Hospital-based Antimicrobial Stewardship

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While there has been growing recognition of antibiotic resistance, the efforts to implement strategies to preserve the effectiveness of our current antibiotics have not been embraced by enough stakeholders.  A recent review provides insight into the antibiotic stewardship (AS) programs that are being implemented by pediatric hospitals (JAMA Pediatrics; 2013; 167: 859-66).  Thanks to Ben Gold for sharing this reference.

AS goals are to “optimize clinical outcomes while minimizing unintended consequences of antimicrobial use, including toxicity, the selection of pathogenic organisms, and the emergence of resistance.”  Five specific goals:

  • timely management of antimicrobial therapy -prompt initiation when indicated, avoid when not indicated (eg. viral illness)
  • appropriate antibiotic selection -minimize redundant antibiotic coverage
  • appropriate antibiotic administration and de-escalation of therapy -reassess after 48-72 hrs whether to discontinue antibiotics, monitor levels when needed
  • use of available expertise and resources at point of care
  • transparent monitoring of antimicrobial data usage

Adoption of AS programs has been accelerating in the past few years.  “A recent survey of 43 children’s hospitals showed that 16 institutions (37%) ..currently have an established AS  program supported by full-time equivalents for a pediatric infectious diseases physician and/or clinical pharmacist.”  Another 15 (35%) are in the preparatory stage of implementing an AS program.

Potential barriers for AS programs:

  • Lack of funding or time –these programs have been reported to yield cost savings
  • Lack of hospital leadership
  • Concerns about physician autonomy

Potential outcome variables to measure:

  • Reduction in adverse events
  • Improved (?) antibiotic resistance trends
  • Reduction (?) in C difficile rates

The authors note that on a national level that AS programs have not been mandated. However, multiple societies, including the Infectious Diseases Society and the Society for Healthcare Epidemiology of America, have recommended their widespread adoption.

Bottomline: Improving hospital antibiotic usage with the use of AS programs will help reduce antibiotic resistance, but it is the tip of the iceberg when it comes to addressing this issue (see related blog posts below).

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Do antivirals lower the risk of Hepatocellular Carcinoma in HBV?

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Meaningful endpoints of therapy are often difficult to demonstrate in clinical studies due to the length of followup that may be needed.  For patients infected with hepatitis B virus (HBV), most clinical studies use surrogate biologic, virologic and histologic markers rather than endpoints like hepatocellular carcinoma (HCC) and death.  In addition, long-term randomized trials with untreated controls are difficult to justify given the success of current treatments in improving these surrogate markers.

A recent Japanese study (Hepatology 2013; 58: 98-107 and editorial pg 18) reports data on a large entecavir-treated cohort (n=472) which was matched with a historical control (retrospective control group, n=1143).  The authors used propensity score matching to eliminate any baseline differences.

Findings:

  • Cumulative incidence of HCC rate at 5 years was 3.7% (for entecavir group) and 13.7% (for controls)
  • Using regression analysis and adjusting for known HCC risk factors, patients treated with entecavir had a hazard ratio of 0.37 for developing HCC.
  • Patients with more risk factors for HCC (eg. older, more active disease, cirrhosis) obtained greater benefit from entecavir treatment (shown in Figure 4 in manuscript)
  • The authors also showed that entecavir-treated patients also had less risk of developing HCC than lamivudine-treated patients
  • Entecavir-treated patients had low rates of resistance (0.8%) at 3.2 years of treatment

Take-home message: suppression of viral replication in HBV cirrhosis patients reduces but does not eliminate the risk of HCC.  In noncirrhotic patients, the magnitude of risk reduction is less.  Thus, patients with active disease should be treated.

Causes of Death with Hepatitis B in U.S.

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A recent study followed 6,689 patients with hepatitis B virus (HBV) between 1996-2005 and analyzed causes of death (Hepatology 2013; 58: 21-30, editorial pg 6). This study used a large prospectively-collected database.

The patients were all part of Kaiser Permanente Northern California health plan.  Patients were not eligible if they were coinfected with HIV or HCV.  Causes of death were divided into HBV-related (eg. decompensated cirrhosis [DCC], hepatocellular carcinoma [HCC]) and other causes, including cancer and cardiovascular.

Among this cohort, 68.3% were Asian-Pacific Islander (API) descent, and 11.8% were white (non-hispanic); the remainder were other or unknown descent.  The cohort had a mean age of 41 years.

Findings:

  • Males had higher overall 10-year death rates than females for total deaths (8.9% versus 4.1%) and for HBV-related deaths (4.8% versus 1.2%).
  • 46.7% of all deaths were HBV-related.
  • Death rate rose with increasing age; approximately 40% of deaths after age 40 were HBV-related.
  • Among HBV-related deaths, the death rate from HCC was twice the rate of DCC
  • “We did not find that subjects of API descent origin were at higher risk of death from HBV-related complications.”  This was unexpected because presumably “they are often infected in childhood and therefore have disease of longer duration.”
  • Limitations included absence of data on alcohol, cigarettes and coffee.  In addition, the study period occurred when treatment options for HBV were more limited.

The accompanying editorial notes wide variability in mortality outcome data depending on the study setting.   “Studies in patients with incidentally detected HBV infection, mostly conducted in blood donors in Western countries, tend to portray a benign course…with…their incidence of complications of chronic liver disease, HCC, or liver-related mortality is not significantly higher than that in hepatitis B surface antigen-negative healthy controls.”  In China, the lifetime risk for an infected patient to die from an HBV-related cause “has been estimated to be up to 50% in men and 15% in women.”

Related blog posts:

Growth after Liver Transplantation

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A retrospective chart review of patients from Australia and Japan who underwent liver transplantation between 1985-2004 provides some insight into the growth potential after liver transplantation (J Pediatr 2013; 163: 537-42).  The study included height data from 98 patients and weight data from 104 patients.

Study characteristics:

  • 58% were Australian and 42% were Japanese
  • 76 of 98 patients were transplanted for biliary atresia
  • 47% were younger than 2 years at the time of transplantation
  • Measurements were recorded pre-transplant, 1, 5, 10 and 15 years later

Findings:

  • Height recovery continued for at least 10 years to reach the 26th percentile (Z-score -0.67) 15 years after transplant.  Australian patients had better height recovery, reaching the 47th percentile (Z-score -0.06).
  • Weight recovery was most pronounced in 1st year after transplantation but also continued for 15 years.
  • The median height, weight, and BMI Z-scores are listed in Table II for all time periods
  • Those most malnourished and growth impaired at transplant exhibited the most catchup but remained significantly shorter and smaller 15 years later.

While the Australian patients had better growth in this study, this may be attributable to the fact that nearly all the Japanese in this study were transplanted before 1996 whereas Australian patients were transplanted over the entire period of the study.  Improvements in post-operative management with improved immunosuppressive treatment regimens (eg. reduced steroids) may have played a role.

Take-home message:  Most pediatric liver transplantation patients can expect to be normal-sized adults.  Those who are very malnourished at the time of transplantation, though, are likely to have some reduction in growth potential.

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Immunization Recommendations from CDC 2013

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The following was copied from the ImproveCareNow Circle Newsletter (conta.cc/145rO5T):

The Centers for Disease Control and Prevention (CDC) offers easy-to-print schedules for regular childhood immunizations and “maintenance”. These are good resources for parents and patients to keep track of their vaccine schedule. You can access them here:

It is important to note: Patients taking immunosuppressant drugs (such as prednisone, 6MP, Methotrexate, biologic agents like Remicade or Enbrel) CANNOT receive a “live vaccine” because they can become ill as a result of the vaccine. This is especially important during fall when the flu vaccine is recommended. The intranasal flu vaccine (flu mist) is a live vaccine and should NOT be given to patients taking immunosuppressant drugs.

Yearly flu [injection] shots are encouraged for kids with IBD because the flu can be very serious in someone taking immunosuppressant drugs or who has a chronic illness.  Also, because the flu is a viral infection it can stimulate the immune system and could cause a flare.

Related blog link:

Protecting the most vulnerable | gutsandgrowth

Why Some Genetic Mutations May Be Helpful: HFE

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When one looks at diseases, it is important to consider that the mutations that cause the disease may confer other selective advantages.

A classic example has been sickle-cell disease.  The heterozygous state is usually asymptomatic and makes an individual less prone to malaria.  “In the USA, where there is no endemic malaria, the prevalence of sickle-cell anaemia among blacks is lower (about 0.25%) than in West Africa (about 4.0%) and is falling. Without endemic malaria, the sickle cell mutation is purely disadvantageous and will tend to be selected out of the affected population via natural selection.” —Sickle–cell disease – Wikipedia, the free encyclopedia

Another common disorder is hemochromatosis.  A recent letter in the New England Journal of Medicine (NEJM 2013; 369: 785-6) explains why having the HFE gene could be advantageous.  According to the authors the genetic mutation arose in Celtic populations who were notably taller than other populations.  As such, the authors hypothesized that the patients with HFE hemochromatosis would have better growth by having an abundant supply of iron during periods of rapid development.

They assessed a cohort of 176 Swiss patients with HFE hemochromatosis.  93% were homozygous for the C282Y mutation, 7% had a compound H63D-C282Y mutation.  All of the patients had verified iron overload determined as a ferritin > 300 mcg/L or a transferrin saturation >45%.

Compared with an age-matched, sex-matched Swiss reference population, men with hemochromatosis (n=120) were 4.3 cm taller on average. In women (n=56), the difference was 3.3 cm.  To avoid bias due to population origin, the cohort was also compared with data from Ireland where the data remained validated.

Take-home message: Extra iron in the first two decades of life promote better growth (and probably other advantages).  However, iron overload later in life can lead to cirrhosis, diabetes, heart disease, and reproductive problems.

Related blog post:

AASLD Hemochromatosis Guidelines:

Anti-TNF therapy for IBD

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In the same issue as the vedolizumab phase 3 studies, there is a succinct review of tumor necrosis antagonist therapy (anti-TNF) therapy for IBD (NEJM 2103; 369: 754-62).

Useful points about IBD:

  • Prevalence of ulcerative colitis (UC) and Crohn’s disease (CD) in North America: 780,000 and 630,00 respectively
  • In first 10 years of CD, cumulative rate of surgery is 40-55%.
  • In first 20 years of UC, rate of colectomy is ~15%.
  • “Recent meta-analysis do not indicate that this drug (mesalamine) has any clinically relevant efficacy in patients with” Crohn’s disease.

Anti-TNF agents:

  • Agents for IBD include infliximab, adalimumab, certolizumab pegol, and golimumab.
  • No head-to-head comparisons have been studied, though the “clinical trials suggest similar efficacy among the available drugs.”
  • Newest approved anti-TNF is golimumab which is administered subcutaneously at a dose of 200 mg at week 0, followed by 100 mg at week 2 and then 100 mg every 4 weeks.
  • A “considerable number of patients with Crohn’s disease (10-40%, depending on selection criteria) do not have a clinically relevant response to currently available TNF inhibitors (primary treatment failure) and among patients with ulcerative colitis, this proportion may be as high as 50%.”
  • “In addition, only about one third to one half of patients with Crohn’s disease have a complete remission, and about two thirds of patients do not have a response that is sustained during 12 months of continuous treatment (secondary treatment failure).”  Many of these patients will respond to dose escalation.
  • The “annual projected cost of each biologic agent for a 70-kg patient with inflammatory bowel disease is approximately $19,000 in the first year and $15,000 in subsequent years.”  These figures exclude the costs associated with administration and dose escalation.

Areas of uncertainty according to the authors:

  • “The value of concomitant treatment with immunosuppressive agents and TNF inhibitors has been debated intensely.”  Combination therapy results in superior efficacy and lower rates of antibodies to anti-TNF agents.  However, “the benefit of combined treatment for more than 12 months is uncertain.”
  • “There are no data to confirm that it (top-down treatment) is actually superior to conventional step-up therapy in terms of disease progression”

Related blog links:

Coming Soon to a Pharmacy Near You (part 2)…

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While yesterday’s post reviewed the data that indicate that vedolizumab is likely to be helpful for ulcerative colitis, only small improvements were noted for patients with Crohn’s disease (NEJM 2013; 369: 711-21, GEMINI 2 studies).

Vedolizumab, “a humanized immunoglobulin G1 monoclonal antibody to α4β7 integrin, modulates gut, but not brain, lymphocyte trafficking.”  The GEMINI 2 studies for Crohn’s disease were similar to the GEMINI 1 studies for UC.  However, even more medical centers (n=285) in more countries (n=39) and more patients (n=1115 with 967 receiving study drug) participated.

Baseline characteristics:

  • Median age: 36.1 years
  • Current Smokers: 26.7%
  • Disease location: 16.2% ileum only, 28.3% colon only, 55.4% ileum/colon
  • Median fecal calprotectin: 686 mcg/gram
  • Concomitant medications: 34.2% steroids only, 16.2% immunosuppressives only, 17% both steroids and immunosuppressives, 32.6% neither steroids or immunosuppressives
  • Median steroid dosage: 20 mg
  • Prior TNF antagonist ≥1:  61.8%
  • Prior surgery for Crohn’s disease: 41.8%
  • Prior fistulizing disease: 36.8%

Results:

  • At week 6, 14.5% of vedolizumab-treated patients and 6.8% of placebo-treated patients were in clinical remission (CDAI ≤150).
  • At week 6, 31.4% of study drug group and 25.7% of placebo group had a CDAI-100 response (≥ 100 point decrease in CDAI score).
  • Among patients with an induction response, 39% and 36.4% of vedolizumab every 8 weeks and every 4 weeks, respectively were in clinical remission at week 52, compared with 21.6% of patients assigned to placebo.
  • Vedolizumab-treated patients had increased serious adverse effects including serious infections.  Nasopharyngitis occurred more frequently.
  • Five deaths were noted during the study, four among the treatment group (Crohn’s/sepsis, intentional overdose, myocarditis, and septic shock).
  • No PML cases have been reported among the 3000 patients exposed to vedolizumab

While the response rate to vedolizumab was modest in Crohn’s disease patients, there are some factors that need to be considered in interpreting this data. Unlike in many trials (According to the study which you would never … – gutsandgrowth), this trial included patients with more disease severity.  The authors note that the effects of anti-integrin therapy could be relatively slower acting in Crohn’s disease due to the transmural nature of the disease.  An alternative explanation would be that the gut-selective targeting by vedolizumab is ineffective in most patients with Crohn’s disease due to the need for a more systemic inhibition with transmural disease.

Bottom-line: Among the small percentage of patients who have a response to vedolizumab at week 6, the rates of clinical remission at week 52 were significantly higher than those who received placebo.

Coming Soon to a Pharmacy Near You (part 1)…

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Vedolizumab!

Two articles indicate that Vedolizumab will be an important agent for treating Ulcerative Colitis (UC).  The first article, NEJM 2013; 369: 699-710, describes two integrated studies (GEMINI 1 studies) in the use of this agent for induction and then for maintenance therapy of UC.

Background: Vedolizumab is a gut-selective blocker of lymphocyte trafficking (see previous post: Vedolizumab -another new IBD treatment | gutsandgrowth).  It is similar to natalizumab which was approved in 2008 for Crohn’s disease.  In phase 3 trials, natalizumab was demonstrated a response in 48% of patients with moderate-to-severe disease, but its large-scale use has been precluded by the potential for reactivation of the John Cunningham (JC) virus and progressive multifocal leukoencephalopathy (PML).

Study design: this study was a phase 3, randomized, double-blind, placebo-controlled study conducted at 211 medical centers in 34 countries from 2008-2012.  At baseline some of the assessments included blood tests, stool for enteric pathogens, chest radiography, stool calprotectin, QuantiFERON-TB Gold assay and sigmoidoscopy.  Intravenous vedolizumab was administered at a dose of 300 mg or placebo at days 1 and 15 during induction; also patients were stratified for glucocorticosteroids, use of immunosuppressives and prior use of TNF antagonists.  In total, 746 patients received vedolizumab and 149 received placebo.

Some of the baseline patient characteristics:

  • Mean age: 40.3 yrs
  • Median prednisone dose: 20 mg
  • Average fecal calprotectin: 899 mcg/gr.
  • Site of disease: 37% pancolitis, 13% rectum/sigmoid only, 37.9% left-sided disease, 12.2% disease proximal to splenic flexure.
  • Prior anti-TNF therapy: 48.2%

Results:

  • Induction: at week 6, 47.1% of vedolizumab and 25.5% of placebo-treated patients had a clinical response
  • Maintenance: at week 52, of patients randomly assigned to continue receiving vedolizumab, 44.8% every 4 weeks, 41.8% every 8 weeks were in clinical remission compared with 15.9% receiving placebo
  • Glucocorticoid-free remission at 52 weeks in 45.2% of patients receiving vedolizumab every 4 weeks, 31.4% receiving every 8 week treatment, and 13.9% of placebo-treated patients.
  • Figure 1 details important changes in Partial Mayo score, IBDQ score, Fecal calprotectin, and prednisone dose changes.  With regard to fecal calprotectin, at week 6 the median calprotectin level had dropped approximately 70%.  Smaller decreases were noted in patients continuing vedolizumab at week 52.
  • Safety: “no important differences” according to the authors between vedolizumab and placebo.  Specifically, there were no cases of PML; however, routine JC virus testing was not performed in this study.  Infusion reactions were seen in three cases (two with detectable antibody). a mild increase in nasopharyngitis was noted.
  • Cancer: 1.1% of placebo-treated patients developed a malignancy (1 colon cancer, 1 transitional-cell carcinoma, 1 squamous-cell carcinomas of skin) and 0.2% of vedolizumab (1 colon cancer)
  • Drug levels: mean vedolizumab concentrations at every 4 week dosing: 38.3 mcg/mL and at every 8 week dosing: 11.2 mcg/mL
  • Antibodies: 3.7% had samples that were positive for anti-vedolizumab antibodies at any time.  1% developed persistent antibody positivity.

Bottom-line: This large study shows that vedolizumab is effective in a large number of patients with UC, many who were refractory to other treatments, including anti-TNF agents.

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