Simon W. Lam

Association Between Colistin Dose and Microbiologic Outcomes in Patients With Multidrug-Resistant Gram-Negative Bacteremia

BACKGROUND Colistin is increasingly used for the treatment of multidrug-resistant gram-negative infections. However, colistin dosing varies greatly and the optimal regimen is unknown. The purpose of this study was to determine if colistin dosing correlates with patient outcomes. METHODS This retrospective study included patients with gram-negative bacteremia treated with intravenous colistin for at least 72 hours. The primary objective was to determine if colistin dose (mg of colistin base activity/kg/day) independently predicts day-7 microbiological success. Secondary objectives included evaluation for an association between colistin dose and 7-day mortality, 28-day mortality, and the development of acute kidney insufficiency (AKI). RESULTS Seventy-six patients were included in the analysis, with 52 patients (68%) achieving 7-day microbiological success. The median colistin dose was significantly higher in patients who achieved microbiological success (2.9 vs 1.5 mg/kg/day; P = .011). After adjusting for baseline severity of illness and concomitant tigecyline use, higher colistin dose independently correlated with microbiological success (adjusted odds ratio per 1 mg/kg/day = 1.74; 95% confidence interval, 1.11-2.71; P = .015). The median colistin dose was also significantly higher among survivors at day 7 (2.7 vs 1.5 mg/kg/day; P = .007). However, no difference was observed in colistin dose when comparing survivors and nonsurvivors at day 28. A significantly higher colistin dose was given to patients who developed AKI during therapy (3.8 vs 1.6 mg/kg/day; P < .001). CONCLUSIONS Higher colistin dose independently predicted microbiological success, which may partially explain the similar association with 7-day mortality. However, higher colistin doses may also precipitate worsening renal function.

Antifungal prophylaxis in liver transplant recipients

Although the overall incidence of fungal infections in liver transplant recipients has declined, these infections still contribute significantly to the morbidity and mortality of patients with risk factors for infection. Although antifungal prophylaxis has been widely studied and practiced, no consensus exists on which patients should receive prophylaxis, with which agent, and for what duration. Numerous studies have attempted to ascertain independent risk factors for invasive fungal infections in liver transplant patients, and these data, in addition to clinical trials, identify several patient groups at exceedingly high risk of fungal infection. These include retransplant patients, patients with renal failure requiring hemodialysis or renal replacement therapy, and those requiring reoperations after transplant. Because the majority of infections occur in the first month after transplantation, prophylaxis should be continued for 4‐6 weeks. However, local epidemiology and research should guide decisions regarding choice of agent as well as overall development of interinstitutional guidelines, because the incidence and spectrum of infection may differ dramatically among institutions. Liver Transpl 15:842–858, 2009.

Real-World Experience with Echinocandin MICs against Candida Species in a Multicenter Study of Hospitals That Routinely Perform Susceptibility Testing of Bloodstream Isolates

ABSTRACT Reference broth microdilution methods of Candida echinocandin susceptibility testing are limited by interlaboratory variability in caspofungin MICs. Recently revised Clinical and Laboratory Standards Institute (CLSI) breakpoint MICs for echinocandin nonsusceptibility may not be valid for commercial tests employed in hospital laboratories. Indeed, there are limited echinocandin susceptibility testing data from hospital laboratories. We conducted a multicenter retrospective study of 9 U.S., Australian, and New Zealand hospitals that routinely tested Candida bloodstream isolates for echinocandin susceptibility from 2005 to 2013. Eight hospitals used Sensititre YeastOne assays. The Candida spp. were C. albicans (n = 1,067), C. glabrata (n = 911), C. parapsilosis (n = 476), C. tropicalis (n = 185), C. krusei (n = 104), and others (n = 154). Resistance and intermediate rates were ≤1.4% and ≤3%, respectively, for each echinocandin against C. albicans, C. parapsilosis, and C. tropicalis. Resistance rates among C. glabrata and C. krusei isolates were ≤7.5% and ≤5.6%, respectively. Caspofungin intermediate rates among C. glabrata and C. krusei isolates were 17.8% and 46.5%, respectively, compared to ≤4.3% and ≤4.4% for other echinocandins. Using CLSI breakpoints, 18% and 19% of C. glabrata isolates were anidulafungin susceptible/caspofungin nonsusceptible and micafungin susceptible/caspofungin nonsusceptible, respectively; similar discrepancies were observed for 38% and 39% of C. krusei isolates. If only YeastOne data were considered, interhospital modal MIC variability was low (within 2 doubling dilutions for each agent). In conclusion, YeastOne assays employed in hospitals may reduce the interlaboratory variability in caspofungin MICs against Candida species that are observed between reference laboratories using CLSI broth microdilution methods. The significance of classifying isolates as caspofungin intermediate and anidulafungin/micafungin susceptible will require clarification in future studies.

Fluconazole versus an echinocandin for Candida glabrata fungaemia: a retrospective cohort study

OBJECTIVES We studied whether fluconazole or echinocandin treatment of Candida glabrata fungaemia results in superior outcomes. METHODS A multicentre, retrospective study was performed with 224 adult patients who received ≥ 5 days of therapy with either fluconazole or an echinocandin as their first antifungal treatment after collection of a blood culture that grew C. glabrata. The primary outcome was day 14 complete response. RESULTS Patients in the echinocandin group were generally more ill, both at baseline and at the time of the index culture. Day 14 complete response was obtained in 58/127 (46%) and 50/97 (52%) of the fluconazole and echinocandin patients, respectively (P=0.383). Logistic regression found intensive care unit admission to be associated with failure [OR 0.456 (0.217-0.957), P=0.038] and echinocandin therapy to be associated with day 14 complete response [OR 2.305 (1.124-4.727), P=0.023]. Twenty-eight day survival was similar between the fluconazole and echinocandin groups and logistic regression did not reveal antifungal therapy choice to be independently predictive of mortality. For patients treated with fluconazole, a dose:MIC ratio >12.5 (when compared with a ratio ≤ 12.5) was associated with a significantly higher day 14 complete response [4/20 (20%) ≤ 12.5 versus 50/102 (49%) >12.5, P=0.025]. CONCLUSIONS Severity of illness and choice of antifungal predict response in patients with C. glabrata fungaemia. Antifungal choice, however, does not influence mortality. In addition, new CLSI C. glabrata fluconazole susceptibility breakpoints are predictive of response when fluconazole is dosed appropriately.

The impact of delaying the initiation of appropriate antifungal treatment for Candida bloodstream infection

We performed a retrospective analysis of the time to initiation of appropriate antifungal therapy for candidemia and in-hospital mortality. The definition of appropriate antifungal therapy was based on in vitro susceptibility results, and in the case of fluconazole, pharmacodynamic parameters. Of 123 patients, the mortality rate in the <24 h, 24-48 h, and >48 h groups was 50%, 28%, and 32%, respectively. Patients who never received antifungal treatment had a 61% mortality rate (difference between groups, P =0.06). Multivariate analysis found APACHE II score (AOR = 1.09, 95% CI: 1.02-1.17 for each point increase) to be the only independent predictor of mortality. The time to initiation of appropriate antifungal therapy did not correlate with in-hospital mortality.

Evolving role of early antifungals in the adult intensive care unit.

Background:Invasive candidiasis (IC) is associated with significant morbidity and mortality in critically ill patients. This, in conjunction with difficulties in diagnosis, underscores the need for novel treatment strategies based on the identification of significant risk factors for IC. Objective:To review the evidence surrounding the use of early antifungals in critically ill adult patients and to present concise and specific recommendations for different early treatment strategies for IC. Data Sources and Data Extraction:Pubmed search from 1966 to July 2008 using the search terms “antifungals, critical care, prophylaxis, preemptive therapy, and empiric therapy.” Examined all relevant peer-reviewed original articles, meta-analyses, guidelines, consensus statements, and review articles. Conclusion:The use of early antifungal therapy should be reserved for patients with a high risk (10% to 15%) of developing IC. Despite a large number of articles published on this topic, there is no single predictive rule that can adequately forecast IC in critically ill patients. Until further prospective validation of existing data is completed, clinicians should assess patients on a case-by-case basis and determine the need for early antifungal treatment strategies based on frequent evaluations of risk factors and clinical status.

Comparison of treatment outcomes with vancomycin alone versus combination therapy in severe Clostridium difficile infection

BACKGROUND The recommended treatment for severe Clostridium difficile infection (CDI) is oral vancomycin alone. Combination therapy with metronidazole is only recommended in cases complicated by shock, ileus, or toxic megacolon. However, patients with severe infection are often treated with combination therapy despite a lack of data supporting this practice. AIM To evaluate differences in outcomes for patients with severe CDI treated with oral vancomycin alone versus combination therapy. METHODS Medical records of 78 patients with severe CDI receiving either oral vancomycin alone or combination therapy for ≥ 72h were retrospectively reviewed. The primary outcome was time to clinical cure of CDI, defined as the first day of resolution of diarrhoea for ≥ 48h without development of a complication. Other endpoints included cure rates, complication rates, and recurrence rates. FINDINGS There was no difference in the incidence of clinical cure between monotherapy and combination therapy (57.1% vs 65.1%, P = 0.49). Median time to clinical cure was 7.0 days for the monotherapy group and 8.0 days for combination therapy (P = 0.19). After adjustment for potential confounders, the hazard ratio of the time to clinical cure for combination therapy compared with monotherapy was 0.58 (P = 0.10). There was no difference in recurrence rate or rates of individual complications between groups; however, there was a significantly higher composite complication rate in the combination therapy group. CONCLUSION These data suggest that there is no difference in treatment outcomes between monotherapy and combination therapy for severe CDI.

Influence of Colistin Dose on Global Cure in Patients with Bacteremia Due to Carbapenem-Resistant Gram-Negative Bacilli

ABSTRACT The increasing prevalence of multidrug-resistant (MDR) nosocomial infections accounts for increased morbidity and mortality of such infections. Infections with MDR Gram-negative isolates are frequently treated with colistin. Based on recent pharmacokinetic studies, current colistin dosing regimens may result in a prolonged time to therapeutic concentrations, leading to suboptimal and delayed effective treatment. In addition, studies have demonstrated an association between an increased colistin dose and improved clinical outcomes. However, the specific dose at which these outcomes are observed is unknown and warrants further investigation. This retrospective study utilized classification and regression tree (CART) analysis to determine the dose of colistin most predictive of global cure at day 7 of therapy. Patients were assigned to high- and low-dose cohorts based on the CART-established breakpoint. The secondary outcomes included microbiologic outcomes, clinical cure, global cure, lengths of intensive care unit (ICU) and hospital stays, and 7- and 28-day mortalities. Additionally, safety outcomes focused on the incidence of nephrotoxicity associated with high-dose colistin therapy. The CART-established breakpoint for high-dose colistin was determined to be >4.4 mg/kg of body weight/day, based on ideal body weight. This study evaluated 127 patients; 45 (35%) received high-dose colistin, and 82 (65%) received low-dose colistin. High-dose colistin was associated with day 7 global cure (40% versus 19.5%; P = 0.013) in bivariate and multivariate analyses (odds ratio [OR] = 3.40; 95% confidence interval [CI], 1.37 to 8.45; P = 0.008). High-dose colistin therapy was also associated with day 7 clinical cure, microbiologic success, and mortality but not with the development of acute kidney injury. We concluded that high-dose colistin (>4.4 mg/kg/day) is independently associated with day 7 global cure.

Lactic acidosis: Clinical implications and management strategies

In hospitalized patients, elevated serum lactate levels are both a marker of risk and a target of therapy. The authors describe the mechanisms underlying lactate elevations, note the risks associated with lactic acidosis, and outline a strategy for its treatment. In hospitalized patients, elevated lactate is both a marker of risk and a target of therapy.

Impact of Combination Antimicrobial Therapy on Mortality Risk for Critically Ill Patients with Carbapenem-Resistant Bacteremia

ABSTRACT There are limited treatment options for carbapenem-resistant Gram-negative infections. Currently, there are suggestions in the literature that combination therapy should be used, which frequently includes antibiotics to which the causative pathogen demonstrates in vitro resistance. This case-control study evaluated risk factors associated with all-cause mortality rates for critically ill patients with carbapenem-resistant Gram-negative bacteremia. Adult patients who were admitted to an intensive care unit with sepsis and a blood culture positive for Gram-negative bacteria resistant to a carbapenem were included. Patients with polymicrobial, recurrent, or breakthrough infections were excluded. Included patients were classified as survivors (controls) or nonsurvivors (cases) at 30 days after the positive blood culture. Of 302 patients screened, 168 patients were included, of whom 90 patients died (53.6% [cases]) and 78 survived (46.4% [controls]) at 30 days. More survivors received appropriate antibiotics (antibiotics with in vitro activity) than did nonsurvivors (93.6% versus 53.3%; P < 0.01). Combination therapy, defined as multiple appropriate agents given for 48 h or more, was more common among survivors than nonsurvivors (32.1% versus 7.8%; P < 0.01); however, there was no difference in multiple-agent use when in vitro activity was not considered (including combinations with carbapenems) (87.2% versus 80%; P = 0.21). After adjustment for baseline factors with multivariable logistic regression, combination therapy was independently associated with decreased risk of death (odds ratio, 0.19 [95% confidence interval, 0.06 to 0.56]; P < 0.01). These data suggest that combination therapy with multiple agents with in vitro activity is associated with improved survival rates for critically ill patients with carbapenem-resistant Gram-negative bacteremia. However, that association is lost if in vitro activity is not considered.