De-escalation of antimicrobial therapy in ICU settings with high prevalence of multidrug-resistant bacteria: a multicentre prospective observational cohort study in patients with sepsis or septic shock.

BACKGROUND: De-escalation of empirical antimicrobial therapy, a key component of antibiotic stewardship, is considered difficult in ICUs with high rates of antimicrobial resistance. OBJECTIVES: To assess the feasibility and the impact of antimicrobial de-escalation in ICUs with high rates of antimicrobial resistance. METHODS: Multicentre, prospective, observational study in septic patients with documented infections. Patients in whom de-escalation was applied were compared with patients without de-escalation by the use of a propensity score matching by SOFA score on the day of de-escalation initiation. RESULTS: A total of 262 patients (mean age 62.2 ± 15.1 years) were included. Antibiotic-resistant pathogens comprised 62.9%, classified as MDR (12.5%), extensively drug-resistant (49%) and pandrug-resistant (1.2%). In 97 (37%) patients de-escalation was judged not feasible in view of the antibiotic susceptibility results. Of the remaining 165 patients, judged as patients with de-escalation possibility, de-escalation was applied in 60 (22.9%). These were matched to an equal number of patients without de-escalation. In this subset of 120 patients, de-escalation compared with no de-escalation was associated with lower all-cause 28 day mortality (13.3% versus 36.7%, OR 0.27, 95% CI 0.11-0.66, P = 0.006); ICU and hospital mortality were also lower. De-escalation was associated with a subsequent collateral decrease in the SOFA score. Cox multivariate regression analysis revealed de-escalation as a significant factor for 28 day survival (HR 0.31, 95% CI 0.14-0.70, P = 0.005). CONCLUSIONS: In ICUs with high levels of antimicrobial resistance, feasibility of antimicrobial de-escalation was limited because of the multi-resistant pathogens isolated. However, when de-escalation was feasible and applied, it was associated with lower mortality.

Bloodstream infections and sepsis in Greece: over-time change of epidemiology and impact of de-escalation on final outcome.

BACKGROUND: Choice of empirically prescribed antimicrobials for sepsis management depends on epidemiological factors. The epidemiology of sepsis in Greece was studied in two large-periods. METHODS: Sepsis due to bloodstream infections (BSI) from July 2006 until March 2013 was recorded in a multicenter study in 46 departments. Patients were divided into sepsis admitted in the emergencies and hospitalized in the general ward (GW) and sepsis developing after admission in the Intensive Care Unit (ICU). The primary endpoints were the changes of epidemiology and the factors related with BSIs by multidrug-resistant (MDR) pathogens; the secondary endpoint was the impact of de-escalation on antimicrobial therapy. RESULTS: 754 patients were studied; 378 from 2006-2009 and 376 from 2010-2013. Major differences were recorded between periods in the GW. They involved increase of: sepsis severity; the incidence of underlying diseases; the incidence of polymicrobial infections; the emergence of Klebsiella pneumoniae as a pathogen; and mortality. Factors independently related with BSI by MDR pathogens were chronic hemofiltration, intake of antibiotics the last three months and residence into long-term care facilities. De-escalation in BSIs by fully susceptible Gram-negatives did not affect final outcome. Similar epidemiological differences were not found in the ICU; MDR Gram-negatives predominated in both periods. CONCLUSIONS: The epidemiology of sepsis in Greece differs in the GW and in the ICU. De-escalation in the GW is a safe strategy.

Invasive fungal infections in the ICU: how to approach, how to treat.

Invasive fungal infections are a growing problem in critically ill patients and are associated with increased morbidity and mortality. Most of them are due to Candida species, especially Candida albicans. Invasive candidiasis includes candidaemia, disseminated candidiasis with deep organ involvement and chronic disseminated candidiasis. During the last decades rare pathogenic fungi, such as Aspergillus species, Zygomycetes, Fusarium species and Scedosporium have also emerged. Timely diagnosis and proper treatment are of paramount importance for a favorable outcome. Besides blood cultures, several laboratory tests have been developed in the hope of facilitating an earlier detection of infection. The antifungal armamentarium has also been expanded allowing a treatment choice tailored to individual patients' needs. The physician can choose among the old class of polyenes, the older and newer azoles and the echinocandins. Factors related to patient's clinical situation and present co-morbidities, local epidemiology data and purpose of treatment (prophylactic, pre-emptive, empiric or definitive) should be taken into account for the appropriate choice of antifungal agent.

Severe mold fungal infections in critically ill patients with COVID-19.

The SARS-CoV-2 pandemic put an unprecedented strain on modern societies and healthcare systems. A significantly higher incidence of invasive fungal co-infections was noted compared with the pre-COVID-19 era, adding new diagnostic and therapeutic challenges in the critical care setting. In the current narrative review, we focus on invasive mold infections caused by Aspergillus and Mucor species in critically ill COVID-19 patients. We discuss up-to-date information on the incidence, pathogenesis, diagnosis and treatment of these mold-COVID-19 co-infections, as well as recommendations on preventive and prophylactic interventions. Traditional risk factors were often not recognized in COVID-19-associated aspergillosis and mucormycosis, highlighting the role of other determinant risk factors. The associated patient outcomes were worse compared with COVID-19 patients without mold co-infection.

Colistin methanesulfonate and colistin pharmacokinetics in critically ill patients receiving continuous venovenous hemodiafiltration.

This report describes the pharmacokinetics of colistin methanesulfonate (CMS) and colistin in five intensive care unit patients receiving continuous venovenous hemodiafiltration. For CMS, the mean maximum concentration of drug in plasma (C(max)) after the fourth dose was 6.92 mg/liter and total clearance (CL) 8.23 liters/h. For colistin, the mean concentration was 0.92 mg/liter and CL/metabolized fraction (f(m)) 18.91 liters/h. Colistin concentrations were below the current MIC breakpoints, and the area under the concentration-time curve for the free, unbound fraction of the drug over 24 h in the steady state divided by the MIC (fAUC/MIC) was lower than recommended, suggesting that a dosage regimen of 160 mg CMS every 8 h (q8h) is inadequate.

Relative fecal abundance of extended-spectrum-ß-lactamase-producing Escherichia coli strains and their occurrence in urinary tract infections in women.

Extended-spectrum-beta-lactamase (ESBL)-producing Escherichia coli (ESBL E. coli) strains are of major concern because few antibiotics remain active against these bacteria. We investigated the association between the fecal relative abundance (RA) of ESBL-producing E. coli (ESBL-RA) and the occurrence of ESBL E. coli urinary tract infections (UTIs). The first stool samples passed after suspicion of UTI from 310 women with subsequently confirmed E. coli UTIs were sampled and tested for ESBL-RA by culture on selective agar. Predictive values of ESBL-RA for ESBL E. coli UTI were analyzed for women who were not exposed to antibiotics when the stool was passed. ESBL E. coli isolates were characterized for ESBL type, phylogroup, relatedness, and virulence factors. The prevalence of ESBL E. coli fecal carriage was 20.3%, with ESBL E. coli UTIs being present in 12.3% of the women. The mean ESBL-RA (95% confidence interval [CI]) was 13-fold higher in women exposed to antibiotics at the time of sampling than in those not exposed (14.3% [range, 5.6% to 36.9%] versus 1.1% [range, 0.32% to 3.6%], respectively; P < 0.001) and 18-fold higher in women with ESBL E. coli UTI than in those with another E. coli UTI (10.0% [range, 0.54% to 100%] versus 0.56% [range, 0.15% to 2.1%[, respectively; P < 0.05). An ESBL-RA of <0.1% was 100% predictive of a non-ESBL E. coli UTI. ESBL type, phylogroup, relatedness, and virulence factors were not found to be associated with ESBL-RA. In conclusion, ESBL-RA was linked to the occurrence of ESBL E. coli UTI in women who were not exposed to antibiotics and who had the same clone of E. coli in urine samples and fecal samples. Especially, a low ESBL-RA appeared to be associated with a low risk of ESBL E. coli infection.

Severe Candida infections in critically ill patients with COVID-19.

The frequency of co-infections with bacterial or fungal pathogens has constantly increased among critically ill patients with coronavirus disease 2019 (COVID-19) during the pandemic. Candidemia was the most frequently reported invasive fungal co-infection. The onset of candidemia in COVID-19 patients was often delayed compared to non-COVID-19 patients. Additionally, Candida invasive infections in COVID-19 patients were more often linked to invasive procedures (e.g., invasive mechanical ventilation or renal replacement therapy) during the intensive care stay and the severity of illness rather than more "classic" risk factors present in patients without COVID-19 (e.g., underlying diseases and prior hospitalization). Moreover, apart from the increased incidence of candidemia during the pandemic, a worrying rise in fluconazole-resistant strains was reported, including a rise in the multidrug-resistant Candida auris. Regarding outcomes, the development of invasive Candida co-infection had a negative impact, increasing morbidity and mortality compared to non-co-infected COVID-19 patients. In this narrative review, we present and critically discuss information on the diagnosis and management of invasive fungal infections caused by Candida spp. in critically ill COVID-19 patients.

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.

Novel Antimicrobial Agents for Gram-Negative Pathogens.

Gram-negative bacterial resistance to antimicrobials has had an exponential increase at a global level during the last decades and represent an everyday challenge, especially for the hospital practice of our era. Concerted efforts from the researchers and the industry have recently provided several novel promising antimicrobials, resilient to various bacterial resistance mechanisms. There are new antimicrobials that became commercially available during the last five years, namely, cefiderocol, imipenem-cilastatin-relebactam, eravacycline, omadacycline, and plazomicin. Furthermore, other agents are in advanced development, having reached phase 3 clinical trials, namely, aztreonam-avibactam, cefepime-enmetazobactam, cefepime-taniborbactam, cefepime-zidebactam, sulopenem, tebipenem, and benapenem. In this present review, we critically discuss the characteristics of the above-mentioned antimicrobials, their pharmacokinetic/pharmacodynamic properties and the current clinical data.

A life-threatening case of disseminated nocardiosis due to Nocardia brasiliensis.

Nocardiosis is a rare disease caused by infection with Nocardia species, aerobic actinomycetes with a worldwide distribution. A rare life-threatening disseminated Nocardia brasiliensis infection is described in an elderly, immunocompromised patient. Microorganism was recovered from bronchial secretions and dermal lesions, and was identified using molecular assays. Prompt, timely diagnosis and appropriate treatment ensured a favorable outcome.

The Effect of Different Colistin Dosing Regimens on Nephrotoxicity: A Cohort Study.

(1) Background: It is not known whether different daily dosing schemes have different effects on colistin nephrotoxicity. We examined the effect of once- versus twice- or thrice-daily doses of colistin on renal function. (2) Methods: We performed a multicenter retrospective cohort study of hospitalized patients with a baseline glomerular filtration rate ≥ 50 mL/min who received intravenously the same colistin dose once (regimen A), twice (regimen B) or thrice daily (regimen C). The primary endpoint was acute kidney injury (AKI), defined as fulfilment of any of the RIFLE (Risk-Injury-Failure-Loss-End stage renal disease) criteria. (3) Results: We included 306 patients; 132 (43.1%) received regimen A, 151 (49.3%) regimen B, and 23 (7.5%) regimen C. Ninety-nine (32.4%) patients developed AKI; there was no difference between regimen A vs. B and C [45 (34.1%) vs. 54 (31.0%), p = 0.57]. In a propensity score−matched cohort, AKI was similar in patients receiving Regimen A, Regimen B, and Regimen C (31.6% vs. 33.3%, p = 0.78). On logistic regression analysis, diabetes was an independent predictor of AKI (OR = 4.59, 95% CI 2.03−10.39, p = 0.001) while eGFR > 80 mL/min (OR = 0.50, 95% CI 0.25−0.99, p = 0.048) was inversely associated with AKI. (4) Conclusions: Colistin once daily is not more nephrotoxic than the standard colistin regimens. The only independent predictor of nephrotoxicity was diabetes mellitus, while eGFR > 80 mL/min had a protective effect.

ESCAPE: An Open-Label Trial of Personalized Immunotherapy in Critically lll COVID-19 Patients.

BACKGROUND: Macrophage activation-like syndrome (MALS) and complex immune dysregulation (CID) often underlie acute respiratory distress (ARDS) in COVID-19. We aimed to investigate the effect of personalized immunotherapy on clinical improvement of critical COVID-19. METHODS: In this open-label prospective trial, 102 patients with ARDS by SARS-CoV-2 were screened for MALS (ferritin >4,420 ng/mL) and CID (ferritin ≤4,420 ng/mL and low human leukocyte antigen (HLA)-DR expression on CD14-monocytes). Patients with MALS or CID with increased aminotransferases received intravenous anakinra; those with CID and normal aminotransferases received tocilizumab. The primary outcome was ≥25% decrease in the Sequential Organ Failure Assessment (SOFA) score and/or 50% increase in the respiratory ratio by day 8; 28-day mortality, change of SOFA score by day 28, serum biomarkers, and cytokine production by mononuclear cells were secondary endpoints. RESULTS: The primary study endpoint was met in 58.3% of anakinra-treated patients and in 33.3% of tocilizumab-treated patients (p: 0.01). Most patients in both groups received dexamethasone as standard of care. No differences were found in secondary outcomes, mortality, and SOFA score changes. Ferritin decreased among anakinra-treated patients; interleukin-6, soluble urokinase plasminogen activator receptor, and HLA-DR expression increased among tocilizumab-treated patients. Survivors by day 28 who received anakinra were distributed to lower severity levels of the WHO clinical progression scale. Greater incidence of secondary infections was found with tocilizumab treatment. CONCLUSION: Immune assessment resulted in favorable anakinra responses among critically ill patients with COVID-19 and features of MALS.

Epidemiology and Incidence of COVID-19-Associated Pulmonary Aspergillosis (CAPA) in a Greek Tertiary Care Academic Reference Hospital.

INTRODUCTION: Invasive pulmonary aspergillosis is an emerging complication among intensive care unit (ICU) patients with COVID-19 (CAPA). In the present study, all CAPA cases during the first year of the pandemic were reviewed in critically ill patients at a 650-bed tertiary Greek COVID-19 reference hospital. METHODS: Data regarding patients admitted to the ICU of Attikon Hospital in Athens, Greece, between 22 March 2020 and 28 February 2021 with a positive PCR for SARS-CoV-2 infection were reviewed. Clinical and microbiological records were analysed including demographic, clinical, laboratory and radiological features, treatment and outcomes. CAPA was determined according to the recent 2020 ECMM/ISHAM definitions. RESULTS: A total of 179 patients were admitted in the ICU and 6 (3.3%) patients were diagnosed with CAPA (4 probable and 2 possible CAPA) with 5/6 with co-infection with multidrug-resistant (MDR) gram-negative pathogens. No patient had a history of immunosuppression. All suffered from acute respiratory distress syndrome. The median (range) time from intubation to diagnosis was 6 (1-14) days. Five patients had positive Aspergillus cultures in bronchial secretions (1 A. fumigatus, 1 A. flavus, 1 A. fumigatus + A. flavus, 1 A. fumigatus + A. terreus and 1 A. terreus) while culture was negative in one patient. All isolates were susceptible to antifungal drugs. Serum galactomannan (GM), pan-Aspergillus PCR and (1,3)-ß-D-glucan (BDG) were positive in 4/6 (67%), 5/6 (83%, 3/5 in two consecutive samples) and 4/6 (67%, in consecutive samples) patients, respectively. GM and PCR positive bronchial secretions had GM indices > 9.95 and PCR Ct < 34. All were treated with antifungal drugs with 5 out of 6 receiving isavuconazole. Mortality was 67% (4/6) with 1/4 attributed to CAPA (two died as a result of bacterial septic shock and one as a result of multiorgan failure). CONCLUSION: The incidence of CAPA in ICU patients was 3.3% and it was associated with approximately a 17% attributable mortality in the setting of MDR gram-negative pathogen co-infections.

Impact of an antibiotic restriction policy on the antibiotic resistance patterns of Gram-negative microorganisms in an Intensive Care Unit in Greece.

The purpose of this study was to investigate the influence of an antibiotic policy programme based on restriction of the empirical use of fluoroquinolones and ceftazidime on the susceptibilities of Gram-negative microorganisms in a general Intensive Care Unit (ICU). The epidemiology of infections caused by the predominant ICU pathogens, i.e. Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae, and their resistance patterns as well as antibiotic consumption were recorded for a 6-month period. An antibiotic restriction policy including ceftazidime and quinolones was applied. After an 18-month period of protocol application, the same parameters were recorded for another 6-month period. Consumption of restricted and overall antibiotics was reduced by 92.5% and 55.4%, respectively. Susceptibilities to ciprofloxacin of the three predominant infection-causing Gram-negative bacilli were significantly increased. Ceftazidime showed an increase in susceptibility only for P. aeruginosa. Similar rates of infectious episodes were recorded in the two periods and no differences were observed either in overall mortality or in ICU ecology as expressed by the type of microorganisms implicated in colonisation and/or infection. The reported data suggest that an antibiotic restriction policy can significantly reduce antimicrobial consumption and antimicrobial resistance rates, although the latter effect can be also influenced by the prevalent resistance mechanisms and the prevalence of imported resistance.

Reduction of Environmental Contamination With Multidrug-Resistant Bacteria by Copper-Alloy Coating of Surfaces in a Highly Endemic Setting.

OBJECTIVE To evaluate the efficacy of copper-coating in reducing environmental colonization in an intensive-care unit (ICU) with multidrug-resistant-organism (MDRO) endemicity DESIGN Interventional, comparative crossover trial SETTING The general ICU of Attikon University hospital in Athens, Greece PATIENTS Those admitted to ICU compartments A and B during the study period METHODS Before any intervention (phase 1), the optimum sampling method using 2 nylon swabs was validated. In phase 2, 6 copper-coated beds (ie, with coated upper, lower, and side rails) and accessories (ie, coated side table, intravenous [i.v.] pole stands, side-cart handles, and manual antiseptic dispenser cover) were introduced as follows: During phase 2a (September 2011 to February 2012), coated items were placed next to noncoated ones (controls) in both compartments A and B; during phase 2b (May 2012 to January 2013), all copper-coated items were placed in compartment A, and all noncoated ones (controls) in compartment B. Patients were randomly assigned to available beds. Environmental samples were cultured quantitatively for clinically important bacteria. Clinical and demographic data were collected from medical records. RESULTS Copper coating significantly reduced the percentage of colonized surfaces (55.6% vs 72.5%; P<.0001), the percentage of surfaces colonized by MDR gram-negative bacteria (13.8% vs 22.7%; P=.003) or by enterococci (4% vs 17%; P=.014), the total bioburden (2,858 vs 7,631 cfu/100 cm2; P=.008), and the bioburden of gram-negative isolates, specifically (261 vs 1,266 cfu/100 cm2; P=.049). This effect was more pronounced when the ratio of coated surfaces around the patient was increased (phase 2b). CONCLUSIONS Copper-coated items in an ICU setting with endemic high antimicrobial resistance reduced environmental colonization by MDROs. Infect Control Hosp Epidemiol 2017;38:765-771.

Association between infections caused by multidrug-resistant gram-negative bacteria and mortality in critically ill patients.

The incidence of gram-negative multidrug-resistant (MDR) bacterial pathogens is increasing in hospitals and particularly in the intensive care unit (ICU) setting. The clinical consequences of infections caused by MDR pathogens remain controversial. The purpose of this review is to summarize the available data concerning the impact of these infections on mortality in ICU patients. Twenty-four studies, conducted exclusively in ICU patients, were identified through PubMed search over the years 2000-2015. Bloodstream infection was the only infection examined in eight studies, respiratory infections in four and variable infections in others. Comparative data on the appropriateness of empirical antibiotic treatment were provided by only seven studies. In ten studies the presence of antimicrobial resistance was not associated with increased mortality; on the contrary, in other studies a significant impact of antibiotic resistance on mortality was found, though, sometimes, mediated by inappropriate antimicrobial treatment. Therefore, a direct association between infections due to gram-negative MDR bacteria and mortality in ICU patients cannot be confirmed. Sample size, presence of multiple confounders and other methodological issues may influence the results. These data support the need for further studies to elucidate the real impact of infections caused by resistant bacteria in ICU patients.

Acquisition of multidrug-resistant Pseudomonas aeruginosa in patients in intensive care units: role of antibiotics with antipseudomonal activity.

A matched case-control study was performed to identify risk factors for acquiring multidrug-resistant Pseudomonas aeruginosa (MDRPA) in intensive care unit (ICU) patients during a 2-year period. MDRPA was defined as P. aeruginosa with combined decreased susceptibility to piperacillin, ceftazidime, imipenem, and ciprofloxacin. Thirty-seven patients who were colonized or infected with MDRPA were identified, 34 of whom were matched with 34 control patients who had cultures that showed no growth of P. aeruginosa. Matching criteria were severity of illness and length of ICU stay, with each control patient staying in the ICU for at least as long as the time period between the corresponding case patient's admission to the ICU and the acquisition of MDRPA. Baseline demographic and clinical characteristics and the use of invasive procedures were similar for case patients and control patients. Multivariate analysis identified duration of ciprofloxacin treatment as an independent risk factor for MDRPA acquisition, whereas the duration of treatment with imipenem was of borderline significance. These data support a major role for the use of antibiotics with high antipseudomonal activity, particularly ciprofloxacin, in the emergence of MDRPA.

Yeast central nervous system infection in a critically ill patient: a case report.

INTRODUCTION: Invasive fungal infections are alarmingly common in intensive care unit patients; invasive fungal infections are associated with increased morbidity and mortality. Risk factors are the increased use of indwelling central venous catheters, the use of broad spectrum antibiotics, parenteral nutrition, renal replacement therapy and immunosuppression. Diagnosis of these infections might be complicated, requiring tissue cultures. In addition, therapy of invasive fungal infections might be difficult, given the rising resistance of fungi to antifungal agents. CASE PRESENTATION: We describe the case of a 28-year-old Greek man with yeast central nervous system infection. CONCLUSIONS: Difficult-to-treat fungal infections may complicate the clinical course of critically ill patients and render their prognosis unfavorable. This report presents a case that was rare and difficult to treat, along with a thorough review of the investigation and treatment of these kinds of fungal infections in critically ill patients.