If S.C. had experienced an accelerated

reaction to penicillin, vancomycin plus aztreonam, or meropenem would be the best

alternative choice (Table 65-5).

11

DOSING CONSIDERATIONS

In general, therapy of meningitis requires the use of high dosages of antimicrobials

administered by the IV route. Table 65-6 lists the recommended dosing regimens for

the treatment of CNS infections. S.C. should receive ceftriaxone in a dosage of 100

mg/kg/day given in one or two doses. A ceftriaxone regimen of 1,000 mg IV Q 12

hours is reasonable for S.C.

ADJUNCTIVE CORTICOSTEROID THERAPY

CASE 65-1, QUESTION 4: What is the rationale for adjunctive corticosteroid therapy in acute bacterial

meningitis, and would it be appropriate for S.C.? How should dexamethasone be dosed and monitored for S.C.?

Corticosteroids, particularly dexamethasone, can reduce cerebral edema and

lower intracranial pressure.

39

In addition, corticosteroids reduce the synthesis and

release of the proinflammatory cytokines TNF-α and IL-1β from monocytes and

astrocytes. These two cytokines play a central role in initiating the cascade of events

that lead to neuronal tissue damage and neurologic sequelae.

40 Theoretically, then,

inhibition of cytokine synthesis by corticosteroids in meningitis should lead to a

decreased risk of hearing loss and other neurologic sequelae. Indeed, a prospective,

randomized, double-blind multicenter trial evaluating the use of dexamethasone in

adults with acute bacterial meningitis supported this theory.

41 A total of 301 patients

were randomized to receive dexamethasone or placebo 15 to 20 minutes before or

with the first dose of antibiotic every 6 hours for 4 days. Dexamethasone reduced the

risk of unfavorable outcome, defined as a Glasgow Coma Scale score of 1 to 4 at 8

weeks (relative risk, 0.59; P = 0.03), and of death (relative risk, 0.48; P = 0.04).

When the outcomes were analyzed based upon culture results, mortality reduction (14

vs. 34 percent) and all unfavorable outcomes (26 vs. 52 percent) were only seen with

dexamethasone therapy in patients with meningitis caused by Streptococcus

pneumoniae. Outcomes in patients with meningitis caused by organisms other than S.

pneumoniae were independent of whether they received dexamethasone or not.

Neither GI bleeding nor other adverse effects were increased in the dexamethasone

group.

In children, several studies have also evaluated the role of adjunctive

dexamethasone therapy in bacterial meningitis. Some prospective placebocontrolled, randomized trials have demonstrated that adjunctive dexamethasone

therapy significantly reduces audiologic and neurologic sequelae in children >2

months of age. H. influenzae, however, was the causative pathogen in most of these

meningitis cases, whereas the number of children with streptococcal and

meningococcal meningitis in these trials was small.

2

,

42–46 As previously mentioned,

the number of Hib cases has decreased dramatically, making the data from these

trials difficult to apply to the present day. More recently, of the 166 patients enrolled

in a trial comparing dexamethasone to placebo, 35 and 26 cases were caused by S.

pneumoniae and N. meningitides, respectively, in the treatment arm. Fewer

audiologic and neurologic sequelae were observed in the dexamethasone-treated

group compared with the placebo group, but the difference did not reach statistical

significance.

47

Most recently, a 2013 Cochrane meta-analysis evaluated data from 25 randomized

trials that included over 4,000 children and adults. In the overall population,

glucocorticoid administration did not significantly reduce mortality. However,

glucocorticoids did reduce mortality in the subgroup of patients with meningitis

caused by S. pneumoniae (RR, 0.84; 95% CI, 0.72–0.98). In studies conducted in

high-income countries, glucocorticoids reduced severe hearing loss (RR, 0.51; 95%

CI, 0.35–0.73), any hearing loss (RR, 0.58; 95% CI, 0.45–0.73), and short-term

neurologic sequelae (RR, 0.64; 95% CI, 0.48–0.85). In the subgroup of over 2,000

children, the administration of dexamethasone did not affect mortality but did reduce

the incidence of severe hearing loss, particularly in those with H. influenzae

meningitis.

48

The 2004 IDSA meningitis guidelines recommend that dexamethasone be initiated

prior to (or concomitant with the first dose of) antimicrobial therapy in all adult

patients with suspected or proven pneumococcal meningitis.

11 Controversy remains

over whether dexamethasone should be continued in adults if the causative agent is

found not to be pneumococcus because the number of patients in the studies with

meningitis caused by other organisms was small.

49 However, the guidelines do

recommend discontinuing dexamethasone if the organism is found to be something

other than S. pneumonia.

11 Regarding pediatrics, the American Academy of

Pediatrics (AAP) Committee on Infectious Diseases suggests that dexamethasone

therapy may be beneficial in children with Hib meningitis if given before or at the

same time as the first dose of antimicrobial therapy.

50 The AAP Committee on

Infectious Diseases also suggests that the decision to use adjunctive dexamethasone

therapy should be individualized but considered for infants and children older than 6

weeks with pneumococcal meningitis.

51 At this time, there can be no firm

recommendation as to whether steroids should be continued in children if the

pathogen is found not to be H. influenzae or S. pneumoniae.

p. 1372

p. 1373

Table 65-6

Suggested Antibiotic Dosing Regimens for Treatment of Central Nervous

System Infections

Daily Dose (interval in hours)

a

Neonates

Antibiotic 0–7 days old 8–28 days old

Infants and

Children Adults

Ampicillin 150 mg/kg (8) 200 mg/kg (6–8) 300 mg/kg (6) 12 g (4)

Aztreonam 8 g (6)

Nafcillin 75 mg/kg (8–12) 100–150 mg/kg (6–

8)

200 mg/kg (6) 12 g (4)

Penicillin G 0.15 mU/kg (8–12) 0.2 mU/kg (6–8) 0.3 mU/kg (4–6) 24 mU (4)

Meropenem 120 mg/kg (8) 6 g (8)

Cephalosporins

Cefotaxime 100–150 mg/kg (8–

12)

150–200 mg/kg (6–

8)

225–300 mg/kg (6–

8)

12 g (4)

Ceftriaxone 80–100 mg/kg (12–

24)

4 g (12)

Ceftazidime 100–150 mg/kg (8–

12)

150 mg/kg (8) 150 mg/kg (8) 6 g (8)

Cefepime 150 mg/kg (8) 6 g (8)

Aminoglycoside

b

,

c

Gentamicin 5 mg/kg (12) 7.5 mg/kg (8) 7.5 mg/kg (8) 5–7 mg/kg (8–24)

Tobramycin 5 mg/kg (12) 7.5 mg/kg (8) 7.5 mg/kg (8) 5–7 mg/kg (8–24)

Amikacin 15–20 mg/kg (12) 30 mg/kg (8) 20–30 mg/kg (8) 15 mg/kg (8–24)

Others

Moxifloxacin 400 mg (24)

Linezolid 1,200 mg (12)

Rifampin 10–20 mg/kg (12) 10–20 mg/kg (12-24) 600 mg (24)

TMP-SMX

d 10–20 mg/kg (6–12) 10–20 mg/kg (6–12)

Vancomycin

c

,

e 20–30 mg/kg (8–12) 30–45 mg/kg (6–8) 60 mg/kg (6) 30–45 mg/kg (8–12)

aRecommended daily dose when renal and hepatic functions are normal.

bConcurrent intraventricular doses of 5–10 mg (gentamicin, tobramycin) or 20 mg (amikacin) often required when

treating gram-negative bacillary meningitis.

cDose should be individualized based on serum level monitoring.

dDose is based on the trimethoprim component.

eConcurrent intraventricular doses of 5–20 mg recommended if response to IV therapy is inadequate.

Source: Tunkel AR et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis.

2004;39:1267.

Thus, S.C. should receive dexamethasone therapy, 0.15 mg/kg/dose given IV Q 6

hours for 2 to 4 days. For S.C., who is 20 kg, this would be 3 mg Q 6 hours, with the

first dexamethasone dose given 15 minutes before initiating ceftriaxone therapy.

Potential adverse effects associated with dexamethasone include GI bleeding,

mental status changes (e.g., euphoria or encephalopathy), increases in blood glucose,

and possibly elevations in blood pressure. For S.C., the complete blood count

(CBC), serum chemistries, and stool guaiac should be monitored daily while he is

receiving dexamethasone. He also should be questioned about possible GI upset and

assessed for changes in mental status (e.g., confusion, combativeness). Given the

short duration of corticosteroid therapy, dexamethasone can be discontinued abruptly

without tapering.

EFFECT ON CENTRAL NERVOUS SYSTEM PENETRATION OF

ANTIBIOTICS

Another important issue to consider is whether dexamethasone, a potent antiinflammatory agent, reduces the ability of antimicrobials to penetrate across the

blood–brain barrier into CSF. Because CSF penetration of the penicillins,

cephalosporins, and vancomycin is greatest when the meninges are inflamed, a

hypothetical concern is that concomitant dexamethasone may reduce CSF

concentrations of these agents, resulting in reduced efficacy. Early animal models

suggest that vancomycin penetration into the CSF is reduced in dexamethasonetreated animals compared with animals not treated with steroids.

52

In a rabbit

meningitis model, the coadministration of dexamethasone and vancomycin resulted in

29% less penetration of vancomycin into the CSF. By increasing the daily dose of

vancomycin in these rabbits, however, therapeutic CSF levels were achieved,

suggesting that giving larger daily doses of vancomycin circumvents the steroid effect

on CNS penetration.

53 Additionally, current human data suggest that CSF penetration

of vancomycin or ceftriaxone is not diminished with concomitant administration of

dexamethasone.

54–57 Based on these encouraging findings, it is recommended that

dexamethasone be utilized in all patients.

11

p. 1373

p. 1374

Neisseria meningitidis Meningitis

DEFINITIVE THERAPY

CASE 65-1, QUESTION 5: Twenty-four hours after admission, S.C.’s culture results from his blood and

CSF samples are available. The CSF culture is growing N. meningitidis (penicillin MIC, 0.06 mg/L), and N.

meningitidis is also growing in both of the two collected blood cultures. What modification in S.C.’s antimicrobial

therapy is necessary at this time?

Once culture and sensitivity results become available, definitive therapy can be

instituted, often with a single agent (Table 65-7).

11

,

36 As suspected, S.C.’s CSF

culture is positive for N. meningitidis. Cefuroxime, a second-generation

cephalosporin, has activity against N. meningitides; however, it is less effective for

meningitis than third-generation cephalosporins and should not be used.

58

,

59 The

reason for the inferiority of cefuroxime relative to ceftriaxone most likely is related

to reduced potency.

58

Because N. meningitidis is susceptible to penicillin and ampicillin currently,

penicillin is the drug of choice. However, S.C.’s questionable history of amoxicillin

rash makes the use of ceftriaxone a reasonable choice (See Table 65-6 for dosing).

MONITORING THERAPY

CASE 65-1, QUESTION 6: What subjective and objective data should be monitored to evaluate the efficacy

and toxicity of treatment of patients with meningitis, and what specifically should be monitored in S.C.?

Clinical signs and symptoms attributable to the disease, such as fever, altered

mental status, and stiff neck, should be checked periodically throughout the day and

monitored for resolution. S.C.’s temperature and mental status should be assessed

often. Accurate assessment of S.C.’s mental status can be difficult because of his

young age. Thus, his baseline level of mental status should be evaluated (e.g.,

whether he is awake and alert, or lethargic and difficult to arouse). If awake and

alert, S.C. should be observed for irritability, because this often is the only sign of

altered mentation. Questions can be used to assess his orientation: Does he know

where he is? Does he know his name? Can he recognize his mother or other family

members? In general, signs of clinical improvement should be evident within 24 to

48 hours for most uncomplicated cases of acute bacterial meningitis, with

defervescence of fever achieved in a mean of 3.3 days in one trial of cefotaxime in

children.

60

Laboratory tests should be monitored as well. A CBC with differential, serum

electrolytes (e.g., Na, K, Cl, HCO3

), blood glucose, and renal function tests (e.g.,

BUN, SrCr) should be performed daily. Abnormal electrolyte results may require

more frequent monitoring. Laboratory abnormalities, such as leukocytosis and

hyponatremia, may take longer to normalize than clinical symptoms. CSF chemistries

usually improve within 48 hours of starting therapy, although CSF WBC and protein

may remain elevated for a week or more.

61

,

62 With effective therapy, the CSF culture

usually is sterile after about 18 to 24 hours of therapy.

58

,

60 Delays in CSF sterilization

are associated with a higher propensity for neurologic complications.

58

If S.C.

responds to therapy in a straightforward manner, he need not to have a repeat lumbar

puncture. If the response is inadequate, as evidenced by persistent fever or

deteriorating mental status, S.C. will require a repeat lumbar puncture to re-examine

the CSF parameters.

11

Table 65-7

Definitive Therapy for Bacterial Meningitis

Pathogen Recommended Treatment Alternative Agents

Haemophilus influenzae

β-Lactamase negative Ampicillin Cefotaxime or ceftriaxone;

aztreonam

β-Lactamase positive Cefotaxime or ceftriaxone Aztreonam

Neisseria meningitidis Penicillin MIC < 0.1 mcg/mL:

penicillin G or ampicillin

Cefotaxime or ceftriaxone;

meropenem

Penicillin MIC 0.1- 1.0 mcg/mL:

cefotaxime or ceftriaxone

Streptococcus pneumoniae Penicillin MIC ≤ 0.06 mcg/mL:

penicillin G or ampicillin

Cefotaxime or ceftriaxone

Penicillin MIC ≥ 0.12 mcg/mL:

cefotaxime or ceftriaxone if

susceptible

Vancomycin or meropenem

Penicillin and

cefotaxime/ceftriaxone

nonsusceptible: vancomycin +

cefotaxime/ceftriaxone ± rifampin

Vancomycin + moxifloxacin

Streptococcus agalactiae Penicillin G or ampicillin +

gentamicin

Cefotaxime or ceftriaxone

Listeria monocytogenes Penicillin G or ampicillin ±

gentamicin

TMP-SMX or meropenem

Enterobacteriaceae

a

Escherichia coli, Klebsiella

species

Cefotaxime or ceftriaxone Cefepime; aztreonam; meropenem

Enterobacter, Serratia species Cefepime; meropenem TMP-SMX; aztreonam

Pseudomonas aeruginosa Cefepime or ceftazidime;

meropenem

Aztreonam

Staphylococcus aureus

a

Methicillin-susceptible (MSSA) Nafcillin or oxacillin Vancomycin ± rifampin;

meropenem

Methicillin-resistant (MRSA) Vancomycin± rifampin TMP-SMX; linezolid

Staphylococcus epidermidis

a Vancomycin ± rifampin TMP-SMX; linezolid

aConcomitant intrathecal therapy may be required for optimal response (most commonly an intrathecal

aminoglycoside for gram-negative or intrathecal vancomycin for gram-positive infections).

MIC, minimum inhibitory concentration; TMP-SMX, trimethoprim–sulfamethoxazole.

p. 1374

p. 1375

In addition to monitoring the therapeutic response, side effects of the antimicrobial

regimen also need to be assessed frequently. Meningitis requires high-dose therapy,

making the likelihood of adverse effects much greater. Currently, S.C. is being

treated with ceftriaxone. The adverse effects most often associated with ceftriaxone

include hypersensitivity reactions, mild pain and phlebitis at the injection site, and GI

complaints.

63 S.C. should be observed for the formation of an antibiotic-related skin

rash or evidence of an accelerated allergic reaction (e.g., hives, wheezing). The IV

catheter site should be observed daily for redness, tenderness, or pain on palpation

of the vein. S.C. should be watched closely for loose stools or diarrhea. Although

mild diarrhea is a common side effect of most antimicrobials that rarely requires a

change in therapy, diarrhea that is severe, persistent, or accompanied by fever,

unexplained leukocytosis, or abdominal cramping should prompt testing for C.

difficile colitis.

59

,

64

CEFTRIAXONE-INDUCED BILIARY PSEUDOLITHIASIS

CASE 65-1, QUESTION 7: After 5 days of treatment, the nurse caring for S.C. notes that his appetite is

markedly diminished, and he complains of an upset stomach. S.C. was afebrile and alert and oriented, but

abdominal examination revealed “guarding,” with pain localized in the right upper quadrant area. Laboratory

data at this time are as follows:

WBC count, 6,000 cells/μL

Hgb, 12.5 g/dL

Hct, 34%

Platelets, 120,000/μL

Na, 135 mEq/L

K, 3.6 mEq/L

Cl, 98 mEq/L

Aspartate aminotransferase (AST), 35 units/L

Alanine aminotransferase (ALT), 33 units/L

Alkaline phosphatase, 110 MU/dL

Total bilirubin, 1.2 mg/dL

Amylase 70 units/L

A stool guaiac is negative. What are possible causes of S.C.’s abdominal discomfort?

A number of possible causes exist for S.C.’s abdominal discomfort. His

corticosteroid therapy may have caused acute GI bleeding; however, the

dexamethasone was discontinued 3 days ago and S.C.’s hemoglobin and hematocrit

values are in the low-normal range. The negative stool guaiac result also argues

strongly against a GI bleed. Acute pancreatitis is unlikely given the normal amylase

result. Viral or drug-induced hepatitis is another possibility but also is unlikely given

his normal AST, ALT, and bilirubin results. An intra-abdominal infection also is

possible, but this is improbable because he is afebrile and has a normal WBC count.

Other causes, such as acute cholecystitis or appendicitis, require further diagnostic

evaluation.

CASE 65-1, QUESTION 8: An abdominal ultrasound reveals sludge in the gallbladder. What is the

significance of this finding in S.C., and how should this abnormality be managed?

The abnormality on S.C.’s abdominal ultrasound explains his right upper quadrant

pain. S.C. has what appears to be a condition known as biliary pseudolithiasis (i.e.,

biliary “sludging”). Biliary sludging can occur in conditions of gallbladder

hypomotility (e.g., recent surgery, burns, total parenteral nutrition) and, in some

instances, can be drug-induced. S.C. has been receiving ceftriaxone for treatment of

his meningitis, and this drug can cause biliary pseudolithiasis.

65

Antibiotic-associated biliary pseudolithiasis is seen almost exclusively with

ceftriaxone. The biliary excretion associated with ceftriaxone results in very high

concentrations of the drug in gallbladder bile. In selected circumstances, the biliary

concentration of ceftriaxone may exceed solubility limits, resulting in formation of a

fine, granular precipitate (i.e., sludge), which differs in composition and ultrasound

features from true gallstones. The precipitate is composed of a ceftriaxone–calcium

complex, the formation of which is dose dependent. Given the high dosages required

for meningitis therapy, it is not surprising that this adverse effect has occurred in

S.C.

65

In the comparative randomized trial between ceftriaxone and cefuroxime cited

previously, evidence of biliary pseudolithiasis on abdominal ultrasonography was

observed in 16 of 35 (46%) patients who received ceftriaxone and in none of 35

patients receiving cefuroxime.

58 Pseudolithiasis usually appears 3 to 10 days

following the start of therapy and, in most instances, it is clinically asymptomatic.

Symptoms similar to acute cholecystitis are evident in some individuals and include

nausea with or without vomiting and abdominal right upper quadrant pain.

65

Prompt recognition of this adverse effect and discontinuation of ceftriaxone

therapy are required to effectively manage biliary pseudolithiasis. Once S.C.’s

ceftriaxone is discontinued, the condition should resolve gradually over a period of

weeks to months; the clinical symptoms should disappear within a few days.

65

Cefotaxime can be substituted for ceftriaxone; cefotaxime is not associated with

biliary complications, and the efficacy of these two agents is equivalent.

63 For S.C.,

the cefotaxime dosage would be 1,000 mg IV every 6 hours (Table 65-6).

DURATION OF THERAPY

CASE 65-1, QUESTION 9: What is the recommended duration of antimicrobial therapy for S.C.?

The optimal duration of therapy for meningitis is difficult to ascertain because few

trials have been designed to address this issue.

66 Although general guidelines exist,

the duration should be individualized based on the response to therapy, the presence

of complicating factors (e.g., immunosuppression), and the specific causative

pathogen. Table 65-8 lists the recommended treatment durations for uncomplicated

cases of bacterial meningitis according to the specific pathogen. Patients such as S.C.

with meningitis caused by N. meningitidis should be treated for 7 days.

11

Complicated cases, such as those with delayed CSF sterilization, require therapy for

longer periods (up to 2 weeks or more).

Table 65-8

Duration of Therapy for Bacterial Meningitis

Etiology Duration of Therapy (days)

Haemophilus influenzae 7

N. meningitidis 7

Streptococcus pneumoniae 10–14

Group B streptococci (Streptococcus agalactiae) 14–21

Listeria monocytogenes ≥21

Gram-negative bacilli 21

p. 1375

p. 1376

PREVENTION OF NEISSERIA MENINGITIDIS MENINGITIS

CASE 65-1, QUESTION 10: S.C. is ready to be discharged home. How can the potential spread of

meningococcal disease be prevented in persons with whom S.C. has contact?

Despite an excellent response to therapy, S.C. still may harbor N. meningitidis in

his nasopharynx and could transmit this organism to individuals with whom he has

close contact.

18

,

67

,

68 Therefore, chemoprophylaxis to prevent secondary cases of N.

meningitidis is indicated for S.C. and his close contacts. In this context, close

contacts include the following: a household member including roommates and young

adults in dormitories, child-care center contacts, and any person directly exposed to

the patient’s oral secretions (e.g., through kissing, mouth-to-mouth resuscitation, or

endotracheal intubation) in the 7 days before symptom onset and until 24 hours after

initiation of appropriate antibiotics.

67

,

69 Health-care personnel and any passenger on

a flight who had direct contact with respiratory secretions or for anyone seated

directly next to an index patient on a prolonged flight (e.g., one lasting ≥8 hours)

should also receive chemoprophylaxis.

69

S.C.’s 7-year-old brother, the children at the day-care center, and close contacts at

the hospital who have been caring for S.C. are at risk for invasive N. meningitidis

disease and should receive chemoprophylaxis. Because the risk of secondary disease

is greatest immediately after onset of disease in the index patient, chemoprophylaxis

should be instituted as soon as possible and ideally within 24 hours.

67 Administering

chemoprophylaxis 14 days or more after identification of the index case is of little

value. Regimens to reduce nasopharyngeal carriage of N. meningitidis include

rifampin, ciprofloxacin, and ceftriaxone. The most frequently used regimen for

children ≥1 month is rifampin, given every 12 hours in a dosage of 10 mg/kg/dose for

2 days. For adults, rifampin given every 12 hours in a dosage of 600 mg for 2 days is

commonly used. The index patient should also receive prophylaxis if he/she was

treated with an agent other than a third-generation cephalosporin as soon as he/she is

able to tolerate oral medications and prior to being discharged from the hospital.

69

Because S.C. is receiving ceftriaxone, he does not need chemoprophylaxis. S.C.’s

brother, parents, and day-care contacts should be treated with appropriate doses of

rifampin as soon as he is diagnosed. Because rifampin is not recommended for

pregnant women, ceftriaxone would be a viable alternative.

Streptococcus pneumoniae Meningitis

CLINICAL FEATURES, PREDISPOSING FACTORS, AND DIAGNOSIS

CASE 65-2

QUESTION 1: A.L., a 58-year-old man with a long history of alcohol abuse, is admitted to the ED febrile and

unresponsive. During the past several days, A.L. has experienced intermittent episodes of fever, chills, SOB,

and a worsening productive cough. A friend visiting A.L. called 9-1-1 when he could not arouse him. A.L.’s

medical records indicate that he has hypertension, adult-onset diabetes mellitus, peptic ulcer disease (PUD), and

chronic obstructive pulmonary disease (COPD). A splenectomy was performed 10 years ago after trauma to

the abdomen. A.L. is divorced and lives alone in a low-income apartment. He has no known drug allergies. His

records show him to be a smoker for more than 30 years. Current medications include hydrochlorothiazide 50

mg every other day, glipizide 5 mg orally (PO) twice daily, famotidine 20 mg PO every bedtime, and

doxycycline PO twice daily as needed for cough and increased sputum production.

On admission to the ED, A.L. had a temperature of 40°C, blood pressure of 90/50 mm Hg, and pulse and

respiratory rates of 115 beats/minute and 25 breaths/minute, respectively. His weight is 59 kg. A.L. was

unresponsive but withdrew all extremities to painful stimuli. His pupils were equal and sluggishly reactive to

light; papilledema and evidence of meningismus were present. Wheezes and crackles were heard throughout

both lung fields, with dense consolidation noted in the left lower lobe. The remainder of his physical examination

was noncontributory.

Stat laboratory tests revealed the following:

WBC count, 18,000 cells/μL, with 80% PMN, 15% bands, 3% lymphocytes, and 2% basophils

Hgb, 10.5 g/dL

Hct, 34%

Platelet count, 250,000/μL

K, 3.0 mEq/L

Glucose, 250 mg/dL

AST, 190 mg/dL

ALT, 140 mg/dL

BUN, 35 mg/dL

SCr, 2.4 mg/dL

The prothrombin time was high normal, and albumin was 3.1 mg/dL. A stat blood alcohol level of 100 mg/dL

was reported, and a urine toxicology screen was negative. A.L.’s serum theophylline concentration was 18

mg/dL. Stool guaiac was positive.

A CT scan showed no evidence of mass lesions or cerebral hematoma. Lumbar puncture yielded the

following results:

CSF opening pressure, 200 mm Hg

Protein, 120 mg/dL

Glucose, 100 mg/dL

WBC count, 8,500 cells/μL, with 92% PMN, 4% monohistiocytes, and 4% lymphocytes

RBC count, 400/μL

Gram-positive, lancet-shaped diplococci were visible on CSF Gram stain. In addition, a sputum Gram stain

revealed numerous WBCs, few epithelial cells, and numerous gram-positive cocci in pairs and in short chains.

Blood, CSF, urine, and sputum cultures are pending. What are the clinical and laboratory features of

pneumococcal meningitis? What features of pneumococcal meningitis are present in A.L.?

A.L. presents to the ED with many signs and symptoms suggestive of

pneumococcal meningitis. He is 56 years of age, and S. pneumoniae is the most

common bacterial etiology for meningitis in adults >30 years of age (Table 65-1). As

is evidenced by A.L.’s presentation, invasive pneumococcal disease often is

associated with significant morbidity, and mortality rates remain high.

1 However,

likely due to the introduction of conjugate vaccines, the incidence of S. pneumoniae

meningitis in the United States has significantly decreased, from 0.8 cases per

100,000 people in 1997 to 0.3/100,000 in 2010.

70 Predisposing factors to invasive

pneumococcal disease include advanced age, cigarette smoking, alcoholism,

diabetes, chronic pulmonary disease, and functional (sickle cell disease) or anatomic

(splenectomy) asplenia. In addition, individuals infected with the human

immunodeficiency virus (HIV) or with other immunocompromising conditions (such

as solid organ or bone marrow transplantation) are at higher risk. Patients with CSF

otorrhea or rhinorrhea induced by closed head trauma or neurosurgical procedures

are more susceptible to develop pneumococcal meningitis as well.

71

A.L. has many predisposing factors for pneumococcal meningitis. He smokes, has

a long history of alcohol abuse, has had a splenectomy, and has diabetes and COPD.

A diagnosis of

p. 1376

p. 1377

pneumococcal meningitis in A.L. is supported by the high fever, stiff neck

(meningismus), and altered mental status. He is unresponsive, which is a definite

negative prognostic factor.

72 Results from CSF chemistries and microbiologic

analysis are highly suggestive of pneumococcal meningitis. A.L. has an elevated

opening CSF pressure and a markedly elevated CSF protein and WBC count with a

predominance of neutrophils on differential examination. The normal CSF glucose

level (100 g/dL) is misleading because A.L. is diabetic. The calculated ratio of CSF

to serum glucose for A.L. is <50%, which is consistent with acute bacterial

meningitis (Table 65-3). The presence of gram-positive, lancet-shaped diplococci in

pairs on the CSF Gram stain strongly supports the diagnosis of pneumococcal

disease. The signs and symptoms of pneumococcal pneumonia (cough, SOB,

increased sputum production, and pulmonary consolidation) as well as the sputum

Gram stain result also lend support to a diagnosis of invasive pneumococcal

infection.

EMPIRIC THERAPY IN ADULTS

CASE 65-2, QUESTION 2: What would be appropriate therapy for A.L?

Table 65-7 provides therapy recommendations for pneumococcal meningitis based

on penicillin and ceftriaxone/cefotaxime susceptibility. Resistance among

pneumococci to penicillin G (MIC ≥0.12 mcg/mL) is a significant concern. In a

surveillance study from 2006 to 2007, 27.5% of S. pneumoniae isolates from patients

with meningitis were resistant to penicillin.

73 S. pneumoniae strains in CSF with MIC

>0.5 mcg/mL to cefotaxime or ceftriaxone are intermediate (1 mcg/mL) or resistant

(≥2 mcg/mL). Reduced activity of ceftriaxone and cefotaxime against penicillinresistant pneumococci affects the therapeutic ratio achieved in CSF and has been

associated with clinical failure. Optimal therapy for fully penicillin-resistant

pneumococcal meningitis should include vancomycin. The combination of

vancomycin and ceftriaxone was superior to either agent given alone in a rabbit

model of penicillin-resistant pneumococcal meningitis. Ceftriaxone or vancomycin

combined with rifampin also may be superior to either drug given alone.

74 With its

potent pneumococcal activity and satisfactory CNS penetration, moxifloxacin may be

an option for pneumococcal meningitis caused by penicillin- and ceftriaxoneresistant isolates.

33 However, clinical data supporting the use of moxifloxacin in this

scenario are lacking. Thus, until more information is available, the combination of

ceftriaxone or cefotaxime with vancomycin represents the most reasonable approach

to empiric therapy for potential penicillin-resistant pneumococcal meningitis.

Until culture and susceptibility results are available, the recommended antibiotic

in this situation is ceftriaxone 2 g given IV Q 12 hours and vancomycin 30 to 45

mg/kg/day IV divided Q 8 to 12 hours. A.L. weighs 59 kg, and because his renal

function is not normal (SrCr, 2.4 mg/dL; creatinine clearance, 30 mL/minute), a

dosage adjustment was made.

CORTICOSTEROID THERAPY FOR ADULT MENINGITIS

CASE 65-2, QUESTION 3: Should A.L. receive corticosteroid therapy in addition to his antibiotic therapy?

A.L. presents with profoundly altered mental status, and his signs and symptoms

are consistent with a fulminant course of disease. His age, underlying medical

problems, likely streptococcal meningitis, and deteriorating clinical status all point

to a poor prognosis and argue for the use of adjunctive dexamethasone. On the other

hand, A.L. is diabetic and has an elevated glucose concentration. He also has PUD,

which may be active given that he is anemic and has a positive stool guaiac result.

High-dose dexamethasone therapy may impact upon his mental status, making

assessment even more difficult. Although each of these issues is a concern, none is so

critical as to preclude the use of corticosteroids. Therefore, dexamethasone given in

a dosage of 10 mg IV Q 6 hours could be instituted before starting ceftriaxone therapy

provided that the diagnosis of bacterial meningitis is confirmed. Dexamethasone can

be continued for up to 4 days if S. pneumoniae is found to be the causative pathogen.

Dexamethasone may be discontinued if S. pneumoniae is not the causative pathogen.

11

To control blood glucose, a sliding-scale dosing schedule of regular insulin is

recommended. A.L.’s PUD should be properly worked up and treated if necessary.

TREATMENT OF PENICILLIN-SUSCEPTIBLE PNEUMOCOCCAL

MENINGITIS

CASE 65-2, QUESTION 4: Results from A.L.’s CSF, blood, and sputum cultures are available and are

positive for S. pneumoniae at each site. Sensitivity testing in CSF revealed an MIC of 0.06 mcg/mL to penicillin,

0.25 mcg/mL to cefotaxime and ceftriaxone, and 0.25 mcg/mL to vancomycin. What therapy is indicated for

A.L.?

A.L. is infected with a strain of S. pneumoniae that is susceptible to penicillin G

(Table 65-7).

75 The dosage usually is 24 million units/day in adults with normal renal

function (Table 65-6). A.L. has renal impairment, however, which means he should

receive a reduced penicillin dosage. For A.L., who has a calculated creatinine

clearance of ~28 mL/minute (according to the method of Cockcroft and Gault), the

daily dose would be 12 to 16 million units, or 3 to 4 million units Q 6 hours. This

revised regimen should provide penicillin serum concentrations similar to those

achieved with high-dose therapy when kidney function is normal. Failure to adjust the

dosage appropriately is equivalent to providing massive doses of penicillin, and

seizures may result.

76

In patients unable to tolerate penicillin G, the best alternatives

are ceftriaxone or cefotaxime (Table 65-7).

11

,

36

Gram-Negative Bacillary Meningitis

CASE 65-3

QUESTION 1: R.R., a 40-year-old, 80-kg man, is admitted to the hospital for a cervical laminectomy with

vertebral fusion. His surgical procedure was complicated by a dural tear. On the third postoperative day,

drainage at his surgical excision site was noted, and R.R. was febrile to 38.2°C. A Gram stain of the drainage

revealed few gram-positive cocci and moderate gram-negative bacilli. Therapy with IV cefazolin 1 g every 8

hours was begun. The following morning, R.R. was oriented to person, place, and time, but he was slightly

obtunded and had a temperature of 40°C. Neck stiffness could not be assessed because of his recent surgery.

A magnetic resonance imaging (MRI) scan of the head and neck was negative, and lumbar puncture yielded

the following CSF results:

WBC count, 3,000 cells/μL, with 95% PMN

Glucose, 20 mg/dL

Protein, 280 mg/dL

What important clinical and laboratory features of gram-negative bacillary meningitis are manifested in R.R.?

EPIDEMIOLOGY

R.R. has developed gram-negative meningitis as a complication of his recent

neurosurgical procedure. Gram-negative organisms are important pathogens

particularly after neurosurgical

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procedures such as craniotomy.

70 Historically, mortality rates from gram-negative

bacillary meningitis have been extremely high, ranging from 40% to 70%. With the

availability of third-generation cephalosporins, some studies report fatalities have

declined to <40%; however, a recent study of 40 adults with spontaneous gramnegative meningitis reported a mortality rate of 53%.

77

Increasing resistance among

certain gram-negative bacilli, such as Enterobacter species and P. aeruginosa,

presents a therapeutic dilemma in that mortality associated with these pathogens is

high and therapeutic options are fewer.

PREDISPOSING FACTORS

Individuals at greatest risk for gram-negative bacillary meningitis include neonates,

the elderly, patients with underlying conditions such as diabetes mellitus or

malignancy, patients with open trauma to the head, and individuals such as R.R.

undergoing neurosurgical procedures.

78 Although meningitis is a rare complication of

clean neurosurgical procedures (e.g., craniotomy, laminectomy), the consequences

can be devastating when it does happen.

77

MICROBIOLOGY

Escherichia coli and K. pneumoniae have historically been the most common gramnegative bacteria causing meningitis; however, rates of pseudomonal meningitis

appear to be increasing.

77

,

79 E. coli is the most common gram-negative cause of

neonatal meningitis, whereas K. pneumoniae is isolated more often in the elderly

population.

80

,

81 The remaining cases are generally divided evenly among Proteus,

Serratia, Enterobacter, Citrobacter, Pseudomonas, and other less common bacilli.

77

CLINICAL FEATURES

In general, clinical laboratory features of gram-negative bacillary meningitis are

similar to other types of bacterial meningitis.

1

,

11 Because of high virulence, gramnegative bacillary meningitis often is a fulminant, rapidly progressive disease. An

exception to this rule is meningitis after neurosurgery.

81 As is evidenced by R.R.’s

clinical presentation, postneurosurgical gram-negative bacillary meningitis can

present in a more subtle fashion. In such patients, many of the symptoms of meningitis

(e.g., altered mental status, stiff neck) are masked by underlying neurologic disease.

Thus, a high index of suspicion is warranted in the postsurgical setting. In addition to

gram-negative bacilli, staphylococci also are associated with postneurosurgical

meningitis.

82 The presence of what looks like staphylococci on R.R.’s wound

drainage fluid is of concern, but the abundance of gram-negative rods on his CSF

Gram stain supports the latter as being the most likely causative pathogen.

TREATMENT OF GRAM-NEGATIVE BACILLARY MENINGITIS

CASE 65-2, QUESTION 2: What empiric therapy is appropriate for A.L. at this time?

Fewer choices are available for treatment of gram-negative bacillary meningitis

than for other meningitides. Ampicillin is active against only E. coli, P. mirabilis,

a n d Salmonella species, but resistance has essentially eliminated its use.

Aminoglycosides are limited by their inability to achieve therapeutic CSF

concentrations, as well as reduced activity in the acidic milieu of purulent CSF.

83

Intraventricular administration, which results in therapeutic CSF concentrations, is

usually reserved for difficult-to-eradicate shunt infections in combination with IV

therapy because of the absence of data supporting their use.

21

,

43 Unlike

intraventricular administration, intralumbar injections will not result in therapeutic

CSF concentrations in the ventricle.

43

Empiric antimicrobial regimens should include an agent with activity against P.

aeruginosa in patients with penetrating head trauma, a CSF shunt, or in patients who

recently underwent a neurosurgical procedure. Because R.R. recently had a

neurosurgical procedure, his empiric therapy should include an antipseudomonal

agent such as cefepime, ceftazidime, or meropenem (Table 65-5).

11 Cefepime has

excellent activity against E. coli and K. pneumoniae and is active against other

enteric gram-negative bacilli as well (Table 65-7).

31 Resistance to third-generation

cephalosporins among Enterobacter, Citrobacter, and Serratia is so prevalent that

these agents cannot be relied on for the treatment of meningitis caused by these

pathogens.

84 With this in mind, therapy of gram-negative meningitis in situations

where third-generation cephalosporin resistance is likely (e.g., nosocomial or

postneurosurgical meningitis) should result in the use of cefepime or meropenem. If a

pathogen is isolated, therapy may be tailored based on culture results, antibiotic

sensitivities, and antibiotic penetration into the CNS. For example, success rates

exceed 80% with cefotaxime and ceftriaxone for gram-negative bacillary meningitis

caused by E. coli or K. pneumoniae.

85

,

86 For R.R., cefazolin should be discontinued,

and treatment with cefepime adjusted for renal insufficiency (2 g IV Q 8 hours)

should be instituted until the return of culture and sensitivities.

TREATMENT OF ENTEROBACTER MENINGITIS

CASE 65-3, QUESTION 3: Culture results from R.R.’s wound drainage and CSF both are positive for

Enterobacter cloacae. Sensitivity data reveal resistance to ceftriaxone, cefepime, ceftazidime, piperacillin–

tazobactam, and aztreonam. Drugs to which the isolate is sensitive include imipenem, meropenem, TMP-SMX,

gentamicin, tobramycin, and ciprofloxacin. What alteration in antimicrobial therapy is most appropriate for R.R.

at this time?

Treatment of meningitis caused by Enterobacter and related species (e.g., Serratia,

Citrobacter species) presents a particular challenge.

31

,

87 Furthermore, some isolates

that are sensitive to third-generation cephalosporins can become resistant during

therapy by virtue of selecting for derepressed mutants.

88 Thus, in contrast to gramnegative bacillary meningitis caused by E. coli and Klebsiella species, alternative

therapies are needed when treating meningitis caused by Enterobacter, Serratia,

Citrobacter, and Pseudomonas species. The isolate is sensitive to imipenem, but the

higher propensity for seizures compared with other β-lactams (including penicillin

G) argues against its use in R.R.

87 Meropenem is not considered to be epileptogenic

and should be used preferentially to imipenem for meningitis.

89 Clinical trials have

evaluated the efficacy and safety of meropenem versus cefotaxime in the treatment of

meningitis in children. Clinical outcomes were similar among the patients

randomized to either group, and the incidence of seizures was similar in the treatment

groups.

90

,

91 Thus, after consideration of the aforementioned options, meropenem

appears to be the best choice of therapy for R.R and carries FDA (Food and Drug

Administration) approval for this indication; however, TMP-SMX, although not

FDA-approved, may be an option as well.

92 Cefepime should be discontinued and, if

confirmed to be susceptible, therapy started with meropenem 2 g IV every 8 hours

adjusted for renal insufficiency.

DURATION OF THERAPY

The optimal duration of therapy for gram-negative bacillary meningitis has not been

clearly established. Because of the high mortality and morbidity associated with

these pathogens and the reduced susceptibility of enteric pathogens to antimicrobial

agents, 21 days has been suggested and should be provided for R.R. (Table 65-8).

11

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p. 1379

Staphylococcus epidermidis Meningitis or Ventriculitis

CLINICAL PRESENTATION OF CEREBROSPINAL FLUID SHUNT

INFECTIONS

CASE 65-4

QUESTION 1: T.A., a 21-year-old woman with a history of congenital hydrocephalus, is admitted to the

neurosurgery unit for worsening mental status and fever. T.A. has a history of multiple revisions and

placements of intraventricular shunts for control of hydrocephalus. Currently, she has a ventriculoperitoneal

(VP) shunt, which was placed 1 month ago and previously had been functioning normally. During the past few

days, T.A. has exhibited worsening obtundation, stiff neck, and a temperature of 39.5°C. A CT scan performed

today reveals enlarged ventricles consistent with acute hydrocephalus.

T.A.’s medical history is noncontributory except for a seizure disorder for which she takes phenytoin 400 mg

PO at bedtime. She also takes Lo-Ovral for birth control. T.A. is allergic to sulfa drugs (severe skin rash). Her

weight on admission is 60 kg.

Laboratory analysis was significant for the following:

WBC count, 14,000 cells/μL, with a differential of 85% PMNs and 10% lymphocytes

BUN, 19 mg/dL

SCr, 0.9 mg/dL

A tap of T.A.’s shunt was performed, and the ventricular fluid was notable for the following results:

Total protein, 150 mg/dL

Glucose, 40 mg/dL

WBC count, 200 cells/μL, with 85% PMNs and 10% lymphocytes

Gram stain of the ventricular fluid showed numerous gram-positive cocci in clusters. What are the subjective

and objective findings of CSF shunt infections, and what manifestations of this type of infection are present in

T.A.?

T.A. likely has meningitis with ventriculitis secondary to infection of her VP shunt.

The most important way to manage hydrocephalus involves the use of devices that

divert (shunt) CSF from the cerebral ventricles to other areas of the body such as the

peritoneum (VP shunts) or atrium (ventriculoatrial shunts).

93 This approach alleviates

increased CSF pressure and substantially reduces morbidity and mortality.

94