Pediatric Infectious Disease Newsletter
-

September 2009  

2009 H1N1 Influenza Vaccine Update
As of September 11, 2009, there continues to be widespread activity throughout Florida. Vaccination is the key to prevention of illness. This includes administration of the seasonal influenza vaccine and the novel H1N1 vaccine (when available).  Physicians should already be administering the seasonal vaccine in their practice.

There have been circulating rumors questioning the safety of the novel H1N1 vaccine. The novel H1N1 vaccine appears to have a similar safety profile as the seasonal influenza vaccines.  "Hundreds of millions of Americans have received seasonal influenza vaccines." The most common side effects are localized tenderness, erthyma, or swelling.  The only contraindication to influenza vaccination is an individual with severe chicken egg allergy or severe allergy to other components of the vaccine.

Vaccination recommendations for the novel H1N1 vaccine:

  • Ages 6 months through 24 years of age
  • Household contacts and caregivers for children <6 months of age
  • Healthcare and emergency medical service personnel
  • Pregnant women
  • Adults 25-64 years of age with health conditions associated with higher risk of medical complications from influenza
CDC expects that side effects from the novel H1N1 vaccine would be similar to the seasonal influenza vaccine.  Any suspected adverse events can be reported to Vaccine Adverse Events Reporting System (VAERS) at www.vaers.hhs.gov.

Centers for Disease Control and Prevention
www.cdc.gov/h1n1flu/
www.cdc.gov/h1n1flu/vaccination/acip.htm
 
Pediatric Deaths Associated with 2009 Pandemic Influenza A (H1N1) Virus Infection
From April 2009 through August 8, 2009, Centers for Disease Control and Prevention (CDC) had received reports of 477 deaths associated with 2009 pandemic influenza A (H1N1) in the United States, including 36 deaths among children aged <18 years.  The following case series included data reported to the CDC on all deaths associated with laboratory-confirmed 2009 pandemic influenza A (H1N1) virus infection occurring in persons aged <18 years through August 8, 2009. Laboratory confirmation was defined as a positive test for 2009 pandemic influenza A (H1N1) virus by reverse transcription--polymerase chain reaction (RT-PCR).  A summary of the report is given below.

Illness onset, duration of illness and death:
Illness occurred during May 9--July 20. Duration of illness before death in the 36 cases was 1 day to 28 days (median: 6 days).  Deaths occurred during May 15--July 28. Six deaths occurred in May, 25 deaths in June, and 5 deaths in July.

Age:
Median age of the patients was 9 years (range: 2 months--17 years); seven (19%) of the 36 children were aged <5 years (five were aged <2 years).

High-risk conditions not related to age:
Twenty-four (67%) had at least one high-risk medical condition and 22 of the 24 children (92%) had neurodevelopmental conditions (e.g., developmental delay or cerebral palsy). Of these 22 children, 13 (59%) had more than one neurodevelopmental diagnosis, and nine (41%) had neurodevelopmental and chronic pulmonary conditions.

Antiviral treatment:
For the 31 children for whom antiviral treatment data were available, 19 (61%) received antiviral treatment, and four of those received treatment within 2 days of illness onset.  Although the majority of children in this case series received antiviral treatment, few received treatment within 2 days of illness onset.

Bacterial coinfections:
Of the 23 children with culture or pathology results reported, 10 (43%) had a laboratory-confirmed bacterial coinfection. The bacteria causing these infections included Staphylococcus aureus (five, including three methicillin-resistant S. aureus), Streptococcus pneumoniae (three), Streptococcus pyogenes (one), and Streptococcus constellatus (one).  Six of the 10 children with a laboratory-confirmed bacterial coinfection were aged ≥5 years and had no recognized high-risk condition.

Perspective:
H1N1 is currently not causing increased deaths in children when compared to the 2003--04, 2004--05, 2005--06, and 2006--07 influenza seasons. Twenty-eight (78%) of the 36 children whose deaths were associated with the H1N1 influenza virus infection were in at least one of two groups previously found to be at increased risk for complications from seasonal influenza: children aged <5 years and those with a high-risk chronic medical condition. The percentage of children with high-risk medical conditions (67%) in this series of H1N1 associated deaths is higher than the percentage reported in recent influenza seasons. During the 2003--04, 2004--05, 2005--06, and 2006--07 seasons, a total of 153, 47, 46, and 73 pediatric deaths were reported through the influenza-associated pediatric mortality reporting system, respectively. During those seasons, the percentages of children with high-risk medical conditions were 47%, 55%, 48%, and 35%, respectively

Of note, among children with high-risk medical conditions, 92% had neurodevelopmental conditions (e.g., developmental delay or cerebral palsy), a finding consistent with the results from a study of influenza-associated mortality during the 2003--04 influenza season.

Six children, who were aged ≥5 years, did not have a high-risk medical condition, and had culture or pathology results reported had an invasive bacterial coinfection. This suggests that bacterial infection, in combination with 2009 pandemic influenza A (H1N1) virus infection, can result in severe disease in children who might be otherwise healthy.

Although the majority of children in this case series received antiviral treatment, few received treatment within 2 days of illness onset.  The delay in treatment may have been the result of difficulties in diagnosing H1N1 because of the poor sensitivity of the current rapid tests used.

MMWR September 4, 2009 / 58(34); 941-947 Surveillance for Pediatric Deaths Associated with 2009 Pandemic Influenza A (H1N1) Virus Infection --- United States, April--August 2009

Health-care providers can find current recommendations online at www.cdc.gov/h1n1flu.
 
Oseltamivir-Resistant Novel Influenza A (H1N1) Virus Infection
The CDC has described two separate reports in the MMWR over the last 2 months of oseltamivir-resistant novel influenza A (H1N1) virus infection. One report was out of Seattle, where two severely immunosuppressed patients developed H1N1 infection. The two patients were not epidemiologically linked and were treated at different hospitals.  The second report was oseltamivir-resistant novel influenza A (H1N1) found in two children receiving prophylaxis that attended summer camp in North Carolina.

In the Seattle report, the first case was a teenage boy with leukemia who recently received a hematopoietic stem cell transplant.  The second case was a female patient in her 40s who had a hematopoietic stem cell transplant for leukemia and had a recurrence of leukemia.  She was being treated with additional immunosuppressive chemotherapy. Initially, both patients were infected with oseltamivir-susceptible viruses.  Oseltamivir resistance developed later during antiviral treatment most likely due to the severe immunosuppression in each patient that resulted in prolonged viral shedding.   This situation is different from influenza in immunocompetent hosts in which viral shedding generally resolves within 7 days. No evidence was found that healthcare personnel or other patient contacts developed an influenza-like illness caused by oseltamivir-resistant novel influenza A (H1N1) virus infection.
 
The oseltamivir resistance in the H1N1 influenza virus in both of these patients resulted from a single mutation called H275Y.  However, both of these oseltamivir-resistant H1N1 viruses were susceptible to zanamivir. Because antiviral resistance can develop during treatment of influenza in immunosuppressed patients, and prolonged viral shedding of up to 18 months has been reported with seasonal influenza, including shedding of oseltamivir-resistant seasonal influenza A virus for more than 1 year, clinicians caring for immunosuppressed patients with novel influenza A (H1N1) virus infection should be aware of the potential for development of antiviral drug resistance during therapy and prolonged viral shedding.
 
The second report, from North Carolina, describes confirmed oseltamivir-resistant 2009 pandemic influenza A (H1N1) virus infection in two previously healthy adolescents who were cabin mates and recipients of oseltamivir in a mass chemoprophylaxis program during an outbreak of ILI at a summer camp. This is the first report of oseltamivir resistance in symptomatic close contacts with confirmed infection. These 2 cases occurred during a camp session in which there was an outbreak of H1N1 involving both campers and staff members. 
 
The oseltamivir-resistant H1N1 isolated from the adolescents harbored H275Y and I223V mutations.  Whether the H275Y and I223V mutations occurred independently, or whether virus with one or both of these mutations circulated more widely in the camp could not be determined. The H275Y mutation has been characterized previously among seasonal influenza A (H1N1) viruses and is associated with resistance to oseltamivir. The I223V mutation has not been reported previously in 2009 pandemic influenza A (H1N1) and the mutation's functional significance is unknown.
The report from North Carolina highlights a potentially adverse outcome from oseltamivir chemoprophylaxis. The World Health Organization has reported multiple instances of oseltamivir-resistant 2009 pandemic influenza A (H1N1) viruses being isolated from persons who developed pandemic H1N1 infection while receiving oseltamivir chemoprophylaxis.

CDC recommendations regarding use of antivirals during the H1N1 pandemic were updated on September 8. Use of antiviral medications for postexposure chemoprophylaxis should be reserved for persons at higher risk for influenza-related complications who have had contact with someone likely to be infected with influenza. Persons who are taking antiviral medications for prevention should be instructed to contact a healthcare provider if illness develops. Persons under antiviral treatment should be instructed to contact a healthcare provider if symptoms worsen. In these cases, providers should consider the possibility of antiviral resistance and consider alternate treatment options.
 
Because the 2009 pandemic influenza A (H1N1) virus is resistant to adamantanes, limited treatment options will be available if widespread oseltamivir resistance develops as zanamivir is not licensed for treatment of children aged <7 years and is contraindicated among persons with underlying airway disease.
 
MMWR September 11, 2009 / 58(35);969-972
MMWR August 21, 2009 / 58(32);893-896
Clinical Pearl: Do not forget about deep soft tissue infections caused by S. pyogenes in the era of CA-MRSA! 
We recently evaluated two hospitalized children with deep soft tissue infections secondary to S. pyogenes. The first patient had a necrotizing soft tissue infection of the leg extending into the fascia.  The 2nd patient developed pyomyositis involving the deep pelvic musculature. Both patients were empirically treated with a combination of penicillin (PCN) and clindamycin.  Trimethoprim-sulfamethoxazole (TMP-SMX) is routinely used for CA-MRSA soft tissue infections and has poor activity against S. pyogenes. 

It is common practice for infectious disease specialists to recommend combination antimicrobial therapy for serious deep tissue infections caused by S. pyogenes.  There is a hypothesis that large inoculums of S. pyogenes reach a stationary phase of growth and PCN may not be as effective as growth of the organism begins to slow down. In addition, the penicillin binding proteins are not as readily available for drug binding in this phase of growth. A 2nd drug, clindamycin is usually added to PCN. Clindamycin inhibits protein synthesis that is not dependent on the phase of growth or inoculum size of the bacteria.  Since clindamycin also inhibits protein synthesis, it may suppress toxin production from S. pyogenes as well.

Bisno AL, Stevens DL. Streptococcal infections of Skin and Soft Tissues. NEJM 1996; 334:240-246
 
Acute Otitis Media: Why is Amoxicillin Failing Against Susceptible Strains?
Pharmacokinetic/Pharmacodynamic (PK/PD) modeling and Monte Carlo simulations suggest that amoxicillin should rarely fail as therapy for Streptococcus pneumoniae and Haemophilus influenzae acute otitis media (AOM) infections, except with highly penicillin resistant S. pneumoniae or beta-lactamase producing H. influenzae strains. However, exceptions to this expectation have been described and failures of amoxicillin to susceptible strains occur.
 
A recent review was completed in Pediatric Drugs, and the analysis of various studies identified for review showed that the intestinal bioavailability of amoxicillin depends on passive diffusion and a saturable pump mechanism that produces variable amoxicillin serum concentrations. Of note, the cephalosporins are not dependent on a saturable pump mechanism. Substantial differences among patients have been noted; a 5-to-30 fold difference and up to a 2-fold difference in serum and middle ear fluid (MEF) concentrations respectively. In addition, 15-35% of children have no detectable amoxicillin in MEF.
 
In conclusion, the data presented in this review suggests that children treated for AOM who do not respond with a full course of high-dose amoxicillin (adherence confirmed) should be re-treated with an agent that is not only stable against bacterial-inactivating enzymes (e.g. beta-lactamases) but also well absorbed after oral administration. Various agents used for AOM and their respective absorption PK data:
Antibacterial Agent Oral Absorption Data
Amoxicillin (Amoxil) 74-92% absorbed
Cefdinir (Omnicef) Estimated absolute bioavailabilty of oral suspension is 25%
Cefpodoxime (Vantin) 50% bioavailability; enhanced with food
Cefuroxime (Ceftin) Tablets: 37-52%; suspension is less bioavailable
Clindamycin (Cleocin) ~90% oral bioavailability
Levofloxacin (Levaquin)
*reserve for highly resistant strains
~99% bioavailability; oral solution should be given 1 hour before or 2 hours after food
 
Pichichero ME and Michael D. Reed. Variations in Amoxicillin Pharmacokinetic/Pharmacodynamic Parameters May Explain Treatment Failures in Acute Otitis Media. Pediatr Drugs. 2009;11(4):243-49
Join Our Mailing List 
Forward to a Friend 
In This Issue
2009 H1N1 Influenza Vaccine Update
Pediatric Deaths Associated with 2009 Pandemic Influenza A (H1N1) Virus Infection
Oseltamivir-Resistant Novel Influenza A (H1N1) Virus Infection
Clinical Pearl: Do not forget about deep soft tissue infections caused by S. pyogenes in the era of CA-MRSA!
Acute Otitis Media: Why is Amoxicillin Failing Against Susceptible Strains?
Infectious Disease Newsletter Feedback
National Shortage of Erythromycin Ophthalmic Ointment for Newborn Prophylaxis of Ophthalmia Neonatorum
Human Papillomavirus Vaccine: Post Licensure Safety Data
An Update on Evidence- Based Clinical Practice Guidelines Immunization Programs for Infants, Children, Adolescents, and Adults
David M. Berman, D.O.
Juan Dumois III, M.D.
Shirley Jankelevich, M.D.
Allison Messina, M.D.
Dale Bergamo, M.D.
Patricia Emmanuel, M.D.
Jorge Lujan-Zilbermann, M.D.
Carina A. Rodriguez, M.D.
Katie Namtu, Pharm.D.

Inpatient Consultation:
All Children's Hospital
Tampa General Hospital
Bayfront Medical Center Nursery

Outpatient Clinics:
Infectious Disease
International Adoption

Phone: 727-767-4160
Fax: 727-767-8270
Email: pidhl@allkids.org
Infectious Disease Newsletter Feedback
Please email your comments and suggestions so we may continue to improve our newsletter! 
National Shortage of Erythromycin Ophthalmic Ointment for Newborn Prophylaxis of Ophthalmia Neonatorum
Secondary to the shortage of Erythromycin ophthalmic ointment, the Centers for Disease Control has made interim recommendations for alternatives to Erythromycin Ophthalmic Ointment. These include gentamicin, tobramycin, and azithromycin ophthalmic ointment. For more information check the American Academy of Pediatrics Member Center.
 
AAP Member Center
Human Papillomavirus Vaccine: Post Licensure Safety Data
The human papillomavirus vaccine (HPVq) was licensed by the Food and Drug Administration in June 2006. The vaccine is administered on a schedule of 0, 2, and 6 months.  Post licensure data has been collected from the Vaccine Adverse Events Reporting System (VAERS) over a 2 year period. VAERS is a passive surveillance system from voluntary reporting. This reporting can come from pharmaceutical companies, health care professional, parents, patients and even lawyers!  As pointed out in this recent article from JAMA, there are always limitation to passive reporting systems and the "potential effect of widespread media coverage stimulating reporting."

Since licensure of the HPVq, 23 million doses have been distributed. Over the 2 year period, there were 12,424 voluntary reports of adverse events following immunization. The highest reporting rates were for syncope, local reactions to vaccination, dizziness, nausea, headache, hypersensitivity reactions, and urticaria, respectively. Thromboembolic events were reported as well over a wide range of time and 90% had another reported risk factor besides the vaccine for venous thromboembolic events.  Many of the syncopal events among females 11-18 years of age occurred after several newly licensed vaccines were added to the schedule. This age group has a higher background rate of syncope than other age groups. Overall, the reporting rate to VAERS for the HPVq is triple the rate of all other vaccines combined, however, this may also be a reflection of more public awareness of this vaccine causing more reporting of events. Post licensure safety of this vaccine is "consistent with safety data from prelicensure trials."

JAMA 2009;302 (7):750-757
An Update on Evidence-Based Clinical Practice Guidelines Immunization Programs for Infants, Children, Adolescents, and Adults
This document replaces the previous guideline published in 2002 and incorporates evidence on new licensed vaccines (human papillomavirus vaccine; live, attenuated influenza vaccine; meningococcal conjugate vaccine; rotavirus vaccine; tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis [Tdap] vaccine; and zoster vaccine), new combination vaccines  (measles, mumps, rubella and varicella vaccine; tetanus, diphtheria, and pertussis and inactivated polio vaccine; and tetanus, diphtheria, and pertussis and inactivated polio/Haemophilus influenzae type b vaccine), and updates on the recommendations of hepatitis A vaccine, second dose of varicella vaccine, and influenza vaccination for all children age 6 months through 18 years. Useful statements for the practitioner, including approaches to barriers to immunizations, addressing vaccine safety with families, and immunizations on selected patient populations (immunocompromised, pregnant women, international travelers, and internationally adopted children) are included. Finally, a comprehensive list of vaccine resource web sites is available as an excellent resource for the pediatrician and primary care provider.

An Update on Evidence-Based Clinical Practice Guidelines by the Infectious Diseases Society of America Clinical on Immunization Programs for Infants, Children, Adolescents, and Adults has been recently published  Pickering, L, Baker, C; Freed G, et al. CID 2009;49:817-40