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Pharmaceutical Health Hazard – Fungal infection, contaminated Methylprednisolone: North Carolina, USA.


Published Date: 2017-02-17 17:16:13
Subject: PRO/EDR> Fungal infection, contaminated drug – USA: (NC) late relapse
Archive Number: 20170217.4846918

Date: Fri 17 Feb 2017
Source: CDC Emerging Infectious Diseases (in press) [edited]

Fungal Contamination of Methylprednisolone Causing Recurrent Lumbosacral Intradural Abscess
Fungal meningitis transmitted through injections of methylprednisolone contaminated with _Exserohilum rostratum_ affected 753 persons and caused 61 deaths in the USA in 2012 (1). More than 13 400 patients were potentially exposed to 1 of 3 contaminated drug lots (2,3). However, whether recommended treatment eliminates this disease is unknown because of limited reports of recurrent disease (4). As of December 2015, CDC had reported 8 cases of _E. rostratum_ meningitis relapses within a median time of 90 days. Reporting recurrent cases informs potential treatment recommendation changes and long-term care guidelines for affected persons. With institutional review board approval from Wake Forest University Medical Center, we describe fungal infection recurrence at 24 months.

A 78-year-old woman sought treatment at the neurosurgery clinic at Wake Forest Medical Center (Winston-Salem, NC, USA), in August 2015 with a 4-month history of acute or chronic lower back pain, leg weakness, and radicular pain in the left side. Non-operative interventions, including narcotics, physical therapy, and epidural steroid injections (L5-S1, July 2015), did not control her symptoms.

The patient had received an injection of contaminated methylprednisolone on [12 Sep 2012]. She was identified as a patient affected by the contamination and contacted as part of the CDC investigation. One month after contact, she was hospitalized for intractable headaches, nausea, and vomiting). PCR results from 2 samples of cerebrospinal fluid (CSF) performed by CDC were positive for _E. rostratum_ (from 16 and 22 Oct 2012). Treatment consisted of intravenous voriconazole, later switched to ambisome [amphotericin B], with a transition to oral voriconazole due to hallucinations. Therapy response was monitored with serial lumbar punctures. Contrast-enhanced magnetic resonance imaging (MRI) of the lumbar region was performed on [18 Nov 2012], and showed an enhancing epidural abscess, spanning T12-S2. Treatment was discontinued on [16 Jan 2013], a decision supported by 10 serially negative CSF fungal cultures and repeat PCR, negative for _E. rostratum_, performed at CDC on [22 Feb 2013]. Lumbar MRI on 1 Feb 2013, showed improvement of the lumbar epidural abscess.

The October 2012 hospitalization was complicated by the patient’s persistent altered mental status and right hemiparesis, which prompted a contrast-enhanced MRI of the brain on [15 Feb 2013], that demonstrated a left transverse sinus thrombus. The condition was monitored, and repeat imaging on [1 Mar 2013], found it to be nearly resolved. The patient appeared to be recovered from her infection at her last infectious disease follow-up in [March 2013].

The patient was hospitalized again in [May 2015] after a fall; she experienced worsening back pain, headaches, and confusion. Brain MRI demonstrated a recurrent dural venous thrombosis, which was treated with anticoagulants. Given concern for recurrent fungal infection, she also underwent lumbar puncture. CSF cell count and chemistries were within normal limits. CSF cultures were negative for fungi.

At home, her acute left leg pain worsened, leaving her nonambulatory, and she sought hospital management. On neurologic examination, she was awake and alert with some delirium/confusion and some mild weakness in the left lower leg. Contrast-enhanced lumbar MRI demonstrated a homogeneous enhancing intradural mass, spanning L4 to the sacrum, with a corresponding T2 hypointense signal (Figure, panels A, B). Diagnosing this lumbosacral intradural mass was not obvious because the differential diagnosis includes neoplasms, infections, and hematomas. Given the patient’s worsening symptoms, we performed nerve decompression and resection of the mass.

During the operation, the patient underwent a laminectomy of L3-L5; intraoperative findings showed an intradural abscess and arachnoiditis, with edema and adherence of the cauda equina nerve roots (Figure). Pathologic examination demonstrated abundant necrotic material containing septate hyphae fungal elements of brown pigment, consistent with a dematiaceous fungus. The material did not undergo PCR, given her clinical history (including PCR) and pathologic findings at recurrence. Her condition was treated with intravenous amphotericin B and voriconazole during her 12-day hospitalization, and she was discharged on oral voriconazole for outpatient treatment, with an anticipated duration of 1 year. At 5-month follow-up, she had complete resolution of her back pain and was full strength with some intermittent left radicular pain.

Only 3 other cases of intradural abscess were reported from the initial outbreak, making this recurrence a notable CNS disease manifestation (5). The patient had several risk factors for recurrence. She had received epidural steroid injections after antifungal treatment; the steroids resulted in an immunocompromised environment, potentially allowing for immune evasion and residual disease. A dural rent during multiple spinal taps or posttreatment epidural steroid injections may have seeded the fungus in the intradural space, which then expanded because antifungal agents demonstrate relatively poor CSF penetration. She also underwent a 3-month initial treatment; at least 6 months of antifungal treatment is currently recommended, although optimal treatment duration remains uncertain because objective criteria for infection clearance are lacking.

Given the potential for recurrence, fungal disease should remain on the differential diagnosis list for patients with prior exposure. In addition, long-term follow-up could identify patients needing further treatment (4).

1. Smith RM, Schaefer MK, Kainer MA, et al: Fungal infections associated with contaminated methylprednisolone injections. N Engl J Med. 2013;369:1598-1609.
2. Kauffman CA, Pappas PG, Patterson TF: Fungal infections associated with contaminated methylprednisolone injections. N Engl J Med. 2013;368:2495-2500.
3. Pappas PG. Lessons learned in the multistate fungal infection outbreak in the United States. Curr Opin Infect Dis. 2013;26:545-550.
4. Smith RM, Tipple M, Chaudry MN, Schaefer MK, Park BJ: Relapse of fungal meningitis associated with contaminated methylprednisolone. N Engl J Med. 2013;368:2535-2536.
5. Chiller TM, Roy M, Nguyen D, et al: Clinical findings for fungal infections caused by methylprednisolone injections. N Engl J Med. 2013;369:1610-1619.

[Authors: Renfrow JJ, Frenkel MB, Hsu W]

[The figures referenced are available at the source URL. – Mod.JH]

Communicated by:

[As far as I know, this case is the longest relapse of disease to date.

These were the numbers reported from CDC as of 6 May 2013 (20130507.1697132) in order to give the reader an idea where the cases were reported from. Michigan and Tennessee led the list.

Cases and deaths with fungal infections linked to steroid injections
State / Total case counts / CNS infections / Joint only / Deaths
Florida / 25 / 25 / 0 / 5
Georgia / 1 / 1 / 0 / 0
Idaho / 1 / 1 / 0 / 0
Illinois / 2 / 2 / 0 / 0
Indiana / 88 / 88 / 0 / 11
Maryland / 26 / 26 / 0 / 3
Michigan / 261 / 236 / 25 / 16
Minnesota / 12 / 12 / 0 / 1
North Carolina / 18 / 18 / 0 / 1
New Hampshire / 14 / 9 / 5 / 0
New Jersey 51 / 50 / 1 / 0
New York / 1 / 1 / 0 / 0
Ohio / 20 / 20 / 0 / 1
Pennsylvania / 1 / 1 / 0 / 0
Rhode Island / 3 / 3 / 0 / 0
South Carolina / 3 / 3 / 0 / 0
Tennessee / 152 / 150 / 2 / 15
Texas / 2 / 2 / 0 / 0
Virginia / 53 / 53 / 0 / 2
West Virginia / 7 / 7/ 0 / 0
TOTALS = 741 / 708 / 33 / 55. – Mod.LL]

A HealthMap/ProMED-mail map can be accessed at:]

See Also

Fungal infection, contaminated drug – USA: (NYC) single oncology clinic 20161117.4636253

Fungal infection, contaminated drug – USA: 2012-2014, follow up 20151030.3755591

Fungal infection, contaminated drug – USA (15): (TN) late relapse, alert 20131010.1993124
Fungal infection, contaminated drug – USA (14) 20130909.1931179
Fungal infection, contaminated drug – USA (13) 20130719.1832516
Fungal infection, contaminated drug – USA (12): mixed cultures 20130616.1773872
Fungal infection, contaminated drug – USA (11): new outbreak, RFI 20130607.1760736
Fungal infection, contaminated drug – USA (10): (FL) new outbreak, RFI 20130604.1755114
Fungal infection, contaminated drug – USA (09): new outbreak, RFI 20130601.1749968
Fungal infection, contaminated drug – USA (08): new outbreak, RFI 20130527.1739593
Fungal infection, contaminated drug – USA (07): new outbreak, RFI 20130525.1737028
Fungal infection, contaminated drug – USA (06): (MI) 20130520.1721489
Fungal infection, contaminated drug – USA (05) 20130507.1697132
Fungal infection, contaminated drug – USA (04) 20130329.1610129
Fungal infection, contaminated drug – USA (03) 20130312.1583406
Fungal infection, contaminated drug – USA (02) 20130130.1521840
Fungal infection, contaminated drug – USA 20130101.1477868

Fungal infection, contaminated drug – USA (17) 20121222.1465161
Fungal infection, contaminated drug – USA (15) 20121214.1439451
Fungal infection, contaminated drug – USA (11): complications 20121106.1391405
Fungal infection, contaminated drug – USA (10) 20121104.1390341
Fungal infection, contaminated drug – USA (05) 20121017.1347138
Fungal infection, contaminated drug – USA (04): more medications 20121016.1345302
Fungal infection, contaminated drug – USA (03): Exserohilum 20121015.1344312
Fungal infection, contaminated drug – USA: Exserohilum 20121014.1341591
Aspergillus meningitis – USA (09): Exserohilum 20121011.1337615
Aspergillus meningitis – USA (06): CDC advice 20121009.1333004
Aspergillus meningitis – USA (04): more cases, 2nd fungus 20121007.1328893
Aspergillus meningitis – USA: (TN, NC) contaminated drug 20121002.1320024

Fungal meningitis, contaminated drug – USA (03) 20021212.6046

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ProMED-mail is a program of the International Society for Infectious Diseases


Contamination, missteps prompt halt to NIH pharmacy operations –  2015/06/07

The National Institutes of Health (NIH) said yesterday it was suspending pharmaceutical operations at its Clinical Center in Bethesda, Md., after the discovery of fungal contamination in a drug ingredient led to the identification of serious manufacturing problems and violations of standard procedures.

Besides suspending PDS operations, the NIH said it is informing patients involved in affected clinical trials about the situation and working to secure other sources for the products. In addition, an outside group of experts will be appointed to make a thorough review and recommend corrective actions.

The news recalls the widespread outbreak of fungal infections that occurred in 2012 as a result of contaminated steroid drugs prepared by the now-defunct New England Compounding Center in Framingham, Mass. That outbreak sickened 751 people, killing 64, and led to changes in FDA oversight of compounding pharmacies.

Jun 4 NIH press release
Related FDA report

14 arrested in connection with deadly meningitis outbreak  –  2014/12/17

(CNN) — Fourteen people have been arrested in connection with a deadly 2012 national outbreak of fungal meningitis linked to steroid injections from a Massachusetts compounding pharmacy, including two charged with 25 acts of second-degree murder.  …The U.S. Centers for Disease Control and Prevention tied 751 cases across 20 states to the steroid injections. A total of 64 people died as a result.

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