Drugs Log

An emerging “superbug” that causes ear infections in children and is resistant to multiple antibiotics can only be treated with an adult medication, researchers report.

Two Rochester, N.Y., pediatricians report finding a multiple antibiotic-resistant strain of Streptococcus pneumoniae that caused ear infections in nine children in their practice over three years. The only antibiotic that was effective in treating these infections was levofloxacin, which isn’t approved by the U.S. Food and Drug Administration for use in children.

“We found a superbug causing ear infections in Rochester — the Legacy strain — that’s resistant to all antibiotics approved by the FDA for use in children,” said the study’s lead author, Dr. Michael Pichichero, a professor of microbiology, immunology and pediatrics at the University of Rochester Medical Center, and a private practice pediatrician with the Legacy Pediatric Group.

The resistant infections accounted for only 1.5 percent of the ear infections in their practice, Pichichero noted.

The findings are published in the Oct. 17 issue of the Journal of the American Medical Association.

Pneumococcal infections are caused by S. pneumoniae, and can include ear infections, sinus infections, pneumonia, meningitis and bloodstream infections. Some of these infections can be life-threatening. Young children are most susceptible to pneumococcal infections, according to the U.S. Centers for Disease Control and Prevention. Fortunately, the serious forms of the disease are rare, causing about 4,500 illnesses each year. However, pneumococcal infections cause more than 3 million ear infections each year, according to the CDC.

While a vaccine (brand name Prevnar) is available that covers seven strains of pneumococcal disease, a strain dubbed serotype 19A isn’t currently one of them. However, the vaccine’s manufacturer, Wyeth Pharmaceuticals, reports that it’s currently in phase III trials of the next generation vaccine, which does include serotype 19A.

“Prevnar is a fantastic vaccine that is taking care of the top seven strains of pneumococcal disease, but after you’ve knocked down the other strains, of course others will become more prominent,” Pichichero explained.

Dr. Peter Paradiso is vice president of scientific affairs for Wyeth Pharmaceuticals. He said, “When we developed Prevnar, we had hoped that the response to serotype 19F would provide some cross-protection against 19A.” When it became clear that there was no cross-protection, and other strains needed to be addressed, Wyeth added six more strains to the next generation vaccine. The company plans to begin the regulatory filings needed for FDA approval sometime in 2009, after the phase III trials are completed, he said.

In the meantime, Pichichero said physicians need to do more ear tap procedures to identify which bacteria are causing antibiotic-resistant ear infections. Doing so, he said, would help avoid the unnecessary use of antibiotics and allow for a more targeted approach to treating ear infections.

From 2003 until 2006, Pichichero and his colleagues saw just over 1,800 youngsters with ear infections, according to the study. Of those children, 212 had ear taps, known as tympanocentesis, a procedure that draws fluid out from behind the ear drum. Much like when a tooth cavity is filled, children are given local anesthetic to make the procedure pain-free.

Using this procedure, the doctors found that 59 of the ear infections were caused by S. pneumoniae. One particular strain of the bacterium — serotype 19A — had developed a new genotype that was resistant to all of the antibiotics approved for use in children. Pichichero and his colleague, Dr. Janet Casey, dubbed this the Legacy strain. Nine children were found to be infected with this strain.

The only antibiotic effective against this superbug is levofloxacin (brand name, Levaquin). But, levofloxacin has never been approved for use in children. Pichichero said that because previous studies on young animals have suggested that the drug might cause irreversible damage to growing cartilage, the “FDA has put significant barriers for the use of the antibiotics in children.” No such effects have been found in adults, and it’s a commonly used antibiotic in adults.

However, in these nine pediatric cases, no other treatments were effective, and the children were at risk of losing their hearing. Since Pichichero had been involved in previous research on levofloxacin’s use in children, he knew the correct dose to administer, and it was effective.

But, he cautioned, because the drug hasn’t been well studied in children, “I would not allow a child to receive levofloxacin unless I knew for sure [that it was the Legacy strain].”

Dr. Katherine Poehling, a pediatrician at Brenner Children’s Hospital at Wake Forest University Baptist Medical Center, said the new findings are worrisome, but “nine cases out of 1,800 doesn’t make me panic. We’ve always had some ear infections that are very hard to treat, but they usually aren’t serotyped to figure out what they are.”

Poehling, who’s been involved in research on the current pneumococcal vaccine, added that the “pneumococcal conjugate vaccine has been extraordinarily successful, and children continue to benefit from this vaccine.”

Paradiso agreed, adding that the current vaccine has caused a dramatic — 99 percent — reduction in infections in the serotypes that are covered by the vaccine.

The CDC recommends that the current vaccine be given to all infants younger than 24 months of age at 2, 4, and 6 months of age, followed by a booster dose at 12-15 months of age.

What is pneumococcal disease?

Pneumococcal disease is defined as infections that are caused by the bacteria Streptococcus pneumoniae, also known as pneumococcus. The most common types of infections caused by this bacteria include middle ear infections, pneumonia, blood stream infections (bacteremia), sinus infections, and meningitis.

Which children are most likely to get pneumococcal disease?

Young children are much more likely than older children and adults to get pneumococcal disease. Children under 2, children in group child care, and children who have certain illnesses (for example sickle cell disease, HIV infection, chronic heart or lung conditions) are at higher risk than other children to get pneumococcal disease. In addition, pneumococcal disease is more common among children of certain racial or ethnic groups, such as Alaska Natives, Native Americans, and African-Americans, than among other groups.

How prevalent is pneumococcal disease?

Each year in the U.S. Streptococcus pneumoniae causes approximately 480 cases of meningitis, 4,000 cases of bacteremia or other invasive disease in children under the age of 5. Children under 2 average more than 1 middle ear infection each year, many of which are caused by pneumococcal infections. Streptococcus pneumoniae is the most common cause of bacteremia, pneumonia, meningitis and otitis media in young children.

Who is at most serious risk?

Children at increased risk of pneumococcal infections include those with anatomic or functional asplenia (including sickle cell disease), patients taking immunosuppressive chemotherapy, those with congenital and acquired immune deficiency (including HIV infections), those with chronic renal disease and healthy Native American, Alaskan Native, and African American children. Children less than 60 months of age in out-of-home day care are at 2-3 fold higher risk of experiencing invasive pneumococcal infections than children in home care.

What are the symptoms of pneumococcal disease?

Meningitis:
High fever, headache, and stiff neck are common symptoms of meningitis in anyone over the age of 2 years. These symptoms can develop over several hours, or they may take 1 to 2 days. Other symptoms may include nausea, vomiting, discomfort looking into bright lights, confusion, and sleepiness. In newborns and small infants, the classic symptoms of fever, headache, and neck stiffness may be absent or difficult to detect, and the infant may only appear slow or inactive, or be irritable, have vomiting, or be feeding poorly.

Pneumonia:
In adults, pneumococcal pneumonia is often characterized by sudden onset of illness with symptoms including shaking chills, fever, shortness of breath or rapid breathing, pain in the chest that is worsened by breathing deeply, and a productive cough. In infants and young children, signs and symptoms may not be specific, and may include fever, cough, rapid breathing or grunting.

Otitis media:
Children who have otitis media (middle ear infection) typically have a painful ear, and the eardrum is often red and swollen. Other symptoms that may accompany otitis media include sleeplessness, fever and irritability.

Blood stream infections:
Infants and young children with blood stream infections-also known as bacteremia-typically have non-specific symptoms including fevers and irritability.

How serious is pneumococcal disease?

Pneumococcal disease is a very serious illness in young children. Pneumococcal infections are now the most common cause of invasive bacterial infection in U. S. children. In the United States it is estimated that pneumococcal infections cause 100 deaths, 450 cases of meningitis, 4,000 cases of bacteremia or other invasive disease, and 3.1 million cases of otitis media (ear infections) annually in children under 5 years of age.

Meningitis is the most severe type of pneumococcal disease. Of children less than 5 years of age with pneumococcal meningitis, about 5% will die of their infection and others may have long-term problems such as hearing loss. Many children with pneumococcal pneumonia or blood stream infections will be ill enough to be hospitalized; about 1% of children with blood stream infections or pneumonia with a blood stream infection will die of their illness. Nearly all children with ear infections recover, although children with recurrent infections can suffer hearing loss.
How is pneumococcal disease spread?

The bacteria are spread through contact between persons who are ill or who carry the bacteria in their throat. Transmission is mostly through the spread of respiratory droplets from the nose or mouth of a person with a pneumococcal infection. It is common for people, especially children, to carry the bacteria in their throats without being ill from it.

How is pneumococcal disease treated/cured?

Pneumococcal disease is treated with antibiotics. Over the last decade, many pneumococci have become resistant to some of the antibiotics used to treat pneumococcal infections; high levels of resistance to penicillin are common.

Can pneumococcal disease in children be prevented?

In late 2000, the FDA licensed a new vaccine for the prevention of pneumococcal disease in children. The new pneumococcal vaccine, Prevnar® (manufactured by Wyeth-Lederle Vaccines), is a vaccine in which the serotypes are conjugated (or linked) to a protein. This new pneumococcal conjugate vaccine has been shown to be highly effective in preventing invasive pneumococcal disease (such as in young children. In a study of the new vaccine among 37,000 infants in California, the vaccine was over 90% effective in preventing invasive disease among the children studied. The children who received the new vaccine also had 7% fewer episodes of otitis media and a 20% decrease in the number of tympanostomy tubes (ear tubes) placed. The vaccine was also shown to decrease the number of episodes of pneumonia.

CDC conducted a study soon after a vaccine was licensed and found that the vaccine was highly effective in preventing disease in children under 5 years of age. The investigators found that the vaccine was 96% effective against pneumococcal disease in healthy children who received one dose or more and 81% effective in children with medical conditions that put them at risk of pneumococcal disease. The vaccine was also highly effective at preventing pneumococcal disease caused by antibiotic-resistant strains.

Prevnar® is indicated for use in infants and toddlers. The vaccine should be given to all infants younger than 24 months of age at 2, 4, and 6 months of age, followed by a booster dose at 12-15 months of age. Children who are unvaccinated and are 7 to 11 months of age should be given a total of 3 doses (2 months apart) and children age 12 to 23 months should be given a total of 2 doses at least two months apart. Most children who are 24 months of age or older only need one dose of the vaccine.

The Advisory Committee on Immunization Practices (ACIP) also recommends the new pneumococcal childhood vaccine be given to children age 24 to 59 months at highest risk of infection, including those with certain illness (sickle cell anemia, HIV infection, chronic lung or heart disease). Vaccine should be considered for all children aged 24-35 months and other children through 59 months of age with a priority for those at higher risk which includes Alaska Natives, American Indians, or African Americans and those children who attend out-of-home day day care for more than 4 hours per week.

The recently licensed pneumococcal conjugate vaccine, Prevnar®, is the first pneumococcal vaccine that can be used in children under the age of 2 years. However, pneumococcal vaccines for the prevention of disease among children and adults who are 2 years and older have been in use since 1977. Pneumovax® and Pnu-Immune® are 23-valent polysaccharide vaccines that are currently recommended for use in all adults who are older than 65 years of age and for persons who are 2 years and older and at high risk for disease such as persons with sickle cell disease, HIV infection, or other immunocompromising condition.

Campaigns for judicious use of antibiotics may also slow or reverse emerging drug resistance found among pneumococcal infection.