed in a heterogenous population that included both low- and high-risk patients. M. genitalium was detected in all specimens sent to our institution for STD detection. Epidemiological and relevant clinical data were collected in the positive cases. Characterization of macrolide-associated resistance was performed by 23S rDNA sequencing. RESULTS: Of the 3540 patients included, 132 (3.7%) were positive for M. genitalium. Another sexually transmitted bacteria was detected in 20.4% of the M. genitalium cases, and Chlamydia trachomatis (11%) was the most frequently co-detected microorganism. Only 61.4% of patients received an adequate initial treatment against M. genitalium. The test of cure (TOC) was performed in 42% of patients, and therapeutic failure was detected in 10 cases. The rate of macrolide resistance was 12.6% and the most prevalent mutation was A2058G. There was an association between macrolide resistance and a previous history of M. genitalium detection (P < 0.001). CONCLUSIONS: Our results support the contribution of the previous use of macrolides in resistant strains. Given the difficulties in performing TOC in all patients, the inclusion of macrolide resistance in the detection test should be mandatory.

Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network.

BACKGROUND: There is scarce data available about epidermal growth factor receptor (EGFR) mutations other than common exon 19 deletions and exon 21 (L858R) mutations. PATIENTS AND METHODS: EGFR exon 18 and/or exon 20 mutations were collected from 10 117 non-small-cell lung cancer (NSCLC) samples analysed at 15 French National Cancer Institute (INCa)-platforms of the ERMETIC-IFCT network. RESULTS: Between 2008 and 2011, 1047 (10%) samples were EGFR-mutated, 102 (10%) with rare mutations: 41 (4%) in exon 18, 49 (5%) in exon 20, and 12 (1%) with other EGFR mutations. Exon 20 mutations were related to never-smoker status, when compared with exon 18 mutations (P < 0.001). Median overall survival (OS) of metastatic disease was 21 months [95% confidence interval (CI) 12-24], worse in smokers than in non-smoker patients with exon 20 mutations (12 versus 21 months; hazard ratio [HR] for death 0.27, 95% CI 0.08-0.87, P = 0.03). Under EGFR-tyrosine kinase inhibitors (TKIs), median OS was 14 months (95% CI 6-21); disease control rate was better for complex mutations (6 of 7, 86%) than for single mutations (16 of 40, 40%) (P = 0.03). CONCLUSIONS: Rare EGFR-mutated NSCLCs are heterogeneous, with resistance of distal exon 20 insertions and better sensitivity of exon 18 or complex mutations to EGFR-TKIs, probably requiring individual assessment.

Linezolid vs glycopeptides in the treatment of glycopeptide-susceptible Enterococcus faecium bacteraemia: A propensity score matched comparative study.

BACKGROUND: The incidence of ampicillin-resistant Enterococcus faecium bacteraemia is increasing. Vancomycin remains the first-line treatment in areas with a high prevalence of glycopeptide-susceptible isolates, but data comparing its clinical outcomes with other treatments are lacking. The objective of this study was to compare the effectiveness and safety of linezolid and glycopeptides for the treatment of glycopeptide-susceptible E. faecium bloodstream infection (GSEF-BSI). METHODS: This retrospective observational cohort study was conducted from January 2006 to May 2018 at the Hospital del Mar, Barcelona, Spain, and compared the clinical outcomes and safety of linezolid and glycopeptides in adult patients with GSEF-BSI. The main outcomes included clinical cure at the end of therapy, 30-day mortality, microbiological eradication and attributable length of stay (LOS). Propensity score matching was performed to reduce potential confounders among groups. RESULTS: In total, 105 patients with GSEF-BSI were included (linezolid, n=38; glycopeptides, n=67). After propensity score matched analysis, 56 (53.3%) patients, 28 in each cohort, entered the final analysis. No differences were observed in any of the main clinical outcomes among patients treated with linezolid or glycopeptides: clinical cure [16/28 (57.1%) vs 13/28 (46.4%), P=0.593], 30-day mortality [8/28 (28.6%) vs 12/28 (42.9%), P=0.403], microbiological eradication [22/28 (78.6%) vs 20/28 (71.4%), P=0.758] and median attributable LOS (18.0 vs 17.0 days, P=0.924). Adverse events were similar in both groups. CONCLUSIONS: Linezolid and glycopeptides showed similar clinical effectiveness and safety in the treatment of GSEF-BSI. Linezolid could be an alternative to glycopeptides in the treatment of GSEF-BSI.

Predictors of outcome in patients with severe sepsis or septic shock due to extended-spectrum ß-lactamase-producing Enterobacteriaceae.

PURPOSE: There are few data in the literature regarding sepsis or septic shock due to extended-spectrum ß-lactamases (ESBL)-producing Enterobacteriaceae (E). The aim of this study was to assess predictors of outcome in septic patients with bloodstream infection (BSI) caused by ESBL-E. METHODS: Patients with severe sepsis or septic shock and BSI due to ESBL-E were selected from the INCREMENT database. The primary endpoint of the study was the evaluation of predictors of outcome after 30 days from development of severe sepsis or septic shock due to ESBL-E infection. Three cohorts were created for analysis: global, empirical-therapy and targeted-therapy cohorts. RESULTS: 367 septic patients were analysed. Overall mortality was 43.9% at 30 days. Escherichia coli (62.4%) and Klebsiella pneumoniae (27.2%) were the most frequent isolates. ß-lactam/ß-lactamase inhibitor (BLBLI) combinations were the most empirically used drug (43.6%), followed by carbapenems (29.4%). Empirical therapy was active in vitro in 249 (67.8%) patients, and escalation of antibiotic therapy was reported in 287 (78.2%) patients. Cox regression analysis showed that age, Charlson Comorbidity Index, McCabe classification, Pitt bacteremia score, abdominal source of infection and escalation of antibiotic therapy were independently associated with 30-day mortality. No differences in survival were reported in patients treated with BLBLI combinations or carbapenems in empirical or definitive therapy. CONCLUSIONS: BSI due to ESBL-E in patients who developed severe sepsis or septic shock was associated with high 30-day mortality. Comorbidities, severity scores, source of infection and antibiotic therapy escalation were important determinants of unfavorable outcome.

Bacillus species pseudo-outbreak: construction works and collateral damage.

We describe the investigation and management of a pseudo-outbreak of Bacillus spp. bacteraemia associated with construction work in an emergency department (ED). During the pseudo-outbreak period 59 out of 3469 (1.7%) blood cultures yielded Bacillus spp. versus 24 out of 7628 (0.31%) in 2012. Material, surfaces, and air samples showed environmental contamination. Cases rapidly declined following the implementation of infection control measures and the end of construction. Construction works at the ED caused environmental contamination that most probably led to the pseudo-outbreak of Bacillus bacteraemia. In hospital settings, the lack of correctly implemented effective barriers during construction may place patients and healthcare providers at risk as well as lead to pseudo-outbreaks.

Esterase EstA6 from Pseudomonas sp. CR-611 is a novel member in the utmost conserved cluster of family VI bacterial lipolytic enzymes.

Strain Pseudomonas sp. CR-611, previously isolated from a subtropical forest soil on tributyrine-supplemented plates, displays phenotypic and physiological properties consistent with those described for Pseudomonas fluorescens. However, no complete match to this species could be found after 16S rDNA comparison. Zymographic analysis of the strain revealed a complex lipolytic system, showing the presence of at least two enzymes with activity on MUF-butyrate. Alignment of Pseudomonas fluorescens lipase/esterase-coding sequences allowed the design of specific primers for family VI lipases, and the isolation and cloning of the resulting gene estA6. The recombinant clone obtained displayed high activity on fatty acid-derivative substrates, indicating that one of the lipolytic enzymes of the strain had been cloned. The enzyme, named EstA6, was then purified and characterized, showing maximum activity on short chain-length substrates under conditions of high temperature and neutral pH. Amino acid sequence alignment of EstA6 with other family VI esterases allowed identification of a highly conserved beta-/gamma-protobacterial cluster in family VI lipases, to which EstA6 belongs.

estA, a gene coding for a cell-bound esterase from Paenibacillus sp. BP-23, is a new member of the bacterial subclass of type B carboxylesterases.

Screening of a gene library from Paenibacillus sp. BP-23 generated in Escherichia coli led to identification of a clone that directed the production of lipolytic activity. From the sequencing data, we found an open reading frame encoding a protein of 485 amino acids with an estimated molecular mass of 53 kDa and a pI of 5.1. Absence of a signal peptide indicated that it was a cell-bound protein. Sequence analysis showed that the protein contained the signature G-XI-S-X2-G included in most serine-esterases and lipases. The cloned protein showed high homology with enzymes belonging to the bacterial subclass of type B carboxylesterases. The enzyme had a significant preference for esters of short-chain fatty acids and showed the kinetics behaviour of a true esterase. Maximum activity was found at pH 7.5 and 37 degrees C, although the enzyme was active in the pH range 6.0- 9.0 and at temperatures up to 45 degrees C. As expected for a serine-esterase, activity was inhibited by phenylmethylsulphonyl fluoride.

[Afatinib (BIBW 2992)]. / L'afatinib (BIBW 2992).

Afatinib (BIBW 2992) is an irreversible multi-target HER receptor tyrosine kinase inhibitor developed in patients with advanced solid tumours. Several phase I studies were conducted in patients with non-small cell lung cancer (NSCLC), as a single agent or in combination. In further phase II or III studies, patients were selected based on the duration of response to first generation EGFR-TKI in previous line (supposed to have greater chance to have an activating EGFR mutation) or based directly on the EGFR activating mutation status. Here, we report and comment the main results of these studies in lung cancer patients. This drug has been approved by the Food and Drug Administration in June 2013 for the first-line treatment of patients with metastatic NSCLC whose tumours have EGFR mutation. In Europe, it has been approved in September 2013 in the same indication.

[Solitary fibrous tumors: Case report of a late relapse]. / Tumeur fibreuse solitaire: cas clinique d'une récidive tardive.

Authors report a case of a woman with a metastasis of a solitary fibrous tumor, 14 years after the diagnosis of a hemangiopericytoma of the soft tissues. This case report allows discussing the pathological features, the therapeutical option and the outcome of these tumors.

[Small cell lung cancer and anti-Hu syndrome]. / Cancer bronchique à petites cellules et syndrome des anticorps anti-Hu.

INTRODUCTION: The anti-Hu associated syndrome is a rare paraneoplastic neurological syndrome, which is principally associated with small-cell lung cancer. OBSERVATION: We report the case of a patient with the following clinical features: dysautonomia with severe gastroparesis, sensory neuropathy and a rhombencephalitis. Tumour regression was obtained with chemotherapy but the patient ultimately died from the neurological complications. CONCLUSION: Neurological syndromes associated in small cell lung cancer with anti-Hu antibodies are very diverse. Cancer evolution is generally speaking more benign than usual with the prognosis linked to the severity of the neurological involvement.

Cloning and characterization of a bacterial cell-bound type B carboxylesterase from Bacillus sp. BP-7.

A clone producing halos on tributyrin plates was isolated from a genomic library of Bacillus sp. BP-7. The insert contained an open reading frame that coded for a protein of 487 amino acids with homology to carboxylesterases. The cloned enzyme showed clear preference for esters of short-chain fatty acids, being classified as an esterase. Maximum activity was found at 45 degrees C and pH 7.5. The enzyme displayed stability in the pH range from 6 to 9.5, and at temperatures from 4 degrees to 45 degrees C. Zymogram analysis of the protein revealed a molecular mass of 53 kDa and a pI of 5.1. The enzyme showed homology to members of the bacterial subclass of type B carboxylesterases, a set of proteins potentially useful for biotechnological applications.

Biochemical studies on cloned Bacillus sp. BP-7 phenolic acid decarboxylase PadA.

Sequence analysis of a Bacillus sp. BP-7 recombinant clone coding for a previously described carboxylesterase revealed the presence of an additional ORF with homology to bacterial hydroxycinnamic acid decarboxylases. Analysis of the amino acid sequence of the encoded enzyme revealed the presence of a single, highly conserved domain of 161 amino acids, with a predicted molecular mass of 19,143 Da and a pI of 5.5. Crude cell extracts from the recombinant clone displayed activity on ferulic, p-coumaric and caffeic acids, with no need for added cofactors. The cloned enzyme, named PadA, displayed maximum activity at 40 degrees C and pH 5.5, being stable over a broad range of pH and up to 45 degrees C. HPLC analysis of the products of catalysis revealed the conversion of phenolic acids to their aromatic 4-vinyl derivatives, with no accumulation of other by-products. PadA was found as a homodimer in the parental Bacillus sp. BP-7 strain and its expression was induced by both hydroxycinnamic acids and their corresponding derivative products. The results obtained suggest that the enzyme could be involved in a stress response for conversion of toxic hydroxycinnamic acids released after plant cell wall degradation.