Philippe Eggimann

Epidemiology of Candida species infections in critically ill non-immunosuppressed patients

A substantial proportion of patients become colonised with Candida spp during hospital stay, but only few subsequently develop severe infection. Clinical signs of severe infection manifest early but lack specificity until late in the course of the disease, thus representing a particular challenge for diagnosis. Mostly nosocomial, invasive candidiasis occurs in only 1-8% of patients admitted to hospitals, but in around 10% of patients housed in intensive care units where it can represent up to 15% of all nosocomial infections. We review the epidemiology of invasive candidiasis in non-immunocompromised, critically ill patients with special emphasis on disease trends over time, pathophysiology, diagnostic approach, risk factors, and impact. Recent epidemiological data suggesting that the emergence of non-albicans candida strains with reduced susceptibility to azoles, previously linked to the use of new antifungals for empiric and prophylactic therapy in immunocompromised patients, may not have occurred in the critically ill. Management of invasive candidiasis in these patients will be addressed in the December issue of The Lancet Infectious Diseases.

Impact of a prevention strategy targeted at vascular-access care on incidence of infections acquired in intensive care.

BACKGROUND Intravascular devices are a leading cause of nosocomial infection. Specific prevention strategies and improved guidelines for the use of intravascular devices can decrease the rate of infection; however, the impact of a combination of these strategies on rates of vascular-access infection in intensive-care units (ICUs) is not known. We implemented a multiple-approach prevention programme to decrease the occurrence of vascular-access infection in an 18-bed medical ICU at a tertiary centre. METHODS 3154 critically ill patients, admitted between October, 1995, and November, 1997, were included in a cohort study with longitudinal assessment of an overall catheter-care policy targeted at the reduction of vascular-access infections and based on an educational campaign for vascular-access insertion and on device use and care. Incidence of ICU-acquired infections was measured by means of on-site surveillance. FINDINGS 613 infections occurred in 353 patients (19.4 infections per 100 admissions). The incidence density of exit-site catheter infection was 9.2 episodes per 1000 patient-days before the intervention, and 3.3 episodes per 1000 patient-days afterwards (relative risk 0.36 [95% CI 0.20-0.63]). Corresponding rates for bloodstream infection were 11.3 and 3.8 episodes per 1000 patient-days, respectively (0.33 [0.20-0.56]) due to decreased rates of both microbiologically documented infections and clinical sepsis. Rates of respiratory and urinary-tract infections remained unchanged, whereas those of skin or mucous-membrane infections decreased from 11.4 to 7.0 episodes per 1000 patient-days (0.62 [0.41-0.93]). Overall, the incidence of nosocomial infections decreased from 52.4 to 34.0 episodes per 1000 patient-days (0.65 [0.54-0.78]). INTERPRETATION A multiple-approach prevention strategy, targeted at the insertion and maintenance of vascular access, can decrease rates of vascular-access infections and can have a substantial impact on the overall incidence of ICU-acquired infections.

Epidemiology of Candidemia in Swiss Tertiary Care Hospitals: Secular Trends, 1991–2000

Candida species are among the most common bloodstream pathogens in the United States, where the emergence of azole-resistant Candida glabrata and Candida krusei are major concerns. Recent comprehensive longitudinal data from Europe are lacking. We conducted a nationwide survey of candidemia during 1991-2000 in 17 university and university-affiliated hospitals representing 79% of all tertiary care hospital beds in Switzerland. The number of transplantations and bloodstream infections increased significantly (P<.001). A total of 1137 episodes of candidemia were observed: Candida species ranked seventh among etiologic agents (2.9% of all bloodstream isolates). The incidence of candidemia was stable over a 10-year period. C. albicans remained the predominant Candida species recovered (66%), followed by C. glabrata (15%). Candida tropicalis emerged (9%), the incidence of Candida parapsilosis decreased (1%), and recovery of C. krusei remained rare (2%). Fluconazole consumption increased significantly (P<.001). Despite increasing high-risk activities, the incidence of candidemia remained unchanged, and no shift to resistant species occurred.

Fluconazole prophylaxis prevents intra-abdominal candidiasis in high-risk surgical patients

OBJECTIVE To evaluate the efficacy and safety of intravenous fluconazole for the prevention of intra-abdominal Candida infections in high-risk surgical patients. DESIGN Randomized, prospective, double-blind, placebo-controlled study. SETTING Two university-affiliated hospitals in Switzerland. PATIENTS Forty-nine surgical patients with recurrent gastrointestinal perforations or anastomotic leakages. INTERVENTIONS Prophylaxis with intravenous fluconazole (400 mg per day) or placebo continued until resolution of the underlying surgical condition. MEASUREMENTS AND MAIN RESULTS Patients were evaluated daily, and specimens for culture were obtained three times per week during prophylaxis. The primary study end points were the frequency of and the time to intra-abdominal Candida infections. Secondary end points were the frequency of candidiasis (intra-abdominal and extra-abdominal) and the emergence or persistence of Candida colonization. Among patients who were not colonized at study entry, Candida was isolated from surveillance cultures during prophylaxis in 15% of the patients in the fluconazole group and in 62% of the patients in the placebo group (relative risk, 0.25; 95% confidence interval, 0.07 to 0.96; p = .04). Candida peritonitis occurred in one of 23 patients (4%) who received fluconazole and in seven of 20 patients (35%) who received placebo (relative risk, 0.12; 95% confidence interval, 0.02 to 0.93; p = .02). In addition, one catheter-related Candida albicans sepsis occurred in a fluconazole-treated patient. Thus, overall, candidiasis developed in two fluconazole patients and seven placebo patients (relative risk, 0.25; 95% confidence interval, 0.06 to 1.06; p = .06). C. albicans accounted for 87% of the Candida species isolated before or during prophylaxis, and all C. albicans strains were susceptible to fluconazole. Fluconazole was well tolerated, and adverse events occurred at similar frequencies in both treatment groups. CONCLUSIONS Fluconazole prophylaxis prevents colonization and invasive intra-abdominal Candida infections in high-risk surgical patients.

Management of candidiasis Management of Candida species infections in critically ill patients

Invasive candidiasis is a feared infection with mortality similar to that of septic shock (40-60%). Improved knowledge of its pathophysiology and the availability of new compounds for antifungal therapy and prophylaxis have contributed to improving the prognosis of severe candidal infections among immunosuppressed patients at the possible cost of the emergence of non-albicans strains of candida with lower susceptibility to azoles. This review focuses on the management of invasive deep-seated candidiasis in critically ill, non-immunocompromised patients. We discuss antifungal use, indications, potential benefit, and main secondary effects. Prevention strategies include pre-emptive antifungal therapy and azole-based prophylaxis. For patients at lower initial risk, pre-emptive therapy should be based on a management strategy that takes into account the presence of definite risk factors and the dynamics of candida colonisation. Among critically ill patients, azole prophylaxis is effective and is not associated with acquisition of resistance; it must be restricted to highly selected groups of patients at high risk only.

Procalcitonin for reduced antibiotic exposure in ventilator-associated pneumonia: a randomised study

In patients with ventilator-associated pneumonia (VAP), guidelines recommend antibiotic therapy adjustment according to microbiology results after 72 h. Circulating procalcitonin levels may provide evidence that facilitates the reduction of antibiotic therapy. In a multicentre, randomised, controlled trial, 101 patients with VAP were assigned to an antibiotic discontinuation strategy according to guidelines (control group) or to serum procalcitonin concentrations (procalcitonin group) with an antibiotic regimen selected by the treating physician. The primary end-point was antibiotic-free days alive assessed 28 days after VAP onset and analysed on an intent-to-treat basis. Procalcitonin determination significantly increased the number of antibiotic free-days alive 28 days after VAP onset (13 (2–21) days versus 9.5 (1.5–17) days). This translated into a reduction in the overall duration of antibiotic therapy of 27% in the procalcitonin group (p = 0.038). After adjustment for age, microbiology and centre effect, the rate of antibiotic discontinuation on day 28 remained higher in the procalcitonin group compared with patients treated according to guidelines (hazard rate 1.6, 95% CI 1.02–2.71). The number of mechanical ventilation-free days alive, intensive care unit-free days alive, length of hospital stay and mortality rate on day 28 for the two groups were similar. Serum procalcitonin reduces antibiotic therapy exposure in patients with ventilator associated pneumonia.

Prospective randomized comparison of imipenem monotherapy with imipenem plus netilmicin for treatment of severe infections in nonneutropenic patients.

Nosocomial pneumonia and sepsis, as well as severe diffuse peritonitis, must be treated early in order to prevent complications such as septic shock and organ dysfunctions. With the availability of new broad-spectrum and highly bactericidal antibiotics, the need of combining beta-lactams with aminoglycosides for the treatment of severe infections should be reassessed. A prospective randomized controlled study was performed to compare imipenem monotherapy with a combination of imipenem plus netilmicin in the empiric treatment of nosocomial pneumonia, nosocomial sepsis, and severe diffuse peritonitis. A total of 313 patients were enrolled, and 280 were assessable. The antibiotic treatment was successful in 113 of 142 patients (80%) given the monotherapy and in 119 of 138 patients (86%) given the combination (P = 0.19). The failure rates for the most important type of infection, i.e., pneumonia, were similar in the two groups, as well as the number of superinfections. While creatinine increase was associated with factors not related to antibiotic therapy for all eight patients of the monotherapy group, no factor other than the antibiotics could be found for 6 of the 14 cases of nephrotoxicity observed in the combination group (P = 0.014). Finally, the emergence of Pseudomonas aeruginosa resistant to imipenem occurred in 8 monotherapy patients and in 13 combination therapy patients. In conclusion, imipenem monotherapy appeared as effective as the combination of imipenem plus netilmicin for the treatment of severe infection. The addition of netilmicin increased nephrotoxicity, and it did not prevent the emergence of P. aeruginosa resistant to imipenem.

β-Glucan Antigenemia Anticipates Diagnosis of Blood Culture–Negative Intraabdominal Candidiasis

RATIONALE Life-threatening intraabdominal candidiasis (IAC) occurs in 30 to 40% of high-risk surgical intensive care unit (ICU) patients. Although early IAC diagnosis is crucial, blood cultures are negative, and the role of Candida score/colonization indexes is not established. OBJECTIVES The aim of this prospective Fungal Infection Network of Switzerland (FUNGINOS) cohort study was to assess accuracy of 1,3-β-d-glucan (BG) antigenemia for diagnosis of IAC. METHODS Four hundred thirty-four consecutive adults with abdominal surgery or acute pancreatitis and ICU stay 72 hours or longer were screened: 89 (20.5%) at high risk for IAC were studied (68 recurrent gastrointestinal tract perforation, 21 acute necrotizing pancreatitis). Diagnostic accuracy of serum BG (Fungitell), Candida score, and colonization indexes was compared. MEASUREMENTS AND MAIN RESULTS Fifty-eight of 89 (65%) patients were colonized by Candida; 29 of 89 (33%) presented IAC (27 of 29 with negative blood cultures). Nine hundred twenty-one sera were analyzed (9/patient): median BG was 253 pg/ml (46-9,557) in IAC versus 99 pg/ml (8-440) in colonization (P < 0.01). Sensitivity and specificity of two consecutive BG measurements greater than or equal to 80 pg/ml were 65 and 78%, respectively. In recurrent gastrointestinal tract perforation it was 75 and 77% versus 90 and 38% (Candida score ≥ 3), 79 and 34% (colonization index ≥ 0.5), and 54 and 63% (corrected colonization index ≥ 0.4), respectively. BG positivity anticipated IAC diagnosis (5 d) and antifungal therapy (6 d). Severe sepsis/septic shock and death occurred in 10 of 11 (91%) and 4 of 11 (36%) patients with BG 400 pg/ml or more versus 5 of 18 (28%, P = 0.002) and 1 of 18 (6%, P = 0.05) with BG measurement less than 400 pg/ml. β-Glucan decreased in IAC responding to therapy and increased in nonresponse. CONCLUSIONS BG antigenemia is superior to Candida score and colonization indexes and anticipates diagnosis of blood culture-negative IAC. This proof-of-concept observation in strictly selected high-risk surgical ICU patients deserves investigation of BG-driven preemptive therapy.

Reduction of nosocomial pneumonia after major burns by trace element supplementation: aggregation of two randomised trials.

IntroductionNosocomial pneumonia is a major source of morbidity and mortality after severe burns. Burned patients suffer trace element deficiencies and depressed antioxidant and immune defences. This study aimed at determining the effect of trace element supplementation on nosocomial or intensive care unit (ICU)-acquired pneumonia.MethodsTwo consecutive, randomised, double-blinded, supplementation studies including two homogeneous groups of 41 severely burned patients (20 placebo and 21 intervention) admitted to the burn centre of a university hospital were combined. Intervention consisted of intravenous trace element supplements (copper 2.5 to 3.1 mg/day, selenium 315 to 380 μg/day, and zinc 26.2 to 31.4 mg/day) for 8 to 21 days versus placebo. Endpoints were infections during the first 30 days (predefined criteria for pneumonia, bacteraemia, wound, urine, and other), wound healing, and length of ICU stay. Plasma and skin (study 2) concentrations of selenium and zinc were determined on days 3, 10, and 20.ResultsThe patients, 42 ± 15 years old, were burned on 46% ± 19% of body surface: the combined characteristics of the patients did not differ between the groups. Plasma trace element concentrations and antioxidative capacity were significantly enhanced with normalisation of plasma selenium, zinc, and glutathione peroxidase concentrations in plasma and skin in the trace element-supplemented group. A significant reduction in number of infections was observed in the supplemented patients, which decreased from 3.5 ± 1.2 to 2.0 ± 1.0 episodes per patient in placebo group (p < 0.001). This was related to a reduction of nosocomial pneumonia, which occurred in 16 (80%) patients versus seven (33%) patients, respectively (p < 0.001), and of ventilator-associated pneumonia from 13 to six episodes, respectively (p = 0.023).ConclusionEnhancing trace element status and antioxidant defences by selenium, zinc, and copper supplementation was associated with a decrease of nosocomial pneumonia in critically ill, severely burned patients.

Nosocomial Bloodstream Infection and Clinical Sepsis

Primary bloodstream infection (BSI) is a leading, preventable infectious complication in critically ill patients and has a negative impact on patients’ outcome. Surveillance definitions for primary BSI distinguish those that are microbiologically documented from those that are not. The latter is known as clinical sepsis, but information on its epidemiologic importance is limited. We analyzed prospective on-site surveillance data of nosocomial infections in a medical intensive care unit. Of the 113 episodes of primary BSI, 33 (29%) were microbiologically documented. The overall BSI infection rate was 19.8 episodes per 1,000 central-line days (confidence interval [CI] 95%, 16.1 to 23.6); the rate fell to 5.8 (CI 3.8 to 7.8) when only microbiologically documented episodes were considered. Exposure to vascular devices was similar in patients with clinical sepsis and patients with microbiologically documented BSI. We conclude that laboratory-based surveillance alone will underestimate the incidence of primary BSI and thus jeopardize benchmarking.