Clinical factors affecting costs in patients receiving systemic antifungal therapy in intensive care units in Greece: Results from the ESTIMATOR study.

Invasive fungal infections are common in intensive care units (ICUs) but there is a great variability in factors affecting costs of different antifungal treatment strategies in clinical practice. To determine factors affecting treatment cost in adult ICU patients with or without documented invasive fungal infection receiving systemic antifungal therapy (SAT) we have performed a prospective, multicentre, observational study enrolling patients receiving SAT in participating ICUs in Greece. During the study period, 155 patients received SAT at 14 participating ICUs: 37 (23.9%) for proven fungal infection before treatment began, 10 (6.5%) prophylactically, 77 (49.7%) empirically and 31 (20.0%) pre-emptively; 66 patients receiving early SAT (55.9%) were subsequently confirmed to have proven infection with Candida spp. (eight while on treatment). The most frequently used antifungal drugs were echinocandins (89/155; 57.4%), fluconazole (31/155; 20%) and itraconazole (20/155; 12.9%). Mean total cost per patient by SAT strategy was €20 458 (proven), €15 054 (prophylaxis), €23 594 (empiric) and €22 184 (pre-emptive). Factors associated with significantly increased cost were initial treatment failure, length of stay (LOS) in ICU before starting SAT (i.e. from admission until treatment start), fever and proven candidaemia (all P≤.05). CONCLUSION: Early administration of antifungal drugs was not a substantial component of total hospital costs. However, there was a significant adverse impact on costs with increasing LOS in febrile patients in ICU for whom diagnosis of fungaemia was delayed before starting SAT, and with initial treatment failure. Awareness of potential candidaemia and initiation of pre-emptive or empirical strategy as early appropriate treatment may improve ICU patient outcomes while reducing direct medical costs.

Validation of the new Sepsis-3 definitions: proposal for improvement in early risk identification.

OBJECTIVES: Sepsis-3 definitions generated controversies regarding their general applicability. The Sepsis-3 Task Force outlined the need for validation with emphasis on the quick Sequential Organ Failure Assessment (qSOFA) score. This was done in a prospective cohort from a different healthcare setting. METHODS: Patients with infections and at least two signs of systemic inflammatory response syndrome (SIRS) were analysed. Sepsis was defined as total SOFA ≥2 outside the intensive care unit (ICU) or as an increase of ICU admission SOFA ≥2. The primary endpoints were the sensitivity of qSOFA outside the ICU and sepsis definition both outside and within the ICU to predict mortality. RESULTS: In all, 3346 infections outside the ICU and 1058 infections in the ICU were analysed. Outside the ICU, respective mortality with ≥2 SIRS and qSOFA ≥2 was 25.3% and 41.2% (p <0.0001); the sensitivities of qSOFA and of sepsis definition to predict death were 60.8% and 87.2%, respectively. This was 95.9% for sepsis definition in the ICU. The sensitivity of qSOFA and of ≥3 SIRS criteria for organ dysfunction outside the ICU was 48.7% and 72.5%, respectively (p <0.0001). Misclassification outside the ICU with the 1991 and Sepsis-3 definitions into stages of lower severity was 21.4% and 3.7%, respectively (p <0.0001) and 14.9% and 3.7%, respectively, in the ICU (p <0.0001). Adding arterial pH ≤7.30 to qSOFA increased sensitivity for prediction of death to 67.5% (p 0.004). CONCLUSIONS: Our analysis positively validated the use of SOFA score to predict unfavourable outcome and to limit misclassification into lower severity. However, qSOFA score had inadequate sensitivity for early risk assessment.

Improving outcomes of severe infections by multidrug-resistant pathogens with polyclonal IgM-enriched immunoglobulins.

The emergence of infections by multidrug-resistant (MDR) Gram-negative bacteria, which is accompanied by considerable mortality due to inappropriate therapy, led to the investigation of whether adjunctive treatment with one polyclonal IgM-enriched immunoglobulin preparation (IgGAM) would improve outcomes. One hundred patients in Greece with microbiologically confirmed severe infections by MDR Gram-negative bacteria acquired after admission to the Intensive Care Unit and treated with IgGAM were retrospectively analysed from a large prospective multicentre cohort. A similar number of patient comparators well-matched for stage of sepsis, source of infection, appropriateness of antimicrobials and co-morbidities coming from the same cohort were selected. All-cause 28-day mortality was the primary end point; mortality by extensively drug-resistant (XDR) pathogens and time to breakthrough bacteraemia were the secondary end points. Fifty-eight of the comparators and 39 of the IgGAM-treated cases died by day 28 (p 0.011). The OR for death under IgGAM treatment was 0.46 (95% CI 0.26-0.85). Stepwise regression analysis revealed that IgGAM was associated with favourable outcome whereas acute coagulopathy, cardiovascular failure, chronic obstructive pulmonary disease and chronic renal disease were associated with unfavourable outcome. Thirty-nine of 62 comparators (62.9%) were infected by XDR Gram-negative bacteria and died by day 28 compared with 25 of 65 cases treated with IgGAM (38.5%) (p 0.008). Median times to breakthrough bacteraemia were 4 days and 10 days, respectively (p <0.0001). Results favour the use of IgGAM as an adjunct to antimicrobial treatment for the management of septic shock caused by MDR Gram-negative bacteria. A prospective randomized trial is warranted.

Pefloxacin versus imipenem in the therapy of nosocomial lung infections of intensive care unit patients.

In a prospective open randomized trial pefloxacin (400 mg, iv, 8-hourly) and imipenem (1 g, iv, 8-hourly) were given for 5-30 days to 35 and 36 ICU patients, respectively, suffering from bronchopneumonia (54) or purulent bronchitis (17). All were spiking high fevers (greater than or equal to 39 degrees C) while 25 and 26 patients in the two groups were under mechanical ventilation. Underlying predisposing disorders, mainly chronic obstructive pulmonary disease, ischaemic heart disease, neurological diseases and traumatic lung injuries, were encountered in almost all. In appropriate bronchial secretion cultures, multiresistant Acinetobacter anitratus (40), Pseudomonas aeruginosa (25), various Enterobacteriaceae (17) and Staphylococcus aureus (6) were isolated. A successful clinical response, as proved by elimination of abnormal lung x-ray findings, temperature normalization and decreases in oxygen requirements, permitting weaning from mechanical ventilation and/or removal of nasotracheal intubation, was observed in 23 patients given pefloxacin (65.7%) and 19 patients given imipenem (52.8%). The differences in clinical outcome did not reach statistical significance. During therapy pathogens persisted in 9 (25.7%) patients given pefloxacin versus 18 (50%) given imipenem (P less than 0.05), while persisters developed resistance to pefloxacin and imipenem in seven and 12 patients, respectively (P less than 0.05). Tolerance was excellent for both antimicrobials. In the therapy of lung infections in ICU patients, pefloxacin when compared to imipenem was associated with more promising results, lower numbers of persisting pathogens and a lower incidence of resistance development.

Pefloxacin versus ceftazidime in the treatment of a variety of gram-negative-bacterial infections.

In a prospective open randomized trial, pefloxacin was given to 53 patients and ceftazidime was given to 50 patients suffering from bronchopneumonia (n = 29), deep soft tissue infection (n = 19), urinary tract infection (n = 28), chronic osteomyelitis in exacerbation (n = 15), chronic otitis media in exacerbation (n = 3), malignant external otitis (n = 3), abdominal abscess (n = 2), septic arthritis (n = 1), acute cholangitis (n = 1), bacterial endocarditis (n = 1), and subacute sinusitis (n = 1). Underlying aggravating factors coexisted in 45 and 41 patients in the pefloxacin and ceftazidime groups, respectively, with 32 and 33 infections characterized as nosocomial and severe in each group, respectively. Pefloxacin was given at a dose of 400 mg intravenously (i.v.) (n = 16) or per os (n = 23) every 8 or 12 h, as well as i.v. followed by per os (n = 14), for 7 to 180 days; and ceftazidime was given at 2 g i.v. every 8 h (n = 45) or 1 g intramuscularly every 8 h (n = 5) for 7 to 56 days. Pseudomonas aeruginosa and various members of the family Enterobacteriaceae predominated in culture specimens. Clinical cure was observed in 38 and 39 patients given pefloxacin and ceftazidime, respectively; 10 and 7 patients were improved; and in 5 and 4 patients treatment failed. Pathogen eradication was observed in 42 and 39 patients, respectively; persistence was observed in 8 and ll patients, respectively, followed by the emergence of resistance in five and four P. aeruginosa strains, respectively (P = not significant). With the exception of photosensitivity rash in seven patients given pefloxacin, all side effects observed in eight and three patients in the pefloxacin and ceftazidime groups, respectively (P < 0.01), were not important and were self-limited. It is concluded that pefloxacin is as effective as ceftazidime in moderate to severe gram-negative-bacterial infections, with similar trends toward development of resistance during therapy.