Argyris Michalopoulos

Colistin therapy for microbiologically documented multidrug-resistant Gram-negative bacterial infections: a retrospective cohort study of 258 patients

It is unclear whether the effectiveness of polymyxins depends on the site of infection, the responsible pathogen, dosage, and monotherapy vs. combination therapy. We investigated colistin therapy in a large, retrospective, single-centre, cohort study. Primary analysis outcomes were infection outcome, survival and nephrotoxicity. Over a 7-year period (October 2000 to October 2007), 258 patients received intravenous (i.v.) colistin for at least 72h for microbiologically documented multidrug-resistant Gram-negative bacterial infections, comprising 170 (65.9%) Acinetobacter baumannii, 68 (26.4%) Pseudomonas aeruginosa, 18 (7.0%) Klebsiella pneumoniae, 1 (0.4%) Stenotrophomonas maltophilia and 1 (0.4%) Enterobacter cloacae. Cure of infection occurred in 79.1% of patients, nephrotoxicity in 10% and hospital survival in 65.1%. In the multivariate analysis, independent predictors of survival were colistin average daily dose [adjusted odds ratio (aOR)=1.22, 95% confidence interval (CI) 1.05-1.42] and cure of infection (aOR=9, 95% CI 3.6-23.1), whilst the proportion of creatinine change (aOR=0.21, 95% CI 0.1-0.45), Acute Physiology and Chronic Health Evaluation (APACHE) II score (aOR=0.89, 95% CI 0.84-0.95) and haematological disease (aOR=0.23, 95% CI 0.08-0.66) were associated with mortality. Effectiveness of colistin was not dependent on the type of pathogen. No independent predictors for nephrotoxicity were observed. The findings of the largest cohort study to date on i.v. colistin show that colistin is a valuable antibiotic with acceptable nephrotoxicity and considerable effectiveness that depends on the daily dosage and infection site.

Continuous versus intermittent intravenous administration of antibiotics: a meta-analysis of randomised controlled trials

Intermittent intravenous administration of antibiotics is the first-line approach in the management of severe infections worldwide. However, the potential benefits of alternate modes of administration of antibiotics, including continuous intravenous infusion, deserve further evaluation. We did a meta-analysis of randomised controlled trials comparing continuous intravenous infusion with intermittent intravenous administration of the same antibiotic regimen. Nine randomised controlled trials studying beta-lactams, aminoglycosides, and vancomycin were included. Clinical failure was lower, although without statistical significance, in patients receiving continuous infusion of antibiotics (pooled OR 0.73, 95% CI 0.53-1.01); the difference was statistically significant in a subset of randomised controlled trials that used the same total daily antibiotic dose for both intervention arms (0.70, 0.50-0.98, fixed and random effects models). Regarding mortality and nephrotoxicity, no differences were found (mortality 0.89, 0.48-1.64; nephrotoxicity 0.91, 0.56-1.47). In conclusion, the data suggest that the administration of the same total antibiotic dose by continuous intravenous infusion may be more efficient, with regard to clinical effectiveness, compared with the intermittent mode. In an era of gradually increasing resistance among most pathogens, the potential advantages of continuous intravenous administration of antibiotics on several clinical outcomes should be further investigated.

Inhaled colistin as adjunctive therapy to intravenous colistin for the treatment of microbiologically documented ventilator-associated pneumonia: a comparative cohort study.

Ventilator-associated pneumonia (VAP) as a result of multidrug-resistant Gram-negative bacteria has contributed to the revival of the use of intravenous (i.v.) colistin. However, the additional administration of inhaled colistin for VAP is controversial. We performed a retrospective cohort study of patients with microbiologically documented VAP who received i.v. colistin with or without inhaled colistin. Seventy-eight patients with VAP received i.v. plus inhaled colistin, whereas 43 patients received i.v. colistin alone. The mean +/- SD daily dosage of i.v. colistin was 7.0 +/- 2.4 and 6.4 +/- 2.3 million international units (IU), respectively (p 0.13); the average daily dosage of inhaled colistin was 2.1 +/- 0.9 million IU. The outcome of infection was cure for 62/78 (79.5%) patients who received i.v. plus inhaled colistin vs. 26/43 (60.5%) patients who received i.v. colistin alone (p 0.025); all-cause in-hospital mortality was 31/78 (39.7%) vs. 19/43 (44.2%), respectively (p 0.63); all-cause intensive care unit (ICU) mortality was 28/78 (35.9%) vs. 17/43 (39.5%), respectively (p 0.92). The use of inhaled colistin was independently associated with the cure of VAP in a multivariable analysis (OR 2.53, 95% CI 1.11-5.76). Independent predictors of mortality were a higher APACHE II score (OR 1.12, 95% CI 1.04-1.20), presence of malignancy (OR 4.11, 95% CI 1.18-14.23) and lower daily dosage of i.v. colistin (OR 0.81, 95% CI 0.68-0.96). The outcome of VAP was better in patients who received inhaled colistin with i.v. colistin than those who received i.v. colistin alone. There was no difference in all-cause in-hospital and ICU mortality between the two groups. Randomized controlled trials are needed to evaluate further the role of inhaled colistin in VAP.

Fluconazole versus itraconazole for antifungal prophylaxis in neutropenic patients with haematological malignancies: a meta‐analysis of randomised‐controlled trials

Fluconazole and itraconazole are used as antifungal prophylaxis in neutropenic patients with haematological malignancies. A meta‐analysis of randomised‐controlled trials (RCTs) was performed in order to compare their safety and effectiveness in this population. Data were obtained from PubMed, Current Contents, Cochrane Central Register for Controlled Trials and references from relevant articles. Five RCTs were included in the analysis. Publication bias and statistically significant heterogeneity was not observed among the analysed studies. Fewer patients were withdrawn due to the development of adverse effects associated with fluconazole when compared with itraconazole [odds ratio (OR)u2003=u20030·27, 95% confidence interval (CI): 0·18–0·41]. On the contrary, prophylactic use of fluconazole resulted in significantly more fungal infections (documented and suspected infections combined, ORu2003=u20031·62, 95% CI: 1·06–2·48). There were no statistically significant differences regarding documented fungal infections (ORu2003=u20031·51, 95% CI: 0·97–2·35), invasive fungal infections (ORu2003=u20031·44, 95% CI: 0·96–2·17), overall mortality (ORu2003=u20030·89, 95% CI: 0·63–1·24) and mortality attributed by the authors to fungal infections (ORu2003=u20031·30, 95% CI: 0·75–2·25) between the two medications. These data suggest that, even though itraconazole is more effective than fluconazole in the prevention of fungal infections in neutropenic patients with haematological malignancies, the development of more adverse effects may limit its use.

Colistin: recent data on pharmacodynamics properties and clinical efficacy in critically ill patients

Recent clinical studies performed in a large number of patients showed that colistin forgotten for several decades revived for the management of infections due to multidrug-resistant (MDR) Gram-negative bacteria (GNB) and had acceptable effectiveness and considerably less toxicity than that reported in older publications. Colistin is a rapidly bactericidal antimicrobial agent that possesses a significant postantibiotic effect against MDR Gram-negative pathogens, such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. The optimal colistin dosing regimen against MDR GNB is still unknown in the intensive care unit (ICU) setting. A better understanding of the pharmacokinetic-pharmacodynamic relationship of colistin is urgently needed to determine the optimal dosing regimen. Although pharmacokinetic and pharmacodynamic data in ICU patients are scarce, recent evidence shows that the pharmacokinetics/pharmacodynamics of colistimethate sodium and colistin in critically ill patients differ from those previously found in other groups, such as cystic fibrosis patients. The AUC:MIC ratio has been found to be the parameter best associated with colistin efficacy. To maximize the AUC:MIC ratio, higher doses of colistimethate sodium and alterations in the dosing intervals may be warranted in the ICU setting. In addition, the development of colistin resistance has been linked to inadequate colistin dosing. This enforces the importance of colistin dose optimization in critically ill patients. Although higher colistin doses seem to be beneficial, the lack of colistin pharmacokinetic-pharmacodynamic data results in difficulty for the optimization of daily colistin dose. In conclusion, although colistin seems to be a very reliable alternative for the management of life-threatening nosocomial infections due to MDR GNB, it should be emphasized that there is a lack of guidelines regarding the ideal management of these infections and the appropriate colistin doses in critically ill patients with and without multiple organ failure.

Inhaled colistin as monotherapy for multidrug-resistant gram (−) nosocomial pneumonia: A case series

BACKGROUNDnReports of patients with polymyxin-only susceptible gram-negative nosocomial pneumonia treated with inhaled, but without concurrent intravenous, colistin are rare.nnnMETHODSnPatients admitted in a tertiary 450-bed tertiary care centre during the period 05/01/2005-05/31/2007 and receiving colistin through nebulization, but not systemically, were included in this retrospective case series.nnnRESULTSnFive patients (three with ventilator-associated pneumonia and two with nosocomial pneumonia) received colistin through nebulization without concomitant intravenous colistin. The isolated pathogens were Acinetobacter baumannii (three cases), Pseudomonas aeruginosa (one case) and the combination of Klebsiella pneumoniae, A. baumannii and P. aeruginosa (one case). They were susceptible only to colistin (three cases) or to colistin and gentamicin (two cases). Intravenous antimicrobial agents given concurrently were piperacillin/tazobactam, meropenem, ceftriaxone and ciprofloxacin; isolated pathogens were resistant to these agents. Four (80%) out of the five patients were cured, survived and were discharged. One patient died. No colistin-related adverse event was observed.nnnCONCLUSIONSnThe experience from this case series and other relevant recent reports suggest that treatment of pneumonia due to polymyxin-only susceptible gram-negative bacilli with inhaled colistin (without concurrent systemic administration) deserves further careful investigation.

Epidemiological aspects of 2009 H1N1 influenza: the accumulating experience from the Northern Hemisphere

Preliminary data regarding the experience of countries of the Northern Hemisphere with pandemic 2009 A(H1N1) influenza have already appeared in the literature. We aimed to evaluate the available published literature describing the epidemiological features of pandemic influenza. We searched PubMed; 35 studies (14 referred to European countries, eight to the USA, five to Mexico, four to Canada, two to Japan, one to Colombia, and one reviewed relevant data reported worldwide) were included. Considerably high hospitalization, intensive care unit (ICU) admission, and fatality rates (up to 93.8, 36.4, and 38.5%, respectively) among the evaluated cases were reported across studies with available relevant data. Young and middle-aged adults constituted the majority of the evaluated pandemic cases, with different disease severity (as indicated by the level of care and outcome). Yet, substantial percentages of elderly individuals were reported among more severely afflicted cases. Otherwise healthy patients constituted substantial percentages among evaluated cases with different disease severity. Pregnant women, obese, and morbidly obese patients also constituted substantial percentages of the cases involved in the included studies. The evaluation of the currently available published evidence contributes to the clarification of the epidemiological features of pandemic 2009 A(H1N1) influenza, which is useful in terms of the individual and public health perspectives.

Candidaemia: incidence, risk factors, characteristics and outcomes in immunocompetent critically ill patients

A matched case-control study was conducted to determine the risk factors for development of candidaemia in patients requiring intensive-care unit (ICU) treatment for more than 48 h. Patients were matched according to length of ICU stay, age, department of admission, year of admission and sex. Forty-five patients with candidaemia were identified (0.6 cases/1000 patient-days). Candidaemia developed mainly in critically ill patients with multiple organ failure and end-stage disease. Candida colonization and gastrointestinal surgery were independently associated with candidaemia. ICU and total in-hospital mortality were 40% and 66.7%, respectively. Candidaemia-related mortality was 20%. Candidaemia treatment failure was the only variable associated with in-hospital mortality (p 0.008).

Impact of definitive therapy with beta-lactam monotherapy or combination with an aminoglycoside or a quinolone for Pseudomonas aeruginosa bacteremia.

Background Bacteremia by Pseudomonas aeruginosa represents one severe infection. It is not clear whether beta-lactam monotherapy leads to similar rates of treatment success compared to combinations of beta-lactams with aminoglycosides or quinolones. Methods Retrospective cohort study from 3 tertiary hospitals (2 in Greece and 1 in Italy). Pseudomonas aeruginosa isolates were susceptible to a beta-lactam and an aminoglycoside or a quinolone. Patients received appropriate therapy for at least 48 hours. Primary outcome of interest was treatment success in patients with definitive beta-lactam combination therapy compared to monotherapy. Secondary outcomes were treatment success keeping the same empirical and definitive regimen, mortality, and toxicity. Results Out of 92 bacteremias there were 54 evaluable episodes for the primary outcome (20 received monotherapy). Treatment success was higher with combination therapy (85%) compared to beta-lactam monotherapy (65%), however not statistically significantly [Odds ratio (OR) 3.1; 95% Confidence Interval (CI) 0.69–14.7, pu200a=u200a0.1]. Very long (>2 months) hospitalisation before bacteremia was the only factor independently associated with treatment success (OR 0.73; 95% CI 0.01–0.95, pu200a=u200a0.046), however this result entailed few episodes. All-cause mortality did not differ significantly between combination therapy [6/31 (19%)] and monotherapy [8/19 (42%)], pu200a=u200a0.11. Only Charlson comorbidity index was associated with excess mortality (pu200a=u200a0.03). Conclusion Our study, in accordance with previous ones, indicates that the choice between monotherapy and combination therapy may not affect treatment success significantly. However, our study does not have statistical power to identify small or moderate differences. A large randomized controlled trial evaluating this issue is justified.

Effects of positive end-expiratory pressure (PEEP) in cardiac surgery patients

The role of positive end-expiratory pressure (PEEP) in the postoperative course of cardiac surgery patients remains questionable. In this prospective study, we examined the effect of different levels of PEEP on arterial oxygenation, SvO2 and PvO2 values, and on haemodynamic indices, during the early postoperative period in cardiac surgery patients. Upon transfer to the ICU, 67 adult patients with normal preoperative respiratory status were randomly assigned to receive zero PEEP (Group A), 5 cmH2O (Group B), or 10 cmH2O PEEP (Group C) during mechanical ventilatory support. PaO2/FIO2 ratio, mixed venous PvO2 and SvO2, and cardiac index, were measured 30 min, 4 h and 8 h after application of mechanical ventilation in the ICU, just prior to extubation, half an hour after extubation, and 4 h post-extubation. We found no statistically significant differences (P = n.s.) in arterial oxygenation expressed by PaO2/FIO2 ratio, SvO2 and PvO2 values, and in cardiac index among the three groups at any study interval. We conclude that low levels of PEEP have no advantage over zero PEEP in improving gas exchange in the early postoperative course of patients following open heart surgery.