Medical Grand Rounds

Update in infectious disease treatment

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References

PREDNISOLONE IS BENEFICIAL IN ACUTE BELL PALSY, ACYCLOVIR IS NOT

Sullivan FM, Swan IR, Donnan PT, et al. Early treatment with prednisolone or acyclovir in Bell palsy. N Engl J Med 2007; 357:1598 1607.

Bell palsy accounts for about two-thirds of cases of acute unilateral facial nerve palsy in the United States. Virologic studies from patients undergoing surgery for facial nerve decompression have suggested a possible association with herpes simplex virus. Other causes of acute unilateral facial nerve palsy include Lyme disease, sarcoidosis, Sjögren syndrome, trauma, carotid tumors, and diabetes. Bell palsy occurs most often during middle age, peaking between ages 30 and 45. As many as 30% of patients are left with significant neurologic residua. Corticosteroids and antiviral medications are commonly used to treat Bell palsy, but evidence for their efficacy is weak.

The study. Sullivan et al12 conducted a double-blind, placebo-controlled, randomized trial over 2 years in Scotland with 551 patients, age 16 years or older, recruited within 72 hours of the onset of symptoms. Patients who were pregnant or breastfeeding or who had uncontrolled diabetes, peptic ulcer disease, suppurative otitis, zoster, multiple sclerosis, sarcoidosis, or systemic infection were excluded. They were randomized to treatment for 10 days with either acyclovir (Zovirax) 400 mg five times daily or prednisolone 25 mg twice daily, both agents, or placebo.

The primary outcome was recovery of facial function based on the House-Brackmann grading system. Digital photographs of patients at 3 and 9 months of treatment were evaluated independently by three experts who were unaware of study group assignment or stage of assessment. These included a neurologist, an otorhinolaryn-gologist, and a plastic surgeon. The secondary outcomes were quality of life, facial appearance, and pain, as assessed by the patients.

Findings. At 3 months, 83% of the prednisolone recipients had no facial asymmetry, increasing to 94% at 9 months. In comparison, the numbers were 64% and 82% in those who did not receive prednisolone, and these differences were statistically significant. Acyclovir was found to be of no benefit at either 3 or 9 months.

The authors concluded that early treatment of Bell palsy with prednisolone improves the chance of complete recovery, and that acyclovir alone or in combination with steroids confers no benefit.

Comments. At about the same time that this study was published, Hato et al13 evaluated valacyclovir (Valtrex) plus prednisolone vs placebo plus prednisolone and found that patients with severe Bell palsy (defined as complete facial nerve paralysis) benefited from antiviral therapy.

Corticosteroids are indicated for acute Bell palsy. In patients with complete facial nerve paralysis, valacyclovir should be considered.

POSACONAZOLE AS PROPHYLAXIS IN FEBRILE NEUTROPENIA

Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007; 356:348 359.

For many years, amphotericin B was the only drug available for antifungal prophylaxis and therapy. Then, in the early 1990s, a number of studies suggested that the triazoles, notably fluconazole (Diflucan), were effective in a variety of clinical settings for both prophylaxis and therapy of serious fungal infections. In 1992 and 1995, two studies found that fluconazole prophylaxis was as effective as amphotericin B in preventing fungal infections in patients undergoing hematopoietic stem cell transplantation.14,15 Based on these studies, clinical practice changed, not only for patients undergoing hematopoietic stem cell transplantation, but also for empiric antifungal prophylaxis in patients receiving myeloablative chemotherapy to treat hematologic malignancies.

Fluconazole is not active against invasive molds, and newer drugs—itraconazole (Sporanox), voriconazole (Vfend), and most recently posaconazole (Noxafil)—were developed with expanded clinical activity. Studies in the 1990s found that itraconazole and voriconazole performed better than fluconazole but did not provide complete prophylaxis.

The study. Cornely et al16 compared posaconazole with fluconazole or itraconazole in 602 patients undergoing chemotherapy for acute myelogenous leukemia or myelodysplasia. Although patients were randomized to either the posaconazole group or the fluconazole-or-itraconazole group, investigators could choose either fluconazole or itraconazole for patients randomized to that group. Most patients in the latter group (240 of 298) received fluconazole.

Patients were at least 13 years old, were able to take oral medications, had newly diagnosed disease or were having a first relapse, and had or were anticipated to have neutropenia for at least 7 days. The study excluded patients with invasive fungal infection within 30 days, significant liver or kidney dysfunction, an abnormal QT interval corrected for heart rate, an Eastern Cooperative Oncology Group performance status score of more than 2 (in bed more than half of the day), or allergy or a contraindication to azoles.

The trial treatment was started with each cycle of chemotherapy and was continued until recovery from neutropenia and complete remission, until invasive fungal infection developed, or for up to 12 weeks, whichever came first.

The primary end point was the incidence of proven or probable invasive fungal infection during the treatment phase. Secondary end points included death from any cause and time to death.

Findings. Posaconazole recipients fared significantly better than patients in the other treatment group with respect to the incidence of proven or probable invasive fungal infection, invasive aspergillosis, probability of death, death at 100 days, and death secondary to fungal infection. Treatment-related severe adverse events were a bit more common with posaconazole.

The authors suggest that posaconazole prophylaxis may have a place in prophylaxis in patients undergoing chemotherapy for acute myelogenous leukemia or myelodysplasia.

Comments. It is not surprising that posaconazole performed better, because the standard treatment arm contained an agent (fluconazole) that did not cover Aspergillus, the most frequently identified source of invasive fungal infection during the treatment phase of the study.

In an editorial accompanying the article, De Pauw and Donnelly17 pointed out that whether posaconazole prophylaxis would be appropriate in a given case depends upon how likely infection is with Aspergillus. An institution with very few Aspergillus infections would have a much higher number needed to treat with posaconazole to prevent one case of aspergillosis than in this study, in which the number needed to treat was 16. Thus, knowledge of local epidemiology and incidence of invasive mold infections should guide selection of the optimal antifungal agent for prophylaxis in patients undergoing myeloablative chemotherapy for acute myelogenous leukemia or myelodysplasia.

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