Medication Summary
Begin empiric antibiotic coverage according to age and presence of overriding physical conditions. Empiric therapy also depends on prevalence of cephalosporin-resistant S pneumoniae (DRSP). In the United States, prevalence is considered high (>2-5%). Patients with severe penicillin (and presumed cephalosporin) allergies often require alternative therapy.
Antimicrobial Agents
Class Summary
These agents are used to treat or prevent infection caused by the most likely pathogen suspected or identified.
Ceftriaxone (Rocephin)
Ceftriaxone is a third-generation cephalosporin with broad-spectrum gram-negative activity. It has lower efficacy against gram-positive organisms but has excellent activity against susceptible pneumococcal organisms. It exerts an antimicrobial effect by interfering with the synthesis of peptidoglycan, a major structural component of the bacterial cell wall. It is an excellent antibiotic for the empiric treatment of bacterial meningitis.
Ceftazidime (Ceptaz, Fortaz)
Ceftazidime is a third-generation cephalosporin with broad-spectrum activity against gram-negative organisms, lower efficacy against gram-positive organisms, and higher efficacy against resistant organisms. By binding to 1 or more of the penicillin-binding proteins, it arrests bacterial cell wall synthesis and inhibits bacterial replication.
Cefotaxime (Claforan)
Cefotaxime is a third-generation cephalosporin that is used to treat suspected or documented bacterial meningitis caused by susceptible organisms, such as H influenzae or N meningitidis. Like other beta-lactam antibiotics, cefotaxime inhibits bacterial growth by arresting bacterial cell wall synthesis.
Penicillin G (Pfizerpen)
A beta-lactam antibiotic, penicillin G inhibits bacterial cell wall synthesis, resulting in bactericidal activity against susceptible microorganisms. It is active against many gram-positive organisms and is the DOC for syphilitic meningitis and susceptible organisms (eg, N meningitidis, penicillin-susceptible S pneumoniae).
Ampicillin (Omnipen, Polycillin)
A bactericidal beta-lactam antibiotic, ampicillin inhibits cell wall synthesis by interfering with peptidoglycan formation. The drug is indicated for L monocytogenes and S agalactiae meningitis, usually in combination with gentamicin.
Vancomycin (Vancocin)
Vancomycin is a glycopeptide antibiotic that is active against staphylococci, streptococci, and other gram-positive bacteria. It exerts antibacterial activity by inhibiting biosynthesis of peptidoglycan and is the DOC for highly penicillin-resistant and ceftriaxone-resistant S pneumoniae and methicillin-resistant S aureus. It is a component of empiric DOC for CNS-shunt–associated meningitis. Because of poor CSF penetration, a higher dose of vancomycin is required for meningitis than for other infections. Use CrCl to adjust the dose in renal impairment.
Gentamicin (Garamycin)
Newer antibiotics are available, but aminoglycosides, such as gentamicin, 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 the dose based on CrCl and changes in the volume of distribution.
Chloramphenicol (Chloromycetin)
Chloramphenicol binds to 50 S bacterial-ribosomal subunits and inhibits bacterial replication by inhibiting protein synthesis. It is effective against gram-negative and gram-positive bacteria.
Trimethoprim/sulfamethoxazole (Bactrim, Bactrim DS)
Trimethoprim/sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid, inhibiting folic acid synthesis. This results in inhibition of bacterial replication.
Meropenem (Merrem)
A broad-spectrum carbapenem antibiotic, meropenem inhibits cell wall synthesis and has bactericidal activity. It is effective against most gram-positive and gram-negative bacteria. Meropenem has slightly increased activity against gram-negative organisms and slightly decreased activity against staphylococci and streptococci compared with imipenem.
Doxycycline (Doryx, Bio-Tab)
Doxycycline inhibits protein synthesis and, therefore, bacterial growth by binding with 30S and possibly 50S ribosomal subunits of susceptible bacteria.
Ciprofloxacin (Cipro)
Ciprofloxacin is a fluoroquinolone that inhibits bacterial DNA synthesis and, consequently, growth by inhibiting DNA gyrase and topoisomerases, which are required for replication, transcription, and translation of genetic material. Quinolones have broad activity against gram-positive and gram-negative aerobic organisms. Ciprofloxacin has no activity against anaerobes. Continue treatment for at least 2 days (7-14 d typical) after signs and symptoms have disappeared.
Clindamycin (Cleocin)
Clindamycin is a semisynthetic antibiotic produced by a 7(S)-chloro-substitution of 7(R)-hydroxyl group of the parent compound lincomycin. It inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. It widely distributes in the body without penetration of the CNS. Clindamycin is protein bound and excreted by the liver and kidneys. It is effective against gram-positive aerobic and anaerobic bacteria (except enterococci).
Antiviral Agents
Class Summary
These agents interfere with viral replication; they weaken or abolish viral activity.
Acyclovir (Zovirax)
A prodrug activated by cellular enzymes, acyclovir inhibits the activity of HSV-1, HSV-2, and varicella-zoster virus by competing for viral DNA polymerase and incorporation into viral DNA. Acyclovir is used in HSV meningitis.
Ganciclovir (Cytovene)
Ganciclovir is a synthetic guanine derivative active against CMV. An acyclic nucleoside analog of 2'-deoxyguanosine, it inhibits the replication of herpes viruses 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.
Foscarnet
Foscarnet is an organic analog of inorganic pyrophosphate that inhibits the replication of known herpesviruses, including CMV, HSV-1, and HSV-2. It inhibits viral replication at the pyrophosphate-binding site on virus-specific DNA polymerases. Foscarnet is used to treat CMV meningitis in immunocompromised hosts at induction doses of 60 mg/kg IV q8h and maintenance doses of 90-120 mg/kg IV q24h.
Antifungal Agents
Class Summary
These agents are used in the management of infectious diseases caused by fungi.
Amphotericin B, conventional (Amphocin, Fungizone)
A polyene antibiotic produced by a strain of S nodosus, this drug can be fungistatic or fungicidal. It binds to sterols, such as ergosterol, in the fungal cell membrane, causing intracellular components to leak with subsequent fungal cell death. The drug is used to treat severe systemic infection and meningitis caused by susceptible fungi (ie, C albicans, H capsulatum, C neoformans). It is 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.
Fluconazole (Diflucan)
Fluconazole has fungistatic activity. It is a 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.
Flucytosine (Ancobon)
Flucytosine is converted to fluorouracil after penetrating fungal cells and inhibits RNA and protein synthesis. It is active against candidal and cryptococcal species and is used in combination with amphotericin B.
Itraconazole (Sporanox)
Itraconazole has fungistatic activity. It is a synthetic triazole antifungal agent that slows fungal cell growth by inhibiting cytochrome P-450-dependent synthesis of ergosterol, a vital component of fungal cell membranes.
Antitubercular Agents
Class Summary
These agents are used in the management of mycobacterial disease in combination with other antitubercular agents.
Rifampin (Rifadin, Rimactane)
Rifampin is used in combination with other antituberculous drugs. It inhibits DNA-dependent bacterial, but not mammalian, RNA polymerase. Cross-resistance may occur.
Isoniazid (Laniazid, Nydrazid)
Isoniazid is a first-line antituberculous drug that is used in combination with other antituberculous drugs to treat meningitis. It is usually administered for at least 12-24 months. A prophylactic dose of pyridoxine (6-50 mg/d) is recommended if peripheral neuropathies secondary to isoniazid therapy develop.
Pyrazinamide (PZA)
Pyrazinamide is a pyrazine analog of nicotinamide; it may be bacteriostatic or bactericidal against M tuberculosis, depending on the drug concentration attained at the site of infection. Pyrazinamide's mechanism of action is unknown.
Ethambutol (Myambutol)
Ethambutol diffuses into actively growing mycobacterial cells (eg, tubercle bacilli). It impairs cell metabolism by inhibiting the synthesis of 1 or more metabolites, which in turn causes cell death. No cross-resistance has been demonstrated. Mycobacterial resistance is frequent with previous therapy. Use in these patients in combination with second-line drugs that have not been administered previously. Administer every 24 hours until permanent bacteriological conversion and maximal clinical improvement is observed. Absorption is not significantly altered by food.
Streptomycin
Streptomycin has bactericidal action and inhibits bacterial protein synthesis. Susceptible organisms include M tuberculosis, Pasteurella pestis, Pasteurella tularensis, H influenzae, Haemophilus ducreyi, donovanosis (granuloma inguinale), Brucella species, Klebsiella pneumonia, Escherichia coli, Proteus species, Aerobacter species, Enterococcus faecalis, and Streptococcus viridans (in endocarditis, with penicillin). Streptomycin is always given as part of total anti-TB regimen.
Vaccines
Class Summary
These agents are used to induce active immunity against pathogens responsible for meningitis.
Meningitis group A C Y and W-135 vaccine (Groups A/C/Y/W-135)
This vaccine is composed of capsular polysaccharide antigens (groups A, C, Y, and W-135) of Neisseria meningitidis. Meningococcal vaccine may be used to prevent and control outbreaks of serogroup C meningococcal disease according to CDC guidelines. It induces formation of bactericidal antibodies to meningococcal antigens. The vaccine is used for active immunization against invasive meningococcal disease caused by inclusive serogroups. Although the vaccine induces antibody response for serogroup A in individuals as young as age 3 months, it is poorly immunogenic for serogroup C in recipients who are younger than age 18-24 months.
Pneumococcal vaccine polyvalent
This vaccine contains capsular polysaccharides of 23 pneumococcal types, which constitute 98% of pneumococcal disease isolates.
Corticosteroids
Class Summary
The use of steroids has been shown to improve the overall outcome of patients with certain types of bacterial meningitis, such as H influenzae, tuberculous, and pneumococcal meningitis. If steroids are given, they should be administered prior to or during the administration of antimicrobial therapy.
Dexamethasone
Dexamethasone has many pharmacologic benefits such as stabilizing cell and lysosomal membranes. It increases surfactant synthesis, increases serum vitamin A concentrations, inhibits prostaglandin and proinflammatory cytokines (eg, TNF-alpha, IL-6, IL-2, and IFN-gamma). 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.
Diuretic Agents
Class Summary
These agents are used to reduce intracranial pressure and treat cerebral edema.
Furosemide (Lasix)
Furosemide is a loop diuretic that increases the excretion of water by interfering with the chloride-binding co-transport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and distal renal tubule. The proposed mechanism for furosemide in lowering intracranial pressure include (1) lowering cerebral sodium uptake, (2) affecting water transport into astroglial cells by inhibiting the cellular membrane cation-chloride pump, and (3) decreasing cerebrospinal fluid production by inhibiting carbonic anhydrase.
Mannitol (Osmitrol)
Mannitol may reduce subarachnoid-space pressure by creating an osmotic gradient between cerebrospinal fluid in arachnoid-space and plasma. Doses of 1 g/kg IV have been used.
Anticonvulsants
Class Summary
Anticonvulsants help to aggressively control seizures if present in acute meningitis, because seizure activity increases intracranial pressure.
Lorazepam (Ativan)
Lorazepam is a sedative hypnotic with a short onset of effect and a relatively long half-life. By increasing the action of gamma-aminobutyric acid (GABA), which is a major inhibitory neurotransmitter in the brain, it may depress all levels of the CNS, including limbic and reticular formation. Doses of lorazepam 0.1 mg/kg IV have been used to control seizures.
Phenytoin (Dilantin)
Phenytoin works on the motor cortex, where it may inhibit the spread of seizure activity. The activity of brain stem centers responsible for the tonic phase of grand mal seizures may also be inhibited. Doses should be individualized. Doses of 15 mg/kg have been used.
Phenobarbital
Phenobarbital elevates the seizure threshold, limits the spread of seizure activity, is a sedative. Doses of 5-10 mg/kg have been recommended.
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[Best Evidence] Dubos F, Korczowski B, Aygun DA, Martinot A, Prat C, Galetto-Lacour A, et al. Serum procalcitonin level and other biological markers to distinguish between bacterial and aseptic meningitis in children: a European multicenter case cohort study. Arch Pediatr Adolesc Med. Dec 2008;162(12):1157-63. [Medline].
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- Table 1. Infectious Agents Causing Aseptic Meningitis Syndrome
- Table 2. Causes of Chronic Meningitis
- Table 3. Changing Epidemiology of Acute Bacterial Meningitis in the United States*
- Table 4. The Most Common Bacterial Pathogens Based on Age and Predisposing Risks
- Table 5. CSF Picture of Meningitis According to Etiologic Agent
- Table 6. Comparison of CSF Findings by Type of Organism
- Table 7. Recommended Empiric Antibiotics According to Predisposing Factors for Patients With Suspected Bacterial Meningitis
- Table 8. Recommended Empiric Antibiotics for Patients With Suspected Bacterial Meningitis and Known CSF Gram Stain Results
- Table 9. Specific Antibiotics and Duration of Therapy for Patients With Acute Bacterial Meningitis
| Category | Agent |
| Bacteria | Partially-treated bacterial meningitis L monocytogenes Brucella species Rickettsia rickettsii Ehrlichia species Mycoplasma pneumoniae Borrelia 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 Blastomyces 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 **Lymphocytic choriomeningitis ***Human immunodeficiency virus | |
| 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 |
| Bacteria | 1978-1981 | 1986 | 1995 | 1998-2007 | |
| H influenzae | 48% | 45% | 7% | 6.7% | |
| Listeria monocytogenes | 2% | 3% | 8% | 3.4% | |
| N meningitidis | 20% | 14% | 25% | 13.9% | |
| S agalactiae | 3% | 6% | 12% | 18.1% | |
| S pneumoniae | 13% | 18% | 47% | 58% | |
| *Nosocomial meningitis is not included. These data include only the 5 major meningeal pathogens. | |||||
| Risk and/or Predisposing Factor | Bacterial Pathogen |
| Age 0-4 weeks | Streptococcus agalactiae (group B streptococci) E coli K1 Listeria 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 P aeruginosa |
| Basilar skull fracture | S pneumoniae H influenzae Group A streptococci |
| CSF shunts | Coagulase-negative staphylococci S aureus Aerobic gram-negative bacilli Propionibacterium acnes |
| Agent | Opening Pressure | WBC count per µL | 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 | Viral Meningitis* | Fungal Meningitis** | |
| Pressure 5-15 cm H2 O | Increased | Normal or mildly increased | Normal or mildly increased in TB. May be increased in fungal. AIDS patients with cryptococcal meningitis have increased risk of blindness, death unless maintained at < 30 cm. |
| Cell count preterm: 0-25 term: 0-22 >6 months: 0-5 mononuclear cells/mm3 | No cell count result can exclude bacterial meningitis. Typically thousands of PMNs, but may be less dramatic or even normal (classically, in very early meningococcal meningitis and in extremely ill neonates). Lymphocytosis with normal CSF chemistries seen in 15-25%, especially when cell counts < 1000 or if partially treated. Approximately 90% of patients with ventriculoperitoneal shunts have CSF WBC count >100 cells/mm3 are infected; CSF glucose usually normal, and organisms are less pathogenic. Cell count and chemistries normalize slowly (over days) with antibiotics. | Usually < 500 cells, nearly 100% mononuclear. Up to 48 hours, significant PMN pleocytosis may be indistinguishable from early bacterial meningitis; this is particularly true with eastern equine encephalitis. Presence of nontraumatic RBCs in 80% of HSV meningoencephalitis, although 10% have normal CSF results | Hundreds of mononuclear cells |
| Micro no organisms | Gram stain 80% sensitive. Inadequate decolorization may mistake H influenzae for gram-positive cocci. Pretreatment with antibiotics may affect stain uptake, causing gram-positive organisms to appear gram negative and decrease culture yield on average 20%. | No organism | India ink 80-90% sensitive for fungi; AFB stain 40% sensitive for TB (increase yield by staining supernate from at least 5 cc CSF) |
| Glucose euglycemia: >50% serum hyperglycemia: >30% serum wait 4 h after glucose load | Decreased | Normal | Sometimes decreased. Aside from fulminant bacterial meningitis, the lowest levels of CSF glucose are seen in TB, primary amebic meningoencephalitis, neurocysticercosis |
| Protein preterm: 65-150 term: 20-170 >6 months: 15-45 mg/dL | Usually >150, may be >1000 | Mildly increased | Increased; >1000 with relatively benign clinical presentation suggestive of fungal disease |
| *Some bacteria (eg, Mycoplasma, Listeria, Leptospira species, Borrelia burgdorferi [Lyme], spirochetes) produce spinal fluid alterations that resemble the viral profile. An aseptic profile also is typical of partially treated bacterial infections (more than 33% of patients have received antimicrobial treatment, especially children) and the 2 most common causes of encephalitis — the potentially curable HSV and arboviruses. **In contrast, tuberculous meningitis and parasites resemble the fungal profile more closely. | |||
| 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* |
| 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. | |
| 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). | |
| 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 | Beta-lactamase-negative | Ampicillin | 7 |
| Beta-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 |
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