The Changing Epidemiology of Bacterial Meningitis

The greatest advance in reducing mortality from bacterial meningitis over the past 20 years has been the advent of widespread immunization. Vaccination has also had another effect: changing which forms of the disease are most prevalent.

"Vaccination is the main factor that has changed the epidemiology of bacterial meningitis in the United States," said Allan R. Tunkel, MD, PhD, the lead author of practice guidelines for bacterial meningitis from the Infectious Diseases Society of America (IDSA). Tunkel is also chair of the Department of Medicine at Monmouth Medical Center in Long Branch, New Jersey.

Most bacterial meningitis was once caused by Haemophilus influenzae, but with widespread childhood immunization against H influenzae type b (Hib) in the developed world starting in the early 1990s, Hib infection has become rare; Streptococcus pneumoniae and Neisseria meningitidis have emerged as the leading causes of bacterial meningitis.

Another relatively recent change in bacterial meningitis has been decreased susceptibility of meningitis-causing bacteria-especially S pneumoniae-to antimicrobial agents. Tunkel explained that in the 1970s in the United States "virtually all pneumococci were exquisitely sensitive to penicillin, but what we've seen over recent years is that pneumococci have become either intermediately susceptible or highly resistant to penicillin."

The emergence of antibiotic-resistant strains has changed the way bacterial meningitis is treated, causing physicians to routinely use vancomycin in combination with a third-generation cephalosporin as empiric therapy for presumed pneumococcal meningitis.

CHANGES DUE TO VACCINES
Twenty to 30 years ago, H influenzae caused about 45% of postneonatal cases of community-acquired bacterial meningitis. S pneumoniae caused 18%, and N meningitidis caused 14%.¹ But the introduction of the Hib conjugate vaccine in the early 1990s changed that equation, causing the number of annual cases of H influenzae meningitis disease in the United States to plummet by 94% between 1986 and 1995. This made S pneumoniae responsible for 47% of cases, N meningitidis responsible for 25%, Listeria monocytogenes responsible for 8%, and H influenzae responsible for 7%.²

Another breakthrough was the introduction of the pneumococcal conjugate vaccine (Prevnar) in 2000. The vaccine, which is given as a 4-dose series for children starting at age 2 months, protects against the 7 most common strains of S pneumoniae that cause invasive disease, including bloodstream infections and meningitis. Since 2000, the American Academy of Pediatrics and the Advisory Committee on Immunization Practices (ACIP) of the CDC have recommended the routine use of pneumococcal conjugate vaccine for children aged 2 to 23 months.

The pneumococcal polysaccharide vaccine (Pneumovax), which protects against 23 strains of S pneumoniae, is recommended for persons older than 65 years. Kaplan added that for children older than 2 years who are at increased risk for infection, many experts recommend a single dose of the pneumococcal conjugate vaccine followed 2 months later by the polysaccharide vaccine.

Cynthia Whitney, MD, MPH, acting chief of the respiratory diseases branch at the CDC in Atlanta, explained that when the pneumococcal conjugate vaccine was introduced, pneumococcal meningitis cases started to drop not only in young children but also in older adults because of increased herd immunity. She said that the main limitation of the vaccine is that it only covers for 7 of the 90-plus serotypes that can cause meningitis.

"There is some concern with the pneumococcal vaccine that we might see an increase in some of the other nonvaccine types, now that 7 are out of the way," she said-a phenomenon that already has been seen with serotype 19A, which is not in the vaccine.³ "The incidence of 19A has increased significantly, but it's still quite small, compared with the drops we've seen in pneumococcal meningitis overall," she said.

Tunkel agreed that the small increase in serotype 19A doesn't appear to be a major problem so far but said that experts were keeping close tabs on the strain. "It does turn out that 19A is frequently antibiotic- resistant," he added. Vaccination does not appear to have led to an increase in antibiotic-resistant strains overall, however. According to a 2006 study (coauthored by Whitney) based on data from the CDC's Active Bacterial Core surveillance, the rate of invasive disease caused by penicillin-nonsusceptible strains decreased from 6.3 to 2.7 cases per 100,000 between 1999 and 2004, a decline of 57%.³

The most recent vaccine advance was the introduction of the meningococcal conjugate vaccine in early 2005 (Menactra) for persons aged 11 to 55 years. The ACIP recommends routine use of this vaccine during the preadolescent health care visit at age 11 or 12 years. Routine vaccination also is recommended for college freshmen living in dormitories and other populations at increased risk, such as military recruits.⁴

The vaccine protects against 4 of the 5 serotypes that cause meningococcal meningitis: A, C, Y, and W-135. "Serogroup Y used to be uncommon, but it's now been a major player for the past 10 years or so," said Whitney. She added that although the vaccine is not currently licensed for children younger than 11 years, she anticipated that it would eventually be approved for use in younger children.

"This would be an important development," said Sheldon L. Kaplan, MD, chief of the Infectious Diseases Service at Texas Children's Hospital in Houston, "because children under 2 years of age are the ones who are most likely to get the disease."

Tunkel said that a shortcoming of the vaccine is its inability to protect against serogroup B, which accounts for a third of the cases seen in the United States. Children aged 2 to 10 years and adults over 55 years who are at risk for meningococcal meningitis should use the meningococcal polysaccharide vaccine (Menomune), which also protects against 4 strains of the disease and has been available since 1981.

INCREASE IN ANTIBIOTIC RESISTANCE
"In recent years, there's been a change in susceptibility of important bacteria to antimicrobial agents," said Tunkel. Antibiotic resistance is not a major issue with N meningitidis, which has never developed much resistance to penicillin in the United States. Resistance has become a significant issue with S pneumoniae, however. Tunkel attributed the emergence of resistant strains to indiscriminate use of antibiotics for many years.

According to a 2006 study,³ 1 in 3 pneumococci causing invasive diseases were antibiotic-resistant, a number that may increase. There also have been treatment failures in bacterial meningitis as a result of resistance to multiple drugs, including cefotaxime and ceftriaxone. Because the use of antibiotics gives resistant bacteria a survival advantage over susceptible bacteria, it's critical that physicians curb their use of unnecessary antibiotics.

Resistant pneumococcal strains appear to be even more pronounced in southern European countries, such as France and Spain, where antibiotics are used far more frequently than in the United States. According to a recent mathematical model published by Laura Temime, MD, and colleagues, frequent use of antibiotics in France may limit the ability of the pneumococcal vaccine to prevent antibiotic-resistant cases of the disease.⁵

Temime, who is assistant professor at the National Institute of Health and Medical Research in Paris, explained that although wide use of the heptavalent conjugate pneumococcal vaccine will lead to a reduction in carriage of vaccine-type pneumococcal strains, especially carriage of resistant strains, it also would lead to serotype replacement with carriage of nonvaccine-type strains. She said that the high rate of antibiotic exposure in a country like France would cause these new, typically low-resistance serotypes to rapidly become more resistant.

"Therefore, high antibiotic use may, in the long term, limit the impact of vaccination on pneumococcal resistance-although this will not be noticeable in short-term observations, such as those made in clinical trials of the vaccine," Temime told Applied Neurology.

Temime predicted that further increases in resistance were likely and recommended that French physicians follow the lead of their US counterparts in reducing their use of antibiotics. Another strategy for reducing the incidence of antibiotic-resistant strains would be to target these serotypes in future vaccines.⁶

Whitney cited 2 additional changes related to bacterial meningitis in recent years. The first is the use of intrapartum penicillin for prevention of neonatal meningitis beginning in 1996; this has reduced the number of neonatal infections caused by group B streptococcal disease. The reduction of Listeria meningitis-which was rare to begin with-over the past 20 years has been achieved through better food handling and increased warnings to pregnant women about avoiding foods such as soft, unpasteurized cheeses.

INTERVENTION
Bacterial meningitis caused by H influenzae is fatal in fewer than 5% of cases,⁷ but meningitis from S pneumoniae is fatal in 16% to 37% of cases⁷ and meningitis from N meningitidis is fatal in about 10%.¹

Bacterial meningitis also may lead to neurological sequelae, such as cognitive impairment, hearing loss, seizures, and paralysis. An estimated 30% to 52% of persons who survive pneumococcal meningitis suffer from such sequelae.⁷ For these reasons, prompt, appropriate treatment of bacterial meningitis is essential.

The first step in treatment, according to the IDSA guidelines, is rapid identification of the condition.⁸ Physicians should be aware that only 44% of adults with community-acquired acute bacterial meningitis present with all 4 symptoms-headache, fever, neck stiffness, and altered mental status-but nearly all patients present with at least 2 of the symptoms.⁹

When acute bacterial meningitis is suspected, the physician should immediately obtain blood samples for culture. The physician also should order a lumbar puncture to determine whether findings in the cerebrospinal fluid (CSF) are consistent with the clinical diagnosis. Because lumbar punctures are dangerous in persons with increased cranial pressure, the physician may first need to order a CT scan of the head. In these cases, the physician should begin administering treatment before the imaging scan or lumbar puncture because any delay in the administration of antibiotics or adjunctive therapy has the potential to increase mortality and morbidity.

The physician should choose an empirical antimicrobial therapy based on the patient's age and various other factors that might have exposed the patient to a particular type of meningitis. For example, an infant younger than 1 month would most likely have bacterial meningitis caused by Streptococcus agalactiae, Escherichia coli, L monocytogenes, or Klebsiella species. The recommended empirical therapy for these patients is ampicillin plus cefotaxime, or ampicillin plus an aminoglycoside. By contrast, a patient older than 50 years would be more likely to have S pneumoniae, N meningitidis, L monocytogenes, or aerobic Gram-negative bacilli as the cause. In this case, the recommended empirical regimen is vancomycin plus ampicillin plus a third-generation cephalosporin. Likewise, a patient with a basilar skull fracture or penetrating trauma is likely to have a different bacterial pathogen than someone who just has had neurosurgery or implantation of a CSF shunt, necessitating a different empiric regimen.

A diagnosis of bacterial meningitis relies on examination of the CSF derived from the lumbar puncture. Signs of bacterial meningitis include an elevated white blood cell count (usually to 1000 to 5000/µL), a predominance of neutrophils (typically between 80% and 95%), and elevation of the CSF protein concentration. Because cultures to identify the organism can take up to 48 hours, physicians should consider the use of a Gram stain to guide treatment.

After CSF analysis has established that a bacterium is the cause of the meningitis and CSF Gram stain has provided a presumptive pathogen, the physician can switch to targeted therapy. This consists of vancomycin plus a third-generation cephalosporin (ceftriaxone or cefotaxime) for S pneumoniae, ampicillin or penicillin G for L monocytogenes or S agalactiae, and a third-generation cephalosporin for H influenzae, N meningitidis, or E coli. The choice of antimicrobial therapy should be further refined after the bacterial pathogen has been isolated and in vitro susceptibility testing has been performed.

ADJUNCTIVE DEXAMETHASONE
One relatively recent change in the treatment of bacterial meningitis has been the use of adjunctive therapy, specifically dexamethasone. Use of this agent in adults increased dramatically after the publication of a prospective, randomized, placebo-controlled, double-blind multicenter trial from the Netherlands in 2002.¹⁰ In the study, 301 adults were randomized to receive either dexamethasone or placebo, with the first dose given 15 to 20 minutes before the first dose of antimicrobial therapy. The study authors found that among the subgroup of patients with pneumococcal meningitis, dexamethasone decreased the percentage of unfavorable outcomes from 52% to 26%.

As a result of these findings, IDSA now recommends using dexamethasone in adults with suspected or proven pneumococcal meningitis. The first dose should be administered 15 to 20 minutes before-or at least no later than-the first dose of antimicrobial therapy.

The role of adjunctive dexamethasone therapy in infants and children with pneumococcal meningitis is controversial. In its own guidelines, ISDA cites the Committee of Infectious Disease of the American Academy of Pediatrics, which recommends that physicians weigh the benefits and risk of this therapy for infants and children 6 weeks and older and cautions that data are not sufficient to demonstrate a clear benefit in this group.

Tunkel explained that there's no evidence to suggest that the use of adjunctive dexamethasone will improve the outcome for resistant strains of pneumococcal meningitis; all the strains tested in the Dutch study were highly susceptible to penicillin. He also cautioned that dexamethasone might potentially harm patients with antibiotic-resistant disease that requires vancomycin, because animal studies suggest that dexamethasone can decrease the penetration of vancomycin into the spinal fluid. "There's the potential that you won't be able to clear the infection as rapidly," he said. For this reason, IDSA instructs physicians to follow up with patients receiving dexamethasone very carefully. If no improvement is seen within 48 hours, a repeated lumbar puncture should be done to assess whether the organism is being cleared from the CSF.

For pneumococcal meningitis that does not respond to recommended therapy, the physician may need to use additional antimicrobial agents, such as rifampin, or an alternative, such as cefepime or meropenem. Another possibility is intrathecal vancomycin. "That's very rarely used because it's never been shown in a clinical study to offer benefit," said Tunkel. "But if you had a patient who was not responding to treatment, you might not have other options."

THE FUTURE
Although the development of new treatments remains critical, the experts interviewed agreed that vaccination is the best way to decrease the burden of bacterial meningitis. "It's far better to prevent the disease than to try to treat it," said Kaplan.

Tunkel said that efforts are under way to make a meningococcal conjugate vaccine available for infants and young children and to develop a meningococcal vaccine that would cover serogroup B. Whitney proposed that the licensed pneumococcal polysaccharide vaccine be used more widely for adults and that new pneumococcal conjugate vaccines covering more strains would help both children and adults.

Kaplan emphasized that the conjugate pneumococcal vaccine for children should include more serotypes, although he cautioned that adding more strains to the vaccine would increase the cost. As an alternative approach, he pointed to efforts to find the protein or series of proteins behind all pneumococcal disease. "If you could find a protein that was common to all serotypes and that protein led to an antibody that was protective, you could create a very safe vaccine that would cover all present and future serotypes," he said.

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