Principle _ Practice of Antimicrobial Usage.ppt

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Principle _ Practice of Antimicrobial Usage.ppt Powered By Docstoc
					Use of laboratory tests in
   infectious disease

      เภสั ชกรหญิงจิตตวดี กมลพุทธ
   M.Sc. in Pharm. (Clinical Pharmacy)
         วัตถุประสงค์ เชิงพฤติกรรม
• นิสิตสามารถอธิบายและประเมินผลทาง
  ห้ องปฎิบัติการในเรื่องโรคติดเชื้อได้

     Pharmaceutical Care


       Optimal outcome
       Non-optimal outcome
           Which agent is the best?
• Obvious drug of choice
• Individulization: IESAC
  – I = Indication
  – E = Efficacy
  – S = Safety
  – A = Adherence
  – C = Cost
• Is an antibiotic indicated on the basis of
  clinical findings?
• Signs and symptoms of infection
• Predisposing factors to infection
  - chemotherapy
• The defenitive answer = Laboratory testing
        Is an antibiotic indicated on the basis
                 of clinical findings?
                                         Obvious infection?
                         Yes                                                           No
                                          Urgent situation*
                         Yes                                                           No

                Treatment                                        Await for diagnosis
*sepsis, febrile neutropenia, possible acute endocarditis, bacterial meningitis, acute necrotizing cellulitis etc .
• Signs and symptoms of infection
• Temperature
  - Normal adult temperature
     mouth = 35.8 - 37.3 c
     axillae = 35.3 - 36.8 c
     rectal = 36.3 - 37.8 c
       Signs and symptoms of infection
• Main clinical manifestation is “FEVER”
• Fever = temperatures greater than 37.8 c
• But not all “FEVER” is infectious diseases
  - Malignancy
  - Autoimmune diseases
  - Drug-induced ( e.g. amphotericin B)
       Signs and symptoms of infection
• Drug-induced fever
  - Generally occurs after 7 - 10 days of therapy
  - Resolves within 48 hours of the drug’s
      Signs and symptoms of infection
• Local signs
  - Pain
  - Inflammation
  - Erythema
• Systemic
  - Chills
  - Rigors
   Laboratory testing
Nonspecific Blood Tests
• CBC: Absolute neutrophil count (ANC)
      -Too high or too low
    Conventional 3     International9
 3,200 - 9,800/mm       3.2 - 9.8 x 10 /L
• Consists of:
   neutrophils
   eosinophils             Granulocytes
   basophils
   lymphocytes
   monocytes
• Leukopenia:          • Leukocytosis:
  - Viral infection      - Bacterial infection
  - Anticonvulsants      - Leukemia
                         - Exercise
                         - Stress
                         - Corticosteroid
     Neutrophils, Polys, Segs, PMNs
        Conventional        International
         54 - 62 %            0.54 - 0.62 I
• with bacterial or parasite infection
• Hemorrhage
• Inflammatory disorder
• Corticosteroids
•   Shift to left (bands) • Shift to right (segs)
    - Infection             - Liver disease
    - Chemotherapeutic - Megaloblastic anemia
       agents               - Hemolysis
    - Leukemia              - Tissue breakdown
    - Hemorrhage            - Surgery
                            - Corticosteroids
         Conventional           International
           3-5%                  0.03 - 0.05 I

•   with bacterial infection (shift to the left)
    Absolute neutrophil counts (ANC)

• Absolute neutrophil counts (ANC)
  = % neutrophils x WBC
• ANC < 100 -- risk of bacteremia
• ANC > 1000 -- low risk of bacteremia
Risk of Infection according to ANC
                                      All Infections
 3   severe            mod mild


     < 100   100-499    500-999   > 1000
      ANC (cells/mm3)
        Erythrocyte Sedimentation Rate
            Conventional           International
Male        0 - 20 mm/hr           0 - 20 mm/hr
Female 0 - 30 mm/hr                0 - 30 mm/hr
  • is the rate at which erythrocytes settle to the
     bottom of the test tube through the force of
  • Monitored in

• is nonspecific
• with:
   chronic inflammation
   infection
   connective tissue disorders
   pregnancy
   nephritis
                      Efficacy and Safety

Pharmacokinetics                                  Infection

                   Toxicity       Immune status

         Drug                                            Organism

Gram-negative   Gram-positive
• Determining likely pathogens
  - Pneumonia
      community- acquired pneumonia
            - Streptococcus pneumoniae
            - Haemophilus influenzae
      nosocomial pneumonia
            - Enterobacter species
            - Pseudomonas aeruginosa
• Determining likely pathogens
  - Infective endocarditis:
       - Streptococcus viridans
       - Streptococcus bovis
       - Staphylococcus aureus
      Microbiological tests and Susceptibility of
•   The Gram’s stain
•   The India ink and potassium hydroxide (KOH) stains
•   The acid-fast bacilli (AFB) stain
•   Cultures
               Gram’s Stain
• One of the quick way to get the pathogens
• Negative results cannot exclude the infection
• Positive result may be contamination. So, other
  evidences are needed ( e.g. epidemiology,
  labs etc.)
                   Gram’s Stain
•   Gram + cocci          Strep, staph, Enterococci
•   Gram + rod            Corynebacterium, Listeria
•   Gram - cocci          Neiserria, Moraxella
•   Gram - rod            Enterobacteriaceae, Pseudo
•   Gram - coccobacilli   Haemophilus

           (Diplococci: Neisseria )

      (Chain, pairs: Streptococcus)

           (Cluster: Staphylococcus)
           Gram-negative Bacilli

 E. coli    H. influenzae   Acinetobacter sp. P. aeruginosa

Enterobacteriaceae           Nonenterobacteriaceae
           Microbiological tests
• The India ink and potassium hydroxide
  (KOH) stains
    - Fungi
• The acid-fast bacilli (AFB) stain
    - Mycobacterium tuberculosis
• Culture is the final identification of the
• Susceptibilities may be needed to guide the
  treatment: disk diffusion, broth dilution
• Useful but generally require 18-24 hours to
               Disk diffusion
- The disk diffusion technique utilizes an agar
   plate on which an inoculum of the organism
   is placed. After inoculation, several
   antimicrobial laden disks are placed upon the
   plate and evidence for bacterial growth is
   observed after 18-24 hours
- If the antimicrobial is active versus the
   pathogen, a zone of inhibition of growth is
   observed around the disk
Disk diffusion
             Susceptibility Tests
• Minimum inhibitory concentration: in vitro data
• Minimum bactericidal concentration (MBC) may
  be needed in severe infection: in vitro data
• Serum bactericidal test (SBT) may be needed in
  severe infection: in vivo data. Useful, but limited
  in practical use
   • ค่ าความเข้ มข้ นตาสุ ดของยาทีสามารถยับยั้งการ
                       ่           ่
     แบ่ งตัวและการเจริญเติบโตของเชื้อได้
                                       MIC = 1 mg/L

(mg/L) C    0.25   0.5     1      2      4      8     16
      • ความเข้ มข้ นตาสุ ดของยาทีสามารถฆ่ าเชื้อได้ ร้อยละ
                      ่             ่
        99.9 จากปริมาณเชื้อเริ่มต้ น
MBC = 4 mg/L                                              25%


           1       2       4                              0.1%
                                …. Antibiotic-free agar

(mg/L) C        0.25   0.5       1         2   4    8      16

  Susceptible                   MIC
                             Breakpoints       ระดับยา A
            Susceptibility Tests
• The National Committee for Clinical
  Laboratory Standards (NCCLS) : susceptible,
  intermediate or resistance
• It is relatively well standardized for aerobic
  gram-negative and gram-positive organisms
• Limitation: anaerobes and fungi
           Susceptibility Tests
• Antibiogram:
  - National Antimicrobial Resistance
  Surveillance Center Thailand (NARST)
  - Hospital: Ramathibodi, Siriraj
• Pharmacokinetic properties (PK)

• Pharmacodynamic properties (PD)
     Pharmacokinetic properties (PK)
• Pharmacokinetic : study of the absorption,
  distribution, metabolism and elimination of
  drugs and their metabolites in the body
• Clinical pharmacokinetics is the application
  of pharmacokinetics to the management of
ยาทีมี F > 80%, แต่ อาหาร/นมมีผลต่ อการดูดซึม
Drugs                F        Effect of food/milk
Cefaclor      well absorbed   Decreased Peak (suspension)
Ceftibuten          >90%      Decreased F with high calorie
Ciprofloxacin 60-80%          Increased Tmax from 1 to 2 hr
Leovofloxacin       99%       Decreased Peak by 14%
Moxifloxacin        86%       Increased Tmax by 2 hr
Metronidazole 100%            Decreased Peak
Ofloxacin          100%       Increaed Tmax
Roxithromycin well absorbed   Decreased F 21% (Food)
Tetracycline 75-80%           Decreased F by 65% (Milk),
                              Decreased F by 46% (Food)
    Pharmacodynamic properties (PD)
• Pharmacodynamic properties: study of drug
  site of action, concentration and the
  magnitude of the effect or effects produced
Susceptibility                  Pharmacokinetics
 MIC/MBC                        Serum/Tissue Conc.

                               Pharmacokinetics                                  Pharmaco
                  bioavailability          distribution
Dose of antibiotic drug         Drug Conc. in systemic           site of infection Interaction
administration                    circulation           distribution               with

                                                                                 toxic cure
Drug-induced fever

   เภสั ชกรหญิงจิตตวดี กมลพุทธ
M.Sc. in Pharm. (Clinical Pharmacy)
• Body temperature is controlled by the
• According to studies of healthy individuals 18-
  40 years, the mean oral temperature is 36.8±
  0.4 c, with low level at 6 A.M. and higher levels at
  4-6 P.M. The maximum normal oral temperature is
  37.2 c at 6 A.M. and 37.7 c at 4 P.M.
• Fever = temperatures greater than 37.8 c
• Fever is an elevation of body temperature that
  exceeds the normal daily variation and occurs in
  conjunction with an increase in the hypothalamic set
• A fever of > 41.5 c is call hyperpyrexia
• This extraordinarily high fever can develop in
  patients with severe infections but most commonly
  occurs in patients with central nervous system
  (CNS) hemorrhages.
               Pathogenesis of fever
• Pyrogens
• Pyrogen is used to describe any substance that causes
• Exogenous pyrogens are derived from outside the patient;
  most are microbial products, microbial toxins, or
• The lipopolysaccharide endotoxin produced by all gram-
  negative bacteria.
• Bacterial pyrogens is produced by gram-positive such as
  the enterotoxins of Staphylococcus aureus.
             Pathogenesis of fever
• Pyrogenic cytokines
• Cytokines are small protiens that regulate immune,
  inflammatory, and hematopoietic processes such as
  interleukin (IL).
• Some cytokines cause fever are called pyrogenic
• Pyrogenic cytokines include IL-1, IL-6, tumor
  necrosis factor (TNF) and interferon (IFN)
• Malignancy hyperthermia
• Autoimmune diseases
• Drug-induced fever
             Drug-induced fever
• In 1964, Cluff’s reported drug-induced fever.
• Up to 30 % of patients admitted to hospital will
  experience a drug reaction and 2-5 % of patients
  admitted to hospital have illnesses caused by drugs.
• The mechanism often poorly understood.
• It is important to differentiate drug fever from fever
  of other causes to avoid costly and potentially
  harmful investigation and administration of
  inappropriate therapy.
        Types of drug-induced fever
•   Fever associated with administration
•   Fever due to pharmacological action
•   Drug fever from altered thermoregulation
•   Drug fever and biochemical defects
•   Indirect drug fever
•   Drug fever secondary to hypersensitivity
        Types of drug-induced fever
• Fever associated with administration
• Administration-related fever is caused by microorganism-
  produced exogenous pyrogens and injection-induced
• The fever occurs during or shortly after the patient receives
  the medication.
• It is usually related to septicemia from contaminated
  materials or thrombophlebitis caused by intravenous
  catheters and drug solutions e.g. cephalothin, vancomycin
  and diazepam.
        Types of drug-induced fever
• Fever associated with administration
• The classical clinical picture is that of septicemia, with
  shaking chills followed by fever.
• Amphotericin B cause fever in a large percentage of patients
  by causing release of endogenous pyrogens.
• Fever with chills in about 50 % of patients who receive i.v.
  for the first time.
• Fever appears 1-2 hours after the start of i.v. infusion and
  subsides within 4 hours after its discontinuance.
• Fever may rise to as high as 40 c.
• The incidence of fever may decrease with continued therapy.
       Types of drug-induced fever
• Fever due to pharmacological action
• Drugs can cause fever due to the pharmacologic
  action are rare.
• Herxheimer reaction
    - Follows in a few hours the initiation of therapy for
    spirochetal diseases e.g. penicillin
    - Patients present with high fever, chills, myalgias,
    hypotension and leukocytosis reach maximum intensity
    about 8 hours after drug administration.
       Types of drug-induced fever
• Fever due to pharmacological action
• The direct effect of chemotherapeutic drugs on
  sensitive neoplasms
      - Massive cellular necrosis release endogenous
  pyrogens which cause fever.
       Types of drug-induced fever
• Drug fever from altered thermoregulation
• Direct effect on the central nervous system
  - e.g. amphetamines, cocaine, phenothiazines
• Decreased heat loss due to vasoconstriction (e.g.
  catecholamines) or decreased sweating (e.g.
  atropine: can cause a temperature up to 41 c)
       Types of drug-induced fever
• Drug fever from altered thermoregulation
• Monoamine oxidase inhibitors increase the
  catecholamine concentrations of tissues
  - Increased metabolic rate and heat production
  e.g. thyroid hormones, cimetidine
• Cimetidine can cause a temperature up to 39.5 c and
  readministering the drug causes fever within 12 hours
       Types of drug-induced fever
• Drug fever and biochemical defects
• Patients with glucose-6-phosphate dehydrogenase
  (G6PD) deficiency in whom hemolysis develops due
  to a drug exposure
  - Fever caused by release of endogenous pyrogen
  from damaged cells.
  - e.g. primaquine phosphate, quinine, sulfonamides
  and quinidine
  - May occur 2-3 days after drugs are ingested
       Types of drug-induced fever
• Drug fever and biochemical defects
• The malignant hyperthermia of anesthesia
  - e.g. succinylcholine, halothane
  - Characterized by fever (43 c), tachycardia, lactic
  acidosis, hyperkalemia, hypocalcemia, arrhythmia
  and rhabdomyolysis
  - Laboratory: raising of the serum creatine
  phosphokinase (CPK) levels and abnormal
  contracture of skeletal muscle
       Types of drug-induced fever
• Drug fever and biochemical defects
• The malignant hyperthermia of anesthesia
  - Patients at risk for this reaction may be identified
  by a history of previous anesthetic reactions or by a
  family history of adverse events during surgical
       Types of drug-induced fever
• Indirect drug fever
• Drugs can cause fever indirectly from overdose or
  excessive use are rare
  - e.g. anticoagulant
• Lysis of red cells can produce a few degrees of fever
       Types of drug-induced fever
• Drug fever secondary to hypersensitivity
• Hypersensitivity reaction is the most common cause
  of drug fever
• Rash, urticaria, eosinophilia, serum sickness or
  drug-induced systemic lupus erythematosus (SLE)
  may accompany the fever
• Fever unassociated with other symptoms occurs in
  3-4 % of patients
       Types of drug-induced fever
• Drug fever secondary to hypersensitivity
• Fever from drug hypersensitivity occurs more often
  in patients with atropy, severe infections and SLE.
• e.g. sulfonamides, penicillin, phenytoin,
  barbiturates, and methyldopa
• Antibiotics: penicillin is the most common antibiotic
  reported to cause fever
• Other antibiotics e.g. streptomycin, vancomycin and
        Types of drug-induced fever
• Drug fever secondary to hypersensitivity
• Phenytoin:
  - Symptoms occur from 2-6 weeks after the drug is
  administered and disappear after the drug is withdrawn
  - Recurrence has been elicited by readministration of the
• Procainamide:
  - Fever of 39 c - 40 c may be seen, develops after 2 weeks
  and may be associated with a maculopapular rash,
  splenomegaly, arthralgias, malaise and eosinophilia
  - The fever subsides within 48 hours after the drug is
        Types of drug-induced fever
• Drug fever secondary to hypersensitivity
• Methyldopa:
  - Fever has been reported in 1-6 % of patients
  - Fever occur 1-3 weeks after starting the initial therapy
  - Temperature range from 37.7 c - 41.5 c
  - Most patients have associated symptoms of malaise,
  chills and diarrhea
  - Readministration of the drug causes recurrence of fever
  within 6-12 hours
        Types of drug-induced fever
• Drug fever secondary to hypersensitivity
• Quinidine:
  - Fever may appear as early as 3 days or as late as 1 year
  after the drug regimen is begun, but most reactions occur
  within 3-19 days
  - Fever is not dose-related and disappears within 14-48 hours
  after the drug is withdrawn
  - Leukocytosis has been reported with quinidine fever
        Types of drug-induced fever
• Drug fever secondary to hypersensitivity
• Allopurinol:
  - A few patients have severe reactions consisting of fever,
  eosinophilia, hepatic and renal dysfunction and severe
  - In about 10 % of patients occur diarrhea, abdominal pain
  or skin rash
        Types of drug-induced fever
• Drug fever secondary to hypersensitivity
• Isoniazid:
  - The incidence of drug fever is low and occurs 1-7 weeks
  after initiating the therapy
  - Fever may appear after the first dose and may or may not
  be associated with hepatitis
  - Hypersensitivity may result in fever, rash, eosinophilia,
  vasculitis and meningoencephalitis
  - Readministering the drug produces fever in 2-3 hours
Agents commonly associated with drug-induced fever
     Atropine            Allopurinol       Captopril
     Amphotericin        Hydralazine       Cimetidine
     Penicillins         Isoniazid         Clofibrate
     Cephalosporins      Rifampicin        Heparin
     Phenytoin           Macrolides        Meperidine
     Procainamide        Clindamycin       HCTZ
     Quinidine           Vancomycin        Methyldopa
     Sulfonamides        Aminoglycosides   Nifedipine
          Diagnosis and treatment
• Drug fever should be suspected in any febrile
  patient receiving any medication.
• Urticaria, skin rash or eosinophilia are suggestive of
  drug fever
• Resolution of fever after withdrawal of a drug is
  strongly suggestive but the recurrence of fever on
  reexposure is definitive evidence of drug fever
• Past history can be of use if the patient can tell of
  previous medications
          Diagnosis and treatment
• Drug-induced fever found in numerous textbooks
  and review articles.
• Considerable variability has been reported in the
  length of time between the initiation of drug therapy
  and the onset of fever due to the drug.
• Drugs can be changed to alternatives of a different
          Diagnosis and treatment
• After stopping the drug, the fever will usually resolve
  within 3 days, although it may take as long as 2 weeks.
• If the fever remits, the physician can definitively
  confirm the diagnosis by re-instituting the agent, which
  characteristically elicits fever again within a few hours.
• This procedure is safe unless drug-induced organ
  damage e.g. interstitial nephritis or hepatitis, has
          Diagnosis and treatment
• When patients are receiving several drugs and
  hypersensitivity fever is suspected, all nonessential
  drug therapy should first be discontinued.
• No matter which mechanism proves responsible of
  drug-induced fever.
• It is only required that the physician always place it
  in the differential diagnosis of a febrile patient
Fever of Unknown Origin

     เภสั ชกรหญิงจิตตวดี กมลพุทธ
  M.Sc. in Pharm. (Clinical Pharmacy)
         วัตถุประสงค์ เชิงพฤติกรรม
• นิสิตสามารถอธิบายความสั มพันธ์ ระหว่ างอาการและ
  อาการแสดง ค่ าทางห้ องปฏิบัติการเพือใช้ ในการ
  ประเมิน Fever of unknown origin (FUO) ได้
• นิสิตสามารถให้ คาปรึกษาแนะนาแก่ ผ้ ูป่วยได้
• Fever of unknown origin (FUO) is one of the
  most challenging tests of the physician.
• FUO has been published in 1930.
• The Petersdorf and Beeson criteria for FUO, which
  standardized its definition in 1961 are:
   - A body temperature > 38.3 c for > 3 weeks; and
   - Failure to establish a diagnosis after 1 week of
• In deference to this new practice environment,
  cases of FUO are codified into 4 distinct
  subclasses of the disorder: classic FUO,
  nosocomial FUO, immune-deficient FUO, and
  human immunodeficiency virus (HIV) -associated
• Between 7-30 % of cases remain undiagnosed
  despite intensive evaluations.
                    Classic FUO
Definition       temp > 38.0 c, > 3 weeks, > 2 visits
                 or 3 days in hospital
Pt. location     Community, clinic, or hospital
Leading causes Cancer, infections, inflammatory
                 conditions, undiagnosed
History emphasis Travel, contacts, animal and insect
                 exposure, medications,
                 immunizations, Family history
                         Classic FUO
Examination               Fundi, oropharynx, temporal artery,
                          abdomen, lymph nodes, spleen, skin
Investigation             Imaging, biopsies, sedimentation rate,
                          skin tests
Management                Observation, outpatient temperature
                          chart, investigations, avoidance of
                          empirical drug treatments
Time course of            Months
Tempo of investigation    Weeks
               Nosocomial FUO
Definition       temp > 38.0 c, > 3 days, not
                 present or incubating on admission
Pt. location     Acute care hospital
Leading causes Nosocomial infections,
                 postoperative complications, drug
History emphasis Operations and procedures,
                 devices, drug treatment
                 Nosocomial FUO
Examination            Wounds, drains, devices,
                       sinuses, urine
Investigation          Imaging, bacterial cultures
Management             Depends on situation
Time course of disease Weeks
Tempo of investigation Days
             Immune-Deficient FUO
Definition       temp > 38.0 c, > 3 days, negative
                 cultures after 48 hrs
Pt. location     Hospital or clinic
Leading causes Majority due to infections, but
                 cause documented in only 40-60 %
History emphasis Stage of chemotherapy, underlying
                 immunosuppressive disorder,
                 drugs administered
            Immune-Deficient FUO
Examination            Skin folds, IV sites, lungs,
                       perianal area
Investigation          CXR, bacterial cultures
Management             Antimicrobial treatment
Time course of disease Days
Tempo of investigation Hours
               HIV-Related FUO
Definition       temp > 38.0 c, > 3 weeks for
                 outpatients, 3days for inpatients,
                 HIV infection confirmed
Pt. location     Community, clinic, or hospital
Leading causes HIV (primary infection), CMV,
                 lymphomas, toxoplasmosis,
History emphasis Drugs, travel, stage of HIV
                     HIV-Related FUO
Examination                Mouth, sinuses, skin, lymph
                          nodes, eyes, lungs, perianal
Investigation              Blood and lymphocyte count;
                          serologic tests; CXR; stool
                          examination; biopsies of lung, bone
                          marrow, and liver for cultures and
                          cytologic tests; brain imaging
Management                Antiviral and antimicrobial
                          protocols, vaccines, good nutrition
Time course of disease    Weeks to months
Tempo of investigation    Days to weeks
               Differential Diagnosis
• Several factors may limit the applicability of research
  literature on FUO to everyday medical practice.
• Factors include
  - The geographic lacation of cases
  - The type of institution reporting results (e.g.
  community hospital, university hospital, ambulatory
  - The specific subpopulations of patients with FUO who
  were studied
        Common etiologies of FUO
• Infections:
  - TB (esp. extrapulmonary)
  - Abdominal abscesses      - HIV
  - Pelvic abscesses         - Sinusitis
  - Dental abscesses         - Epstien-Barr virus
  - Endocarditis
  - Osteomyelitis
  - Cytomegalovirus
        Common etiologies of FUO
• Malignancies
  - Chronic leukemia
  - Lymphoma
  - Metastatic cancers
  - Renal cell carcinoma
  - Colon carcinoma
  - Hepatoma
  - Pancreatic carcinoma
        Common etiologies of FUO
• Autoimmune conditions
  - Adult Still’s disease *
  - Polymyalgia rheumatica
  - Temporal arteritis *
  - Rheumatoid arthritis
  - Inflammatory bowel disease
  - Systemic lupus erythematosus
        Common etiologies of FUO
• Miscellaneous
  - Drug-induced fever
  - Complications from cirrhosis
  - Hepatitis (alcoholic)
  - Deep venous thrombosis
            Infants and Children
• Respiratory infections cause classic FUO in infants
   more often than in children older than 12 months
  or adults.
• Kawasaki disease is predominantly a problem of
  children younger than 5 years.
               Elderly Persons
• Patients  65 yrs: high frequency with connective
  tissue diseases.
• Infections are identified as the cause of FUO,
  intra-abdominal abscesses, complicated urinary
  tract infections (UTI), tuberculosis, and
  endocarditis have predominated.
• Unfortunately, these diagnoses are frequently
  missed or delayed because associated symptoms
  are subacute and nonspecific.
  Final diagnosis in elderly vs younger patients
Diagnosis               65 yrs n=152 (%)    65 yrs n=201 (%)
Infections                      33 (21%)             72 (35%)
 Abscess                        6                    25
 Endocarditis                   2                    14
 Tuberculosis                   4                    20
 Viral infections               8                    1
 Other                          13                   12
Tumors                          8 (5%)               37 (19%)
Multisystem diseases            27 (17%)             57 (28%)
Miscellaneous                   39 (26%)             17 (8%)
No diagnosis                    45 (29%)             18 (9%)
               Nosocomial FUO
• Nosocomial FUO is a hospital-associated disorder
  in patients first manifest fever after having been
  hospitalized for at least 24 hrs.
• Risk factors
  - Surgical procedures
  - Urinary instrumentation
  - Respiratory tract instrumentation
  - Intravascular devices         - drug therapy
              Nosocomial FUO
• Examples of such disorders commonly offered, but
  not yet verified in actual surveys of nosocomial
  - septic thrombophlebitis
  - recurrent pulmonary emboli
  - Clostridium difficile colitis
  - Drug fever
 Immune-deficient fever of unknown origin
• The number of patients with neutropenia or
  impaired cell-mediated immunity, or both,
  resulting from cytotoxic therapy or hematologic
  malignant neoplasms is rising.
• Many episodes of fever in immune-deficient
  patients are short-lived, because they either
  respond quickly to treatment or are rapidly fatal
 Immune-deficient fever of unknown origin
• Infection has been identified as the cause of the
  fever in 60% or more of cases.
• The diagnosis has been presumptive, based on a
  favorable clinical response to antimicrobial
  therapy, rather than on the result of definitive
 Immune-deficient fever of unknown origin
• Infections caused by pyogenic bacteria are the
  most common cause of fever during episodes of
• These generally respond well to antibiotic therapy,
  whether or not the etiologic microorganism is
                HIV-Related FUO
• Although acute HIV infection remains an important
  cause of classic FUO, the virus also makes patients
  susceptible to opportunistic infections.
• The differential diagnosis of FUO in patients who are
  HIV positive includes infectious etiologies such as
  Mycobacterium tuberculosis, Mycobacterium avium
  complex (MAC), Pneumocystis carinii pneumonia,
  toxoplasmosis and cytomegalovirus.
             Causes of HIV-Related FUO
Cause                                          Percentage

Tuberculosis                                          35.5
Mycobacterium avium complex (MAC)                     11.5
Visceral leishmaniasis                                9.9
Pneumocystis carinii pneumonia                        5.6
Mycobacteria other than tuberculosis and MAC          4.5
Non-Hodgkin’s lymphoma                                4.2
Bacterial infections                                  3.9
Cytomegalovirus infection                             2.5
        Causes of HIV-Related FUO (cont.)
Cause                                Percentage

Toxoplasmosis                               2.4
Cryptococcosis                              1.5
Fever due to HIV                            1.3
Histoplasmosis                              0.5
Drug-induced fever                          0.5
Other causes                                2.2
Unknown                                     6.7
Nonspecified                                7.2
 Fever of unknown origin in other geographic regions
• The spectrum of disease in developing countries
  differs from that in the developed world.
• FUO in Spain over 25 years, including 914
  patients, demonstrated that brucellosis accounted
  for 16 % of infectious diagnoses and 8 % were due
  to parasitic causes.
• Studies of prolonged fever in Egypt note that 16 %
  of cases were diagnosed with a parasitic infection.
 Fever of unknown origin in other geographic regions
• Typhoid fever, tuberculosis, and melioidosis has
  been reported as a common cause of FUO in South
  East Asia.
• HIV infection is an important consideration
  throughout the developing and developed world.
• History and physical examination
• In the history, particular attention should be given to
  recent travel, exposure to pets and other animals, the
  work environment, and recent contact with persons
  exhibiting similar symptoms.
• The past medical history must be examined for
  previously diagnosed conditions (e.g. lymphoma,
  rheumatic fever, or prior abdominal disorder) the
  reactivation of which might account for the source of
• History and physical examination
• A complete list of the patient’s medications must
  be obtained, so that each can be evaluated as a
  potential source of drug-induced fever.
• Laboratory investigation
• The serologic tests for microbial pathogens.
• Imaging studies: Computed tomography (CT),
  ultrasound imaging
• Invasive procedures
  - Excisional biopsy
  - Needle biopsy
     Example of physical finding in patients with FUO
Body site         Physical finding     Diagnosis
Head              sinus tenderness     Sinusitis
Temporal artery   nodule s             Temporal arteritis
                  reduced pulsations
Oropharynx        ulceration           Disseminated histoplasmosis
                   tender tooth        Periapical abscess
Thyroid           enlargement          Thyroiditis
    Example of physical finding in patients with FUO (cont.)
Body site         Physical finding Diagnosis
Heart             murmur               Infective endocarditis
Rectum            tenderness           Abscess
Lower extremities Deep venous          Thrombosis or
                  tenderness           thrombophlebitis
Skin and nails petechiae               Vasculitis
                  splinter hemorrhages endocarditis
• Therapeutic trials
• The limitations and risks of empirical therapeutic
  - Inappropriate therapy
  - The false impression of successful therapeutic
• Fever caused by malignant neoplasms respond to
  NSAIDs e.g naproxen
• Therapeutic trials
• The limitations and risks of empirical therapeutic trials
  - Therapeutic trials, even when successful in reducing
  fever, may delay both the diagnosis and appropriate
  treatment of FUO.
• Empirical therapeutic trials are probably best reserved
  for few patients who has a rapidly progressive,
  potentially fatal illness or all other approaches have
  failed and patient who is too ill for therapy to be
  withheld pending further observation.
• The management of FUO is that therapy should be
  delayed until the cause of the fever has been
• In neutropenic FUO, the principles of treatment
  are different because of the relatively high
  prevalence of serious bacterial infections
  responsible for these fevers.
• Febrile neutropenic patients should generally
  received broad-spectrum antimicrobial therapy
  immediated after samples for appropriate cultures
  have been obtained.
• The prognosis of FUO is determined by both the
  cause of the fever and the underlying disease or
  diseases on which the disorder is superimposed.
• Elderly patients and those with malignant
  neoplasms have the poorest prognosis.
                  Selected causes
• Lymphoma
• Fever is well-recognized manifestation of malignant
  neoplasms, esp. the hematopoietic system or metastases
  to the liver.
• Fevers have been reported to be characteristic of fever
  associated with lymphomas, esp. Hodgkin’s disease.
• Different mechanisms have been postulated to cause
  such fevers: tumor necrosis, inflammation, and
  increased heat production by the tumor cells.
                  Selected causes
• Endocarditis
• Endocarditis is less common cause of FUO.
• Microorganisms causing endocarditis are generally
  easily identified.
• Microorganisms circulate continuously in the blood
  stream and blood culture techniques are highly efficient
  in isolating the bacterial species.
• The few cases that remain as causes of FUO belong to
  the special category of culture-negative endocarditis.
                Selected causes
• Endocarditis
• The incidence of culture-negative endocarditis has
  been reported between 2.5-31%.
• Microorganisms that cause endocarditis are
  difficult to isolate, e.g. the HACEK group
  (Haemophilus spp., Actinobacillus
  actinomycetemcomitans, Cardiobacterium spp.,
  Eikenella spp., and Kingella spp.), can be isolated
  within 5-7 days.
                Selected causes
• Endocarditis
• Bartonella spp. may require prolonged incubation
  for 2-3 weeks.
• Fungal endocarditis should be considered in
  intravenous drug users, patients with prosthetic
  heart valves and received prolonged i.v. antibiotic
                 Selected causes
• Adult Still’s Disease
• Its clinical features include high fever, arthralgias
  or arthritis, a transient maculopapular rash,
  lymphadenopathy, hepatosplenomegaly or
  abnormal liver function tests and sore throat.
• Leukocytosis is generally marked, and rheumatoid
  factor and antinuclear antibody tests are negative.
                   Selected causes
• Intra-abdominal abscess
• Localizing symptoms, such as abdominal pain, nausea,
  vomiting, or diarrhea, are common in liver and
  intraperitoneal abscesses and in chronic cholecystitis.
• Tenderness is also characteristic of most cases of liver,
  splenic, and intraperitoneal abscess.
• Infective endocarditis, biliary tract disease, and
  pancreatitis are associated with abscesses in the spleen,
  liver, and pancreas, respectively.

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