Clinical outcome of wild-type AmpC-producing Enterobacterales infection in critically ill patients treated with ß-lactams: a prospective multicenter study.

BACKGROUND: ß-lactams are the main antibiotics used against wild-type AmpC-producing Enterobacterales (wtAE). However, they may fail or select AmpC-overproducing mutants. Our aim was to assess factors associated with clinical failure of ß-lactams in the treatment of wtAE infection. METHODS: From September 2017 to December 2020, we prospectively included all consecutive patients treated by definitive ß-lactams therapy for wtAE infection in four university ICUs. Clinical failure was defined as inadequate response to antimicrobial therapy leading to death or to the switch for a broader-spectrum antibiotic. RESULTS: 177 patients were included and 29.4% progressed to clinical failure. E. cloacae was the most prevalent species (42.4%) and ventilator-associated pneumonia (VAP) was the most frequent wtAE infection (69.5%). Cefepime and cefotaxime were used as definitive antibiotic treatment in 42.9% and 27.7% of patients, respectively. Occurrence of AmpC-overproduction was documented in 5.6% of patients and was associated with clinical failure (p = 0.004). In multivariate analysis, VAP (p < 0.001, OR 11.58 [95% CI 3.11-43.02] and K. aerogenes (p = 0.030, OR 3.76 [95% CI 1.13-12.46]) were independently associated with clinical failure. Conversely, cefotaxime as definitive treatment was found inversely associated with the risk of clinical failure (p = 0.022, OR 0.25 [95% CI 0.08-0.82]). After inverse probability weighting, cefotaxime showed a 20% risk reduction of clinical failure (95% CI 5-35%, p = 0.007) whatever the location of infection, the SOFA score on the day of wtAE infection, or the bacterial species. CONCLUSIONS: Clinical failure in the treatment of wtAE infections is associated with the infection site and the causal microorganism. Additionally, cefotaxime use is probably protective against clinical failure in wtAE infection.

Colorectal cancer-associated microbiota contributes to oncogenic epigenetic signatures.

Sporadic colorectal cancer (CRC) is a result of complex interactions between the host and its environment. Environmental stressors act by causing host cell DNA alterations implicated in the onset of cancer. Here we investigate the stressor ability of CRC-associated gut dysbiosis as causal agent of host DNA alterations. The epigenetic nature of these alterations was investigated in humans and in mice. Germ-free mice receiving fecal samples from subjects with normal colonoscopy or from CRC patients were monitored for 7 or 14 wk. Aberrant crypt foci, luminal microbiota, and DNA alterations (colonic exome sequencing and methylation patterns) were monitored following human feces transfer. CRC-associated microbiota induced higher numbers of hypermethylated genes in murine colonic mucosa (vs. healthy controls' microbiota recipients). Several gene promoters including SFRP1,2,3, PENK, NPY, ALX4, SEPT9, and WIF1 promoters were found hypermethylated in CRC but not in normal tissues or effluents from fecal donors. In a pilot study (n = 266), the blood methylation levels of 3 genes (Wif1, PENK, and NPY) were shown closely associated with CRC dysbiosis. In a validation study (n = 1,000), the cumulative methylation index (CMI) of these genes was significantly higher in CRCs than in controls. Further, CMI appeared as an independent risk factor for CRC diagnosis as shown by multivariate analysis that included fecal immunochemical blood test. Consequently, fecal bacterial species in individuals with higher CMI in blood were identified by whole metagenomic analysis. Thus, CRC-related dysbiosis induces methylation of host genes, and corresponding CMIs together with associated bacteria are potential biomarkers for CRC.

Durability of antimicrobial activity of antibiotic-impregnated external ventricular drains: a prospective study.

BACKGROUND: Antibiotic-impregnated external ventricular drains (AI-EVDs) have a debated efficacy in clinical studies. OBJECTIVES: Our aim was to assess the durability of antimicrobial activity of AI-EVDs used in clinical settings. METHODS: From April 2017 to January 2018, all consecutive AI-EVDs (Bactiseal™) inserted in adult patients were prospectively included. After removal, each AI-EVD was cultured and assessed for antimicrobial activity on both internal and external sides of AI-EVDs. Catheters were each challenged with a single Staphylococcus strain [MSSA, MRSA or methicillin-resistant Staphylococcus epidermidis (MRSE)]. MS was used to measure residual concentrations of rifampicin and clindamycin. RESULTS: Sixty-five AI-EVDs were included (56 patients). Among these, 21 were challenged with MSSA, 23 with MRSA and 21 with MRSE. Five ventriculostomy-related colonizations (9%) and two ventriculostomy-related infections (4%) occurred. Staphylococcus was the main bacterium responsible for colonization (4/5). AI-EVD inhibition decreased significantly against MRSA and MRSE according to duration of catheterization (for external and internal sides, P < 0.02) and overall volume of CSF drained (P < 0.005 for both sides against MRSE, P < 0.005 for external side against MRSA), but not against MSSA. Clindamycin concentration was not correlated with duration of catheterization or CSF volume drained, but <20% of initial concentration was recovered even after 5 days of AI-EVD dwelling. Conversely, rifampicin concentration showed a rapid and significant decline correlated to duration and CSF volume (P < 0.001 and P = 0.03, respectively). CONCLUSIONS: Antimicrobial activity of AI-EVDs dropped quickly in vivo. Antimicrobial impregnation did not prevent AI-EVD colonization by susceptible strains in 9% of the cases.

Prediction of Early Intracranial Hypertension After Severe Traumatic Brain Injury: A Prospective Study.

OBJECTIVE: This study aimed to assess the reliability of clinical features, noninvasive transcranial Doppler-related pulsatility index (PI) calculation, and optic nerve sheath diameter (ONSD) measured by ultrasound (US) and initial computed tomography (CT) scan (Marshall CT scan classification) in predicting the occurrence of early (<24 hours) high intracranial pressure (EHICP) (>20 mm Hg) after severe traumatic brain injury (TBI). METHODS: We conducted an observational prospective study in a level 1 trauma center. Patients were measured simultaneously for PI and US ONSD in the triage zone. Patients were categorized into 2 groups: those who had EHICP after TBI (EHICP+) and those who did not (EHICP-). RESULTS: Fifty-four patients were included; 32 were categorized as EHICP+ and 22 as EHICP-. PI >1.4 did not correlate with EHICP+ patients (69% vs. 46%, P = 0.09). US ONSD measurement was higher in the EHICP+ group (6.25; range, 6-6.95 vs. 5.7; range, 5.2-6.4; P = 0.005). The area under the receiver operating characteristic curve for US ONSD as a predictor of developing EHICP was 0.73 (95% confidence interval [CI], 0.59-0.86). CT ONSD measurement was higher in the EHICP+ group (6.71; range, 6.35-7.87 vs. 6.25; range, 5.8-6.93; P = 0.04). The area under the receiver operating characteristic curve for CT ONSD measurement as a predictor for EHICP+ was 0.67 (95% CI, 0.53-0.81). The diffuse injury III and IV categories in the Marshall CT scan classification were associated with the occurrence of EHICP (P = 0.004). CONCLUSIONS: None of the clinical features or noninvasive tools assessed in this study enabled clinicians to strictly ascertain EHICP. Further studies are needed to establish their potential role before intracranial pressure probe insertion.

Multidrug-Resistant Acinetobacter baumannii Ventriculostomy-Related Infection, Treated by a Colistin, Tigecycline, and Intraventricular Fibrinolysis.

BACKGROUND: Acinetobacter baumannii meningitis and ventriculitis are difficult issues, because of the low diffusion of antibiotics in the cerebrospinal fluid and bacterial multidrug resistance. The presence of an infected intraventricular hematoma, constituting an equivalent of undrained abscess, may promote biofilm formation and failure of medical treatment. CASE DESCRIPTION: In this case of ventriculostomy-related infection after ventricular hemorrhage, Acinetobacter baumannii was sensitive only to colistin and tigecycline. Despite a combination therapy involving intraventricular injections of colistin, we observed clinical and bacteriologic failure. Therefore, at day 4 of antibiotic therapy, we performed intraventricular fibrinolysis, which dissolved the clot, enabling sterilization of the cerebrospinal fluid after 48 hours. CONCLUSION: This clinical case suggests the usefulness of intraventricular fibrinolysis to lyse the clot and optimize the action of antibiotics.

Natural history of ventriculostomy-related infection under appropriate treatment and risk factors of poor outcome: a retrospective study.

OBJECTIVEThe authors aimed to describe the natural history of ventriculostomy-related infections (VRIs) under appropriate treatment and to assess risk factors for poor outcome.METHODSAll patients older than 18 years in whom an external ventricular drain (EVD) had been implanted and who had developed a VRI requiring treatment were included in this retrospective study. D0 was defined as the first day of antibiotic administration. Clinical and biological parameters were compared each day beginning with D1 and ending with D10 to those of D0. The authors defined D0 in a control group as the day a CSF culture came back positive, without any sign of infection. The authors then searched for poor prognostic factors in the VRI group.RESULTSAmong 567 patients requiring an EVD between January 2007 and October 2017, 39 developed a VRI. Most were monomicrobial infections, and 47 microbes were responsible (45% were gram-positive cocci). Clinical parameters differed significantly from the control group during the first 2 days and then returned to baseline. The CSF parameters differed significantly from the control group for a longer period, returning to baseline after 5 days. CSF sterilization occurred in a median time of 2 days. An intrathecal route or EVD exchange was not associated with a poor outcome. No clinical or biological parameter between D3 and D5 was linked to outcome.CONCLUSIONSClinical status improved faster than CSF parameters (before and after D5, respectively). Some CSF parameters remained abnormal until D10. Body temperature and microbiological cultures normalized faster than other parameters.

Determinants of Transcutaneous Ear Lobe CO2 Tension (PtCO2) at 37°C During On-Pump Cardiac Surgery.

OBJECTIVE: There are no available criteria for determining the optimal flow rate and mean arterial pressure level in patients undergoing cardiopulmonary bypass (CPB). Transcutaneous carbon dioxide tension (PtCO2) has been proposed for microcirculation monitoring and it could be useful for guiding hemodynamic optimization under CPB. The goal of this exploratory study was to determine the factors that influence PtCO2 variations during CPB. DESIGN: Cutaneous ear lobe CO2 tension was monitored along with hemodynamic parameters every 10 minutes during CPB, until aortic unclamping. SETTING: French university teaching hospital. PARTICIPANTS: Patients scheduled for cardiac surgery requiring CPB were prospectively included. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: A total of 41 patients were included (520 observations). There was a statistically significant association between PaCO2 and PtCO2 (beta = 0.493 [0.154-0.832], p = 0.043), mostly when PaCO2 was outside the normal range. When PaCO2 was normal, PtCO2 was inversely correlated with mean arterial pressure (after adjustment for PaCO2 and body temperature: Beta -0.245, SE = 0.037, p<0.001) but not with CPB flow rate (p = 0.11). CONCLUSION: The factors that influence PtCO2 during CPB cardiac surgery are PaCO2, body temperature, and mean arterial pressure. When PaCO2 is normal, a PtCO2 elevation might be explained by insufficient mean arterial pressure. Whether low PtCO2 values during CPB should trigger the administration of vasoconstrictors remains to be evaluated.