Gökhan Metan

Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data

BACKGROUND Neuraminidase inhibitors were widely used during the 2009-10 influenza A H1N1 pandemic, but evidence for their effectiveness in reducing mortality is uncertain. We did a meta-analysis of individual participant data to investigate the association between use of neuraminidase inhibitors and mortality in patients admitted to hospital with pandemic influenza A H1N1pdm09 virus infection. METHODS We assembled data for patients (all ages) admitted to hospital worldwide with laboratory confirmed or clinically diagnosed pandemic influenza A H1N1pdm09 virus infection. We identified potential data contributors from an earlier systematic review of reported studies addressing the same research question. In our systematic review, eligible studies were done between March 1, 2009 (Mexico), or April 1, 2009 (rest of the world), until the WHO declaration of the end of the pandemic (Aug 10, 2010); however, we continued to receive data up to March 14, 2011, from ongoing studies. We did a meta-analysis of individual participant data to assess the association between neuraminidase inhibitor treatment and mortality (primary outcome), adjusting for both treatment propensity and potential confounders, using generalised linear mixed modelling. We assessed the association with time to treatment using time-dependent Cox regression shared frailty modelling. FINDINGS We included data for 29,234 patients from 78 studies of patients admitted to hospital between Jan 2, 2009, and March 14, 2011. Compared with no treatment, neuraminidase inhibitor treatment (irrespective of timing) was associated with a reduction in mortality risk (adjusted odds ratio [OR] 0·81; 95% CI 0·70-0·93; p=0·0024). Compared with later treatment, early treatment (within 2 days of symptom onset) was associated with a reduction in mortality risk (adjusted OR 0·48; 95% CI 0·41-0·56; p<0·0001). Early treatment versus no treatment was also associated with a reduction in mortality (adjusted OR 0·50; 95% CI 0·37-0·67; p<0·0001). These associations with reduced mortality risk were less pronounced and not significant in children. There was an increase in the mortality hazard rate with each days delay in initiation of treatment up to day 5 as compared with treatment initiated within 2 days of symptom onset (adjusted hazard ratio [HR 1·23] [95% CI 1·18-1·28]; p<0·0001 for the increasing HR with each days delay). INTERPRETATION We advocate early instigation of neuraminidase inhibitor treatment in adults admitted to hospital with suspected or proven influenza infection. FUNDING F Hoffmann-La Roche.

Carbapenem-resistant Escherichia coli and Klebsiella pneumoniae isolates from Turkey with OXA-48-like carbapenemases and outer membrane protein loss

Treatment options are limited in infections caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, with carbapenems generally preferred. Disturbingly, however, carbapenem-resistant strains are emerging worldwide. Here we report two clinical isolates, one Escherichia coli and one Klebsiella pneumoniae, each with high-level carbapenem resistance (imipenem minimum inhibitory concentration of 32 microg/mL). They were isolated following imipenem therapy from two hospital patients who had received imipenem therapy in different regions of Turkey. Both isolates produced OXA-48-like carbapenemases, enzymes so far reported only from Turkey. Both isolates also had group 1 CTX-M-type ESBLs and had lost major outer membrane proteins. OXA-48-like carbapenemases appear to be scattered in Turkey and surveillance to determine their prevalence is warranted.

A review of cutaneous anthrax and its outcome.

Anthrax is still an endemic disease in some countries in the world and has become a re-emerging disease in western countries with recent intentional outbreak. The aim of this study was to review our clinical experience with cutaneous anthrax cases. From the patients files, transmission of the diseases, clinical findings and severity of infection, treatment and outcome of patients were recorded. Twenty-two cases were diagnosed as cutaneous anthrax in the last 7 years. Of these cases, 10 cases were severe form of cutaneous anthrax, 10 cases were mild form and 2 cases were toxemic shock due to cutaneous anthrax. The incubation period was between 1 and 17 days. The main clinical characteristics of the cases with severe cutaneous anthrax were fever, hemorrhagic bullous lesions surrounded by an extensive erythema and edema, and leukocytosis. Two cases with toxemic shock had low systolic blood pressure, apathy and toxemic appearance, leukocytosis, hypoalbuminemia & hyponatremia. Penicillin G was given in 15 cases, amoxicillin in 4 and other antibiotics in 3 cases for 3-10 days. Skin lesion left deep tissue scar in 4 cases and were grafted. Physicians working in endemic areas and also in western countries should be aware of all clinical forms of anthrax.

Factors influencing survival in patients with multi-drug-resistant Acinetobacter bacteraemia.

OBJECTIVES The incidence of multi-drug-resistant (MDR) Acinetobacter strains is increasing and therapeutic options are limited. However, controversy exists regarding the mortality attributable to antimicrobial resistance. The aim of this study was to analyse the clinical features and outcomes of patients with MDR Acinetobacter calcoaceticus-Acinetobacter baumannii complex (Acb complex) bacteraemia and determine the factors influencing survival by using 14-day mortality as the main outcome measure. METHODS An observational study was conducted at a tertiary care hospital in Turkey from February 2007 to March 2008. Only one bacteraemic episode from one patient was included in the study. RESULTS A total of 100 clinically significant Acb complex bacteraemic episodes were detected. The overall mortality was 63% in 14 days. According to univariate analysis, diabetes mellitus, haematological malignancy, unknown source of bacteraemia, septic shock, resistance to carbapenems, and inappropriate empirical therapy were associated with mortality amongst patients with Acb complex bacteraemia. Multivariate analysis showed that diabetes mellitus (RR, 1.68; 95% CI, 1.22-1.76), carbapenem resistance (RR, 1.63; 95% CI, 1.19-1.89), and septic shock (RR, 1.65; 95% CI, 1.23-1.85) were independent risk factors for 14-day mortality. CONCLUSION Although severe underlying diseases play an important role in the clinical outcome of patients with Acb complex bacteraemia, carbapenem resistance and inappropriate therapy are of great concern. Special attention should be paid to infection control practices in the hospitals where MDR Acinetobacter infections are endemic, and well-controlled prospective clinical trials are needed to determine the optimal antimicrobial therapy in critically ill patients suspected of having MDR Acinetobacter bacteraemia.

Human anthrax in Turkey from 1990 to 2007.

Anthrax is an endemic disease in Turkey, among other countries of the world. The potential of Bacillus anthracis as a bioterrorism agent makes anthrax an important global issue. The aim of the present study was to review human anthrax in Turkey during the last decade. Human anthrax cases recorded from 1990 to 2005 were obtained from the website of the Turkish Ministry of Health, and those recorded between 1995 and 2005 were plotted on a map of Turkey. Papers on anthrax published from Turkey between 1990 and 2007 were collected and reviewed. Most cases were recorded from the central and eastern parts of Turkey. Three of the reports appeared in international journals prior to 1990, 10 reports appeared in the 1990s, and 24 reports appeared after the anthrax events of 2001 in the United States of America. These reports included 926 cases, 426 of which could be reviewed: 413 (96.9%) cases of cutaneous anthrax, 8 (1.9%) cases of gastrointestinal anthrax, and 5 (1.2%) cases of anthrax meningitis. Of all the affected patients, 95.2% had contact with contaminated materials. All human origin isolates were sensitive to penicillin and did not produce beta-lactamase. Most of the patients (88.7%) had received penicillin G. Total mortality was 2.8%. Anthrax is an endemic disease in Turkey, and acquisition of infection is generally through contact with ill or dying animals or animal products. Sheep and cattle are generally involved. Most clinical disease in humans is cutaneous anthrax, although other clinical forms are seen and have a greater mortality. Penicillin remains the drug of choice in treating the disease. Controlling anthrax in humans depends on controlling the infection in animals.

Natural Exposure to Cutaneous Anthrax Gives Long-Lasting T Cell Immunity Encompassing Infection-Specific Epitopes

There has been a long history of defining T cell epitopes to track viral immunity and to design rational vaccines, yet few data of this type exist for bacterial infections. Bacillus anthracis, the causative agent of anthrax, is both an endemic pathogen in many regions and a potential biological warfare threat. T cell immunity in naturally infected anthrax patients has not previously been characterized, which is surprising given concern about the ability of anthrax toxins to subvert or ablate adaptive immunity. We investigated CD4 T cell responses in patients from the Kayseri region of Turkey who were previously infected with cutaneous anthrax. Responses to B. anthracis protective Ag and lethal factor (LF) were investigated at the protein, domain, and epitope level. Several years after antibiotic-treated anthrax infection, strong T cell memory was detectable, with no evidence of the expected impairment in specific immunity. Although serological responses to existing anthrax vaccines focus primarily on protective Ag, the major target of T cell immunity in infected individuals and anthrax-vaccinated donors was LF, notably domain IV. Some of these anthrax epitopes showed broad binding to several HLA class alleles, but others were more constrained in their HLA binding patterns. Of specific CD4 T cell epitopes targeted within LF domain IV, one is preferentially seen in the context of bacterial infection, as opposed to vaccination, suggesting that studies of this type will be important in understanding how the human immune system confronts serious bacterial infection.

WSES guidelines for management of Clostridium difficile infection in surgical patients

In the last two decades there have been dramatic changes in the epidemiology of Clostridium difficile infection (CDI), with increases in incidence and severity of disease in many countries worldwide. The incidence of CDI has also increased in surgical patients. Optimization of management of C difficile, has therefore become increasingly urgent. An international multidisciplinary panel of experts prepared evidenced-based World Society of Emergency Surgery (WSES) guidelines for management of CDI in surgical patients.

Which patient is a candidate for empirical therapy against Stenotrophomonas maltophilia bacteraemia? An analysis of associated risk factors in a tertiary care hospital

Stenotrophomonas maltophilia is an emerging nosocomial pathogen with a tendency to be resistant to several antibiotics commonly used to treat nosocomial infections. Early recognition of the risk factors for bacteraemia caused by S. maltophilia could potentially improve the prognosis in these cases. Most data have been obtained from a limited number of descriptive studies. In this retrospective case-control study, we investigated the risk factors for S. maltophilia bacteraemia. We compared cases with 2 different control groups; non-bacteraemic patients and those with bacteraemia caused by Escherichia coli. 37 cases were matched with 37 control patients with nosocomial E. coli bacteraemia and 74 non-bacteraemic patients. The demographic information was extracted from the chart of the patients. When the effects of multiple factors were analysed simultaneously, the presence of a central venous catheter and carbapenem use were associated with an increased risk for bacteraemia caused by S. maltophilia compared with both the non-bacteraemic and bacteraemic control groups. We found a mortality rate of 21.6% in cases vs non-bacteraemic controls; however, this was not a statistically significant difference from that observed in patients with E. coli bacteraemia.

Impact of Initial Antimicrobial Therapy in Patients with Bloodstream Infections Caused by Stenotrophomonas maltophilia

The impact of inappropriate initial antimicrobial therapy on the outcomes of patients with bloodstream infections caused by antibiotic-resistant gram-negative bacilli is not well defined. Recently, in an interesting study by Kang et al., inappropriate initial antimicrobial therapy was found to be associated with an adverse outcome, particularly in patients with a high-risk source of bacteremia caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., and Pseudomonas aeruginosa (1). In addition to the source of bacteremia, presentation with septic shock, P. aeruginosa infection, and an increasing acute physiology, age, and chronic health evaluation (APACHE II) score were poor prognostic factors in this study. Stenotrophomonas maltophilia is an emerging nosocomial pathogen with a tendency to be resistant to several antibiotics commonly used to treat nosocomial infections. Although a recent study reported no significant difference in the outcomes of patients who received appropriate therapy and outcomes of patients who received inappropriate therapy (2), at least two case-controlled studies described inappropriate therapy as an independent risk factor for mortality (3, 4). At our center (Hacettepe University School of Medicine Hospital, a 1,000-bed tertiary-care teaching hospital), we evaluated the factors that influenced the outcomes in patients with bacteremia caused by S. maltophilia. We retrospectively reviewed the reports of our clinical microbiology laboratory to identify the study patients during a six-year period from 1998 to 2004. Case patients were defined as those who were >16 years of age, had at least one blood culture positive for S. maltophilia, and had clinical signs of systemic infection. The mortality rate 30 days after the onset of bacteremia was used as the main outcome measure. Appropriate therapy was defined as one or more agents active against S. maltophilia, given adequate dose and route of administration, not later than 24 h after the blood culture was obtained. All statistical analyses were performed by using SPSS software (version 10.0; SPSS, Chicago, IL). Numerical data were reported (medians and interquartile ranges). To test for the differences between quantitative variables between appropriate and inappropriate therapies, independent-sample t tests were used for normally distributed variables. Differences between categorical variables were analyzed by the chi-square test with the continuity correction or the Fisher exact test where appropriate. Fifty-six patients with S. maltophilia bacteremia were identified. A total of 41 patients were included in the analysis. Fifteen cases whose medical records contained missing data were excluded from the study. The overall 30-day mortality rate was 31.7%. The patients who died within 30 days after the onset of S. maltophilia bacteremia had a longer duration of hospitalization and a higher rate of intensive care unit stay (at the time of initial bacteremia), as well as an increased need for mechanical ventilation and presentation with septic shock (Table ​(Table1).1). Twelve (29.2%) patients had received inappropriate therapy. Eight (66.7%) patients who were treated inappropriately died, compared to 5 (17.2%) of 29 who died though they received an appropriate antibiotic(s). Six of 8 (75.0%) patients who died were on carbapenems when S. maltophilia bacteremia developed. TABLE 1. Demographic characteristics of the patients with bloodstream infection caused by S. maltophilia In this limited study, we have shown a higher mortality rate for the bacteremic patients who did not receive appropriate therapy against S. maltophilia. We believe this issue should be further evaluated by case-controlled studies with a higher number of patients who had similar comorbid factors. In addition, the practicing physician should consider S. maltophilia as the causative organism in a patient who deteriorates under carbapenem therapy.

Clinical Experience with Tigecycline in the Treatment of Carbapenem-Resistant Acinetobacter Infections

Abstract Tigecycline is a promising therapeutic option against many current multidrug resistant pathogens. The aim of this retrospective study was to determine the clinical and microbiological outcomes of patients treated with tigecycline for serious infections caused by carbapenem-resistant Acinetobacter calcoaceticus Acinetobacter baumannii complex (Acb-complex). A retrospective study was conducted to define the patients who received tigecycline for carbapenem-resistant Acb-complex infections between 1 June, 2008 and 1 may, 2009. A total of 21 patients were eligible for the study. The median age of the patients was 48 years and 6 patients were female. Eighteen patients were treated with tigecycline for carbapenem-resistant Acb-complex as the sole microorganism while 3 received it for polymicrobial infections. All Acb-complex isolates were susceptible to tigecycline. The most common indication of tigecycline treatment was surgical-site infections (SSI) followed by ventilator associated pneumonia (VAP). Tigecycline was the sole antibiotic administered in 7 patients while concurrent antibiotics were used in 14 patients. The median duration of tigecycline therapy was 14days. Two patients died within 14 days of initiating treatment, representing an attributable mortality rate of 9.5% while 4 patients died within 30 days representing a crude mortality rate of 19.1%. Seventeen out of 21 patients had successful clinical outcomes, cure in 11 patients and improvement in 6. Fourteen of 21 patients had microbiological failure. Correlation between microbiological response with clinical outcome was poor. Clinical failure was more common in patients with VAP. Patients with bacteremia were more likely to have microbiological failure while microbiological outcome was better in patients with SSI. In this retrospective study, 81% (17 of 21) of the patients infected with carbapenem-resistant Acb-complex had a positive outcome under tigecycline therapy. However, these preliminary results should be evaluated cautiously in the absence of well-controlled studies.