AUTHOR INFORMATION

Section 1 of 11

Authored by Raymund R Razonable, MD, Senior Associate Consultant, Assistant Professor of Medicine, Division of Infectious Diseases, Department of Medicine, Mayo Clinic College of Medicine

Coauthored by Michael R Keating, MD, Consultant, Assistant Professor of Medicine, Division of Infectious Diseases, Department of Medicine, Mayo Clinic College of Medicine

Raymund R Razonable, MD, is a member of the following medical societies: American Society for Microbiology, American Society of Transplantation, Infectious Diseases Society of America, and International Immunocompromised Host Society

Edited by Joseph Richard Masci, MD, Chief of Infectious Diseases, Associate Director, Associate Professor, Department of Internal Medicine, Division of Infectious Diseases, Elmhurst Hospital Center, Mount Sinai School of Medicine; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; John W King, MD, Professor, Department of Internal Medicine, Section of Infectious Diseases, Louisiana State University Health Sciences Center at Shreveport; Eleftherios Mylonakis, MD, PhD, Assistant Professor of Medicine, Harvard Medical School, Assistant in Medicine, Division of Infectious Disease, Massachusetts General Hospital; and Burke A Cunha, MD, MACP, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital

Author's Email:	Raymund R Razonable, MD
Editor's Email:	Joseph Richard Masci, MD

eMedicine Journal, June 27 2005, VOLUME 6, Number 6

INTRODUCTION

Section 2 of 11

Background: Meningitis is inflammation of the meninges that results in the occurrence of meningeal symptoms (eg, headache, nuchal rigidity, photophobia) and an increased number of white blood cells in the cerebrospinal fluid (CSF), ie, pleocytosis. Depending on the duration of symptoms, meningitis may be classified as acute or chronic. Acute meningitis denotes the evolution of symptoms within hours to several days, while chronic meningitis has an onset and duration of weeks to months. The duration of symptoms of chronic meningitis characteristically is at least 4 weeks. In many instances, these syndromes overlap because they share many etiologic agents.

Numerous infectious and noninfectious causes of meningitis exist. Examples of common noninfectious causes include medications (eg, nonsteroidal anti-inflammatory drugs, antibiotics) and carcinomatosis. The focus of this article is the infectious causes of meningitis. Infectious agents that cause encephalitis without concomitant meningitis are not discussed extensively in this article.

Meningitis can also be classified according to etiology. Acute bacterial meningitis denotes a bacterial cause of this syndrome. This is usually characterized by an acute onset of meningeal symptoms and neutrophilic pleocytosis. Depending on the specific bacterial cause, the syndrome may be called, for example, Streptococcus pneumoniae meningitis, meningococcal meningitis, or Haemophilus influenzae meningitis. Fungal and parasitic causes of meningitis are also termed according to their specific etiologic agent, such as cryptococcal meningitis, Histoplasma meningitis, and amebic meningoencephalitis.

Aseptic meningitis is a broad term that denotes a nonpyogenic cellular response, which may be caused by many different etiologic agents. In many cases, a cause is not apparent after initial evaluation. Patients characteristically have an acute onset of meningeal symptoms, fever, and cerebrospinal pleocytosis that is usually prominently lymphocytic. After an extensive workup, many of these cases are found to have a viral etiology and then can be reclassified as acute viral meningitis (eg, enterovirus meningitis, herpes simplex virus [HSV] meningitis). While viruses cause most cases of aseptic meningitis, it can also be caused by bacterial, fungal, mycobacterial, and parasitic agents.

Pathophysiology: Three major pathways exist by which an infectious agent (ie, bacteria, virus, fungus, parasite) gains access to the central nervous system (CNS) and causes disease.

Initially, the infectious agent colonizes or establishes a localized infection in the host. This may be in the form of colonization or infection of the skin, nasopharynx, respiratory tract, gastrointestinal tract, or genitourinary tract. Most meningeal pathogens are transmitted through the respiratory route, as exemplified by the nasopharyngeal carriage of Neisseria meningitides (meningococcus) and nasopharyngeal colonization with S pneumoniae (pneumococcus).

From this site, the organism invades the submucosa by circumventing host defenses (eg, physical barriers, local immunity, phagocytes/macrophages) and gains access to the CNS by (1) invasion of the bloodstream (ie, bacteremia, viremia, fungemia, parasitemia) and subsequent hematogenous seeding of the CNS, which is the most common mode of spread for most agents (eg, meningococcal, cryptococcal, syphilitic, and pneumococcal meningitis); (2) a retrograde neuronal (ie, olfactory and peripheral nerves) pathway (eg, Naegleria fowleri, Gnathostoma spinigerum); or (3) direct contiguous spread (ie, sinusitis, otitis media, congenital malformations, trauma, direct inoculation during intracranial manipulation).

Certain respiratory viruses are thought to enhance the entry of bacterial agents into the intravascular compartment, presumably by damaging mucosal defenses. Once inside the bloodstream, the infectious agent must escape immune surveillance (eg, antibodies, complement-mediated bacterial killing, neutrophil phagocytosis). Subsequently, hematogenous seeding into distant sites occurs, including the CNS. The specific pathophysiologic mechanisms by which the infectious agents gain access into the subarachnoid space remain unclear.

Once inside the CNS, the infectious agents likely survive because host defenses (eg, immunoglobulins, neutrophils, complement components) appear to be limited in this body compartment. The presence and replication of infectious agents remain uncontrolled and incite a cascade of meningeal inflammation. This process of meningeal inflammation has been an area of extensive investigation in recent years that has led to a better understanding of meningitis pathophysiology.

Key advances in the pathophysiology of meningitis include the pivotal role of cytokines (eg, tumor necrosis factor-alpha [TNF-alpha], interleukin [IL]-1), chemokines (IL-8), and other proinflammatory molecules in the pathogenesis of pleocytosis and neuronal damage during bacterial meningitis. Increased CSF concentrations of TNF-alpha, IL-1, IL-6, and IL-8 are characteristic findings in patients with bacterial meningitis.

The proposed interplay among these mediators of inflammation is as follows:

• The exposure of cells (eg, endothelium, leukocytes, microglia, astrocytes, meningeal macrophages) to bacterial products released during replication and death incites the synthesis of cytokines and proinflammatory mediators. Recent data indicate that this process is likely initiated by the ligation of the bacterial components (eg, peptidoglycan, lipopolysaccharide) to pattern recognition receptors such as the Toll-like receptors.

• TNF-alpha and IL-1 are the most prominent among the cytokines that mediate this inflammatory cascade. TNF-alpha is a glycoprotein derived from activated monocyte-macrophages, lymphocytes, astrocytes, and microglial cells. IL-1, previously known as endogenous pyrogen, is also produced primarily by activated mononuclear phagocytes and is responsible for the induction of fever during bacterial infections. Both molecules have been detected in the CSF of individuals with bacterial meningitis. In experimental models of meningitis, they appear early during the course of disease and have been detected within 30-45 minutes of intracisternal endotoxin inoculation.

• Many secondary mediators, such as IL-6, IL-8, nitric oxide, prostaglandins (PGE2), and platelet activation factor (PAF), are presumed to amplify this inflammatory event, either synergistically or independently. IL-6 induces acute-phase reactants in response to bacterial infection. The chemokine IL-8 mediates neutrophil chemoattractant responses induced by TNF-alpha and IL-1. Nitric oxide is a free radical molecule that can induce cytotoxicity when produced in high amounts. PGE2, a product of cyclooxygenase, appears to participate in the induction of increased blood-brain barrier (BBB) permeability. PAF, with its myriad of biologic activities, is believed to mediate the formation of thrombi and the activation of clotting factors within the vasculature. However, the precise roles of all these secondary mediators in meningeal inflammation remain unclear and should be investigated further.

• Overall, the net result is vascular endothelial injury and increased BBB permeability leading to the entry of many blood components into the subarachnoid space. In many patients, this contributes to vasogenic edema and elevated CSF protein. In response to the cytokines and chemotactic molecules, neutrophils migrate from the bloodstream and penetrate the damaged BBB, producing the profound neutrophilic pleocytosis characteristic of bacterial meningitis. The increased CSF viscosity resulting from the influx of plasma components into the subarachnoid space and diminished venous outflow lead to interstitial edema, and the products of bacterial degradation, neutrophils, and other cellular activation lead to cytotoxic edema.

• The ensuing cerebral edema (ie, vasogenic, cytotoxic, interstitial) significantly contributes to intracranial hypertension and a consequent decrease in cerebral blood flow. Anaerobic metabolism ensues, which contributes to increased lactate concentration and hypoglycorrhachia. In addition, hypoglycorrhachia results from decreased glucose transport into the spinal fluid compartment. Eventually, if this uncontrolled process is not modulated by effective treatment, transient neuronal dysfunction or permanent neuronal injury results.

• The level of cytokines, including IL-6, TNF-alpha, and interferon-gamma, has been found to be elevated in patients with aseptic meningitis.

Another important component or complication of meningitis is the development of increased intracranial pressure (ICP). The pathophysiology of this complication is complex and may involve many proinflammatory molecules as well as mechanical elements. Interstitial edema (secondary to obstruction of CSF flow, as in hydrocephalus), cytotoxic edema (swelling of cellular elements of the brain through the release of toxic factors from the bacteria and neutrophils), and vasogenic edema (increased BBB permeability) all are thought to play a role in the development of increased ICP.

Frequency:

• In the US: The incidence of meningitis varies with the specific etiologic agent.

  Bacterial meningitis remains a significant cause of morbidity and mortality throughout the world. The attack rate in the United States is reported at 3 cases per 100,000 population. Previously, the 3 most common pathogens that accounted for more than 80% of cases included H influenzae type B (HIB), N meningitidis, and S pneumoniae. Over the past decade, the epidemiology has changed substantially because of 2 important developments as follows:

  First, the widespread use of the HIB vaccination has decreased the incidence of HIB meningitis by more than 90% (see Table 1). Because of this, bacterial meningitis is becoming more of a disease of adults, with the median age of patients shifting from younger than 2 years to 25 years. A total of 255 cases of invasive H influenzae disease among children younger than 5 years was reported to US Centers for Disease Control and Prevention (CDC) in 1998 (in contrast to 20,000 cases of invasive disease among children in 1987). This shift has reportedly been less dramatic in the developing countries where the use of the HIB vaccine is not as widespread.

  Table 1. Changing Epidemiology of Acute Bacterial Meningitis in the United States*
  

  Bacteria	1978-1981	1986	1995
  H influenzae	48%	45%	7%
  Listeria monocytogenes	2%	3%	8%
  N meningitidis	20%	14%	25%
  Streptococcus agalactiae	3%	6%	12%
  S pneumoniae	13%	18%	47%

  *Nosocomial meningitis is not included. These data include only the 5 major meningeal pathogens.

  Secondly, the emergence of bacterial resistance, especially penicillin-resistant S pneumoniae, has been increasing worldwide, and the reported rates are 41-56% in Southeast Asia and the Far East. In the United States in 1998, the CDC conducted a study on 3335 isolates from 8 states and found 10.2% intermediate penicillin resistance (minimum inhibitory concentration [MIC] of 0.1-1 mcg/mL) and 13.6% highly resistant (MIC > 2 mcg/mL) strains. The geographic distribution of this resistance is variable, and knowledge of this is important when deciding on local empiric antibiotic therapy (see Medication).

  Viruses are the major causes of aseptic meningitis syndrome, an illness that is reported to occur with an incidence rate of 10.9 cases per 100,000 person-years. If appropriate diagnostic methods are performed, a specific viral etiology is identified in 55-70% of cases of aseptic meningitis. Of these, enteroviruses account for 90% of cases. HSV accounts for 0.5-3% of cases of aseptic meningitis and is most commonly associated with primary genital infection and is less likely during recurrences. Mumps is the most common cause of aseptic meningitis in unimmunized populations, occurring in 30% of all patients with mumps. It affects males 2-5 times more often than females.

• Internationally: The incidence of meningitis is presumed to be higher in developing countries because of less access to preventative services such as vaccination.

Mortality/Morbidity: Mortality from meningitis varies with the specific etiologic agent.

• The mortality rate for viral meningitis (without encephalitis) is less than 1%. In patients with deficient humoral immunity (eg, agammaglobulinemia), enterovirus meningitis may have a fatal outcome.

• Bacterial meningitis was uniformly fatal before the antimicrobial era. With the advent of antimicrobial therapy, the overall mortality rate from bacterial meningitis has decreased but remains alarmingly high. It is reported to be approximately 25%. Among the common causes of acute bacterial meningitis, the highest mortality rate is observed with pneumococcus. The reported mortality rates for each specific organism are 19-26% for S pneumoniae meningitis, 3-6% for H influenzae meningitis, 3-13% for N meningitidis meningitis, and 15-29% for L monocytogenes meningitis.

Race:

• Meningitis affects people of all races.

• In the United States, black people have a higher reported rate of meningitis than white people and Hispanic people.

Sex: The attack rate for bacterial meningitis is reported to be 3.3 male cases per 100,000 population compared to 2.6 female cases per 100,000 population.

Age:

• Meningitis occurs in people of all age groups, but very young individuals (infants and young children) and elderly individuals (>60 y) are more predisposed to the infection.

• Depending on their ages, individuals are also predisposed to certain etiologic agents. Escherichia coli K1 and S agalactiae meningitis are common among the neonatal group, and L monocytogenes meningitis is common among neonates and elderly individuals. See Table 2 for bacterial agents common among different age groups.

• The introduction of HIB immunization has shifted the median age of patients with bacterial meningitis from 15 months in 1986 to 25 years in 1995.

CLINICAL

Section 3 of 11

History:

• The classic presentation of meningitis includes fever, headache, neck stiffness, photophobia, nausea, vomiting, and signs of cerebral dysfunction (eg, lethargy, confusion, coma).



• The triad of fever, nuchal rigidity, and change in mental status is found in only two thirds of patients.



• The classic presentation of acute meningitis is the onset of symptoms within hours to a few days, compared to weeks for chronic meningitis.



• Atypical presentation may be observed in certain groups.


• • Elderly individuals, especially those with underlying comorbidities (eg, diabetes, renal and liver disease), may present with lethargy and an absence of meningeal symptoms.
  
  
  
  • Patients with neutropenia may present with subtle symptoms of meningeal irritation.
  
  
  
  • Other immunocompromised hosts, including organ and tissue transplant recipients and patients with HIV and AIDS, may also have an atypical presentation.
  
  
  
• Clues in the patient’s clinical history may suggest the specific etiologic agent. Detailed epidemiologic and predisposing risks should be assessed.


• • The time of the year is an important variable because many infections are seasonal. Enteroviruses are observed worldwide, and infections occur during late summer and early fall in temperate climates and year-round in tropical regions. In contrast, mumps, measles, and varicella zoster viruses occur more commonly during winter and spring seasons. Arthropod-borne viruses occur during the warmer months (eg, St. Louis encephalitis, California encephalitis virus group).
  
  
  
  • History of exposure to a patient with a similar illness is an important epidemiological clue when determining etiology (eg, individuals who were in close contact with an index case of meningococcemia).
  
  
  
  • Elicit a history of sexual contact and high-risk behavior. HSV meningitis is associated with primary genital HSV infection and HIV infection.
  
  
  
  • The geographic location and a travel history are important in the evaluation of patients. Histoplasma capsulatum and Blastomyces dermatitidis are considered in patients with exposure to endemic areas of the Mississippi and Ohio River valleys. Coccidioides immitis is considered in regions of the southwestern United States, Mexico, and Central America. Borrelia burgdorferi is considered in regions of the northeastern and north central United States.
  
  
  
  • The intake of unpasteurized milk and cheese predisposes to brucellosis and L monocytogenes infection.
  
  
  
  • Animal contacts should be elicited. Patients with rabies could present atypically with aseptic meningitis, and rabies should be suspected in a patient with a history of animal bite (eg, skunk, raccoon, dog, fox, bat). Exposure to rodents suggests infection with lymphocytic choriomeningitis (LCM) virus and Leptospira infection. Laboratory workers dealing with these animals also are at increased risk of contracting LCM.
  
  
  
• Record evidence of systemic viral infection (ie, myalgias, fatigue, anorexia).


• • The presence of exanthemas; symptoms of pericarditis, myocarditis, or conjunctivitis; or syndromes of pleurodynia, herpangina, and hand-foot-and-mouth disease suggest enterovirus infection.
  
  
  
  • A history of recurrent bouts of benign aseptic meningitis suggests Mollaret syndrome, which is caused by HSV.
  
  
  
• The presence of a ventriculoperitoneal shunt and a history of recent cranial surgery should be elicited.



• The presence of cochlear implants with a positioner has been associated with a higher risk of bacterial meningitis.

Physical:

• Signs of cerebral dysfunction are common, including confusion, irritability, delirium, and coma. These are usually accompanied by fever and photophobia.



• Signs of meningeal irritation are observed only in approximately 50% of patients with bacterial meningitis, and their absence certainly does not rule out meningitis.


• • Kernig sign: In a supine patient, flex the hip to 90° while the knee is flexed at 90°. An attempt to further extend the knee produces pain in the hamstrings and resistance to further extension.
  
  
  
  • Brudzinski sign: Passively flex the neck while the patient is in a supine position with extremities extended. This maneuver produces flexion of the hips in patients with meningeal irritation.
  
  
  
  • Nuchal rigidity: Resistance to passive flexion of the neck is also a sign.
  
  
  
• Cranial nerve palsies may be observed as a result of increased ICP or the presence of exudates encasing the nerve roots.



• Focal neurologic signs may develop as a result of ischemia from vascular inflammation and thrombosis.



• Seizures occur in approximately 30% of patients.



• Papilledema and other signs of increased ICP may be present.


• • Coma, increased blood pressure with bradycardia, and cranial nerve III palsy may be present.
  
  
  
  • The presence of papilledema also suggests a possible alternate diagnosis (eg, brain abscess).
  
  
  
• Systemic findings upon physical examination may provide clues to the etiology.


• • Morbilliform rash with pharyngitis and adenopathy may suggest a viral etiology (eg, Epstein-Barr virus [EBV], cytomegalovirus [CMV], adenovirus, HIV). Macules and petechiae that rapidly evolve into purpura suggest meningococcemia (with or without meningitis). Vesicular lesions in a dermatomal distribution suggest varicella zoster virus. Genital vesicles suggest HSV-2 meningitis.
  
  
  
  • Sinusitis or otitis suggests direct extension into the meninges, usually with S pneumoniae and H influenzae. Rhinorrhea or otorrhea suggest a CSF leak from a basilar skull fracture, with meningitis most commonly caused by S pneumoniae.
  
  
  
  • Hepatosplenomegaly and lymphadenopathy suggest a systemic disease, including viral (eg, mononucleosislike syndrome in EBV, CMV, and HIV) and fungal (eg, disseminated histoplasmosis) disease.
  
  
  
  • The presence of a murmur suggests infective endocarditis with secondary bacterial seeding of the meninges.
  
  
  
  • Evidence of parotitis is observed in some cases of mumps meningitis.
  
  
  
  • The presence of a ventriculoperitoneal shunt or a cochlear implant may suggest a bacterial cause of meningitis.
  
  
  
• In contrast to bacterial meningitis, patients with aseptic meningitis syndrome usually appear clinically nontoxic with no vascular instability.

Causes:

• Acute bacterial meningitis: The widespread use of HIB vaccine has dramatically changed the epidemiology of bacterial meningitis during the past decade (see Table 1). Once the most common cause of bacterial meningitis in all age groups, the incidence of H influenzae meningitis has dramatically decreased from 48% to 7% of all cases. The rate for N meningitidis has remained constant at 14-25%, and this organism accounts for many cases among 2- to 18-year-old patients. S pneumoniae has become the most common cause in all age groups (see Table 2).

  Table 2. The Most Common Bacterial Pathogens Based on Age and Predisposing Risks
  

  Risk and/or Predisposing Factor	Bacterial Pathogen
  Age 0-4 weeks	S agalactiae (group B streptococci) E coli K1 L monocytogenes
  Age 4-12 weeks	S agalactiae E coli H influenzae S pneumoniae N meningitidis
  Age 3 months to 18 years	N meningitidis S pneumoniae H influenzae
  Age 18-50 years	S pneumoniae N meningitidis H influenzae
  Age older than 50 years	S pneumoniae N meningitidis L monocytogenes Aerobic gram-negative bacilli
  Immunocompromised state	S pneumoniae N meningitidis L monocytogenes Aerobic gram-negative bacilli
  Intracranial manipulation, including neurosurgery	Staphylococcus aureus Coagulase-negative staphylococci Aerobic gram-negative bacilli, including Pseudomonas aeruginosa
  Basilar skull fracture	S pneumoniae H influenzae Group A streptococci
  CSF shunts	Coagulase-negative staphylococci S aureus Aerobic gram-negative bacilli Propionibacterium acnes



• • S pneumoniae
    • S pneumoniae, a gram-positive coccus, remains an important bacterial pathogen in humans. It is a common colonizer of the human nasopharynx (5-10% of healthy adults and 20-40% of healthy children). It causes meningitis by escaping the local host defenses and phagocytic mechanisms, either through choroid plexus seeding from bacteremia or through direct extension from sinusitis or otitis media.

    • Presently, it is the most common bacterial cause of meningitis, accounting for 47% of cases. It is also associated with one of the highest mortality rates among the bacterial agents that cause meningitis (19-26%).

    • It is the most common bacterial agent in meningitis associated with basilar skull fracture and CSF leak.

    • It may be associated with other foci of infection, such as pneumonia, sinusitis, or endocarditis (ie, Austrian syndrome).

    • Patients with hyposplenism, hypogammaglobulinemia, multiple myeloma, glucocorticoid treatment, defective complement (C1-C4), diabetes mellitus, renal insufficiency, alcoholism, malnutrition, and chronic liver disease are at increased risk.

  • N meningitidis
    • N meningitis is a gram-negative diplococcus that is carried in the nasopharynx of otherwise healthy individuals. It initiates invasion by penetrating the airway epithelial surface. The precise mechanism by which this occurs is unclear, but recent viral or mycoplasmal infection has been reported to disrupt the epithelial surface and facilitate invasion by meningococcus. Most sporadic cases (95-97%) are caused by serogroups B, C, and Y, while the A and C strains are observed in epidemics ( <3% of cases).

    • Presently, it is the leading cause of bacterial meningitis in children and young adults, accounting for 59% of cases. The incidence of H influenzae meningitis has declined.

    • Risk factors include (1) deficiencies in terminal complement components (eg, membrane attack complex, C5-C9), which increases attack rates but is associated with surprisingly lower mortality rates; (2) properdin defects that increase the risk of invasive disease; (3) antecedent viral infection, household crowding, chronic medical illness, corticosteroid use, and active or passive smoking; and (4) overcrowding, as is observed in college dormitories (college freshmen living in dormitories are at highest risk) and military facilities, which has been reported for a clustering of cases.
  
  
  
  • H influenzae
    • H influenzae is a small, pleomorphic, gram-negative coccobacilli that is frequently found as part of the normal flora in the upper respiratory tract of humans. Since the implementation of the HIB vaccine, the carriage rates for the B strain have decreased from 2-4% to less than 1%. It can spread from one individual to another by airborne droplets or direct contact with secretions.

    • Meningitis is the most serious acute manifestation of systemic infection. This is primarily caused by the encapsulated type B strain.

    • It primarily affects infants younger than 2 years. Its isolation in adults suggests the presence of an underlying medical disorder, including paranasal sinusitis, otitis media, alcoholism, CSF leak following head trauma, functional or anatomic asplenia, and hypogammaglobulinemia.
  
  
  
  • L monocytogenes
    • L monocytogenes is a small gram-positive bacillus that causes 8% of bacterial meningitis cases and is associated with one of the highest mortality rates (22%).

    • It is widespread in nature and has been isolated in the human stool of 5% of healthy adults. Most human cases appear food-borne. It is a common food contaminant, with a recovery rate of up to 70% from raw meat, vegetables, and meats. Outbreaks have been associated with consumption of contaminated coleslaw, milk, cheese, and alfalfa tablets.

    • Persons at risk include pregnant women, infants and children, elderly individuals (>60 y), patients with alcoholism, adults who are immunosuppressed (eg, steroid use, transplant recipients, patients with AIDS), individuals with chronic liver and renal disease, individuals with diabetes, and those with conditions of iron overload (eg, hemochromatosis or transfusion-induced iron overload).
  
  
  
  • S agalactiae
    • S agalactiae (group B streptococci) is a gram-positive coccus that is isolated from the lower gastrointestinal tract. It also colonizes the female genital tract at a rate of 5-40%, which explains why it is the most common (70%) agent of neonatal meningitis. It has also been reported in adults, primarily affecting individuals older than 60 years. The overall case-fatality rate in adults is 34%.

    • A recent increase has been noted in the incidence of invasive disease caused by this organism.

    • Predisposing risks in adults include diabetes mellitus, pregnancy, alcoholism, hepatic failure, renal failure, and corticosteroid treatment.

    • In 43% of adult cases, no underlying disease is present.

  • Aerobic gram-negative bacilli (eg, E coli, Klebsiella pneumoniae, Serratia marcescens, P aeruginosa, Salmonella species)
    • As a group, the gram-negative bacilli can cause meningitis in certain groups of patients. E coli is a common agent of meningitis among neonates.

    • Other predisposing risk factors include (1) neurosurgical procedures or intracranial manipulation; (2) old age; (3) immunosuppression; (4) high-grade gram-negative bacillary bacteremia; and (5) disseminated strongyloidiasis, which has been reported as a classic cause of gram-negative bacillary bacteremia (as a result of the translocation of gut microflora with the Strongyloides stercoralis larva during hyperinfection syndrome).
  
  
  
  • Staphylococcus species (S aureus and coagulase-negative staphylococci)
    • Staphylococci species are gram-positive cocci that are part of the normal skin flora.

    • Meningitis caused by staphylococci is associated with the following risk factors: (1) status postneurosurgery and posttrauma, (2) presence of CSF shunts, and (3) infective endocarditis and paraspinal infection.

    • Staphylococcus epidermidis is the most common cause of meningitis in patients with CNS (ie, ventriculoperitoneal) shunts.
  
  
  
• Aseptic meningitis syndrome: Aseptic meningitis is the most common infectious syndrome affecting the CNS. Most episodes are caused by a viral pathogen, but they can also be caused by bacteria, fungi, or parasites (see Table 3). Importantly, partially treated bacterial meningitis accounts for a large number of meningitis cases with a negative microbiologic workup.

  Table 3. Infectious Agents Causing Aseptic Meningitis Syndrome

  Category	Agent
  Bacteria	Partially-treated bacterial meningitis L monocytogenes Brucella species Rickettsia rickettsii Ehrlichia species Mycoplasma pneumoniae B burgdorferi Treponema pallidum Leptospira species Mycobacterium tuberculosis Nocardia species
  Parasites	N fowleri Acanthamoeba species Balamuthia species Angiostrongylus cantonensis G spinigerum Baylisascaris procyonis S stercoralis Taenia solium (cysticercosis)
  Fungi	Cryptococcus neoformans C immitis B dermatitidis H capsulatum Candida species Aspergillus species
  Viruses	Enterovirus Poliovirus Echovirus Coxsackievirus A Coxsackievirus B Enterovirus 68-71
  	Herpesvirus HSV-1 and HSV-2 Varicella-zoster virus EBV CMV HHV*-6 HHV-7
  	Paramyxovirus Mumps virus Measles virus
  	Togavirus Rubella virus
  	Flavivirus Japanese encephalitis virus St. Louis encephalitis virus
  	Bunyavirus California encephalitis virus La Crosse encephalitis virus
  	Alphavirus Eastern equine encephalitis virus Western equine encephalitis virus Venezuelan encephalitis virus
  	Reovirus Colorado tick fever virus
  	Arenavirus LCM virus
  	Rhabdovirus Rabies virus
  	Retrovirus HIV

  *Human herpes virus

• Acute viral meningitis: Viral meningitis comprises most aseptic meningitis syndromes. The viral agents for aseptic meningitis include the following:
  • Enterovirus
    • Enterovirus belongs to the family Picornaviridae. It is classified further to include polioviruses (3 serotypes), coxsackievirus A (23 serotypes), coxsackievirus B (6 serotypes), echovirus (31 serotypes), and the newly recognized enterovirus serotypes 68-71.

    • They are distributed worldwide, and the infection rates vary depending on the season of the year and the age and socioeconomic status of the population.

    • The virus is usually spread by fecal-oral or respiratory routes and occurs during summer and fall in temperate climates and year-round in tropical regions.

    • Most of the infections occur in individuals who are younger than 15 years, with the highest attack rates in children who are younger than 1 year.

    • The nonpolio enteroviruses (NPEV) account for approximately 90% of cases of viral meningitis in which a specific pathogen can be identified.

    • Echovirus 30 was reported as the cause of an epidemic in Japan in 1991 and also as the cause of 20% of the cases of aseptic meningitis reported to the CDC in 1991.

    • In patients with deficient humoral immunity (eg, agammaglobulinemia), enterovirus meningitis may have a fatal outcome.


• • Herpesvirus
    • The Herpesviridae family consists of large DNA-containing enveloped viruses. Eight members are known to cause human infections, and all have been implicated in meningitis syndromes, with the exception of HHV-8 or Kaposi sarcoma–associated virus.

    • HSV-1 is a cause of encephalitis, while HSV-2 more commonly causes meningitis. Although more commonly associated with HSV-2, both viruses have been implicated to cause Mollaret syndrome, a recurrent but benign aseptic meningitis syndrome.

    • EBV, or HHV-4, and CMV, or HHV-5, may manifest as meningitis during the mononucleosis syndrome.

    • Varicella zoster virus (VZV), or HHV-3, and CMV are causes of meningitis in immunocompromised hosts, especially patients with AIDS and transplant recipients.

    • HHV-6 and HHV-7 have been reported to cause meningitis in transplant recipients.
  
  
  
  • Arthropod-borne viruses
    • The most common arthropod-borne viruses are St. Louis encephalitis virus (a flavivirus), Colorado tick fever, and California encephalitis virus (bunyavirus group, including La Crosse encephalitis virus).

    • St. Louis encephalitis virus is a mosquito-borne flavivirus that may cause a febrile syndrome, aseptic meningitis syndrome, and encephalitis. The infection usually occurs during the summer and early fall, with symptoms typical of acute aseptic meningitis. In the United States, the last epidemic of St. Louis encephalitis was in Florida in 1990. Twenty-four cases were reported to the CDC in 1998, with most cases originating from Louisiana.

    • Other members of the flavivirus group that may cause aseptic meningitis include tick-borne encephalitis virus and Japanese encephalitis virus.

    • California encephalitis is a common childhood disease of the CNS that is caused by a virus in the genus Bunyavirus. Most of the cases of California encephalitis are probably caused by mosquito-borne La Crosse virus. The infection usually occurs during the summer and early fall, with symptoms typical of acute aseptic meningitis.
    
    
  • Lymphocytic choriomeningitis virus
    • LCM virus is a member of the arenaviruses, a family of single-stranded RNA-containing viruses with rodents as the animal reservoir.

    • The infection occurs worldwide, and most human cases occur among young adults during autumn.

    • The modes of transmission include aerosols and direct contact with rodents.

    • Outbreaks have also been traced to infected laboratory mice and hamsters.

    • Following exposure, an incubation period of approximately 5-10 days ensues, followed by a nonspecific febrile illness and an acute onset of aseptic meningitis. This may be associated with orchitis, arthritis, myocarditis, and alopecia.
  
  
  
  • Human immunodeficiency virus
    • Aseptic meningitis syndrome may be the presenting symptom in a patient with acute HIV infection. This usually is part of the mononucleosislike acute seroconversion phenomenon.

    • Always suspect HIV as a cause of aseptic meningitis in a patient with risk factors such as intravenous drug use and in individuals who practice high-risk sexual behaviors.
  
  
  
  • Other viruses causing meningitis
    • Patients with meningitis caused by the mumps virus usually present with the triad of fever, vomiting, and headache. It follows the onset of parotitis (salivary gland enlargement occurs in 50% of patients), which clinically resolves in 7-10 days.

    • Adenovirus (serotypes 1, 6, 7, and 12) has been associated with cases of meningoencephalitis. Chronic meningoencephalitis has been reported with serotypes 7, 12, and 32. The infection is usually acquired through a respiratory route.

• Chronic meningitis: Chronic meningitis is a constellation of signs and symptoms of meningeal irritation associated with CSF pleocytosis that persists for longer than 4 weeks. The agents responsible for chronic meningitis are listed in Table 4.

  Table 4. Causes of Chronic Meningitis

  Category	Agent
  Bacteria	M tuberculosis B burgdorferi T pallidum Brucella species Francisella tularensis Nocardia species Actinomyces species
  Fungi	C neoformans C immitis B dermatitidis H capsulatum Candida albicans Aspergillus species Sporothrix schenckii
  Parasites	Acanthamoeba species N fowleri Angiostrongylus cantonensis G spinigerum B procyonis Schistosoma species S stercoralis Echinococcus granulosus

• Chronic bacterial meningitis
  • Brucella species are small gram-negative coccobacilli that cause zoonoses as a result of infection with Brucella abortus, Brucella melitensis, Brucella suis, and Brucella canis.

  • Transmission to humans occurs following direct or indirect exposure to infected animals (eg, sheep, goat, cattle).

  • It has a worldwide distribution and is common in the Middle East, India, Mexico, and Central and South America. In the United States following the control of bovine infections, incidence has decreased to less than 0.5 cases per 100,000 population, and only 79 cases were reported to the CDC in 1998.

  • Direct infection of the CNS occurs in fewer than 5% of cases, with most patients presenting with acute or chronic meningitis.

  • Persons at risk include individuals who had contact with infected animals (eg, sheep, goat, cattle) or their products (eg, intake of unpasteurized milk products). Veterinarians, abattoir workers, and laboratory workers dealing with these animals also are at risk.

DIFFERENTIALS

Section 4 of 11

Brain Abscess

Other Problems to be Considered:

Noninfectious meningitis, including medication-induced meningeal inflammation
Meningeal carcinomatosis
CNS vasculitis
Stroke
Encephalitis

WORKUP

Section 5 of 11

Lab Studies:

• The cornerstone in the diagnosis of meningitis is examination of the CSF.


• • In general, whenever the diagnosis of meningitis is strongly considered, promptly perform a lumbar puncture.

  • Measure the opening pressure and send the fluid for cell count (and differential count), chemistry (ie, CSF glucose and protein), and microbiology (ie, Gram-stain and cultures).

  • Special studies, such as serology and nucleic acid amplification, may also be performed depending on clinical suspicion.

    Table 5. CSF Picture of Meningitis According to Etiologic Agent

    Agent	Opening Pressure	WBC count per mL	Glucose (mg/dL)	Protein (mg/dL)	Microbiology
    Bacterial meningitis	200-300	100-5000; >80% PMNs*	<40	>100	Specific pathogen demonstrated in 60% of Gram stains and 80% of cultures
    Viral meningitis	90-200	10-300; lymphocytes	Normal, reduced in LCM and mumps	Normal but may be slightly elevated	Viral isolation, PCR† assays
    Tuberculous meningitis	180-300	100-500; lymphocytes	Reduced, <40	Elevated, >100	Acid-fast bacillus stain, culture, PCR
    Cryptococcal meningitis	180-300	10-200; lymphocytes	Reduced	50-200	India ink, cryptococcal antigen, culture
    Aseptic meningitis	90-200	10-300; lymphocytes	Normal	Normal but may be slightly elevated	Negative findings on workup
    Normal values	80-200	0-5; lymphocytes	50-75	15-40	Negative findings on workup

    *Polymorphonuclear lymphocytes
    †Polymerase chain reaction

  
  
  
• Bacterial meningitis


• • Examination of the CSF in patients with acute bacterial meningitis reveals the characteristic neutrophilic pleocytosis (usually hundreds to a few thousand, with >80% PMN cells). In some cases of L monocytogenes meningitis (25-30%), a lymphocytic predominance may occur. Low CSF WBC count (<20 cells/mL) in the presence of a high bacterial load suggests a poor prognosis.

  • The opening pressure (reference range is 80-200 mm H₂O) may be elevated, suggesting some form of increased ICP from cerebral edema.

  • The CSF glucose (reference range is 40-70 mg/dL) is less than 40 mg/dL in 60% of patients. Obtain a simultaneous blood glucose determination for comparison purposes. Some patients may have elevated blood sugar levels as a result of underlying diabetes mellitus, and the predictive value of the CSF and blood sugar ratio may not be accurate in these circumstances.

  • The CSF protein (reference range is 20-50 mg/dL) is usually elevated.

  • CSF Gram stain permits rapid identification of the bacterial cause in 60-90% of patients with bacterial meningitis. The presence of bacteria is 100% specific, but the sensitivity for detection is variable. The likelihood of detection is higher in the presence of a higher bacterial concentration and diminishes with prior antibiotic use.

  • CSF bacterial cultures yield the bacterial cause in 70-85% of cases. The yield diminishes significantly in patients who have received antimicrobial therapy. In these cases, some experts advocate the use of a CSF bacterial antigen assay. This is a latex agglutination technique that can detect the antigens of HIB, S pneumoniae, N meningitidis, E coli K1, and S agalactiae. Its theoretical advantage is the detection of the bacterial antigens even after microbial killing, as is observed following antibacterial therapy. Others, however, have shown that it may not be better than the Gram stain. It is specific (a positive result indicates a diagnosis of bacterial meningitis), but a negative finding on bacterial antigen test does not rule out meningitis (50-95% sensitivity).

  • Obtain blood cultures and appropriate cultures from possible sites of infection. Obtain these promptly and prior to the administration of an antibacterial agent. The utility of these cultures is most evident in cases when the performance of a lumbar puncture is delayed by the need for head imaging (risk for herniation in a patient with focal neurologic deficit or coma) and when antimicrobial therapy is rightfully initiated before the lumbar puncture and neuroimaging tests.
  
  
  
• Acute viral meningitis


• • The CSF picture of acute viral meningitis is different from the CSF picture of bacterial meningitis.

  • The opening pressure usually is within the reference range.
  
  
  
  • The CSF cell count usually is in the few hundreds (100-1000 cells/mL) with a predominance of lymphocytes. Some cases of echovirus, mumps, and HSV meningitis may produce a neutrophilic picture early in the course of disease.

  • The CSF glucose level usually is within the reference range, but some cases of LCM, HSV, mumps, and polio may cause low CSF glucose levels.

  • CSF protein may be within the reference range but is usually elevated.

  • Virus isolation from the CSF can be performed. It has a sensitivity of 65-70% for enteroviruses. Alternatively, enterovirus isolation from throat and stool viral cultures may also be used to indirectly implicate it as the cause of the meningitis. Mumps viral culture from the CSF has a low sensitivity (30-50%). LCM virus may be cultured in blood early in the disease or later in the urine.

  • The use of nucleic acid amplification (eg, PCR) has revolutionized the diagnosis of herpes simplex meningitis. The availability of this technique has confirmed HSV as the cause of the recurrent Mollaret meningitis. This technique has also been applied to the diagnosis of enterovirus infections and the other herpesvirus infections. The PCR assay for enteroviruses has been demonstrated to be substantially more sensitive than culture and is 94-100% specific.

  • In addition, the demonstration of a 4-fold rise between acute and convalescent sera traditionally has been used to document meningeal infection with these viral pathogens.
  
  
  
• Cryptococcal meningitis


• • The diagnosis of cryptococcal meningitis relies on the identification of the pathogen in the CSF.

  • The CSF is characterized by a lymphocytic pleocytosis (10-200 lymphocytes), a reduced glucose level, and an elevated protein level.

  • The CSF opening pressure may be elevated at times, suggesting increased ICP.

  • C neoformans may be cultured from the CSF. Other methods of identification have included India ink preparation and the detection of CSF cryptococcal antigen. India ink has a sensitivity of only 50%, but it is highly diagnostic if positive. Because of the low sensitivity of the India ink preparation, many centers have adapted the use of CSF cryptococcal antigen determination, a test with a sensitivity of greater than 90%. However, the CSF cryptococcal antigen determination is not universally available. In instances when the India ink is negative but the clinical suspicion for cryptococcal meningitis is high, the CSF specimen may be sent to reference laboratories that can perform CSF cryptococcal antigen determination to confirm the diagnosis. In addition, the titer of the antigen could serve to monitor the response to treatment.

  • Also obtain blood cultures to determine if cryptococcal fungemia is present.
  
  
  
• Other fungal meningitis


• • The CSF picture of other fungal meningitis is similar to the CSF picture of cryptococcal meningitis, usually with lymphocytic pleocytosis.

  • Eosinophilic pleocytosis has rarely been associated with C immitis meningitis.

  • The definitive diagnosis usually relies on the demonstration of the specific fungal agent (eg, H capsulatum, C immitis, B dermatitidis, Candida species) from clinical specimens, including the CSF. This could be in the form of fungal culture isolation (eg, C albicans growth from CSF). More commonly, fungal serology is used in the diagnosis of many cases of fungal meningitis because isolating them from culture has been difficult (eg, presence of histoplasma antigen in the CSF). However, note that the serology for B dermatitidis is not accurate and a negative serology finding does not rule out the diagnosis.
  
  
  
• Syphilitic meningitis


• • The CSF in syphilitic meningitis is characterized by mild lymphocytic pleocytosis.

  • Abnormal CSF protein (elevated) and CSF glucose (decreased) may be observed in 10-70% of cases.

  • Isolating T pallidum from the CSF is extremely difficult and time consuming. The spirochete could be demonstrated using dark-field or phase-contrast microscopy on specimens collected from skin lesions (eg, chancres and other syphilitic lesions).

  • The diagnosis is usually supported by the CSF Venereal Disease Research Laboratory (VDRL) test, which has a sensitivity of 30-70% (a negative result on the CSF VDRL test does not rule out syphilitic meningitis) and a high specificity (a positive test result suggests the disease). Always take care to not contaminate the CSF with blood during spinal fluid collection (eg, traumatic tap).

  • Perform serologic tests to detect syphilis, such as the nontreponemal (ie, rapid plasma reagent [RPR] or VDRL test) and specific treponemal (ie, fluorescent treponemal antibody absorption [FTA-Abs], Treponema pallidum hemoagglutination [TPHA], microhemagglutination-Treponema pallidum [MHA-TP]) tests to support the diagnosis. These also guide the success of therapy. The titer of the nonspecific treponemal tests decreases and usually reverts back to negative or undetectable levels following treatment.
  
  
  
• Lyme neuroborreliosis


• • The CSF in patients with Lyme meningitis is characterized by low-grade lymphocytic pleocytosis, low glucose, and elevated protein. Oligoclonal bands reactive to B burgdorferi antigens may be present.

  • Demonstration of the specific antibody to B burgdorferi aids in the diagnosis. Comparison between the antibody response in the CSF and the serum is a helpful diagnostic test. A CSF-to-serum ratio of greater than 1 suggests intrathecal antibody production and neuroborreliosis.

  • The culture for B burgdorferi has a low yield.

  • The recent availability of the CSF Lyme PCR assay offers a rapid, sensitive, and specific method of diagnosis. This assay is gaining popularity as the method of choice for diagnosis of Lyme meningitis. Findings on blood Lyme PCR are usually negative.
  
  
  
• Tuberculosis meningitis


• • The CSF of patients with tuberculosis meningitis is characterized by a predominantly lymphocytic pleocytosis, usually in the hundreds.

  • The opening CSF pressure is usually elevated.

  • A characteristic hypoglycorrhagia (glucose <40 mg/dL) is present, and the protein is usually elevated, especially if a CSF block is present.

  • The demonstration of the acid-fast bacilli (eg, with auramine-rhodamine stain, Ziehl-Neelsen stain, Kinyoun stain) in the CSF is difficult and usually requires a large volume of CSF.

  • Meningeal biopsy, with the demonstration of caseating granulomas and acid-fast bacilli on the smear, may prove useful because it has a higher yield than the CSF acid-fast bacilli smear.

  • The culture for Mycobacterium usually takes several weeks and may delay definitive diagnosis.

  • Recently, M tuberculosis detection assays employing nucleic acid amplification have become available and have the advantage of a rapid, sensitive, and specific method of tuberculosis detection.

  • The need for mycobacterial growth in cultures remains because this offers the advantage of performing drug susceptibility assays.
  
  
  
• Parasitic meningitis


• • PAM caused by N fowleri is characterized by a neutrophilic pleocytosis, low glucose, elevated protein, and red blood cells. Mononuclear pleocytosis may be observed in patients with subacute or chronic forms of PAM. Demonstration of the trophozoites, with the characteristic amoeboid movement, using wet preparations of the CSF has been used for diagnosis. Alternatively, the amoeba could be demonstrated in biopsy specimens.
  
  
  
  • Suspect meningitis caused by A cantonensis, G spinigerum, and B procyonis in the presence of exposure, profound peripheral blood eosinophilia, and characteristic eosinophilic pleocytosis. Demonstrating the larva antemortem is usually difficult, and diagnosis relies on clinical presentation and a compatible epidemiological history. Serologic tests may aid in the diagnosis. G spinigerum meningitis may mimic cerebrovascular disease because it may cause cerebral hemorrhage.
  
  
  

Imaging Studies:

• Computed tomography scans of the head and magnetic resonance imaging of the brain do not aid in the diagnosis of meningitis. Some patients may show meningeal enhancement, but its absence does not rule out the condition.



• The practice of obtaining CT scans of the head may lead to the unnecessary delay in the performance of diagnostic lumbar puncture and the initiation of antibiotic therapy. The delay in the institution of antimicrobial therapy may be detrimental to the total outcome in these patients. The occurrence of cerebral herniation following the lumbar tap procedure rarely occurs in individuals with no focal neurologic deficits and no evidence of increased ICP. If it occurs, it usually happens within 24 hours following the lumbar puncture and should always be considered in the differential diagnosis if the patient's neurologic status deteriorates.



• Neuroimaging is indicated in patients with prolonged fever, focal neurologic symptoms and signs, evidence of increased ICP, and suspected basilar fracture. It is also indicated for evaluation of the paranasal sinuses. These studies are helpful in the detection of CNS complications of bacterial meningitis, such as hydrocephalus, cerebral infarct, brain abscess, subdural empyema, and venous sinus thrombosis.

Procedures:

• Perform lumbar puncture promptly in all patients whenever a strong clinical suspicion for meningitis exists.



• Neurosurgical procedures are performed in consultation with a neurosurgical service in the presence of severe intracranial hypertension, evidence of paranasal and mastoid infection that requires surgical drainage, skull fractures, foreign body–associated infections (eg, ventriculoperitoneal shunts), or an associated abscess formation.

TREATMENT

Section 6 of 11

Medical Care:

General guidelines

The urgent performance of lumbar puncture for CSF examination is warranted in individuals in whom meningitis is clinically suspected.

In the absence of focal neurologic deficit, radiographic imaging of the head should not preclude performing a lumbar puncture. In addition, the performance of radiographic imaging should not defer the institution of empiric antimicrobial therapy.

Institute empiric antimicrobial therapy (ie, antibacterial treatment with antivirals and antifungal therapy in selected cases) as soon as possible (see Table 6 and Table 7). This is usually based on the known predisposing factors and/or initial CSF Gram-stain results.

Significant delays in instituting antimicrobial treatment in individuals with bacterial meningitis could lead to significant morbidity and mortality.

The chosen antibiotic should attain adequate levels in the CSF. Achieving this usually depends on the drug’s lipid solubility, its molecular size, its protein-binding capability, and the state of inflammation at the meninges. The penicillins, certain cephalosporins (ie, third- and fourth-generation cephalosporins), the carbapenems, fluoroquinolones, and rifampin provide high CSF levels.

Monitor for possible drug toxicity during the treatment (eg, with blood counts and renal and liver function monitoring).

The dose of the chosen antimicrobial agent should always be adjusted based on the renal and hepatic function of the patient. At times, obtaining serum drug concentrations may be necessary to ensure adequate levels and to avoid toxicity in drugs with a narrow therapeutic index (eg, vancomycin, aminoglycosides).

Once the pathogen has been identified and antimicrobial susceptibilities determined, the antibiotics may be modified for optimal treatment (see Table 8).

Strongly consider the use of steroids as adjunctive treatment of bacterial meningitis. If steroids are given, they should be administered prior to or during the administration of antimicrobial therapy. Recent data indicate that the use of steroids improves the overall outcome of patients with certain types of bacterial meninigitis.

Practice vigilance to monitor for the occurrence of complications from the disease (eg, hydrocephalus, seizures, hearing defects) and its treatment (eg, drug toxicity, hypersensitivity).

Table 6. Recommended Empiric Antibiotics According to Predisposing Factors for Patients With Suspected Bacterial Meningitis

Predisposing Feature	Antibiotic(s)
Age 0-4 weeks	Ampicillin plus cefotaxime or an aminoglycoside
Age 1-3 months	Ampicillin plus cefotaxime plus vancomycin*
Age 3 months to 50 years	Ceftriaxone or cefotaxime plus vancomycin*
Age older than 50 years	Ampicillin plus ceftriaxone or cefotaxime plus vancomycin*
Impaired cellular immunity	Ampicillin plus ceftazidime plus vancomycin*
Neurosurgery, head trauma, or CSF shunt	Vancomycin plus ceftazidime

*Vancomycin is added empirically to the initial regimen if the presence of penicillin-resistant S pneumoniae is suspected or if a high incidence of resistance is reported in the community.

Table 7. Recommended Empiric Antibiotics for Patients With Suspected Bacterial Meningitis and Known CSF Gram Stain Results

Gram Stain Morphology	Antibiotic(s)
Gram-positive cocci	Vancomycin plus ceftriaxone or cefotaxime
Gram-negative cocci	Penicillin G*
Gram-positive bacilli	Ampicillin plus an aminoglycoside
Gram-negative bacilli	Broad-spectrum cephalosporin† plus an aminoglycoside

*Use ceftriaxone if penicillin-resistant N meningitidis occurs in the community.
†Ceftriaxone is preferred. Ceftazidime is used when Pseudomonas infection is likely (eg, neurosurgical procedures).

Table 8. Specific Antibiotics and Duration of Therapy for Patients With Acute Bacterial Meningitis

Bacteria	Susceptibility	Antibiotic(s)	Duration (Days)
S pneumoniae	Penicillin MIC <0.1 mg/L	Penicillin G	10-14
	MIC 0.1-1 mg/L	Ceftriaxone or cefotaxime
	MIC > 2 mg/L	Ceftriaxone or cefotaxime
	Ceftriaxone MIC >0.5 mg/L	Ceftriaxone or cefotaxime plus vancomycin or rifampin
H influenzae	Lactamase-negative	Ampicillin	7
	Lactamase-positive	Ceftriaxone or cefotaxime
N meningitidis	...	Penicillin G or ampicillin	7
L monocytogenes	...	Ampicillin or penicillin G plus an aminoglycoside	14-21
S agalactiae	...	Penicillin G plus an aminoglycoside, if warranted	14-21
Enterobacteriaceae	...	Ceftriaxone or cefotaxime plus an aminoglycoside	21
P aeruginosa	...	Ceftazidime plus an aminoglycoside	21

• Antimicrobial therapy for bacterial meningitis
  • S pneumoniae
    • The increasing incidence of penicillin-resistant strains has changed the management of pneumococcal meningitis.

    • The third-generation cephalosporins (ceftriaxone 2-4 g/d or cefotaxime 8-12 g/d) with vancomycin (2-3 g/d, adjusted to therapeutic serum levels) are first-line empiric therapy, depending on the resistance patterns in the community.

    • The use of corticosteroids such as dexamethasone as adjunctive treatment for pneumococcal meningitis is now supported by recent studies demonstrating significant benefit with regards to reduction in case-fatality rate and neurologic sequelae.

    • Vancomycin has poor CSF penetration. The addition of dexamethasone could further decrease CSF penetration (see Use of steroids). When dexamethasone is used, an alternative for vancomycin is rifampin (600 mg/d).

    • The efficacy of fluoroquinolones and newer agents, such as linezolid, has not been investigated in detail, and their use as first-line agents is not recommended.

    • Penicillin G (24 million U/d) remains the drug of choice for penicillin-susceptible strains.
  • N meningitidis
    • The antimicrobial therapy of choice is penicillin G (24 million U/d) or ampicillin (12 g/d).

    • Ceftriaxone (2-4 g/d) is used in the presence of resistant strains (MIC of 0.1-1 mcg/mL).

    • Data on the use of corticosteroids as adjunctive treatment of meningococcal meningitis are not as strong as those for pneumococcal meningitis. The systematic review on this topic indicates that the reduction in mortality and neurologic sequelae did not reach statistical significance.
  • H influenzae
    • Third-generation cephalosporins (ceftriaxone 4 g/d or cefotaxime 8-12 g/d) are first-line empiric therapy. Resistance to chloramphenicol and ampicillin is common.

    • The efficacy of dexamethasone (0.15 mg/kg q6h) in decreasing the incidence of hearing loss and neurologic sequelae has been clearly demonstrated in children.
  • L monocytogenes
    • Ampicillin (12 g/d) or penicillin G (24 million U/d) is the drug of choice.

    • The addition of gentamicin (3-5 mg/kg/d, divided tid) may add synergy.

    • The third-generation cephalosporins are inactive against L monocytogenes.

    • In patients who are allergic to penicillin, use trimethoprim-sulfamethoxazole (TMP-SMX) at 10 mg/kg/d of the TMP component.


• • Aerobic gram-negative bacilli
    • Third-generation cephalosporins are the drugs of choice. Cefepime is also commonly used. An aminoglycoside may be added for synergy.

    • In cases of P aeruginosa meningitis, the agent of choice among the third-generation cephalosporins is ceftazidime (2 g IV q8h). Ceftriaxone and cefotaxime are not effective against P aeruginosa.

    • The use of imipenem is limited because of seizure potential.

    • Quinolones are under investigation but are not currently recommended as first-line agents.

  • S agalactiae
    • Treat meningitis caused by S agalactiae with ampicillin (12 g/d) and an aminoglycoside.

    • Alternatives include third-generation cephalosporins and vancomycin.

  • Staphylococcus species
    • Treat meningitis caused by S aureus with nafcillin (9-12 g/d) or oxacillin (9-12 g/d).

    • Vancomycin (2-3 g/d, adjusted to serum levels) is the alternative in patients who are allergic to penicillin and is the first-line therapy for methicillin-resistant S Aureus (MRSA) strains.

    • Vancomycin is the first-line therapy for coagulase-negative staphylococci. Adding rifampin (600 mg/d) may have a synergistic effect.

    • The use of newer agents such as linezolid and daptomycin for the treatment of staphylococcal meningitis remains investigational.
  
  
  
  • Use of steroids
    • The present understanding of the pathogenesis of bacterial meningitis has led to multiple therapeutic trials that involve means to attenuate the detrimental effects of the host defenses (eg, inflammatory response to the bacterial products and the products of neutrophil activation) while eradicating bacteria with antibiotics.

    • Foremost among these measures is the use of steroids. However, in the experimental meningitis model, the use of steroids has been associated with decreased antimicrobial penetration into the CSF and decreased bactericidal activity of some antimicrobials, such as vancomycin. Recent clinical data, however, indicate that steroid use may offer benefit in certain cases of acute bacterial meningitis.

    • The use of adjunctive dexamethasone (0.15 mg/kg per dose q6h for 2-4 d) decreases hearing loss and neurologic sequelae in children and infants with meningitis caused by HIB. The studies that support this largely have been carried out during the era when HIB was the most common meningeal pathogen.

    • More recent studies indicate that adjunctive steroids are also beneficial in the treatment of meningitis caused by bacterial pathogens other than HIB. In a large cohort of patients with acute meningitis due to Pneumococcus, Meningococcus, and other bacteria, the administration of adjunctive dexamethasone was significantly associated with a reduction in mortality and other unfavorable outcomes. The benefit was most apparent in cases due to pneumococcus.

    • The recent accumulation of scientific evidence about the benefits of steroid use suggests that it should be considered as adjunctive treatment in most adult patients in whom acute bacterial meningitis is suspected.

    • The timing of dexamethasone administration is crucial. If used, it should be administered before or with the first dose of antibacterial therapy. This is to counteract the initial inflammatory burst consequent to antibiotic-mediated bacterial killing. A more intense inflammatory reaction has been documented following the massive bacterial killing induced by antibiotics.

• Viral meningitis
  • Most viral meningitides are benign and self-limited. Often, they only require supportive care and do not require specific therapy. In certain instances, specific antiviral therapy may be indicated, if available.

  • In patients with immune deficiency (eg, agammaglobulinemia), immunoglobulin replacement has been used to treat chronic enterovirus infections.

  • The antiviral management of herpes meningitis is controversial. Acyclovir (10 mg/kg IV q8h) has been administered for HSV-1 and HSV-2 meningitis. Some experts do not advocate antiviral therapy unless associated encephalitis is present because the condition usually is benign and self-limited. This is exemplified by Mollaret syndrome, a recurrent but benign syndrome of lymphocytic pleocytosis that is now attributed to HSV.

  • Ganciclovir (induction dose of 5 mg/kg IV q12h, maintenance dose of 5 mg/kg q24h) and foscarnet (induction dose of 60 mg/kg IV q8h, maintenance dose of 90-120 mg/kg IV q24h) are used for CMV meningitis in immunocompromised hosts.

  • Instituting highly active antiretroviral therapy (HAART) may be necessary for patients with HIV meningitis that occurs during an acute seroconversion syndrome.

• Fungal meningitis
  • A number of different regimens have been demonstrated to be effective in the treatment of fungal meningitis. The following treatment options have been shown to be effective in many cases.
  • Treatment of AIDS-related cryptococcal meningitis (ie, C neoformans)
    • Induction therapy: Administer amphotericin B (0.7-1 mg/kg/d IV) for at least 2 weeks, with or without flucytosine (100 mg/kg PO) in 4 divided doses. Liposomal preparations of amphotericin B may be beneficial, but optimal doses have not been determined.

    • Consolidation therapy: Administer fluconazole (400 mg/d for 8 wk). Itraconazole is an alternative if fluconazole is not tolerated.

    • Maintenance therapy: Long-term antifungal therapy with fluconazole (200 mg/d) is most effective (superior to itraconazole and amphotericin B at 1 mg/kg/wk) to prevent relapse. The risk of relapse is high in patients with AIDS.

    • In many cases, cryptococcal meningitis is complicated by increased ICP. Measuring the opening pressure during the lumbar puncture is strongly advised. Make an effort to reduce such pressure by repeated lumbar puncture, a lumbar drain, or a shunt. Medical maneuvers, such as administration of mannitol, have also been used.

  • Treatment of cryptococcal meningitis (ie, C neoformans) in patients without AIDS
    • Induction/consolidation: Administer amphotericin B (0.7-1 mg/kg/d) plus flucytosine (100 mg/kg/d) for 2 weeks. Then, administer fluconazole (400 mg/d) for a minimum of 10 weeks.

    • A lumbar puncture is recommended after 2 weeks to document sterilization of the CSF. If the infection persists, longer therapy is recommended. Solid organ transplant recipients require prolonged therapy.

  • C immitis
    • The preferred treatment for meningitis caused by C immitis is oral fluconazole (400 mg/d). Some physicians initiate therapy with a higher dose of fluconazole (as high as 1000 mg/d) or in combination with intrathecal amphotericin B.

    • Itraconazole (400-600 mg/d) has been reported to be comparably effective.

    • Duration of treatment usually is life long.
  
  
  
  • H capsulatum
    • The optimal treatment of H capsulatum meningitis is unclear.

    • Amphotericin B at 0.7-1 mg/kg/d to complete a total dose of 35 mg/kg has been used.

    • Fluconazole (800 mg/d) for an additional 9-12 months may be used to prevent relapse.

    • Long-term fluconazole maintenance therapy at 800 mg/d may be used for those who relapse despite having received a full course of treatment. Patients with further relapse despite long-term suppression are candidates for intraventricular amphotericin B.

    • Itraconazole, although it has better anti-Histoplasma activity, is not encouraged because of poor CSF penetration.

    • This infection is associated with a poor outcome; 20-40% of patients with meningitis succumb to the infection despite amphotericin B therapy, and 50% of responders relapse following discontinuation of treatment.

  • Candida species
    • The preferred initial therapy for candidal meningitis is amphotericin B (0.7mg/kg/d). Flucytosine (25 mg/kg qid) is usually added and adjusted to maintain serum levels of 40-60 mcg/mL.

    • Azole therapy may be used for follow-up therapy or suppressive treatment.

    • The risk of relapse is high, and the duration of treatment is arbitrary. Some recommend continuing treatment for a minimum of 4 weeks following the complete resolution of symptoms. The removal of prosthetic materials (eg, ventriculoperitoneal shunts) is a significant component of therapy in candidal meningitis associated with neurosurgical procedures.
  
  
  
  • S schenckii
    • Amphotericin B is the treatment of choice.

    • Using itraconazole to achieve lifelong suppression may be attempted after initial therapy with amphotericin B.

    • Fluconazole has less anti-Sporothrix activity compared to itraconazole.

    • The duration of treatment in AIDS-related cases is life long.

• Tuberculous meningitis
  • Depending on the resistance pattern in the community and the results of susceptibility testing (once available), always treat tuberculous meningitis with a combination of drugs.

  • Isoniazid (INH) and pyrazinamide (PZA) attain good CSF levels (approximate blood levels). Rifampin (RIF) penetrates the BBB less efficiently but still attains adequate CSF levels.

  • The use of a combination of the first-line drugs (ie, INH, RIF, PZA, ethambutol, streptomycin) is advocated. The dosage is similar to what is used for pulmonary tuberculosis (ie, INH 300 mg qd, RIF 600 mg qd, PZA 15-30 mg/kg qd, ethambutol 15-25 mg/kg qd, streptomycin 7.5 mg/kg q12h).

  • Evidence regarding the appropriate duration of treatment is conflicting. A treatment duration of 12 months is the minimum, and some experts suggest a duration of at least 2 years.

  • The use of corticosteroids is indicated for individuals with stage 2 or stage 3 disease (ie, patients with evidence of neurologic deficits or changes in their mental function). The recommended dose is 60-80 mg/d, which may be tapered gradually during a span of 6 weeks. The rationale lies in the reduction of inflammatory effects associated with mycobacterial killing by the antimicrobial agents.

• Spirochetal meningitis
  • Syphilitic meningitis
    • The treatment of choice for neurosyphilis requires the parenteral administration of aqueous crystalline penicillin G (2-4 million U/d IV q4h) for 10-14 days, often followed with intramuscular (IM) benzathine penicillin G (2.4 million U).

    • Alternatively, administer procaine penicillin G (2.4 million U/d IM) plus probenecid (500 mg PO qid) for 14 days, followed by IM benzathine penicillin G (2.4 million U).

    • Patients with HIV who have neurosyphilis are treated similarly.

    • Repeat CSF examination is performed regularly (eg, every 6 mo) following treatment to document the success of therapy. Failure of the cell count to normalize or the serologic titers to fall may warrant re-treatment.

    • Because penicillin G is considered the medical treatment of choice, patients who are allergic to penicillin should undergo penicillin desensitization in order to receive optimal treatment.

  • Lyme meningitis
    • Neurologic complications of Lyme disease (other than Bell palsy) ideally require parenteral antibiotic administration.

    • The drug of choice is ceftriaxone (2 g/d) for 14-28 days. The alternative therapy is penicillin G (20 million U/d) for 14-28 days.

    • Doxycycline (100 mg PO/IV bid) for 14-28 days or chloramphenicol (1 g qid) for 14-28 days has also been used.

• Parasitic meningitis
  • Primary amebic meningoencephalitis caused by N fowleri is usually fatal. The few survivors reported in the scientific literature have benefited from early diagnosis and treatment with high-dose intravenous and intrathecal amphotericin B or miconazole and rifampin.



• The treatment for helminthic (ie, A cantonensis, G spinigerum) eosinophilic meningitis has largely been supportive in nature. This includes adequate analgesia, therapeutic CSF aspiration, and the use of anti-inflammatory agents such as corticosteroids. The use of antihelminthic therapy may be contraindicated because clinical deterioration and death may occur following severe inflammatory reactions to the dying worms.

Surgical Care:

• In certain cases of increased ICP, repeated lumbar puncture or the insertion of a ventricular drain may be necessary to relieve the effects of increased ICP.



• Consultations with neurosurgical service may be needed when a skull fracture is suspected or an abscess formation is demonstrated.

Consultations:

• Consultation with an infectious diseases specialist



• Consultation with a neurosurgeon in cases of severe intracranial hypertension, suspicion of basilar skull fracture, and abscess formation

Diet: No strict dietary restriction is necessary. To diminish the risks of aspiration, nothing by mouth is recommended for patients with altered levels of consciousness.

MEDICATION

Section 7 of 11

This section discusses antimicrobials commonly used to treat meningitis. Antimicrobials recommended for specific pathogens are discussed in Medical Care.

Drug Category: Antimicrobial agents -- Treat or prevent infection caused by the most likely pathogen suspected or identified.

Drug Name	Ceftriaxone (Rocephin) -- Third-generation cephalosporin with broad-spectrum gram-negative activity. Lower efficacy against gram-positive organisms but excellent activity against susceptible pneumococcal organisms. Exerts antimicrobial effect by interfering with synthesis of peptidoglycan, a major structural component of bacterial cell wall. Excellent antibiotic for empiric treatment of bacterial meningitis.
Adult Dose	2 g IV q24h
Pediatric Dose	75 mg/kg IV followed by 100 mg/kg/d IV divided bid; not to exceed 4 g/d
Contraindications	Documented hypersensitivity; neonates with hyperbilirubinemia caused by increased risk of kernicterus
Interactions	Probenecid may increase levels by decreasing its elimination half-life; coadministration with ethacrynic acid, furosemide, and aminoglycosides may increase nephrotoxicity
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in renal impairment; caution in breastfeeding women and people with penicillin allergy; caution in gallbladder, biliary tract, liver, or pancreatic disease

Drug Name	Cefotaxime (Claforan) -- Third-generation cephalosporin used to treat suspected or documented bacterial meningitis caused by susceptible organisms such as H influenzae or N meningitides. Like other beta-lactam antibiotics, inhibits bacterial growth by arresting bacterial cell wall synthesis.
Adult Dose	2-3 g IV q4-6h; not to exceed 12 g/d
Pediatric Dose	<12 years: 200 mg/kg/d IV divided q6h; not to exceed 12 g/d >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Probenecid may increase levels by prolonging its half-life; coadministration with furosemide and aminoglycosides may increase nephrotoxicity
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in severe renal impairment; has been associated with severe antibiotic-associated pseudomembranous colitis; may cause transient neutropenia and thrombocytopenia; may cause transient elevation in liver enzymes; caution in penicillin allergy

Drug Name	Penicillin G (Pfizerpen) -- Beta-lactam antibiotic. Inhibits bacterial cell wall synthesis, resulting in bactericidal activity against susceptible microorganisms. Active against many gram-positive organisms. DOC for syphilitic meningitis and susceptible organisms (eg, N meningitides, penicillin-susceptible S pneumoniae).
Adult Dose	Up to 24 million U/d IV divided q4h or as continuous IV infusion
Pediatric Dose	100,000-400,000 U/kg/d IV divided q4h; not to exceed 24 million U/d
Contraindications	Documented hypersensitivity
Interactions	Probenecid can increase effects; coadministration of tetracyclines can decrease effects
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in impaired renal function, seizure disorder, and hypersensitivity to cephalosporins

Drug Name	Vancomycin (Vancocin) -- Glycopeptide antibiotic active against staphylococci, streptococci, and other gram-positive bacteria. Exerts antibacterial activity by inhibiting biosynthesis of peptidoglycan. DOC for highly penicillin-resistant and ceftriaxone-resistant S pneumoniae and methicillin-resistant S aureus. Component of empiric DOC for CNS-shunt–associated meningitis. Because of poor CSF penetration, higher dose is required for meningitis than for other infections. Use CrCl to adjust dose in renal impairment.
Adult Dose	Meningitis: 1 g IV q8h; adjust dose based on measured peak and trough levels, which are dependent on body weight and renal clearance Nonmeningitis infections: 15-30 mg/kg/d IV in divided doses
Pediatric Dose	40 mg/kg/d IV divided qid
Contraindications	Documented hypersensitivity; history of severe hearing loss
Interactions	Erythema, histaminelike flushing, and anaphylactic reactions may occur when administered with anesthetic agents; when taken concurrently with aminoglycosides, risk of nephrotoxicity may increase above that with aminoglycoside monotherapy; effects in neuromuscular blockade may be enhanced when coadministered with nondepolarizing muscle relaxants
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in renal failure and neutropenia; red man syndrome is caused by IV infusion that is too rapid (dose administered over a few min) but rarely occurs when dose is administered as a 2-h administration or as PO or IP administration; red man syndrome is not an allergic reaction

Drug Name	Ampicillin (Omnipen, Polycillin) -- Bactericidal beta-lactam antibiotic that inhibits cell wall synthesis by interfering with peptidoglycan formation. Indicated for L monocytogenes and S agalactiae meningitis, usually in combination with gentamicin.
Adult Dose	12 g/d IV divided q3-4h
Pediatric Dose	200 mg/kg/d IV divided q4-6h; not to exceed 12 g/d
Contraindications	Documented hypersensitivity
Interactions	Probenecid and disulfiram elevate levels; allopurinol decreases effects and has additive effects on ampicillin rash; may decrease effects of PO contraceptives
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in renal failure; evaluate rash and differentiate from hypersensitivity reaction

Drug Name	Gentamicin (Garamycin) -- Newer antibiotics are available, but aminoglycosides remain significant in treating severe infections. Aminoglycosides inhibit protein synthesis by irreversibly binding to 30s ribosome. In meningitis or gram-negative meningitides, administer intrathecally because of poor CNS penetration. Dosing regimens are numerous; adjust dose based on CrCl and changes in volume of distribution.
Adult Dose	Serious infections and normal renal function: 3 mg/kg/d IV q8h Loading dose: 1-2.5 mg/kg IV Maintenance: 1-1.5 mg/kg IV q8h Extended dosing regimen for life-threatening infections: 5 mg/kg/d IV/IM q6-8h Follow each regimen by at least a trough level drawn on the third or fourth dose (0.5 h before dosing); may draw a peak level 0.5 h after 30-min infusion
Pediatric Dose	<5 years: 2.5 mg/kg/dose IV/IM q8h >5 years: 1.5-2.5 mg/kg/dose IV/IM q8h or 6-7.5 mg/kg/d divided q8h; not to exceed 300 mg/d; monitor as in adults
Contraindications	Documented hypersensitivity; non–dialysis-dependent renal insufficiency
Interactions	Coadministration with other aminoglycosides, cephalosporins, penicillins, and amphotericin B may increase nephrotoxicity; aminoglycosides enhance effects of neuromuscular blocking agents, thus, prolonged respiratory depression may occur; coadministration with loop diuretics may increase auditory toxicity of aminoglycosides; possible irreversible hearing loss of varying degrees may occur (monitor regularly)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Narrow therapeutic index (not intended for long-term therapy); caution in renal failure (not on dialysis), myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission; adjust dose in renal impairment

Drug Category: Antiviral agents -- Interfere with viral replication; weaken or abolish viral activity.

Drug Name	Acyclovir (Zovirax) -- Prodrug activated by cellular enzymes. Inhibits activity of HSV-1, HSV-2, and varicella zoster virus by competing for viral DNA polymerase and incorporation into viral DNA. Used in HSV meningitis.
Adult Dose	1500 mg/m2/d or 10 mg/kg IV q8h for 14-28 d (encephalitis caused by HSV)
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Concomitant use of probenecid or zidovudine prolongs half-life and increases CNS toxicity
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in renal failure or when using nephrotoxic drugs, can precipitate in renal tubules; may cause delirium, lethargy, and seizures

Drug Name	Ganciclovir (Cytovene) -- Synthetic guanine derivative active against CMV. An acyclic nucleoside analog of 2'-deoxyguanosine that inhibits replication of herpes viruses both in vitro and in vivo. Levels of ganciclovir-triphosphate are as much as 100-fold greater in CMV-infected cells than in uninfected cells, possibly because of preferential phosphorylation of ganciclovir in virus-infected cells.
Adult Dose	Induction: 5 mg/kg IV over 1 h q12h for 14-21 d (do not use PO ganciclovir for induction treatment) Maintenance PO: 500 mg q4h or 1 g tid for life Maintenance IV: 5 mg/kg qd for 5-7 d/wk
Pediatric Dose	<3 months: Not established >3 months: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Concomitant administration with cytotoxic drugs, such as dapsone, vinblastine, Adriamycin, pentamidine, flucytosine, vincristine, amphotericin B, TMP/SMX combinations, or other nucleoside analogs, may result in additive toxicity in bone marrow, spermatogonia, and germinal layers of skin and GI mucosa (coadminister only if potential benefits outweigh risks); coadministration with imipenem and cilastatin may cause generalized seizures (use only if potential benefits outweigh risks); serum creatinine may increase following concurrent use with either cyclosporine or amphotericin B; in the presence of probenecid, ganciclovir renal clearance is reduced; bioavailability may increase when didanosine is administered either 2 h prior to or simultaneously with ganciclovir; bioavailability may decrease in the presence of zidovudine, while bioavailability of zidovudine is increased in the presence of ganciclovir
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Clinical toxicity includes granulocytopenia, anemia, and thrombocytopenia; half-life and plasma/serum concentrations may be increased as a result of reduced renal clearance; dosages > 6 mg/kg IV may result in increased toxicity; rapid infusions may result in increased toxicity; initially, reconstituted solutions of IV ganciclovir have a high pH (11); phlebitis or pain may occur at site of IV infusion despite further dilution in IV fluids; should be accompanied by adequate hydration; photosensitization (ie, photoallergy, phototoxicity) may occur

Drug Category: Antifungal agents -- Management of infectious diseases caused by fungi.

Drug Name	Amphotericin B, conventional (Amphocin, Fungizone) -- Polyene antibiotic produced by a strain of S nodosus; can be fungistatic or fungicidal. Binds to sterols, such as ergosterol, in the fungal cell membrane, causing intracellular components to leak with subsequent fungal cell death. Used to treat severe systemic infection and meningitis caused by susceptible fungi (ie, C albicans, H capsulatum, C neoformans). Also available in liposomal (AmBisome) and lipid-complex (Abelcet) formulations. Amphotericin B does not penetrate the CSF well. Intrathecal amphotericin may be needed in addition.
Adult Dose	Conventional: 0.7-1.0 mg/kg/d IV infusion; not to exceed 1.5 mg/kg/d Liposomal: 3-5 mg/kg/d IV infusion Lipid-complex: 5 mg/kg/d IV infusion
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Antineoplastic agents may enhance the potential of amphotericin B for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; the risk of renal toxicity is increased with cyclosporine
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in renal insufficiency, monitor renal function, serum electrolytes (eg, magnesium, potassium), liver function, CBC count, and hemoglobin concentrations; resume therapy at lowest level (eg, 0.25 mg/kg) when therapy is interrupted for longer than 7 d; hypoxemia, acute dyspnea, and interstitial infiltrates may occur in patients with neutropenia who are receiving leukocyte transfusions (separate time of amphotericin infusion from time of leukocyte transfusion); fever and chills are not uncommon after first few administrations of drug; rare acute reactions may include hypotension, bronchospasm, arrhythmias, and shock

Drug Name	Fluconazole (Diflucan) -- Fungistatic activity. Synthetic PO antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes.
Adult Dose	200-800 mg PO qd; not to exceed 1000 mg/d
Pediatric Dose	3-6 mg/kg PO qd for 14-28 d or 6-12 mg/kg qd depending on severity of infection
Contraindications	Documented hypersensitivity
Interactions	Levels may increase with hydrochlorothiazides; fluconazole levels may decrease with long-term coadministration of rifampin; may increase concentrations of theophylline,