Narrow-Spectrum Antibiotics Effective for Pediatric Pneumonia.

Narrow-spectrum antibiotics have similar efficacy and cost-effectiveness as broad-spectrum antibiotics in the treatment of pediatric community-acquired pneumonia (CAP), according to the findings of a retrospective study.

Derek J Williams, MD, MPH, from Vanderbilt University School of Medicine in Nashville, Tennessee, and colleagues published their findings online October 28 in Pediatrics.

“The 2011 Pediatric Infectious Diseases Society/Infectious Diseases Society of America…guideline for the management of children with [CAP] recommends narrow-spectrum antimicrobial therapy for most hospitalized children,” the authors write. “Nevertheless, few studies have directly compared the effectiveness of narrow-spectrum agents to the broader spectrum third-generation cephalosporins commonly used among hospitalized children with CAP.”

Therefore, the researchers used the Pediatric Health Information System database to assess the hospital length of stay (LOS) and associated healthcare costs of children aged 6 months to 18 years who were diagnosed with pneumonia between July 2005 and June 2011 and treated with either narrow-spectrum or broad-spectrum antibiotics. The authors excluded children with potentially severe pneumonia, those at risk for healthcare-associated infections, and those with mild disease requiring less than 2 days of hospitalization.

Narrow-spectrum therapy consisted of the exclusive use of penicillin or ampicillin, whereas broad-spectrum treatment was defined as the exclusive use of parenteral ceftriaxone or cefotaxime.

The median LOS for the entire study population (n = 15,564) was 3 days (interquartile range, 3 – 4 days), and LOS was not significantly different between the narrow-spectrum and broad-spectrum treatment groups (adjusted difference [aD], 0.12 days; P = .11), after adjustments for covariates including age, sex, and ethnicity.

Similarly, the investigators found no differences in the proportion of children requiring intensive care unit admission in the first 2 days of hospitalization (adjusted odds ratio [aOR], 0.85; 95% CI, 0.25 – 2.73) or hospital readmission within 14 days (aOR, 0.85; 95% CI, 0.45 – 1.63) were noted between the groups.

Narrow-spectrum treatment was also linked to a similar cost of hospitalization (aD, −$14.4; 95% CI, −$177.1 to $148.3) and cost per episode of illness (aD, −$18.6; 95% CI, −$194 to $156.9) as broad-spectrum therapy.

The researchers note that the limitations of the study were mostly related to its retrospective nature, including potential confounding by indication, the absence of etiologic and other clinical data, and a relative lack of objective outcome measures.

“Clinical outcomes and costs for children hospitalized with CAP are not different when empirical treatment is with narrow-spectrum compared with broad-spectrum therapy,” the authors write. “Programs promoting guideline implementation and targeting judicious antibiotic selection for CAP are needed to optimize management of childhood CAP in the United States.”

Antipsychotic Drugs May Triple Kids’ Diabetes Risk.

Antipsychotic medications such as Seroquel, Abilify andRisperdal can triple a child’s risk of developing type 2 diabetes within the first year of usage, according to a new study.

Powerful antipsychotics traditionally were used to treat schizophrenia. Now the majority of prescriptions for antipsychotic medications are for treatment of bipolar disorder, ADHD and mood disorders such as depression, according to prior research.

But antipsychotic drugs make a child much more likely to develop type 2 diabetes than the medications typically prescribed for these other psychiatric conditions, said corresponding author Wayne Ray, director of the division of pharmacoepidemiology at the Vanderbilt University School of Medicine, in Nashville, Tenn.

“We found that children who received antipsychotic medications were three times as likely to develop type 2 diabetes,” Ray said. “It’s well known that antipsychotics cause diabetes in adults, but until now the question hadn’t been fully investigated in children.”

Antipsychotics appear to increase diabetes risk by causing dramatic weight gain in children and by promoting insulin resistance, Ray said.

The boom in the use of antipsychotic medication has been particularly dramatic among children. Antipsychotic prescriptions have increased sevenfold for kids in recent years and nearly fivefold for teens and young adults aged 14 to 20, according to a 2012 study from Columbia University.

For the current study, which was published Aug. 21 in the journal JAMA Psychiatry, the researchers reviewed the records of nearly 29,000 kids aged 6 to 24 in the Tennessee Medicaid program who had recently started taking antipsychotic drugs for reasons other than schizophrenia or related psychoses.

They compared those kids to more than 14,000 matched control patients who had started taking other types of psychiatric medications, including mood stabilizers such as lithium; antidepressants; psychostimulants such as Adderall and Ritalin; alternative ADHD medications such as clonidine and guanfacine; and anti-anxiety drugs known as benzodiazepines.

Within the first year, users of antipsychotic drugs had triple the risk for type 2 diabetes compared to users of other psychiatric medications.

The risk continued to rise with cumulative antipsychotic dose, and remained high for as long as a year after kids were taken off their antipsychotics. When the researchers looked only at kids 17 and younger, the findings held.

“Diabetes can develop relatively soon after beginning these drugs,” Ray said. “We found that the risk was increased within the first year of use, and this is consistent with case reports. The risk may need to be considered even for relatively short periods of use.”

The specific antipsychotic medication used with children didn’t seem to have any effect on reducing risk of diabetes.

“In our study, we didn’t see a difference between different types of drugs,” Ray said. “It may be an effect of the whole class of antipsychotics.” The majority of participants were taking “atypical” antipsychotics, also called second-generation antipsychotics.

Another expert agreed that the study results are cause for concern.

The findings should lead doctors and parents to question the “off-label” use of antipsychotic drugs for conditions other than schizophrenia and psychosis, said Dr. Ken Duckworth, medical director of the National Alliance on Mental Illness.

“There aren’t many antipsychotic medications that are FDA-approved for use in children,” Duckworth said. “When you’re using a compound that doesn’t have an indication, you have to be very careful about the risk/benefit assessment of that medication. You want to make sure you’ve reviewed all the alternative medicines and alternative strategies.”

Ray agreed, arguing that doctors should consider all other alternative treatments before resorting to antipsychotics.

If children must be placed on antipsychotics, then doctors and parents need to keep a close eye on them for early warning signs of diabetes. “Frequent monitoring of the factors that lead to diabetes would be important, including weight and glucose intolerance,” Ray said.

In the past 20 years, growing numbers of U.S. children and teens – especially overweight kids – have been diagnosed with type 2 diabetes, formerly known as adult onset diabetes. This puts them at risk of developing other serious health conditions such as heart disease and kidney disease.

Although the study found an association between the use of antipsychotics and a greatly increased risk of childhood type 2 diabetes, it did not prove a cause-and-effect relationship.


Feds Investigate Antipsychotic Prescribing in Children.

The US Department of Health and Human Services’ Office of Inspector General (OIG) has launched a probe into the prescribing of atypical antipsychotic medications to children under Medicaid.

“We will determine the extent to which children ages 18 and younger had Medicaid claims for atypical antipsychotic drugs during the selected time frame,” the office said in a summary of the plan.

“On the basis of medical record reviews, we will also determine the extent to which the atypical antipsychotic drug claims were for off-label uses and for indications not listed in one or more of the approved drug compendia.”

The time frame is a 6-month period from January to June 2011, when 84,654 children were prescribed antipsychotics in the 5 states selected for the probe, where Medicaid prescriptions are the highest — California, Texas, Illinois, New York, and Florida — said OIG spokesperson Donald White.

Psychiatric experts have been recruited to evaluate approximately 700 of the medical records as part of the ongoing effort, White told Medscape Medical News.

“We are currently conducting the medical record reviews, and the probe will likely last several months, possibly into 2014,” he said.

Lack of Funding for CBT

The probe is focusing on atypical antipsychotics such as aripiprazole (Abilify, Otsuka Pharmaceutical Co., Ltd.), risperidone (Risperdal, Ortho-McNeil-Janssen Pharmaceuticals, Inc.), quetiapine fumarate (Seroquel, AstraZeneca Pharmaceuticals LP), and olanzapine (Zyprexa, Eli Lilly and Company).

A previous probe by the OIG on the overuse of antipsychotics in nursing homes, which resulted in action by the Centers for Medicare and Medicaid Services (CMS) to reduce the use of the drugs by 15%, was launched in response to a request from Congress; however, the new probe was launched by the OIG itself, White said.

Concern over the overprescribing of antipsychotics to children in the Medicaid program is not new — a 2004 study found that children in the healthcare system from low-income families were 4 times as likely to be prescribed antipsychotics as those who were privately insured.

As reported by Medscape Medical News, a more recent study showed that the use of antipsychotic medications among Medicaid-insured children from low- or very-low-income families soared 7-fold to 12-fold between 1997 and 2006.

Among side effects of concern associated with atypical antipsychotics are weight gain and diabetes, and little is known on the long-term neurologic effects of the drugs used in early childhood.

One important reason why the prescribing of antipsychotics to children is believed to be higher among children under Medicaid coverage is that the system simply is not as accommodating to the best-known alternative — cognitive-behavioral therapy, according to Pensacola, Florida–based child psychiatrist Scott R. Benson, MD.

“The reimbursement for the kind of cognitive-behavioral therapy that could help these children is lower with Medicaid, so children who are covered by private insurance may have access to a better range of therapies,” he told Medscape Medical News.

“But part of this is our own fault on a professional level — we [psychiatrists] have not made a good enough case for the value of psychotherapy in helping children,” added Dr. Benson, who is a member of the American Psychiatric Association.

Infants, Toddlers Prescribed Atypicals

Dr. Benson said clinicians too often associate the option of cognitive-behavioral therapy with being arduous and time-consuming.

“The patient doesn’t necessarily have to be coming in 3 times a week over 10 years — there is plenty of evidence showing, especially for children who have been traumatized, that even short-term therapy, maybe once-a-week visits over 20 weeks, can be a very effective treatment.”

Among the more alarming figures regarding prescribing atypical antipsychotics to children are those showing prescriptions to the very young, including toddlers and infants.

As reported in a recent article in the Wall Street Journal, the inspector general’s 5-state probe found 482 children aged 3 years and younger who were prescribed antipsychotics during the 6-month period in question, including 107 children who were aged 2 years and younger.

Six children prescribed the drugs were younger than 1 year, and 1 was listed as being 1 month old.

Importantly, the records did not identify the diagnoses involved, and Dr. Benson speculated that some may have included children with certain severe disorders, such as autism.

“It’s important to remember that the majority of these prescriptions are not even written by child psychiatrists,” he said. “In the case of the very young children, these may have represented prescriptions from neurologists who were treating patients with severe autistic disorders.”

Quick Fix?

Others, however, may have been practitioners such as pediatricians, who, facing heavy patient loads, are often under pressure to make a quick diagnosis and reach for a quick fix — an antipsychotic.

“A practitioner may observe a few behaviours, say ‘that’s terrible,’ and simply prescribe something the patient doesn’t really need because there wasn’t enough time or interest in doing the kind of good, standard evaluation that all of us would expect for our children,” Dr. Benson said.

“Certainly all patients deserve that, regardless of their insurance situation.”

A complex range of psychiatric issues may cause a child to appear dysregulated, and a full evaluation is essential before writing that prescription, said Mary Margaret Gleason, MD, an assistant professor in child psychiatry and pediatrics at Tulane University in New Orleans, Louisiana.

“Especially in younger children, the causes of impulsive or disruptive behaviors can be quite broad,” she toldMedscape Medical News.

“A thorough assessment looking into psychological, environmental, and biological factors that might cause someone to look impulsive and disruptive needs to be done to know what is driving the impulsivity.”

“One of the biggest things that needs to be looked at, for instance, is if the child has been exposed to trauma, and if someone is considering using a medication that has as long a list of potential side effects as atypical antipsychotics, they do need to really be certain of what they’re treating first.”

Source: Medscape/com


Drug Targeting Tumor Suppressor Shows Promise in First Human Study.

An experimental drug that reactivates mutant forms of the tumor suppressor protein p53 is safe for humans, according to results from a phase I trial. The drug, APR-246, also stimulated signaling pathways that control p53 in tumor cells isolated from peripheral blood.

The study, published in the Journal of Clinical Oncology, was led by Dr. Sören Lehmann of Karolinska University Hospital in Stockholm.

The findings represent “a major step forward in targeting the most frequently altered pathway in cancer,” wrote Drs. Brian D. Lehmann and Jennifer A. Pietenpol of Vanderbilt University School of Medicine in an accompanying article.

The p53 protein suppresses tumor growth by increasing the expression of genes that slow the cell cycle, that prevent cells from dividing, or that cause programmed cell death (apoptosis). At least half of all tumors develop inactivating mutations in TP53, the gene that produces p53, allowing the tumor to evade this regulation. APR-246 counteracts TP53 mutations by restoring the gene-regulatory activity of mutant p53 protein and by inducing the death of cancer cells.

The 22 participants enrolled in the trial had various forms of leukemia, hormone-refractory metastatic prostate cancer, non-Hodgkin lymphoma, or multiple myeloma. These patients were included because prostate cancers have a high rate of TP53 mutations and because, in preclinical studies, leukemia cells were particularly sensitive to drugs that target p53.

The patients received intravenous infusions of APR-246 for 4 consecutive days. After a follow-up period of 17 days, the most common side effects were fatigue, dizziness, headache, and confusion.

While the trial was not designed to assess the drug’s antitumor effects, several patients showed clinical responses. To investigate the biologic activity of APR-246, Dr. Lehmann and his colleagues analyzed circulating tumor cells obtained before and after the 4-day treatment from the six patients who had these cells. Four of these patients had fewer proliferating cells after receiving APR-246. The investigators also observed signs of apoptosis and increased expression of several p53 target genes.

Microarray analysis of RNA isolated from the circulating tumor cells showed changes in genes responsible for regulating cell growth and death. The level of expression of genes that promote apoptosis appeared to correlate with the dose of APR-246.

Trials are being designed to investigate the effects of higher exposures to APR-246 through longer infusion times and of combining APR-246 with other chemotherapy drugs, most of which depend on a functional version of p53 to be effective.

Source: NCI