Upraising Stenotrophomonas maltophilia in Critically Ill Patients: A New Enemy?

Stenotrophomonas maltophilia (S. maltophilia), an important pathogen in immuno-compromised patients, has recently gained attention in patients admitted in intensive care units (ICU). We sought to investigate clinical features of infections caused by S. maltophilia in ICU patients and identify risk factors for mortality. We conducted a retrospective study in two multivalent non-COVID-19 ICUs of tertiary-teaching hospitals in Greece and Spain, including patients with isolated S. maltophilia from at least one clinical specimen along with clinical signs of infection. A total of 103 patients (66% male) were analyzed. Median age was 65.5 (54-73.3) years and mean APACHE II and SOFA scores upon ICU admission were 18.36 (±7.22) and 18.17 (±6.95), respectively. Pneumonia was the predominant clinical syndrome (72.8%), while 22% of cases were among hemato/oncology patients. Crude 28-day mortality rate was 54.8%, even though, 14-day clinical and microbiological response was 96%. Age, APACHE II on ICU admission, hemato-oncologic disease, and multi-organ failure were initially identified as potential predictors of mortality. In the multivariable analysis, only increasing age and hemato-oncologic disease were shown to be independent risk factors for 28-day mortality. High all-cause mortality was observed in critically ill patients with predominantly respiratory infections by S. maltophilia, despite initial clinical and laboratory response after targeted treatment. The study elucidates a potentially worrisome emerging pathogen in the ICU.

Colistin versus meropenem in the empirical treatment of ventilator-associated pneumonia (Magic Bullet study): an investigator-driven, open-label, randomized, noninferiority controlled trial.

BACKGROUND: Colistin is recommended in the empirical treatment of ventilator-associated pneumonia (VAP) with a high prevalence of carbapenem-resistant gram-negative bacilli (CR-GNB). However, the efficacy and safety of colistin are not well defined. METHODS: A multicenter prospective randomized trial conducted in 32 European centers compared the efficacy and safety of colistin (4.5 million unit loading dose followed by a maintenance dose of 3 million units every 8 h) versus meropenem (2 g every 8 h), both in combination with levofloxacin (500 mg every 12 h) for 7-14 days in patients with late VAP. Between May 2012 and October 2015, 232 patients were randomly assigned to the 2 treatment groups. The primary endpoint was mortality at 28 days after randomization in the microbiologically modified intention-to-treat (mMITT) population. Secondary outcomes included clinical and microbiological cure, renal function at the end of the treatment, and serious adverse events. The study was interrupted after the interim analysis due to excessive nephrotoxicity in the colistin group; therefore, the sample size was not achieved. RESULTS: A total of 157 (67.7%) patients were included in the mMITT population, 36 of whom (22.9%) had VAP caused by CR-GNB. In the mMITT population, no significant difference in mortality between the colistin group (19/82, 23.2%) and the meropenem group (19/75, 25.3%) was observed, with a risk difference of - 2.16 (- 15.59 to 11.26, p = 0.377); the noninferiority of colistin was not demonstrated due to early termination and limited number of patients infected by carbapenem-resistant pathogens. Colistin plus levofloxacin increased the incidence of renal failure (40/120, 33.3%, versus 21/112, 18.8%; p = 0.012) and renal replacement therapy (11/120, 9.1%, versus 2/112, 1.8%; p = 0.015). CONCLUSIONS: This study did not demonstrate the noninferiority of colistin compared with meropenem, both combined with levofloxacin, in terms of efficacy in the empirical treatment of late VAP but demonstrated the greater nephrotoxicity of colistin. These findings do not support the empirical use of colistin for the treatment of late VAP due to early termination. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01292031. Registered 9 February 2011.

The Role of Minocycline in the Treatment of Nosocomial Infections Caused by Multidrug, Extensively Drug and Pandrug Resistant Acinetobacter baumannii: A Systematic Review of Clinical Evidence.

Treatment options for multidrug resistant Acinetobacter baumannii strains (MDR-AB) are limited. Minocycline has been used alone or in combination in the treatment of infections associated with AB. A systematic review of the clinical use of minocycline in nosocomial infections associated with MDR-AB was performed according to the PRISMA-P guidelines. PubMed-Medline, Scopus and Web of Science TM databases were searched from their inception until March 2019. Additional Google Scholar free searches were performed. Out of 2990 articles, 10 clinical studies (9 retrospective case series and 1 prospective single center trial) met the eligibility criteria. In total, 223 out of 268 (83.2%) evaluated patients received a minocycline-based regimen; and 200 out of 218 (91.7%) patients with available data received minocycline as part of a combination antimicrobial regimen (most frequently colistin or carbapenems). Pneumonia was the most common infection type in the 268 cases (80.6% with 50.4% ventilator-associated pneumonia). The clinical and microbiological success rates following minocycline treatment were 72.6% and 60.2%, respectively. Mortality was 20.9% among 167 patients with relevant data. In this systematic review, minocycline demonstrated promising activity against MDR-AB isolates. This review sets the ground for further studies exploring the role of minocycline in the treatment of MDR-AB associated infections.

Characteristics, risk factors and outcomes of Clostridium difficile infections in Greek Intensive Care Units.

BACKGROUND: Clostridium difficile is one of the major causes of diarrhoea among critically ill patients and its prevalence increases exponentially in relation to the use of antibiotics and medical devices. We sought to investigate the incidence of C. difficile infection in Greek units, and identify potential risk factors related to C. difficile infection. METHODS: A prospective multicenter cohort analysis of critically ill patients (3 ICUs from 1/1/2014 to 31/12/2014). RESULTS: Among 970(100%) patients, 95(9.79%) with diarrhoea, were included. Their demographic, comorbidity and clinical characteristics were recorded on admission to the unit. The known predisposing factors for the infection were recorded and the diagnostic tests to confirm C. difficile were conducted, based on the current guidelines. The incidence of C. difficile infection was 1.3% (n = 13). All-cause mortality in patients with diarrhoea, C. difficile infection and attributable mortality in patients with C. difficile infection was 28%, 38.5% and 30.8% respectively. Sequential Organ Failure Assessment (SOFA) scores on admission were significantly lower and prior C. difficile infection was more common in patients with current C. difficile infection. Regarding other potential risk factors, no difference was found between groups. No factor was independently associated with C. difficile infection. CONCLUSIONS: C. difficile infection is low in Greek intensive care units, but remains a serious problem among the critically-ill. Mortality was similar to reports from other countries. No factor was independently associated with C. difficile infection.

Inhaled Antimicrobials for Ventilator-Associated Pneumonia: Practical Aspects.

Positive experience with inhaled antibiotics in pulmonary infections of patients with cystic fibrosis has paved the way for their utilization in mechanically ventilated, critically ill patients with lower respiratory tract infections. A successful antibiotic delivery depends upon the size of the generated particle and the elimination of drug impaction in the large airways and the ventilator circuit. Generated droplet size is mainly affected by the type of the nebulizer employed. Currently, jet, ultrasonic, and vibrating mesh nebulizers are marketed; the latter can deliver optimal antibiotic particle size. Promising novel drug-device combinations are able to release drug concentrations of 25- to 300-fold the minimum inhibitory concentration of the targeted pathogens into the pulmonary alveoli. The most important practical steps of nebulization include pre-assessment and preparation of the patient (suctioning, sedation, possible bronchodilation, adjustment of necessary ventilator settings); adherence to the procedure (drug preparation, avoidance of unnecessary tubing connections, interruption of heated humidification, removal of heat-moisture exchanger); inspection of the procedure (check for residual in drug chamber, change of expiratory filter, return sedation, and ventilator settings to previous status); and surveillance of the patient for adverse events (close monitoring of the patient and particularly of peak airway pressure and bronchoconstriction). Practical aspects of nebulization are very important to ensure optimal drug delivery and safe procedure for the patient. Therefore, the development of an operational checklist is a priority for every department adopting this modality.

Elderly versus non-elderly patients with intra-abdominal candidiasis in the ICU.

BACKGROUND: Intra-abdominal candidiasis (IAC) has a considerable cost in terms of mortality and morbidity. We sought to study the epidemiology, characteristics and outcome of elderly (>75 years old) versus non-elderly patients with IAC and risk factors for mortality in elderly patients. METHODS: Post-hoc analysis of a retrospective multinational cohort study over a 3-year period (2011-2013). RESULTS: Of 482 patients, 124 (25.7%) were elderly and 358 (74.3%) were non-elderly. The mean age was 80.4±3.9 and 56.3±13.8 years, respectively. Fifty-four of 124 (43.5%) and 75/358 (20.9%) died until the end of observation. The majority of isolates were Candida albicans. Echinocandins were the most prescribed initial agent. Elderly patients were more likely to have a higher APACHE II Score, and to suffer from chronic obstructive pulmonary disease and heart disease. Non-elderly patients were more likely to be treated with immunosuppressants and steroids, and to have received solid organ transplantation. Mortality was significantly higher in the elderly group. Regarding risk factors for mortality in elderly patients, non-survivors were more likely to be males, reoperated, develop septic shock, receive vasopressors, suffer from end-stage renal disease (ESRD), and have inadequate abdominal source control within 48 hours. They had a higher APACHE II Score and a higher number of acquired organ dysfunction. ESRD and inadequate abdominal source control were significantly associated with mortality. CONCLUSIONS: Factors independently predicting mortality in elderly patients with IAC were ESRD and inadequate abdominal source control. Elderlies were found to have more pulmonary and cardiac morbidities and had higher mortality than non-elderlies.

Duration of therapy of ventilator-associated pneumonia.

PURPOSE OF REVIEW: Ventilator-associated pneumonia (VAP) is a major cause of morbidity and mortality in the critical care setting. It incurs great additional cost and the antibiotics prescribed for patients with VAP account for the majority of total antibiotic prescriptions. The increased cost of VAP as well as the emergence of antimicrobial resistance and the potential adverse events because of treatment indicate that the application of shorter antibiotic regimens for the treatment of VAP poses as a one-way choice. RECENT FINDINGS: According to the findings of relevant randomized controlled trials, patients receiving short-course regimens for the treatment of VAP have significantly more antibiotic-free days without any negative impact on mortality. Additionally, no other differences were found regarding other secondary outcomes. However, there were higher relapse rates in patients with VAP because of nonfermenting Gram-negative bacilli and there was a lower emergence of multidrug-resistant pathogens. SUMMARY: The shortening of the duration of treatment for VAP is promising, as long as a holistic approach that combines methods ensuring the adequate sterilization of septic foci, the optimization of antibiotic levels, the multifaceted delivery of antimicrobials in the lung and the usage of biomarkers that allow the monitoring of the disease course and the effectiveness of administered treatment are incorporated in clinical practice.

How to treat fungal infections in ICU patients.

Fungal infections represent a major burden in the critical care setting with increasing morbidity and mortality. Candidiasis is the leading cause of such infections, with C. albicans being the most common causative agent, followed by Aspergillosis and Mucormycosis. The diagnosis of such infections is cumbersome requiring increased clinical vigilance and extensive laboratory testing, including radiology, cultures, biopsies and other indirect methods. However, it is not uncommon for definitive evidence to be unavailable. Risk and host factors indicating the probability of infections may greatly help in the diagnostic approach. Timely and adequate intervention is important for their successful treatment. The available therapeutic armamentarium, although not very extensive, is effective with low resistance rates for the newer antifungal agents. However, timely and prudent use is necessary to maximize favorable outcomes.

Characteristics, risk factors and outcomes of carbapenem-resistant Klebsiella pneumoniae infections in the intensive care unit.

OBJECTIVE: To study the characteristics, risk factors and outcomes of intensive care unit (ICU) patients with carbapenem-resistant (CRKp) and carbapenem-susceptible (CSKp) Klebsiella pneumoniae infections. METHODS: A retrospective cohort of patients with K. pneumoniae infections in an eight-bed ICU between January 2006 and October 2009. RESULTS: During the study period, 104 patients were diagnosed with K. pneumoniae infection (80 CRKp and 24 CSKp). Isolation of CRKp increased gradually during the study period, while isolation of CSKp remained constant. The mean age of patients was 66.3 ± 14.3 years. The mean APACHE II score was 17.9 ± 6.9. The median duration of ICU stay until the infection was 15 days. Thirty five patients (33.7%) had primary and 30 (28.8%) had secondary bacteremia. Seventy-two patients (69.2%) died in the ICU. No independent risk factors for development of CRKp infections were identified in the multivariate analysis. Treatment failure (p = 0.001) was the only independent predictor of mortality in the multivariate analysis (APACHE II, shock, multi-organ failure, respiratory failure, acute renal failure, acidosis and extensive-drug resistance were included in the model). No difference in mortality was found between patients with CRKp and CSKp isolates. CONCLUSIONS: Infection due to K. pneumoniae in the ICU was associated with high mortality. Control of the infection was the most important determinant of the outcome of critically ill patients.

Short- vs long-duration antibiotic regimens for ventilator-associated pneumonia: a systematic review and meta-analysis.

BACKGROUND: We performed a systematic review and meta-analysis of short- vs long-duration antibiotic regimens for ventilator-associated pneumonia (VAP). METHODS: We searched PubMed and Cochrane Central Registry of Controlled Trials. Four randomized controlled trials (RCTs) comparing short (7-8 days) with long (10-15 days) regimens were identified. Primary outcomes included mortality, antibiotic-free days, and clinical and microbiologic relapses. Secondary outcomes included mechanical ventilation-free days, duration of mechanical ventilation, and length of ICU stay. RESULTS: All RCTs included mortality data, whereas data on relapse and antibiotic-free days were provided in three and two out of four RCTs, respectively. No difference in mortality was found between the compared arms (fixed effect model [FEM]: OR = 1.20; 95% CI, 0.84-1.72; P = .32). There was an increase in antibiotic-free days in favor of the short-course treatment with a pooled weighted mean difference of 3.40 days (random effects model: 95% CI, 1.43-5.37; P < .001). There was no difference in relapses between the compared arms, although a strong trend to lower relapses in the long-course treatment was observed (FEM: OR = 1.67; 95% CI, 0.99-2.83; P = .06). No difference was found between the two arms regarding the remaining outcomes. Sensitivity analyses yielded similar results. CONCLUSIONS: Short-course treatment of VAP was associated with more antibiotic-free days. No difference was found regarding mortality and relapses; however, a strong trend for fewer relapses was observed in favor of the long-course treatment, being mostly driven by one study in which the observed relapses were probably more microbiologic than clinical. Additional research is required to elucidate the issue.

An ESICM systematic review and meta-analysis of procalcitonin-guided antibiotic therapy algorithms in adult critically ill patients.

PURPOSE: We sought to perform a systematic review and meta-analysis of procalcitonin(PCT)-guided antibiotic therapy algorithms for critically ill adult patients. METHODS: We performed a search in PubMed and in the Cochrane Central Register of Controlled Trials. Seven evaluable randomised clinical trials (RCTs) were identified and analysed. Primary outcomes included the duration of antibiotic therapy for the first episode of infection and 28-day mortality. Secondary outcomes included length of ICU stay, length of hospitalisation, antibiotic-free days within the first 28 days of hospitalisation, recurrences, and superinfections. RESULTS: Data on the duration of antibiotic therapy for the first episode of infection were provided in five out of seven included RCTs, while data on 28-day mortality were provided in all of the included RCTs. Duration of antibiotic therapy for the first episode of infection was reduced in favour of PCT-guided treatment [pooled weighted mean difference (WMD) = -3.15 days, random effects model, 95 % confidence interval (CI) -4.36 to -1.95, P < 0.001]. There was no difference in 28-day mortality between the compared arms [fixed effect model (FEM), odds ratio = 0.96, 95 % CI 0.79-1.15, P = 0.63). Antibiotic-free days were increased within the first 28 days of hospitalisation in favour of the PCT-guided treatment arm (pooled WMD = 3.08 days, FEM, 95 % CI 2.06-4.10, P < 0.001). No difference was found regarding the remaining outcomes. Sensitivity analyses including studies of higher quality and studies using the TRACE method to measure PCT yielded similar results. CONCLUSIONS: Procalcitonin-guided antibiotic therapy algorithms could help in reducing the duration of antimicrobial administration without having a negative impact on survival.

Resistance to polymyxins: Mechanisms, frequency and treatment options.

Polymyxins act by binding to lipid A moiety of the bacterial lipopolysaccharide and subsequently disintegrating the bacterial membranes. The most important mechanism of resistance includes modifications of the bacterial outer membrane structure, including lipopolysaccharide. Lipopolysaccharide modification is mostly mediated by PmrA/PmrB and PhoP/PhoQ two-component regulatory systems. These mechanisms exist with some differences in many gram-negative bacterial species. Resistance to polymyxins is generally less than 10%. In specific regions, such as the Mediterranean basin, Korea and Singapore, they tend to be higher. Heteroresistance to polymyxins is associated with exposure to polymyxins and especially suboptimal therapeutic dosage. Polymyxin combination regimens, tigecycline and fosfomycin may be useful options for the treatment of polymyxin-resistant gram-negative infections.

Colistin therapy for microbiologically documented multidrug-resistant Gram-negative bacterial infections: a retrospective cohort study of 258 patients.

It is unclear whether the effectiveness of polymyxins depends on the site of infection, the responsible pathogen, dosage, and monotherapy vs. combination therapy. We investigated colistin therapy in a large, retrospective, single-centre, cohort study. Primary analysis outcomes were infection outcome, survival and nephrotoxicity. Over a 7-year period (October 2000 to October 2007), 258 patients received intravenous (i.v.) colistin for at least 72h for microbiologically documented multidrug-resistant Gram-negative bacterial infections, comprising 170 (65.9%) Acinetobacter baumannii, 68 (26.4%) Pseudomonas aeruginosa, 18 (7.0%) Klebsiella pneumoniae, 1 (0.4%) Stenotrophomonas maltophilia and 1 (0.4%) Enterobacter cloacae. Cure of infection occurred in 79.1% of patients, nephrotoxicity in 10% and hospital survival in 65.1%. In the multivariate analysis, independent predictors of survival were colistin average daily dose [adjusted odds ratio (aOR)=1.22, 95% confidence interval (CI) 1.05-1.42] and cure of infection (aOR=9, 95% CI 3.6-23.1), whilst the proportion of creatinine change (aOR=0.21, 95% CI 0.1-0.45), Acute Physiology and Chronic Health Evaluation (APACHE) II score (aOR=0.89, 95% CI 0.84-0.95) and haematological disease (aOR=0.23, 95% CI 0.08-0.66) were associated with mortality. Effectiveness of colistin was not dependent on the type of pathogen. No independent predictors for nephrotoxicity were observed. The findings of the largest cohort study to date on i.v. colistin show that colistin is a valuable antibiotic with acceptable nephrotoxicity and considerable effectiveness that depends on the daily dosage and infection site.

Meta-analysis on surgical infections.

Meta-analysis on surgical infections may be a useful tool that can provide more accurate outcome estimates than other conventional types of studies. Published meta-analyses in surgical infections tend to focus mainly on the use of antimicrobial prophylaxis and on the comparison of different procedures or techniques for the treatment of surgical infections. The majority concern surgical infections in abdominal surgery. However, mortality is reported as primary outcome in few meta-analyses. Meta-analyses focusing exclusively on surgical infections, reporting data on mortality as a primary outcome, and comparing different antibiotic regimens for the treatment of surgical infections should be conducted.

Effectiveness and safety of short vs. long duration of antibiotic therapy for acute bacterial sinusitis: a meta-analysis of randomized trials.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Treatment guidelines generally support that a 10-14-day antibiotic regimen should be administered to uncomplicated acute bacterial sinusitis patients. However, the level of evidence for such a recommendation is rather weak. Treatment of such duration may have disadvantages compared with a shorter duration but equally effective regimen, including the promotion of bacterial drug resistance, poorest patient compliance, higher toxicity, and a greater overall economic burden. WHAT THIS STUDY ADDS: The findings of this meta-analysis suggest that short-course antibiotic treatment has similar effectiveness to longer-course treatment for patients with acute uncomplicated bacterial sinusitis, when treatment is warranted. However, we should underscore the importance of the clinician's own assessment, so that antimicrobial therapy should not inappropriately be curtailed in a patient not adequately responding to the regimen administered. We sought to evaluate the effectiveness and safety of short-course antibiotic treatment for acute bacterial sinusitis (ABS) compared with longer duration treatment. We performed a meta-analysis of randomized controlled trials (RCTs), identified by searching PubMed and the Cochrane Central Register of Controlled Trials. We included RCTs that compared short-course (up to 7 days) vs. long-course therapy (> or =2 days longer than short-course), with the same antimicrobial agent, in the same daily dosage, for patients with ABS. Twelve RCTs (10 double-blinded) involving adult patients with radiologically confirmed ABS were included. There was no difference in the comparison of short-course (3-7 days) with long-course treatment (6-10 days) regarding clinical success [12 RCTs, 4430 patients, fixed effect model (FEM), odds ratio (OR) 0.95, 95% confidence interval (CI) 0.81, 1.12]; microbiological efficacy; relapses; adverse events (10 RCTs, 4172 patients, random effects model, OR 0.88, 95% CI 0.71, 1.09); or withdrawals due to adverse events. In the sensitivity analysis comparing 5- vs. 10-day regimens, clinical success was similar, although adverse events were fewer with short-course treatment (5 RCTs, 2151 patients, FEM, OR 0.79, 95% CI 0.63, 0.98). Although antibiotics for acute sinusitis should be reserved for select patients with substantial probability of bacterial disease, accurate clinical diagnosis is often difficult to attain. Short-course antibiotic treatment had comparable effectiveness to a longer course of therapy for ABS. Shortened treatment, particularly for patients without severe disease and complicating factors, might lead to fewer adverse events, better patient compliance, lower rates of resistance development and fewer costs.