• No results found

Kanamycin and Gentamicin Treatment of Neonatal Sepsis and Meningitis

N/A
N/A
Protected

Academic year: 2020

Share "Kanamycin and Gentamicin Treatment of Neonatal Sepsis and Meningitis"

Copied!
7
0
0

Loading.... (view fulltext now)

Full text

(1)

ARTICLES

PEDIATRICS Vol. 56 No. 5 November 1975 695

Kanamycin

and Gentamicin

Treatment

of Neonatal

Sepsis

and Meningitis

Margan J. Chang, M.D., Marilyn Escobedo, M.D., Donald C. Anderson, M.D., Laura Hillman, M.D., and Ralph D. Feigin, M.D.

From the Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, and the Divisions of infectious Diseases and Neonatology, St. Louis Children Hospital, St. Louis, Missouri

ABSTRACT. Mortality from neonatal meningitis due to

gram-negative microorganisms remains 50% despite use of aminoglycoside antibiotics. Blood was obtained on 238 occasions from 77 neonates with putative or documented sepsis; paired blood and cerebrospinal fluid (CSF) samples

were obtained on 14 occasions from ten neonates with meningitis. Kanamycin and gentamicin were measured by a

radioisotopic assay procedure. Kanamycin was administered

at 15 mg/kg/day in three divided doses intravenously; serum

concentrations peaked at one hour (mean, 7.77sg/m1). Centamicin was administered at 7.5 mg/kg/day in three divided doses intravenously; serum concentrations peaked at

two hours (mean, 5.34g/mI). Both aminoglycosides

gener-ally were nondetectable within the CSF; survival of neonates

with gram-negative meningitis correlated specifically with

the sensitivity of their isolates to ampicillin which was

administered concurrently. This study suggests that alterna-tive approaches to the treatment of neonatal sepsis should be

explored; administration of an antibiotic which crosses the

blood-cerebrospinal fluid barrier more readily should be

considered. Pediatrics, 56:695-699, 1975, NEONATAL SEPSIS,

MENINGITIS, KANAMYCIN, GENTAMICIN.

recently, gentamicin has been recommended in dosages of 6 to 7.5 mg/kg/day.5 Serum and cerebrospmal fluid (CSF) concentrations of gentamicin have been measured following admin-istration intravenously at these higher dosages6 but the number of observations is limited.

Generally, kanamycin and gentamicin have

been

measured by microbiological assay

proce-dures

which, at best, are accurate only to within 10% and which lack precision; variability of 19% to 23% in replicate determinations has been

reported.26

The present study was designed to measure serum and CSF concentrations of kanamycin and gentamicin in neonates with putative or docu-mented sepsis and meningitis using a more re-liable radioisotopic assay and to determine whether the intravenous route of administration of aminoglycosides provides higher CSF concen-trations of aminoglycosides than those noted following intramuscular administration.

Kanamycin

and gentamicin have been used ex-tensively for over a decade for the treatment of neonatal sepsis and meningitis due to gram-negative microorganisms. During this period of time, mortality from neonatal gram-negative

meningitis has remained close to 5#{216}%#{149}1 Most of the original pharmacodynamic studies of kanamycin and gentamicin were performed

utilizing dosages of 0.8 mg to 4.5 mg/kg/day of

gentamicin and 15 mg/kg/day of kanamycin ad-ministered by the intramuscular route.24 More

(Received April 10; revision accepted for publication May

15, 1975.)

Supported in part by funds provided by Bristol Laboratories and by the Schering Corporation. Dr. Feigin is the recipient

of Public Health Service Research Career Development

Award No. 1K04A146206 from the National Institute of

Allergy and Infectious Diseases.

ADDRESS FOR REPRINTS: (R.D.F.) Department of

Pedi-atrics, St. Louis Children’s Hospital, 500 South

Kingshigh-way, St. Louis, Missouri 63110.

at Viet Nam:AAP Sponsored on September 8, 2020

www.aappublications.org/news

(2)

MATERIALS AND METHODS

Blood was obtained on 238 occasions from 77

neonates for determination of kanamycin or

gentamicin concentrations. The gestational ages

of the neonates studied varied from 28 to 40 weeks. Kanamycin was administered to neonates with putative or documented sepsis or meningitis in a dose of 15 mg/kg/24 hr in three divided doses intravenously; each dose was infused over a

period

of one hour. Gentamicin was administered at 7.5 mg/kg/24 hr in three divided doses

intra-venously in a similar manner. All neonates

received ampicillin (150 to 200 mg/kg/24 hr; the specific dose was dependent upon the gestational

age of the infant) intravenously in four divided

doses. Blood was obtained for measurement of aminoglycoside concentrations at one hour (end of infusion), two, three, six, or eight hours

(imme-diately prior to a subsequent dose). To minimize the number of samples obtained from any

mdi-vidual patient, reference was made to a predeter-mined sequence of numbers which specified the time following a dose and the days for sampling in each patient. Paired blood and CSF samples were obtained on 14 occasions from ten neonates with documented meningitis.

Kanamycin and gentamicin were measured by the radioisotopic method of Smith and associates.7 This assay utilizes an R-factor-mediated enzyme that adenylates kanamycmn, gentamicin, or tobra-mycin. The enzyme is released from a mutant strain of Escherichia coli K12 W677/HSR 66 by an osmotic shocking procedure. This assay has an

accuracy of 0.6% to 4% at serum aminoglycoside

concentrations between 0tg and 30ig/ml7 and, in

our laboratory, the precision (reproducibility) has varied by less than 1%. The assay has been shown to be equally accurate for the measurement of

aminoglycosides in hemolyzed serum and results

are not affected by the presence in test sera of ampicillin, benzyl penicillin, carbenicillin, cepha-lothin, chioramphenicol, nafcillin, oxacillin, or

polymyxin.7

The accuracy of the assay also is not affected when serum specimens from patients

with renal dysfunction and concentrations of

blood urea nitrogen up to 80 mg/ 100 ml are

substituted for specimens from healthy persons.7

. RESULTS

Analysis of variance was performed on serum

aminoglycoside concentrations at each time

interval and on each successive day of therapy. No statistically significant differences were found

in aminoglycoside concentrations obtained at the

same time interval but on successive days of therapy. For this reason, data obtained at the

same time interval but on successive days were

pooled for purposes of further statistical evalua-tion.

Mean serum concentrations obtained following

administration of kanamycmn intravenously at 5

mg/kg/dose are shown in Table I. Kanamycin could not be detected in serum obtained

imme-diately prior to onset of therapy. Kanamycin

concentrations obtained immediately prior to

initiation of an infusion after day 1 are those

reported for the eight-hour time interval. Serum concentrations of kanamycmn peaked at one hour

(

mean, 7.77tg/ml). Individual serum concentra-tions of kanamycin at one hour varied widely from less than 1g to more than 20tg/ml as

reflected by the large standard deviation (Table

I). Individual concentrations of kanamycin at three hours following a dose also varied from less

than 1tg to more than 20g/ml on each day of

therapy. Marked and unpredictable variability in kanamycin concentration was noted from patient to patient and even within the same individual but on different days of treatment.

Mean serum concentrations of gentamicin are

shown

in Table II. Individual concentrations of

gentamicin ranged from less than 1g to 16.3tg/ ml at one hour, from less than ljtg to 16.7tg/ml at

two hours, and from less than 1tg to 5.2g/ml at

three hours following administration of a dose. Thus, extreme variability of gentamicin concen-tration was noted in neonates despite a uniform

dose schedule and a reliable route of

administra-tion. Kanamycin activity was detectable in 44 of

46 specimens and gentamicin activity was

detect-able in 11 of 13 specimens at eight hours following administration of a dose.

Concomitant blood and CSF concentrations of

kanamycmn were measured in six neonates with

meningitis on nine occasions. The CSF samples were obtained between one and three hours fol-lowing a dose of kanamycin and on the second

day of intravenous therapy. Kanamycin was not detectable in any of the CSF samples despite

serum

concentrations which were similar to those

found in neonates without meningitis (Table I). One patient with E. coli meningitis had a serum concentration of kanamycin of 1 1tg/ml but no

kanamycm was found in the CSF. Five of these six

neonates survived their meningitis (group B, beta-hemolytic streptococci were isolated from three

and E. coli from two; no organism was isolated from the CSF of one patient with marked CSF

pleocytosis). All of the patients were treated concomitantly with ampicillin; the organisms

isolated from all the survivors were sensitive to this antibiotic. In one 6-day-old full-term infant

with E. coli meningitis, a lumbar puncture was

at Viet Nam:AAP Sponsored on September 8, 2020

www.aappublications.org/news

(3)

TABLE I

SERUM CONCENTRATIONS OF KANAMYCIN0

DISCUSSION

Administered intravenously, 2.5 mg/kg/dose.

ARTICLES 697

performed 48 hours following initiation of

ampi-cillin and kanamycin therapy. The CSF which

was obtained was sterile. When this sample of CSF was serially diluted and tested for antimicro-bial activity using the E. coli originally isolated from the CSF of this patient, it proved to be bactericidal in a dilution of 1:2 and inhibitory in a

dilution

of 1:4. When 1,600 units of $-lactamase

(Neutrape,

Riker Laboratories, Inc.) were added

to the CSF and the CSF was tested for

antimicro-bial activity, none could be demonstrated. Thus, the antimicrobial activity of the CSF and recov-ery of this patient could be attributed to ampi-cillin alone.

Concomitant blood and CSF samples were obtained from four neonates with meningitis due to gram-negative organisms on five occasions

(Table III). Gentarnicin was not detectable in the CSF of three neonates; a gentamicin

concentra-tion of 1.4tg/ml was found on day 3 in the CSF of one patient (patient 1, Table III) although it had been nondetectable in the CSF of the same pa-tient after 24 hours of therapy.

The peak serum concentrations of kanamycin and gentamicin noted in this study following

ad-ministration intravenously were equal to or greater than those reported previously in neo-nates who received these antibiotics in equivalent dosage by the intramuscular route.2’”” Marked variability in kanamycin and gentamicin concen-trations within serum has been reported

previous-iy,2;..(lo bit it was possible that the variability

observed

was related to differences in the rate of absorption from an intramuscular site of adminis-tration or could be attributed, in part, to the lack of precision which is inherent in the microbio-logic assay procedures employed. Information ob-tamed in this study cannot be compared specifi-cally to previous reports since kanamycin and gentamicin concentrations were measured with a radioisotope assay. Despite the greater accuracy and precision of this procedure, compared to the microbiologic assay,7 and the use of uniform dosage schedules and a reliable route of adminis-tration, marked variability in the concentrations of both aminoglycosides was demonstrated. Al-though the unpredictable variability in kana-mycin and gentamicin concentrations remains

unexplained, these studies serve to reemphasize

the need to monitor carefully aminoglycoside concentrations in all patients receiving these antibiotics.

Other investigators have evaluated the

suscep-tibility of gram-negative organisms to kanamycin

and

gentamicin and have reported that the

con-Time After

AdminLs- No.

tration Mean (Total

(hr) (p.g/ml) SD SEM 159)

1 7.77 6.56 0.94 49

2 5.48 2.89 1.09 8

3 6.56 5.49 0.90 37

6 6.81 6.19 1.38 19

8 5.40 3.77 0.60 46

#{149}Administered intravenously, 5 mg/kg/dose.

TABLE II

SERUM CONCENTRATIONS OF CENTAMICIN#{176}

Time After

AdminLs- No.

tration Mean (Total

-(hr) (itg/ml) SD SEM 79)

1 5.06 4.42 0.92 23

2 5.34 6.47 2.89 5

3 3.20 1.57 0.37 18

6 2.64 2.59 0.58 20

8 1.53 1.40 0.44 13

0

centration of aminoglycosides found in some

patients may not be sufficient to inhibit the

organism causing infection.2”’” The minimal

inhibitory

concentration (MIC) of gentamicin for

73% of the strains of E. coli, 94% of the strains of Kiebsiella enterobacter, and 86% of strains of

Pseudomonas aeruginosa reported by one group

of investigators was 6.25tg/ml. Only 65% of E. coli and 75% of K. enterobacter isolates obtained

in our laboratory would have been susceptible to the mean peak serum concentrations of

kana-mycin and gentamicin obtained in this study.

Thus,

even when septicemia with these organisms occurs without meningitis, senim concentrations

of kanamycin and gentamicin might not be

adequate to treat some of these patients.

Bacterial meningitis has been associated with increased permeability of the blood-cerebrospinal

fluid barrier providing the best opportunity for

antibiotics in the blood to enter the CSF. The concentrations of kanamycin and gentamicin

noted within the CSF in this study were clearly inadequate (nondetectable in most cases) to

exceed the MIC of the gram-negative organisms which were isolated.

It is apparent that some neonates with

menin-gitis due

to gram-negative organisms survive their

at Viet Nam:AAP Sponsored on September 8, 2020

www.aappublications.org/news

(4)

TABLE III

SERUM AND CSF CONCENTRATIONS OF GENTAMICIN IN NEONATES WITH GRAM-NEGATIVE MENINGITIS

Patient Diagnosis Outcome

Day of

Therapy

Time After

Onset of

Infusion (hr) Specimen

Gentamicin Concentration

(g/ml)

1 E. coli meningitis Died

1 4 Blood

5.6

CSF <1.0

3 5 Blood 33

CSF 1.4

2 Klebsiella meningitis Died 1

5

Blood 6.6

CSF <1.0

3 E. coli sepsis & meningitis Died 1 1 Blood

1.3 CSF <1.0

4 E. coil sepsis & meningitis Died 6 8.5 Blood

1.7

CSF <1.0

#{176}Gentamicin was administered intravenously every eight hours, 2.5 mg/kg/dose.

disease despite concentrations of aminoglycoside

within the CSF which appear to be inadequate. It is equally clear that some neonates will die from

meningitis despite adequate concentrations with-in the CSF of an antimicrobial agent to which the

infecting organism is susceptible. There are several possible explanations for these

observa-tions: (1) Measurement of the concentration of an

aminoglycoside within CSF removed by lumbar

puncture may not reflect accurately the

concen-tration of the antibiotic at the meninges or within the ventricular system. (2) Because of the various host factors which are important in vivo, treat-ment results may not be predicted directly from

data

which attempt to relate the concentration of

an antibiotic achieved in vivo with the MIC of the

organism for that antibiotic measured in vitro. (3)

The MIC of an organism as measured by serial

dilutions of the organism in broth in the

labora-tory does not correlate directly with the serum or CSF bactericidal titer for the same organism, since bactericidal titers generally are performed

as dilutions of serum in broth. (4) When survival

follows treatment of gram-negative meningitis

with ampicillin or carbenicillin and an aminogly-coside antibiotic, the beneficial response may reflect a response to the antibiotics which have been administered with the aminoglycosides or to

a synergistic effect between the two.

Although each of the factors noted above may be invoked to explain the survival of some neo-nates with meningitis due to gram-negative

orga-nisms

who have been treated with

aminoglyco-sides by the parenteral route, we would suspect

that, in large part, survival can be attributed to concomitant treatment with an antibiotic which has reached the site of infection in concentrations

sufficient to inhibit the infecting microorganism.

For example, the responses of four neonates with

gram-negative meningitis who were treated with

gentamicin by Klein and associates9 could not be

attributed to gentamicin in any case. Three of the

four infants had meningitis due to Proteus mira-bilis, an organism generally sensitive to ampicillin and penicillin. One of their patients whose re-sponse was satisfactory was treated for 18 days with gentamicin and penicillin, a second died 18

hours after therapy was initiated, and a third received gentamicin for only 24 hours and recov-ered subsequently on a regimen of ampicillin and

kanamycin. In one infant with meningitis due to a

strain of E. coli which was sensitive to gentamicin,

its administration intramuscularly failed to

ster-ilize the CSF and the subsequent use of combined

intrathecally and parenterally administered gen-tamicin also proved ineffective. Treatment with chloramphenicol was followed by eradication of the disease process.

Survival in our neonates with meningitis who

received kanamycin could be attributed to con-comitant treatment with ampicillin; the

orga-msms isolated were uniformly sensitive to

ampi-cillin in vitro. Similarly all of our neonates with E. coli or Klebsiella meningitis treated with genta-micin died; in each case the organism proved to

be resistant to ampicillin.

IMPLICATIONS

We must conclude that parenteral administra-tion of kanamycin or gentamicin using dosages which are presently recommended for neonatal

meningitis due to gram-negative organisms may

not be justified even when those organisms are

at Viet Nam:AAP Sponsored on September 8, 2020

www.aappublications.org/news

(5)

ARTICLES

699

sensitive to these antibiotics in vitro. Evidence

currently available suggests the need for combined parenteral and intrathecal or intra-ventricular administration of aminoglycosides in

patients whose initial specimen of CSF contains

gram-negative microorganisms. Intrathecal or

intraventricular administration of the aminogly-coside should be repeated daily until the CSF has been rendered sterile.

It should be pointed out that instillation of an

aminoglycoside in the lumbar subarachnoid space does not ensure adequate concentrations at the

meninges covering the brain or within the yen-tricular system.” It is also apparent that in some

patients in whom the bactericidal activity of lumbar CSF against the pathogenic organism is high as a result of intrathecal administration, cultures of the lumbar CSF remain positive.’2 In

addition, even intraventricular administration of

an aminoglycoside has not always been associated with a bacteriologic or clinical response to treat-ment.’

Chloramphenicol crosses the blood-cerebrospi-nal fluid barrier readily and many gram-negative organisms are sensitive to this antibiotic. Chlo-ramphenicol was utilized for the treatment of

neonatal sepsis and meningitis in the 1950’s and

early 1960’s. Supportive care for the distressed neonate which was available at that time cannot be compared to that which is available today. The

gray

baby syndrome which may occur in neonates treated with chioramphenicol has not been

re-ported at doses less than 80 mg/kg/day in

neo-nates of any gestational age.”’ The continuing high mortality and morbidity from neonatal

meningitis due to gram-negative organisms

despite parenteral and even intrathecal adminis-tration of aminoglycosides suggests that reap-praisal of the role of chioramphenicol for treat-ment of neonates whose initial CSF specimens contain gram-negative organisms is justified. If this antibiotic is utilized, it has been suggested that the dose should not exceed 25 mg/kg/day in premature infants or 50 mg/kg/day in full-term

infants during the first week of life.’4 A rapid and

precise assay for chloramphenicol in serum and

CSF has been developed and should permit

regu-lation of dosage in each patient so as to maximize

therapeutic efficacy while minimizing the risk of

a toxic reaction.2

REFERENCES

1. Mathies AW Jr. Wehrle PE: Management of bacterial meningitis in children. Pediatr Clin North Am 15:185, 1968.

2. McCracken GH Jr, Jones LG: Gentamicin in the neo-natal period. Am J Dis Child 120:524, 1970.

3. Riley HD, Rubio T, Hinz W, et a!: Clinical and

laboratory evaluation of gentamicin in infants and

children. J Infect Dis 124:S236, 1971.

4. Simon HJ, Axline SC: Clinical pharmacology of

kana-mycin in premature infants. Ann NY Acad Sci

132:1020, 1966.

5. McCracken GH Jr, Eichenwald HF: Antimicrobial

ther-apy: Therapeutic recommendations and review of

newer drugs. J Pediatr 85:297, 1974.

6. McCracken CH Jr, Chrane DF, Thomas ML:

Pharma-cologic evaluation of gentamicin in newborn

infants. J Infect Dis 124:5214, 1971.

7. Smith DH, Van Otto B, Smith AL: A rapid chemical assay for gentamicin. N Engi J Med 286:583,

1972.

8. Bauer AW, Kirby WH, Sherris JC, et a!: Antibiotic

susceptibility testing by a standardized single disk

method. Am J Clin Pathol 40:493, 1966. 9. Klein JO, Herschel M, Therakan RM, et a!: Gentamicin

in serious neonatal infections: Absorption, excretion

and clinical results in 25 cases. J Infect Dis

124:S224, 1971.

10. Kaye D, Levison ME, Labovitz ED: The

unpredicta-bility of serum concentrations of gentamicin:

Phar-macokinetics of gentamicin in patients with normal

and abnormal renal function. J Infect Dis 130:150,

1974.

11. Moellering RC Jr. Fischer EG: Relationship of

intra-ventricular gentamicin levels to cure of meningitis. J Pediatr 81:534, 1972.

12. Rahal JJ, Hyams PC, Simberkoff MS, et a!: Combined intrathecal and intramuscular gentamicin for gram negative meningitis. N EngI J Med 290:1394,

1974.

13. Burns LE, Hodgman JE, Cass AB: Total circulatory

collapse in premature infants receiving chloram-phenicol. N Engi J Med 261:1318, 1959.

14. Weiss CF, Glazko AJ, Weston JK: Chloramphenicol in

the newborn infant. N Engl J Med 262:787, 1960. 15. Sutherland JM: Fatal cardiovascular collapse of infants

receiving large amounts of chioramphenicol. Am J

Dis Child 97:761, 1959.

16. Lambdin MA, Waddell WW Jr, Birdsong M: Chloram-phenicol toxicity in the premature infant. Pediatrics

25:935, 1960.

17. Ziegra SR, Storm RR: Dosage of chloramphenicol in

premature infants. J Pediatr 58:852, 1961.

18. Lischner H, Seligman SJ, Krammer A, Parmelee AH: An

outbreak of neonatal deaths among term infants

associated with administration of chioramphenicol.

J Pediatr 59:21, 1961.

19. Pendileton ME, Jewett JF: Committee on maternal

welfare-three unexpected deaths. N EngI J Med 263:515, 1961.

20. Smith AL, Rosenberg IR, Smith DH, Emerson BB:

Enzymatic microassay of chloramphenicol. Pediatr

Res 9:345, 1975.

ACKNOWLEDGMENT

The authors express their appreciation to Dr. Richard E.

Marshall for permitting us to study neonates under his care

and to the house staff of St. Louis Children’s Hospital for

their assistance. We express our special appreciation to Dr.

Arnold Smith without whose advice and help we could not have established the ammoglycoside assay procedure in our

laboratory. The technical assistance of Mrs. Judy Wilson and

Mr. Joel Campbell is gratefully acknowledged. at Viet Nam:AAP Sponsored on September 8, 2020

www.aappublications.org/news

(6)

1975;56;695

Pediatrics

Feigin

Margan J. Chang, Marilyn Escobedo, Donald C. Anderson, Laura Hillman and Ralph D.

Kanamycin and Gentamicin Treatment of Neonatal Sepsis and Meningitis

Services

Updated Information &

http://pediatrics.aappublications.org/content/56/5/695

including high resolution figures, can be found at:

Permissions & Licensing

http://www.aappublications.org/site/misc/Permissions.xhtml

entirety can be found online at:

Information about reproducing this article in parts (figures, tables) or in its

Reprints

http://www.aappublications.org/site/misc/reprints.xhtml

Information about ordering reprints can be found online:

at Viet Nam:AAP Sponsored on September 8, 2020

www.aappublications.org/news

(7)

1975;56;695

Pediatrics

Feigin

Margan J. Chang, Marilyn Escobedo, Donald C. Anderson, Laura Hillman and Ralph D.

Kanamycin and Gentamicin Treatment of Neonatal Sepsis and Meningitis

http://pediatrics.aappublications.org/content/56/5/695

the World Wide Web at:

The online version of this article, along with updated information and services, is located on

American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 1975 by the

been published continuously since 1948. Pediatrics is owned, published, and trademarked by the

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has

at Viet Nam:AAP Sponsored on September 8, 2020

www.aappublications.org/news

References

Related documents

This paper describes the different methods related to the analysis of urine for diagnosis of medical diseases using digital image processing.. The images of the

Effects of radiographic contrast media on markers of complement activation and apoptosis in patients with chronic coronary artery disease undergoing coronary angiography. Fauser

Adding the 16S rRNA sequence of the type strain of the not yet validly published species ‘ Olsenella umbonata’.. (FN178463) to the tree (data not shown) did not change the

investigated nucleosome dynamics relative to chromatin binding by androgen receptor and used H3K4me2 ChIP-Seq to describe nucle- osome depletion overlapping transcription factor

( 2012a ) tried to incorporate the DNA mutation process into the original protocol and reported that the enhanced origami bird protocol does promote an understanding of the

(Special Issue on National Conference on Advance Design and Optimization Techniques in Engineering Application) [7] Computational Drag Analysis of Passenger Car Using Splines

Kalaichelvan, Mycobased biosynthesis of silver nanoparticles and studies of its synergistic antibacterial activity combined with cefazolin antibiotic against selected