BLOCK 3 PATH TEST PREP QUESTION

Term
1 / 43
A. Amphotericin B
B. Caspofungin
C. Fluconazole
D. Flucytosine
E. Griseofulvin
F. Itraconazole
G. Nystatin
H. Terbinafine

1. The antifungal spectrum of this drug is limited to Candida and Aspergillus species.

2. This drug has the broadest antifungal spectrum but is used only in case of severe mycoses because of its toxicity.

3. The mechanism of action of this drug involves the inhibition of the synthesis of β-glucan, an essential constituent of a fun- gal cell wall.
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Terms in this set (43)
A. Amphotericin B
B. Caspofungin
C. Fluconazole
D. Flucytosine
E. Griseofulvin
F. Itraconazole
G. Nystatin
H. Terbinafine

1. The antifungal spectrum of this drug is limited to Candida and Aspergillus species.

2. This drug has the broadest antifungal spectrum but is used only in case of severe mycoses because of its toxicity.

3. The mechanism of action of this drug involves the inhibition of the synthesis of β-glucan, an essential constituent of a fun- gal cell wall.
1. B
2. A
3. B
A 42-year-old HIV-positive woman was recently diagnosed with invasive histoplasmosis and started a therapy with am- photericin B. Which of the following molecular actions most likely mediated the therapeutic effect of the drug in the pa- tient's disease?

A. Activation of fungal cytochrome P-450 enzymes
B. Pore formation in fungal cell membrane
C. Inhibition of fungal cytochrome P-450 enzymes
D. Inhibition of fungal mitosis
E. Pore formation in the fungal cell wall
B Amphotericin B binds to fungal cell membranes and causes the formation of artificial pores through which ions and small molecules are lost. This causes the death of the fungal cell.
A, C−E See correct answer explanation.
A 39-year-old man living in New Mexico was recently di- agnosed with pulmonary coccidioidomycosis. A treatment was started with a drug that acts by inhibiting the fungal P-450 system. Which of the following drugs was most likely administered?
A. Amphotericin B
B. Nystatin
C. Fluconazole
D. Flucytosine
E. Griseofulvin
F. Terbinafine
C Coccidioides immitis is sensitive to amphotericin B and anti- fungal azoles. Azole antifungals, primarily fluconazole and itraconazole, have replaced amphotericin B as initial therapy for most chronic pulmonary and disseminated infections. Amphotericin B is now usually reserved for patients with rap- idly progressive coccidioidal infections. Azoles act by inhibit- ing the cytochrome P-450 system in fungal cells. The inhibition blocks the synthesis of ergosterol in the fungal cell mem- brane, leading to an antifungal effect. Relative selectivity occurs because the affinity for mammalian P-450 isozymes is less than that for the fungal isozymes. However, azoles can also block mammalian P-450 isozymes in the liver, which can explain the increased plasma concentration of many other drugs when coadministered with azoles.
A, B, D−F These drugs do not block the fungal synthesis of ergosterol
A 42-year-old man with AIDS was admitted to the hospital because of a recent onset of tonic-clonic seizures. Physical ex- amination suggested acute meningitis, and lab tests indicated cryptococcal infection. A treatment with amphotericin B and flucytosine was initiated but had to be suspended due to the appearance of severe adverse effects. An alternative treatment was initiated. Which of the following drugs would be most appropriate for the patient at this time?
A. Terbinafine B. Griseofulvin C. Nystatin
D. Caspofungin E. Fluconazole
E Cryptococcal meningitis is common in patients with AIDS and is always fatal if untreated. Amphotericin B and flucyto- sine represents the standard therapy but is associated with frequent adverse reactions, including renal insufficiency and bone marrow suppression. Fluconazole is a useful alternative in patients who experience severe adverse effects. The anti- fungal spectrum of azoles includes Cryptococcus neoformans, but fluconazole is the preferred azole in case of meningitis because it easily crosses the blood−brain barrier. AIDS pa- tients with cryptococcal meningitis frequently are treated in- definitely with fluconazole to prevent recurrence of clinical disease.
A, B Terbinafine and griseofulvin are effective only against superficial mycoses due to dermatophytes.
C Nystatin is structurally similar to amphotericin B and has the same mechanism of action and the same antifungal spec- trum in vitro, but it is too toxic to be used systemically.
D Caspofungin is effective only against Candida and Asper- gillus species.
A 53-year-old man presented to the clinic because of pain- ful, erosive, markedly pruritic lesions on the glans penis, scrotum, and inguinal region for the past week. The man had a 10-year history of poorly controlled diabetes mellitus. Phys- ical examination showed irregular, shallow, erythematous ulcerations. A wet preparation of ulcer secretions showed budding cells with pseudohyphae. A diagnosis was made, and an oral therapy was prescribed. Which of the following drugs would be appropriate for this patient?
A. Nystatin
B. Metronidazole
C. Fluconazole
D. Acyclovir
E. Mebendazole
F. Griseofulvin
C The patient's symptoms and lab results suggest he was suffering from genital candidiasis, which can occur in people without underlying illnesses but is more common in those with diabetes mellitus or with the use of certain drugs (broad- spectrum antibiotics, corticosteroids, or immunosuppressants). Budding yeast cells and pseudohyphae of Candida albicans, the most common Candida species causing candidiasis, can be detected by microscopic examination of biologic specimens. C. albicans is sensitive to most antifungal drugs, but for geni- tal candidiasis, a topical or oral azole derivative or topical ny- statin is the first-line treatment. Oral and topical therapies are therapeutically equivalent.
A Nystatin is effective against Candida species, but it is used only topically because of its toxicity.
B, D, E These agents are not antifungal drugs.
F Griseofulvin is not effective against C. albicans.
A 40-year-old woman with AIDS was admitted to the hospi- tal because of fever (103.2°F, 39.5°C), cough, and chest pain over the past 12 hours. Physical examination revealed verru- cose and vesicular skin lesions on her arms and face, and a chest x-ray showed scattered pulmonary lesions compatible with a granulomatous process. A blood culture displayed typical yeasts with chlamydospores. Which of the following correctly pairs the most likely offending pathogen with the appropriate treatment?
A. Cryptococcus neoformans: amphotericin B
B. Trichophyton tonsurans: griseofulvin
C. Histoplasma capsulatum: fluconazole
D. Aspergillus fumigatus: fluconazole
E. Candida albicans: amphotericin B
E The patient's signs, symptoms, and x-ray suggest a systemic mycosis. Lab results confirm the diagnosis of systemic candi- diasis, which accounts for about 80% of major systemic fungal infections. Amphotericin B, antifungal azoles, and echinocan- dins are first-line agents for systemic candidiasis.
A−D All of these fungal infections are paired with the ap- propriate treatment, but they do not produce chlamydospores in blood cultures.
A 43-year-old woman recently diagnosed with chromoblas- tomycosis started a treatment that included a drug that acts by inhibiting fungal DNA synthesis. Which of the following drugs was most likely given?
A. Fluorouracil
B. Cytarabine
C. Flucytosine
D. Griseofulvin
E. Fluconazole
F. Terbinafine
C Flucytosine is accumulated in fungal cells and is converted by a cytosine deaminase to 5-fluorouracil (selectivity occurs because mammalian cells do not accumulate and do not de- aminate flucytosine). Fluorouracil is in turn metabolized to 5-deoxyfluorouridylic acid, a potent inhibitor of thymidylate synthetase, the enzyme responsible for converting deoxyu- ridine monophosphate to deoxythimidine monophosphate. This reduces the availability of thymidylic acid, impairing DNA synthesis. The drug is not used alone but is given to- gether with itraconazole in chromoblastomycosis to avoid the development of resistance.
A, B Fluorouracil and cytarabine can inhibit DNA synthesis in mammalian cells but are not accumulated in fungal cells and therefore are devoid of antifungal activity.
D−F These antifungal drugs do not inhibit DNA synthesis.
A 30-year-old Mexican man who was a lifelong resident of the San Joaquin Valley, California, was admitted to the hos- pital because of a 4-day history of low-grade fever (99.9°F, 37.7°C), severe headache, irritability, and fatigue. Physical examination showed stiff neck and Kerning sign. Microscopic analysis of the spinal fluid revealed spherules filled with endospores. Which of the following drugs was most likely administered to this patient for an appropriate therapy?
A. Itraconazole
B. Nystatin
C. Terbinafine
D. Fluconazole
E. Flucytosine
F. Zidovudine
D The patient' signs and symptoms suggest the diagnosis of meningitis, and the lab results confirm that the man was suffering from meningeal coccidioidomycosis. The infection is caused by Coccidioides immitis, a soil mold that lives in semiarid regions of the globe, including the southwestern United States. Inhalation of the arthrospores leads to a pri- mary infection that is asymptomatic in 60% of individuals. Others develop a flulike self-limited illness called valley fever or desert rheumatism. Following inhalation, the arthrospores form spherules that contain endospores. In biologic speci- mens, these spherules are diagnostic of C. immitis infection. In less than 1% of individuals, a secondary or disseminated infection evolves within a year after the primary one. This secondary infection is often life-threatening and can affect many parts of the body and tissues, but the most frequent are the bone, joints, and meninges. Untreated meningitis is always fatal.
C. immitis is sensitive to amphotericin B and antifungal azoles. Fluconazole is the first-line agent for meningeal coc- cidioidomycosis. It easily crosses the blood−brain barrier, and cerebrospinal fluid concentrations are 50 to 90% of plasma concentrations.
A Itraconazole is effective against C. immitis, but penetra- tion into the brain is negligible.
B, C These antifungal drugs are not effective against C. immitis.
E, F These agents are not antifungal drugs.
A 31-year-old man with AIDS was admitted to the emer- gency department with fever (102.4°F, 39.1°C), headache, confusion, muddled thinking, and vomiting. Physical exam- ination revealed nuchal rigidity, diplopia, and loss of vision. An agglutination test of the spinal fluid for capsular poly- saccharide antigen turned out to be positive. Which of the following treatments would be most appropriate for this patient?
A. Ampicillin and erythromycin
B. Saquinavir and foscarnet
C. Pyrimethamine and sulfadiazine
D. Amphotericin B and flucytosine
E. Tolnaftate and nystatin
F. Terbinafine and griseofulvin
D The patient's history, signs and symptoms, and lab re- sults suggest the diagnosis of cryptococcal meningitis. After toxoplasmosis, cryptococcosis is the most common central nervous system infection associated with AIDS. Cryptococcus neoformans is a yeast that is characterized by a thick poly- saccharide capsule. During infection, the capsular polysac- charide is dissolved in spinal fluid and can be detected by an agglutination test that is diagnostic of cryptococcosis. C. neoformans is sensitive to amphotericin B, flucytosine, and antifungal azoles. The current treatment recommended for acute cryptococcal meningitis is amphotericin B plus flucytosine. Synergism between the two drugs has been demonstrated in vitro and in vivo. It may be related to en- hanced penetration of flucytosine through the amphotericin- damaged fungal cell membrane.
A−C These agents are not antifungal drugs.
E, F These antifungal drugs are not effective against C. neoformans.
A 68-year-old man hospitalized because of prostate cancer developed fever (103.8°F, 39.9°C) 4 days after prostatectomy despite empirical antibacterial therapy. He had a urinary cath- eter and was treated with a combination of broad-spectrum antibiotics. The patient had been suffering from chronic renal insufficiency for the past year. Urinalysis showed many bud- ding yeasts and cultures that were positive for Candida albi- cans. Which of the following drugs would be appropriate for systemic antifungal treatment of this patient?
A. Amphotericin B
B. Caspofungin
C. Piperacillin
D. Metronidazole
E. Griseofulvin
F. Nystatin
B The patient is suffering from candiduria, a condition often related to the placement of an indwelling urinary catheter, especially if the patient is taking broad-spectrum antibiotics, as in this case. Eradication of Candida in the urine includes the removal of the catheter and an antifungal treatment. Treatment options include amphotericin B, fluconazole, and an echinocandin such as caspofungin. However, in this patient, amphotericin B, which directly damages renal tu- bules, is contraindicated because of chronic renal dysfunc- tion. Echinocandins are the newest class of antifungal drugs. They act by inhibiting the synthesis of β-glucan, an essential constituent of the fungal cell wall. Their antifungal spectrum is limited to Candida and Aspergillus species. Echinocandins are approved for treatment of mucocutaneous or dissemi- nated candidiasis.
A See correct answer explanation.
C, D Piperacillin and metronidazole are not antifungal drugs.
E Though an antifungal drug, griseofulvin is not effective against C. albicans.
A 37-year-old woman suffering from AIDS was recently diagnosed with systemic candidiasis, and an intravenous antifungal treatment was prescribed. One week later, the following lab results were obtained: serum creatinine 5.9 mg/dL (normal: 0.6−1.2 mg/dL), blood urea nitrogen (BUN) 53 mg/dL (normal 7−18 mg/dL), plasma potassium 2.3 mmol/L (normal 3.5−5.0 mmol/L). Which of the following drugs most likely caused these abnormal lab results? A. Amphotericin B B. Fluconazole C. Griseofulvin D. Flucytosine E. Cyclosporine F. TobramycinA The lab results indicate that the patient was suffering from renal insufficiency. Amphotericin B is the drug of choice for many systemic mycoses, but it can cause serious, dose-dependent renal dysfunction due to direct damage of renal tubules. Azotemia, renal tubular acidosis, and K+ wast- ing are the most prominent symptoms. B−D These antifungal drugs do not cause renal toxicity. E, F These agents are nephrotoxic but are not antifungal drugs.A 29-year-old man presented to his physician with an annu- lar lesion with raised borders on his left hand. Microscopic examination of skin scrapings revealed branching hyphae. The diagnosis of tinea manus was made, and the patient was prescribed terbinafine. Which of the following skin struc- tures was most likely the site of action of the prescribed drug? A. Stratum basale B. Stratum spinosum C. Stratum corneum D. Pigment layer E. Hair follicle F. Hair shaftC Tinea manus is a cutaneous mycosis caused by dermato- phytes that infect only the superficial, keratinized tissues. These fungi are probably restricted to the nonviable, kerati- nized tissues (stratum corneum, hairs, nails) because most are unable to grow at 37°C (98.6°F). Dermatophytoses can be treated locally with several antifungal drugs, but a first-line agent for systemic treatment is terbinafine. The drug has good oral bioavailability and is deposited in newly formed keratinized tissues, where it exerts its antifungal action. A, B, D, E See correct answer explanation. F Terbinafine can be deposited in the hair shaft, where it can cure tinea capitis, but in this case, the fungus is in the skin's stratum corneum, not in the hair.A 9-year-old girl was brought to the pediatrician by her mother because the girl had several small hairless patches on her scalp. Upon close physical examination, patches look- ing like black dots were seen on the skin surface. Microscopic examination revealed a dense sheath of spores around the hair. Which of the following drugs given orally would be ap- propriate for this patient? A. Acyclovir B. Metronidazole C. Terbinafine D. Vancomycin E. Amphotericin B F. FlucytosineC The microscopic examination of the hair suggests the diag- nosis of "black dots" tinea capitis, a skin mycosis caused by T. tonsurans. Cutaneous mycoses are caused by fungi (mainly dermatophytes) that infect only the superficial keratinized tissues. Dermatophytes are sensitive to terbinafine, antifun- gal azoles, griseofulvin, and amphotericin B, but the first two are agents of choice in cutaneous mycoses because they are deposited in newly forming skin, where they bind to keratin, protecting the skin from the infection. Griseofulvin is less frequently used today because of its toxicity. A, B, D These agents are not antifungal drugs. E Amphotericin B is only used topically for cutaneous mycoses. F Flucytosine is a systemic antifungal drug but is not ef- fective against dermatophytes.A 34-year-old man with AIDS was admitted to the hospital because of fever (103.7°F, 39.8°C), severe headache, and men- tal confusion. Further exams led to the diagnosis of crypto- coccal meningitis. An intravenous (IV) dose of hydrocortisone was administered, then an antibiotic therapy was started that included an IV infusion of amphotericin B. Hydrocorti- sone was most likely given to decrease which of the follow- ing drug-related adverse effects? A. Red man syndrome B. Nephrotoxicity C. Hepatotoxicity D. Infusion reaction E. Hemolytic anemia F. Exfoliative dermatitisA 33-year-old woman presented to her gynecologist with a 4-day history of perineal pruritus and a nonmalodorous, thick, cheesy vaginal discharge. The only medication the woman was taking was an oral contraceptive. A wet prepa- ration of vaginal secretion showed budding yeast cells and pseudohyphae. A diagnosis was made, and a local therapy was prescribed. Which of the following correctly pairs the most likely offending pathogen with the appropriate treatment? A. Candida albicans: griseofulvin B. C. albicans: terbinafine C. C. albicans: nystatin D. Blastomyces dermatitidis: caspofungin E. B. dermatitidis: terbinafine F. B. dermatitidis: nystatinC The patient's symptoms and lab results suggest that she was suffering from vulvovaginal candidiasis, the most common opportunistic mycosis of the genital tract in women taking oral contraceptives. Other predisposing factors are pregnancy, menstruation, diabetes mellitus, and use of broad-spectrum antibiotics, corticosteroids, or immunosuppressive drugs. Budding yeast cells and pseudohyphae of Candida albicans, the most common Candida species causing candidiasis, can be detected by microscopic examination of biologic speci- mens. Local therapy of vulvovaginal candidiasis includes azoles and nystatin. Cure rates for uncomplicated vulvovagi- nal candidiasis are 80 to 95% with topical or oral azoles and 70 to 90% with nystatin. A, B, D−F All of these mycoses are incorrectly paired with the appropriate therapeutic agent.A 34-year-old man presented with fever (103.5°F, 39.6°C), cough, increasing dyspnea, and bloody sputum. The man, suffering from a non-Hodgkin lymphoma, was in the hos- pital for the second cycle of chemotherapy. A chest x-ray disclosed diffuse alveolar infiltrates on the right lobe and multiple small cavitary lesions on the left lobe. Bronchoalve- olar lavage revealed fungal forms typical of the Aspergillus genus. Which of the following drugs would be appropriate for this patient? A. Flucytosine B. Terbinafine C. Griseofulvin D. Voriconazole E. NystatinD Fungi of the genus Aspergillus usually coexist with man in harmless symbiosis. In special circumstances, however, some species may play an opportunistic role in producing disease in humans. Patients with chemotherapy-induced neutropenia or impaired immune responses from any cause are at high risk for invasive pulmonary aspergillosis, as in this case. Recent studies indicate that the isolation of asper- gilli in bronchoalveolar lavage fluid correlates strongly with histologic evidence of parenchymal invasion. The disease must be treated aggressively with amphotericin B or voriconazole, which most experts now consider a first-line agent. Despite treatment, the mortality rate remains high (30−90%). A Flucytosine is effective in vitro against Aspergillus species but is not clinically effective in case of invasive aspergillosis. B, C These antifungal drugs are not effective against Asper- gillus species. E Nystatin is too toxic for parenteral administration and is only used topically.A 63-year-old woman recently diagnosed with onychomy- cosis started a treatment with terbinafine. Inhibition of which of the following enzymes most likely mediated the thera- peutic effect of the drug in the patient's disease? A. Thymidylate synthase B. Lanosterol synthetase C. Squalene epoxidase D. Transpeptidase E. 7α-hydroxylaseC Terbinafine is an antifungal drug that inhibits fungal squalene epoxidase, the enzyme that catalyzes the conver- sion of lanosterol into ergosterol. The inhibition leads to the accumulation of squalene, which is toxic to dermatophytes. The drug is deposited in keratinized tissue and is used in the treatment of dermatophytoses, mainly onychomycosis. The drug is fungicidal and is therefore more effective than griseo- fulvin, which is fungistatic. A, B, D, E See correct answer explanation.A 36-year-old HIV-positive man living near the Mississippi River was admitted to the hospital with a 3-week history of cough, productive yellow sputum, and progressive dyspnea of exertion, as well as a 14-lb (6.4-kg) weight loss. Physical examination disclosed prominent hepatospenomegaly and diffuse lymphadenopathy. Pertinent lab results on admis- sion were CD4+ lymphocyte count 320 cells/mm3 (normal > 500 cells/mm3), lactate dehydrogenase 5000 IU/L (normal < 600 IU/L). A blood stain showed neutrophils containing small uninucleated, encapsulated microorganisms. A diag- nosis was made, and an appropriate pharmacotherapy was started. Which of the following drugs would be most appro- priate for this patient? A. Amphotericin B B. Isoniazid C. Terbinafine D. Streptomycin E. NystatinA The fact that uninucleated, encapsulated microorganisms are found intracellularly suggests an infection with Histo- plasma capsulatum. Other intracellular microorganisms are either multinucleate, such as blastomyces, or not encapsu- lated, such as the intracellular stage of several pathogenic protozoa. Infection with H. capsulatum is extremely com- mon. In the vast majority of cases, it is subclinical, or it may manifest itself as a mild, self-limited pneumonia. Progressive disseminated histoplasmosis usually occurs in people with suppressed cell-mediated immunity, especially if they are from endemic areas (Mississippi River valleys and the Carib- bean basin), as in this case. Most laboratory findings are nonspecific, but the lactate dehydrogenase level can reach 10 times above normal. Progressive disseminated histoplas- mosis has a high fatality rate. Amphotericin B remains the first-line agent, but mild cases can be treated initially with parenteral azolesA 45-year-old farmer complained to his physician of a red itchy rash over his thorax and arms. One week earlier, the man had been diagnosed with a fungal infection on his face and started an appropriate drug treatment. After physical examination, the physician told the patient that the rash was most likely a photosensitivity reaction to the drug. Which of the following drugs most likely caused the adverse effect in this patient? A. Flucytosine B. Amphotericin B C. Caspofungin D. Griseofulvin E. Doxycycline F. CiprofloxacinD The location of the fungal infection suggests that the pa- tient was most likely suffering from tinea barbae, a derma- tophytosis most often caused by fungi of the Trichophyton genus. Griseofulvin and terbinafine are the agents of choice. Griseofulvin can cause both a phototoxic and a photoallergic reaction in sun-exposed areas. Other antifungal drugs that can cause photosensitivity effects are antifungal azoles. A−C These antifungal drugs are not effective against der- matophytosis, and they do not cause photosensitivity. E, F These antibiotics can cause photosensitivity but are not effective against fungal infections.A 42-year-old HIV-positive woman was admitted to the emergency department with the admitting diagnosis of pneumonia. Further exams led to the diagnosis of cryptococ- cal pneumonia, and a treatment with liposomal amphoteri- cin B was started. Which of the following best explains the primary advantage of liposomal preparations over the regu- lar colloidal suspension of amphotericin B? A. Decreased interactions with other drugs B. Increased antifungal activity spectrum C. Decreased systemic toxicity D. Decreased drug clearance E. Increased oral bioavailabilityC In liposomal preparations of amphotericin B, the drug is contained inside lipid delivery vehicles. The drug binds to the lipids of these vehicles with an affinity that is lower than that for fungal ergosterol but higher than that for human cholesterol. Thus, the drug is more likely to be delivered to fungi than to human cells. Moreover, some fungi contain li- pases that can liberate free amphotericin B directly at the site of infection. Therefore, the liposomal preparations allow a reduction of toxicity; that is, they improve the therapeutic index of the drug. However, although laboratory experiments found very large differences between the lethal dose of lipo- somal formulations and those of regular formulations, the clinical improvement obtained with the liposomal vehicles is, at best, moderate. A Decreased interactions with other drugs could occur, but this is not the main advantage of liposomal preparations. B Amphotericin B is the active molecule, and the antifun- gal activity spectrum is the same. D The clearance of liposomal preparations can be de- creased or increased, but this is not the reason for their advantage over the regular preparation. E Intestinal absorption of all amphotericin B formula- tions is negligible.A 34-year-old man with AIDS was admitted to the emer- gency department and diagnosed with severe invasive can- didiasis. He was initially treated with an antifungal drug to rapidly reduce fungal burden, and the drug was then re- placed with another agent for chronic therapy. Which of the following pairs of drugs were most likely given? A. Amphotericin B and terbinafine B. Caspofungin and griseofulvin C. Caspofungin and metronidazole D. Amphotericin B and fluconazole E. Amphotericin B and mebendazole F. Caspofungin and terbinafineD Because of its broad spectrum of fungicidal activity, am- photericin B remains the first-line agent for nearly all severe fungal infections. Due to toxicity, the drug is often used ini- tially to rapidly reduce fungal load and then is replaced by another less toxic antifungal agent, as in this case. A−C, E, F All of these pairs include at least one drug that is not effective against systemic candidiasis.A 45-year-old woman with AIDS had been receiving fluco- nazole for an esophageal Candida infection. The therapy was initially effective, but over time its efficacy decreased, and the physician thought that development of resistance had occurred. Which of the following was most likely the mech- anism of fungal resistance to fluconazole in this patient? A. Gene-induced changes in fungal topoisomerase II B. Increased fungal metabolism of the drug C. Gene-induced changes in fungal cytochrome P-450 enzymes D. Decreased activity of fungal multiefflux pump E. Gene-induced changes in fungal RNA polymerase F. Decreased fungal permeability to the drugC Fungal resistance to drugs in the azole class tends to occur gradually over the course of prolonged drug therapy. In Can- dida infections, resistance occurs by way of mutations in the gene that encodes for an enzyme of the P-450 system. These mutations prevent the azole drug from binding and inhibit- ing the enzyme. Development of resistance to one azole in this way confers resistance to all drugs in the class. A, B, D−F These actions are not involved in the mycobacte- rial resistance to fluconazole.A 33-year-old man had been receiving a multidrug treat- ment for pulmonary tuberculosis. After 3 months of therapy, susceptibility testing showed that the mycobacterium was resistant to isoniazid and ethambutol. Which of the follow- ing was most likely the mechanism of mycobacterial resistance to ethambutol in this patient? A. Gene-induced changes in bacterial topoisomerase II B. Increased bacterial metabolism of the drug C. Gene-induced changes in bacterial arabinosyl transferase D. Decrease activity of the bacterial multiefflux pump E. Gene-induced changes in bacterial RNA polymerase F. Decreased bacterial permeability to the drugC A general mechanism of resistance to antimycobacterial drugs is related to mutation of genes that encode for the syn- thesis of enzymes that are inhibited by the drug. This muta- tion inhibits binding of the drug to the enzyme, preventing antibacterial activity. Ethambutol resistance is thought to result primarily from mutation in the gene that encodes for mycobacterial arabinosyl transferase, the enzyme specifically inhibited by the drug. A, B, D−F These actions are not involved in the mycobac- terial resistance to ethambutol.A 44-year-old man who recently moved from Mexico to Los Angeles presented to the hospital because of a diffuse skin disease. Skin examination showed macules, nodules, and plaques over his face and thorax. Further exams led to the diagnosis of lepromatous leprosy, and an appropriate ther- apy was started. Which of the following drugs should be included in the therapeutic regimen of this patient? A. Ampicillin B. Ceftriaxone C. Metronidazole D. Dapsone E. Fluconazole F. IvermectinD Leprosy is an exceedingly rare disease in the developed world, but about 5000 cases are reported each year in the United States, mainly in immigrants from Mexico and Cen- tral America, as in this case. Lepromatous leprosy is the most severe form of the disease because life-threatening complica- tions (erythema nodosum leprosum and necrotizing skin reaction) can develop. Dapsone, a sulfone derivative, is the mainstay of therapy. The drug concentrates in the infected skin, which explains, at least in part, its undisputed efficacy. Other drugs active against Mycobacterium leprae are rifampin, clofazimine, macrolides, tetracyclines, and fluoroquinolones. A−C, E, F These antibiotics are not effective against M. leprae.A 13-year-old boy had been receiving a multidrug treatment for bone tuberculosis. After 4 months of therapy, suscepti- bility testing showed that the mycobacterium was resistant to isoniazid and rifampin. Which of the following was most likely the mechanism of mycobacterial resistance to rifam- pin in this patient? A. Blockade of mycolic acid synthesis B. Gene-induced changes in bacterial topoisomerase II C. Gene-induced changes in bacterial RNA polymerase D. Gene-induced changes in bacterial peptidyl transferase E. Increased bacterial acetylation of the drugC Resistance to rifampin results primarily from mutation in the gene that codes for the β subunit of RNA polymerase. This mutation prevents binding of rifampin to the enzyme. A, B, D, E These enzymes are not involved in the bacterial resistance to rifampin.A 57-year-old man complained of a tingling sensation in his limbs and that his arms sometimes felt heavy. The man, who had been suffering from type II diabetes for 10 years, had been recently diagnosed with pulmonary tuberculosis and had been receiving isoniazid and rifampin for 1 month. The concomitant use of which of the following drugs would have most likely prevented the patient's neurologic symptoms? A. Folic acid B. Pyridoxine C. Cyanocobalamin D. Vitamin B2 E. Folinic acidB The patient is most likely suffering from isoniazid-induced peripheral neuropathy. Neurotoxicity is the most common ad- verse effect of isoniazid when the daily dose exceeds 6 mg/kg (unless pyridoxine is given concurrently), likely because the drug promotes the excretion of pyridoxine, a vitamin in- volved in several metabolic transformations, including the synthesis of some neurotransmitters (gamma-aminobutyric acid, norepinephrine, and serotonin). The risk of neurotoxic- ity is increased in slow acetylators, alcoholics, and diabetics, as in this case. Peripheral neuropathy is the main sign of iso- niazid neurotoxicity (it can affect as many as 20% of patients at risk), but high doses can also provoke memory loss, confu- sion, hallucinations, and seizures. Most neurotoxic effects can be prevented or corrected by pyridoxine supplementation without losing the antibacterial effect, A, C−E These drug are useless in isoniazid-induced neuro- toxicity.A 35-year-old man recently diagnosed with pulmonary tu- berculosis started a treatment with isoniazid, rifampin, pyr- azinamide, and ethambutol, but 2 months later, susceptibility testing revealed a Mycobacterium tuberculosis resistant to isoniazid and pyrazinamide. These drugs were discontinued, and two other drugs were prescribed. Which of the following pairs of drugs would be most appropriate for the patient at this time? A. Amikacin and vancomycin B. Ethionamide and azithromycin C. Imipemen and doxycycline D. Ceftriaxone and linezolid E. Streptomycin and moxifloxacinE The starting treatment of this patient is standard for ac- tive TB, but when resistance occurs, the treatment must be changed. There is no standard regimen for multidrug- resistant TB, but it is critical to avoid adding or substituting a single drug to a failing regimen. Adding one drug at a time leads to the sequential selection of drug resistance. There- fore, two or more previously unused drugs, chosen among the second-line agents, should be substituted. Second-line agents include some aminoglycoside antibiotics (mainly streptomycin; amikacin is also active), ethionamide, cycloser- ine, p-aminosalicylic acid, and fluoroquinolones. Most fluo- roquinolones have excellent antimycobacterial activity in vitro; moxifloxacin seems the most active clinically. A−D All of these combinations contain at least one drug that is not active against Mycobacterium tuberculosis.A 62-year-old man presented to the hospital complaining of anorexia, nausea and vomiting, and abdominal discomfort. He also had pain on motion and stiffness in several joints. The man, recently diagnosed with renal tuberculosis, started a four-drug combination regimen 1 month ago. Lab results showed serum aspartate aminotransferase of 280 U/L (nor- mal 8−20 U/L) and serum uric acid of 25 mg /dL (normal 3.0−8.2 mg/dL). Which of the following drugs most likely caused the patient symptoms and signs? A. Rifampin B. Pyrazinamide C. Isoniazid D. Streptomycin E. AzithromycinB The gastrointestinal symptoms and the high aminotrans- ferase levels (which suggest some liver dysfunction), together with the joint pain and hyperuricemia, strongly indicate that pyrazinamide is the drug that caused these adverse effects. Hepatotoxicity is the major limiting adverse effect of pyra- zinamide, is dose-related, and is far less common today with current dosing regimens. Arthralgia is also common and dose-related. Hyperuricemia is seen in more than 50% of pa- tients taking the drug and is likely due to inhibition of uric acid secretion. A Rifampin very rarely causes hepatitis but can substan- tially increase the risk of hepatotoxicity when given to- gether with pyrazinamide. However, it does not cause hyperuricemia. C Isoniazid can cause hepatotoxicity, but hyperuricemia is very rarely reported. D, E These drugs do not cause hepatotoxicity or hyper- uricemia.A 30-year-old man with AIDS was recently diagnosed with pulmonary tuberculosis and started a multidrug treatment with isoniazid, rifampin, pyrazinamide, and ethambutol. Which of the following best explains why ethambutol was added to the therapeutic regimen? A. To enhance the antibacterial activity of pyrazinamide B. To provide antibacterial activity against atypical myco- bacteria C. To prevent the neurotoxic effects of isoniazid D. To prevent Pneumocystis jiroveci pneumonia E. To delay the emergence of drug resistanceE The main reason for the use of any drug combination in the therapy of TB is to delay the emergence of resistance. In the case of ethambutol, this is by far the primary reason, as the drug has only weak bacteriostatic activity against Mycobacterium tuberculosis and cannot add significant anti- bacterial effect to a given therapeutic regimen. A−D All of these options are irrational.A 64-year-old alcoholic woman suffering from pulmonary tuberculosis complained of anorexia, nausea, and abdominal discomfort. She had been receiving isoniazid, ethambutol, and rifampin for 2 months. Lab results revealed an aspartate aminotransferase level of 330 U/L (normal 8−20 U/L). Which of the following best explains the reason for the patient's signs and symptoms? A. Rifampin-induced hemolytic anemia B. Rifampin-induced induction of the P-450 system C. Isoniazid-induced neuropathy D. Isoniazid-induced hepatitis E. Ethambutol-induced peripheral neuritis F. Ethambutol-induced hepatitisD The symptoms of the patient and the lab results indicate that she was most likely suffering from isoniazid-induced hepatitis, which is the most frequent major toxic effect of isoniazid. It occurs in about 1% of patients and can lead to potentially fatal multilobular necrosis. The risk increases with age and in alcoholics, as in this case. A−C, E These disorders cause neither the symptoms re- ported by the patient nor an increase in aminotransferase level. F Ethambutol-induced hepatitis is a very rare disorder.A 66-year-old man recently diagnosed with pulmonary tuberculosis started a three-drug treatment with isoniazid, rifampin, and ethambutol. The man, who had been suffering from atrial fibrillation for 4 years, was currently being treated with propranolol and warfarin. At this point, which of the following changes in the patient's therapeutic regimen would be appropriate? A. Increase the dose of warfarin. B. Decrease the dose of propranolol. C. Add pyrazinamide to the current therapy. D. Substitute isoniazid with streptomycin. E. Substitute propranolol with digoxin.A Rifampin is a strong inducer of the hepatic P-450 system and can increase the metabolism of many drugs, including glucocorticoids, oral contraceptives, methadone, β-blockers, and warfarin. Therefore, the dose of warfarin should be in- creased to maintain an appropriate anticoagulant effect. B The dose of propranolol should be raised, not reduced, because the metabolism of the drug is increased. C−E All of these options are irrational.A 47-year-old Hispanic man recently diagnosed with pulmo- nary tuberculosis started a multidrug treatment. One of the drugs he was given is active against most mycobacteria, many gram-positive and -negative bacteria, chlamydiae, rickett- siae, and poxviruses. Which of the following drugs has such a broad antibacterial spectrum? A. Isoniazid B. Rifampin C. Streptomycin D. Ethambutol E. PyrazinamideB The antimicrobial spectrum of rifampin is broad. The drug is active against most mycobacteria; most gram-positive bac- teria, including methicillin-resistant staphylococci; and many gram-negative bacteria, including Escherichia coli, Proteus, Klebsiella, Legionella, Brucella, Haemophilus, Chlamydia, and Rickettsia species and poxviruses. A, D, E These drugs are active only against mycobacteria. C Aminoglycoside antibiotics are active mainly against gram-negative aerobic bacteria.A 10-year-old girl was brought to the emergency department by her mother, who said that her daughter had high fever (103.3°F, 39.6°C) and was irritable and lethargic. Physical ex- amination showed nuchal rigidity and a positive Brudzinski sign. Subsequent exams led to the diagnosis of meningo- coccal meningitis. Which of the following drugs would have been appropriate prophylaxis for the health personnel as- sisting this girl? A. Amikacin B. Piperacillin C. Isoniazid D. Doxycycline E. RifampinE Rifampin is the drug of first choice for chemoprophylaxis of close contacts of patients with meningococcal meningitis. The potential for a close contact to become infected with Neisseria meningitidis is 500 to 800 times greater than for the total population. The drug should be administered as soon as possible because the risk of secondary disease is greatest within 2 to 5 days after exposure to the index case. Other drugs used for chemoprophylaxis include ceftriaxone and ciprofloxacin. A−D These antibiotics are not active against N. meningitidis.A 34-year-old HIV-positive woman was admitted to the hospital because of a 4-week history of fatigue, increasing abdominal girth, exertional dyspnea, nocturnal dyspnea, and peripheral edema. Vital signs were pulse 80, blood pressure 90/70 mm Hg. Physical examination revealed prominent ex- ternal jugular veins that became more distended during in- spiration. The heart was slightly enlarged, and a third sound was noted in early diastole. A computed tomography scan showed a large pericardial effusion, and pericardiocentesis removed 500 mL of bloody fluid with a high protein content. A diagnosis of hemorrhagic pericarditis was made, and an appropriate therapy was prescribed. Which of the following pairs of drugs would be most appropriately included in the patient's regimen? A. Piperacillin and tobramycin B. Trimethoprim-sulfamethoxazole C. Ciprofloxacin and azithromycin D. Isoniazid and rifampin E. Streptomycin and erythromycinD This patient demonstrates many of the clinical features of constrictive pericarditis, including an inspiratory increase of systemic venous pressure (Kussmaul sign), third heart sound, and narrow pulse pressure. The slow development of symptoms and the large amount of bloody fluid removed by pericardiocentesis indicate subacute effusive-constrictive pericarditis. The two most common causes for hemorrhagic pericarditis are tuberculosis (TB) and metastatic carcinoma. Because the patient is HIV positive, TB is much more likely. In fact, TB is the leading cause of death in HIV-infected peo- ple worldwide. Antimycobacterial therapy should be carried out if a TB origin can be diagnosed, is suspected, or cannot be excluded in a patient with chronic constrictive pericarditis. Isoniazid and rifampin are the leading drugs for TB even if, as in this case, a four-drug regimen including pyrazinamide and ethambutol should be administered because TB pericar- ditis is a serious infection, and HIV patients are also at risk of developing TB meningitis. A−C, E These combinations contain at least one drug not active against Mycobacterium tuberculosis.A 44-year-old woman complained of blurred vision and inability to distinguish green objects from red objects. The woman, recently diagnosed with cavitary pulmonary tuber- culosis, had been receiving a three-drug combination regi- men for 2 months. An eye examination indicated a narrowing of her visual field. Which of the following drugs most likely caused these adverse effects? A. Isoniazid B. Pyrazinamide C. Streptomycin D. Ethambutol E. CiprofloxacinD The signs and symptoms of the patient are most likely due to ethambutol-induced optic neuritis, a serious adverse ef- fect of the drug that is dose- and duration-related. Because of this, periodic visual acuity testing is desirable during eth- ambutol therapy. Recovery is usually, but not always, com- plete when the drug is discontinued. A−C, E These drugs do not cause optic neuritis.A 28-year-old man underwent a tuberculin skin test (Man- toux method) that turned out to be positive. The man was the husband of a woman who had uncomplicated pulmonary tuberculosis treated at home with a multiple-drug regi- men. The man was prescribed a drug to be taken daily for 6 months. Which of the following drugs was most likely given? A. Amikacin B. Ethambutol C. Isoniazid D. Ciprofloxacin E. PyrazinamideC Isoniazid is the drug of choice to prevent tuberculosis in skin test converters and in close contacts of patients with active disease, as in this case. The drug is given as the sole agent for at least 6 and up to 12 months. In people at high risk of infection with multidrug-resistant strains (i.e., HIV- positive patients), preventive therapy is usually performed with more than one drug. A, B, D, E These drugs are not used for prophylaxis of tu- berculosis unless the patient is at high risk of infection.A 34-year-old woman who was HIV positive presented with fever (100.8°F, 38.2°C), profuse night sweats, poor appetite, and a 20-lb (4.5-kg) weight loss over the past 5 months. Phys- ical examination revealed a cachectic female with prominent oral thrush and mild splenomegaly. Her CD4+ lymphocyte count was 45 cells/mm3 (normal > 500 cells/mm3), and a DNA probe test confirmed the diagnosis of Mycobacterium avium complex infection. An appropriate multidrug regimen was started. Which of the following drugs was most likely included in the patient's pharmacotherapy? A. Ceftriaxone B. Linezolid C. Metronidazole D. Clarithromycin E. VancomycinD MAC infection is common in end-stage AIDS patients, and the risk of developing the infection is the highest when the CD4+ lymphocyte count is less than 50 cells/mm3, as in this case. MAC is much less susceptible than Mycobacterium tuberculosis to most antimycobacterial drugs, and in most cases disseminated MAC is incurable and therapy is lifelong. Drug regimens for MAC should include at least three drugs, and one of these must be a macrolide, such as clarithromycin or azithromycin, as these are the only antibiotics for which a correlation between in vitro susceptibility tests for MAC and clinical response has been demonstrated. Other drugs active against MAC are rifampin, ethambutol, ethionamide, imipe- nem, and fluoroquinolones. A−C, E These drugs are not active against MAC.A 63-year-old man recently diagnosed with pulmonary tu- berculosis started a multidrug treatment that included eth- ambutol. Inhibition of which of the following enzymes most likely mediated the therapeutic efficacy of the drug in the patient's disease? A. Dihydrofolate reductase B. Peptidyl transferase C. Arabinosyl transferase D. Enolpyruvate transpherase E. Dihydropteroate synthetase F. TransglycosylaseC Ethambutol inhibits arabinosyl transferase, disrupting the synthesis of arabinogalactan, an essential component of the mycobacterial cell wall. The ultimate effect is bacteriostatic. A This enzyme is inhibited by trimethoprim. B This enzyme is inhibited by chloramphenicol. D This enzyme is inhibited by fosfomycin. E This enzyme is inhibited by sulfonamides. F This enzyme is inhibited by vancomycin.A 36-year-old Black man recently diagnosed with pulmonary tuberculosis started a drug treatment that included rifampin. Inhibition of which of the following enzymes most likely me- diated the therapeutic efficacy of rifampin in the patient's disease? A. DNA-dependent RNA polymerase B. Arabinosyl transferase C. Transpeptidase D. Topoisomerase II E. RNA-dependent DNA polymeraseA Rifampin inhibits DNA-dependent RNA polymerase in my- cobacteria and other sensitive microorganisms by binding to the β subunit of the enzyme to form a stable drug−enzyme complex. This leads to suppression of initiation of chain for- mation in RNA synthesis. The ultimate effect is bactericidal. B This enzyme is inhibited by ethambutol. C This enzyme is inhibited by β-lactam antibiotics. D This enzyme is inhibited by fluoroquinolones. E This enzyme is inhibited by reverse transcriptase inhibitors.A 49-year-old Asian woman recently diagnosed with tubercu- losis started an appropriate multidrug therapy. Which of the drugs she was taking is inactivated by hepatic acetylation, the rate of which depends on genetic background? A. Streptomycin B. Ethambutol C. Rifampin D. Isoniazid E. PyrazinamideD Isoniazid is metabolized by hepatic acetylation, which is under genetic control. Patients may be fast acetylators (mainly among people of Asian origin) or slow acetylators (mainly among people of European and African origin). Fast acetyla- tors require higher dosage than slow acetylators to obtain equivalent therapeutic effects. A−C, E These drugs are not metabolized by acetylation.A 56-year-old Hispanic man diagnosed with bone tuberculo- sis started a multidrug treatment, but 4 months later, the disease was minimally improved, and susceptibility testing showed a complete resistance to isoniazid. A high level of re- sistance of tubercle bacilli to isoniazid involves a decrease in the activity of which of the following enzymes? A. Catalase-peroxidase B. DNA-dependent RNA polymerase C. Topoisomerase II D. Acetyltransferase E. TranspeptidaseA Isoniazid is a prodrug that must be converted into the active compound by a mycobacterial catalase-peroxidase. Resistance is often associated with the deletion of the katG gene that codes for the synthesis of catalase peroxidase. In this way, activation of the prodrug cannot occur. B−E These enzymes are not involved in the mechanism of resistance of mycobacteria to isoniazid.A 31-year-old homosexual man was found to be HIV positive. Currently, he did not have symptoms of tuberculosis, but his tuberculin skin test was positive. A treatment with isoniazid was prescribed. The inhibition of synthesis of which of the following endogenous compounds most likely mediated the therapeutic effect of the drug in this patient? A. Mycolic acids B. Peptidoglycan C. Arabinosyl transferase D. Topoisomerase II E. DNA-dependent RNA polymeraseA Isoniazid is used alone for the prophylaxis of tuberculosis in at-risk patients, including those who are HIV positive, as in this case. The drug inhibits the synthesis of mycolic acids, which are specific constituents of the mycobacterial cell wall. This can explain, at least in part, why isoniazid is effective only against mycobacteria. B The synthesis of peptidoglycan is inhibited by β-lactam antibiotics. C Arabinosyl transferase is inhibited by ethambutol. D Topoisomerase II is inhibited by fluoroquinolones. E DNA-dependent RNA polymerase is inhibited by rifamycins.A. Amikacin B. Ciprofloxacin C. Clarithromycin D. Ethambutol E. Ethionamide F. Isoniazid G. Pyrazinamide H. Rifampin I. Streptomycin 1. This drug imparts a harmless orange color to urine, sweat, and tears. 2. This drug is effective against some atypical mycobacteria but not against Mycobacterium tuberculosis.1. H 2. C