the dosage of clindamycin–primaquine was 600 mg clindamycin TID and
primaquine 30 mg/day. All patients with moderately severe PCP (A-a oxygen
gradient >45) were treated with prednisone (40 mg BID for 5 days, then once daily
for 3 weeks). Rash was the most frequent dose-limiting toxicity (TMP-SMX, 19%;
dapsone–TMP, 10%; clindamycin–primaquine, 21%). Hematologic toxicities were
observed more frequently in the clindamycin–primaquine arm. Elevated LFTs (5
times above baseline) were more frequent in the TMP-SMX arm. The clindamycin–
primaquine group demonstrated better quality of life scores at Day 7, but by Day 21,
these differences became less significant.
clindamycin–primaquine demonstrated equal efficacy in patients with mild-tomoderate PCP.
J.R. should be hospitalized to better manage his severe adverse reaction and to
complete his treatment of PCP. Because of his severe reaction to TMP-SMX,
dapsone–TMP should not be administered because dapsone is a sulfone with a risk
of cross-reactivity in patients with severe sulfonamide allergies. IV pentamidine is
an option for J.R., but its toxicity suggests that it should be reserved for patients with
more severe PCP presentation. Atovaquone is a reasonable option for patients with
mild PCP who are intolerant of TMP-SMX and have no evidence of GI dysfunction,
but it is not as effective as TMP-SMX or IV pentamidine. Clindamycin–primaquine
is as efficacious as TMP-SMX for the treatment of mild-to-moderate PCP and can be
administered PO. Consequently, it is the drug of choice in this patient.
clindamycin–primaquine for 14 days, completing a 21-day course of PCP therapy
CASE 77-1, QUESTION 4: Should J.R. receive corticosteroid therapy with PCP treatment? If so, when
should corticosteroids be initiated, and what would be a reasonable regimen for patients with PCP?
Corticosteroids have an important role in the management of patients with acute
PCP who are clinically ill and have a low PO2
12 Many patients who are started on PCP therapy have an
acute period of clinical deterioration, which may be associated with an acute
inflammatory reaction to the rapid killing of Pneumocystis. Particularly among
patients with moderate-to-severe PCP (A-a oxygen gradient >35 mm Hg or Pao2 <70
mm Hg on room air), the use of prednisone during the first 72 hours of treatment may
prevent fatal acute deterioration.
51 Corticosteroids may also have some benefits in
patients exhibiting acute respiratory failure after 72 hours of conventional PCP
52 The recommended dose of prednisone is 40 mg given PO BID for 5 days,
then 40 mg/day for 5 days, and then 20 mg/day for 11 days, for a total of 21 days.
Patients requiring IV corticosteroids may receive methylprednisolone at 75% of the
prednisone dose. The major concern using glucocorticoids is the activation of latent
infections (such as TB) or exacerbation of an active undiagnosed condition
(especially fungal infections). However, the beneficial role of corticosteroids as
adjunctive therapy outweighs the relative risk of short-term steroid use in this
54 More common side effects of short-term corticosteroids include
ulcerative esophagitis, increased appetite, weight gain, sodium and fluid retention,
headache, and elevated LFTs. Corticosteroids should be used with caution in the
presence of uncontrolled diabetes, active GI bleeding, and uncontrolled hypertension.
Considering his mild hypoxemia (Pao2
, >70 mm Hg), J.R. is not a candidate for
CASE 77-1, QUESTION 5: J.R. was hospitalized and responded well to treatment. He now is a candidate
The early recognized efficacy of TMP-SMX prophylaxis
widespread application of prophylaxis and the development of guidelines for PCP
12 HIV-infected patients not receiving HAART or
Pneumocystis prophylaxis were associated with a PCP prevalence of 8.4%, 18.4%,
and 33.3% at 6, 12, and 36 months, respectively, in patients with a CD4 count of less
55 These data have formed the basis on which patients receive PCP
prophylaxis. In addition to patients with CD4 counts of less than 200, other patients
at a risk for PCP include those with a CD4 count of less than 14%, a history of an
AIDS-defining illness, a history of oropharyngeal candidiasis, and possibly those
with CD4 counts of 200 to 250.
12 J.R. refused primary prophylaxis and developed
PCP. Secondary prophylaxis is necessary for J.R. to prevent recurrence and should
be continued for life or until immune reconstitution occurs as a result of antiretroviral
The same agents and dosing schedules are recommended for primary (before an
acute event) and secondary (after an acute event) prophylaxis of PCP.
one double-strength tablet daily, is the most efficacious prophylactic regimen; a
single-strength tablet given daily is less toxic and nearly as efficacious. Patients with
a history of non–life-threatening rash or fever caused by TMP-SMX may benefit from
rechallenge with the original (or half) dose, or a dose escalation technique
(desensitization regimen). Desensitization is preferred to switching to an alternative
agent and is more successful than the direct rechallenge method.
involves initiating very low doses of TMP-SMX and gradually increasing to the
maximum dose over the course of days to weeks. In addition, patients who develop
PCP while receiving prophylactic doses of TMP-SMX usually respond to full
therapeutic doses for acute therapy. However, J.R. had a life-threatening reaction to
TMP-SMX and should not be rechallenged or desensitized, and another agent should
The alternative agents used for prophylaxis include dapsone, dapsone plus
pyrimethamine (with leucovorin), atovaquone suspension, and aerosolized
pentamidine administered by the Respirgard II nebulizer (Table 77-2). TMP-SMX
confers additional protection against toxoplasmosis and certain bacterial infections.
Regimens containing dapsone plus pyrimethamine or atovaquone with or without
pyrimethamine also protect against toxoplasmosis.
12 Although yet to be confirmed in
clinical trials, other options include oral clindamycin–primaquine, intermittently
administered IV pentamidine, oral pyrimethamine–sulfadiazine, and aerosolized
pentamidine administered by other nebulizing devices.
efficacious than dapsone or aerosolized pentamidine in the prevention of PCP.
Extrapulmonary (e.g., lymph nodes, spleen, liver, bone marrow, adrenal gland, and
GI tract) P. carinii has been noted in patients receiving inhaled pentamidine
58 a finding rarely observed with IV administration. In addition,
aerosolized pentamidine alters the usual chest radiograph findings associated with
PCP, potentially complicating the diagnosis of this disease. Upper lobe infiltrates,
cystic lesions, pneumothoraces, cavitary lesions with nodular infiltrates, and pleural
effusions have been associated with aerosolized pentamidine prophylaxis.
The guidelines for primary prophylaxis suggest that prophylactic antimicrobial
therapy can be discontinued when CD4 counts rise above the threshold associated
with a risk for infection (i.e., <200 for PCP).
12 Many studies support the practice of
secondary PCP prophylaxis in patients whose CD4 counts have increased to
greater than 200 for at least 3 months.
12 A European cohort study found that primary
PCP rates were very low in patients with CD4 counts of 101 to 200 cells/μL and a
viral load of less than 400 copies/mL regardless of prophylaxis, indicating that
discontinuation of prophylaxis may be safe in patients with a CD4 count greater than
100 cells/μL who are on effective antiretrovirals.
59 The guidelines recommend that
prophylaxis be reintroduced if the CD4 count decreases to less than 200 or if PCP
recurs at a CD4 count of greater than 200.
12 J.R. responded well to his PCP treatment
with clindamycin–primaquine in the hospital. However, because this regimen is
unproven for secondary prophylaxis, it cannot be recommended. Considering his
intolerance to TMP-SMX, the best selections would be dapsone (with or without
pyrimethamine) or atovaquone suspension.
TOXOPLASMA GONDII ENCEPHALITIS
from other patients and health-care workers to prevent the spread of this organism?
T. gondii is a parasitic protozoan that can infect people and is spread by
environmental factors, such as the consumption of raw or undercooked meats and
contact with cat feces. Immunocompetent persons infected with T. gondii may
develop mild symptoms resembling infectious mononucleosis. However, these
symptoms are generally transient and not associated with significant sequelae in
immunocompetent patients (except in pregnant women). Recrudescent disease from
T. gondii is problematic in patients with a suppressed cellular immune system,
including those infected with HIV. Any HIV-positive patient infected with T. gondii
is at a risk for developing clinical disease, particularly at CD4 counts less than 100,
12 W.O. presents with encephalitis (an inflammation of the
brain or brainstem), the most frequent manifestation of T. gondii in HIV-positive
All HIV-infected patients should be tested for IgG antibody to T. gondii after HIV
diagnosis to detect latent infection. In the United States, as many as 70% of healthy
adults are seropositive to Toxoplasma. The prevalence of Toxoplasma encephalitis
among HIV-positive patients varies depending on the geographic region. In the
United States, only 3% to 10% of AIDS patients actually develop encephalitis. In
countries such as France, El Salvador, and Tahiti, where uncooked meat commonly is
ingested, seropositivity is greater than 90% by the fourth decade of life. Toxoplasma
encephalitis may develop in as many as 25% to 50% of AIDS patients in these
The two major routes of transmission of Toxoplasma to humans are oral and
congenital. W.O. need not be isolated from other patients and health-care workers.
HIV-infected patients should be advised not to eat raw and undercooked meat
(internal temperature of meat should be at least 165°F–170°F), especially patients
who are IgG-negative for T. gondii. Patients should wash their hands after touching
uncooked meats and soil, and fruits and vegetables must be washed before eating.
HIV-infected patients should avoid stray cats, keep their cats inside, and change the
litter box daily. If no one else is available to change the litter box, patients should
wash their hands thoroughly afterward.
CASE 77-2, QUESTION 2: Is there sufficient clinical evidence to establish a presumptive diagnosis of
Toxoplasma encephalitis in W.O.?
The diagnosis of Toxoplasma encephalitis usually is presumptive because
demonstration of cysts or trophozoites in brain tissue is required for a definitive
diagnosis. The clinical signs and symptoms of Toxoplasma encephalitis can be either
focal (indicating a specific region of the brain that is infected or inflamed) or
generalized (indicating diffuse inflammation of the brain). Toxoplasma encephalitis
usually occurs in patients with CD4 counts of less than 100. Serum titers of
antibodies against T. gondii typically reflect past infection with the organism and
unfortunately do not help delineate whether acute infection is present. In addition,
cerebrospinal fluid (CSF) polymerase chain reaction for Toxoplasma is not always a
Brain biopsy is reserved for patients with symptoms of encephalitis who are
seronegative and for those who do not respond to presumptive antitoxoplasmosis
61 Because of the nonspecific diagnosis of Toxoplasma encephalitis, a high
index of suspicion for other causes of encephalitis (e.g., central nervous system
[CNS] lymphoma or TB) should be maintained throughout the treatment period for
presumed Toxoplasma encephalitis. W.O. has overwhelming clinical evidence
suggestive of Toxoplasma encephalitis. He is HIV-positive, has a CD4 count of less
than 100, a positive Toxoplasma titer of 1:256 IgG, and a ring-shaped lesion in the
brainstem on MRI. The development of this infection, in addition to the decline in
CD4 T cells and the increase in plasma HIV RNA concentrations, may signal
antiretroviral failure. W.O.’s current antiretroviral therapy should be reassessed,
including his adherence to the regimen.
CASE 77-2, QUESTION 3: Should W.O. have been receiving prophylactic therapy for T. gondii?
Similar to many other OIs associated with HIV, therapy for toxoplasmosis can be
categorized into primary prophylaxis, treatment of acute disease, and secondary
prophylaxis. Primary prophylaxis is currently recommended for HIV-infected
patients with CD4 counts of less than 100 who are also IgG-positive for T. gondii
(Table 77-2). Many of the agents used to prevent PCP have activity against T. gondii:
TMP-SMX, dapsone–pyrimethamine–leucovorin, and atovaquone with or without
pyrimethamine/leucovorin are effective as primary prophylaxis for T. gondii.
increased use of prophylaxis with these agents has significantly decreased the
incidence of Toxoplasma encephalitis.
12 The double-strength TMP-SMX tablet once
daily is recommended as the first-line prophylaxis. Data do not support the use of
or aerosolized pentamidine for Toxoplasma prophylaxis. Similarly, data are
conflicting regarding the efficacy of pyrimethamine as monotherapy for primary
Primary prophylaxis may be discontinued in patients who have responded to
HAART with an increase in the CD4 counts to greater than 200 for more than 3
months. In addition, data support reinstituting primary prophylaxis when CD4 counts
W.O. is currently receiving inhaled pentamidine for PCP prophylaxis. Considering
his CD4 count and IgG seropositivity, he should have received primary prophylaxis
CASE 77-2, QUESTION 4: How should W.O.’s presumptive Toxoplasma encephalitis be treated?
The first-line treatment of acute Toxoplasma encephalitis consists of a
combination of sulfadiazine 4 g/day in three or four daily divided doses and
pyrimethamine as a single 200-mg loading dose, followed by 50 to 75 mg/day as a
single daily dose plus leucovorin 10 to 25 mg PO every day.
should be continued for 6 weeks after resolution of symptoms (a treatment course of
approximately 8 weeks) followed by maintenance therapy (secondary prophylaxis).
Sulfadiazine toxicity may limit the completion of a full course of therapy in as many
64 However, successful desensitization has been documented.
W.O.’s clinical and radiologic response should be monitored closely, and other
diagnoses should be considered if there is no improvement.
Alternative therapy includes pyrimethamine plus leucovorin with clindamycin 600
to 900 mg IV every 6 hours or 600 mg PO every 6 hours for at least 6 weeks. One
controlled trial compared the efficacy and tolerability of pyrimethamine plus
sulfadiazine versus pyrimethamine plus clindamycin. Although both regimens were
effective, pyrimethamine–sulfadiazine was superior to pyrimethamine–clindamycin.
The rate of adverse events was similar with both regimens; however,
pyrimethamine–clindamycin led to fewer discontinuations than pyrimethamine–
sulfadiazine (11% vs. 30%, respectively).
66 TMP-SMX may be considered a
treatment option, particularly in patients who cannot take an oral regimen because the
only widely available parenteral sulfonamide is the sulfamethoxazole component of
TMP-SMX. However, there is less in vitro activity and less clinical data to support
the use of TMP-SMX as monotherapy for toxoplasmosis.
anticonvulsants should be given to patients with Toxoplasma encephalitis and a
history of seizures, and corticosteroids may be warranted for focal lesions or edema
but should be used cautiously.
use of the sulfadiazine component for the treatment of Toxoplasma encephalitis?
As with other sulfonamides in HIV-infected patients, rashes commonly occur with
64 Similar to TMP-SMX, various desensitization regimens have
; however, it may be simpler to use alternative regimens.
Renal function should be monitored throughout therapy. Elevated serum creatinine
(SCr) levels, hematuria, or decreased urine output may occur secondary to
sulfadiazine-induced crystalluria. The water solubility of sulfadiazine is less than
that of other sulfonamides; therefore, hydration (2–3 L/day) is needed to prevent
crystalline nephropathy, and aggressive hydration and alkalinization can be used in
CASE 77-2, QUESTION 6: What toxicities are associated with the pyrimethamine component?
Pyrimethamine can suppress bone marrow function; thus, concomitant therapy with
other medications that suppress marrow function (e.g., zidovudine [AZT] or
ganciclovir) may not be tolerated. Leucovorin (10–25 mg/day) is always given in
conjunction with pyrimethamine to maintain bone marrow function, although it may
not always be successful. Leucovorin doses can be increased to 50 to 100 mg/day in
divided doses if needed to reverse bone marrow suppression.
folinic acid) should be avoided because it can be used for growth by protozoal
organisms, potentially antagonizing pyrimethamine–sulfadiazine activity.
preparations containing large quantities of folic acid should be discontinued during
W.O. is not taking any medications that would make him particularly susceptible to
the myelosuppressive effects of pyrimethamine, and he is not neutropenic.
Consequently, he should be given sulfadiazine and pyrimethamine.
SUPPRESSIVE THERAPY (SECONDARY PROPHYLAXIS)
CASE 77-2, QUESTION 7: Once W.O. has completed acute therapy for his Toxoplasma encephalitis, should
he receive suppressive therapy?
Most antiprotozoal agents do not eradicate the cyst form of T. gondii. Therefore,
patients should be administered lifelong suppressive therapy unless immune
reconstitution occurs as a consequence of HAART.
12 A commonly used regimen for
patients who cannot tolerate sulfonamides is pyrimethamine plus clindamycin.
However, only the combination of pyrimethamine plus sulfadiazine provides
protection against PCP as well. Additionally, two small studies of patients receiving
maintenance therapy for Toxoplasma encephalitis have suggested that sulfadiazine–
pyrimethamine is more effective than clindamycin–pyrimethamine or pyrimethamine
66 The use of atovaquone with or without pyrimethamine is also effective as
prophylaxis for both Toxoplasma and PCP, but it is significantly more expensive and
is only available as a less palatable liquid formulation.
Patients receiving secondary prophylaxis are at a low risk for recurrence of
Toxoplasma encephalitis when they have completed their initial therapy, remain
asymptomatic, and have a sustained increase in their CD4 count to greater than 200
after more than 6 months of HAART. Clinicians may obtain a brain MRI as part of
the evaluation to determine the end point of therapy. Discontinuation of primary and
secondary toxoplasmosis prophylaxis is safe if patients are receiving HAART and
their CD4 count has increased to greater than 200 for at least 3 months. Secondary
prophylaxis should be reintroduced if the CD4 count decreases to less than 200.
W.O. will be continued on sulfadiazine–pyrimethamine for suppressive therapy for
his Toxoplasma encephalitis because his CD4 count has decreased to less than 100.
W.O. is currently receiving aerosolized pentamidine for PCP prophylaxis, but
because sulfadiazine–pyrimethamine is also protective against PCP, the aerosolized
pentamidine can be discontinued. Clindamycin–pyrimethamine is an inferior option
because it does not protect against PCP.
not wish to undergo desensitization?
Clindamycin 1,200 mg IV or PO every 6 hours or 600 mg PO every 6 hours plus
pyrimethamine and leucovorin at standard doses.
pyrimethamine and leucovorin plus azithromycin (1.2–1.5 g/day), clarithromycin (1 g
BID), or atovaquone (750 mg PO 4 times a day) has shown promise in a limited
reading road signs when he drives. His most recent laboratory results were as follows:
Viral load, 80,000 copies/mL (3 months ago)
WBC count, 1,200 cells/L, with 63% polymorphonuclear neutrophil leukocytes
of the retina in his left eye.
What is the likely cause of P.Z.’s visual problems?
P.Z. has an inflammation of the retina (retinitis), most likely because of CMV.
Many HIV-infected patients have been previously infected with CMV, and
reactivation typically occurs when CD4 counts are less than 50. Before HAART, the
prevalence of CMV disease in patients with AIDS was 30%; however, the incidence
of new cases of CMV end-organ disease has declined by 75% to 80% since the
advent of HAART and is estimated to be less than 6 cases per 100 person-years.
Although CMV can cause colitis, pneumonitis, esophagitis, hepatitis, and neurologic
disease, retinitis is the most common manifestation of active infection in AIDS
patients, accounting for 75% to 85% of CMV end-organ disease. One investigation
describing patients with CMV retinitis in the post-HAART era found a diverse
demographic group with infection; most of them had received HAART, and as
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