Chapter 2

Empiric Therapy Based on Clinical Syndrome

Burke A. Cunha, MD, John L. Brusch, MD, Ronald L. Nichols, MD

Genovefa Papanicolaou, MD, Jean E. Hage, MD

Raymond S. Koff, MD, John H. Rex, MD, Dennis J. Cleri, MD

Cheston B. Cunha, MD, Staci A. Fischer, MD

David Schlossberg, MD

This chapter is organized by clinical syndrome, patient subset, and in some cases, specific organism­. . Clinical summaries immediately follow each treatment grid.. Unless otherwise specified,­ this chapter pertains to infectious diseases and antimicrobial agents in adults. For ­pediatric infectious diseases and antimicrobial therapy see Chapter 7. Therapeutic ­recommendations are based on antimicrobial effectiveness, reliability, cost, safety, and resistance potential. . The antimicrobial dosages in this section ­represent the usual dosages for normal renal and hepatic function in adults. . For any treatment category (i. .e. ., preferred IV therapy, alternate IV therapy, PO therapy), in any given grid category drugs listed are equivalent alternatives and not ranked.

Dosage adjustments, side effects, drug interactions,­ and other important prescribing information are

described in the individual drug ­summaries in Chapter 11.. Use of any drug should be preceded by careful review of the package insert, which provides indications and dosing approved by the U..S.. Food and Drug Administration.. “IV-to-PO Switch” in the last column of the shaded title bar in each ­treatment grid indicates the clinical syndrome should be treated either by IV therapy alone or IV followed by PO therapy, but not by PO therapy alone.. “PO Therapy or IV-to-PO Switch” indicates the clinical syndrome can be treated by IV therapy alone, PO therapy alone, or IV followed by PO therapy (unless otherwise indicated in the footnotes under each treatment grid).. Most patients on IV therapy should be switched to PO equivalent therapy after clinical improvement­ ..

Empiric Therapy of CNS Infections

Acute Bacterial Meningitis (ABM) (see Color Atlas for CSF Gram stains)

Clinical Presentation:  Abrupt onset of fever, headache, stiff neck..

Diagnosis:  CSF gram stain/culture..

Acute Bacterial Meningitis (Normal Hosts)

Diagnostic Considerations:  Gram stain of centrifugated CSF is still the best diagnostic test. . CSF antigen/CIE are unhelpful in establishing the diagnosis (many false-negatives).. Blood cultures are positive for ABM pathogen in 80–90%.. Typical CSF findings include a WBC count of 100–5000 cells/mm3, elevated opening pressure, elevated protein and lactic acid levels (> 4–6 mmol/L), and a positive CSF gram stain.. If the WBC is extremely high (> 20,000 cells/mm3), suspect brain abscess with rupture into the ventricular system, and obtain a CT/MRI to confirm.. S.. pneumoniae meningitis is associated with cranial nerve abnormalities, mental status changes, and neurologic sequelae.. With H.. influenzae or S.. pneumoniae meningitis, obtain a head CT/MRI to rule out other CNS pathology..

Pitfalls:  If ABM is suspected, always perform lumbar puncture (LP) before obtaining a CT scan, since early antibiotic therapy is critical to prognosis.. A CT/MRI should be obtained before LP only if a mass lesion/suppurative intracranial process is of primary concern, after blood cultures have been drawn.. A stiff neck on physical examination has limited diagnostic value in the elderly, since nuchal ­rigidity may occur without meningitis (e..g.., cervical arthritis) and meningitis may occur without nuchal rigidity­.. Recurrence of fever during the first week of H.. influenzae meningitis is commonly due to subdural­ effusion, which usually resolves spontaneously over several days.. Meningococcal meningitis may occur with or without meningococcemia.. On gram stain, S.. pneumoniae may be ­mistaken for H.. influenzae, and Listeria may be mistaken for S.. pneumoniae.. Meningococcal meningitis­ may occur in those who received the meningococcal vaccine especially serogroup B not in meningococcal vaccine..

Therapeutic Considerations:  Do not reduce meningeal antibiotic dosing as the patient improves.. Repeat LP if the patient is not responding to antibiotics after 48 hours; lack of response may be due to therapeutic failure, relapse, or a Noninfectious CNS disorder.. For S.. pneumoniae meningitis, obtain penicillin MICs on all CSF isolates.. Penicillin-resistant strains are susceptible to meningeal doses of betalactam antibiotics (e. .g. ., ceftriaxone). . All but the most highly penicillin-resistant pneumococci are still effectively treated with meningeal doses of beta-lactams.. Highly resistant pneumococcal strains (rare in the CSF) may be treated for 2 weeks with meropenem 2 gm (IV) q8h, or, linezolid 600 mg (IV) q12h.. Dexamethasone 0..15 mg/kg (IV) q6h × 4 days may be given to children with ABM to reduce the incidence/severity of neurologic sequelae, although the value of steroids in adult ABM is unclear; if used, give dexamethasone 30 minutes before the initial antibiotic dose..

Prognosis:  Often fatal without treatment.. Case-fatality rates in treated adults are 10–20%.. Neurological deficits on presentation are associated with a poor prognosis.. Permanent ­neurological deficits are more frequent with S.. pneumoniae than H.. influenzae, even with prompt therapy.. In meningococcal meningitis with meningococcemia, prognosis is related to the number of petechiae, with few or no neurological deficits in survivors..

Acute Bacterial Meningitis (Elderly Malignancy)

Diagnostic Considerations:  Diagnosis by CSF gram stain/culture. . ABM pathogens include usual pathogens in normal hosts plus Listeria monocytogenes, a gram-positive, aerobic, bacillus.. Listeria is the most common ABM pathogen in patients with malignancies, and is a common pathogen in the elderly.. With Listeria meningitis, CSF cultures are positive in 100%, but CSF gram stain is negative in 50%.. Meningeal carcinomatosis is suggested by multiple cranial nerve abnormalities..

Pitfalls:  “Diphtheroids”isolated from CSF should be speciated to rule out Listeria.. Listeria are motile and hemolytic on blood agar plate, diphtheroids are not..

Therapeutic Considerations:  Elderly patients and cancer patients with ABM require empiric ­coverage of Listeria plus other common pathogens in normal hosts (N.. meningitidis, H.. ­influenzae, S.. pneumoniae).. ­Third-generation cephalosporins are not active against Listeria..

Prognosis:  Related to underlying health of host..

Acute Bacterial Meningitis (CNS Shunt Infections)

Diagnostic Considerations:  Diagnosis by CSF gram stain/culture.. S.. epidermidis meningitis usually occurs only with infected prosthetic implant material (e..g.., CNS shunt)..

Pitfalls:  Blood cultures are usually negative for shunt pathogens.. CSF P.. acnes cultures usually ­represent skin contamination.. P.. acnes is rarely a CNS shunt pathogen..

Therapeutic Considerations:  15% of S. . epidermidis strains are resistant to nafcillin/clindamycin. . In addition to systemic antibiotics in meningeal doses, adjunctive intraventricular/intrathecal antibiotics are sometimes given to control shunt infections before shunt removal.. If vancomycin is used to treat CNS S.. aureus (MSSA/MRSA) infection, I..T.. dosing needed in addition to IV therapy..

Prognosis:  Good if prosthetic material is removed..

Acute Nonbacterial Meningitis/Chronic Meningitis

Viral (Aseptic) Meningitis

Clinical Presentation:  Headache, low-grade fever, mild meningismus, photophobia. . Natalizumab (NTZ) predisposes to HSV and VZV meningitis or meningoencephalitis..

Diagnostic Considerations:  Diagnosis by specific serological tests/viral culture.. HSV-2 genital ­infections are often accompanied by mild CNS symptoms, which usually do not require anti-viral therapy.. HSV-1, usually more severe, causes meningitis, meningoencephalitis, or encephalitis.. HSV HHV-6, and WNE meningitis is indistinguishable clinically from other causes of viral meningitis.. EBV meningitis is usually associated with clinical/laboratory features of EBV infectious mononucleosis; suspect the diagnosis in a patient with a positive monospot­ and unexplained meningoencephalitis.. VZV meningitis is typically associated with cutaneous vesicular lesions (H.. zoster).. VZV meningitis may be later (weeks/months) followed by a CVA.. LCM meningitis begins as a “flu-like” illness usually in the fall after hamster contact, and may have low CSF glucose.. Enterovirus meningitis is often associated with a maculopapular rash, non-exudative pharyngitis, diarrhea, and rarely low CSF glucose.. Aseptic meningitis due to mumps may present without parotid swelling ± acute deafness.. Drug induced aseptic meningitis may have eosinophils in the CSF and little/no fever..

Pitfalls:  Consider NSAIDs, TMP–SMX, and IV immunoglobulin as causes of drug induced aseptic meningitis..

Therapeutic Considerations:  Treat specific pathogen..

Prognosis:  Without neurological deficits, full recovery is the rule..

Primary Amebic Meningoencephalitis (PAM) (Naegleria fowleri)

Clinical Presentation:  Acquired by freshwater exposure containing the protozoa, often by jumping into a lake/pool.. Affects healthy children/young adults.. Organism penetrates cribriform plate and enters CSF.. Symptoms occur within 7 days of exposure and may be indistinguishable from fulminant bacterial meningitis, including headache, fever, anorexia, vomiting, signs of meningeal inflammation, altered mental status, coma.. May complain of unusual smell/taste sensations early in infection.. CSF has RBCs and very low glucose..

Diagnostic Considerations:  Diagnosis by demonstrating organism in CSF. . Worldwide distribution. . Free-living freshwater amoeba flourish in warmer climates.. Key to diagnosis rests on clinical suspicion based on history of freshwater exposure in previous 1–2 weeks..

Pitfalls:  CSF findings resemble bacterial meningitis, but RBCs present.. Therapeutic Considerations:  Often fatal despite early treatment.. Prognosis:  Frequently fatal..

Granulomatous Amebic Meningoencephalitis (Acanthamoeba sp.)

Clinical Presentation:  Insidious onset with focal neurologic deficits ± mental status changes, ­seizures, fever, headache, hemiparesis, meningismus, ataxia, visual disturbances.. May be associated with Acanthamoeba keratoconjunctivitis, skin ulcers, or disseminated disease.. Usually seen only in immunocompromised/debilitated patients..

Diagnostic Considerations:  Diagnosis by demonstrating organism in brain biopsy specimen.. CT/MRI shows mass lesions.. “Stellate cysts”characteristic of Acanthamoeba.. Worldwide distribution.. Strong association with extended wear of contact lenses.. Differentiate from N.. fowleri by culture..

Pitfalls:  Not associated with freshwater exposure, unlike primary amebic meningoencephalitis ­(Naegleria fowleri).. Resembles subacute/chronic meningitis.. No trophozoites in CSF.. Skin lesions may be present for months before onset of CNS symptoms..

Therapeutic Considerations:  No proven treatment.. Often fatal despite early treatment.. Prognosis:  Usually fatal..

Neuroborreliosis (CNS Lyme Disease)

Clinical Presentation:  May have mild neck stiffness not frank nucal rigidity.. Low grade fever < 102˚F usually ~ 100–101˚F.. Recent tick exposure.. Often without rash.. Sore throat in some, WBC count WNL, mildly ↑ AST/ALT in some..

Diagnostic Considerations: Diagnosed by demonstrating B.. burgdorferi antibody production in the CNS.. A CSF-to-serum IgM Lyme titer ratio > 1:1 is diagnostic..

Pitfalls:  If CNS symptoms present with acute Lyme disease, rash may be absent and serology may be negative early.. Neuroborreliosis cannot be reliably diagnosed using CSF­-to-serum IgM if antibiotics given before the LP (antibiotics change the ratio and render it useless)..

Therapeutic Considerations:

Prognosis:  Related to underlying health of host.. Prognosis with neuroborreliosis is good even with delayed treatment..

TB Meningitis (Mycobacterium tuberculosis)

Clinical Presentation:  Subacute onset of nonspecific symptoms.. Fever usually present ± headache, nausea, vomiting.. Acute presentation and cranial nerve palsies uncommon..

Diagnostic Considerations:  Diagnosis by CSF AFB smear/culture; PCR of CSF is specific but not very sensitive.. CSF may be normal but usually shows a mild lymphocytic pleocytosis, ↓ glucose, ↑ protein, and few RBCs.. Adenosine deaminase (ADA) levels ↑..

Pitfalls:  CSF may have PMN predominance early, before developing typical lymphocytic predominance.. Eosinophils in CSF is not a feature of TB, and should suggest another diagnosis.. Chest x-ray, PPD, and CSF smear/culture may be negative.. ADA levels more highly elevated in TB than in ABM, listeria, neurobrucellosis..

Therapeutic Considerations:  Dexamethasone 4 mg (IV or PO) q6h × 4–8 weeks is useful to reduce CSF inflammation if given early.. Proteinaceous TB exudates may obstruct ventricles and cause hydrocephalus, which is diagnosed by CT/MRI and may require shunting..

Prognosis:  Poor prognostic factors include delay in treatment, neurologic deficits, or ­hydrocephalus..

Fungal (Cryptococcal) Meningitis (Cryptococcus neoformans)

Clinical Presentation:  Insidious onset of nonspecific symptoms.. Headache most common.. Chronic cases may have CNS symptoms for weeks to months with intervening asymptomatic periods. . Acute manifestations are more common in AIDS, chronic steroid therapy, lymphoreticular malignancies. . 50–80% of patients are abnormal hosts..

Diagnostic Considerations:  C.. neoformans is the most common cause of fungal meningitis, and the only encapsulated yeast in the CSF to cause meningitis.. Diagnosis by CSF India ink preparations showing encapsulated yeasts/cryptococcal latex antigen by latex agglutination/culture.. Rule out HIV and other underlying immunosuppressive diseases..

Pitfalls: False + crytococcal antigen may occur with BBL Port-A-Cul transport vials. CSF latex antigen titer may not return to zero.. Continue treatment until titers decline/do not decrease further, and until CSF culture is negative for cryptococci.. India ink preparations showing encapsulated yeasts of CSF are useful for initial infection, but should not be relied on to diagnose recurrent episodes, since smears may be positive despite negative CSF cultures (dead cryptococci may remain in CSF for years).. Diagnosis of recurrences rests on CSF culture..

Therapeutic Considerations:  Treat until CSF is sterile or CSF latex antigen titer is zero or remains near zero on serial lumbar punctures.. After patient defervesces on amphotericin B/5FC, switch to oral fluconazole × 10 weeks.. Lipid amphotericin may be used if amphotericin­ B cannot be tolerated.. HIV patients require life-long suppressive therapy with fluconazole 200 mg (PO) q24h.. Expert consultation is strongly advised..

Prognosis:  Good. . Poor prognostic factors include no CSF pleocytosis, many organisms in CSF, and altered consciousness on admission..

Encephalitis

*Severe HSV encephalitis may require a longer duration of therapy, i..e.., 14-21 days..

Herpes Encephalitis (HSV-1)

Clinical Presentation:  Acute onset of fever and change in mental status without nuchal rigidity.. Natalizumab (NTZ) predisposes to HSV meningitis, meningoencephalitis, or encephalitis..

Diagnostic Considerations:  EEG is best early (< 72 hours) presumptive test, showing unilateral temporal lobe abnormalities.. Brain MRI is abnormal before CT scan, which may require several days before a temporal lobe focus is seen.. Definitive diagnosis is by CSF PCR for HSV-1 DNA.. Usually presents as encephalitis or meningoencephalitis; RBCs in CSF ~ CNS damage Early/mild HSE may have no RBCs in CSF.. CSF may have PMN predominance and low glucose levels, unlike other viral causes of meningitis..

Pitfalls:  HSV-2 HSE rare in young adults; HSV-2 aseptic menigitis common HSV-2 HSE occurs in the elderly/immunosuppres.. In normal hosts, HHV-6 may mimic HSV-1 encephalitis with a frontal/temporal focus on EEG..

Therapeutic Considerations:  HSV is treatable.. Treat as soon as possible, since neurological deficits may be mild and reversible early on, but severe and irreversible later..

Prognosis:  Related to extent of brain injury and early anti-HSV therapy..

Arboviral Encephalitis

Clinical Presentation:  Acute onset of fever, headache, change/decrease in mental status days to weeks after insect bite (e..g.., mosquito/tick).. WNE is suggested by encephalitis ± with highly elevated ferritin levels ± new onset tremors or flaccid paralysis.. EEG: diffuse slowing ± ↑ activity basal ganglia/thalamus.. Prognosis ~ severity of neurologic deficits and degree/duration of relative lymphopenia/ferritin levels..

Diagnostic Considerations:  Diagnosis by specific arboviral serology.. Pitfalls:  Usually occurs in summer/fall.. SIADH common, may occur.. Therapeutic Considerations:  Only supportive therapy is available at present..

Prognosis:  Permanent neurological deficits are common, but not predictable.. May be fatal..

Mycoplasma Encephalitis

Clinical Presentation:  Acute onset of fever and change in mental status without nuchal rigidity.. Diagnostic Considerations:  Diagnosis suggested by CAP with sore throat, otitis, E.. multiforme, soft stools/diarrhea—with elevated IgM mycoplasma titers, and very high (≥ 1:1024) cold agglutinin titers.. CSF shows mild mononucleosis/pleocytosis and normal/low glucose..

Pitfalls:  CNS findings may overshadow pulmonary findings..

Therapeutic Considerations:  Macrolides not effective for CNS infection.  Doxycycline rapidly ↓ mycoplasma shedding in oropharyngeal secretions (vs.. prolonged shedding with macrolides)..

Prognosis:  With early treatment, prognosis is good without neurologic sequelae..

Listeria Encephalitis

Clinical Presentation:  Fever/mental confusion (encephalitis/cerebritis) ± nuchal rigidity (meningoencephalitis)..

Diagnostic Considerations:  Diagnosis by LP.. Suspect Listeria if CSF with “purulent profile” plus RBCs.. Listeria seen on Gram stain of CSF in 50%; but culture positive in 100%..

Pitfalls:  Not to be confused with other gram-positive bacilli (skin contaminants) isolated from CSF (diphtheroids).. Listeria are motile and hemolytic on blood agar..

Therapeutic Considerations:  3rd generation cephalosporins not active against Listeria.. In penicillintolerant patients, use meningeal dose ampicillin (not penicillin)..

Prognosis:  Good with early/adequate treatment.. Related to degree of T lymphocyte dysfunction..

CMV Encephalitis (see p. 329)

Toxoplasma Encephalitis (see p. 331)

Brain Abscess/Subdural Empyema/Cavernous Vein

Thrombosis/Intracranial Suppurative Thrombophlebitis