Association Between Minimum Inhibitory Concentration, Beta-lactamase Genes and Mortality for Patients Treated With Piperacillin/Tazobactam or Meropenem From the MERINO Study.

INTRODUCTION: This study aims to assess the association of piperacillin/tazobactam and meropenem minimum inhibitory concentration (MIC) and beta-lactam resistance genes with mortality in the MERINO trial. METHODS: Blood culture isolates from enrolled patients were tested by broth microdilution and whole genome sequencing at a central laboratory. Multivariate logistic regression was performed to account for confounders. Absolute risk increase for 30-day mortality between treatment groups was calculated for the primary analysis (PA) and the microbiologic assessable (MA) populations. RESULTS: In total, 320 isolates from 379 enrolled patients were available with susceptibility to piperacillin/tazobactam 94% and meropenem 100%. The piperacillin/tazobactam nonsusceptible breakpoint (MIC >16 mg/L) best predicted 30-day mortality after accounting for confounders (odds ratio 14.9, 95% confidence interval [CI] 2.8-87.2). The absolute risk increase for 30-day mortality for patients treated with piperacillin/tazobactam compared with meropenem was 9% (95% CI 3%-15%) and 8% (95% CI 2%-15%) for the original PA population and the post hoc MA populations, which reduced to 5% (95% CI -1% to 10%) after excluding strains with piperacillin/tazobactam MIC values >16 mg/L. Isolates coharboring extended spectrum ß-lactamase (ESBL) and OXA-1 genes were associated with elevated piperacillin/tazobactam MICs and the highest risk increase in 30-day mortality of 14% (95% CI 2%-28%). CONCLUSIONS: After excluding nonsusceptible strains, the 30-day mortality difference from the MERINO trial was less pronounced for piperacillin/tazobactam. Poor reliability in susceptibility testing performance for piperacillin/tazobactam and the high prevalence of OXA coharboring ESBLs suggests that meropenem remains the preferred choice for definitive treatment of ceftriaxone nonsusceptible Escherichia coli and Klebsiella.

Daptomycin In Vitro Activity against Methicillin-Resistant Staphylococcus aureus Is Enhanced by d-Cycloserine in a Mechanism Associated with a Decrease in Cell Surface Charge.

The killing activity of daptomycin against an isogenic pair of daptomycin-susceptible and daptomycin-nonsusceptible (DNS) methicillin-resistant Staphylococcus aureus (MRSA) strains was enhanced by the addition of certain cell wall agents at 1× MIC. However, when high inocula of the DNS strain were used, no significant killing was observed in our experiments. Cytochrome c binding assays revealed d-cycloserine as the only agent associated with a reduction in the cell surface charge for both strains at the concentrations used.

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 (p<0.0001). All genotyped KPC producers harboured blaKPC-2 and belonged to two clones, among which the hyperepidemic Greek clone, related to those from the United States and Israel, predominated. Most metallo-beta-lactamase (MBL) producers carried the blaVIM-1 gene and belonged to several clones, whereas all but one isolate with blaVIM-12 were clustered within a five-month period, arising from one clone. Resistance to non-beta-lactam antibiotics was also increased among CPKP. They were almost invariably resistant to ciprofloxacin and trimethoprim-sulfamethoxazole. Resistance to colistin increased from 3.5% (4/115) in 2008 to 20.8% (25/120) in 2010, and resistance to tigecycline also increased. Following reinforcement of infection control measures, prevalence of CPKP (mainly KPC) has been reduced since mid-2009 (from 46% in 2009 to 38.3% in 2010). In view of the exhaustion of available therapies, investment in infection control resources and optimal antibiotic use is urgently required.

Key predictors and burden of meticillin-resistant Staphylococcus aureus infection in comparison with meticillin-susceptible S. aureus infection in an Australian hospital setting.

BACKGROUND: Staphylococcus aureus is associated with significant mortality and increased burden on the healthcare system. Relatively few reliable estimates are available regarding the impact of meticillin-resistant S. aureus (MRSA) infection compared with meticillin-susceptible S. aureus (MSSA) infection. AIMS: To compare patients with MRSA infection and MSSA infection to identify differences in inpatient mortality, length of stay and costs of hospital services, and identify predictors of MRSA as a cause of S. aureus infection. METHODS: An analytical, retrospective, longitudinal study using non-identifiable linked data on adults admitted to hospitals of a health district in Australia with a diagnosis of S. aureus infection over a 10-year period. The main outcome measure was 30-day inpatient mortality. Secondary endpoints included total overnight stays, all-cause inpatient mortality, and hospitalization costs within 1 year of index admission. FINDINGS: Inpatient mortality at 30, 100 and 365 days was estimated to be significantly greater for patients with MRSA infection. The mean additional cost of MRSA infection when controlling for additional factors was $5988 and 4 nights of additional hospital stay per patient within 1 year of index admission. Key predictors of MRSA infection were: date of index admission; higher comorbidity score; greater socio-economic disadvantage; admission to hospital other than via the emergency department; older age; and prior admission to hospital within 28 days of index admission. CONCLUSIONS: MRSA infection is associated with increased inpatient mortality, costs and hospital length of stay compared with MSSA infection. Efforts are required to alleviate the additional burden of MRSA infection on patients and healthcare systems.

Polymorphisms of Cx(3)CR1 and CXCR6 receptors in relation to HAART therapy of HIV type 1 patients.

The chemokine polymorphisms CXCR6-3E/K, In1.1T/C, H7 haplotype, CX(3)CR1-V249I, and CX(3)CR1-T280M have been shown to affect the course of HIV infection. We studied their influence on immunologic and virologic response to HAART in a group of 143 HIV-1 patients. We performed Kaplan-Meier analysis using the following end-point criteria: (1) time from HAART initiation to undetectable viral load (VL < 50 copies/ml), (2) maximum duration of viral suppression, (3) time from HAART administration until CD4 elevation above 200 cells/microl for patients with baseline CD4 below 200 cells/microl and above 500 cells/microl for patients with baseline CD4 between 200 and 500 cells/microl, respectively, and (4) time from HAART initiation until CD4 reduction below baseline values. Our results revealed an improved immunologic response to HAART in patients with the CX(3)CR1-249I or CX(3)CR1-280M allele. On the contrary, patients with initial VL suppression due to HAART showed a faster virologic failure in the presence of the CXCR6-3K allele. The In1.1T/C polymorphism and H7 haplotype did not reveal any specific effect on HAART response.

The burden of healthcare-associated Clostridium difficile infection in a non-metropolitan setting.

OBJECTIVE: Healthcare-associated Clostridium difficile infection (HCA-CDI) remains a major cause of morbidity and mortality in industrialized countries. However, few data exist on the burden of HCA-CDI in multi-site non-metropolitan settings. This study examined the introduction of an antimicrobial stewardship programme (ASP) in relation to HCA-CDI rates, and the effect of HCA-CDI on length of stay (LOS) and hospital costs. METHODS: A comparative before-and-after intervention study of patients aged ≥16 years with HCA-CDI from December 2010 to April 2016 across the nine hospitals of a non-metropolitan health district in New South Wales, Australia was undertaken. The intervention comprised a multi-site ASP supported by a clinical decision support system, with subsequent introduction of email feedback of HCA-CDI cases to admitting medical officers. MAIN OUTCOME MEASURES: HCA-CDI rates, comparative LOS and hospital costs, prior use of antimicrobials and proton pump inhibitors, and appropriateness of CDI treatment. RESULTS: HCA-CDI rates rose from 3.07 to 4.60 cases per 10,000 occupied bed-days pre-intervention, and remained stable at 4 cases per 10,000 occupied bed-days post-intervention (P=0.24). Median LOS (17 vs six days; P<0.01) and hospital costs (AU$19,222 vs $7861; P<0.01) were significantly greater for HCA-CDI cases (N=91) than for matched controls (N=172). Half of the patients with severe HCA-CDI (4/8) did not receive initial appropriate treatment (oral vancomycin). CONCLUSIONS: HCA-CDI placed a significant burden on the regional and rural health service through increased LOS and hospital costs. Interventions targeting HCA-CDI could be employed to consolidate the effects of ASPs.

International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).

New clinical, laboratory and experimental insights, since the 1999 publication of the Sapporo preliminary classification criteria for antiphospholipid syndrome (APS), had been addressed at a workshop in Sydney, Australia, before the Eleventh International Congress on antiphospholipid antibodies. In this document, we appraise the existing evidence on clinical and laboratory features of APS addressed during the forum. Based on this, we propose amendments to the Sapporo criteria. We also provide definitions on features of APS that were not included in the updated criteria.

Seronegative spondyloarthropathies in Greece: a population-based study of prevalence, clinical pattern, and management. The ESORDIG study.

The objective of this study was to determine the prevalence, clinical pattern, and management of seronegative spondyloarthropathies (SpA) in the general adult population of Greece. This population-based study was conducted on a target adult (> or =19-year-old) population of 14,233 subjects by rheumatologists who visited households in nine dispersed areas. An interview (standardized questionnaire) was conducted, clinical evaluation and laboratory investigation were done, and established diagnostic classification criteria were used. The age-adjusted and sex-adjusted prevalence (prevalence(asa)) of SpA was 0.49% [95% confidence interval (CI): 0.38-0.60], with a male to female ratio of 5.5:1; the prevalence increased with age until the 59- to 68-year-old age group and declined thereafter. The prevalence(asa) of ankylosing spondylitis (AS) and psoriatic arthritis (PsA) was 0.24% (95% CI: 0.16-0.32) and 0.17% (95% CI: 0.10-0.24), respectively. The mean age (years) at onset was younger in AS (25.83 +/- 6.5) than in PsA (45.24 +/- 12.94) (p < 0.01). Familial clustering was noticed in 5.3% of AS probands. Sacroiliitis was observed in 39.8% and asymmetrical oligoarthritis in 40.6% of PsA patients. Fifty-nine percent of SpA patients had previously visited rheumatologists (91.3% diagnosed correctly vs 11.6% of those who visited other specialists, p < 0.0005); 56.5% of the former had taken disease-modifying antirheumatic drugs compared to none of the latter. The SpA in Greeks are as common as in other European Caucasians, with a high male preponderance. The PsA onset occurs at an older age than AS and frequently presents with a spondylitic pattern. The correct diagnosis was arrived at and appropriate treatment was given when patients consulted rheumatologists.

Absence of mutations in the VHL gene but frequent loss of heterozygosity at 3p25-26 in non-small cell lung carcinomas.

In this study we have examined 79 primary non-small cell lung tumours for the presence of mutations of the VHL gene as well as for allelic imbalance at the gene surrounding loci. While allelic imbalance was found in 83% of specimens, frequently affecting the whole 3p25-p26 region, no mutations were detected in the VHL coding region. The fractional regional loss (FRL) was significantly higher in squamous cell carcinomas (0.746) than adenocarcinomas (0.493) (Wilcoxon P=0.002). This is the first investigation of the VHL gene mutational status in primary lung tumours. Our results indicate that mutation is not a common means of VHL inactivation in NSCLC.

Voriconazole concentrations and outcome of invasive fungal infections.

Twenty-five patients with proven or probable invasive fungal infections (IFIs) who experienced two or more episodes of voriconazole therapeutic drug monitoring (TDM) at a tertiary referral hospital were reviewed to explore the association between serum trough concentrations and outcomes of IFI. Microbiological and/or clinical success, in addition to IFI-related mortality, was assessed. We performed two separate analyses, one based on the initial trough voriconazole concentration at steady state, and the other on the median trough voriconazole concentration (derived from repeated TDM episodes) for each patient. Large interpatient and intrapatient variability of trough plasma voriconazole concentrations was observed, with no correlation between dose and concentration (r = 0.065). Classification and regression tree analysis revealed an association between IFI-related mortality and initial trough voriconazole concentrations, with patients more likely to die when their initial steady-state concentration was ≤0.35 mg/L (p 0.004; OR 11, 95% CI 2.9-41.2). Successful outcomes were more likely among patients with a median trough voriconazole concentration >2.2 mg/L (p 0.003; OR 2.7, 95% CI 1.4-5). Nineteen adverse events, with four severe events, were documented in 14 patients. Patients with severe adverse events had higher median voriconazole concentrations than the remaining cohort (2.38 mg/L vs. 1.30 mg/L; p <0.04). All adverse events resolved after cessation of voriconazole treatment. Our data suggest that voriconazole TDM is appropriate for all patients as soon as steady state is achieved. For non-responding patients with low trough concentrations, the association with IFI-related mortality indicates the need for dose adjustments to achieve and sustain voriconazole concentrations.

Risk stratification and outcome of cellulitis admitted to hospital.

OBJECTIVES: To identify risk factors associated with mortality and adverse outcome of community acquired cellulitis/erysipelas requiring hospital admission. METHODS: A retrospective analysis of 395 episodes of cellulitis/erysipelas admitted to a tertiary referral hospital between January 1999 and December 2006. RESULTS: Mortality was 2.5% (10/395). There were 112 complications (28.4%). Median hospitalisation was 5 days. Factors independently associated with mortality, adverse outcome and prolonged stay (>7 days) were bacteraemia and albumin <30 g/L. A risk stratification model was designed based on factors independently associated with adverse outcome: altered mental status, neutrophilia/paenia, discharge from the cellulitic area, hypoalbuminaemia and history of congestive cardiac failure. Adverse outcome risk among patients with scores <4, 6-9 and >9 was <20%, 55% and 100%, respectively. All patients who died had admission score >or=4. Factors independently associated with prolonged hospitalisation were: age >60, symptom duration >4 days, hypoalbuminaemia, bacteraemia, isolation of MRSA and time to effective antibiotics >8 h. MRSA was more frequent among patients admitted during 2003-2006 (OR 2.43, 95% CI: 1-12-5.27). Streptococci accounted for most bacteraemia (11/20). Infectious Disease physician input was independently associated with shorter hospitalisation. CONCLUSIONS: Cellulitis/erysipelas requiring hospitalisation confers considerable morbidity and mortality. Clinical markers present on admission can be used to stratify patient risk of mortality and adverse outcome.

Serum levels of interleukin-15 and interleukin-10 and their correlation with proliferating cell nuclear antigen in multiple myeloma.

In order to determine prognostic factors characterizing multiple myeloma (MM) cell kinetics, bone marrow proliferative activity and serum Interleukin-10 (IL-10), and Interleukin-15 (IL-15) levels were measured in 40 newly diagnosed MM patients, compared with 10-age and sex-matched-healthy controls. Cell proliferation was evaluated by employing a monoclonal antibody directed against the proliferating cell nuclear antigen (PCNA), whereas IL-10 and IL-15 were measured with quantitative sandwich enzyme immunoassay methods. IL-15, IL-10 and PCNA were higher in the patient group than in controls (P<0.001). IL-10 levels, and PCNA increased significantly with increasing Durie-Salmon disease stage (I-III, P<0.002, and P=0.001, respectively). Serum IL-15 levels in MM stage III patients were elevated in comparison with stages I and II, the difference however, did not reach statistical significance. There was a significant positive correlation between serum IL-15 and IL-10 levels (r: 0.372, P<0.01), and between serum IL-10 and PCNA (r: 0.608, P<0.0001), as well as a positive correlation of serum IL-15 with PCNA, which marginally failed to reach statistical significance. Serum IL-15 levels are elevated in MM patients, increase with advancing stage, and correlate with Il-10 and PCNA. These proliferative factors may be useful in assessing disease progression in MM.

The burden of the rheumatic diseases in the general adult population of Greece: the ESORDIG study.

OBJECTIVE: To estimate the burden of rheumatic diseases in terms of disability and health-care utilization in the Greek general adult population. METHODS: The study was conducted on the total adult population of seven communities (8547 subjects), as well as on 2100 out of 5686 randomly selected subjects in an additional two communities. Rheumatologists visited the participants at their homes to assess the prevalence of six morbidity indicators concerning disability and health-care utilization associated with rheumatic diseases or other major disease groups. RESULTS: The participation rate in the study was 82.1%. The prevalence of chronic health problems, long-term disability, short-term disability, physician office visits and prescription or non-prescription drug use due to rheumatic diseases in the total target adult population was 14.3, 4.3, 2.9, 2.8, 7.2 and 2.0%, respectively. Compared with all other major disease groups, rheumatic diseases were the most common cause of chronic health problems (38.7%), long-term disability (47.2%), short-term disability (26.2%) and physician office visits (20.5%), while they ranked second for the use of prescription (24.0%) or non-prescription drugs (17.7%). Rheumatic diseases were the main cause of morbidity in five out of six indicators in subjects aged < or =65 yr. Logistic regression analysis revealed an association of female gender, age > or =45 yr and obesity with almost all morbidity indicators related to rheumatic diseases. CONCLUSION: These findings suggest that rheumatic diseases constitute a major public health problem and should be considered in planning undergraduate and postgraduate medical education, research and health-care services.

Differential expression and mutation of the ras family genes in human breast cancer.

The expression of ras mRNA levels in 27 human sporadic breast cancer specimens was examined, and compared to the corresponding adjacent normal tissue using the RT-PCR technique. Eighteen out of the 27 specimens (67%) exhibited two- to four-fold increased expression of ras mRNA levels, compared to corresponding normal tissue. The rates of augmented mRNA expression were similar among the three ras genes. A statistically significant correlation of overexpression of ras genes in specimens classified as Stage I disease was observed, compared to tumors in a more advanced stage (II or III). The incidence of codon 12 point mutations of the K-ras gene in fresh tissue samples was also assessed in 61 human sporadic breast cancer cases. Point mutations were detected in four (6.5%) out of the 61 cases examined; no correlation was found with any clinicopathological parameter. This is the first report to our knowledge of the differential expression of the ras family genes in breast carcinoma. Our findings indicate that the aberrant expression of ras genes may be an initial event in breast cancer oncogenesis and that K-ras point mutations are rarely involved in the development of mammary neoplasias.

Von Hippel-Lindau tumour suppressor gene is not involved in sporadic human breast cancer.

OBJECTIVE: Mutations of the von Hippel-Lindau (vhl) gene, as well as allelic loss at the gene region (3p25-26) have been described in sporadic cases of the tumour types participating in VHL disease, but also in cancers not associated with the syndrome. In this study, we attempted mutation analysis of the vhl gene, as well as detection of allelic loss at 3p25-26 in sporadic human breast cancer. METHODS: Eighty-two tumour specimens were screened for loss of heterozygosity (LOH) at the vhl region, and compared to the adjacent, histologically normal tissue. Furthermore, mutations within the three exons of vhl in the same panel of tumours were detected using SSCP and heteroduplex analysis and direct sequencing. RESULTS: To our knowledge this is the first mutational analysis reported for the vhl gene in breast cancer, however we failed to reveal any mutations in the specimens examined. All the cases were informative for at least one of the microsatellite markers tested, 24 (29.2%) exhibited LOH at 3p25-26. Clinical and pathological data were available for all tumours examined, however no significant correlations were encountered. CONCLUSION: These results strongly indicate against a critical involvement of the tumour suppressor vhl in breast carcinogenesis.

Is there room for general practice in penitentiary institutions: screening and vaccinating high-risk groups against hepatitis.

OBJECTIVE: The purpose of this study was to determine the prevalence of hepatitis markers in inmates and staff of the Penitentiary of Neapolis on Crete and discuss the role of GPs in identifying and vaccinating susceptible subjects. METHOD: Forty-five prisoners and 20 house workers were invited to participate in the study. Hepatitis B (HBV) markers (HBsAg and anti-HBc) and hepatitis C antibodies (anti-HCV) were tested. Vaccination against hepatitis B was administered to all susceptible subjects. RESULTS: Hepatitis B carriage was found in 10 people, six of whom were prisoners. Fifteen of the subjects tested were found to be positive for anti-HBc, six of whom were house workers. Anti-HCV were found to be positive in seven prisoners and one worker. A vaccination programme against hepatitis B was introduced in 27 susceptible subjects (58.7% of unexposed subjects) and was completed in 22. CONCLUSION: Prisoners and staff at Neapolis Prison constitute a high-risk group for hepatitis B and C. Compliance rate in screening was high and GPs were successful in having a desirable response rate in the administration of vaccines.