ACUTE THERAPY

Prompt diagnosis and immediate initiation of therapy are essential for the

management of acute infections. Most common OIs can be classified into one of two

groups. The first group consists of infections that can be treated by conventional or

investigational agents. These include PCP, TB, cryptococcosis, CMV, MAC, and

histoplasmosis. Treatment may result in either effective or moderately effective

resolution. These infections may recur if chronic suppressive or secondary

prophylaxis is discontinued without an accompanying elevation in the CD4 count and

viral load suppression. The second group includes pathogens for which no

therapeutic regimen is currently effective. These include cryptosporidiosis,

microsporidiosis, and PML.

SECONDARY PROPHYLAXIS OR CHRONIC SUPPRESSIVE THERAPY

Secondary prophylaxis is used to prevent recurrence of an OI once the patient has

developed signs and symptoms of active infection. In some cases, secondary

prophylaxis regimens can be discontinued after patients achieve a certain CD4 level.

The USPHS and IDSA strongly recommend secondary prophylaxis for PCP,

toxoplasmosis (reduced dosage), MAC, CMV, Salmonella species, and infections

caused by endemic fungi and C. neoformans.

12

Discontinuation of Secondary Prophylaxis or Chronic Suppressive Therapy

The USPHS/IDSA guidelines recommend discontinuing primary or secondary

prophylaxis for certain pathogens with HAART-related increases in CD4 count to

specified threshold levels.

12 Criteria for discontinuing chemoprophylaxis are based

on specific clinical studies and vary by duration of CD4 count increase and duration

of treatment of the initial episode of disease (in the case of secondary prophylaxis).

Secondary PCP prophylaxis may be discontinued among patients whose CD4

counts have increased to greater than 200 for more than 3 months while on HAART.

Secondary prophylaxis for disseminated MAC may be discontinued among patients

who have completed 12 months of MAC therapy, have no signs or symptoms of

MAC, and have had a CD4 count of greater than 100 for more than or equal to 3

months in response to HAART. Similarly, secondary prophylaxis for toxoplasmosis

may be discontinued in patients who have completed initial therapy, have no signs or

symptoms of infection, and have had CD4 counts of greater than 200 for more than 3

months. Using the same criteria, patients with cryptococcosis can discontinue

secondary prophylaxis if they have had CD4 counts of greater than or equal to 200

for more than 6 months. Maintenance therapy for CMV can be discontinued safely in

patients who have maintained a CD4 count of greater than 100 for greater than 6

months on HAART.

12

,

16 The decision to stop CMV prophylaxis should be made in

consultation with an ophthalmologist and is influenced by factors such as the

magnitude and duration of CD4 increases and viral load suppression, anatomic

location of retinal lesions, and vision in the contralateral eye.

Although there are considerable data concerning the discontinuation of primary

and secondary prophylaxis, there are no data regarding restarting prophylaxis if the

CD4 count decreases again to levels at which the patient is likely to again be at risk

for OIs. For primary prophylaxis, the same CD4 count threshold for stopping or

restarting therapy is recommended. For PCP prophylaxis, the current guidelines use a

CD4 count of 200 as the threshold for restarting both primary and secondary

prophylaxis. For toxoplasmosis, the CD4 threshold is 100 to 200, and for MAC, it is

50.

12

PNEUMOCYSTIS JIROVECI PNEUMONIA

As an indication of the relative obscurity of this organism, no comprehensive text on

PCP was available until 1983.

35 Since that time, this organism has been reclassified

from a protozoan to a fungus on the basis of ribosomal RNA sequence comparisons.

The morphologic resemblance of P. carinii to a protozoan has led to its life cycle

being described as a cyst form, with up to eight sporozoites per cyst. The trophozoite

or extracystic form has different staining characteristics (i.e., it does not stain with

Toluidine Blue O or Grocott-Gomori stains) compared with the cyst or sporozoites.

In addition, current literature refers to PCP as P. jiroveci as opposed to the original

terminology of Pneumocystis carinii. The former species is the one responsible for

infectivity in humans. P. jiroveci pneumonia is the second leading opportunistic

infection affecting HIV-infected patients in the United States.

2 Hospitalizations and

hospital mortality for AIDS-associated PCP have decreased significantly in the last

20 years; however, there has been a shift in the overall population at risk for PCP

over time with a greater proportion of patients with PCP who are black, female, or

from the southern region of the United States.

36

Clinical Presentation

CASE 77-1

QUESTION 1: J.R. is a 38-year-old, HIV-seropositive man who was diagnosed 5 years ago when he had an

outbreak of herpes zoster. He refused antiretroviral therapy and was determined to treat himself using natural

teas and herbs. J.R. developed a mild, nonproductive cough that has persisted for the last 4 weeks. He has also

had a low-grade fever but denies any chills or pleuritic chest pain. His chest radiograph demonstrates a diffuse,

symmetric, interstitial infiltrate. Arterial oxygen partial pressure (Pao2

) is 80 mm Hg. His last CD4 count

approximately 3 months ago was 180 cells/μL, and his viral load was 60,000 copies/mL. He refused primary

PCP prophylaxis. After hypertonic saline nebulization for sputum induction and subsequent bronchoalveolar

lavage, examination of the specimens with the modified Giemsa stain revealed both intracystic bodies and

extracystic trophozoites. How is the clinical presentation of J.R. consistent with PCP?

The clinical features of PCP in AIDS patients differ from those of non-AIDS

patients in that a more subtle onset, with mild fever, a cough, tachypnea, and dyspnea,

is typically seen in HIV-infected patients.

12 J.R.’s low-grade fever and mild,

nonproductive cough of 4 weeks’ duration are consistent with this description of

PCP. His history of HIV infection and the finding of trophozoites on Giemsa stain

further support a diagnosis of PCP. The characteristic diffuse interstitial pulmonary

infiltrates on J.R.’s chest radiograph are consistent with PCP. Limited data exist with

regard to the latent state of P. jiroveci after host infection. Some investigators

hypothesize that most persons are asymptomatic unless the host immune system

becomes impaired. Others believe that the infection is caused by reinfection as

opposed to reactivation.

37

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Antimicrobial Selection

CASE 77-1, QUESTION 2: A diagnosis of PCP is made and J.R. agrees to be treated. What patient factors

are important to consider when selecting an antimicrobial? What would be a reasonable drug for J.R., and how

might his course of PCP be monitored?

The treatment of acute PCP is determined by the degree of clinical severity on

presentation. The arterial oxygen status on presentation is an important indicator of

overall outcome. Key factors to consider when initiating therapy for PCP include

arterial blood gas findings, whether it is an initial or repeat episode of PCP, the need

for parenteral therapy, and a prior history of adverse drug reactions or

hypersensitivity. Concomitant therapy must also be considered.

Patients with PCP often can be classified as having mild, moderate, or severe

disease, based on their oxygenation. Patients with mild PCP often have a room air

alveolar-arterial (A-a) oxygen gradient of less than 35 or Pao2 greater than 70 mm

Hg, and patients with moderate or severe disease have an A-a greater than 35 mm Hg

or Pao2 greater than 70 mm Hg. With the advent of corticosteroid use for moderateto-severe cases of PCP (discussed later), it is useful to calculate the A-a gradient or

Pao2

. The A-a gradient (normal range, 5–15 mm Hg) can be calculated as PIO2 −

(1.25 × Paco2

) − Pao2

, where PIO2

is the partial pressure of inspired oxygen (150 mm

Hg in room air), and Paco2 and Pao2 are arterial levels of CO2 and O2

, respectively,

expressed in mm Hg.

Several other clinical tests have been used to identify and monitor PCP. The

lactate dehydrogenase concentration in serum or bronchoalveolar lavage fluid has

been used to aid in diagnosis, monitor therapy, and to predict the outcome of PCP.

However, it is a nonspecific value and should not be used alone. Chest radiographs

also vary with PCP. The most common picture is one of bilateral diffuse interstitial

pneumonitis, but atypical patterns, such as pleural effusion, cavities, pneumatoceles,

and nodules, may also occur. A normal chest radiograph is associated with improved

clinical outcome.

The natural course of PCP among untreated HIV-infected patients is progressive

dyspnea and hypoxemia. Increasing patient age, subsequent episode of PCP, low

hemoglobin, low partial pressure of oxygen breathing room air, the presence of

medical comorbidity, and pulmonary KS are all early predictors of mortality from

PCP at hospital admission.

38 The treatment of PCP in AIDS patients (compared with

non–HIV-infected patients) indicates that a longer duration of therapy is needed.

35

Some patients may experience worsening hypoxemia during the first 3 to 5 days after

the treatment is initiated. This period of clinical worsening is least tolerated by those

patients with moderate-to-severe PCP (Pao2 <70 mm Hg). In sicker patients, this

period may lead to respiratory failure and the need for intubation. Although many

would associate the need for intensive care unit admission as a poor prognostic

factor, many patients do well despite the need for mechanical ventilation and IV

antibiotics. In light of the role of corticosteroids, patients with PCP and respiratory

failure may be viewed as manageable if treated aggressively (Table 77-2).

TRIMETHOPRIM–SULFAMETHOXAZOLE

The decision to hospitalize a patient is based on the severity of his or her illness.

Patients who present with mild PCP with reasonable oxygenation and without

evidence of clinical deterioration can be managed as outpatients. Patients with

reasonably good gas exchange (i.e., Pao2 >70 mm Hg) but with signs of clinical

deterioration most often are admitted to the hospital and given oxygen by nasal

cannula and are usually started on IV TMP-SMX (15–20 mg/kg/day TMP and 75–

100 mg/kg/day SMX) for 21 days.

12

,

39 The dosing of IV TMP-SMX must be modified

in patients with renal dysfunction. TMP reversibly inhibits dihydrofolate reductase,

and sulfamethoxazole competes with para-aminobenzoic acid in the production of

dihydrofolate, synergistically blocking thymidine biosynthesis.

Table 77-2

Treatment of Pneumocystis jiroveci Pneumonia

Regimen Dose Route Adverse Effects/Comments

Approved

TMP-SMX 15–20 mg/kg TMP (75–100 mg/kg

SMX) daily administered IV or PO

every 6–8 hours or two DS tablets

TID

IV, PO Hypersensitivity, hyperkalemia, rash, fever,

neutropenia ↑LFTs, and nephrotoxicity (15

mg/kg/day preferred to 20 mg/kg/day

because of reduced toxicity)

Pentamidine

isethionate

4 mg/kg IV daily for 60–90 minutes ×

21 days

IV Pancreatitis, hypotension, hypoglycemia,

hyperglycemia, and nephrotoxicity

Atovaquone

a 750 mg BID with meals × 21 days

(suspension)

PO Headache, nausea, diarrhea, rash, fever,

and ↑LFTs

TMP

a +

dapsone

15 mg/kg/day PO Pruritus, GI intolerance, and bone marrow

suppression

100 mg/day × 21 days PO Methemoglobinemia and hemolytic anemia

(contraindicated in G6PD deficiency)

Clindamycin +

primaquine

600 mg IV every 8 hours or 300–450

mg PO every 6 hours

PO or IV Rash and diarrhea

15–30 mg (base) daily × 21 days PO Methemoglobinemia and hemolytic anemia

(contraindicated in G6PD deficiency)

Prednisone Within 72 hours of anti-Pneumocystis

therapy 40 mg every 12 hours × 5

days, then 40 mg daily × 5 days, then

20 mg/day × 11 days

PO Initiation in patients with moderately severe

or severe disease

Pao2 <70 mm Hg or A-a gradient >35 mm

Hg

aUsed only in mild to moderate Pneumocystis jiroveci pneumonia. A-a, alveolar-arterial gradient; BID, twice a

day; CNS, central nervous system; DS, double strength; GI, gastrointestinal; G6PD, glucose-6 phosphate

dehydrogenase; IV, intravenous; PO, oral; Pao2

, arterial partial pressure of oxygen; LFTs, liver function tests;

TMP-SMX, trimethoprim–sulfamethoxazole.

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TMP-SMX is the drug of choice for PCP unless the patient has a history of lifethreatening intolerance. In the treatment of PCP, TMP-SMX is either as effective as

or superior to all alternative agents. A good response may be expected in more than

70% of patients receiving TMP-SMX. TMP-SMX is often prescribed orally (PO)

because of its high bioavailability. The usual dose is 15 mg/kg (dosed by the TMP

component) divided every 8 hours for 21 days. Because one double-strength tablet of

TMP-SMX contains 160 mg TMP plus 800 mg SMX, a standard regimen is two

double-strength tablets 3 times per day (or every 8 hours).

Although the TMP-SMX regimen is very efficacious, 25% to 50% of patients may

be intolerant. Adverse effects include an erythematous, maculopapular, morbilliform

rash, and, less commonly, severe urticaria, exfoliative dermatitis, and Stevens–

Johnson syndrome. GI intolerance (nausea, vomiting, and abdominal pain) is

common.

12 Hematologic side effects may include leukopenia, anemia, and

thrombocytopenia. Neurologic toxicities, hyperkalemia, and hepatitis may also occur.

Most patients who exhibit a mild hypersensitivity (skin rash) reaction can be

managed with antipruritics or antihistamines without discontinuation of TMP-SMX.

In some patients with mild hypersensitivity reactions, the agent can be restarted after

the rash has resolved, using gradual dosage escalation or rapid oral desensitization to

reduce adverse effects.

40 Patients with severe adverse reactions should be switched

to another agent rather than being rechallenged with this drug (See also Chapter 32,

Drug Hypersensitivity Reactions).

Because J.R. seems to have a mild-to-moderate case of PCP (Pao2

, 80 mm Hg),

has not previously experienced an episode of PCP, and has no history of adverse

effects to TMP-SMX, an outpatient course of TMP-SMX would be reasonable.

ALTERNATIVES TO TRIMETHOPRIM– SULFAMETHOXAZOLE

CASE 77-1, QUESTION 3: J.R. experienced exfoliative dermatitis on Day 7 of TMP-SMX treatment. What

other drugs could be prescribed to treat his PCP?

Because J.R. presents with a serious adverse effect to TMP-SMX, it should be

discontinued and he should not be rechallenged or desensitized. Instead, he should be

treated with an alternative regimen (Table 77-2).

IV pentamidine isethionate can be used to treat acute PCP. The mechanism of

action is unknown, but it may be related to interference with oxidative

phosphorylation, inhibition of nucleic acid biosynthesis, or interference with

dihydrofolate reductase. Pentamidine is generally more toxic than TMP-SMX.

41

In a

5-year review of 106 courses of IV pentamidine, 76 (72%) patients had adverse

reactions (nephrotoxicity, dysglycemia, hepatotoxicity, hyperkalemia, and

hyperamylasemia). Drug discontinuation occurred in 31 (18%) of the severe cases.

Nephrotoxicity and hypoglycemia were the most common causes of drug

discontinuation. Nephrotoxicity occurred in 25% to 50% of the patients with

dehydration and concurrent nephrotoxic drugs among the risk factors. Hypoglycemia

was noted in 5% to 10% of patients after 5 to 7 days of treatment or several days

after discontinuation of treatment. Hyperglycemia is a consequence of decreased βcells and results in diabetes mellitus in 2% to 9% of patients. Other less common

adverse effects and toxicities include thrombocytopenia, orthostatic hypotension,

ventricular tachycardia, leukopenia, nausea, vomiting, abdominal pain, and

anorexia.

41

Patients receiving IV pentamidine should be monitored closely, and serum

concentrations of glucose, potassium, blood urea nitrogen (BUN), and creatinine

should be obtained daily or every other day during treatment. Other tests for periodic

monitoring include a complete blood count (CBC), liver function tests (LFTs),

amylase, lipase, and calcium.

41 Renal toxicity often responds to a reduction in the

dosage of pentamidine to 3 mg/kg/day or 4 mg/kg every 48 hours (creatinine

clearance <10 mL/minute); however, the drug should be discontinued in patients who

exhibit signs and symptoms of pancreatitis. Risk factors for pentamidine-induced

pancreatitis include prior episodes of pancreatitis and concurrent therapy with other

drugs known to cause pancreatitis. Nebulized pentamidine should not be considered

as an alternative to IV pentamidine for the treatment of PCP.

42

Atovaquone suspension, 750 mg twice a day (BID), is available for the treatment

of mild-to-moderate PCP. Atovaquone interrupts protozoan pyrimidine synthesis and

demonstrates activity against P. jiroveci and Toxoplasma gondii in animal models.

Atovaquone is approved by the US Food and Drug Administration (FDA) for the

treatment of mild-to-moderate PCP in patients intolerant of TMP-SMX. Atovaquone

is also an alternative for primary and secondary prophylaxis for both PCP and

toxoplasmosis.

12 Atovaquone is well tolerated compared with other PCP therapies.

Adverse effects include rash, fever, elevated LFTs, and emesis. Atovaquone is safer,

but less effective, than TMP-SMX in patients with mild-to-moderate PCP.

43 When

compared with IV pentamidine in the treatment of mild-to-moderate PCP, atovaquone

and pentamidine were equally efficacious; however, pentamidine was significantly

more toxic.

44 Most atovaquone studies were performed using the moderately

absorbed oral tablets; reformulation of this drug as a suspension has improved

bioavailability by at least 30%. Concomitant administration of fatty foods with

atovaquone doubles the absorption.

An oral regimen of dapsone plus TMP is another alternative to TMP-SMX.

Dapsone–TMP can be used to treat mild-to-moderate PCP in patients intolerant of

TMP-SMX. Dapsone is a sulfone antimicrobial that is used for leprosy. Although

monotherapy (200 mg/day) with dapsone is ineffective for the treatment (not

prophylaxis) of PCP, the addition of TMP (20 mg/kg/day) to dapsone (100 mg/day)

is an effective alternative regimen.

45

In a small comparative trial of TMP–dapsone

versus TMP-SMX, the response rates of 93% and 90% were observed,

respectively.

46 When dapsone is coadministered with TMP, the resulting plasma

concentrations for both drugs are higher than when either drug is taken alone. In

combination with TMP, a pyrimidine, synergistic inhibition of folic acid synthesis

occurs.

47 Dapsone–TMP should not be used in sulfonamide-allergic patients with a

history of type I hypersensitivity reaction, toxic epidermal necrolysis, or Stevens–

Johnson syndrome. Dapsone is associated with hematologic toxicities, including

hemolytic anemia, methemoglobinemia, neutropenia, and thrombocytopenia. Patients

with glucose-6-phosphate dehydrogenase (G6PD) deficiency cannot detoxify

hydrogen peroxide and are at an increased risk for hematologic toxicity from

dapsone.

Success rates of 70% to 100% have been reported with clindamycin (600 mg IV

every 6 hours or 600 mg PO 3 times a day [TID]) given in conjunction with 30

mg/day of primaquine base. Although skin rashes are common with this combination,

these often subside with continued therapy. Some patients experience toxicities

(fever, rash, granulocytopenia, and methemoglobinemia) requiring

discontinuation.

48–50 As with dapsone, before starting primaquine, patients should be

screened for G6PD deficiency. Patients who test positive for G6PD deficiency are at

a risk for developing hemolytic anemia.

A double-blind efficacy and toxicity study of 181 patients with mild-to-moderate

PCP compared three oral drug regimens: TMP-SMX versus dapsone–TMP versus

clindamycin–primaquine. The doses of TMP-SMX and dapsone–TMP were weightbased, and

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