1. Management 0f Opportunistic Infections Associated with HIV (131)
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2. Pneumocystis Jirovescii Pneumonia
PCP continues to be a common complication of HIV infection in North America and Western Europe, although in some areas of the world it is much less commonly recognized.
Although specific prophylaxis and ART have reduced the number of cases, many patients do not recognize that they have HIV infection until they present with PCP.

3. Other patients fails to take prophylactic medications; some develop PCP despite prophylaxis, especially if the regimen does not include TMP-SMX; and some do not have a sustained response to ART.
Therefore, PCP continues to be a substantial cause of morbidity and mortality.

4. Pneumocystis disease most often manifests as pulmonary dysfunction in patients with HIV infection.
Patients may have chest tightness or exercise intolerance as very early symptoms, before CXR results are abnormal and before ABG reveal hypoxemia.
Even with very mild manifestations, organisms can be recovered readily from sputum, or BAL, allowing initiation of therapy on an outpatient basis at a stage when prognosis is excellent.

5. In large series of patients, PCP can be distinguished from bacterial pneumonia or tuberculosis by the duration of symptoms, the character of sputum, and the radiologic manifestations.
However, in individual cases, it is much more difficult to reliably distinguish PCP from a variety of other infectious and non infectious disease, including TB, histoplasmosis, and nonspecific interstitial pneumonitis.
Therefore, it is important to establish a specific diagnosis to ascertain that the correct pathogen is being treated and to avoid the toxicities, cost, and inconvenience of unnecessary drugs.

6. Oral TMP-SMX is the treatment of choice for acute PCP because of its convenience of administration, high degree of efficacy, and manageability of associated toxicities.
There is no clear reason to prefer intravenous over oral TMP-SMX in adherent patients without obvious GI dysfunction.
Patients usually improve clinically within 4 to 8 days, in terms of fever, respiratory rate, arterial-alveolar gradient, and dyspnea.
Although there may be an initial worsening during the first 8 to 72 hours of therapy if adjunctive corticosteroid therapy is not given.

7. Common adverse reaction to TMP-SMX include rash, nausea, vomiting, granulocytopenia, transaminase elevations, nephritis, and hyperkalemia.
The rashes, which commonly occur between days 8 and 12 of therapy, may be limited in extent and associated with a degree of pruritus that the patient can tolerance for 21 days.
They are more frequent in patients with higher CD4 T-cell counts.
Life threatening desquamating processes (e.g., Stevens-Johnson syndrome) are rare in AIDS patients, although a few fatal cases have been reported.

8. Severe febrile, hypotensive episodes that resemble septic shock in terms of hemodynamics have also been reported.
Granulocytopenia is most often a dose related phenomenon that may resolve partially or completely if the dose of TMP-SMX is reduced by 25%.
Granulocytopenia responds to leucovorin administration only rarely.

9. Parenteral pentamidine is effective therapy for PCP.
Renal dysfunction, hypoglycemia, hyperglycemia, granulocytopenia, and hypotension are reported in 10% to 50% of patients.
If pentamidine is administered over a period of at least 60 minutes in 100 to 150 mL of dextrose in water, clinically important hypotension is unusual.
The renal dysfunction associated with pentamidine can be severe.
Hypoglycemia can be a life threatening complication of pentamidine therapy; it can occur at any juncture during therapy or for many weeks after therapy has been completed.

10. Hypoglycemia occurs more frequently in patients who have pentamidine induced renal dysfunction.
Life threatening hypoglycemia is sufficiently uncommon, however, that this effective agent is still recommended for patients with severe disease who can not tolerate TMP-SMX or TMP-dapson.
Lowering the dose of parenteral pentamidine from 4 to 3 mg/kg/day has been advocated to reduce toxicity; whether this also reduces efficacy is unknown.

11. Dapsone (100 mg orally every day) plus TMP (5mg/kg orally every 8 hours or 300 mg orally every 8 hours) appears to be as effective as TMP-SMX but less toxic.
Skin rashes are very common among HIV infected patients treated with dapsone, but a 21 day course of therapy can usually be completed without interruption.
Oral dapsone alone has some efficacy when 100 mg is admistered every day for 21 days,but there is probably not enough activity to warrant use of this agent as single therapy.

12. Atovaquone is a hydroxynaphthoquinone that appear to affect mitochondrial electron transport in microorganisms, and therefore has a mechanism of action distinct from that of TMP-SMX or pentamidine.
Atovaquone is available as an oral suspension but is not available in parenteral form.
For patients with mild to moderate PCP, it has a high degree of efficacy and is extremely well tolerated.
The primary toxicity associated with atovaquone is skin rash.
Atovaquone (750 mg PO bid with food), is a reasonable treatment option for patients with mild to moderate PCP who cannot tolerate TMP-SMX and who are good candidates for oral therapy.

13. Clindamycin ( mg IV q6h to q8h) plus primaquine (15 to 30 mg PO daily), is also effective therapy for PCP.
Despite the fact that primaquine can be given only orally, this regimen has been used successfully in patients with mild, moderate, and severe disease.
Clindamycin plus primaquine is associated with considerable toxicity, including rash, serum transaminase elevation, diarrhea, and hemolysis.
It is a reasonable oral regimen for patients who are unable to tolerate other regimens.

14. Trimetrexate is a potent inhibitor of dihydrofolate reductase that effective therapy against PCP when used either alone or in combination with a sulfonamide.
It must be given in conjunction with high dose leucovorin (20 mg q6h IV or orally every 6 hours), which rescues mammalian cells without diminishing the anti pneumocystis effect of the drug.
Leukopenia is its major adverse effect.
The relapse rate after trimetrexate therapy is high, 60% patients experience relapse within the first 60 days if prophylaxis is not given.

15. Regardless of which specific agent is chosen as the initial therapy for PCP, adjunctive corticosteroid therapy is indicated for any patient whose initial room air Po2 is lower than 70 mm HG.
The frequencies of ventilatory failure and mortality can be reduced substantially by the prompt use of corticosteroid.
The safety of the 21 days regimen is well substantiated; reactivation of tuberculosis, CMV, or Kaposi’s sarcoma is unusual.
Interestingly, the frequency of TMP-SMX related rash is not diminished by corticosteroids.

16. If a patient has not improved after 5 to 10 days of therapy, a repeat diagnostic procedure should be considered to determine whether another treatable pathogen is present.
BAL is the procedure of choice.
TBB (biopsy), often can be performed to assess for the presence of CMV and can be very helpful in establishing the presence of fungal or mycobacterial processes.
Pneumocystis, is often present in lavage or tissue for at least 3 to 4 weeks after initiation of therapy, even in patients who respond promptly, so its presence after 7 to 10 days of therapy does not necessarily imply that therapy is ineffective.

17. A decision regarding therapeutic efficacy should be based on clinical and laboratory parameters such as oxygenation, ventilation, and fever.
The presence of extensive intra alveolar exudate or extensive fibrosis after 7 to 10 days of therapy is probably a more ominous sign.
Open lung biopsy is rarely necessary to establish a diagnosis of PCP, but it can be useful for identify other processes.
Kaposi’s sarcoma of the lung is usually apparent on bronchoscopy because of endobronchial lesions that are obvious to thr bronchoscopist.

18. Kaposi’s sarcoma of the lung is one treatable process that is difficult or impossible to diagnose reliably from cytology or from transbronchial biopsy specimens.
Nodular lesions on chest CT scans, extensive intrabronchial lesions, and the presence of a bloody pleural effusion may be helpful clues that Kaposi’s sarcoma is the cause of pulmonary dysfunction.
CMV and lymphoma are other process that may be identified by cytology or by some form of biopsy more readily than by sputum assessment.

19. If pneumocystis infection is the only identifiable cause of the pulmonary dysfunction after 7 to 10 days of therapy and no improvement has been observed, there are several therapeutic alternatives:
(1) switch from TMP-SMX to parenteral pentamidine or vice-versa.
(2) add corticosteroids to conventional therapy if they have not already been added.
(3) switch to IV trimetrexate (with or without parenteral sulfonamidee in the form of TMP-SMX).
(4) switch to IV clindamycin with oral primaquine.
(5) use two specific therapy concurrently (e.g., TMP-SMX plus pentamidine).

20. PREVENTION of PCP
Prevention of PCP is a major priority in the management of HIV infection.
At least 80% to 90% of HIV infected patients in North America develop an episode at some point if they have received neither anti pneumocystis prophylaxis nor ART.
Most primary episodes of PCP occur
in patients with CD4 T-cell count lower than 200 cell/mL or
in patients with unexplained oropharyngeal candidiasis.

21. Other documented predictors of the occurrence of PCP, independent of the CD4 T-cell counts, are
high HIV viral load,
wasting syndrome,
previous AIDS defining event, and
prior pneumonia of any type.

22. Secondary prophylaxis (the presence of second or subsequent episodes of PCP) is conventionally indicated for every one who has had a documented PCP episode, because the 1 year recurrence rate is approximately 65% for patients who receive no prophylaxis.
Discontinuation of prophylaxis is reasonable for patients who respond to ART and who manifest CD4 T-cell counts that are persistently about 200 cell/ ml.

23. TMP-SMX is the preferred prophylactic regimen for any HIV infected patients who can tolerate it.
TMP-SMX is much more effective prophylaxis than aerosolized pentamidine or dapsone containing regimens.
Daily dapsone or weekly dapsone-pyrimethamine has an efficacy comparable to that of aerosolized pentamidine.
Dapsone-pyrimethamine regimens, are effective as prophylaxis against toxoplasmosis.

24. (1) TMP-SMX, 1 DS PO daily or 1 SS daily or 1 DS PO tiw.
(2) Dapsone 100 mg PO daily or 50 mg PO bid.
(3) Dapsone 50 mg PO daily + pyrimethamine 50 mg PO weekly + leucovorin 25 mg PO weekly.
(4) Aerosolized pentamidine 300 mg via respigard nebulizer every month.
(5) Atovaquone 1500 mg PO daily.
(6) Atovaquone 1500 mg + pyrimethamin 25 mg + leucovorin 10 mg PO daily.

25. Management of Opportunistic Infections Associated with Human Immunodeficiency Virus Infection (131)
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26. Toxoplasma gondii
9/7/2018

27. Toxoplasma gondii (see Chapter 280) causes disease in patients with HIV infection primarily by reactivation of latent disease rather than by primary infection.160
Patients almost always have immunoglobulin G antibodies against Toxoplasma (although insensitive enzyme-linked immunosorbent assays [ELISAs] may fail to detect such antibodies), have fairly advanced disease (CD4+ T-cell counts <50 cells/mm3), and have not been receiving TMP-SMX prophylaxis.
Because the seroprevalence of toxoplasmosis is much higher in some areas, such as Western Europe (50% to 80%) and South America than in the United States (11%) (i.e., there is a higher incidence of latent infection), those areas have much higher frequencies of AIDS-associated toxoplasmosis because the latent disease has the potential to reactivate when patients are severely immunosuppressed.
9/7/2018

28. In patients with HIV infection, toxoplasmosis manifests most often as cerebral disease presenting as fever, headache, confusion, motor defects, and seizures.
Retinochoroiditis, pneumonitis, disseminated disease, and a sepsis-like syndrome have all been reported, but these are not as frequent as focal lesions of the central nervous system (CNS).
9/7/2018

29. If an HIV-infected patient with a CD4+ T-cell count of less than 100 cells/mm3 presents with a space-occupying cerebral lesion that involves gray matter, the differential diagnosis should focus on two entities:
1- toxoplasmosis and
2- lymphoma.
Fungal, mycobacterial, and viral processe also manifest as space-occupying lesions, but these pathogens are the causative organisms less commonly in the United States and Western Europe than Toxoplasma and lymphoma.
Progressive multifocal leukoencephalopathy should manifest differently because it affects primarily white matter.
The incidence of malignant neoplasms that are not included as “AIDS defining conditions” is increasing; thus, clinicians must also be alert to the possibility that CNS masses represent metastatic tumor.
Also, in the era of ART, CNS lymphoma appears to be increasing in frequency compared with CNS toxoplasmosis.
9/7/2018

30. However, no imaging technique is completely specific.
Clinical or imaging characteristics help to distinguish lymphoma from toxoplasmosis but are not definitive.
Magnetic resonance imaging (MRI) is more sensitive than CT for radiologic diagnosis of Toxoplasma encephalitis.
Positron emission tomography (PET) or single-photon emission computed tomography (SPECT) may also be helpful in distinguishing Toxoplasma encephalitis from primary CNS lymphoma.
However, no imaging technique is completely specific.
9/7/2018

31. Sensitivity may be low after specific therapy has been started.
If safe and feasible, a lumbar puncture should be performed for T. gondii PCR assay.
A positive cerebrospinal fluid (CSF) PCR assay for Epstein-Barr virus (EBV) appears to be moderately specific for primary CNS lymphoma;
some positive results have been documented in patients with proven cerebral toxoplasmosis, that is, the CSF is EBV positive but the lesion is caused by Toxoplasma.
For toxoplasmosis, detection of the organism by PCR of CSF should be highly suggestive that Toxoplasma is the causative agent; the test is not standardized, however, across laboratories.
Published results have shown that some laboratories can achieve high specificity but low sensitivity.
Sensitivity may be low after specific therapy has been started.
9/7/2018

32. Although most cases of Toxoplasma encephalitis are diagnosed by response to empirical therapy, or by PCR assay of the CSF,
an unequivocal diagnosis of Toxoplasma encephalitis requires a brain biopsy, which is most commonly performed by a stereotactic CT-guided needle biopsy.
Hematoxylin and eosin stains can be used for detection of T. gondii, but sensitivity is significantly increased if immunoperoxidase or immunofluorescent staining is used.
9/7/2018

33. If an HIV-infected patient with a circulating CD4+ T-cell count less than 50 cells/mm3 and positive serum anti-Toxoplasma antibody presents with a CNS mass lesion involving gray matter, most clinicians would treat the patient empirically for toxoplasmosis.
A definitive diagnostic study (i.e., brain biopsy) has morbidity associated with it, and the diagnostic yield may be only 50% if toxoplasmosis is the cause depending on the size of the biopsy and skill of the pathologist.
The cysts and tachyzoites of T. gondii can be difficult to recognize in fragments of necrotic brain tissue, and even several small needle biopsy samples may miss the area that has abundant organisms.
9/7/2018

34. When patients are treated with either sulfadiazine-pyrimethamine or clindamycin-pyrimethamine, unequivocal improvement clinically and radiologically should occur within 10 to 21 days.
If such improvement does not occur, a biopsy should be performed to establish whether the cause is an infectious or a neoplastic process other than toxoplasmosis.
Pyrimethamine and sulfadiazine are becoming more difficult to find in some regions.
TMP-SMX has not been as extensively evaluated in published literature as pyrimethamine and sulfadiazine, but several small trials or observational cohorts suggest that TMP-SMX has comparable efficacy and safety to sulfadiazine plus pyrimethamine.
TMP-SMX has the advantage of being available as an oral or an intravenous preparation.
9/7/2018

35. Doses of corticosteroids should be tapered as soon as feasible.
Corticosteroids to reduce inflammation may be necessary in patients with signs of increased intracranial pressure.
There are no well-defined parameters to determine when corticosteroid therapy is indicated: clinical judgment must be used.
The administration of corticosteroids can make early evaluation of the clinical and radiologic response to specific therapy difficult because the observed improvement may be solely the result of corticosteroid therapy and unrelated to the anti-Toxoplasma regimen employed.
Doses of corticosteroids should be tapered as soon as feasible.
9/7/2018

36. Although some clinicians institute antiseizure drugs prophylactically, it is reasonable to initiate such therapy only if a seizure occurs.
For patients who have a clinical and radiologic response, anti- Toxoplasma therapy should be continued lifelong, in the absence of an ART-induced rise in the CD4+ T-cell count, because relapses occur in the same sites manifesting initially if therapy is discontinued, even after 8 to 12 months of treatment.
If the CD4+ T-cell count rises substantially (e.g., to levels >200 cells/mm3) and the patient has received at least 6 months of therapy, anti-Toxoplasma therapy can be safely discontinued, provided that the lesion has largely resolved on cerebral imaging and the patient is neurologically stable (see Table
131-3).8
9/7/2018

37. Treatment failures are unusual for patients with toxoplasmosis who are able to tolerate both pyrimethamine and sulfadiazine.
Radiologically proven failures in patients who are adhering to their drug regimen should raise the possibility that toxoplasmosis is not the correct or the only diagnosis.
Adverse reactions to sulfadiazine (leukopenia, rash, elevated levels of aminotransferases, nausea, nephritis) and to pyrimethamine (leukopenia, thrombocytopenia) are common.
9/7/2018

38. Trimethoprim- or pyrimethamine-induced leukopenia often does not respond to leucovorin therapy, although a short course of leucovorin (10 to 20 mg orally or intravenously every 6 hours) should be administered.
For patients unable to tolerate sulfadiazine, clindamycin plus pyrimethamine is also effective (see Table 131-2).
9/7/2018

39. Dapsone-pyrimethamine and atovaquone also have substantial efficacy.
Immune reconstitution syndromes associated with toxoplasmosis have only rarely been reported.
The potential for such syndromes to occur should be considered before initiating ART, especially in patients who have elevated intracranial pressure.
TMP-SMX offers considerable protection as primary prophylaxis for Toxoplasma-seropositive patients with CD4+ T-cell counts less than 100 cells/mm3.
Dapsone-pyrimethamine and atovaquone also have substantial efficacy.
9/7/2018

40. Treatment of acute infection (TE) preferred therapy
Pyrimethamine 200 mg PO 1 time, followed by weight-based therapy:
If <60 kg, pyrimethamine 50 mg PO once daily + sulfadiazine 1000 mg PO q6h + leucovorin mg PO once daily
If ≥60 kg, pyrimethamine 75 mg PO once daily + sulfadiazine 1500 mg PO q6h + leucovorin mg PO once daily Leucovorin dose can be increased to 50 mg daily or bid.
Duration for acute therapy:
At least 6 wk; longer duration if clinical or radiologic disease is extensive or response is incomplete at 6 wk

41. Chronic maintenance therapy:
Pyrimethamine mg PO daily + sulfadiazine mg PO daily (in two to four divided doses) + leucovorin mg PO daily

42. Treatment of acute infection (alternative therapy)
Pyrimethamine (leucovorin)* + clindamycin 600 mg IV or PO q6h, or
TMP-SMX (TMP 5 mg/kg and SMX 25 mg/kg) IV or PO bid, or
Atovaquone 1500 mg PO bid with food + pyrimethamine (leucovorin), or
Atovaquone 1500 mg PO bid with food + sulfadiazine mg PO q6h (weight-based dosing, as in preferred therapy), or
Atovaquone 1500 mg PO bid with food, or
Pyrimethamine (leucovorin)* + azithromycin mg PO daily

43. Chronic maintenance therapy: alternative therapy
Clindamycin 600 mg PO q8h + (pyrimethamine mg + leucovorin mg) PO daily, or
TMP-SMX DS 1 tablet bid, or
Atovaquone mg PO bid + (pyrimethamine 25 mg + leucovorin 10 mg) PO daily, or
Atovaquone mg PO bid + sulfadiazine mg PO daily (in two to four divided doses), or
Atovaquone mg PO bid with food

44. Other Comment
Adjunctive corticosteroids (e.g., dexamethasone) should only be administered when clinically indicated to treat mass effect associated with focal lesions or associated edema; discontinue as soon as clinically feasible.
Anticonvulsants should be administered to patients with a history of seizures and continued through acute treatment but should not be used as seizure prophylaxis.
If clindamycin is used in place of sulfadiazine, additional therapy must be added to prevent PCP.

45. CANDIDA SPECIES
Stomatitis, esophagitis, vaginitis, and proctitis caused by Candida albicans infection are common.
This disease often respond to topical therapy (nystatin or clotrimazole), oral therapy (itra, posa, or fluconazole), or intravenous therapy (fluconazole, voriconazole, caspofungin, micafungin, anidulafungin, or one of several amphotericin B preparations).
Fluconazole is the most convenient drug and is therefore preferred unless there is a strong suspicion that the pathogen is fluconazole resistant.
Itraconazole, and voriconazole are also effective.

46. Fluconazole, itraconazole, and voriconazole all inhibit certain hepatic enzymes of the cytochrome P-450 class, resulting in elevated levels of drugs, such as PI, and NNRTIs.
There is usually no urgency to institute antifungal therapy for any of these candidal mucosal disorders.
Esophagitis is rarely associated with bleeding, perforation, fungemia, or disseminated fungal disease, in contrast to the experience with neutropenic patients after chemotherapy.

47. Stomatitis, esophagitis, and proctitis often recur after therapy is discontinued if CD4 T-cell count remain low.
Fluconazole administration may have to be continued for life if recurrences are frequent or severe, and CD4 T-cell counts remain low.
Patients with no response to topical or oral azole after 2 weeks usually have CD4 T-cell counts lower than 50 cells/µL and extensive prior exposure to fluconazole.
The reasons for therapeutic failure need to be assessed, focusing on adherence to dosage regimens and drug interactions as well as resistance of organisms to fluconazole.

48. If there is no response to a 7 day course of oral fluconazole (200mg or more every day), higher doses of fluconazole are rarely effective.
Other option include itraconazole-cyclodextran solution, voriconazole, posaconazole, an echinocandin, or intravenous amphotericin B.
Candida isolates that are clinically and microbiologically resistant to fluconazole have been described in patients taking fluconazole for prolonged period.
Disseminated candidiasis is not characteristic of AIDS, if candidemia occurs, it is usually associated with an IV catheter.
Treatment is similar to that in other patient populations, with particular attention directed at removing contaminated IV lines or discontinuing therapies that may be producing neutropenia.

49. Fluconazole 100 mg PO daily
Preferred therapy oropharyngeal candidiasis; initial episodes (7 to 14 day treatment)
Fluconazole 100 mg PO daily
Clotrimazole troches 10 mg Po 5 times daily
Nystatin suspension 4-6 mL qid
Miconazole mucoadhesive tablet PO daily
ALTERNATIVE :
Itraconazole oral solution 200 mg PO daily
Posaconazole oral solution 400 mg PO bid 1 day, then 400 mg daily

50. Preferred therapy esophageal candidiasis; (14-21 days)
Fluconazole 100 mg (up to 400 mg) PO or IV daily
Itraconazole oral solution 200 mg PO daily
ALTERNATIVE :
Voriconazole 200 mg PO or IV bid
Posaconazole 400 mg PO bid
Caspofungin 50 mg IV daily
Micafungin 150 mg IV daily
Anidulafungin 100 mg IV 1 day, then 50 mg IV daily
Amphotericin B 0.6 mg/kg IV daily

51. Preferred therapy fluconazole refractory oropharyngeal or esophageal candidiasis;
Itraconazole oral solution >200 mg daily
Posaconazole oral solution 400 mg PO bid
ALTERNATIVE:
Amphotericine B 0.3 mg/kg IV daily
lipid formulation of amphotericin B 3-5 mg/kg IV daily
Anidulafungin 100 mg IV 1 day, then 50 mg IV daily
Caspofungin 50 mg IV daily
Micafungin 150 mg IV daily
Voriconazole 200 mg PO or IV bid

52. CRYPTOCOCCAL NEOFORMANS
Meningitis is the most frequent manifestation of cryptococcosis in HIV infected patients.
Patients usually present with fever, headache, neck stiffness, or photophobia.
Most have CD4 T-cell counts lower than 50 cells/µL.
Patients can also present with pulmonary or cutaneous manifestations with or without apparent neurologic disease.

53. Patients with meningitis have CSF that typically demonstrates elevated protein and mononuclear cells and decreased glucose.
In some patients, one or all of these parameters may be normal.
The CSF and serum cryptococcal antigen tests are almost always positive, and 75% of patients have an elevated opening pressure.

54. Baseline factors predicting a poor therapeutic response in patients with meningitis include
altered mental status,
CSF antigen titer greater than 1:32,
decreased CSF leukocyte count (fewer than 20 cells/mm),
age younger than 35 years,
positive blood cultures for Cryptococcus,
and perhaps hyponatremia and positive CNS culture for Cryptococcus.

55. The best studied therapy for cryptococcal meningitis is amphotericin B (0.7 mg/kg IV daily, with or without flucytosin) given IV until clinical improvement has occurred and at least for 2 weeks.
Followed by fluconazole, 400 mg orally every day for 8 weeks, followed by fluconazole, 200mg orally every day for life unless CD4 T-cell counts rise above 100 to 200/µL.
Flucytosin (100mg/kg PO daily in 4 divided doses for at least 2 weeks), which reduces the rate of relapse, is associated with potential bone marrow suppression and hepatotoxicity.
For maintenance therapy, fluconazole is more effective than itraconazole.

56. There is considerable interest in using alternative drugs to amphotericin B to improve convenience, reduce toxicity, and further improve efficacy.
Loposomal amphotericin B (4-6 mg/kg IV daily), preparations are effective therapies for cryptococcal meningitis, although it is not unequivocally established that they are as effective as the nonlipid formulation.
There is no compelling reason to use voriconazole or posaconazole for therapy of cryptococcosis.

57. The condition of patients with cryptococcal disease may deteriorate because of the consequences of increased ICP.
Clinical signs of increased pressure need to be sought, especially at presentation and during acute induction period.
The baseline opening pressure should be measured at the time of the initial LP in patients with FND or altered mental status.
An imaging study of the CNS may be useful before the initial LP and subsequently if the clinical status deteriorates.

58. If the opening pressure is high (>25 cm H2O), consideration should be given to reducing pressure by repeated LP or by insertion of a CSF drain or shunt.
One approach used by experienced clinicians is to remove the volume of CSF that reduces opening pressure by 50%.
Corticosteroids, mannitol, and acetazolamide are not recommended.
Patients being treated successfully for cryptococcal meningitis should demonstrate a decline in the CSF cryptococcal antigen titer.

59. Many experts would repeat the CSF culture after 2 weeks, a positive culture after 2 weeks of therapy predicts relapse.
Maintenance fluconazole therapy can be stopped for patients who are asymptomatic, have completed 6 months of therapy, and have had a sustained increase in CD4 T-cell counts with ART to more than 100 to 200 cells/mm for at least 6 months.
Some clinicians would repeat the LP before stopping therapy, to assess the antigen titer and the presence of viable organisms, but there is no evidence that this is necessary.

60. About 30% of patients with cryptococcal meningitis will develop IRIS when ART is initiated.
The manifestations of IRIS are difficult to distinguish from treatment failure.
Some clinicians would withhold ART for at least 2 weeks after starting anticryptococcal therapy to reduce the likelihood of IRIS.
IRIS can be severe, with substantial headache, fever, photophobia, lymphadenopathy, or pneumonitis.
Short course of corticosteroids may be indicated in such settings.

61. Aspergilosis
Aspergilosis is recognized as a cause of pseudomembranous, tracheobronchitis, pneumonia, sinusitis, and disseminated disease in patients with HIV disease.
Diagnosis is difficult to confirm without visualization of hyphae in tissue.
Therapy is often unsuccessful because of both poor host immune function (patients often have a CD4 T-cell count lower than 50 cells/µL or a neutrophil count lower than 500 cells/µL) and the presence of extensive disease at the time of diagnosis.

62. Strong consideration should be given to surgical resection of the most obviously affected tissue as an adjunct to medical therapy.
Treatment with voroconazole or high dose amphotericin B or liposomal amphotericin is the standard approach.
Whether combination therapy offers improved efficacy over voriconazole or amphotericin B monotherapy remains to be determined.

63. Aspergilosis, invasive
PREFERRED THERAPY:
Voriconazole 6 mg/kg q12h 1 day, then 4 mg/kg q12h IV, followed by voriconazole PO 200 mg q12h after clinical improvement.
Duration of therapy: until CD4 count >200 cell/µg and with evidence of clinical response.
ALTERNATIVE THERAPY:
Amphotericin B 1 mg/kg/day IV
Lipid formulation of amphotericin B 5 mg/kg/day IV
Caspofungin 70 mg IV 1 day, then 50 mg IV daily
Posaconazole 400 mg PO bid

64. Prevention and Prophylaxis of Aspergilosis

65. Prevention of invasive aspergilosis in high risk patients is difficult.
Nosocomial outbreaks of aspergilosis have been linked to construction, contaminated ventilation system, and possibly contaminated water.
For high risk patients such as those undergoing hematopoietic stem cell transplantation, the use of high efficiency particulate air (HEPA) filters, frequent air exchanges, and positivepressure ventilation has been recommended to limit exposures in the hospital setting.
Infection control measures such as construction barriers will limit exposure to aerosols.

66. In addition, attention to routine maintenance and cleaning of showers and water systems may further reduce risk.
Some patients will still develop infection with this precautions, and an increasing number of immunosuppressed patients receive care outside of the hospital setting so that community acquired infection is common.
Efficacy of antifungal prophylaxis has been limited until recently because of the toxicity of amphotericin B and the limited activity of other oral agents against Aspergilosis.

67. Agents evaluated in this setting include low dose amphotericin B, low doses of lipid formulations of amphotericin B, and nasal and aerosolized forms of amphotericin B.
None of which has demonstrated conclusively to be beneficial in a large randomized clinical trials.
Recent studies of aerosolized formulations of lipid amphotericin B demonstrate its safety and potential efficacy in lung transplant recipients at high risk for invasive aspergilosis.
Itraconazole has bee suggested to have benefit against prevention of molds, but its poor tolerance in high risk patients has also limited its use.

68. In a single study of fungal prophylaxis in patients with CGD, itraconazole appeared to reduce the incidence of serious fungal infections, including those due to Aspergilosis.
Two recent randomized trials have established the safety and efficacy of posaconazole in high risk patients and reduced the noumber of breakthrough fungal infections including invasive aspergilosis.
Although posaconazole was generally well tolerated, more serious adverse drug events occurred with posaconazole therapy so that a risk benefit analysis should be considered when recommending posaconazole prophylaxis.
From the results of this trials, guidelines recommend the use of posaconazole prophylaxis in patients with AML or with GVHD who are high risk for invasive aspergilosis.

69. Histoplasmosis
Histoplasmosis is a common, life threatening, opportunistic infection in patients with HIV infection in certain geographic areas such as the Mississippi and Ohio River valleys of the United States, Puerto Rico, and much of Latin America.
Patients with low CD4 T-cells, especially those with counts lower than 150 cells/µL, are likelyto present with extrapulmonary manifestation such as fever, meningitis, abdominal pain, diarrhea, or shock.
Diagnosis is characteristically established by direct microscopy or culture (BAL, B.M, or blood) or by antigen detection (urine, blood, or BAL). µ

70. Although a sensitive and specific assay is available only from specialized laboratories, the sensitivity of the test is high in urine (95%), serum (85%), BAL (70%), and CSF (50%).
Histoplsma meningitis can be especially difficult to document and must sometimes be treated presumptively in patients with disseminated disease.
Acute therapy for moderate or severe non meningeal disease should consist of IV amphotericin B for at least 14 days, for most patients.
Meningeal disease requires a longer course of amphotericin B (i.e., at least 1 year).

71. Itraconazole is also effective but should probably be reserved as initial therapy for patients with very mild disease.
Liposomal amphotericin B has been used successfully to treat disseminated disease.
For long term maintenance therapy, oral itraconazole is recommended for a minimum of 12 months.
Serum and urine H.capsulatum polysaccharide antigens are useful for monitoring both the initial and the long term phases of treatment.
These tests predict treatment failure or relapse.

72. Coccidioidomycosis