Meningitis in the Elderly: An Approach to Diagnosis and Treatment in an Era of Antimicrobial Resistance

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1 Meningitis in the Elderly: An Approach to Diagnosis and Treatment in an Era of Antimicrobial Resistance By Loren G. Miller, M.D., and Chester Choi, M.D. About 2,500 years ago, Hippocrates authored the first written account of a central nervous system (CNS) infection, 1 but it was not until the past 50 years that effective antibiotic treatment with high cure rates for such infections became possible. Recently, however, successful cure of CNS infections is threatened by the emergence of antibiotic-resistant bacteria, especially penicillin-resistant Streptococcus pneumoniae (PRSP). Thus, the approach to the management of many infections, including meningitis, has become more complex. Meningitis can strike patients of all ages, including the elderly, with devastating results. A survey of 27 states that was conducted from 1978 to 1981 estimated the incidence of bacterial meningitis to be approximately three cases per 100, In a 1990 study in the United States, the rate of meningitis in those older than 60 years was estimated to be approximately two to nine cases per 100,000, suggesting that the elderly may have a higher attack rate of meningitis compared with that of the general population. 3 A survey of bacterial meningitis in 1995 by the Centers for Disease Control and Prevention (CDC) found that the rates of the five most common bacterial pathogens (S. pneumoniae, Neisseria meningitidis, Haemophilus influenzae, group B streptococcus, and Listeria monocytogenes) averaged 2.8 cases per 100,000 in those older than 60 years of age. 4 The diagnosis of meningitis in the older adult presents unique challenges, because the typical signs and symptoms of the disease may be absent. Many serious conditions, such as myocardial infarction, 5 hyperthyroidism, 6 and intraabdominal infections 7 can present in an atypical manner in the elderly; similarly, meningitis may have atypical manifestations in the older patient. This article reviews the pathophysiology, diagnosis, and treatment of meningitis in older adults. Pathophysiology: How Pathogens Enter the CNS In the elderly, bacteria cause most cases of meningitis; therefore, the pathogenesis of bacterial, rather than nonbacterial, meningitis is described. The CNS is effectively protected from most microbial invasions by the meninges and other barrier defenses. Once bacteria penetrate this barrier, however, host defenses are insufficient to adequately control an infection and bacterial replication may exceed one million organisms per ml of cerebrospinal fluid (CSF).

2 replication may exceed one million organisms per ml of cerebrospinal fluid (CSF). The entry of bacteria is established primarily via two routes. 8 The first is invasion of the CNS by a microorganism during an episode of bacteremia. This may begin with colonization of the nasopharynx and subsequent local invasion to reach the blood stream. If the bacteria are able to evade host defense mechanisms such as neutrophil phagocytosis and complement-system activation, they can then seed the meninges. Once they gain access to the CSF, few host defenses are present to limit their growth and the serious sequelae of meningitis may ensue from bacterial effects and from incitement of host inflammatory mediators and other processes. A similar bacteremia may originate from distant sites of infection such as abscesses or urinary tract infections. A second mechanism for the development of meningitis involves bacteria penetrating an acquired mechanical break in the meningeal barrier. These cases most commonly occur after trauma or a neurosurgical procedure. Presenting Signs and Symptoms of Meningitis in the Elderly As described herein, elderly patients can present with atypical findings in cases of meningitis. A "classic" abrupt onset of fever, headache, and meningismus may occur in an elderly patient, but less specific signs of altered mental status or obtundation may occur in almost 50% of cases. Other signs and symptoms are summarized in Table I. Interestingly, Kernig's and Brudzinski's signs are unreliable in elderly patients. Kernig's sign was originally described in seated patients and described the inability to extend the knee from the 90 degree position to the 135 degree position. The test has been extrapolated to supine patients in whom the hips are flexed to 90 degrees and the attempts to extend the knee from 90 to 135 degrees meet with resistance. Brudzinski's nape of the neck sign describes the flexion of the hip and knee in reaction to flexion of the neck. In one study, investigators examined hospitalized elderly patients who did not have meningitis and found that 12% had positive Kernig's signs and 18% had positive Brudzinski's signs. 9 Furthermore, nuchal rigidity was found in 35% of these patients. These latter findings are believed to result from cervical spondylosis and to a lesser extent, Parkinson's disease. Because of these false-positive and false-negative results, such meningeal signs are of questionable utility when evaluating an elderly patient for meningitis. The diagnosis of meningitis is best established by clinical suspicion and confirmation with a lumbar puncture. Typical findings in the CSF are summarized in Table II. 10 Characteristically, white blood cells (WBCs) are increased in the CSF. In cases of bacterial, mycobacterial, and fungal meningitis, the protein is characteristically elevated and glucose levels are low. In cases of viral meningitis, there is a CSF pleocytosis, usually with a lymphocytic predominance, but usually the protein and glucose are normal or near normal. Bacterial Pathogens Bacteria cause the majority of cases of meningitis in the elderly. In younger adults, S.

3 Bacteria cause the majority of cases of meningitis in the elderly. In younger adults, S. pneumoniae and N. meningitis cause the vast majority of cases of bacterial meningitis. 4 These organisms are important in the elderly as well; however, older adults have increased susceptibility to unusual pathogens such as group B streptococci, L. monocytogenes, Escherichia coli, and other gram-negative organisms. Several case series of meningitis in the elderly also demonstrate increased rates of Staphylococcus aureus and coagulase-negative Staphylococcus (Table III). Staphylococci are very infrequent causes of "community-acquired" meningitis, however, and are seen predominantly in postneurosurgical patients. S. pneumoniae.case 1. A 75-year-old man with a history of alcoholism was evaluated after several days of weakness and anorexia. In the emergency room he was febrile, drowsy, and confused. On examination his neck was supple and Kernig's and Brudzinski's signs were negative. His head and neck, cardiac, and pulmonary examinations were within normal limits except for resting tachycardia. Laboratory tests revealed an elevated peripheral WBC count of 14,800 per ml with a PMN predominance and mild renal insufficiency. The urinalysis, chest x-ray, and computerized tomography (CT) of the head were normal. A lumbar puncture revealed 16,000 WBCs per ml with 99% neutrophils. The protein was elevated to 1,600 mg/ dl and glucose depressed to 5 mg/dl. The laboratory reported that numerous gram-positive diplococci were present on Gram's stain of the CSF and this patient's CSF ultimately grew S. pneumoniae. This organism, often referred to as the pneumococcus, is overwhelmingly the most common cause of meningitis in the older adult. S. pneumoniae meningitis had an incidence of 1.9 per 100,000 per year in the U.S. in 1995 with a case fatality rate of 21% in all ages. 4 Pneumococcal meningitis occurred more than three times more often than the next most common bacterial cause of meningitis in the elderly (L. monocytogenes) in this survey. Risk factors for infection with this organism include alcoholism, asplenia, chronic liver or renal disease, and malignancies; however, frequently no underlying immune disorder is found. Patients may have contiguous or distant foci of pneumococcal infection such as pneumonia, otitis media, sinusitis, mastoiditis, or endocarditis. 11 This case highlights some of the dilemmas clinicians face in the treatment of pneumococcal meningitis. In the past, treatment consisted of high doses of intravenous penicillin G (20 to 24 million units/day), because virtually all strains were highly sensitive to penicillin. High doses are used to help achieve adequate levels in the CSF, because penicillins penetrate the bloodbrain barrier only in the face of inflammation. Although there are limited data on the optimum length of treatment in adults, most experts recommend at least 10 to 14 days of intravenous therapy. 12 Penicillin-resistant S. pneumoniae (PRSP). During this decade, the prevalence of PRSP is rising rapidly in the U.S. and worldwide. 13 A recent report identified alcoholism and previous exposure to beta-lactam antibiotics as risk factors for acquiring PRSP. 14 There was a trend for advanced age (65 years and older) being a risk factor for acquisition of this organism, but this was not statistically significant. Advanced age was, however, an outright risk factor for acquisition of multidrug-resistant pneumococci (that is, organisms resistant to penicillin and a second nonbeta-lactam antibiotic such as erythromycin or trimethoprim-sulfamethoxazole).

4 second nonbeta-lactam antibiotic such as erythromycin or trimethoprim-sulfamethoxazole). S. pneumoniae can be divided into three groups based on the results of penicillin or oxacillin susceptibility testing. Pneumococci with an MIC < 0.1 µg/ml are considered penicillin sensitive, whereas those with an MIC of 0.1 to 1 µg/ml are classified as intermediately sensitive to penicillin. Highly resistant strains have MICs to penicillin of >= 1 µg/ml. 15 The 1995 CDC survey found 64% of S. pneumoniae isolated from the CSF were sensitive to penicillin, 21% had intermediate susceptibility, and 14% were highly resistant. 4 The antibiotic treatment of S. pneumoniae meningitis is summarized in Table IV. Sensitive pneumococci should be treated with penicillin. Alternative therapies include the third-generation cephalosporins such as ceftriaxone and cefotaxime, or vancomycin for those with severe penicillin allergies. Intermediately sensitive pneumococci are generally susceptible to thirdgeneration cephalosporins such as ceftriaxone and cefotaxime. 16 Meningitis due to highly penicillin-resistant pneumococci is not effectively treated with penicillin or third-generation cephalosporins alone. For this infection, vancomycin combined with cefotaxime or ceftriaxone is considered the treatment of choice by most experts. 12,15 Vancomycin has disadvantages when used to treat infections of the CNS, in that the drug penetrates poorly into the CSF. The inflamed meninges of meningitis may help facilitate vancomycin penetration, but CSF levels after standard dosing are variable. Fortunately, virtually all pneumococcal strains are sensitive to vancomycin. Clinical studies of the treatment of highly penicillin-resistant pneumococcal meningitis with vancomycin are lacking, and some experts recommend adding rifampin, rather than vancomycin, to cefotaxime or ceftriaxone. 12,15 Rifampin should not be used as the sole agent for treating pneumococcal meningitis, because these bacteria may develop resistance during therapy. Certainly there is interest in determining the effectiveness of other antimicrobial agents for PRSP meningitis. Recent studies demonstrate that meropenem, a newly approved carbapenem with broad-spectrum activity against a variety of gram-positive and gram-negative bacteria, may be an effective agent for this infection. 15 Although carbapenems are beta-lactam drugs and thus related to penicillins and cephalosporins, it appears that only a small percentage of highly penicillin-resistant pneumococci are also resistant to the carbapenems. 17 Meropenem is probably preferable for treating meningitis over the other commercially available carbapenem, imipenem, because the latter drug may lower the patient's seizure threshold, especially in those with diseases of the CNS such as meningitis. 18 Newer quinolone antibiotics also show early promise in treating PRSP. Trovafloxacin, a quinolone antibiotic recently approved for use in the U.S., appears to have in vitro efficacy against PRSP, as do levofloxacin and sparfloxacin. 15,19 Older quinolones such as ciprofloxacin and ofloxacin have not been effective agents for S. pneumoniae. 20 Despite their promise, there are currently insufficient studies to recommend the use of quinolones in the treatment of bacterial meningitis in older adults. The empiric choice of antibiotic therapy for S. pneumoniae meningitis prior to the availability of antibiotic sensitivity data is a difficult problem. For example, in the patient in case 1, antibiotic susceptibility results were not likely to be available until 24 to 72 hours after admission. In

5 susceptibility results were not likely to be available until 24 to 72 hours after admission. In communities in which pneumococci with high-level resistance to penicillin are seen, empiric therapy for pneumococcal meningitis includes cefotaxime or ceftriaxone plus vancomycin until drug sensitivities are known. Many public health departments and hospital laboratories are collecting data on the prevalence of PRSP. Unfortunately, no immediate solution to the problem of PRSP appears imminent. Other bacterial pathogens. Case 2. The patient was an 80-year-old woman brought to the hospital by her housekeeper because of altered mental status, fever, and seizure. Her past medical history was only remarkable for hypertension. On admission she was febrile, tachycardic, and hypotensive; she had a normal CT scan of the head. A lumbar puncture revealed a CSF with 2700 WBCs per ml and 89% neutrophils, 2 red blood cells (RBCs) per ml, a protein of 193 mg/dl, and a glucose of 29 mg/dl. Cefotaxime and ampicillin were started intravenously. Gram's stain revealed gram-positive bacilli that were later identified as L. monocytogenes. The patient was treated with intravenous ampicillin and eventually made a full recovery. This case highlights several important points. First, as compared with younger patients, older adults have a higher incidence of meningitis caused by less common pathogens. Whereas S. pneumoniae, N. meningitidis, and H. influenzae cause the majority of cases of meningitis in younger adults, 4 less common organisms such as L. monocytogenes, group B streptococci, Klebsiella, and other gram-negative organisms are seen with increased prevalence in older patients In the 1995 survey of bacterial meningitis in the U.S., L. monocytogenes was the second most common cause of bacterial meningitis in the elderly after S. pneumoniae. N. meningitidis and group B streptococci were the third most common causes of bacterial meningitis in those 60 years of age and older. 4 The available published case series describing meningitis in the older adult are summarized in Table III. Empiric antibiotic choices for bacterial meningitis.treatment for common etiologies of bacterial meningitis are listed in Table IV. Most experts recommend using a third-generation cephalosporin (which treats S. pneumoniae, N. meningitidis, H. influenzae, and most aerobic gram-negative bacilli) plus ampicillin (which treats L. monocytogenes) as empiric treatment of meningitis if the organism is not definitively identified. As mentioned, in areas with a high prevalence of penicillin-resistant pneumococcus, the use of vancomycin plus the thirdgeneration cephalosporin should strongly be considered. 12,15 Vancomycin has not been extensively studied in the treatment of meningitis due to Listeria; however, in vitro testing does demonstrate significant activity for vancomycin versus Listeria, and vancomycin should be adequate for initial therapy while cultures are pending. Other pathogens.case 3. The patient was a 60-year-old Hispanic woman who was admitted for fever and progressively altered mental status over four days. Of note, she had moved to the U.S. from Mexico three years prior. On examination her neck was mildly stiff. A head CT scan with and without contrast was negative. Lumbar puncture revealed 530 WBCs per ml with 96% lymphocytes, 5 RBCs per ml, a protein of 220 mg/dl, and a glucose of 29 mg/dl. Gram's stain was negative. Ceftriaxone and ampicillin were begun. After 48 hours, the patient's mental status and fever did not improve. The admission chest X-ray showed a left upper lobe infiltrate on reevaluation. Sputum was induced and stains were positive for acid-fast bacilli eventually identified as Mycobacterium tuberculosis. The patient was finally treated with four antituberculous drugs and responded well.

6 This case highlights several points. First, tuberculous meningitis is a rare infection, but should be suspected when the Gram's stain of CSF is negative and there is a lymphocytic predominance with a lowered CSF glucose. Other possible pathogens in this situation include Cryptococcus neoformans or other fungi or noninfectious etiologies such as lymphoma, carcinoma, sarcoidosis, drugs, or collagen vascular diseases. Special stains, cultures, and serologies for specific diseases may be required for the diagnosis of these entities. Viruses are very rare causes of meningitis in the older adult. Tuberculous meningitis.tuberculosis has been reported to cause up to 13% of cases of meningitis in the elderly. 21,24 Tuberculous meningitis often has an insidious onset that may last days to weeks. Perhaps encephalitis would better describe the symptoms of this infection, because altered mental status is a common symptom and meningismus is less common. Those with tuberculous meningitis typically have additional nonspecific symptoms such as malaise, low-grade fever, or intermittent headache. Later symptoms may include personality changes, protracted headache, confusion, vomiting, and cranial nerve palsies. 26 The diagnosis of this infection requires a high index of suspicion. Even in the presence of active and established tuberculous meningitis, the CSF acid-fast bacilli smears are usually negative, the culture results will be delayed, and empiric treatment may be required. This patient's CSF profile is typical of tuberculous meningitis, with lymphocytic predominance in the CSF and a lowered glucose and elevated protein. The CSF profiles of bacterial, viral, tuberculous, and fungal meningitis may overlap, however (Table II). Thus, the definitive diagnosis of the etiology of the meningitis rests on microbiological culture results combined with clinical assessment. Cryptococcal meningitis and other fungal meningitis.c. neoformans has accounted for as many as 4% of cases of meningitis in the elderly, even in the absence of infection with HIV. 21,22,25 The diagnosis is made by cryptococcal antigen testing of the CSF, although a positive serum cryptococcal antigen may also be useful for diagnosis because it signifies disseminated infection. The cryptococcal antigen test in CSF is highly sensitive and specific; fungal cultures, although helpful, are not as reliably positive in cases of cryptococcal meningitis. 10 An India ink preparation can also be performed on the CSF; whereas this test is less sensitive than cryptococcal antigen for diagnosis, its advantage lies in the rapidity in which the test results can be obtained. Other fungal organisms such as Coccidiodes immitis, Candida albicans, Blastomyces dermatiditis, and Histoplasma capsulatum may also cause meningitis in older adults in rare cases. Viral and "aseptic" meningitis."aseptic" meningitis is a term that is sometimes mistakenly used synonymously with viral meningitis. Ascribing all cases of meningitis with negative cultures to viral infection is problematic, because some mycobacterial, fungal, and, rarely, bacterial causes may have negative CSF cultures (Table II). Furthermore, equating "aseptic" with "viral" in the elderly may be misleading diagnostically, because viral meningitis is very uncommon in this age group, accounting for fewer than 2% of cases Fortunately the CSF profile of viral meningitis is usually distinct from other causes of meningitis. As opposed to bacterial, mycobacterial, and fungal infections, the CSF protein and glucose are usually normal or near

7 normal and WBCs rarely rise above 1, Most younger patients with viral meningitis improve without antibiotic treatment, 27 but the natural course of viral meningitis in the elderly is less clear because there are few available studies. The diagnosis is often one of exclusion, and viral serologies are rarely necessary. Prevention The prevention of meningitis would clearly be preferable to encountering established and perhaps difficult-to-treat disease. A 23-valent polysaccharide vaccine has been available since 1983 for prevention of infections caused by S. pneumoniae. Although it does not provide immunity against all pneumococcal serotypes, it may induce immunity to those serotypes that account for more than 85% of clinical infections. 28 The CDC's Immunization Practices Advisory Committee recommends that all individuals older than age 65 be vaccinated. 29,30 Unfortunately, the pneumococcal vaccine is underutilized in the U.S.; in one study, only 14% of persons older than 65 years had been vaccinated. 31 The duration of immunity provided to older adults needs to be clarified. A recent Finnish study found antibody response to strains of S. pneumoniae waned to near prevaccination levels three to four years after immunization in persons older than 65 years of age. 32 Others have demonstrated much more prolonged antibody response in healthy adults. 32 Such data suggest that a repeat vaccination may be needed, although this is controversial. 34 Routine revaccination is now recommended for persons 65 years of age and older whose last vaccination was five years or more previously and who were less than 65 years of age at that time. It is also recommended for those in the highest risk groups and for those whose antibody levels are most likely to decline rapidly. These groups include persons with functional or anatomic asplenia, HIV infection, leukemia, lymphoma, Hodgkin's disease, multiple myeloma, generalized malignancy, chronic renal failure, nephrotic syndrome, and other conditions associated with immunosuppression. It is also indicated in those receiving immunosuppressive chemotherapy, including long-term systemic corticosteroids. 29 Adverse effects from the vaccine are rare among the elderly, 34,35 and risks from revaccination appear to be very low as well. It is difficult to overemphasize the importance of immunizing elderly patients against these increasingly antibiotic-resistant organisms. Conclusion The diagnosis of meningitis in the elderly can be problematic, because older individuals may not have the typical signs and symptoms of meningitis as are seen in younger patients. The majority of cases of meningitis in older adults are caused by bacteria. In areas where PRSPs are frequently encountered, empiric therapy of meningitis should consist of high-dose intravenous cefotaxime or ceftriaxone plus ampicillin. If the Gram's stain of the CSF suggests S. pneumoniae, the most common cause of meningitis in the elderly, intravenous vancomycin should be substituted for ampicillin in the regimen. In cases in which no pathogen can be identified and the patient is not improving, diagnostic studies for fungi and mycobacteria should be obtained. Empiric therapy for tuberculosis should be considered based on clinical suspicion. Finally, all patients older than 65 years and those with other specific risks should receive the 23-valent pneumococcal vaccine

8 receive the 23-valent pneumococcal vaccine About the Author From the Department of Medicine, St. Mary Medical Center, Long Beach; and the Department of Medicine, UCLA, Los Angeles, California. Reference 1. Scheld WM, Whitley RJ, Durack DT. Preface to the first edition. In: Scheld WM, Whitley RJ, Durack DT, eds. Infections of the Central Nervous System, 2nd ed. Philadelphia: Lippincott-Raven, 1997:xv. 2. Scheld WF, et al. Bacterial meningitis in the United States, 1978 though The national bacterial meningitis severance study. J Am Med Assoc 1985;253: Wenger JD, et al. Bacterial meningitis in the United States 1986: Report of a multistate surveillance study. J Infect Dis 1190;162: Schuchat A, et al. Bacterial meningitis in the United States in N Engl J Med 1997;337: MacDonald JB. Presentation of acute myocardial infarction in the elderly--a review. Age Ageing 1984;13: Gambert SR. Hyperthyroidism in the elderly. Clin Geriatr Med 1995;11: Cooper GS, Shles DM, Salata RA. Intraabdominal infection: differences in presentation and outcome between younger patients and the elderly. Clin Infect Dis 1994;19: Tunkel AR, Scheld WM. Pathogenesis and pathophysiology of bacterial infections. In: Scheld WM, Whitley RJ, Durack DT, eds. Infections of the Central Nervous System, 2nd ed. Philadelphia: Lippincott-Raven, 1997: Puxty JA, Fox RA, Horan MA. The frequency of physical signs usually attributed to meningeal irritation in elderly patients. J Am Geriatr Soc 1983;31: Fishman RA. Cerebrospinal Fluid in Diseases of the Nervous System. Philadelphia: W. B. Saunders, 1992: Tunkel AR, Scheld WM. Acute meningitis. In: Mandel GL, Bennett JE, Dolin R, eds. Principles and Practices of Infectious Diseases, 4th ed. New York: Churchill Livingstone, 1995: Quagliarello VJ, Scheld WM. Treatment of bacterial meningitis. N Engl J Med 1997;336: Tomasz A. Antibiotic resistance in Streptococcus pneumoniae. Clin Infect Dis 1997;24:S Clavo-Sanchez AJ, et al. Multivariate analysis of risk factors for infection due to penicillin-resistant and multidrug resistant Streptococcus pneumoniae: A multicenter study. Clin Infect Dis 1997;24: Bradley JS, Scheld WM. The challenge of penicillin-resistant Streptococcus pneumoniae meningitis: Current antibiotic therapy in the 1990s. Clin Infect Dis 1997;24:S Haas DW, Stratton CW, Griffin JP, Weeks L, Alls SC. Diminished activity of ceftizoxime in comparison to cefotaxime and ceftriaxone against Streptococcus pneumoniae. Clin Infect Dis 1995;20:

9 17. Craig WA. The pharmacology of meropenem, A new carbapenem antibiotic. Clin Infect Dis 1997;24:S Hellinger WC, Brewer NS. Imipenem. Mayo Clin Proc 1991; 66: Baquero F, Canton R. In-vitro activity of sparfloxacin in comparison with currently available antimicrobials against respiratory tract pathogens. J Antimicrob Chemother 1996; 37:Suppl A: Lee BL, et al. Infectious complications with respiratory pathogens despite ciprofloxacin therapy. New Engl J Med 1991;325: Gorse GJ, et al. Bacterial meningitis in the elderly. Arch Intern Med 1984;144: Bernman RE, Meyers BR, Mendelson MH, Sacks HS, Hirschman SZ. Central nervous system infections in the elderly. Arch Intern Med 1989;149: Newton JE, Wilczynski PJG. Meningitis in the elderly. Lancet. 1979;2: Rasmussen HJ, Sorenson HT, Moller-Petersen J, Mortensen FV, Neilsen B. Bacterial meningitis in elderly patients: Clinical picture and course. Age Aging 1992;21: Domingo P, et al. Acute bacterial meningitis in the elderly. Arch Intern Med 1990;150: Leonard JM, Des Prez RM. Tuberculous meningitis. Infect Dis Clin North Am 1990;4: Maxson S, Jacobs RF. Viral meningitis: Tips to rapidly diagnose treatable causes. Postgrad Med 1993;93: Robbins JB, et al. Considerations for formulation of the second-generation pneumococcal capsular polysaccharide vaccine with emphasis on the cross-reactive types within groups. J Infect Dis 1983;148: Centers for Disease Control. Pneumococcal polysaccharide vaccine. Morb Mortal Wkly Rep 1997;46: Centers for Diseases Control. Recommendations of the Immunization Practices Advisory Committee: pneumococcal polysaccharide vaccine. Morb Mortal Wkly Rep 1989;38:64-68, Gardner P; Schaffner W. Immunization of adults. New Engl J Med 1993;328: Sankilampi U, Hokanen PO, Blouigu A, Leinonen M. Persistence of antibodies to pneumococcal capsular polysaccharide vaccine the elderly. J Infect Dis 1997;176: Mufson MA, Krause HE, Schiffman G, Highey DF. Pneumococcal antibody levels one decade after immunization of healthy adults. Am J Med Sci 1987;293: Rodriguez R, Dyer PD. Safety of pneumococcal revaccination. J Gen Intern Med 1995;10: Honkanen PO, Keistinen T, Kivela S. Reactions following administration of influenza vaccine alone or with pneumococcal vaccine to the elderly. Arch Intern Med 1996; 156:

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