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47th Interscience Conference on Antimicrobial Agents and Chemotherapy

Chicago, Illinois / September 17-20, 2007

Findings from a retrospective chart review of early experience with the novel echinocandin caspofungin were presented here by Dr. Thomas Patterson, Professor of Medicine and Director, San Antonio Center for Medical Mycology, Texas. Eighteen practitioners across a number of US centres were asked to complete case forms on 268 patients who received caspofungin in the early days following its approval in the US for salvage therapy in invasive aspergillosis.

They first identified patients most likely to develop invasive fungal disease, the majority in this cohort occurring in either bone marrow transplant recipients (39%) or those with hematological malignancies (19%). Other important risk groups included solid-organ transplant recipients, patients with AIDS and those with solid tumours. Researchers also identified factors that predisposed patients to develop invasive fungal infections. These included who had received antibiotics within the previous two weeks (72%); the presence of a central line catheter (66%); fever in excess of 38º C (61%); an absolute neutrophil count (ANC) of <500 cells/mm3 (35%); and an ICU stay within the previous seven days (29%).

Almost one-third of the cohort (32%) received caspofungin as salvage therapy for the treatment of invasive aspergillosis, including 22% who had pulmonary manifestations of the infection. Another 46% received caspofungin for the treatment of Candida infections, including 24% for candidemia. Others reported that they used the echinocandin for the treatment of febrile neutropenia, for purposes of prophylaxis or other reasons, including urinary tract infections.

“High antifungal failure rates at 52% occurred in aspergillosis [patients],” researchers noted, including a 45% mortality rate within seven days of the end of therapy. Nevertheless, as Dr. Patterson noted, “If you look at the responses in this group, they reflect very closely the data submitted for approval of caspofungin for salvage therapy, so basically these patients were pretty similar.”

Furthermore, bone marrow transplant recipients as well as those with hematological malignancies made up almost 60% of the retrospective review cohort, and in such patients, “a 35% response rate [complete responses (CRs) 21%, partial responses (PRs) 14%] is probably not an unreasonable outcome as mortality is going to be high from underlying disease in these patients,” Dr. Patterson added. When caspofungin was used for the primary treatment of candidemia, there was a 75% CR rate, while when used as salvage therapy, there was a 63% CR rate. Some 22% of candidemia patients died within seven days of receiving the compound as primary therapy once it was discontinued, while there was a 27% failure rate including those who died within seven days after treatment cessation when it was given as salvage.

Reassuring Findings

Most patients (93%) who received caspofungin on a prophylactic basis did not develop a fungal infection while on therapy. Investigators were not able to identify the type of patients who received antifungal prophylaxis in this review. However, as Dr. Patterson observed, the fact that 7% of them still developed documented infection despite antifungal prophylaxis suggests that they were very high-risk patients. “I think this review simply supports the clinical responses we see in the real world, so basically the fact that these patients do respond to the doses we usually use in the clinic is reassuring and toxicities are few,” Dr. Patterson concluded.

High-risk Settings

The value of prophylactic antifungal therapy in high-risk settings, notably the ICU, is controversial but there are several compelling reasons to consider its use in this setting. As pointed out by Dr. Luis Ostrosky-Zeichner, Mycosis Study Group and Associate Professor of Medicine, University of Texas at Houston, it costs about $44,000 to treat a single invasive fungal infection and mortality rates still hover around 40%. Prevention of such costly infections would clearly be desirable.

A pilot study in which the benefit of giving prophylactic caspofungin in the ICU was explored as a means of preventing intra-abdominal candidiasis also yielded intriguing results. “We had previously shown that 30% to 40% of surgical patients with recurrent gastrointestinal perforation, anastomotic leakage or acute necrotizing pancreatitis develop intra-abdominal candidiasis,” Dr. Oscar Marchetti, Division of Infectious Diseases, University of Lausanne, Switzerland, informed delegates. With a shift towards non-albicans Candida species, notably C. glabrata and C. krusei as a cause of these infections, the Swiss group sought to evaluate the efficacy and safety of caspofungin prophylaxis in ICU patients hospitalized for either recurrent gastrointestinal perforations, anastomotic leakage or acute pancreatitis.

A total of 19 individuals were enrolled, median age 69, the majority of them males. All patients received antibacterial therapy in addition to caspofungin, which was given for a median of 16 days. At the start of therapy, 69% of patients were colonized with C. albicans while at the end of treatment, virtually all of them remained colonized. Yet caspofungin prophylaxis was successful in 95% of the group, with only one patient having a breakthrough episode of intra-abdominal candidiasis. There was also no shift towards non-albicans Candida species during caspofungin prophylaxis, investigators added, and no adverse events requiring treatment discontinuation were observed.

Dr. Ostrosky-Zeichner presented findings from a double-blind, placebo-controlled study, where patients who met “prediction rule criteria” on days 3 to 5 of their ICU stay were randomized to either caspofungin 50 mg/day (n=27) or to placebo (n=11) for as long as they were in the ICU. The prediction rule for randomization included an expected length of stay in excess of 48 hours plus either the need for antibiotics or a central catheter line on days 1 to 3 and at least two other factors, including the need for total parenteral nutrition, dialysis, surgery, pancreatitis, steroids or other immunosuppressants.

“Unfortunately, we had to stop the study earlier than we wanted as enrolment was very slow,” reported Dr. Ostrosky-Zeichner. Nevertheless, investigators were able to demonstrate in their initial experience that caspofungin prophylaxis appeared to be both safe and effective in preventing fungal infections in the ICU, he added.

For example, out of 18 patients in the active-treatment group who completed the study through 14 days of follow-up, only one patient (4%) developed a case of invasive candidiasis compared to three out of seven patients treated with placebo who also completed the trial. “Rates of adverse events in the caspofungin group were not higher than in the placebo group,” investigators noted, “and deaths were not related to treatment.” The group also noted that while the trial was limited in size, their prediction rule “may be highly predictive” of invasive candidiasis. Summary

The echinocandin caspofungin has proven effective, and is indicated as empirical therapy for presumed fungal infections in febrile neutropenic patients, the treatment of invasive candidiasis including candidemia, intra-abdominal abscesses and peritonitis as well as pleural-space infections. It is also a critically important option for the treatment of invasive aspergillosis in patients who are refractory to, or intolerant of, other antifungals and it has been approved for esophageal candidiasis as well. Results from preliminary exploration of its use for the prevention of serious fungal infections in high-risk patients appear promising and warrant further study in order to avoid these costly infections and potentially save lives.