Antibiotic Therapy Strategies for Treating Gram-Negative Severe Infections in the Critically Ill: A Narrative Review.

INTRODUCTION: Not enough data exist to inform the optimal duration and type of antimicrobial therapy against GN infections in critically ill patients. METHODS: Narrative review based on a literature search through PubMed and Cochrane using the following keywords: "multi-drug resistant (MDR)", "extensively drug resistant (XDR)", "pan-drug-resistant (PDR)", "difficult-to-treat (DTR) Gram-negative infection," "antibiotic duration therapy", "antibiotic combination therapy" "antibiotic monotherapy" "Gram-negative bacteremia", "Gram-negative pneumonia", and "Gram-negative intra-abdominal infection". RESULTS: Current literature data suggest adopting longer (≥10-14 days) courses of synergistic combination therapy due to the high global prevalence of ESBL-producing (45-50%), MDR (35%), XDR (15-20%), PDR (5.9-6.2%), and carbapenemases (CP)/metallo-ß-lactamases (MBL)-producing (12.5-20%) Gram-negative (GN) microorganisms (i.e., Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumanii). On the other hand, shorter courses (≤5-7 days) of monotherapy should be limited to treating infections caused by GN with higher (≥3 antibiotic classes) antibiotic susceptibility. A general approach should be based on (i) third or further generation cephalosporins ± quinolones/aminoglycosides in the case of MDR-GN; (ii) carbapenems ± fosfomycin/aminoglycosides for extended-spectrum ß-lactamases (ESBLs); and (iii) the association of old drugs with new expanded-spectrum ß-lactamase inhibitors for XDR, PDR, and CP microorganisms. Therapeutic drug monitoring (TDM) in combination with minimum inhibitory concentration (MIC), bactericidal vs. bacteriostatic antibiotics, and the presence of resistance risk predictors (linked to patient, antibiotic, and microorganism) should represent variables affecting the antimicrobial strategies for treating GN infections. CONCLUSIONS: Despite the strategies of therapy described in the results, clinicians must remember that all treatment decisions are dynamic, requiring frequent reassessments depending on both the clinical and microbiological responses of the patient.

Acute kidney injury (AKI) in patients with Covid-19 infection is associated with ventilatory management with elevated positive end-expiratory pressure (PEEP).

BACKGROUND: Acute kidney injury (AKI) in Covid-19 patients admitted to the intensive care unit (ICU) is common, and its severity may be associated with unfavorable outcomes. Severe Covid-19 fulfills the diagnostic criteria for acute respiratory distress syndrome (ARDS); however, it is unclear whether there is any relationship between ventilatory management and AKI development in Covid-19 ICU patients. PURPOSE: To describe the clinical course and outcomes of Covid-19 ICU patients, focusing on ventilatory management and factors associated with AKI development. METHODS: Single-center, retrospective observational study, which assessed AKI incidence in Covid-19 ICU patients divided by positive end expiratory pressure (PEEP) tertiles, with median levels of 9.6 (low), 12.0 (medium), and 14.7 cmH2O (high-PEEP). RESULTS: Overall mortality was 51.5%. AKI (KDIGO stage 2 or 3) occurred in 38% of 101 patients. Among the AKI patients, 19 (53%) required continuous renal replacement therapy (CRRT). In AKI patients, mortality was significantly higher versus non-AKI (81% vs. 33%, p < 0.0001). The incidence of AKI in low-, medium-, or high-PEEP patients were 16%, 38%, and 59%, respectively (p = 0.002). In a multivariate analysis, high-PEEP patients showed a higher risk of developing AKI than low-PEEP patients (OR = 4.96 [1.1-21.9] 95% CI p < 0.05). ICU mortality rate was higher in high-PEEP patients, compared to medium-PEEP or low-PEEP patients (69% vs. 44% and 42%, respectively; p = 0.057). CONCLUSION: The use of high PEEP in Covid-19 ICU patients is associated with a fivefold higher risk of AKI, leading to higher mortality. The cause and effect relationship needs further analysis.

Therapeutic Drug Monitoring of Dalbavancin Treatment in Severe Necrotizing Fasciitis in 3 Critically Ill Patients: A Grand Round.

BACKGROUND: Dalbavancin, albeit indicated for the treatment of skin structure infections, is used for a much wider range of infections. This drug is characterized by a long half-life (more than 200 hours), a favorable safety profile, and an activity against a wide array of gram-positive organisms, including several strains of Staphylococci and Enterococci. METHODS: In this study, we presented 3 cases of critically ill patients treated with dalbavancin. All patients were therapeutically monitored for plasma dalbavancin concentrations; ultrafiltrate dalbavancin concentrations were assessed in a patient undergoing continuous renal-replacement therapy. Dalbavancin concentrations were measured using a validated liquid chromatographic method coupled with mass spectrometry. RESULTS: All 3 severely ill patients experiencing necrotizing fasciitis were successfully treated during the acute phase with dalbavancin. Dalbavancin clearance in patient 3 (0.334 L/h) was considerably increased compared with values measured in the other 2 patients (0.054 and 0.075 L/h) and with data reported in the literature (0.04-0.06 L/h). CONCLUSIONS: Our case reports presented preliminary evidence that dalbavancin can be considered a therapeutic option for necrotizing fasciitis in intensive care unit patients. The role of hypoalbuminemia during dalbavancin exposure merits further investigation.

On classifying sepsis heterogeneity in the ICU: insight using machine learning.

OBJECTIVES: Current machine learning models aiming to predict sepsis from electronic health records (EHR) do not account 20 for the heterogeneity of the condition despite its emerging importance in prognosis and treatment. This work demonstrates the added value of stratifying the types of organ dysfunction observed in patients who develop sepsis in the intensive care unit (ICU) in improving the ability to recognize patients at risk of sepsis from their EHR data. MATERIALS AND METHODS: Using an ICU dataset of 13 728 records, we identify clinically significant sepsis subpopulations with distinct organ dysfunction patterns. We perform classification experiments with random forest, gradient boost trees, and support vector machines, using the identified subpopulations to distinguish patients who develop sepsis in the ICU from those who do not. RESULTS: The classification results show that features selected using sepsis subpopulations as background knowledge yield a superior performance in distinguishing septic from non-septic patients regardless of the classification model used. The improved performance is especially pronounced in specificity, which is a current bottleneck in sepsis prediction machine learning models. CONCLUSION: Our findings can steer machine learning efforts toward more personalized models for complex conditions including sepsis.

The effect of prolonged steep head-down laparoscopy on the optical nerve sheath diameter.

Both the steep head-down position and pneumoperitoneum increase the intracranial pressure (ICP), and their combination for a prolonged period during laparoscopic radical prostatectomy (LRP) might influence the central nervous system homeostasis. Changes in optic nerve sheath diameter (ONSD) may reflect those in ICP. This study aims to quantify the change in ONSD in response to peritoneal CO2 insufflation and steep Trendelenburg position during LRP. ONSD was measured by ultrasound in 20 patients undergoing LRP and ten awake healthy volunteers. In patients, ONSD was assessed at baseline immediately after induction of general anesthesia in supine position, 10 and 60 min from baseline in a 25° head-down position during pneumoperitoneum, and after deflation of pneumoperitoneum with the patient supine at 0° angle. ONSD in controls was assessed at baseline with the patient lying supine, after 10 and 60 min of 25° head-down position, and 10 min after repositioning at 0° angle. ONSD increased significantly in both patients and controls (p < 0.0001) without between-group differences. The mean increase was 10.3% (95% CI 7.7-12.9%) in patients versus 7.5% (95% CI 2.5-12.6%) in controls (p = 0.28), and didn't affect the time to recovery from anesthesia. In the studied patients, with a limited increase of end-tidal CO2 and airway pressure, and low volume fluid infusion, the maximal ONSD was always below the cut-off value suspect for increased ICP. ONSD reflects the changes in hydrostatic pressure in response to steep Trendelenburg position, and its increase might be minimized by careful handling of general anesthesia.

Perioperative serum brain natriuretic peptide and cardiac troponin in elective intracranial surgery.

BACKGROUND: There are some intracranial insults which are associated with cardiac abnormalities. Studies of these abnormalities have never been carried out in elective intracranial neurosurgery for the removal of brain tumors. Our prospective study aims at quantifying serum cardiac troponin T (cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) before and after elective intracranial neurosurgery for tumor resection in patients with no history of cardiac abnormality. METHODS: Pre- and postoperative serum cTnT and NT-proBNP were measured in 108 patients submitted to elective major intracranial surgery for the removal of neoplastic lesions. We tested potentially predictive models for these biomarker serum levels. RESULTS: cTnT was undetectable both before and after surgery. Median (IQR) basal NT-proBNP was 35 (18-69) pg/mL and 110 (51-191) pg/mL after surgery. In a multiple linear regression model, basal NT-proBNP was predicted by age, gender, BMI, and the presence of "mass effect" (midline shift or effaced perimesencephalic cisterns on preoperative CT scan) (whole model P < 0.0001; R (2) = 0.3502; and Adjusted R (2) = 0.3247). Postoperative NT-proBNP increase was predicted by baseline NT-proBNP level (whole model P < 0.0001; R (2) = 0.5106; and Adjusted R (2) = 0.5052). CONCLUSION: An intracranial mass effect is associated with higher NT-proBNP serum levels in patients with a brain neoplasm. Following elective intracranial surgery for brain tumor resection NT-proBNP values increase.