Active Cooling Improves Transport of Infants With Hypoxic-Ischemic Encephalopathy.

Newborns with hypoxic-ischemic encephalopathy (HIE) do better with active cooling during transport, a new paper says.

Servo-controlled active cooling during transport of full-term infants with HIE improved their temperature stability and reduced their transfer time in comparison to passive cooling, researchers said October 21 in Pediatrics.

All babies cooled using the active approach were within the target temperature range when they arrived at the regional unit for treatment, versus 39% of the passively controlled infants, Dr. Topun Austin of Rosie Hospital in Cambridge, UK, and his colleagues found.

HIE occurs in two of every 1,000 newborns in developed countries, and in 10-20 per 1,000 babies in the developing world, Dr. Austin explained in an interview with Reuters Health. Therapeutic hypothermia, which involves cooling babies from their normal temperature of 37 degrees C to 33.5 degrees C, has been shown to help prevent brain damage in these infants.

“If you cool them by just a few degrees, a lot of these babies will have a normal neurological outcome at 18 months,” the investigator said. “It’s quite a dramatic improvement with quite an inexpensive treatment.”

One approach to cooling babies with HIE is to simply remove their clothes, Dr. Austin added, but this “passive cooling” approach can lead to overcooling. With active cooling, the baby is placed on a fluid-filled mattress. A rectal probe monitors the infant’s temperature, and the mattress is automatically heated or cooled to ensure that the target temperature is maintained.

Until now, no studies have compared outcomes with passive vs active cooling. To do so, Dr. Austin and his team reviewed data from a regional neonatal transfer team for 134 infants. The first 64 were treated with passive cooling; the other 70 infants were treated with active cooling after the purchase of a servo-controlled mattress.

Cooling started at an average of 46 minutes of age for the active group, vs 120 minutes for the control group. Median stabilization time was 153 minutes for the control group versus 133 minutes for the active group, while age at arrival was 504 minutes for the control group and 452 for the active group.

Dr. Austin and his colleagues are now investigating strategies for identifying infants with HIE as early as possible.

“It is important for the policy maker to make active cooling available during transport and maybe in the areas at medium and far distance from the referral centers,” said Dr. Mohamed Tagin, a neonatal fellow at the Hospital for Sick Children in Toronto, in email to Reuters Health. Dr. Tagin did not participate in the new study.

“I do agree that the active cooling process should be monitored at a tertiary care facility where appropriate monitoring and expertise are available for such complicated management,” Dr. Tagin added. “It is however very important to commence cooling as soon as the criteria for moderate to severe HIE have been fulfilled, given the available evidence about the improvement of the long-term outcome for those newborns.”

Dr. Tagin continued, “It is important when we discuss the issue of cooling to highlight that patient identification and early management is the most important step and often times it is done by a midwife or a family physician far away from further support. As the situation is stressful enough to those individuals, I believe there should be a system in place to give clear advice over the phone and maybe this already should be preceded with some training to different scenarios.”

But while active cooling should be the standard of care, he said, in the meantime “cooling should not be delayed, and passive cooling with frequent / continuous monitoring should be commenced once the patient has been identified.”

FDA Label Changes Underline Risks With Ezogabine

The US Food and Drug Administration (FDA) has announced approval of changes to labeling for the antiseizure medication ezogabine (Potiga, Valeant Pharmaceuticals International) to underline previously reported risks for retinal abnormalities, potential vision loss, and skin discoloration, all of which may become permanent.

“The revised label includes a new boxed warning, the most serious type of warning FDA gives,” because of this risk for retinal abnormalities, a statement from FDA notes. “We advise that Potiga use be limited to patients who have not responded adequately to several alternative therapies to decrease the frequency of seizures, or epilepsy, and for whom the benefits of treatment outweigh the risks.”

The risks were previously described in a Drug Safety Communication in April 2013, and reported by Medscape Medical News at that time.

The agency is further recommending that patients undergo eye examinations by an ophthalmic professional prior to starting ezogabine, and every 6 months during treatment. “These exams should include visual acuity and dilated fundus photography, with additional vision testing as necessary,” the FDA statement notes. “Patients whose vision cannot be monitored should generally not take Potiga.”

It is not clear which patients are at risk for these retinal changes, how long it may take for them to be detected, the rate of progression, or their reversibility after treatment withdrawal, the advisory adds.

“If retinal pigmentary abnormalities or vision changes are detected, Potiga should be stopped unless no other suitable seizure treatment options are available and the benefits of treatment outweigh the potential risk of vision loss,” the statement said. “In addition, health care professionals should stop Potiga treatment in patients who do not show substantial clinical benefit after adequate dose titration.”

Patients are advised, though, not to stop taking the drug before consulting their healthcare provider.

The new label also includes warnings about the risk for discoloration of the skin, nail, mucous membrane, and white of the eye that were also outlined in the previous statement in April. If patients develop such discoloration, an alternate treatment should be considered, the new label advises.

All of these recommendations have been added to the label’s Warnings and Precautions section and the patient Medication Guide, which should be included with each prescription that is filled.

“FDA is working on modifying the current Risk Evaluation and Mitigation Strategy (REMS) for Potiga to address the risk of retinal pigmentary abnormalities, potential vision loss, and skin discoloration,” the statement concludes.

Leukemia Drug Ponatinib (Iclusig) Pulled From Market.

At the request of the US Food and Drug Administration (FDA), the leukemia drug ponatinib (Iclusig) has been temporarily pulled from the market by its manufacturer, Ariad Pharmaceuticals, because of safety concerns.

“We will continue to evaluate the drug to further understand its risks and potential patient populations in which the benefits of the drug may outweigh the risks,” said the FDA in a statement.

The company will suspend marketing and sales of ponatinib because of the risk for life-threatening blood clots and severe narrowing of blood vessels.

Ponatinib is indicated for adults with chronic-phase, accelerated-phase, or blast-phase chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia who do not tolerate or no longer benefit from other therapies, such as imatinib (Gleevec, Novartis).

This action follows an FDA investigation into ponatinib, initiated earlier this month, that revealed “an increased frequency of blood clots and narrowing of blood vessels since the drug was approved in December 2012,” according to an agency statement.

New data indicate that approximately 24% of patients in the phase 2 clinical trial (median treatment duration, 1.3 years) and approximately 48% of patients in the phase 1 clinical trial (median treatment duration, 2.7 years) experienced serious adverse vascular events. The events include fatal and life-threatening heart attack, stroke, loss of blood flow to the extremities resulting in tissue death, and severe narrowing of blood vessels in the extremities, heart, and brain requiring urgent surgical procedures to restore blood flow.

In the phase 2 trial, heart failure, including fatalities, occurred in 8% of patients treated with the drug. Serious adverse reactions involving the eyes, which led to blindness or blurred vision, also occurred.

In some patients, fatal and serious adverse events have occurred as early as 2 weeks after starting ponatinib therapy.

Currently, the FDA cannot identify a dose level or exposure duration that is safe.

Patients on ponatinib who are not responding should stop treatment and seek an alternative, according to the FDA.

For patients who are responding to ponatinib and whose healthcare professionals determine that the potential benefits outweigh the risks, the agency recommends that they continue to be treated under a single-patient Investigational New Drug (IND) application or under an expanded-access registry program while FDA investigation continues.

More information on obtaining access to treatment under an IND can be found on the FDA Web site.

Clinicians should not start treating new patients with ponatinib unless no other treatments are available and all other available therapies have failed, according to the FDA.

When the FDA approved ponatinib 10 months ago, it required the label to feature a boxed warning about the risk for blood clots. Clinical trials conducted prior to approval reported serious arterial blood clots in 8% of patients treated with the drug, and venous blood clots in 3%.

FDA Okays First Single-Entity Extended-Release Hydrocodone.

The US Food and Drug Administration (FDA) has approved the first single-entity extended-release formulation of hydrocodone bitartrate (Zohydro ER, Zogenix Inc) for the management of pain severe enough to require daily around-the-clock long-term treatment and for which alternative options are inadequate.

“Zohydro ER, a Schedule II controlled substance under the Controlled Substances Act, is the first FDA-approved single-entity (not combined with an analgesic such as acetaminophen) and extended-release hydrocodone product,” a statement from FDA released today notes.

“Zohydro ER will offer prescribers an additional therapeutic option to treat pain, which is important because individual patients may respond differently to different opioids.”

This formulation belongs to the class of extended-release/long-acting (ER/LA) opioids, the statement notes. “Due to the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with ER/LA opioid formulations, Zohydro ER should be reserved for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain,” the FDA release said.

It is not approved for as-needed pain relief.

In addition, the labeling approved for this drug conforms to updated labeling requirements for all ER/LA opioids announced by the FDA on September 10 and reported at that time by Medscape Medical News, the first opioid to be labeled in this way, the statement notes.

“The new class of labeling and stronger warnings will more clearly describe the risks and safety concerns associated with ER/LA opioid analgesics, along with the appropriate use of these medications,” the FDA said. “These warnings are expected to improve the safety of all such medicines by encouraging more appropriate prescribing, patient monitoring, and patient counseling practices.”

Schedule II drugs can be dispensed only by prescription, and no refills are allowed. Stringent record-keeping, reporting, and physical security requirements are also in place for these substances.

The FDA will require postmarketing studies of this agent to assess the “known serious risks of misuse, abuse, increased sensitivity to pain (hyperalgesia), addiction, overdose, and death associated with long-term use beyond 12 weeks,” the FDA release said. “These studies will also be required for other ER/LA opioid analgesics.”

Safety of this new formulation of hydrocodone is based on clinical studies that have included more than 1100 patients with chronic pain. Efficacy is based on a clinical study that enrolled more than 500 patients with chronic low back pain and showed a significant improvement in chronic pain vs placebo.

It will also be part of the ER/LA Opioids Analgesics risk evaluation and mitigation strategy (REMS) approved in 2012. The REMS requires companies to make educational programs on how to safety prescribe these agents to healthcare professionals and provide medication guides and patient counseling documents with information on safe use, storage, and disposal of ER/LA opioids.

The most common adverse effects of this single-entity hydrocodone are constipation, nausea, somnolence, fatigue, headache, dizziness, dry mouth, vomiting, and pruritus.

In December 2012, FDA’s Anesthetic and Analgesic Drug Advisory Committee of independent experts voted 11 to 2, with 1 abstention, to recommended against approval of this agent for the treatment of moderate to severe chronic pain.

Most panel members voted that the drug had met regulatory requirements for safety and efficacy, as indicated by their responses to questions on efficacy and safety. However, for the last question voted on — “Based on the data presented and discussed today, do the efficacy, safety and risk-benefit profile of Zohydro ER support the approval of this application?” — most had negative responses.

The main concern of those voting against approval was that the potential for abuse of these agents; because the product does not include acetaminophen, they feared the potential for abuse might be even greater.

Tuberculosis: Test Speeds Diagnosis, Time to Treatment.

The Xpert MTB/RIF (Cepheid) test improved tuberculosis (TB) diagnosis and reduced time to treatment, but not long-term TB-related morbidity, according to the results of a multicenter, randomized, controlled trial.

“Despite already being rolled-out in many countries, our study is the first to look at the feasibility of the Xpert test in a real-life clinical setting in southern Africa,” lead author Keertan Dheda, MBBcH, from the Department of Medicine, University of Cape Town, South Africa, said in a news release. The study results were published online October 28 in the Lancet.

The researchers enrolled adult patients with symptoms suggestive of active TB at 5 primary care facilities in South Africa, Zimbabwe, Zambia, and Tanzania. They randomly assigned patients to either Xpert MTB/RIF testing, performed at the clinic by a nurse who received 1 day of training, or to sputum smear microscopy. On the basis of local World Health Organization–compliant guidelines, participants with a negative test result were managed empirically.

The main study endpoint, analyzed by intention to treat, was TB-related morbidity, measured with the TB score and Karnofsky performance score at 2 months and 6 months after randomization in culture-positive patients who had started anti-TB treatment.

Of 758 assigned patients to smear microscopy between April 12, 2011, and March 30, 2012, 182 were culture positive, as were 185 of 744 patients assigned to Xpert MTB/RIF. Among culture-positive patients, median TB score and median Karnofsky performance score in culture-positive patients did not differ between groups at 2 or at 6 months.

Diagnostic Performance of Point-of-Care MTB/RIF

Compared with microscopy, point-of-care MTB/RIF had higher sensitivity (83% vs 50%; P = .0001), but similar specificity (95% vs 96%; P = .25). Compared with laboratory-based MTB/RIF, point-of-care MTB/RIF had similar sensitivity (83%; P = .99), but higher specificity (92%; P = .0173).

Of 744 tests with point-of-care MTB/RIF, 34 (5%) failed, as did 82 (6%) of 1411 with laboratory-based MTB/RIF (P = .22). More patients in the MTB/RIF group than in the microscopy group had a same-day diagnosis (24% vs 13%; P < .0001) and same-day treatment initiation (23% vs 15%; P = .0002).

Because of the lower dropout rate, more culture-positive patients in the MTB/RIF group were receiving treatment by study end (8% untreated in the MTB/RIF group vs 15% in the microscopy group; P = .0302). By day 56, however, the proportions of all patients receiving treatment were similar (43% vs 42%, respectively; P = .6408).

“Although earlier diagnosis by the Xpert test did not reduce overall severity of TB-related illness, and moreover did not reduce the overall number TB cases treated over the course of the study, it has substantial benefits over smear microscopy including improved rates of same-day diagnosis and reducing treatment drop-out,” Dr. Dheda said in the release.

Cost-Effectiveness May Be a Concern

Limitations of this study include about 20% loss to follow-up of patients with culture-confirmed TB, mostly resulting from staffing problems at 1 site, and possible lack of generalizability to seriously ill patients or those with extrapulmonary TB.

“Whilst Xpert may not be the ideal point of care TB test in particularly poorly resourced settings, in countries like South Africa where the clinic infrastructure is relatively good, rates of drug-resistant TB are high, and patient drop-out are significant problems, within clinic placement of Xpert in TB hotspots might be appropriate and enable earlier diagnosis of drug-resistant TB thus likely reducing community-based transmission,” Dr. Dheda noted. “Nevertheless, prevention of TB and adherence to TB treatment is critical and remains a major priority.”

In an accompanying comment, Christian Wejse, MD, PhD, associate professor, GloHAU, Center for Global Health, Department of Public Health, Aarhus University, Denmark, wonders about the cost-effectiveness of Xpert testing.

“At a cassette cost of US$10 (reduced price for low-resource settings), testing large numbers of people with suspected tuberculosis will put substantial pressure on already resource-limited tuberculosis programmes in which the drugs for treatment might not always be available,” Dr. Wejse writes. “Hence, the provocative question raised by this study is whether tuberculosis elimination is most likely to be advanced by distributing GeneXpert machines to all peripheral health facilities in the world, or by investing the same amount in ensuring that health facilities have the set-up available in this study—ie, well trained and paid staff, electricity, and reagents.”

Antibody Index Test May Aid PML Diagnosis on Natalizumab.

A new test that compares JC virus (JCV) antibody levels in cerebrospinal fluid (CSF) with those in serum might be a useful complementary tool in the diagnostic workup for progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS) treated with natalizumab (Tysabri, Biogen Idec), a new study suggests.

The study was presented by Clemens Warnke, MD, Heinrich Heine University, Düsseldorf, Germany, at the recent 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). 

Dr. Warnke explained that PML caused by JCV can be difficult to diagnose because early symptoms can be mistaken for a relapse in MS.

“At present, JCV-DNA detection by polymerase chain reaction (PCR) in cerebrospinal fluid is used for diagnosis of PML. However, false-negatives often occur, leading to delayed diagnosis and poor patient outcome in some cases,” he said. “So we need more tests to allow earlier diagnosis.”

“Our main findings are when you have clinical suspicion of PML — changes in behavior, personality, and motor function untypical for MS in patients treated with natalizumab, we might suspect it to be PML,” he told Medscape Medical News.

He and his colleagues have proposed using the anti-JCV antibody specificity index (ASI-JCV) as an additional test for JCV DNA detection. This involves measuring the JCV antibody level in both serum and CSF and calculating the proportion of antibodies in CSF compared with serum.

In this study, Dr. Warnke and colleagues calculated the anti-JCV antibody specificity index in 25 patients who had developed PML while receiving natalizumab and in 47 patients also taking natalizumab who had not developed PML. Results showed that none of the control patients had JCV antibodies in CSF, whereas CSF antibodies were detected in more than 60% of the patients with PML.

And while all patients with natalizumab-associated PML exhibited an ASI-JCV of 0.47 or higher, this was seen in none of the 47 patients with MS treated with natalizumab who did not develop PML (P < .0001).

Dr. Warnke stressed that this test would not replace the PCR test for JCV DNA. “But levels of JCV DNA detection and the antibody index tests do not exactly correlate, so here is an argument for using the antibody index alongside the DNA test for additional diagnostic value,” he suggested.

“If we assume an estimate of 70% to 80% for the early diagnosis of PML using PCR, maybe we can increase this up to 85% using this antibody index test as well,” he added.

The antibody index test is not yet commercially available.

“We have developed our own test and now use it at our hospital,” he noted. “But it is not an established procedure yet. It is still a clinical research tool which needs further validation.”


Antibiotics for All but Very Mild C difficile.

On October 29, the European Society of Clinical Microbiology and Infection (ESCMID) issued updated guidelines for Clostridium difficile infection (CDI), reviewing treatment options of antibiotics, toxin-binding resins and polymers, immunotherapy, probiotics, and fecal or bacterial intestinal transplantation. The new recommendations, published online October 5 in Clinical Microbiology and Infection, advise antibiotic treatment for all but very mild cases of CDI.

CDI, which is potentially fatal, is now the leading cause of healthcare-acquired infections in hospitals, having surpassed methicillin-resistant Staphylococcus aureus.

“[A]fter the recent development of new alternative drugs for the treatment of CDI (e.g. fidaxomicin) in US and Europe, there has been an increasing need for an update on the comparative effectiveness of the currently available antibiotic agents in the treatment of CDI, thereby providing evidence-based recommendations on this issue,” write Sylvia B. Debast, from the Centre for Infectious Diseases, Leiden University Medical Center The Netherlands, and colleagues from the ESCMID Committee.

The new guideline, which updates the 2009 ESCMID recommendations now used widely in clinical practice, summarizes currently available CDI treatment options and offers updated treatment recommendations on the basis of a literature search of randomized and nonrandomized trials.

The ESCMID and an international team of experts from 11 European countries developed recommendations for different patient subgroups, including initial nonsevere disease, severe CDI, first recurrence or risk for recurrent disease, multiple recurrences, and treatment of CDI when patients cannot receive oral antibiotics.

Antibiotic Recommended in Most Cases

Specific recommendations include the following:

·         For nonepidemic, nonsevere CDI clearly induced by antibiotic use, with no signs of severe colitis, it may be acceptable to stop the inducing antibiotic and observe the clinical response for 48 hours. However, patients must be monitored very closely and treated immediately for any signs of clinical deterioration.

·         Antibiotic treatment is recommended for all cases of CDI except for very mild CDI, which is actually triggered by antibiotic use. Suitable antibiotics include metronidazole, vancomycin, and fidaxomicin, a newer antibiotic that can be given by mouth.

·         For mild/moderate disease, metronidazole is recommended as oral antibiotic treatment of initial CDI (500 mg 3 times daily for 10 days).

·         Fidaxomicin may be used in all CDI patients for whom oral antibiotic treatment is appropriate. Specific indications for fidaxomicin may include first-line treatment in patients with first CDI recurrence or at risk for recurrent disease, in patients with multiple recurrences of CDI, and in patients with severe disease and nonsevere CDI.

These recommendations were based on 2 large phase 3 clinical studies that compared 400 mg/day oral fidaxomicin with 500 mg/day oral vancomycin, the standard of care. The rate of CDI recurrence was lower with fidaxomicin, but the cure rate was similar for both treatments.

·         For severe CDI, suitable oral antibiotic regimens are vancomycin 125 mg 4 times daily (may be increased to 500 mg 4 times daily) for 10 days, or fidaxomicin 200 mg twice daily for 10 days.

·         In life-threatening CDI, there is no evidence supporting the use of fidaxomicin.

·         In severe CDI or life-threatening disease, the use of oral metronidazole is strongly discouraged.

·         For multiple recurrent CDI, fecal transplantation is strongly recommended.

·         Total abdominal colectomy or diverting loop ileostomy combined with colonic lavage is recommended for CDI with colonic perforation and/or systemic inflammation and deteriorating clinical condition despite antibiotic treatment.

·         Additional measures for CDI management include discontinuing unnecessary antimicrobial therapy, adequate fluid and electrolyte replacement, avoiding antimotility medications, and reviewing proton pump inhibitor use.