Changing Epidemiology of Bacterial Meningitis in the United States

Changing Epidemiology of Bacterial Meningitis in the United States William R. Short, MD and Allan R. Tunkel, MD, PhD Address Department of Medicine, Medical College of Pennsylvania/Hahnemann University, 3300 Henry Avenue, Philadelphia, PA 19129, USA. E-mail: allan.tunkel@drexel.edu Current Infectious Disease Reports 2000, 2:327 331 Current Science Inc. ISSN 1523 3847 Copyright 2000 by Current Science Inc. Bacterial meningitis is an important cause of morbidity and mortality in the United States and throughout the world. Over the past 20 years, there have been significant changes in the epidemiology of bacterial meningitis. The most important change is the decrease in the frequency of Haemophilus influenzae type b as the most common etiologic agent of bacterial meningitis, since the H. influenzae type b conjugate vaccine was introduced. Streptococcccus pneumoniae is now the major cause of bacterial meningitis in the US and bacterial meningitis is now a disease predominantly of adults, rather than of infants and children. Emergence of antimicrobial resistance in S. pneumoniae has also altered the approach to antimicrobial therapy in patients with pneumococcal meningitis, indicating the need to use preventive strategies to reduce the frequency of this serious infection. Recent licensure of the heptavalent pneumococcal conjugate vaccine will likely decrease the overall incidence of pneumococcal meningitis. Introduction Recognition of the epidemiologic changes that have recently occurred in bacterial meningitis in the United States is essential for appropriate patient management. Here, we will highlight recent epidemiologic changes in the frequency of isolation of various meningeal pathogens since the introduction of the Haemophilus influenzae type b conjugate vaccine, detail the emergence of antimicrobial resistance in Streptococcus pneumoniae, and review expected epidemiologic trends. Familiarity with these changes is critical to providing optimal antimicrobial therapy and enacting the public health measures that are necessary to decrease the morbidity and mortality associated with this disease. Etiologic Agents Early studies of the epidemiology of bacterial meningitis in the 1950s, 1960s, and 1970s were retrospective, community-based, and conducted in relatively small patient populations [1 3]; as such, they did not accurately define the attack rates of bacterial meningitis in the US. In the late 1970s, the Centers for Disease Control (CDC), in collaboration with the Conference of State and Territorial Epidemiologists, acted on the need to determine optimally the trends associated with the etiologic agents of bacterial meningitis. The result was a nationwide surveillance system to gather prospective information concerning the incidence, risk factors, and causative agents of bacterial meningitis in the US. Since the system was implemented, three studies describing the epidemiologic changes in bacterial meningitis in the US over the past 20 years (Table 1) have yielded important public health information about this disorder. The first study examined the epidemiology of 13,974 cases of bacterial meningitis from 27 US states from 1978 through 1981 [4]. H. influenzae was the most common etiologic agent, accounting for 48.3% of cases, followed by Neisseria meningitidis (19.6%), and S. pneumoniae (13.3%). The overall attack rate (approximately 3.0 cases per 100,000 population) of bacterial meningitis did not change significantly during the study period, although there was variability based on gender, race, and age. The attack rates were higher among male patients than female patients (3.3 versus 2.6 cases per 100,000 population); among blacks than whites and Hispanics; and among children younger than 1 year of age particularly among neonates (younger than 1 month of age) than older victims. Among children younger than 1 year, group B streptococci were the most commonly isolated bacteria, followed by gram-negative enteric bacilli, Listeria monocytogenes, H. influenzae, S. pneumoniae, and N. meningitidis. Attack rates also rose among patients older than 60 years of age, with S. pneumoniae the most common pathogen isolated, followed by gram-negative bacilli and other microorganisms (ie, H. influenzae, N. meningitidis, group B streptococcus, and L. monocytogenes). This study indicated bacterial meningitis to be predominantly a disease of the very young and the elderly. However, the study had a major drawback, in that it used a voluntary reporting system; only 30% to 40% of cases were reported during the study period. In 1986, the local health departments of 5 states Missouri, New Jersey, Oklahoma, Tennessee, and Washington and Los Angeles county collaborated with the CDC in a laboratory-based surveillance study. The study focused on all

328 CNS and Eye Infections Table 1. Frequency of isolation of the 5 major meningeal pathogens in patients with bacterial meningitis in the US Microorganism Percentage of total cases 1978-1981 1986 1995 Haemophilus influenzae 48 45 7 Neisseria meningitidis 20 14 25 Streptococcus pneumoniae 13 18 47 Streptococcus agalactiae 3 6 12 Listeria monocytogenes 2 3 8 Data from Schonian et al. [4]; Woodruff [5]; and Cardosa et al. [13 ] cases of bacterial meningitis caused by the five most common meningeal pathogens, H. influenzae, S. pneumoniae, N. meningitidis, group B streptococcus, and L. monocytogenes). From a population of almost 34 million persons, 2158 cases were reported [5]. Because the study used laboratorybased surveillance rather than voluntary reporting, the overall incidence of bacterial meningitis was 2 to 3 times higher than that of the previous report. H. influenzae was again the most common etiologic agent identified (45% of cases), followed by S. pneumoniae (18%) and N. meningitidis (14%). Group B streptococcus remained the most common etiologic agent of bacterial meningitis in children younger than 1 month of age. There was little change in the frequency of isolation of the major meningeal pathogens in patients with bacterial meningitis in this study. Based on this finding, preventive strategies using vaccines were aggressively pursued. Prior to 1990, vaccination against invasive H. influenzae type b was based on the generation of an immune response against the capsular polysaccharide of the organism, which induced protective responses in older children and adults, but was did not induce an immune response in neonates. In December 1987 a H. influenzae type b conjugate vaccine was introduced; it induces immune responses in young infants by converting the organism s polysaccharide into a T cell-dependent antigen [6,7 ]. In October 1990, after its efficacy was demonstrated in a prospective study of more than 60,000 infants who received doses at 2, 4, and 6 months of age, the Food and Drug Administration (FDA) approved this vaccine for use [8]. Three H. influenzae type b conjugate vaccines are currently approved for clinical use. The American Academy of Pediatrics currently recommends universal immunization of infants with one of the licensed conjugate vaccines beginning at 2 months of age [9]. Since introduction of the conjugate vaccines, the number of cases of H. influenzae type b meningitis has decreased more than 90% throughout the world [10 12]. A follow-up laboratory-based surveillance study of bacterial meningitis cases was performed in the US 5 years after the approval of the H. influenzae type b conjugate vaccine [13 ]. It reviewed 248 cases of meningitis in 22 counties of 4 states Georgia, Tennessee, Maryland, and California with a total population of more than 10 million persons. In it, the most common cause of bacterial meningitis was S. pneumoniae (47% of cases), followed by N. meningitidis (25%), group B streptococcus (12%), L. monocytogenes (8%), and H. influenzae (7%). The incidence of bacterial meningitis caused by H. influenzae declined substantially, from 2.9 cases per 100,000 population in 1986 [5] to 0.2 cases per 100,000 population in 1995 [13 ], with little or no change in the incidence of bacterial meningitis caused by the other major meningeal pathogens. The median age of patients with bacterial meningitis was 25 years, versus a median age of 15 months prior to the introduction of the H. influenzae type b conjugate vaccine, which now makes bacterial meningitis primarily a disease of adults, in the US. Microorganism-specific case fatality rates were generally similar to those in the previous studies, with some decrease in mortality in patients with meningitis caused by S. agalactiae and L. monocytogenes (Table 2). The frequency of isolation of various etiologic agents of bacterial meningitis also varied according to patient age [13 ]. Among neonates, group B streptococcus was the most common cause of meningitis (70% of cases), followed by Escherichia coli; L. monocytogenes was isolated in about 20% of patients. In the group aged 1 to 23 months, S. pneumoniae (45% of cases) and N. meningitidis (31%) were the leading causes. In persons aged 2 to 18 years, N. meningitidis was most frequently isolated (59% of cases). In adults older than 18 years, S. pneumoniae accounted for the majority (62%) of the cases of bacterial meningitis. In persons age 60 and older, S. pneumoniae once again was the most common etiologic agent of bacterial meningitis, followed by L. monocytogenes. Antimicrobial Resistance in S. pneumoniae An important change in the epidemiology of bacterial meningitis has been the emergence of antimicrobial resistance in S. pneumoniae [14 ]. Penicillin resistance in S. pneumoniae was first experimentally induced in mice in 1943, although it was not until 1967 that the first penicillin-resistant isolate was identified, in a patient with hypogammaglobulinemia and brochiectasis. Penicillin resistance results from multiple

Changing Epidemiology of Bacterial Meningitis in the United States Short and Tunkel 329 Table 2. Case fatality rates of bacterial meningitis in the US, based on the isolated microorganism Microogranism Percentage of Total Cases 1978-1981 1986 1995 Streptococcus pneumoniae 26 19 21 Haemophilus influenzae 6 3 6 Neisseria meningitidis 10 13 3 Streptococcus agalactiae 22 12 7 Listeria monocytogenes 29 22 15 Data from Schonian et al. [4]; Woodruff [5]; and Cardosa et al. [13 ] Table 3. Minimal inhibitory concentration (MIC) breakpoints for antimicrobial agents used to treat pneumococcal meningitis Antimicrobial Agent MIC (?g/ml) Susceptible Intermediate Resistant Penicillin G <0.06 0.12-1.0 >2.0 Cefotaxime or ceftriaxone <0.5 1 >2.0 Chloramphenicol <4.0 - >8.0 Trimethoprim-sulfamethoxazole <0.5/9.5 1/19-2/38 >4/76 Adapted from Akhtar et al. [14 ] alterations of several of the penicillin-binding proteins, which are chromosomally mediated but do not cause any loss or gain of pneumococcal virulence. Recommendations of the National Committee on Clinical Laboratory Standards on the minimal inhibitory concentration (MIC) breakpoints determining pneumococcal susceptibility to various antimicrobial agents are found in Table 3 [14 ]. Risk factors for infection with drug-resistant S. pneumoniae include patient age extremes (especially younger than 6 years), recent antimicrobial therapy, coexisting illness or underlying disease, human immunodeficiency virus [HIV] infection, other immunodeficiencies, day-care center environment, recent or current hospitalization, and institutionalization (eg, nursing home, prison). Since the initial report of penicillin resistance in 1967, the incidence of antimicrobial resistance in pneumococci has increased throughout the world; recent studies have documented the frequency of penicillin-resistant pneumococci to be 41% in Southeast Asia [15], 13% in Brazil [16], and 56% in Taiwan [17]. Antimicrobial resistance has also been increasing in the US. In a study recently performed in Atlanta, 25% of pneumococcal isolates were resistant to penicillin (7% were highly resistant) [18 ]. Further, 26% were resistant to trimethoprim-sulfamethoxazole; 15% to erythromycin; 9% to cefotaxime; and 25% to multiple antimicrobial agents. The incidence of invasive pneumococcal infection was 30 cases per 100,000 population in this study. Trends indicating increasing antimicrobial resistance in pneumococci have made an impact on the approach to antimicrobial therapy in bacterial meningitis. Anecdotal reports have described cases of meningitis caused by pneumococcal strains resistant to penicillin or third-generation cephalosporins and the clinical failure of therapy using those drugs [19]. This has led to recommendations for combination therapy with vancomycin plus a third-generation cephalosporin (either cefotaxime or ceftriaxone), pending susceptibility testing [20 ]. Continued surveillance of antimicrobial resistance patterns is critical to make recommendations for antimicrobial therapy in patients with pneumococcal meningitis. Future Trends Following the dramatic success of the H. influenzae type b conjugate vaccine in prevention of invasive Haemophilus disease, the development of effective vaccines against the other meningeal pathogens might also be expected to further decrease the incidence of this devastating infection. Use of the pneumococcal vaccine (Pneumovax; Merck Frosst, Kirkland, Quebec, Canada) is currently recommended for the prevention of bacteremic pneumococcal disease in a select group of high-risk persons [21]. Highrisk factors include age 65 years or more; age 2 to 64 years combined with chronic cardiovascular disease; chronic pulmonary disease; diabetes mellitus; alcoholism; chronic liver disease; cerebrospinal fluid leaks; and functional or anatomic asplenia. Also at high risk are persons who are variously immunocompromised (ie, those with HIV infection, hematologic or generalized malignancies, chronic renal failure or nephrotic syndrome; those receiving immunosuppressive therapy; and those who have received an organ or bone marrow transplant). The vaccine is composed of capsular polysaccharide from 23 serotypes of

330 CNS and Eye Infections S. pneumoniae, which account for approximately 85% to 90% of the bacteremic infections; however, this vaccine is not immunogenic in infants. A recently-developed heptavalent pneumococcal conjugate (ie, serotypes 4, 6B, 9V, 14, 18C, 19F, 23F) vaccine uses a carrier protein composed of a non-toxic mutant diphtheria toxin, CRM197. In an initial study, the safety and immunogenicity of the vaccine were evaluated in 212 healthy 2-month-old infants who were equally randomized to receive 4 doses of either the heptavalent pneumococcal conjugate vaccine (PNCRM7) or an investigational meningococcal group C conjugate vaccine, which was used as the control [22]. The study demonstrated that there are fewer local reactions among patients who received PNCRM7 than among patients in the control group, although mild fever was commonly associated with both vaccines. All 7 serotypes were immunogenic, although the concentration of pneumococcal antibodies decreased in patients from around 7 months of age to 12 to 15 months of age. However, after a subsequent dose of the vaccine, the concentration of pneumococcal antibodies rose to a higher level than was previously obtained with vaccine administration at 2, 4, and 6 months of age. A large multicenter study of safety and efficacy was then conducted at Northern California Kaiser Permanente in Oakland, CA. This controlled, double-blind trial enrolled approximately 38,000 children, half of whom received the pneumococcal 7-valent conjugate vaccine, given at 2, 4, 6, and 12 to 15 months of age [23 ]. The vaccine was 97.4% effective in preventing invasive pneumococcal disease (including meningitis) caused by the 7 strains of pneumococcus in the vaccine, and 93.9% effective in preventing invasive disease caused by all pneumococcal serotypes. On February 17, 2000, the FDA approved the pneumococcal 7-valent conjugate vaccine (Prevnar; Wyeth-Ayerst, Radnor, PA) for the prevention of invasive pneumococcal disease. It is approved for all infants to the age of 23 months of age, as a series of inoculations administered at 2, 4, 6, and 12-15 months of age [24]. The vaccine is not indicated for use in adults or as a substitute for other approved pneumococcal polysaccharide vaccines for highrisk children older than 2 years. A recent study anaylzed the cost-effectiveness of pneumococcal conjugate vaccination of healthy infants and young children, hypothesizing a US birth cohort of 3.8 million infants [25 ]. It was estimated that vaccination would prevent more than 12,000 cases of meningitis and bacteremia, as well as 116 deaths due to pneumococcal infection for each US birth cohort. Thus, pneumococcal conjugate vaccination has the potential to be cost-effective relative to other preventive health strategies. At the manufacturer s list price of $58 per dose, infant vaccination would cost society $80,000 per life-year saved for all pneumococcal infections (a cost of $280,000 for use against meningitis). It is interesting to use these hypothetical data to project the likely benefits of vaccination. However, subsequent laboratory-based surveillance data will be required to determine how successful the 7-valent pneumococcal conjugate vaccine will be in reducing the incidence and improving the outcome of pneumococcal meningitis in the US. Conclusions To effectively treat bacterial meningitis, it is necessary to be familiar with recent epidemiologic changes. The widespread use of the H. influenzae type b conjugate vaccine dramatically decreased the incidence of meningitis caused by H. influenzae type b; S. pneumoniae is now the leading cause of bacterial meningitis in the US. Thus, S. pneumoniae must be considered the potential causative agent of bacterial meningitis in all age groups. In pneumococcal meningitis cases, familiarity with the local resistance patterns will provide guidance in the use of empiric antimicrobial therapy pending susceptibility testing of the microorganism. It is hoped that the recent licensure of the heptavalent pneumococcal conjugate vaccine will lead to a substantial decrease in the incidence of pneumococcal meningitis in the US. References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance 1. Carpenter RR, Petersdorf RG: The clinical spectrum of bacterial meningitis. Am J Med 1962, 33:262 275. 2. Fraser DW, Henke CE, Feldman RA: Changing patterns of bacterial meningitis in Olmsted County, Minnesota, 1935 1970. J Infect Dis 1973, 128:300 307. 3. Fraser DW, Geil CC, Feldman RA: Bacterial meningitis in Bernalillo County, New Mexico: a comparison with three other American populations. Am J Epidemiol 1974, 100:29 34. 4. Schlech WF III, Ward JI, Band JD, et al.: Bacterial meningitis in the United States, 1978 through 1981. The national bacterial meningitis surveillance study. JAMA 1985, 253:1749 1754. 5. Wenger JD, Hightower AW, Facklam RR: the Bacterial Meningitis Study Group: Bacterial meningitis in the United States, 1986: report of a multistate surveillance study. J Infect Dis 1990, 162:1316 1323. 6. Adams WG, Deaver KA, Cochi SL, et al.: Haemophilus influenzae Study Group: Decline of childhood Haemophilus influenzae type b disease in the Hib vaccine era. JAMA 1993, 269:221 226. 7. Ahmad H, Chapnick EK: Conjugate polysaccharide vaccines. Infect Dis Clin North Am 1999, 13:113 133. This article discusses conjugate polysaccharide vaccines for Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis; availability of these vaccines may reduce the incidence of diseases caused by these microorganisms. 8. Centers for Disease Control and Prevention: FDA approval of use of Haemophilus b conjugate vaccine for infants. MMWR 1990, 339:698. 9. American Academy of Pediatrics, Committee on Infectious Diseases: Recommended childhood immunization schedule United States, January-December 2000. Pediatrics 2000, 105:148 151. 10. Robbins JB, Schneerson R, Anderson P, Smith DH: Prevention of systemic infections, especially meningitis, caused by Haemophilus influenzae type b. JAMA 1996, 276:1181 1185.

Changing Epidemiology of Bacterial Meningitis in the United States Short and Tunkel 331 11. Van Alphen L, Spanjaard L, Van der Ende A, et al.: Effect of nationwide vaccination of 3-month-old infants in The Netherlands with conjugate Haemophilus influenzae type b vaccine: high efficacy and lack of herd immunity. J Pediatr 1997, 131:869 873. 12. Mulholland K, Hilton S, Adegbola R, et al.: Randomised trial of Haemophilus influenzae type-b tetanus protein conjugate for prevention of pneumonia and meningitis in Gambian infants. Lancet 1997, 349:1191 1197. 13. Schuchat A, Robinson K, Wenger JD, et al.: Bacterial meningitis in the United States in 1995. N Engl J Med 1997, 337:970 976. This laboratory-based surveillance study of cases of bacterial meningitis in the United States 5 years after licensure of the Haemophilus influenzae type b conjugate vaccine shows that Streptococcus pneumoniae is now the most common etiologic agent of bacterial meningitis in the United States. 14. Campbell GD, Silberman R: Drug-resistant Streptococcus pneumoniae. Clin Infect Dis 1998, 26:1188 1195. This is a recent review of the mechanisms, risk factors, and approach to management in patients with antimicrobial-resistant S. pneumoniae infections. 15. Song JH, Lee NY, Ichiyama S, et al.: Spread of drug-resistant Streptococcus pneumoniae in Asian countries: Asian network for surveillance of resistant pathogens (ANSORP) study. Clin Infect Dis 1999, 28:1206 1211. 16. Ko AI, Reis JN, Coppola SJ, et al.: Clonally related penicillinnonsusceptible Streptococcus pneumoniae serotype 14 from cases of meningitis in Salvador, Brazil. Clin Infect Dis 2000, 30:78 86. 17. Fung CP, Hu BS, Lee SC, et al.: Antimicrobial resistance of Streptococcus pneumoniae isolated in Taiwan: an islandwide surveillance study between 1996 and 1997. J Antimicrob Chemother 2000, 45:49 55. 18. Hofmann J, Cetron MS, Farley MM, et al.: The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta. N Engl J Med 1995, 333:481 485. This epidemiologic study of the prevalence of antimicrobial-resistant Streptococcus pneumoniae in Atlanta indicates that 25% of pneumococcal isolates are resistant to penicillin. 19. Klugman KP, Madhi SA: Emergence of drug resistance. Impact on bacterial meningitis. Infect Dis Clin North Am 1999, 13:637 646. 20. Tunkel AR, Scheld WM: Acute meningitis. In Principles and Practice of Infectious Diseases edn 5. Edited by Mandell GL, Bennett JE, Dolin R. Philadelphia: Churchill-Livingstone; 1999:959 997. This chapter provides a recent discussion of the epidemiology, clinical presentation, diagnosis, and management of acute bacterial meningitis. It reviews specific recommendations for the approach to patients with antimicrobial-resistant meningeal pathogens. 21. Centers for Disease Control and Prevention: Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1997, 46(RR-8):1 23. 22. Rennels MB, Edwards KM, Keyserling HL, et al.: Safety and immunogenicity of heptavalent vaccine conjugated to CRM197 in United States infants. Pediatrics 1998, 101:604 611. 23. Black S, Shinefield H, Fireman B, et al.:efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J 2000, 19:187 195. These authors report the trial of the efficacy of the heptavalent pneumococcal conjugate vaccine, which demonstrates an efficacy of 97.4% in the prevention of invasive pneumococcal infections caused by the 7 serotypes of pneumococcus in the vaccine. 24. US Department of Health and Human Services: First pneumococcal vaccine approved for infants and toddlers. HHS News; February 17, 2000. 25. Lieu TA, Ray GT, Black SB, et al.: Projected cost-effectiveness of pneumococcal conjugate vaccination of healthy infants and young children. JAMA 2000, 283:1460 1468. These authors project the efficacy and cost-effectiveness of the heptavalent pneumococcal conjugate vaccine in a hypothetical cohort of 3.8 million infants in the United States.