Question

A macrolide antibiotic is required to treat an infection in a 63-year-old penicillin-sensitive woman who is also receiving digoxin and warfarin therapy. Which one of the following agents is the best option for this patient?

linezolid

erythromycin ethylsuccinate

gentamicin

azithromycin

telithromycin

erythromycin

clindamycin

tobramycin

amikacin

clarithromycin

erythromycin estolate

quinupristin/dalfopristin

Answer 1

Linezolide can be given to this patient.

Linezolid does not affect cytochrome P-450; therefore, induced interactions are unlikely to occur.No pharmacokinetic interactions are observed in patients taking warfarin (Coumarin).

Linezolide doesnot cause digoxin toxicity unlike macrolides.

Linezolid is a synthetic antibiotic belonging to a new class of antimicrobials called the oxazolidinones. Linezolid disrupts bacterial growth by inhibiting the initiation process of protein synthesis—a mechanism of action that is unique to this class of drugs.

The primary mechanisms by which antibiotic medications interact with warfarin to increase the risk of major bleeding is through disruption of intestinal flora that synthesize vitamin K,2 and inhibition of cytochrome p450 isozymes which metabolize warfarin.

The fundamental mechanisms of interaction between warfarin and antibiotics are two-fold:

• Antimicrobial agents disrupt gastrointestinal flora that synthesize vitamin K.
• Antimicrobials inhibit cytochrome p450 (CYP450) enzymes (primarily CYP2C9 and 3A4), which are responsible for the metabolism of warfarin.

The antibiotics most likely to interfere with warfarin are TMP/SMX, ciprofloxacin, levofloxacin, metronidazole, fluconazole, azithromycin, and clarithromycin

Low-risk agents include clindamycin, cephalexin, and penicillin G. When prescribing an antibiotic for a patient taking warfarin, it is important not only to be aware of the agents that should be avoided, but also the agents that do not require more frequent monitoring of INR.

Azithromycin,Clarithromycin,Erythromycin
increases moderate/C Monitor for increased INR and for signs of bleeding when initiating a macrolide, and for decreases when discontinuing.

According to a single dose study, Azithromycin is considered unlikely to interact with warfarin. Unlike other macrolide antibiotics, it is not hepatically metabolized and did not produce an interaction with warfarin.

Clarithromycin increases INR and has moderate risk of bleeding ,causes Inhibition of warfarin metabolism (via CYP3A4)
Monitor INR. Consider empiric warfarin dose reduction by 15-25%

Erythromycin (including ophthalmic
formulations) increases INR, moderate risk of bleeding and decrease in warfarin metabolism (via CYP3A4)
Monitor INR. Consider empiric warfarin dose reduction by 10-15%

Warfarin is particularly susceptible to many mechanisms of drug interactions due to its pharmacokinetic features: it is well
absorbed, 99% protein-bound, and metabolized via CYP450 enzymes. S-warfarin, which is metabolized by CYP2C9, is 2-5 times more active than the R-enantiomer, which is metabolized by CYP3A4. Drugs that induce or inhibit these enzymes can interact with warfarin, with more severe interactions seen with CYP2C9 interactions. These types of interactions take about 5 steady states to reach their full effect, with induction taking longer than inhibition. Another type of interaction is warfarin displacement from plasma proteins by other highly protein bound drugs.
There are also some interactions that affect the pharmacodynamics of warfarin. Warfarin acts to block the reduction of
vitamin K. Reduced vitamin K is needed for the carboxylation of the vitamin k dependent clotting factors (II, VII, IX and X).
Therefore, drugs that alter the amount of vitamin K in the body can effect INR. Broad-spectrum antibiotics are thought to act
by altering intestinal flora, therefore hindering the body’s ability to synthesize vitamin K. Finally, drugs that can effect bleeding and thrombosis through other mechanisms (e.g. platelet function), can interact with warfarin without changing the INR.

Macrolide antibiotics appear to be able to enhance the oral bioavailability of digoxin by altering the gastrointestinal flora that metabolize digoxin to less active dihydro metabolites, thus leading to increased serum digoxin concentrations and possible digoxin toxicity in select patients stabilized on digoxin therapy. This interaction may be of clinical importance in up to 10% of the population. Currently, the orally administered erythromycin, clarithromycin, and roxithromycin have been implicated.