Plasma fluoride level as a predictor of voriconazole-induced periostitis in patients with skeletal pain.

BACKGROUND: Voriconazole is a triazole antifungal medication used for prophylaxis or to treat invasive fungal infections. Inflammation of the periosteum resulting in skeletal pain, known as periostitis, is a reported side effect of long-term voriconazole therapy. The trifluorinated molecular structure of voriconazole suggests a possible link between excess fluoride and periostitis, as elevated blood fluoride has been reported among patients with periostitis who received voriconazole. METHODS: Two hundred sixty-four patients from Michigan were impacted by the multistate outbreak of fungal infections as a result of contaminated methylprednisolone injections. A retrospective study was conducted among 195 patients who received voriconazole therapy at St Joseph Mercy Hospital during this outbreak. Twenty-eight patients who received both bone scan and plasma fluoride measurements for skeletal pain were included in the statistical analyses. Increased tracer uptake on bone scan was considered positive for periostitis. The primary outcome measure was the correlation between plasma fluoride and bone scan results. RESULTS: Blood fluoride (P < .001), alkaline phosphatase (P = .020), daily voriconazole dose (P < .001), and cumulative voriconazole dose (P = .027) were significantly elevated in patients who had periostitis compared with those who did not. Discontinuation or dose reduction of voriconazole resulted in improvement of pain in 89% of patients. CONCLUSIONS: High plasma fluoride levels coupled with skeletal pain among patients who are on long-term voriconazole therapy is highly suggestive of periostitis. Initial measurement of fluoride may be considered when bone scan is not readily available. Early detection should be sought, as discontinuation of voriconazole is effective at reversing the disease.

Magnetic resonance imaging screening to identify spinal and paraspinal infections associated with injections of contaminated methylprednisolone acetate.

IMPORTANCE: Injection of contaminated methylprednisolone has resulted in an unprecedented nationwide outbreak of Exserohilum rostratum fungal infections, manifested initially as meningitis and/or basilar stroke. Insidious onset of spinal or paraspinal infection at the injection site has been increasingly reported and is occurring months after receipt of injection with the contaminated drug. The clinical findings are often subtle and similar to those that led the patient to undergo the methylprednisolone injection. OBJECTIVE: To determine if patients who had not presented for medical care but who had received contaminated methylprednisolone developed spinal or paraspinal infection at the injection site using contrast-enhanced magnetic resonance imaging (MRI) screening. DESIGN, SETTING, AND PARTICIPANTS: There were 172 patients who had received an injection of contaminated methylprednisolone from a highly contaminated lot (No. 06292012@26) at a pain facility but had not presented for medical care related to adverse effects after the injection. Screening MRI was performed between November 9, 2012, and April 30, 2013. MAIN OUTCOMES AND MEASURES: Number of persons identified with previously undiagnosed spinal or paraspinal infection. RESULTS: Of the 172 patients screened, MRI was abnormal in 36 (21%), showing epidural or paraspinal abscess or phlegmon, arachnoiditis, spinal osteomyelitis or diskitis, or moderate to severe epidural, paraspinal, or intradural enhancement. Of the 115 patients asked about new or worsening back or neck pain, lower extremity weakness, or radiculopathy symptoms, 35 (30%) had at least 1 symptom. Thirty-five of the 36 patients with abnormal MRIs met the Centers for Disease Control and Prevention (CDC) case definition for probable (17 patients) or confirmed (18 patients) fungal spinal or paraspinal infection. All 35 patients were treated with antifungal agents (voriconazole, with or without liposomal amphotericin B), and 24 required surgical debridement. At the time of surgery, 17 of 24 patients (71%), including 5 patients who denied having symptoms, had laboratory evidence of fungal infection. CONCLUSIONS AND RELEVANCE: Among patients who underwent screening MRI to look for infection at the site of injection of contaminated methylprednisolone, 21% had an abnormal MRI, and all but one met CDC criteria for probable or confirmed fungal spinal or paraspinal infection. Screening MRI led to identification of patients who had minimal or no symptoms of spinal or paraspinal infection and allowed early initiation of medical and surgical treatment.

Human Dectin-1 deficiency impairs macrophage-mediated defense against phaeohyphomycosis.

Subcutaneous phaeohyphomycosis typically affects immunocompetent individuals following traumatic inoculation. Severe or disseminated infection can occur in CARD9 deficiency or after transplantation, but the mechanisms protecting against phaeohyphomycosis remain unclear. We evaluated a patient with progressive, refractory Corynespora cassiicola phaeohyphomycosis and found that he carried biallelic deleterious mutations in CLEC7A encoding the CARD9-coupled, ß-glucan-binding receptor, Dectin-1. The patient's PBMCs failed to produce TNF-α and IL-1ß in response to ß-glucan and/or C. cassiicola. To confirm the cellular and molecular requirements for immunity against C. cassiicola, we developed a mouse model of this infection. Mouse macrophages required Dectin-1 and CARD9 for IL-1ß and TNF-α production, which enhanced fungal killing in an interdependent manner. Deficiency of either Dectin-1 or CARD9 was associated with more severe fungal disease, recapitulating the human observation. Because these data implicated impaired Dectin-1 responses in susceptibility to phaeohyphomycosis, we evaluated 17 additional unrelated patients with severe forms of the infection. We found that 12 out of 17 carried deleterious CLEC7A mutations associated with an altered Dectin-1 extracellular C-terminal domain and impaired Dectin-1-dependent cytokine production. Thus, we show that Dectin-1 and CARD9 promote protective TNF-α- and IL-1ß-mediated macrophage defense against C. cassiicola. More broadly, we demonstrate that human Dectin-1 deficiency may contribute to susceptibility to severe phaeohyphomycosis by certain dematiaceous fungi.

Use of highly active antiretroviral therapy in patients with renal insufficiency.

Antiretroviral agents, especially nucleoside reverse transcriptase inhibitors, require significant dosage adjustments in patients who have renal dysfunction and the human immunodeficiency virus (HIV). Some antiretroviral agents and fixed combination preparations are contraindicated in this population. In addition, many preferred antiretroviral regimens may be difficult to administer conveniently in patients with decreased creatinine clearance or in those receiving renal replacement therapies. Some highly active antiretroviral therapy regimens, however, can be used conveniently in patients with HIV and altered renal function.

Selecting antifungal agents for the treatment of invasive fungal infections in patients with renal failure.

The use of antifungal agents in patients with renal insufficiency requires careful consideration of not only the degree of renal insufficiency, but also other factors such as the fungal organism involved, site of infection and antifungal pharmacokinetics. Given the increase in the antifungal armamentarium, it is essential to have a comprehensive understanding of these agents to enable tailored therapy in this unique, but not uncommon patient population. This review will focus on the currently available data on this subject, providing guidelines for the use of antifungals in patients with renal failure.

Phenylpiperidine selective serotonin reuptake inhibitors interfere with multidrug efflux pump activity in Staphylococcus aureus.

Structural variants of phenylpiperidine selective serotonin reuptake inhibitors (P-SSRIs) inhibited the function of two unique Staphylococcus aureus multidrug efflux pumps. The most active compound was the paroxetine isomer NNC 20-7052, which had an IC(50) for ethidium, acriflavine, and pyronin Y efflux of 9, 53, and 18% of its MIC, respectively, against the NorA pump. The unbalanced effect of NNC 20-7052 on the efflux of different substrates suggests the possibility that P-SSRIs function by a physical interaction with NorA. Under the conditions employed pump inhibition partially extended to the resistance-nodulation-division (RND) pump AcrAB-TolC, but not to the Pseudomonas aeruginosa RND pumps MexAB-OprM or MexCD-OprJ.

Antifungal drugs in pregnancy: a review.

The use of any medication in pregnant women requires careful consideration of benefit to the mother versus risk posed to the fetus. Fungal infections are not uncommon in pregnant women; in fact, the incidence of certain infections such as Candida vaginitis is increased in this patient population. A variety of antimycotic agents are currently available to treat systemic or mucocutaneous fungal infections. Many of these agents are capable of penetrating the placental barrier and entering fetal cord blood, therefore adverse effects of these agents on the fetus are a valid concern. The use of topical azoles for the treatment of superficial fungal infections is safe and efficacious. However, there are some data suggesting a dose-related increase in the risk of teratogenicity associated with the use of systemic azoles. Amphotericin B remains the drug of choice for the treatment of systemic fungal infections in pregnancy. There are serious risks of fetal malformations associated with the use of griseofulvin, ketoconazole, voriconazole, flucytosine and potassium iodide. These drugs are contraindicated in pregnancy. There are insufficient data regarding the use of caspofungin in pregnancy. This article will review available data regarding the safety of antifungal drug use in pregnant women.

Spinal and paraspinal fungal infections associated with contaminated methylprednisolone injections.

BACKGROUND: A nationwide outbreak of fungal infections was traced to injection of Exserohilum-contaminated methylprednisolone. We describe our experience with patients who developed spinal or paraspinal infection after injection of contaminated methylprednisolone. METHODS: Data were assembled from the Michigan Department of Community Health, electronic medical records, and magnetic resonance imaging (MRI) reports. RESULTS: Of 544 patients who received an epidural injection from a contaminated lot of methylprednisolone at a pain clinic in southeastern Michigan, 153 (28%) were diagnosed at our institution with probable or confirmed spinal or paraspinal fungal infection at the injection site. Forty-one patients had both meningitis and spinal or paraspinal infection, and 112 had only spinal or paraspinal infection. Magnetic resonance imaging abnormalities included abscess, phlegmon, arachnoiditis, and osteomyelitis. Surgical debridement in 116 patients revealed epidural phlegmon and epidural abscess most often. Among 26 patients with an abnormal MRI but with no increase or change in chronic pain, 19 (73%) had infection identified at surgery. Fungal infection was confirmed in 78 patients (51%) by finding hyphae in tissues, positive polymerase chain reaction, or culture. Initial therapy was voriconazole plus liposomal amphotericin B in 115 patients (75%) and voriconazole alone in 38 patients (25%). As of January 31, 2014, 20 patients remained on an azole agent. Five patients died of infection. CONCLUSIONS: We report on 153 patients who had spinal or paraspinal fungal infection at the site of epidural injection of contaminated methylprednisolone. One hundred sixteen (76%) underwent operative debridement in addition to treatment with antifungal agents.

Clostridium difficile colitis: a review.

Clostridium difficile has become an increasingly important nosocomial pathogen and is one of the most common causes of hospital-acquired diarrhea. The incidence of C difficile infection (CDI) is increasing worldwide. Overuse of antibiotics is felt to be a major contributing factor leading to the increased incidence of CDI. The clinical manifestations of CDI vary from a mild form of the disease to fulminant diarrhea, leading to significant patient morbidity and mortality. The increasing incidence of CDI has a major impact on increasing health care costs. This article will summarize the epidemiology, pathogenesis, clinical manifestations, laboratory diagnosis, and treatment options for CDI, as well as infection-control measures for the prevention of CDI.