Lila Bouadma

Predictors of insufficient amikacin peak concentration in critically ill patients receiving a 25 mg/kg total body weight regimen

PurposeAmikacin requires pharmacodynamic targets of peak serum concentration (Cmax) of 8–10 times the minimal inhibitory concentration, corresponding to a target Cmax of 60–80xa0mg/L for the less susceptible bacteria. Even with new dosing regimens of 25xa0mg/kg, 30xa0% of patients do not meet the pharmacodynamic target. We aimed to identify predictive factors for insufficient Cmax in a population of critically ill patients.MethodsProspective observational monocentric study of patients admitted to a general ICU and requiring a loading dose of amikacin. Amikacin was administered intravenously at the dose of 25xa0mg/kg of total body weight. Independent determinants of Cmaxxa0<xa060xa0mg/L were identified by mixed model multivariate analysis.ResultsOver a 1-year period, 181 episodes in 146 patients (SAPS 2xa0=xa051 [41–68]) were included. At inclusion, the SOFA score was 8 [6–12], 119 (66xa0%) episodes required vasopressors, 150 (83xa0%) mechanical ventilation, and 81 (45xa0%) renal replacement therapy. The amikacin Cmax was 69 [54.9–84.4] mg/L. Overall, 60 (33xa0%) episodes had a Cmaxxa0<xa060xa0mg/L. The risk of Cmaxxa0<xa060xa0mg/L associated with BMIxa0<xa025xa0kg/m2 varied across quarters of inclusion. Independent risk factors for Cmaxxa0<xa060xa0mg/L were a BMIxa0<xa025xa0kg/m2 over the first quarter (odds ratio (OR) 15.95, 95xa0% confidence interval (CI) [3.68–69.20], pxa0<xa00.001) and positive 24-h fluid balance (OR per 250-mL increment 1.06, 95xa0% [CI 1.01–1.11], pxa0=xa00.018).ConclusionsDespite an amikacin dose of 25xa0mg/kg of total body weight, 33xa0% of patients still had an amikacin Cmaxxa0<xa060xa0mg/L. Positive 24-h fluid balance was identified as a predictive factor of Cmaxxa0<xa060xa0mg/L. When total body weight is used, low BMI tended to be associated with amikacin underdosing. These results suggest the need for higher doses in patients with a positive 24-h fluid balance in order to reach adequate therapeutic targets.

Continuous renal replacement therapy versus intermittent hemodialysis in intensive care patients: impact on mortality and renal recovery.

PurposeThe best renal replacement therapy (RRT) modality remains controversial. We compared mortality and short- and long-term renal recovery between patients treated with continuous RRT and intermittent hemodialysis.MethodsPatients of the prospective observational multicenter cohort database OUTCOMEREA™ were included if they underwent at least one RRT session between 2004 and 2014. Differences in patients’ baseline and daily characteristics between treatment groups were taken into account by using a marginal structural Cox model, allowing one to substantially reduce the bias resulting from confounding factors in observational longitudinal data analysis. The composite primary endpoint was 30-day mortality and dialysis dependency.ResultsAmong 1360 included patients with RRT, 544 (40.0xa0%) and 816 (60.0xa0%) were initially treated by continuous RRT and intermittent hemodialysis, respectively. At dayxa030, 39.6xa0% patients were dead. Among survivors, 23.8xa0% still required RRT. There was no difference between groups for the primary endpoint in global population (HR 1.00, 95xa0% CI 0.77–1.29; pxa0=xa00.97). In patients with higher weight gain at RRT initiation, mortality and dialysis dependency were significantly lower with continuous RRT (HR 0.54, 95xa0% CI 0.29–0.99; pxa0=xa00.05). Conversely, this technique appeared to be deleterious in patients without shock (HR 2.24, 95xa0% CI 1.24–4.04; pxa0=xa00.01). Six-month mortality and persistent renal dysfunction were not influenced by the RRT modality in patients with dialysis dependence at ICU discharge.ConclusionContinuous RRT did not appear to improve 30-day and 6-month patient outcomes. It seems beneficial for patients with fluid overload, but might be deleterious in the absence of hemodynamic failure.

Clinical spectrum and outcomes of patients with encephalitis requiring intensive care.

Our aim was to characterize the clinical profile, temporal changes and outcomes of patients with severe encephalitis.

Neurological complications of infective endocarditis: new breakthroughs in diagnosis and management.

Neurological complications are frequent in infective endocarditis (IE) and increase morbidity and mortality rates. A wide spectrum of neurological disorders may be observed, including stroke or transient ischemic attack, cerebral hemorrhage, mycotic aneurysm, meningitis, cerebral abscess, or encephalopathy. Most complications occur early during the course of IE and are a hallmark of left-sided abnormalities of native or prosthetic valves. Ischemic lesions account for 40% to 50% of IE central nervous system complications. Systematic brain MRI may reveal cerebral abnormalities in up to 80% of patients, including cerebral embolism in 50%, mostly asymptomatic. Neurological complications affect both medical and surgical treatment and should be managed by an experimented multidisciplinary team including cardiologists, neurologists, intensive care specialists, and cardiac surgeons. Oral anticoagulant therapy given to patients presenting with cerebral ischemic lesions should be replaced by unfractionated heparin for at least 2 weeks, with a close monitoring of coagulation tests. Recently published data suggest that after an ischemic stroke, surgery indicated for heart failure, uncontrolled infection, abscess, or persisting high emboli risk should not be delayed, provided that the patient is not comatose or has no severe deficit. Surgery should be postponed for 2 to 3 weeks for patients with intracranial hemorrhage. Endovascular treatment is recommended for cerebral mycotic aneurysms, if there is no severe mass effect. Recent data suggests that neurological failure, which is associated with the location and extension of brain injury, is a major determinant for short-term prognosis.

Impact of respiratory viruses in hospital-acquired pneumonia in the intensive care unit: A single-center retrospective study

n Abstractn n Backgroundn Data on the frequency and role of respiratory viruses (RVs) in hospital-acquired pneumonia (HAP) are still scarce.n n n Objectivesn We assessed the proportion of RVs and their impact on the outcome of hospital-acquired pneumonia (HAP) in the intensive care unit (ICU).n n n Study designn Cases of HAP were retrospectively selected among patients who underwent screening for RVs by multiplex PCR (mPCR) in the ICU of a French tertiary care hospital from May 2014 to April 2016. ICU length of stay and in-hospital mortality were compared between four groups defined according to the identified pathogens: virus only (V), virus/bacteria (V/B), bacteria only (B) and no pathogen (Neg). When available, previous mPCR was retrieved in order to assess possible chronic viral carriage.n n n Resultsn Overall, 95/999 (10%) ICU patients who underwent mPCR had HAP (V(17,18%), V/B(13,14%), B(60,63%), Neg(5,5%)). Median age was 61 years and 45 (47%) were immunocompromised. Influenza (27%) and rhinovirus (27%) were the most common RVs. V/B group had higher mortality rate than B and V groups (62% vs. 40% and 35%, p=0.3) and a significantly longer length of stay (31days (18–48)) than V group (5days (3–11), p=0.0002)) and B group (14.5days (5.5–25.5), p=0.007)). Among the 15 patients with available mPCR tests before viral HAP, seven were negative and eight were positive corresponding to long-term carriage of community-acquired viruses.n n n Discussionn RVs were detected in 32% of HAP patients who underwent mPCR. Two situations were encountered: (i) acute acquired viral infection; (ii) long-term viral carriage (mostly rhinovirus) especially in immunocompromised patients complicated by a virus/bacteria coinfection. The latter was associated with a longer length of stay and a trend toward a higher mortality.n n

Update on ventilator-associated pneumonia

Ventilator-associated pneumonia (VAP) is the most frequent life-threatening nosocomial infection in intensive care units. The diagnostic is difficult because radiological and clinical signs are inaccurate and could be associated with various respiratory diseases. The concept of infection-related ventilator-associated complication has been proposed as a surrogate of VAP to be used as a benchmark indicator of quality of care. Indeed, bundles of prevention measures are effective in decreasing the VAP rate. In case of VAP suspicion, respiratory secretions must be collected for bacteriological secretions before any new antimicrobials. Quantitative distal bacteriological exams may be preferable for a more reliable diagnosis and therefore a more appropriate use antimicrobials. To improve the prognosis, the treatment should be adequate as soon as possible but should avoid unnecessary broad-spectrum antimicrobials to limit antibiotic selection pressure. For empiric treatments, the selection of antimicrobials should consider the local prevalence of microorganisms along with their associated susceptibility profiles. Critically ill patients require high dosages of antimicrobials and more specifically continuous or prolonged infusions for beta-lactams. After patient stabilization, antimicrobials should be maintained for 7–8 days. The evaluation of VAP treatment based on 28-day mortality is being challenged by regulatory agencies, which are working on alternative surrogate endpoints and on trial design optimization.

Systematic overdosing of oxa- and cloxacillin in severe infections treated in ICU: risk factors and side effects

BackgroundOxacillin and cloxacillin are the most frequently used penicillins for the treatment of severe methicillin-susceptible Staphylococcus aureus infections in intensive care units (ICUs), especially endocarditis. International recommendations do not suggest any adaptation of the dosage in case of renal impairment. We wanted to assess the risk factors for overdosing in ICU and the related observed side effects.MethodsAll patients with a therapeutic drug monitoring of oxa- or cloxacillin between 2008 and 2014 were included. The target range of trough concentration for total antibiotic activity was considered to be 20–50xa0mg/L. Data concerning the infection, the given treatment, the renal function, and the attributed side effects of overdosing were collected. A logistic regression model was used to compute the measured trough concentrations.ResultsSixty-two patients were included in this study. We found a median trough plasma concentration of 134.3xa0mg/L (IQR 65.3–201xa0mg/L). Ten patients (16.1%) reached the target concentration; all other patients (83.9%) were overdosed. Eleven patients (17.7%) experienced neurological side effects attributed to a high antibiotic concentration, i.e. persistent coma and delirium. When adjusted on the dosage used, the risk of overdosing was significantly associated with a creatinine clearance <10xa0mL/min (with or without hemodialysis).ConclusionWith the suggested dose of 12xa0g/day for cloxacillin treatment in case of endocarditis and severe infections occurring in ICU, 83.9% of patients are largely overdosed. Considering the observed side effects, doses should be accurately monitored and reduced, particularly when renal replacement therapy is needed.

Chlorhexidine use in adult patients on ICU

Chlorhexidine (CHG) is a biguanide cationic antiseptic molecule, which has been incorporated into mouthwash solutions, dental gels, dressings, washcloths and central venous catheters (CVC). It has become the first-choice antiseptic to reduce healthcare-associated infections. However, the widespread use of CHG has raised concerns about increasing rates of resistance and cross-resistance to antibiotics. In this short review the antimicrobial characteristics of CHG including microbial resistance and its main clinical applications in ICU are presented.

Oral care with chlorhexidine: beware!

Pneumonia in hospitalized patients is usually induced by aspiration of oral pathogens into the lower respiratory system. Oral care with chlorhexidine for the prevention of pneumonia is an appealing alternative because it appears to be safe, effective, and less likely to select for antibiotic resistance than oropharyngeal or digestive decontamination [1, 2]. The evidence that chlorhexidine is safe and effective, however, may be less robust than it seems (Table 1). First, our perception that chlorhexidine oral care prevents ventilator-associated pneumonia (VAP) may be biased. While multiple meta-analyses of randomized controlled trials have reported lower VAP rates, this is not the case if one stratifies by blinding status [3]. Lower VAP rates are only present on meta-analysis of open label studies, not double-blind studies. This suggests a problem with ascertainment bias. Second, chlorhexidine can have adverse effects on the oral mucosa. Plantiga and colleagues, for example, documented erosive oral lesions, ulcerations, white/yellow plaques, and bleeding mucosa in 9.8% of patients treated with 2% oral chlorhexidine [4]. Fortunately, these lesions disappeared after stopping chlorhexidine. More disturbingly, two recent meta-analyses of randomized controlled trials and two observational studies have reported that oral chlorhexidine, paradoxically, may increase mortality risk [3, 5–7]. The mechanism leading to higher mortality rates is unclear, but it may be that some patients aspirate chlorhexidine and develop acute respiratory distress syndrome [8]. In addition, some patients may suffer allergic reactions, including anaphylaxis [9–11]. Finally, the presumption that oral care with chlorhexidine has no impact on resistance may be incorrect. Biocide and antibiotic efflux pump genes are present in bacteria and can confer resistance to chlorhexidine; widespread use of chlorhexidine may accelerate the spread of acquired resistance [12]. A recent study documented decreased susceptibility to chlorhexidine in a quarter of Escherichia coli isolates associated with pneumonia in ICU patients [13]. In an article recently published in Intensive Care Medicine, Deschepper et al. [14] add further concern that oral care with chlorhexidine may be harmful in some patients. These investigators performed a hospital-wide retrospective observational cohort analysis on the effects of chlorhexidine oral care on hospital mortality. They included 82,274 patients, of whom 11,138 (14%) received chlorhexidine. Thee results showed that oral chlorhexidine was associated with an increased risk of death (OR 2.92; 95% CI 2.62–3.26). The association was strongest in patients with the lowest baseline risk of death. The

Functional outcomes in adults with tuberculous meningitis admitted to the ICU: a multicenter cohort study

BackgroundTuberculous meningitis (TBM) is a devastating infection in tuberculosis endemic areas with limited access to intensive care. Functional outcomes of severe adult TBM patients admitted to the ICU in nonendemic areas are not known.MethodsWe conducted a retrospective multicenter cohort study (2004–2016) of consecutive TBM patients admitted to 12 ICUs in the Paris area, France. Clinical, biological, and brain magnetic resonance imaging (MRI) findings at admission associated with a poor functional outcome (i.e., a score of 3–6 on the modified Rankin scale (mRS) at 90xa0days) were identified by logistic regression. Factors associated with 1-year mortality were investigated by Cox proportional hazards modeling.ResultsWe studied 90 patients, of whom 61 (68%) had a score on the Glasgow Coma Scale ≤ 10 at presentation and 63 (70%) required invasive mechanical ventilation. Brain MRI revealed infarction and hydrocephalus in 38/75 (51%) and 25/75 (33%) cases, respectively. A poor functional outcome was observed in 55 (61%) patients and was independently associated with older age (adjusted odds ratio (aOR) 1.03, 95% CI 1.0–1.07), cerebrospinal fluid protein level ≥ 2xa0g/L (aOR 5.31, 95% CI 1.67–16.85), and hydrocephalus on brain MRI (aOR 17.2, 95% CI 2.57–115.14). By contrast, adjunctive steroids were protective (aOR 0.13, 95% CI 0.03–0.56). The multivariable adjusted hazard ratio of adjunctive steroids for 1-year mortality (47%, 95% CI 37%–59%) was 0.23 (95% CI 0.11–0.44). Among survivors at 1xa0year, functional independence (mRS of 0–2) was observed in 27/37 (73%, 95% CI 59%–87%) cases.ConclusionsA poor functional outcome in adult TBM patients admitted to the ICU in a nonendemic area is observed in 60% of cases and is independently associated with elevated cerebrospinal fluid protein level and hydrocephalus. Our data also suggest a protective effect of adjunctive steroids, with reduced disability and mortality, irrespective of immune status and severity of disease at presentation. One-year follow-up revealed functional independence in most survivors.