the pharmacokinetics of cefoperazone

THE PHARMACOKINETICS OF CEFOPERAZONE

IN PREMATURE INFANTS

by

Patsy Elizabeth Millar

A project submitted University of Utah in partial

for the

to the faculty of the fulfillment of the requirements degree of

Doctor of Pharmacy

College of Pharmacy

University of Utah

May 1981

I have read the clinical research project report of Patsy Elizabeth Millar in its final form and have found that 1) its format, citations, and bibliographic style are consistent and acceptable; 2) its illustrative materials including figures, tables, and charts are in place; and 3) the final manuscript is satisfactory to the Supervisory Committee and is ready for submission to the Doctor of Pharmacy Committee.

, /ff/ Chairman, Supervisory Committee

Approved for the,Department of Pharmacy Practice

Chairman

Approved for the Doctor of Pharmacy Committee

Zypbju CUUiJ, I Chairmfli, Doctor of Pharthacy Committee

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UNIVERSITY. OF UTAH COLLEGE OF PHARMACY

SUPERVISORY COMMITTEE APPROVAL

of a clinical research project report submitted by

Patsy Elizabeth Millar

We, the undersigned, have read this clinical research project report and have found it to be of satisfactory quality for a Doctor of Pharmacy Degree.

n , m/

UjML

Chai in, Supervisory Committee

njiabSupervisoryCommi 11ee

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1 Member, Supervisory Committee

/Date 1/

Member, Supervisory Committee

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ACKNOWLEDGEMENTS

I would like to express my appreciation and sincere thanks to

the members of my research committee, Dr. John Bosso, Dr. Kelly Mutchie,

Dr. Gary Chan, and Dr. John Matsen, for the time and consideration they

have donated to the evaluation and writing of this research paper.

I am especially grateful to Dr. John Bosso, who is my academic

advisor and chairman of my research committee, for his constant

willingness to provide guidance and encouragement throughout the past

two years.

Most importantly, I want to thank my family for love and support

throughout these two years.

TABLE OF CONTENTS

Page

LIST OF FIGURES v

LIST OF TABLES vi

INTRODUCTION 1

MATERIALS AND METHODS 6

Patient Population 6

Institutional Review and Informed Consent 6

Study Design 6

Drug Administration and Dosage 7

Drug Level Determination 7

Monitoring of Subjects 7

Laboratory Studies 8

RESULTS 8

DISCUSSION AND CONCLUSION 10

FIGURES 13

TABLES 19

APPENDIX A 27

REFERENCES 29

CURRICULUM VITAE 33

LIST OF FIGURES

Page

Figure 1. Serum Concentration of Cefoperazone Versus Time - Patient 1 13




Figure 5. Mean Serum Concentration Versus Time 17

LIST OF TABLES

Page

Table I. Minimum Inhibitory Concentration (MIC) of

Cefoperazone Against Selected Organisms 19

Table II. Pharmacokinetic Parameters of Cefoperazone . . . . 20

Table III. Cefoperazone Serum Levels at End of 15 Minute Infusion 21

Table IV. Patient Characteristics and Laboratory Parameters: Patient 1 22

Table V. Patient Characteristics and Laboratory Parameters: Patient 2 23

Table VI. Patient Characteristics and Laboratory Parameters: Patient 3 24

Table VII. Patient Characteristics and Laboratory Parameters: Patient 4 25

INTRODUCTION

Sepsis and bacterial meningitis are associated with a high degree

of morbidity and mortality in the newborn period. In a recent review

by Freedman et al̂ " regarding neonatal sepsis, it was stated that the

most common etiologic agents isolated (384 isolates recovered from

359 neonates) during a 13 year period (1966-1978) were Escherichia

coli (31.7 percent), Group B Streptococcus (25.3 percent), Klebsiella-

Enterobacter (14.6 percent), Staphylococcus aureus (6.3 percent),

Haemophilus spp. (2.9 percent), Pseudomonas spp. (2.3 percent), Proteus

spp. (1.6 percent), and Streptococcus pneumoniae (0.8 percent). The

mortality rate of infants with septicemia during the study period was

26 percent. During the 13 year series, 49 cases of meningitis as-

sociated with sepsis were documented of which 18 cases were due to Group

B Streptococcus, 15 to Escherichia coli, and four to Klebsiella. Siegel 2

and McCracken reported that Group B Streptococcus and Escherichia coli

are responsible for approximately 60 percent of all cases of neonatal

sepsis and meningitis. Groover reported an incidence of meningitis of

0.4 per 1,000 live births. Morbidity associated with meningitis is high.

Approximately 14 percent of affected children experience possible residual

effects, and 27.5 to 29 percent suffer severe or significant permanent 4

handicaps. The mortality rate secondary to meningitis in the newborn 3-5

period ranges from 40 to 80 percent. Factors that predispose the

neonate to the development of sepsis and meningitis are the immature

immune system, chorioamnionitis, prolonged labor, premature rupture of

membranes, maternal infections, coexisting congenital malformation, low 2 6 7

birth weight, and prematurity. ' '

2

Morbidity and mortality associated with sepsis and meningitis re-

main high despite the administration of antimicrobial agents effective

against the most common causative organisms, Escherichia coli and Group

B Streptococcus. The goal of treatment of sepsis and meningitis is to

attain and maintain blood and cerebrospinal fluid (CSF) levels of the

appropriate antimicrobial sufficient to eradicate the etiologic or-8 9

ganism and prevent relapse. ' The currently accepted antiinfective

treatment for neonatal sepsis or meningitis is the concurrent intra-

venous administration of ampicillin and g e n t a m i c i n . ® ' I f

Staphylococcus aureus is suspected, a penicillinase-resistant penicillin,

such as methicillin, is substituted for ampicillin. It has been sug-

gested that intrathecal or intraventricular instillation of amino-

glycosides combined with intravenous administration may be no more ef-

fective than intravenous administration alone, in the treatment of gram 12-15

negative meningitis. This may be partially due to the fact that

aminoglycosides diffuse poorly throughout the CSF compartment after

intrathecal administration and also to the unidirectional flow of CSF

out of the ventricules. However, adequate ventricular levels are

achieved after intraventricular administration, but a higher mortality 13

rate is associated with this form of therapy. Therefore, intraventri-13

cular administration is not recommended as routine therapy. Higher

intravenous doses of aminoglycosides, which might result in sustained

therapeutic concentrations throughout the CSF space, are precluded by

the narrow therapeutic index of these agents.

As a possible alternative to the current management of neonatal

sepsis or meningitis, a new cephalosporin, cefoperazone (T-1551), has

17-20 * been demonstrated to achieve adequate blood and CSF levels for the

treatment of Escherichia coli, other Enterobacteriaceae, and Pseudomonas

aeruginosa. If these findings can be reproduced in neonates, cefopera-

zone may provide a more effective alternative to current therapeutic

regimens.

Cefoperazone (sodium 7-[D(~)-a-(4-ethyl- 2,3-dioxo- 1-piperazine-

carboxamide)-a-(4-hydroxyphenyl) acetamido]-3-[(l-methyl-lH-tetrazol-5-

yl) thiomethyl]-3-cephem-4-carboxylate), is an investigational, semi-

synthetic, beta-lactam antibiotic. Its mechanism of action is the

inhibition of synthesis of the peptidoglycan component of the bacterial

cell wall. Cefoperazone has been shown to possess a broad antibacterial

spectrum with activity against many gram-positive and gram-negative 21-27

microorganisms. In vitro studies indicate that cefoperazone is a

highly active bactericidal agent against the microorganisms that com-

monly cause neonatal sepsis and meningitis, including indole-positive

Proteus spp., Escherichia coli, Staphylococcus aureus, Klebsiella spp.,

and Group B Streptococcus (Table I). In addition, cefoperazone is

reported to be effective against organisms that are resistant to the 22 23 28 29

penicillins, other cephalosporins, and/or the aminoglycosides. ' ' '

Cefoperazone also exhibits considerable stability in the presence of

beta-lactamase producing bacteria.23.25,26 30-32

Clinical trials with cefoperazone have been conducted. A

total of 466 adult patients were treated with cefoperazone for urinary

tract infections, respiratory infections, liver biliary duct infections, * Unpublished data, Pfizer Incorporated

4 30 septicemia, and other infections. Cefoperazone was clinically ef-

fective in 79.6 percent of all patients treated. When considering

the bacteriological activity, the overall eradication rate for gram-

negative organisms including Pseudomonas aeruginosa, Klebsiella spp.,

Escherichia coli, Haemophilus influenza, Enterobacter spp. , and Proteus

spp. was 81 percent (182/225) and that for gram-positive organisms

including Staphylococcus aureus, Streptococcus pneumoniae, and 30

Streptococcus faecalis was 90 percent (36/40). Side effects consisting

of skin eruptions, pyrexia and/or diarrhea occurred in 4.8 percent of

patients while elevated serum glutamic-oxaloacetic transaminase (SGOT),

serum glutamic-pyruvic transaminase (SGPT), alkaline phosphatase values,

and eosinophil counts occurred in 6.4 percent of patients treated with 31

cefoperazone. Shibata evaluated 756 surgical patients, the majority

of whom were 40 to 80 years of age, who were being treated with cefo-

perazone. The clinical efficacy rate was 77.9 percent. The clinical

efficacy rates related to isolated organisms were 93.3 percent against

Staphylococcus epidermidis, 100 percent against Streptococcus spp.,

92.2 percent against Escherichia coli, 65.8 percent against Pseudomonas

aeruginosa, and 71.1 percent against Klebsiella spp.. Elevation of

SGOT, SGPT, alkaline phosphatase, and occurrence of skin eruptions,

pyrexia and/or diarrhea were present in 2.8 percent of patients. A 32

comparative, double-blind study of cefoperazone in chronic complicated

urinary tract infections was performed using carbenicillin as a control

(232 patients). The clinical efficacy of cefoperazone in 116 patients

was 59 percent. Carbenicillin was effective in 30 percent in the other

116 patients. The eradication rates for bacteria with respect to

cefoperazone were 84 percent for Escherichia coli, 50 percent for

5

Serratia spp., and 54 percent for Pseudomonas spp.. Skin eruptions,

pyrexia and/or diarrhea occurred in 3.5 percent of the 116 patients.

Elevated SGOT, SGPT, and alkaline phosphatase occurred in 9.5 percent

of patients.

The pharmacokinetics of the drug in adults have been determined."'"'7 ^

The serum levels of cefoperazone rise rapidly after intravenous adminis-19

tration, and show a clear dose-dependent relationship. Effective

serum levels appear to be maintained over a 12-hour period, with 12-

hour levels ranging from 1.2 to 7.2 mcg/ml.^'^ Biliary concentrations

of cefoperazone have been found to be in the low thousands (1,600 to 19 17—20

1,900 mcg/ml). In these four studies, the serum half-life is re-ported to be approximately two hours. Protein binding averaged about

33 34 90 percent, ' and the urinary excretion of unchanged drug was 25 percent.^ ^ No metabolites have been detected in the urine, and a

19 major route of elimination appears to be through biliary excretion.

Due to low urinary excretion, cefoperazone does not accumulate sig-

nificantly in renal disease.^ Values reported for the apparent

volume of distribution are conflicting, with a two-fold variation

(6.5 ± 0.9 to 11.4 ± 0.7 liters).

Because of its demonstrated spectrum of antimicrobial action and

low incidence of side effects, cefoperazone is worth investigating for

use in premature or compromised full-term infants in whom treatment of

suspected sepsis or meningitis presently involves the use of two or more

antibiotics at considerable expense and risk of untoward reactions.

Cefoperazone's antibacterial spectrum includes most organisms encountered

in this patient population, posing the possibility of a single drug 24 35-39

treatment regimen that also may be less toxic. '

6

The objectives of this study were to determine the pharmacokinetics

of cefoperazone when administered as a single intravenous dose to pre-

mature infants, and to detect any toxicity as reflected by changes in

standard laboratory parameters and clinical signs and/or symptoms.

MATERIALS AND METHODS

Patient Population

Premature infants of either sex with a gestational age between 32

and 38 weeks were included. The patients were to be receiving a two to

five-day course of intravenous antibiotic(s) prescribed for suspected

infection. Exclusion criteria included evidence of renal or hepatic

impairment (i.e., blood urea nitrogen >30 mg/dl or serum creatinine >1.5

mg/dl, direct bilirubin >2 mg/dl) documented history of allergy or other

intolerance to cephalosporin, cefamycin, or penicillin antibiotics,

patients with less than one intravenous or arterial line, infants of

diabetic mothers, and infants less than 32 weeks or greater than 38 weeks

of gestational age.

Institutional Review and Informed Consent

The study was approved by the Institutional Review Board of the

University of Utah and the Pharmacy and Therapeutics Committee of

University Hospital prior to initiation. Informed written consent was

obtained from the parents or guardians of all subjects (Appendix A).

One copy was given to the person signing the form; one copy was placed

in the patient's medical record and one copy was kept by the investigator.

Study Design

The study was an open, non-comparative trial of a single dose of

cefoperazone given in addition to the last dose of prescribed antibiotic

therapy for suspected bacterial infection (2-5 day treatment). Blood

samples were obtained at 5, 10, 15, 30, 60, 120, 240, 480, and 720 min-

utes post-infusion of a single dose for determination of cefoperazone

levels and pharmacokinetic parameters. Routine tolerance studies were

performed before and after treatment with cefoperazone to monitor

possible side effects.

Drug Administration and Dosage

Each subject participating in the study received one 50 mg/kg dose

of cefoperazone in addition to the last dose of prescribed antibiotic

therapy for suspected sepsis and/or bacterial meningitis. All doses

were administered by a nurse by intravenous infusion over 15 minutes.

The cefoperazone was reconstituted with 3.5 ml of sterile water and

diluted to an appropriate concentration with D.W just prior to

administration.

Drug Level Determination

Serum cefoperazone levels were determined by a high pressure liquid * chromatography method.

Monitoring of Subj ects

The following clinical signs were observed and recorded before

cefoperazone administration and hourly for 48 hours post-dose: vital

signs, temperature, injection site, lethargy, irritability, feeding,

ankle clonus, moro, and general muscle tone.

Developed by Pfizer Incorporated

Laboratory Studies

Blood samples were obtained from each patient for the following

clinical laboratory studies immediately prior to cefoperazone adminis-

tration and at 12 and 24 hours post-dose:

A. Hemogram: hemoglobin, hematocrit, white blood cell count

with differential, red blood cell count, reticulocyte count,

and platelet count

B. Complete urinalysis

C. Blood urea nitrogen

D. Liver function: SGOT, SGPT

and total bilirubin

RESULTS

Four "premature infants were studied. The estimated gestational age

for one male and two female infants was 34 weeks, and the third female

infant was 32 weeks. At the time of entry into the study, the infants

were between three and six days of age.

The examination of the serum level data via plots of log serum

concentration (C ) versus time indicated the beta (elimination) phase P appeared to begin within two hours after the administration of cefo-

perazone. It was not possible to validate the data collected during

the alpha (distribution) phase due to the inadvertent collection of

samples by the nurse from the same catheter through which the drug was

administered. Linear regression of the natural log (In) of serum con-

centration versus time was performed with a programmable calculator

?

(all r _> 0.84) by the method of least squares analysis. All pharmaco-

kinetic parameters are presented in Table II. The elimination rate

constant was determined from the slope of this line. The elimination

rate ranged from 0.06 to 0.25 hours \ with a mean of 0.15 hours "K The

beta half-life ranged from 2.7 to 11.5 hours, with a mean of 6.28 hours.

The following formula was used for calculation of beta half-life:

0.693 tlj = k i el

where t% = half-life and k - = beta elimination rate constant. The el

volume of distribution ranged from 0.35 to 0.78 1/kg, with a mean of

0.99 1/kg. This was determined by extrapolating the line of In C^

versus time back to the y-axis, which estimates the initial cefoperazone

serum concentration at time zero (assuming a one compartment model), and

using the following formula: Vd = ° C

Po

where V, = apparent volume of distribution C = serum concentration at d Po time 0, and D = dose (mg/kg). The total body clearance ranged from

87.5 to 170 ml/hr/kg, with a mean of 113.2 ml/hr/kg. The following

formula was used for calculation of clearance (Cl^): CL = V, x k . b d el

The plots of the serum levels of cefoperazone versus time during the beta

phase are presented in Figure 1-4. The plot of mean concentration versus

time is presented in Figure 5.

No significant changes were detected in any of the laboratory values

(Table IV-VII) and no clinically evident side effects were noted.

10

DISCUSSION AND CONCLUSIONS

This study was performed in order to determine the pharmacokinetics

of cefoperazone when administered as a single intravenous dose to pre-

mature infants, and to detect any toxicity as reflected by changes in

standard laboratory parameters and clinical signs and/or symptoms.

Neither toxicities nor adverse effects were noted in any of the infants. 30-32

These results differ from the adult studies of cefoperazone in which

a small percentage of patients experienced skin eruptions, pyrexia,

diarrhea, and/or elevations in laboratory parameters. The lack of these

reactions in these infants may be due to the small number of patients

studied. As one might expect, the pharmacokinetics of cefoperazone in

premature infants appear to differ considerably from that reported for

adults.

As mentioned in the results section, it was discovered after the

study was completed that the blood samples were inadvertently collected

from the same catheter through which the drug was administered. The

drug was administered by retrograde infusion in the intravenous line

and because of diffusion and dilution, there is no way of knowing that

all of the drug was infused during the 15 minutes. This was unfortunate

because it necessitated discarding some data and therefore the kinetics

of the alpha distribution phase could not be determined. It is recom-

mended that in future studies, the drug should be given in a separate

line by intravenous push to avoid this problem.

The major problems afflicting these premature infants were hyaline

membrane disease and possible sepsis. At the time of the writing of

this report, cefoperazone had not been administered to healthy neonates,

so it is difficult to draw any conclusions with respect to how a

11

patient's disease state may influence the clearance of this drug. No

obvious correlations were observed between gestational age, age at the

time of study, or disease state and clearance of the drug. It cannot

be explained why patient #3 exhibited a longer beta half-life. The

gestational age and age at the time of entrance into the study were 34

weeks and 4 days, respectively. He was not the youngest infant in the

study, nor did he differ from the other infants with respect to con-

current medical problems (i.e., respiratory distress) or predisposition

to bacterial infection. Tests of renal and liver function did not

differ appreciably from the other infants.

The purpose of defining a drug's pharmacokinetic characteristics

is to design appropriate dosing regimens. Based on the kinetic para-

meters calculated in this study and utilizing the relationship:

, -kel(T) ^ _ dose exp P_in Vd . -kel (t) m m i - e X p

where C = minimum serum concentration and T = dosing interval, and Pmin utilizing the mean values for pharmacokinetic parameters determined, one

would expect that with a 100 mg7kg dose every 12 hours that the MIC's

for the more common organisms encountered in this age group would be

exceeded over most of the dosing interval, (C = 19.99 mcg/ml). Pmin

Due to the small patient population and the problems encountered

in this study, additional studies are needed to more firmly establish

the elimination kinetics of cefoperazone in premature infants and

establish the appropriate dose and dosage regimen.

FIGURES

Serum cefoperazone concentration (mcg/ml)

19

Table I. Minimum Inhibitory Concentration (MIC) of Cefoperazone

Against Selected Organisms

Test Organisms Number of Isolates

Geometric Mean

Range of MIC (mcg/ml)

E. coli 49 0.14 0.03-32

Klebsiella spp. 37 0.50 0.03-250

Enterobacter spp. 35 0.27 0.03-16

Indole-positive Proteus spp.

18 1.71 1-8

Pseudomonas aeruginosa 52 5.70 0.5-125

Haemophilus influenza 19 0.13 0.007-0.25

Staphylococcus aureus

penicillinase positive 31 1.71 1-2

penicillinase negative 16 1.19 1-2

g-hemolytic Streptococcus

Group A 13 0.12 0.06-0.25

Non-group A 12 0.25 0.125-0.50

Enterococci 30 14.90 8-32

Table II. Pharmacokinetic Parameters of Cefoperazone

Patient k ei (hr V (hr)b C P o (mcg/ml)C Vd (l/kg)d Clb (ml/hr/kg)e r 2 for k e l f

1 0. .10 6. .93 56. .83 0. .88 88. .00 0, .93

2 0. .18 3, .85 52. .98 0. .95 170, .10 1, .00

3 0. .06 11. .55 28. ,22 1, .79 107, ,20 0. .87

4 0. .25 2. .77 142. ,59 0. .35 87, .50 0. .84

Mean 0. .15 6. ,28 70. .16 0. .99 113. .20 -

± SD ±0. .08 ±3. ,93 ±49. .93 ±0. .59 ±39. .02 -

a = elimination rate constant

b = elimination half-life

c = serum concentration at time = zero

d = apparent volume of distribution

e = total body clearance

f = coefficient of determination for k , el

ro o

21

Table III. Cefoperazone Serum Levels at End of 15 Minute Infusion

Patient

2 hours Post-

Infusion

4 hours Post-

Infusion

8 hours Post-

Infusion

12 hours Post-

Infusion

1 50 32 28 16

2 35 27 13 6

3 28 20 18 15

4 70 50 40 5

Mean Standard Deviation

45.75 ± 18.59

32.25 ± 12.82

24.75 ± 11.93

10.50 ± 5.80

ECCLES HEALTH SCIENCES LIBRARY J

22

Table I . Patient Characteristics and Laboratory Parameters: Patient

Patient: 1 Sex: Female Weight: 1840 gm Gestational Age: 34 weeks Age at Study Entrance Time: 4 days old

HEMATOLOGY 12 hours 24 hours

Pre-Dose Post-Dose* Post-Dose

Hemoglobin gm% 14.1 15.7 Hematocrit % 40.0 45.4 WBC k/cmm 10.5 14.1

Neutrophils % 59 50 Monocytes % 01 03 Lymphocytes 29 42 Eosinophils % 10 05 Basophils % 01 00

Platelets k/cmm 381 185 Reticulocytes 8.8 8.4

URINALYSIS

Specific gravity 1.008 1.004 1.004 pH 6.0 6.0 6.0 Albumin gm/24 hr neg neg neg Glucose gm/24 hr neg neg neg Acetone neg neg neg WBC/HPF 0 0 0 RBC/HPF 0 0 0 Casts neg neg neg

CHEMISTRY

Blood Urea Nitrogen 13

T. Bilirubin mg% 10.2 12.3 12.3 SGOT IU/L 45 28 45 SGPT IU/L 21 19 23

* Sample lost by lab

Table V. Patient Characteristics and Laboratory Parameters: Patient

23


12 hours 24 hours Pre-Dose Post-Dose Post-Dose

HEMATOLOGY

Hemoglobin gm% 14.0 14.1 14.9 Hematocrit % 40.0 40.1 42.7 WBC k/cmm 7.4 5.2 7.0

Neutrophils % 32 40 37 Monocytes % 00 03 09 Lymphocytes % 64 50 44 Eosinophils % 03 07 08 Basophils % 02 00 02

Platelets k/cmm 255 187 186 Reticulocytes % 10.4 4.1 3.9

URINALYSIS

Specific gravity pH Albumin gm/24 hr Glucose gm/24 hr Acetone WBC/HPF RBC/HPF Casts

1.007 7.0 neg trace neg few 0 neg

1.003 7.0 neg neg neg occ 0 neg

1.007 6.0 neg neg neg rare 0 neg

CHEMISTRY

Blood Urea Nitrogen


24

Table VI. Patient Characteristics and Laboratory Parameters: Patient

Patient: 3 Sex: Male Weight: 1950 gm Gestational Age: 34 weeks Age at Study Entrance Time: 4 days old

12 hours 24 hours Pre-Dose Post-Dose Post-Dose

HEMATOLOGY




URINALYSIS Specific gravity 1.003 1.003 1.007 pH 7.0 6.0 6.0 Albumin gm/24 hr neg neg neg Glucose gm/24 hr neg neg neg Acetone neg neg neg WBC/HPF 0 0 occ RBC/HPF 0 0 occ Casts neg neg neg

CHEMISTRY

Blood Urea Nitrogen »

3 3 2


Table VII. Patient Characteristics and Laboratory Parameters: Patient 4

25


12 hour 24 hours Pre-Dose Post-Dose Post-Dose

HEMATOLOGY




URINALYSIS

Specific gravity 1.006 1.005 1.007 pH 8.0 6.0 7.0 Albumin gm/24 hr neg neg neg Glucose gm/24 hr neg neg neg Acetone neg neg neg WBC/HPF 0 0 0 RBC/HPF 0 0 0 Casts neg neg neg

CHEMISTRY

Blood Urea Nitrogen 16 16 14


V XI<IN3<I<IV

27

CONSENT AND AGREEMENT TO PARTICIPATE AS AN

EXPERIMENTAL SUBJECT IN CLINICAL RESEARCH

Date

Your child is suspected of having an infection for which his (or her) doctors have prescribed antibiotics. It is the purpose of this study, in which you are being invited to participate, to determine the best dose of a new antibiotic, cefoperazone, in premature infants. The manner in which we intend to accomplish this is to give cefoperazone as the last dose in your child's current antibiotic therapy regimen. After the dose is given, we will draw a number of blood samples which will enable us to determine the best dose of cefoperazone for pre-mature infants. The amount of blood drawn, per sample, will be less than 1/10 teaspoonful for a total of 4/5 teaspoonful. In addition, we will monitor for possible cefoperazone side effects by monitoring the child's blood and nervous system.

The risks of participating in this study are limited to those of cefoperazone and include rash, fever, and diarrhea. All blood removed will be replaced by transfusion, which is normally done for all rou-tine tests done in the Newborn Intensive Care Unit. Although there are no direct benefits from participating in this study, future patients may benefit from the use of appropriate doses of cefoperazone, which may be more effective and safer than currently used agents.

Medical treatment or compensation for physical injury: In the event you sustain physical injury resulting from the research project in which you are participating, the University of Utah will provide you, without charge, emergency and temporary medical treatment not otherwise covered by insurance. Furthermore, if your injuries are caused by negligent acts or omissions of University employees acting in the course and scope of their employment, the University may be liable, subject to limita-tions prescribed by law, for additional medical costs and other damages you sustain. If you believe that you have suffered a physical injury as a result of participation in this research program, please contact the Office of Research Administration, Phone No. 581-6903.

The above clinical research project in which I have volunteered to participate as an experimental subject has been fully explained to me, and I understand the purpose of the project and the potential benefits to be derived therefrom. I have also had explained to me, and fully understand, the procedures that will be carried out on my person and the potential risks and discomforts that are involved. The precautions that will be taken to protect my welfare have been explained to me, and I understand that all possibility of injury cannot be avoided, even when these precautions are followed. Nevertheless, I voluntarily assume these risks in order to advance medical knowledge.

I acknowledge that I have had a fair opportunity to ask questions about the above procedures. I understand that I am free to withdraw my consent

28

and to discontinue participation in the project at any time without pre-judice. I agree that data from these experiments may be used for medi-cal and scientific purposes, including publication, with the understanding that my identity will not be revealed unless I expressly consent thereto.

If patient is a minor or unable to sign, complete the following, in addition to the above:

As legal guardian of the above-named patient, I verify that I understand the nature of these procedures, and that I am legally authorized to sign for this patient.

Patient is a minor

Patient: Signature:

Age Signature of Parent or Guardian

Patient is unable to sign because

Signature of Legal Guardian

Hospital No.: Witness:

Responsible Investigator's Signature:

Protocol No. & Title:

29

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Am J Dis Child 135:140, 1981.

2. Siegel JD et al: Sepsis neonatorum. New Engl J Med 304:642, 1981.

3. Groover RV et al: Purulent meningitis of newborn infants. New

Engl J Med 264:1115, 1961.

4. Bosso JA: Bacterial meningitis. Drug Intell Clin Pharm 9:

242, 1975.

5. Huggarty RJ et al: Acute bacterial meningitis. Adv Pediatr 13:

129, 1964.

6. Overall JC: Neonatal bacterial meningitis. J Pediatr 76:499,

1970.

7. Klein JD et al: Bacterial infections. Infectious Diseases of the

Fetus and Newborn Infant, WB Saunders Co, Philadelphia, PA, p 747,

1976.

8. McCracken GH: The rate of bacteriologic response to antimicrobial

therapy in neonatal meningitis. Am J Dis Child 123:547,

1972.

9. McCracken GH et al: Relation between E. coli K1 capsular polysac-

charide antigen and clinical outcome in neonatal meningitis. Lancet

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10. Wehrle PF et al: Acute bacterial meningitis in The Critically 111

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11. Zoumboulakis D et al: Gentamicin in the treatment of purulent

meningitis in neonates and infants. Acta Paediatr Scand 62:55, 1973.

30

12. McCracken GH et al: A controlled study of intrathecal antibiotic

therapy in gram-negative meningitis of infancy. J Pediatr 89:66,

1976.

13. McCracken GH et al: Intravenous gentamicin therapy in gram-negative

bacillary meningitis of infancy. Report of the second neonatal

meningitis cooperative study group. Lancet 1:787» 1980.

14. Anon: Intralumbar and intraventricular therapy of bacterial meningi-

tis. Med Lett Drugs Ther 19:94, 1977.

15. Anon: Hazard of intraventricular antibiotics in neonatal meningitis.

Med Lett Drugs Ther 21:52, 1979.

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31

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33 CURRICULUM VITAE

PATSY ELIZABETH MILLAR

PERSONAL

Address and Telephone:

Home: 722 Medical Plaza South Salt Lake City, UT 84112 (801) 582-9973

Office: Department of Pharmacy Practice College of Pharmacy University of Utah Salt Lake City, UT 84112 (801) 581-5941

Birth: June 6, 1956 Greensboro, North Carolina

Marital Status: Single

EDUCATIONAL BACKGROUND

Bachelor of Science in Pharmacy, University of North Carolina Chapel Hill, North Carolina, May 13, 1979

Doctor of Pharmacy, University of Utah, Salt Lake City, Utah Anticipated graduation, June 13, 1981

EDUCATIONAL EXPERIENCES

Doctor of Pharmacy

Clinical rotations:

Adult Internal Medicine (18 weeks), University and Holy Cross Hospitals

Nutrition-Parenteral (3 weeks), Primary Children's Medical Center Pediatrics (15 weeks), University Hospital and Primary Children's

Medical Center Pediatric Neurology (3 weeks), Primary Children's Medical Center Neonatology (6 weeks), University Hospital Pediatric Nephrology (6 weeks), University Hospital and Primary

Children's Medical Center Obstetrics and Gynecology (6 weeks), University Hospital and Utah

State Division of Health Ambulatory Care (6 weeks), University Hospital Pediatric Clinic,

and Veteran's Administration Geriatric Unit Psychiatry (6 weeks), Veterans' Administration Hospital Drug Information (6 weeks), University Hospital Surgery (6 weeks), University Hospital Pediatric Oncology (3 weeks), University Hospital

34

PHARMACY PRACTICE EXPERIENCES

Pharmacist's Aide, volunteer, Veteran's Administration Regional Out-Patient Pharmacy, Winston-Salem, North Carolina, September 1973 to June 1974.

Pharmacy Intern, Veteran's Administration Regional Out-Patient Pharmacy, Winston-Salem, North Carolina, July to August of 1974-1976.

Pharmacy Intern, Bobbitt's Community Pharmacy, Winston-Salem, North Carolina, May 1977 to August 1977.

National Pharmaceutical Council-Student American Pharmaceutical Association Summer Intern: McNeil Laboratories, Incorporated, Fort Washington, Pennsylvania, May 1978 to August 1978.

Pharmacist's Aide, Manufacturing Division, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, August 1978 to December 1978.

Pharmacy Intern, Cherokee Indian Reservation Clinic, Cherokee, North Carolina, February 1979 to April 1979.

Pharmacist, part-time, Intermountain Regional Poison Control Center, -Salt Lake City, Utah, June 1980 to present.

RESEARCH PROJECTS

THC-Ophthalmic Solution, preparation and manufacturing, assisting Dr. James Olsen, Director of the Drug Product Program: to be used for human clinical trial studies, August 1978 to December 1978.

Long-Acting, Implantable Naltrexone Polymer Composite, preparation and manufacturing, assisting Dr. James Olsen: to be used for human clinical trial studies, August 1978 to December 1978.

The setting of the first two projects was in Chapel Hill, North Carolina, School of Pharmacy, University of North Carolina.

The Pharmacokinetics of Cefoperazone in Premature Infants, Patsy E. Millar, John A. Bosso, Pharm.D., Kelly Mutchie, Pharm.D., Gary Chan, M.D., John Matsen, M.D., funded by Pfizer Laboratories. Fulfills research requirements of the Doctor of Pharmacy Program.

TEACHING FELLOWSHIPS

In Ambulatory Care for instruction of undergraduate students on clinical clerkships, Winter Quarter, 1980. In Internal Medicine for instruction of undergraduate students on clinical clerkships, Spring Quarter, 1981.

35

PRESENTATIONS

"Electrophysiology of the Heart" and "The Use of Antiarrhythmic Agents in Adults", presented to Internal Medicine housestaff, University Hospital, November 1979.

"Treatment of Deep Vein Thrombosis and Pulmonary Embolus", a presentation to the medical and nursing staff at the Veteran's Administration Hospital, Geriatric Therapeutic Unit, January 1980.

"Pelvic Inflammatory Disease", a presentation to the medical and nursing staff of the Maternal and Infant Care Department at the Utah State Division of Health, June 1980.

"Pharmacokinetics of Aminoglycosides", presented to Internal Medi-cine housestaff, University Hospital, July 1980.

"Theophylline: Review of Pharmacology, Pharmacokinetics, and an Explanation of Various Dosage Forms", presented to Internal Medicine housestaff, University Hospital, July 1980; presented to Pediatric housestaff, Primary Children's Medical Center, November 1980.

"Intralipid Therapy and Fatty Acid Deficiency", and "The Use of Amino Acid Preparations in Total Parenteral Nutrition", presented

^to the Pediatric Medical Nutrition Team, Primary Children's Medical Center, October 1980.

"Gout", presented to first-year Doctor of Pharmacy candidates taking Advanced Pharmacotherapeutics, March 1981.

PUBLICATIONS

Dietary Formulations Formulary, University of Utah Hospital Formulary Catalog, 1980-1981, Patsy E. Millar.

PROFESSIONAL ORGANIZATIONS

American Society of Hospital Pharmacists American Pharmaceutical Association (past) North Carolina Pharmaceutical Association (past) American Association of the College of Pharmacy Rho Chi Honor Society (Pharmacy) Phi Lambda Sigma Honorary Leadership Society (Pharmacy)

PROFESSIONAL ACTIVITIES

Council of Students (COSt)/American Association of the Colleges of Pharmacy (AACP).

36

PROFESSIONAL ACTIVITIES (Continued)

COSt Region III Representative; Voting delegate to the Annual AACP Conventions, 1976, 1977, 1978

Reorganization of COSt Decision Makers Participant, 1977

Member, AACP Finance Committee, 1977-1978

Student American Pharmaceutical Association:

Local and Regional

Vice-President, 1976-1977

President, 1977-1978

Co-Chairperson, Venereal Disease Awareness Program, 1977-1978

Member, Diabetes and Hypertension Screening Committees, 1977-1978

Chairperson of Workshop, "Pharmaceutical Services in Nursing Homes", presented at the SAPhA Regional Convention, 1977

Chairperson, Public Relations Committee; Member, "Alcohol and Women, Alcohol and Youth" Committee, sponsored by the North Carolina Women's

- Auxiliary, 1978-1979

Delegate to SAPhA Regional Convention, 1976

Attended SAPhA Regional Convention, 1978

Delivered the Invocation at the NCPhA-Women's Auxiliary Fall Convention, 1977

Delivered the SAPhA Annual Report at the NCPhA State Convention, 1978

National:

Delegate to SAPhA National Conventions, 1976, 1977

Member, "Utilization of Chapter Material" Committee, 1977-1978

Attended SAPhA National Convention, 1978

Phi Lambda Sigma Honorary Leadership Society:

Member, Committee on Membership, 1977, 1978, 1979

Delegate to Phi Lambda Sigma National Convention, 1978

Vice-President, 1978-1979, local chapter

37

PROFESSIONAL ACTIVITIES (Continued)

Member, Better Employer/Employee Relations Committee, attended seminar, sponsored by NCPhA, 1977

Member, Selection Committee for the School of Pharmacy Student Body Award, 1977, 1978

Member, Pharmacy Senate and Tripartite Committee (composed of members of the NCPhA, N.C. Board of Pharmacy, Pharmacy School Faculty, and pharmacy student), 1977, 1978, 1979

Updated Pharmacy School Museum; Organized Industrial Seminar (purpose to orient interested pharmacy students to the National Pharmaceutical Council-SAPhA Summer Intern Program), 1978

Pharmacist, Yellowstone National Park-Lake Hosiptal, June 29-July 6, 1980

Volunteer at Camp UTADA, a camp for diabetic children, Salt Lake City, Utah, August 1980

Volunteer at Cystic Fibrosis Camp, Salt Lake City, Utah, August 1980

Charter Member, University of North Carolina School of Pharmacy Alumni Association, 1980

PROFESSIONAL AWARDS AND HONORS

Recipient of the Andrews Award. Given to a fourth year pharmacy student who has approached his/her pharmacy school education with a positive attitude of "finding what is right and not what is wrong" with pharmacy, 1978

The National Dean's List, 1978-1979

Recipient of the North Carolina Pharmaceutical Research Foundation Special Award. "This is not an annual award; presented in 1979 to a senior student for unique local, regional, and national contributions in pharmacy education and practice." 1979

Recipient of the Division of Pharmacy Practice Achievement Award, 1979. "An award to a graduate who has demonstrated a high degree of professional motivation and concern about the role of the pharmacist in the delivery of health care."

Member, Outstanding Young Women of America^. 1979

Member, International Youth in Achievement, 1980. Permanent recogni-tion in an international biographical reference work.

Member, The World Who's Who of Women, 1981. Permanent recognition in an international biographical reference work.

the pharmacokinetics of cefoperazone

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