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Relapse of Hemophilus influenzae type b meningitis during intravenous therapy with ampicillin
Volume 74 Number 5
Brief clinical and laboratory observations
78 1
REFERENCES 1. Fleming, P. C., Murray, J. D. M., Fujiwara, M. W., Prichard, J. S., and McNaughton, G. A.: AmpieilIin in the treatment of bacterial meningitis, Antimicrob. Agents & Ghemother.--1966 6: 47, 1967. 2. Barrett, F. F., Eardley, W. A., Yow, M. D., and Leverett, H. A.: Ampicillin in the treatment of acute'suppurative meningitis, J. PZDIAT. 69: 343, 1966. 3. Mathies, A. W., Jr., Leedom, J. M., Thrupp, L. D., Ivler, D., Portnoy, B., and Wehrle, P. F.: Experience with ampicillin in bacterial meningitis, Antimierob. Agents & Chemother. --1965 5:6107 1966. 4. Wehrle, P. F., Mathies, A. W., Jr., and Leedom, J. M.: Management of bacterial meningitis, in Clinical Neurosurgery, vol. 14, The Congress of Neurological Surgeons, 1967, p. 72. 5. Leedom, J. M., and Wehrle, P. F.: Personal communication. 6. Cherry, J. D., and Sheenan, C. P.: Bacterio-
Relapse of Hemopbilus influenzae type b meningitis during intravenous therapy Mtb ampicillin Stephen J. Coleman, M.D., Elizabeth B. Auld, M.D., James D. Connor, M.D., Sanford B. Rosenman, Ph.D., and George H. Warren, Ph.D. MIAMI, FLA., AND RADNOR, PA.
A M v I c I I, L I • has been p r o v e d effective in the t r e a t m e n t of meningitis due to He-
mophilus influenzae, DipIococcus pneumoniae, a n d Neisseria meningitidis. 1-3 Recently, From the University of Miami School of Medicine, Miami, and the Research Division, Wyeth Laboratories, Inc., Radnor.
7.
8. 9.
10.
11.
logic relapse in Haemophilus influenzae meningitis, New England J. Med. 278: 1001, 1968. Young, L. M., Haddow, J. E., and Klein, J. O.: Relapse following ampicillin treatment of acute Hemophilas influenzae meningitis, Pediatrics 41: 516, 1968. Greene, H. L.: Failure of ampicillin in meningitis, Lancet 1: 861, 1968. Thrupp, L. D., Leedom, J. M., Ivler, D., Wehrle, P. F., Portnoy, B., and Mathies, A. W., Jr.: Ampicillin levels in the cerebrospinal fluid during treatment of bacterial meningitis, Antimicrob. Agents & Chemother. --1965 5: 206, 1966. Taber, L. H., Yow, M. D., and Nieberg, F. G.: Penetration of broad-spectrum antibiotics into cerebrospinal fluid, Ann. New York Acad. Se. 145: 473, 1967. Lepper, M. H., and Spies, H. W.: Nontubereulous bacterial infections of the nervous system, GP 25: 82, 1962.
however, 3 cases of H. influenzae meningitis have been r e p o r t e d in patients who failed to respond to ampicillin. 4-G I n none of the child r e n was the organism shown to be resistant; in fact, there have been no reports of ampicillin-resistant strains of H. influenzae type b recovered from patients with meningitis. R a t h e r , all t r e a t m e n t failures m a y be due to i n a d e q u a t e cerebrospinal fluid concentrations of the drug. T h i s possibility a p p e a r s to be a r e a l i t y in the following case, in w h i c h d r u g levels were m e a s u r e d a n d related to the sensitivity of the infecting microorganism.
CASE REPORT C. S., a 21-month-old Negro girl, was admitted to Jackson Memorial Hospital, Miami, with a 2 week history of intermittent fever and vomiting. During this period she had been treated for tonsillitis with oral penicillin V daily and parenteral procaine penicillin every other day. Physical examination upon admission revealed a well-developed, 26 pound infant whose only abnormal findings were marked irritability and a rectal temperature of 101.4 ~ F. A lumbar puncture produced cloudy spinal fluid containing 1,250 white blood cells per cubic millimeter with 36 per cent segmented neutrophils, protein of 96 mg. per 100 ml., and
782
Brie[ clinical and laboratory observations
sugar of 43 mg. per 100 ml. The hemoglobin was 8.0 Gm. per 100 ml. and the peripheral white blood count was 13,000, with 64 per cent neutrophils, 25 per cent lymphocytes, and 5 per cent monocytes. A sickle cell preparation was negative. The urine sediment contained 10 to 15 white blood cells per high power field. Antibiotic therapy was instituted at the time of admission (Table I). Ampicillin (Polycillin, Bristol Laboratories), 135 mg. per kilogram per day, was administered intravenously in 6 divided doses, each being infused over a 20 minute period. H. influenzae type b was recovered from the initial cerebrospinal fluid and blood cultures, but 12 hours later the cultures were sterile. The child improved clinically and became afebrile in 36 hours. She remained afebrile but somewhat irritable until the fifth hospital day, when her temperature rose to 103 ~ F. Ampicillin was continued at the same dosage and the patient again became afebrile in 24 hours. On the seventh day, it was reported that H. influenzae persisted in the spinal fluid. However, since the strain isolated was sensitive to ampicillin in disc sensitivity tests, ampicillin was continued, with the dosage increased to 200 mg. per kilogram per day. From day 7 to day 14, the pa-
The Journal of Pediatrics May 1969
tient remained afebrile and asymptomatic, but spinal fluid culture on the ninth hospital day was later reported positive for H. influenzae. On day 14 the temperature again rose to 101 ~ F. and a culture of the cerebrospinal fluid was again positive for H. influenzae. Disc sensitivity studies showed the organism to be sensitive to ampiciliin, penicillin, and chloramphenicol. Bilateral subdural taps were performed. The right subdural space contained 2 ml. of serosanguinous fluid; the left contained 2 ml. of grossly bloody fluid. Cultures of these fluids were negative. A radiologic survey of the bony skeleton, including a skull series, showed no abnormalities. On the fourteenth hospital day ampicillin was discontinued and chloramphenicol (Chloromycetin, Parke, Davis & Co.), 100 mg. per kilogram per day, was started. After 24 hours the dosage was reduced to a level of 50 mg. per kilogram per day. The resulting blood levels ranged from 3.1 to 8.0 /zg per milliliter. Therapy was continued with chloramphenicol for 14 days. Repeat cultures of the cerebrospinal fluid and blood were sterile. Two weeks after discharge, the physical examination was normal and the cerebrospinal fluid was sterile.
T a b l e I. L a b o r a t o r y results
Cerebrospinal fluid Protein Sugar RBC (rag.~ (rag.~ (mm. 3) 100 ml.) 100 ml.)
Blood Culture ~
culture ~
43
H. inf.
H. inf.
91
58
Neg.
ND
20
63
74
H. inf.
Neg.
25
400
43
49
It. inf.
Neg.
366
3
6
34
76
H. inf.
Neg.
Chloramphenicol (after 6 days)
74
0
14
30
50
Neg.
ND
Day 28
Chloramphenicol (after 14 days)
19
0
3
25
50
Neg.
Neg.
Day 30
No chloramphenicol for 2 days
32
0
0
19
57
Neg.
ND
WBC (ram. s)
% Segs
1,250
36
15
96
10-12 hours Ampicillin, 135 rag./ Kg./day
900
13
480
Day 5
Ampicillin, 135 mg./ Kg./day
550
68
Day 9
Ampicillin, 200 mg./ Kg./day
425
Day 14
Ampicillin, 200 nag./ Kg./day
Day 20
Therapy
Time Admission
__
*H. inf. = H. influenzae, type b; Neg. = negativeculture;ND = not done.
Volume 74 Number 5
METHODS
Cerebrospinal fluid and serum specimens taken 2 hours after intravenous infusion of the last dose of ampicillin (before chloramphenicol) were immediately frozen and remained so until assayed for the concentration of ampicillin. The serum sample was diluted in pooled normal antibiotic-free human serum and bioassayed vs. Sarcina lutea 9341 by agar cup method utilizing anhydrous ampicillin as the standard. The cerebrospinal fluid was diluted in 1 per cent phosphate buffer, p H 6.0, and similarly assayed. The cerebrospinal fluid contained 0.275 t~g per milliliter ampicillin and the serum 15.8 /~g per milliliter. The sensitivity of H. influenzae was determined by a plate method in which the antibiotic was incorporated in a chocolate agar. The bacilli obtained from the cerebrospinal fluid on day 14 were sensitive to ampicillin in a concentration of 0.4 /zg per milliliter. DISCUSSION
This is the first report of relapse during ampicillin treatment of H. influenzae type b meningitis in which the antibiotic was given by interval intravenous infusion throughout the entire therapeutic course, and in a dose, generally accepted as therapeutic, for the last 7 days. This case and that reported by Gold and associates 1~ in this issue of the JOURNAL bring the total cases to 5, in which relapses occurred, during or after, ampicillin treatment. Young and associates 4 reported on a patient treated with ampicillin for H. influenzae meningitis in whom there was a relapse with orbital cellulitis and bacteremia without central nervous system involvement. Cherry and Sheenan 5 documented a bacteriologic relapse with orally administered ampicillin. The antibiotic was first administered intravenously for 4 days at a level of 200 rag. per kilogram per day, and finally orally for 2 days at 120 mg. per kilogram per day. Relapse occurred about the ninth or tenth day, as evidenced by recovery of H. influenzae from the spinal fluid and blood. T h e blood and spinal fluid levels of ampicillin were not
Brief clinical and laboratory observations
783
reported, and no data were given regarding the quantitative sensitivities of the microorganism. Resumption of intramuscular ampicillin at 200 mg. per kilogram per day ultimately resulted in cure of the infection. Greene 6 wrote of a patient with bacteriologic and clinical relapse after 5 days of intravenous ampieillin in a dose of 200 mg. per kilogram per 24 hours. T h e levels of ampicillin obtained in spinal fluid are variable, ~ tending to vary directly with cellular response and lnversely with time, i n the course of therapy in bacterial meningitis2 The level of ampicillin required to kill different strains of H. influenzae has been reported as 0. 025 to 1.6 /~g per milliliter.a, 3, 7, a Two of the 20 patients with meningitis studied by Barrett and associates 1 had low spinaI fluid levels of ampicillin-levels less than the minimal inhibitory concentration ( M I C ) of 38 of the 41 strains of H. influenzae recovered. In the patient reported here, the concentration of ampicillin in spinal fluid 2 hours after the last intravenous dose on the fourteenth day was approximately 1.7 per cent of the simultaneous serum concentration and 70 per cent of the bactericidal level for this particular strain of H. influenzae. This concentration of ampicillin in serum, 15.8 /~g per milliliter, was 40 times the bactericidal level, and it presumably reached an even higher level shortly after each of the 4 hour injections. The dosage of ampicillin seems to have been adequate for eradication of the systemic infection, since all blood cultures following the initial institution of therapy were sterile. H a d the higher dosage of ampicillin been given during the early course, the CNS infection then might have been eradicated, since acute inflammation favors passage of ampicillin across the blood brain barrier. The persistence of H. influenzae in spinal fluid probably was due to the low concentration of ampicillin attained in cerebrospinal fluid or may have occurred secondary to reseeding from large accumulations of purulent exudates at the base of the brain or sulci. We feel that the latter explanation is unlikely, since the patient's clinical course was gen-
7 84
Brief clinical and laboratory observations
erally benign and the spinal fluid protein was not greatly elevated originally and decreased dramatically with therapy. No harboring loci could be found, such as parameningeal or intracerebral abscesses, subdural empyema, middle ear infection, or mastoid osteomyelitis. Cherry and Sheenan ~ suggested that the most likely cause of bacteriologic relapse in ampicillin-treated type B meningitis is inadequate penetration of the cerebrospinal fluid. This case points to low penetration and emphasizes the need for instituting and maintaining high dosage levels of ampieillin throughout the therapeutic coursei Only this case of H. influenzae type b meningitis has failed to respond to intravenous ampicillin in our experience; 60 other consecutive cases have been treated in our pediatric service during the past 24 months, at dosage levels of 200 to 400 rag. per kilogram per 24 hours, with good results.
The Journal of Pediatrics May 1969
3.
4.
5.
6. 7.
8.
9.
REFERENCES 1. Barrett, F. F., Eardley, W. A., Yow, M. D., and Leverett, H. A.: Ampicillin in the treatment of acute suppurative meningitis, J. PEDIAT.69: 343, 1966. 2. Fleming, P. C., Murray, J. D. M., Fujiwara,
Quantitation of IgA and IgM in umbilical cord serum of normal nevborn infants George W. Brasher, M.D., and Thomas F. Hartley, M.D. TEMPLE,
TEXAS
From the Scott and White Clinic.
10.
M. W., Prichard, J. S., and McNaughton, G. A.: Ampicillin in the treatment of bacterial meningitis, Antimicrob. Ag0ents & Chemother. --1966 6: 47, 1967. Mathies, A. W., Jr., Leedom, J. M., Thrupp , L. D., Ivler, D., Portnoy, B., and Wehrle, P. F.: Experience with ampicillin in bacterial meningitis, Antimicrob. Agents & Chemother: --1965 5: 610, 1966. Young, L. M., tIaddow, J. E., and Klein, J. O.: Relapse following ampicillin treatment of acute Hemophilus influenzae meningitis, Pediatrics 41: 516, 1968. Cherry, J. D., and Sheenan, C. P.: Bacteriologic relapse in Haemophilus influenzae meningitis, New England J. Med. 278: 1001, 1968. Greene, tI. L.: Failure of ampicillin in meningitis, Lancet 1: 861, 1968. Taber, L. H., Yow, M. D., and Nieberg, F. G.: Penetration of broad-spectrum antibiotics into cerebrospinal fluid, Ann. New York Acad. Sc. 145: 473, 1967. Klein, J. O., and Finland, M.: Ampicillin activity in vitro and absorption and .excretion in normal young men, Am. J. M. Sc. 245: 544, 1963. Thrupp, L. D., Leedom, J. M., Ivler, D., Wehrle, P. F., Portnoy, B., and Mathies, A, W.: Ampicillin levels in the cerebrospinal fluid during treatment of bacterial meningitis, Antimicrob. Agents & Chemother.-1965 5: 206, 1966. Gold, A. J,, Lieberman, E., and Wright, H. T.: Bacteriologic re!apse during ampicillin treatment of Hemophilus influenzae meniflgifts, J. PEBIAT. 74: 779, 1969.
I~ N o W Z E D G ~. concerning the synthesis of immunoglobulins by the h u m a n fetus has advanced rapidly during the past few years. N o longer is a newborn infant considered to be in an immunologic "null" State incapable of responding to antigenic stimuli? Smith and Eitzman 2 have shown that the newborn infant is capable of making antibodies Under appropriate conditions. O t h e r authors a, 4 have demonstrated that the h u m a n fetus is capable of synthesizing I g G a n d I g M at as early as 20 weeks of gestation. A logical extension of this line of thinking is that antigenie stimulation in the form of intrauterine infection should lead to the presence of increased immunoglobulins at the time of birth. Studies by Stiehm and associates s and
Brief clinical and laboratory observations
78 1
REFERENCES 1. Fleming, P. C., Murray, J. D. M., Fujiwara, M. W., Prichard, J. S., and McNaughton, G. A.: AmpieilIin in the treatment of bacterial meningitis, Antimicrob. Agents & Ghemother.--1966 6: 47, 1967. 2. Barrett, F. F., Eardley, W. A., Yow, M. D., and Leverett, H. A.: Ampicillin in the treatment of acute'suppurative meningitis, J. PZDIAT. 69: 343, 1966. 3. Mathies, A. W., Jr., Leedom, J. M., Thrupp, L. D., Ivler, D., Portnoy, B., and Wehrle, P. F.: Experience with ampicillin in bacterial meningitis, Antimierob. Agents & Chemother. --1965 5:6107 1966. 4. Wehrle, P. F., Mathies, A. W., Jr., and Leedom, J. M.: Management of bacterial meningitis, in Clinical Neurosurgery, vol. 14, The Congress of Neurological Surgeons, 1967, p. 72. 5. Leedom, J. M., and Wehrle, P. F.: Personal communication. 6. Cherry, J. D., and Sheenan, C. P.: Bacterio-
Relapse of Hemopbilus influenzae type b meningitis during intravenous therapy Mtb ampicillin Stephen J. Coleman, M.D., Elizabeth B. Auld, M.D., James D. Connor, M.D., Sanford B. Rosenman, Ph.D., and George H. Warren, Ph.D. MIAMI, FLA., AND RADNOR, PA.
A M v I c I I, L I • has been p r o v e d effective in the t r e a t m e n t of meningitis due to He-
mophilus influenzae, DipIococcus pneumoniae, a n d Neisseria meningitidis. 1-3 Recently, From the University of Miami School of Medicine, Miami, and the Research Division, Wyeth Laboratories, Inc., Radnor.
7.
8. 9.
10.
11.
logic relapse in Haemophilus influenzae meningitis, New England J. Med. 278: 1001, 1968. Young, L. M., Haddow, J. E., and Klein, J. O.: Relapse following ampicillin treatment of acute Hemophilas influenzae meningitis, Pediatrics 41: 516, 1968. Greene, H. L.: Failure of ampicillin in meningitis, Lancet 1: 861, 1968. Thrupp, L. D., Leedom, J. M., Ivler, D., Wehrle, P. F., Portnoy, B., and Mathies, A. W., Jr.: Ampicillin levels in the cerebrospinal fluid during treatment of bacterial meningitis, Antimicrob. Agents & Chemother. --1965 5: 206, 1966. Taber, L. H., Yow, M. D., and Nieberg, F. G.: Penetration of broad-spectrum antibiotics into cerebrospinal fluid, Ann. New York Acad. Se. 145: 473, 1967. Lepper, M. H., and Spies, H. W.: Nontubereulous bacterial infections of the nervous system, GP 25: 82, 1962.
however, 3 cases of H. influenzae meningitis have been r e p o r t e d in patients who failed to respond to ampicillin. 4-G I n none of the child r e n was the organism shown to be resistant; in fact, there have been no reports of ampicillin-resistant strains of H. influenzae type b recovered from patients with meningitis. R a t h e r , all t r e a t m e n t failures m a y be due to i n a d e q u a t e cerebrospinal fluid concentrations of the drug. T h i s possibility a p p e a r s to be a r e a l i t y in the following case, in w h i c h d r u g levels were m e a s u r e d a n d related to the sensitivity of the infecting microorganism.
CASE REPORT C. S., a 21-month-old Negro girl, was admitted to Jackson Memorial Hospital, Miami, with a 2 week history of intermittent fever and vomiting. During this period she had been treated for tonsillitis with oral penicillin V daily and parenteral procaine penicillin every other day. Physical examination upon admission revealed a well-developed, 26 pound infant whose only abnormal findings were marked irritability and a rectal temperature of 101.4 ~ F. A lumbar puncture produced cloudy spinal fluid containing 1,250 white blood cells per cubic millimeter with 36 per cent segmented neutrophils, protein of 96 mg. per 100 ml., and
782
Brie[ clinical and laboratory observations
sugar of 43 mg. per 100 ml. The hemoglobin was 8.0 Gm. per 100 ml. and the peripheral white blood count was 13,000, with 64 per cent neutrophils, 25 per cent lymphocytes, and 5 per cent monocytes. A sickle cell preparation was negative. The urine sediment contained 10 to 15 white blood cells per high power field. Antibiotic therapy was instituted at the time of admission (Table I). Ampicillin (Polycillin, Bristol Laboratories), 135 mg. per kilogram per day, was administered intravenously in 6 divided doses, each being infused over a 20 minute period. H. influenzae type b was recovered from the initial cerebrospinal fluid and blood cultures, but 12 hours later the cultures were sterile. The child improved clinically and became afebrile in 36 hours. She remained afebrile but somewhat irritable until the fifth hospital day, when her temperature rose to 103 ~ F. Ampicillin was continued at the same dosage and the patient again became afebrile in 24 hours. On the seventh day, it was reported that H. influenzae persisted in the spinal fluid. However, since the strain isolated was sensitive to ampicillin in disc sensitivity tests, ampicillin was continued, with the dosage increased to 200 mg. per kilogram per day. From day 7 to day 14, the pa-
The Journal of Pediatrics May 1969
tient remained afebrile and asymptomatic, but spinal fluid culture on the ninth hospital day was later reported positive for H. influenzae. On day 14 the temperature again rose to 101 ~ F. and a culture of the cerebrospinal fluid was again positive for H. influenzae. Disc sensitivity studies showed the organism to be sensitive to ampiciliin, penicillin, and chloramphenicol. Bilateral subdural taps were performed. The right subdural space contained 2 ml. of serosanguinous fluid; the left contained 2 ml. of grossly bloody fluid. Cultures of these fluids were negative. A radiologic survey of the bony skeleton, including a skull series, showed no abnormalities. On the fourteenth hospital day ampicillin was discontinued and chloramphenicol (Chloromycetin, Parke, Davis & Co.), 100 mg. per kilogram per day, was started. After 24 hours the dosage was reduced to a level of 50 mg. per kilogram per day. The resulting blood levels ranged from 3.1 to 8.0 /zg per milliliter. Therapy was continued with chloramphenicol for 14 days. Repeat cultures of the cerebrospinal fluid and blood were sterile. Two weeks after discharge, the physical examination was normal and the cerebrospinal fluid was sterile.
T a b l e I. L a b o r a t o r y results
Cerebrospinal fluid Protein Sugar RBC (rag.~ (rag.~ (mm. 3) 100 ml.) 100 ml.)
Blood Culture ~
culture ~
43
H. inf.
H. inf.
91
58
Neg.
ND
20
63
74
H. inf.
Neg.
25
400
43
49
It. inf.
Neg.
366
3
6
34
76
H. inf.
Neg.
Chloramphenicol (after 6 days)
74
0
14
30
50
Neg.
ND
Day 28
Chloramphenicol (after 14 days)
19
0
3
25
50
Neg.
Neg.
Day 30
No chloramphenicol for 2 days
32
0
0
19
57
Neg.
ND
WBC (ram. s)
% Segs
1,250
36
15
96
10-12 hours Ampicillin, 135 rag./ Kg./day
900
13
480
Day 5
Ampicillin, 135 mg./ Kg./day
550
68
Day 9
Ampicillin, 200 mg./ Kg./day
425
Day 14
Ampicillin, 200 nag./ Kg./day
Day 20
Therapy
Time Admission
__
*H. inf. = H. influenzae, type b; Neg. = negativeculture;ND = not done.
Volume 74 Number 5
METHODS
Cerebrospinal fluid and serum specimens taken 2 hours after intravenous infusion of the last dose of ampicillin (before chloramphenicol) were immediately frozen and remained so until assayed for the concentration of ampicillin. The serum sample was diluted in pooled normal antibiotic-free human serum and bioassayed vs. Sarcina lutea 9341 by agar cup method utilizing anhydrous ampicillin as the standard. The cerebrospinal fluid was diluted in 1 per cent phosphate buffer, p H 6.0, and similarly assayed. The cerebrospinal fluid contained 0.275 t~g per milliliter ampicillin and the serum 15.8 /~g per milliliter. The sensitivity of H. influenzae was determined by a plate method in which the antibiotic was incorporated in a chocolate agar. The bacilli obtained from the cerebrospinal fluid on day 14 were sensitive to ampicillin in a concentration of 0.4 /zg per milliliter. DISCUSSION
This is the first report of relapse during ampicillin treatment of H. influenzae type b meningitis in which the antibiotic was given by interval intravenous infusion throughout the entire therapeutic course, and in a dose, generally accepted as therapeutic, for the last 7 days. This case and that reported by Gold and associates 1~ in this issue of the JOURNAL bring the total cases to 5, in which relapses occurred, during or after, ampicillin treatment. Young and associates 4 reported on a patient treated with ampicillin for H. influenzae meningitis in whom there was a relapse with orbital cellulitis and bacteremia without central nervous system involvement. Cherry and Sheenan 5 documented a bacteriologic relapse with orally administered ampicillin. The antibiotic was first administered intravenously for 4 days at a level of 200 rag. per kilogram per day, and finally orally for 2 days at 120 mg. per kilogram per day. Relapse occurred about the ninth or tenth day, as evidenced by recovery of H. influenzae from the spinal fluid and blood. T h e blood and spinal fluid levels of ampicillin were not
Brief clinical and laboratory observations
783
reported, and no data were given regarding the quantitative sensitivities of the microorganism. Resumption of intramuscular ampicillin at 200 mg. per kilogram per day ultimately resulted in cure of the infection. Greene 6 wrote of a patient with bacteriologic and clinical relapse after 5 days of intravenous ampieillin in a dose of 200 mg. per kilogram per 24 hours. T h e levels of ampicillin obtained in spinal fluid are variable, ~ tending to vary directly with cellular response and lnversely with time, i n the course of therapy in bacterial meningitis2 The level of ampicillin required to kill different strains of H. influenzae has been reported as 0. 025 to 1.6 /~g per milliliter.a, 3, 7, a Two of the 20 patients with meningitis studied by Barrett and associates 1 had low spinaI fluid levels of ampicillin-levels less than the minimal inhibitory concentration ( M I C ) of 38 of the 41 strains of H. influenzae recovered. In the patient reported here, the concentration of ampicillin in spinal fluid 2 hours after the last intravenous dose on the fourteenth day was approximately 1.7 per cent of the simultaneous serum concentration and 70 per cent of the bactericidal level for this particular strain of H. influenzae. This concentration of ampicillin in serum, 15.8 /~g per milliliter, was 40 times the bactericidal level, and it presumably reached an even higher level shortly after each of the 4 hour injections. The dosage of ampicillin seems to have been adequate for eradication of the systemic infection, since all blood cultures following the initial institution of therapy were sterile. H a d the higher dosage of ampicillin been given during the early course, the CNS infection then might have been eradicated, since acute inflammation favors passage of ampicillin across the blood brain barrier. The persistence of H. influenzae in spinal fluid probably was due to the low concentration of ampicillin attained in cerebrospinal fluid or may have occurred secondary to reseeding from large accumulations of purulent exudates at the base of the brain or sulci. We feel that the latter explanation is unlikely, since the patient's clinical course was gen-
7 84
Brief clinical and laboratory observations
erally benign and the spinal fluid protein was not greatly elevated originally and decreased dramatically with therapy. No harboring loci could be found, such as parameningeal or intracerebral abscesses, subdural empyema, middle ear infection, or mastoid osteomyelitis. Cherry and Sheenan ~ suggested that the most likely cause of bacteriologic relapse in ampicillin-treated type B meningitis is inadequate penetration of the cerebrospinal fluid. This case points to low penetration and emphasizes the need for instituting and maintaining high dosage levels of ampieillin throughout the therapeutic coursei Only this case of H. influenzae type b meningitis has failed to respond to intravenous ampicillin in our experience; 60 other consecutive cases have been treated in our pediatric service during the past 24 months, at dosage levels of 200 to 400 rag. per kilogram per 24 hours, with good results.
The Journal of Pediatrics May 1969
3.
4.
5.
6. 7.
8.
9.
REFERENCES 1. Barrett, F. F., Eardley, W. A., Yow, M. D., and Leverett, H. A.: Ampicillin in the treatment of acute suppurative meningitis, J. PEDIAT.69: 343, 1966. 2. Fleming, P. C., Murray, J. D. M., Fujiwara,
Quantitation of IgA and IgM in umbilical cord serum of normal nevborn infants George W. Brasher, M.D., and Thomas F. Hartley, M.D. TEMPLE,
TEXAS
From the Scott and White Clinic.
10.
M. W., Prichard, J. S., and McNaughton, G. A.: Ampicillin in the treatment of bacterial meningitis, Antimicrob. Ag0ents & Chemother. --1966 6: 47, 1967. Mathies, A. W., Jr., Leedom, J. M., Thrupp , L. D., Ivler, D., Portnoy, B., and Wehrle, P. F.: Experience with ampicillin in bacterial meningitis, Antimicrob. Agents & Chemother: --1965 5: 610, 1966. Young, L. M., tIaddow, J. E., and Klein, J. O.: Relapse following ampicillin treatment of acute Hemophilus influenzae meningitis, Pediatrics 41: 516, 1968. Cherry, J. D., and Sheenan, C. P.: Bacteriologic relapse in Haemophilus influenzae meningitis, New England J. Med. 278: 1001, 1968. Greene, tI. L.: Failure of ampicillin in meningitis, Lancet 1: 861, 1968. Taber, L. H., Yow, M. D., and Nieberg, F. G.: Penetration of broad-spectrum antibiotics into cerebrospinal fluid, Ann. New York Acad. Sc. 145: 473, 1967. Klein, J. O., and Finland, M.: Ampicillin activity in vitro and absorption and .excretion in normal young men, Am. J. M. Sc. 245: 544, 1963. Thrupp, L. D., Leedom, J. M., Ivler, D., Wehrle, P. F., Portnoy, B., and Mathies, A, W.: Ampicillin levels in the cerebrospinal fluid during treatment of bacterial meningitis, Antimicrob. Agents & Chemother.-1965 5: 206, 1966. Gold, A. J,, Lieberman, E., and Wright, H. T.: Bacteriologic re!apse during ampicillin treatment of Hemophilus influenzae meniflgifts, J. PEBIAT. 74: 779, 1969.
I~ N o W Z E D G ~. concerning the synthesis of immunoglobulins by the h u m a n fetus has advanced rapidly during the past few years. N o longer is a newborn infant considered to be in an immunologic "null" State incapable of responding to antigenic stimuli? Smith and Eitzman 2 have shown that the newborn infant is capable of making antibodies Under appropriate conditions. O t h e r authors a, 4 have demonstrated that the h u m a n fetus is capable of synthesizing I g G a n d I g M at as early as 20 weeks of gestation. A logical extension of this line of thinking is that antigenie stimulation in the form of intrauterine infection should lead to the presence of increased immunoglobulins at the time of birth. Studies by Stiehm and associates s and