Infectious Diseases II Patient Cases PDF

Infectious Diseases II Patient Case 2. Six months after F.G. (from patient case 1) starts appropriate therapy, his CD4 count is 720 cells/mm3, and his viral load is undetectable. Two years later, his CD4 count decreases to 310 cells/mm3, and his viral load is 15,000 copies/mL. Resistance testing d...

Infectious Diseases II Patient Case 2. Six months after F.G. (from patient case 1) starts appropriate therapy, his CD4 count is 720 cells/mm3, and his viral load is undetectable. Two years later, his CD4 count decreases to 310 cells/mm3, and his viral load is 15,000 copies/mL. Resistance testing detects resistance to dolutegravir. His HIV regimen is changed to abacavir, lamivudine, and darunavir/ritonavir. Which of the following tests must be performed before starting abacavir? A. Liver function tests because of the risk of hepatotoxicity. B. HLA-B*5701 allele screening because of the risk of a serious hypersensitivity reaction. C. Hemoglobin A1C and a lipid panel because of the risk of endocrine disturbances. D. Bilirubin because of the risk of hyperbilirubinemia. II. OPPORTUNISTIC INFECTIONS: PATIENTS WITH HIV Herpes Zoster 400 Kaposi’s Sarcoma 350 Oral Candidiasis Non-Hodgkin’s Lymphoma 300 CD4 Count (cells/mm3) Pneumocystis jiroveci Pneumonia 250 Herpes Simplex Virus infections 200 Cryptococcal meningitis Toxoplasmosis 150 MAI and Cytomegalovirus 100 50 HIV-related Opportunistic Infections Figure 1. Relationship between CD4 count and risk of HIV-related opportunistic infections. MAI = Mycobacterium avium-intracellulare. A. Initiating Potent Combination ART in the Setting of Acute Opportunistic Infections 1. Opportunistic infections with no effective therapy require prompt initiation of ART: cryptosporidiosis, microsporidiosis, promyelocytic leukemia, and Kaposi sarcoma. 2. ART should begin within 2 weeks of acute opportunistic infections, except for tuberculosis (TB), in which therapy should begin within 2 weeks when the CD4 count is less than 50 cells/mm3 and by 8–12 weeks for all others, and cryptococcal meningitis, in which therapy should begin 5 weeks after diagnosis (because of immune reconstitution inflammatory syndrome [IRIS]). B. Pneumocystis jiroveci (formerly carinii) Pneumonia (PJP) 1. Clinical presentation a. Fever, shortness of breath, and nonproductive cough b. Elevated lactate dehydrogenase c. Diffuse pulmonary infiltrates d. In general, with CD4 counts less than 200 cells/mm3 e. Hypoxemia with elevated alveolar-arterial (A-a) gradient and decreased Po2; A-a gradient = 150 − Po2 − Pco2 ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-261 Infectious Diseases II Patient Cases 3. Three years later, F.G. (from patient cases 1–2) has not responded to any of his ART regimens because of resistance or intolerance. His CD4 count has decreased to 135 cells/mm3. For which infection is it most important that F.G. receive primary prophylaxis? A. Pneumocystis jiroveci pneumonia (PJP). B. Cryptococcal meningitis. C. Cytomegalovirus (CMV). D. Mycobacterium avium complex (MAC). 4. B.L. is a 44-year-old HIV-positive man who arrives at the emergency department severely short of breath. He is an extremely nonadherent patient and has not seen a health care provider in more than 3 years. A chest radiograph shows pulmonary infiltrates in both lung fields. The results of the laboratory tests are as follows: sodium 147 mEq/L, potassium 4.2 mEq/L, chloride 104 mEq/L, bicarbonate 25.2 mEq/L, glucose 107 mg/ dL, blood urea nitrogen 38 mg/dL, serum creatinine 1.1 mg/dL, aspartate aminotransferase 28 IU/L, alanine aminotransferase 32 IU/L, lactate dehydrogenase 386 IU/L, alkaline phosphate 75 IU/L, pH 7.45, Po2 63 mm Hg, Pco2 32 mm Hg, and oxygen saturation 85%. His CD4 count is 98 cells/mm3. Sputum Gram stain is negative, as is silver stain. Which is the best therapy for B.L.? A. Pentamidine intravenously with adjuvant prednisone therapy for 21 days. B. Trimethoprim/sulfamethoxazole orally for 21 days. C. Trimethoprim/sulfamethoxazole intravenously with adjuvant prednisone therapy for 21 days. D. Atovaquone orally for 21 days. 2. Diagnosis a. Induced sputum, bronchoalveolar lavage, or transbronchial biopsy b. Methenamine silver stain of sputum sample 3. Therapy a. Trimethoprim/sulfamethoxazole (preferred) i. Dose: 15–20 mg/kg/day of trimethoprim divided every 6–8 hours for 21 days (intravenously for moderate to severe PJP); trimethoprim/sulfamethoxazole double strength 2 tablets three times daily or weight based (for mild to moderate PJP) ii. Adverse effects (80% of patients, with 20%–60% requiring discontinuation) (a) Nausea and vomiting (b) Rash (c) Anemia, thrombocytopenia, leucopenia (d) Renal impairment or hyperkalemia (small increases in serum creatinine occur because of competition between trimethoprim and creatinine for renal secretion) iii. Prophylactic dose (a)  Preferred: Trimethoprim/sulfamethoxazole double strength or single strength once daily (pediatric dose, 150 mg/m 2 per dose of trimethoprim and 750 mg/m2 per dose of sulfamethoxazole) (b) Alternative: Trimethoprim/sulfamethoxazole double strength three times/week b. Clindamycin and primaquine (alternative) i. Dose: Clindamycin 600 mg every 6 hours or 900 mg every 8 hours intravenously plus primaquine 30 mg daily (for moderate to severe disease) or 450 mg every 6 hours or 600 mg every 8 hours orally and primaquine base 30 mg/day for 21 days (for mild to moderate disease) ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-262 Infectious Diseases II ii. Adverse effects (a) Rash (b) Anemia, methemoglobinemia (test for glycose-6-phosphate dehydrogenase [G6PD] deficiency) (c) Diarrhea c. Pentamidine (alternative) i. Dose: 4 mg/kg/day intravenously for 21 days (for moderate to severe disease) ii. Adverse effects (a) Hypotension (b) Rash (c) Electrolyte disturbances (d) Hypoglycemia or hyperglycemia (e) Pancreatitis iii. Prophylactic dose for patients with immunocompromising conditions: 300 mg by nebulization (Respirgard) once monthly (can predose with β-agonist to diminish respiratory irritation) d. Trimethoprim and dapsone (alternative) i. Dose: 15 mg/kg/day of trimethoprim divided every 8 hours and dapsone 100 mg/day for 21 days (only for mild to moderate PJP) ii. Adverse effects (a) Nausea and vomiting (b) Anemia (test for G6PD deficiency) iii. Prophylactic dose: Dapsone 100 mg/day (pediatric dose, 1 mg/kg/day) alone or 50 mg/day or 200 mg/week with 50–75 mg of pyrimethamine and 25 mg of leucovorin weekly e. Atovaquone (Mepron) (alternative) i. Dose: 750 mg twice daily for 21 days given with a high-fat meal (only for mild to moderate PJP) ii. Pediatric dose (less than 40 kg) = 40 mg/kg/day divided twice daily iii. Equal to trimethoprim/sulfamethoxazole for PJP but not an antibacterial iv. Potential for decreased efficacy in patients with diarrhea (because of poor absorption) v. Adverse effects (a) Nausea and vomiting (b) Rash (c) Transient increase in liver function tests (d) Insomnia, headache, fever vi. Prophylactic dose = 1500 mg once daily f. Adjuvant therapy: Corticosteroids i. Used in patients with severe PJP (A-a gradient of 35 or more or Po2 of 70 mm Hg or less); start within 72 hours ii. Decreases mortality iii. Dose: 40 mg twice daily of prednisone for 5 days, followed by 40 mg/day for 5 days, then 20 mg/day for remainder of PJP therapy (use cautiously in patients with TB) 4. Prophylaxis a. Secondary prophylaxis in patients after PJP (may be discontinued if CD4 count is more than 200 cells/mm3 for 3 months or longer because of potent combination ART) b. Primary prophylaxis in patients with CD4 count less than 200 cells/mm3 (may be discontinued if CD4 count is more than 200 cells/mm3 for 3 months or longer because of potent combination ART) c. Consider stopping primary or secondary prophylaxis in patients with CD4 counts of 100-200 cells/ mm3 if HIV plasma RNA level is below limits of detection for at least 3-6 months. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-263 Infectious Diseases II C. Toxoplasmosis 1. Description a. Toxoplasma gondii (protozoan) b. Felines are the hosts for sporozoite production. To decrease risk change litter box daily, wash hands after changing litter box or have someone else change the litter box, and, ideally, keep the cat indoors. c. From 15% to 68% of adults in the United States are seropositive for T. gondii. d. Secondary to undercooked beef, lamb, pork, or raw shellfish (stress avoidance in patients with HIV) e. Case-defining illness in 2.1% of patients with AIDS 2. Signs and symptoms a. Fever, headache, altered mental status b. Focal neurologic deficits (60%): Hemiparesis, aphasia, ataxia, visual field loss, nerve palsies c. Seizures (33%) d. CSF: Mild pleocytosis, increased protein, normal glucose 3. Diagnosis a. Brain biopsy: Only definitive diagnosis but generally reserved for patients who do not respond to specific therapy or when other workup suggests an etiology other than toxoplasmosis b. Antibodies or T. gondii isolation in serum or CSF c. Magnetic resonance imaging scan or computed tomographic scan: Multiple, bilateral, hypodense, ring-enhancing mass lesions (magnetic resonance imaging scan more sensitive than computed tomographic scan) 4. Therapy a. Preferred therapy i. Pyrimethamine 50–75 mg/day (loading dose of 200 mg) plus ii. Sulfadiazine 1000–1500 mg every 6 hours (watch crystalluria) (a) Bone marrow suppression: Thrombocytopenia, granulocytopenia, anemia (b) Add folinic acid (leucovorin) 10-25 mg/day to reduce bone marrow–suppressive effects of pyrimethamine. (c) Duration: at least 6 weeks and after signs and symptoms resolve b. Alternative therapy i. Clindamycin 600 mg intravenously or orally every 6 hours plus pyrimethamine (see above) – Use for sulfa intolerance or nonresponse to preferred therapy ii. Trimethoprim/sulfamethoxazole 5 mg/kg of trimethoprim intravenously or orally twice daily iii. Atovaquone 1500 mg orally twice daily plus pyrimethamine/leucovorin (see above) iv. Atovaquone 1500 mg orally twice daily plus sulfadiazine (see above) v. Atovaquone 1500 mg orally twice daily 5. Prophylaxis a. Relapse rates approach 80% without maintenance therapy. b. Toxoplasma-seropositive patients with a CD4 count of 100 cells/mm3 or less should receive primary prophylaxis. c. Primary prophylaxis i.  Trimethoprim/sulfamethoxazole double strength once daily or dapsone/pyrimethamine/ leucovorin or atovaquone with or without pyrimethamine at doses used for PJP prophylaxis ii. May be discontinued if the CD4 count is more than 200 cells/mm3 for 3 months or longer because of potent combination ART iii. Consider stopping primary prophylaxis in patients with CD4 counts of 100-200 cells/mm3 if HIV plasma RNA level is below limits of detection for at least 3-6 months. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-264 Infectious Diseases II d. Secondary prophylaxis i. Pyrimethamine 25–50 mg/day plus leucovorin 10–25 mg/day with sulfadiazine 2–4 g/day ii. Clindamycin 600 mg orally every 8 hours plus pyrimethamine (see above) – Use for sulfa intolerance or non-response to preferred therapy. iii. Trimethoprim/sulfamethoxazole double strength orally twice daily iv. Atovaquone 750–1500 mg orally twice daily plus pyrimethamine/leucovorin (see above) v. Atovaquone 750–1500 mg orally twice daily plus sulfadiazine (see above) vi. Atovaquone 750–1500 mg orally twice daily vii. May be discontinued if the CD4 count is more than 200 cells/mm3 and patient is asymptomatic for 6 months or longer because of potent combination ART D. Candida Infections 1. Oral Candida infections (thrush) a. More than 90% of patients with AIDS sometime during their illness b. Signs and symptoms i. Creamy white, curdlike patches on the tongue and other oral mucosal surfaces ii. Pain, decreased food and fluid intake 2. Candida esophagitis a. Not always an extension of oral thrush (30% do not have oral thrush) b. Signs and symptoms: Painful swallowing, obstructed swallowing, substernal pain 3. Diagnosis a. Signs and symptoms of infection b. Fungal cultures, potassium hydroxide smear c. Endoscopic evaluation 4. Therapy a. Oropharyngeal candidiasis (treat 7–14 days) i. Fluconazole 100 mg orally daily. ii. Alternative: Itraconazole solution 200 mg orally daily or posaconazole suspension 400 mg orally daily (after twice daily on day 1) or miconazole buccal tablets 50 mg orally daily or clotrimazole tro­ches 10 mg orally five times daily or nystatin 5 mL (100,000 units/mL): swish and swallow four or five times daily b. Esophageal candidiasis (treat 14–21 days) i. Fluconazole 100–400 mg orally or intravenously daily or itraconazole solution 200 mg orally daily ii. Alternative: Voriconazole, caspofungin, micafungin, anidulafungin, amphotericin B deoxycholate, lipid formulation of amphotericin B, posaconazole or isavuconazole c. Vulvovaginal candidiasis i. Fluconazole 150 mg orally for one dose or topical azoles for 3–7 days ii. Alternative: Itraconazole solution 200 mg orally daily for 3–7 days E. Cryptococcosis 1. Cryptococcus neoformans 2. Occurs in 6%–10% of patients with AIDS 3. In general, occurs in patients with CD4 counts less than 50 cells/mm3 4. Acute mortality is 10%–25%, and 12-month mortality is 30%–60%. 5. Worldwide distribution a. Found in aged pigeon droppings and nesting places (e.g., barns, window ledges) b. Organism must be aerosolized and inhaled; it then disseminates hematogenously. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-265 Infectious Diseases II Patient Cases 5. G.H. is a 33-year-old HIV-positive man who presents to the clinic with a severe headache that has gradually worsened during the past 3 weeks. He also has memory problems and is always tired. He has refused ART in the past, and his most recent CD4 count was 75 cells/mm3. He is given a diagnosis of cryptococcal meningitis. Which is the best treatment for G.H.? A. Amphotericin B deoxycholate 0.7–1 mg/kg/day plus fluconazole 800 mg daily for 2 weeks, followed by fluconazole 400 mg/day for 8 weeks. Begin ART in the first 1–2 weeks of therapy. B. Liposomal amphotericin B 3–4 mg/kg/day plus flucytosine 25 mg/kg every 6 hours for 2 weeks, followed by fluconazole 400 mg/day for 8 weeks. Begin ART after 5 weeks of antifungal therapy. C. Fluconazole 1200 mg/day for 10–12 weeks. Begin ART fluconazole 800 mg daily. D. Lipid-formulated amphotericin B 3–4 mg/kg/day plus fluconazole 800 mg/day for 2 weeks, followed by fluconazole 400 mg/day for 8 weeks. Begin ART in the first 1-2 weeks of therapy. 6. After being treated for cryptococcal meningitis, G.H. is initiated on potent combination ART. For 2, 6, and 8 months after starting the therapy, his CD4 counts are 212, 344, and 484 cells/mm3, respectively. Which is the best follow-up therapy for G.H. now? A. Continue fluconazole maintenance therapy. B. Give maintenance therapy with fluconazole for at least 1 year; then, it can be discontinued because the CD4 counts have increased. C. Continue maintenance therapy with fluconazole until CD4 counts are greater than 500 cells/mm3. D. Discontinue maintenance therapy with fluconazole. 6. Signs and symptoms a. Almost always meningitis (66%–84%) b. Usually present for weeks or months (1 day to 4 months; average 31 days) c. Insidious onset i. Low-grade fever (80%–90%) ii. Headaches (80%–90%) iii. Altered sensorium (20%): Irritability, somnolence, clumsiness, impaired memory and judgment, behavioral changes iv. Seizures may occur late in the course (less than 10%). v. Minimal nuchal rigidity, meningismus, photophobia 7. Diagnosis a. Cerebrospinal fluid (CSF) changes including: i. Positive CSF cultures ii. CSF cryptococcal antigen titer (91%) iii. Elevated opening pressure greater than 20 cm H2O b. Serum cryptococcal antigen greater than 1:8 8. Induction therapy (duration: 2 weeks) a. Preferred: i. Liposomal amphotericin B 3–4 mg/kg/day plus flucytosine 25 mg/kg every 6 hours ii. Amphotericin B deoxycholate 0.7–1 mg/kg/day plus flucytosine 25 mg/kg every 6 hours (only if cost is an issue and the risk of renal dysfunction is low) b. Alternatives: i. Amphotericin B lipid complex 5 mg/kg/day plus flucytosine 25 mg/kg every 6 hours ii. Liposomal amphotericin B 3–4 mg/kg/day plus fluconazole 800–1200 mg/day iii. Amphotericin B deoxycholate 0.7–1 mg/kg/day plus fluconazole 800–1200 mg/day ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-266 Infectious Diseases II iv. Liposomal amphotericin B 3–4 mg/kg/day alone v. Fluconazole 800–1200 mg/day plus flucytosine 25 mg/kg every 6 hours vi. Fluconazole 1200 mg/day alone vii. Amphotericin B deoxycholate 0.7–1.0 mg/kg/day alone viii. Liposomal amphotericin B 3–4 mg/kg/day plus flucytosine 25 mg/kg every 6 hours for 1 week, followed by fluconazole 1200 mg/day 9. Consolidation therapy (duration: at least 8 weeks, beginning after induction therapy) a. Fluconazole 800 mg daily (dose can be decreased to 400 mg daily if CSF is negative and ART is started) 10. Maintenance therapy – Preferred: Fluconazole 200 mg/day for at least 1 year 11. Outcome a. Delay initiating combination ART in patients with cryptococcal meningitis for 2–10 weeks because of the risk of IRIS. b. Therapeutic response: 42%–75% c. Relapse: 50%–90% (with about 100% mortality) 12. Prophylaxis a. Relapses usually occur within first year after therapy (less often with potent combination ART). b. Secondary prophylaxis: Fluconazole 200 mg/day (may consider discontinuing after a minimum of 1 year of chronic maintenance therapy if CD4 count is more than 100 cells/mm3 for 3 months or longer after potent combination ART and patient remains asymptomatic; reinitiate if CD4 count decreases to less than 100 cells/mm3) c. Primary prophylaxis: Not indicated (decreases the incidence of cryptococcosis but does not decrease mortality and may lead to resistance) Patient Case 7. J.C. is a 36-year-old HIV-positive woman with severe anemia. She has been tested for iron deficiency and has been taken off zidovudine and trimethoprim/sulfamethoxazole. She has also started to lose weight and to have severe diarrhea. A blood culture is positive for Mycobacterium avium-inracellulare (MAI). Which treatment is best for J.C.? A. Clarithromycin plus ethambutol for 2 weeks, followed by maintenance with clarithromycin alone. B. Azithromycin plus ethambutol for at least 12 months. C. Clarithromycin plus isoniazid for 2 weeks, followed by maintenance with clarithromycin alone. D. Ethambutol plus rifabutin indefinitely. F. Mycobacterium avium Complex (MAC) 1. Organism characteristics a. Complex is similar (main species are M. avium and Mycobacterium intracellulare, which are not differentiated microbiologically). b. Ubiquitous in soil and water and are transmitted through inhalation, ingestion, or inoculation by the respiratory or gastrointestinal (GI) tract c. Usually occurs in patients with HIV having a CD4 count less than 50 cells/mm3 d. MAC is independently associated with risk of death, and treatment prolongs survival. 2. Signs and symptoms (nonspecific) a. Weight loss, intermittent fevers, chills, night sweats, abdominal pain, diarrhea, chronic malabsorption, and progressive weakness b. Anemia c. Elevated alkaline phosphatase ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-267 Infectious Diseases II 3. Diagnosis a. Blood or lymph node culture b. Bone marrow biopsy c. Stool cultures (do not treat if cultured only in the stool) 4. Therapy a. Preferred therapeutic regimen is macrolide plus ethambutol: Clarithromycin 500 mg (7.5–15 mg/ kg) twice daily or azithromycin 500–600 mg/day (10–20 mg/kg) if drug interactions or intolerance to clarithromycin, plus ethambutol 15 mg/kg/day for 12 months b. Other agents: Consider adding to preferred therapy if advanced immunosuppression (CD4 count less than 50 cells/mm3), high mycobacterial loads (more than 2 log CFU/mL of blood), or in the absence of effective ART. i. Rifabutin (Mycobutin) 300 mg/day (rifabutin dose chosen on the basis of other antiretrovirals because of drug-drug interactions) ii. A fluoroquinolone such as levofloxacin 500 mg oral daily or moxifloxacin 400 mg oral daily iii. An aminoglycoside such as amikacin 10–15 mg/kg intravenously daily or streptomycin 1 g intravenously or intramuscularly daily c. Chronic maintenance therapy or secondary prophylaxis may be discontinued after 12 months of therapy if CD4 count is more than 100 cells/mm3 for 6 months or longer because of potent combination ART and if patient is asymptomatic. Restart if CD4 count drops below 100 cells/mm3. 5. Primary prophylaxis in patients with CD4 counts less than 50 cells/mm3 who are not receiving ART or who have viremia on current ART (may be discontinued upon initiation of effective ART); primary prophylaxis not recommended if patients are immediately initiated on ART a. Clarithromycin 500 mg orally twice daily: Lower incidence of MAC bacteremia (vs. placebo) b. Azithromycin 1200 mg orally once weekly c. Azithromycin 600 mg orally twice weekly d. Alternative: Rifabutin 300 mg/day (150 mg orally twice daily with food if there are GI adverse effects) G. Cytomegalovirus (CMV) 1. Characteristics of CMV infection a. Fifty-three percent of Americans age 18–25 years are CMV positive. b. Eighty-one percent of Americans older than 35 years are CMV positive. c. More than 95% of men who have sex with men are CMV positive. d. About 90% of CMV infections are asymptomatic (if illness occurs, it resembles mononucleosis). e. Virus remains latent in the host after initial infection but may reactivate if patient becomes immunocompromised (especially cell-mediated immunity). 2. Diagnosis of CMV infection is usually made on the basis of clinical manifestations 3. Manifestations of CMV a. Retinitis i. Occurs in 10%–15% of patients with AIDS; is the clinically most important CMV infection ii. In general, patients have CD4 counts less than 50 cells/mm3 and high plasma HIV RNA concentrations. iii. Begins unilaterally and spreads bilaterally iv. Early complaints: “Floaters,” pain behind the eye v. In general, progressive; no spontaneous resolution (blindness in weeks to months) vi. Rate of progression is 26%, even with treatment; retinal detachment very common b. Other manifestations i. Esophagitis or colitis ii. Pneumonitis iii. Neurologic ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-268 Infectious Diseases II 4. Therapy for CMV infections a. CMV retinitis i. Sight-threatening lesions (a) Valganciclovir 900 mg orally twice daily for 14–21 days, followed by 900 mg orally daily, with or without intravitreal injections of ganciclovir or foscarnet for 1–4 doses over a period of 7–10 days (b) Alternative therapy (all regimens include intravitreal injections as listed above): (1) Ganciclovir 5 mg/kg intravenously every 12 hours for 14–21 days, followed by ganciclovir 5 mg/kg intravenously daily or valganciclovir 900 mg orally daily (2) Foscarnet 60 mg/kg intravenously every 8 hours or 90 mg/kg intravenously every 12 hours for 14–21 days, then 90–120 mg/kg intravenously daily (3) Cidofovir 5 mg/kg weekly intravenously for 2 weeks; then 5 mg/kg every other week with saline hydration and probenecid ii. Peripheral lesions (a) Valganciclovir 900 mg orally twice daily for 14–21 days, followed by 900 mg orally daily for the first 3–6 months until ART-induced immune recovery. (b) Alternative therapy: (1) Ganciclovir 5 mg/kg intravenously 5–7 times weekly (2) Foscarnet 90–120 mg/kg intravenously daily (3) Cidofovir 5 mg/kg every other week intravenously with saline hydration and probenecid b. Other CMV infections i. Esophagitis or colitis (a) Ganciclovir 5 mg/kg intravenously every 12 hours, followed by valganciclovir 900 mg orally twice daily when tolerated (b) Alternative therapy: (1) Foscarnet 60 mg/kg intravenously every 8 hours or 90 mg/kg intravenously every 12 hours (2) Valganciclovir 900 mg orally twice daily (if tolerable) ii. Pneumonitis – Use ganciclovir or foscarnet at retinitis doses. iii. Neurologic – Combination of ganciclovir and foscarnet at retinitis doses 5. Consider waiting up to 2 weeks after initiating CMV therapy to start ART in a treatment-naive patient 6. Prophylaxis a. Secondary prophylaxis is necessary for all patients (see individual drugs for specific doses); it may be discontinued if the CD4 count is more than 100 cells/mm3 for 3–6 months or longer because of potent combination ART and signs/symptoms (including active lesions) have resolved. Reinitiate secondary prophylaxis if the CD4 count decreases to less than 100 cells/mm3. b. Primary prophylaxis not recommended. In patients with CD4 counts less than 50 cells/mm3, regular funduscopic examinations are recommended. III. TUBERCULOSIS (TB) A. Mycobacterium tuberculosis 1. Factors associated with acquiring TB a. Exposure to people with active pulmonary TB b. Geographic location c. Low socioeconomic status d. Nonwhite race e. Male sex f. HIV infection g. Foreign birth ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-269 Infectious Diseases II 2. Epidemiology (Figure 2) Number of persons with reported cases of tuberculosis, 1986-2021 All Persons US-Born Persons Foreign-Born Persons 30000 25000 Cases 20000 15000 10000 5000 20 20 20 18 20 16 20 14 20 12 20 10 20 08 20 06 20 04 20 02 20 00 19 98 19 96 19 94 19 92 19 90 19 88 19 86 0 Year Figure 2. Epidemiology of tuberculosis. B. Pathophysiology (Figure 3) 1. Person-to-person transmission: Airborne droplets carrying M. tuberculosis are inhaled. 2. Infection primarily pulmonary but can occur in other organ systems Inhaled droplet bypasses mucociliary system and becomes implanted in the bronchioles or alveoli Activated alveolar macrophages ingest and destroy over 90% of the inhaled tubercle bacilli In patients with diminished cell-mediated immunity the delayed hypersensitivity reaction is greater and the caseous center expands With continued delayed hypersensitivity reaction (immunocompromised patients) the caseous center liquifies which provides a viable environment for bacillary growth – now growth occurs extracellularly Erosion of bronchial tissue occurs and cavities form Remaining 10% multiply within the macrophages and are released when the macrophage dies In susceptible patients bacilli continue to grow – the caseous center enlarges destroying adjacent lung tissue Patients with normal immune systems destroy bacilli escaping from the caseous center leading to little to no tissue destruction Note: This caseous liquification and bacillary growth can occur even in “normal” patients – therefore antimicrobial therapy is necessary Released bacilli attract monocytes and macrophages forming the primary tubercle – growth occurs within the macrophages with destruction of neither bacilli or macrophages occurring Delayed hypersensitivity kills the bacilli-laden macrophages resulting in formation of a tubercle with a caseous center Bacilli die in the caseous center Positive TST Asymptomatic Bacilli remain dormant in the caseous center Positive TST Asymptomatic (for life?) Approximately 10% of those infected develop clinical tuberculosis Figure 3. Pathophysiology of tuberculosis. TST = tuberculin skin test ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-270 Infectious Diseases II C. Diagnosis (Table 8) Table 8. Diagnosis of Tuberculosis Nonspecific Signs and Symptoms Radiology Microbiology Cough Malaise Weight loss Fever, chills Night sweats Pleuritic pain Chest radiograph: patchy or nodular infiltrates in upper lobes; cavitary lesions Sputum smear for AFB Sputum culture for Mycobacterium tuberculosis Rapid detection through PCR probe AFB = acid-fast bacillus; PCR = polymerase chain reaction. Patient Case 8. J.M. is a 42-year-old man who works at a long-term care facility and was recently exposed to a patient with TB; he was not wearing personal protective equipment. A TST is placed, and 48 hours later, he has an 18-mm induration. This is the first time he has reacted to this test. His chest radiograph is negative. Which is best in view of J.M.’s positive TST? A. No treatment is necessary, and J.M. should have another TST in 8–10 weeks. B. J.M. should have another TST in 1 week to see whether this is a booster effect. C. J.M. should be monitored closely, but no treatment is necessary because he is older than 35 years. D. J.M. should be initiated on rifampin 600 mg/day plus isoniazid 300 mg/day for 3 months. 1. Tuberculin skin test (TST) (Table 9) a. Recommended dose is 5 tuberculin units/0.1 mL. b. Mantoux method i. Intradermal injection of tuberculin into forearm ii. Measure diameter of induration after 48–72 hours. c. False-negative tests occur in 15%–20% of people infected with M. tuberculosis, primarily in those recently infected or anergic. d. Only 8% of people vaccinated with bacille Calmette-Guérin (BCG) at birth will react 15 years later. 2. Interferon-gamma release assays (IGRA) a. QuantiFERON-TB Gold and T-SPOT.TB b. Blood test that detects the release of interferon gamma in response to M. tuberculosis infection c. Less sensitivity but greater specificity than the TST for predicting future active infection 3. Booster effect a. The TB test can restimulate hypersensitivity in those exposed in the past. b. Occurs within 1 week of the test and persists for more than 1 year c. Those with negative TST reactions can be retested in 1 week; if positive, result should be attributed to boosting of a subclinical hypersensitivity; chemoprophylaxis is not necessary. 4. TB screening of health care workers a. Baseline screening when starting employment (TST or IGRA) b. If baseline screening positive and health care worker is asymptomatic and unlikely infected, repeat. c. If repeat screening is positive, treat for latent TB. d. No need for annual screening after baseline. e. Recheck TST or IGRA after known TB exposure. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-271 Infectious Diseases II Table 9. Testing for Latent Tuberculosis Infection Likelihood of Infection with M. tuberculosis (see below) Risk of Progressing to Tuberculosis if Infected (see below) Criterion for Positive Skin Test (mm) Likely Low to intermediate ≥ 10 Likely High ≥5 Unlikely Low to high ≥ 15 Groups with increased likelihood to be infected (i.e., “likely”) • Household contact or recent exposure of an active case • M  ycobacteriology laboratory personnel • Immigrants from high-burden countries • Residents and employees of high-risk congregate settings Recommended testing* IGRA recommended if history of BCG vaccine or unlikely to return to have TST read (otherwise IGRA suggested) TST is acceptable alternative IGRA or TST (data insufficient to recommend one over the other) Do not test with either IGRA or TST (may be done for employee health surveillance) Risk of Developing Tuberculosis Low: • No risk factors Intermediate: • Diabetes • Chronic renal failure • Intravenous drug use High: • Children < 5 years • HIV infection • Immunosuppressive therapy • Abnormal chest x-ray consistent with prior TB • Silicosis * For children under 5 years of age use TST rather than an IGRA in all situations D. Therapy 1. Treatment of latent TB infection a. The goal is to prevent latent (asymptomatic) infection from progressing to clinical disease. b. Treatment of latent TB infection is recommended for the following people: i. HIV infected persons ii. Close contacts of people with a diagnosed infectious TB iii. People with abnormal chest radiographs that show fibrotic lesions, likely to represent old, healed TB iv. Immunosuppressed persons (e.g., organ transplant recipients, taking the equivalent of more than 15 mg/day of prednisone for more than 1 month, receiving TNF-alpha antagonists) v. Foreign-born people from high-prevalence countries (immigration within 5 years) vi. Persons who inject drugs vii. People working at or living in high-risk congregate settings (e.g., correctional facilities, nursing homes, homeless shelters, hospital, and other health care facilities) viii. Mycobacteriology laboratory personnel ix. Children under 4 years of age, or children and adolescents exposed to adults in high-risk categories c. Dosing regimens i. Patients who are not infected with HIV (a) Rifapentine 900 mg plus isoniazid 900 mg weekly for 12 weeks (with directly observed therapy) (b) Rifampin 600 mg daily for 4 months ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-272