A US Food & Drug Administration (FDA) Drug Safety Communication concerning a New Class Warning for all gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging (MRI) has been released. Gadolinium has been found to remain in patients’ bodies, including the brain, for months to years.¹

The FDA concluded that the benefit of all approved GBCAs outweighs any potential risks because gadolinium retention has not been directly linked to adverse health effects in patients with normal kidney function. To date, the only known adverse health effect related to gadolinium retention is a rare condition called nephrogenic systemic fibrosis that occurs in a small subgroup of patients with preexisting kidney failure. However, the FDA has recently received reports of adverse events involving multiple organ systems in patients with normal kidney function.¹

After a review by the Medical Imaging Drugs Advisory Committee, the FDA is requiring several actions¹:

• the development of a new Patient Medication Guide for GBCAs
• a requirement that every patient must read educational information before receiving a GBCA
• manufacturers of GBCAs must conduct human and animal studies to further assess the safety of these contrast agents.

FDA recommendations for your practice

The FDA advises that health care professionals should consider the retention characteristics of each agent when choosing a GBCA for patients who might be of higher risk for gadolinium retention.^1,2 These patients include¹:

• those requiring multiple lifetime doses
• pregnant women
• children
• patients with inflammatory conditions.

There are 2 types of GBCAs based on chemical structure: linear and macrocyclic. Linear GBCAs result in more retention and retention for a longer time than macrocyclic GBCAs.² A list of FDA-approved GBCAs with their chemical structures is found here: https://www.fda.gov/Drugs/DrugSafety/ucm589213.htm.²

Recommendations also state that repeated GBCA imaging studies be minimized when possible, particularly closely spaced MRI studies. However, necessary GBCA MRI scans should not be avoided or deferred.¹

Report adverse effects

Health care professionals and patients are encouraged to report adverse effects or side effects related to the use of GBCAs to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program found here: https://www.accessdata.fda.gov/scripts/medwatch/index.cfm?action=reporting.home.

A US Food & Drug Administration (FDA) Drug Safety Communication concerning a New Class Warning for all gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging (MRI) has been released. Gadolinium has been found to remain in patients’ bodies, including the brain, for months to years.¹

The FDA concluded that the benefit of all approved GBCAs outweighs any potential risks because gadolinium retention has not been directly linked to adverse health effects in patients with normal kidney function. To date, the only known adverse health effect related to gadolinium retention is a rare condition called nephrogenic systemic fibrosis that occurs in a small subgroup of patients with preexisting kidney failure. However, the FDA has recently received reports of adverse events involving multiple organ systems in patients with normal kidney function.¹

After a review by the Medical Imaging Drugs Advisory Committee, the FDA is requiring several actions¹:

• the development of a new Patient Medication Guide for GBCAs
• a requirement that every patient must read educational information before receiving a GBCA
• manufacturers of GBCAs must conduct human and animal studies to further assess the safety of these contrast agents.

FDA recommendations for your practice

The FDA advises that health care professionals should consider the retention characteristics of each agent when choosing a GBCA for patients who might be of higher risk for gadolinium retention.^1,2 These patients include¹:

• those requiring multiple lifetime doses
• pregnant women
• children
• patients with inflammatory conditions.

There are 2 types of GBCAs based on chemical structure: linear and macrocyclic. Linear GBCAs result in more retention and retention for a longer time than macrocyclic GBCAs.² A list of FDA-approved GBCAs with their chemical structures is found here: https://www.fda.gov/Drugs/DrugSafety/ucm589213.htm.²

Recommendations also state that repeated GBCA imaging studies be minimized when possible, particularly closely spaced MRI studies. However, necessary GBCA MRI scans should not be avoided or deferred.¹

Report adverse effects

Health care professionals and patients are encouraged to report adverse effects or side effects related to the use of GBCAs to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program found here: https://www.accessdata.fda.gov/scripts/medwatch/index.cfm?action=reporting.home.

A US Food & Drug Administration (FDA) Drug Safety Communication concerning a New Class Warning for all gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging (MRI) has been released. Gadolinium has been found to remain in patients’ bodies, including the brain, for months to years.¹

The FDA concluded that the benefit of all approved GBCAs outweighs any potential risks because gadolinium retention has not been directly linked to adverse health effects in patients with normal kidney function. To date, the only known adverse health effect related to gadolinium retention is a rare condition called nephrogenic systemic fibrosis that occurs in a small subgroup of patients with preexisting kidney failure. However, the FDA has recently received reports of adverse events involving multiple organ systems in patients with normal kidney function.¹

After a review by the Medical Imaging Drugs Advisory Committee, the FDA is requiring several actions¹:

• the development of a new Patient Medication Guide for GBCAs
• a requirement that every patient must read educational information before receiving a GBCA
• manufacturers of GBCAs must conduct human and animal studies to further assess the safety of these contrast agents.

FDA recommendations for your practice

The FDA advises that health care professionals should consider the retention characteristics of each agent when choosing a GBCA for patients who might be of higher risk for gadolinium retention.^1,2 These patients include¹:

• those requiring multiple lifetime doses
• pregnant women
• children
• patients with inflammatory conditions.

There are 2 types of GBCAs based on chemical structure: linear and macrocyclic. Linear GBCAs result in more retention and retention for a longer time than macrocyclic GBCAs.² A list of FDA-approved GBCAs with their chemical structures is found here: https://www.fda.gov/Drugs/DrugSafety/ucm589213.htm.²

Recommendations also state that repeated GBCA imaging studies be minimized when possible, particularly closely spaced MRI studies. However, necessary GBCA MRI scans should not be avoided or deferred.¹

Report adverse effects

Health care professionals and patients are encouraged to report adverse effects or side effects related to the use of GBCAs to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program found here: https://www.accessdata.fda.gov/scripts/medwatch/index.cfm?action=reporting.home.

Background: Although neck and low back pain are leading causes of pain and disability, there is no consensus first-line pharmacologic therapy for treatment. Recent research has pointed to acetaminophen as being ineffective, which – in combination with increased awareness of opioid dependency and adverse risks – could lead to greater use of NSAIDs.

Study design: Systematic review and meta-analysis.

Setting: Randomized controlled trials.

Background: Although neck and low back pain are leading causes of pain and disability, there is no consensus first-line pharmacologic therapy for treatment. Recent research has pointed to acetaminophen as being ineffective, which – in combination with increased awareness of opioid dependency and adverse risks – could lead to greater use of NSAIDs.

Study design: Systematic review and meta-analysis.

Setting: Randomized controlled trials.

Background: Although neck and low back pain are leading causes of pain and disability, there is no consensus first-line pharmacologic therapy for treatment. Recent research has pointed to acetaminophen as being ineffective, which – in combination with increased awareness of opioid dependency and adverse risks – could lead to greater use of NSAIDs.

Study design: Systematic review and meta-analysis.

Setting: Randomized controlled trials.

Malpractice premiums continue to inch down but wide disparities in total cost still linger across states.

Internists, general surgeons, and obstetrician-gynecologists experienced a respective 1% drop in their medical liability premiums last year, according to the 2017 Medical Liability Monitor Annual Rate Survey. The rate drop follows an ongoing trend of decreasing premiums over the last decade.

“The takeaways for doctors are really all good ones in that the rates remain very stable,” said Paul A. Greve Jr. senior vice president/senior consultant for Willis Towers Watson Health Care Practice and coauthor of the 2017 MLM Survey report. “The market for physician coverage remains very competitive because there are so many players involved for what is really a shrinking number of buyers, so the groups and individual physicians that are buying are seeing favorable pricing.”

[email protected]

Malpractice premiums continue to inch down but wide disparities in total cost still linger across states.

Internists, general surgeons, and obstetrician-gynecologists experienced a respective 1% drop in their medical liability premiums last year, according to the 2017 Medical Liability Monitor Annual Rate Survey. The rate drop follows an ongoing trend of decreasing premiums over the last decade.

“The takeaways for doctors are really all good ones in that the rates remain very stable,” said Paul A. Greve Jr. senior vice president/senior consultant for Willis Towers Watson Health Care Practice and coauthor of the 2017 MLM Survey report. “The market for physician coverage remains very competitive because there are so many players involved for what is really a shrinking number of buyers, so the groups and individual physicians that are buying are seeing favorable pricing.”

[email protected]

Malpractice premiums continue to inch down but wide disparities in total cost still linger across states.

Internists, general surgeons, and obstetrician-gynecologists experienced a respective 1% drop in their medical liability premiums last year, according to the 2017 Medical Liability Monitor Annual Rate Survey. The rate drop follows an ongoing trend of decreasing premiums over the last decade.

“The takeaways for doctors are really all good ones in that the rates remain very stable,” said Paul A. Greve Jr. senior vice president/senior consultant for Willis Towers Watson Health Care Practice and coauthor of the 2017 MLM Survey report. “The market for physician coverage remains very competitive because there are so many players involved for what is really a shrinking number of buyers, so the groups and individual physicians that are buying are seeing favorable pricing.”

[email protected]

Surgical therapies remain the preferred treatment for the management of basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), according to new practice guidelines issued by the American Academy of Dermatology.

Nonsurgical approaches such as cryotherapy, photodynamic therapy, and radiation may be considered for low-risk cancers if surgery is contraindicated, but these methods have lower cure rates, according to the guidelines. Christopher K. Bichakjian, MD, professor of dermatology, University of Michigan, Ann Arbor, and Murad Alam, MD, professor of dermatology, Northwestern University, Chicago, cochaired the work groups that developed the guidelines.

[email protected]

Surgical therapies remain the preferred treatment for the management of basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), according to new practice guidelines issued by the American Academy of Dermatology.

Nonsurgical approaches such as cryotherapy, photodynamic therapy, and radiation may be considered for low-risk cancers if surgery is contraindicated, but these methods have lower cure rates, according to the guidelines. Christopher K. Bichakjian, MD, professor of dermatology, University of Michigan, Ann Arbor, and Murad Alam, MD, professor of dermatology, Northwestern University, Chicago, cochaired the work groups that developed the guidelines.

[email protected]

Surgical therapies remain the preferred treatment for the management of basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), according to new practice guidelines issued by the American Academy of Dermatology.

Nonsurgical approaches such as cryotherapy, photodynamic therapy, and radiation may be considered for low-risk cancers if surgery is contraindicated, but these methods have lower cure rates, according to the guidelines. Christopher K. Bichakjian, MD, professor of dermatology, University of Michigan, Ann Arbor, and Murad Alam, MD, professor of dermatology, Northwestern University, Chicago, cochaired the work groups that developed the guidelines.

[email protected]

Varying degrees of nonadherence to hydroxychloroquine (HCQ) treatment characterize the great majority of patients with systemic lupus erythematosus on Medicaid who are newly prescribed the antimalarial, an administrative claims database study has revealed.

Investigators from Brigham and Women’s Hospital, Boston, used prescription refill data to assess nonadherence, hoping to gain greater insight into predictors of nonadherence to HCQ than past studies of nonadherence to the drug, which have been limited by their small and cross-sectional nature and the fact that they often relied on self-reported measures of adherence that were unable to capture the dynamic nature of adherence behavior over time.

Alliance/thinkstockphotos.com

SOURCE: Feldman C et al. Semin Arthritis Rheum. 2018 Jan 8. doi: 10.1016/j.semarthrit.2018.01.002

Varying degrees of nonadherence to hydroxychloroquine (HCQ) treatment characterize the great majority of patients with systemic lupus erythematosus on Medicaid who are newly prescribed the antimalarial, an administrative claims database study has revealed.

Investigators from Brigham and Women’s Hospital, Boston, used prescription refill data to assess nonadherence, hoping to gain greater insight into predictors of nonadherence to HCQ than past studies of nonadherence to the drug, which have been limited by their small and cross-sectional nature and the fact that they often relied on self-reported measures of adherence that were unable to capture the dynamic nature of adherence behavior over time.

Alliance/thinkstockphotos.com

SOURCE: Feldman C et al. Semin Arthritis Rheum. 2018 Jan 8. doi: 10.1016/j.semarthrit.2018.01.002

Varying degrees of nonadherence to hydroxychloroquine (HCQ) treatment characterize the great majority of patients with systemic lupus erythematosus on Medicaid who are newly prescribed the antimalarial, an administrative claims database study has revealed.

Investigators from Brigham and Women’s Hospital, Boston, used prescription refill data to assess nonadherence, hoping to gain greater insight into predictors of nonadherence to HCQ than past studies of nonadherence to the drug, which have been limited by their small and cross-sectional nature and the fact that they often relied on self-reported measures of adherence that were unable to capture the dynamic nature of adherence behavior over time.

Alliance/thinkstockphotos.com

SOURCE: Feldman C et al. Semin Arthritis Rheum. 2018 Jan 8. doi: 10.1016/j.semarthrit.2018.01.002

Mucorales fungi are ubiquitous organisms commonly inhabiting soil and can cause opportunistic infections. The majority of infections are caused by 3 genera: Rhizopus, Mucor, and Rhizomucor.¹ Infection occurs by inhalation or by direct contact with damaged skin. Mucorales infections can have cutaneous, rhinocerebral, pulmonary, gastrointestinal, and central nervous system manifestations. Pulmonary mucormycosis is often rapidly progressive with angioinvasion and fulminant necrosis causing acute dyspnea, hemoptysis, and chest pain. More indolent pulmonary Mucorales infections can mimic a pulmonary mass with occasional cavitation found on imaging studies similar to other fungal infections (eg, Aspergillus).² Risk factors include severe uncontrolled diabetes mellitus (DM), recurrent diabetic ketoacidosis (DKA), immunosuppression due to congenital or acquired causes, hematologic malignancies, and chronic renal failure.³ The authors present a case of a patient with recurrent DKA and pulmonary mucormycosis.

Case Presentation

A 62-year-old male with DM and a more than 30-pack-year smoking history presented to the emergency department with abdominal pain and chest pain ongoing for about 1 week. The patient had a history of frequent admissions with DKA and medication nonadherence.

On admission, the patient was hemodynamically stable. His vital signs were: temperature 97.4° F, heart rate 89 bpm, respirations 24 breathes per minute, blood pressure 146/86 mm Hg, and oxygen saturation 94% on ambient air. The patient appeared ill but the physical examination was otherwise unremarkable. Laboratory results revealed a white blood cell count of 24,400 with neutrophilic predominance, blood glucose 658 mg/dL, creatinine clearance 2.16 mL/min/1.73 m², sodium level 124 mEq/L, bicarbonate 6 mEq/L, anion gap 27 mEq/L, 6.8 pH, partial pressure of CO₂ 11 mm Hg, and lactic acid 2.3 mmol/L.

The patient admitted for DKA management and placed on an insulin drip. Although he did not have a fever or cough productive of sputum or hemoptysis, there was concern that pneumonia might have precipitated DKA. A chest X-ray revealed a patchy, right suprahilar opacity (Figure 1).

The patient was placed on vancomycin 1,000 mg every 12 hours and cefepime 2,000 mg every 12 hours for possible hospital-acquired pneumonia because of his history of recent DKA hospitalization. Once the patient’s anion gap was closed and metabolic acidosis was resolved, the insulin drip was discontinued, and the patient was transferred to the general medical ward for further management. There, he continued to report having chest pain. A computed tomography (CT) scan without contrast of the chest (contrast was held due to recent acute kidney injury) revealed right hilar soft tissue density obstructing the bronchus intermidius, which had resulted in a right-lung collapse and right-sided pleural effusion (Figure 2). The left lung was clear, and there was no evidence of nodularity.

Given the patient’s extensive smoking history, the initial concern was for pulmonary malignancy. The decision was made to proceed with bronchoscopy with endobronchial ultrasound-guided transbronchial needle biopsy. Endobronchial brushings and biopsies of R11, 7, right bronchus intermedius, and right upper lobe were obtained. Gross inspection of the airway revealed markedly abnormal-appearing mucosa involving the take off to the right upper lobe and the entire bronchus intermedius with friable, cobblestoned, and edematous mucosa. Biopsies and immunostaining for occult carcinoma markers, including CD-56, TTF-1, Synaptophysin A, chromogranin, AE1/AE3, and CK-5/6, were negative for malignancy. Final microbiologic analysis was positive for Mucor. There was no evidence of bacterial or mycobacterial growth.

Due to continued suspicion for malignancy and lack of histologic yield, the patient underwent a repeat endobronchial ultrasound-guided needle biopsy. On this occasion, gross inspection revealed significant mucosal necrosis and extensive, extrinsic bronchial compression starting from the right bronchial division and notable throughout the right middle and lower lobes (Figure 3).

Bronchial washings revealed necrotic material with rare fungal hyphae present. Biopsies yielded necrotic material or lung tissue containing nonseptate hyphae with rare, right-angle branching consistent with Mucor (Figures 4 and 5). Malignancy was not present in the specimens obtained.

Based on the bronchoscopy results, thoracic surgery and infectious disease specialists were consulted. Surgical intervention was not recommended because of concerns for potential postoperative complications. The infectious disease specialists recommended initiation of liposomal amphotericin B at 10 mg/kg/d. Magnetic resonance imaging of the head showed parietal lobe enhancement with restricted diffusion most consistent with prior infarct. Paranasal sinus disease also was demonstrated. The latter findings prompted further evaluation. The patient underwent right and left endoscopic resection of concha bullosa as well as left maxillary endoscopic antrostomy. Gross examination showed thick mucosa in left concha bullosa, polypoid changes anterior to bulla ethmoidalis, and clear left maxillary sinus. The procedure had to be aborted when the patient experienced cardiac arrest secondary to ventricular fibrillation; he was successfully resuscitated.

Samples from the contents of right and left sinuses as well as left concha bullosa were submitted to pathology, showing benign respiratory mucosa with chronic inflammation and foci of bone without fungal elements. There was no other evidence of disseminated mucormycosis. The patient had a prolonged hospital course complicated by progressive hypoxemia, acute kidney injury, and toxic metabolic encephalopathy. Three months after his original diagnosis, he sustained another cardiac arrest in the hospital. Shortly after achieving return of spontaneous circulation and initiation of invasive mechanical ventilation, the family elected to withdraw care. The family declined an autopsy.

Discussion

This article describes a case of subacute pulmonary mucormycosis in a patient with recurrent DKA. Although patients with poorly controlled DM commonly present with the rhinocerebral form of mucormycosis, pulmonary involvement with a subacute course has been described. Determining the final diagnosis for the current patient was challenging due to the subtlety of his respiratory symptoms and the inconsistent initial findings on chest radiography. A pulmonary disease was finally suspected when a mass was found on the CT scan. However, the middle mediastinal mass was more suspicious for malignancy, particularly given the patient’s smoking history and persistent hyponatremia. In fact, the lack of any neoplastic findings on the initial endobronchial biopsy prompted the health care team to pursue a second biopsy that was consistent with mucormycosis.

This case demonstrates the challenges of prompt diagnosis and treatment of this potentially fatal infection. Furthermore, the extent of the disease at diagnosis precluded this patient from having a surgical intervention, which has been associated with better outcomes than those of medical management alone. Finally, it remains unknown whether the patient had an underlying malignancy, which could have increased the likelihood of pulmonary mucormycosis; the biopsy yield may have been confounded by repeated sampling of necrotic material caused by mucormycosis. Further investigation of any potential pulmonary neoplasm was limited by the patient’s clinical condition and the poor prognosis due to the extent of infection.

Mucorales is an order of fungi comprised of 6 main families that have potential to cause a variety of infections. The genera Mucor, Rhizopus, and Rhizomucor cause the majority of infections.¹ Mucormycosis (infection with Mucorales) is generally a rare fungal infection with an incidence of about 500 cases per year in the U.S. However, the incidence is increasing with an aging population, higher prevalence of DM and chronic kidney disease, and a growing population of immunocompromised patients due to advances in cancer therapy and transplantation. Risk factors for pulmonary mucormycosis include conditions associated with congenital and acquired immunodeficiency: hematologic malignancies, uncontrolled DM, solid tumors, and organ transplantation.²

Presentation

Notably, there seems to be an association between specific organ system involvement and predisposing conditions. Pulmonary mucormycosis occurs much less frequently than does the rhinocerebral form in patients with DKA but occurs more commonly in patients with neutropenia that is due to chemotherapy or hematopoietic stem cell transplantation (HSCT) for the treatment of hematologic malignancies.²

The mechanisms for preferential site infection are not well understood with current knowledge of mucormycosis pathogenesis. Current research demonstrates monocytes and neutrophils may play a vital role in the body’s defense against Mucor by both phagocytosis and oxidative damage. Chemotaxis and oxidative cell lysis seem to be compromised in states of hyperglycemia and acidosis. Iron metabolism repeatedly has been shown to play a role in the pathogenesis of mucormycosis. Specifically, patients receiving deferoxamine seem to have a predisposition to Mucorales infections, presumably due to the increased iron supply to the fungus.⁴ Notably, systemic acidosis also facilitates higher concentrations of available serum iron.

One of the main characteristics of mucormycosis is its ability to aggressively invade blood vessels, causing thrombosis and necrosis and subsequently disseminate hematogenously or through the lymphatic system. This property, at least in large part, depends on endothelial cell damage following phagocytosis of fungus by these cells.

Of note, some of the azole class of drugs (eg, voriconazole), which may be used for antifungal prophylaxis in patients with hematologic malignancies accompanied by neutropenia, have been implicated in predisposition to mucormycosis.² It also is commonly seen in patients undergoing HSCT. Patients with DM and DKA also can present with pulmonary mucormycosis but generally have a more indolent course unless they develop pulmonary hemorrhage.³ Infection usually occurs by inhalation.

Patients may report dyspnea, cough, and chest pain, which is sometimes accompanied by a fever. Presentation is generally indistinguishable from other causes of pneumonia, and the routinely obtained sputum cultures are usually not diagnostically significant.

Radiographic findings are variable and may include pulmonary nodules, consolidations, masses, and cavitary lesions.¹ Due to tissue invasion, a CT scan of the chest might demonstrate a mass crossing mediastinal tissue planes. Definitive diagnosis requires a biopsy with a demonstration of characteristic broad-based nonseptate hyphae with tissue invasion as well as a positive culture (Figures 4 and 5).⁵ Due to nonspecific symptoms as well as laboratory and imaging findings, a biopsy and, therefore, definitive diagnosis are often delayed. However, postponing medical and surgical therapy for mucormycosis has been associated with worse outcomes.⁶ With the absence of easily available serologic tests and unspecific symptoms in early disease, many mucormycosis cases are diagnosed postmortem.

Treatments

Recently described therapy advancements have indicated improved outcomes.⁷ Nevertheless, prognosis remains universally poor with 65% to 70% mortality for patients with cases of isolated pulmonary mucormycosis.⁸ Many of these patients succumb to sepsis, respiratory failure, and hemoptysis. Patients with pulmonary mucormycosis usually die of dissemination rather than of the sequelae of the pulmonary disease. In fact, pulmonary infection seems to have the highest incidence of dissemination in patients with neutropenia. Surgical therapy seems to have more favorable outcomes than treatment with antifungals alone, especially when considering infection primarily affecting 1 lung.⁸

Amphotericin B remains the first-line agent for treatment of pulmonary mucormycosis. Retrospective studies show that this agent remains one of the few with activity against Mucor with reported successful outcomes. Specifically, the liposomal formulation seems to have greater efficacy.⁹ Strong prospective data are lacking. An increasing body of evidence supports a potential benefit from adding echinocandins.¹⁰ Although these agents have minimal activity against mucormycosis in vitro, adjunctive therapy to amphotericin resulted in better survival. Alternative regimens include the combination of amphotericin with posaconazole or itraconazole. Both these agents seem to have in vitro activity against mucormycosis pathogens, although poor absorption of these agents puts the potential benefit of such combinations in question.

In patients unable to tolerate polyenes due to adverse effects (AEs), the use of posaconazole as monotherapy has been reported with positive results. One retrospective study reported treatment success in up to 60% and stable disease in 21% of patients at 12 weeks. This study included 24 out of 36 patients with pulmonary mucormycosis.¹¹ Significantly fewer AEs and oral administration makes posaconazole an attractive alternative treatment for mucormycosis and needs further prospective evaluation.

Novel therapies have been attempted, though without success thus far. One randomized clinical trial conducted on patients with mucormycosis attempted to determine whether capitalizing on iron metabolism by Mucor by providing adjunctive deferasirox, an iron chelator, would lead to an initial improvement in mortality. However, outcomes did not improve and resulted in higher mortality rates at 90 days in the intervention group.¹²

Reversal of underlying conditions remains the cornerstone of successful therapy. If possible, it is important to cease immunosuppression by avoiding corticosteroids, correcting acidosis and hyperglycemia, and discontinuing aluminum and iron chelators.¹³ This approach becomes problematic in patients with DM with poor glucose control due to nonadherence or lack of resources and in situations where the underlying condition is difficult to treat or the treatment puts patients at risk for mucormycosis (eg, malignancies). Surgery in addition to antifungal therapy should be pursued wherever possible for definitive therapy.

Mucorales fungi are ubiquitous organisms commonly inhabiting soil and can cause opportunistic infections. The majority of infections are caused by 3 genera: Rhizopus, Mucor, and Rhizomucor.¹ Infection occurs by inhalation or by direct contact with damaged skin. Mucorales infections can have cutaneous, rhinocerebral, pulmonary, gastrointestinal, and central nervous system manifestations. Pulmonary mucormycosis is often rapidly progressive with angioinvasion and fulminant necrosis causing acute dyspnea, hemoptysis, and chest pain. More indolent pulmonary Mucorales infections can mimic a pulmonary mass with occasional cavitation found on imaging studies similar to other fungal infections (eg, Aspergillus).² Risk factors include severe uncontrolled diabetes mellitus (DM), recurrent diabetic ketoacidosis (DKA), immunosuppression due to congenital or acquired causes, hematologic malignancies, and chronic renal failure.³ The authors present a case of a patient with recurrent DKA and pulmonary mucormycosis.

Case Presentation

A 62-year-old male with DM and a more than 30-pack-year smoking history presented to the emergency department with abdominal pain and chest pain ongoing for about 1 week. The patient had a history of frequent admissions with DKA and medication nonadherence.

On admission, the patient was hemodynamically stable. His vital signs were: temperature 97.4° F, heart rate 89 bpm, respirations 24 breathes per minute, blood pressure 146/86 mm Hg, and oxygen saturation 94% on ambient air. The patient appeared ill but the physical examination was otherwise unremarkable. Laboratory results revealed a white blood cell count of 24,400 with neutrophilic predominance, blood glucose 658 mg/dL, creatinine clearance 2.16 mL/min/1.73 m², sodium level 124 mEq/L, bicarbonate 6 mEq/L, anion gap 27 mEq/L, 6.8 pH, partial pressure of CO₂ 11 mm Hg, and lactic acid 2.3 mmol/L.

The patient admitted for DKA management and placed on an insulin drip. Although he did not have a fever or cough productive of sputum or hemoptysis, there was concern that pneumonia might have precipitated DKA. A chest X-ray revealed a patchy, right suprahilar opacity (Figure 1).

The patient was placed on vancomycin 1,000 mg every 12 hours and cefepime 2,000 mg every 12 hours for possible hospital-acquired pneumonia because of his history of recent DKA hospitalization. Once the patient’s anion gap was closed and metabolic acidosis was resolved, the insulin drip was discontinued, and the patient was transferred to the general medical ward for further management. There, he continued to report having chest pain. A computed tomography (CT) scan without contrast of the chest (contrast was held due to recent acute kidney injury) revealed right hilar soft tissue density obstructing the bronchus intermidius, which had resulted in a right-lung collapse and right-sided pleural effusion (Figure 2). The left lung was clear, and there was no evidence of nodularity.

Given the patient’s extensive smoking history, the initial concern was for pulmonary malignancy. The decision was made to proceed with bronchoscopy with endobronchial ultrasound-guided transbronchial needle biopsy. Endobronchial brushings and biopsies of R11, 7, right bronchus intermedius, and right upper lobe were obtained. Gross inspection of the airway revealed markedly abnormal-appearing mucosa involving the take off to the right upper lobe and the entire bronchus intermedius with friable, cobblestoned, and edematous mucosa. Biopsies and immunostaining for occult carcinoma markers, including CD-56, TTF-1, Synaptophysin A, chromogranin, AE1/AE3, and CK-5/6, were negative for malignancy. Final microbiologic analysis was positive for Mucor. There was no evidence of bacterial or mycobacterial growth.

Due to continued suspicion for malignancy and lack of histologic yield, the patient underwent a repeat endobronchial ultrasound-guided needle biopsy. On this occasion, gross inspection revealed significant mucosal necrosis and extensive, extrinsic bronchial compression starting from the right bronchial division and notable throughout the right middle and lower lobes (Figure 3).

Bronchial washings revealed necrotic material with rare fungal hyphae present. Biopsies yielded necrotic material or lung tissue containing nonseptate hyphae with rare, right-angle branching consistent with Mucor (Figures 4 and 5). Malignancy was not present in the specimens obtained.

Based on the bronchoscopy results, thoracic surgery and infectious disease specialists were consulted. Surgical intervention was not recommended because of concerns for potential postoperative complications. The infectious disease specialists recommended initiation of liposomal amphotericin B at 10 mg/kg/d. Magnetic resonance imaging of the head showed parietal lobe enhancement with restricted diffusion most consistent with prior infarct. Paranasal sinus disease also was demonstrated. The latter findings prompted further evaluation. The patient underwent right and left endoscopic resection of concha bullosa as well as left maxillary endoscopic antrostomy. Gross examination showed thick mucosa in left concha bullosa, polypoid changes anterior to bulla ethmoidalis, and clear left maxillary sinus. The procedure had to be aborted when the patient experienced cardiac arrest secondary to ventricular fibrillation; he was successfully resuscitated.

Samples from the contents of right and left sinuses as well as left concha bullosa were submitted to pathology, showing benign respiratory mucosa with chronic inflammation and foci of bone without fungal elements. There was no other evidence of disseminated mucormycosis. The patient had a prolonged hospital course complicated by progressive hypoxemia, acute kidney injury, and toxic metabolic encephalopathy. Three months after his original diagnosis, he sustained another cardiac arrest in the hospital. Shortly after achieving return of spontaneous circulation and initiation of invasive mechanical ventilation, the family elected to withdraw care. The family declined an autopsy.

Discussion

This article describes a case of subacute pulmonary mucormycosis in a patient with recurrent DKA. Although patients with poorly controlled DM commonly present with the rhinocerebral form of mucormycosis, pulmonary involvement with a subacute course has been described. Determining the final diagnosis for the current patient was challenging due to the subtlety of his respiratory symptoms and the inconsistent initial findings on chest radiography. A pulmonary disease was finally suspected when a mass was found on the CT scan. However, the middle mediastinal mass was more suspicious for malignancy, particularly given the patient’s smoking history and persistent hyponatremia. In fact, the lack of any neoplastic findings on the initial endobronchial biopsy prompted the health care team to pursue a second biopsy that was consistent with mucormycosis.

This case demonstrates the challenges of prompt diagnosis and treatment of this potentially fatal infection. Furthermore, the extent of the disease at diagnosis precluded this patient from having a surgical intervention, which has been associated with better outcomes than those of medical management alone. Finally, it remains unknown whether the patient had an underlying malignancy, which could have increased the likelihood of pulmonary mucormycosis; the biopsy yield may have been confounded by repeated sampling of necrotic material caused by mucormycosis. Further investigation of any potential pulmonary neoplasm was limited by the patient’s clinical condition and the poor prognosis due to the extent of infection.

Mucorales is an order of fungi comprised of 6 main families that have potential to cause a variety of infections. The genera Mucor, Rhizopus, and Rhizomucor cause the majority of infections.¹ Mucormycosis (infection with Mucorales) is generally a rare fungal infection with an incidence of about 500 cases per year in the U.S. However, the incidence is increasing with an aging population, higher prevalence of DM and chronic kidney disease, and a growing population of immunocompromised patients due to advances in cancer therapy and transplantation. Risk factors for pulmonary mucormycosis include conditions associated with congenital and acquired immunodeficiency: hematologic malignancies, uncontrolled DM, solid tumors, and organ transplantation.²

Presentation

Notably, there seems to be an association between specific organ system involvement and predisposing conditions. Pulmonary mucormycosis occurs much less frequently than does the rhinocerebral form in patients with DKA but occurs more commonly in patients with neutropenia that is due to chemotherapy or hematopoietic stem cell transplantation (HSCT) for the treatment of hematologic malignancies.²

The mechanisms for preferential site infection are not well understood with current knowledge of mucormycosis pathogenesis. Current research demonstrates monocytes and neutrophils may play a vital role in the body’s defense against Mucor by both phagocytosis and oxidative damage. Chemotaxis and oxidative cell lysis seem to be compromised in states of hyperglycemia and acidosis. Iron metabolism repeatedly has been shown to play a role in the pathogenesis of mucormycosis. Specifically, patients receiving deferoxamine seem to have a predisposition to Mucorales infections, presumably due to the increased iron supply to the fungus.⁴ Notably, systemic acidosis also facilitates higher concentrations of available serum iron.

One of the main characteristics of mucormycosis is its ability to aggressively invade blood vessels, causing thrombosis and necrosis and subsequently disseminate hematogenously or through the lymphatic system. This property, at least in large part, depends on endothelial cell damage following phagocytosis of fungus by these cells.

Of note, some of the azole class of drugs (eg, voriconazole), which may be used for antifungal prophylaxis in patients with hematologic malignancies accompanied by neutropenia, have been implicated in predisposition to mucormycosis.² It also is commonly seen in patients undergoing HSCT. Patients with DM and DKA also can present with pulmonary mucormycosis but generally have a more indolent course unless they develop pulmonary hemorrhage.³ Infection usually occurs by inhalation.

Patients may report dyspnea, cough, and chest pain, which is sometimes accompanied by a fever. Presentation is generally indistinguishable from other causes of pneumonia, and the routinely obtained sputum cultures are usually not diagnostically significant.

Radiographic findings are variable and may include pulmonary nodules, consolidations, masses, and cavitary lesions.¹ Due to tissue invasion, a CT scan of the chest might demonstrate a mass crossing mediastinal tissue planes. Definitive diagnosis requires a biopsy with a demonstration of characteristic broad-based nonseptate hyphae with tissue invasion as well as a positive culture (Figures 4 and 5).⁵ Due to nonspecific symptoms as well as laboratory and imaging findings, a biopsy and, therefore, definitive diagnosis are often delayed. However, postponing medical and surgical therapy for mucormycosis has been associated with worse outcomes.⁶ With the absence of easily available serologic tests and unspecific symptoms in early disease, many mucormycosis cases are diagnosed postmortem.

Treatments

Recently described therapy advancements have indicated improved outcomes.⁷ Nevertheless, prognosis remains universally poor with 65% to 70% mortality for patients with cases of isolated pulmonary mucormycosis.⁸ Many of these patients succumb to sepsis, respiratory failure, and hemoptysis. Patients with pulmonary mucormycosis usually die of dissemination rather than of the sequelae of the pulmonary disease. In fact, pulmonary infection seems to have the highest incidence of dissemination in patients with neutropenia. Surgical therapy seems to have more favorable outcomes than treatment with antifungals alone, especially when considering infection primarily affecting 1 lung.⁸

Amphotericin B remains the first-line agent for treatment of pulmonary mucormycosis. Retrospective studies show that this agent remains one of the few with activity against Mucor with reported successful outcomes. Specifically, the liposomal formulation seems to have greater efficacy.⁹ Strong prospective data are lacking. An increasing body of evidence supports a potential benefit from adding echinocandins.¹⁰ Although these agents have minimal activity against mucormycosis in vitro, adjunctive therapy to amphotericin resulted in better survival. Alternative regimens include the combination of amphotericin with posaconazole or itraconazole. Both these agents seem to have in vitro activity against mucormycosis pathogens, although poor absorption of these agents puts the potential benefit of such combinations in question.

In patients unable to tolerate polyenes due to adverse effects (AEs), the use of posaconazole as monotherapy has been reported with positive results. One retrospective study reported treatment success in up to 60% and stable disease in 21% of patients at 12 weeks. This study included 24 out of 36 patients with pulmonary mucormycosis.¹¹ Significantly fewer AEs and oral administration makes posaconazole an attractive alternative treatment for mucormycosis and needs further prospective evaluation.

Novel therapies have been attempted, though without success thus far. One randomized clinical trial conducted on patients with mucormycosis attempted to determine whether capitalizing on iron metabolism by Mucor by providing adjunctive deferasirox, an iron chelator, would lead to an initial improvement in mortality. However, outcomes did not improve and resulted in higher mortality rates at 90 days in the intervention group.¹²

Reversal of underlying conditions remains the cornerstone of successful therapy. If possible, it is important to cease immunosuppression by avoiding corticosteroids, correcting acidosis and hyperglycemia, and discontinuing aluminum and iron chelators.¹³ This approach becomes problematic in patients with DM with poor glucose control due to nonadherence or lack of resources and in situations where the underlying condition is difficult to treat or the treatment puts patients at risk for mucormycosis (eg, malignancies). Surgery in addition to antifungal therapy should be pursued wherever possible for definitive therapy.

Mucorales fungi are ubiquitous organisms commonly inhabiting soil and can cause opportunistic infections. The majority of infections are caused by 3 genera: Rhizopus, Mucor, and Rhizomucor.¹ Infection occurs by inhalation or by direct contact with damaged skin. Mucorales infections can have cutaneous, rhinocerebral, pulmonary, gastrointestinal, and central nervous system manifestations. Pulmonary mucormycosis is often rapidly progressive with angioinvasion and fulminant necrosis causing acute dyspnea, hemoptysis, and chest pain. More indolent pulmonary Mucorales infections can mimic a pulmonary mass with occasional cavitation found on imaging studies similar to other fungal infections (eg, Aspergillus).² Risk factors include severe uncontrolled diabetes mellitus (DM), recurrent diabetic ketoacidosis (DKA), immunosuppression due to congenital or acquired causes, hematologic malignancies, and chronic renal failure.³ The authors present a case of a patient with recurrent DKA and pulmonary mucormycosis.

Case Presentation

A 62-year-old male with DM and a more than 30-pack-year smoking history presented to the emergency department with abdominal pain and chest pain ongoing for about 1 week. The patient had a history of frequent admissions with DKA and medication nonadherence.

On admission, the patient was hemodynamically stable. His vital signs were: temperature 97.4° F, heart rate 89 bpm, respirations 24 breathes per minute, blood pressure 146/86 mm Hg, and oxygen saturation 94% on ambient air. The patient appeared ill but the physical examination was otherwise unremarkable. Laboratory results revealed a white blood cell count of 24,400 with neutrophilic predominance, blood glucose 658 mg/dL, creatinine clearance 2.16 mL/min/1.73 m², sodium level 124 mEq/L, bicarbonate 6 mEq/L, anion gap 27 mEq/L, 6.8 pH, partial pressure of CO₂ 11 mm Hg, and lactic acid 2.3 mmol/L.

The patient admitted for DKA management and placed on an insulin drip. Although he did not have a fever or cough productive of sputum or hemoptysis, there was concern that pneumonia might have precipitated DKA. A chest X-ray revealed a patchy, right suprahilar opacity (Figure 1).

The patient was placed on vancomycin 1,000 mg every 12 hours and cefepime 2,000 mg every 12 hours for possible hospital-acquired pneumonia because of his history of recent DKA hospitalization. Once the patient’s anion gap was closed and metabolic acidosis was resolved, the insulin drip was discontinued, and the patient was transferred to the general medical ward for further management. There, he continued to report having chest pain. A computed tomography (CT) scan without contrast of the chest (contrast was held due to recent acute kidney injury) revealed right hilar soft tissue density obstructing the bronchus intermidius, which had resulted in a right-lung collapse and right-sided pleural effusion (Figure 2). The left lung was clear, and there was no evidence of nodularity.

Given the patient’s extensive smoking history, the initial concern was for pulmonary malignancy. The decision was made to proceed with bronchoscopy with endobronchial ultrasound-guided transbronchial needle biopsy. Endobronchial brushings and biopsies of R11, 7, right bronchus intermedius, and right upper lobe were obtained. Gross inspection of the airway revealed markedly abnormal-appearing mucosa involving the take off to the right upper lobe and the entire bronchus intermedius with friable, cobblestoned, and edematous mucosa. Biopsies and immunostaining for occult carcinoma markers, including CD-56, TTF-1, Synaptophysin A, chromogranin, AE1/AE3, and CK-5/6, were negative for malignancy. Final microbiologic analysis was positive for Mucor. There was no evidence of bacterial or mycobacterial growth.

Due to continued suspicion for malignancy and lack of histologic yield, the patient underwent a repeat endobronchial ultrasound-guided needle biopsy. On this occasion, gross inspection revealed significant mucosal necrosis and extensive, extrinsic bronchial compression starting from the right bronchial division and notable throughout the right middle and lower lobes (Figure 3).

Bronchial washings revealed necrotic material with rare fungal hyphae present. Biopsies yielded necrotic material or lung tissue containing nonseptate hyphae with rare, right-angle branching consistent with Mucor (Figures 4 and 5). Malignancy was not present in the specimens obtained.

Based on the bronchoscopy results, thoracic surgery and infectious disease specialists were consulted. Surgical intervention was not recommended because of concerns for potential postoperative complications. The infectious disease specialists recommended initiation of liposomal amphotericin B at 10 mg/kg/d. Magnetic resonance imaging of the head showed parietal lobe enhancement with restricted diffusion most consistent with prior infarct. Paranasal sinus disease also was demonstrated. The latter findings prompted further evaluation. The patient underwent right and left endoscopic resection of concha bullosa as well as left maxillary endoscopic antrostomy. Gross examination showed thick mucosa in left concha bullosa, polypoid changes anterior to bulla ethmoidalis, and clear left maxillary sinus. The procedure had to be aborted when the patient experienced cardiac arrest secondary to ventricular fibrillation; he was successfully resuscitated.

Samples from the contents of right and left sinuses as well as left concha bullosa were submitted to pathology, showing benign respiratory mucosa with chronic inflammation and foci of bone without fungal elements. There was no other evidence of disseminated mucormycosis. The patient had a prolonged hospital course complicated by progressive hypoxemia, acute kidney injury, and toxic metabolic encephalopathy. Three months after his original diagnosis, he sustained another cardiac arrest in the hospital. Shortly after achieving return of spontaneous circulation and initiation of invasive mechanical ventilation, the family elected to withdraw care. The family declined an autopsy.

Discussion

This article describes a case of subacute pulmonary mucormycosis in a patient with recurrent DKA. Although patients with poorly controlled DM commonly present with the rhinocerebral form of mucormycosis, pulmonary involvement with a subacute course has been described. Determining the final diagnosis for the current patient was challenging due to the subtlety of his respiratory symptoms and the inconsistent initial findings on chest radiography. A pulmonary disease was finally suspected when a mass was found on the CT scan. However, the middle mediastinal mass was more suspicious for malignancy, particularly given the patient’s smoking history and persistent hyponatremia. In fact, the lack of any neoplastic findings on the initial endobronchial biopsy prompted the health care team to pursue a second biopsy that was consistent with mucormycosis.

This case demonstrates the challenges of prompt diagnosis and treatment of this potentially fatal infection. Furthermore, the extent of the disease at diagnosis precluded this patient from having a surgical intervention, which has been associated with better outcomes than those of medical management alone. Finally, it remains unknown whether the patient had an underlying malignancy, which could have increased the likelihood of pulmonary mucormycosis; the biopsy yield may have been confounded by repeated sampling of necrotic material caused by mucormycosis. Further investigation of any potential pulmonary neoplasm was limited by the patient’s clinical condition and the poor prognosis due to the extent of infection.

Mucorales is an order of fungi comprised of 6 main families that have potential to cause a variety of infections. The genera Mucor, Rhizopus, and Rhizomucor cause the majority of infections.¹ Mucormycosis (infection with Mucorales) is generally a rare fungal infection with an incidence of about 500 cases per year in the U.S. However, the incidence is increasing with an aging population, higher prevalence of DM and chronic kidney disease, and a growing population of immunocompromised patients due to advances in cancer therapy and transplantation. Risk factors for pulmonary mucormycosis include conditions associated with congenital and acquired immunodeficiency: hematologic malignancies, uncontrolled DM, solid tumors, and organ transplantation.²

Presentation

Notably, there seems to be an association between specific organ system involvement and predisposing conditions. Pulmonary mucormycosis occurs much less frequently than does the rhinocerebral form in patients with DKA but occurs more commonly in patients with neutropenia that is due to chemotherapy or hematopoietic stem cell transplantation (HSCT) for the treatment of hematologic malignancies.²

The mechanisms for preferential site infection are not well understood with current knowledge of mucormycosis pathogenesis. Current research demonstrates monocytes and neutrophils may play a vital role in the body’s defense against Mucor by both phagocytosis and oxidative damage. Chemotaxis and oxidative cell lysis seem to be compromised in states of hyperglycemia and acidosis. Iron metabolism repeatedly has been shown to play a role in the pathogenesis of mucormycosis. Specifically, patients receiving deferoxamine seem to have a predisposition to Mucorales infections, presumably due to the increased iron supply to the fungus.⁴ Notably, systemic acidosis also facilitates higher concentrations of available serum iron.

One of the main characteristics of mucormycosis is its ability to aggressively invade blood vessels, causing thrombosis and necrosis and subsequently disseminate hematogenously or through the lymphatic system. This property, at least in large part, depends on endothelial cell damage following phagocytosis of fungus by these cells.

Of note, some of the azole class of drugs (eg, voriconazole), which may be used for antifungal prophylaxis in patients with hematologic malignancies accompanied by neutropenia, have been implicated in predisposition to mucormycosis.² It also is commonly seen in patients undergoing HSCT. Patients with DM and DKA also can present with pulmonary mucormycosis but generally have a more indolent course unless they develop pulmonary hemorrhage.³ Infection usually occurs by inhalation.

Patients may report dyspnea, cough, and chest pain, which is sometimes accompanied by a fever. Presentation is generally indistinguishable from other causes of pneumonia, and the routinely obtained sputum cultures are usually not diagnostically significant.

Radiographic findings are variable and may include pulmonary nodules, consolidations, masses, and cavitary lesions.¹ Due to tissue invasion, a CT scan of the chest might demonstrate a mass crossing mediastinal tissue planes. Definitive diagnosis requires a biopsy with a demonstration of characteristic broad-based nonseptate hyphae with tissue invasion as well as a positive culture (Figures 4 and 5).⁵ Due to nonspecific symptoms as well as laboratory and imaging findings, a biopsy and, therefore, definitive diagnosis are often delayed. However, postponing medical and surgical therapy for mucormycosis has been associated with worse outcomes.⁶ With the absence of easily available serologic tests and unspecific symptoms in early disease, many mucormycosis cases are diagnosed postmortem.

Treatments

Recently described therapy advancements have indicated improved outcomes.⁷ Nevertheless, prognosis remains universally poor with 65% to 70% mortality for patients with cases of isolated pulmonary mucormycosis.⁸ Many of these patients succumb to sepsis, respiratory failure, and hemoptysis. Patients with pulmonary mucormycosis usually die of dissemination rather than of the sequelae of the pulmonary disease. In fact, pulmonary infection seems to have the highest incidence of dissemination in patients with neutropenia. Surgical therapy seems to have more favorable outcomes than treatment with antifungals alone, especially when considering infection primarily affecting 1 lung.⁸

Amphotericin B remains the first-line agent for treatment of pulmonary mucormycosis. Retrospective studies show that this agent remains one of the few with activity against Mucor with reported successful outcomes. Specifically, the liposomal formulation seems to have greater efficacy.⁹ Strong prospective data are lacking. An increasing body of evidence supports a potential benefit from adding echinocandins.¹⁰ Although these agents have minimal activity against mucormycosis in vitro, adjunctive therapy to amphotericin resulted in better survival. Alternative regimens include the combination of amphotericin with posaconazole or itraconazole. Both these agents seem to have in vitro activity against mucormycosis pathogens, although poor absorption of these agents puts the potential benefit of such combinations in question.

In patients unable to tolerate polyenes due to adverse effects (AEs), the use of posaconazole as monotherapy has been reported with positive results. One retrospective study reported treatment success in up to 60% and stable disease in 21% of patients at 12 weeks. This study included 24 out of 36 patients with pulmonary mucormycosis.¹¹ Significantly fewer AEs and oral administration makes posaconazole an attractive alternative treatment for mucormycosis and needs further prospective evaluation.

Novel therapies have been attempted, though without success thus far. One randomized clinical trial conducted on patients with mucormycosis attempted to determine whether capitalizing on iron metabolism by Mucor by providing adjunctive deferasirox, an iron chelator, would lead to an initial improvement in mortality. However, outcomes did not improve and resulted in higher mortality rates at 90 days in the intervention group.¹²

Reversal of underlying conditions remains the cornerstone of successful therapy. If possible, it is important to cease immunosuppression by avoiding corticosteroids, correcting acidosis and hyperglycemia, and discontinuing aluminum and iron chelators.¹³ This approach becomes problematic in patients with DM with poor glucose control due to nonadherence or lack of resources and in situations where the underlying condition is difficult to treat or the treatment puts patients at risk for mucormycosis (eg, malignancies). Surgery in addition to antifungal therapy should be pursued wherever possible for definitive therapy.

Photo by Bill Branson

Adding carfilzomib (K) to treatment with lenalidomide and dexamethasone (Rd) can improve overall survival (OS) in patients with relapsed or refractory multiple myeloma (MM), according to research published in the Journal of Clinical Oncology.

Final results from the phase 3 ASPIRE trial showed that KRd reduced the risk of death by 21% and extended OS by 7.9 months, when compared to Rd.

In patients at first relapse, KRd was associated with an OS improvement of 11.4 months.

“Results from the final analysis of the phase 3 ASPIRE trial . . . are significant, as they further validate carfilzomib, lenalidomide, and dexamethasone as a standard-of-care regimen for patients with relapsed or refractory multiple myeloma,” said study author Keith Stewart, MBChB, of Mayo Clinic in Scottsdale, Arizona.

“Furthermore, these data showed that early use of carfilzomib, lenalidomide, and dexamethasone at first relapse provided nearly 1 additional year of survival for patients, regardless of prior treatment with bortezomib or transplant.”

ASPIRE enrolled 792 MM patients who had received a median of 2 prior therapies (range, 1-3). They were randomized to receive KRd (n=396) or Rd (n=396). Baseline characteristics were well balanced between the treatment arms.

Details on patients and treatment, as well as interim results from ASPIRE, were reported at the 2014 ASH Annual Meeting and published in NEJM in January 2015.

Treatment update

In the final analysis, there were 340 patients in the KRd arm and 358 in the Rd arm who stopped study treatment.

Reasons for discontinuation (in the KRd and Rd arms, respectively) were disease progression (n=188 and 224), adverse events (AEs, n=79 and 85), other reasons (n=61 and 35), withdrawn consent (n=10 and 12), and noncompliance (n=2 and 1).

A total of 182 patients in the KRd arm and 211 in the Rd arm received subsequent treatment for MM. These treatments were generally balanced between the KRd and Rd arms.

The median time to next treatment from the time of randomization was 39.0 months in the KRd arm and 24.4 months in the Rd arm (hazard ratio [HR]=0.65 P<0.001).

Survival

Interim ASPIRE data had shown a significant improvement in progression-free survival (PFS) and a trend toward improved OS in patients who received KRd. Now, researchers have observed a significant improvement in both endpoints with KRd.

The data cutoff for the final analysis was April 28, 2017. For PFS, the median follow-up was 48.8 months in the KRd arm and 48.0 months in the Rd arm.

The median PFS was 26.1 months in the KRd arm and 16.6 months in the Rd arm (9.5-month improvement, HR=0.66; P<0.001). The 3-year PFS rates were 38.2% and 28.4%, respectively. And the 5-year PFS rates were 25.6% and 17.3%, respectively.

The median follow-up for OS was 67.1 months. The median OS was 48.3 months in the KRd arm and 40.4 months in the Rd arm (7.9-month improvement, HR=0.79, P=0.0045).

The researchers also performed subgroup analyses according to prior lines of therapy, prior bortezomib exposure at first relapse, and prior transplant at first relapse.

In patients who had received 1 prior line of therapy, the median OS was 47.3 months in the KRd arm and 35.9 months in the Rd arm (11.4-month improvement, HR=0.81). For patients with 2 or more prior lines of therapy, the median OS was 48.8 months and 42.3 months, respectively (6.5-month improvement, HR=0.79).

Among patients with prior bortezomib exposure at first relapse, the median OS was 45.9 months in the KRd arm and 33.9 months in the Rd arm (12-month improvement, HR=0.82). Among patients without prior bortezomib exposure at first relapse, the median OS was 48.3 months and 40.4 months, respectively (7.9-month improvement, HR=0.80).

Among patients with prior transplant at first relapse, the median OS was 57.2 months in the KRd arm and 38.6 months in the Rd arm (18.6-month improvement, HR=0.71).

Safety

The incidence of treatment-emergent AEs was 98% in the KRd arm and 97.9% in the Rd arm. The incidence of grade 3 or higher AEs was 87% and 83.3%, respectively. The incidence of serious AEs was 65.3% and 56.8%, respectively.

Treatment discontinuation due to an AE occurred in 19.9% of patients in the KRd arm and 21.5% of patients in the Rd arm.

AEs of interest (in the KRd and Rd arms, respectively) included acute renal failure (9.2% and 7.7%), cardiac failure (7.1% and 4.1%), ischemic heart disease (6.9% and 4.6%), hypertension (17.1% and 8.7%), hematopoietic thrombocytopenia (32.7% and 26.2%), and peripheral neuropathy (18.9% and 17.2%).

Fatal AEs were reported in 11.5% of patients in the KRd arm and 10.8% of those in the Rd arm.

Fatal AEs reported in at least 2 patients in the KRd arm included (in the KRd and Rd arms, respectively) cardiac disorders (2.6% and 2.3%), pneumonia (1.5% and 0.8%), sepsis (0.8% for both), myocardial infarction (0.8% and 0.5%), acute respiratory distress syndrome (0.8% and 0%), death (0.5% for both), and cardiac arrest (0.5% and 0.3%).

This trial was funded by Onyx Pharmaceuticals, Inc.

Photo by Bill Branson

Adding carfilzomib (K) to treatment with lenalidomide and dexamethasone (Rd) can improve overall survival (OS) in patients with relapsed or refractory multiple myeloma (MM), according to research published in the Journal of Clinical Oncology.

Final results from the phase 3 ASPIRE trial showed that KRd reduced the risk of death by 21% and extended OS by 7.9 months, when compared to Rd.

In patients at first relapse, KRd was associated with an OS improvement of 11.4 months.

“Results from the final analysis of the phase 3 ASPIRE trial . . . are significant, as they further validate carfilzomib, lenalidomide, and dexamethasone as a standard-of-care regimen for patients with relapsed or refractory multiple myeloma,” said study author Keith Stewart, MBChB, of Mayo Clinic in Scottsdale, Arizona.

“Furthermore, these data showed that early use of carfilzomib, lenalidomide, and dexamethasone at first relapse provided nearly 1 additional year of survival for patients, regardless of prior treatment with bortezomib or transplant.”

ASPIRE enrolled 792 MM patients who had received a median of 2 prior therapies (range, 1-3). They were randomized to receive KRd (n=396) or Rd (n=396). Baseline characteristics were well balanced between the treatment arms.

Details on patients and treatment, as well as interim results from ASPIRE, were reported at the 2014 ASH Annual Meeting and published in NEJM in January 2015.

Treatment update

In the final analysis, there were 340 patients in the KRd arm and 358 in the Rd arm who stopped study treatment.

Reasons for discontinuation (in the KRd and Rd arms, respectively) were disease progression (n=188 and 224), adverse events (AEs, n=79 and 85), other reasons (n=61 and 35), withdrawn consent (n=10 and 12), and noncompliance (n=2 and 1).

A total of 182 patients in the KRd arm and 211 in the Rd arm received subsequent treatment for MM. These treatments were generally balanced between the KRd and Rd arms.

The median time to next treatment from the time of randomization was 39.0 months in the KRd arm and 24.4 months in the Rd arm (hazard ratio [HR]=0.65 P<0.001).

Survival

Interim ASPIRE data had shown a significant improvement in progression-free survival (PFS) and a trend toward improved OS in patients who received KRd. Now, researchers have observed a significant improvement in both endpoints with KRd.

The data cutoff for the final analysis was April 28, 2017. For PFS, the median follow-up was 48.8 months in the KRd arm and 48.0 months in the Rd arm.

The median PFS was 26.1 months in the KRd arm and 16.6 months in the Rd arm (9.5-month improvement, HR=0.66; P<0.001). The 3-year PFS rates were 38.2% and 28.4%, respectively. And the 5-year PFS rates were 25.6% and 17.3%, respectively.

The median follow-up for OS was 67.1 months. The median OS was 48.3 months in the KRd arm and 40.4 months in the Rd arm (7.9-month improvement, HR=0.79, P=0.0045).

The researchers also performed subgroup analyses according to prior lines of therapy, prior bortezomib exposure at first relapse, and prior transplant at first relapse.

In patients who had received 1 prior line of therapy, the median OS was 47.3 months in the KRd arm and 35.9 months in the Rd arm (11.4-month improvement, HR=0.81). For patients with 2 or more prior lines of therapy, the median OS was 48.8 months and 42.3 months, respectively (6.5-month improvement, HR=0.79).

Among patients with prior bortezomib exposure at first relapse, the median OS was 45.9 months in the KRd arm and 33.9 months in the Rd arm (12-month improvement, HR=0.82). Among patients without prior bortezomib exposure at first relapse, the median OS was 48.3 months and 40.4 months, respectively (7.9-month improvement, HR=0.80).

Among patients with prior transplant at first relapse, the median OS was 57.2 months in the KRd arm and 38.6 months in the Rd arm (18.6-month improvement, HR=0.71).

Safety

The incidence of treatment-emergent AEs was 98% in the KRd arm and 97.9% in the Rd arm. The incidence of grade 3 or higher AEs was 87% and 83.3%, respectively. The incidence of serious AEs was 65.3% and 56.8%, respectively.

Treatment discontinuation due to an AE occurred in 19.9% of patients in the KRd arm and 21.5% of patients in the Rd arm.

AEs of interest (in the KRd and Rd arms, respectively) included acute renal failure (9.2% and 7.7%), cardiac failure (7.1% and 4.1%), ischemic heart disease (6.9% and 4.6%), hypertension (17.1% and 8.7%), hematopoietic thrombocytopenia (32.7% and 26.2%), and peripheral neuropathy (18.9% and 17.2%).

Fatal AEs were reported in 11.5% of patients in the KRd arm and 10.8% of those in the Rd arm.

Fatal AEs reported in at least 2 patients in the KRd arm included (in the KRd and Rd arms, respectively) cardiac disorders (2.6% and 2.3%), pneumonia (1.5% and 0.8%), sepsis (0.8% for both), myocardial infarction (0.8% and 0.5%), acute respiratory distress syndrome (0.8% and 0%), death (0.5% for both), and cardiac arrest (0.5% and 0.3%).

This trial was funded by Onyx Pharmaceuticals, Inc.

Photo by Bill Branson

Adding carfilzomib (K) to treatment with lenalidomide and dexamethasone (Rd) can improve overall survival (OS) in patients with relapsed or refractory multiple myeloma (MM), according to research published in the Journal of Clinical Oncology.

Final results from the phase 3 ASPIRE trial showed that KRd reduced the risk of death by 21% and extended OS by 7.9 months, when compared to Rd.

In patients at first relapse, KRd was associated with an OS improvement of 11.4 months.

“Results from the final analysis of the phase 3 ASPIRE trial . . . are significant, as they further validate carfilzomib, lenalidomide, and dexamethasone as a standard-of-care regimen for patients with relapsed or refractory multiple myeloma,” said study author Keith Stewart, MBChB, of Mayo Clinic in Scottsdale, Arizona.

“Furthermore, these data showed that early use of carfilzomib, lenalidomide, and dexamethasone at first relapse provided nearly 1 additional year of survival for patients, regardless of prior treatment with bortezomib or transplant.”

ASPIRE enrolled 792 MM patients who had received a median of 2 prior therapies (range, 1-3). They were randomized to receive KRd (n=396) or Rd (n=396). Baseline characteristics were well balanced between the treatment arms.

Details on patients and treatment, as well as interim results from ASPIRE, were reported at the 2014 ASH Annual Meeting and published in NEJM in January 2015.

Treatment update

In the final analysis, there were 340 patients in the KRd arm and 358 in the Rd arm who stopped study treatment.

Reasons for discontinuation (in the KRd and Rd arms, respectively) were disease progression (n=188 and 224), adverse events (AEs, n=79 and 85), other reasons (n=61 and 35), withdrawn consent (n=10 and 12), and noncompliance (n=2 and 1).

A total of 182 patients in the KRd arm and 211 in the Rd arm received subsequent treatment for MM. These treatments were generally balanced between the KRd and Rd arms.

The median time to next treatment from the time of randomization was 39.0 months in the KRd arm and 24.4 months in the Rd arm (hazard ratio [HR]=0.65 P<0.001).

Survival

Interim ASPIRE data had shown a significant improvement in progression-free survival (PFS) and a trend toward improved OS in patients who received KRd. Now, researchers have observed a significant improvement in both endpoints with KRd.

The data cutoff for the final analysis was April 28, 2017. For PFS, the median follow-up was 48.8 months in the KRd arm and 48.0 months in the Rd arm.

The median PFS was 26.1 months in the KRd arm and 16.6 months in the Rd arm (9.5-month improvement, HR=0.66; P<0.001). The 3-year PFS rates were 38.2% and 28.4%, respectively. And the 5-year PFS rates were 25.6% and 17.3%, respectively.

The median follow-up for OS was 67.1 months. The median OS was 48.3 months in the KRd arm and 40.4 months in the Rd arm (7.9-month improvement, HR=0.79, P=0.0045).

The researchers also performed subgroup analyses according to prior lines of therapy, prior bortezomib exposure at first relapse, and prior transplant at first relapse.

In patients who had received 1 prior line of therapy, the median OS was 47.3 months in the KRd arm and 35.9 months in the Rd arm (11.4-month improvement, HR=0.81). For patients with 2 or more prior lines of therapy, the median OS was 48.8 months and 42.3 months, respectively (6.5-month improvement, HR=0.79).

Among patients with prior bortezomib exposure at first relapse, the median OS was 45.9 months in the KRd arm and 33.9 months in the Rd arm (12-month improvement, HR=0.82). Among patients without prior bortezomib exposure at first relapse, the median OS was 48.3 months and 40.4 months, respectively (7.9-month improvement, HR=0.80).

Among patients with prior transplant at first relapse, the median OS was 57.2 months in the KRd arm and 38.6 months in the Rd arm (18.6-month improvement, HR=0.71).

Safety

The incidence of treatment-emergent AEs was 98% in the KRd arm and 97.9% in the Rd arm. The incidence of grade 3 or higher AEs was 87% and 83.3%, respectively. The incidence of serious AEs was 65.3% and 56.8%, respectively.

Treatment discontinuation due to an AE occurred in 19.9% of patients in the KRd arm and 21.5% of patients in the Rd arm.

AEs of interest (in the KRd and Rd arms, respectively) included acute renal failure (9.2% and 7.7%), cardiac failure (7.1% and 4.1%), ischemic heart disease (6.9% and 4.6%), hypertension (17.1% and 8.7%), hematopoietic thrombocytopenia (32.7% and 26.2%), and peripheral neuropathy (18.9% and 17.2%).

Fatal AEs were reported in 11.5% of patients in the KRd arm and 10.8% of those in the Rd arm.

Fatal AEs reported in at least 2 patients in the KRd arm included (in the KRd and Rd arms, respectively) cardiac disorders (2.6% and 2.3%), pneumonia (1.5% and 0.8%), sepsis (0.8% for both), myocardial infarction (0.8% and 0.5%), acute respiratory distress syndrome (0.8% and 0%), death (0.5% for both), and cardiac arrest (0.5% and 0.3%).

This trial was funded by Onyx Pharmaceuticals, Inc.

Rivaroxaban

The US Food and Drug Administration’s (FDA) Mini-Sentinel surveillance system has revealed no new safety concerns associated with rivaroxaban use in patients with nonvalvular atrial fibrillation.

Results from this surveillance showed the risk of ischemic stroke was lower in patients who received rivaroxaban than in those who received warfarin.

Rivaroxaban was also associated with a lower risk of intracranial hemorrhage but a higher risk of gastrointestinal bleeding compared to warfarin.

These findings were published in Pharmacoepidemiology & Drug Safety.

About the surveillance

The FDA’s Sentinel Initiative began in 2008 as a multi-year effort to create a national electronic system for monitoring the safety of approved and FDA-regulated medical products using existing electronic healthcare data from multiple sources.

The initiative is the FDA’s response to the Food and Drug Administration Amendments Act (FDAAA), and it includes Mini-Sentinel, a working pilot project to develop an active surveillance system and complement existing methods of safety surveillance.

Rivaroxaban results

Researchers analyzed Mini-Sentinel data for patients with nonvalvular atrial fibrillation who initiated treatment with rivaroxaban or warfarin from November 2011 to April 2015.

To examine the safety of both products, methodologies included assessing ICD-9-CM codes from inpatient claims and evaluating rates of gastrointestinal bleeding, ischemic stroke, and intracranial hemorrhage.*

The incidence of ischemic stroke was higher among patients on warfarin (268/80,180) than among those on rivaroxaban (82/36,512). The adjusted incidence rate per 1000 person-years was 9.57 among rivaroxaban users and 17.10 among warfarin users. The adjusted hazard ratio was 0.61 (95% CI, 0.47-0.79).

The incidence of gastrointestinal bleeding was higher among patients on rivaroxaban (423/36,173) than among those on warfarin (651/79,520). The incidence rate was 50.20 among rivaroxaban users and 34.82 among warfarin users. The hazard ratio was 1.47 (95% CI, 1.29-1.67).

The incidence of intracranial hemorrhage was higher among patients on warfarin (143/79,529) than among those on rivaroxaban (46/36,171).The incidence rate was 5.41 among rivaroxaban users and 7.49 among warfarin users. The hazard ratio was 0.71 (95% CI, 0.50-1.01).

*Total patient numbers differed in the analyses for each endpoint. For example, there were 80,180 warfarin users in the ischemic stroke analysis and 79,520 warfarin users in the analysis of gastrointestinal bleeding.

Rivaroxaban

The US Food and Drug Administration’s (FDA) Mini-Sentinel surveillance system has revealed no new safety concerns associated with rivaroxaban use in patients with nonvalvular atrial fibrillation.

Results from this surveillance showed the risk of ischemic stroke was lower in patients who received rivaroxaban than in those who received warfarin.

Rivaroxaban was also associated with a lower risk of intracranial hemorrhage but a higher risk of gastrointestinal bleeding compared to warfarin.

These findings were published in Pharmacoepidemiology & Drug Safety.

About the surveillance

The FDA’s Sentinel Initiative began in 2008 as a multi-year effort to create a national electronic system for monitoring the safety of approved and FDA-regulated medical products using existing electronic healthcare data from multiple sources.

The initiative is the FDA’s response to the Food and Drug Administration Amendments Act (FDAAA), and it includes Mini-Sentinel, a working pilot project to develop an active surveillance system and complement existing methods of safety surveillance.

Rivaroxaban results

Researchers analyzed Mini-Sentinel data for patients with nonvalvular atrial fibrillation who initiated treatment with rivaroxaban or warfarin from November 2011 to April 2015.

To examine the safety of both products, methodologies included assessing ICD-9-CM codes from inpatient claims and evaluating rates of gastrointestinal bleeding, ischemic stroke, and intracranial hemorrhage.*

The incidence of ischemic stroke was higher among patients on warfarin (268/80,180) than among those on rivaroxaban (82/36,512). The adjusted incidence rate per 1000 person-years was 9.57 among rivaroxaban users and 17.10 among warfarin users. The adjusted hazard ratio was 0.61 (95% CI, 0.47-0.79).

The incidence of gastrointestinal bleeding was higher among patients on rivaroxaban (423/36,173) than among those on warfarin (651/79,520). The incidence rate was 50.20 among rivaroxaban users and 34.82 among warfarin users. The hazard ratio was 1.47 (95% CI, 1.29-1.67).

The incidence of intracranial hemorrhage was higher among patients on warfarin (143/79,529) than among those on rivaroxaban (46/36,171).The incidence rate was 5.41 among rivaroxaban users and 7.49 among warfarin users. The hazard ratio was 0.71 (95% CI, 0.50-1.01).

*Total patient numbers differed in the analyses for each endpoint. For example, there were 80,180 warfarin users in the ischemic stroke analysis and 79,520 warfarin users in the analysis of gastrointestinal bleeding.

Rivaroxaban

The US Food and Drug Administration’s (FDA) Mini-Sentinel surveillance system has revealed no new safety concerns associated with rivaroxaban use in patients with nonvalvular atrial fibrillation.

Results from this surveillance showed the risk of ischemic stroke was lower in patients who received rivaroxaban than in those who received warfarin.

Rivaroxaban was also associated with a lower risk of intracranial hemorrhage but a higher risk of gastrointestinal bleeding compared to warfarin.

These findings were published in Pharmacoepidemiology & Drug Safety.

About the surveillance

The FDA’s Sentinel Initiative began in 2008 as a multi-year effort to create a national electronic system for monitoring the safety of approved and FDA-regulated medical products using existing electronic healthcare data from multiple sources.

The initiative is the FDA’s response to the Food and Drug Administration Amendments Act (FDAAA), and it includes Mini-Sentinel, a working pilot project to develop an active surveillance system and complement existing methods of safety surveillance.

Rivaroxaban results

Researchers analyzed Mini-Sentinel data for patients with nonvalvular atrial fibrillation who initiated treatment with rivaroxaban or warfarin from November 2011 to April 2015.

To examine the safety of both products, methodologies included assessing ICD-9-CM codes from inpatient claims and evaluating rates of gastrointestinal bleeding, ischemic stroke, and intracranial hemorrhage.*

The incidence of ischemic stroke was higher among patients on warfarin (268/80,180) than among those on rivaroxaban (82/36,512). The adjusted incidence rate per 1000 person-years was 9.57 among rivaroxaban users and 17.10 among warfarin users. The adjusted hazard ratio was 0.61 (95% CI, 0.47-0.79).

The incidence of gastrointestinal bleeding was higher among patients on rivaroxaban (423/36,173) than among those on warfarin (651/79,520). The incidence rate was 50.20 among rivaroxaban users and 34.82 among warfarin users. The hazard ratio was 1.47 (95% CI, 1.29-1.67).

The incidence of intracranial hemorrhage was higher among patients on warfarin (143/79,529) than among those on rivaroxaban (46/36,171).The incidence rate was 5.41 among rivaroxaban users and 7.49 among warfarin users. The hazard ratio was 0.71 (95% CI, 0.50-1.01).

*Total patient numbers differed in the analyses for each endpoint. For example, there were 80,180 warfarin users in the ischemic stroke analysis and 79,520 warfarin users in the analysis of gastrointestinal bleeding.

University of Manchester

The antimicrobial agent triclosan may be able to fight drug-resistant malaria, according to research published in Scientific Reports.

For this work, researchers used an artificially intelligent “robot scientist” named Eve to perform a high-throughput screen of potential antimalarial compounds.

The screen revealed that triclosan is effective against Plasmodium parasites that have grown resistant to the antimalarial drug pyrimethamine.

Researchers have known for some time that triclosan inhibits in vitro growth of Plasmodium parasites. They assumed this was because triclosan inhibits the enzyme enoyl reductase (ENR).

However, subsequent work showed that improving triclosan’s ability to target ENR had no effect on parasite growth in the blood.

With the current study, researchers discovered that triclosan also affects parasite growth by inhibiting an enzyme called dihydrofolate reductase (DHFR), which is the target of the antimalarial drug pyrimethamine.

The researchers conducted growth competition experiments with 3 yeast strains dependent on a DHFR enzyme from Plasmodium falciparum, a DHFR enzyme from Plasmodium vivax, and human DHFR.

The team used Eve to screen compounds and identify drugs that inhibit the parasite targets but not the human counterpart.

The researchers found that triclosan was able to target and act on DHFR in both wild-type and pyrimethamine-resistant P falciparum and P vivax parasites.

Because triclosan inhibits both ENR and DHFR, the researchers think it may be possible to target Plasmodium parasites at both the liver and blood stages.

“The discovery by our robot ‘colleague’ Eve that triclosan is effective against malaria targets offers hope that we may be able to use it to develop a new drug,” said study author Elizabeth Bilsland, PhD, of the University of Campinas in Brazil.

“We know it is a safe compound, and its ability to target 2 points in the malaria parasite’s life-cycle means the parasite will find it difficult to evolve resistance.”

Eve was developed to speed up the drug discovery process by automatically developing and testing hypotheses to explain observations, run experiments using laboratory robotics, interpret the results to amend hypotheses, and then repeat the cycle.

“Artificial intelligence and machine-learning enables us to create automated scientists that do not just take a ‘brute force’ approach but, rather, take an intelligent approach to science,” said Ross King, PhD, a professor at the University of Manchester in the UK who led the development of Eve.

“This could greatly speed up the drug discovery process and potentially reap huge rewards.”

University of Manchester

The antimicrobial agent triclosan may be able to fight drug-resistant malaria, according to research published in Scientific Reports.

For this work, researchers used an artificially intelligent “robot scientist” named Eve to perform a high-throughput screen of potential antimalarial compounds.

The screen revealed that triclosan is effective against Plasmodium parasites that have grown resistant to the antimalarial drug pyrimethamine.

Researchers have known for some time that triclosan inhibits in vitro growth of Plasmodium parasites. They assumed this was because triclosan inhibits the enzyme enoyl reductase (ENR).

However, subsequent work showed that improving triclosan’s ability to target ENR had no effect on parasite growth in the blood.

With the current study, researchers discovered that triclosan also affects parasite growth by inhibiting an enzyme called dihydrofolate reductase (DHFR), which is the target of the antimalarial drug pyrimethamine.

The researchers conducted growth competition experiments with 3 yeast strains dependent on a DHFR enzyme from Plasmodium falciparum, a DHFR enzyme from Plasmodium vivax, and human DHFR.

The team used Eve to screen compounds and identify drugs that inhibit the parasite targets but not the human counterpart.

The researchers found that triclosan was able to target and act on DHFR in both wild-type and pyrimethamine-resistant P falciparum and P vivax parasites.

Because triclosan inhibits both ENR and DHFR, the researchers think it may be possible to target Plasmodium parasites at both the liver and blood stages.

“The discovery by our robot ‘colleague’ Eve that triclosan is effective against malaria targets offers hope that we may be able to use it to develop a new drug,” said study author Elizabeth Bilsland, PhD, of the University of Campinas in Brazil.

“We know it is a safe compound, and its ability to target 2 points in the malaria parasite’s life-cycle means the parasite will find it difficult to evolve resistance.”

Eve was developed to speed up the drug discovery process by automatically developing and testing hypotheses to explain observations, run experiments using laboratory robotics, interpret the results to amend hypotheses, and then repeat the cycle.

“Artificial intelligence and machine-learning enables us to create automated scientists that do not just take a ‘brute force’ approach but, rather, take an intelligent approach to science,” said Ross King, PhD, a professor at the University of Manchester in the UK who led the development of Eve.

“This could greatly speed up the drug discovery process and potentially reap huge rewards.”

University of Manchester

The antimicrobial agent triclosan may be able to fight drug-resistant malaria, according to research published in Scientific Reports.

For this work, researchers used an artificially intelligent “robot scientist” named Eve to perform a high-throughput screen of potential antimalarial compounds.

The screen revealed that triclosan is effective against Plasmodium parasites that have grown resistant to the antimalarial drug pyrimethamine.

Researchers have known for some time that triclosan inhibits in vitro growth of Plasmodium parasites. They assumed this was because triclosan inhibits the enzyme enoyl reductase (ENR).

However, subsequent work showed that improving triclosan’s ability to target ENR had no effect on parasite growth in the blood.

With the current study, researchers discovered that triclosan also affects parasite growth by inhibiting an enzyme called dihydrofolate reductase (DHFR), which is the target of the antimalarial drug pyrimethamine.

The researchers conducted growth competition experiments with 3 yeast strains dependent on a DHFR enzyme from Plasmodium falciparum, a DHFR enzyme from Plasmodium vivax, and human DHFR.

The team used Eve to screen compounds and identify drugs that inhibit the parasite targets but not the human counterpart.

The researchers found that triclosan was able to target and act on DHFR in both wild-type and pyrimethamine-resistant P falciparum and P vivax parasites.

Because triclosan inhibits both ENR and DHFR, the researchers think it may be possible to target Plasmodium parasites at both the liver and blood stages.

“The discovery by our robot ‘colleague’ Eve that triclosan is effective against malaria targets offers hope that we may be able to use it to develop a new drug,” said study author Elizabeth Bilsland, PhD, of the University of Campinas in Brazil.

“We know it is a safe compound, and its ability to target 2 points in the malaria parasite’s life-cycle means the parasite will find it difficult to evolve resistance.”

Eve was developed to speed up the drug discovery process by automatically developing and testing hypotheses to explain observations, run experiments using laboratory robotics, interpret the results to amend hypotheses, and then repeat the cycle.

“Artificial intelligence and machine-learning enables us to create automated scientists that do not just take a ‘brute force’ approach but, rather, take an intelligent approach to science,” said Ross King, PhD, a professor at the University of Manchester in the UK who led the development of Eve.

“This could greatly speed up the drug discovery process and potentially reap huge rewards.”

Brief primary care cognitive-behavioral therapy (CBT) among youth who decline antidepressant therapy appears cost-effective, results of a study found.

“In this study, we demonstrate that brief primary care CBT is a cost-effective treatment option for adolescents with depression and likely generates cost savings over 2 years,” said John F. Dickerson, PhD, of Kaiser Permanente Center for Health Research, Portland, Ore., and his associates

Rawpixel/Thinkstock

Brief primary care cognitive-behavioral therapy (CBT) among youth who decline antidepressant therapy appears cost-effective, results of a study found.

“In this study, we demonstrate that brief primary care CBT is a cost-effective treatment option for adolescents with depression and likely generates cost savings over 2 years,” said John F. Dickerson, PhD, of Kaiser Permanente Center for Health Research, Portland, Ore., and his associates

Rawpixel/Thinkstock

Brief primary care cognitive-behavioral therapy (CBT) among youth who decline antidepressant therapy appears cost-effective, results of a study found.

“In this study, we demonstrate that brief primary care CBT is a cost-effective treatment option for adolescents with depression and likely generates cost savings over 2 years,” said John F. Dickerson, PhD, of Kaiser Permanente Center for Health Research, Portland, Ore., and his associates

Rawpixel/Thinkstock