A novel aminoglycoside antibiotic is developed that is intravenously administered and excreted unchanged in urine with an elimination half-life of 4 hours. Two different dosing regimens are tested in a clinical trial: smaller doses given 3 times a day and a higher dose given once a day. The total administered drug amount per kilogram of body weight per day (mg/kg/day) is the same in both regimens. Serum drug concentration is monitored in both groups and is shown in the graph below:[Blue: once-daily (extended interval) dosing, Green: multiple-daily dosing, MIC: minimum inhibitory concentration] It is found that both regimens are effective against gram-negative pathogens, with clinical improvement occurring slightly earlier on average with once-daily dosing. Which of the following best explains the efficacy of once-daily dosing despite the short half-life of this antibiotic?

Question

A novel aminoglycoside antibiotic is developed that is intravenously administered and excreted unchanged in urine with an elimination half-life of 4 hours.  Two different dosing regimens are tested in a clinical trial: smaller doses given 3 times a day and a higher dose given once a day.  The total administered drug amount per kilogram of body weight per day (mg/kg/day) is the same in both regimens.  Serum drug concentration is monitored in both groups and is shown in the graph below:[Blue: once-daily (extended interval) dosing, Green: multiple-daily dosing, MIC: minimum inhibitory concentration]  It is found that both regimens are effective against gram-negative pathogens, with clinical improvement occurring slightly earlier on average with once-daily dosing.  Which of the following best explains the efficacy of once-daily dosing despite the short half-life of this antibiotic?

Quizplus · Accepted Answer

11ec160b_3bfa_dbbe_9249_49ef312fe319_MD0001_00 The 2 major factors influencing the effectiveness of antimicrobial agents are the drug concentration at the target site and the amount of time that microbes are exposed to the drug. The relative contribution of these factors to drug efficacy depends on the particular agent. In general, antibiotics can be classified into 2 categories based on which factor is more important: Concentration-dependent killing: Antibiotics with this pattern of activity (eg, aminoglycosides, fluoroquinolones) have a persistent, suppressive effect on bacterial growth following a limited exposure, resulting in increased killing ability when drug levels at the site of infection are maximized. The higher the peak drug level compared to the minimum inhibitory concentration (MIC), the greater the antimicrobial activity. As such, higher-dose, extended-interval (ie, once-daily) regimens are frequently used to optimize bacterial killing. Time-dependent killing: Antibiotics with this activity pattern (eg, beta-lactams [penicillins, cephalosporins], clindamycin) have minimal persistent effects and are dependent on long exposure durations for their antimicrobial activity. They are more effective when serum concentrations exceed the MIC for a prolonged period. Therefore, more frequent, multiple-daily dosing regimens are used to maintain plasma concentrations greater than the MIC for as long as possible. (Choice B) The therapeutic index (ie, [toxic dose]/[effective dose]) is a measurement of the relative safety of a drug; it is an intrinsic property upon which drug dosing regimens are devised. A relatively high therapeutic index is usually necessary to prevent toxicity with extended-interval dosing because the administered drug amounts lead to higher serum levels than seen with more frequent dosing regimens. (Choice C) Most drugs exhibit a sigmoid-shaped dose response curve that shows no effect until a threshold concentration is exceeded. After this occurs, the effects increase with increasing drug concentration until a saturation threshold (ie, maximum effect) is reached. In contrast to this sigmoidal response, the risk of cancer following exposure to ionizing radiation shows a linear dose-response relationship (ie, risk increases proportionately with increased exposure). (Choice D) The threshold dose is the lowest dose at which drug effects are first seen. In this case, both dosing regimens cause serum concentrations to rise above the MIC. Furthermore, the extended-interval dosing regimen results in less total time above the MIC but still demonstrates effectiveness. Therefore, a low dosing threshold does not explain the effectiveness of extended-interval dosing. (Choice E) In this example, both treatment regimens were effective, with extended-interval dosing having a slightly better response time. Because serum concentrations with the extended-interval regimen remain above the MIC for a much shorter period of time compared to multiple-daily dosing, time-dependent killing does not contribute significantly to overall drug efficacy. Educational objective: Antibiotics exhibiting concentration-dependent killing can be administered using relatively high doses given at lower frequency. This allows for effective microbial killing while preventing adverse effects that may occur with prolonged systemic exposure.

A Novel Aminoglycoside Antibiotic Is Developed That Is Intravenously Administered