P&T News: October 1996, Vol. 17, No. 4
Christine M. Jamjian, Pharm D, and Stephen C. Bergquist,
MS
Peer Review Status: Internally Peer Reviewed by Drs. Bradley
Britgan, Jack Stapleton, and Ronald Jones
Over the past ten to fifteen years, research has focused on maximizing the efficacy of AG while minimizing toxicity. Key areas of research salient to less frequent AG dosing have included:
Based on the above cited information, ODD of AG appears to be an alternate way to administer these drugs. When administered once daily, AG will reduce renal cortical accumulation, which results in reduction in tissue concentration dependent nephrotoxicity. Higher peak levels obtained with the ODD regimen will also ensure maximal bactericidal activity. ODD of AG will produce lower trough concentrations which might limit adaptive resistance. Since AG exert a long post-antibiotic effect (2 or more hours), lower troughs should not jeopardize their clinical efficacy.
This review will critically evaluate the clinical trials that have been conducted to compare the efficacy and toxicity of the once daily dosing regimens to the traditional multiple daily dosing (MDD) regimens for amikacin, gentamicin, tobramycin, and netilmicin. Recommendations on the clinical use of this dosing approach will also be provided.
Efficacy
Several studies have been conducted to establish the safety and
efficacy of ODD AG.7-26 Some study designs have been prospective,
comparative, open-labeled, and randomized. The main objective of most
studies has been to establish the efficacy of the ODD regimen by
comparing the clinical cure and the bacteriological cure to the
traditional MDD regimen. The AG used in the studies have included
amikacin, gentamicin, netilmicin, and tobramycin. Patients have had a
wide variety of infections, and the treatment duration has varied
among trials. The types of infections that ODD AG studies examined
include: upper urinary tract infections, intra-abdominal infections,
lower respiratory infections, endocarditis, suspected or documented
septicemia, gynecologic and obstetric infections, soft tissue and
bone infections, and febrile neutropenic patients.7-26 The studies
that enrolled patients with different types of infections did not
stratify their results based on their infection sites. Because of the
severity of these infections, AG were rarely used as monotherapy;
penicillin, cephalosporins, and metronidazole were frequently added.
Patients with urinary tract infections were the only group who
received AG as single agents. While duration of therapy with AG
varied from one to sixteen days.7-26 there was no significant
difference between the ODD and MDD AG regimens in terms of the
average duration of treatment.
These studies conducted to establish the efficacy of the ODD AG regimen shared several limiting factors in methodology: 1) Clinical cure definitions varied between studies, and some studies did not define this end point. 2) Resolution of an infection required the elimination of several objective and subjective signs and symptoms. The evaluation of subjective signs and symptoms was performed by a health care professional who was not blinded to the treatment, creating potential bias among the studies performed. 3) AG were rarely used as single agents; penicillins and cephalosporins were frequently added for synergy. As a result, evaluation of efficacy of the ODD AG component of the regimen was difficult. 4) Stratification of results based on the type of infections was not always performed.
The vast majority of studies have demonstrated that the ODD AG and MDD AG regimens are equally effective in terms of achieving clinical and bacteriological cure.7-2l,23 In a prospective, open, randomized study, the efficacy and safety of ODD gentamicin was compared to a three times daily dosing regimen in 123 non-neutropenic patients with severe infections.8 Both regimens were equally effective in their clinical and bacteriological responses.8 The duration of treatment was also comparable in both groups (5.4 days in ODD group vs 6.1 days in MDD group, p=NS). Only three studies to date have demonstrated that ODD is superior to MDD AG.22,24,25 In a study conducted by Mauraden et al,24 ODD netilmicin achieved an 88% clinical cure as compared to 68% in the three times daily regimen. Bacteriological elimination was similar in both groups: 90% in the ODD regimen and 88% in the three times daily group. However, no statistical analysis was performed on these results. Giamarellou et al25 also showed that ODD of amikacin was superior to twice daily dosing in producing clinical cure (p<0.05). The bacteriological response was equivalent in both regimens, but the twice daily group included more seriously ill patients than the ODD regimen. Van der Aumera et al22 investigated the rate of killing and the post antibiotic effect, in addition to clinical efficacy, of ODD and twice daily netilmicin. The rate of killing was higher in the ODD group against P. aeruginosa and S. marcescens. Furthermore, the investigators showed that the duration of the post antibiotic effect correlated with the strain and the time of sampling (p < 0.01). When the time of sampling was closer to the peak, the duration of the post-antibiotic effect was longer; the overall clinical efficacy was not significantly different between the two regimens.
In conclusion, the ODD AG regimen appears to be at least as effective as the conventional MDD regimen in terms of achieving bacteriological and clinical cures. However, more studies are required to specify which patient populations can be best treated with the ODD regimen.
Nephrotoxicity
Because aminoglycoside-induced nephrotoxicity is associated with
a high trough concentration, ODD should be an ideal regimen to avoid
this complication. AG cause renal toxicity by accumulating in the
renal tissues. These agents lead to the inhibition of intracellular
phospholipase Al and A2 in the proximal tubules, consequently
resulting in the buildup of phospholipid within the Iysosomes. Once a
threshold is reached, cell death and tubular necrosis ensues.30 Since
the renal cortical uptake of AG is saturable, longer dosing intervals
appear to decrease renal accumulation and, thus, reduce
nephrotoxicity.
Several studies have been conducted in order to assess the risk of nephrotoxicity with ODD AG.7-25 Most of the clinical trials have found no significant difference between the MDD and the ODD regimens.7,9,2l-25 In an open, randomized, multicenter study, Maller et al9 evaluated the efficacy and safety of amikacin given once or twice daily. A multivariate analysis could not correlate nephrotoxicity with the dosing regimen. Several studies7,11-25 have duplicated the conclusion of Maller et al, while two trials8,21 have reported a significantly lower nephrotoxicity with ODD as compared to MDD of AG. Prins et al8 demonstrated that 5 % of patients treated with ODD gentamicin had an increase in their serum creatinine (SrCr) versus 24% of patients receiving gentamicin in divided doses (p=0.016). Similarly, Marik et al21 showed the ODD regimen of amikacin to cause less nephrotoxicity than the twice daily regimen (p=0.01).
Since SrCr is not a totally reliable indicator for measuring renal function and glomerular filtration rate, some investigators have used other parameters to monitor renal function. Nordstrom et al14 used EDTA clearance to measure creatinine clearance; no significant differences between the ODD and MDD regimens were noted. The urinary excretion of phospholipids has been shown to correlate to Iysosomal phospholipidosis and, thus, might predict renal toxicity.l9 Amikacin ODD has been shown to significantly reduce urinary phospholipids excretion. 18 ,19 The effect of netilmicin on phospholipid excretion was not influenced by the regimen used. 18, 19
Three studies examined the correlation of renal toxicity to serum AG concentrations.8,13,16 Prins et al8 noted that gentamicin initial trough concentrations were elevated in patients who developed nephrotoxicity (1.2 vs 0.5 mg/L in the ODD group, 2.3 vs 1.3 mg/L in the MDD group). Maller et al13 and de Vries et al16 also reported higher serum trough concentrations of amikacin and netilmicin, respectively, in those patients with renal toxicity.
A review of the numerous published studies provides a clear trend towards equal or greater safety, but several flaws in the studies should be noted: 1) Patients enrolled in these studies were strictly monitored; therefore, dosing and frequency were adjusted in patients who had high troughs. Monitoring alone can reduce the renal toxicity associated with AG. 2) SrCr is not the most sensitive indicator of renal function. 3) The use of other nephrotoxic drugs was not always discussed by the investigators. 4) Patients with renal insufficiency were excluded from the reviewed trials. And, 5) some studies noted that nephrotoxicity with the ODD regimen takes longer to appear (12 days versus 9 days) when compared with a MDD regimen. 16,17
Ototoxicity
Aminoglycoside-induced ototoxicity can be permanent. Animals
studies have shown that the penetration of AG into the inner ear
perilymph, the organ of Corti, and the lateral wall affects toxicity.
The ototoxicity is due to the destruction of vestibular and cochlear
sensory cells by AG.30 The introduction of AG into the perilymph has
been shown to linearly correlate with the dose administered, and
elimination from these compartments is slow. AG penetration into the
organ of Corti and the lateral wall is rapid and saturable. An
association between peak and trough AG serum concentrations and
ototoxicity has never been proven. The duration of treatment, total
dose administered, and advanced age appear to be better determinants
of ototoxicity.31 Following an AG insult, patients are usually unable
to perceive high-frequency sound ranges. Headache, nausea, and
vomiting are usually associated with vestibular toxicity.
To determine the risk of developing vestibulotoxicity on an ODD regimen versus a MDD regimen of amikacin, 20 healthy volunteers were studied.26 The investigators showed no significant difference between the two groups in developing ototoxicity. The overall reported incidence of auditory and vestibular toxicity in the studies comparing ODD and MDD AG remains low,7-25 but patients were not always evaluated by the more sensitive tests, audiometry and nystagmography. Some investigators have reported the results of their clinical evaluation of ototoxicity;l0,l2,20,2l,24 however, due to the nature of the patient population studied, the administration of these tests to sedated or unresponsive patients was impossible. In conclusion, both ODD and MDD AG regimens are likely equivalent in terms of their ototoxicity risk.
Dosing of Once Daily Aminoglycosides
The doses of AG used in the ODD regimen varied among studies.
Gentamicin doses ranged from 4 to 7 mg/kg/day,8,l4,27 whereas
tobramycin daily doses ranged from 5 to 15 mg/kg.72627 The higher
doses for tobramycin were used in cystic fibrosis patients. The vast
majority of data concerning the dosage of once daily AG is derived
from work carried out at the Hartford Hospital (Hartford,
Connecticut).27 Either gentamicin or tobramycin at 7 mg/kg given over
60 minutes was administered once daily to 2,184 patients. The dose
was calculated by using a computer simulation model that achieved a
peak concentration of 20 mcg/mL, which approximates ten times the MIC
for P. aeruginosa, the pathogen usually associated with the highest
susceptible range MICs. Patients' actual body weights were used for
dosing unless the individual was obese, in which case the adjusted
body weight was used. For patients with creatinine clearances less
than 60 mL/min, the dosing interval was extended (see Table 1). In
patients with creatinine clearances less than 20 mL/min, the dose was
held until the drug concentration fell to 1 to 2 mcg/mL. A
prospective evaluation of 58 patients receiving this ODD regimen, and
follow-up of additional clinician reports, noted no apparent
alterations in clinical response.27
|
Table 1. Dosing and Monitoring Parameters for Once-Daily Dosing of Aminoglycosides | |
|
Dosage Regimens of ODD AG[27] |
|
|
DRUG |
DOSING REGIMEN |
|
Gentamicin |
7 mg/kg/day |
|
Dosage Internal for Extended Interval Aminoglycoside Dosing Based on Creatinine Clearance[27] | |
|
CREATININE CLEARANCE |
INTERVAL |
|
> 60 mL/minute |
Every 24 hours |
|
Monitoring Parameters[27] |
|
|
TIME OF SAMPLING |
CONCENTRATION DESIRED |
|
6 to 14 hours after the start of infusion |
Plot concentration on nomogram |
The Providence Medical Center (Portland, Oregon) used once daily gentamicin and tobramycin at a more conservative dose of 5 mg/kg infused over 60 minutes. Patients with creatinine clearances below 90 mL/min were excluded from this protocol. The experience with 100 patients (a 1991 report) was satisfactory in terms of clinical response and safety.32
Patient Selection Criteria
The use of ODD of aminoglycoside therapy is safe in patients with
urinary tract, intra-abdominal, pulmonary, or pelvic infections
because of the availability of sufficient clinical data to
demonstrate the efficacy and safety of this dosing regimen. The
experience of ODD of AG in neutropenic patients is limited to a
single small trial.20 In addition, ODD AG efficacy has not been
studied in a sufficient number of pediatric patients or in
staphylococcal or enterococcal endocarditis where AG are used for
synergy.2' Conditions in which the volume of distribution is altered
significantly may not be optimal for the use of ODD of AG. Such
conditions include: ascites, cystic fibrosis, burns of greater than
20% of total body surface area, pregnancy, and end stage renal
disease29 (see Table 2). Use in such conditions should be undertaken
with careful AG level monitoring (see Monitoring section below).
|
Table 2. Patient Selection Guidelines | |
|
Appropriate Candidates for ODD AG |
Patient Conditions Where Limited Data on ODD AG Exist |
|
Urinary tract infections |
Pregnancy |
Monitoring
The traditional monitoring of AG does not apply to a once daily
dosing regimen because of the high peak concentrations achieved and
the drug-free period at the end of the dosing interval. At Hartford
Hospital, the ODD AG regimen is monitored by checking a single random
blood sample 6 to 14 hours after the start of the 60-minute infusion.
The level is plotted on a ODD AG nomogram that would determine the
adequate interval (Figure 1). The nomogram is based on a 7 mg/kg/day
dosing regimen of gentamicin or tobramycin. It is useful in detecting
patients with creatinine clearances that differ from the calculated
clearance values. If patients are treated with an AG for longer
than five days, a random drug concentration should be reviewed
weekly.27 Patients with unstable renal function require a more
frequent monitoring of their levels.
The Providence Medical Center uses an 18-hour post-dose concentration to monitor ODD AG regimens. A level of less than or equal to 1 mcg/mL ensures adequate renal clearance. No specific recommendations for interval adjustment are provided by this group if the level is > 1 mcg/mL.32
Summary and Conclusion
Once daily dosing with aminoglycosides appears to be at least as
effective as the multiple daily dosing regimens. Although this dosing
scheme does not seem to definitively offer major advantages in terms
of reducing toxicity in well-monitored patients, ODD of AG can
potentially decrease the costs of AG therapy by reducing nursing
time, infusion material, and serum drug concentrations monitoring, as
well as simplify administration (i.e., fewer IV lines) in patients
receiving multiple IV medications.33 The greatest experience with ODD
of AG is in individuals with urinary tract, abdominal, pulmonary, and
pelvic infections. Uncomplicated urinary tract infections are the
only cases where AG might be successful as monotherapy.
The best guidelines for dosing and monitoring of ODD of AG are found in Table 1 and Figure 1.27 Based on extensive prior experience, these investigators recommend a dose of 7 mg/kg/day for both gentamicin and tobramycin. Drug serum concentrations should be checked 6 to 14 hours after the initial dose. The random level should be evaluated using a nomogram (Figure 1). If the patient's renal function is stable, no further monitoring is required, unless the drug is continued for more than five days. When AG are continued for longer than five days, weekly random drug concentrations should be checked.27 Patients whose renal function is fluctuating need to have frequent monitoring of their serum AG concentrations.
References
AMIFOSTINE Injection: 500 mg per ml, 10 ml vial Amifostine (Ethyol[R] - U.S. Bioscience) is an organic thiophosphate that reduces the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian or non-small cell lung cancer.
CALCITONIN SALMON Nasal Spray: 2200 I.U. per ml, 2 ml bottles The nasal spray formulation (Miacalcin[R] - Sandoz) of calcitonin salmon is indicated for the treatment of postmenopausal osteoporosis in women who are greater than five years postmenopause with low bone mass.
DEXFENFLURAMINE Capsule: 15 mg Dexfenfluramine (Redux[R] - Wyeth Ayerst) is indicated for the management of obesity. Use of dexfenfluramine has been associated with an increased incidence of primary pulmonary hypertension. NOTE: The prescribing of dexfenfluramine is restricted to attending clinica faculty (staff) physicians.
INTERFERON BETA-1A Injection: 30 mcg per 1 ml Interferon beta-la (Avonex[R] - Biogen) is indicated for the treatment of relapsing forms of multiple sclerosis to slow the accumulation of physical disability and decrease the frequency of clinical exacerbations.
IRINOTECAN Injection: 20 mg per ml, 5 ml vial Irinotecan (Camptosar0 - Upjohn & Pharmacia) is an antineoplastic agent indicated for the treatment of metastatic carcinoma of the colon or rectum in patients whose disease has recurred or progressed following 5-fluorouracil-based therapy.
PHENTERMINE Resin Complex Capsule: 15 ma, 30 mg Phentermine resin complex (Ionamin[R] - Fisons) is a sympathomimetic amine indicated for short-term use for the management of exogenous obesity in conjunction with calorie restriction. NOTE: The prescribing of phentermine is restricted to attending clinical faculty (staff) physicians.
POLYSACCHARIDE IRON COMPLEX Capsule: 150 mg elemental iron Polysaccharide iron complex (Niferex[R]-150 - Central) capsules are indicated for the treatment of iron deficiency anemia.
SEVOFLURANE Inhalation: 250 ml bottle Sevoflurane (Ultane[R] - Abbott) is an inhalational anesthetic indicated for the induction of general anesthesia in adult and pediatric patients.
TRAMADOL Tablet: 50 mg Tramadol (Ultram[R] - McNeil) is a centrally acting analgesic indicated for the management of moderate to moderately severe pain. TRAMADOL DOES HAVE THE POTENTIAL TO PRODUCE DRUG DEPENDENCY AND WITHDRAWAL SYMPTOMS; SEIZURES AND ANAPHYLACTOID REACTIONS HAVE ALSO BEEN REPORTED WITH ITS USE. NOTE: Tramadol will only be stocked for outpatient use in the Ambulatory Care Pharmacy; the prescribing of tramadol is restricted to attending clinical (staff) physicians.
ADDITIONAL ACTIONS
CARBAMAZEPINE (TEGRETOL-XR[R]) EXTENDED-RELEASE TABLET 100 ma, 200 ma, 400 mg The extended-release tablets were added to stock; they provide twice daily dosing and more uniform plasma drug levels.
CORTICOTROPIN REPOSITORY (H.P. ACTHAR[R] GEL) 80 UNIT PER ML INJECTION This strength replaces the 40 unit per ml product which is no longer commercially available.
MUPIROCIN 2% NASAL OINTMENT This product (Bactroban[R] Nasal) was added to stock for the eradication of nasal colonization with methicillin-resistant Staphylococcus aureus in patients and health care workers as part of an extensive infection control program.
OCTREOTIDE (SANDOSTATIN[R]) INJECTION The 200 mcg per ml, 5 ml multidose vial and the 1000 mcg per ml, 5 ml multidose vial were added to stock as replacements for the single-use 100 mcg per I ml ampul and the 500 mcg per 1 ml ampul.
DRUGS DELETED FROM STOCK
CORTICOTROPIN (ACTHAR/19 GEL) 40 UNITS PER ML REPOSITORY INJECTION Discontinued by the manufacturer. An 80 unit per ml, 5 ml vial (H.P. Acthar[R] Gel) is available.
OCTREOTIDE INJECTION 100 MCG PER 1 ML AMPUL AND S00 MCG PER 1 ML AMPUL. Replaced with multidose vials.