Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

17th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)

Munich, Germany / March 31-April 3, 2007

As confirmed by Prof. Eckard Müller, Professor and Vice Chairman of Anesthesiology, Intensive Care and Emergency Medicine, University Clinic Bochum, Germany, fungal infections are on the rise. He pointed to an increase in sepsis fungal infections in the US of more than 200% in the hospital setting within the last two decades (Martin et al. N Engl J Med 2003;348(16):1546-54). Referring to the Tarragona strategy, “Individualization of therapy is probably one of the most important messages,” Prof. Müller told delegates. Treatment within the first 48 to 72 hours is also of crucial importance, as mortality increases by 8.6% for every hour of delay, according to one recent study. “That is why we should hit hard and hit early,” Prof. Müller recommended.

Treatment Strategies

In the intensive care unit (ICU), severe candida infections may be encountered at a rate of 1 to 5%, as reported by Dr. Philippe Eggimann, Department of Intensive Medicine, University Hospital of Lausanne, Switzerland. “It will usually take one to two weeks for the infection to become documented by blood cultures and it is during this time that we may have the opportunity to do something,” Dr. Eggimann told delegates. Amphotericin B, fluconazole, caspofungin and voriconazole could all be used for treatment, as comparable success rates have been reported. “Experts agree that the choice would then be guided by not only local epidemiological data but also by the tolerance of these drugs,” he noted.

This question was addressed in a double-blind, comparative trial of caspofungin 50 mg/day and amphotericin B 1 mg/kg/day in 224 patients with invasive candidiasis (Mora-Duarte et al. N Engl J Med 2002;347(25):2020-9). While there was no significant difference overall, Dr. Eggimann observed, a significantly larger proportion of patients could be treated for more than five days with the echinocandin and there were highly significantly lower rates of overall side effects, toxicity and treatment duration in favour of caspofungin. Of these 224 patients, a subset of 97 patients that stayed in the ICU was also studied. In this cohort, there was a trend of lower fungal mortality with caspofungin (P=0.06). “Much more important,” Dr. Eggimann noted, “side effects were reduced highly significantly [P=0.01] in favour of caspofungin.” Of note, none of the patients taking the echinocandin had to stop treatment compared to 30% with amphotericin B. “As a result of many contraindications that have to be applied for most critically ill patients, it is no longer possible to start treatment with amphotericin B and we have to move rapidly to the new-generation drugs,” Dr. Eggimann proposed.

Drawing on numerous studies on antifungal prophylaxis, Dr. Eggimann was able to detect a threshold value of about 10% invasive candidiasis “above which it is possible to consider prophylaxis.” A recent analysis sought to identify risk factors that would justify prophylaxis. Researchers used data from 2890 ICU patients in seven units with a relatively low rate of candidiasis (3%) to establish a clinical prediction rule whereby any systemic antibiotic or presence of central venous catheter and at least two other factors—total parenteral nutrition (days 1-3), any dialysis (days 1-3), any major surgery (days 7-0), pancreatitis (days -7-0), any use of steroids (days -7-3) or use of other immunosuppressive agents (days -7-0)—resulted in a risk ratio of 4.36 (Ostrosky-Zeichner et al. Eur J Clin Microbiol Infect Dis 2007;26(4):271-6).

Summarizing his own experience, Dr. Eggimann recommended empirical treatment for patients that are colonized by Candida spp, who carry any of the known risk factors and who are unstable or septic. For non-colonized patients from documented high-risk groups, prophylaxis is advised. For all other patients, a bi-weekly active search for colonization should be performed and when a colonization index ³0.5 is determined, empirical treatment should also be administered. Applying this strategy in Switzerland, stabilization in the rate of candidemia was observed between 1991 and 2000. Despite an important increase in the use of antifungals, no shift in the epidemiology was observed.

Invasive Aspergillosis

Addressing the “hot spots” in the management of invasive aspergillosis, Dr. Dimitrios Kontoyiannis, Professor of Medicine, Director of Mycology Research Program, Department of Infectious Diseases and Infection Control, University of Texas M.D. Anderson Cancer Center, Houston, reported, “While voriconazole may be considered the drug of first choice by most experts, it should also be noted that this drug is limited sometimes by non-linear pharmacokinetics and broad variation of plasma levels.” One treatment that might deal with voriconazole failures in invasive aspergillosis is caspofungin, which has demonstrated a response rate of between 40 and 56% in a number of recent trials. “This is interesting because one of the dogmas in the field was that caspofungin probably would not work as well in immunosuppressed patients. Yet echinocandins are active in invasive aspergillosis and controlled studies will have to show how good it is in comparison to others,” Dr. Kontoyiannis indicated.

At the recent ASH meeting in Orlando, a study was presented on caspofungin as first-line therapy for invasive fungal infections in 28 patients with hematologic malignancies and severe neutropenia. The response rate of 85% was achieved with no breakthrough infection and without dose modification. The treatment was well tolerated and there were no discontinuations due to adverse events.

The important question of a high-loading regimen vs. standard dosing in the treatment of invasive aspergillosis and other mould infections in immunocompromised patients was addressed in the AmBiLoad trial. There was no statistically significant difference in survival between the high dose of caspofungin 10 mg/kg/day, given for the first 14 days, vs. standard dosing of 3 mg/kg/day.

Other Study Findings

During another presentation here during the scientific sessions, new data were presented from the COMBISTRAT (AmBisome in Combination with Caspofungin for the Treatment of Invasive Aspergillosis) in immunocompromised patients. The pilot study followed 30 patients for 12 weeks. A partial or complete response at the end of treatment was achieved by 67% with the combination treatment vs. 27% with the high-dose amphotericin B regimen; survival at week 12 was 100% vs. 86.7%, respectively.

In a prospective, multicentre study, the efficacy and safety of caspofungin in liver transplant recipients at high risk for invasive fungal infections was evaluated. An interim analysis of the first 41 patients showed a median duration of prophylaxis of 21 days. For 16 patients (39%), the dose had to be lowered from the target of 50 mg q.i.d. to 35 mg due to transplant-related liver dysfunction. Four (9.8%) more patients discontinued due to treatment-related altered liver function tests after eight to 19 days of therapy, but otherwise the treatment was well tolerated. Caspofungin prophylaxis was successful in 36 patients (88%) and among survivors in a follow-up period of up to 100 days, only one experienced an invasive Mucor surgical wound infection. “These results suggest promise for the prophylactic use of caspofungin in high-risk liver-transplant recipients,” concluded the authors on behalf of the Spanish Transplantation Infection Study Group.