Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial.

Early increase of soluble urokinase plasminogen activator receptor (suPAR) serum levels is indicative of increased risk of progression of coronavirus disease 2019 (COVID-19) to respiratory failure. The SAVE-MORE double-blind, randomized controlled trial evaluated the efficacy and safety of anakinra, an IL-1α/ß inhibitor, in 594 patients with COVID-19 at risk of progressing to respiratory failure as identified by plasma suPAR ≥6 ng ml-1, 85.9% (n = 510) of whom were receiving dexamethasone. At day 28, the adjusted proportional odds of having a worse clinical status (assessed by the 11-point World Health Organization Clinical Progression Scale (WHO-CPS)) with anakinra, as compared to placebo, was 0.36 (95% confidence interval 0.26-0.50). The median WHO-CPS decrease on day 28 from baseline in the placebo and anakinra groups was 3 and 4 points, respectively (odds ratio (OR) = 0.40, P < 0.0001); the respective median decrease of Sequential Organ Failure Assessment (SOFA) score on day 7 from baseline was 0 and 1 points (OR = 0.63, P = 0.004). Twenty-eight-day mortality decreased (hazard ratio = 0.45, P = 0.045), and hospital stay was shorter.

ß-Lactam plus aminoglycoside or fluoroquinolone combination versus ß-lactam monotherapy for Pseudomonas aeruginosa infections: a meta-analysis.

The objective of this review was to compare the effectiveness and safety of ß-lactam combined with aminoglycoside or fluoroquinolone with that of ß-lactam monotherapy for the treatment of Pseudomonas aeruginosa infections. We searched Scopus and PubMed databases and synthesised the outcomes of the individual studies in a meta-analysis. Both non-randomised studies and randomised controlled trials (RCTs) that evaluated outcomes of patients with P. aeruginosa infections receiving treatment with ß-lactams alone or in combination with an aminoglycoside or a fluoroquinolone were included. Studies including patients with cystic fibrosis were excluded. Nineteen articles (eight RCTs) were included (1721 patients with P. aeruginosa infections). Patients receiving combination therapy had no difference in mortality compared with patients receiving ß-lactam monotherapy either as definitive (risk ratio=0.97, 95% confidence interval 0.77-1.22) or as empirical treatment (1.02, 0.78-1.34). In the definitive treatment group, no difference in mortality was found between combination therapy and monotherapy for patients with bacteraemia (0.95, 0.67-1.34) or severe infections (0.96, 0.75-1.24). Patients receiving definitive combination therapy had non-significantly higher clinical cure compared with patients receiving ß-lactam monotherapy (1.36, 0.99-1.86). A higher clinical cure rate was observed for patients receiving empirical treatment with combination therapy (1.23, 1.05-1.43). There was no difference in clinical cure either for RCTs (1.29, 0.91-1.83) or for non-randomised studies (1.18, 0.97-1.45). In conclusion, no benefit in mortality was observed in patients receiving combination therapy for P. aeruginosa infections. A well-designed multicentre RCT is warranted to address this important issue.

Home versus ambulatory and office blood pressure in predicting target organ damage in hypertension: a systematic review and meta-analysis.

OBJECTIVE: Studies have shown that ambulatory blood pressure (BP) is more closely related to preclinical target organ damage than office measurements. A review and meta-analysis of studies investigating the association of home BP measurements with target organ damage was performed. METHODS: A PubMed and Cochrane Library search (1950-2011) revealed 23 studies reporting comparative data of home BP versus ambulatory and/or office measurements in terms of their association with several indices of target organ damage. Correlation coefficients were pooled by random-effects model meta-analysis. RESULTS: Fourteen studies (n = 2485) assessing echocardiographic left ventricular mass index (LVMI) showed similar correlations with home (coefficients r = 0.46/0.28, systolic/diastolic) as with ambulatory BP (0.37/0.26, P = NS for difference versus home BP), and superior to office measurements (r = 0.23/0.19, P < 0.001/0.009 for difference versus home BP). Four methodologically heterogeneous studies assessing the glomerular filtration rate (n = 609) could not be pooled or lead to a concrete result. Four studies assessing carotid intima-media thickness (n = 1222), three assessing pulse wave velocity (n = 720) and two assessing urinary protein excretion (n = 156) showed no difference in pooled correlation coefficients with home versus office BP measurements. With all the measurement methods SBP was more closely associated with target organ damage than DBP. CONCLUSION: These data suggest that home BP is as good as ambulatory monitoring and superior to office measurements in regard to their association with preclinical organ damage assessed by echocardiographic LVMI. More research is required to evaluate the relationship of home BP with other indices of target organ damage.

Impact of definitive therapy with beta-lactam monotherapy or combination with an aminoglycoside or a quinolone for Pseudomonas aeruginosa bacteremia.

BACKGROUND: Bacteremia by Pseudomonas aeruginosa represents one severe infection. It is not clear whether beta-lactam monotherapy leads to similar rates of treatment success compared to combinations of beta-lactams with aminoglycosides or quinolones. METHODS: Retrospective cohort study from 3 tertiary hospitals (2 in Greece and 1 in Italy). Pseudomonas aeruginosa isolates were susceptible to a beta-lactam and an aminoglycoside or a quinolone. Patients received appropriate therapy for at least 48 hours. Primary outcome of interest was treatment success in patients with definitive beta-lactam combination therapy compared to monotherapy. Secondary outcomes were treatment success keeping the same empirical and definitive regimen, mortality, and toxicity. RESULTS: Out of 92 bacteremias there were 54 evaluable episodes for the primary outcome (20 received monotherapy). Treatment success was higher with combination therapy (85%) compared to beta-lactam monotherapy (65%), however not statistically significantly [Odds ratio (OR) 3.1; 95% Confidence Interval (CI) 0.69-14.7, p = 0.1]. Very long (>2 months) hospitalisation before bacteremia was the only factor independently associated with treatment success (OR 0.73; 95% CI 0.01-0.95, p = 0.046), however this result entailed few episodes. All-cause mortality did not differ significantly between combination therapy [6/31 (19%)] and monotherapy [8/19 (42%)], p = 0.11. Only Charlson comorbidity index was associated with excess mortality (p = 0.03). CONCLUSION: Our study, in accordance with previous ones, indicates that the choice between monotherapy and combination therapy may not affect treatment success significantly. However, our study does not have statistical power to identify small or moderate differences. A large randomized controlled trial evaluating this issue is justified.

Home blood pressure monitoring in the diagnosis and treatment of hypertension: a systematic review.

BACKGROUND: It is recognized that for the reliable assessment of blood pressure (BP) and the accurate diagnosis of hypertension, out-of-office BP measurement with ambulatory (ABPM) or home BP monitoring (HBPM) is often required. The clinical usefulness of ABPM is well established. However, despite the wide use of HBPM, only in the last decade convincing evidence on its usefulness has accumulated. METHODS: Systematic review of the evidence on applying HBPM in the diagnosis and treatment of hypertension (PubMed, Cochrane Library, 1970-2010). RESULTS: Sixteen studies in untreated and treated subjects assessed the diagnostic ability of HBPM by taking ABPM as reference. Seven randomized studies compared HBPM vs. office measurements or ABPM for treatment adjustment, whereas many studies compared HBPM with office measurements in assessing the antihypertensive drug effects. Several studies with different design investigated the role of HBPM vs. office measurements in improving patients' compliance with treatment and hypertension control rates. The evidence on the cost-effectiveness of HBPM is limited. The studies reviewed consistently showed moderate diagnostic agreement between HBPM and ABPM, and superiority of HBPM compared to office measurements in diagnosing uncontrolled hypertension, assessing antihypertensive drug effects and improving patients' compliance and hypertension control. Preliminary evidence suggests that HBPM has the potential for cost savings. CONCLUSIONS: There is conclusive evidence that HBPM is useful for the initial diagnosis and the long-term follow-up of treated hypertension. These data are useful for the optimal application of HBPM, which is widely used in clinical practice. More studies on the cost-effectiveness of HBPM are needed.

Unusual climatic conditions and infectious diseases: observations made by Hippocrates

About 2500 years ago, Hippocrates made noteworthy observations about the influence of climate on public health. He believed that people living in cities with different climate may suffer from different diseases. Hippocrates also observed that abrupt climatic changes or unusual weather conditions affect public health, especially the incidence and severity of various infectious diseases, including gastrointestinal infections, tuberculosis, and central nervous system infections. We believe that Hippocrates’ scientific observations are great early historic examples that stress to modern infectious diseases researchers and clinicians the need to study intensively the effect of the occurring global climate changes to infectious diseases in order to help in the prevention of possible epidemics of infections (AU)

Hace unos 2.500 años, Hipócrates realizó notables observaciones sobre la influencia del clima sobre la salud pública. Creía que las personas que vivían en ciudades con diferencias climáticas podían padecer distintas enfermedades. Hipócrates observó también que los cambios climáticos bruscos o las condiciones climáticas poco habituales afectan a la salud pública, especialmente en la incidencia y la gravedad de varias enfermedades infecciosas, como las infecciones gastrointestinales, la tuberculosis y las infecciones del sistema nervioso central. Creemos que las observaciones científicas de Hipócrates constituyen importantes ejemplos históricos que indican a los modernos clínicos e investigadores de las enfermedades infecciosas la necesidad de estudiar exhaustivamente el efecto de los cambios climáticos mundiales actuales sobre las enfermedades infecciosas, a fin de ayudar en la prevención de posibles epidemias de enfermedades de este tipo (AU)

Case-control studies reporting on risk factors for emergence of antimicrobial resistance: bias associated with the selection of the control group.

The optimal control group for case-control studies examining antibiotics as risk factors for the emergence of antimicrobial resistance is patients selected randomly from the total hospital population, while the selection of patients with a susceptible bacterium is deemed suboptimal. We sought to theoretically elaborate on potential parameters that introduce bias associated with the use of randomly selected control subjects, based on personal experience and data from the literature. In addition, we considered parameters that introduce potential bias associated with the definition of case patients. Parameters that may introduce potential bias associated with the randomly selected control subjects are use of antibiotics in the community (background exposure), availability of an antibiotic in a country, ability to purchase specific antibiotics or health care, the bacterial resistance pattern in the country, in vitro evaluation issues, source of admitting patients (nursing home or community), type of hospital to which patients are admitted (general or disease specific), and ward of hospital to which patients are admitted. Parameters that may introduce potential bias associated with the case definition are multidrug resistance versus resistance to only one antibiotic, resistance phenotype of the microbe, multistep versus one-step development of resistance, appropriateness versus adequacy of antibiotic treatment, antibiotic synergy, details regarding the daily dose and duration of administration of the specific antibiotic, and use of other antibiotics. In conclusion, selection of control subjects from the hospital population is also associated with bias. The most acceptable solutions to evaluate the risk factors for antimicrobial resistance are probably the case-control-control study design and the case-case-control study design.

Unusual climatic conditions and infectious diseases: observations made by Hippocrates.

About 2500 years ago, Hippocrates made noteworthy observations about the influence of climate on public health. He believed that people living in cities with different climate may suffer from different diseases. Hippocrates also observed that abrupt climatic changes or unusual weather conditions affect public health, especially the incidence and severity of various infectious diseases, including gastrointestinal infections, tuberculosis, and central nervous system infections. We believe that Hippocrates' scientific observations are great early historic examples that stress to modern infectious diseases researchers and clinicians the need to study intensively the effect of the occurring global climate changes to infectious diseases in order to help in the prevention of possible epidemics of infections.

Daptomycin versus other antimicrobial agents for the treatment of skin and soft tissue infections: a meta-analysis.

BACKGROUND: Skin and soft tissue infections (SSTIs) are common in everyday clinical practice. Daptomycin has been shown to achieve very good concentrations in skin and soft tissues. OBJECTIVE: To compare the effectiveness and toxicity of daptomycin with that of other antimicrobials for the treatment of SSTIs. METHODS: PubMed, Scopus, and the Cochrane Central Register of Controlled Trials were searched for articles published up to March 2009. Comparative studies in which daptomycin was used in the intervention group were included in this meta-analysis. The primary outcome of interest was clinical success; secondary outcomes were microbiologic success, clinical success in subsets with complicated SSTIs (cSSTIs) or infections due to methicillin-resistant Staphylococcus aureus (MRSA), clinical success of daptomycin-versus vancomycin-treated patients, time to clinical cure, treatment-related adverse events, withdrawal from treatment due to toxicity, all-cause mortality, and development of resistance. RESULTS: Four studies were included in the analysis (3 were randomized controlled trials [RCTs]). Vancomycin and semisynthetic penicillins were used in the comparator arm. Three studies reported on patients with cSSTIs. The intention-to-treat (ITT) population was 1557 patients. No statistically significant difference between daptomycin and comparators was found regarding clinical success in clinically evaluable (OR 0.89; 95% CI 0.63 to 1.25 in the 3 RCTs and OR 1.34; 95% CI 0.38 to 4.66 with all 4 studies included), ITT, MRSA-infected patients, and those with cSSTIs. Two studies reported that significantly fewer patients with cSSTIs required prolonged treatment in the daptomycin arm and that clinical cure was faster than with comparators. No difference between the compared regimens was found in other outcomes. CONCLUSIONS: Daptomycin is effective and safe for the treatment of SSTIs. Studies evaluating the optimal duration of daptomycin therapy for cSSTIs, comparing daptomycin with new agents, and focusing on proven MRSA SSTIs will be helpful for the further evaluation of the drug.

Failure to control risk factors among patients with type 2 diabetes; experience from a Greek cohort.

We reviewed the records of 313 diabetic patients attending a diabetes clinic for at least two years. Despite improvements in the control rates of cardiovascular risk factors, only 8.9% of the patients reached all the metabolic target goals simultaneously at the end, indicating a gap between guidelines and clinical practice.

Thrombotic microangiopathy associated with gemcitabine: rare but real.

Gemcitabine-associated thrombotic thrombocytopenic purpura is a rare complication of gemcitabine treatment with an incidence ranging from 0.015 to 1.4%. Clinically, this disease manifests as haemolytic anaemia, thrombocytopenia and renal insufficiency; hypertension and neurological and pulmonary symptoms are also known complications. The risk of thrombotic thrombocytopenic purpura increases as the cumulative dose of gemcitabine approaches 20,000 mg/m(2). The pathophysiology of this disease entity is unknown although several theories, involving both immune and non-immune mechanisms, have been proposed. The most effective treatment is discontinuation of gemcitabine, the provision of antihypertensive medications as needed, and consideration of plasmapheresis or use of immunoadsorption column in severe cases.

Trends in the methodological quality of published randomized controlled trials on antibacterial agents.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Randomized controlled trials (RCTs) are believed to be one of the best methods of clinical research because they can minimize systematic errors of various types. Temporal trends in the various aspects of RCTs have been studied in several medical fields (e.g. nephrology, hepatology, oncology). However, there is lack of data regarding the trends in the methodological quality of RCTs focusing on antimicrobial agents. WHAT THIS STUDY ADDS: Several important methodological aspects of RCTs on antibacterial agents, such as description of randomization, double blinding, description of the blinding and allocation concealment, have not improved during the last 30 years. AIM To investigate the trends of the methodological quality of randomized controlled trials (RCTs) of antimicrobial agents published during the last 30 years. METHODS: We randomly selected from the Cochrane Central Register of Controlled Trials database 70 RCTs of antibacterial agents that were published during a 30-year study period (1975-2005); specifically, we randomly selected 10 RCTs published during each of the following years: 1975, 1980, 1985, 1990, 1995, 2000 and 2005. In each of the selected RCTs, we searched for information on various methodological aspects and graded the methodological quality of the RCTs to evaluate trends for possible improvement. RESULTS: No improvement was noted in most of the analysed methodological aspects of the RCTs during the 30-year study period. Description of randomization, double blinding, description of the blinding, and allocation concealment were rather scarce among the evaluated RCTs, without observing a trend for improvement during the study period. We noted improvement in reporting power of the study calculations, baseline data as well as in reporting the presence or not of statistical significance and the statistical cut-off of significance. In only 1/70 RCTs were all 13 of the examined methodological quality aspects met and in one more RCT 12 of them were met. CONCLUSIONS: We did not observe considerable improvement in the quality of the reporting and methodology of RCTs on antibacterial agents during the last 30 years. The methodological quality aspects that need most improvement are those that help safeguard against various types of biases.

Comparison of utility of blood cultures from intravascular catheters and peripheral veins: a systematic review and decision analysis.

Blood cultures are sometimes obtained from intravascular catheters for convenience. However, there is controversy regarding this practice. The authors compared the diagnostic test characteristics of blood cultures obtained from intravascular catheters and peripheral veins. Relevant studies for inclusion in this review were identified through PubMed (January 1970-October 2005) and the Cochrane Central Register of Controlled Trials. Studies that reported clear definitions of true bacteraemia were included in the analysis. Two reviewers independently extracted the data. Six studies were included in the analysis, providing data for 2677 pairs of blood cultures obtained from an intravascular catheter and a peripheral venipuncture. A culture obtained from an intravascular catheter was found to be a diagnostic test for bacteraemia with better sensitivity (OR 1.85, 95 % CI 1.14-2.99, fixed effects model) and better negative predictive value (almost with statistical significance) (OR 1.55, 95 % CI 0.999-2.39, fixed effects model) but with less specificity (OR 0.33, 95 % CI 0.18-0.59, random effects model) and lower positive predictive value (OR 0.41, 95 % CI 0.23-0.76, random effects model) compared to a culture taken by peripheral venipuncture. In a group of 1000 patients, eight additional patients with true bacteraemia would be identified and 59 falsely diagnosed as having bacteraemia by a blood culture obtained from an intravascular catheter compared to results of the peripheral blood culture. Given the consequences of undertreating patients with bacteraemia, the authors believe that, based on the available evidence, at least one blood culture should be obtained from the intravascular catheter.

Albendazole for the treatment of human echinococcosis: a review of comparative clinical trials.

BACKGROUND: Albendazole has been used in various ways in the treatment of cystic echinococcosis (CE). METHODS: We reviewed the available evidence regarding the role of albendazole for the treatment of patients with CE. The available comparative clinical trials (randomized or not) that examined the use of albendazole in CE were identified from the PubMed and the ISI Web of Science databases. Relevant data from the trials were extracted and evaluated. RESULTS: Thirteen studies were included in the review. Albendazole is superior to placebo for inoperable, symptomatic patients (1 study). In addition, in 4 trials that tested albendazole as a preoperative adjuvant therapy, the drug resulted in degeneration of hydatid cysts at the time of surgery in a considerable proportion of patients. Furthermore, combined therapy with albendazole and PAIR (Puncture, Aspiration, Injection of scolicidal agent, and Re-aspiration) technique was found more effective than albendazole or PAIR treatment alone, in a randomized controlled trial examining this issue. Finally, although existing evidence shows some superiority for albendazole compared to mebendazole, there is no definite proof about this. CONCLUSIONS: Although the available comparative trials provide considerable evidence for the role of albendazole in patients with CE, there are some important clinical questions that remained unanswered by the studies. One of them is whether the combination of albendazole with praziquantel is superior to albendazole alone when both effectiveness and drug toxicity are taken into account. Also, further studies should also compare the combination of albendazole/PAIR with albendazole/surgery focusing on both short and long term outcomes.

Outcomes after medical and surgical treatment of diverticulitis: a systematic review of the available evidence.

There is still controversy regarding the appropriate management of diverticulitis of the colon in cases when both surgical and conservative treatment may be an option. We performed a systematic review of the available evidence regarding the outcomes after medical and surgical treatment of diverticulitis from studies published after 1980 and indexed in the PubMed database. We included original studies that reported comparative data for at least one outcome in medically- and surgically-treated patients with transverse or left colon diverticulitis. The main outcomes of interest were mortality, morbidity, and recurrence of diverticulitis after medical or surgical treatment. There were 21 studies fulfilling our inclusion criteria out of 1360 initially identified as possibly relevant. More patients were treated conservatively in the included studies compared to emergency surgery (24 862 vs 6504). Emergency surgery was the main option for patients with severe complications of diverticular disease, including peritonitis. In most studies, in-hospital mortality for patients treated surgically was generally higher than that of patients treated medically, whereas there were insufficient comparative data regarding mortality during follow up. However, readmission to the hospital due to diverticular disease during follow up was more common in the group of patients treated conservatively compared to those treated surgically (4358/23 446 [18.6%]vs 22/359 [6.1%]). Conservatively-treated patients, with a first or second episode of diverticulitis, required surgery for recurrent disease during follow up in a maximum of 45% of cases, with larger studies reporting percentages lower than 11%. It should be emphasized that medical and surgical treatments have not ever been compared in a randomized controlled trial in patients with diverticulitis (without generalized peritonitis that is a surgical emergency). Although medical treatment results in more readmissions due to recurrence, it may be reasonable to avoid surgical therapy in the vast majority of patients with acute diverticulitis. It is unclear what the best treatment option is for younger patients (<50 years), namely whether elective surgery should be considered with the first episode of diverticulitis.

Antibiotic-lock therapy for long-term catheter-related bacteremia: a review of the current evidence.

Catheter-related bloodstream infections (CRBSIs) are a major cause of morbidity and mortality, especially among patients receiving hemodialysis, parenteral nutrition and chemotherapy. Antibiotic-lock therapy (ALT) represents a promising technique in the modern treatment of CRBSIs. In this review, we attempt to clarify the potential role of ALT in the treatment of long-term catheter-related bacteremia, based on the available evidence from published studies reporting on this issue. We identified 28 articles that were considered appropriate to be included in our review, only three of which were comparative studies. There is some evidence that ALT administered concurrently with systemic therapy may represent a significant therapeutic approach for CRBSIs involving long-term catheters. Prolonged infection-free catheter survival in the reported series is suggestive of sterilization of the catheters by ALT. The only reported comparison shows better outcome with ALT than with catheter exchange. Immunodeficient states, such as HIV, and the use of totally implanted devices instead of tunneled catheters may predispose to CRBSI treatment failure. No serious adverse effects, such as emergence of resistance or increased infectious complications, were found to be associated with the use of ALT in the reviewed studies. However, more comparative studies should be performed to examine this important therapeutic issue further.

Helicobacter pylori infection in symptomatic HIV-seropositive and -seronegative patients: a case-control study.

We conducted a case-control study in a Greek hospital to evaluate the prevalence and morbidity of Helicobacter pylori in HIV-infected patients. HIV-seropositive patients were infected by H. pylori less often than HIV-seronegative controls [12/58 (20.7%) versus 38/58 (65.5%),p < 0.001]. The mean CD4 count was lower for H. pylori-negative than H. pylori-positive HIV-infected patients (p < 0.007). Also, among HIV patients, prior use of antibiotics or proton pump inhibitors was more common in those without H. pylori infection, however, this difference was not statistically significant (p = 0.06). The grading of the density of H. pylori infection and the grading of the histomorphological findings according to the Sydney classification were similar between HIV-seropositive and -seronegative patients with H. pylori infection.

Do high doses of quinolones decrease the emergence of antibacterial resistance? A systematic review of data from comparative clinical trials.

OBJECTIVE: To evaluate whether the use of high doses of quinolones may reduce the development of antimicrobial resistance. DATA SOURCES: Relevant studies were identified from PubMed and the Cochrane Central Register of Controlled Trials (until June 2006). STUDY SELECTION AND DATA EXTRACTION: We performed a systematic review of the available data from comparative clinical studies reporting on the emergence of resistance when using different daily doses of quinolones. DATA SYNTHESIS: Twelve studies reported comparative data regarding the emergence of antimicrobial resistance. Development of resistance occurred in patients of 5/12 studies included in the review, with no statistical difference between the compared arms. CONCLUSIONS: Although data from laboratory studies are indicative of a benefit from using high daily doses of quinolones in order to minimize the emergence of antimicrobial resistance, the data from the reviewed trials are limited and can neither support nor reject this finding. However, it seems that if a true benefit exists this is rather small and regards mainly isolates with initially high minimum inhibitory concentrations. Further comparative clinical studies focusing on this issue are justified.