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`Therapeutic Drug Monitoring:
`June 1996 - Volume 18 - Issue 3 - pp 263 -266
`Article
`
`Once -Daily Aminoglycoside Dosing: Impact on Requests and
`Costs for Therapeutic Drug Monitoring
`Nicolau, David P. "; Wu, Alan H. 6.t; Finocchiaro, Sebastian'; Udeh, Elizabeth`; Chow,
`Moses S. S.'; Quintilianl, Richard§; Nightingale, Charles H.§
`
`Article Outline
`
`fl Author Information
`
`'Division of Infectious Diseases, Departments of `Pharmacy, 'Pathology and Laboratory
`Medicine, and §Office for Research, Hartford Hospital, Hartford, Connecticut, U.S.A.
`
`Received January 19, 1995; accepted October 9, 1995.
`
`Address correspondence and reprint requests to Dr. D. P. Nicolau at Division of Infectious
`Diseases, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, U.S.A.
`
`E Abstract
`
`Summary: Recently, much Interest has focused on the use of once-daily aminoglycosides
`(ODA) In the medical literature. In late 1992, we implemented a hospital -wide ODA
`program for adult patients at our 850 -bed community- teaching hospital. In the first phase of
`implementation, therapeutic drug monitoring (TDM) was accomplished with the use of a
`random serum concentration and a nomogram that had been developed at our institution.
`In the second phase, serum drug concentrations were eliminated on patients with normal
`renal function. The fully implemented program resulted in a 40% decrease in the request
`for gentamlcin and tobramycin serum concentrations as compared with historic ordering
`pattems for conventional aminoglycoside dosing regimens. In addition, the incidence of
`nephrotoxicity was also reduced from 3 to 5% with conventional aminoglycoside dosing, to
`1.2 and 1.3% for phases 1 and 2, respectively. Furthermore, the elimination of TDM
`requests totaling 300 for gentamicin and 50 for tobramycin per month Is expected to result
`in an annual Institutional savings of >$100,000.
`
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`meraPeutic drug monitoring, once-daily aminopivcosäe,O
`
`Aminoglycosides are potent antimicrobials against gram -negative
`bacteria and continue to be widely used in hospitalized patients. The
`conventional method for administering these agents is to give 1.5 to
`2.0 mg/kg of the antibiotic every 8 h with therapeutic drug monitoring
`(TDM) of peak (blood sampled optimally 30 min after the end of the
`intravenous infusion) and trough serum concentrations (blood
`sampled immediately before the next dose). Although nephrotoxicity
`has generally been associated with peak and trough concentrations
`that exceed 12 mg /L and 2.0 mg /L, respectively, contemporary data
`
`EXHIBIT
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`Related Links
`
`Articles in PubMed by David P. Nlcolau
`Articles In Google Scholar by David P. Nicolau
`Other arboles in this Journal by David P.
`
`Fresenius Kabi, Exhibit 1030
`IPR2015-00223
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`

`
`Nicolau
`
`MOST RECENT ACTIVITY
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`R qu st' and Costs r Thentapettntut "..
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`Once-Daily Amtno3 ycu dc Dosing: impact
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`Positive impact of a therapeutic drug -
`monitoring program on total aminoglycoside
`dose and cost of hospitalization.
`
`Clinical Predictors of Subtherapeutic
`Aminoglycoside Levels in Trauma Palien
`Undergoing Once -Daily Dosing
`
`Impact of clinical decision support guidelines
`on therapeutic drug monitoring of gentamicin
`in newborns.
`
`Pitfalls in TDM of antibiotic drugs: analytical
`and modelling issues.
`
`suggest that these previously accepted concepts of aminoglycoside
`toxicity are incorrect (1 -4). Recently reports have shown that
`maximum bactericidal activity is best achieved when aminoglycoside
`concentrations reach- 10-fold concentrations of the minimum inhibitory
`concentrations (MICs) (2). This incorporation of once -daily
`aminogtycoside (ODA) dosing strategies into clinical practice is an
`attempt to maximize the bactericidal activity and minimize the
`toxicìties associated with this class of antimicrobials. At present, data
`from clinical trials using this dosing approach suggest equal efficacy
`and a reduction in nephrotoxicity with ODA protocols (2).
`
`In October of 1992, we implemented the use of a hospital -wide ODA
`program in our 850 -bed community- teaching hospital (5,2) Adult
`patients prescribed aminoglycosides after that time were
`automatically converted to our ODA program, which uses a fixed 7
`mg /kg intravenous dose of gentamicin or tobramycin administered
`over a 60 -min period at intervals of a24 h in patients with creatinine
`clearances >60 mL /min. Using this regimen, a peak concentration of
`20 mg /L is expected. Although the resultant concentration is above
`the conventional toxic value for gentamicin and tobramycin peaks,
`the use of ODA produces trough concentrations that reach D mg /L,
`thereby limiting drug accumulation and the potential for
`nephrotoxicity (3,4). Patients with further reductions in renal function
`receive the same doses at increased intervals [every 36 h for
`clearances of 40 -6D mL /min, and every 48 h for clearances of 20 -40
`m(lmin (5,e)).
`This program also eliminated the need for conventional
`aminoglycoside TDM using the peak- and -trough methodology.
`Patients receiving our ODA program have TDM assessments using a
`random serum concentration obtained between 6 to 14 h after the
`start of the infusion from the initial aminoglycoside dose. However,
`beginning in April 1994, the TDM monitoring protocol for patients
`receiving the ODA program was modified to eliminate the initial
`random serum concentration in patients with normal renal function. In
`this report, we compare the impact of an ODA program with that of
`conventional dosing regimens on the requests for and costs
`associated with aminoglycoside TDM.
`
`aack Lo Tun I Artide Outline
`
`MATERIALS AND METHODS
`
`We retrospectively compared the request for TDM over three
`different periods before and after implementation of the once -daily
`administration program. The baseline data (pre -ODA) was collected
`over a three -month period in 1991. Data obtained from this period
`represent the request for serum aminoglycoside concentrations with
`the use of conventional aminoglycoside dosing regimens derived by
`the clinical pharmacists.
`
`In the first phase of the ODA program, data collection began =6
`months after the initiation of the program. All adult patients except
`those with ascites, total body surface area bum >20 %, pregnancy,
`enterococcat endocarditis, or end -stage renal disease {including
`dialysis) were considered eligible to receive ODA. All patients initiated
`on ODA had a random serum concentration obtained after the first or
`second dose. Aminoglycoside concentrations were assessed on our
`nomogram (Fig. 1), and the patient's dosing interval was modified as
`suggested. Once a patient was stabilized on a regimen, therapeutic
`monitoring was ordered at weekly intervals using the same random
`concentration methodology (5'6) After 500 patients received ODA,
`an evaluation of the dosing intervals revealed that 74% of the
`population was dosed every 24 h, 17% every 36 h, 7% every 48 h,
`and 2% >48 h ts7, in addition, the median length of therapy with the
`ODA regimen was 3 days. An evaluation of the nephrotoxicity in this
`patient population revealed a 1.2% incidence, as compared with our
`historic rate of 5% in patients receiving conventional aminoglycoside
`regimens for a similar duration of therapy.
`
`During the second phase, TDM was eliminated on many of the
`patients enrolled in the program. This modification in ODA {phase 2)
`was based on the low incidence of toxicity with the program, the
`presentation of nephrotoxicity at a median of 8 days (i.e., the
`increase in serum creatinine), the short duration of therapy in the
`majority of patients, and the fact that most patients receiving ODA
`
`Fig
`Innttamt Toots
`
`
`
`

`
`have good renal function (e.g., every-24 -h dosing interval). Criteria
`were developed and approved by the Hartford Hospital Therapeutics
`Committee to withhold the random concentration in patients: (a)
`receiving 24 -h dosing regimens, (b) without concurrently
`administered nephrotoxic agents (e.g., amphoterìcìn, cyclosporine,
`vancomycin), (c) without exposure to contrast media, (d) not
`quadriplegic or amputee, (e) not in the intensive care unit, and (f)
`>60 years old. Although the initial random serum concentration is
`withheld in eligible patients, monitoring of the serum creatinine
`continued to occur every 2 to 3 days. For patients who continued on
`the ODA regimen for z5 days, a random concentration was obtained
`on the 5th day and weekly, thereafter.
`
`Requests for aminoglycoside serum concentrations of gentamicin and
`tobramycin were averaged over the months of April, May, and June
`in all three study periods of 1991, 1993, and 1994, Because the
`hospital's census was variable over the three study periods, all
`results were normalized to a daily patient census of 600. Serum
`concentrations were classified as either peak, trough, or random,
`Mean (standard deviation, SD) values for each classification were
`computed. All aminoglycoside assays were performed using
`fluorescence polarization immunoassay (TD /FLx, Abbott Laboratories,
`Abbott Park, IL, U.S.A), Creatinine clearances were estimated from
`serum creatinine concentrations using the Cockcroft -Gault relation
`(7). Serum creatinine concentrations were measured on an
`Ektachem 700 chemistry analyzer (Rochester, NY, U.S.A.). The rate
`of nephrotoxicity was evaluated over an 8 -month period (April to
`November, 1994) during phase 2 and compared with the nephrotoxic
`rate for the pre -ODA dosing period and phase 1 of ODA.
`Nephrotoxicity was defined as a 0.5 mg /dL increase in baseline
`serum creatinine concentrations (a).
`
`Buck to Top I erode Outüne
`
`RESULTS
`
`Figure 2 illustrates the request for TDM of gentamicin during the
`three phases of the study, demonstrating an overall reduction of 40%
`( =300 TDM requests /month), A similar pattern was observed for
`tobramycin, resulting in a reduction of 50 TDM requests /month.
`During the use of conventional pre -ODA aminoglycoside regimens,
`equal numbers of requests for peak and trough concentrations were
`observed, reflecting the standard therapeutic monitoring practice in
`place at that time. Mean (SD) peak and trough concentrations during
`this phase were 4.9 (1.5) and 1,5 (1.2) mg /L for gentamicin and 5.6
`(5.2) and 1.7 (1.3) mg /L for tobramycin. During phase 1 of ODA,
`many requests for peaks and troughs were replaced by those for
`random samples. The remaining requests for peaks and troughs
`were from patients excluded from the ODA program (e.g., pediatric
`patients). Mean concentration values were similar to those obtained
`during the pre -ODA period. During both periods, the aminoglycoside
`peaks appeared to be at the low end of the therapeutic range,
`whereas the trough concentrations appeared to be at the high end of
`the acceptable values. Mean (SD) random blood concentrations were
`3..7 (4.7) and 4.1 (5.3) mg /L for gentamicin and tobramycin. Average
`serum concentrations for peak, trough, and random samples
`obtained during the phase 2 study period were similar to those
`obtained during the previous two periods.
`
`A total of 602 subjects was enrolled in phase 2 of the ODA program,
`During this period, eight (1.3 %) patients experienced an increase in
`serum creatinine that exceeded our previously described threshold of
`a 0,5 mg /dL above the preaminoglycoside baseline value. However,
`because this criterion does not differentiate between the likelihood of
`aminoglycoside- induced toxicity and the associated increase in
`serum creatinine but rather is based on a deviation from the baseline
`value during aminoglycoside therapy, it indicates that the reported
`incidence also accounts for other mechanisms of renal injury fsl. On
`the discontinuation of the ODA regimen, the serum creatinine
`declined to values observed before the initiation of therapy in all
`patients. This rate is not statistically different from the 1.2% rate
`observed for the ODA program with therapeutic monitoring {phase 1)
`and is substantially better than the historic rate of 5% for the pre -
`ODA period.
`
`Fig. 2
`Image Took
`
`
`
`

`
`Back to Top I Article Outline
`
`Reductions in the need far TDM of amínoglycosides will become
`increasingly important for clinical laboratories as reimbursement
`practices change from a fee -for- service basis to capitation and
`managed care. in the former environment, hospital laboratories were
`encouraged to perform more tests on hospitalized patients so as to
`maximize charges and revenues and reduce unit costs. As a result,
`most laboratories experienced unprecedented growth during the past
`20 years, and requests for TDM have kept pace with this growth. In
`addition to improvements in the automation of analytic methods. the
`implementation of pharmacokinetic services and the need to monitor
`blood concentrations of new drugs also contributed to higher testing
`volumes (9). In the evolving environment of managed care, a
`maximum capitated per diem is given to all insured participants of
`the program. As expenses beyond the per diem will be absorbed by
`the care provider, laboratories are now encouraged to perform fewer
`tests. Reducing the use of TDM assays will be difficult in fight of two
`decades of unprecedented growth. Implementation of ODA protocols
`may be one method for reducing expenses associated with
`aminoglycosìde monitoring without increasing the rate of toxicity,
`Implementation of this methodology also results in a reduction of the
`costs associated with the preparation and administration of these
`antimicrobials. Since the onset of the program, we conservatively
`estimate that ODA saved ei$40,000 in drugs, supplies, and labor for
`the 2,200 patients enrolled in the program. In addition, the reduction
`of TOM requests for the aminoglycoside (gentamicin, 300 per month;
`tobramycin, 50 per month) will result in additional institutional savings
`of >$100,000 {using an estimate of $25.00 /reportable test for
`reagents, equipment, labor, and overhead) for a tertiary-care hospital
`with a 600 -bed occupancy. Our previous study documented the
`safety and apparent effectiveness of the ODA approach (5). This
`study now demonstrates the substantial cost saving related to the
`reduction of required serum aminoglycoside concentrations with our
`ODA dosing method,
`
`sock to Top ; Arcuce 4a:I4,e
`
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`Therapeutic Drug Monitoring
`Clinical Relevance of Therapeutic Drug Monitoring of Digoxin and Gentamicin
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`
`Back to Tor Artvi"
`
`Keywords:
`
`Therapeutic drug monitoring; Once -daily aminoglycoside; Cost effectiveness; Nephrotoxicity; Managed
`care
`
`© Lippincott -Raven Publishers
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