HOW WELL DO PATIENTS TAKE ORAL PENICILLIN? A COLLABORATIVE STUDY IN PRIVATE PRACTICE

(1)

HOW

WELL

DO

PATIENTS

TAKE

ORAL

PENICILLIN?

A

COLLABORATIVE

STUDY

IN

PRIVATE

PRACTICE

Evan Charney, M.D., Rufus Bynum, M.D., Donald Eldredge, M.D., Donald Frank, M.D.,

James B. MacWhinney, M.D., Neal McNabb, M.D., Albert Schemer M.D.,

Edwin A. Sumpter, M.D, and Howard Iker, Ph.D.

Department of Pediatrics, University of Rochester School of Medicine and Dentistry and Strong Memorial Hospital, Rochester, New York

188

it is as important to know what patient has

the disease as what disease the patient has.

T

HERE have been a number of studies in

the recent past concerning patient

compliance with a variety of medical

regimens,’ and several in the past decade

concerned specifically with the taking of

penicillin either for therapy for

streptococ-cal pharyngitis or for rheumatic fever

prophylaxis.7 In one study with clinic

pa-tients only 18% of the children completed

the penicillin therapy as prescribed. Two

recent studies from private 67

(

pub-lished while the current study was under

way

)

have concluded that more of those pa-tients receive their full 10 days of

treat-ment. The authors of these latter studies

suggest that either the nature of the patient seen or the private practice relationship itself may account for their better results.

The present study was done to obtain the

following specific information:

1. What percent of children are taking

oral penicillin five days and nine days fol-lowing its prescription for either strepto-coccal pharyngitis or otitis media?

2. \Vhat characteristics of patient, physi-cian, or disease differentiate those who take

the medication from those who do not?

This study was a collaborative effort be-tween seven pediatricians in private prac-tice (in three separate practice groups) and

The Department of Pediatrics at the

Uni-versity of Rochester School of Medicine and Dentistry. All of the patients are from the private practices of the three groups in Rochester

(

Monroe County

)

, New York.

The first problem, of course, is to deter-mine whether or not the child has taken the penicillin without influencing his behavior by the study itself. In previous studies ci-ther the parents were asked directly wheth-en or not the child had taken the me(licine,

the number of pills were counted on a

home visit or in the physician’s office, or

the child’s urine was examined for the pres-ence of penicillin.-#{176} Although there are

some disadvantages to all of these

tech-niques, it was decided to use the urine

col-lection technique and overcme the

disad-vantage of not being able to detect missed doses in more than the day of collection by

obtaining specimens from sonic patients at

five days and some at nine days after onset of treatment.

SARCINA LUTEA METHOD FOR DETECTION OF PENICILLIN IN URINE

A preliminary evaluation of this method

was made prior to the start of the study to

determine its accuracy, reliability, and ap-plicability for use in a private office labora-tory. Grove and Randall’ state that as little as 0.005 units per milliliter o penicillin can be detected in the urine, and Bergman5

(Received January 16; revision accepted for publication March 1 1, 1967.)

Supported in part by Children’s Bureau Grant # 148, United States Department of Health, Education, and Welfare.

Funds for purchasing culture material and equipment supplied by Wyeth Laboratories, Philadelphia,

Pennsylvania.

The authors represent a group of practitioners and full-time staff from the University of Rochester Medical School engaged in a program of collaborative clinical research.

ADDRESS FOR REPRINTS: (E.G.) Strong Memorial Hospital, 260 Grittenden Boulevard, Rochester, New York 14620.

(2)

HOURS AFTER DOSE

in urine following single dose of Pen-V, 125 mg. The

children are ages 2 to 12 years. ARTICLES

FIG. 1. Penicillin

noted that peilicillin was still detectable 16

hours after the last dose. The following

technique was used.

A 3 in. blank sterile filter paper disc* was

dipped in the urine specimen to be tested

and then placed on a sheep’s blood agar

plate that had been completely streaked

with an undiluted broth culture

(

at least 24 hours old

)

of S. lutea. The plate was

incu-bated for at least 18 hours at 37#{176}C,at

which time a zone of inhibition was clearly

evident arouiid the disc if penicillin was

present in concentration greater than 0.08

‘,i.g/ml. All of 103 urine specimens

contain-ing penicillin showed an inhibition zone

around the filter paper disc. A total of 98

urine specimens from patients who had no

penicillin for at least three days were tested

and 91 of these showed no inhibition zone.

Of the remaining seven cases, four patients

had taken other antibiotics and three had

taken a variety of medicines but no

anti-biotics. Thus, three of 98 specimens showed inhibition of S. lutea growth, presumably due to some factor other than antibiotic. In

these three cases the radius of the zone of

inhibition was less than 10 mm. We were

o Obtained from Baltimore Biological

Labora-tory, Baltimore, Maryland.

unable to differentiate penicillin from other

inhibitors with any consistency by the use

of penicillinase impregnated discs. In short,

the technique seems to have no false

nega-tives

(

penicillin taken but not evident in

urine

)

and only an occasional false positive

which showed less inhibition than that

caused by penicillin.

The technique has several other

advan-tages. Contamination of the urine specimen with a variety of gram positive and gram

negative organisms does not alter the zone

of inhibition. The presence of albumin, leti-kocytes, or erthrocytes in the urine does not

affect the test. The urine specimen can be

left unrefrigerated for at least 12 hours

(

we did not test any for a longer period

)

or re-frigerated for at least 48 hours before any change in the inhibition zone is evident.

The forceps used to hold the filter disc

needs to be rinsed thoroughly with tap

water between specimens or else sufficient penicillin may remain on it to give a false positive result for the next urine tested.

Finally, the technique was standardized for an oral dose of 200,000 units of potas-sium phenoxymethyl penicillin

(

Penicillin

V-K). Figure 1 compares the radius of

(3)

TABLE I

FAKE It

Days after

renictuin

rrescrioea

ATE AT 5 AND 9DAYS 0 N 459 PATIENTS

i aee _± No

Take

. Dzsqua/-1

.

ifled

.

Total .

Patients

Five (lays 79 9 10 9 107

Nine days 155 37 84 76 35

‘Fake-penieilliii taken within 15 hours.

Intermediate ( ±)-some penicillin between H and

0 hours.

No take-no penicillin for at least 18 hours.

l)isqualified-urine specimen returned more than 24

hours after (late requested, patient seen in interim by

(loctor, or patient unable to keep appointment.

standardization the child was considered to

be a no-taker if there was a zone of

inhibi-tion of less than 5 mm around the filter

paper disc

(

no penicillin for at least 18

hours

)

. He was considered a taker if there was a zone of greater than 10 mm of inhibi-tion

(

some penicillin within past 15 hours), and an intermediary case if the inhibition

zone was between 5 and 10 mm. Some of

the children receiving liquid penicillin

un-doubtedly took less than full 5 ml per dose.

The results in Figure 1 are based on what

parents give their children when “1

tea-spoon” is prescribed, and the range of

peni-cillin levels might well be narrower if the

dose were more precise. Since the study

was to be done on penicillin given by

par-ents at home, it was felt that this curve

would better reflect actual practice than

one constructed from a precise 5 ml dose.

METHOD

A preliminary study was done with 96

patients to determine whether the method

of obtaining the urine specimen influenced the “take rate.” No statistically significant

difference was found when the urine was

collected in the doctor’s office

(

mother told

only to bring child back for recheck

)

or

when the mother returned with both a

urine specimen collected at home and a

questionnaire filled out.

The major portion of the study was then

conducted between May and June of 1965

and December 1965 and April 1966. All

children between 2 and 12 years of age were included in the study if oral penicillin was prescribed for either streptococcal pharyngitis

(

proved by culture

)

or otitis media. The parent was given a prescription

(

to be filled at their local pharmacy

)

for ci-ther 150 ml of potassium phenoxymethyl penicillin

(

Penicillin V-K

)

or 30 tablets

(

200,000 units each

)

and instructed to take 1 teaspoon

(

or 1 pill

)

three times a day for the full 10 days. They were asked to return

a urine specimen collected from the child

on either the fifth or ninth day of therapy

(

alternate patients

)

. We made no special

check on whether the medicine was

actual-ly purchased. However, of a sample 28 families interviewed at home during a later phase of the study, all had the penicillin.

At the end of the study, but without

knowing the urine results, each practitioner completed an adjective check list

(

modified

from Cough9

)

describing the mother in

order to obtain an appraisal of her

person-ality characteristics; he then predicted

whether or not the child had taken the pen-icillin.

RESULTS

A total of 459 children, age 1.5 to 14

years

(

median 5 years

) ,

were begun in the study. The number of patients in each cat-egory is indicated in Table I. The families

were largely middle and upper middle

class, mostly suburban and many in profes-sional occupations.

The possible influence of a variety of

factors on “take rate” was investigated.

Statistical analysis was one between the

“take” and “no take” groups using the

Chi-Square method. The children with

phar-yngitis completed the full course of

ther-apy somewhat more frequently than those

with otitis media (66% and 51%,

respec-tively). This difference approaches but

does not reach significance at the 5% level

(X2 2.92, p = .10). It was felt that the

difference may be a meaningful one,

(4)

‘FABLE II

Patients

Iota I gruiij

I’liaryiigitis aloite

Not ill

()titis media alone %lildly ill

(lf 2

p= .10

(lf 2

p= .90

%‘2=7 .18

df= 2

l= #{176}5

\I0TI1EIiS E.T1\1STF: OF EVE1I1TY 01’ I)ISESSE AT FIRST DocTon \ISIT

. S’ignifieant

: 1)egree (if Sererzt,j- . Take \o Tale Differenee

Not ill 14 (5 ) 13(48

\IiI(IIV ill 41 (6P ) 26 (39(

\Io(lerately or severely ill 94 (71 ) 38 (9’

Not iii 8 (73(,() 3 (7(;)

bIiI(lIyill 17 (7P ) 7 (‘29 )

Moderately or severely ill ‘37 (73 1 14 (‘27w)

6(38) 10(6)

4(56’) 19(44)

Moderately or severely ill 57 (70j 4 (30 )

disease separately as well as for the

com-biiied group. Significant differences (p =

< .05) for otitis media alone are marked with an asterisk0, for pharyngitis alone with a dagger.

Disease or Drug Factors

I. Otitis media or pharyngitis.

2. Degree of severity at onset, as

per-ceived by mother.#{176}

3. Degree of severity at onset, as per-ceiVe(l by doctor.

4. Duration of symptoms

(

as rated by mother).

5. Type of ieiiicillin given

(

pill or liq-uid).

6. Other medicines given concurrently or

not.

7. Throat culture taken or not (for otitis media).

Patient or Family Factors

1. Age of child. 2. Sex of child.

3. Number of children in family. 4. Position of child in family.

5. Intercurrent illness in other family

members (with and without regular medi-cine being given).

6. Educational level of parents.

7. Previous serious illness in child.

Doctor or Patient-Doctor Factors

1. Individual doctor.

2. Practice.

3. Number of years family cared for by that doctor.f

4. \Vhether patient seen by own doctor

or by partner.#{176}

5. Doctor’s description of mother’s

per-sonality h#{176}

f

Only four of these factors proved to

differ significantly between the “takers” and the “non-takers;” the mother’s perception of severity of disease at onset, whether or not the medicine was prescribed by the child’s

“usual doctor,” the number of years the

family had been cared for by that practice, and the mother’s personality characteristics. Specific data for the first three of these are

shown in Tables II-IV.

In general the mothers considered their

child’s illness more severe than the doctor

(5)

stan-Patients Prescribed by Take

Significant

No Take Differenee

Own physician

Total group ---

---Partner

105 (78) ‘39 (27%) .V 7.59

--- (1f’ I

37 (46) p < .01

---43 (54(’)

Own physician

Pharyngitis alone --

--- Partner

40 (74) 14 (26 ) X = 0.()6

--- (If = 1

9 (31 ) p= .80

20 (69 )

()titis media alone

Own physician 65 (72) 25 (28)

Partner 23 (45%) 28 (55’)

dardize the definition of “mild,”

“moder-ate,” or “severe” illness. It is of particular

interest that the children who took all the

penicillin were not symptomatic for any

longer time than those who did not

corn-plete therapy. Both “takers” and “non-tak-ers” were well, on the average, on the third day of treatment.

An attempt was made to assess the

importance of the mother’s personality

through use of an adjective check list

(

modified from Gough,i copies available on

request

)

. Ten of the 62 adjectives showed

significant differences between “take” and

“no take’ groups at the p < .05 level, two of

these at the p < .01 level. Table V lists these

10 adjectives. The remaining adjectives

were applied more or less evenly to both

groups. The “takers” are ascribed more

pos-itive adjectives than the “nontakers,” and

the reverse holds true for the negative ad-jectives. The intermediate and disqualified

groups in general are rated between two

extremes. Despite the fact that it was

known that the overall take rate was about

two-thirds, the doctors could not predict

this with better than chance accuracy. During the latter portion of the study

two first year medical students

inter-viewed 28 families between 1 and 3 weeks

after they had returned a urine specimen.

Costas Hercules and Norman Spack.

The students were unaware of whether the

child had taken the full penicillin course

prior to their interview. This number of

in-terviews is not large enough to warrant

de-tailed presentation but certain of the infor-mation obtained is Iertinent. The student

interviewed the mother in all cases and

asked to see the penicillin bottle at the end

of the interview in order to check the

amount of unused penicillin. Sixteen of the children were “takers,” 10 were

“non-tak-ers,” and 2 were “intermediate” by the

urine criterion. All of the mothers knew the

nature of the illness their child had had,

and all correctly identified the medicine

that had been prescribed and knew’ the

cor-rect dosage and intended duration of thera-py. In four cases the parents admitted that the child did not take all the penicillin and this finding was confirmed by the urine test.

The remaining six, however, claimed that

their child had used at least 4 of the 5 oz of

penicillin prescribed but there was no

peni-cillin present in the urine. One parent had more than 1 oz of penicillin remaining, but

the child’s urine contained penicillin. On

the basis of these findings it would seem

that the urine test is indeed a stricter

crite-non of take rate than a pill count, a fact

previously noted.5

As far as the students could determine

there were no more significant family crises or recent upsetting events in the

“non-tak-TABLE III

%Vo PRESCRIBES PENICILLIN?

9.09

(If =1

(6)

Take

116 (69)

29 (541;)

52 (80)

Less than 4

9 (47(;)

64 (62)

More than 4

Io(s3;)

39 (38w)

20(57w) TABLE IV

YEARS FAMILY UNDER CARE BY PHYSICIAN

Patients I’ears Under Care

Less than 4

lotal group

More than 4

Less than 4

Pliaryngitis alone

More than 4

Otitis media alone

Significant ‘so Take

Difference

52 (‘31’) .V2=3.6()

(If 1

25 (46) P= .06

13 (20 ) X=6.32

(If = I

= <#{149}0

X2=0.1()

(1f1

15(43)

ers” as opposed to the “takers.” Indeed, few

upsetting events were reported in either

group. None of the mothers seemed aware

of the purpose of the study, although most

knew that their child had been involved in

one. Before asking to see the penicillin bot-tle

(

the last question in the interview

)

the

students attempted to predict whether the

child had been given the full course of

medicine. They were unable to do so with

better than chance accuracy.

COMMENT

Only 56% of the children completed the prescribed 10-day course of penicillin ther-apy. Another 13% had taken some

penicil-lin but not in the past 15 hours. This is

certainly a better compliance rate than the

19% rate that has been reported from a

clinic population5 but considerably lower

than the 89% and 99% rate reported on

pa-tients with streptococcal pharyngitis from

other private practice settings.6’7 In one of

the private practice studies Leistyna and

Macauley gave each parent a printed

in-formation sheet on the hazards of strepto-coccal infection at the time the medicine was prescribed and this may well have em-phasized the necessity for complete therapy in the parent’s mind. They also asked their patients to return with the penicillin bottle at the end of therapy. If this will improve

patient compliance perhaps it ought to be

considered for use in routine practice!

The factors that do not distinguish the

“takers” from the “non-takers” are perhaps as interesting as the ones that do. The age

and sex of the child, the duration of his

symptoms, the doctor’s estimate of severity of the disease, the educational level of the

parents, and intercurrent illness in other

family members all seem unrelated to how well the medicine was taken. Streptococcal

phaiyngitis may be considered by the

fami-ly a more serious disease than otitis media

and this may account for its somewhat

bet-ter completion rate, although the children appeared equally ill with either disease.

The child who is thought by either the

mother or the doctor to be asymptomatic

but has an inflamed ear had less than a

50% chance of completing his full,

pre-scribed course. Probably the most

impres-sive correlations seem related to aspects of the patient-doctor relationship. If penicillin

was prescribed by a member of the

pedi-atric group other than the child’s “usual doe-tor”-in particular for otitis media-the pa-tient clearly was less likely to get the full

course. We did not specifically ask how

well the parent knew the other doctor, but

the physicians in each of the three groups

work closely toegether and rotate night

coverage so that some contact with all the

doctors in the group would be quite likely.

(7)

TABLE V

PERCENT OF PATIENTS ASSIGNED ADJECFIVE

.4djerlire T(ik(r’ Inter-

J)iquuli-- tuker., mediate tied

Responsible’ Organized’ Efficient’ Industrious’ Intelligent’ Clear thinkingt l.ogieiI’ Trusting’ :Iat,irc’ Unreliable’ Predicated “take

Predicated “no take

S:I (It; 70 75

3, :3-2 46 15

55 4 4t 41

55 16 53 4l

71 3t 67 31

41 ‘1(1 ei 16

15 O 1

59 In 46 44

30 10 17 47

7 1 S 11

64 61 6 47

4 35 9

Total patients rated I I I .56 t4

3-Difference between takers and non-takers significant: ‘p <03,

t p<.01

three group practices as well as all three

combined, which further strengthens the validity of the result.

Are mothers who are more likely to follow their doctor’s advice indeed more responsi-ble, reliable, and intelligent; or, does this

perception by the doctor reflect a warmer

and closer relationship with the family

which in turn leads to better compliance? Certainly both factors may operate togeth-er. It is of particular interest that the

pedia-tricians were unable to predict how well

the patients took their medication despite having differentiated the two groups by the adjective list. No one doctor was significant-ly better than any other at this prediction.

The disqualified patients do not differ

from those ‘ho completed the study in

type of disease, age of child, or severity of illness. They most resemble the

intermedi-ate group in the adjective description but

have somewhat fewer adjectives checked

per mother than either the “takers” or the

“non-takers,” perhaps reflecting less familiar-ity with the pediatrician.

We would draw several conclusions from

this study. Of most importance, too many

children do not receive their full course of

oral therapy. Second, the likelihood that a

child will receive his full course of

treat-ment seems as much related to factors in

the patient-doctor relationship or in the

personality of the individual mother as in

anything else. Third, studies which purport

to show advantages of one treatment

regi-men over another or seek to define optimal duration of therapy must include particular

care in evaluating how well the patients

have taken the medicine. Is the consistent superiority of intramuscular benzathine

penicillin over various oral therapy

regi-mens in the treatment of streptococcal pharyngitis due to the drug itself or the fact

that its take rate is assured? Is 10 days of

oral therapy truly superior to 7 days, or are patients more likely to take the medicine for at least 7 days if medicine is prescribed for a longer time? The evidence presented here does not presume to answer these

questions but merely indicates a need for

their clarification. Finally, we are once

again impressed with the fact that the phy-sician’s responsibility does not end with the

prescription of appropriate therapy and

must extend to a concern with the

practi-cality and acceptance of the therapy. In light of this, the alternative of a single in-tramuscular injection of benzathine penicil-un is to be seriously considered, especially if the physician does not know the family vell, or if the child does not appear very ill.

SUMMARY

A study of how well children took oral

penicillin when prescribed for streptococcal pharyngitis or otitis media was conducted in three private pediatric group practices.

The presence of penicillin in the urine, as

determined by the Sarcina lutea culture

method, was used to assess the compliance rate. A total of 459 patients were

studied-107 at five days of therapy and 352 at nine days.

Eighty-one percent of the patients were

taking the penicillin as prescribed on the

fifth day, and 56% were taking it on the

ninth day. Another 13% were erratic takers

at the end of therapy. The children with

pharyngitis were somewhat more likely to

complete therapy than those with otitis

(8)

EDIT0II’s NOTE: See the Commentary beginning on page 157 of this issue. an attempt to differentiate those who

com-plied with the therapy from those who did

not. The take rate was unrelated to age or

sex of the child, duration of symptoms, or doctor’s estimate of severity of disease at onset. It was correlated with mother’s

esti-mate of severity, whether or not their

usual doctor prescribed the medicine, and certain personality traits of the mother as perceived by the pediatrician. The implica-lions of the study for the use of oral thera-py in children are discussed.

REFERENCES

1. Davis, M. S., and Eichhorn, R. L. : Compliance

with medical regimen: A panel study. J. Health Hum. Behavior, 4:240, 1963.

2. Mohler, D. N., Wallin, D. C., and Dreyfus,

E. C.: Studies in home treatment of

strep-tococcal disease, I. New Eng. J. Med., 252:

1116, 1955.

3. Mohler, D. N., Wallin, D. C., Dreyfus, E. C.,

and Bakst, H. J.: Studies in home

treat-ment of streptococcal disease II. New Eng.

J. Me(l., 254:45, 1956.

4. Feinstein, A. B., \Vood, II. F., Epstein, J. P.,

Taranta, A., Simpson, R., and Tursky E.:

Controlled study of three methods of

pro-phylaxis against streptococcal infection in

pop-ulation of rheumatic children II. New Eng. J.

Med., 260:697, 1959.

5. Bergman, A. B., and Werner, R. J.: Failure of

children to receive penicillin by mouth. New Eng. J. Med., 268:1334, 1963.

6. Leistyna, j. A., and Macauley, J. C. : Therapy

of streptococcal infections. Amer. J. Dis.

Child., 111:22, 1966.

7. Jackson, H., Cooper, J., Nellinger, W., and

Olsen, A. : Streptococcal pharyngitis in rural

practice. J.A.M.A., 197:385, 1966.

8. Crove, D. C., and Randall, W. A. : Assay

I’Iethods of Antibiotics: A Laboratory

Man-ual. New York: Medical Encyclopedia, Inc.,

Chapter 2, 1958.

9. Cough, H. C. : The adjective check list as a

personality assessment research technique.

Psychol. Rep., 6: 107, 1960.

Acknowledgment

The authors wish to thank Dr. Lowell Glasgow

for his helpful suggestions regarding the S. lutea

technique and Dr. Robert Haggertv for his advice

and encouragement in establishing the

collabora-tive research program and his guidance with this

(9)

1967;40;188

Pediatrics

Neal McNabb, Albert Scheiner, Edwin A. Sumpter and Howard Iker

Evan Charney, Rufus Bynum, Donald Eldredge, Donald Frank, James B. MacWhinney,

STUDY IN PRIVATE PRACTICE