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CDC: Voriconazole recommended as treatment for fungal meningitis

The death toll has reached 23 in the fungal meningitis outbreak as of Oct. 22, the CDC reported.There have been a total of 297 cases.

Three of the cases are possible peripheral joint infections, according to Tom Chiller, MD, deputy chief of Mycotic Disease Branch of CDC. Chiller provided an update of the outbreak at ID Week 2012.

In 45 cases, the fungus Exserohilum rostratum has been confirmed. There was also one confirmed case of Aspergillus and one confirmed case of Cladosporium.

The CDC and FDA have confirmed the presence of Exserohilum rostratum in unopened medication vials of preservative-free methylprednisolone acetate, strengthening the link betweeen steriod injections and the fungal meningitis outbreak and joint infections.

“These infections are extremely rare and complications from an injection are even more rare,” Chiller said.

Chiller said that CDC testing has found the presence of Exserohilum rostratum in unopened vials of preservative-free methylprednisolone acetate produced by the New England Compound Company. Two other fungi were also identified: Rhodotorulalaryngis and Rhizopusstolonifer. These two fungi are not known to be human pathogens, Chiller said. All three fungi were found in one of the three known affected lots of the drug. The other two lots have not yet been tested.

The recommended treatment for Exserohilum rostratum infections in this outbreak is voriconazole, according Carol Kauffman, MD, professor of internal medicine at University of Michigan and chief of infectious disease at the VA Ann Arbor Healthcare System. Patients should receive 6 mg/kg of voriconazole every 12 hours.

Kauffman said that the drug is associated with toxicity at high levels, including hallucinations and other effects on the central nervous system. According to Thomas Patterson, MD, professor of medicine at the University of Texas Health Science Center in San Antonio, measurement of voriconazole levels is crucial to treatment.

“We want high, therapeutic levels, but we don’t want toxic levels,” Patterson said. “Serum trough levels should be between 2 and 5 mcg/mL.”

The original drug recommendation for treatment was combination voriconazole and liposomal amphotericin B, the latter because of the index case being confirmed as Aspergillus.

“We didn’t know what we were dealing with, so we started with high-dose voriconazole and high-dose liposomal amphotericin B,” Kauffman said. “As things evolved, it became clear that Exserohilum rostratum was the cause, which is treated with voriconazole. Amphotericin B should still be considered for additional treatment in patients with severe infection or progressive disease.”

The incubation period of the fungal meningitis appears to range from 4 day to 42 days. However, Chiller cautioned that this number was obtained from individuals from whom the incubation period could definitely be determined, mostly patients who received only one injection. Many patients received several injections, making the incubation period harder to determine. In a similar outbreak approximately 10 years ago, the longest documented incubation period was 152 days.

“We need to be cautious in thinking that we’re out of the woods after a few weeks,” Chiller said. “We’re talking about being vigilant for months.”

The CDC has been using polymerase chain reaction (PCR) to determine the presence of the Exserohilum rostratum fungus. Chiller said that traditional diagnostic methods of fungi don’t typically yield many cultures, which makes diagnosis of the infection difficult. PCR is typically used in research settings, not as a diagnostic tool.

According to Patterson, Exserohilum rostratum is a black mold found in plants, water and soil. It usually causes superficial diseases, but invasive disease has clearly been reported, he said.

“Without question, there are a number of black molds that can cause neurologic disease,” Patterson said.

The death toll has reached 23 in the fungal meningitis outbreak as of Oct. 22, the CDC reported.There have been a total of 297 cases.

Three of the cases are possible peripheral joint infections, according to Tom Chiller, MD, deputy chief of Mycotic Disease Branch of CDC. Chiller provided an update of the outbreak at ID Week 2012.

In 45 cases, the fungus Exserohilum rostratum has been confirmed. There was also one confirmed case of Aspergillus and one confirmed case of Cladosporium.

The CDC and FDA have confirmed the presence of Exserohilum rostratum in unopened medication vials of preservative-free methylprednisolone acetate, strengthening the link betweeen steriod injections and the fungal meningitis outbreak and joint infections.

“These infections are extremely rare and complications from an injection are even more rare,” Chiller said.

Chiller said that CDC testing has found the presence of Exserohilum rostratum in unopened vials of preservative-free methylprednisolone acetate produced by the New England Compound Company. Two other fungi were also identified: Rhodotorulalaryngis and Rhizopusstolonifer. These two fungi are not known to be human pathogens, Chiller said. All three fungi were found in one of the three known affected lots of the drug. The other two lots have not yet been tested.

The recommended treatment for Exserohilum rostratum infections in this outbreak is voriconazole, according Carol Kauffman, MD, professor of internal medicine at University of Michigan and chief of infectious disease at the VA Ann Arbor Healthcare System. Patients should receive 6 mg/kg of voriconazole every 12 hours.

Kauffman said that the drug is associated with toxicity at high levels, including hallucinations and other effects on the central nervous system. According to Thomas Patterson, MD, professor of medicine at the University of Texas Health Science Center in San Antonio, measurement of voriconazole levels is crucial to treatment.

“We want high, therapeutic levels, but we don’t want toxic levels,” Patterson said. “Serum trough levels should be between 2 and 5 mcg/mL.”

The original drug recommendation for treatment was combination voriconazole and liposomal amphotericin B, the latter because of the index case being confirmed as Aspergillus.

“We didn’t know what we were dealing with, so we started with high-dose voriconazole and high-dose liposomal amphotericin B,” Kauffman said. “As things evolved, it became clear that Exserohilum rostratum was the cause, which is treated with voriconazole. Amphotericin B should still be considered for additional treatment in patients with severe infection or progressive disease.”

The incubation period of the fungal meningitis appears to range from 4 day to 42 days. However, Chiller cautioned that this number was obtained from individuals from whom the incubation period could definitely be determined, mostly patients who received only one injection. Many patients received several injections, making the incubation period harder to determine. In a similar outbreak approximately 10 years ago, the longest documented incubation period was 152 days.

“We need to be cautious in thinking that we’re out of the woods after a few weeks,” Chiller said. “We’re talking about being vigilant for months.”

The CDC has been using polymerase chain reaction (PCR) to determine the presence of the Exserohilum rostratum fungus. Chiller said that traditional diagnostic methods of fungi don’t typically yield many cultures, which makes diagnosis of the infection difficult. PCR is typically used in research settings, not as a diagnostic tool.

According to Patterson, Exserohilum rostratum is a black mold found in plants, water and soil. It usually causes superficial diseases, but invasive disease has clearly been reported, he said.

“Without question, there are a number of black molds that can cause neurologic disease,” Patterson said.

    Perspective
    Lyle Petersen

    Lyle Petersen

    One important aspect is that this outbreak investigation began with one case. As with many large outbreaks, a single case investigation heralded the discovery of a much bigger problem. The same thing happened with West Nile virus: one alert physician in New York City realized something unusual with a couple of patients and notified the health department. These experiences emphasize the role of all physicians in identifying outbreaks early so that interventions can be promptly implemented.

    This outbreak shares many of the attributes of public health emergencies we’ve faced in recent years. An unknown, uncommon, or poorly understood pathogen emerges, potentially involving thousands of exposed people over a broad geographic area. In this instance, we don’t know its clinical spectrum, how best to treat it and for how long, and the best way to diagnose it. We are learning as we go along.

    The key to recognizing an outbreak such as this is having alert physicians and diagnostic laboratories working in concert with a responsive public health system that can follow up on potential problems. In addition, effective interaction between practicing physicians and academic centers and the public health system is necessary to sort out myriad clinical issues that arise with a new entity such as this.

    • Lyle Petersen, MD
    • Infectious Disease News Editorial Board member

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