Embed Size (px)
Citation preview
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Sept. 1979, p. 353-3610066-4804/79/09-0353/09$02.00/0
Vol. 16, No. 3
Correlation of Aminoglycoside Dosages with SerumConcentrations During Therapy of Serious Gram-Negative
Bacillary DiseaseMICHAEL T. REYMANN,* JAMES A. BRADAC, C. GLENN COBBS, AND WILLIAM E. DISMUKES
Division of Infectious Diseases, Department ofMedicine, University ofAlabama Medical Center,Birmingham, Alabama 35294
Received for publication 23 February 1979
We prospectively evaluated serum aminoglycoside (AMG) concentrations in120 patients who received gentamicin or tobramycin for serious gram-negativebacillary disease. AMG serum concentrations were assayed by microbiologicaland radioimmunoassay techniques. Correlation between the two assay methodswas good. When AMG doses were based on total body weight, there was nosignificant correlation between AMG dosage administered and serum concentra-tions in patients with either normal or abnormal renal function. The use of idealbody weight for calculation ofAMG dosage improved this correlation significantlyexcept in hemodialysis patients. AMG-induced nephrotoxicity occurred in 13patients. No significant association was noted between the occurrence of toxicityand the specific AMG given or with other commonly recognized risk factors.Among study groups, peak AMG serum concentrations failed to exceed theminimal inhibitory concentration of the infecting organism in 17 to 33% of thecases. Serum inhibitory levels of '1:8 were not associated with improved survival.There was no significant difference in mortality between the gentamicin- andtobramycin-treated groups. We advise base-line serum AMG levels in seriously illpatients with gram-negative bacillary disease and additional bacteriological stud-ies in selected situations.
A major factor limiting the use of aminogly-coside (AMG) antibiotics is their narrow thera-peutic-toxic ratio, particularly as it relates to theoccurrence of nephro- and ototoxicity. A numberof studies have suggested a relationship betweentoxicity and elevated AMG serum concentra-tions (9, 10, 12, 14, 20). In addition, attemptshave been made to correlate "therapeutic" AMGserum concentrations with clinical efficacy (16,24). However, many commonly used AMG dos-age schedules do not give predictable AMG se-rum concentrations. Moreover, there is no gen-eral consensus on the optimal dosage in milli-grams per kilogram per day and the most precisemethod for adjustment of dosage interval basedon the variation in the renal function of a pa-tient. Serum creatinine, measured creatinineclearance, "calculated" creatinine clearance, andcomputer-assisted techniques have been utilizedin the development of formulas and/or nomo-grams for dosage regimens which vary either (i)the dosage interval (variable frequency regimen)or (ii) the dose which is given at the standardinterval of every 8 h (variable dosage regimen).We performed a prospective clinical study to
evaluate two commonly used AMGs, gentamicin
and tobramycin, in patients with serious gram-negative bacillary disease. Our objectives were:(i) to assess the relationship between AMG dos-age and achieved serum concentrations with sev-eral currently used dosage regimens in patientswith normal and impaired renal function, (ii) tocompare serum concentrations obtained withthe minimal inhibitory concentration (MIC) ofantibiotic against the infecting organism, and(iii) to determine the effect of carefully con-trolled serum concentrations on efficacy and tox-icity.
(These results were presented in part at the10th International Congress of Chemotherapy,Zurich, Switzerland, 18-24 September 1977.)
MATERIALS AND METHODSClinical material. A total of 120 patients were
enrolled in the study; these patients were hospitalizedat the University of Alabama Medical Center betweenSeptember 1976 and July 1977. Requirements for ad-mission to the study were: (i) age of >16 years and (ii)documented or suspected gram-negative bacillary dis-ease (i.e., bacteremia, peritonitis, pneumonia, menin-gitis, or soft tissue infection) for which an AMG ap-peared appropriate for initial therapy. Of the 120patients 104 (87%) were treated with at least one other
353
Dow
nloa
ded
from
http
s://j
ourn
als.
asm
.org
/jour
nal/a
ac o
n 17
Feb
ruar
y 20
22 b
y 17
5.11
4.73
.100
.
ANTIMICROB. AGENTS CHEMOTHER.
antibiotic in addition to the AMG during the period oftreatment. No patients with urinary tract infectionalone were studied.
Patients were identified for study by two methods:(i) daily surveillance of all positive blood and cerebro-spinal fluid cultures in the clinical laboratories and (ii)daily review of pharmacy records of patients begun on
AMGs during each preceding 24-h period. Patientsreceiving an AMG for <24 h were placed into thestudy group appropriate for their renal function (seebelow). The remaining patients (i.e., those not previ-ously begun on AMG treatment) were assigned by pairrandomization to gentamicin or tobramycin within theappropriate study group based on renal function. In-formed consent was obtained in each instance.
Patients were grouped according to pretreatmentrenal function; a normal serum creatinine was definedas c1.3 mg/100 ml. Equal numbers of patients withineach group received gentamicin and tobramycin. Thepatient groups and AMG dosage regimens are given inTable 1.
All dosages of AMG were based on total bodyweight. AMG dosage in group IA was determined bythe attending physician (within the range noted inTable 1), and dosage alterations in this group were
made solely for peak levels of >10 fg/ml. These 30patients are considered a control group in our dataanalysis. In all other groups, we determined AMGdosage, and doses were changed in an attempt to (i)maintain peak concentrations in the therapeutic rangeof 4 to 10 itg/ml, (ii) optimize peak levels with respectto the MIC of the infecting pathogen and the inhibi-tory capacity of the serum of the patient when thesedata were readily available, and (iii) maintain troughconcentrations of <2.0 ,tg/ml.Serum aminoglycoside concentration deter-
minations. Peak and trough serum gentamicin or
tobramycin levels were obtained for each patient. Peaklevels were obtained 15 min after an intravenous in-fusion or 1 h after an intramuscular injection. Troughlevels were obtained 1 h before the next dose ofAMG.The number of levels determined for each patient
was based on the duration of AMG therapy. Levelswere obtained during the first study day and subse-quently every 2 to 3 days while the patient remainedon AMG therapy. Each serum specimen was assayedby two methods: (i) a microbiological assay utilizingthe agar well diffusion technique and Bacillusglobigiias the test organism (33), and (ii) a radioimmunoassayusing a commercially marketed assay kit with "I asthe radioactive label (Monitor Science). The microbi-ological assay was performed daily, and the appropri-ate beta-lactamase was added to serum specimensfrom patients receiving concurrent therapy with pen-
icillins or cephalosporins. Sera were run in triplicate,and plates were read after an overnight incubation.The assay value used in data analysis represents themean of the three assay results per specimen. Theradioimmunoassay was performed every 2 to 3 weekson specimens which had been refrigerated at -40°C.Samples were run in duplicate, and a standard curve
was constructed for each group of sera.Bacteriology. Disk susceptibility testing was per-
formed on all isolates by the standardized Kirby-Bauertechnique (4). The MIC and the minimum bactericidalconcentration of the appropriate AMG were deter-mined by the broth dilution technique, using brain-heart infusion broth (32). Sera from specimens con-
taining peak AMG concentrations were used to per-form serum inhibitory and serum bactericidal assaysby a modification of the method of Schlicter, utilizingbrain-heart infusion broth (2), in those patients fromwhom a gram-negative bacillus was isolated. Theseserum assays were performed during the first few daysof treatment and at approximately 4 to 5-day intervalsfor patients who received prolonged AMG therapy.
Monitoring of toxicity. Base-line blood urea ni-trogen, creatinine, and urinalysis were obtained for all
patients before the initiation of antibiotic therapy.During the treatment period, these tests were repeatedevery 2 to 3 days. These values were used in theadjustment of dosage intervals in patients with abnor-mal renal function. Nephrotoxicity was defined as an
increase in serum creatinine of -0.5 mg/100 ml over
the pretreatment value during or immediately afterAMG therapy. Nephrotoxicity was judged to be AMGinduced if there was no other clinically evident cause,
such as significant hypotension, septic shock, hepato-renal syndrome, etc. Nephrotoxicity risk factors as-sessed for each patient included the following: (i) peakserum concentrations of >10 pg/ml, (ii) trough serum
concentrations of >2 ytg/ml, (iii) volume depletiondetermined either by clinical parameters (i.e., gastroin-testinal bleeding, excessive diuresis, etc.) or by mea-
surement of cardiovascular pressure or pulmonary ar-
tery pressures, (iv) concurrent therapy with cephalo-sporins or furosemide, (v) prior AMG therapy of >3days, and (vi) underlying renal disease with pretreat-ment serum creatinine of >1.3 mg/100 ml.
Ototoxicity was monitored clinically by inquiringabout symptoms of auditory or vestibular dysfunction.Whenever feasible, base-line and posttreatment audi-ometry were performed. However, because of logisticalproblems and the critical nature of the illnesses ofmany patients, pre- and posttreatment audiogramswere obtained on only 12 patients. Therefore, we haveexcluded an assessment of ototoxicity from the discus-sion which follows.
TABLE 1. Patient groups and dosagesGroup No. of patients Renal function Aminoglycoside doseaIA 30 Creatinine c 1.3 mg/100 mg 1.0-1.5 mg/kg q8hIB 30 Creatinine < 1.3 mg/100 mg 1.5 mg/kg q8hIIA 20 Creatinine > 1.3 mg/100 mg 1.5 mg/kg q(lOxCr)IIB 20 Creatinine > 1.3 mg/100 mg 0.75 mg/kg 1(5xCr)III 20 Hemodialysis 1.0 mg/kg after dialysis
a q8h, Every 8 h; q(lOxCr), 10 times the serum creatinine; q(5xCr), 5 times the serum creatinine.
354 REYMANN ET AL.
Dow
nloa
ded
from
http
s://j
ourn
als.
asm
.org
/jour
nal/a
ac o
n 17
Feb
ruar
y 20
22 b
y 17
5.11
4.73
.100
.
VOL. 16, 1979
Comparisons of assay values in groupIIB, and III was by a standard one-wavariance. Individual comparisons betweeby Duncan's new multiple-range testresponses for each patient were calculajected to analysis. Comparisons betwAMGs were carried out by using Studentt test. Associations between assay metho4by calculating correlation coefficients. Astween factors represented in two-waytables were tested by calculating chi-sqiAll computations were performed by ustical analysis system (1).
RESULTS
Comparison of assay methodillustrates the relationship betweerobtained for peak AMG serum levelassay methods employed, bioassay a
munoassay. Each point on the grapthe mean peak gentamicin or tobricentration for one patient. Correlatthe two methods was good (r = 0comparison of trough concentrationassay methods showed a very good(r = 0.885).Relationship of dosage to sen
tration. A mean of 4.0 peak ancAMG levels was obtained for all stiIn evaluating the relationship of ASachieved serum concentrations ndifference was noted between thetained for gentamicin and those (
tobramycin. For this reason, no dmade with regard to the specific Aistered in the figures and discussior
Figure 2 shows the relationship b(dosage and achieved peak serum coin groups IA, IB, IIA, IIB, and III
16
14
RIA 12
(mcg/ml) 10
8
6
4
2
-0 2 4 6 8 10
BIOASSAY (Mcgm%)
FIG. 1. Comparison of microbioadioimmunoassay (RIA) methods for Alcentration determinations. Each pointmean peak gentamicin or tobramycinfor one patient. mcg, Microgram.
AMG DOSAGES AND SERUM LEVELS 355
is IA, IB, IIA, on the graphs represents the mean peak concen-iy analysis of tration for a single patient. In no group is theren means were a significant positive correlation between dosage(29). Average of antibiotic and serum level (P values rangeeanhde stub- from 0.172 to 0.811). From groups IA and IB, we
's two-sample evaluated 54 patients who had at least one set of,Is were tested consecutive trough and peak serum levels whichssociations be- allowed the determination of an absolute in-contingency crease in AMG serum concentration (i.e., a peak
aare statistics. minus trough difference). Comparing AMG dos-;ing the statis- age (in milligrams per kilogram) with the peak
minus trough difference, an improved correla-tion was found; for group IA r = 0.44 and forgroup IB r = 0.46.
Is. Figure 1 Because of recent data regarding the distri-a the values bution characteristics of the AMGs and theLs by the two study of antibiotic dosage based on ideal bodyand radioim- weight (15), we retrospectively analyzed the ef-h represents fect of this var$able in the 34 patients fromamycin con- groups IA and IB whose heights were available.,ion between (All lean body weights utilized in our retrospec-1.770). A like tive analysis were derived from actuarial tablesLs by the two for average body weight based upon age, sex,i correlation and height.) Figure 3 illustrates the relationship
between AMG dose in milligrams per kilogramam concen- of ideal body weight and achieved peak serum1 3.6 trough concentration in patients with normal renaludy patients. function (groups IA and IB). When analyzed inAG dosage to this fashion, there is an improvement in theo significant correlation of these two variables (r = 0.625, Presults ob- = 0.0001) as compared with that found in this
obtained for group of 34 patients when actual body weightlistinction is was used for the calculation of AMG dosage (rkMG admin- = 0.42, P = 0.015). In contrast, when a similara below. analysis was made of the 16 hemodialysis pa-etween AMG tients from group III for whom an ideal bodytncentrations weight was available, no improvement was notedEach point (r = 0.05, P = 0.84) when compared with results
obtained when actual body weight was used tocalculate AMG dosage (r = 0.147, P = 0.535).Bacteriology. A gram-negative bacillus was
identified as the responsible pathogen in 96 of*= 770 the 120 study patients. During the period ofP= 0001 study participation, each patient from whom a
pathogen was isolated received an AMG towhich his or her organism was susceptible. MICsand minimum bactericidal concentrations weredetermined for one of these isolates. These val-ues were used to evaluate the adequacy ofachieved serum concentrations. Table 2 com-pares the AMG dosage (in milligrams per kilo-gram) with the ratio of peak serum concentra-
12 14 16 tion to the MIC of AMG for the infecting orga-nism; 17 to 33% of serum concentrations in thethree dosage ranges did not exceed the MIC of
MG serum con- the infecting organism. The cumulative percent-represents the age of peak levels which were more than fourconcentration times the MIC was 72 to 77%. When this method
of evaluation was used, there was no significant
* 0
Dow
nloa
ded
from
http
s://j
ourn
als.
asm
.org
/jour
nal/a
ac o
n 17
Feb
ruar
y 20
22 b
y 17
5.11
4.73
.100
.
356 REYMANN ET AL.
GROUP I A
16
Is
14DOSE
(mg/kg)1 3
1 2
1.0
0.9
ANTIMICROB. AGENTS CHEMOTHER.
GROUP I A
i.7fr z.086pa .652
1.6
DOSE(m i/.5)
1.4
D 2 4 6 8 10SERUM AMINOGLYCOSIDE LEVEL (h%II%)
GROUP I
12
rz 318pz 172
S
. 0 * *
* 0
2 3 4 5 6 7 8 9SERUM AmINOGLYCOSIDE LEVEL (mc%,a)
GROUP I 8
r -.045p8.811
4 6 8 10SERUM AMINOGLYCOSIDE LEVEL (fCm%)
GROUP m
1.9Fr= -.I50p= .527
1.8 F
1.7DOSE
("V/kg)1.6
1.5
1.4
12
0 g
0 0
0 2 3 4 5 6SERUM AMWOGLYCOSIDE LEVEL ("'%)
r' -.147p. .535
* 00 %
0 0
2 4 6 8 10 12 14
SERUM AMINOGLYCOSIDE LEVEL (flC%,g)
FIG. 2. Relationship between dosage and serum AMG concentration in the five study groups. Eachpoint represents the mean peak AMG concentration for one patient. mcg, Microgram.
improvement in the "adequacy" of peak serumconcentrations as the dosage of AMG was in-creased. A comparison ofgroup IA and the otherstudy groups revealed no significant difference(P > 0.40) with regard to peak concentration-MIC ratio achieved at any given dosage.Nephrotoxicity. We performed an analysis
of nephrotoxicity by using the criteria enumer-
ated above. The 20 hemodialysis patients (groupIII) were excluded from this analysis. The over-
all incidence of nephrotoxicity occurring duringAMG therapy was 34% (34 of 100). Table 3defines the frequency with which identifiednephrotoxicity risk factors occurred in both the66 patients without evidence of renal impair-ment and the 34 patients who met our criteria
2.4 [
. 0
00 * 0* 0 0a0 * 0 0* *0* 0 0
2.2
2.0DOSE
(Mg)1).81.6
1.4
2.0
1.8DOSE(mg4g)
1.6
7
1.4 F
1.2
00
0 *0 0
9 0 0
0
9 0
0 0
0 0 0 0 00 0
00 0 0
1.3i
.
* 0
:-0
.
Dow
nloa
ded
from
http
s://j
ourn
als.
asm
.org
/jour
nal/a
ac o
n 17
Feb
ruar
y 20
22 b
y 17
5.11
4.73
.100
.
VOL. 16, 1979
for renal toxicity. Volume depletion was foundto be a more frequent characteristic of the ne-phrotoxic patients (P < 0.005). There was nosignificant difference in the two groups withregard to the occurrence of other specified riskfactors (P > 0.10). In addition, there was nosignificant relationship between the specificAMG received and the development of nephro-toxicity (P > 0.20).Of the 34 patients with renal toxicity, 13 were
judged to have nephrotoxicity induced by AMGtherapy. Nephrotoxicity in the remaining 21 pa-tients was judged to be secondary to hypoten-
Al
1.8
DOSE(mC/kg 18W)
4
r 6260 p'000l
* It*-* 0
*
I
.- 0I.,
0 2 4 6 8 10 12
SERUM AMINOGLYCOSIDE LEVEL ("9',mi)FIG. 3. Relationship between AMG dosage based
on ideal body weight (IBW) and serum AMG concen-tration for groups IA and IB. Each point representsthe mean peak AMG concentration for one patient.mcg, Microgram.
TABLE 2. Comparison of dosage administered withratio ofpeak serum concentration to MIC
% of patients with a ratio of peak serum con-
Dose (mg/kg) centration to MIC of:cl >1-4 >4-8 >8
1.0 17 60 13 101.1-1.5 27 46 17 10>1.5 33 39 14 14
AMG DOSAGES AND SERUM LEVELS 357
sion, volume depletion, sepsis, or underlyingrenal disease. With the exception of the morefrequent occurrence of underlying renal diseasein those patients with renal toxicity judged to beunrelated to AMG (P < 0.05), no significantdifference in risk factors was found for the twogroups of patients with nephrotoxicity shown inTable 3 (P > 0.10). Of the 13 patients withAMG-induced renal damage, 8 had received gen-tamicin and 5 had received tobramycin. Thus, inthese two groups with nephrotoxicity, there wasno significant relationship between the specificAMG received and development of toxicity (P> 0.20).Trough serum concentrations of gentamicin
and tobramycin were examined to determinetheir relationship to the occurrence of nephro-toxicity. Trough levels of >2.0 jig/ml were justas common in patients not demonstrating evi-dence of nephrotoxicity as in those who diddevelop renal impairment. In the patients with-out evidence of nephrotoxicity, 18 of 66 (27%)had at least one trough level of >2.0 ,ug/ml, andamong the 34 patients with nephrotoxicity dueto all causes, trough levels of >2.0 ,ug/ml oc-
curred in 14 of 34 or 41% (P> 0.10). In addition,elevated trough levels occurred with equal fre-quency in patients judged to have AMG-inducednephrotoxicity (6 of 13 patients) and those withnephropathy due to other causes (8 of 12).
In group UB patients who received their AMGby a schedule which has characteristics of bothvariable dosage regimens and variable frequencyregimens, there was a higher frequency oftroughlevels of >2.0 ,ug/ml (21 versus 10 to 15% forother groups; P > 0.10). However, the incidenceof nephrotoxicity was not significantly greater inthis study group.
Nephrotoxicity occurred in 7 of 30 (23%) groupIA patients compared with 6 of 70 (8.6%) pa-tients in the other study groups (P < 0.10).Assessment of risk factors revealed only a sig-nificantly higher incidence (P < 0.05) of prior
TABLE 3. Frequency of occurrence of risk factors associated with nephrotoxicityNo. with elevated AMG No. taking concurrent
levels No. with vol- drugs No. with No. with un-Patient group Not.ofpa- ume deple- prior AMG derlying renal
tients Peak of >10 Trough of >2 tion Furosemide Cephalo- therapy disease~Ag/ml fig/mlaprn
No nephrotox- 66 5 (8)a 18 (27) 4 (6)b 17 (26) 38 (58) 3 (4) 17 (26)icity
NephrotoxicityAMG induced 13 2 (15) 6 (46) 5 (38) 4 (30) 10 (77) 2 (15) 1 (8)COther causes 21 1 (5) 8 (38) 5 (24) 10 (48) 15 (71) 1 (5) 9 (43)c
Total 34 3 (9) 14 (41) 10 (29)b 14 (41) 25 (74) 3 (9) 10 (29)a Numbers in parentheses are percentages.b P < 0.005.C P < 0.05.
1 6
2
Dow
nloa
ded
from
http
s://j
ourn
als.
asm
.org
/jour
nal/a
ac o
n 17
Feb
ruar
y 20
22 b
y 17
5.11
4.73
.100
.
358 REYMANN ET AL.
AMG therapy in the group IA patients.Mortality. The overall mortality of patients
in all groups was 37% (44 of 120 patients) (Table4). Patients were recorded as deaths in thisanalysis if they died during or shortly after thecourse of antibiotic therapy, regardless of causeof death. Mortality was 32% (19 of 60) in genta-micin-treated patients and 42% (26 of 60) intobramycin-treated patients. This difference wasnot significant (P > 0.20). By using the McCabesystem for classifying patients into rapidly fatal,ultimately fatal, and nonfatal groups on the basisof underlying disease (22), there was no signifi-cant difference (P > 0.20) in the distribution ofour study patients with regard to the specificAMG administered.The overall mortality in group IA was 20% (6
to 30 patients) compared with 42% (38 of 90) inthe other study groups (P < 0.05). However,within each McCabe category (rapidly fatal, ul-timately fatal, and nonfatal) group IA mortalitydid not differ significantly from the other studypatients. Evaluation revealed a skewed distri-bution of group LA patients into the nonfatalMcCabe group (P < 0.10).
Evaluation of the 93 patients for whom serumbacteriostatic activity data were available re-vealed a mortality of 32% (16 of 50 patients)among those with a serum inhibitory level of<1:8 and a mortality of 37% (16 of 43) amongthose with an inhibitory level of :1:8 (P > 0.50).When these patients were analyzed with regardto the severity of underlying disease accordingto the McCabe system, there was no significantdifference between the group with inhibitorylevels of <1:8 and the group with inhibitorylevels of:-1:8.
DISCUSSIONWe found good correlation between the serum
concentration values obtained by the two assaymethods employed (i.e., -microbiological assayand radioimmunoassay). Comparative studies ofmicrobiological assay and radioimmunoassaymethods by other investigators have also shownno significant differences in the results obtained(30). It is within the capability of most hospitalclinical laboratories to utilize one ofthe availableAMG assay techniques.
TABLE 4. Mortality duringAMG therapyNo. of deaths/total no.
Agent Ultimnately fa-Rapidly fatal tal Nonfatal
Gentamicin 10/15 (67)a 8/30 (27) 1/15 (7)Tobramycin 16/19 (84) 8/27 (30) 1/14 (7)
a Numbers in parentheses are percentages.
ANTIMICROB. AGENTS CHEMOTHER.
The pharmacokinetics of gentamicin and to-bramycin are almost identical (21, 25). For thisreason, we chose to make no distinction betweenthe two antibiotics in our discussion of variousdosage regimens.In a group of patients with variable degrees of
renal dysfunction, Cutler et al. (8) determinedthat the gentamicin half-life was equal to ap-proximately three to four times the serum cre-atinine in hours. McHenry et al. (23) found thesame relationship between half-life and serumcreatinine in their overall patient group; how-ever, they noted that estimated and measuredhalf-lives varied by 20 to 60% in 5 of their 29patients. Because of a concern about prolongedsubtherapeutic serum concentrations, Chan etal. (7) compared AMG elimination to creatinineclearance and constructed a nomogram for usein a variable dosage regimen. It was found thatpatients with creatinine clearance of >70 ml/min demonstrated normal elimination of genta-micin. In patients with creatinine clearance <70ml/min, it was possible to calculate maintenancedoses to be given every 8 h in order to achievemore therapeutic serum concentrations.As an alternative to the use ofurine collections
in the calculation of creatinine clearance, Siers-back-Nielsen et al. have provided a nomogramwhich incorporates the patient's age, serum cre-atinine, and weight in order to determine creat-inine clearance (28). Similarly, Jelliffe has de-vised a formula for estimating creatinine clear-ance (17).There is a question, however, about the ade-
quacy of any of these methods in terms of broadapplicability to patients who are receivingAMGs. Sawchuk et al. (26) found a significantpatient-to-patient variability in gentamicin half-life even with normal renal function. They noteda marginal correlation between serum creatinineand half-life (r = 0.50) and only a slightly im-proved relationship between gentamicin clear-ance and creatinine clearance (r = 0.69). Thepredictability of serum concentrations was im-proved by the direct calculation of half-life andthe volume of distribution for each patient. Suchan approach, however, is unlikely to find wideuse among clinicians since logistically difficultdeterminations are necessary in each patient.The unpredictability of AMG concentrationsand half-lives has also been emphasized by otherinvestigators (3, 18).Our results substantiate the premise that se-
rum AMG concentrations are unpredictable inthe population at large regardless of the renalfunction of a patient. A wide range of peak AMGlevels was seen in the group as a whole whenidentical doses (in milligrams per kilogram) wereadministered to individual patients within the
Dow
nloa
ded
from
http
s://j
ourn
als.
asm
.org
/jour
nal/a
ac o
n 17
Feb
ruar
y 20
22 b
y 17
5.11
4.73
.100
.
AMG DOSAGES AND SERUM LEVELS 359
group. Although we found an improved correla-tion when we compared AMG dosage to peakminus trough differences in 54 patients fromgroups IA and IB, analysis of our data by thismethod still fails to show a level of correlationacceptable for optimal clinical results. In addi-tion, our use of higher (1.5 to 2.0 mg/kg) loadingor maintenance doses could not be relied on theassure therapeutic levels. Zaske et al. have re-cently emphasized this same point in a study of14 burn patients receiving AMGs (34). However,Echeverria et al. (11) did note that individualpatients tended to have predictable peak con-centrations with repeated doses, once a dose-response base line had been established by mon-itoring serum levels.
Hull and Sarubbi have reported their experi-ence with a computer-assisted program of AMGdosage by utilizing creatinine clearance and idealbody weight rather than total body weight forcalculation of both dosage and dosage interval(15). These investigators found an excellent cor-relation between predicted and measured gen-tamicin serum levels (r = 0.87). A nomogram forcalculation of dosage was developed and, whenit was used in 16 study patients, no significantdifference was found between measured and pre-dicted serum levels.In the analysis of our data, we found a signifi-
cant improvement in the correlation betweendose of AMG per kilogram of ideal body weightand serum concentration in patients with normalrenal function. This approach seems theoreti-cally sound based on the observed pharmacoki-netics and volume of distribution of gentamicinand tobramycin. The explanation for why theuse of ideal body weight in our hemodialysispatients failed to improve the correlation be-tween dosage and serum level is unclear, but thisfailure suggests that even this method has limi-tations.
Nephrotoxicity has been recognized as a majorfactor in the limitation of AMG usage. Theincidence of this occurrence with gentamicin hasbeen variably reported as being from 9 to 50%(9, 14, 20) and is dependent, in part, upon themethodology and criteria for nephrotoxicityused in each study. For the most part, the azo-temia associated withAMG therapy is reversibleupon discontinuation of the antibiotic. Histolog-ical examination reveals primarily proximal tu-bular necrosis, manifested clinically by risingblood urea nitrogen and creatinine and de-creased ability to concentrate urine (5, 13). Riskfactors for development of nephrotoxicity arenot fully agreed upon. Among those previouslyreported are preexisting renal disease, elevatedAMG serum levels, concomitant use of othernephrotoxic agents, dehydration, advanced pa-
tient age, and prior courses of AMGs (6, 20).Among our 34 nephrotoxic patients, volume de-pletion was significantly more common. How-ever, no identifiable risk factor was found todistinguish the patients with AMG-related tox-icity from those with toxicity related to anothercause.Dahlgren et al. noted in a clinical study of 86
patients that trough serum gentamicin levels of>2 ,ug/ml were associated with a higher risk ofnephrotoxicity (9). Goodman et al. also reporteda significant correlation between trough serumconcentrations of >4 ug/ml and the develop-ment or progression of renal insufficiency (14).In our patient groups, 10 to 21% of all troughlevels exceeded 2 lg/ml. Although there was atrend toward more frequent elevation of troughconcentrations in group IIB patients, who re-ceived doses every half interval, this was notsignificant (P > 0.10). No significant differencein the occurrence of trough levels of >2 ug/mlwas found when the 66 patients without altera-tions of renal function were compared with the34 patients who developed nephrotoxicity duringAMG therapy (P > 0.10). Evaluation of these 34patients who developed nephrotoxicity showedthat elevated trough levels occurred with equalfrequency in patients judged to have AMG-re-lated renal injury (6 of 13 patients) and thosewith nephropathy due to other causes (8 of 21).Although our data do not establish a signifi-
cant difference between gentamicin and tobra-mycin with respect to the risk of nephrotoxicity,several recent studies have shown that tobra-mycin has significantly lower nephrotoxic poten-tial in experimental animals (13, 31). This differ-ence may be partially accounted for by thegreater concentration of gentamicin in the renalcortex (27). Presently, there are no data gatheredin a controlled comparative clinical study tosupport a difference in nephrotoxicity betweengentamicin and tobramycin.The importance of AMG serum determina-
tions, in terms of improving efficacy of therapy,is not well established. In our study patients, 17to 33% of all peak serum concentrations failed toexceed the MIC of the infecting organism. Ourresults are comparable to those of McHenry etal., who found that the MICs of their pathogenswere not exceeded in 22 to 34% of their cases(23). Other investigators have reported that 32to 60% of peak levels are <4 ,tg/ml, a proposedtherapeutic miniimum, after doses of 1.2 to 1.7mg/kg (3, 18).
In our study, achievement of a serum inhibi-tory level of 21:8 did not correlate with im-proved survival. In contrast, Klastersky et al., ina study of patients with gram-negative bacillaryinfections, observed that serum bacteriostatic
VOL. 16, 1979
Dow
nloa
ded
from
http
s://j
ourn
als.
asm
.org
/jour
nal/a
ac o
n 17
Feb
ruar
y 20
22 b
y 17
5.11
4.73
.100
.
ANTIMICROB. AGENTS CHEMOTHER.
activity of l1:8 dilution was associated with a"cure"p rate of greater than 80% (19). Antibioticsynergism may cause discrepancies between theanticipated inhibition of bacteria growth basedon MIC and that observed in a serum inhibitoryassay. Pending additional confirmation of thefindings of Klastersky et al., the assurance thatthe AMG serum concentration is adequateshould also be a concern. An adequate AMGpeak serum concentration can be arbitrarily de-fined as one which is in the generally acceptedtherapeutic range (4 to 10 ,ug/ml) or which in-hibits growth of the pathogenic organism in adilution of 1:8 or greater.Based on the foregoing information, available
from our study and others, we advise the deter-mination ofAMG dosage and dosage interval byusing creatinine clearance in accordance withthe nomogram and tables provided by Hull andSarubbi (15). During AMG therapy of patientswith serious gram-negative bacillary disease, wemeasure peak and trough serum AMG concen-trations early in the course of therapy, to estab-lish the base-line responsiveness of each patient.Additional bacteriological studies, such as MIC,minimum bactericidal concentration, and seruminhibition assays, should also be performed inselected situations (e.g., endocarditis, meningitis,and apparent treatment failures). These, in con-junction with AMG serum concentrations,should help to determine the optimal antibioticdosage regimen.
ACKNOWLEDGMENTSWe are indebted to Dr. Edwin Bradley, Department of
Biostatistics, University of Alabama School of Medicine, forhis statistical asastance. We also thank Deborah Duke, DonnaReagin, Dale Schulz, and Janet Haldeman of the Division ofInfectious Diseases and Ed Collins of the Univeraity HospitalPharmacy for their asistance.
LITERATURE CITED1. Barr, A., J. Goodnight, J. Sall, and J. Helwig. 1976.
A user's guide to SAS 76. Sparks Press, Raleigh, N.C.2. Barry, A. L, and L D. Sabath. 1974. Special tests:
bactericidal activity and activity of antimicrobics incombination, p. 431-435. In E. H. Lennette, E. H.Spaulding, and J. P. Truant (ed.), Manual of clinicalmicrobiology. American Society for Microbiology,Washington, D.C.
3. Barza, M., R. B. Brown, D. Shen, M. Gibaldi, and LWeinstein. 1975. Predictability of blood levels of gen-tamicin in man. J. Infect. Dis. 132:165-174.
4. Bauer, A. W., W. KL M. Kirby, J. C. Sherris, and KLTurck. 1966. Antibiotic susceptibility testing by a stan-dardized single disk method. Am. J. Clin. Pathol. 36:493-496.
5. Bennett, W. M., D. N. Gilbert, D. Houghton, and G.A. Porter. 1977. Gentamicin nephrotozicity-morpho-logic and pharmacologic features. West. J. Med. 126:65-68.
6. Bennett, W. K., M. N. Hartnett, D. Gilbert, D. Hough-ton, and G. A. Porter. 1976. Effect of sodium intakeon gentamicin nephrotoxicity in the rat. Proc. Soc. Ezp.Biol. Med. 151:736-738.
7. Chan, R. A., E. J. Benner, and P. D. Hoeprich. 1972.Gentamicin therapy in renal failure: a nomogram fordosage. Ann. Intern. Med. 76:773-778.
8. Cutler, R. E., A. K. Gyselynck, W. P. Fleet, and A.W. Forrey. 1972. Correlation of serum creatinine con-centration and gentamicin half-life. J. Am. Med. Assoc.219:1037-1041.
9. Dahlgren, J. G., E. T. Anderson, and W. L. Hewitt.1975. Gentamicin blood levels: a guide to nephrotoxic-ity. Antimicrob. Agents Chemother. 8:58-62.
10. Dobbs, S. M., and G. E. Mawer. 1976. Intravenousinjection of gentamicin and tobramycin without impair-ment of hearing. J. Infect. Dis. 134(Suppl.):S114-S117.
11. Echeverria, P., G. R. Siber, J. Paisley, A. L Smith,D. H. Smith, N. Jaffe, and R. D. Paed. 1975. Age-dependent dose response to gentamicin. J. Pediatr. 87:805808.
12. Federspil, P., W. Schatzle, and E. Tiesder. 1976. Phar-macokinetics and ototoxicity of gentamicin, tobramycinand amikacin. J. Infect. Dis. 134(Suppl.):S200-S205.
13. Gilbert, D. N., C. Plamp, P. Starr, W. M. Bennett, D.C. Houghton, and G. Porter. 1978. Comparativenephrotoxicity of gentamicin and tobramycin in rats, p.936-937. In W. Siegenthaler and R. Luthy (ed.), Currentchemotherapy. Proceeding of the 10th InternationalCongress of Chemotherapy, vol. 2. American Societyfor Microbiology, Washington, D.C.
14. Goodman, E. L, J. Van Gelder, R. Holmes, A. R.Hull, and J. P. Sanford. 1975. Prospective compara-tive study of variable dosage and variable frequencyregimens for administration of gentamicin. Antimicrob.Agents Chemother. 8:434-438.
15. Hull, J. H., and F. A. Sarubbi. 1976. Gentamicin serumconcentrations: pharmacokinetic predictions. Ann. In-tern. Med. 85:183-189.
16. Jackson, G. G., and L J. Riff. 1971. Pseudomonasbacteremia: pharmacologic and other bases for failureoftreatmentwithgentamicin. J. Infect. Dis. 124(Suppl.):185-191.
17. Jelliffe, R. W. 1973. Creatinine clearance. Bedside esti-mate. Ann. Intern. Med. 79:604605.
18. Kaye, D., M. E. Levison, and E. D. Labovitz. 1974. Theunpredictability of serum concentrations of gentamicin:pharmacokinetics of gentamicin in patients with nornaland abnormal renal function. J. Infect. Dis. 130:150-154.
19. Klastersky, J., D. Daneau, G. Swings, and D. Weerts.1974. Antibacterial activity in serum and urine as atherapeutic guide in bacterial infections. J. Infect. Dia.129:187-193.
20. Lerner, S. A., R. Seligsohn, and G. J. Matz. 1977.Comparative clinical studies of ototoxicity of amikacinand gentamicin. Am. J. Med. 42:919-923.
21. Lockwood, W. R., and J. D. Bower. 1973. Tobramycinand gentamicin concentrations in the serum of normaland anephric patients. Antimicrob. Agents Chemother.3:125-129.
22. McCabe, W. RK 1973. Gram-negative bacteremia. Dis.Mon. Dec., p. 10.
23. McHenry, M. C., T. L. Gavan, R. W. Gifford, Jr., N.A. Geurkink, R. A. Van Ommen, KL A. Town, andJ. G. Wagner. 1974. Gentamicin dosages for renalinsufficiency. Adjustments based on endogenous creat-inine clearance and serum creatinine concentration.Ann. Intem. Med. 74:192-197.
24. Noone, P., T. KL C. Parsons, J. R. Pattison, R. C. B.Slack, D. Garfield-Davies, and K. Hughes. 1974.Experience in monitoring gentamicin therapy duringtreatment of serious gram-negative sepsis. Br. J. Med.1:477-481.
25. Regamey, C., R. C. Gordon, and W. M. KL Kirby. 1973.Comparative phannacokinetics of tobramycin and gen-tamicin. Clin. Pharmacol. Ther. 14:396-403.
360 REYMANN ET AL.
Dow
nloa
ded
from
http
s://j
ourn
als.
asm
.org
/jour
nal/a
ac o
n 17
Feb
ruar
y 20
22 b
y 17
5.11
4.73
.100
.
AMG DOSAGES AND SERUM LEVELS 361
26. Sawchuk, R. J., D. E. Zaske, R. J. Cipoile, W. A.Wargin, and R. G. Strate. 1977. Kinetic model forgentamicin dosing with the use of individual patientparameters. Clin. Pharmacol. Ther. 21:362-369.
27. Schentag, J. J., G. Lasezkay, M. E. Plaut, W. J.Jusko, and T. J. Cumbo. 1978. Tissue accumulationand prolonged washout of gentamicin and tobramycinin humans, p. 957-949. In W. Siegenthaler and R. Luthy(ed.), Current chemotherapy. Proceedings of the 10thInternational Congress of Chemotherapy, vol. 2. Amer-ican Society for Microbiology, Washington, D.C.
28. Siersback-Nielsen, K., J. M. Hansen, J. Kampmann,and M. Kristensen. 1971. Rapid evaluation of creati-nine clearance. Lancet i: 1133-1134.
29. Steel, R., and J. Tome. 1960. Principles and proceduresof statistics. McGraw-Hill, New York.
30. Stevens, P., L. S. Young, and W. L Hewitt. 1975.Radioimmunoassay, acetylating radio-enzymatic asayand microbioassay of gentamicin: a comparative study.
J. Lab. Clin. Med. 86:349-359.31. Thompson, W. L, N. R. Reiner, and D. D. Bloxham.
1978. Gentamicin and tobramycin nephrotoxicity indogs given continuous or once daily intravenous injec-tions, p. 941-942. In W. Siegenthaler and R. Luthy (ed.),Current chemotherapy. Proceedings of the 10th Inter-national Congress of Chemotherapy, vol. 2. AmericanSociety for Microbiology, Washington, D.C.
32. Washington, J. A., I1, and A. L. Barry. 1974. Dilutiontest procedures, p. 410-417. In E. H. Lennette, E. H.Spaulding, and J. P. Truant (ed.), Manual of clinicalmicrobiology. American Society for Microbiology,Washington, D.C.
33. Winters, R. E., K. D. Litwack, and W. L Hewitt. 1971.Relation between dose and levels of gentamicin inblood. J. Infect. Dis. 124(Suppl.):S90-S95.
34. Zaske, D. E., R. J. Sawehuk, D. N. Gerding, and R. G.Strate. 1976. Increased dosage requirements of genta-micin in burn patients. J. Trauma 16:824-828.
VOL. 16, 1979
Dow
nloa
ded
from
http
s://j
ourn
als.
asm
.org
/jour
nal/a
ac o
n 17
Feb
ruar
y 20
22 b
y 17
5.11
4.73
.100
.
