WBR0636

Author	[[PageAuthor::Serge Korjian M.D. (Reviewed by Serge Korjian)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Pharmacology
Sub Category	SubCategory::Infectious Disease
Prompt	[[Prompt::A new antibiotic agent is being studied for the treatment of multi-drug resistant gram-positive infection. The pharmaceutical company responsible for creating this drug explains that its mechanism of action involves 2 separate molecules that act synergistically at the same pathway. Which of the following combinations has a similar mechanism of action?]]
Answer A	AnswerA::Imipenem/cilastatin
Answer A Explanation	AnswerAExp::Cilastatin is used in combination with imipenem to inhibit the degradation of imipenem in the renal tubules by blocking renal dehydropeptidase 1. It has no synergistic activity with imipenem.
Answer B	AnswerB::Piperacillin/Tazobactam
Answer B Explanation	[[AnswerBExp::Since piperacillin is susceptible to penicillinase, tazobactam, an inhibitor of penicillinase (beta-lactamase) is administered in combination to increase the efficacy of the drug. Although the mechanism is synergistic, it does not act on a combined pathway.]]
Answer C	AnswerC::Pyrimethamine/leucovorin
Answer C Explanation	AnswerCExp::Leucovorin is usually co-administered with pyrimethamine to decrease the risk of myelosuppression. It has no synergistic activity.
Answer D	AnswerD::Izoniazid/Rifampin
Answer D Explanation	AnswerDExp::Izoniazid acts by inhibiting mycolic acid synthesis while rifampin inhibits the DNA dependent RNA polymerase. They do not act synergistically at the same pathway.
Answer E	AnswerE::Quinupristin/Dalfopristin
Answer E Explanation	AnswerEExp::Quinupristin and Dalfopristin act synergistically to inhibit protein synthesis by inhibiting both peptide bond formation and translocation.
Right Answer	RightAnswer::E
Explanation	[[Explanation::Quinupristin and Dalfopristin are 2 members of the streptogramin family of antibiotics that act by inhibiting protein synthesis. Streptogramins are 2 types: streptogramin A (dalfopristin) and B (quinupristin). Quinupristin binds to the 23S ribosomal unit of the 50S subunit. It acts like a macrolide by blocking translocation and chain elongation. It even competes with macrolides for thee same binding site. Dalfopristin, on the other hand, acts by a mechanism similar to clindamycin. It binds to the 50S ribosomal subunit and inhibits peptide bond formation by blocking peptidyltransferase. The binding of dalforpristin is facilitated by quinupristin binding. The drugs are always used in combination, since alone they each exhibit weak bacteriostatic activity. When combined, their effect is bactericidal. Another example of a drug combination that acts synergistically at the same pathway is trimethoprim and sulfamethoxazole (TMP/SMX) both of which inhibit DNA synthesis at the folate pathway. Educational Objective: Quinupristin and Dalfopristin act synergistically to inhibit protein synthesis by binding at the 50S ribosomal subunit. References: Harms JM, Schlünzen F, Fucini P, Bartels H, Yonath A. Alterations at the peptidyl transferase centre of the ribosome induced by the synergistic action of the streptogramins dalfopristin and quinupristin. BMC Biol. 2004;2(1):4.]]
Approved	Approved::Yes
Keyword	WBRKeyword::Antibiotics, WBRKeyword::Synergy, WBRKeyword::Dalfopristin, WBRKeyword::Quinupristin, WBRKeyword::Streptogramins, WBRKeyword::Mechanism of action
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