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Guidelines for Prevention and Treatment of Opportunistic Infections among HIV-Infected Children

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Title: Guidelines for Prevention and Treatment of Opportunistic Infections among HIV-Infected Children


1
Guidelines for Prevention and Treatment of
Opportunistic Infections among HIV-Infected
Children
  • Recommendations from Centers for Disease Control
    and Prevention,
  • the National Institutes of Health, the HIV
    Medicine Association of
  • the Infectious Diseases Society of America, the
    Pediatric Infectious
  • Diseases Society, and the American Academy of
    Pediatrics

2
About This Presentation
These slides were developed using the April 2008
Guidelines. The intended audience is clinicians
involved in the care of patients with HIV.
Users are cautioned that, because of the rapidly
changing field of HIV care, this information
could become out of date quickly. Finally, it is
intended that these slides be used as prepared,
without changes in either content or attribution.
Users are asked to honor this intent. Expert
opinion should be sought for complex treatment
regimens. AETC NRC
3
Contents
  • Introduction (slide 7)
  • Bacterial infections (slide 13)
  • Serious and recurrent bacterial infections,
    bartonellosis, syphilis
  • Mycobacterial infections (slide 45)
  • TB, MAC
  • Fungal infections (slide 76)
  • Aspergillosis, candidiasis, coccidiomycosis,
    cryptococcosis, histoplasmosis, PCP
  • Parasitic infections (slide 138)
  • Cryptosporidiosis/microsporidiosis, malaria,
    toxoplasmosis
  • Viral infections (slide 167)
  • CMV, HBV, HCV, HHV-6/7, HHV-8, HSV, HPV, PML,
    VZV

4
Diagnosis of HIV in HIV-Exposed Infants
  • HIV infected
  • HIV positive by HIV DNA or RNA PCR on 2 separate
    samples
  • or
  • If gt18 months and not breast-fed, positive by
    either antibody or PCR

5
ART and Management of OIs
  • Highly active antiretroviral therapy (ART)
    reduces the incidence of OIs and improves
    survival independent of antimicrobial prophylaxis
  • ART does not replace the need for OI prophylaxis
    in children with severe immunosuppression
  • ART in the setting of acute or latent OIs can
    lead to immune reconstitution inflammatory
    syndrome (IRIS)

6
Immune Reconstitution Inflammatory Syndrome
(IRIS)
  • Definition temporarily worsening of symptoms of
    inflammation or infection related to starting ART
  • Occurs after initiation of ART as immunity is
    restored
  • Results from an exaggerated immune response (eg,
    activation of latent or occult TB)
  • Treatment consists of nonsteroidal
    antiinflammatory drugs for moderate cases and
    corticosteroids for severe cases

7
Introduction
  • Mother-to-child transmission of OI is an
    important mode of acquisition
  • HIV-infected women coinfected with OI are more
    likely to transmit (eg, CMV, HCV)
  • HIV-infected women or HIV-infected family members
    are sources of horizontal transmission (eg, TB)

8
Differences between Adults and Children
  • OI in children often reflects primary infection
    rather than reactivation
  • OI occurs at a time when infants immune system
    is immature
  • Different disease manifestations (eg, children
    more likely to have nonpulmonic and disseminated
    TB)
  • Classical features of infection may not be present

9
Difficulty of Diagnosing OI in Children
  • Inability to describe symptoms
  • Antibody-based tests confounded by maternal
    transfer of antibody
  • Sputum difficult to obtain without invasive
    procedures

10
Frequency of OI among HIV-Infected Children
  • Pre-HAART era, most common OIs occurring at gt1
    events/100 child years
  • Serious bacterial infections (bacteremia and
    pneumonia), herpes zoster, Pneumocystis jiroveci
    (carinii) pneumonia, candidiasis, Mycobacterium
    avium complex
  • Pre-HAART era, most common OIs occurring at lt1
    events/100 child years
  • Cytomegalovirus, toxoplasmosis,
    cryptosporidiosis, TB, systemic fungal infections

11
Changes in Frequency of OI among HIV-Infected
Children
Infection Pre-HAART Rate per 100 Child Years Post-HAART Rate per 100 Child Years
Bacterial pneumonia 11.1 2.2
Herpes zoster 2.9 1.1
Disseminated Mycobacterium avium 1.8 0.14
Pneumocystis jiroveci 1.3 0.09
12
Treating OI among HIV-Infected Children
Rating of treatment recommendations is based on
opinion of working group
  • Letter indicating strength of recommendation (eg,
    A, B, C)
  • Roman numeral indicating nature of evidence (eg,
    I, II, III)

13
Serious Recurrent Bacterial Infections
Epidemiology
  • Most common infection in pre-HAART era (15/100
    child years)
  • Because of difficulties in obtaining appropriate
    diagnostic specimens, bacterial pneumonia is
    often a presumptive diagnosis in a child with
    fever, pulmonary symptoms, and an abnormal chest
    radiogram
  • Bacteremia more common in HIV-infected children
    with pneumonia

14
Serious Recurrent Bacterial Infections Epidemiolo
gy (2)
  • Bacteria isolated include Streptococcus
    pneumoniae, Haemophilus influenzae type B,
    Staphylococcus aureus, Escherichia coli,
    Pseudomonas aeruginosa, nontyphoid Salmonella
  • S pneumoniae accounts for gt50 of bacteremia
  • Incidence of S pneumoniae and H influenzae may be
    lower in regions where vaccines are administered

15
Serious Recurrent Bacterial Infections Epidemiolo
gy (3)
  • Increased risk of Haemophilus influenzae B,
    invasive meningococcal disease
  • Gram-negative bacteremia more common in children
    with advanced disease
  • Case mortality with gram-negative bacteremia gt40
  • Central venous catheter increases risk of
    bacterial infections

16
Serious Recurrent Bacterial Infections Clinical
Manifestations
  • Clinical presentation dependent on type of
    bacterial infection (eg, bacteremia, sepsis,
    vasculitis, septic arthritis, pneumonia,
    meningitis, sinusitis)
  • Presentation similar to that of HIV-uninfected
    children
  • Classical signs, symptoms, and laboratory tests
    may be missing in many HIV-infected children

17
Serious Recurrent Bacterial Infections Diagnosis
  • Isolation of pathogenic organism from normally
    sterile sites blood, bone marrow, CSF
  • Diagnosis of pneumonia by radiograph and physical
    findings
  • Culture of catheter tips
  • Sputum cultures may be difficult to obtain
  • Additional studies such as ultrasound should be
    considered
  • Assays for detection of bacterial antigens when
    available may be helpful

18
Serious Recurrent Bacterial Infections Prevention
  • Routine use of conjugated pneumococcal and
    Haemophilus influenzae B vaccine (not routinely
    available in resource-poor countries)
  • Avoid raw and undercooked foods, unsterilized
    water, unpasteurized milk products
  • Hand washing and other precautions
  • Avoid pets
  • Caution with all foods when traveling

19
Serious Recurrent Bacterial Infections Prevention
H influenza B
  • Children lt5 years of age should be given H
    influenza B (Hib) conjugate vaccine
  • Consider use in children gt5 years
  • Incompletely immunized children should receive 2
    doses gt8 weeks apart
  • Pneumococcal conjugate vaccines (A II)
  • gt5 years consider Hib conjugate vaccine 2 doses
    1-2 months apart
  • Children 2-59 months should receive the
    heptavalent pneumococcal vaccine (PCV) at 2, 4,
    6, and 12-15 months

20
Serious Recurrent Bacterial Infections Prevention
S pneumoniae
  • Previously unimmunized children aged 7-23 months
    should receive 2-3 doses of PCV
  • Incompletely immunized children should receive 2
    doses of PCV gt8 weeks apart
  • Children gt2 years of age should receive 23 valent
    PCV (gt2 months after last conjugate vaccine)
  • Reimmunize with PCV in 3-5 years in children aged
    lt10 years or after 5 years in children aged gt10
    years

21
Serious Recurrent Bacterial Infections Prevention
  • Trimethoprim sulfamethoxazole (TMP-SMX)
    prophylaxis reduces bacterial infection and new
    and recurrent episodes of malaria
  • Atovaquone plus azithromycin provides prophylaxis
    for MAC as well as PCP
  • Discontinue prophylaxis in children on ART with
    CD4 percentage gt15 with caution

22
Serious Recurrent Bacterial Infections Treatment
  • Patients with suspected serious bacterial
    infections should be treated empirically and
    promptly without waiting for laboratory results
  • Consider local prevalence of resistance of common
    infectious agents
  • Response of mildly immunodeficient children is
    similar to that of HIV-uninfected children

23
Serious Recurrent Bacterial Infections Treatment
(2)
  • Treat HIV-infected children outside the neonatal
    period with empiric therapy until cultures are
    available (A III)
  • Use extended spectrum cephalosporin such as
    ceftriaxone or cefotaxime
  • Consider addition of azithromycin for
    hospitalized patients with pneumonia
  • Add clindamycin or vancomycin if MRSA is suspected

24
Serious Recurrent Bacterial Infections Treatment
Failure
  • Consider bacterial resistance if treatment
    failure occurs
  • Consider nonbacterial cause such as TB, PCP,
    meningitis (Cryptococcus or TB)
  • Look for catheter-related infections
  • Occult abscess

25
Bartonellosis Epidemiology
  • Bartonella henselae and Bartonella quintana are
    primary species causing bacillary angiomatosis
    and peliosis
  • Bartonella bacteremia also occurs in HIV-infected
    individuals but is relatively uncommon in
    HIV-infected children
  • Bartonella henselae is associated with cat
    scratch disease in the general population

26
Bartonellosis Epidemiology (2)
  • Household cat is the primary vector
  • Eradication of flea infestation may be important
    in preventing infection, as contamination of cat
    claws is a possible mechanism of human infection
  • 90 of patients with cat scratch disease have a
    history of recent contact with cats
  • The vector for Bartonella quintana is the human
    body louse

27
Bartonellosis Clinical Manifestations
  • Clinical manifestations determined by host
    response
  • Localized disease consisting of suppurative
    regional lymphadenopathy is most common in
    patients with an intact immune system
  • Systemic infection is more common among
    immunocompromised individuals

28
Bartonellosis Clinical Manifestations
Bacillary angiomatosis
  • Rare disorder occurring in severely
    immunocompromised individuals
  • Characterized by cutaneous and subcutaneous
    angiomatous papules
  • Can be confused with Kaposi sarcoma
  • Nodules may be observed in the subcutaneous
    tissue and can erode to the skin

29
Bartonellosis Clinical Manifestations
Bacillary peliosis
  • Characterized by angiomatous masses in the
    visceral organs
  • The liver is most frequently infected
  • Individuals with bacillary peliosis and bacillary
    angiomatosis may have relapsing fevers
  • Dissemination can result in osteomyelitis,
    endocarditis, encephalopathy, seizures,
    neuroretinitis, and transverse myelitis
  • Nonspecific symptoms include fever, chills, night
    sweats, anorexia, weight loss, abdominal pain,
    vomiting, and diarrhea

30
Bartonellosis Diagnosis
  • Diagnosis usually made by means of a biopsy with
    demonstration of small gram-negative bacilli
  • Isolated with difficulty from blood and tissue
    culture
  • Indirect fluorescent antibody and enzyme
    immunoassay tests are available at some
    laboratories
  • Cross-reactivity among Bartonella species and
    other bacteria is common
  • PCR is the most sensitive means of diagnosis

31
Bartonellosis Prevention
  • Reduce exposure to cats and cat fleas
  • Treat infestations of body lice
  • Consider risk of ownership of cats, especially
    for individuals who are severely immunocompromised

32
Bartonellosis Treatment
  • Treatment of cat scratch disease in
    immunocompetent individuals is mainly supportive
  • In vitro and in vivo antibiotic susceptibilities
    do not correlate well with efficacy
  • Drug of choice is erythromycin or doxycycline
  • Clarithromycin and azithromycin treatment has
    been associated with clinical responses

33
Bartonellosis Treatment (2)
  • Severe disease requires IV administration
  • Treatment should be given for 3 months for
    bacillary angiomatosis and 4 months for bacillary
    peliosis central nervous system disease,
    osteomyelitis and other severe systemic
    infections
  • Add rifampin to either erythromycin or
    doxycycline for severely infected
    immunocompromised individuals

34
Bartonellosis Treatment Failure
  • Immunocompromised individuals who experience
    treatment failure should be re-treated for 4-6
    months
  • Immunocompromised HIV-infected adults who
    experience relapse have been treated with
    long-term suppression with doxycycline or a
    macrolide when CD4 counts are lt200 cells/µL
  • There are no data for children

35
Syphilis Epidemiology
  • Perinatal transmission of Treponema pallidum at
    any stage of pregnancy or during delivery
  • Illicit drug use during pregnancy increases risk
    of maternal and congenital syphilis
  • Rate of congenital syphilis 50 times greater
    among infants born to HIV-infected mothers
  • Half of new infections are in women 15-24 years
    of age

36
Syphilis Clinical Manifestations
  • Untreated early syphilis in pregnancy leads to
    spontaneous abortion, stillbirth, hydrops,
    preterm delivery, death in up to 40 of
    pregnancies
  • 47 of infants born to mothers with inadequately
    treated syphilis have clinical, radiographic, or
    laboratory findings consistent with congenital
    syphilis

37
Syphilis Clinical Manifestations (2)
  • 60 of infants with congenital syphilis have
    hepatomegaly, jaundice, skin rash, nasal
    discharge, anemia, thrombocytopenia, osteitis,
    periostitis, osteochondritis, or pseudoparalysis
  • Late manifestations include mental retardation,
    keratitis, deafness, frontal bossing, Hutchinson
    teeth, saddle nose, Clutton joints

38
Syphilis Diagnosis
  • Use combination of physical, radiologic,
    serologic, and direct microscopic results, as
    standard serologic tests detect only IgG
  • All infants born to mothers with reactive
    nontreponemal and treponemal tests should be
    evaluated with a quantitative nontreponemal test
    (eg, slide test, RPR, automated reagin test)

39
Syphilis Diagnosis (2)
  • Darkfield microscopy or direct fluorescent
    antibody staining
  • Presumptive diagnosis any infant, regardless of
    physical findings, born to an untreated or
    inadequately treated mother with syphilis

40
Syphilis Prevention Congenital Syphilis
  • Routinely screen all pregnant women with
    serologic testing during first prenatal visit
  • Obtain information regarding the treatment of
    sexual partners for sexually transmitted diseases
  • Serologic testing of mothers serum is preferable
  • Routine screening of newborns serum or umbilical
    cord blood is not recommended

41
Syphilis Prevention Acquired Syphilis
  • Routine discussion of sexual behaviors that place
    individuals at risk of syphilis and HIV
  • Routine serologic screening for syphilis annually
    for all sexually active HIV-infected individuals
  • The occurrence of syphilis in an HIV infected
    individual is an indication of high-risk behavior
  • Individuals undergoing screening or treatment for
    syphilis should be evaluated for all sexually
    transmitted diseases

42
Syphilis Treatment Congenital Syphilis
  • Treat all infants whose mothers have untreated or
    inadequately treated syphilis not treated or
    initiated treatment 4 weeks prior to delivery
  • Treat if mother treated with penicillin but no
    4-fold decrease in nontreponemal antibody titer,
    or a 4-fold increase suggesting relapse or
    reinfection
  • Treat infants regardless of maternal history if
    examination suggests syphilis darkfield or
    fluorescent antibody test positive or
    nontreponemal serologic titer 4-fold higher
    than maternal level (A II)

43
Syphilis Treatment Congenital Syphilis (2)
  • Aqueous crystalline penicillin G 100,000-150,000
    units/kg/day given as 50,000 units/kg/dose IV
    Q12H for 7 days, followed by Q8H for a total of
    10 days (A II)
  • Diagnosis after 1 month of age, increase dosage
    to 50,000 units/kg IV Q6H for 10 days

44
Syphilis Treatment Acquired Syphilis
  • Treat acquired syphilis with single dose of
    benzathine penicillin G 50,000 units/kg IM
  • Treat late latent disease with benzathine
    penicillin G 50,000 units/kg IM once weekly for 3
    doses (A III)
  • Alternative therapies among HIV-infected patients
    have not been evaluated
  • Treat neurosyphilis with aqueous penicillin G
    200,000 to 300,000 units/kg IV Q6H for 10-14 days
  • Follow up with examinations at 1, 2, 3, 6, and 12
    months and serologic tests at 3, 6, and 12
    months if titers continue to be positive or
    increase, consider retreatment (A III)

45
Mycobacterium tuberculosis Epidemiology
  • 14,000 new cases of TB in United States in 2006
    (6 among children lt15 years of age)
  • 1.1 of these were HIV infected
  • Incidence of TB in HIV-infected children 100
    times higher than in uninfected
  • In South Africa, as many as 48 of children with
    TB were coinfected with HIV

46

Mycobacterium tuberculosis Epidemiology (2)
  • CD4 count is not a sufficient indicator of TB
    risk
  • Primarily infection by contact with adults in
    daily environment
  • In most cases, TB represents the progression of
    primary infection rather than a reactivation of
    disease
  • All confirmed and suspected TB cases should be
    reported to health authorities

47

Mycobacterium tuberculosis Epidemiology (3)
  • BCG induced M tuberculosis has been reported in
    HIV-infected children vaccinated at birth
  • In the United States, resistance to any of the
    first-line anti-TB drugs occurs in 15 of
    children
  • Internationally, rate of multiple drug-resistant
    (MDR) TB is increasing

48

Mycobacterium tuberculosis Epidemiology (4)
  • Extrapulmonary and miliary TB more common in
    children lt4 years old
  • Congenital TB has been reported
  • Drug-resistant TB can be transmitted
  • Patients should be treated under assumption that
    drug resistance profiles of source and patient
    are similar

49
Mycobacterium tuberculosis Clinical
Manifestations
  • Younger children progress more rapidly (possibly
    due to delayed diagnosis)
  • Nonspecific symptoms fever, weight loss, failure
    to thrive
  • Pulmonary TB most likely appears as infiltrate
    with hilar adenopathy
  • Clinical presentation of TB similar in
    HIV-infected and HIV-uninfected children
  • Extrapulmonary marrow, lymph node, bone, pleura,
    pericardium, peritoneal

50
Mycobacterium tuberculosis Diagnosis
  • Difficult to diagnose maintain a degree of
    suspicion
  • M tuberculosis detected in up to 50 of gastric
    aspirate in HIV-uninfected children (obtain 3
    consecutive morning gastric aspirates)
  • Usually requires linking TB in child to contact
    along with positive radiograph, positive skin
    test (TST), or physical examination

51
Mycobacterium tuberculosis Diagnosis (2)
  • Cornerstone for latent TB is the TST
  • TST not of value if BCG immunization has been
    administered
  • Annual TB testing recommended for HIV-infected
    children
  • HIV-infected children may have a negative TST
  • Sensitivity to TST may be reduced if other viral
    infection, such as measles, is present

52
Mycobacterium tuberculosis Diagnosis (3)
  • Assays for interferon gamma release following
    stimulation of lymphocytes have been approved by
    the FDA for diagnosis of TB (eg, QuantiFERON-TB)
  • Tests for sputum using nucleic acid amplification
    approved but not fully evaluated in children
  • Patients with a positive test for latent TB
    infection (LTBI) should have any chest radiograph
    and clinical evaluation to rule on active disease

53
Mycobacterium tuberculosis Diagnosis (4)
  • MDR TB should be suspected in a child with TB
    disease if the child has
  • Close contact with the patient with MDR TB
  • Contact with a TB patient who died while on
    treatment when there is reason to suspect MDR TB
  • Bacteriologically proven TB that has not
    responded to first-line drugs
  • Exposure to source cases that remain smear or
    culture positive 2 months after treatment
  • History of living in a region with a high
    prevalence of MDR TB

54
Mycobacterium tuberculosis Prevention
  • Children who are homeless, live in institutional
    settings, or have close family contacts in
    communities with high rates of coinfection with
    TB and HIV are particularly susceptible
  • BCG immunization is not routinely administered in
    the United States and should NOT be administered
    to HIV-infected children because of risk of BCG
    dissemination
  • Treat HIV-infected children for LTBI if they have
    a positive TST result

55
Mycobacterium tuberculosis Prevention (2)
  • HIV-infected children should be treated if they
    are exposed to a person who has contagious TB
  • Duration of preventive treatment for children
    should be 9 months with isoniazid 10-15 mg/kg/day
    (A II) or 20-30 mg/kg twice weekly (B II)
  • If isoniazid resistance is suspected, use
    rifampin for 4-6 months

56
Mycobacterium tuberculosis Treatment
  • Treatment principles similar in HIV-infected and
    HIV-uninfected children
  • Initiate treatment as soon as possible in
    children with suspected TB
  • If already on ART, review drug interactions
  • Use of DOT increases adherence, decreases
    resistance, treatment failure, and relapse

57
Mycobacterium tuberculosis Treatment (2)
  • Initial treatment (induction phase)
  • 4 drugs isoniazid, rifampin, pyrazinamide, plus
    either ethambutol or streptomycin (A I)
  • If the organism is found to be susceptible to
    isoniazid, rifampin, and pyrazinamide during the
    2-month intensive phase, ethambutol (or
    streptomycin) can be discontinued
  • Use ethionamide as alternative to ethambutol for
    CNS disease (A III)

58
Mycobacterium tuberculosis Treatment (3)
  • If clinical response occurs and organism is
    susceptible to isoniazid and rifampin after 2
    months, continue treatment with isoniazid and
    rifampin 2-3 times weekly or daily during the
    continuation phase
  • Children with severe immunosuppression should
    receive only daily or 3-times-weekly treatment
    during the continuation phase
  • Ethionamide can be used as alternative to
    ethambutol for TB meningitis
  • Minimum treatment is 6-9 months for children with
    active pulmonary TB and 12 months for
    extrapulmonary disease (A III)

59
Mycobacterium tuberculosis Treatment (4)
  • Isoniazid
  • Dosage 10-15 mg/kg orally once daily (maximum
    300 mg daily)
  • Hepatic toxicity increases with rifampin
  • Peripheral neuritis, mild CNS toxicity, gastric
    upset

60
Mycobacterium tuberculosis Treatment (5)
  • Rifampin
  • Dosage 10-20 mg/kg orally once daily (maximum
    600 mg daily)
  • Side effects include rash hepatitis jaundice
    GI upset orange coloring of urine, tears, sweat
  • Rifampin can accelerate clearance of PIs (except
    RTV) and NNRTIs

61
Mycobacterium tuberculosis Treatment (6)
  • Rifabutin (B III)
  • Dosage 10-20 mg/kg orally once daily
  • Limited data in children
  • Peripheral leukopenia, elevated liver enzymes,
    pseudojaundice, GI upset
  • Increases hepatic metabolism of certain PIs
    reduce rifabutin dosage by 50 when given with
    RTV, IDV, NFV, APV
  • Increase dosage of rifabutin by 50-100 when
    given with EFV

62
Mycobacterium tuberculosis Treatment (7)
  • Pyrazinamide
  • Dosage 20-40 mg/kg orally once daily (maximum 2
    g daily)
  • Hepatic toxicity, rash, arthralgia, GI upset
  • Ethambutol
  • Dosage 15-25 mg/kg orally daily (maximum 2.5 g
    daily)
  • Toxicity includes optic neuritis, rash, nausea

63
Mycobacterium tuberculosis Treatment (8)
  • Secondary drugs
  • Ethionamide 15-20 mg/kg orally divided into 2 or
    3 doses daily (maximum dosage 1 g daily)
  • Streptomycin 20-40 mg/kg daily IM (maximum
    dosage 1 g daily)
  • Alternatives kanamycin, amikacin, capreomycin,
    quinolones, cycloserine, paraaminosalicylic acid
  • Steroids may be indicated for TB meningitis

64
Mycobacterium tuberculosis Treatment (9)
  • Treatment of TB in setting of ART may be
    complicated by unfavorable pharmacokinetic
    interactions and overlapping toxicities
  • Use of rifampin precludes treatment with protease
    inhibitors but may allow treatment with NNRTIs
  • Starting treatment with NNRTIs is preferred
    because of fewer interactions with rifampin-based
    TB therapy (B II)
  • Efavirenz is the preferred NNRTI for children gt3
    years of age whereas nevirapine is preferred for
    children lt3 years of age

65
Mycobacterium tuberculosis Treatment (10)
  • Children already receiving ART should receive
    immediate treatment for TB accompanied by a
    review of overlapping toxicities and drug-drug
    interactions
  • Drug-resistant TB should be treated with a
    minimum of 3 drugs, including 2 or more
    bactericidal isolate-susceptible drugs
  • Regimens may include 3-6 drugs
  • Adjunct treatment with corticosteroids may be
    indicated for children with TB meningitis

66
Mycobacterium tuberculosis Monitoring and
Adverse Effects
  • Monthly monitoring of clinical and
    bacteriological responses to treatment
  • Side effects of drugs include nausea, vomiting,
    hepatotoxicity, nephrotoxicity, and optic
    neuritis with ethambutol
  • IRIS associated with new onset of systemic
    symptoms in HIV-infected individuals receiving
    ART
  • Data on occurrence of IRIS in children are
    incomplete
  • Treatment with corticosteroids has been used in
    severe cases

67
Mycobacterium avium Complex Disease Epidemiology
  • Multiple related species of non-TB mycobacteria
    M avium, M intracellulare, M paratuberculosis
  • Second most common OI in children after PCP but
    decreases in incidence with ART
  • Associated with soil exposure and racial
    susceptibility
  • Acquired by means of inhalation, ingestion, or
    inoculation

68
Mycobacterium avium Complex Disease
Epidemiology (2)
  • 72 of children with isolated pulmonary MAC
    develop disseminated MAC by 8 months
  • May appear as isolated lymphadenitis
  • Frequency increases with age and declining CD4
    T-cell count

69
Mycobacterium avium Complex Disease Prevention
  • Most effective means of prevention is to preserve
    immune function with ART
  • Offer prophylaxis for MAC as follows (A II)
  • CD4 T-cell risk factor for occurrence
  • lt750 cells/µL lt1 year lt500 cells/µL 1-2 years
    lt75 cells/µL 2-5 years lt 50 cells/µL gt6 years
  • Use either clarithromycin or azithromycin (A II)
  • Studies suggest that prophylaxis may be
    discontinued when CD4 percentages reach 20 to
    25 while on stable ART

70
Mycobacterium avium Complex Disease Clinical
Manifestations
  • Recurrent fever, weight loss, failure to thrive,
    neutropenia, night sweats, chronic diarrhea,
    malabsorption, abdominal pain
  • Lymphadenopathy, hepatomegaly, splenomegaly
  • Respiratory symptoms uncommon among children
  • Laboratory abnormalities include anemia,
    leukopenia, and thrombocytopenia

71
Mycobacterium avium Complex Disease Diagnosis
  • Isolation of organism from biopsy, blood, bone
    marrow, lymph node, or other tissue
  • Histology demonstrating macrophage containing
    acid-fast bacilli strongly indicates MAC
  • Culture is essential for differentiating from TB
  • Isolation from stool or respiratory does not
    necessarily indicate invasive disease

72
Mycobacterium avium Complex Disease Treatment
  • Preserve immune function through optimal
    treatment of HIV infection
  • Initiate treatment with 2 or more drugs (eg,
    clarithromycin or azithromycin plus ethambutol)
    (A I)
  • Consider rifabutin as third drug in severely ill
    patients (C I)
  • Caution in using rifabutin as it may increase
    toxicity of other ARVs and increase clearance of
    PIs and NNRTIs

73
Mycobacterium avium Complex Disease Treatment
(2)
  • Note cautions in use of these drugs with ARVs
  • If rifabutin cannot be used or if drug failure
    occurs, consider ciprofloxacin, amikacin,
    streptomycin, and a quinolone
  • Lifelong suppressive therapy required after
    initial therapy
  • IRIS may occur as indicated by new onset of
    symptoms
  • Toxicities of drugs include nausea, vomiting,
    liver toxicity, hypersensitivity reactions and,
    with ethambutol, optic neuritis

74
Mycobacterium avium Complex Disease Treatment
(3)
  • Clarithromycin 7.5-15 mg/kg orally twice daily
    (maximum 500 mg twice daily) (A I)
  • Azithromycin 10-12 mg/kg once daily (maximum 500
    mg daily) (A II)
  • Ethambutol 15-25 mg/kg single oral dose (maximum
    1 g) (A I)

75
Mycobacterium avium Complex Disease Treatment
(4)
  • Rifabutin 10-20 mg/kg orally once daily (maximum
    300 mg daily) (A I)
  • Ciprofloxacin 20-30 mg/kg IV or orally once
    daily (maximum 1.5 g)
  • Amikacin 15-30 mg/kg/day IV divided every 12-24
    hours (maximum 1.5 g) (C III)

76
Aspergillosis Epidemiology
  • Aspergillus species are ubiquitous molds found in
    soil, on plants, and in decomposing organic
    materials
  • The most common species causing aspergillosis are
    A fumigatus and A flavus
  • Rare but frequently lethal infection
  • Risk factors include low CD4 count, neutropenia,
    corticosteroids, concurrent malignancy with
    chemotherapy, HIV-related phagocytic impairment,
    previous respiratory infections, broad-spectrum
    antibiotic exposure

77
Aspergillosis Clinical Manifestations
  • Pulmonary aspergillosis is the most common
    presentation
  • Invasive pulmonary aspergillosis associated with
    fever, cough, dyspnea, pleuritic pain
  • Additional manifestations include necrotizing
    tracheobronchitis, pseudomembranous
    tracheobronchitis, CNS involvement, cutaneous,
    sinus, middle ear and mastoid infection

78
Aspergillosis Diagnosis
  • Usually isolated from the blood but also readily
    isolated from lung, sinus, brain, and skin biopsy
  • Definitive diagnosis includes histopathologic
    demonstration of organisms in biopsy specimens
  • Presumptive diagnosis of respiratory tract
    infection can be made if Aspergillus species is
    recovered from respiratory sample

79
Aspergillosis Diagnosis (2)
  • Chest radiograph demonstrates either diffuse
    interstitial pneumonitis or localized
    wedge-shaped infiltrates
  • CT of chest may be used to identify a halo sign
  • Cavitation and air crescent formation in chest
    CDT more frequent in older children and adults

80
Aspergillosis Prevention
  • Consider excluding plants and flowers from rooms
    and avoiding food items such as nuts and spices
  • Erect suitable barriers between patient care and
    construction sites, clean shower heads routinely
    as well as hot-water faucets and air-handling
    systems

81
Aspergillosis Treatment
  • Voriconazole is recommended for treatment of
    invasive aspergillosis
  • Adult data indicate that voriconazole is superior
    to amphotericin B but data in children are
    limited
  • Recommended dosage for children is 6-8 mg/kg IV
    (or 8 mg/kg orally) Q12H, followed by 7 mg/kg IV
    or orally twice daily
  • Treatment is continued for 12 weeks

82
Aspergillosis Adverse Effects and Treatment
Failure
  • Voriconazole side effects include reversible
    dose-dependent visual disturbances, elevated
    liver enzymes, and occasional skin rash
  • Amphotericin toxicity is associated primarily
    with fever, chills, and nephrotoxicity
  • Efficacy of antifungal therapy for aspergillosis
    is poor
  • Experimental approaches include evaluation of
    caspofungin

83
Candida Infections Epidemiology
  • Most common fungal infections in HIV-infected
    children
  • Thrush and diaper dermatitis occur in 50-85 of
    HIV-infected children
  • In pre-ART era, oropharyngeal candidiasis found
    in 94 of children with Candida esophagitis
  • Disseminated candidiasis rare in children except
    those with CMV or HSV coinfection, and those with
    central venous catheter

84
Candida Infections Epidemiology (2)
  • A substantial percentage of children with
    fungemia receive oral, systemically absorbable
    azole antifungals (eg, ketoconazole)
  • Complications include disseminated infection of
    bone, liver, and kidney endophthalmitis
  • Mortality from disseminated candidiasis gt90 in
    children with fever and symptoms gt14 days

85
Candida Infections Clinical Manifestations
  • Thrush and erythematous, hyperplastic, and
    angular cheilitis
  • Esophageal candidiasis may present with
    odynophagia, dysphagia, or retrosternal pain
  • Children may develop nausea, vomiting, or weight
    loss and dehydration
  • New onset of fever in individuals with central
    venous catheters
  • Systemic fungemia may lead to endophthalmitis

86
Candida Infections Diagnosis
  • Culture and KOH preparation with microscopic
    demonstration of budding yeast cells in wet
    mounts or biopsy
  • Blood culture using lysis centrifugation
  • Cobblestone appearance on barium swallow
  • Perform endoscopy in refractory cases to look for
    CMV, HSV, MAC coinfections
  • Research studies or evaluating detection of
    candidate antigens for early diagnosis

87
Candida Infections Prevention
  • Routine primary prophylaxis of candidiasis in
    HIV-infected children is not indicated
  • Candida organisms are common commensals on
    mucosal surfaces in healthy individuals and no
    measures are available to reduce exposure

88
Candida Infections Treatment
  • Treat early uncomplicated oropharyngeal
    candidiasis (OPC) with topical therapy
  • Cotrimoxazole 10 mg troches 4-5 times/day for 2
    weeks (B II)
  • Nystatin suspension 4-6 mL (400,000-600,000
    units/mL) 4 times/day
  • Amphotericin B suspension (100 mg/mL) 1 mL 4
    times/day

89
Candida Infections Treatment (2)
  • Oral systemic therapy for OPC
  • Fluconazole 3-6 mg/kg orally once daily for 7-14
    days (A I)
  • Itraconazole 2.5 mg/kg orally BID for 7-14 days
    (A I)
  • Ketoconazole 5-10 mg/kg/day orally divided into
    2 doses given for 14 days (D II)
  • Amphotericin oral suspension or IV for OPC
    refractory to other treatment

90
Candida Infections Treatment (3)
  • Esophageal disease
  • Treat both diagnosed esophageal disease and
    children with OPC and esophageal symptoms (A I)
  • Initiate treatment with
  • Fluconazole 6 mg/kg/day orally or IV on day 1
    followed by 3-6 mg/kg for 14-21 days (A I)
  • Itraconazole oral solution 2.5 mg/kg/dose given
    twice daily or 5 mg/kg once daily for 14-21 days
    (A I)
  • Consider low-dose IV amphotericin B minimum of 7
    days for refractory disease (B II)

91
Candida Infections Treatment (4)
  • Esophageal disease
  • Other therapies not fully evaluated in children
  • Voriconazole loading dose of 6 mg/kg IV Q12H on
    day 1, followed by 4 mg/kg Q12H thereafter after
    stabilization, change to oral dosing
  • Caspofungin available only in IV form lt50 kg
    dosage range 0.8-1.6 mg/kg daily gt50 kg, adult
    dosing

92
Candida Infections Treatment (5)
  • Invasive disease
  • Remove central venous catheter
  • Amphotericin B (A I)
  • 0.5-1.5 mg/kg once daily IV over course of 1-2
    hours, administered in 5 dextrose at final
    concentration of 0.1 mg/mL
  • For mild to moderate disease, begin at 0.25-0.5
    mg/kg and increase as tolerated to 1.5 mg/kg
  • Once stabilized, administer 1.5 mg/kg every other
    day (B III)
  • Treat for 3 weeks after last positive blood
    culture of symptoms

93
Candida Infections Treatment (6)
  • Invasive disease alternative therapy
  • Fluconazole in stable patients with uncomplicated
    candidemia without previous azole treatment
    (identification of Candida species essential C
    krusei and C glabrata are resistant) (E III)
  • Amphotericin lipid formulations (limited
    pediatric experience)
  • Amphotericin lipid complex (ABLC, Abelcet)
  • Liposomal amphotericin lipid complex (AmBisome)
  • Amphotericin B cholesteryl sulfate complex (ABCD)

94
Candida Infections Treatment (7)
  • Treatment under development
  • Caspofungin, micafungin, and anidulafungin have
    been studied in battles with HIV infection,
    neutropenic children at risk of fungal infection
    in children with documented candidiasis
  • Data on HIV-infected children are limited

95
Candida Infections Treatment (8)
  • Amphotericin toxicity
  • Nephrotoxicity azotemia, hypokalemia
  • Nephrotoxicity can be minimized by hydration with
    0.9 saline intravenously 30 minutes before
    amphotericin B infusion
  • Infusion-related chills, fever, and vomiting
    pretreat with acetaminophen or diphenhydramine
  • Rarely hypotension, arrhythmias, neurotoxicity,
    hepatic toxicity

96
Candida Infections Treatment (9)
  • Fluconazole, itraconazole, ketoconazole toxicity
  • Inhibition of CYP450-dependent hepatic enzymes
    can result in either decreased levels of azole
    when administered with other drugs with hepatic
    metabolism or increased levels of other drugs
    with hepatic metabolism
  • Nausea, vomiting, rash, pruritus, Stevens-Johnson
    syndrome (rare), increased liver enzymes,
    hepatitis, leukopenia, anemia, hemolytic anemia,
    alopecia (fluconazole)

97
Candida Infections Treatment Failure
  • Oral pharyngeal and esophageal candidiasis
  • Initial failure should be treated with oral
    fluconazole, itraconazole, oral amphotericin B,
    or low-dose IV amphotericin B
  • Invasive disease
  • Amphotericin B lipid formulations can be used for
    children who cannot tolerate amphotericin B, have
    disseminated Candida infection that is resistance
    to amphotericin B, or are at risk of
    nephrotoxicity

98
Coccidioidomycosis Epidemiology
  • Increased risk of infection with Coccidioides
    immitis and Coccidioides posadasii among
    HIV-infected children in endemic areas (eg,
    southwestern United States, northern Mexico,
    Central and South America)
  • Primary infection of newborn rare
  • In utero and perinatal transmission of C immitis
    reported
  • Reports of infection in nonendemic areas usually
    due to reactivation

99
Coccidioidomycosis Clinical Manifestations
  • Fever and dyspnea most common presentation
  • Chills, weight loss, lymphadenopathy, chest pain,
    diffuse reticulonodular pulmonary infiltrates,
    meningitis
  • Disseminated disease associated with erythema
    multiforme erythema nodosum erythematous
    maculopapular rash arthralgia bone, joint, and
    CNS infection

100
Coccidioidomycosis Diagnosis
  • Direct examination and culture of respiratory
    secretions and CSF or biopsy of lesions
  • Blood cultures positive in 15 of cases
  • Complement fixation assay detects IgG antibody,
    positive IgM assays suggest active or recent
    infection, complement fixation titers gt 116
    correlate with presence and severity of
    extrapulmonary infection

101
Coccidioidomycosis Prevention
  • Difficult to avoid exposure in endemic areas
  • Exposure can be reduced by avoiding activities
    that predispose to inhalation of spores such as
    disturbing contaminated soil, being outdoors
    during dust storms

102
Coccidioidomycosis Treatment
  • Limited data in children recommendations based
    on adult data
  • Treat diffuse pulmonary disease or disseminated
    disease with amphotericin B dosage of 0.5-1.5
    mg/kg/day until clinical improvement occurs (A
    II)
  • Follow with chronic suppressive fluconazole or
    itraconazole therapy (A II)
  • Alterative therapy fluconazole 5-6 mg/kg BID or
    itraconazole 4-10 mg/kg BID for 3 days followed
    by 2-5 mg/kg BID (B III)

103
Coccidioidomycosis Treatment (2)
  • CNS infection, including meningitis
  • High-dose fluconazole 5-6 mg/kg BID
  • If unresponsive to fluconazole, use IV
    amphotericin B augmented by intrathecal
    amphotericin B (C I)

104
Coccidioidomycosis Monitoring, Adverse Events
and Toxicity
  • Monitoring of complement fixing IgG antibody is
    useful
  • Toxicity of antifungal drugs includes fevers,
    chills, nausea and vomiting, nephrotoxicity
  • Interaction of all antifungal agents with ARVs
    should be investigated fluconazole and
    itraconazole appear to be safe in combination
    with ARVs
  • Voriconazole should be avoided in patients on PIs
    or NNRTIs

105
Cryptococcosis Epidemiology
  • Most infections caused by Cryptococcosis
    neoformans and Cryptococcosis gattii
  • Infection occurs primarily in tropical and
    subtropical areas
  • Low incidence of infection in children,
    especially with use of ART
  • Children usually infected during 6-12 year age
    range
  • Usually severely immunosuppressed

106
Cryptococcosis Clinical Manifestations
  • Meningoencephalitis most common manifestation
  • Fever, headache, altered mental status evolving
    over days to weeks
  • Acute illness with nuchal rigidity, seizures,
    focal neurologic signs observed in developing
    countries
  • Translucent, umbilicated, papules, nodules,
    ulcers, infiltrated plaques seen in disseminated
    disease
  • Pulmonary cryptococcosis unusual in children

107
Cryptococcosis Diagnosis
  • Microscopic examination of CSF on India
    ink-stained wet mounts
  • Detection of cryptococcal antigen in CSF, serum,
    bronchoalveolar lavage fluid (can be negative in
    culture-positive meningitis)
  • Fungal cultures from CSF, sputum, and blood
    cultures can identify the organism
  • Antigen levels useful in evaluating response to
    treatment and relapse
  • Pulmonary disease diagnosed by bronchoalveolar
    lavage and direct examination of India
    ink-stained specimens

108
Cryptococcosis Prevention
  • No proven strategies to prevent exposure
  • Believed to be acquired by inhalation of
    aerosolized particles from the environment

109
Cryptococcosis Treatment
  • Not well studied in children infection is often
    fatal in the absence of treatment
  • CNS Disease
  • Amphotericin B induction (0.7-1.5 mg/kg/day IV)
    combined with 2 weeks of flucytosine (25
    mg/kg/dose given 4 times daily) followed by
    fluconazole for a minimum of 8 weeks
  • After symptoms are controlled, treat with
    fluconazole or itraconazole maintenance
  • Use amphotericin B alone if flucytosine is not
    tolerated
  • Fluconazole plus flucytosine is an alternative to
    amphotericin B (limited data in children)

110
Cryptococcosis Treatment (2)
  • Pulmonary and extrapulmonary cryptococcosis
  • No clinical trials on the outcome of non-CNS
    cryptococcosis in HIV-infected patients
  • Treat with amphotericin B with or without the
    addition of fluconazole (A III)
  • Fluconazole or itraconazole should be continued
    long-term

111
Cryptococcosis Monitoring and Drug Toxicity
  • Amphotericin toxicity
  • Nephrotoxicity azotemia, hypokalemia
  • Nephrotoxicity can be minimized by hydration with
    0.9 saline intravenously 30 minutes before
    amphotericin B infusion
  • Infusion-related chills, fever, and vomiting
    pretreat with acetaminophen or diphenhydramine
  • Rarely hypotension, arrhythmias, neurotoxicity,
    hepatic toxicity

112
Cryptococcosis Monitoring and Drug Toxicity (2)
  • Flucytosine toxicity
  • Bone marrow anemia, leukopenia, thrombocytopenia
  • Liver, GI, and renal toxicity
  • Fluconazole toxicity
  • Potential interaction with ARV should be
    evaluated before initiating treatment (A III)

113
Cryptococcosis IRIS and Treatment Failure
  • IRIS related to cryptococcosis can present within
    weeks
  • Optimal treatment of patients experiencing
    treatment failure has not been defined
  • Patients failing initial azole treatment should
    be switched to amphotericin B in combination with
    flucytosine
  • Consider use of liposomal amphotericin B
  • Experience with posaconazole or voriconazole is
    limited

114
Histoplasmosis Epidemiology
  • Pathogen is Histoplasma capsulatum
  • Incidence of disseminated histoplasmosis in
    HIV-infected children in the United States is
    lt0.4
  • Incidence is higher in countries such as Brazil,
    Argentina, and Mexico (2.7 to 3.8)
  • No evidence of dissemination of maternal
    infection to the fetus or greater severity of
    infection during pregnancy

115
Histoplasmosis Clinical Manifestations
  • Prolonged fever is the most common presentation
  • Malaise, weight loss, and nonproductive cough
  • Primary pulmonary focus leads to widespread
    dissemination in children
  • Pulmonary manifestations common
  • Physical findings include hepatosplenomegaly,
    erythematous nodular coetaneous lesions, CNS
    involvement with meningitis
  • Anemia, thrombocytopenia, elevated liver
    transaminases
  • Progressive disseminated histoplasmosis (PDH) is
    fatal if untreated

116
Histoplasmosis Diagnosis
  • Serologic testing using CF and immunodiffusion is
    insensitive in the presence of HIV infection.
  • Positive in most patients but not useful for
    diagnosis of acute infection
  • For diagnosis of CNS disease, a combination of
    CSF antibody, antigen, and culture is most
    sensitive
  • Skin testing not recommended for diagnosis

117
Histoplasmosis Diagnosis (2)
  • Culture of Histoplasma from blood or other
    sources
  • Detection of H capsulatum polysaccharide antigen
    in urine, blood, CSF, or bronchoalveolar lavage
    using EIA
  • EIA sensitivity greater in disseminated disease
    or acute pulmonary disease greater in urine than
    in serum
  • Antigen levels decline with treatment and
    correlate with both response to treatment and
    relapse

118
Histoplasmosis Prevention
  • Most infections occur without a recognized
    history of exposure
  • Sites and conditions commonly implicated include
    outbreaks of soil contamination with bird or bat
    droppings, older urban and rural structures, and
    decaying vegetation

119
Histoplasmosis Treatment
  • Limited data for children recommendations based
    on adult data
  • PDH is fatal without treatment and should be
    treated with either amphotericin B or
    itraconazole
  • Fluconazole has been used successfully as an
    alternative for patients with mild disease and
    for those who cannot tolerate itraconazole

120
Histoplasmosis Treatment (2)
  • Amphotericin B for patients with severe
    disseminated disease requiring hospitalization
    and for those who are immunocompromised
  • Amphotericin B induction dosage 1 mg/kg for 4-6
    weeks followed by itraconazole chronic
    suppressive therapy for 12 months (A I)
  • After successful treatment of acute disease, use
    chronic lifelong suppressive therapy with
    itraconazole
  • Liposomal amphotericin B alternative in event of
    amphotericin B intolerance

121
Histoplasmosis Monitoring and Adverse Effects
  • Antigen levels should be monitored during
    treatment and for 1 year thereafter
  • Adverse effects of amphotericin B include
    nephrotoxicity, infusion related fever, chills,
    nausea, and vomiting
  • Azole drugs inhibit CYP450-dependent hepatic
    enzymes, warranting careful review of drug
    interactions when using ARVs

122
Pneumocystis jiroveci (carinii) Epidemiology
  • Organisms are found worldwide in the lungs of
    humans and lower animals
  • Antibody in 80 of normal children by 4 years
  • Most common AIDS indicator disease in children
  • Incidence highest in first year of life, peaking
    at 3-6 months
  • Accounted for 57 of AIDS-defining illnesses in
    infants age lt1 year pre-ART
  • CD4 T-cell count not a good indicator of risk in
    infants lt1 year old
  • Infection now unusual owing to routine
    prophylaxis with TMP-SMX

123
Pneumocystis jiroveci (carinii) Clinical
Manifestations
  • Fever, tachypnea, cough, dyspnea, poor feeding,
    weight loss
  • Abrupt or insidious onset
  • Bibasilar rales with evidence of hypoxia and
    respiratory distress
  • Extrapulmonary locations spleen, liver, colon,
    pancreas, ear, eye, GI tract, bone marrow, heart,
    kidney, lymph nodes, CNS

124
Pneumocystis jiroveci (carinii) Diagnosis
  • Hypoxia with low arterial oxygen pressure
    (alveolar-arterial oxygen gradient gt30 mmHg)
  • Definitive diagnosis requires demonstrating
    organism
  • Induced sputum (difficult lt2 years)
  • Bronchoscopy with bronchoalveolar lavage
  • Fiberoptic bronchoscopy with biopsy generally
    not recommended

125
Pneumocystis jiroveci (carinii) Diagnosis (2)
  • Open lung biopsy most sensitive
  • Requires thoracotomy, chest tube drainage
  • Organisms seen on biopsy with
  • Gomori methenamine silver stain
  • Toluidine blue stain
  • Giemsa or Wright stain
  • Monoclonal antibody
  • DNA PCR for Pneumocystis MSG gene in fluids,
    lavage sensitive but less specific than
    histology

126
Pneumocystis jiroveci (carinii) Prevention
  • Need for isolation of hospitalized patients has
    not been demonstrated, but when prophylaxis
    cannot be given, may need to isolate patient or
    susceptible contacts
  • Infants born to HIV-infected mothers should be
    considered for prophylaxis at 4-6 weeks of age
    and continued until 1 year of age (A II)

127
Pneumocystis jiroveci (carinii) Prevention (2)
  • Chemoprophylaxis with TMP-SMX recommended as
    follows, based on CD4 counts and patient age
  • 6 years CD4 count lt200 cells/µL or CD4
    percentage lt15
  • 1 to 5 years CD4 count lt500 cells/µL or CD4
    percentage lt15
  • All HIV-infected infants lt12 months of age
    regardless of CD4 count or percentage

128
Pneumocystis jiroveci (carinii) Treatment
  • TMP-SMX (A I)
  • gt2 months 15-20 mg/kg/day of TMP component IV in
    3-4 divided doses
  • Infuse over course of 1 hour
  • Administer for 21 days
  • Can be given orally in children with mild to
    moderate disease
  • Lifelong prophylaxis indicated

129
Pneumocystis jiroveci (carinii) Treatment (2)
  • Adverse reactions
  • Rash
  • Stevens-Johnson syndrome (rare)
  • Neutropenia, thrombocytopenia, megaloblastic or
    aplastic anemia

130
Pneumocystis jiroveci (carinii) Treatment (3)
  • Pentamidine isethionate
  • Recommended for patients with intolerance to
    TMP-SMX or clinical failure with TMP-SMX (A I)
    do not combine use
  • 4 mg/kg/day IV once daily over period of 60-90
    minutes
  • Consider oral atovaquone after 7-10 days (B III)

131
Pneumocystis jiroveci (carinii) Treatment
Alternatives
  • Atovaquone (B I)
  • Limited data in children
  • 30-40 mg/kg/day divided into 2 doses, given with
    fatty foods
  • Infants 3-24 months may require 45 mg/kg/day
    divided into 2 doses, given with fatty foods (A
    II)
  • Adverse reactions include rash, nausea, diarrhea,
    increased liver enzymes

132
Pneumocystis jiroveci (carinii) Treatment
Alternatives (2)
  • Clindamycin/primaquine
  • Used for mild to moderate PCP in adults no data
    in children (C III)
  • Primaquine contraindicated in G6PD deficiency

133
Pneumocystis jiroveci (carinii) Treatment
Alternatives (3)
  • Clindamycin/primaquine
  • Pediatric clindamycin dosing based on other uses
    20-40 mg/kg/day IV divided into 3 or 4 doses,
    administered for 21 days
  • Primaquine dosing based on malaria 0.3 mg/kg
    daily of the base, administered orally for 21
    days
  • Adverse reactions include rash, nausea, diarrhea,
    pseudomembranous colitis

134
Pneumocystis jiroveci (carinii) Treatment
Alternatives (4)
  • Dapsone/TMP
  • Use for mild to moderate PCP in adults no data
    in children (C III)
  • Dapsone dosage lt13 years 2 mg/kg/day orally once
    daily (A II) for 21 days
  • TMP 15/mg/kg/day orally divided into 3 daily
    doses for 21 days
  • Adverse reactions include rash, anemia,
    thrombocytopenia, increased liver enzymes

135
Pneumocystis jiroveci (carinii) Treatment
Adjunct
  • Corticosteroids
  • Consider use in moderate to severe PCP
  • Use within 72 hours of diagnosis
  • Results in reduced respiratory failure, decreased
    ventilation requirements, and decreased mortality

136
Pneumocystis jiroveci (carinii) Treatment
Adjunct (2)
  • Corticosteroids
  • Dosing recommendations vary
  • Prednisone 40 mg BID for 1-5 days 40 mg once
    daily days 6-10 20 mg once daily days 11-21
  • Alternative prednisone 1 mg/kg BID days 1-5 0.5
    mg/kg BID days 6-10 0.5 mg/kg once daily days
    11-21

137
Pneumocystis jiroveci (carinii) Monitoring and
Adverse Events
  • Short courses of corticosteroids have been used
    in some cases of PCP of moderate to severe
    intensity starting within 72 hours of diagnosis
    (A I)
  • As with other coinfection, IRIS may occur
    following initiation of ART but has been
    described infrequently in PCP
  • Most common adverse reaction to TMP-SMX includes
    rash and rarely erythema multiforme or
    Stevens-Johnson syndrome
  • Pentamidine is associated with renal toxicity,
    usually occurring 2 weeks after initiation of
    treatment

138
Cryptosporidiosis/Microsporidiosis Epidemiology
  • Protozoal parasites that cause enteric illness in
    humans and animals
  • Human infection primarily caused by C hominis, C
    parvum, C meleagridis
  • Microsporida include E bieneusi and E
    intestinalis
  • Infection results from ingestion of oocysts
    excreted in feces of humans or animals
  • Invade intestinal tract mucosa causing watery,
    nonbloody diarrhea, dehydration, malnutrition

139
Cryptosporidiosis/Microsporidiosis Epidemiology
(2)
  • Person-to-person transmission in child care
    centers
  • Oocysts can contaminate water supplies
  • Outbreaks associated with contaminated drinking
    water and swimming pools
  • Incidence declined since advent of ART

140
Cryptosporidiosis/Microsporidiosis Clinical
Manifestations
  • Frequent watery, nonbloody diarrhea
  • Abdominal cramps, fatigue, vomiting, anorexia,
    weight loss, poor weight gain
  • Fever and vomiting more common in children
  • Liver involvement causes abdominal pain and
    elevated alkaline phosphatase
  • Less common myositis, cholangitis, sinusitis,
    hepatitis, CNS disease
  • Different species may cause different clinical
    syndromes (eg, Encephalitozoon hellem associated
    with keratoconjunctivitis, sinusitis, prostatic
    abscess)

141
Cryptosporidiosis/Microsporidiosis Diagnosis
  • Cryptosporidiosis
  • Concentrated stool samples demonstrating oocysts
  • Evaluate at least 3 separate stool samples
  • Monoclonal antibody fluorescein stain and EIA for
    antigen have enhanced specificity and sensitivity

142
Cryptosporidiosis/Microsporidiosis Diagnosis (2)
  • Microsporidia
  • Use thin smears of unconcentrated stool-formalin
    suspension or duodenal aspirates stained with
    trichrome or chemofluorescent agents
  • Consider endoscopy in all patients with diarrhea
    gt2 months duration
  • PCR techniques still in research

143
Cryptosporidiosis/Microsporidiosis Prevention
  • Avoid direct contact with fecal material from
    adults, diaper-age children, and infected animals
  • Carefully investigate sources of drinking water
    and recreational activities involving water
  • HIV-infected children should not be allowed to
    drink water directly from lakes or rivers
  • Outbreaks of cryptosporidiosis occasionally have
    been linked to municipal water contamination
  • Some experts recommend that severely
    immunocompromised HIV-infected patients should
    not share a room with patients who have
    cryptosporidiosis

144
Cryptosporidiosis/Microsporidiosis Treatment
  • Immune restoration following antiretroviral
    treatment frequently results in clearing
  • Supportive care, hydration, electrolyte
    replenishment, nutritional supplements
  • Available treatment inconsistently effective

145
Cryptosporidiosis Treatment
  • No agents have been consistently effective
  • Nitazoxanide effective for Cryptosporidium and
    Giardia lamblia (B I for children and C III for
    HIV-infected children)
  • Nitazoxanide dosage 100 mg orally BID for
    children 1-3 years 200 mg BID for children 4-11
    years
  • Limited data paromomycin, azithromycin

146
Microsporidiosis Treatment
  • Albendazole 7.5 mg/kg orally BID maximum dosage
    400 mg orally BID (A II)
  • Fumagillin limited data for adults, no data for
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