Once a Day vs. Three Times a Day Dosing
Persistent misunderstanding about proper gentamicin dosing has led to ototoxicity in many patients. Following is a history and explanation of the changing attitudes about gentamicin dosing.
Prior to 1990, intravenous gentamicin was given 3 times a day. When the gentamicin was infused, the blood level went up (peak level) and dropped over the next 8 hours (trough level) as the gentamicin was excreted in the urine. These blood levels are expressed as micrograms of gentamicin per milliliter of blood serum (mcg/ml), or milligrams of gentamicin per liter (mg/L). These terms are equivalent. The goal was to keep the trough level above a concentration that was effective in killing the infection, but low enough so that significant accumulation with the next dose would not occur. Generally, the target was a level between 1 and 2 mg/L.
This is an illustration of how the blood level of gentamicin might fluctuate when 5 mg/kg/day of gentamicin is given in three divided doses, and when given once a day. [from Cohen & Powderly: Infectious Diseases, 2nd ed., Copyright © 2004 Mosby p. 1812. Note that the serum gentamicin level takes about a day to become stable. The actual levels are for illustration only, and not necessarily indicative of actual blood levels.
Beginning in the early 1990's, researchers began to experiment with Once Daily Dosing, (ODA), also called pulse dosing. The rationale for ODA was based on two observations:
1) The damaging effects of gentamicin (and other aminglycosides) on the kidney cells is greater the higher the blood level of gentamicin or other aminoglycoside becomes, but only to a certain point when raising the serum aminoglycoside or gentamicin concentration has no further damaging effect, and
2) Certain bacteria continue to die for up to 8 hours after the serum level of gentamicin drops below the 2 mg/L value (post-antibiotic effect, or PAE).
By giving one daily big dose, the bacteria are being killed for 24 hours, but the time that the kidney cells are being bathed in the toxic aminoglycoside is reduced. ODA was extensively studied at the Hartford Hospital in Hartford, Connecticut, by David Nicolau and others, and the results were published in 1995. Nicolau, D.P., Freeman, C.D., Belliveau, P.P., Nightingale, C.H., Ross, J.W. & Quintiliani, R. (1995). Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrobial Agents and Chemotherapy 39, 650–5.[Abstract] This paper is referred to as the “Hartford Study” and is often cited as the basis for ODA therapy today. While the paper refers to the broad class of aminoglycosides, 94% of the patients in the study received gentamicin.
Basically, the study showed that if gentamicin is given at a high dose once a day, it is just as effective as giving gentamicin 3 times a day, but there is less kidney damage, and giving gentamicin once a day is less expensive for hospitals. The paper advocated taking a serum aminoglycoside level 8 hours after the first dose to determine further dosing from a chart known as the “Hartford Nomogram.”
Dr. Nicolau and his colleagues wrote an excellent scientific paper based on sound research and methods. Unfortunately, the devil is in the details, not in generalizations. Dr. Nicolau and his colleagues provided all of the details. If hospital pharmacologists and physicians critically read the complete paper, (or even the abstract), they would see that the study provided no statistical evidence of reduced inner ear toxicity, (ototoxicity), with ODA, and that the average course of treatment for all of the 2,184 patients was only 4.5 days.
"Our patient population received 9.741 days of ODA therapy with median length of therapy of 3 (mean, 4.5; range. 1 to 26) days. The percentage of patients receiving ODA according to the duration of therapy was as follows: <=3 days, 50%; 4 to 5 days, 13%; 6 to 7 days, 17%; 8 to 10 days, 9%; 11 to 14 days, 6.5%; >14 days, 4.5%. Thirty-seven percent of the patients received 6 or more days of therapy."
Across the country, certain hospital pharmacologists took up the mantra that high doses of gentamicin (7 mg/kg/day) were now safe if given once a day rather than three times a day, and encouraged physicians to switch to ODA. Not only is ODA less expensive than 3 times a day dosing, but gentamicin is a very inexpensive antibiotic. Chanting this mantra, not even lip service was usually initially given to length of treatment or to the potential for ototoxicity. No consideration seems to have been given by these particular hospital pharmacologists to the fact that the average length of treatment in the Hartford study was 4.5 days, that only 4.5% of the patients received gentamicin for more than 14 days, and that the one patient that suffered irreversible ototoxicity received gentamicin at a high dose for 5 weeks.
Studies have been published warning of ototoxicity in ODA administration. Selected references are:
Singer, C., Smith, C. & Krieff, D. (1996). Once-daily aminoglycoside therapy: potential ototoxicity. Antimicrobial Agents and Chemotherapy 40, 2209–11. [Abstract]
El Bakri, F., Pallett, A., Smith, A. G. & Duncombe, A. S. (1998). Ototoxicity induced by once-daily gentamicin. Lancet 351, 1407–8. [MedlineLink]
This lack of understanding persists today, although several institutions have now placed stricter monitoring requirements on long-term gentamicin use, especially where high doses are used. If gentamicin is necessary, ODA may well be the best means of administration. However, if doses of gentamicin 5 mg/kg/day or higher are given for more than 7-10 days, especially if there is little or no monitoring, the potential for malpractice increases. Often these cases of high gentamicin doses given for long periods of time are based on the physician’s or pharmacologist's erroneous belief that as long as ODA is used, there is no danger of ototoxicity.
The use of the Hartforn Nomogram is discussed in Cohen and Powderly, Infectious Diseases, 2nd ed., Mosby, 2004 at p. 1812:
"Monitoring of patients on once-daily aminoglycoside therapy involves measuring a single random aminoglycoside serum concentration 6–14 hours following a 60-minute infusion of the 7mg/kg dose of gentamicin or tobramycin. Depending upon where the concentration falls on a nomogram [see figure], the patient is then given the same 7mg/kg dose every 24, 36 or 48 hours. If the concentration falls on the line of the nomogram that separates the dosing intervals, then the longer interval is chosen. If the random level falls off the nomogram, then the dosing interval should be based on more frequent serum concentration determinations to decide on the most appropriate time for the next dose.
Although it is unnecessary to draw two serum samples in most patients, it may be necessary to obtain additional levels in some patients with rapidly changing creatinine clearance. If once-daily aminoglycoside therapy is continued beyond 4 days, a random concentration should be obtained on the fifth day, and then weekly thereafter. Serum creatinine should be measured every 2–3 days."
Since gentamicin does not penetrate into fat, special consideration needs to be given for obese patients. The following is excerpted from Cohen and Powderly, Infectious Diseases, 2nd ed., Mosby, 2004 at p. 1812:
"Although a dosing weight may be individualized for each patient, dosing is usually based on actual body weight unless the patient is obese [i.e. greater than 20% over ideal body weight (IBW)]. Calculation of IBW is accomplished by the following formulas:
• IBWmale = 50kg + 2.3kg for every inch (2.54cm) over 5 feet (1.524m);
• IBWfemale = 45.5kg + 2.3kg for every inch (2.54cm) over 5 feet (1.524m).
For the obese patient, a dosing weight can be calculated using the following: obese dosing weight = IBW + 0.4 (actual body weight — IBW)."
Certain bacteria have demonstrated synergistic killing when exposed to an aminoglycoside such as gentamicin and another antibiotic, usually a beta-lactame. There are a lot of variables related to using gentamicin in synergy with other antibiotics. Synergistic dosing of gentamicin is different than monotherapy dosing. The beta lactame acts by breaking town the cell wall of the target organism, allowing gentamicin to diffuse inward to the ribosomal system, which is its site of action. If the beta lactame and gentamicin have a synergistic effect on the particular organism, 2-3 mg/kg/day of gentamicin for the first few days of therapy is typically sufficient. Using a higher dose of gentamicin when it is given with other synergistic antibiotics is not necessarily a potential violation of the standard of care, but it may be. Generally, these issues must be resolved by a competent infectious disease consultant familiar with aminoglycoside therapy.