BETHESDA, MD 11 October 2012—Interim federal recommendations for the treatment of fungal meningitis in patients who received epidural injections of methylprednisolone acetate made by the New England Compounding Center call for long-term, high-dose combination antifungal therapy with agents that penetrate the central nervous system (CNS).
The Centers for Disease Control and Prevention (CDC) recommends i.v. voriconazole and liposomal amphotericin B as initial therapy for patients who meet the current case definition for fungal meningitis.
Both the case definition and CDC's treatment recommendations are subject to revision as the outbreak unfolds. Clinicians should check the agency's website frequently to ensure that they are acting on the most recent recommendations.
According to CDC, the antifungal therapy for patients with meningitis should be administered in addition to routine empirical treatment for potential bacterial pathogens.
CDC Medical Epidemiologist Tom Chiller said during an October 10 conference call that broad-spectrum antifungal therapy is advisable because it is "unclear as to how many potential fungal pathogens could be involved" in the outbreak.
Laboratory tests have confirmed the presence of Exserohilum species in 10 patients and Aspergillus species in 1.
Chiller said Exserohilum is a rare and unique type of black mold that has not previously been known to cause meningitis.
"There is very little known about this organism in the CNS," he said.
For patients who meet CDC's current case definition for fungal meningitis, the recommended dosage of voriconazole is 6 mg/kg administered every 12 hours. Chiller said the dosage should be maintained "for as long as the patients tolerate it."
Liposomal amphotericin B should be administered intravenously at a dosage of 7.5 mg/kg/day, according to CDC. The agency stated that liposomal amphotericin B is preferred over other lipid formulations of the drug.
The optimal duration of therapy is unknown but is presumed to be lengthy.
"We fully expect that patients will probably need to be on antifungal therapy for, certainly, weeks to months. Unfortunately, with fungi, we know that short-course therapy does not work, especially with molds. And we would be concerned about recurrence after therapy is stopped," Chiller said.
He said CDC is aware that high dosages of both drugs, but especially amphotericin B, can cause toxicity.
"Given that many of the patients that are receiving these medicines are elderly, we anticipate and are already seeing problems with renal function due to amphotericin," he noted.
The guidance document states that the amphotericin B dosage can be reduced to 5 mg/kg/day in elderly patients and others who are at risk for kidney toxicity. In addition, a liter of 0.9% sodium chloride injection administered before starting the amphotericin B infusion may reduce the risk of kidney toxicity.
Chiller said that transitioning patients to outpatient therapy is possible but difficult given the currently recommended drug regimens.
Infusion of the two antifungals in accordance with their FDA-approved labeling takes a total of seven hours: two hours twice a day for voriconazole, and three hours once a day for liposomal amphotericin B, with the infusion bag shaken after the first two hours.
Chiller said that although voriconazole comes in an oral formulation that penetrates the CNS, no oral formulation of liposomal amphotericin B is available. Thus, he said, patients would need to continue long-term outpatient infusion therapy to receive that drug.
He also noted that long-term compliance with oral voriconazole therapy could be difficult to monitor, and nonadherent patients are at risk for recurrence of meningitis.
For now, CDC does not recommend any treatment for patients who are asymptomatic. But the agency advised clinicians to order cerebrospinal fluid (CSF) tests in patients with even mild symptoms that could indicate infection.
Patients who have normal CSF test results and symptoms suggestive of infection should be monitored but not treated, according to CDC. If a patient's symptoms progress, the agency recommends immediately obtaining and testing a new CSF sample.
Chiller noted that because fungi are difficult to culture, a positive CSF culture result is not necessary to confirm clinically diagnosed fungal meningitis.
Symptoms of fungal meningitis include headache, fever, stiff neck, or photophobia and a CSF profile showing >5 white blood cells, regardless of glucose or protein levels.
The current case definition for fungal meningitis includes patients with fungal or nonbacterial, nonviral meningitis of subacute onset or basilar stroke following an epidural injection on or after May 21, 2012; or spinal osteomyelitis or epidural abscess at the site of epidural or sacroiliac injection on or after May 21, 2012.
Although no cases of fungal infection at other injection sites have been reported, Chiller said this could become an issue. CDC has included in its case definition for the outbreak patients with septic arthritis or osteomyelitis of a peripheral joint diagnosed following joint injection after May 21, 2012.
Chiller said the agency is drafting treatment recommendations for patients with joint infections.
As of October 10, 137 cases of fungal meningitis, including 12 fatal cases, had been reported to CDC. Cases have been reported in 10 states.
Chiller said almost all of the deaths during the outbreak have resulted from "stroke or some complication of a stroke."