Population pharmacokinetics of colistin and the relation to survival in critically ill patients infected with colistin susceptible and carbapenem-resistant bacteria.

OBJECTIVES: The aim was to analyse the population pharmacokinetics of colistin and to explore the relationship between colistin exposure and time to death. METHODS: Patients included in the AIDA randomized controlled trial were treated with colistin for severe infections caused by carbapenem-resistant Gram-negative bacteria. All subjects received a 9 million units (MU) loading dose, followed by a 4.5 MU twice daily maintenance dose, with dose reduction if creatinine clearance (CrCL) < 50 mL/min. Individual colistin exposures were estimated from the developed population pharmacokinetic model and an optimized two-sample per patient sampling design. Time to death was evaluated in a parametric survival analysis. RESULTS: Out of 406 randomized patients, 349 contributed pharmacokinetic data. The median (90% range) colistin plasma concentration was 0.44 (0.14-1.59) mg/L at 15 minutes after the end of first infusion. In samples drawn 10 hr after a maintenance dose, concentrations were >2 mg/L in 94% (195/208) and 44% (38/87) of patients with CrCL ≤120 mL/min, and >120 mL/min, respectively. Colistin methanesulfonate sodium (CMS) and colistin clearances were strongly dependent on CrCL. High colistin exposure to MIC ratio was associated with increased hazard of death in the multivariate analysis (adjusted hazard ratio (95% CI): 1.07 (1.03-1.12)). Other significant predictors included SOFA score at baseline (HR 1.24 (1.19-1.30) per score increase), age and Acinetobacter or Pseudomonas as index pathogen. DISCUSSION: The population pharmacokinetic model predicted that >90% of the patients had colistin concentrations >2 mg/L at steady state, but only 66% at 4 hr after start of treatment. High colistin exposure was associated with poor kidney function, and was not related to a prolonged survival.

Combining VITEK® 2 with colistin agar dilution screening assist timely reporting of colistin susceptibility.

OBJECTIVES: The rise in carbapenem resistance among Gram-negative bacteria has renewed interest in colistin. Recently, the EUCAST-CLSI Polymyxin Breakpoints Working Group declared that broth microdilution (BMD) is the only valid method for colistin susceptibility testing. BMD is not easily incorporated into the routine work of clinical laboratories, and usually this test is incorporated serially, resulting in delayed susceptibility reporting. We tested a strategy of combining VITEK® 2 with a 2 µg/mL colistin agar dilution (VITEK® 2/AD) screening plate to improve performance and time to reporting of colistin susceptibility. METHODS: Colistin susceptibility for 364 clinical isolates was determined by VITEK® 2/AD and compared with the reference standard BMD according to the ISO 20776-1:2007 and CLSI guidelines. The EUCAST colistin susceptibility breakpoint of ≤2 µg/mL was used. Escherichia coli NCTC 13846 served as quality control strain. Agreement, very major error (VME) and major error rates were determined using ISO 20776-2:2007. RESULTS: The VME rate for VITEK® 2 alone was 30.6% (15/49, 95% CI 18.3-45.4%), and was reduced to 10.2% (5/49, 95% CI 3.4-22.2%) using the VITEK® 2/AD combined testing. The combined testing had categorical agreement with BMD of 97% (354/364, 95% CI 95.0-98.7%), and a major error (ME) rate of 1.6% (5/315, 95% CI 0.5-3.7%). Using the combined testing, even against challenging strains, 349 (95.8%, 95% CI 93.3-97.7%) colistin susceptibility results could be reported, and only 15 isolates required further analysis by BMD. DISCUSSION: Our method is simple to apply and allows rapid reporting of colistin susceptibility.

Hydroxymethylglutaryl-CoA reductase inhibitors (statins) for the treatment of sepsis in adults - A systematic review and meta-analysis.

OBJECTIVES: The pleiotropic effect of hydroxymethylglutaryl-CoA reductase inhibitors (statins) might have a beneficial effect in sepsis through several mechanisms. The aim was to assess the efficacy and safety of statins, compared with placebo, for the treatment of sepsis in adults. METHODS: We searched the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2017, Issue 12), OVID MEDLINE (from 1966 to January 2018), Embase (Ovid SP, from 1974 to January 2018), and LILACS (from 1986 to January 2018). We also searched the trial registries ISRCTN and ClinicalTrials.gov to January 2018. The eligibility criteria were randomized controlled trials comparing the treatment of statins versus placebo in adult patients who were hospitalized due to sepsis. Participants were adults (16 years and older) hospitalized because of sepsis or who developed sepsis during admission. Interventions were treatment with hydroxymethylglutaryl-CoA reductase inhibitors (statins) versus no treatment or placebo. We performed a systematic review of all randomized controlled trials published until January 2018, assessing the efficacy and safety of statins in sepsis treatment. Two primary outcomes were assessed: 30-day overall mortality and deterioration to severe sepsis during management. Secondary outcomes were hospital mortality, need for mechanical ventilation and drug related adverse events. RESULTS: Fourteen trials evaluating 2628 patients were included. Statins did not reduce 30-day all-cause mortality neither in all patients (risk ratio (RR) 0.96, 95% confidence interval (CI) 0.83-1.10), nor in a subgroup of patients with severe sepsis (RR 0.97, 95% CI 0.84-1.12). The certainty of evidence for both outcomes was high. There was no change in the rate of adverse events between study arms (RR 1.24, 95% CI 0.94 to 1.63). The certainty of evidence for this outcome was high. CONCLUSIONS: The use of statin therapy in adults for the indication of sepsis is not recommended.

Risk factors and prognosis of complicated urinary tract infections caused by Pseudomonas aeruginosa in hospitalized patients: a retrospective multicenter cohort study.

PURPOSE: Complicated urinary tract infections (cUTIs) are among the most frequent health-care-associated infections. In patients with cUTI, Pseudomonas aeruginosa deserves special attention, since it can affect patients with serious underlying conditions. Our aim was to gain insight into the risk factors and prognosis of P. aeruginosa cUTIs in a scenario of increasing multidrug resistance (MDR). METHODS: This was a multinational, retrospective, observational study at 20 hospitals in south and southeastern Europe, Turkey, and Israel including consecutive patients with cUTI hospitalized between January 2013 and December 2014. A mixed-effect logistic regression model was performed to assess risk factors for P. aeruginosa and MDR P. aeruginosa cUTI. RESULTS: Of 1,007 episodes of cUTI, 97 (9.6%) were due to P. aeruginosa. Resistance rates of P. aeruginosa were: antipseudomonal cephalosporins 35 of 97 (36.1%), aminoglycosides 30 of 97 (30.9%), piperacillin-tazobactam 21 of 97 (21.6%), fluoroquinolones 43 of 97 (44.3%), and carbapenems 28 of 97 (28.8%). The MDR rate was 28 of 97 (28.8%). Independent risk factors for P. aeruginosa cUTI were male sex (OR 2.61, 95% CI 1.60-4.27), steroid therapy (OR 2.40, 95% CI 1.10-5.27), bedridden functional status (OR 1.79, 95% CI 0.99-3.25), antibiotic treatment within the previous 30 days (OR 2.34, 95% CI 1.38-3.94), indwelling urinary catheter (OR 2.41, 95% CI 1.43-4.08), and procedures that anatomically modified the urinary tract (OR 2.01, 95% CI 1.04-3.87). Independent risk factors for MDR P. aeruginosa cUTI were age (OR 0.96, 95% CI 0.93-0.99) and anatomical urinary tract modification (OR 4.75, 95% CI 1.06-21.26). Readmission was higher in P. aeruginosa cUTI patients than in other etiologies (23 of 97 [23.7%] vs 144 of 910 [15.8%], P=0.04), while 30-day mortality was not significantly different (seven of 97 [7.2%] vs 77 of 910 [8.5%], P=0.6). CONCLUSION: Patients with P. aeruginosa cUTI had characteristically a serious baseline condition and manipulation of the urinary tract, although their mortality was not higher than that of patients with cUTI caused by other etiologies.

A decision support model to predict the presence of an acute infiltrate on chest radiograph.

A chest infiltrate is needed to make a diagnosis of community-acquired pneumonia, but chest X-rays might be time consuming, entail radiation exposure, and demand resources that are not always available. We sought to derive a model to predict whether a patient will have an infiltrate on chest X-ray (CXR). This prospective observational study included patients visiting the Emergency Department of Beilinson Hospital in the years 2003-2004 (derivation cohort) and 2010-2011 (validation cohort), who had undergone a CXR, and were suspected of having a respiratory infection. We excluded all patients with possible healthcare associated infections. A logistic regression model was derived and applied to the validation cohort. A total of 1,555 patients met inclusion criteria: 993 in the derivation cohort and 562 in the validation cohort with 287 (29%) and 226 (40%) having an infiltrate, respectively. The derivation model area-under-the curve (AUC) was 0.79 (95% CI 0.76-0.82). We categorized the patients into three groups-presence or absence of infiltrate, or undetermined. In the validation cohort, 70 (12%) patients were classified as 'no infiltrate'; 3 (4%) of them had an infiltrate, 367 (65%) were classified as 'infiltrate'; 190 (52%) of them had an infiltrate on CXR, and 125 (46%) were classified as 'undetermined'; 33 (26%) of them with an infiltrate on CXR. Using this prediction model for the evaluation of patients with suspected respiratory infection in an ED setting may help avoid over 10% of CXRs.

The effect of statins on the outcome of Clostridium difficile infection in hospitalized patients.

UNLABELLED: Several studies have shown an association between exposure to statins and favorable clinical outcomes for various types of infections. We aimed to assess the impact of statin use on mortality, disease severity and complications among hospitalized patients with Clostridium difficile infection (CDI). Data were analyzed from a retrospectively collected database of 499 patients diagnosed with CDI during 2009-2014. We compared infection outcomes between 178 statin (36 %) users and 321 (64 %) non-users. On multivariate analysis, we found that statin use did not have a significant impact on 30-day mortality (OR = 1.54; 95 % CI, 0.85-2.79; p = 0.15) or any significant effect on CDI severity and complication. Concomitant statin use has no significant impact on short-term mortality or effect on CDI severity and complications among hospitalized patients with CDI. However, patients in the statin group were older and had higher Charlson score compared with the non-statin group. Whether these factors affected a possible impact of statins on the disease course remains to be investigated. KEY MESSAGES: • Clostridium difficile is the most common cause of infectious nosocomial diarrhea among hospitalized adult patients in the developed countries. • There is an increasing morbidity and mortality of CDI patients due to the emergence of new strains of high virulence. • Recent studies demonstrated that prior statin use has protective and ameliorating effects on morbidity and mortality among CDI patients. • Our study showed that concomitant statin use has no significant impact on short-term mortality, CDI severity and its complications.

Association of vancomycin serum concentrations with efficacy in patients with MRSA infections: a systematic review and meta-analysis.

Recent Infectious Diseases Society of America guidelines for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections recommend maintaining vancomycin trough concentrations of 15-20 mg/L for serious infections. We conducted a systematic review and meta-analysis of all studies assessing the impact of low (<15 mg/L) vs. high (≥ 15 mg/L) vancomycin trough level on the efficacy of MRSA infections treatment. Four prospective and 12 retrospective studies were included (2003 participants). No significant difference was demonstrated between low and high vancomycin trough level for the outcome of all-cause mortality (odds ratio (OR) 1.07, 95% confidence interval (CI) 0.78-1.46, I(2) = 28%). In studies evaluating mainly MRSA pneumonia, there was significantly higher mortality with low vancomycin level (OR 1.78, 95% CI 1.11-2.84). No significant difference was demonstrated in treatment failure rates (OR 1.25, 95% CI 0.88-1.78, I(2) = 51%). However, excluding one outlier study from the analysis, treatment failure became significantly higher in patients with low vancomycin trough level (OR 1.46, 95% CI 1.12-1.91, I(2) = 16%). Microbiologic failure rates were significantly higher in patients with low vancomycin levels (OR 1.56, 95% CI 1.08-2.26, I(2) = 0%). Nephrotoxicity was significantly higher with vancomycin levels of ≥ 15 mg/L. However, no cases of irreversible renal damage were reported. Current data on the effectiveness of higher vancomycin trough levels in the treatment of MRSA infections are limited to few prospective and mainly retrospective studies. Our findings support the current recommendations for maintaining vancomycin trough levels of ≥ 15 mg/L in the treatment of severe MRSA infections, although no difference in all-cause mortality was observed.

Predicting Clostridium difficile infection in diabetic patients and the effect of metformin therapy: a retrospective, case-control study.

Data on risk factors for Clostridium difficile infection (CDI) in diabetic patients are scarce. Recently, it has been shown that metformin increases the Bacteroidetes/Firmicutes ratio; therefore, it may yield a protective effect against CDI. We aimed to assess risk factors for CDI in diabetic patients beyond antibiotic treatment, and to determine the impact of metformin therapy on the development of CDI in these patients. In this retrospective, case-control study, all consecutive CDI diabetic patients, from January 2009 to December 2013, were included and compared to consecutive diabetic patients without CDI, hospitalized during the same period and in the same departments. Of 7,670 patients tested for C. difficile toxins, 486 were diabetics. Of them, 150 (30.8 %) were positive for C. difficile toxins and 336 (69.1 %) were negative. On multivariate analysis, metformin treatment was associated with a significant reduction in CDI [odds ratio (OR) = 0.58; 95 % confidence interval (CI), 0.37-0.93; p = 0.023], while heart failure was associated with significantly higher rates of CDI (OR = 1.654; 95 % CI, 1.007-2.716; p = 0.047), together with poor functional status, previous hospitalization, and abdominal surgery. Our findings suggest that, in diabetic patients, in addition to the well-recognized risk factors, heart failure is an additional risk factor for CDI, while metformin treatment seems to have a protective effect against the development of CDI. The exact mechanisms underlying this protective effect remain to be fully understood.

Predicting bacteraemia in validated models--a systematic review.

Bacteraemia is associated with high mortality. Although many models for predicting bacteraemia have been developed, not all have been validated, and even when they were, the validation processes varied. We identified validated models that have been developed; asked whether they were successful in defining groups with a very low or high prevalence of bacteraemia; and whether they were used in clinical practice. Electronic databases were searched to identify studies that underwent validation on prediction of bacteraemia in adults. We included only studies that were able to define groups with low or high probabilities for bacteraemia (arbitrarily defined as below 3% or above 30%). Fifteen publications fulfilled inclusion criteria, including 59 276 patients. Eleven were prospective and four retrospective. Study populations and the parameters included in the different models were heterogeneous. Ten studies underwent internal validation; the model performed well in all of them. Twelve performed external validation. Of the latter, seven models were validated in a different hospital, using a new independent database. In five of these, the model performed well. After contacting authors, we found that none of the models was implemented in clinical practice. We conclude that heterogeneous studies have been conducted in different defined groups of patients with limited external validation. Significant savings to the system and the individual patient can be gained by refraining from performing blood cultures in groups of patients in which the probability of true bacteraemia is very low, while the probability of contamination is constant. Clinical trials of existing or new models should be done to examine whether models are helpful and safe in clinical use, preferably multicentre in order to secure utility and safety in diverse clinical settings.

Monomicrobial necrotizing fasciitis in a single center: the emergence of Gram-negative bacteria as a common pathogen.

BACKGROUND: Necrotizing fasciitis (NF) is a life-threatening soft tissue infection. It is usually caused by Streptococcus pyogenes and other Gram-positive bacteria. Several reports, however, emphasize the importance of Gram-negative rods in this infection. METHODS: We retrospectively studied all cases of monomicrobial necrotizing fasciitis hospitalized in our center during the years 2002-2012. We compared clinical characteristics and outcomes of patients with Gram-negative versus Gram-positive infection. RESULTS: Forty-five cases were reviewed, 19 caused by Gram-negative organisms, 10 of them Escherichia coli, and 26 caused by Gram-positive organisms, 10 of them S. pyogenes. Compared to Gram-positive infections, patients with Gram-negative infections were more likely to have a baseline malignancy (9/19, 47.4%) or to have undergone recent surgery (4/19, 42.3%). The 30-day mortality was higher among Gram-negative infected patients (8/19, 42.1% vs. 8/26, 30.8%). Creatine phosphokinase (CPK) was elevated in a minority of patients with Gram-negative necrotizing fasciitis, and its absolute value was lower than in Gram-positive necrotizing fasciitis. CONCLUSIONS: In our center, 42% of monomicrobial necrotizing fasciitis cases were found to be caused by Gram-negative organisms, mostly E. coli. These infections usually appeared in immunocompromised or postoperative patients, often presented with normal CPK levels, and were associated with high mortality rates.

Factors associated with influenza vaccination among adult cancer patients: a case-control study.

Influenza vaccination is recommended for cancer patients; however, adherence is low. We aimed to identify predictive factors for vaccination among cancer patients. We conducted a case-control analysis of a patient cohort in the 2010-2011 influenza season. We included adult cancer patients with solid malignancies undergoing chemotherapy, and haematological patients with active disease. Patients who died between October and November 2010 (N = 43) were excluded from analysis. Cases received the 2011 seasonal influenza vaccine, and controls did not. Data were obtained from patients' records, and validated through personal interviews. We collected socio-demographic information, and data on the malignancy and co-morbidities and triggers for vaccination and non-vaccination. We performed bivariate and multivariable analyses, in which vaccination status was the dependent variable. Of 806 patients included in analysis, 387 (48%) were vaccinated. Variables associated with vaccination on bivariate analysis were older age, higher socio-economic status, lower crowding index, marital status (widowed > married > single), malignancy type (haematological > solid tumours) and time from diagnosis, low-risk malignancy, diabetes, past vaccination, country of birth (non-Russian origin), and physicians' recommendations. Predictive factors found to be independently associated with vaccination on multivariable analysis were past vaccinations, low-risk malignancy, and country of birth. In the analysis conducted among interviewees (N = 561), recommendations from the oncologist (OR 10.7, 95% CI 5.4-21.2) and from the primary-care physician (OR 3.35, 95% CI 2.05-5.49) were strong predictors for vaccination. We conclude that 'habitual vaccinees' continue influenza vaccinations when ill with cancer. Physicians' recommendations, especially the oncologist's, have a major influence on patients' compliance with influenza vaccination.

Surgical site infections following craniotomy focusing on possible post-operative acquisition of infection: prospective cohort study.

Neurosurgery is characterized by a prolonged risk period for surgical site infection (SSI), mainly related to the presence of cerebrospinal fluid (CSF) drains. We aimed to examine factors associated with post-neurosurgical SSIs, focusing on post-operative factors. A prospective cohort study was conducted in a single center over a period of 18 months in Israel. Included were adult patients undergoing clean or clean-contaminated craniotomy, including craniotomies with external CSF drainage or shunts. SSIs were defined by the Centers for Disease Control and Prevention (CDC) criteria for healthcare-associated infections. All patients were followed up for 90 days and those with foreign body insertion for 1 year. We compared patients with and without SSI. A multivariable regression analysis for SSI was conducted including uncorrelated variables significantly associated with SSI. A total of 502 patients were included, with 138 (27.5%) undergoing emergent or urgent craniotomy. The overall SSI rate was 5.6% (28 patients), of which 3.2% (16 patients) were intracerebral. Non-elective surgery, external CSF drainage/monitoring devices, re-operation, and post-operative respiratory failure were independently associated with subsequent SSI. External CSF devices was the only significant risk factor for intracerebral SSIs (p < 0.001). Internal shunts or other foreign body insertions were not associated with SSIs. A phenotypically identical isolate to that causing the SSI was isolated from respiratory secretions prior to the SSI in 4/9 patients with microbiologically documented intracerebral SSIs. Patients with SSIs had longer hospital stay, poorer functional capacity on discharge, and higher 90-day mortality. We raise the possibility of post-operative infection acquisition through external CSF devices. Standard operating procedures for their maintenance are necessary.

Macrolides vs. quinolones for community-acquired pneumonia: meta-analysis of randomized controlled trials.

The relative efficacy, safety and ecological implications of macrolides vs. quinolones in the treatment of community-acquired pneumonia (CAP) are debatable. We performed a systematic review and meta-analysis of randomized controlled trials comparing any macrolide vs. any quinolone for the treatment of CAP among adult inpatients or outpatients, as monotherapy or both in combination with a beta-lactam. We did not limit inclusion by pneumonia severity, publication status, language or date of publication. The primary outcomes assessed were 30-day all-cause mortality and treatment failure. Two authors independently extracted the data. Fixed effect meta-analysis of risk ratios (RRs) with 95% confidence intervals was performed. Sixteen trials (4989 patients) fulfilling inclusion criteria were identified, mostly assessing outpatients with mild to moderate CAP. All-cause mortality was not significantly different for macrolides vs. quinolones, RR 1.03 (0.63-1.68, seven trials), with a low event rate (2%). Treatment failure was significantly lower with quinolones, RR 0.78 (0.67-0.91, 16 trials). The definition of failure used in the primary studies was not clearly representative of patients' benefit. Microbiological failure was lower with quinolones, RR 0.63 (0.49-0.81, 13 trials). All adverse events, adverse events requiring discontinuation and any premature antibiotic discontinuation were significantly more frequent with macrolides, mainly on account of gastrointestinal adverse events. Resistance development was not assessed in the trials. Randomized controlled trials show an advantage of quinolones in the treatment of CAP with regard to clinical cure without need for antibiotic modification at end of treatment and gastrointestinal adverse events. The clinical significance of this advantage is unclear.