A 55-year-old man with a history of well-controlled diabetes and hypertension presents to the emergency department (ED) with a 5- day history of worsening headache and fever. He requests that the light in his room to be turned off as it worsens his headache. Review of systems is otherwise significant only for cough productive of clear phlegm for the last 1 week and intermittent dizziness for 24 hours before presentation. His vital signs are:
He is alert and oriented to time, place, and person. Systemic examination, including a detailed neurological examination, is normal except for a 2/6 ejection systolic murmur in the aortic region and mild nuchal rigidity. Kernig signs are positive. Diagnostic lumbar puncture (LP) is planned.
Which of the following sequences of diagnostic and therapeutic steps is MOST appropriate for the care of this patient?
Correct Answer: C
There are multiple factors that determine the optimal sequence of events in cases of suspected community-acquired meningitis. In an ideal scenario without any absolute indication for head imaging, a patient with suspected bacterial meningitis has blood cultures drawn, LP performed, and consideration for steroid therapy in quick succession before timely initiation of appropriate empiric antimicrobial therapy.
Appropriate empiric antimicrobial therapy should be initiated as soon as possible. A delay in the administration of appropriate antimicrobials for bacterial meningitis by 6 to 8 hours has been associated with an increased fatality risk from <5% to 45% and up to 75% for delay of 8 to 10 hours. If interventions are likely to substantially delay antimicrobial administration, the benefits of such interventions should be carefully weighed against the potential of increased mortality risk associated with delayed antimicrobial administration—if a significant delay is anticipated, antimicrobials should take precedence.
Blood cultures should always be obtained before administration of antimicrobials for any infection where microbiological diagnosis has not been achieved.
A CT head is sometimes obtained before LP to look for signs of increased intracranial pressure that can place a patient at risk of brain herniation from the sudden CSF loss during LP. However, in the absence of an absolute indication, this can inadvertently lead to increased door-toantibiotic time, which in turn affects mortality. Therefore, screening of patients for clinical signs of raised intracranial pressure and factors that are known to predispose to complications of LP is strongly encouraged. The Infectious Diseases Society of America (IDSA) recommends a CT head before performance of LP only in the following circumstances:
When taken together, these criteria have a negative predictive value of 97% and a negative likelihood ratio of 0.1 for an abnormal CT head. Therefore, in the absence of any of the above findings, it is deemed safe to proceed with LP without head imaging.
The administration of steroids before or with empiric antimicrobial therapy in patients with suspected pneumococcal meningitis has been associated with a trend toward lower mortality as well as fewer neurological sequelae, a benefit that is lost if steroids are given after initiation of antimicrobials. If suspicion of pneumococcal meningitis is confirmed by LP, steroid therapy should be continued for 4 days.
A 66-year-old woman is brought to the ED after being found down in her home by her maid; no family member is reachable. On arrival, she has:
Her mental status is altered with a Glasgow Coma Scale (GCS) of 8, but her physical examination is otherwise normal including a nonfocal neurological examination. Soon after presentation, she has multiple emetic episodes and is intubated for airway protection. A head CT shows no signs of an acute intracranial process. A urine toxicology screen is negative. Empiric antimicrobial therapy with vancomycin and ceftriaxone is initiated after blood cultures are obtained, and she is transferred to the ICU for further care. Contact is finally established with her husband who reports that she had been having severe headaches, body aches, and fever for the past few days. He also reports that she has a history of osteoarthritis and well-controlled diabetes and was in a motor vehicle accident several years ago requiring emergent splenectomy. Her vaccination status is not known. An LP is performed approximately 13 hours after initial antibiotics administration, which shows:
CSF gram stain is negative, and cultures have no growth at 48 hours. Multiplex polymerase chain reaction (PCR) on CSF is positive for Neisseria meningitidis.
Which of the following interpretations of the CSF findings is MOST correct?
Correct Answer: D
In suspected bacterial meningitis, LP should ideally precede empiric antibiotic therapy. However, multiple factors including overreliance on CT imaging before LP have increasingly led to delay in LP until after initiation of antimicrobials. Antimicrobials can affect measurements of CSF glucose, protein, and potentially other indices as well, and decrease the yield of CSF cultures making accurate diagnosis more challenging. The data on postantimicrobial CSF analysis is very limited, is largely retrospective, and mostly extrapolated to the adult population from pediatric literature. CSF culture has a reported sensitivity of 88% for microbiological diagnosis, which decreases to 70% with any prior antibiotic use and sensitivity declines further as the duration of time receiving antibiotics increases. As duration of antimicrobial therapy increases, CSF glucose levels increase and CSF protein levels decrease as compared with preantimicrobial measurements, which is likely a reflection of pathogen clearance from the CSF. Complete clearance of meningococcus from the CSF occurs within 2 hours of antimicrobial therapy initiation, and pneumococcus clearance begins around 4 hours into therapy. Other pathogens seem to be more persistent. However, it is important to note that CSF pleocytosis and neutrophilic count are not as readily affected by antibiotics, and the counts are relatively preserved even after 24 hours of antimicrobial therapy. The following parameters predict bacterial infection with high accuracy and should therefore inform differential diagnosis even in the absence of microbiological data and regardless of administration of antimicrobial therapy:
A 42-year-old woman is admitted to the neurological ICU after presenting with worsening mentation and the finding of a new intracranial mass on MRI. She is intubated for airway protection and has a external ventricular drain (EVD) placed for management of obstructive hydrocephalus. On ICU day 1, she is afebrile and hemodynamically stable. Over the next 3 days, she has a low-grade fever (99.5-100°F), and on ICU day 5, she has a fever of 100.8°F. CSF drawn from the EVD on day 4 to day 6 shows the following results:
Based on the CSF results, what is the most appropriate next step in management?
The patient has evidence of a ventriculostomy-related infection and should be treated with broad-spectrum empiric IV antimicrobial therapy. Healthcare-associated ventriculitis and meningitis (HAVM) accounts for a significant proportion of CNS infections seen in institutions with neurosurgical facilities. However, diagnosis of HAVM based on CSF findings can be challenging especially in the setting of a known neurological disease process or recent neurosurgical intervention. The microbiology of healthcare-associated meningitis differs fundamentally from community-acquired meningitis. The most common pathogens in the healthcare setting are Staphylococcus aureus, Staphylococcus epidermidis, Propionibacterium acnes, and Enterobacteriaceae (including Serratia in the postoperative setting).
CSF drain–related ventriculitis has an incidence of 8% to 9% per patient or per EVD placement. However, the diagnosis is often difficult to establish in critically ill patients where clinical examination and symptomatic assessment are limited. Clinical symptoms which should raise suspicion for HAVM include CSF pleocytosis, hypoglychorrachia, increasing CSF protein and/or cell counts, and positive CSF gram stain or cultures. In general, an isolated positive CSF gram stain and/or culture is not considered diagnostic for HAVM, and contamination or colonization is more likely. Given the indolent nature of some pathogens common in this setting (eg Staphylococcus epidermidis, Propionibacterium acnes), CSF cultures may take several days to show growth, which may mislead clinicians and delay the diagnosis of HAVM. Lozier’s classification is often used to support treatment decisions for HAVM:
Empiric therapy for HAVM is directed at the common pathogens and often consists of IV vancomycin and a third or fourth generation cephalosporin to provide Pseudomonas coverage. Intrathecal therapy is usually reserved for poor response to IV therapy or when pathogens are known to have high minimum inhibitory concentrations (MICs), which are not likely to be attainable via the IV route. In a penicillin- or cephalosporin-allergic patient, aztreonam may be used instead of a cephalosporin.
A 42-year old woman is brought to the ED from home after she was difficult to arouse from sleep in the morning. She has no significant past medical history but had been complaining of malaise for 1 week as well as new onset headache and fever for 2 days before presentation. She has not had other symptoms except for cold sores, which she gets this time every year. She had also been taking care of her 7-year-old grandson who had fevers and a severe nonproductive cough. In the ED, her vital signs are:
On examination, she is only responsive to noxious stimuli with eye opening and withdrawal of all four extremities. Her pupils are reactive to light bilaterally; there is no nuchal rigidity. Skin examination is normal with no visible rash. Heart, lung, and abdominal examination are unremarkable. During the examination, she has a generalized tonic-clonic seizure and is intubated for airway protection. A head CT is performed, which does not show any acute abnormality. An LP is performed, and results are pending. She is started on vancomycin, ceftriaxone, and dexamethasone for concern of bacterial meningitis. After that, a brain MRI is also performed, which shows altered signal in the left orbitofrontal cortex with enhancement on postgadolinium images.
What further diagnostic and therapeutic interventions are MOST appropriate at this time?
The patient’s presentation and imaging findings are classic for HSV encephalitis. Empiric therapy should include high-dose IV acyclovir while awaiting HSV PCR on CSF, which is the test of choice for definitive diagnosis.
Encephalitis or encephalomyelitis should be considered in the differential diagnosis for any patient presenting with behavioral changes, altered mental status, and/or depressed level of consciousness. In the absence of nuchal rigidity and peripheral symptoms, this should be high on the differential. The presence of parenchymal involvement on brain imaging is virtually diagnostic of encephalitis. Microbiological diagnosis is usually made by serological tests or PCR on CSF.
HSV is the most common cause of encephalitis (including both infectious and noninfectious causes) in adults. 90% of the cases are caused by HSV-1 during primary infection (more common in young adults) or recurrence (more common in older adults) from latent virus reactivation either as peripheral infection spreading to the CNS or de novo reactivation within the CNS. Temporal lobe involvement is pathognomic but less commonly the temporal lobe may be spared with involvement of other areas such as the orbitofrontal cortex, cingulate gyrus, or insula. This patient’s presentation of an episode of orolabial herpes followed by fever, headaches, and altered consciousness is classic for HSV encephalitis. Highdose acyclovir 10 mg/kg/dose IV every 8 hours should be started empirically if HSV encephalitis is a consideration even before diagnostics are performed as mortality is high with delay in therapy. The diagnostic test of choice is HSV DNA PCR performed on CSF. This test is highly sensitive and specific but may be falsely negative very early in the course of the disease. If the clinical suspicion for HSV encephalitis is high, especially if supported by imaging findings, then acyclovir should be continued despite an initial negative PCR and an LP should be repeated with HSV PCR retesting in 3 to 7 days. Serologies are not helpful in the diagnosis of HSV encephalitis either in the serum or on CSF.
VZV is a neurotropic virus that establishes latency in ganglionic cells of the nervous system during primary infection and dermatomal reactivation can occur in times of immunocompromise (old age, immunosuppression, HIV/AIDS). CNS manifestations of infection range from strokes and subarachnoid hemorrhages to arterial ectasias, but encephalitis is also a common presentation. Unlike HSV, VZV IgG detection in CSF is more sensitive than VZV PCR for diagnosis. Treatment is with high-dose IV acyclovir as well.
A 66-year-old man is brought to the ED with a 3-week history of generalized malaise and worsening right-sided headaches not responding to acetaminophen or ibuprofen. He has a past medical history significant for hypertension, hyperlipidemia, moderate obesity, and recurrent otitis media and had an episode of pneumonia about 4 years ago. He is awake, alert, and well-oriented. Vital signs are within normal limits. Heart and lung sounds are normal, abdomen is soft and nontender, and neurological examination including cranial nerves is normal and symmetrical. Complete blood count and metabolic panel are within normal limits except for a mild leukocytosis and mild hyponatremia. Erythrocyte sedimentation rate (ESR) is 62 mm/h and a nasal swab for methicillin-resistant Staphylococcus aureus is negative by PCR. A CT of the head without contrast shows a single 2 cm lesion in the right temporal lobe with mild surrounding edema, which the radiologist reports as concerning for an abscess. Also seen are some microvascular ischemic changes and opacification of right mastoid air cells. The patient is started on vancomycin and piperacillin/tazobactam and transferred to the neurological ICU for further management.
Which of the following changes to the antibiotic regimen is MOST appropriate for this patient
This patient has a temporal lobe abscess associated with recurrent otitis media infection and mastoiditis. He does not have a history of transplantation or immunocompromise, and MRSA PCR is negative. Consequently there is no need of antimicrobial coverage for methicillinresistant Staphylococcus aureus (MRSA), atypical bacteria, fungi, or parasites. He should be empirically treated with a third-generation cephalosporin and metronidazole.
Although cryptogenic brain abscesses do occur, most focal brain parenchymal infections are associated with either a contiguous focus of infection (dental infection, otitis media, mastoiditis, sinusitis, meningitis), introduced directly by disruption of physical barriers in the area (recent dental or neurological procedure, head trauma), or via hematogenous spread from distant source (endocarditis, lung infection). When the source is adjacent, there is usually only a solitary abscess, whereas multiple abscesses are commonly seen with hematogenous spread from more distant sources. The location of the abscess also can provide some clues to the etiology. The causative organisms in these cases are typically the ones causing the primary infection. However, underlying host characteristics can predispose to brain abscesses by unusual or atypical bacteria, parasites, and/or fungi, for example in patients with HIV, solid organ transplant (SOT), hematopoietic stem cell transplant (HSCT), neutropenia, other forms of immunosuppression, or in those with diabetes and cyanotic heart disease (see table). The source of infection and the predisposing factors should therefore be taken into consideration while designing an empiric antimicrobial regimen.
Based on the principles discussed above, the empiric antibiotic therapy for suspected brain abscess can be summarized as:
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