1. A 52-year-old man presents with fever, confusion, and a focal seizure. Magnetic resonance imaging shows temporal lobe abnormalities, and cerebrospinal fluid (CSF) polymerase chain reaction (PCR) is positive for HSV-1. The team must begin antiviral therapy for herpes simplex encephalitis. Which therapy is appropriate, and what pharmacokinetic property supports it?
A) Oral valacyclovir, because oral therapy achieves the same CSF levels as intravenous dosing in encephalitis
B) Intravenous ganciclovir, because HSV encephalitis requires anti-CMV therapy
C) Intravenous acyclovir, because acyclovir penetrates the cerebrospinal fluid to approximately 50% of plasma levels, achieving therapeutic central nervous system concentrations
D) Intravenous foscarnet, because acyclovir cannot cross into the central nervous system
E) Intravenous cidofovir, because only cidofovir reaches the brain
ANSWER: C
Rationale:
Herpes simplex encephalitis is treated with intravenous acyclovir, which is appropriate because acyclovir distributes widely and achieves cerebrospinal fluid (CSF) concentrations approximately 50% of plasma levels — adequate central nervous system penetration to treat virus replicating in the brain. Standard dosing is intravenous acyclovir 10 mg/kg every 8 hours for 14 to 21 days.
Option A: Option A is incorrect: oral therapy does not reliably reproduce intravenous CSF exposure in encephalitis; intravenous acyclovir is the standard.
Option B: Option B is incorrect: HSV encephalitis is caused by herpes simplex virus and treated with acyclovir, not ganciclovir, which targets CMV.
Option D: Option D is incorrect: acyclovir does penetrate the central nervous system (about 50% of plasma in CSF); foscarnet is reserved for resistant disease.
Option E: Option E is incorrect: cidofovir is not first-line for HSV encephalitis, and acyclovir does reach the brain; cidofovir is reserved for resistant or refractory infection.
2. A 60-year-old kidney transplant recipient is treated for CMV disease with adequate-dose intravenous ganciclovir, but after two weeks the CMV viral load has failed to decline by even 1 log10 and the patient has a history of prior ganciclovir exposure. Genotypic resistance testing is sent. While awaiting results, what is the most appropriate next step and its rationale?
A) Switch to foscarnet, because failure of viral load to fall by at least 1 log10 after two weeks of adequate ganciclovir with prior drug exposure suggests UL97-mediated resistance, and foscarnet retains activity against UL97-mutant CMV without requiring viral activation
B) Double the ganciclovir dose, because resistance is overcome by higher exposure
C) Switch to acyclovir, because it is active against ganciclovir-resistant CMV
D) Stop all antivirals and observe, since resistance cannot be treated
E) Add oral valganciclovir to intravenous ganciclovir for synergy
ANSWER: A
Rationale:
Failure of CMV viral load to decline by at least 1 log10 after two weeks of adequate ganciclovir, particularly with prior ganciclovir exposure, is a recognized trigger to suspect resistance and send genotypic testing (UL97, UL54). UL97 mutations are the most common cause of ganciclovir resistance. Foscarnet is the appropriate switch because it acts directly on the viral DNA polymerase without requiring UL97-mediated activation and generally retains activity against UL97-mutant CMV.
Option B: Option B is incorrect: a UL97 mutation impairs activation of ganciclovir, so higher doses do not overcome it.
Option C: Option C is incorrect: acyclovir has no meaningful activity against CMV because CMV lacks viral thymidine kinase.
Option D: Option D is incorrect: resistant CMV is treatable — foscarnet (or, with combined mutations, cidofovir or combination therapy) is used; stopping therapy risks progressive disease.
Option E: Option E is incorrect: valganciclovir is simply oral ganciclovir and shares the same UL97 dependence, so combining the two does not address resistance.
3. A 34-year-old man with advanced untreated HIV (CD4 count 30 cells/microliter) presents with floaters and decreased vision. Dilated examination reveals CMV retinitis, and one lesion lies within 1500 micrometers of the fovea, threatening central vision. He is able to absorb oral medications. Which initial systemic regimen is appropriate, and what local adjunct should be considered for the sight-threatening lesion?
A) Topical antiviral drops alone, since CMV retinitis is a surface infection
B) Oral acyclovir induction, since it is first-line for CMV retinitis
C) Foscarnet monotherapy only, with no role for any local therapy
D) Letermovir, because it is first-line treatment for established CMV retinitis
E) Oral valganciclovir induction (900 mg twice daily), with intravitreal ganciclovir or foscarnet injection considered as an adjunct for the immediately sight-threatening zone 1 lesion to achieve rapid local viral suppression
ANSWER: E
Rationale:
For CMV retinitis in an HIV patient who can absorb oral medications, valganciclovir 900 mg twice daily for induction (followed by 900 mg once daily maintenance) is the first-line systemic regimen. For an immediately sight-threatening lesion in zone 1 (within 1500 micrometers of the optic disc or fovea), intravitreal ganciclovir or foscarnet injection is used as an adjunct to achieve rapid local viral suppression before systemic therapy takes full effect.
Option A: Option A is incorrect: CMV retinitis is an intraocular infection requiring systemic antiviral therapy, not topical drops.
Option B: Option B is incorrect: acyclovir is not effective against CMV because CMV lacks viral thymidine kinase.
Option C: Option C is incorrect: foscarnet is not the routine first-line agent here, and intravitreal injection is in fact an appropriate adjunct for the sight-threatening lesion.
Option D: Option D is incorrect: letermovir is approved for CMV prophylaxis in transplant recipients, not as first-line treatment of established CMV retinitis.
4. A 41-year-old woman with advanced HIV has extensive, progressive, necrotic perianal HSV ulceration that has continued to worsen despite seven days of adequate intravenous acyclovir. Acyclovir-resistant HSV, typically from a thymidine kinase mutation, is strongly suspected. Which agent is the treatment of choice?
A) High-dose oral valacyclovir
B) Foscarnet
C) Higher-dose intravenous acyclovir
D) Oral ganciclovir
E) Oseltamivir
ANSWER: B
Rationale:
Foscarnet is the agent of choice for acyclovir-resistant HSV. Lack of clinical response after five to seven days of adequate intravenous acyclovir, especially in advanced HIV, suggests a thymidine kinase (TK) mutation that prevents acyclovir activation. Because foscarnet acts directly on the viral DNA polymerase and requires no viral kinase, it remains effective against TK-deficient acyclovir-resistant strains.
Option A: Option A is incorrect: valacyclovir is a prodrug of acyclovir and depends on the same TK activation, so it cannot overcome TK-mediated resistance.
Option C: Option C is incorrect: increasing the acyclovir dose does not help when the virus cannot phosphorylate the drug at all.
Option D: Option D is incorrect: ganciclovir depends on phosphorylation for activation and is not the standard choice for TK-mutant acyclovir-resistant HSV; foscarnet is preferred.
Option E: Option E is incorrect: oseltamivir is an influenza neuraminidase inhibitor with no activity against HSV.
5. A 58-year-old transplant recipient with refractory CMV is being considered for cidofovir. His baseline creatinine clearance is 45 mL/min and a urine dipstick shows 2+ proteinuria. The consulting team reviews whether and how cidofovir can be given. Which statement is correct?
A) Cidofovir can be given at full dose without precautions because his renal function is adequate
B) Cidofovir should be infused rapidly without hydration to limit tubular contact time
C) Cidofovir requires no probenecid as long as saline is given
D) Cidofovir is contraindicated in this patient because creatinine clearance below 55 mL/min and significant pre-existing proteinuria preclude its use; when cidofovir is used in eligible patients, mandatory probenecid before and after each dose plus saline preloading and creatinine and urine-protein monitoring are required
E) Cidofovir is preferred specifically in renal impairment because it is renally protective
ANSWER: D
Rationale:
Cidofovir is contraindicated when creatinine clearance is below 55 mL/min or when there is significant pre-existing proteinuria, both of which are present here, because its OAT1-mediated proximal tubular uptake causes dose-dependent nephrotoxicity that can be irreversible. In eligible patients, the mandatory protocol includes oral probenecid before and after each dose, intravenous saline preloading, and monitoring of serum creatinine and urine protein, with the drug withheld for a creatinine rise of 0.3 mg/dL or proteinuria of 2+ or greater.
Option A: Option A is incorrect: his renal function and proteinuria actually contraindicate cidofovir; full-dose unprotected administration would be dangerous.
Option B: Option B is incorrect: rapid infusion without hydration worsens nephrotoxicity; saline preloading is required.
Option C: Option C is incorrect: probenecid is mandatory with cidofovir, not optional, because it blocks the OAT1 uptake driving toxicity.
Option E: Option E is incorrect: cidofovir is nephrotoxic, not renally protective, and is contraindicated in significant renal impairment.
6. A 49-year-old hematopoietic stem cell transplant recipient is 12 days into intravenous ganciclovir induction for CMV disease when the absolute neutrophil count drops sharply. The CMV is still responding virologically. Recognizing the dose-limiting toxicity of ganciclovir, what is the most appropriate management?
A) Manage the ganciclovir-induced myelosuppression by reducing or holding ganciclovir and supporting the absolute neutrophil count with granulocyte colony-stimulating factor (G-CSF), or switching to foscarnet, which lacks myelosuppression, if continued anti-CMV therapy is essential
B) Continue ganciclovir unchanged, since neutropenia is unrelated to ganciclovir
C) Switch to cidofovir, because it reliably reverses neutropenia
D) Add acyclovir to boost the neutrophil count
E) Stop all CMV therapy permanently regardless of viral status
ANSWER: A
Rationale:
Myelosuppression, particularly neutropenia, is the dose-limiting toxicity of ganciclovir, with neutrophil nadirs typically occurring within the first two weeks. Appropriate management is to reduce or hold ganciclovir and support the absolute neutrophil count with granulocyte colony-stimulating factor (G-CSF), or to switch to foscarnet — which lacks myelosuppression — when continued anti-CMV therapy is essential.
Option B: Option B is incorrect: the neutropenia is the recognized dose-limiting toxicity of ganciclovir, not an unrelated finding.
Option C: Option C is incorrect: cidofovir does not reverse neutropenia; its toxicity is nephrotoxicity, and it would not be chosen to fix marrow suppression.
Option D: Option D is incorrect: acyclovir does not raise neutrophil counts and has no role here.
Option E: Option E is incorrect: permanently stopping CMV therapy in active disease risks progression; the marrow toxicity is managed by dose modification, G-CSF, or switching agents rather than abandoning treatment.
7. A 29-year-old woman at 24 weeks gestation is diagnosed with primary genital HSV. She is counseled about treatment now and about reducing the chance of a cesarean delivery performed for active lesions at term. Which approach is appropriate?
A) Avoid all antivirals in pregnancy and manage symptomatically only
B) Treat with ganciclovir, the preferred agent for genital HSV in pregnancy
C) Treat the primary episode with acyclovir or valacyclovir (Pregnancy Category B agents supported by extensive safety data), and offer suppressive valacyclovir from 36 weeks gestation to reduce HSV shedding and recurrent lesions at delivery, lowering the rate of cesarean delivery performed for active HSV
D) Use foscarnet, which has the best pregnancy safety profile
E) Defer any therapy until after delivery regardless of symptoms
ANSWER: C
Rationale:
Acyclovir and valacyclovir are Pregnancy Category B agents supported by extensive human safety data and are appropriate for primary genital HSV in pregnancy. Suppressive valacyclovir started at 36 weeks gestation reduces HSV shedding and recurrent lesions at delivery, thereby lowering the rate of cesarean delivery performed for active HSV disease. This combines acute treatment with a term suppression strategy.
Option A: Option A is incorrect: acyclovir and valacyclovir are safe and effective in pregnancy, so withholding antivirals is not appropriate.
Option B: Option B is incorrect: ganciclovir targets CMV and is generally avoided in pregnancy; it is not used for genital HSV.
Option D: Option D is incorrect: foscarnet is generally avoided in pregnancy and does not have the best safety profile; acyclovir and valacyclovir carry the favorable data.
Option E: Option E is incorrect: deferring treatment of symptomatic primary genital HSV is not appropriate, and term suppression specifically reduces delivery complications.
8. A 47-year-old CMV-seropositive man is undergoing allogeneic hematopoietic stem cell transplantation. The team wants to prevent CMV reactivation during the period of profound immunosuppression but is concerned about adding to the expected post-transplant myelosuppression. Which prophylactic agent best meets these needs, and why?
A) Valganciclovir, because it has no myelosuppressive potential
B) Letermovir, because it is approved for CMV prophylaxis in CMV-seropositive hematopoietic stem cell transplant recipients, inhibits the UL56 terminase (a target distinct from the DNA polymerase, so no cross-resistance with ganciclovir/foscarnet/cidofovir), and lacks myelosuppression
C) Acyclovir, because it provides reliable CMV prophylaxis without marrow toxicity
D) Cidofovir, because it is the standard oral prophylactic agent in transplant
E) Foscarnet, because it is the preferred first-line prophylaxis and is marrow-sparing and nephroprotective
ANSWER: B
Rationale:
Letermovir is approved for CMV prophylaxis in CMV-seropositive hematopoietic stem cell transplant (HSCT) recipients. It inhibits the CMV terminase complex via the UL56 subunit — a target distinct from the DNA polymerase — so it has no cross-resistance with ganciclovir, foscarnet, or cidofovir, and critically it lacks myelosuppression and has good oral bioavailability. These features make it especially attractive when avoiding further marrow toxicity is a priority.
Option A: Option A is incorrect: valganciclovir is oral ganciclovir and does carry myelosuppressive potential, so it does not meet the marrow-sparing requirement.
Option C: Option C is incorrect: acyclovir does not provide reliable CMV prophylaxis because CMV lacks viral thymidine kinase.
Option D: Option D is incorrect: cidofovir is a toxic intravenous agent reserved for resistant disease, not a standard oral prophylactic.
Option E: Option E is incorrect: foscarnet is not first-line prophylaxis and is markedly nephrotoxic, not nephroprotective.
9. A 55-year-old man receiving foscarnet for ganciclovir-resistant CMV develops perioral numbness, tingling in the fingers, and carpopedal spasm during an infusion. Serum calcium is low. Recognizing the mechanism behind this complication, what is the explanation and appropriate response?
A) Hyperkalemia from foscarnet, treat with potassium binders
B) Hypernatremia from foscarnet, treat with free water
C) Hyperglycemia from foscarnet, treat with insulin
D) Lactic acidosis from foscarnet, treat with bicarbonate
E) Hypocalcemia from foscarnet chelating divalent cations; manage by repleting calcium (and magnesium, potassium, and phosphate as needed), monitoring electrolytes with each infusion, and ensuring saline hydration
ANSWER: E
Rationale:
Foscarnet chelates divalent cations, and the resulting hypocalcemia produces the classic neuromuscular signs of perioral paresthesias, tingling, and carpopedal spasm (tetany). Management is to replete calcium — and to monitor and correct magnesium, potassium, and phosphate, which are also commonly disturbed — checking electrolytes with each infusion and maintaining saline hydration to protect renal function.
Option A: Option A is incorrect: foscarnet is associated with hypokalemia rather than hyperkalemia, and the tetanic symptoms point to hypocalcemia.
Option B: Option B is incorrect: hypernatremia is not the characteristic foscarnet electrolyte effect and would not cause tetany.
Option C: Option C is incorrect: hyperglycemia is not a recognized characteristic foscarnet effect and does not explain these neuromuscular signs.
Option D: Option D is incorrect: the syndrome described is hypocalcemic tetany from cation chelation, not lactic acidosis.
10. A 63-year-old kidney transplant recipient has two weeks of diarrhea, hematochezia, and abdominal pain. Blood CMV polymerase chain reaction (PCR) is negative, but CMV gastrointestinal disease is clinically suspected. How should the diagnosis be confirmed, and what is the appropriate treatment?
A) Rely on the negative blood PCR to exclude CMV and treat empirically for bacterial colitis only
B) Diagnose by blood PCR alone, which is always positive in CMV colitis
C) Start acyclovir while awaiting stool studies
D) Confirm by tissue biopsy demonstrating CMV cytopathic effect (intranuclear owl-eye inclusions) or positive immunohistochemistry, because blood CMV PCR may be negative in isolated gastrointestinal disease, and treat with intravenous ganciclovir induction
E) Begin letermovir, the treatment of choice for CMV colitis
ANSWER: D
Rationale:
In isolated CMV gastrointestinal disease, blood CMV PCR may be negative, so diagnosis requires tissue biopsy demonstrating CMV cytopathic effect — the characteristic intranuclear owl-eye inclusions — or positive immunohistochemistry. Treatment of CMV end-organ disease such as colitis is intravenous ganciclovir induction (5 mg/kg every 12 hours) until symptoms resolve and viral load is undetectable, with transition to oral valganciclovir for maintenance.
Option A: Option A is incorrect: a negative blood PCR does not exclude isolated gastrointestinal CMV disease, so it should not be used to rule it out.
Option B: Option B is incorrect: blood PCR is not always positive in CMV colitis; tissue diagnosis is needed when it is negative.
Option C: Option C is incorrect: acyclovir has no meaningful activity against CMV.
Option E: Option E is incorrect: letermovir is approved for CMV prophylaxis, not as treatment for established CMV colitis.
11. A 50-year-old lung transplant recipient has CMV that has progressed through ganciclovir and then foscarnet. Genotypic testing now reveals combined UL97 and UL54 mutations producing high-level multidrug resistance. Recognizing what these combined mutations imply, which option represents an appropriate next strategy?
A) Return to standard-dose ganciclovir monotherapy, since resistance reverses over time
B) Consider cidofovir (if renal function permits and with the mandatory probenecid and saline protocol) or combination therapy such as foscarnet plus ganciclovir, because combined UL97 plus UL54 mutations confer high-level multidrug resistance that leaves these as the remaining options
C) Switch to acyclovir, which is unaffected by UL97 and UL54 mutations
D) Use oseltamivir, since neuraminidase is not encoded by UL97 or UL54
E) Begin letermovir monotherapy as definitive treatment of established multidrug-resistant CMV disease
ANSWER: B
Rationale:
Combined UL97 and UL54 mutations produce high-level multidrug resistance affecting ganciclovir and foscarnet, which leaves cidofovir (when renal function permits and with the mandatory probenecid plus saline protocol) or combination therapy such as foscarnet plus ganciclovir as the remaining options, sometimes alongside investigational agents. Recognizing the genotype directs therapy toward these salvage strategies.
Option A: Option A is incorrect: resistance does not spontaneously reverse, and returning to ganciclovir monotherapy would not control a UL97/UL54-mutant strain.
Option C: Option C is incorrect: acyclovir has no meaningful CMV activity regardless of resistance pattern because CMV lacks viral thymidine kinase.
Option D: Option D is incorrect: oseltamivir is an influenza neuraminidase inhibitor with no activity against CMV.
Option E: Option E is incorrect: letermovir is approved for prophylaxis, not as definitive treatment of established multidrug-resistant CMV disease.
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