Posaconazole therapeutic drug monitoring in a regional hospital setting

BACKGROUND: Posaconazole therapeutic drug monitoring (TDM) is recommended to promote effective antifungal prophylaxis, but its utility has yet to be optimized. Breakthrough invasive fungal infections have been reported with serum concentrations/L, but there is little evidence to determine the optimal serum concentration for efficacy or concentrations associated with toxicity. Challenges for effective monitoring are greater in settings without posaconazole TDM facilities because of the long turnaround time before receipt of results. METHODS: Thirty-eight TDM episodes were performed on 18 patients in a regional center in Australia during a 30-month period. Australian guidelines recommend a trough serum concentration of ≥700 mcg/L. The response to concentrations below the recommendation threshold (700 mcg/L), the final serum plasma concentration for each patient, and the appropriateness of TDM were evaluated. RESULTS: A total of 19 (50%) concentrations were recorded to be \u3c 700 mcg/L. Of these 19 concentrations, the drug dose was increased on only 4 occasions. Eleven of 18 patients (61%) had initial concentrations CONCLUSIONS: The results demonstrate a lack of confidence and consistency in ordering, interpreting, and following up posaconazole concentrations. Therefore, the use of TDM should be carefully considered, especially in regional centers. Such settings should consider the practicalities of posaconazole TDM and try to improve the process to ensure consistency and optimization of patient care

Circulating osteopontin: a dual marker of bone destruction and angiogenesis in patients with multiple myeloma

The matrix protein osteopontin has been shown to be a marker of osteoclastic activity in multiple myeloma patients, as well as a regulator of angiogenesis. We measured serum levels of osteopontin in 50 untreated multiple myeloma patients (in 25, also after treatment) and examined the relation to markers of osteolytic and angiogenic activity. The median (range) of serum osteopontin was 85 (5-232) in the patient group vs. 36 (2-190) ng/ml in the control group. Serum osteopontin levels were significantly higher in patients with advanced stage or grade of myeloma disease. All patients with serum osteopontin levels >100 ng/ml had advanced stage (II or III) or high grade bone disease, whereas stage I or low grade patients had serum osteopontin levels <100ng/ml. Serum osteopontin levels significantly decreased after treatment. There was a positive correlation of osteopontin with the bone turnover marker N-terminal propeptide of procollagen type I (NTx) and the angiogenic markers vascular endothelial growth factor (VEGF) and bone marrow microvessel density (r: 0.35, 0.47 and 0.30 respectively, p < 0.05). These results support osteopontin as a dual marker of bone destruction and angiogenic activity in myeloma patients. Osteopontin represents a useful biomarker for monitoring myeloma disease activity

Microbiological and molecular characteristics of carbapenemase-producing klebsiella pneumoniae endemic in a tertiary Greek hospital during 2004-2010

We report 570 carbapenemase-producing Klebsiella pneumoniae (CPKP) clinical isolates in a 1,040-bed Greek tertiary hospital during 2004 to 2010. The first CPKP (VIM-producing) was isolated in September 2004. Despite initial containment, VIM producers have become endemic since 2006. KPC-producing K. pneumoniae was first isolated in August 2007 from a patient who came from Israel, spread rapidly, and outcompeted VIM. Overall, 267 (47%) VIM-producing and 301 (53%) KPC-producing strains were isolated, including 141 (24.7%) from patients with bacteraemia. Two isolates carrying both VIM and KPC were isolated in two consecutive months in 2009, but not since. The prevalence of CPKP increased from 0% in 2003 to 38.3% in 2010 (

The importance of colonization pressure in multiresistant Acinetobacter baumannii acquisition in a Greek intensive care unit

INTRODUCTION: We investigated the role of colonization pressure on multiresistant Acinetobacter baumannii acquisition and defined patient-related predictors for carriage at admission and acquisition during hospitalization in intensive care unit (ICU) patients. METHODS: This was a 12-month, prospective, cohort study of all patients admitted to a single ICU of a tertiary hospital. Screening samples were collected at ICU admission to identify imported carriers, and weekly during hospitalization to identify acquisition. Colonization pressure (carriers' patient-days × 100/all patients' patient-days) and the absolute number of carriers were calculated weekly, and the statistical correlation between these parameters and acquisition was explored. Multivariable analysis was performed to identify predictors for A. baumannii carriage at admission and acquisition during hospitalization. A. baumannii isolates were genotyped by repetitive-extragenic-palindromic polymerase chain reaction (PCR; rep-PCR). RESULTS: At ICU admission, 284 patients were screened for carriage. A. baumannii was imported in 16 patients (5.6%), and acquisition occurred in 32 patients (15.7%). Acquisition was significantly correlated to weekly colonization pressure (correlation coefficient, 0.379; P = 0.004) and to the number of carriers per week (correlation coefficient, 0.499; P <0.001). More than one carrier per week significantly increased acquisition risk (two to three carriers, odds ratio (OR), 12.66; P = 0.028; more than four carriers, OR, 25.33; P = 0.004). Predictors of carriage at admission were infection at admission (OR, 11.03; confidence interval (CI), 3.56 to 34.18; P < 0.01) and hospitalization days before ICU (OR, 1.09; CI, 1.01 to 1.16; P = 0.02). Predictors of acquisition were a medical reason for ICU admission (OR, 5.11; CI, 1.31 to 19.93; P = 0.02), duration of antibiotic administration in the unit (OR, 1.24; CI, 1.12 to 1.38; P < 0.001), and duration of mechanical ventilation (OR, 1.08; CI, 1.04 to 1.13; P = 0.001). All strains were multiresistant. Rep-PCR analysis showed one dominant cluster. CONCLUSIONS: Acquisition of multiresistant A. baumannii in ICU patients is strongly correlated to colonization pressure. High levels of colonization pressure and more than two carriers per week independently increase acquisition risk. Patient-related factors, such as infection at admission and long hospitalization before the ICU, can identify imported A. baumannii carriers. Medical patients with extended administration of antibiotics and long duration of mechanical ventilation in the ICU were the most vulnerable to acquisition

The importance of colonization pressure in multiresistant Acinetobacter baumannii acquisition in a Greek intensive care unit

Introduction: We investigated the role of colonization pressure on multiresistant Acinetobacter baumannii acquisition and defined patient-related predictors for carriage at admission and acquisition during hospitalization in intensive care unit (ICU) patients. Methods: This was a 12-month, prospective, cohort study of all patients admitted to a single ICU of a tertiary hospital. Screening samples were collected at ICU admission to identify imported carriers, and weekly during hospitalization to identify acquisition. Colonization pressure (carriers’ patient-days × 100/all patients’ patient-days) and the absolute number of carriers were calculated weekly, and the statistical correlation between these parameters and acquisition was explored. Multivariable analysis was performed to identify predictors for A. baumannii carriage at admission and acquisition during hospitalization. A. baumannii isolates were genotyped by repetitive-extragenic-palindromic polymerase chain reaction (PCR; rep-PCR). Results: At ICU admission, 284 patients were screened for carriage. A. baumannii was imported in 16 patients (5.6%), and acquisition occurred in 32 patients (15.7%). Acquisition was significantly correlated to weekly colonization pressure (correlation coefficient, 0.379; P = 0.004) and to the number of carriers per week (correlation coefficient, 0.499;

Whole Genome Characterization of the Mechanisms of Daptomycin Resistance in Clinical and Laboratory Derived Isolates of Staphylococcus aureus

Background: Daptomycin remains one of our last-line anti-staphylococcal agents. This study aims to characterize the genetic evolution to daptomycin resistance in S. aureus. Methods: Whole genome sequencing was performed on a unique collection of isogenic, clinical (21 strains) and laboratory (12 strains) derived strains that had been exposed to daptomycin and developed daptomycin-nonsusceptibility. Electron microscopy (EM) and lipid membrane studies were performed on selected isolates. Results: On average, six coding region mutations were observed across the genome in the clinical daptomycin exposed strains, whereas only two mutations on average were seen in the laboratory exposed pairs. All daptomycin-nonsusceptible strains had a mutation in a phospholipid biosynthesis gene. This included mutations in the previously described mprF gene, but also in other phospholipid biosynthesis genes, including cardiolipin synthase (cls2) and CDP-diacylglycerol-glycerol-3-phosphate 3-phosphatidyltransferase (pgsA). EM and lipid membrane composition analyses on two clinical pairs showed that the daptomycin-nonsusceptible strains had a thicker cell wall and an increase in membrane lysyl-phosphatidylglycerol. Conclusion: Point mutations in genes coding for membrane phospholipids are associated with the development of reduced susceptibility to daptomycin in S. aureus. Mutations in cls2 and pgsA appear to be new genetic mechanisms affecting daptomycin susceptibility in S. aureus

Novel antimicrobial agents against multi-drug-resistant Gram-positive bacteria: an overview

Antimicrobial resistance threatens to compromise the treatment of bacterial infectious diseases. Strains resistant to most (if not all) antibiotics available have emerged. Gram-positive such representatives include strains of Methicillinresistant Staphylococcus aureus (MRSA), Vancomycin-resistant Enterococci (VRE) and highly-resistant to penicillin Streptococcus pneumoniae. Although the phenomenon of antimicrobial drug resistance is expanding, limited number of new antibiotics has been successfully developed in the last few decades. Several novel antimicrobial agents, however, are currently in diverse phases of development and undergoing clinical trials. This review will summarize the main candidates for novel antibacterial agents active against Gram-positive multi-resistant pathogens along with the discussion of some patents relevant to the topic

Systematic review and meta-analysis of linezolid versus daptomycin for treatment of vancomycin-resistant enterococcal bacteremia

Limited therapeutic options exist for the treatment of vancomycin-resistant Enterococcus (VRE) bacteraemia; the most commonly used are daptomycin and linezolid. We attempted a systematic review and meta-analysis on the comparative efficacy of those two agents. Studies comparing daptomycin to linezolid treatment for VRE bacteraemia, published until August 2012 were identified from MEDLINE, EMBASE, CENTRAL, ISI Web of Science and SCOPUS databases. All comparative studies on patients older than 18 years old that provided mortality data were considered eligible for this systematic review and meta-analysis. Τhe primary outcome of the meta-analysis was 30-day all-cause mortality. Ten retrospective studies including 967 patients were identified. Patients treated with daptomycin had significantly higher 30-day all-cause mortality (OR: 1.61, 95% CI: 1.08 to 2.40) and infection-related mortality (OR: 3.61, 95% CI: 1.42 to 9.20) rates compared to those treated with linezolid. When data from all ten studies were combined overall mortality was also significantly increased among patients treated with daptomycin (OR: 1.41, 95% CI: 1.06 to 1.89). These findings were confirmed when odds ratios adjusted for potential confounders were pooled. Relapse rates among patients treated with daptomycin were also higher (OR: 2.51, 95% CI: 0.94 to 6.72), although this difference did not reach statistical significance. Adverse event rates were not significantly different between the two groups. Notwithstanding the absence of randomized prospective data, available evidence suggests that mortality rates may be higher with daptomycin compared with linezolid among patients treated for VRE bacteraemia