Fever of Unknown Origin Synonyms and related keywords: fever without a focus, fever of unknown etiol

1
Fever of Unknown OriginSynonyms and related
keywords fever without a focus, fever of unknown
etiology, fever without a source, fever
without localizing signs, fever withiout a focus,
pediatric fever.

• V. MIHÁL

2
Description

• definition - present at least 7-10 days
  (children) 3 weeks (adults), temperature gt 101
  degrees F (38.2 degrees C), unknown etiology
  after 1 week investigation in hospital
• use 100.4 (38) rectally in children
• often fever without localizing signs admitted
  before FUO

3
Definition of FUO

• Fever is defined as a rectal temperature
  exceeding 38C (100.4F). Direct the initial
  evaluation of these patients toward identifying
  occult bacteremia or other serious bacterial
  infections. Address the following questions
• What laboratory studies are indicated for various
  age ranges?
• Which patients need in-depth evaluation and
  treatment?
• Which patients need treatment with antibiotics?
• Which patients should be hospitalized?
• Which patients can be sent home safely, and what
  follow-up is appropriate for them?
• Are the diagnosis and treatment modalities for
  each patient cost-effective?
• What is the potential morbidity associated with
  testing and treatment?
• What are the parental (and patient) preferences
  for testing and treatment?

4
Background

• Infants or young children who have fevers with no
  obvious source of infection present a diagnostic
  dilemma.
• Healthcare providers see these patients on a
  daily basis.
• As many as 20 of childhood fevers have no
  apparent cause.
• A small but significant number of these patients
  may have a serious bacterial infectionthe risk
  is greatest among febrile infants and children
  younger than 36 monthsmaking proper diagnosis
  and management important.
• Physical examination and patient history do not
  always identify patients with occult bacteremia
  or serious bacterial infection.
• Serious infections that are not recognized
  promptly and treated appropriately can cause
  significant morbidity or mortality.

5
FUO

• This article focuses primarily on infants and
  young children aged 2-36 months and reflects
  the significant changes in the care of the
  febrile infant and child over the past 10 years.
• The article Fever in the Young Infant addresses
  the diagnosis and treatment of febrile infants
  younger than 2 months.

6
Causes of FUO

• 1 cancer, 2 infection (1 in children),
  collagen-vascular disease, drugs (barbiturates,
  antibiotics, antihypertensives, antiarrhythmic,
  phenytoin, antihistamine, salicylates,
  cimetidine, bleomycin, allopurinol), factitious,
  pulmonary embolism, inflammatory bowel disease,
  subacute thyroiditis, retroperitoneal hematoma
• most children have common illness with uncommon
  presentation
• most common infectious FUO in children -
  salmonellosis, rickettsial disease, infectious
  mononucleosis, cytoplasmic inclusion body
  disease, hepatitis, TB
• PFABA syndrome with periodic fever, aphthous
  stomatitis, pharyngitis and cervical adenitis (J
  Pediatr 1999 Jul135(1)15, 98 in J Watch 1999
  Aug 1519(16)131), editorial can be found in J
  Pediatr 1999 Jul135(1)1
• consider Kawasaki disease in children with
  prolonged unexplained fever (Pediatr Infect Dis J
  2004 Aug23(8)782 in Pediatric Notes 2004 Oct
  728(41)164)

7
(No Transcript)
8
Pathophysiology

• Meningitis and sepsis are serious etiologies of
  fever in infants and young children.
• Neonates' immature immune systems place them at
  greater risk of systemic infection. Hematogenous
  spread of infection is most common in this age
  group or in patients who are immunocompromised.
  For these same reasons, infants who have a focal
  bacterial infection have a greater risk of
  developing sepsis.
• The following are among the most common bacterial
  etiologies of serious bacterial infection in this
  age group
• Streptococcus pneumoniae
• Group B streptococci
• Neisseria meningitidis
• Haemophilus influenzae type b
• Listeria monocytogenes

9
Frequency

• Fever accounts for 10-20 of pediatric visits to
  health care providers.
• Mortality/Morbidity Patients with no easily
  identified source of infection have a small but
  significant risk of a serious bacterial
  infection.
• If not recognized and treated appropriately and
  promptly, this can cause morbidity or
  mortality.
• Age This article focuses on the diagnosis and
  treatment of febrile children aged 2-36
  months.

10
History I

• Obtaining an accurate history from the parent or
  caregiver is important the history obtained
  should include the following information
• Fever history What was child's temperature prior
  to presentation, and how was temperature
  measured? Consider fever documented at home by a
  reliable parent or caregiver the same as fever
  found on presentation. (Accept parental reports
  of maximum temperature.)
• Fever at presentation
• If the physician believes the infant has been
  bundled excessively, and if a repeat temperature
  taken 15-30 minutes after unbundling is normal,
  the infant should be considered afebrile.
• Always remember that normal or low temperature
  does not preclude serious, even life-threatening,
  infectious disease.

11
History II

• Current level of activity or lethargy
• Activity level prior to fever onset (ie, active,
  lethargic)
• Current eating and drinking pattern
• Eating and drinking pattern prior to fever onset
• Appearance Fever sometimes makes a child appear
  rather ill.
• Vomiting or diarrhea
• Ill contacts
• Medical history
• Immunization history (especially recent
  immunizations)
• Urinary output - Number of wet diapers

12
Physical I

• While performing a complete physical examination,
  pay particular attention to assessing hydration
  status and identifying the source of infection.
• Physical examination of every febrile child
  should include the following
• Record vital signs.
• Temperature Rectal temperature is the standard.
  Temperature obtained via tympanic, axillary, or
  oral methods may not truly reflect the patient's
  temperature.
• Pulse rate
• Respiratory rate
• Blood pressure

13
Physical II

• Measure pulse oximetry levels.
• Pulse oximetry may be a more sensitive predictor
  of pulmonary infection than respiratory rate in
  patients of all ages, but especially in infants
  and young children.
• Pulse oximetry is mandatory for any child with
  abnormal lung examination findings, respiratory
  symptoms, or abnormal respiratory rate, although
  keep in mind that respiratory rate increases when
  children are febrile.
• Record an accurate weight on every chart.
• All pharmacologic and procedural treatments are
  based on the weight in kilograms.
• In urgent situations, estimating methods (eg,
  Broselow tape, weight based on age) may be used.

14
Physical III

• During the examination, concentrate on
  identifying any of the following
• Toxic appearance, which suggests possible signs
  of lethargy, poor perfusion, hypoventilation or
  hyperventilation, or cyanosis (ie, shock)
• A focus of infection that is the apparent cause
  of the fever
• Minor foci (eg, otitis media OM, pharyngitis,
  sinusitis, skin or soft tissue infection)
• Identifiable viral infection (eg, bronchiolitis,
  croup, gingivostomatitis, viral gastroenteritis,
  varicella, hand-foot-and-mouth disease)
• Petechial or purpuric rashes, often thought to be
  associated with invasive bacteremia
• Purpura, which is associated more often with
  meningococcemia than is the presence of petechiae
  alone

15
The Yale Observation Scale

• For all patients aged 3-36 months, management
  decisions are mostly based on the degree of
  toxicity and the height of temperature.
• The Yale Observation Scale is a reliable method
  for determining degree of illness.
• It consists of 6 variables quality of cry,
  reaction to parent stimulation, state variation,
  color, hydration, and response.
• A score of 10 or less has a 2.7 risk of serious
  bacterial infection.
• A score of 16 or greater has a 92 risk of
  serious bacterial infection.
• Regarding the height of temperature, Hoberman et
  al found that 6.5 of patients with a temperature
  of 39.0C (102.2F) or more had a UTI and that
  white females with that temperature had a 17
  incidence of UTI (Hoberman, 1994).
• In this age group, the prevalence of bacteremia
  correlates with the height of fever.
• Children with temperatures from 39-39.5C
  (102.2-103F) have an approximate 2-4 risk of
  having occult bacteremia.
• Those with temperatures higher than 39.5C
  (103F) have an approximate 5 chance of having
  occult bacteremia.

16
Yale Observation Scale McCarthy et al.,
Pediatrics 1982 70 802-9

17
Causes I

• Several common bacteria cause serious bacterial
  infections (SBI).
• S pneumoniae
• S pneumoniae is the leading cause of nearly all
  common bacterial upper respiratory tract
  infections (eg, pneumonia, sinusitis, OM).
• This organism is the most common cause of
  meningitis in the United States.
• It is the most common cause of occult bacteremia.
• N meningitidis
• H influenzae type b
• L monocytogenes
• E coli

18
Causes II

• E coli
• E coli is the most common cause of urinary tract
  infections (UTIs).
• Among febrile children with UTIs, 75 have
  pyelonephritis, with consequences that, if
  missed, include renal scarring in 27-64 of
  patients, a 23 risk of hypertension, a 10 risk
  of renal failure, and a 13 risk of preeclampsia
  as adults.
• Approximately 13-15 of end-stage renal disease
  is believed to be related to undertreated
  childhood UTIs.

19
Lab Studies I

• Recommended laboratory studies for children with
  fever of unknown etiology are based upon the
  child's appearance, age, and temperature. (Begin
  IV or IM antibiotic administration for all
  infants who appear ill once urine and blood
  specimens are obtained.
• Perform the following for children who do not
  appear toxic
• Perform a complete blood count (CBC) with manual
  differential.
• Draw and hold blood cultures, pending receipt of
  CBC results. Send blood culture for analysis if
  white blood cell (WBC) count exceeds 15,000 or if
  absolute neutrophil count (ANC) exceeds 10,000.
• Perform urinalysis (UA) by bladder
  catheterization and urine culture based on the
  following criteria
• All males younger than 6 months and all
  uncircumcised males younger than 12 months
• All females younger than 24 months and older
  female children if symptoms suggest a UTI
• Consider cerebrospinal fluid (CSF) studies and
  culture. (Obtain CSF if meningitis is suspected.)
• Consider obtaining a stool culture to measure
  fecal WBCs and stool guaiac for diarrhea.

20
Lab Studies II

• Perform the following for children who appear
  toxic
• Perform a CBC with manual differential.
• Send blood cultures.
• Consider obtaining a chest radiograph. Chest
  radiography should be performed for patients with
  a WBC count greater than 20,000.
• Perform UA by bladder catheterization and urine
  culture based on the following criteria
• All males younger than 6 months and all
  uncircumcised males younger than 12 months
• All females younger than 24 months and older
  female children if symptoms suggest a UTI
• Obtain CSF and perform studies and culture if any
  suspicion of meningitis exists. (Administer
  antibiotics before performing the lumbar puncture
  LP if any delay is anticipated.)
• Consider obtaining a stool culture to measure
  fecal WBCs and stool guaiac for diarrhea.
• Admit these patients for further treatment
  pending culture results, administer parenteral
  antibiotics (see Treatment).

21
Imaging Studies

• Chest radiography is part of any thorough
  evaluation of a febrile child.
• Chest radiography is indicated when the patient
  has tachypnea, retractions, focal auscultatory
  findings, or oxygen saturation level (SO2) on
  room air of less than 95.
• Although viral etiologies are considered the
  cause of most pediatric pneumonias, 51 of
  pediatric patients with pneumonia have serologic
  evidence of bacterial infection.
• Chest radiographs should be obtained if WBC is
  gt20,000. One study found a high correlation with
  WBC greater than 20,000 and pneumonia, even with
  a lack of clinical findings suggestive of
  pneumonia.

22
Medical Care

• For children who appear ill, conduct a complete
  evaluation to identify occult sources of
  infection. Follow the evaluation with empiric
  antibiotic treatment and admit the patient to a
  hospital for further monitoring and treatment
  pending culture results.
• Patients aged 2-36 months may not require
  admission if they meet the following criteria
• Patient was healthy prior to onset of fever.
• Patient has no significant risk factors.
• Patient appears nontoxic and otherwise healthy.
• Patient's laboratory results are within reference
  ranges defined as low risk.
• Patient's parents (or caregivers) appear reliable
  and have access to transportation if the child's
  symptoms should worsen.

23
(No Transcript)
24
ROCHESTER LOW RISK CRITERIA lt60 DAYDagan R et
al., J Ped 1988 112 355-60

• Infant appears well, non-toxic
• Infant has been previously well
• born at term (gt37 weeks)
• no antenatal or perinatal antimicrobial
  therapy
• no treatment for unexplaind
  hypebilirubinemia
• not hospitalized longer than the mother
  at birth
• no previous hospitalization
• no recent antibiotic use
• no chronic or underlying diseases
• Infant has no evidence of bacterial infection
• no skin, sift tissue, bone, joint, or ear
  infection
• The following laboratotry parameters are met
• WBC count 5000-15000/mm3
• absolute band count lt1500
• urinanalysis WBC count lt10/hpf

25
Febrile infants aged 1-2 months I

• Provide a full evaluation and conservative
  treatment (including possible hospital admission
  for close monitoring and parenteral antibiotic
  administration) for any febrile infant who
  appears ill.
• Febrile infants who appear healthy and have no
  obvious source of infection require further
  evaluation before disposition is decided.
• High-risk patients in this age group are patients
  with a significant medical history (eg, premature
  infants, infants with prolonged neonatal
  intensive care unit stays, those who had
  complicated births, those with congenital heart
  disease).

26
Febrile infants aged 1-2 months II

• Low-risk patients in this age group are
  previously healthy infants who do not appear
  toxic and who exhibit no focal bacterial
  infection on physical examination (excluding
  otitis media). Consider the child's home
  environment (ie, social situation, presence of a
  reliable caregiver, availability of
  transportation and telephone) before placing an
  infant in the low-risk group. Laboratory test
  results for a low-risk designation must include
  the following
• Normal UA results (ie, negative nitrite findings
  and/or lt10 WBC/high-power field hpf)
• WBC count of 5000-15,000
• If diarrhea is present, no heme and few to no
  WBCs in stool
• CSF with fewer than 8 WBC/mm3 in bloodless
  specimen
• Negative CSF Gram stain findings
• Bands not exceeding 20 of neutrophils
• No infiltrate on chest radiograph, if performed

27
Treatment

• Parenteral antibiotics are the drugs of choice to
  treat febrile or ill-appearing neonates.
• Selection of medications depends upon the
  patient's age. Coverage for Listeria with
  ampicillin is essential for infants younger than
  6 weeks.
• Typically, cefotaxime or gentamicin is added
  (ceftriaxone may be avoided because of bilirubin
  displacement from serum protein-binding sites,
  but this is not universally recommended nor
  practiced).
• Treatment of fever in this age group is somewhat
  controversial.

28
Medical/Legal Pitfalls

• The biggest pitfall is not considering the
  possibility that a febrile infant has a
  potentially life-threatening illness.
• If not treated promptly, a small percent of
  febrile infants who have no obvious source of
  serious bacterial infection may suffer serious
  sequelae or death.
• Physicians who approach their patients as if this
  is a possibility and who provide appropriate
  evaluation and treatment are doing their best to
  avoid a poor outcome.
• Stress to parents and caregivers the importance
  of follow-up care after patients are discharged.
• Also stress that an infant whose symptoms worsen
  should be evaluated prior to the scheduled
  follow-up appointment or taken to the nearest
  emergency department for treatment.

29
Treatment I

• Treatment recommendations for children with fever
  of unknown etiology are based upon the child's
  appearance, age, and temperature.
• For children who do not appear toxic, treatment
  recommendations are as follows
• Consider no antibiotics however, if ANC is
  greater than 10,000, administer ceftriaxone (50
  mg/kg/dose).
• Schedule a follow-up appointment within 24-48
  hours and instruct parents to return with the
  child sooner if the condition worsens.
• Hospital admission is indicated for children
  whose conditions worsen or whose evaluation
  findings suggest a serious infection

30
Treatment II

• For children who appear toxic, treatment
  recommendations are as follows
• Admit child for further treatment pending
  culture results, administer parenteral
  antibiotics.
• Initially administer ceftriaxone, cefotaxime, or
  ampicillin/sulbactam (50 mg/kg/dose).

31
Consultations, Diet, Activity

• Consultations The need to consult with
  specialists depends upon the specialty of the
  physician who initially evaluated the patient and
  the ultimate source of fever. Typically, general
  pediatricians easily manage febrile infants on
  both an inpatient and outpatient follow-up basis.
  
• Diet Patient tolerance is the only restriction
  on diet. Physicians should monitor intake and
  output as an indication of the patient's status
  because these measurements may provide the first
  evidence of a disturbance that indicates illness.
  
• Activity Patient tolerance also determines
  activity level, which should be monitored for
  changes (eg, lethargy, irritability).

32
Review of Systems (ROS)

• prolonged fever and weight loss (cancer)
• myalgias, arthralgias (connective tissue disease)
  
• dyspnea, cough (TB, multiple pulmonary emboli,
  sarcoidosis)
• abdominal pain (intra-abdominal abscess, IBD,
  cancer)

33
(No Transcript)
34
(No Transcript)
35
(No Transcript)
36
Bachur RG et al., Pediatrics, 2001 108, 2, 311-16
37
Bachur RG et al., Pediatrics, 2001 108, 2, 311-16
38
Bachur RG et al., Pediatrics, 2001 108, 2, 311-16
39
Imaging studies

• PET scan may be useful in fever of unknown
  origin 58 patients with documented fever gt 3
  weeks and no diagnosis after 3 days of
  in-hospital evaluation underwent positron
  emission tomography using 18-F-fluorodeoxyglucose,
  PET scan was abnormal in 46 patients and helped
  determine diagnosis in 24 40 patients had both
  PET scans and gallium scans, both suggested
  diagnosis in 10, PET scan suggested diagnosis in
  an additional 4 (Clin Infect Dis 2001
  Feb32(2)191 in J Watch 2001 Mar 121(5)43)
• Society of Nuclear Medicine procedure guidelines
  for 111-indium-leukocyte scintigraphy for
  suspected infection/inflammation can be found at
  National Guideline Clearinghouse 2005 Jul 257088
  
• Society of Nuclear Medicine procedure guidelines
  for 99m Tc-exametazine (HMPAO)-labeled leukocyte
  scintigraphy for suspected infection/inflammation
  can be found at National Guideline Clearinghouse
  2005 Jul 257087
• Society of Nuclear Medicine procedure guideline
  for gallium scintigraphy in inflammation can be
  found at National Guideline Clearinghouse 2005
  Jul 257086
• American College of Radiology (ACR)
  Appropriateness Criteria for fever without source
  (pediatric) can be found at National Guideline
  Clearinghouse 2006 Apr 148602

40
Empiric antibiotic regimens for children with
sepsis, including possible meningitis

• early neonatal sepsis (0-4 wks) most likely
  caused by group B streptococci,
  aminoglycoside-susceptible coliform bacilli or
  Listeria monocytogenes empirical therapy
  includes ampicillin and gentamicin alternative
  would be ampicillin and cefotaxime or ceftriaxone
  with cefotaxime preferred since ceftriaxone can
  displace bilirubin and worsen hyperbilirubinemia
  (Pediatr 19880873)
• late-onset neonatal sepsis (4-8 weeks) includes
  group B strep and coliform bacilli plus
  Streptococcus pneumoniae, Neisseria meningitidis
  and Haemophilus influenzae older infants can be
  treated with ampicillin with cefotaxime or
  ceftriaxone
• in older infant and child (8 weeks - 12 years),
  most likely organisms are pneumococcus,
  meningococcus, H. flu, group A strep,
  gram-negative bacilli, S. aureus cefotaxime or
  ceftriaxone is suggested initial therapy
  alternative is ampicillin and chloramphenicol
  (chloramphenicol levels required)

41
Empiric antibiotic regimens for children with
sepsis, including possible meningitis

• gt 12 years most likely organisms are
  pneumococcus, S. aureus, meningococcus, group A
  strep, gram-negative bacilli initial choice is
  ampicillin or penicillin G alternatives include
  cefotaxime, ceftriaxone, chloramphenicol
  (chloramphenicol levels required)
• add vancomycin if suspected pneumococcal
  meningitis history of central venous catheter or
  recent NICU admission (to cover
  methicillin-resistant Staphyloccus epidermidis)
  or risk of methicillin-resistant S. aureus
• add clindamycin or metronidazole if
  intra-abdominal infection suspected

42
MAJOR RECOMMENDATIONS Background Information and
Definitions 111Indium (111In)-leukocyte
scintigraphy is a diagnostic imaging test which
displays the distribution of radiolabeled
leukocytes in the body. Regional, whole-body,
planar, and/or single photon emission computed
tomography (SPECT) scintigrams of specific
anatomic regions are obtained for suspected
infection/ inflammation. In osteomyelitis,
regional or whole-body bone scintigraphy may be
used in conjunction with 111In-leukocyte
scintigraphy to detect sites of abnormal bone
remodeling. Bone marrow scintigraphy using
99mTc-sulfur colloid can be a useful adjunct to
assess marrow distribution at suspected
osteomyelitis sites, particularly when the site
is adjacent to orthopedic hardware and the
neuropathic joint. Gallium scintigraphy is
usually preferred in patients with (a)
neutropenia or (b) nonsuppurative or
lymphocyte-mediated infections. 99mTc-HMPAO
(exametazime)-labeled leukocyte scintigraphy is a
frequently used option for acute infections,
particularly in pediatric patients.
43
Examples of Clinical or Research Applications

• To detect sites of infection/inflammation in
  patients with fever of unknown origin
• To localize an unknown source of sepsis and to
  detect additional site(s) of infection in
  patients with persistent or recurrent fever and a
  known infection site
• To survey for site(s) of abscess or infection in
  a febrile postoperative patient without
  localizing signs or symptoms. Fluid collections,
  ileus, bowel gas, fluid, and/or healing wounds
  reduce the specificity of computed tomography
  (CT) and ultrasound.
• To detect site(s) and extent of inflammatory
  bowel disease. 99mTc-labeled leukocytes may be
  preferable for this indication.
• To detect and follow up osteomyelitis primarily
  when there is increased bone remodeling secondary
  to joint prostheses, nonunited fractures, or
  sites of metallic hardware from prior bone
  surgery
• To detect osteomyelitis in diabetic patients when
  degenerative or traumatic changes, neuropathic
  osteoarthropathy, or prior osteomyelitis have
  caused increased bone remodeling
• To detect osteomyelitis involving the skull in
  postoperative patients and for follow-up of
  therapy
• To detect mycotic aneurysms, vascular graft
  infections, and shunt infections

44
Other diagnostic testing

• if focal neurological signs - CT head to rule out
  abscess, cancer
• if lethargy, confusion - LP to rule out
  meningoencephalitis, cancer
• if lymphadenopathy - HIV titer lymph node biopsy
  to rule out lymphoma, cancer
• if cough, dyspnea - bronchoscopy, consider
  gastric aspirate for AFB, consider V/Q scan
• if hepatosplenomegaly or abdominal pain - CT
  abdomen
• if cardiac murmur - echocardiography
• if hepatic dysfunction - liver biopsy
• review of liver biopsy can be found in N Engl J
  Med 2001 Feb 15344(7)495, commentary can be
  found in N Engl J Med 2001 Jun 28344(26)2030

45
Other diagnostic testing II

• if headache, tenderness over temporal artery -
  temporal artery biopsy
• if bone pain - bone scan, metastatic bone series,
  protein immunoelectrophoresis
• if guaiac-positive stool - colonoscopy or barium
  enema and sigmoidoscopy
• if hematuria - renal ultrasound, IVP, cystoscopy
• bone marrow exam in suspected lymphoma, leukemia,
  miliary TB
• gallium scan and exploratory laparotomy rarely
  helpful

46
Systemic inflammatory response syndrome, sepsis,
septic shock
47
Sepsis and Sepsis-Related Conditions Defined
according to the Criteria Proposed by the
American College of Chest Physicians/Society of
Critical Care Medicine
Gibot, S. et. al. Ann Intern Med 20041419-15
48
Prognosis

• over the last 10-15 years, new antibiotics and
  more sophisticated critical care have not changed
  high mortality rate of severe sepsis
• worsening neurologic, coagulation and renal
  dysfunction over first 3 days predicts increased
  mortality
• prospective study of 287 patients with sepsis
  syndrome in intensive care units pulmonary
  dysfunction was most common organ failure but not
  associated with 30-day mortality other organ
  failures were less common at onset but
  significantly associated with 30-day mortality
  rate (Crit Care Med 2000 Oct28(10)3405 in JAMA
  2001 Jan 17285(3)270)

49
Goal-directed therapy included

• central venous catheter that measured central
  venous oxygen saturation
• crystalloid 500 mg every 30 minutes as needed to
  maintain central venous pressure 8-12 mmHg
• vasopressors or vasodilators as needed to
  maintain mean arterial pressure 65-90 mmHg
• transfusion of red cells to hematocrit gt 30
• inotropic agents (dobutamine) as needed to
  maintain central venous oxygen saturation gt 70

50
Initial doses of IV antibiotics

• ampicillin 100-150 mg/kg (50 mg/kg in neonates),
  maximum 4 g
• cefotaxime 50-75 mg/kg, maximum 3 g
• ceftriaxone 100 mg/kg, maximum 2 g
• ceftazidime 75 mg/kg (50 mg/kg in neonates),
  maximum 2 g
• chloramphenicol 25 mg/kg, maximum 1 g
• doxycycline (usually not recommended in children
  lt 7) 2 mg/kg, maximum 100 mg
• gentamicin 2.5 mg/kg, maximum 100 mg (see also
  Single-daily dosing of aminoglycosides)
• penicillin G 50,000 units/kg, maximum 4 million U
  
• rifampin 20 mg/kg, maximum 600 mg

51
Corticosteroids

• steroids may increase or decrease mortality
  depending on dosing
• systematic review of 5 randomized trials of
  long-term (5-7 days) low-dose (mean total 1.2 g
  hydrocortisone equivalents) in sepsis or septic
  shock found improved survival and shock reversal
  
• meta-analysis of 8 earlier randomized trials of
  short-term (1-2 days) high-dose (mean total 24 g
  hydrocortisone equivalents) steroids found
  increased mortality and vasopressor dependence
  (Ann Intern Med 2004 Jul 6141(1)47
• low-dose corticosteroids for at least 5 days may
  reduce mortality
• systematic review of 15 trials of corticosteroids
  for severe sepsis or septic shock with 2,023
  patients did not find significant reduction in
  overall 28-day mortality but conclusions limited
  by heterogeneity which appeared related to
  different dosing strategies systematic review
  last updated 2003 Sep 19 (Cochrane Library 2004
  Issue 1CD002243), similar report can be found in
  BMJ 2004 Aug 28329(7464)480,