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.

Emergence of sequence type 11 Klebsiella pneumoniae coproducing NDM-1 and VIM-1 metallo-ß-lactamases in a Greek hospital.

Sequence type 11 Klebsiella pneumoniae, coproducing NDM-1 and VIM-1 metallo-ß-lactamases, were isolated in a Greek hospital. blaNDM-1 was part of a Tn125 derivative, located on an ~90-kb plasmid similar to the NDM-1-encoding plasmid pB-3002cz. blaVIM-1 was located in an In-e541-like integron, carried on a multireplicon (IncA/C and IncR) plasmid of ~180kb.

Rapid dissemination of colistin and carbapenem resistant Acinetobacter baumannii in Central Greece: mechanisms of resistance, molecular identification and epidemiological data.

BACKGROUND: Colistin-resistant/carbapenem-resistant Acinetobacter baumannii is a significant challenge for antibiotic treatment and infection control policies. Since 2012, in Central Greece an increase of colistin/pan- resistant A. baumannii has occurred, indicating the need for further analysis. METHODS: A total of 86 colistin-resistant/carbapenem-resistant out of 1228 A. baumannii clinical isolates, consecutively collected between 2012 and 2014 in a tertiary Greek hospital of Central Greece, as well as one environmental isolate from surveillance cultures were studied. Molecular typing and mechanisms of resistance to colistin and to carbapenems were assessed, whereas, epidemiological and clinical data of the patients were reviewed. RESULTS: During the study period, the rate of colistin resistance gradually increased and reached 21.1 % in 2014. All colistin-resistant/carbapenem-resistant A. baumannii belonged to 3LST ST101 clone that corresponds to the international clonal lineage II. Carbapenem resistance was associated with the presence of bla oxa-23-like, while resistance to colistin probably correlated with G54E and R109H amino acid substitutions in PmrA and PmrC, respectively. CONCLUSIONS: Epidemiological data of the patients indicated that the first detection of colistin-resistant/carbapenem-resistant ST101 clone in the University Hospital of Larissa (UHL) was associated with a patient who previously had received colistin, while, the movement of the infected patients into the hospital probably resulted to its spread.

Intermittent recruitment with high-frequency oscillation/tracheal gas insufflation in acute respiratory distress syndrome.

In acute respiratory distress syndrome (ARDS), recruitment sessions of high-frequency oscillation (HFO) and tracheal gas insufflation (TGI) with short-lasting recruitment manoeuvres (RMs) may improve oxygenation and enable reduction of subsequent conventional mechanical ventilation (CMV) pressures. We determined the effect of adding HFO-TGI sessions to lung-protective CMV on early/severe ARDS outcome. We conducted a prospective clinical trial, subdivided into a first single-centre period and a second two-centre period. We enrolled 125 (first period, n = 54) patients with arterial oxygen tension (P(a,O(2)))/inspiratory oxygen fraction (F(I,O(2))) of <150 mmHg for >12 consecutive hours at an end-expiratory pressure of ≥ 8 cmH(2)O. Patients were randomly assigned to an HFO-TGI group (receiving HFO-TGI sessions with RMs, interspersed with lung-protective CMV; n = 61) or CMV group (receiving lung-protective CMV and RMs; n = 64). The primary outcome was survival to hospital discharge. Pre-enrolment ventilation duration was variable. During days 1-10 post-randomisation, P(a,O(2))/F(I,O(2))), oxygenation index, plateau pressure and respiratory compliance were improved in the HFO-TGI group versus the CMV group (p < 0.001 for group × time). Within days 1-60, the HFO-TGI group had more ventilator-free days versus the CMV group (median (interquartile range) 31.0 (0.0-42.0) versus 0.0 (0.0-23.0) days; p < 0.001), and more days without respiratory, circulatory, renal, coagulation and liver failure (p ≤ 0.003). Survival to hospital discharge was higher in the HFO-TGI group versus the CMV group (38 (62.3%) out of 61 versus 23 (35.9%) out of 64 subjects; p = 0.004). Intermittent recruitment with HFO-TGI and RMs may improve survival in early/severe ARDS.

Nosocomial MRSA pneumonia: data from recent clinical trials.

MRSA infections, especially pneumonia have been associated with considerable morbidity and mortality and the management of MRSA infections is considered as an issue of high priority for scientific societies. Many studies which have been published during the last 10 years have provided evidence for MRSA pneumonia epidemiology, diagnosis and treatment. The main regime of antibiotic treatment recommended for MRSA pneumonia is either vancomycin or linezolid. Despite its pK/pD superiority over vancomycin, linezolid has to date failed to show clear advantage over vancomycin in recent clinical trials.

Adjunctive therapies in severe pneumonia in critical care patients.

AIM: To review available evidence for the role of adjunctive therapies in severe pneumonia. METHODS: We focused on therapies that have attracted recently interest such as glucocorticosteroids (GCs), statins and recombinant activated protein-C. RESULTS: Experimental animal and human studies showed that GCs are able to modulate the inflammatory response and may offer a benefit in patients with severe sepsis. Randomized trials in pneumonia are few, mostly limited in septic shock and ARDS patients. Recombinant activated protein C is a potent anticoagulant and profibrinolytic enzyme which can inhibit the systemic inflammatory response. Available data, although limited, showed that activated protein C can reduce mortality in severe sepsis, especially in severe pneumonia due to S. Pneumoniae. Statins have pleiotropic properties which can affect the inflammatory cascade. The use of statins has been found to be associated with decreased mortality in some studies with pneumina whereas the use of statins was associated with increased risk of death in others. However, data come from observational or retrospective studies. CONCLUSION: Treatment with GCs may modulate the inflammatory response in critically ill patients with pneumonia but a clear effect of steroids on survival is debatable. The administration of GCs should be considered in patients with severe pneumonia when vasopressor dependent septic shock. Activated protein-C may be considered in patients with severe CAP or HAP and sepsis or organ failure. The role of statins in the management of severe pneumonia remains controversial until data from clinical trails will be available.

Pulmonary hypertension in COPD: pathophysiology and therapeutic targets.

The incidence of mild to moderate pulmonary hypertension (PH) is highly prevalent, reaching to 50% in advanced chronic obstructive pulmonary disease (COPD). However, a subpopulation (1-4% in most studies) with grim prognosis despite moderate airflow limitation, present with "out-of-proportion" severe PH, is arbitrarily defined by a mean PH ≥ 40 mmHg, at rest. The sequence of changes that lead to PH in COPD begins at early disease stages by the impairment of endothelial function, which is associated with impaired release of endothelium-derived vasodilating (nitric oxide, prostacyclin) and vasoconstrictive agents (endothelin-1) and imbalance among them. PH in COPD is caused by vasoconstriction and remodelling of pulmonary arteries, which is characterized by the intimal proliferation of poorly differentiated smooth muscle cells and the deposition of elastic and collagen fibres. Hypoxia, inflammation and toxic effects of cigarette smoke, independently or additively interacting, are confirmed factors leading to PH. To date, long-term supplemental oxygen remains the primary treatment in COPD patients with PH. The administration of new vasodilators (prostanoids, endothelin-1 receptor antagonists and phosphodiesterase-5 inhibitors) dedicated to idiopathic pulmonary arterial hypertension in the disproportionate subgroup of patients with "out-of-proportion" PH may be considered in the setting of clinical trials. The use of these drugs in COPD patients with PH < 40 mmHg may worsen gas exchange, and to date, has no proven benefit. Future treatments must target more directly pathogenetic mechanisms. Therefore, novel agents have been proposed and are under active investigation, including 5-HT receptor antagonists, Rho-kinase inhibitors, statins and stem cell therapy.

Pulmonary arterial hypertension in a patient with common variable immunodeficiency and unilateral bronchiectasis: Successful treatment with iloprost.

The present study describes a case of severe pulmonary arterial hypertension (PAH) associated with unilateral lung destruction due to bronchiectasis in a patient with common variable immunodeficiency (CVID). Initially, the patient's treatment included antibiotics, oral anticoagulants, diuretics, and immunoglobulin replacement therapy. However, the patient's condition improved significantly only after inhaled iloprost was administered. Three months later, his PAH was almost reversed. The hemodynamic response of our patient suggests that inhaled iloprost may have a role in the treatment of sustained PAH related to unilateral lung destruction.

Losartan controlled blood pressure and reduced left ventricular hypertrophy but did not alter arrhythmias in hypertensive men with preserved systolic function.

The effect of antihypertensive therapy on arrhythmias is controversial. An initial study in patients with chronic heart failure indicated that losartan, an angiotensin II receptor antagonist, may possess antiarrhythmic properties. However, the effect of AT1 receptor antagonists on arrhythmias of subjects with good systolic function has never been evaluated. Thirty-nine men with primary hypertension (18 without left ventricular hypertrophy [LVH], and 21 with LVH, aged 48.2 +/-8.6 and 50.5 +/-6.0 years, respectively), 15 healthy normotensive subjects (47.9 +/-8.5 years), and 14 highly trained athletes (34.1 +/-1.6 years) were studied. Transthoracic echocardiography and 24-hour Holter ambulatory monitoring were performed at baseline (without treatment). Hypertensive patients underwent the same examinations after 8 months of losartan administration. The prevalence and complexity of ventricular arrhythmias, and the frequency of supraventricular arrhythmias were increased in hypertensive patients with LVH compared to normotensive controls and athletes, at baseline. A similar significant reduction of blood pressure (BP) was noted in both groups of patients (p < 0.001). The LVH was reduced in hypertensives with LVH (the left ventricular mass index by 12%, the interventricular septum by 8.1%, the posterior wall by 7%, all p < 0.01). However, the arrhythmias did not change in either group of patients, even if all hypertensives were considered as 1 group. In conclusion, an 8-month course with losartan was effective in lowering BP and reducing LVH. However, the increased arrhythmias, which were registered in hypertensive patients with LVH at baseline, did not change.

Early gastrostomy reduces the rate of ventilator-associated pneumonia in stroke or head injury patients.

Presence of a nasogastric tube is a risk factor for the development of ventilator-associated pneumonia (VAP). Alternatively, gastrostomy can be used for administration of enteral feedings. To determine whether early performance of gastrostomy affects frequency of VAP, a randomised, controlled study was carried out in patients mechanically ventilated for stroke or head injury. In the gastrostomy group, patients underwent the procedure within 24 h of intubation. A nasogastric tube was inserted in controls. Individual subjects were studied for 3 weeks. In total, 20 subjects (mean age 48+/-15.2 yrs) were allocated to the gastrostomy group, and 21 to the control group (46.6+/-15.4 yrs). Of these groups, two (10%) and eight (38.1%) developed VAP, respectively. Four patients with gastrostomy and three controls did not complete the study (due to weaning from ventilatory support or death). After excluding these subjects, difference in VAP frequency persisted: two out of 16 subjects with gastrostomy had VAP (12.5%) versus eight out of 18 controls (44.4%). There were no differences in duration of hospitalisation or mortality between the two groups. In conclusion, in patients mechanically ventilated for stroke or head injury early gastrostomy is associated with a lower frequency of ventilator-associated pneumonia compared with a nasogastric tube.

Cirrhosis-related intrathoracic disease. Imaging features in 1038 patients.

BACKGROUND/AIMS: To describe imaging features of cirrhosis-related intrathoracic disease. METHODOLOGY: Chest CTs of 1038 cirrhotic patients (mean age 53 yrs; range, 17-79) were evaluated for: bronchoarterial ratio (BAR), arteriovenous malformations, interstitial opacities, emphysema, and pleural effusions. Lymphangiography, pulmonary angiography, cardiac ultrasound and scintigraphy were selectively performed. RESULTS: Mean BAR was 0.83+/-0.19. In two patients with hepatopulmonary syndrome (HPS), mean BAR was 0.55. HRCT detected interstitial lung opacities in 15 patients. Signs of fibrosis were seen in 7 (only two associated to biliary cirrhosis) and interstitial edema in 8. Accurate pattern recognition was achieved in 10/15 cases (66.6%). Of the 93 patients with emphysema only one had documented alpha1-AT deficiency (1.08%). Multiple type 1 vascular dilatations were visualized in two patients with HPS. Hepatic hydrothorax was present in 49 patients (4.72%); right-sided in 34 (69.4%), bilateral in 9 (18.4%) and left-sided in 6 (12.2%). Hepatic chylothorax was confirmed in 3 patients. Lymphangiography demonstrated the site of leakage and the engorged thoracic duct. CONCLUSIONS: CT can identify intrathoracic pathology associated with liver disease. Decreased BAR is highly specific for HPS. However, a multimodality approach is necessary to depict cases of liver origin.

Losartan reduces left ventricular hypertrophy proportionally to blood pressure reduction in hypertensives, but does not affect diastolic cardiac function.

In contrast to the well-recognized salutary effects of angiotensin-converting enzyme inhibition, the value of angiotensin II type I (ATl)-receptor blockade on left ventricular hypertrophy (LVH) is controversial. In addition, the data on the influence of this therapy on cardiac diastolic function are scarce. Thirty-nine patients with moderate primary hypertension, LVH, and normal systolic function received losartan, 50 to 100 mg daily. Transthoracic echocardiography was performed at baseline and after 6 months of treatment. Thirty-one patients completed and were included in the study (16 males, 61.1 +/- 1.0 years). The patients were divided into responders if mean blood pressure (BP) decreased > 5 mm Hg at the end of the study (20 patients) and non-responders (mean BP decrease < or = 5 mm Hg, 11 patients). The BP and the LVH were significantly reduced (systolic BP by 10.0%, diastolic BP 6.5%, mean BP 8.2%, left ventricular mass index [LVMI] 6.2%, interventricular septum 5.8%, posterior wall 3.0%) (p< or =0.02), attributed to the reduction of BP and LVH in responders; the LVH in non-responders did not alter with treatment. A significant correlation was noted between changes in BP and LVMI (r=0.60, p<0.001). The systolic cardiac function remained normal. The Doppler parameters usually used to assess the diastolic function of the LV (early diastolic filling velocity [E wave], late diastolic filling velocity [A wave], ratio of E/A waves, isovolumic relaxation time), which were abnormal at baseline, did not change with treatment. The size of the left atrium increased (p<0.05) at the end of the study. In conclusion, a 6-month course with losartan decreased BP and LVH. However, the LVH regression was rather associated with the reduction of the hemodynamic stimulus per se, than any trophic effect of the drug in the myocardium. The diastolic cardiac function remained abnormal with treatment.

Pulmonary hypertension, interstitial lung fibrosis, and lung iron deposition in thalassaemia major.

Although restrictive lung disease is the predominant abnormality of pulmonary function in patients with thalassaemia major (TM), its aetiology and its association with pulmonary hypertension (PH) detected in some patients with TM remains unknown. We report a patient with TM, iron overload, frequent pulmonary infections, and progressive severe precapillary PH over the previous 5 years. A severe restrictive pattern and interstitial lung fibrosis were revealed by pulmonary function tests and high resolution computed tomography, respectively. This presentation suggests that interstitial fibrosis may complicate lung involvement in TM and can significantly contribute to the development of PH.

Echocardiographic and ambulatory electrocardiographic findings in elite water-polo athletes.

The aim of this study was to investigate the echocardiographic and electrocardiographic findings in top water-polo athletes and test the hypothesis that their hearts exhibit dilatation associated with hypertrophy secondary to the mixed type (isotonic and isometric) of exercise they are subjected to. Eighteen athletes of the Greek national water-polo team and 15 healthy sedentary men serving as controls were studied. All underwent an echocardiogram, a standard 12-lead ECG and 24-h ECG monitoring. In athletes, as compared to healthy controls, an increase was detected in the following indices: left ventricular (LV) end-diastolic diameter index (EDDI-LV) (by 10%; P = 0.02), interventricular septal thickness (IVS) (by 32%; P<0.001), thickness of the posterior wall (PW) (by 29%; P<0.001), relative wall thickness (IVS + PW/EDD-LV) (by 12%; P < 0.001) and LV mass index (by 82%; P < 0.001). Mild asymmetric thickening of the septum (IVS/PW = 1.40 and 1.37) was measured in two athletes. LV fractional shortening was normal. Standard 12-lead ECG abnormalities (LV hypertrophy or abnormal repolarization pattern) were observed in 33% of athletes. Athletes had sinus bradycardia during day and night, respiratory arrhythmia (RA) (83% vs 40% of controls; P = 0.03) and sinus pauses (SP) (39% vs 0% of controls; P = 0.02), with occassional arrhythmias and conduction abnormalities. We conclude that top water-polo athletes have dilatation combined with substantial hypertrophy and normal systolic function of the LV In addition they present bradycardia, RA and SP, with occassional arrhythmias and conduction abnormalities.