A 68-year-old man comes to the physician because of headache, fatigue, and nonproductive cough for 1 week. He appears pale. Pulmonary examination shows no abnormalities. Laboratory studies show a hemoglobin concentration of 9.5 g/dL and an elevated serum lactate dehydrogenase concentration. A peripheral blood smear shows normal red blood cells that are clumped together. Results of cold agglutinin titer testing show a 4-fold elevation above normal. An x-ray of the chest shows diffuse, patchy infiltrates bilaterally. Treatment is begun with an antibiotic that is also used to promote gut motility. Which of the following is the primary mechanism of action of this drug?

Inhibition of peptide translocation at the 50S ribosomal subunit

Inhibition of bacterial RNA polymerase

Inhibition of folic acid synthesis

Free radical creation within bacterial cells

Inhibition of transpeptidase cross-linking at the cell wall

A 55-year-old man with a history of hypertension and benign prostate hyperplasia presents for follow-up 4 days into the treatment of a urinary tract infection with trimethoprim-sulfamethoxazole. His symptoms have resolved, and he reports no problems with urination, with the exception of a weak urine stream and hesitancy, which he has had for the past 2 years. At the time of this visit, the patient is afebrile; the blood pressure is 130/88 mm Hg and the heart rate is 80/min. There is no flank tenderness. A urinalysis reveals no leukocytes and is negative for esterase. The urinalysis reveals 2 red blood cells (RBCs)/ high power field (HPF), and there are no casts on urinary sediment analysis. The physician, however, notices the following abnormality: Prior treatment BUN 12 mg/dL Creatinine 1.2 mg/dL Today’s visit BUN 13 mg/dL Creatinine 2.1 mg/dL

Reassure the patient, stop trimethoprim-sulfamethoxazole and repeat the measurement in 1–2 weeks

Admit the patient for further management of acute interstitial nephritis

Admit the patient for further management of acute tubular necrosis

Schedule a cystoscopy for urethral obstruction

Schedule an intravenous pyelography for urinary obstruction

A 30-year-old man comes to the emergency department because of the sudden onset of back pain beginning 2 hours ago. Beginning yesterday, he noticed that his eyes started appearing yellowish and his urine was darker than normal. Two months ago, he returned from a trip to Greece, where he lived before immigrating to the US 10 years ago. Three days ago, he was diagnosed with latent tuberculosis and started on isoniazid. He has worked as a plumber the last 5 years. His temperature is 37.4°C (99.3°F), pulse is 80/min, and blood pressure is 110/70 mm Hg. Examination shows back tenderness and scleral icterus. Laboratory studies show: Hematocrit 29% Leukocyte count 8000/mm3 Platelet count 280,000/mm3 Serum Bilirubin Total 4 mg/dL Direct 0.7 mg/dL Haptoglobin 15 mg/dL (N=41–165 mg/dL) Lactate dehydrogenase 180 U/L Urine Blood 3+ Protein 1+ RBC 2–3/hpf WBC 2–3/hpf Which of the following is the most likely underlying cause of this patient's anemia?

Absence of uridine 5'-monophosphate

Defective ankyrin in the RBC membrane

Inhibition of aminolevulinate dehydratase

An 8-year-old boy is brought to the emergency department by his parents because of sudden onset of abdominal pain beginning an hour ago. The parents report that their son has also had an episode of dark urine earlier that morning. Three days ago, he was diagnosed with a urinary tract infection and was treated with trimethoprim-sulfamethoxazole. He emigrated from Liberia to the US with his family 3 years ago. There is no personal history of serious illness. His immunizations are up-to-date. Vital signs are within normal limits. Examination shows diffuse abdominal tenderness and scleral icterus. The spleen is palpated 1–2 cm below the left costal margin. Laboratory studies show: Hemoglobin 10 g/dL Mean corpuscular volume 90 μm3 Reticulocyte count 3% Serum Bilirubin Total 3 mg/dL Direct 0.5 mg/dL Haptoglobin 20 mg/dL (N=41–165 mg/dL) Lactate dehydrogenase 160 U/L Urine Blood 3+ Protein 1+ RBC 2–3/hpf WBC 2–3/hpf Which of the following is the most likely underlying cause of this patient's symptoms?

Deficient glucose-6-phosphate dehydrogenase

Defective RBC membrane proteins

A 45-year-old woman presents to the emergency department with fever, cough, tonsillar enlargement, and bleeding lips. She has a diffuse blistering rash that encompasses the palms and soles of her feet, in total covering 55% of her total body surface area (TBSA). The upper epidermal layer easily slips away with slight rubbing. Within 24 hours the rash progresses to 88% TBSA involvement and the patient requires mechanical ventilation for respiratory distress. Which of the following is the most likely etiology of this patient’s condition?

Deficiency of C-1 esterase inhibitor

Sulfonamides and trimethoprim for USMLE Step 2 CK: High-Yield Pharmacology Lessons

Mechanism of Action - Folate Synthesis Crashers

Sulfonamides and trimethoprim disrupt the bacterial synthesis of tetrahydrofolate (THF), an essential cofactor for purine and DNA synthesis. This sequential blockade is bactericidal.

Sulfonamides: Structural analogs of PABA (para-aminobenzoic acid).
- Competitively inhibit dihydropteroate synthase.
Trimethoprim: Structural analog of dihydrofolic acid.
- Inhibits dihydrofolate reductase (DHFR).

📌 Mnemonic: SULFA drugs inhibit Synthase; Trimethoprim inhibits reducTase.

⭐ Humans are unaffected by sulfonamides as we acquire folate from our diet, lacking the PABA pathway. Trimethoprim has a several thousand-fold higher affinity for bacterial DHFR than human DHFR, ensuring selective toxicity.

Clinical Uses - The TMP-SMX Hit List

📌 TMP = Treats Many Pathogens

Uncomplicated UTIs & Prostatitis
Respiratory Infections:
- Pneumocystis jirovecii (PJP) - drug of choice for treatment & prophylaxis.
- Community-Acquired MRSA pneumonia.
GI Infections: Shigella, Salmonella (though resistance is common).
Encephalitis & Abscesses:
- Toxoplasma gondii (prophylaxis & treatment).
- Nocardia (drug of choice).
Niche Pathogens: Stenotrophomonas maltophilia.

⭐ Prophylaxis for PJP is initiated in HIV patients when their CD4 count drops below 200 cells/mm³.

Adverse Effects - When Good Drugs Go Bad

Sulfonamides (Sulfa Drugs)

Hypersensitivity: Rashes, urticaria, fever. Can progress to life-threatening Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN).
Photosensitivity: Severe sunburns.
Nephrotoxicity: Crystalluria leading to acute interstitial nephritis. Advise patients to stay hydrated.
Hematologic:
- Hemolytic anemia in patients with G6PD deficiency.
- Aplastic anemia (rare).
Kernicterus: In newborns; displaces bilirubin from albumin. Contraindicated in pregnancy (3rd trimester) & neonates.
Drug Interactions: Potentiates warfarin, phenytoin.

📌 Mnemonic: SULFA

Stevens-Johnson syndrome
Urticaria / Urine (crystalluria)
Leukopenia / Light sensitivity
Folate deficiency (hematologic)
Aplastic anemia / Anemia (hemolytic)

⭐ Exam Favorite: Always check for G6PD deficiency before prescribing sulfonamides. The resulting oxidative stress leads to acute hemolytic anemia, presenting with jaundice, dark urine, and fatigue.

Trimethoprim (TMP)

Hematologic: Megaloblastic anemia, leukopenia, granulocytopenia ("TMP Treats Marrow Poorly").
- Reversible with folinic acid (leucovorin) rescue.
Metabolic: Hyperkalemia (blocks epithelial sodium channel in collecting duct, similar to amiloride).

Sulfonamides inhibit dihydropteroate synthase and trimethoprim inhibits dihydrofolate reductase, causing a sequential blockade of folate synthesis.

The combination (TMP-SMX) is bactericidal and shows strong synergy.

Primary uses include UTIs, Pneumocystis jirovecii (PJP) pneumonia treatment and prophylaxis, and Nocardia infections.

Key sulfa toxicities: hypersensitivity (Stevens-Johnson syndrome), hemolysis in G6PD deficiency, and nephrotoxicity (crystalluria).

Trimethoprim can cause megaloblastic anemia and hyperkalemia.

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